Clinical trial NCT02666430
Conditions: Type 1 Diabetes Mellitus
Sponsor: Mylan Inc.
Start date: 2015-12-01; Completion date: 2017-07-01
Enrollment: 127 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this extension study is to assess the safety and efficacy of Mylan's insulin glargine and Lantus® in T1DM patients.

Detailed description:
This multi-center, open-label, randomized clinical extension study in patients with T1DM will assess safety and efficacy of Mylan's insulin glargine and Lantus®.

Patients with an established diagnosis of T1DM per American Diabetes Association 2014 criteria who were randomized to the Lantus® treatment arm of the Mylan Glargine 3001 study, and who have completed the 52-week treatment period on Lantus® will be eligible to be screened for the MYL-1501D-3003 study.

Arms: arm 1: Patients will be administered either Mylan insulin glargine or Lantus® subcutaneously, once daily in combination with lispro and titrated based on blood glucose readings per standard of care for a total of thirty-six (36) weeks, split into three cycles of twelve (12) weeks each. arm 2: Patients will be administered either Mylan insulin glargine or Lantus® subcutaneously, once daily in combination with lispro and titrated based on blood glucose readings per standard of care for a total of thirty-six (36) weeks, split into three cycles of twelve (12) weeks each.
Interventions: intervention 1: Mylan's insulin glargine intervention 2: Lantus®
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
TITLE PAGE: PHASE 3 CLINICAL TRIAL 
 
AN OPEN-LABEL, RANDOMIZED, MULTI-CENTER, PARALLEL-GROUP 
CLINICAL TRIAL COMPARING THE EFFICACY AND SAFETY OF MYLAN’S 
INSULIN GLARGINE WITH LANTUS® IN TYPE 1 DIABETES MELLITUS 
PATIENTS: AN EXTENSION STUDY 
 
 
Compound Number: 
NA 
Compound Name (if applicable): 
Insulin Glargine 
US IND Number (if applicable): 
IND 105279 
European Clinical Trial Database 
(EudraCT) Number (if applicable): 
2015-004353-40 
Protocol Number: 
MYL-1501D-3003 
Phase: 
3 
Sponsor: 
Mylan GmbH  
Thurgauerstrasse 40, 8050 Zürich 
Switzerland 
Status: 
Final 
Version: 
2.0 
Date 
06-May-2016 
 
 
 
This document is property of MYLAN. Information provided herein is strictly confidential and is available for 
review to investigators, Regulatory Authorities and Ethical Committees/Institutional Review Boards. It is 
intended solely for the guidance of the clinical investigation and may not be disclosed to parties not associated 
with the clinical investigation (except where required by applicable law) or used for any purpose without the 
prior written consent of MYLAN. In the event of any actual or suspected breach of this obligation, MYLAN 
must be promptly notified. 


Insulin Glargine 
Final Protocol V 2.0 
PROTOCOL# VERSION 
MYL-1501D-
2.0 
3003 
MYL-1501D-3003 
06-May-2016 
APPROVAL SIGNATURES 
PROTOCOL TITLE 
EFFECTIVE 
DATE 
An Open-label, Randomized, Multi-center, 06-May-2016 
Parallel-Group Clinical Trial Comparing the 
Efficacy and Safely of Mylan's Insulin 
Glargine with Lantus® in Type 1 Diabetes 
Mellitus Patients-An Extension Study. 
1, the undersigned, have read this protocol and confinn that lo lhe besl of my knowledge the 
protocol accurately describes the planned conduct of the study, meets all necessary requirements 
of appropriate Standard Operating Procedures (SOPs) and has been reviewed and endorsed by 
the appropriate persons for Clinical Operations, Clinical Development and Statistics. 
Abhijit Shrikrishna Barve, MD, PhD, MBA 
Head, Clinical Sciences 
Mylan Phannaceuticals, Inc 
Michael Ankersen, PhD, MBA 
Clinical Project Lead - Diabetes 
Mylan Phannaccuticals, Inc 
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1JJP,,,;4-r11~-~Yf.!_~~~:t::L-
Principnl Biostntistician 
Mylan Phannaceuticals, Inc 
MYLAN C0Nr1DENT1AL 
Page2 
Date 
'1-mav-J.c(6 
J 


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Document History 
Document 
Version Date 
Summary of Changes 
MYL-1501D-3003 
Clinical Trial Protocol 
1.0, 09-Oct-2015 
N/A 
MYL-1501D-3003 
Clinical Trial Protocol 
Amendment 
2.0, 06-May-2016 • Approval Signatures page:  
Version and effective date are changed. 
Sponsor’s personnel and designations 
changed (Approval Signatures). 
• In the section Contact Details For 
Reporting Serious Adverse Events, the 
sentence “Any SAE occurring in a 
subject from consent until 28 days after 
the last dose of the study drug must be 
reported” has been replaced with “Any 
SAE occurring in a subject from 
consent until his/her last study 
visit/phone visit (scheduled or 
unscheduled) must be reported”. 
• The Synopsis and section 2.1, the 
wording of the Primary and the 
Secondary objective of 
Immunogenicity, were modified for 
clarity. 
• The Synopsis and sections 3.1 and 9.1, 
number of patients (from estimated 110 
patient to estimated 138 patients) and 
sites (from estimated 80 to estimated 
70) were modified. 
• The Synopsis, Schedule of Activities, 
Study Flowchart [Figure 1], Sections 
1.1, 3, 3.1, 6.1, 6.2, table 3 were 
modified to include additional treatment 
period, weeks 24-36. 
• The following changes made to the 
Schedule of Activities: 
• Clarification made regarding certain 
data captured in MYL-GAI-3001 that 
will be reused in MYL-1501D-3003 
(Footnotes #8 and #11).  
• Clarification on informed consent 
made (Footnote #3). 


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• Clarification made regarding ongoing 
adverse events from MYL-GAI-3001 
(Footnote #8). 
• Clarification made that allergic 
reactions, AEs and SAEs will be 
captured during the follow up period 
(Footnote #12). 
• Sections 1.1, Background and 
Rationale. Explanation and rationale for 
the study design change is provided. 
• Section 5.4 - Clarification made 
regarding opened and expired study 
medication. 
• Synopsis and Section 6.2. To minimize 
missing data, clarification added that 
patients who have been prematurely 
withdrawn from treatment will be 
followed up until the 40 week follow-up 
call in case consent is provided. 
• Schedule of Activities, Section 7.3, 
Table 4. Blood collection for 
immunogenicity analysis added at 4, 26, 
28, 32 and 36 weeks. 
• Sections 7.3 and 7.4.10. Details of 
central laboratories for immunogenicity 
and safety analyses modified. 
• Sections 7.3.1 and 7.3.2. Methodology 
for immunogenicity assessments were 
modified. 
• Sections 7.4.1 and 7.4.2. Clarifications 
made regarding medical history and 
prior and concomitant medications. 
• Section 7.5.4. Clarification made 
regarding dilated ophthalmoscopy/ 
retinal photography testing. 
• Section 8.3. Clarification made 
regarding the collection period for AEs 
and SAEs; text on reporting for 
withdrawn patients removed, as this is 
covered in. 
• Section 9. Modifications made 
throughout the data analysis/statistical 
methods section. 
• Section 9.2.1. Text regarding primary 


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endpoint  modified to accommodate 
addition of treatment period. 
• Section 9.2.2. The primary analysis 
population changed from ITT to 
mITT; descriptive text on analysis 
populations added. 
• Section 9.7. The primary efficacy 
analysis changed from non-inferiority 
to equivalence. 
• Investigator Agreement Page added to 
body of protocol (previously appended 
separately). 
• Minor editorial and formatting 
corrections made throughout the 
protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CONTACT DETAILS FOR REPORTING SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any event which is fatal or life-threatening, requires or 
prolongs hospitalization, is significantly or permanently disabling or incapacitating, constitutes a 
congenital anomaly or birth defect, is medically significant, or requires medical or surgical 
intervention to prevent one of these outcomes (please see section 8.2.4 for a detailed definition). 
Any SAE occurring in a subject from consent until his/her last study visit/phone-visit (scheduled 
or unscheduled) must be reported. 
The Investigator will ensure that the SAE reporting form is completed and emailed/faxed by the 
Investigator to the Pharmacovigilance department, Mylan, within 24 hours of learning of the 
occurrence of any SAE, even if the SAE does not appear to be drug-related. The original SAE 
reporting form, together with the email/fax confirmation sheet, must be kept with the case report 
forms at the study site. More details are provided in the protocol. 
 
Pharmacovigilance Department 
Name 
Global Product Safety & Risk Management  
Mylan  
Email ID 
PV MAIL HUB FOR IMMEDIATE SAFETY REPORTS: 
pvclinical@mylan.com  
Phone number 
+1.304.554.6641 for Americas 
+44 (0)1707. 853. 000 for sites outside Americas (e.g., Europe, 
APAC, South Africa etc.) 
Fax number 
+1.304.285.6409 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
Table of Contents 
TITLE PAGE: PHASE 3 CLINICAL TRIAL ............................................................................................................ 1 
APPROVAL SIGNATURES ........................................................................................................................................ 2 
CONTACT DETAILS FOR REPORTING SERIOUS ADVERSE EVENTS ......................................................... 3 
TABLE OF CONTENTS .............................................................................................................................................. 7 
LIST OF ABBREVIATIONS ..................................................................................................................................... 12 
PROTOCOL SYNOPSIS ............................................................................................................................................ 14 
SCHEDULE OF ACTIVITIES .................................................................................................................................. 18 
 
INTRODUCTION ...................................................................................................................................... 21 
 
Background and Rationale ............................................................................................................................ 21 
 
Clinical data on Lantus® ............................................................................................................................... 23 
 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................. 23 
 
Objectives ..................................................................................................................................................... 23 
 
STUDY DESIGN ........................................................................................................................................ 24 
 
Study Duration .............................................................................................................................................. 25 
 
Allocation to Treatment ................................................................................................................................ 25 
 
Patient Numbering ........................................................................................................................................ 25 
 
Blinding ........................................................................................................................................................ 26 
 
Breaking the Blind ........................................................................................................................................ 26 
 
PATIENT SELECTION ............................................................................................................................ 28 
 
Inclusion Criteria .......................................................................................................................................... 28 
 
Exclusion Criteria ......................................................................................................................................... 29 
 
STUDY TREATMENTS AND CONCOMITANT MEDICATION ...................................................... 29 
 
Study Medication .......................................................................................................................................... 29 
 
Mealtime insulin ........................................................................................................................................... 30 
 
Ancillary Supplies ........................................................................................................................................ 30 
 
Drug Storage ................................................................................................................................................. 31 
 
Drug Accountability ..................................................................................................................................... 33 
 
Dispensing .................................................................................................................................................... 33 


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Administration .............................................................................................................................................. 34 
 
Return of Study Drug.................................................................................................................................... 34 
 
Treatment Compliance .................................................................................................................................. 34 
 
Concomitant Medication .............................................................................................................................. 34 
 
STUDY PROCEDURES ............................................................................................................................ 36 
 
Visit Schedules and SMBG Profiles ............................................................................................................. 36 
 
Patient Withdrawal ....................................................................................................................................... 37 
 
STUDY ASSESSMENTS AND METHODS ............................................................................................ 38 
 
Handling of Blood Samples .......................................................................................................................... 38 
 
Efficacy Assessments ................................................................................................................................... 38 
7.2.1. HbA1c .................................................................................................................................................................. 38 
7.2.2. Fasting Plasma Glucose (FPG) ............................................................................................................................ 38 
7.2.3. Body Weight and BMI......................................................................................................................................... 38 
7.2.4. 8-point SMBG profiles ........................................................................................................................................ 39 
7.2.5. Daily Insulin Doses.............................................................................................................................................. 39 
 
Immunogenicity Assessments....................................................................................................................... 39 
7.3.1. Anti-Drug Antibody............................................................................................................................................. 40 
7.3.2. Antibodies against Host Cell Protein Antibodies (anti-HCP) .............................................................................. 42 
 
Safety Assessments ....................................................................................................................................... 43 
7.4.1. Medical History ................................................................................................................................................... 43 
7.4.2. Prior and Concomitant Medication ...................................................................................................................... 43 
7.4.3. Vital Signs ........................................................................................................................................................... 43 
7.4.4. Physical Examination .......................................................................................................................................... 43 
7.4.5. Electrocardiogram................................................................................................................................................ 43 
7.4.6. Local and Systemic Allergic Reactions ............................................................................................................... 44 
7.4.7. Adverse Events and Serious Adverse Events ...................................................................................................... 44 
7.4.8. Hypoglycemic Events .......................................................................................................................................... 44 
7.4.9. Safety Related to Device Use .............................................................................................................................. 44 
7.4.10. Safety Laboratory Assessments ......................................................................................................................... 46 
 
Other Assessments ........................................................................................................................................ 47 
7.5.1. Demographic Variables ....................................................................................................................................... 47 


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7.5.2. Pregnancy Test .................................................................................................................................................... 47 
7.5.3. Study Treatment Non-Compliance ...................................................................................................................... 47 
7.5.4. Dilated Ophthalmoscopy / retinal photography ................................................................................................... 48 
7.5.5. Patient Diary ........................................................................................................................................................ 48 
7.5.6. Hypoglycemia ...................................................................................................................................................... 48 
 
ADVERSE EVENT REPORTING ........................................................................................................... 51 
 
Adverse events .............................................................................................................................................. 51 
 
Definitions .................................................................................................................................................... 52 
8.2.1. Adverse Events .................................................................................................................................................... 52 
8.2.2. Adverse Drug Reaction ........................................................................................................................................ 52 
8.2.3. Unexpected Adverse Event/Adverse Drug Reaction ........................................................................................... 53 
8.2.4. Serious Adverse Events ....................................................................................................................................... 53 
 
Management of Adverse Events ................................................................................................................... 55 
8.3.1. Collection ............................................................................................................................................................ 55 
8.3.2. Evaluation ............................................................................................................................................................ 56 
 
