AN OPEN-LABEL, RANDOMIZED, MULTICENTER, PHASE 3 STUDY TO COMPARE THE IMMUNOGENICITY, EFFICACY, AND SAFETY OF GAN & LEE PHARMACEUTICALS INSULIN GLARGINE INJECTION TO LANTUS® IN ADULT SUBJECTS WITH TYPE 2 DIABETES MELLITUS
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Sponsor: Gan and Lee Pharmaceuticals, USA

AN OPEN-LABEL, RANDOMIZED, MULTICENTER, PHASE 3 STUDY TO 
COMPARE THE IMMUNOGENICITY, EFFICACY, AND SAFETY OF GAN & LEE 
PHARMACEUTICALS INSULIN GLARGINE INJECTION TO LANTUS® 
(INSULIN GLARGINE INJECTION) IN ADULT SUBJECTS WITH TYPE 2 
DIABETES MELLITUS  
Test Drug: 
Gan & Lee Insulin Glargine Injection 
Protocol Number: GL-GLAT2-3002 
Study Phase: 3 
Protocol Name: Gan & Lee Insulin Glargine Target Type (2) Evaluating Research: 
GLITTER(2) 
IND Number: 125072 
EudraCT Number: 2017-001415-36 
Date and Version: 
25 April 2019– Amendment 3 
01 November 2018– Amendment 2 
18 April 2018 – Amendment 1 
15 August 2017 – Version 3.0  
08 May 2017 – Version 2.0 
24 March 2017 – Version 1.0 
Sponsor: 
Gan & Lee Pharmaceuticals USA  
520 US Highway 22 East, Suite 302 
Bridgewater, NJ 08807 USA 
Phone: +1 888 288 5395 
Contract Research Organization: 
PRA Health Sciences 
4130 ParkLake Avenue, Suite 400 
Raleigh, NC 27612 USA 
Phone: +1 919 786 8200 
Fax: +1 919 786 8201 
PRA Medical Monitors: 
Kyle Patrick, DO 
Magdalena Przekwas-Jaruchowska, MD 
PRA Drug Safety Contact (Serious Adverse 
Event Reporting): 
Phone: 1 800 772 2215 or 1 434 951 3489 
Fax: 1 888 772 6919 or 1 434 951 3482 
E-mail: CHOSafety@prahs.com
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) as set 
forth in the International Council for Harmonisation (ICH) guidelines on GCP (ICH E6), and 
applicable local regulatory requirements. 
CONFIDENTIAL 
This document is a confidential communication of Gan & Lee Pharmaceuticals USA. Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein shall be 
published or disclosed without prior written approval, except that this document may be disclosed to the 
appropriate Institutional Review Board(s)/Independent Ethics Committee(s) under the condition that they 
keep it confidential. 

 
 
 
 
 
Investigator 
 
I have read and agree to the protocol GL-GLAT2-3002 entitled ‘An Open-Label, 
Randomized, Multicenter, Phase 3 Study to Compare the Immunogenicity, Efficacy, and 
Safety of Gan & Lee Pharmaceuticals Insulin Glargine Injection to Lantus® (Insulin Glargine 
Injection) in Adult Subjects with Type 2 Diabetes Mellitus.’ I am aware of my 
responsibilities as an Investigator under the guidelines of GCP, local regulations (as 
applicable) and the study protocol. I agree to conduct the study according to these 
responsibilities and to appropriately direct and assist the staff under my control, who will be 
involved in the study. 
 
Protocol Amendment 3 
 
 
 
 
 
25 April 2019  
Clinical Site:  
 
 
Site Number: 
 
 
Site Principal Investigator: 
 
 
 
Print Name 
 
Title 
 
 
 
 
Signature 
 
Date 
 
 
3

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
1. 
SYNOPSIS 
NAME OF SPONSOR: Gan & Lee Pharmaceuticals USA 
PROTOCOL No.:GL-GLAT2-3002 
NAME OF STUDY TREATMENT: Gan & Lee Insulin Glargine Injection 
TITLE OF STUDY: An Open-label, Randomized, Multicenter, Phase 3 Study to Compare the 
Immunogenicity, Efficacy, and Safety of Gan & Lee Pharmaceuticals Insulin Glargine Injection to Lantus® 
(Insulin Glargine Injection) in Adult Subjects with Type 2 Diabetes Mellitus  
STUDY CENTERS: Approximately 65 sites are planned in the United States  
STUDY PERIOD: Subjects randomized to the Gan & Lee 
Insulin Glargine Injection group and the Lantus® group will 
receive treatment for 26 weeks. 
PHASE OF DEVELOPMENT: Phase 3 
PLANNED STUDY DATES: The study started in 2017 and is expected to end in 2019 
OBJECTIVES: 
Primary Objective: 
• 
To evaluate equivalence of Gan & Lee Insulin Glargine Injection and Lantus® in terms of 
immunogenicity  
 
Secondary Objectives: 
• 
Immunogenicity: To evaluate the percentage of subjects with negative anti-insulin antibodies (AIA) 
at baseline who develop confirmed positive AIA up to visit Week 26, the percentage of subjects 
with at least a 4-fold increase in titers compared to baseline value, mean change from baseline in 
AIA titers between treatment groups, the percentage of subjects with confirmed positive AIA who 
develop any anti-insulin neutralizing antibodies up to visit Week 26, and the percentage of subjects 
in each treatment group with confirmed positive AIA up to visit Week 26 
• 
Safety: To evaluate the safety of Gan & Lee Insulin Glargine Injection in comparison with that of 
Lantus® 
• 
Efficacy: To evaluate the efficacy of Gan & Lee Insulin Glargine Injection in comparison with that 
of Lantus® 
 
Exploratory Objective: 
• 
To investigate the retrospective hypoglycemic rate and time in hypoglycemia and hyperglycemia 
using continuous glucose monitoring (CGM) data 
STUDY DESIGN AND METHODOLOGY: The purpose of this equivalence study is to compare the 
immunogenicity, safety, and efficacy of Gan & Lee Insulin Glargine Injection with that of the reference 
medicinal product, Lantus®, in adult subjects with type 2 diabetes mellitus.  
At the screening visit, subjects will sign the informed consent form (ICF), they will be screened for 
eligibility, and the following information will be collected: adverse events, medical history (including 
diabetes mellitus and thyroid disease history), prior and concomitant medications, vital signs, height, body 
weight, and body mass index (BMI). The following procedures will be performed: 12-lead electrocardiogram 
(ECG), physical examination, and blood collection for fasting blood glucose (FBG) test, glycosylated 
hemoglobin (HbA1c), AIA, routine hematology and chemistry testing (complete blood count, metabolic 
chemistry panel with serum lipids, thyroid-stimulating hormone [TSH], and free thyroxine [T4]). A 
urinalysis, and for women of childbearing potential, a urine pregnancy test will be performed. At this visit, 
the subject will be issued a glucometer, test strips, and other supplies, and the Investigator or designee will 
provide instruction and conduct training on how to use the glucometer for prospective capillary blood 
glucose monitoring to document hypoglycemic episodes in a prospective manner. Subjects will be allowed to 
keep the glucometer after the study, per local ethical and legal guidelines and regulations. Subjects will also 
receive a Hypoglycemic Events Record in which they will record information about any hypoglycemic 
events that occur during their participation in the study. At this visit, the subject will have an Abbott 
FreeStyle Libre Pro Flash Glucose Monitoring System sensor applied to the back of the upper arm. The 
sensor, which calibrates itself during the first 12 to 24 hours after application, will be worn for 8 days and 
will record the interstitial glucose concentration every 15 minutes. Data from the 2nd through the 8th day of 
wear will be used for the analysis. The subject will also be issued a Mealtime & Insulin Dose Record for the 
4

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
8-day period, in which they will record the time of their meals and insulin use. After 8 days, the subject may 
remove the sensor and bring it to the randomization visit in a provided biohazard bag; if the end of the 8-day 
continuous glucose monitoring (CGM) period coincides with the date of the randomization visit, the sensor 
can be removed at the visit by site staff. The information obtained through CGM will have no direct impact 
on treatment advice and is intended for research purposes only. Subjects will bring both their Hypoglycemic 
Events Record and their Mealtime & Insulin Dose Record to the randomization visit. Between the screening 
and randomization visits, subjects already taking basal insulin will have their insulin dose optimized based 
on their fasting glucose results, and will also have any appropriate adjustments in their other antidiabetes 
medication (OAM) dosing that may be required because of the optimization of their insulin dosing. Subjects 
not currently on insulin will have their OAM dosing optimized in preparation for starting basal insulin 
therapy. 
Subjects who meet the study eligibility criteria will be centrally randomized 1:1 in an open-label fashion to 
receive either Gan & Lee Insulin Glargine Injection or Lantus® for 26 weeks. Subjects currently taking 
insulin will continue using their OAMs and will substitute investigational product (IP) for their basal insulin. 
Subjects not currently taking insulin will continue their OAMs, will add IP, and will have the dosing 
optimized. 
The Sponsor will ensure that all insulins will be provided to all subjects regardless of medical insurance or 
reimbursement issues. This applies to the non-study insulins and this should be discussed with the Study 
Monitor. 
At the randomization visit (Visit 2), subjects will receive a supply of insulin pens with IP. The Investigator or 
designee will train the subject on all study procedures and proper dose administration. 
All subjects will attend 9 clinic visits (the screening visit, the randomization visit, and visits at Weeks 2, 4, 8, 
12, 16, 20, and 26), 2 brief visits during which a CGM sensor will be applied (8-10 days before the visits at 
Weeks 12 and 26), and they will be contacted by telephone at Weeks 6, 10, 14, 18, and 22. The Week 26 
visit (Visit 9) will be the end-of-treatment visit.  
At all visits and phone contacts (except for visits to apply a CGM sensor), the Investigator or designee will 
review glucose results (especially focusing on hypoglycemia), adverse events, changes in concomitant 
medications, and changes in IP, bolus insulin, and OAM use. At all study visits, the following procedures 
will be performed: vital signs, body weight, urinalysis, urine pregnancy testing for women of childbearing 
potential, and an FBG test. 
Additional procedures at study visits are as follows: at Weeks 8, 16, and 26, blood for HbA1c will be 
collected; at Weeks 12 and 26, subjects will wear their CGM sensor to the site for the staff to safely remove 
it; they will bring their Mealtime & Insulin Dose Record for the site staff to review, and blood will be 
collected for routine hematology and chemistry, TSH, and free T4; at Weeks 12 and 26, blood will be 
collected for AIA; and at Week 26, a 12-lead ECG and physical examination will be performed.  
If a subject discontinues the study prematurely (early termination – ET), site personnel will make a 
reasonable effort to perform all study activities scheduled for Visit 9 (EOT visit). Additionally, it is also very 
important for site personnel to encourage subjects to visit the site at Week 26 + 4 weeks (and Week 12 + 1 
week, if applicable) when blood samples can be obtained for the AIA and HbA1c measurements. 
Site personnel will contact the subjects by telephone approximately 30 days after study completion to query 
for serious adverse event information only. 
 
STUDY POPULATION AND MAIN CRITERIA FOR INCLUSION/EXCLUSION:  
Subjects cannot be enrolled or randomized until all inclusion criteria (including test results) are confirmed. 
Inclusion Criteria:  
1. Male or nonpregnant, nonlactating female subjects between the ages of 18 and 75 years, inclusive 
2. Ability to provide written, personally signed, and dated informed consent to participate in the study, in 
accordance with the ICH GCP Guideline E6 and all applicable regulations, before initiating any 
study-related procedures 
3. Ability to understand and fully comply with all study procedures and restrictions 
5

Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
4.
Subjects with a confirmed diagnosis of type 2 diabetes mellitus who meet one of the following:
a.
If insulin-naïve, subjects should have been on at least 2 approved OAMs for at least 12 weeks
before screening, and the clinician has decided to add insulin therapy
b.
If already being treated with a basal and/or bolus insulin, subjects should have been treated with
insulin for at least 6 months in addition to at least 1 approved OAM, and must not have changed
the type or brand of insulin within 6 months prior to screening
5.
HbA1c values as follows:
a.
If insulin-naïve, HbA1c ≤ 11.0%
b.
If previously on a basal insulin regimen, HbA1c ≥ 7.0% and ≤ 11.0%
6.
Body mass index (BMI) ≤ 45 kg/m2
7.
Adherence to a prudent diet and exercise regimen recommended by the medical provider, and
willingness to maintain these consistently for the duration of the study
8.
Concomitant medications are allowed, provided that no significant dosing changes are anticipated during
the study (see the exclusion criteria below for specific prohibited concomitant medications); for
concomitant thyroid medications, subjects must have been on a stable dosage for 90 days before
screening
Exclusion Criteria: 
1. Participation in another clinical study or use of any study drug within 30 days before screening
2. Previous use of a biosimilar insulin, either basal or bolus
3. Diabetic ketoacidosis within a year before screening
4. Brittle type 2 diabetes mellitus within the year before screening (e.g., multiple hospitalizations related to 
diabetes mellitus and/or severe hypoglycemia for which the subject required 3rd party assistance)
5. Any severe, delayed sequela of diabetes mellitus, e.g., worsening end-stage renal disease, advanced 
coronary artery disease, or myocardial infarction within the year before screening, or autonomic 
peristaltic problems, e.g., gastroparesis
6. Anticipated change in insulin used during the study (change in dosage is allowed, but change in type or 
brand of insulin will result in the subject being withdrawn from the study)
7. Inadequately controlled thyroid disease, defined as a TSH or free T4 value > the upper limit of normal
8. BMI > 45 kg/m2
9. Any clinically significant (in the opinion of the Investigator) hematology or chemistry test results at 
screening, including any liver function test > 3x the upper limit of normal (subjects with elevated 
bilirubin due to Gilbert syndrome are eligible to participate)
10.  Documented history of anti-insulin antibodies
11.  Treatment with glucocorticosteroids, immunosuppressants, or cytostatic agents within 60 days before 
screening (newly-prescribed or high-dose corticosteroids are prohibited; chronically administered oral, 
inhaled, topical, or intra-articular corticosteroids at a stable dosage are allowed if no increase in dose is 
anticipated during the study; See Appendix 3 [Section 17.3] for a list of allowed and prohibited 
concomitant medications)
12.  Current use of medication intended to cause weight loss or weight gain
13.  Alcohol or substance use disorder within the 2 years before screening
14.  Any previous or anticipated treatment with interferons
15.  Any history of malignant disease within 5 years before screening, except for adequately treated basal 
cell carcinoma
16.  Severe concomitant physical or psychiatric diseases or conditions
17.  A history of a positive test result for HIV, hepatitis B, or hepatitis C; any subject who has a positive test 
result during the study may continue at the discretion of the Investigator
6

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
18. Any history of pancreatitis or pancreatectomy 
19. Any diagnosis or condition that requires the subject to undergo procedures that could decrease antibodies 
in plasma or that would require treatment with immunosuppressant agents 
20. Any condition e.g., splenectomy, autoimmune disease, or rheumatologic disease, that could affect 
immunologic responses, could indicate an altered immune system, or could require treatment with a 
prohibited medication 
21. Any unresolved infection or a history of active infection within 30 days before screening other than mild 
or viral illness (as judged by the Investigator)  
22. Any other disease or condition that in the opinion of the Investigator could confound the study results or 
limit the subject’s ability to participate in the study or comply with follow-up procedures; or any other 
factor that would indicate a significant risk of loss to follow up 
23. Intolerance or history of hypersensitivity to insulin glargine or any excipient of IP 
24. Inability or unwillingness to wear the CGM sensor as required for the study, or to comply with the 
concomitant medication requirements in the FreeStyle Libre Pro Indications and Important Safety 
Information, during the CGM periods  
NUMBER OF SUBJECTS: Enrollment is planned for 550 subjects overall (275 subjects per treatment 
group). The primary analysis for immunogenicity will be 2 one-sided equivalence tests with α=0.05. This 
sample size was chosen to achieve over 80% power on the equivalence test of proportion of subjects under 
the margins dependent on the observed treatment-induced AIA rate. Sample size calculations were 
performed using EAST Version 6.4. 
STUDY TREATMENT(S): Test Product, Dose and Mode of Administration: Gan & Lee Insulin 
Glargine Injection solution for subcutaneous injection, 100 U/mL, in the integrated, disposable 3.0-mL pre-
filled Gan & Lee injector pen 
Reference Therapy, Dose and Mode of Administration: Lantus® (insulin glargine injection) solution for 
subcutaneous injection, 100 U/mL, in the SoloStar® 3-mL pre-filled insulin pen 
Lantus® contains insulin glargine, an insulin analog, and has a prolonged duration of action. Lantus® and Gan 
& Lee Insulin Glargine should be administered once daily at any time but at the same time each day. To be 
consistent with current Lantus® labeling, twice-daily dosing of IP is strictly prohibited. The dose regimen 
(dose and timing) should be individually adjusted. In patients with type 2 diabetes mellitus, Lantus® and Gan 
& Lee Insulin Glargine Injection can also be given together with OAMs.  
DURATION OF TREATMENT: Subjects in both groups will receive study treatment for 26 weeks 
STUDY EVALUATIONS:  
Primary Endpoint 
• 
Immunogenicity: The percentage of subjects in each treatment group who develop treatment-
induced AIAs, defined as newly confirmed positive AIA development or important (at least a 
4-fold) increase in titers, after baseline and up to visit Week 26 
Key Secondary Endpoint 
• 
Efficacy: The change in HbA1c from baseline at visit Week 26  
Other Secondary Endpoint 
• 
Immunogenicity 
o 
The percentage of subjects in each treatment group with negative AIA at baseline who 
develop confirmed positive AIA after baseline and up to visit Week 26 
o 
The percentage of subjects in each treatment group with confirmed positive AIA at 
baseline and at least a 4-fold increase in titers after baseline and up to visit Week 26 
o 
The mean change from baseline in each treatment group in AIA titers after baseline and up 
to visit Week 26 
o 
The percentage of subjects in each treatment group with confirmed positive AIA after 
baseline and up to visit Week 26 who develop any anti-insulin neutralizing antibodies after 
baseline and up to visit Week 26 
7

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
o 
The percentage of subjects in each treatment group with confirmed positive AIA after 
baseline and up to visit Week 26 
• 
Safety 
o 
The incidence and severity of all treatment-emergent adverse events and the following 
subgroups: 
 
Hypoglycemia, which will be fully documented prospectively in the 
Hypoglycemic Events Record 
 
Serious adverse events, including fatal events 
 
Adverse events leading to termination of the study treatment and/or early 
withdrawal from the study 
 
IP-related adverse events 
 
Injection site reactions 
o 
The incidence of clinically significant laboratory abnormalities 
o 
The incidence of clinically significant abnormalities in ECG and vital signs 
• 
Efficacy 
o 
The number and percentage of subjects who achieve an FBG test result of ≤ 8.0 mmol/L 
(≤ 144.0 mg/dL) at visit Week 26 
o 
The number and percentage of subjects who achieve a HbA1c of < 7.0% at visit Week 26 
Exploratory Endpoints 
• 
Retrospective CGM hypoglycemic rate 
• 
Time in hypoglycemia and hyperglycemia 
STATISTICAL METHODS:  
The primary analysis for immunogenicity will be an equivalence test using the 2 one-sided tests (TOST) 
approach with α=0.05 via a test of difference in proportions based on normal approximation (-margin, 
+margin) where the margin is dependent on the observed treatment-induced AIA rate in Lantus®. The 
estimand of interest on the immunogenicity analysis is the difference in treatment-induced AIA rates regardless 
if all subjects tolerate or adhere to study treatment or receive other insulin treatments. Intercurrent events will 
be handled according to the treatment policy strategy. Treatment policy strategy is defined as the strategy that 
considers “The occurrence of the intercurrent event is irrelevant: the value for the variable of interest is used 
regardless of whether or not the intercurrent event occurs” (ICH E9 R1) addendum. The key secondary analysis 
will be to evaluate equivalence (FDA)/noninferiority (EMA) of Gan & Lee Insulin Glargine Injection relative 
to Lantus® for HbA1c by comparing the 90% confidence interval (CI) (-0.4%, 0.4%) for equivalence using the 
TOST approach and by comparing the upper limit of the 95% CI with 0.4% from a pattern mixture model that 
uses multiple imputation analyzed using Analysis of Covariance (ANCOVA) with treatment included as a 
fixed effect and baseline HbA1c included as a covariate. Separately in each treatment group, the imputation 
will use the outcomes of patients who completed the study (including subjects who discontinued treatment, 
but provided a visit Week 26 HbA1c sample) to impute outcomes in patients without actual visit Week 26 
recorded results under the missing at random assumption. Full details of the multiple imputation procedure 
will be specified in the SAP. Analysis of HbA1c will follow a hierarchical testing strategy: first, 
equivalence/noninferiority will be tested with a margin of 0.4%; secondly, if and only if the test using a margin 
of 0.4% is significant, then equivalence/noninferiority will be tested using a margin of 0.3%. Analyses of 
HbA1c in the testing hierarchy will be conducted on the Full Analysis Set consisting of all randomized subjects 
according to randomized treatment with supportive analyses on the Per Protocol Analysis Set. A tipping point 
analysis with varying assumptions about the differences on each treatment arm between outcomes in patients 
who withdrew from the study early and outcomes in patients who completed the study will be performed.  
Categorical variables will be summarized using counts and percentages. Continuous variables will be 
summarized using the number of observations, mean, standard deviation, median, minimum and maximum. 
The secondary immunogenicity variables of the percentage of subjects with negative AIA at baseline who 
develop confirmed positive AIA up to visit Week 26 and the percentage of subjects with confirmed positive 
AIA after baseline and up to visit Week 26 will be compared between treatment groups using a normal test 
of difference in proportions. The difference in proportions will be estimated along with the corresponding 
90% CI using Wald method for risk difference without continuity correction. The secondary immunogenicity 
variables of the percentage of subjects in each treatment group with confirmed positive AIA at baseline and 
8

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
at least a 4-fold increase in titers after baseline and up to visit Week 26 and the percentage of subjects with 
confirmed positive AIA after baseline and up to visit Week 26 who develop any anti-insulin neutralizing 
antibodies after baseline and up to visit Week 26, will be compared between treatment groups using an exact 
test of difference in proportions. The difference in proportions will be estimated along with the 
corresponding 90% CI in the Safety Analysis Set. The exact confidence limits are computed by inverting 2 
separate one-sided exact tests that are based on the score statistic. The mean change from baseline in each 
treatment group in AIA titers after baseline and up to visit Week 26 will be tabulated descriptively. 
Safety variables will be summarized descriptively in the Safety Analysis Set consisting of all randomized 
subjects according to actual treatment received. All reported adverse events will be assigned a system organ 
class and preferred term according to the Medical Dictionary for Regulatory Activities and graded according 
to Common Toxicity Criteria for Adverse Events version 4.03. The number and percentage of subjects with 
adverse events (all adverse events, hypoglycemia, serious adverse events [including fatal], adverse events 
leading to termination of study treatment and/or early withdrawal from the study, IP-related adverse events, 
and injection site reactions) will be presented. Vital signs, body weight and BMI, ECG, and laboratory 
results will be summarized by treatment and visit. 
The secondary efficacy variables of number and percentage of subjects achieving a HbA1c value < 7.0% at 
visit Week 26  and the number and percentage of subjects achieving a FBG test result of ≤ 8.0 mmol/L 
(≤ 144.0 mg/dL) in each treatment group will be compared using a test of difference of proportions based on 
the normal approximation and CIs.  
The retrospective CGM hypoglycemic rate and time in hypoglycemia and hyperglycemia will be 
summarized for subjects in the Safety Analysis Set. 
DATE AND VERSION: 25 April 2019; Amendment 3 
9

Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
2.
TABLE OF CONTENTS
1.
SYNOPSIS .................................................................................................................. 4 
2.
TABLE OF CONTENTS ........................................................................................ 10 
3.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 15 
4.
ETHICS .................................................................................................................... 17 
4.1 
Ethics Committee ...................................................................................................... 17 
4.2 
Ethical Conduct of the Study ..................................................................................... 17 
4.3 
Subject Information and Consent .............................................................................. 17 
5.
STUDY ADMINISTRATIVE STRUCTURE ....................................................... 18 
6.
INTRODUCTION ................................................................................................... 19 
6.1 
Disease Review ......................................................................................................... 19 
6.2 
Compound Review – Insulin Glargine ...................................................................... 19 
6.2.1 
Nonclinical Studies .................................................................................................... 19 
6.2.2 
Clinical Studies .......................................................................................................... 19 
6.3 
Clinical Study Rationale ............................................................................................ 20 
7.
STUDY OBJECTIVES ........................................................................................... 21 
7.1 
Primary Study Objective ........................................................................................... 21 
7.2 
Secondary Study Objectives ...................................................................................... 21 
7.2.1 
Immunogenicity ......................................................................................................... 21 
7.2.2 
Safety ......................................................................................................................... 21 
7.2.3 
Efficacy ...................................................................................................................... 21 
7.3 
Exploratory Objective................................................................................................ 21 
8.
INVESTIGATIONAL PLAN ................................................................................. 22 
8.1 
Overall Study Design and Plan .................................................................................. 22 
8.2 
Discussion of Study Design ....................................................................................... 27 
8.3 
Study Duration ........................................................................................................... 27 
8.4 
Study Population ....................................................................................................... 27 
8.4.1 
Inclusion Criteria ....................................................................................................... 27 
8.4.2 
Exclusion Criteria ...................................................................................................... 28 
8.4.3 
Withdrawal and Replacement of Subjects ................................................................. 29 
8.4.3.1 
Criteria for Subject Withdrawal ................................................................................ 29 
8.4.3.2 
Replacement of Subjects ........................................................................................... 30 
8.5 
Treatment ................................................................................................................... 30 
8.5.1 
Treatments Administered .......................................................................................... 30 
8.5.2 
Study Treatment Formulation .................................................................................... 31 
8.5.2.1 
Gan & Lee Insulin Glargine Injection ....................................................................... 31 
8.5.2.2 
Lantus® ...................................................................................................................... 31 
10

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
8.5.3 
Dose and Administration of the Investigational Product ........................................... 31 
8.5.4 
Study Treatment Labeling and Packaging ................................................................. 32 
8.5.5 
Blinding of Study Medication ................................................................................... 32 
8.5.6 
Study Treatment Storage and Accountability ............................................................ 32 
8.5.6.1 
Study Treatment Storage ........................................................................................... 32 
8.5.6.2 
Study Treatment Accountability ................................................................................ 32 
8.5.7 
Gan & Lee Insulin Glargine Injection Pen and the Lantus® SoloStar® ..................... 33 
8.5.8 
Dose Adjustments and Dose Escalation .................................................................... 33 
8.5.8.1 
Subjects Already on Basal Insulin ............................................................................. 33 
8.5.8.2 
Subjects Not Currently on Basal Insulin Therapy ..................................................... 33 
8.5.8.3 
Hypoglycemia ............................................................................................................ 34 
8.5.9 
Previous and Concomitant Therapy .......................................................................... 35 
8.5.10 
Treatment Compliance .............................................................................................. 35 
8.5.11 
Assignment to Treatment........................................................................................... 35 
8.5.12 
Unblinding Procedures .............................................................................................. 35 
8.6 
Study-Related Devices .............................................................................................. 35 
8.6.1 
Glucometer, Test Strips, and Related Supplies ......................................................... 35 
8.6.2 
FreeStyle Libre Pro Flash Glucose Monitoring System ............................................ 36 
8.7 
Primary and Secondary Endpoints ............................................................................ 37 
8.7.1 
Primary Endpoint ....................................................................................................... 37 
8.7.2 
Key Secondary Endpoint ........................................................................................... 37 
8.7.3 
Other Secondary Endpoints ....................................................................................... 37 
8.7.3.1 
Immunogenicity ......................................................................................................... 37 
8.7.3.2 
Safety ......................................................................................................................... 37 
8.7.4 
Efficacy ...................................................................................................................... 38 
8.8 
Exploratory Endpoints ............................................................................................... 38 
9. 
STUDY EVALUATIONS BY VISIT ..................................................................... 39 
9.1 
Visit 1: Screening: From Day -14 Through Day -1 ................................................... 39 
9.2 
Visit 2: Randomization (Day 1) ................................................................................. 40 
9.3 
Visits 3 and 4: Weeks 2 and 4 (±3 Days) .................................................................. 40 
9.4 
Telephone Contacts: Weeks 6, 10, 14, 18, and 22 (± 3 Days) ................................... 40 
9.5 
Visit 5: Week 8 (± 3 Days) ........................................................................................ 41 
9.6 
Weeks 11 and 25: Brief Visit for CGM Sensor Application ..................................... 41 
9.7 
Visit 6: Week 12 (± 3 Days) ...................................................................................... 41 
9.8 
Visit 7: Week 16 (± 3 Days) ..................................................................................... 41 
9.9 
Visit 8: Week 20 (± 3 Days) ...................................................................................... 42 
9.10 
Visit 9 (EOT Visit): Week 26 (± 3 Days) .................................................................. 42 
11

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
9.11 
Early Termination Visit ............................................................................................. 43 
9.12 
Follow-up Telephone Call ......................................................................................... 43 
10. 
METHODS OF ASSESSMENT ............................................................................. 44 
10.1 
Pregnancy Testing ..................................................................................................... 44 
10.2 
Physical Examination ................................................................................................ 44 
10.3 
Vital Signs and Body Weight .................................................................................... 44 
10.4 
Electrocardiogram ..................................................................................................... 44 
10.5 
Clinical Laboratory Testing ....................................................................................... 45 
10.6 
Urinalysis ................................................................................................................... 45 
11. 
SAFETY MEASUREMENTS AND VARIABLES .............................................. 46 
11.1 
Adverse Events .......................................................................................................... 46 
11.2 
Serious Adverse Events ............................................................................................. 46 
11.3 
Adverse Events of Special Interest ............................................................................ 46 
11.4 
Reporting of Serious Adverse Events to PRA ........................................................... 47 
11.5 
Monitoring of Subjects with Adverse Events ............................................................ 47 
11.5.1 
Abnormal Laboratory Test Results ............................................................................ 47 
11.5.2 
Abnormal Physical Examination Findings or ECG Changes .................................... 48 
11.6 
Overdose of Study Medication .................................................................................. 48 
11.7 
Pregnancy .................................................................................................................. 48 
12. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS .............................. 49 
12.1 
Data Management ...................................................................................................... 49 
12.2 
Sample Size Estimation ............................................................................................. 49 
12.3 
Statistical Analysis Plan ............................................................................................ 50 
12.4 
Randomization ........................................................................................................... 50 
12.5 
Analysis Sets ............................................................................................................. 51 
12.5.1 
Safety Analysis Set .................................................................................................... 51 
12.5.2 
Full Analysis Set ........................................................................................................ 51 
12.5.3 
Per Protocol Set ......................................................................................................... 51 
12.6 
Statistical Methods .................................................................................................... 51 
12.6.1 
Missing Data .............................................................................................................. 51 
12.6.2 
Demographic and Baseline Data ............................................................................... 52 
12.6.3 
Subject Disposition .................................................................................................... 52 
12.7 
Primary Endpoint ....................................................................................................... 53 
12.7.1 
Incidence of Treatment-Induced Anti-Insulin Antibodies ......................................... 53 
12.8 
Key Secondary Endpoint ........................................................................................... 53 
12.8.1 
Change from Baseline in HbA1c at 26 Weeks ........................................................... 53 
12.9 
Other Secondary Endpoints ....................................................................................... 54 
12

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
12.9.1 
Immunogenicity ......................................................................................................... 54 
12.9.1.1 
Subjects with Negative Anti-Insulin Antibodies at Baseline Who Develop Confirmed 
Anti-Insulin Antibodies ............................................................................................. 54 
12.9.1.2 
Subjects with a 4-fold Increase in Titers ................................................................... 54 
12.9.1.3 
Change in Anti-Insulin Antibody Titer ..................................................................... 54 
12.9.1.4 
Subjects with Confirmed Anti-Insulin Antibodies Who Develop Anti-Insulin 
Neutralizing Antibodies ............................................................................................. 54 
12.9.1.5 
Subjects Who Develop Confirmed Anti-Insulin Antibodies ..................................... 54 
12.9.2 
Safety ......................................................................................................................... 54 
12.9.3 
Efficacy ...................................................................................................................... 55 
12.9.3.1 
Proportion of Subjects Achieving Glycemic Control ................................................ 55 
12.10 
Exploratory Variables ................................................................................................ 55 
12.11 
Data Safety Monitoring Board .................................................................................. 55 
13. 
MONITORING PROCEDURES (QUALITY ASSURANCE) ............................ 56 
13.1 
Risk and Quality Tolerance Limits and Routine Monitoring .................................... 56 
13.2 
Inspections and Auditing Procedures ........................................................................ 56 
14. 
STUDY MANAGEMENT AND MATERIALS .................................................... 57 
14.1 
Electronic Case Report Forms ................................................................................... 57 
14.2 
Data Collection .......................................................................................................... 57 
14.3 
Source Documents Maintenance ............................................................................... 57 
14.4 
Record Maintenance .................................................................................................. 58 
14.5 
Confidentiality ........................................................................................................... 58 
15. 
ADMINISTRATION PROCEDURES .................................................................. 60 
15.1 
Regulatory Approval ................................................................................................. 60 
15.2 
Protocol Amendments ............................................................................................... 60 
15.3 
Protocol Adherence and Deviations .......................................................................... 60 
15.4 
Publication Policy ...................................................................................................... 61 
15.5 
Clinical Study Report ................................................................................................ 61 
15.6 
Contractual and Financial Details .............................................................................. 61 
15.7 
Insurance, Indemnity, and Compensation ................................................................. 61 
15.8 
Discontinuation of the Study ..................................................................................... 61 
15.9 
Study Center File Management ................................................................................. 62 
16. 
REFERENCE LIST ................................................................................................ 63 
17. 
APPENDICES .......................................................................................................... 65 
17.1 
Appendix 1: Declaration of Helsinki ......................................................................... 65 
17.2 
Appendix 2: Elements of Informed Consent ............................................................. 71 
17.3 
Appendix 3: Allowed and Prohibited Concomitant Medications .............................. 73 
 