Special Situations ......................................................................................................................................... 62 
8.4.1. Pregnancy ............................................................................................................................................................ 62 
8.4.2. Overdose, Medication Errors and Other Events .................................................................................................. 63 
 
Abnormal Test Findings ............................................................................................................................... 63 
 
DATA ANALYSIS/STATISTICAL METHODS ..................................................................................... 64 
 
Sample Size Determination .......................................................................................................................... 64 
 
General Considerations ................................................................................................................................. 64 
9.2.1. Primary End Point ............................................................................................................................................... 65 
9.2.2. Study Population .................................................................................................................................................. 65 
9.2.3. Handling Missing Values .................................................................................................................................... 65 
9.2.4. Pooling ................................................................................................................................................................. 66 
9.2.5. Multiplicity Adjustment ....................................................................................................................................... 66 
9.2.6. Statistical Methods .............................................................................................................................................. 66 
 
Patient Disposition ........................................................................................................................................ 66 
 
Protocol Violation ......................................................................................................................................... 67 
 
Patient Characteristics .................................................................................................................................. 67 


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Concomitant Medication .............................................................................................................................. 67 
 
Primary Efficacy Analysis ............................................................................................................................ 67 
 
Secondary Efficacy Analyses ....................................................................................................................... 67 
 
Safety Analyses ............................................................................................................................................ 68 
9.9.1. Treatment Exposure ............................................................................................................................................. 68 
9.9.2. Immunogenicity Profiles Analyses ...................................................................................................................... 68 
9.9.3. Hypoglycemia Analyses ...................................................................................................................................... 69 
9.9.4. Adverse Event Analyses ...................................................................................................................................... 70 
9.9.5. Vital Signs ........................................................................................................................................................... 70 
9.9.6. Laboratory Measurement ..................................................................................................................................... 70 
9.9.7. ECG ..................................................................................................................................................................... 70 
9.9.8. Device Safety Assessment ................................................................................................................................... 71 
 
Subgroup Analyses ....................................................................................................................................... 71 
 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................ 71 
 
Study Monitoring .......................................................................................................................................... 71 
 
Audits and Inspections .................................................................................................................................. 72 
 
DATA HANDLING AND RECORD KEEPING ..................................................................................... 72 
 
Electronic Case Report Forms ...................................................................................................................... 72 
 
Record Retention .......................................................................................................................................... 73 
 
Data Confidentiality...................................................................................................................................... 74 
 
Source Data Access ...................................................................................................................................... 74 
 
Responsibilities Related to Devices .............................................................................................................. 74 
11.5.1. Investigator Records and Reports (See Appendix V - Letter of Approval of Pen Use by the 
Investigator) .................................................................................................................................................. 74 
 
PROTOCOL AMENDMENTS, DEVIATIONS AND COMPLIANCE ................................................ 75 
 
ETHICS ....................................................................................................................................................... 76 
 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)..................................................... 76 
 
Ethical Conduct of the Study ........................................................................................................................ 77 
 
Patient Information and Consent .................................................................................................................. 77 
 
DEFINITION OF END OF TRIAL .......................................................................................................... 77 
 
End of Trial in a Member State .................................................................................................................... 78 


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End of Trial in all Other Participating Countries .......................................................................................... 78 
 
SPONSOR DISCONTINUATION CRITERIA ....................................................................................... 78 
 
PUBLICATION OF STUDY RESULTS .................................................................................................. 79 
 
Communication of Study Results ................................................................................................................. 79 
 
Publications by Investigators ........................................................................................................................ 79 
 
REFERENCES ........................................................................................................................................... 80 
 
APPENDICES ............................................................................................................................................. 82 
Appendix I - Questionnaire to Assess Hypoglycemia Unawareness ............................................................................. 83 
Appendix II - Suggested Guidance for Insulin Dose Titration ...................................................................................... 84 
Appendix III - 4-Point and/or 8-Point Glucose Estimation Time Points ....................................................................... 85 
Appendix IV - Sample Patient Diary Information ......................................................................................................... 86 
Appendix V - Letter of Approval of Pen Use by the Investigator (for US Sites only) .................................................. 87 
 
TABLES 
Table 1: Humalog Kwikpen Usage Instructions .............................................................................................. 33 
Table 2: Medications That Are Likely to Interfere with Diabetes Control ...................................................... 36 
Table 3: SMBG Profile Requirements by Visit ............................................................................................... 37 
Table 4: Blood Volume Needed for Immunogenicity Analysis ....................................................................... 39 
Table 5: Central Laboratory Details for Safety Sample Shipment .................................................................. 46 
Table 6: Clinical Severity of Adverse Events .................................................................................................. 56 
Table 7: Action Taken for an Adverse Event .................................................................................................. 57 
Table 8: Definition of Suspected Relationship between the Events and Trial Medication .............................. 58 
 
FIGURES 
Figure 1: Study Flowchart ............................................................................................................................... 27 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADA 
American Diabetes Association 
ADR 
adverse drug reaction 
AE(s)  
adverse event(s) 
ALT  
alanine transaminase 
ANCOVA 
analysis of covariance 
AST  
aspartate transaminase 
BMI  
body mass index 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
DCCT 
Diabetes Control and Complications Trial 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration (United States) 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
HbA1c 
glycosylated hemoglobin 
HBsAg 
hepatitis B surface antigen 
HCP 
host cell protein 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator’s brochure 


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Abbreviation 
Definition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IEC 
independent ethics committee  
IRB 
institutional review board 
ITT 
Intention to treat 
IU 
International Unit 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
JNC 
Joint National Committee 
LDL 
low density lipoprotein 
LOCF 
last observation carried forward 
MDP 
manic depressive psychosis 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
neutralizing antibody 
NPH  
neutral protamine Hagedorn 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PP 
Per protocol 
SAE(s)  
serious adverse event(s) 
SD 
standard deviation 
SMBG 
self-monitored blood glucose  
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
WHO 
World Health Organization 


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PROTOCOL SYNOPSIS  
Title  
An Open-label, Randomized, Multi-center, Parallel-Group Clinical Trial Comparing the Efficacy 
and Safety of Mylan’s Insulin Glargine with Lantus® in Type 1 Diabetes Mellitus Patients: An 
Extension Study 
Objectives 
To compare the following variables when Mylan’s insulin glargine and Lantus® are 
interchanged: 
Primary objective 
• 
Demonstrate the equivalence of changes in HbA1C between two treatment sequence 
groups 
 
Secondary objective 
• 
Change in basal insulin dose per unit body weight (U/Kg/day)  
• 
Immunogenicity: incidence and change from baseline in the relative levels of ADA, 
incidence and change from baseline in the relative levels of anti-HCP antibodies. 
• 
Rate of hypoglycemic events per 30 days and occurrence of hypoglycemia  
• 
Occurrence of local reactions, systemic reactions and other adverse events 
• 
Change in fasting plasma glucose  
• 
Change in 8-point SMBG profile  
• 
Device-related safety assessments 
Proposed 
Number of 
Sites  
From approximately 70 selected sites, approximately 69 patients will be included in each arm, 
with a target of approximately 138 randomized patients in both arms together. 
Study 
Population 
Patients with an established diagnosis of T1DM per ADA 2014 criteria who were randomized to 
the Lantus® treatment arm of the MYL-GAI-3001 study, and who have completed the 52-week 
treatment period on Lantus® will be eligible to be screened for the MYL-1501D-3003 study.   
Duration of 
Patient 
Participation  
The maximum possible duration of patient participation in the extension study is approximately 
40 weeks, which includes: 
1. Randomized comparative treatment period 1: 12 weeks. 
2. Randomized comparative treatment period 2: 12 weeks. 
3. Randomized comparative treatment period 3: 12 weeks. 
4. Follow-up period: 4 weeks. 
Study Design 
This multi-center, open-label, randomized clinical extension study in patients with T1DM will 
assess interchangeability of Mylan’s insulin glargine and Lantus® with respect to safety and 
efficacy. 
Patients with an established diagnosis of T1DM per ADA 2014 criteria who were randomized to 
the Lantus® treatment arm of the MYL-GAI-3001 study, and who have completed the 52-week 
treatment period on Lantus® will be eligible to be screened for the MYL-1501D-3003 study. 
There will be 2 treatment arms (with 3 sequences) in the extension study.  
Patients randomized to Lantus® during MYL-GAI-3001 will be randomized to either Lantus® or 
Mylan’s insulin glargine for 12 weeks. After this first 12 weeks of treatment, those on Mylan’s 
insulin glargine will be switched to Lantus® while those on Lantus® will continue on Lantus® for 
another 12 weeks to complete the second treatment period. After 24 weeks of treatment, those 
patients who were randomized to Mylan’s insulin glargine and had a switch to Lantus® will 
undergo an additional switch to Mylan’s insulin glargine for an additional 12 weeks to complete 
the third treatment period. Those patients who are on Lantus® since the start of the study and did 
not have any switch, will continue on Lantus® for another 12 weeks to complete the third 


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treatment period. 
After 36 weeks of treatment, patients will go back to the approved medications (as prescribed) 
and will be followed up for safety for another 4 weeks (Mylan will not provide any medications 
from 36 weeks of treatment onwards). The 36 to 40 week safety data will also be captured. 
During the 36-weeks treatment period, the titration (if needed) of both Mylan’s insulin glargine 
and Lantus® should be kept to a minimum, unless there are safety concerns.  
The week 52 visit for MYL-GAI-3001 will also serve as the week 0 visit for the extension study.  
Number of 
Patients 
From approximately 70 selected sites, approximately 69 patients will be included in each arm, 
with a target of approximately 138 randomized patients in both arms together. 
Inclusion 
Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
extension study: 
1. Patients who have completed the 52-week treatment period (irrespective of their age at the 
completion of MYL-GAI-3001) of MYL-GAI-300 and were assigned to Lantus® in MYL-
GAI-3001.   
2. Patients or their legal representatives must give written and signed informed consent before 
starting any protocol-specific procedures.  
3. The patient is able and willing to comply with the requirements of the extension study 
protocol including the 8-point SMBG, completion of the patient diary records as per the 
instructions and following a recommended diet and exercise plan for the entire duration of 
the extension study. 
4. Female patients complying with the following: 
o 
Female patients of childbearing potential must be using oral contraception or two 
other acceptable methods of contraception (e.g., intra-uterine device plus condom, 
spermicidal gel plus condom, diaphragm plus condom, etc.) from the time of 
randomization throughout the entire study. 
o 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
o 
Postmenopausal females must have had no menstrual bleeding for at least 1 year 
prior to inclusion to MYL-1501D-3003.    
o 
Female patients who report surgical sterilization must have had the procedure at 
least 6 months prior to inclusion to MYL-1501D-3003.  
o 
All female patients of childbearing potential, must have negative pregnancy test 
results at baseline (week 0) and at each clinic visit as per the SCHEDULE OF 
ACTIVITIES. 
o 
If female patients have male partners who have undergone vasectomy, the 
vasectomy must have occurred more than 6 months prior to inclusion in MYL-
1501D-3003. 
Exclusion 
Criteria 
Patients meeting any of the following criteria will not be included in the extension study: 
1) History or presence of a medical condition or disease that in the Investigator’s opinion 
would place the patient at an unacceptable risk from trial participation. 
2) History of clinically significant (i.e., significant enough to alter the insulin dose requirement, 
as per the Investigator) acute bacterial, viral or fungal systemic infections in the 4 weeks 
prior to inclusion / randomization (recorded while collecting patient history) in the MYL-
1501D-3003 extension study. 
3) Patients scheduled to receive another investigational drug during the extension study period. 
4) Any major elective surgery requiring hospitalization planned during the extension study 
period. 
5) Moderate insulin resistance, defined as requiring insulin (Basal + Prandial) of ≥1.5 U/kg/day 
(Lantus® in U/kg/day or Mylan’s insulin glargine in IU/kg/day). 
Withdrawal 
Criteria  
If, for any reason, a patient discontinues the trial prematurely, the patient may be followed up 


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upon consent and as described in the following withdrawal criteria: 
Following are the withdrawal criteria:  
1. Withdrawal of consent. 
2. For female patients, diagnosis of pregnancy or stated intention to become pregnant. Effort 
should be made so that the pregnant women still report to the site and are followed until 
delivery or termination.  
3. Repeated protocol non-compliance. 
4. At the investigator’s discretion, (following discussion with the sponsor medical monitor), 
for safety issues such as severe hypoglycemia or hypoglycemic unawareness. The site 
should follow-up these patients as per the SCHEDULE OF ACTIVITIES until the 40 week 
follow-up call. 
5. At the investigator’s discretion, (following discussion with the sponsor medical monitor), 
in certain situations such as significant intercurrent illness, hospitalization for surgery, or 
an SAE. The site should follow-up these patients as per the SCHEDULE OF ACTIVITIES 
until the 40 week follow-up call. 
Study 
Treatments  
Investigational Products  
• 
Mylan’s insulin glargine (test product) 100 IU/mL 
• 
Lantus® from Sanofi-Aventis sourced from the US (US listed drug) 100 U/mL 
Both investigational products will be provided in a pre-filled disposable pen with a 3 mL 
cartridge. 
Mealtime insulin 
• 
Humalog® (insulin lispro injection, 100 U/mL), manufactured by Eli Lilly (administered in 
Humalog Kwikpen® disposable pens).  
All patients will continue on insulin lispro for the complete trial. The Investigator will inform the 
patients of the doses to be used and the titration scheme to be followed (if needed during the 
study). During the trial period dose titration (if needed) will be kept to a minimum.  
Concomitant 
Medications 
and Therapy  
Other than study drugs, insulin, insulin analogs and other anti-diabetes medications as well as 
glucocorticoid therapy (oral, intravenous, inhaled or other routes that produce systemic effects) 
should not be taken during the study (prohibited medications).  
A list of restricted medications that may interfere with the effect of insulin is given in the below 
table. No drugs listed in this table should be started during the treatment period. 
All treatments being taken by the patients following signing the ICF in addition to the trial 
treatment (investigational products and mealtime insulin) during the trial are regarded as 
concomitant medications and must be documented in the CRF. Mylan’s insulin glargine, 
Lantus® and insulin lispro will not be considered as concomitant medications. 
 