13

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
List of Tables 
Table 1: Study Procedures and Assessments .................................................................................. 25 
Table 2: Identity of the Investigational Medicinal Products .......................................................... 31 
Table 3: Basal Insulin Dose Adjustment Based on Fasting Glucose Result .................................. 33 
Table 4: Similarity Margins for Actual Observed Event Rate of Proposed Biosimilar to Insulin 
Glargine for Various Immunogenicity Event Rates ............................................. 50 
Table 5: Imputation Rules for Missing Data in the Primary Immunogenicity Analysis ................ 52 
 
List of Figures 
Figure 1: Study Diagram ................................................................................................................ 24 
 
14

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
3. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Term 
Definition 
AIA 
Anti-Insulin Antibody 
ANCOVA 
Analysis of Covariance 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CGM 
Continuous Glucose Monitoring 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCCT 
Diabetes Control and Complications Trial 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EOT 
End of treatment 
FAS 
Full Analysis Set 
FBG 
Fasting Blood Glucose 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated Hemoglobin (Glycated Hemoglobin) 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IXRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NPH 
Neutral Protamine Hagedorn 
OAM 
Other Antidiabetes Medication 
PP 
Per Protocol 
PRA  
Pharmaceutical Research Associates (PRA Health Sciences) 
QTL 
Quality Tolerance Limit 
SAP 
Statistical Analysis Plan 
TOST 
2 One-sided Equivalence Test 
TSH 
Thyroid-Stimulating Hormone 
15

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
Term 
Definition 
US/USA 
United States/United Sates of America 
WHO 
World Health Organization 
WMA 
World Medical Association 
16

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
4. 
ETHICS 
4.1 Ethics Committee 
This study will be conducted in compliance with institutional review board (IRB) and ICH 
GCP Guidelines - including Title 21 Part 56 of the United States of America (USA) Code of 
Federal Regulations (CFR) relating to IRBs and GCP as described in the United States Food 
and Drug Administration (FDA) CFR (21 CFR § 50, 56, 312) - in accordance with applicable 
ICH regulations regarding clinical safety data management (E2A, E2B(R3)), and with ICH 
regulations regarding scientific integrity (E4, E8, E9, and E10). In addition, this study will 
adhere to all local regulatory requirements, and requirements for data protection. 
Before initiating a trial/study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IRB for the study protocol/amendment(s), written ICF, 
any consent form updates, subject recruitment procedures (e.g., advertisements), and any 
written information to be provided to subjects and a statement from the IRB that these 
materials comply with GCP requirements. The IRB approval must identify the protocol 
version as well as the documents reviewed. 
4.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the Note for Guidance on GCP (ICH 
Harmonised Tripartite Guideline E6 (R1)/Integrated Addendum E6 (R2); FDA CFR (21 CFR 
§ 50, 56, 312), the general guidelines indicated in the Declaration of Helsinki (Seoul 2008) 
(Appendix 1 [Section 17.1]) and all applicable regulatory requirements. 
4.3 Subject Information and Consent 
The Investigator will explain the benefits and risks of participation in the study to each 
subject, the subject’s legally acceptable representative, or impartial witness, and obtain 
written informed consent. Written informed consent must be obtained prior to the subject 
entering the study and before initiation of any study-related procedure (including 
administration of investigational product [IP]).  
The Sponsor will provide a sample ICF, based on the elements of informed consent in 
Appendix 2 (Section 17.2). The final, version-dated form must be agreed to by the Sponsor 
and the IRB/IEC and will contain all elements in the sample form, in language readily 
understood by the subject. Each subject’s original consent form, personally signed and dated 
by the subject or by the subject’s legally acceptable representative, and by the person who 
conducted the informed consent discussion, will be retained by the Investigator. The 
Investigator will supply all enrolled subjects with a copy of their signed informed consent. 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the consent of the subject. In this instance, approval 
should always be given by the IRB/IEC and existing subjects informed of the changes and 
reconsented. This is documented in the same way as previously described. 
17

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
5. 
STUDY ADMINISTRATIVE STRUCTURE 
Gan & Lee Pharmaceuticals USA 
520 US Hwy 22 East, Suite 302 
Bridgewater, NJ 08807, USA 
Jia Lu, MD, PhD, Sr. Director, Clinical Sciences  
Melissa Israel, Executive Director – Global Clinical Operations 
Contract Research Organization: 
PRA Health Sciences 
4130 ParkLake Avenue, Suite 400 
Raleigh, NC 27612, USA 
Tel: (919) 786-8200 
Fax: (919) 786-8201 
Kyle Patrick, DO, Medical Monitor 
Magdalena Przekwas-Jaruchowska, MD, PhD, Medical Monitor  
Clinical Laboratories: 
Central Laboratory: Eurofins Global Central Laboratory 
2430 New Holland Pike, Suite D100, Lancaster, PA 17601, USA 
Specialty Laboratory: WuXi AppTec/XenoBiotic Laboratories Inc. 
 
107 Morgan Lane, Plainsboro, NJ 08536, USA 
Interactive Web Response System (IXRS):  
Bioclinica 
2005 S. Easton Road, Suite 304 
Doylestown, PA 18901, USA 
Clinical Study Medication Management:  
Almac Group US Headquarters  
25 Fretz Road, 
Souderton, PA 18964, USA 
Clinical Study Equipment Management:  
Abbott Diabetes Care Inc.  
1360 South Loop Road, 
Alameda, CA 94502, USA  
 
Continuous Glucose Monitoring Data Capture:  
Precision Digital Health, Inc. 
15615 Alton Pkwy 
Irvine, CA 92618, USA 
18

Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
6.
INTRODUCTION
6.1 Disease Review 
Diabetes is a chronic, progressive disease that, if inadequately treated, can lead to significant 
morbidity, including macrovascular and microvascular complications, and significantly 
increased mortality [1].  
Type 2 diabetes is characterized by insulin resistance, hyperglycemia, and in the initial stages 
of the disease, hyperinsulinemia. Even before overt hyperglycemia occurs, dysfunction of the 
β-cells of the pancreas has been demonstrated. Increased secretion of insulin may for a time 
compensate for insulin resistance, but with progressive loss of β-cell function or mass, 
production of endogenous insulin decreases [2]. 
In addition to comprehensive management of lipids and cardiovascular risk factors, the 
reduction of hyperglycemia is the primary goal of therapy. Initial treatment strategies for 
managing hyperglycemia in patients with type 2 diabetes include lifestyle interventions with 
modest exercise and weight loss, and the addition of medications to enhance insulin 
sensitivity, such as thiazolidinediones, metformin, and secretagogues. Newer drug classes 
include glucagon-like peptide-1 agonists, sodium-glucose transporter-2 inhibitors, and 
dipeptidyl peptidase 4 inhibitors. At some point, many patients may require the addition of 
basal insulin, either because of difficulty achieving glycemic control despite combination 
therapy with oral drugs or insufficient secretion of endogenous insulin [3]. 
6.2 Compound Review – Insulin Glargine 
Insulin glargine is a biosynthetic insulin analog with a longer duration of action than human 
insulin. The substitution of glycine for asparagine at A21 and the addition of 2 arginines at 
the C-terminus of the B chain result in stabilization of the molecule, leading to delayed and 
prolonged absorption after subcutaneous injection [4]. 
6.2.1 Nonclinical Studies 
An extensive characterization and comparison of structural and biofunctional properties of 
Gan & Lee Insulin Glargine injection and Lantus® has been conducted [5]. The structural 
characterization including primary, secondary, tertiary and quaternary structures; size, 
hydrophobicity and charge heterogeneities; cell-based biofunctionality including the binding 
to the receptors of insulin and insulin-like growth factor-1, and the activation of the insulin-
signaling cascade and the stimulation of glucose uptake were demonstrated to be similar 
between Gan & Lee Insulin Glargine Injection and Lantus®. For in vitro and in vivo 
pharmacologic and toxicologic studies and clinical studies, reference is made to NDA 
021081 [4]. 
6.2.2 Clinical Studies 
In 2016, Study GL-GLA-001, a phase I, exploratory, randomized, double-blind, 2-way 
crossover pilot study, demonstrated bioequivalence of Gan & Lee Insulin Glargine Injection 
and United States (US)-sourced Lantus®. Although this exploratory study provided a 
statistically robust conclusion of biosimilarity based on pharmacokinetics, it was not powered 
to provide robust statistical conclusions in terms of pharmacodynamics. Gan & Lee Insulin 
19

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
Glargine Injection was well tolerated, and treatment-emergent adverse events were 
comparable to those with Lantus®. There were no significant signals that would indicate a 
difference in the safety profile between the treatments. A pivotal phase I study will be 
performed concurrently to assess the pharmacokinetic and pharmacodynamic effects of Gan 
& Lee Insulin Glargine Injection compared with US- and European-sourced Lantus®. 
6.3 Clinical Study Rationale 
The purpose of this study is to compare Gan & Lee Insulin Glargine Injection100 U/mL with 
Lantus®, Sanofi-Aventis’ brand of insulin glargine injection 100 U/mL, and evaluate 
equivalence in terms of immunogenicity, safety, and efficacy, in subjects with type 2 diabetes 
mellitus. 
Insulin analogs are more costly than conventional insulins, and limited access to affordable 
insulin may keep some patients from accessing important treatment options, leading to 
unnecessary complications [1, 6]. 
Biosimilar products may result in significant price reductions compared to the cost of the 
reference products, even if the reductions are not of the magnitude seen with many 
generics [7]. 
Biosimilar drugs are not identical to the reference product. Because even small differences in 
the primary structure can result in clinically significant functional differences, there are 
concerns about potential risks to patients [7]. Insulin glargine has been shown to exhibit 
proliferative and anti-apoptotic effects in vitro in colorectal cancer cells; however, clinical 
studies have produced conflicting results regarding an association between insulin glargine 
and cancer risk [8]. And although a number of observational studies in 2009 found an 
association between insulin glargine and an increased risk for breast cancer in patients with 
type 2 diabetes, a recent study of more than 12,000 subjects with type 2 diabetes who were 
newly started on insulin glargine showed no increase in the risk of breast cancer after a 
median 5-year follow-up period among those who were insulin-naive. A nonsignificant 
increase in risk was found among subjects who had switched to insulin glargine from other 
insulins [9]. 
Because biosimilar insulins have immunogenic potential, the European Medicines Agency 
(EMA) and the FDA require an evaluation of safety and immunogenicity between biosimilars 
and their reference products, and the EMA has indicated these studies should be of sufficient 
duration (at least 6 to 12 months) to detect these differences. This study is designed in 
accordance with the guidance documents provided by the EMA [10] and the FDA [11]. 
The immunogenicity assessment will use the one-assay [12] and tiered approach [13]. 
Samples collected at all time points (including pre-dose) from both treatment groups will first 
be tested using the validated electrochemiluminescence method [14]. The rate and degree of 
immunogenicity, and data interpretation will also include consideration of other clinical 
attributes such as (but not limited to) symptoms of hypersensitivity or injection site reactions 
and the pharmacokinetic profile. 
20

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
7. 
STUDY OBJECTIVES  
7.1 Primary Study Objective 
• To evaluate equivalence of Gan & Lee Insulin Glargine Injection and Lantus® in 
terms of immunogenicity 
7.2 Secondary Study Objectives 
7.2.1 Immunogenicity 
• To evaluate the percentage of subjects with negative anti-insulin antibodies (AIAs) at 
baseline who develop confirmed positive AIA up to visit Week 26, the percentage of 
subjects with at least a 4-fold increase in titers compared to baseline value, mean 
change from baseline in AIA titers between treatment groups, the percentage of 
subjects with confirmed positive AIA who develop any anti-insulin neutralizing 
antibodies up to visit Week 26, and the percentage of subjects in each treatment group 
with confirmed positive AIA up to visit Week 26 
7.2.2 Safety 
• To evaluate the safety of Gan & Lee Insulin Glargine Injection in comparison with 
that of Lantus® 
7.2.3 Efficacy 
• To evaluate the efficacy of Gan & Lee Insulin Glargine Injection in comparison with 
that of Lantus® 
7.3 Exploratory Objective 
• To investigate the retrospective hypoglycemic rate and time in hypoglycemia and 
hyperglycemia using continuous glucose monitoring (CGM) data 
21

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
8. 
INVESTIGATIONAL PLAN 
8.1 Overall Study Design and Plan 
The purpose of this equivalence study is to compare the immunogenicity, safety, and efficacy 
of Gan & Lee Insulin Glargine Injection with that of the reference medicinal product, 
Lantus®, in adults with type 2 diabetes mellitus.  
At the screening visit, subjects will sign the informed consent form (ICF), they will be 
screened for eligibility, and the following information will be collected: adverse events, 
medical history (including diabetes mellitus and thyroid disease history), prior and 
concomitant medications, vital signs, height, body weight, and body mass index (BMI). The 
following procedures will be performed: 12-lead electrocardiogram (ECG), physical 
examination, and blood collection for fasting blood glucose (FBG) test, HbA1c, AIA, routine 
hematology and chemistry testing (complete blood count, metabolic chemistry panel with 
serum lipids, thyroid-stimulating hormone [TSH] and free thyroxine [T4]). A urinalysis, and 
for women of childbearing potential, a urine pregnancy test will be performed. At this visit, 
the subject will be issued a glucometer, test strips, and other supplies, and the Investigator or 
designee will provide instruction and conduct training on how to use the glucometer for 
prospective glucose monitoring to document hypoglycemic episodes in a prospective 
manner. Subjects will be allowed to keep the glucometer after the study, per local ethical and 
legal guidelines and regulations. Subjects will also receive a Hypoglycemic Events Record in 
which they will record information about any hypoglycemic events that occur during their 
participation in the study. 
During the 2 weeks between screening and randomization, subjects already on basal insulin 
will have their insulin dosing optimized according to Table 3 in Section 8.5.8. They will also 
have any appropriate adjustments in their other antidiabetes medications (OAM) dosing that 
may be required because of the optimization of their insulin dosing. Subjects who are insulin-
naïve will have their OAM dosing optimized to prepare them for starting basal insulin 
therapy. 
Also, at the screening visit, the subject will have a FreeStyle Libre Pro Flash Glucose 
Monitoring sensor applied to the back of the upper arm according to the manufacturer’s 
instructions. 
The FreeStyle Libre Pro Flash Monitoring System is approved by the EMA for people 
18 years of age or older with diabetes. The FreeStyle Libre Pro Flash Glucose Monitoring 
System sensor, which requires 12 to 24 hours to calibrate itself after application, will be worn 
for 8 days and will record the interstitial fluid glucose every 15 minutes. Data from the 2nd 
through the 8th days of wear will be used for each analysis. The sensor will be blinded to the 
subject and no subject action will be needed. The subject will also be issued a Mealtime & 
Insulin Dose Record in which they will record the time of their meals and insulin use. After 
8 days, the subject may remove the sensor, place in the biohazard bag provided, and bring it 
with them to the randomization visit. If the end of the 8-day continuous glucose monitoring 
(CGM) period coincides with the date of the randomization visit, the sensor can be removed 
at the visit by the site staff. Subjects will bring both their Hypoglycemic Events Record and 
their Mealtime & Insulin Dose Record to the randomization visit.  
22

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
Subjects who meet the study eligibility criteria will be centrally randomized 1:1 in an open-
label fashion to receive either Gan & Lee Insulin Glargine Injection or Lantus® for 26 weeks. 
Subjects currently taking insulin will continue using their OAMs and will substitute IP for 
their basal insulin as described in Section 8.5.8. Subjects not currently taking basal insulin 
will continue their OAMs, add IP, and undergo insulin dosing optimization and adjustments 
in OAM dosing as needed as described in Section 8.5.8. 
The Sponsor will ensure that all insulins will be provided to all subjects regardless of medical 
insurance or reimbursement issues.  
At the randomization visit (Visit 2), subjects will receive supply of insulin pens with IP and 
the Investigator or designee will train subjects on all study procedures and proper dose 
administration. 
Subjects in both treatment groups will be assessed every 2 weeks after Visit 2 (randomization 
visit) through Week 22 (telephone call) and then at Week 26; they will attend 9 clinic visits 
(the screening visit, the randomization visit, and at Weeks 2, 4, 8, 12, 16, 20, and 26), 2 brief 
visits during which a CGM sensor will be applied (8-10 days before the visits at Weeks 12 
and 26), and they will be contacted by telephone at Weeks 6, 10, 14, 18, and 22. The Week 
26 visit (Visit 9) will be the end-of-treatment visit. 
At all visits and phone contacts (except for visits to apply a CGM sensor) the Investigator or 
designee will review glucose results (especially looking for hypoglycemia), adverse events, 
changes in concomitant medications, and changes in IP, bolus insulin, and OAM use. At all 
study visits, the following procedures will be performed: vital signs, body weight, urinalysis, 
urine pregnancy testing for women of childbearing potential, and an FBG test. 
Additional procedures at study visits are as follows: at Weeks 8, 16, and 26, blood for HbA1c 
will be collected; during the visits at Weeks 12 and 26, subjects will wear their CGM sensors 
to the site for the site staff to safely remove it, and they will bring their Mealtime & Insulin 
Dose Record for the site staff to review, and, blood will be collected for routine hematology 
and chemistry, TSH, free T4, and AIA testing; and at Week 26, a 12-lead ECG and physical 
examination will be performed. Figure 1 and Table 1 show the study design and study-related 
procedures, respectively. 
If a subject discontinues the study prematurely, site personnel will make a reasonable effort 
to perform all study activities scheduled for Visit 9 (end of treatment [EOT] visit). 
Additionally, it is very important for site personnel to encourage subjects to visit the site at 
Week 26 (± 4 weeks) (and Week 12 ± 1 week if applicable) for a blood sample to be 
obtained for AIA and HbA1c measurements. 
23

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
Figure 1: Study Diagram 
 
  
 
 
 
 
 
 
 
 
 
24

 Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
  Amendment 3_ 25 April 2019 
Table 1: Study Procedures and Assessments
Visit 
1 
2 
3 
4 
TC 
5 
TC 
--- 
6 
TC 
7 
TC 
8 
TC 
--- 
9a 
FU 
TC 
Day or Week 
Day -14 
thru Day -1
Day 1 
Week 2 
±3d
Week 4 
±3d
Week 6 
±3d
Week 8 
±3d
Week 10 
±3d
Week 11 
Week 12 
±3d
Week 14 
±3d
Week 16 
±3d
Week 18 
±3d
Week 20 
±3d
Week 22 
±3d
Week 25 
Week 26 
±3d
30 d ±3d 
after Visit 
Informed Consent 
X 
Eligibility 
X 
Medical History 
X 
Randomization 
X 
Concomitant Medicationsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, Body Weight, BMIc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology & Chemistryd 
X 
X 
X 
Fasting Blood Glucose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
X 
X 
X 
Pre-dose Blood Sample for AIA 
X 
X 
X 
UA, Pregnancy Teste
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG
X 
X 
Physical Examination 
X 
X 
Glucometer and Supplies Issued, and 
Training 
X 
Apply CGM Sensor and Issue Mealtime & 
Insulin Dose Recordf 
X 
X 
X 
Collect CGM Sensor, Review Mealtime & 
Insulin Dose Record 
X 
X 
X 
25

 Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
  Amendment 3_ 25 April 2019 
Visit 
1 
2 
3 
4 
TC 
5 
TC 
--- 
6 
TC 
7 
TC 
8 
TC 
--- 
9a 
FU 
TC 
Day or Week 
Day -14 
thru Day -1
Day 1 
Week 2 
±3d
Week 4 
±3d
Week 6 
±3d
Week 8 
±3d
Week 10 
±3d
Week 11 
Week 12 
±3d
Week 14 
±3d
Week 16 
±3d
Week 18 
±3d
Week 20 
±3d
Week 22 
±3d
Week 25 
Week 26 
±3d
30 d ±3d 
after Visit 
IP and Other Supplies Issuedg 
X 
X 
X 
X 
X 
X 
X 
Subject Training on IPh 
X 
Review Insulin & OAM Use, Glucose Results, 
& Hypoglycemic Events Recordi  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect Used Insulin Kits 
X 
X 
X 
X 
X 
X 
X 
AIA = anti-insulin antibody; BMI = body mass index; CGM = continuous glucose monitoring; d = Day; ECG = electrocardiogram; HbA1c = glycosylated hemoglobin; IP = investigational product; OAM 
= other anti-diabetes medication; TC = telephone call; UA - urinalysis 
a Any subject who withdraws from the study before Week 26 will perform all study activities scheduled for Visit 9 (EOT visit). Additionally, it is very important for site personnel to encourage subjects to 
visit the site at Week 26 (± 4 weeks) (and Week 12 ± 1 week if applicable) for a blood sample to be obtained for AIA and HbA1c measurements  
b At screening, prior and concomitant medications will be collected. At every visit (except for visits to apply a CGM sensor) or telephone call, the Investigator or designee will inquire about concomitant 
medications, including insulin products taken before the first dose of IP.  
c Height and body weight will be measured at the screening visit, and at subsequent visits, only body weight will be measured. The BMI will be calculated and recorded whenever the body weight is 
measured. 
d Routine laboratory testing will include a complete blood count, a metabolic chemistry panel with serum lipids, a thyroid stimulating hormone and free thyroxine. 
e Women of childbearing potential will have a urine pregnancy test at screening and at each clinic visit. 
f At the screening visit and at Weeks 11 and 25, subjects will attend a brief visit to have a CGM sensor applied. This visit should take place between 8 and 10 days before the scheduled visits at Weeks 12 
and 26, respectively. Subjects will also be given a Mealtime & Insulin Dose Record to be completed during the 8-day CGM period that they will bring to the next visit. 
g At these visits, subjects will be issued a supply of IP sufficient to last until the next clinic visit. They can also obtain more supplies for glucometer testing if needed.  
h At Visit 2, the Investigator or designee will instruct the subject on all study procedures including proper IP administration.  
i Subjects will bring the Hypoglycemic Events Record to each visit for review.  
j Only serious adverse events to be queried. 
Note: See Section 8.5.8 for details about insulin and OAM dose optimization. 
26

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
8.2 Discussion of Study Design 
This open-label study is designed to evaluate Gan & Lee Insulin Glargine Injection compared 
with that of Lantus® in subjects with type 2 diabetes to determine equivalence. Subjects will 
continue using their bolus insulin (which should not be changed for the duration of the study, 
with the exception of a dose change) and will substitute IP for their basal insulin. Subjects 
not currently using a basal insulin will add IP to their treatment. 
8.3 Study Duration 
Subjects will participate for 26 weeks. Recruitment will stop when approximately 
275 subjects have been randomized to each treatment group. The study will end when the last 
subject completes the end-of-treatment visit, or discontinues the study treatment, whichever 
occurs first. 
This study duration has been used in comparisons between other biosimilar basal insulin 
analogs and their reference products. 
8.4 Study Population 
The study population will be selected from subjects with type 2 diabetes who meet all the 
inclusion criteria and none of the exclusion criteria. Subject race and ethnicity will be 
collected according to FDA guidance [15]. 
8.4.1 Inclusion Criteria 
Subjects must satisfy all of the following entry criteria before they will be allowed to 
participate in the study: 
1. Male or nonpregnant, nonlactating female subjects between the ages of 18 and 75 years, 
inclusive 
2. Ability to provide written, personally signed, and dated informed consent to participate in 
the study, in accordance with the ICH GCP Guideline E6 and all applicable regulations, 
before initiating any study-related procedures 
3. Ability to understand and fully comply with all study procedures and restrictions. 
4. Subjects with a confirmed diagnosis of type 2 diabetes mellitus who meet one of the 
following:  
a. If insulin-naïve, subjects should have been on at least 2 approved OAMs for at least 
12 weeks before screening, and the clinician has decided to add insulin therapy  
b. If already being treated with a basal insulin, subjects should have been treated with 
insulin for at least 6 months in addition to at least 1 approved OAM, and must not 
have changed the type or brand of insulin within 6 months prior to screening  
5. HbA1c values as follows:  
a. If insulin-naïve, HbA1c ≤ 11.0% 
b. If previously on a basal insulin regimen, HbA1c ≥ 7.0% and ≤ 11.0% 
6. Body mass index (BMI) ≤ 45 kg/m2 
7. Adherence to a prudent diet and exercise regimen recommended by the medical provider, 
and willingness to maintain these consistently for the duration of the study 
27

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
8. Concomitant medications are allowed, provided that no significant dosing changes are 
anticipated during the study (see the exclusion criteria below and 
Appendix 3 [Section 17.3] for specific allowed and prohibited concomitant medications); 
for concomitant thyroid medications, subjects must have been on a stable dosage for 
90 days before screening 
8.4.2 Exclusion Criteria 
1. Participation in another clinical study or use of any study drug within 30 days before 
screening 
2. Previous use of a biosimilar insulin, either basal or bolus 
3. Diabetic ketoacidosis within a year before screening 
4. Brittle type 2 diabetes mellitus within the year before screening (e.g., multiple 
hospitalizations related to diabetes mellitus and/or severe hypoglycemia for which the 
subject required 3rd party assistance) 
5. Any severe, delayed sequela of diabetes mellitus, e.g., worsening end-stage renal disease, 
advanced coronary artery disease, or myocardial infarction within the year before 
screening, or autonomic peristaltic problems, e.g., gastroparesis 
6. Anticipated change in insulin used during the study (change in dosage is allowed, but 
change in type or brand of insulin will result in the subject being withdrawn from the 
study) 
7. Inadequately controlled thyroid disease, as reflected by a TSH value or free T4 > the 
upper limit of normal 
8. BMI > 45 kg/m2 
9. Any clinically significant (in the opinion of the Investigator) hematology or chemistry 
test results at screening, including any liver function test > 3 × the upper limit of normal 
(subjects with elevated bilirubin due to Gilbert syndrome are eligible to participate)  
10. Documented anti-insulin antibodies in the past 
11. Treatment with glucocorticosteroids, immunosuppressants, or cytostatic agents within 
60 days before screening (newly-prescribed or high-dose corticosteroids are prohibited; 
chronically administered oral, inhaled, topical, or intra-articular corticosteroids at a stable 
dosage are allowed if no increase in dose is anticipated during the study; see 
Appendix 3 [Section 17.3] for a list of allowed and prohibited medications) 
12. Current use of medication intended to cause weight loss or weight gain 
13. Alcohol or substance use disorder within the 2 years before screening 
14. Any previous or anticipated treatment with interferons 
15. Any history of malignant disease within 5 years before screening, except for adequately 
treated basal cell carcinoma 
16. Severe concomitant physical or psychiatric diseases or conditions 
17. A history of a positive test result for HIV, hepatitis B, or hepatitis C; any subject who has 
a positive result during the study may continue at the discretion of the Investigator 
18. Any history of pancreatitis or pancreatectomy 
28

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
19. Any diagnosis or condition that requires the subject to undergo procedures that could 
decrease antibodies in plasma or that would require treatment with immunosuppressant 
agents 
20. Any condition e.g., splenectomy, autoimmune disease, or rheumatologic disease, that 
could affect immunologic responses, could indicate an altered immune system, or could 
require treatment with a prohibited concomitant medication 
21. Any unresolved infection or a history of active infection within 30 days before screening 
other than mild or viral illness (as judged by the Investigator)  
22. Any other disease or condition that in the opinion of the Investigator could confound the 
study results or limit the subject’s ability to participate in the study or comply with 
follow-up procedures; or any other factor that would indicate a significant risk of loss to 
follow up 
23. Intolerance or history of hypersensitivity to insulin glargine or any excipient of IP 
24. Inability or unwillingness to wear the CGM sensor as required for the study, or to comply 
with the concomitant medication requirements in the FreeStyle Libre Pro Indications and 
Important Safety Information, during the CGM periods  
8.4.3 Withdrawal and Replacement of Subjects 
8.4.3.1 Criteria for Subject Withdrawal 
In accordance with the Declaration of Helsinki (Appendix 1 [Section 17.1]) and other 
applicable regulations, a subject has the right to withdraw from the study at any time and for 
any reason without prejudice to his or her future medical care by the physician or at the 
institution. 
Subjects may also be withdrawn from the study for any of the following reasons: 
• The Investigator decides that the subject should be withdrawn. If this decision is 
made because of an intolerable adverse event or a clinically significant laboratory 
abnormality, the study medication is to be discontinued and appropriate treatment is 
to be provided. The Sponsor or designee is to be notified immediately. 
• The subject requires a change in the type or brand of insulin (other than a change in 
dosage) 
• The subject is unwilling to continue in the study 
• Lack of compliance with protocol 
• The Investigator or the Sponsor stops the study per Section 15.8  
• The subject fails to respond to the study medication at an acceptable level, and the 
subject or Investigator determine another treatment is preferable. 
• The subject fails to return to the clinic for scheduled visits and does not respond to 
telephone calls or written attempts at communication. 
29

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
• If a subject becomes pregnant during the study, she will discontinue IP immediately, 
report the pregnancy to the Investigator, and attend an end-of-treatment visit. If the 
female partner of a male subject becomes pregnant, the subject may continue in the 
study but the pregnancy should be reported. See Section 11.7 of this document for 
more details about pregnancy reporting procedures. 
The reason for withdrawal will be recorded in the clinical records and the electronic Case 
Report Form (eCRF). All subjects who are withdrawn from the study will attend an end-of-
treatment clinic visit (see Section 9.10). All subjects who are withdrawn from the study 
should be offered appropriate follow-up medical care. 
8.4.3.2 Replacement of Subjects 
Subjects who withdraw from the study will not be replaced. 
8.5 Treatment 
8.5.1 Treatments Administered 
Subjects will be randomized to receive either Lantus® or Gan & Lee Insulin Glargine 
Injection for subcutaneous injection. Details of each product are shown in Table 2. 
30

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
Table 2: Identity of the Investigational Medicinal Products 
Drug Name 
Gan & Lee Insulin Glargine Injection 
Lantus® 
Manufacturer 
Gan & Lee Pharmaceuticals, China 
Sanofi-Aventis Deutschland GmbH, 
Germany 
Formulation 
Solution 
Solution 
Strength 
100 U/mL 
100 U/mL 
Route of 
administration 
Subcutaneous 
Subcutaneous 
 
Lantus® contains insulin glargine, an insulin analog, and has a prolonged duration of action. 
Lantus® and Gan & Lee Insulin Glargine should be administered once daily at any time but at 
the same time each day. To be consistent with current Lantus® labeling, twice-daily dosing of 
IP is strictly prohibited. The dose regimen (dose and timing) should be individually adjusted. 
In patients with type 2 diabetes mellitus, Lantus® and Gan & Lee Insulin Glargine Injection 
can also be given together with OAMs. 
Gan & Lee Insulin Glargine will be contained in Gan & Lee injector pens (3.0-mL pre-filled 
glass cartridge) for multiple dose administration. 
Lantus® will be provided in 3.0-mL SoloStar® pre-filled pens. 
Subjects will follow instructions provided by the Investigator and/or designee regarding 
proper dose administration of IP and use of the insulin pens, glucometer and related supplies, 
and the frequency of glucose testing. 
8.5.2 Study Treatment Formulation 
8.5.2.1 Gan & Lee Insulin Glargine Injection 
The experimental drug is Gan & Lee Insulin Glargine Injection manufactured by Gan & Lee 
Pharmaceuticals (Beijing, China). This formulation is a clear, colorless, sterile solution for 
subcutaneous injection, and the concentration is 100 U/mL. 
8.5.2.2 Lantus® 
The active comparator, Lantus® (insulin glargine injection) solution for subcutaneous 
injection, is a basal insulin analog manufactured by Sanofi-Aventis. This formulation is a 
clear, colorless, sterile solution, and the concentration is 100 U/mL. 
8.5.3 Dose and Administration of the Investigational Product 
The dosage of IP should be determined by the physician, according to the requirement of the 
subject. Insulin glargine preparations should be given by subcutaneous injection only.  
Subcutaneous administration should be in the upper arms, thighs, buttocks, or abdomen. Use 
of injection sites should be rotated according to clinical practice. 
31

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
When administered subcutaneously, care should be taken when injecting insulin glargine to 
ensure that a blood vessel has not been entered. After injection, the site of injection should 
not be massaged. 
8.5.4 Study Treatment Labeling and Packaging 
Both Gan & Lee Insulin Glargine Injection and Lantus® will be supplied and appropriately 
labeled in accordance with all national and local regulatory requirements. 
8.5.5 Blinding of Study Medication 
Not applicable to this open-label study 
8.5.6 Study Treatment Storage and Accountability 
8.5.6.1 Study Treatment Storage 
Investigational product must be kept in an appropriate, limited-access, secure location. The 
storage area should be labeled “For Investigational Use.” The Investigator or designee must 
maintain a log of temperature for the refrigerator in which IP is stored and must record and 
evaluate the temperature of the storage site in accordance with all applicable standards. 
8.5.6.1.1 Gan & Lee Insulin Glargine Injection 
Before opening, store Gan & Lee Insulin Glargine Injection in a refrigerator at 36 to 46o F 
(2 to 8°C). Do not freeze or place next to the freezer or a freezer pack. Keep the unopened 
Gan & Lee Insulin Glargine Injection pens in the outer carton to protect from light. After its 
first use, the pen must be stored not above 30°C (86oF), for a maximum of 4 weeks. Do not 
refrigerate. Keep the pen protected from light. 
8.5.6.1.2 Lantus® 
Lantus® should not be stored in the freezer and should not be allowed to freeze. Discard 
Lantus® if it has been frozen. Protect Lantus® from direct heat and light. Unopened Lantus® 
that is not in use should be stored refrigerated at 36° to 46°F (2° to 8°C). After a Lantus® 
SoloStar® insulin pen is opened and in use, it should be stored at room temperature below 
86°F (30°C) for a maximum of 28 days. Once opened, the Lantus® SoloStar® pen should not 
be refrigerated. 
8.5.6.2 Study Treatment Accountability 
The Investigator is required to document the receipt, issue, and return or destruction of IP 
provided by the Sponsor, in accordance with GCP. 
No IP may be dispensed to any person not enrolled in the study. The Investigator or designee 
will count and reconcile drug supplies at the site before either returning them to Gan & Lee 
Pharmaceuticals or designee at the end of the study. 
32