Drug classes that are known to augment the 
blood glucose lowering effect of insulin such 
as: 
Drugs and drug classes that are known to 
decrease the blood glucose lowering effect of 
insulin such as: 
1. salicylates at doses more than 
>2 g/day 
2. sulfa antibiotics 
3. angiotensin 
converting 
enzyme 
inhibitors 
4. disopyramide 
5. fibrates 
6. fluoxetine 
7. monoamine oxidase inhibitors 
1. danazol 
2. niacin 
3. diuretics 
4. sympathomimetic agents  
5. glucagon 
6. isoniazid 
7. somatropin 
8. thyroid hormones 
9. oral contraceptives 


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8. propoxyphene 
9. pentoxifylline 
10. somatostatin analogs 
11. bromergocryptine (bromocryptine) 
12. anabolic steroids. 
10. estrogens 
11. progestogens 
12. protease inhibitors  
13. phenothiazine derivatives 
14. atypical antipsychotic medications 
(e.g. olanzapine and clozapine). 
 


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SCHEDULE OF ACTIVITIES 
     
Visits 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
 
V9 
 
V10 
 
V11 
 
V12 
V131 
(EOT) 
V142 
(FU) 
  Extension Study Week 
0 
2 
4 
8 
12 
14 
16 
20 
24 
26 
28 
32 
36 
40 
                                                            Extension Study Day 
0 
14±3 28±3 56±3 84±3 98±7 112±7 140±7 168±7 182±7 196±7 224±7 252±7 
280±7 
Informed Consent3 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous and current insulin usage history 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated Ophthalmoscopy / Retinal photography testing4  
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Standard-of-care specifics5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Age, Gender, Race 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight, Height and BMI11 
√ 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Pregnancy Test6 
√ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Medical History and Concomitant Illness 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Vitals signs measurement (sitting) 
√ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Physical examination 
√ 
x 
 
 
x 
x 
 
 
x 
x 
 
 
x 
 
12-lead ECG (supine) 
√ 
 
 
 
x 
x 
 
 
x 
x 
 
 
x 
 
Fresh Randomization with capture of old randomization number7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record AEs and SAEs, local and systemic allergic reactions and 
hypoglycemic events8  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x12 
Record device safety information (disposable needle or pen) 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Fasting Plasma Glucose 
√ 
 
 
x 
x 
 
 
x 
x 
 
 
 
x 
 
HbA1c Assay 
√ 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
HIV, HBsAg, and HCVAb 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sampling for hematology, blood chemistry and urinalysis9 
√ 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
Fasting lipid profile 
√ 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
Sampling for immunogenicity  
√ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Review 8-point SMBG Profile performed in the week before the 
visit 10 
√ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dose review of Mylan’s insulin glargine/Lantus® and insulin 
lispro and instruction 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Dispense Trial Medication and ancillary supplies 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
 


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Visits 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
 
V9 
 
V10 
 
V11 
 
V12 
V131 
(EOT) 
V142 
(FU) 
  Extension Study Week 
0 
2 
4 
8 
12 
14 
16 
20 
24 
26 
28 
32 
36 
40 
                                                            Extension Study Day 
0 
14±3 28±3 56±3 84±3 98±7 112±7 140±7 168±7 182±7 196±7 224±7 252±7 
280±7 
Drug Accountability and Compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dispense patient diary 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Review patient diary 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
1. 
At the EOT the Investigator will discuss with the patient the prescription medication that the patient should take after the end of the extension study, and provide dosing instructions. 
(Mylan will not provide any medications from 36 weeks of treatment onwards) 
2. 
Follow-up visit will be a telephone contact.  
3. 
Informed consent should be signed on the Day “0” prior to initiating any study related activities  
4. 
Dilated Ophthalmoscopy / Retinal photography testing should be performed once within one of the visits during the 28 days of enrolment  
5. 
Standard–of-care specifics includes assessment and documentation of the following - Training on self-management of diabetes, lifestyle modification measures (includes maintenance of 
appropriate body weight, following recommended physical activity, avoidance of smoking and following the recommended diet); and monitoring to prevent complications. 
6. 
Urine pregnancy test will be conducted at specified visits. Results of the pregnancy test should be confirmed as negative before dispensing trial drug(s). 
7. 
The MYL-GAI-3001 randomization number should also be captured during the new randomization along with the new randomization numbers.  
8. 
Hypoglycemia that had occurred before MYL-1501D-3003 week 0 visit will be noted in source document and will be used for comparisons. . Ongoing adverse events from MYL-GAI-
3001 will be recorded as adverse events. 
9. 
A routine urine dipstick will be performed by the site. A urinalysis by microscopic urinalysis may be performed by the central lab if the dipstick result is abnormal, and if requested by 
the Investigator.  
10. The 8-point SMBG profile measurement needs to be done by the patient at home on any 3 days (of which 2 days should be consecutive) in the week of the visit (i.e. during the 7 days 
before the day of the visit). 
11. Only body weight will be measured at EOT visit. Height at V1 of MYL-GAI-3001 will be used to calculate BMI. 
12. Allergic reactions, AEs and SAEs will be captured. 
‘√’ represents information already collected in the MYL-GAI-3001 trial. The same information should be used in this extension study.  
‘x’ represents new information to be collected in the extension study. 
AE: adverse event; BMI: body mass index; ECG: electrocardiogram; EOT: end of treatment; HbA1c: glycosylated hemoglobin; HBsAg: hepatitis B surface antigen; HCVAb: hepatitis C 
virus antibody; HIV: Human Immunodeficiency Virus; SAE: serious adverse event; SMBG: self-monitored blood glucose.  
Hematology panel will include hemoglobin, hematocrit, white blood cell count with differentials, red blood cell count with indices (mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration) and platelet count.  
Blood chemistry panel will include blood urea / BUN, serum creatinine, creatinine kinase, uric acid, serum bilirubin (total and direct), total protein, serum albumin, ALT, AST, alkaline 
phosphatase, LDH, lipase, sodium, potassium, calcium, magnesium, chloride, and bicarbonate.  
For the urinalysis a routine urine dip will be performed by the site, using supplies provided by the central laboratory. This will include assessment of specific gravity, pH, and semi-
quantitative "dipstick" evaluation of glucose, protein, bilirubin, ketones, leukocytes and blood. If the investigators want to do detailed urine testing, the site will send a urine sample to the 
central laboratory for microscopic evaluation. Microscopic examination will include WBC, RBC, casts, cast type, crystals, epithelial cells, renal cells, mucus threads, bacteria, yeast, and 
Trichomonas) 
Physical examination activities will include the following assessments: general appearance, head, ears, eyes, nose and throat (including thyroid), skin, respiratory system, cardiovascular 


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system, abdomen, lymph nodes, musculoskeletal system, gastrointestinal system (including mouth) and neurological system; and a diabetic foot examination 


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INTRODUCTION 
Insulin secretion in healthy subjects is characterized by relatively constant basal insulin 
secretion with a post-prandial surge. Type 1 diabetes mellitus (T1DM) is characterized by 
loss of the insulin-producing beta-cells of the islets of Langerhans in the pancreas, leading to 
a deficiency of insulin. The primary cause of beta-cell loss is a T-cell mediated autoimmune 
attack [1]. The principal treatment of patients with T1DM is initiation of insulin and diet 
control and careful monitoring of blood glucose levels. 
Long-acting insulin analogs have proven efficacy and offer good glucose control over 24 
hours for a single dose. Insulin glargine is a long-acting insulin analogue allowing once-daily 
administration to cover basal insulin requirements for over 24 hours. Mylan’s insulin 
glargine is a human insulin analogue of r-DNA origin produced in the host organism Pichia 
pastoris. P pastoris is a methylotropic yeast that has been successfully used in the production 
of proteins.  
Extension Study Population: Patients with an established diagnosis of T1DM per ADA 
2014 criteria [4] who were randomized to the Lantus® treatment arm of the MYL-GAI-3001 
study, and who have completed the 52-week treatment period on Lantus® will be eligible to 
be screened for the MYL-1501D-3003 study. 
 
Background and Rationale 
Mylan’s insulin glargine is being developed globally as a biosimilar to Lantus. In the US, this 
development is currently following the 505(b)(2) pathway, but will according to the US 
Food, Drug and Cosmetic (FD&C) Act in the future follow the 351(k) pathway. Hence, 
criteria for both regulatory pathways will be pursued.1 
The aim of this extension study is to demonstrate that Mylan’s insulin glargine and Lantus® 
have equivalent safety and efficacy in T1DM patients, when one treatment is substituted with 
the other. Under the 505(b)(2) pathway this is called “therapeutic equivalence” while under 
                                                 
1  By March 23, 2020 insulin glargine under section 505 of the FD&C Act shall be deemed to be licensed under section 351 
of the Public Health Service (PHS)  Act (see section 7002(e)(4) of the BPCI Act) (ref: FDA draft guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf) as a 
biosimilar 


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351(k) this is termed “interchangeability”. Following the transition from 505(b)(2) to 351(k), 
the clinical equivalence data will be considered to support the interchangeability of Mylan’s 
insulin glargine and Lantus.  Although FDA has not yet issued clear guidelines on 
interchangeability, interactions with the Agency indicate that in order to show 
interchangeability between the reference drug and the test drug, the primary endpoint should 
be assessed for equivalence between two treatment arms; one exposed to continuous use of 
reference and one exposed to repeated switches, which is defined as at least four (4) periods 
of adequate durations [three (3) switches or transitions]. Within the 3 switches, the patients 
will be switched from reference drug to test drug and back again. The Lantus® arm of MYL-
GAI-3001 will represent the first of the four periods.  
The extension study will be conducted open-label since the 2 formulations have different 
manufacturers and thus distinct packaging. To avoid bias in the evaluation of the critical 
endpoints, blinded analysis of immunogenicity and HbA1c data is planned.  
Patients who successfully completed 52 weeks in MYL-GAI-3001 will be eligible to 
participate in the extension study. Patients exposed to different types of insulins may have 
different immune responses following exposure to trial drug. This confounding effect will be 
minimized as only patients who have been on Lantus® (besides mealtime insulin lispro) for 
the last 52 weeks prior to the randomization will be included in the trial.  
Patients on Lantus® during MYL-GAI-3001 will be randomized to Mylan’s insulin glargine 
or Lantus® for 12 weeks; following which, those on Mylan’s insulin glargine will be 
switched to Lantus®, and those on Lantus® will continue on Lantus® for another 12 weeks. 
During the consecutive 12-week comparative treatment periods, diabetes treatment will be 
either maintained or further controlled (if needed) by titrating the dose of Lantus® or Mylan’s 
insulin glargine, if necessary. After the 24 weeks of treatment, those patients who were 
randomized to Mylan’s insulin glargine and had a switch to Lantus® will undergo an 
additional switch to Mylan’s insulin glargine for an additional 12 weeks to complete the third 
treatment period. Those patients who are on Lantus® since the start of the study and did not 
have any switch will continue on Lantus® for another 12 weeks to complete the third 
treatment period. 


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All patients will continue on insulin lispro for the entire duration of the study. After 
completion of the 36 week treatment, patients will go back to the approved medications (as 
prescribed earlier, prior to their participation in the MYL-GAI-3001 study) on their own and 
will be followed up for safety for another 4 weeks (Mylan will not provide any medications 
during the safety follow-up period). The 36 to 40 week safety data will be captured. This 
4-week follow-up visit is to confirm that patients are safe on the prescribed medications.  
Twelve weeks exposure is considered adequate to assess the efficacy with respect to HbA1c, 
as well as to compare the safety between the treatment groups. If switching from Lantus® to 
Mylan’s insulin glargine or from Mylan’s insulin glargine to Lantus® have an impact on the 
efficacy or the safety, a discernible difference in efficacy or safety parameters is expected 
versus the group of patients who are continuing on Lantus® throughout.  
 
Clinical data on Lantus®  
The only reference safety document for Mylan’s insulin glargine is the Investigator’s 
Brochure [6]. The only reference safety document for the comparator is the current United 
States Prescribing Information of Lantus® [7]. 
 
 STUDY OBJECTIVES AND ENDPOINTS 
 
Objectives  
To compare the following variables when Mylan’s insulin glargine and Lantus® are 
interchanged: 
Primary objective 
• Demonstrate the equivalence of changes in HbA1C between two treatment 
sequence groups 
Secondary objective 
• Change in basal insulin dose per unit body weight (U/Kg/day)  
• Immunogenicity: incidence and change from baseline in the relative levels of 
ADA, incidence and change from baseline in the relative levels of anti-HCP 
antibodies.  
• Rate of hypoglycemic events per 30 days; and occurrence of hypoglycemia  


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• Occurrence of local reactions, systemic reactions and other adverse events 
• Change in fasting plasma glucose  
• Change in 8-point SMBG profile  
• Device-related safety assessments 
 STUDY DESIGN 
A schematic representation of the extension study is given in Figure 1. This multi-center, 
open-label, randomized clinical extension study in patients with T1DM will assess 
interchangeability of Mylan’s insulin glargine and Lantus® with respect to the safety and 
efficacy. 
Patients with an established diagnosis of T1DM per ADA 2014 criteria who were 
randomized to the Lantus® treatment arm of the MYL-GAI-3001 study, and who have 
completed the 52-week treatment period on Lantus® will be eligible to be screened for the 
MYL-1501D-3003 extension study. All patients will continue on insulin lispro for the entire 
duration of the study. 
There will be 2 treatment arms (with 3 sequences) in the extension study.  
• Patients randomized to Lantus® during MYL-GAI-3001 study will be randomized to 
either Lantus® or Mylan’s insulin glargine for 12 weeks.  
• After this first 12 weeks of treatment, those on Mylan’s insulin glargine will be 
switched to Lantus® while those on Lantus® will be continued on Lantus® for another 
12 weeks to complete the second treatment period. 
• After the 24 weeks of treatment, those patients which were initially randomized to 
Mylan’s insulin glargine and had a switch to Lantus® will have an additional switch to 
Mylan’s insulin glargine for additional 12 weeks to complete the third treatment 
period. Those on Lantus® since the start of the study, who did not have any switch 
will continue on Lantus® for another 12 weeks to complete the third treatment period. 
After 36 weeks of treatment, patients will go back to the approved medications (as prescribed 
earlier) and followed up for safety for another 4 weeks. The 36 to 40 week safety data will be 
captured/documented (Mylan will not provide any medications during the safety follow-up 
period). 