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
8.5.7 Gan & Lee Insulin Glargine Injection Pen and the Lantus® SoloStar® 
The Gan & Lee Insulin Glargine Injection pen and the Lantus® SoloStar® are disposable, 
multiple-dose, “dial and push”-type variable dose pens intended for the subcutaneous 
administration of insulin. The injector pen and the drug product (in a 3.0-mL pre-filled glass 
cartridge) form a single integral product and will be used in conjunction with needles in a 
suitable range of sizes to be determined by the Investigator’s team. The 3-mL pre-filled glass 
cartridge contains 300 units of insulin and a maximum deliverable dose of 1 to 80 units with 
a dose increment of 1 unit. The Investigator or designee will train subjects regarding proper 
use and handling of the insulin pens for the study and instruct subjects to bring used insulin 
kits to clinic visits when all the pens needed in a kit have been used. At the end-of-treatment 
visit, subjects will bring all used and unused kits to the clinic. 
8.5.8 Dose Adjustments and Dose Escalation 
8.5.8.1 Subjects Already on Basal Insulin 
During the 2 weeks between screening and randomization, subjects will have their insulin 
dosing optimized according to Table 3. They will also have any appropriate adjustments in 
their OAM therapy that may be required because of the optimization of their insulin dosing. 
8.5.8.2 Subjects Not Currently on Basal Insulin Therapy 
8.5.8.2.1 Pre-Randomization 
During the 2 weeks between screening and randomization, subjects will have their OAM 
dosing optimized to prepare them for starting basal insulin therapy. 
8.5.8.2.2 Post-Randomization Insulin and OAM Optimization 
Subjects will be prescribed a dose of Lantus® or Gan & Lee Insulin Glargine Injection that 
will be individually adjusted according to the metabolic status of the subject and at the 
discretion of the clinical investigational team at the site. During the 4 weeks following 
randomization, these subjects will have their insulin dosing optimized according to Table 3. 
They will also have any appropriate adjustments in their OAMs that may be required because 
of the optimization of their insulin dosing. Optimizing the dose before the randomization 
visit will reduce the need for dose adjustments during the study. Subjects will follow the 
instructions provided by the Investigator regarding any dose adjustments and other details 
regarding the clinical management of glucose and insulin. 
Table 3: Basal Insulin Dose Adjustment Based on Fasting Glucose Result 
Lowest Average Fasting Plasma Glucose 
(Pre-Breakfast) Value for 3 Days 
Adjust Basal Insulin Dose (Units per Dose) 
> 271 mg/dL (> 15.1 mmol/L) 
+ 6 U 
181 – 270 mg/dL (10.1 – 15.0 mmol/L) 
+ 4 U 
151 – 180 mg/dL (8.4 – 10.0 mmol/L) 
+ 2 U 
33

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
Lowest Average Fasting Plasma Glucose 
(Pre-Breakfast) Value for 3 Days 
Adjust Basal Insulin Dose (Units per Dose) 
131 – 150 mg/dL (7.3 – 8.3 mmol/L) 
+ 1 U 
71 – 130 mg/dL (> 3.9 – 7.2 mmol/L)  
(Target Level) 
Maintain Current Dose 
56 – 70 mg/dL (3.1 – 3.9 mmol/L) 
- 2 U 
< 56 mg/dL (< 3.1 mmol/L) 
- 4 U 
 
8.5.8.3 Hypoglycemia 
The time of occurrence of hypoglycemia may change with a change of insulin regimen, 
depending on the action profile of the insulins used. Because Lantus® has a more sustained 
basal insulin supply, fewer nocturnal but more frequent early morning episodes of 
hypoglycemia can be expected. Particular caution should be exercised, and intensified blood 
glucose monitoring is advisable for subjects in whom hypoglycemic episodes might be of 
particular clinical relevance, such as subjects with significant stenoses of the coronary 
arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications 
of hypoglycemia), and for subjects with proliferative retinopathy, particularly if they have 
not been treated with photocoagulation (risk of transient amaurosis following hypoglycemia). 
Subject adherence to the prescribed medication, diet, and exercise regimens; correct insulin 
administration; and awareness of symptoms are essential to reduce the risk of hypoglycemia. 
The prolonged effect of subcutaneous insulin glargine may delay recovery from 
hypoglycemia. If normal or decreased HbA1c values are noted, the Investigator should 
consider the possibility of recurrent, unrecognized (especially nocturnal) episodes of 
hypoglycemia. 
Investigators will advise each subject about circumstances in which warning symptoms of 
hypoglycemia may be different, diminished, or absent, and that hypoglycemia (and possible 
loss of consciousness) may occur before the subject is aware of any symptoms. 
Some factors that may increase the susceptibility to hypoglycemia and require particularly 
close monitoring and possible dose adjustment include: 
• Markedly improved glycemic control after starting the study treatment 
• A known tendency to gradually develop hypoglycemia 
• Older subject age 
• Switching from animal insulin to human insulin 
• Autonomic neuropathy 
• A long history of diabetes 
• Psychiatric illness 
• A change in the site of injection from one body area to another 
• Conditions that may improve insulin sensitivity such as decreased stress 
• Unusual, increased, or prolonged physical activity 
34

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
• Intercurrent illness such as vomiting or diarrhea 
• Inadequate intake of food and/or liquids 
• Missed meals 
• Alcohol consumption 
• Uncompensated endocrine disorders such as hypothyroidism, anterior pituitary or 
adrenocortical insufficiency 
• Concomitant medications that may enhance the blood glucose-lowering effect and 
increase susceptibility to hypoglycemia, such as angiotensin converting-enzyme 
inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, 
pentoxifylline, propoxyphene, salicylates, and sulfonamide antibiotics 
• Concomitant medications that block the sympathetic nervous system such as beta-
blockers 
 
8.5.9 Previous and Concomitant Therapy 
Administration of concomitant medications must be reported in the appropriate section of the 
eCRF, with dosage information, dates of administration, and indication for use. Investigators 
and site staff should use generic names for concomitant medications if possible. All fields 
should be completed on the eCRF. See Appendix 3 (Section 17.3) for a list of allowed and 
prohibited concomitant medications. 
8.5.10 Treatment Compliance 
Investigators and site staff will review each subject’s treatment medication use at scheduled 
clinic visits and telephone calls, and at any interim clinic visits, and study treatment 
compliance will be assessed. 
8.5.11 Assignment to Treatment 
Randomization will be performed through IXRS. The Investigator or designee will access the 
IXRS to randomize enrolled subjects. The IXRS system will assign a unique randomization 
number and study medication kit number. No subject may be randomized more than once, 
and no randomization number will be assigned to more than 1 subject. 
8.5.12 Unblinding Procedures 
Not applicable for this open-label study. 
8.6 Study-Related Devices 
8.6.1 Glucometer, Test Strips, and Related Supplies  
At the screening visit, each subject will be issued with a glucometer, test strips, and other 
supplies for use during the study to document hypoglycemic episodes in a prospective 
manner. The Investigator or qualified site staff will train each subject on the correct use of 
these supplies and any related procedures, and subjects can obtain additional supplies as 
35

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
needed at subsequent study visits. Subjects will also be issued a Hypoglycemic Events 
Record in which they will fully record information prospectively about any hypoglycemic 
events. They will bring this record to each study visit except those brief visits for application 
of a CGM sensor. Subjects will be allowed to keep the glucometer after the study per local, 
ethical and legal guidelines and regulations. 
8.6.2 FreeStyle Libre Pro Flash Glucose Monitoring System 
The FreeStyle Libre Pro Flash Glucose Monitoring System is a glucose-monitoring device 
indicated for detecting trends and tracking patterns in persons (age 18 and older) with 
diabetes. 
The FreeStyle Libre Pro Flash Glucose Monitoring System aids in understanding the 
person’s glucose profile and detecting episodes of hyperglycemia and hypoglycemia. 
Interpretation of the FreeStyle Libre Pro Flash Glucose Monitoring System readings will be 
based on the trends and patterns analyzed through time using the reports available. 
The FreeStyle Libre Pro Flash Glucose Monitoring System consists of a sensor with an 
applicator, and reader that is used to start the sensor on the subject and gather the glucose 
data at the end of the CGM period. The sensor has a small, flexible filament that is inserted 
just under the skin. The sensor can be worn for up to 14 days. Multiple subjects can have 
their sensor started by the same reader. Once applied, a sensor will measure and store the 
glucose readings every 15 minutes. Each site will have a single reader that will be used for all 
their subjects. Readings from the FreeStyle Libre Pro Flash Glucose Monitoring System will 
not be made available to subjects in real time and so they will continue performing glucose 
self-testing with the glucometer according to the Investigator’s instructions. The FreeStyle 
Libre Pro Flash Glucose Monitoring System will be used for data collection purposes only 
and will not be used to make treatment decisions. The system does not require any subject 
action. 
At the screening visit and between 8 and 10 days before the visits at Weeks 12 and 26, 
subjects will attend a brief visit so the Investigator or designee can apply a CGM sensor to 
the back of the upper arm according to the instructions in the FreeStyle Libre Pro User 
Guide. Subjects will also receive a Mealtime & Insulin Dose Record in which they will 
record the time of meals and insulin doses for the 8-day CGM period. 
Eight days after the screening visit, the subject may remove the sensor and will bring it to the 
randomization visit in a provided biohazard bag; if the end of the 8-day CGM period 
coincides with the date of the randomization visit, the sensor can be removed at the visit by 
site staff. Subjects will bring both their Hypoglycemic Events Record and their Mealtime & 
Insulin Dose Record to the randomization visit. 
For the visits at Weeks 12 and 26, the subject will have worn the sensor for the 8-day CGM 
period before the visit, and the site staff will remove the sensor at the visit. The Investigator 
36

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
or designee will use the reader to retrieve the data from the sensor, and the 8-day Mealtime & 
Insulin Dose Record will be collected and reviewed. The data from the sensor does not need 
to be uploaded at the time of the visit, but the Investigator will retain each subject’s sensor 
until it is confirmed the data have been successfully uploaded. Each sensor will be labeled 
with the subject and visit number and will be stored in a secure location until the end of the 
study after confirmation of successful upload. 
Investigators and staff will review the FreeStyle Libre Pro Flash Glucose Monitoring System 
warnings and limitations and instruct subjects about the need to avoid medications and 
conditions that could interfere with the results. 
8.7 Primary and Secondary Endpoints 
8.7.1 Primary Endpoint 
• The percentage of subjects in each treatment group who develop treatment-induced 
AIAs, defined as newly confirmed positive AIA development or important (at least a 
4-fold) increase in titer, after baseline and up to visit Week 26 
8.7.2 Key Secondary Endpoint 
• Efficacy 
o The change in HbA1c from baseline at visit Week 26  
8.7.3 Other Secondary Endpoints 
8.7.3.1 Immunogenicity 
• The percentage of subjects in each treatment group with negative AIA at baseline 
who develop confirmed positive AIA after baseline and up to visit Week 26 
• The percentage of subjects in each treatment group with confirmed positive AIA at 
baseline and at least a 4-fold increase in titers after baseline and up to visit Week 26 
• The mean change from baseline in each treatment group in AIA titers after baseline 
and up to visit Week 26 
• The percentage of subjects in each treatment group with confirmed positive AIA after 
baseline and up to visit Week 26 who develop any anti-insulin neutralizing antibodies 
after baseline and up to visit Week 26 
• The percentage of subjects in each treatment group with confirmed positive AIA after 
baseline and up to visit Week 26 
8.7.3.2 Safety 
• The incidence and severity of all treatment-emergent adverse events and the 
following subgroups: 
• Hypoglycemia, which will be fully documented prospectively in the 
Hypoglycemic Events Record 
• Serious adverse events, including fatal events 
37

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
• Adverse events leading to termination of the study treatment and/or early 
withdrawal from the study 
• IP-related adverse events  
• Injection site reactions 
• The incidence of clinically significant laboratory abnormalities 
• The incidence of clinically significant abnormalities in ECG and vital signs 
8.7.4 Efficacy 
• The number and percentage of subjects who achieve an FBG test result of 
≤ 8.0 mmol/L (≤ 144.0 mg/dL) at visit Week 26 
• The number and percentage of subjects who achieve a HbA1c of < 7.0% at visit 
Week 26  
8.8 Exploratory Endpoints 
• Retrospective CGM hypoglycemic rate 
• Time in hypoglycemia and hyperglycemia 
38

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
9. 
STUDY EVALUATIONS BY VISIT 
See Section 10 for information about subject assessments. 
9.1 Visit 1: Screening: From Day -14 Through Day -1 
At the screening visit, subjects will provide informed consent and will be evaluated for 
eligibility to participate in the study. After the subject signs the ICF, the following 
information will be collected or procedures performed: 
• Eligibility screening  
• Adverse events  
• Medical history (including diabetes mellitus and thyroid disease history) 
• Prior and concomitant medications (including insulin)  
• Vital signs, height, body weight, and BMI  
• 12-lead ECG 
• Physical examination 
• Venous blood samples will be collected for the following tests: 
o Routine hematology and chemistry testing including free T4 and TSH 
(See Section 10.5 for details) 
o FBG test 
o HbA1c 
o AIA (blood should be collected before the subject administers the regular 
insulin dose) 
• Urine samples will be collected for urinalysis and, for women of childbearing 
potential, a urine pregnancy test  
• A capillary blood glucometer, test strips, and other supplies will be issued and the 
Investigator or designee will provide instruction and conduct training on how to use 
the glucometer 
• The Investigator or designee will apply a CGM sensor and issue an 8-day Mealtime & 
Insulin Dose Record, and will instruct the subject about the purpose of the CGM, the 
need to continue performing glucose self-testing with the glucometer, care of the 
sensor, and how to complete the Mealtime & Insulin Dose Record (subjects will be 
instructed to bring the record back to their next visit) 
• Subjects will also receive a Hypoglycemic Events Record in which they will record 
information about any hypoglycemic events during their participation in the study  
• During the 2-week period between the screening and randomization visits, subjects 
already taking a basal insulin will have their dose optimized based on fasting glucose 
results according to Section 8.5.8, and will have their OAM doses adjusted as needed 
as a result of insulin dose optimization. Subjects not currently on basal insulin therapy 
will have their OAM dose optimized in preparation for starting basal insulin. 
39

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
9.2 Visit 2: Randomization (Day 1) 
At Visit 2, eligible subjects will be centrally randomized 1:1 in an open-label fashion to 
receive either Gan & Lee Insulin Glargine Injection or Lantus®. The following information 
will be collected or procedures performed:  
• Concomitant medications and adverse events  
• Vital signs, body weight, and BMI 
• Venous blood will be collected for the following test:  
o FBG test 
• Urine samples will be collected for urinalysis and, for female subjects of childbearing 
potential, a urine pregnancy test  
• Insulin and OAM use and glucose results since the previous visit and the 
Hypoglycemic Events Record will be reviewed 
• The CGM sensor that was applied at the screening visit will be collected (either 
provided in a biohazard bag from the subject, or collected from arm if the end of the 
8-day CGM period coincides with the date of the randomization visit)  
• The 8-day Mealtime & Insulin Dose Record will be collected and reviewed 
• Additional glucose testing supplies will be issued if needed 
•  IP will be issued  
• The Investigator or designee will provide instruction and conduct training on all study 
procedures and proper dose administration 
• Subjects not currently on basal insulin therapy will enter a 4-week dose-optimization 
period during which the basal insulin dose will be adjusted according to Section 8.5.8, 
and their OAM dosage will also be adjusted as needed as a result of insulin dose 
optimization. 
9.3 Visits 3 and 4: Weeks 2 and 4 (±3 Days) 
At each clinic visit, the following information will be collected or procedures performed:  
• Concomitant medications and adverse events  
• Review of insulin and OAM use, glucose results, and the Hypoglycemic Events 
Record 
• Vital signs, body weight, and BMI 
• Venous blood will be collected for the following test:  
o FBG test 
• Urine samples will be collected for urinalysis and, for female subjects of childbearing 
potential, a urine pregnancy test  
• IP and other supplies will be issued if needed, and any used insulin kits will be 
collected for accountability 
9.4 Telephone Contacts: Weeks 6, 10, 14, 18, and 22 (± 3 Days) 
At these weeks, the Investigator or designee will call the subjects and collect information 
about concomitant medications; adverse events; IP, bolus insulin, and OAM use; and glucose 
results. The subject will be asked about any hypoglycemic events and ensure that they have 
been recorded in the Hypoglycemic Events Record. 
40

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
9.5 Visit 5: Week 8 (± 3 Days) 
At this visit, the following information will be collected or procedures performed:  
• Concomitant medications and adverse events  
• Review of insulin and OAM use, glucose results, and the Hypoglycemic Events 
Record 
• Vital signs, body weight, and BMI 
• Venous blood will be collected for the following tests:  
o FBG test 
o HbA1c 
• Urine samples will be collected for urinalysis and, for female subjects of childbearing 
potential, a urine pregnancy test  
• IP and other supplies will be issued if needed, and any used insulin kits will be 
collected for accountability 
9.6 Weeks 11 and 25: Brief Visit for CGM Sensor Application 
Between 8 and 10 days before the Week 12 and 26 visits, each subject will attend a brief visit 
during which a new CGM sensor will be applied, and they will also receive a new 8-day 
Mealtime & Insulin Dose Record in which they will record the time of meals and insulin 
dosing during the 8-day CGM period. 
9.7 Visit 6: Week 12 (± 3 Days) 
At this visit, the following information will be collected or procedures performed:  
• Concomitant medications and adverse events  
• Review of insulin and OAM use, glucose results, and the Hypoglycemic Events 
Record  
• Vital signs, body weight, and BMI 
• Venous blood will be collected for the following tests:  
o FBG test 
o Routine hematology and chemistry testing including free T4 and TSH  
o AIA (blood should be collected before the subject administers the regular 
insulin dose) 
• Urine samples will be collected for urinalysis and, for female subjects of childbearing 
potential, a urine pregnancy test  
• IP and other supplies will be issued if needed, and any used insulin kits will be 
collected for accountability 
• The CGM sensor that was applied at Week 11 will be collected from the subject’s 
arm  
• The 8-day Mealtime & Insulin Dose Record will be collected and reviewed 
9.8 Visit 7: Week 16 (± 3 Days) 
At this visit, the following information will be collected or procedures performed: 
• Concomitant medications and adverse events  
• Review of insulin and OAM use, glucose results, and the Hypoglycemic Events 
Record 
41

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
• Vital signs, body weight, and BMI 
• Venous blood will be collected for the following tests:  
o FBG test 
o HbA1c 
• Urine samples will be collected for urinalysis and, for female subjects of childbearing 
potential, a urine pregnancy test  
• IP and other supplies will be issued if needed, and any used insulin kits will be 
collected for accountability 
9.9 Visit 8: Week 20 (± 3 Days) 
At this visit, the following information will be collected or procedures performed:  
• Concomitant medications and adverse events  
• Review of insulin and OAM use, glucose results, and the Hypoglycemic Events 
Record 
• Vital signs, body weight, and BMI 
• Venous blood will be collected for the following test:  
o FBG test 
• Urine samples will be collected for urinalysis and, for female subjects of childbearing 
potential, a urine pregnancy test  
• IP and other supplies will be issued if needed, and any used insulin kits will be 
collected for accountability 
9.10 
Visit 9 (EOT Visit): Week 26 (± 3 Days) 
Subjects will visit the study site for the last time at Week 26 of the Treatment Period 
(Visit 9). The Investigator or designee will perform the following procedures and 
assessments: 
• Concomitant medications and adverse events  
• Review of insulin and OAM use, glucose results, and the Hypoglycemic Events 
Record 
• The CGM sensor that was applied at Week 25 will be collected from the subject’s 
arm  
• The 8-day Mealtime & Insulin Dose Record will be collected and reviewed 
• Vital signs, body weight, and BMI  
• Venous blood will be collected for the following tests:  
o Routine hematology and chemistry tests, and free T4 and TSH  
o FBG test 
o HbA1c 
o AIA (blood should be collected before the subject administers insulin) 
• Urine samples will be collected for urinalysis and, for female subjects of childbearing 
potential, a urine pregnancy test  
• 12-lead ECG 
• Physical examination 
• All remaining IP kits will be collected for accountability 
• Any other applicable end-of-treatment procedures will be carried out 
42

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
9.11 
Early Termination Visit 
For any subject who is withdrawn before completing all study visits, the Investigator will 
ensure that the following steps are taken at an early termination (ET) visit: 
• Conduct an ET visit performing study activities listed under Visit 9 (Section 9.10 no 
later than 14 days after withdrawal or discontinuation from the study 
• If the subject fails to attend a scheduled ET visit, site staff will make at least 
2 attempts to contact the subject via telephone and 2 attempts via written 
communications delivered by courier (delivery should be confirmed and 
documented). If the subject does not respond to any of these attempts at 
communication, he or she will be considered lost to follow-up 
• Complete all appropriate eCRF pages, providing the date of and explanation for the 
subject’s withdrawal/discontinuation 
• When indicated, the Investigator should arrange for appropriate follow-up medical 
care for the subjects 
If a subject discontinues the study prematurely, it is very important for site personnel 
to encourage subjects to visit the site at Week 26 (± 4 weeks) (and Week 12 ± 1 week, if 
applicable) for a blood sample to be obtained for AIA and HbA1c measurements. 
9.12 
Follow-up Telephone Call 
Site personnel will contact the subjects by phone approximately 30 days after the study 
completion to collect serious adverse event information. 
43

Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
10.
METHODS OF ASSESSMENT
10.1 
Pregnancy Testing
Subjects who are pregnant at screening or planning to become pregnant during the study will
be excluded from participation in the study. All women of childbearing potential will have a
urine pregnancy test at screening and at each clinic visit. Unless a female subject meets at
least 1 of the following criteria, she will be considered to be of childbearing potential:
•
Postmenopausal, defined as 12 consecutive months with no menses without an
alternative medical cause
•
Surgically or congenitally sterile
•
Diagnosed as infertile and not undergoing treatment to restore fertility
10.2 
Physical Examination 
Physical examinations will be performed by a physician or delegate who must be listed on 
the 1572 as a sub-investigator. This responsibility should be documented on the Site 
Signature & Duty Delegation Log. The examination will include the following organs or 
organ systems: general appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular 
system, respiratory system, abdominal system and nervous system (including a neurological 
examination; with an assessment of the reflexes, motor and sensory nerve assessment, 
sensory checks [extremities] and mental status assessment).  
The examining physician or delegate will document an assessment of normal or abnormal for 
each body system on the Physical Exam source document. Any abnormal finding deemed to 
be clinically relevant by the Investigator will be reported as an adverse event. See 
Section 11.1 for more details about reporting adverse events. 
10.3 
Vital Signs and Body Weight 
Systolic blood pressure and diastolic blood pressure will be measured on the same arm 
(preferentially on the left arm) after the subject has been in a supine/sitting position for 
5 minutes. Pulse will be recorded simultaneously with blood pressure measurements.  
Body weight (kg) will be measured without shoes or jacket. Height will be recorded at 
screening to calculate BMI. 
During the study, the Investigator may repeat vital signs for safety reasons. Clinically 
relevant abnormal findings will be reported as adverse events. 
10.4 
Electrocardiogram 
Computerized 12-lead ECG recordings will be obtained, after the subject has been supine for 
5 minutes. Each lead will be recorded for at least 3-5 beats at a speed of 25 mm/sec paper 
speed and 10 mm/mV amplitude. At a minimum, heart rate, P, PR, QRS, QT and corrected 
QT intervals (msec) will be recorded from the 12-lead ECG. A copy of all ECGs will be 
retained on site and these may be collected for central review if required (i.e., in case 
emerging ECG data necessitate expert evaluation). 
44

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
For the purposes of screening, the Investigator or a designee will evaluate whether the ECG 
is normal or abnormal, and if abnormal, whether the abnormality will exclude the subject 
from participating in the study. 
Investigators may repeat ECGs for quality or safety reasons. Any abnormal finding deemed 
to be clinically relevant by the Investigator will be reported as an adverse event. Subjects 
with clinically relevant cardiovascular side effects or adverse events, or clinically relevant 
ECG changes must be withdrawn from the study (see Section 8.4.3). 
10.5 
Clinical Laboratory Testing 
The following routine clinical laboratory tests will be performed as indicated in Table 1 and 
Section 9. 
• Complete blood count (red blood cell [RBC] count, white blood cell [WBC] count, 
hemoglobin, hematocrit, platelet count, RBC indices, and a 5-part WBC differential 
[percentages of neutrophils, lymphocytes, monocytes, eosinophils, and basophils])  
• Chemistry metabolic panel, including glucose, creatinine, blood urea nitrogen, 
sodium, potassium, chloride, bicarbonate, calcium, total protein, total and conjugated 
bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, 
and creatine kinase  
• Serum lipid panel including total cholesterol, low-density lipoprotein, high-density 
lipoprotein, and triglycerides 
•  TSH and free T4  
The following additional blood tests will be performed at specific visits as outlined in 
Table 1 and Section 9. More information about sample collection and handling will be 
included in the respective laboratory manuals. 
• AIA (blood should be collected before the subject administers insulin) 
• FBG test (venous) 
• HbA1c 
10.6 
Urinalysis 
Urinalysis, including glucose, protein, and ketones, will be performed at each study visit in 
the clinic. 
45

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
11. 
SAFETY MEASUREMENTS AND VARIABLES 
11.1 
Adverse Events  
The definitions and reporting procedures provided in this protocol comply with the current 
CFR 21 Part 312. An adverse event is any untoward medical occurrence or worsening of a 
pre-existing condition, regardless of the relationship to the investigational medicinal product. 
An adverse event can therefore be any unfavorable or unintended sign, including an 
abnormal laboratory finding, symptom or disease temporally associated with the use of an 
investigational medicinal product whether or not considered related to the investigational 
medicinal product.  
Adverse events will be recorded beginning at the screening visit. Nonserious adverse events 
will be recorded from the time informed consent is signed through the subject’s last study 
visit (or termination if the subject terminates early from the study for any reason). Serious 
adverse events will be collected from the time informed consent is signed through and 
including 30 calendar days after the last dose of treatment with IP. 
The Investigator or designee will record all adverse events on the eCRF, regardless of the 
Investigator’s assessment of causality, including a description of the event, severity, time of 
occurrence, duration, any action (e.g., treatment and follow-up tests), the event outcome, and 
the Investigator’s assessment of the relationship to the study treatment. 
11.2 
Serious Adverse Events  
A serious adverse event is any untoward medical occurrence or effect that meets any of the 
following criteria: 
• 
results in death 
• 
is life-threatening (refers to events during which a subject was actually at risk of death, 
and not to events that might have become life-threatening if they had occurred in a more 
severe form or if the subject had not received treatment) 
• 
requires hospitalization or causes prolongation of existing inpatient hospitalization  
• 
results in persistent or significant disability or incapacity 
• 
is a congenital abnormality/birth defect in the offspring of a study subject 
• 
is an important medical event that does not meet any of the above criteria but may require 
medical intervention to prevent the outcomes listed above, or is considered important by 
the Investigator; examples of important medical events include:  
o Bronchospasm requiring treatment in the emergency department or at home 
o Development of a blood dyscrasia 
o Diagnosis of a substance use disorder 
11.3 
Adverse Events of Special Interest 
An adverse event of special interest is a noteworthy serious or nonserious event that a 
Sponsor may want to carefully monitor because it might be a potential precursor or prodrome 
for a more serious condition in susceptible individuals. In this study, hypoglycemia will be 
monitored as an adverse event of special interest. When an adverse event of hypoglycemia is 
46

Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
entered into the electronic data capture system, the system will prompt the user to provide 
additional information. 
11.4 
 Reporting of Serious Adverse Events to PRA 
In addition to completing all eCRFs related to serious adverse events, the Investigator or 
designee must report all serious adverse events to PRA Drug Safety within 24 hours after 
learning about the event, even if the information is incomplete. 
PRA Drug Safety Contact Information: 
PRA Health Sciences – Charlottesville, VA, USA 
Drug Safety Helpline: 1-800-772-2215 or 1-434-951-3489 
Fax: 1-888-772-6919 or 1-434-951-3482 
E-mail: CHOSafety@prahs.com
To be valid, the initial serious adverse event report must include the following minimal data: 
•
A reporting source (the Investigator’s name and/or site number, and contact
information)
•
A subject identifier
•
The identity of IP
•
A serious adverse event term, description, or outcome
Investigators will provide the following additional data as soon as possible, but these data are 
not required for the initial report if they are not immediately available: 
•
Event start date
•
Event end date if known; the end date is the date on which serious criteria were no
longer met; i.e., the event was no longer serious
•
Severity (Grades 1, 2, 3, 4, or 5 according to the Common Terminology Criteria for
Adverse Events [CTCAE] version 4.03)
•
The Investigator’s assessment of causality (unrelated, unlikely related, possibly
related, probably related, or definitely related)
•
Any serious criteria that apply to the event (see Section 11.2)
Investigators will submit follow-up reports for serious adverse events whenever additional 
pertinent information becomes available and will provide copies of all pertinent documents 
such as hospital records, admission and discharge summaries, surgical records, laboratory 
reports, autopsy reports, and other documents when requested and applicable. 
11.5 
Monitoring of Subjects with Adverse Events 
Each subject must be carefully monitored for adverse events, including clinically significant 
abnormal laboratory test results, physical examination findings, and ECG results. At each 
study visit or communication, the Investigator or designee will ask subjects about any new 
symptoms or worsening of baseline symptoms that could indicate an adverse event. 
11.5.1 Abnormal Laboratory Test Results 
Changes or abnormalities in clinical laboratory results judged to be clinically significant by 
the Investigator will be recorded as adverse events. If an unexplained abnormal laboratory 
test result occurs, the Investigator or designee will promptly repeat the test and monitor the 
47

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
subject until the result has returned to the normal range or an adequate explanation of the 
abnormality is found. 
11.5.2 Abnormal Physical Examination Findings or ECG Changes 
Changes or abnormalities in physical examination findings or ECGs judged to be clinically 
significant by the Investigator will be recorded as adverse events. 
11.6 
Overdose of Study Medication 
Any overdose of the study medication, with or without associated adverse events, must be 
reported to PRA Drug Safety. Overdose will be reported in the eCRF. All reports of 
overdoses must be filed in the Study Center File. Any adverse event associated with the 
overdose will be reported on relevant adverse event/serious adverse event sections in the 
eCRF. 
Investigators will instruct subjects how to manage the dose of their study medication and 
other medications for diabetes, and procedures to be followed if an overdose occurs. Subjects 
will be instructed to seek medical assistance immediately if they experience an overdose of 
study medication and to notify the Investigator as soon as feasible. 
11.7 
Pregnancy 
Pregnancy itself is not regarded as an adverse event unless the Investigator suspects an IP 
may have interfered with the effectiveness of a contraceptive medication. However, any 
pregnancy during the study and the outcome of the pregnancy (spontaneous miscarriage, 
elective termination, normal birth or congenital anomaly) must be reported to PRA. 
If a subject becomes pregnant during the study, she will discontinue IP immediately and 
report the pregnancy to the Investigator. The subject will attend an end-of-treatment visit and 
should be followed by the Investigator through childbirth or termination of the pregnancy. 
The Investigator will submit an initial report upon learning of the pregnancy, and a follow-up 
form when the outcome of the pregnancy is known. If the female partner of a male subject 
becomes pregnant, the subject may continue in the study but the pregnancy should be 
reported in the same manner as described above. Any congenital anomaly or birth defect in 
the offspring of the subject will be reported as a serious adverse event. Investigators should 
contact the Medical Monitor if questions arise. 
48

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
12. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
The data management and statistical analysis of this study will be performed by PRA Health 
Sciences. 
12.1 
Data Management 
An electronic clinical database (Medidata Solutions) will be used and a Data Management 
Plan will be prepared by PRA Health Sciences. 
Previous and concomitant medications will be coded using the latest available WHO Drug 
Reference Dictionary. Coexistent diseases and adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
When the database has been declared to be complete and accurate, the database will be 
locked. Any changes to the database after that time can be made only by written agreement 
between Gan & Lee Pharmaceuticals USA and PRA Health Sciences. 
12.2 
Sample Size Estimation 
Enrollment is planned for 550 subjects overall (275 subjects per treatment group). The 
primary analysis for immunogenicity will be an equivalence test using the 2 one-sided tests 
(TOST) approach with α=0.05. This sample size was chosen to achieve over 80% power on 
the equivalence test of proportion of subjects under the margins dependent on the observed 
treatment-induced AIA rate. For example, a sample size of 550 will provide approximately 
85% power on the equivalence test of proportion of subjects with treatment-induced AIA 
using an event rate of 30% and a margin of 12% (Table 4). The treatment-induced AIA is 
defined as newly confirmed positive AIA development or important (at least a 4-fold) 
increase in AIA titers, after baseline and up to visit Week 26. For this sample size of 550, no 
dropouts are considered in the calculation. Subjects will be encouraged to come back for 
assessments even if they have discontinued treatment early. 
The similarity margin, based on the actual observed event rate for the intended reference 
product, will be used for final analysis after database lock as summarized in Table 4. Linear 
interpolation will be used for values between AIA rates in the table. 
49