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During the 36-week treatment period, the titration (if needed) of both Mylan’s insulin 
glargine and Lantus® should be kept to a minimum and the recommended titration algorithm 
should be followed, unless there are safety concerns.  
The week 52 visit for the MYL-GAI-3001 study will also serve as the week 0 visit for the 
extension study.  
 
Study Duration  
The maximum possible duration of patient participation in the extension study is 
approximately 40 weeks, which includes: 
• 
Treatment period 1: 12 weeks of randomized comparative treatment (Week 0 to 
Week 12).  
• 
Treatment period 2: 12 weeks of randomized comparative treatment (Week 12 
to Week 24).  
• 
Treatment period 3: 12 weeks of randomized comparative treatment (Week 24 
to Week 36).  
• 
Follow-up period: 4 weeks of follow-up visit (Week 36 to Week 40) 
Number of Patients:  
From approximately 70 selected sites, approximately 69 patients will be included in each 
arm, with a target of approximately 138 randomized patients in both arms together. 
 
Allocation to Treatment 
Patients on Lantus® will be randomized 1:1 to receive either Mylan’s insulin glargine 
or Lantus® using an IVRS/IWRS. Change of dosing from morning to bedtime or vice versa 
will not be permitted.  
If a patient discontinues, the patient will not be allowed to re-enter the extension study. 
 
Patient Numbering 
The center numbers will remain the same as those assigned by the sponsor/designee in 
MYL-GAI-3001. New unique randomization numbers will be assigned by the IVRS/IWRS 
system to the patients enrolled into the MYL-1501D-3003 extension study.   


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Blinding 
This is an open-label study. To minimize bias, treatment assignments will not be revealed to 
the central laboratory for the safety (immunogenicity) and efficacy (HbA1c) analyses. A 
document listing the trial team members who are blinded and unblinded will be maintained. 
 
 Breaking the Blind  
The Investigator and the patients will not be blinded to treatment assignments.   


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Figure 1: Study Flowchart 
 
Randomization (1:1) 
Mylan's Insulin Glargine 
plus insulin lispro 
(12 weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mylan's Insulin Glargine 
plus insulin lispro  
(12 weeks) 
 
Lantus®  
plus insulin lispro  
(12 weeks) 
Lantus®  
plus insulin lispro  
(12 weeks) 
Lantus®  
plus insulin lispro  
(12 weeks) 
 
 
 
 
Lantus®  
plus insulin lispro  
(12 weeks) 
End of Trial Visit 
(36 weeks) 
Follow-up Visit 
(40 weeks) 


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 PATIENT SELECTION 
 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
extension study: 
1. Patients who have completed the 52-week treatment period (irrespective of their age at 
the completion of MYL-GAI-3001) of MYL-GAI-3001 and were assigned to Lantus® in 
that study.   
2. Patients or their legal representatives must give written and signed informed consent 
before starting any protocol-specific procedures.  
3. The patient is able and willing to comply with the requirements of the extension study 
protocol including the 8-point SMBG, completion of patient diary records as instructed 
and following a recommended diet and exercise plan for the entire duration of the 
extension study. 
4. Female patients complying with the following: 
• Female patients of childbearing potential must be using oral contraception or two 
other acceptable methods of contraception, (e.g., intra-uterine device plus condom, 
spermicidal gel plus condom, diaphragm plus condom, etc.) from the time of 
randomization throughout the entire study. 
• Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Postmenopausal females must have had no menstrual bleeding for at least 1 year prior 
to inclusion in MYL-1501D-3003 study.  
• Female patients who report surgical sterilization must have had the procedure at least 
6 months prior to inclusion to MYL-1501D-3003 study. 
• All female patients of childbearing potential, must have negative pregnancy test 
results at baseline (week 0) and at each clinic visit as per the SCHEDULE OF 
ACTIVITIES. 


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• If female patients have male partners who have undergone vasectomy, the vasectomy 
must have occurred more than 6 months prior to inclusion in MYL-1501D-3003 
study. 
 
Exclusion Criteria 
Patients meeting any of the following criteria will not be included in the extension study: 
1. History or presence of a medical condition or disease that in the Investigator’s 
opinion would place the patient at an unacceptable risk from trial participation. 
2. History of clinically significant (i.e., significant enough to alter the insulin dose 
requirement, as per the Investigator) acute bacterial, viral or fungal systemic 
infections in the 4 weeks prior to inclusion / randomization (recorded while collecting 
patient history) into MYL-1501D-3003. 
3. Patients scheduled to receive another investigational drug during the extension study 
period. 
4. Any major elective surgery requiring hospitalization planned during the extension 
study period. 
5. Moderate insulin resistance, defined as requiring insulin (basal + prandial) of 
≥1.5 U/kg/day (Lantus® in U/kg/day or Mylan’s insulin glargine in IU/kg/day). 
 
STUDY TREATMENTS AND CONCOMITANT MEDICATION 
The investigational products used in this trial are Mylan’s insulin glargine and Lantus® (from 
Sanofi-Aventis). All patients will receive insulin lispro as mealtime medication.  
 
Study Medication 
• Mylan’s insulin glargine (test product) 100 IU/mL 
• Lantus® 100 U/mL (Sanofi-Aventis), sourced from the US (USLD, reference product)  
Both investigational products will be provided by the sponsor in pre-filled disposable pens 
with a 3 mL cartridge. Mylan’s insulin glargine formulation for injection is a sterile, clear 
solution with a pH of 4. Each mL contains 100 units of insulin glargine (equivalent to 3.64 
mg). The excipients of the formulation are identical to those of Lantus® [6]. Please refer to 


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the Investigator’s Brochure [6] for more details on Mylan’s insulin glargine, and the United 
States prescribing information [7] for more details on Lantus®.  
At the end of MYL-GAI-3001, an equivalent dose (dose of Lantus® at the end of MYL-GAI-
3001) of Mylan’s insulin glargine or Lantus® (based on the assigned treatment) will be 
provided for 12 weeks. For the following 12 weeks, patients on Mylan’s insulin glargine will 
receive the same dose of Lantus®; while patients on Lantus® will continue on the same dose 
of Lantus®. After 24 weeks of treatment, those patients who were randomized to Mylan’s 
insulin glargine and had a switch to Lantus® will undergo an additional switch to Mylan’s 
insulin glargine for an additional 12 weeks to complete the third treatment period. For those 
patients who are on Lantus® since the start of the study and did not have any switch will 
continue on Lantus® for another 12 weeks to complete the third treatment period. 
Change in dose should be made only if there is safety concerns as per the Investigator’s 
judgement.  
 
Mealtime insulin 
• Humalog® (insulin lispro injection, 100 U/mL), manufactured by Eli Lilly 
(administered in Humalog Kwikpen® - disposable pens).  
The mealtime insulin will be provided by the sponsor.  
HUMALOG 100 units per mL (U-100) is available as 3 mL Humalog KwikPen (prefilled).  
Complete information on Humalog® and the Humalog Kwikpen® - disposable pen is 
available in the Humalog® SmPC and US prescribing information [10,11]. 
All patients will continue on insulin lispro for the entire duration of the study. The 
Investigator will inform the patients of the doses to be used and the titration scheme to be 
followed (if needed during the study). During the trial period dose titration (if needed) will be 
kept to a minimum.  
 
Ancillary Supplies 
The following ancillary supplies will be provided by the sponsor: glucose monitor, control 
solution for calibration of the glucometer, glucose monitor strips, alcohol swabs, lancet 
device, disposable lancets, sharps container, insulated bag to transport insulin, needles, and 
patient diary.  


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Drug Storage 
The Investigator must ensure the availability of proper storage conditions and temperature 
monitoring equipment at the site. A temperature log for trial products stored at the site must 
be maintained. The Investigator or Investigator’s authorized staff will check the storage 
temperature daily on working days and record the results in the temperature log. If storage 
conditions deviate from the described storage conditions or the medication is damaged in any 
way, the monitor must be contacted without delay. The monitor must notify the sponsor of 
any temperature deviations or damaged products. The sponsor or designee will assess the 
extent of the temperature deviation or damage and will inform the monitor in writing whether 
the product may be used or not. 
Mylan’s insulin glargine 100 IU/mL 
Unopened Mylan’s insulin glargine disposable pen injector: Mylan’s insulin glargine 
should be stored in a refrigerator (2°C to 8°C). It cannot be used if it has been frozen.  
Open (In-Use) Mylan’s insulin glargine disposable pen injector: Mylan’s insulin glargine 
can be kept at room temperature (below 25ºC) for up to 28 days once the disposable pen has 
been put to use. It should not be exposed to heat or direct sunlight. It should never be used 
after the expiry date printed on the pack. 
Lantus® 100 U/mL 
Unopened Lantus® disposable insulin pen injector: Lantus® should not be stored in the 
freezer and should not be allowed to freeze. Lantus® if it has been frozen should not be used. 
Unopened Lantus® pen injectors should be stored in a refrigerator at 2°C–8°C, and discarded 
in case expired at the end of the study based on the Sponsor instructions. Unopened Lantus® 
pen injectors kept at room temperature should be discarded at the end of the study based on 
the Sponsor instructions.  
Open (In-Use) Lantus® disposable insulin device: The opened (in-use) Lantus® pen 
injector should not be refrigerated but should be kept at room temperature (below 86°F/30°C) 
away from direct heat and light. The opened (in-use) Lantus® pen injector must be discarded  
at the end of the study based on the Sponsor instructions . 
Please refer to the United States prescribing information for storage conditions for Lantus® 
[7]. 


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Humalog® 
Please refer to the Summary of Product Characteristics [10] (if Europe sourced) or US 
prescribing information [11] (if US sourced) for Humalog® storage instructions.  
Humalog® should not be used after the expiration date. Unopened HUMALOG should be 
stored in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use 
HUMALOG if it has been frozen. In-use HUMALOG KwikPen should be stored at room 
temperature, below 86°F (30°C) and must be used within 28 days or be discarded at the end 
of the study based on the Sponsor instructions, even if they still contain HUMALOG. It 
should be protected from direct heat and light (Table 1).  


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Table 1: Humalog Kwikpen Usage Instructions 
 
Not In-Use (Unopened) 
Room Temperature 
(Below 86°F [30°C]) 
Not In-Use (Unopened) 
Refrigerated 
In-Use (Opened) Room 
Temperature, (Below 
86°F [30°C]) 
3 mL Humalog KwikPen 
(prefilled)  
28 days 
Until expiration date 
 
28 days, do not 
refrigerate. 
 
 
 
Drug Accountability 
The sponsor will supply sufficient quantities of the investigational product to allow 
completion of this extension trial. Upon receipt of the investigational product supplies at the 
site, the designated trial staff member should count and verify that the shipment contains all 
the items noted in the shipment inventory.  
The Investigator or designated staff must notify the monitor if there was a temperature 
deviation during shipment to the site (if information is available) or if the products are in any 
way damaged (Temp Tale® information should ensure accurate temperature monitoring). The 
Investigator or designee should temporarily quarantine compromised drug until notified by 
the monitor of actions to be taken (release for use or permanent quarantine for return and 
destruction). The monitor must notify the sponsor of any temperature deviations or damaged 
products. The sponsor or designee will assess the extent of the temperature deviation or 
damage and will inform the monitor in writing whether the product may be used or not.  
The Investigator must keep complete and accurate records for the receipt, storage, 
dispensing, and return or destruction of investigational products and mealtime insulin.  
 
Dispensing 
It is the responsibility of the Investigator to ensure that investigational products and mealtime 
insulin are dispensed only to trial patients. The Investigator or designee will dispense the 
required number of investigational product doses to ensure that the trial patient has sufficient 
supplies until the next dispensing visit.  
Patients will be requested to return all used and unused medications to the site at each visit. 
The usability of the returned medications will be assessed. Returned medications may be 
again dispensed to the same patient, provided it was stored as per specification and will not 
cross the expiry date before the next visit.  


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The site will store the returned medication until the monitor has performed accountability 
and informs the site of the processes for destruction or return of the medication.  
 
Administration 
Insulin glargine should be administered as a subcutaneous injection. It should be taken at 
approximately the same time every day. The preferred site is in the abdomen. The other 
possible sites of administration are the upper arm and thigh (upper leg). The injection sites 
should be rotated to reduce risk of lipodystrophy. Refer to the Investigator’s Brochure [6] 
and US prescribing information [7]. Insulin lispro will be administered as per the 
Investigator’s advice and as per the prescribing information [10,11]. 
The dosage of insulin will be adjusted based on SMBG profile, performed by the patients at 
home, so that patients attain the following glycemic targets (ADA 2014 criteria) [4]: 
• Fasting pre-prandial SMBG between 70 to 130 mg/dL (3.9-7.2 mmol/L) 
If the measured SMBG is <70 mg/dL (3.9 mmol/L) or if the patient has symptoms suggestive 
of hypoglycemia, he/she can call the Investigator or designee, if required. The insulin dose 
will be altered by the Investigator or designee, if required, based on the values. Any increase 
in total insulin dose per day of >6 units during any titration step should be performed with 
caution.  
 
Return of Study Drug 
After the completion of the extension study, the monitor will perform the final drug 
accountability check and inform the site of the return/destruction procedures for the unused 
and partly used medication.  
 
Treatment Compliance 
All reasonable and appropriate methods will be used to ensure compliance to the protocol for 
administration of trial medication.  
 
Concomitant Medication 
Other than study drugs, insulin, insulin analogs and other anti-diabetes medications as well as 
glucocorticoid therapy (oral, intravenous, inhaled or other routes that produce systemic 
effects) should not be taken during the study (prohibited medications). A list of restricted 


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medications that may interfere with insulin is given in Table 2. No drugs listed in this table 
should be started during the treatment period. 


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Table 2: Medications That Are Likely to Interfere with Diabetes Control 
Drug classes that are known to augment the 
blood glucose lowering effect of insulin such as: 
Drugs and drug classes that are known to decrease 
the blood glucose lowering effect of insulin such as: 
1. salicylates at doses more than >2 g/day 
2. sulfa antibiotics 
3. angiotensin converting enzyme inhibitors 
4. disopyramide 
5. fibrates 
6. fluoxetine 
7. monoamine oxidase inhibitors 
8. propoxyphene 
9. pentoxifylline 
10. somatostatin analogs 
11. bromergocryptine (bromocryptine) 
12. anabolic steroids. 
 
1. danazol 
2. niacin 
3. diuretics 
4. sympathomimetic agents  
5. glucagon 
6. isoniazid 
7. somatropin 
8. thyroid hormones 
9. oral contraceptives 
10. estrogens 
11. progestogens 
12. protease inhibitors  
13. phenothiazine derivatives 
14. atypical 
antipsychotic 
medications 
(e.g. 
olanzapine and clozapine). 
 
All treatments being taken by the patients following signing the ICF in addition to the trial 
treatment (investigational products and mealtime insulin) during the trial are regarded as 
concomitant medications and must be documented in the CRF. Mylan’s insulin glargine, 
Lantus® and insulin lispro will not be considered as concomitant medications. 
 STUDY PROCEDURES  
This trial includes randomized comparative treatment period-1, randomized comparative 
treatment period-2, randomized comparative treatment period-3 and a follow-up period. 
Specific activities involved in each period are described in the SCHEDULE OF 
ACTIVITIES. 
Throughout the trial, every reasonable effort should be made to follow the timing of 
assessments and procedures for each patient. Deviations from the schedule should be 
avoided. The allowed time window for each visit is shown in the SCHEDULE OF 
ACTIVITIES. 
 
Visit Schedules and SMBG Profiles 
Table 3 shows the SMBG profiling requirements at each visit.  
 


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Table 3: SMBG Profile Requirements by Visit 
 
Weeks 0 to 36 
Week 40 (FU) 
Mandatory clinic visit with 3 day 8-point SMBG in the week 
preceding the visit 
Week 0 to week 
36 visits  
- 
Telephone visit  
As advised by the 
Investigator 
SMBG will be 
performed for FU visit, 
as suggested by the 
Investigator at Week 
36 visit (EOT)* 
*Additional visits or profiles to be performed as advised by the Investigator 
EOT: end of treatment; FU: follow-up visit: SMBG: self-monitored blood glucose. 
 
Patient Withdrawal 
If, for any reason, a patient discontinues the trial prematurely, the patient may be followed up 
upon consent and as described in the following withdrawal criteria: 
Following are the withdrawal criteria:  
1. Withdrawal of consent. 
2. For female patients, diagnosis of pregnancy or stated intention to become pregnant. 
Effort should be made so that the pregnant women still report to the site and are 
followed until delivery or termination.  
3. Repeated protocol non-compliance. 
4. At the investigator’s discretion (following discussion with the sponsor medical 
monitor), for safety issues such as severe hypoglycemia or hypoglycemic unawareness. 
The site should follow-up these patients as per the SCHEDULE OF ACTIVITIES until 
the 40 week follow-up call. 
5. At the investigator’s discretion, (following discussion with the sponsor medical 
monitor), in certain situations such as significant intercurrent illness, hospitalization for 
surgery, or an SAE. The site should follow-up these patients as per the SCHEDULE OF 
ACTIVITIES until the 40 week follow-up call. 
Investigators must attempt to contact patients who fail to attend scheduled visits (by 
telephone or other means), to exclude the possibility of an AE being the cause of withdrawal. 
Should an AE be the cause for withdrawal, the AE must be documented, reported, and 
followed-up as described in Section 8. If withdrawal was not due to an AE the 


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Investigator should inquire about the reason for withdrawal. If applicable, request all 
withdrawn patients to bring back all unused investigational product(s) and return them at the 
final visit. The attempts to contact patients who fail to attend scheduled visits should be 
documented in the patient files as should the reasons for withdrawal.  
No further evaluations should be performed, and no additional data should be collected if the 
patient withdraws from the trial and also withdraws consent for disclosure of future 
information. Data collected before patient withdrawal of consent will be retained and 
continue to be used, or destroyed if required per local regulation and rules. 
 STUDY ASSESSMENTS AND METHODS 
 
Handling of Blood Samples 
Laboratory analysis will be conducted at central laboratories identified by the sponsor. The 
laboratory will provide specific sample kits to the Investigator site prior to the visit of 
patients. Instructions for collecting, handling, storing and shipping samples will be provided 
in the laboratory manuals.  
 
Efficacy Assessments  
7.2.1. HbA1c 
HbA1c assessments will be performed as shown in the SCHEDULE OF ACTIVITIES. The 
measurement will be performed by the central laboratory for safety and efficacy samples. 
7.2.2. Fasting Plasma Glucose (FPG) 
FPG assessments will be performed as shown in the SCHEDULE OF ACTIVITIES. The 
measurement will be performed by the central laboratory for safety and efficacy samples.  
7.2.3. Body Weight and BMI 
Weight will be recorded by the site as specified in the SCHEDULE OF ACTIVITIES. The 
Investigator will calculate the BMI (using the formula BMI=weight in kg/ height in m2; for 
BMI calculation, the previous recorded weight will be used until new weight recording).  


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7.2.4. 8-point SMBG profiles 
8-point SMBG profile measurements will be performed by the patient at home and recorded 
in the patient diary, as specified in the SCHEDULE OF ACTIVITIES. One 8-point SMBG 
profile set includes measurements of SMBG values on 3 days, performed in the week 
preceding the next visit (of the three days, 2 should be consecutive). The time points for the 
8-point SMBG are provided in Appendix III. The patient should document the 3 pre-visit 
measurements in the diary, and will be advised to similarly document any additional 
estimations.  
On days in which SMBG is not mandated by protocol, patients will be advised to 
self-monitor their blood glucose 4 times a day.  
7.2.5. Daily Insulin Doses  
Patients will be asked to document the dose of Mylan’s insulin glargine/Lantus® and insulin 
lispro taken on the days when they perform 8-point SMBG profiles (from week 0 to week 
24). Doses must be recorded in the patient diary. This data will be transcribed to the eCRF 
after the patient diary is collected, by the Investigator or designee. The patient should 
document the 3 pre-visit doses in the diary; and will be advised to document any additional 
doses. 
 
Immunogenicity Assessments 
Blood samples for the assessment of immunogenicity will be collected as specified in the 
SCHEDULE OF ACTIVITIES and in the table below (Table 4).  
Table 4: Blood Volume Needed for Immunogenicity Analysis 
Assessme
nts 
Randomiza
tion3  
2 
wee
ks 
4 
wee
ks 
8 
wee
ks 
12 
wee
ks 
14 
wee
ks 
16 
wee
ks 
20  
wee
ks 
24 
wee
ks 
26 
wee
ks 
28 
wee
ks 
32 
wee
ks 
36 
wee
ks 
 
Volume Collected (mL) 
 
 
 
 
Anti-drug 
antibody 
(ADA)1 
15  
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
Neutralizi
ng 
Antibody 
(NAb)1 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
Anti-HCP 
Antibody1 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
Drug 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 


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Assessme
nts 
Randomiza
tion3  
2 
wee
ks 
4 
wee
ks 
8 
wee
ks 
12 
wee
ks 
14 
wee
ks 
16 
wee
ks 
20  
wee
ks 
24 
wee
ks 
26 
wee
ks 
28 
wee
ks 
32 
wee
ks 
36 
wee
ks 
 
Volume Collected (mL) 
 
 
 
 
concentra
tion2  
1Blood samples will be drawn into serum separator tubes (SST). 
2Blood samples will be drawn into K2EDTA plasma tubes. 
3Results of the samples collected as part of MYL-GAI-3001 trial will be used. 
The clinical laboratory will provide specific sample kits to the Investigator site prior to the 
visit of patients. Instructions for collecting, handling, storing and shipping of clinical samples 
will be provided in the laboratory manuals. Samples and lab results collected at 
randomization will be considered as baseline.  
The central laboratories are: 
Samples from Europe will be sent to 
 
Q2 (Squared) Solutions 
The Alba Campus, Rosebank 
 Livingston, EH54 7EG 
UK 
Samples from US will be sent to 
 
Q2 (Squared) Solutions27027 Tourney Road, 
Suite 2E 
Valencia, CA 91355 
USA 
 
The site must store the immunogenicity and drug concentration samples at -20°C ± 5°C or 
lower and ship the samples in batches on a monthly basis to the central laboratory where they 
will be stored at -80 ± 5°C or below. Primary and backup samples should not be sent in the 
same shipment. Both immunogenicity and drug concentration samples must be shipped 
frozen on dry ice. Temperature monitoring devices (e.g. Temp Tale®) must be included in all 
sample shipments. 
7.3.1. Anti-Drug Antibody 
Two conventional radioimmunoprecipitation assays (RIPA) were employed for the 
assessment of anti-drug antibodies (ADA).  A two assay approach, applied in a blinded 
fashion, was utilized due to the potential structural differences between drug products arising 
from the different host cells used in production.  The two assays were identical except for the 
use of a unique tracer: 125I-Lantus, designated for the ‘LAN assay’, and 125I-MYL IG, 
designated as the ‘MIG assay’.  In both assays samples underwent a pre-treatment step that 


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included acid dissociation to release any anti-insulin antibodies complexed with free drug, 
followed by charcoal adsorption of the free insulin analog.  The treated samples were then 
incubated with a fixed amount of each tracer under the following conditions: 
• 
Assay buffer only (no inhibitor) 
• 
Assay buffer containing excess unlabeled MYL IG 
• 
Assay buffer containing excess unlabeled Lantus 
• 
Assay buffer containing excess unlabeled Human Insulin 
ADA complex formation with the tracers is measured via gamma counting and expressed as 
a percentage of bound to total radioactivity (%B/T). 
 
In keeping with the multi-tiered sample analysis recommendations for immunogenicity 
testing from published white papers (12, 13), and current regulatory guidance (14), the assay 
design employed a screening tier (no inhibition), confirmatory tier (competitive inhibition 
with excess drug), and characterization tier (competitive inhibition with excess human 
insulin) that were assessed simultaneously.  Since inhibition with excess drug and human 
insulin were included within the assessment of each sample, the total anti-drug antibody and 
insulin cross reactivity results were reported in terms of percent specific binding (%SB), 
which is the difference between the %B/T for the uninhibited and the inhibited samples for 
each assay.  Analogous to titer values, the %SB is the relative amount of antibody present in 
the samples.  Cut-points for these assessments were determined based on %SB during assay 
validation and applied during sample analysis for scoring total and cross reactive ADA 
positive samples: 
 
 
 
 
 
 
In addition, drug-specific ADA was assessed by determining the %B/T difference between 
samples inhibited with excess Lantus and MYL IG in each assay: 
 
Assay 
Assessment 
Assessment Definition 
MIG 
Total ADA 
%B/T (no inhibitor) - %B/T (excess MYL IG) 
Cross-reactive ADA 
%B/T (no inhibitor) - %B/T (excess human insulin) 
LAN 
Total ADA 
%B/T (no inhibitor) - %B/T (excess LAN) 
Cross-reactive ADA 
%B/T (no inhibitor) - %B/T (excess human insulin) 


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Assay 
Assessment 
Assessment Definition 
MIG 
Drug specific ADA 
%B/T (excess LAN) - %B/T (excess MYL IG) 
LAN 
Drug specific ADA 
%B/T (excess MYL IG) - %B/T (excess LAN) 
 
For this assessment no cut-point was determined or applied, and the results are reported as 
%B/T. 
 
Drug concentration samples were obtained to support an alternative format for 
immunogenicity testing (bridging ELISA).  With the use of a RIPA format, drug 
concentration testing is not required. 
 
Assessment of total antibody positive samples for the presence of neutralizing antibodies will 
be conducted at the discretion of the clinical team. 
7.3.2. Antibodies against Host Cell Protein Antibodies (anti-HCP)   
The multi-tiered sample analysis approach for immunogenicity testing will also be employed 
for the detection of antibodies directed against host cell proteins present in the drug product. 
In keeping with the multi-tiered sample analysis recommendations for immunogenicity 
testing, the assay design employed screening (no inhibition), confirmatory (competitive 
inhibition with excess HCP), and titer tiers.   However, since a high positive rate of pre-
existing antibodies is anticipated due to ubiquitous exposure of the general population to 
yeast proteins, sample analysis is limited to the screening and confirmatory tiers. Relative 
anti-HCP antibody levels over time will be estimated using sample ECL response in the 
screening assay.  
The assay employed for anti-HCP antibody evaluation will be fully validated using a 
surrogate positive control antibody, developed from host cell protein antigens (Pichia 
pastoris). Host antigens for the reference product (from the host Escherichia coli K12) are not 
available to develop a parallel assay for Lantus anti–HCP antibodies. In order to maintain 
blinded analysis, both treatment arms will be evaluated with the assay. Any change in the 
sample analysis method will be mentioned in the sample analysis plan. 