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
Table 4: Similarity Margins for Actual Observed Event Rate of Proposed Biosimilar to 
Insulin Glargine for Various Immunogenicity Event Rates 
Treatment-induced AIA Rate for the 
Reference Product 
Margin 
Power 
10% 
7.9% 
83% 
15% 
9.3% 
83%  
20% 
10.5% 
84% 
25% 
11.3% 
84% 
30% 
12.0% 
85% 
35% 
12.5% 
85% 
40% 
12.8% 
85% 
45% 
13.0% 
85% 
50% 
13.1% 
85% 
55% 
13.0% 
85% 
60% 
12.8% 
85% 
65% 
12.5% 
85% 
70% 
12.0% 
85% 
75% 
11.3% 
84% 
80% 
10.5% 
84% 
85% 
9.3% 
83% 
90% 
7.9% 
83% 
AIA = anti-insulin antibodies. 
Sample size calculations were performed using EAST Version 6.4. 
12.3 
Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be written and finalized prior to any lock of the study 
database. The SAP will provide a detailed description of the statistical methods and expand 
on the details provided in the protocol. Additional analyses may be added. Table, listing and 
figures shells will also be provided. 
12.4 
Randomization 
Subjects will be randomized in a 1:1 ratio to Gan & Lee Insulin Glargine Injection or 
Lantus® treatment. 
Registration and randomization will take place using a centralized IXRS. At registration, the 
IXRS will assign a unique subject identification number that will be used on all of that 
subject’s eCRFs and serious adverse event report forms. 
The study is not blinded. However, to avoid the introduction of operational bias into final 
study results and to increase the interpretability and reliability of the data, certain roles of the 
Sponsor and study team will be blinded. Details will be provided in the Data Blinding and 
Documentation of Aggregate Data Dissemination Plan (hereafter referred to as the Blinding 
Plan). 
50

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
12.5 
Analysis Sets 
12.5.1 Safety Analysis Set 
The Safety Analysis Set is composed of all randomized subjects who receive any IP, even a 
partial dose (Gan & Lee Insulin Glargine Injection or Lantus®). Subjects in the Safety 
Analysis Set will be grouped according to the treatment they actually received. All safety and 
immunogenicity endpoints will be analyzed using the Safety Analysis Set. 
12.5.2 Full Analysis Set  
The Full Analysis Set (FAS) is composed of all randomized subjects. Subjects in the FAS 
will be grouped according to planned treatment. All efficacy endpoints will be analyzed 
using the FAS based on the subject’s randomized treatment. 
12.5.3 Per Protocol Set 
The Per Protocol (PP) Analysis Set is composed of all randomized subjects who received at 
least 1 partial dose and do not have any important protocol deviations during the first 
26 weeks of the study. Subjects in the PP Analysis Set will be grouped according to actual 
treatment received. The PP Analysis Set will be used for sensitivity analyses of confirmed 
positive AIA and HbA1c and demography summary. 
12.6 
Statistical Methods 
In general, categorical variables will be summarized using counts and percentages. 
Continuous variables will be summarized using the number of observations (n), mean, and 
standard deviation, median, minimum 25th and 75th percentiles, and maximum. All 
summaries will be presented by treatment groups as well as the total. All statistical analyses 
will be performed using SAS®. The SAS® version number will be noted in the SAP.  
12.6.1 Missing Data 
Missing data will be imputed for the primary immunogenicity analysis in the manner shown 
in Table 5. 
51

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
Table 5: Imputation Rules for Missing Data in the Primary Immunogenicity Analysis 
 
Baselinea 
Visit 
Week 12 
Visit 
Week 26 
Result/Imputation Rule 
1. 
x 
x 
x 
No imputation. 
2. 
x 
x 
o 
Subject will be counted as developing a treatment-
induced AIA, impute visit Week 26 as positive result 
3. 
x 
o 
x 
Subject will be counted as developing a treatment-
induced AIA, impute visit Week 12 as positive result 
4. 
x 
o 
o 
Subject will be counted as developing a treatment-
induced AIA, impute visit Week 12 and visit Week 26 
as positive result 
5. 
o 
x 
x 
Subject will be counted as developing a treatment-
induced AIA if visit Week 12, visit Week 26, or 
unscheduled assays up to visit Week 26 indicate 
positive result; otherwise, subject will be counted as 
not developing a treatment-induced AIA (all assays up 
to visit Week 26 are negative). 
6. 
o 
x 
o 
Subject will be counted as developing a treatment-
induced AIA, impute visit Week 26 as positive result  
7. 
o 
o 
x 
Subject will be counted as developing a treatment-
induced AIA, impute visit Week 12 as positive result 
8. 
o 
o 
o 
Subject will be counted as developing a treatment-
induced AIA, impute visit Week 12 and visit Week 26 
as positive result 
AIA = anti-insulin antibodies; o = AIA data missing, x = AIA data not missing. 
a No imputation will be performed for missing baseline values. 
Additional sensitivity analyses on the imputation, which explore the limitation(s) of the data 
or assumption(s) of the primary analysis being evaluated in each sensitivity analysis and how 
the analysis addresses each, will also be discussed in the SAP. 
Missing data will be imputed for the HbA1c analysis. The robustness of the imputation will 
be explored via sensitivity analyses using multiple imputation and including a tipping point 
analysis. Full details of the multiple imputation procedure will be presented in the SAP. 
12.6.2 Demographic and Baseline Data 
Demographic information and baseline characteristics will be summarized for the FAS, 
Safety Analysis Set, and PP Set. Descriptive statistics will be provided for age, sex, race, 
ethnicity, baseline body weight, height, and BMI. 
Medical history conditions will be coded using most current version of MedDRA at time of 
database lock. The number and percentage of subjects with each medical history term will be 
summarized by MedDRA system organ class and preferred term. 
12.6.3 Subject Disposition 
The number and percentage of subjects screened, randomized and treated in the study will be 
presented, together with the number and percentage of subjects who withdrew from the study 
prematurely, with a breakdown of the corresponding reasons for withdrawal. 
52

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
A tabulation of the number and percentage of subjects randomized in each center will be 
presented. 
12.7 
Primary Endpoint 
12.7.1 Incidence of Treatment-Induced Anti-Insulin Antibodies 
The primary analysis for immunogenicity will be an equivalence test using the TOST 
approach with α=0.05, which is algebraically equivalent to comparing the limits of the 90% 
confidence interval (CI) for treatment-induced AIA development via a test of difference in 
proportions based on normal approximation to (-margin, +margin) where the margin is 
dependent on the observed treatment-induced AIA rate in Lantus® and is defined in Table 4. 
The estimand of interest for the primary immunogenicity analysis is the difference in 
treatment-induced AIA rates regardless if all subjects tolerate or adhere to study treatment or 
receive other insulin treatments. Intercurrent events will be handled according to the 
treatment policy strategy. Treatment Policy strategy is defined as the strategy that considers 
“The occurrence of the intercurrent event is irrelevant: the value for the variable of interest is 
used regardless of whether or not the intercurrent event occurs” (See ICH E9 R1 addendum 
[16]). Sensitivity analyses including worst-case imputation and using a ‘Composite Strategy’ 
will be conducted. 
12.8 
Key Secondary Endpoint 
12.8.1 Change from Baseline in HbA1c at 26 Weeks 
The key secondary analysis will be to evaluate equivalence (FDA)/noninferiority (EMA) of 
Gan & Lee Insulin Glargine Injection relative to Lantus® for HbA1c by comparing the 90% 
CI with (-0.4%, 0.4%) for equivalence using the TOST approach and by comparing the upper 
limit of the 95% CI with 0.4% for noninferiority from a pattern mixture model that uses 
multiple imputation analyzed using Analysis of Covariance (ANCOVA) with treatment 
included as a fixed effect and baseline HbA1c included as a covariate. Separately in each 
treatment group, the imputation will use the outcomes of patients who completed the study 
(including the subjects who discontinued treatment, but provided a visit Week 26 HbA1c 
sample) to impute outcomes in patients without actual visit Week 26 recorded results under 
the missing at random assumption. Full details of the multiple imputation procedure will be 
specified in the SAP. Analysis of HbA1c will follow a hierarchical testing strategy: first, 
equivalence/noninferiority will be tested with a margin of 0.4%; secondly, if and only if the 
test using a margin of 0.4% is significant, then equivalence/noninferiority will be tested using 
a margin of 0.3%. Analyses of HbA1c in the testing hierarchy will be conducted on the Full 
Analysis Set consisting of all randomized subjects according to randomized treatment with 
supportive analyses on the Per Protocol Analysis Set. A tipping point analysis with varying 
assumptions about the differences on each treatment arm between outcomes in patients who 
withdrew from the study early and outcomes in patients who completed the study will be 
performed. The estimand of interest for the HbA1c analysis is the difference in change from 
baseline for HbA1c using the “treatment policy strategy.” 
53

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
12.9 
Other Secondary Endpoints 
12.9.1 Immunogenicity 
12.9.1.1 Subjects with Negative Anti-Insulin Antibodies at Baseline Who Develop 
Confirmed Anti-Insulin Antibodies  
The percentage of subjects in each treatment group with negative AIA at baseline who 
develop confirmed positive AIA after baseline and up to visit Week 26 will be compared 
using a normal test of difference in proportions.  
12.9.1.2 Subjects with a 4-fold Increase in Titers 
The percentage of subjects in each treatment group with confirmed positive AIA at baseline 
who have at least a 4-fold increase in titers after baseline and up to visit Week 26 will be 
compared using an exact test of difference in proportions. 
12.9.1.3 Change in Anti-Insulin Antibody Titer 
The mean change from baseline in each treatment group in AIA titers at visit Week 12 and 
visit Week 26 will be summarized descriptively in subjects with confirmed positive AIA at 
baseline. 
12.9.1.4 Subjects with Confirmed Anti-Insulin Antibodies Who Develop Anti-Insulin 
Neutralizing Antibodies 
The percentage of subjects in each treatment group with confirmed positive AIA after 
baseline and up to visit Week 26 who develop any anti-insulin neutralizing antibodies after 
baseline and up to visit Week 26 will be compared using an exact test of difference in 
proportions. 
12.9.1.5 Subjects Who Develop Confirmed Anti-Insulin Antibodies 
The percentage of subjects in each treatment group with confirmed positive AIA after 
baseline and up to visit Week 26 will be compared using a normal test of difference in 
proportions. 
12.9.2 Safety 
All reported adverse events will be assigned a system organ class and preferred term 
according to MedDRA and graded according to CTCAE version 4.03. The number and 
percentage of subjects with treatment-emergent adverse events (all adverse events, 
hypoglycemia, serious adverse events [including fatal events], adverse events leading to 
termination of the study treatment and/or early withdrawal from the study, and IP-related 
adverse events, and injection site reactions) will be presented. Vital signs, body weight and 
BMI, ECG, and laboratory parameters will be summarized by treatment and visit. 
 
 
54

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
12.9.3 Efficacy  
12.9.3.1 Proportion of Subjects Achieving Glycemic Control 
The following secondary efficacy variables will be analyzed using a test of difference of 
proportions based on normal approximation and CIs:  
• The number and percentage of subjects who achieve an FBG test result of 
≤ 8.0 mmol/L (≤ 144.0 mg/dL) at visit Week 26 
• The number and percentage of subjects who achieve a HbA1c of < 7.0% at visit 
Week 26 
12.10 Exploratory Variables 
The retrospective CGM hypoglycemic rate and time in hypoglycemia and hyperglycemia 
will be summarized for subjects in the Safety Analysis Set. 
12.11 Data Safety Monitoring Board 
A Data Safety Monitoring Board is not planned unless determined to be clinically indicated. 
55

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
13. 
MONITORING PROCEDURES (QUALITY ASSURANCE) 
The Sponsor has ethical, legal, and scientific obligations to conduct this study in accordance 
with established research principles and ICH GCP guidelines. To fulfill these obligations and 
to stay apprised of study progress, the Sponsor's monitors or representatives will visit the 
investigative sites during study conduct, in addition to maintaining telephone and written 
communication. On-site visits, telephone calls, and regular inspection of the eCRFs will be 
conducted to assess subject enrollment, compliance with protocol procedures, completeness 
and accuracy of data entered on the eCRFs, verification of eCRF data against original source 
documents, and occurrence of adverse events. The Investigator must provide the monitor 
with full access to all source and study documents. 
13.1 
Risk and Quality Tolerance Limits and Routine Monitoring 
Sponsor assigned monitors will conduct regular site visits to the investigational facilities for 
the purpose of monitoring various aspects of the study. The Investigator must agree to 
Sponsor-authorized personnel having direct access to the clinical (or associated) files and 
clinical study supplies (dispensing and storage areas) for all study subjects considered for 
study entry for the purpose of verifying entries made in the eCRFs, and assist with their 
activities, if requested. Adequate time and space for monitoring visits should be made 
available by the Investigator. 
The site must complete the eCRFs in a timely manner and on an ongoing basis to allow 
regular review by the study monitor. 
Perceived risks and quality tolerance limits (QTLs) will be identified and documented before 
the start of the study. 
The Sponsor will review risk control measures periodically to ascertain whether the 
implemented quality management activities remain effective and relevant. The quality 
management approach and any important deviations from the predefined QTLs (and remedial 
actions adopted) will be described in the clinical study report. 
13.2 
Inspections and Auditing Procedures 
The Sponsor or its representative may conduct audits at the investigative sites including, but 
not limited to, drug supply, presence of required documents, the informed consent process, 
and comparison of eCRFs with source documents. All medical records (progress notes) must 
be available for audit. The Investigator agrees to participate with audits conducted at a 
convenient time in a reasonable manner. 
Government regulatory authorities may also inspect the investigative site during or after the 
study. The Investigator or designee should contact the Sponsor/contract research organization 
(CRO) immediately if this occurs. He/she must cooperate fully with regulatory authorities or 
other audits conducted at a convenient time in a reasonable manner. 
The purpose of an audit is to assess whether ethics, regulatory and quality requirements are 
fulfilled. 
56

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
14. 
STUDY MANAGEMENT AND MATERIALS 
14.1 
Electronic Case Report Forms 
Electronic CRFs will be used to store and transmit subject information. The file structure and 
format for the eCRF will be provided by the Sponsor or their representative and should be 
handled in accordance with the instructions provided. 
The eCRFs must be reviewed, electronically signed, and dated by the Investigator. 
Access to eCRFs will be strictly password-protected and limited to personnel directly 
participating in the study. Data should be entered into the eCRF completely by the examining 
personnel or the study coordinator. The eCRF must be completed as soon as possible after 
any subject evaluation or communication. If data is to be changed due to erroneous input or 
other reason, an electronic audit trail will track these changes. The eCRFs and computers that 
store them must be accessible to study monitors and other regulatory auditors. 
14.2 
Data Collection 
During each study visit or telephone contact, the Investigator or designee will maintain 
progress notes in the subject’s medical records to document all significant observations. At a 
minimum, these notes will contain: 
• 
The date of the visit and the corresponding week or visit number in the study schedule 
• 
The subject’s general condition and status remarks by the subject, including any 
significant medical findings. The severity, frequency, duration, and resolution of any 
reported adverse event, and the Investigator's assessment as to whether or not the 
reported event is IP-related 
• 
Changes in concomitant medications or dosages 
• 
A general reference to the procedures completed 
• 
The signature or initials of all physicians and other qualified medical designees making 
an entry in the medical record (or electronic equivalent) 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the medical record as described 
above.  
14.3 
Source Documents Maintenance 
Source documents contain the results of original observations and activities of a clinical 
investigation. Source documents include, but are not limited to, medical records (progress 
notes), computer printouts, screening logs and recorded data from automated instruments.  
All source documents from this study will be maintained by the Investigator and made 
available for inspection by authorized persons. The original signed ICF for each subject shall 
be filed with records kept by the Investigator and a copy shall be given to the subject. 
57

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
14.4 
Record Maintenance 
All data derived from the study will remain the property of Gan & Lee Pharmaceuticals. 
Records must be retained in accordance with the current ICH Guidelines on GCP. All 
essential study documents including records of subjects, source documents, eCRFs and IP 
inventory must be kept on file. 
US FDA regulations (21 CFR 312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including eCRFs, consent 
forms, laboratory test results, and medical inventory records, must be retained by the 
Principal Investigator for 2 years after marketing application approval. If no application is 
filed, these records must be kept 2 years after the investigation is discontinued and the US 
FDA and the applicable national and local health authorities are notified. The Sponsor or 
their representative will notify the Principal Investigator of these events. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of IPs. However, essential documents may be 
retained for a longer period if required by the applicable regulatory requirements or by 
agreement with the Sponsor. The Sponsor is responsible for informing the Investigator when 
these documents need no longer be retained. 
The Investigator will not dispose of any records relevant to this study without written 
permission from the Sponsor and will provide the Sponsor the opportunity to collect such 
records. The Investigator shall take responsibility for maintaining adequate and accurate hard 
copy source documents of all observations and data generated during this study. Such 
documentation is subject to inspection by the Sponsor, its representatives and regulatory 
authorities. 
If an Investigator moves, withdraws from an investigation, or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept responsibility. 
Notice of transfer must be made to and agreed by the Sponsor. 
14.5 
Confidentiality 
All information obtained during the conduct of the study with respect to the subject’s state of 
health will be regarded as confidential. For disclosure of any such information, an agreement 
will be obtained in writing.  
The Investigator must ensure that each subject’s anonymity is maintained. On eCRFs and 
other documents submitted to the Sponsor or the CRO, subjects must not be identified by 
name. Instead, subjects will be known only by the unique subject number allocated to them 
to ensure confidentiality on all study documentation. The Investigator will keep a separate 
log of these codes. 
To comply with government regulatory guidelines and to ensure subject safety, it may be 
necessary for the Sponsor and its representative, the CRO personnel, the local research 
review board, or the health authorities to review subjects’ medical records as they relate to 
this study. Only the subject’s unique number on the eCRFs will identify him/her, but their 
58