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Safety Assessments 
7.4.1. Medical History 
Medical history will be recorded at randomization and must include any clinically relevant 
prior diagnosis, concomitant diseases and abnormalities, documentation of drug allergies, 
prior systemic and local allergic reactions to insulin. The medical history should be checked 
against the inclusion and exclusion criteria.  
7.4.2. Prior and Concomitant Medication 
All treatments being taken by the patients at the time of randomization and all treatments 
given in addition to the trial treatment (investigational products), are regarded as concomitant 
treatments and must be documented in the eCRF.  
During the extension study the Investigator should ensure that no medications listed in  
Table 2 are initiated.  
7.4.3. Vital Signs  
Vital signs are body temperature, respiratory rate, sitting pulse, and blood pressure (both 
systolic and diastolic). The patient should be resting in sitting position for at least 5 minutes 
before the measurements are performed. The vital signs will be recorded as specified in the 
SCHEDULE OF ACTIVITIES. 
7.4.4. Physical Examination  
Complete physical examination data will be recorded as specified in the SCHEDULE OF 
ACTIVITIES and will include the following assessments: general appearance, head, ears, 
eyes, nose and throat (including thyroid), skin, respiratory system, cardiovascular system, 
abdomen, lymph nodes, musculoskeletal system, gastrointestinal system (including mouth) 
and neurological system; and a diabetic foot examination.  
7.4.5. Electrocardiogram 
A 12-lead ECG will be done as specified in the SCHEDULE OF ACTIVITIES. The ECG 
will be performed in supine position after at least 5 minutes resting in the supine position. 
The results will be assessed qualitatively as normal or as abnormal with the abnormalities 
specified.  


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7.4.6. Local and Systemic Allergic Reactions 
Local and systemic allergic reactions will be recorded as specified in the SCHEDULE OF 
ACTIVITIES. The Investigator should ask the patient at each trial visit about allergic 
reactions and check the injection site(s) for possible local allergic reactions. 
If a patient develops any type of allergic reaction, routine evaluations for identifying the 
cause and type of allergic reaction need to be done. These may include skin biopsy, blood 
sample collection for further testing, skin tests for detecting allergens or other standard 
methods considered essential by the Investigator.  
7.4.7. Adverse Events and Serious Adverse Events 
Adverse events and SAEs will be recorded as specified in the SCHEDULE OF ACTIVITIES 
from the time of signing the informed consent form until the end of the follow-up visit. After 
the follow-up visit, any SAEs reported by the patients will be recorded if they are deemed 
related to trial drugs by the Investigator.  
7.4.8. Hypoglycemic Events  
Patients will be instructed to record all hypoglycemic events in the patient diary from week 0 
through the EOT visit. The hypoglycemic events will be reviewed by the Investigator and 
transcribed into the eCRF by the Investigator or designee after the diary has been collected. 
Details of the different types of hypoglycemic events are provided in section 7.5.6.1. Severe 
and serious hypoglycemic episodes will be reported to the sponsor immediately, according to 
section 8.3.2.8. 
7.4.9. Safety Related to Device Use 
Adverse events could potentially result from device failure or user error. These safety issues 
will be identified, documented, investigated and if appropriate, reported. Any SAE associated 
with a device issue will be reported to the sponsor immediately according to section 8.3.2.8.  
7.4.9.1. Adverse Events Associated with Device and Device Complaints 
All AEs associated with the device will be captured according to section 8.3, including an 
assessment of causality by the Investigator. Any device-related complaints will be 
investigated at the discretion of the sponsor. 


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7.4.9.2. Investigator’s Responsibility 
• 
During enrollment, patients will be instructed to document in their diary and inform 
the Investigator (during the next scheduled visit) about any difficulties encountered 
during the administration of the drug.  
• 
Patients will be instructed to immediately report to the Investigator any suspected 
failure of the device to deliver the intended dose, or an SAE associated with the 
device. 
• 
For AEs associated with use of the device, the Investigator will record the AE term in 
the eCRF to capture both the adverse consequence as well as the association with the 
device (e.g. injection site pain from accidental needle stick). 
• 
The Investigator will record in the eCRF whether or not the device issue resulted in 
an AE; an assessment of whether the AE was related to the drug, the device, or both; 
and any other relevant information about the patient’s condition. 
• 
Any device-related complaint resulting in an SAE will be reported to Mylan within 
24 hours (per section 8.3.2.8). 
• 
Even in the absence of a report by the patient of device failure or a device related AE, 
if the Investigator sees that the pen is broken/damaged or disassembled, the 
Investigator will replace the device and send the damaged device to the CRO/Mylan. 
7.4.9.3. Sponsor’s Responsibility 
• 
For SAEs, Mylan will independently evaluate whether the SAE was drug-related or 
related to an adverse device effect. 
• 
In the event that the information available in the eCRF is inadequate for root cause 
analysis, Mylan will send a questionnaire to the Investigator, asking for more details. 
• 
All SAEs related to the use of the needle, which is a legally marketed device, will be 
recorded and reported to Mylan for investigation and reporting to the needle 
manufacturer, if deemed necessary, based on the outcome of the investigation.  
• 
Information regarding the circumstances, evaluation, investigation and analysis of all 
device deficiencies will be included in the clinical study report (CSR). 


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7.4.10. Safety Laboratory Assessments  
Safety and efficacy laboratory assessments will be performed by the following central 
laboratory: 
Table 5: Central Laboratory Details for Safety Sample Shipment 
Samples from Europe will be sent to 
 
Q2 (Squared) Solutions 
The Alba Campus, Rosebank 
 Livingston, EH54 7EG 
UK 
Samples from US will be sent to 
 
Q2 (Squared) Solutions27027 Tourney Road, 
Suite 2E 
Valencia, CA 91355 
USA 
 
7.4.10.1. Hematology, Blood Chemistry, and Urine Analysis 
Blood samples for hematology, blood chemistry, and urine samples for urine analysis will be 
collected and analyzed as specified in the SCHEDULE OF ACTIVITIES. 
Hematology panel includes hemoglobin, hematocrit, white blood cell count with 
differentials, red blood cell count with indices (mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration) and platelet count.  
Blood chemistry panel includes blood urea / BUN, serum creatinine, creatinine kinase, uric 
acid, serum bilirubin (total and direct), total protein, serum albumin, ALT, AST, alkaline 
phosphatase, LDH, lipase, sodium, potassium, calcium, magnesium, chloride, and 
bicarbonate.  
For the urinalysis a routine urine dip will be performed by the site using supplies provided by 
the central laboratory. This will include assessment of specific gravity, pH, and semi-
quantitative "dipstick" evaluation of glucose, protein, bilirubin, ketones, leukocytes and 
blood. If the Investigators want to do detailed urine testing, the site will send a urine sample 
to the central laboratory for microscopic evaluation. Microscopic examination will include 
WBC, RBC, casts, cast type, crystals, epithelial cells, renal cells, mucus threads, bacteria, 
yeast, and Trichomonas. 


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7.4.10.2. Fasting Lipid Profile 
Blood samples for fasting lipid profiles will be collected and analyzed as specified in 
the SCHEDULE OF ACTIVITIES. The lipid profile includes total cholesterol, high density 
lipoprotein (HDL), LDL and triglycerides. For this protocol ‘fasting’ will be defined as no 
intake of food or drink (except water) for at least 10 hours.  
 
Other Assessments 
7.5.1. Demographic Variables 
Demographic variables will be documented at visit 1 and include date of birth (in Germany, 
only age OR year of birth), gender and race (Asian, American Indian, Alaska Native, Black, 
Caucasian, Hispanic, Native Hawaiian, Hispanic, others).  
7.5.2. Pregnancy Test 
Pregnancy tests will be performed as specified in the SCHEDULE OF ACTIVITIES. Sites 
will receive test strips for the urine pregnancy tests from the central laboratory. The result of 
the urine pregnancy test must be available before trial medication is dispensed. During the 
week 0, visit 1, the medication will be dispensed after confirming the urine pregnancy test 
performed during EOT visit of MYL-GAI-3001 study is negative. 
7.5.3. Study Treatment Non-Compliance 
Patients will be identified as study treatment non-compliant if they meet any of the following 
criteria: 
• 
Missing either total meal time insulin or basal insulin doses for 5 consecutive 
days. 
• 
Missing either total meal time insulin or basal insulin doses for more than 30 
accumulative days for completer or more than 20% treatment days for drop-out  
• 
Taking more than one administration of basal insulin (If multiple injections are 
required to deliver the required quantity of drug due to logistic reasons, then it is 
considered as one administration) for 10 days cumulative  
• 
Taking more than the prescribed basal insulin dose for more than 30 days 
cumulative. 


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7.5.4. Dilated Ophthalmoscopy / retinal photography 
Dilated Ophthalmoscopy / Retinal photography testing should be performed once within one 
of the visits during the 28 days of enrolment.  
7.5.5. Patient Diary 
Patients will receive patient diaries as specified in the SCHEDULE OF ACTIVITIES. The 
following will be recorded by the patient in the diary: 
• Results of the 8-point SMBG measurements (on 3 days in the week before the next visit, 
of which 2 should be consecutive days) 
• Mylan’s insulin glargine/Lantus® and mealtime insulin doses on days where a 8-point 
SMBG is performed 
• Hypoglycemic events experienced by the patient  
• Adverse events experienced by the patient 
• Disposable pen and needle -related issues 
The Investigator will instruct the patient on the recording and measurement in detail of these 
assessments and will review the diary as specified in the SCHEDULE OF ACTIVITIES. 
During review the Investigator should assess patient compliance with the trial procedures and 
based on the results of the 8-point SMBG check if a dose adjustment is required. The entries 
in the patient diary will be transcribed into the eCRF by the Investigator or designee.  
7.5.6. Hypoglycemia  
Hypoglycemia is a state produced by a lower than normal level of glucose in the blood. This 
may develop, if for example:  
• The patient misses or delays meals or there is a change in diet  
• The patient takes a higher dose of trial drug than prescribed  
• The patient consumes alcohol  
• The patient does more intense or longer physical exercise or work than normal,  
• The patient is recovering from an injury, operation, fever or other illness, or from 
other forms of stress.  


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7.5.6.1. Classification 
A. Severe Hypoglycemia 
An event is considered as severe hypoglycemia if it requires the assistance of another person 
to actively administer carbohydrate, glucagon, or other resuscitative actions which results in 
neurological recovery, regardless of the availability of a blood glucose measurement. These 
episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. 
Plasma glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of normal plasma glucose is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration.    
B. Documented Symptomatic Hypoglycemia  
An event during which typical symptoms of hypoglycemia are accompanied by a measured 
plasma glucose concentration ≤70 mg/dL (3.9 mmol/L). 
C. Asymptomatic Hypoglycemia  
An event not accompanied by typical symptoms of hypoglycemia but with a measured 
plasma glucose concentration ≤70 mg/dL (3.9 mmol/L). 
D. Probable Symptomatic Hypoglycemia 
Characteristic symptoms of hypoglycemia with no blood glucose level measurement that 
resolved with food intake, subcutaneous glucagon, or intravenous glucose. 
E. Relative Hypoglycemia 
An event during which the patient reports any of the typical symptoms of hypoglycemia, and 
interprets the symptoms as indicative of hypoglycemia, but with a measured plasma glucose 
concentration > 70 mg/dL (3.9 mmol/L). 
F. Nocturnal Hypoglycemia 
Nocturnal hypoglycemia will include hypoglycemia that occurs from the time the patient 
goes to bed at night till the time he or she wakes up. This may include any of the above 5 
types of hypoglycemia.  


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Note: A diagnosis of severe hypoglycemia as per above classification will always be 
considered as a serious adverse event. Other hypoglycemic episodes which fulfils ICH 
criteria for seriousness (life-threatening, hospitalization etc.) or represent important medical 
events based on Investigator’s judgment should also be reported to sponsor within 24 hours. 
7.5.6.2. Identification of Hypoglycemia 
Symptoms of hypoglycemia include but are not limited to the following: palpitations, 
sweating, hunger, nervousness and shakiness, perspiration, dizziness or light–headedness, 
sleepiness, confusion, difficulty speaking, feeling anxious or weak. Neuroglycopenic 
manifestations may include seizure, coma, and even death. 
Patients will be instructed to be alert for signs and symptoms of hypoglycemia; and if 
possible to take glucose meter readings at the time of the episode and to record the details of 
the episode with any remedial action taken and the blood glucose level (if it was checked) in 
their diary. 
Investigators will instruct the patients on self-management of hypoglycemic episodes. 
Investigators will also instruct patients on remedial actions to be taken during the episodes of 
severe hypoglycemia. Patients will be encouraged to call the trial site if they experience 
hypoglycemia. 
7.5.6.3. Management of Hypoglycemia 
The following steps are recommended for managing hypoglycemic episodes:  
1. The patient should begin with 15 to 20 grams carbohydrate (e.g., 3-4 teaspoons of 
table sugar dissolved in water, 1 tablespoon of honey, ¾ cup of juice or regular soft 
drink, 3-4 glucose tablets).  
2. Subsequently, if the glucose level is ≤50 mg/dL, then the patient will be asked to 
consume 20 to 30 grams carbohydrate (e.g., 4-6 teaspoons of table sugar dissolved in 
water, 2 tablespoons of honey, 4/5 cup of juice or regular soft drink, 4-5 glucose 
tablets).  
3. Patient will be asked to recheck blood glucose after 15 minutes and to repeat 
hypoglycemia treatment if the blood glucose does not return to normal after 15 


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minutes. If the next meal is more than 1 hour away, patients should follow with 
additional carbohydrate or a snack.  
4. If hypoglycemia persists after the second treatment, patient or companion should be 
instructed to contact the Investigator.  
It is recommended that the patients always carry some sugar lumps, sweets, biscuits, or 
sugary fruit juice.  
For an event of severe hypoglycemia the patient can be treated with glucagon (0.5 to 1 mg) 
given intramuscularly or subcutaneously by a person who has received appropriate training, 
or glucose given intravenously by a medical professional. Intravenous glucose can also be 
given if the patient does not respond to glucagon within 10 to 15 minutes. Upon regaining 
consciousness administration of oral carbohydrate is recommended in order to prevent a 
relapse. 
Full hypoglycemic episode documentation includes time of occurrence, duration, time of 
recovery, remedial measures undertaken, recording the symptoms and plasma glucose / 
SMBG levels at the beginning and end of the episode with time and date, and classification 
in to different subtypes (Refer to section 7.5.6.1). 
7.5.6.4. Reporting of hypoglycemic episodes 
Hypoglycemic events and any associated symptoms are recorded only on the hypoglycemic 
episodes page of the CRF. Severe hypoglycemia and those episodes meeting any of the ICH 
seriousness criteria (section 8.2.4) are also to be notified as SAEs to the Mylan Global 
Product Safety and Risk Management department, as described in section 8.3.2.8; and 
entered on the SAE and AE pages. 
 ADVERSE EVENT REPORTING 
 
Adverse events 
All observed or patient-reported AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as outlined in this section.  
The Investigator must pursue and obtain information adequate both to determine the outcome 
of all AEs and to assess whether it meets the criteria for classification as an SAE requiring 


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immediate notification to Mylan (the term “Mylan” includes Mylan’s designated 
representative). The Investigator is required to assess causality and should obtain sufficient 
information to determine the causality of all AEs. All AEs will be followed till the event is 
resolved, deemed to be stable, or until the event is found to be due to another known cause 
(concurrent condition or medication) and clinical judgment indicates that further evaluation 
is not warranted with the sponsor concurring with that assessment.  
 
Definitions  
8.2.1. Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product that does not necessarily have a causal 
relationship with the product. An AE can therefore be any unfavorable and unintended sign 
(including a new, clinically important abnormal laboratory finding), symptom, or disease, 
temporally associated with drug administration, whether or not related to the product. 
The above definition covers also cases of  
• Exacerbation of pre-existing diseases or conditions. 
o Pre-existing diseases or conditions (reported at time of randomization in 
medical history) will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality of the disease or condition.  
Events occurring in patients treated with the active comparator are also considered AEs. An 
AE will be defined as a treatment-emergent adverse event (TEAE) if the first onset (or 
worsening, in the case of pre-existing disease) is after the first administration of Mylan’s 
insulin glargine or Lantus® after randomization through follow-up visit or 28 days after last 
dose [for patients that do not have a follow-up visit].  
8.2.2. Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose of the 
investigation products should be considered adverse drug reactions (ADRs). The phrase 
“responses to an investigational product” means that a causal relationship between an 
investigational product and an AE is at least a reasonable possibility. All AEs judged by 


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either the reporting Investigator or the sponsor as having a reasonable causal relationship to 
an investigational product will be designated as ADRs. 
All AEs, with the causal relationship to the trial drug reported as “possible”, “probable” or 
“definite” will be considered ADRs. If the relationship to the trial drug is not given, then the 
AE must be treated as if the relationship were “possible.” 
8.2.3. Unexpected Adverse Event/Adverse Drug Reaction 
An unexpected AE or ADR is defined as one whose nature or severity is not consistent with 
the applicable reference safety information designated for the trial. For example, hepatic 
necrosis would be unexpected (greater severity) if the IB only listed elevated hepatic 
enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (greater specificity) if the IB only listed cerebral vascular accidents. 
The reference safety document for Mylan’s insulin glargine is the Investigator’s Brochure. 
The reference safety documents for Lantus® will be the current US prescribing information 
[7].  
8.2.4. Serious Adverse Events 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. 
o NOTE: The term “life-threatening” in the definition of “serious” refers to an 
event in which the patient was at risk of death at the time of the event. It does 
not refer to an event which hypothetically might have caused death if it were 
more severe. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly. 
o NOTE: A congenital anomaly in an infant born to a mother who was exposed 
to the trial drug during pregnancy is considered an SAE. However, a newly 
diagnosed pregnancy in a patient that has received the trial drug is not 
considered an SAE unless it is suspected that the trial drug interacted with a 
contraceptive method and led to the pregnancy. The patient with newly 


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diagnosed pregnancy will discontinue receiving trial treatment and will be 
followed-up every 3 months until delivery or termination to gather 
information about the outcome of the pregnancy.  
• Is an important medical event. 
o NOTE: Important Medical Event: Medical and scientific judgment should 
be exercised in deciding whether it is appropriate to consider other situations 
serious, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient 
and / or may require intervention to prevent one of the other outcomes listed 
in the definition above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
o For this protocol, any cancer, including localized basal cell carcinoma, is 
considered an important medical event, to be reported as a SAE.  
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
o NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an 
overnight stay. Events NOT to be reported as SAEs are hospitalizations for 
the following:  
 Routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition.  
 Treatment, which was elective or pre-planned, for a pre-existing 
condition that is unrelated to the indication under trial and did not 
worsen. 
 Admission to a hospital or other institution for general care due to 
social or economic reasons (e.g., no access to local ambulatory 
medical care). 
 Treatment on an emergency, outpatient basis for an event not fulfilling 
any of the definitions of serious given above and not resulting in 
hospital admission. 
 
Hospitalization also does not include the following: 
• Rehabilitation facilities. 


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• Hospice facilities. 
• Respite care (e.g., caregiver relief). 
• Skilled nursing facilities. 
• Nursing homes. 
 
Any non-serious AE that is determined by the medical monitor/sponsor to be serious (per 
company policy or regulatory requirements) will be communicated to the Investigator for 
reclassification. To assist in the determination of case seriousness further information may be 
requested from the Investigator to provide clarity and understanding of the event in the 
context of the clinical trial. 
 
Management of Adverse Events 
AEs or SAEs will be collected from the time the patient signs the informed consent form 
until the end of the follow-up visit or phone-visit. Pre-existing diseases or conditions 
(reported at visit 1 in medical history) will not be considered AEs unless there is an increase 
in the frequency or severity, or a change in the quality of the disease or condition. An SAE 
deemed related to the trial drug by the Investigator in consultation with sponsor will be 
reported even after the follow-up visit if reported by patients. AEs and SAEs would also be 
recorded at phone calls. All SAEs should be immediately (within 24 hours) reported as per 
Section 8.3.2.8. 
8.3.1. Collection 
The Investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an AE or SAE, as described previously. At each visit, the patient 
will be allowed time to spontaneously report any issues since the last visit or evaluation. The 
Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions, 
such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 


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Any clinically relevant observations made by the Investigator during the visit will also be 
considered AEs. 
The patient’s diary should also be reviewed at each trial visit for adverse events. At week 0 
visit when trial diaries are issued, patients will be appropriately educated by the trial designee 
on what constitutes an adverse event and instructed to record adverse events in the trial diary 
in a timely manner.  
8.3.2. Evaluation 
8.3.2.1. Severity Assessment of Adverse Events 
The clinical severity of an AE will be graded using the NCI-CTCAE Criteria Version 4.03. A 
copy of these criteria will be provided to each trial site. If an AE is not listed in the CTCAE, 
its clinical severity will be classified as follows: 
Table 6: Clinical Severity of Adverse Events 
The Investigator will use the terms defined below to describe the maximum intensity of the AE.  
Grade 1 – MILD 
Does not interfere with patient's usual function. 
Grade 2 – MODERATE 
Interferes to some extent with patient's usual function. 
Grade 3 – SEVERE 
Interferes significantly with patient's usual function. 
Grade 4 - LIFE-THREATENING 
Risk of death at time of event 
Grade 5 – DEATH 
Death related to AE  
 
If an AE is graded 4 or 5 according to the above criteria, then the AE meets the criteria for an 
SAE and the Investigator should immediately notify the sponsor or designee as described in 
section 8.3.2.8.  
It is important to distinguish between severe AEs and SAEs. Severity is a classification of 
intensity based on the CTCAE grading or on the above table, whereas an SAE is an AE that 
meets any of the regulatory specified criteria required for designation as seriousness 
described in section 8.2.4. 
8.3.2.2. Action Taken 
The possible actions taken for an AE are described in Table 7. 


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Table 7: Action Taken for an Adverse Event 
Dose reduced  
The dose regimen was reduced by changing its frequency, strength, or 
amount. 
Dose increased 
The dose regimen was increased by changing its frequency, strength, or 
amount. 
Treatment interrupted 
The treatment was temporarily interrupted. 
Treatment withdrawn 
The treatment was permanently discontinued.  
Concomitant therapy or 
procedures 
Treatment was needed as a result of the AE (the concomitant treatment 
should be recorded on the relevant page of the CRF). 
Unknown 
Not known, not observed, not recorded, or refused. 
No action taken 
The AE did not require any intervention. 
Not applicable 
AE occurred after study medication was permanently withdrawn or 
patient completed the treatment period. 
8.3.2.3. Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
All ongoing AEs without fatal outcome (i.e. did not cause death) will be recorded as not 
recovered/not resolved at the time of death. 
*Only select fatal as an outcome when the AE results in death. If more than one AE is 
possibly related to the patient’s death, the outcome of death should be indicated for the AE 
which is the most plausible cause of death in the opinion of the Investigator.  
Note: although “fatal” is usually an event outcome, events such as sudden death or 
unexplained death should be reported as SAEs.  
8.3.2.4. Causality Assessment of Adverse Events 
An Investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE. The 
Investigator must make an assessment of the relationship of each AE (serious and 
non-serious) to the trial treatment(s) and record this relationship in the CRF. 


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In addition, if the Investigator determines an AE or SAE is associated with trial procedures, 
the Investigator must record this information about the causal relationship in the source 
documents and CRF, as appropriate, and report the assessment in accordance with the 
reporting requirements, as applicable, AE or SAE. 
Factors that need to be considered when making a causality assessment include: 
• Temporal relationship (e.g., time of onset) 
• Clinical and pathological characteristics of the event(s) 
• Pharmacological plausibility 
• Exclusion of confounding factors (medical and medication history) 
• Drug Interactions 
• De-challenge/re-challenge 
• Dose relationship 
 
A suspected relationship (definite, probable, and possible) between the events and the trial 
medication means, in general, that there are facts (evidence) or arguments to suggest a causal 
relationship. Receipt of additional or clarifying information may warrant reassessment of 
causality. The Investigator is responsible for assessing relationship of AEs to trial treatment 
in accordance with the following definitions: 
Table 8: Definition of Suspected Relationship between the Events and Trial Medication 
DEFINITELY 
Causal relationship is certain 
For Example: the temporal relationship between 
drug exposure and the adverse event (AE) 
onset/course is reasonable, there is a clinically 
compatible response to de-challenge, other causes 
have been eliminated; the event must be definitive 
pharmacologically or phenomenologically, using a 
satisfactory re-challenge procedure if necessary. 
PROBABLY 
High degree of certainty for 
causal relationship 
For Example: the temporal relationship between 
drug exposure and AE onset/course is reasonable, 
there is a clinically compatible response to de-
challenge (re-challenge is not required), and other 
causes have been eliminated or are unlikely. 
POSSIBLY 
Causal relationship is 
uncertain 
For Example: the temporal relationship between 
drug exposure and the AE onset/course is 
reasonable or unknown, de-challenge information 
is either unknown or equivocal, and while other 
potential causes may or may not exist, a causal 
relationship to study drug does not appear probable 
UNLIKELY 
Not reasonable related 
For Example: Event or laboratory test abnormality, 


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although a causal relationship 
cannot be ruled out 
with a time to drug intake that makes a relationship 
improbable (but not impossible), or disease or other 
drugs provide plausible explanations 
UNRELATED/NOT 
RELATED 
No possible relationship 
The temporal relationship between drug exposure 
and the AE onset/course is unreasonable or 
incompatible, or a causal relationship to study drug 
is impossible 
 
If the relationship to the trial treatment(s) is considered to be unlikely or not 
related/unrelated, an alternative suspected etiology should preferably be provided (e.g., 
concomitant medications, intercurrent condition) wherever applicable and available. 
8.3.2.5. Documentation 
All AEs occurring within the period of observation for the trial must be documented in the 
CRF with the following information; where appropriate (the period of observation for the 
study is described in Section 8.3): 
• AE name or term in standard medical terminology. 
• When the AE first occurred (start date and time); SAE start date is defined as the date 
the AE became serious. 
• When the AE stopped (stop date and time or date and time of last observation if 
ongoing, i.e., recovering or not recovered). 
• Severity of the AE. 
• Seriousness criteria (hospitalization, death, etc.). 
• Action taken with trial medication as a result of AE. 
• Outcome. 
• Investigator’s opinion regarding the AE relationship to the trial treatments. 
Hypoglycemic events and associated signs/symptoms will only be recorded on the 
hypoglycemic episodes page of the CRF, unless they are SAEs. 
8.3.2.6. Treatment of Adverse Events 
AEs that occur during the trial will be treated, if necessary, by established standards of care. 
If such treatment constitutes a deviation from the protocol, the reason should be documented 
in the CRF; this can include temporary interruption of trial treatment. The decision about 
whether the patient may resume the trial treatment will be made by the sponsor after 
consultation with the Investigator and/or medical monitor. 