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
full names may be made known to a drug regulatory authority or other authorized 
government or health care officials, if necessary, and to personnel designated by the Sponsor. 
Documents that are not for submission to the Sponsor or the CRO (e.g., consent forms) will 
be maintained by the Investigator in strict confidence, except to the extent necessary to allow 
monitoring by the Sponsor and the CRO, and auditing by regulatory authorities. No 
documents identifying subjects by name will leave the investigative site and subject identity 
will remain confidential in all publications related to the study. 
59

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
15. 
ADMINISTRATION PROCEDURES 
15.1 
Regulatory Approval 
Gan & Lee Pharmaceuticals USA or their appointed agents will be responsible for ensuring 
that appropriate regulatory authority approvals are obtained, according to local country 
requirements. 
No subject may enter the study until this approval has been obtained. A copy of the approval 
(where one is provided, according to local country requirements) will be provided to the 
Investigator and to the IRB(s)/IEC(s). 
15.2 
Protocol Amendments 
In accordance with ICH E6 Guideline for GCP the Investigator should not implement any 
deviation from, or changes to the protocol without agreement by the Sponsor and 
documented approval from the IRB/IECs of a protocol amendment, except where necessary 
to eliminate an immediate hazard(s) to study subjects, or when the change(s) involves only 
logistical or administrative aspects of the study (e.g., change in monitor(s), change of 
telephone number(s)). 
Any change to the protocol must be handled as a protocol amendment. Any potential 
amendment must be approved by the Sponsor. A written amendment must be submitted to 
the appropriate regulatory authorities and to the IRB/IECs assuming this responsibility. The 
Investigator must await IRB/IEC approval of protocol amendments before implementing the 
changes, except where necessary to eliminate apparent immediate hazard to subjects. In these 
cases, the IRB/IEC must be notified within 5 days of the change. 
All amendments to the protocol must be approved in writing by both the appropriate 
regulatory authorities and the IRB/IEC, except for administrative amendments, which require 
notification but not written approval. Once approved, the protocol amendment will be 
distributed to all recipients of the original protocol, with instructions to append the 
amendment to the protocol. 
If, in the judgment of the local IRB/IEC, the Investigator and/or Sponsor, the protocol 
amendment alters the study design, procedures and/or increases the potential risk to the 
subject, the currently approved written ICF will require modification. The modified ICF must 
also be reviewed and approved by the Sponsor, appropriate regulatory authorities, and the 
IRB/IEC. In such cases, repeat informed consent must be obtained from subjects enrolled in 
the study before participation continues. 
15.3 
Protocol Adherence and Deviations 
The Investigators and all staff involved with the study must read the protocol thoroughly and 
follow the instructions contained in it. However, exceptions will be made in emergency 
situations when the protection, safety, or well-being of the subject requires immediate 
intervention based on the judgment of the Investigator or a responsible, appropriately trained, 
and credentialed professional(s) designated by the Investigator as a Sub-Investigator. 
60

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
In the event of a significant protocol deviation due to an emergency, accident, or error, the 
Investigator or designee must contact the Medical Monitor at the earliest possible time by 
telephone. This allows for an early joint decision to be made as to whether or not the subject 
should continue in the study. The Investigator, the Sponsor, and the Medical Monitor will 
document this decision. 
15.4 
Publication Policy 
After completion of the study, the Investigator(s) may prepare a joint publication with the 
Sponsor. The Investigator(s) must undertake not to submit any part of the data from this 
protocol for publication without the prior consent of Gan & Lee Pharmaceuticals USA. 
15.5 
Clinical Study Report 
A final clinical study report will be prepared according to the ICH guideline on Structure and 
Contents of Clinical Study Reports. A final clinical study report will be prepared regardless 
of whether the study is completed or prematurely terminated. The Sponsor will provide each 
Investigator with a copy of the final report for retention.  
15.6 
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and the 
Sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
Sponsor and Investigator responsibilities in relation to the study. The contract should describe 
whether costs for pharmacy, laboratory and other protocol-required services are being paid 
directly or indirectly. Financial Disclosure Statements will need to be completed, as requested 
by FDA CFR 21 part 54. 
15.7 
Insurance, Indemnity, and Compensation 
Gan & Lee Pharmaceuticals USA undertakes to maintain an appropriate clinical study 
insurance policy. 
Deviations from the study protocol - especially the prescription of a dose other than that 
scheduled in the study protocol, other modes of administration, other indications, and longer 
treatment periods - are not permitted and shall not be covered by the statutory subject 
insurance scheme. 
15.8 
Discontinuation of the Study 
This study may be terminated by the Sponsor. Reasons for discontinuation of the study may 
include the following situations: 
• Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study 
• Discontinuation of study drug development  
The study may also be terminated prematurely if both the Investigators and the Sponsor agree 
such action is in the best interests of subjects and is justified on either medical or ethical 
grounds. Should early termination be necessary, subjects should stop taking the study 
medication immediately. Every documented effort should be made by the Investigator to 
61

Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
ensure that the subject returns to the site as soon as possible to complete one final EOT visit. 
In terminating the study, Gan & Lee Pharmaceuticals USA, PRA, and the Investigators will 
ensure that adequate consideration is given to the protection of the subjects’ interests. 
The Investigator or Sponsor depending on the local regulation will be responsible for 
informing IRBs/IECs of the early termination of the trial. 
15.9 
Study Center File Management 
The Investigator is responsible for assuring that the Study Center File is maintained in 
accordance with GCP standards. 
62

Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
16.
REFERENCE LIST
1. Global Report on Diabetes 2016. World Health Organization website.
http://www.who.int/diabetes/global-report/en/. Accessed November 21, 2016.
2. Stumvoll M, Goldstein BJ, and van Haeften TW. Type 2 Diabetes: Principles of 
Pathogenesis and Therapy. Lancet. 2005;365:1333-1346.
3. Inzucchi SE, Bergenstal RM, Buse JB, eDiamant M, Ferrannini E, Nauck M, et al. 
Management of Hyperglycemia in Type 2 Diabetes 2015: A Patient-Centered Approach –
Update to a Position Statement of the American Diabetes Association and the European 
Association for the Study of Diabetes. Diabetes Care. 2015;38:140-149.
4. Lantus (insulin glargine) [package insert]. Bridgewater, NJ: Sanofi-Aventis US;
August 2015.
5. Gan & Lee Pharmaceuticals Insulin Glargine Injection [Investigational Brochure Edition 
1.0]. Beijing, China: Gan & Lee Pharmaceuticals; June 2015
6. Cameron CG, Bennett HA. Cost-Effectiveness of Insulin Analogs for Diabetes Mellitus. 
CMAJ. 2009;180(4):400-407.
7. Heinemann L, Hompesch M. Biosimilar Insulins: How Similar is Similar? Diabetes Sci 
Technol. 2011;5(3):741-754.
8. Qin J, Teng J-A, Zhu Z, Chen J-X, and Wu Y-Y. Glargine Promotes Human Colorectal 
Cancer Cell Proliferation Via Upregulation of MiR-95. Horm Metab Res. 
2015;47:861-865.
9. Peeters PJHL, Bazelier MT, Leufkens HGM, et al. Insulin Glargine Use and Breast 
Cancer Risk: Associations with Cumulative Exposure. Acta Oncologica. 
2016;55(7):851-858.
10. Guideline on Non-Clinical and Clinical Development of Similar Biological Medicinal 
Products Containing Recombinant Human Insulin and Insulin Analogues. Effective 26 
February 2015. European Medicines Agency website.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/
WC500184161.pdf Accessed December 16, 2016.
11. United States Food and Drug Administration. Guidance for Industry: Scientific 
Considerations for Demonstrating Biosimilarity to a Reference Product. April 2015. 
https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf Accessed
December 16, 2016.
12. Cai X-Y, Thomas J, Cullen C, Gouty D. Challenges of Developing and Validating 
Immunogenicity Assays to Support Comparability Studies for Biosimilar Drug 
Development. Bioanalysis 2012;4(17):2169–2177.
13. FDA Draft Guidance for Industry: Assay Development and Validation for 
Immunogenicity Testing of Therapeutic Protein Products. April 2016. FDA website. 
https://www.fda.gov/downloads/Drugs/Guidances/UCM192750.pdf. Accessed December 
16, 2016.
63

Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
14. Method Validation report for Glargine ADA (Method Validation of an 
Electrochemiluminescence Immunoassay for the Detection of Anti-Glargine Antibody in 
Human Serum, Study Number XBL16003, Report Number RPT04158).
15. Guidance for Industry and Food and Drug Administration Staff. Collection of Race and 
Ethnicity Data in Clinical. October 26, 2016. FDA website.
https://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126396. Accessed 
January 6, 2017.
16. EMA/CHMP/ICH/436221/2017_dated 30 August 2017. ICH E9 (R1) Addendum on 
estimands and sensitivity analysis in clinical trials to the guideline on statistical principles 
for clinical trials.
64

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
17. 
APPENDICES 
17.1 
Appendix 1: Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. The Declaration is intended to be read as a 
whole and each of its constituent paragraphs should not be applied without consideration of 
all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
65

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and burdens. 
9. Medical research is subject to ethical standards that promote respect for all human subjects 
and protect their health and rights. Some research populations are particularly vulnerable and 
need special protection. These include those who cannot give or refuse consent for 
themselves and those who may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement 
should reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal experimentation. 
The welfare of animals used for research must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment. 
14. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, Sponsors, 
institutional affiliations, other potential conflicts of interest, incentives for subjects and 
provisions for treating and/or compensating subjects who are harmed as a consequence of 
participation in the research study. The protocol should describe arrangements for post-study 
access by study subjects to interventions identified as beneficial in the study or access to 
other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must be 
independent of the researcher, the Sponsor and any other undue influence. It must take into 
66

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
consideration the laws and regulations of the country or countries in which the research is to 
be performed as well as applicable international norms and standards but these must not be 
allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information about any 
serious adverse events. No change to the protocol may be made without consideration and 
approval by the committee. 
16. Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. The responsibility for the protection of research subjects must 
always rest with the physician or other health care professional and never the research 
subjects, even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this population 
or community and if there is a reasonable likelihood that this population or community stands 
to benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved in 
the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment 
of the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians must immediately stop a study when the risks are found to outweigh the 
potential benefits or when there is conclusive proof of positive and beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on their 
physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
67

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks 
of the study and the discomfort it may entail, and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential subjects as well as to the 
methods used to deliver the information. After ensuring that the potential subject has 
understood the information, the physician or another appropriately qualified individual must 
then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed. 
25. For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations where 
consent would be impossible or impractical to obtain for such research or would pose a threat 
to the validity of the research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent should be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be included in 
a research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the population represented by the potential subject, the research cannot instead be 
performed with competent persons, and the research entails only minimal risk and minimal 
burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorized representative. The potential subject’s dissent should be 
respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research population. In 
such circumstances the physician should seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot be delayed, 
the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been approved by a research ethics 
68

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
committee. Consent to remain in the research should be obtained as soon as possible from the 
subject or a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and accuracy of their 
reports. They should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results should be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent that 
the research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following circumstances: 
• The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
• Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo or no treatment will not be subject to any risk of serious 
or irreversible harm. Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the patient 
or a legally authorized representative, may use an unproven intervention if in the physician's 
judgement it offers hope of saving life, re-establishing health or alleviating suffering.  
 
 
69

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
Where possible, this intervention should be made the object of research, designed to evaluate 
its safety and efficacy. In all cases, new information should be recorded and, where 
appropriate, made publicly available.
70

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
17.2 
Appendix 2: Elements of Informed Consent 
ELEMENTS OF INFORMED CONSENT 
Both the informed consent discussion and the written ICF and any other written information 
to be provided to subjects should include explanations of the following: 
• That the study involves research 
• The purpose of the study 
• The study treatment(s) and the probability for random assignment to each treatment 
• The study procedures to be followed including all invasive procedures 
• The subject’s responsibilities 
• Those aspects of the study that are experimental 
• The reasonably foreseeable risks or inconveniences to the subject and, when applicable, 
to an embryo, fetus, or nursing infant 
• The reasonably expected benefits; when there is no intended clinical benefit to the 
subject, the subject should be made aware of this. 
• The alternative procedure(s) or course(s) of treatment that may be available to the 
subject, and their important potential benefits and risks 
• The compensation and/or treatment available to the subject in the event of study-related 
injury 
• The anticipated prorated payment, if any, to the subject for participating in the study 
• The anticipated expenses, if any, to the subject for participating in the study 
• That the subject’s participation in the study is voluntary and that the subject may refuse 
to participate or withdraw from the study, at any time, without penalty or loss of benefits 
to which the subject is otherwise entitled 
• That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be 
granted direct access to the subject’s original medical records for verification of clinical 
study procedures and/or data, without violating the confidentiality of the subject, to the 
extent permitted by the applicable laws and regulations and that, by signing a written 
ICF, the subject or the subject’s legally acceptable representative is authorizing such 
access 
• That records identifying the subject will be kept confidential and, to the extent permitted 
by the applicable laws and/or regulations, will not be made publicly available. If the 
results of the study are published, the subject’s identity will remain confidential 
• That the subject or the subject’s legally acceptable representative will be informed in a 
timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study 
• The person(s) to contact for further information regarding the study and the rights of 
study subjects, and whom to contact in the event of study-related injury 
71

 
  
 
Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
 
 
• The foreseeable circumstances and/or reasons under which the subject’s participation in 
the study may be terminated 
• The expected duration of the subject’s participation in the study 
• The approximate number of subjects involved in the study
72

Protocol No. GL-GLAT2-3002 
Gan & Lee Insulin Glargine vs Lantus® in Adults with Type 2 Diabetes 
Amendment 3_ 25 April 2019 
17.3 
Appendix 3: Allowed and Prohibited Concomitant Medications 
These medication lists are not comprehensive. Please contact your Clinical Research 
Associate if you have questions about medications not listed here.  
DPP4i = dipeptidyl peptidase 4 inhibitor; GLP1-R = glucagon-like peptide 1 receptor; SGLT2i = sodium 
glucose transport 2 inhibitor 
a Subjects will replace their previous basal insulin with the investigational product for the duration of the study. 
bTopamax® and Cycloset® are allowed only if NOT used for obesity. The approved indications for Topamax® 
are headache, seizures, and neuropathy; the approved indication for Cycloset® is diabetes. 
Prohibited Medications 
Biosimilar Insulins 
Obesity Medications 
 Mylan/Biocon – glargine 
Phentermine 
 Pfizer – glargine 
Belviq® (lorcaserin) 
 Merck – glargine 
Contrave® (naltrexone/bupropion) 
 Eli Lilly - Basaglar® (glargine) 
Saxenda® (liraglutide 3.0 mg) 
 Sanofi - Humalog® (lispro) 
Qysmia® (phentermine and topiramate extended-release) 
Alli® (orlistat; available over-the-counter) 
Other 
Newly-prescribed or high-dose corticosteroids (chronically administered oral, inhaled, topical, or 
intra-articular corticosteroids at a stable dose are allowed if no increase in dose is anticipated 
during the study) 
Immunosuppressants or immune response-modifying drugs 
Cytostatic agents 
Any medication intended to cause weight loss or weight gain 
The use of pre-exposure prophylactic (PREP) HIV medications must be reviewed with the 
Medical Monitor.  
Allowed Medications 
Basal Insulins Allowed at Study Entrya 
DPP4i: 
 Lantus® (insulin glargine) 
 Januvia® (sitagliptin) 
 Toujeo® (insulin glargine) 
 Nesina® (alogliptin) 
 Soliqua® (insulin glargine and lixisenatide) 
 Onglyza® (saxagliptin) 
 Tresiba® (insulin degludec) 
 Tradjenta® (linagliptin) 
 Levemir® (insulin detemir [rDNA origin]) 
 Neutral protamine Hagedorn 
SGLT2i: 
Jardiance (empagliflozin) 
GLP1-R Agonists 
Farziga (dapagliflozin) 
 Bydureon® (exenatide long-acting) 
Invokana (canagliflozin) 
 Byetta® (exenatide) 
 Trulicity® (dulaglutide) 
Other: 
 Tanzeum® (albiglutide) 
 Metformin® 
 Victoza® (liraglutide; up to 1.8 mg daily dose) 
 Topamax® (topiramate)b 
 Lyxumia® (lixisenatide) 
 Cycloset® (bromocriptine mesylate)b 
 Ozempic® (semaglutide) 
73