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8.3.2.7. Follow-up 
Any AE will be followed-up to a satisfactory resolution, until it becomes stable, or until it 
can be explained by another known cause (i.e., concurrent condition or medication) and 
clinical judgment indicates that further evaluation is not warranted. All findings relevant to 
the final outcome of an AE must be reported in the patient’s medical record and recorded on 
the appropriate CRF page. 
8.3.2.8. Notification 
For SAEs, the active reporting period to Mylan, begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the trial, 
i.e., prior to undergoing any trial-related procedure and/or receiving investigational product, 
through and including the follow up visit. Should an Investigator be made aware of any SAE 
occurring any time after the active reporting period, the SAE must be promptly reported to 
Mylan only in case of reasonable causality (i.e. suspected ADR). 
The SAE reporting form (paper form only) is to be completed for all serious adverse events, 
signed by the Investigator, and emailed or faxed with supporting documentation (e.g., CRFs, 
hospital records, laboratory reports). Patient identity details (such as but not limited to name 
or clinic/hospital number) must not be visible on SAE forms or any supporting 
documentation provided by the Investigator. These should be “blacked out”, and replaced 
with the site and patient’s trial identification number on every page. 
At that time of first notification, the Investigator/designee should provide the following 
information via the SAE report form:  
• Protocol number 
• Reporter (trial site and Investigator) 
• Suspected trial treatment 
• Patient’s trial number  
• SAE term 
• The seriousness criteria that were met 
• Investigator’s opinion of the relationship to the trial treatments 
• Severity 


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• Patient’s age 
• Date of first dose of trial treatment 
• Date of last dose of trial treatment, if applicable 
• Start and stop (if applicable) of the event (date and time) 
• A brief description of the event, outcome to date, and any actions taken 
• Concomitant medication at onset of the event 
• Relevant past history information 
• Relevant laboratory test findings 
 
If the initial notification of an SAE is by telephone, within 24 hours of the initial telephone 
notification the Investigator must email the written SAE report form that describes the SAE 
to the Mylan Global Product Safety and Risk Management department. 
The Investigator may be requested by Mylan to obtain specific additional follow-up 
information in an expedited fashion. This information collected for SAEs is more detailed 
than that captured on the AE CRF. In general, this will include a description of the SAE in 
sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality. Information on other possible causes of the event, such 
as concomitant medications and illnesses must be provided. In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Mylan.  
Any missing or additional relevant information concerning the SAE should be provided on a 
follow-up SAE Report Form. Ensure that any additional information requested by the 
sponsor or designee about the event, as outlined above (e.g., hospital reports, autopsy report) 
is provided to the sponsor as soon as it is available. 
Sponsor Contact Information for Immediately Reportable Events 
Email is the preferred method of communication. 
All SAEs must be notified within 24 hours to:  
Global Product Safety & Risk Management, Mylan 
PV MAIL HUB FOR IMMEDIATE SAFETY REPORTS: 
pvclinical@mylan.com 
In case an acknowledgment is not received within 24 hours, forward via 


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Fax +1.304.285.6409  
8.3.2.9. Regulatory Reporting 
All AEs, including suspected serious unexpected AEs will be reported in accordance with 
applicable local regulations. The Investigator is required to comply with applicable 
regulations (including local law and guidance) regarding notification to her/his regulatory 
authorities, ethics committees (ECs) and institutions. 
Suspected unexpected serious adverse reactions (SUSARs), SAEs and other cases required 
by the concerned competent authorities will be reported by the sponsor or the sponsor’s 
representative to all concerned parties within the prescribed timeframe. The sponsor or 
representative will also submit periodic safety reports (for e.g., Development Safety Update 
Reports) as required by international regulations. 
 
Special Situations 
The Investigator should report any case of pregnancy within 24 hours via the pregnancy 
report form. Pregnancy exposures must be followed until a final outcome is determined (e.g., 
parturition, spontaneous or scheduled termination). 
8.4.1. Pregnancy 
All women of childbearing potential who participate in the trial should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during 
trial participation. Women should be instructed to contact the Investigator immediately if 
pregnancy occurs or is suspected. 
Pregnancy testing will be conducted throughout the trial, as detailed in the schedule of 
assessments. A woman who is found to be pregnant at the week 0 visit will be excluded from 
the trial. A woman who becomes pregnant during the trial will be immediately discontinued 
from trial treatment. Early discontinuation visit assessments should be performed as soon as 
possible after learning of the pregnancy. This information should be captured in the 
pregnancy form and reported to Mylan Global Product Safety and Risk Management within 
24 hours from the time of initial knowledge, even if beyond the closure of the clinical 
database.  


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While pregnancy itself is not considered an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or an 
SAE. A spontaneous abortion is always considered to be a SAE and will be reported to the 
sponsor within 24 hours of knowledge of the event. 
Elective termination (i.e., without medical reasons) of an uncomplicated pregnancy is 
considered to be an elective procedure and not an AE, nevertheless, Mylan requests that the 
outcome (e.g., elective termination) be reported within 24 hours and sent as a follow-up on 
the Delivery and Infant Follow-up Form).  
The Investigator is also responsible for following up the pregnancy at 3 monthly intervals 
until delivery or termination, informing the sponsor about its outcome.   
8.4.2. Overdose, Medication Errors and Other Events 
Overdose per se of either study treatment or a concomitant medication will not be reported as 
an AE; unless it is an intentional overdose taken with possible suicidal/self-harming intent. 
Signs, symptoms, and clinical sequelae associated with intentional overdose are to be 
recorded on the AE CRF page. Dosing and other medication errors are to be recorded as 
protocol deviations. 
 
Abnormal Test Findings  
Abnormal laboratory findings per se (e.g., clinical chemistry, hematology) or other abnormal 
assessments (e.g., ECG, X-rays, and vital signs) are not reported as AEs. However, abnormal 
findings that are deemed clinically significant or are associated with signs and/or symptoms 
must be recorded as AEs if they meet the definition of an AE (and recorded as an SAE if they 
meet the criteria of being serious). Clinically significant abnormal laboratory or other 
abnormal findings that are detected after trial drug administration or that are present at 
baseline and worsen following the administration of trial drug are included as AEs (and 
SAEs, if serious). The Investigator should exercise his or her medical judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. Broad guidance for determining whether an abnormal objective test finding 
should be reported as an AE follows:  
• The test result is associated with accompanying symptoms and/or 


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• The test result requires additional diagnostic testing or medical/surgical intervention 
and/or 
• The test result leads to a change in trial dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the trial, additional concomitant drug treatment, 
or other therapy; and/or 
• The test result is considered to be an AE by the Investigator or sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute 
an AE.   
Any abnormal test result determined by retest to be an error does not require reporting as an 
AE. 
 DATA ANALYSIS/STATISTICAL METHODS 
 
Sample Size Determination   
Approximately 138patients with type 1 diabetes will participate in this trial. Approximately 
69 patients will be randomized to one of the two sequence groups (Mylan sequence group: 
Mylan’s insulin glargine switch to Lantus® sequence group and switch back to Mylan’s 
insulin glargine or Lantus Sequence Group: Lantus® to Lantus® to Lantus® sequence group) 
in a 1:1 ratio. No replacement of patient will be performed if patient discontinued 
prematurely from the study. For the modified intent-to-treat (mITT) population, power to 
demonstrate equivalence with ±0.4% limits will be 90% with 10% patients who don’t have at 
least one baseline and one last period HbA1c data. The power is calculated assuming no true 
mean group difference and a 0.61% standard deviation. This standard deviation is based on 
published results for clinical studies with Lantus® [12]. 
 
General Considerations 
Statistical analysis of this trial will be the responsibility of Mylan or designated clinical 
contract organizations. 
Any change to the data analysis methods will be mentioned in the statistical analysis plan. 
Any additional analysis, and the justification for making the change, will be described in the 
clinical study report. Additional exploratory analyses of the data will be conducted as 
deemed appropriate. 


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For the statistical analysis, baseline is visit 1, which includes the post study measurements of 
the main study MYL-GAI-3001. 
9.2.1. Primary End Point 
The HbA1c difference of change from baseline between two periods at 12 weeks from week 
36.  If week 36 HbA1c is missing then last non-missing values from period 3 will be used.      
9.2.2. Study Population 
The primary analysis will be based on the mITT population.  
• The ITT population includes all randomized patients (including patients who receive 
incorrect treatment, do not complete the trial or do not comply with the protocol or 
used prohibited medication) and have baseline (week 0 visit) and at least one post-
baseline value. ITT population will be used for secondary variable analyses. 
• The mITT population includes all randomized patients (including patients who 
receive incorrect treatment, do not complete the trial or do not comply with the 
protocol or used prohibited medication) and have at least one baseline (week 0 visit) 
HbA1c value and one post-baseline HbA1c value at treatment period 3. The mITT 
will be used for primary analysis. 
• Per Protocol (PP) population. The PP population includes patients who complete at 
least one baseline and one period 3 values and do not have protocol violations that 
impact the primary outcome. The subjects excluded from the PP population will be 
identified before database lock.  PP population will be used for sensitivity analysis for 
primary variable.  
 
• The safety population includes patients who take at least one dose of the trial 
medication. For safety analyses, patients will be categorized according to the 
treatment that they actually received. Safety population will be mainly used for safety 
population. 
9.2.3. Handling Missing Values 
No missing data will be imputed  


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9.2.4. Pooling 
No data pooling will be performed. 
9.2.5. Multiplicity Adjustment  
No adjustment for multiplicity will be performed. 
9.2.6. Statistical Methods 
For primary endpoint analysis, equivalence for efficacy will be supported if the two sided 
95% confidence interval for the difference of mean between two sequence groups (endpoint 
of change from baseline of Mylan sequence group minus endpoint of Lantus sequence) for 
HbA1c is within ±0.4%. 
For sequence comparison analysis for continuous variables, analysis of covariance 
(ANCOVA) will be used (unless otherwise specified) with the terms of geographic region 
and sequence group as fixed effects and baseline value as covariate in the model. For 
continuous variables with more than one measurements within period, a repeated measures 
analysis employing a restricted maximum likelihood (REML)-based, mixed-effects model 
approach (MMRM) will be used for treatment comparison. For continuous variables without 
baseline value, analysis of variance will be used (unless otherwise specified). The baseline 
values for this study are the measurements after 52 weeks in MYL-GAI-3001. Paired t-test 
will be performed for change from baseline comparisons for each post-baseline visits. For 
categorical data analyses, Fisher’s exact or Chi-squared tests will be used. All tests of 
treatment effects will be conducted at a two-sided alpha level of 0.05 or with 2-sided 95% 
confidence intervals. 
 
Patient Disposition 
The percent of randomized patients who completed the trial or discontinue early will be 
summarized for each sequence group. The comparison of patient discontinuations across 
sequence groups will be performed using the Fisher’s exact test.  


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Protocol Violation 
A list of significant protocol violations will be provided. A summary by sequence group at 
each period will also be provided, and sequence group comparison will be performed using 
the Fisher’s exact test. Other protocol deviations will be listed in the appendices. 
 
Patient Characteristics 
Patient characteristics will be obtained at the week 0 visit; and will be listed and summarized 
by sequence group, and overall. The summaries will include descriptive statistics for 
continuous and categorical measures. Parameters will be compared by sequence group using 
a two sample t-test for continuous measures. A Pearson's chi-square test or Fisher’s exact test 
will be used to test categorical measures. Patient characteristics include but are not limited to: 
age, gender, origin, race, weight, body mass index, duration of diabetes, baseline HbA1c and 
baseline fasting plasma glucose. 
 
Concomitant Medication 
Categorical use of concomitant medication taken by at least 10% patient and overall will be 
summarized by treatment. All concomitant medications used will be listed. Sequence groups 
will be compared by Chi-squared test.  
 
Primary Efficacy Analysis 
The primary endpoint is change from baseline in HbA1c value at 36 weeks. ANCOVA will 
be performed; and the model will include region and sequence group as fixed effect and 
baseline value (52 weeks in MYL-GAI-3001) as covariate using mITT population. The 
ANCOVA will produce a 95% confidence interval for the difference between two treatment 
sequence groups for mean change from baseline HbA1c at endpoint. Equivalence of Mylan’s 
insulin glargine to Lantus® will be established if the 95% confidence interval is within ±0.4% 
equivalence limits. Descriptive statistical summaries for actual measurements and change 
from baseline will be displayed by visit and endpoint for each sequence group using ITT 
population.   
In order to check the sensitivity of the result, primary analysis will be also performed on PP 
population using same model mentioned above. 
 


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Secondary Efficacy Analyses 
In addition to the primary efficacy analysis for HbA1c, the following efficacy measures (both 
actual and change in values) will be summarized for each sequence at each post-baseline 
visits. Sequences will be compared using the MMRM ANCOVA model (similar to HbA1c 
analysis). The dependent variable will be the differences of change from baseline between 
two periods. The MMRM model will include the fixed, categorical effect of region and 
sequence group, visit, sequence group-by-visit interaction and the other as fixed effect terms 
region, and baseline value as covariates.  
Descriptive statistical summaries for actual values and change from baseline will be 
displayed by visit and endpoint for each sequence group. ITT population will be applied to 
secondary efficacy analyses. 
• Fasting plasma glucose; 
• SMBG value: individual pre-meal, individual post-meal, individual 2-hour excursion 
after meal, bedtime, overall (average) pre-meal, overall post-meal, overall excursion, 
4-point average (pre-meal + bedtime), and daily average;  
• Daily prandial insulin, basal insulin, and total insulin dose (U/kg) for days of 8-point 
profiles.  
 
Safety Analyses 
Safety analysis will be based on safety population which includes all enrolled patients who 
take at least one dose of trial medication. 
9.9.1. Treatment Exposure 
Total treatment duration days will be summarized for each sequence arm. The sequence 
group will be compared using t-test.  
9.9.2. Immunogenicity Profiles Analyses 
Continuous immunogenicity variables such as cross-reacting antibodies percent binding will 
be analyzed using the MMRM ANCOVA model, similar to the primary and secondary 
efficacy analyses.  The model will include the fixed, categorical effect of region and 


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sequence group, visit, sequence group-by-visit interaction and the other as fixed effect terms 
region, and baseline value as covariates.  The p-value for sequence difference and 95% 
confidence interval will be constructed. If the normal distribution assumption is severely 
violated, then non-parametric analysis will be performed using Wilcoxon rank-sum test for 
sequence comparison.  
Descriptive statistical summaries for actual measurements and change from baseline will be 
displayed by visit for each sequence group. For categorical variables such as ADA positive 
and negative, frequency table will be presented by visit for each period for each sequence. 
Fisher’s exact test will be used for sequence comparison by visit. 
9.9.3. Hypoglycemia Analyses 
Hypoglycemia rate per patient per 30 days will be analyzed using MMRM ANCOVA model 
secondary for sequence group comparison. The model will include the fixed, categorical 
effect of region and sequence group, visit, sequence group-by-visit interaction and the other 
as fixed effect terms region, and baseline value as covariates.  The p-value for sequence 
difference and 95% confidence interval will be constructed.  The rate per patient per 30 days 
calculated between two visits is defined as total number of episodes between two visits 
divided by the number of days between the visits, multiplied by 30 days. This rate will also 
be calculated per patient for nocturnal hypoglycemia episodes. In case the normal 
distribution assumption is severely violated, then non-parametric analysis will be performed 
using Wilcoxon rank-sum test for sequence group comparison. 
Incidence of all hypoglycemic episodes and nocturnal hypoglycemic episodes will be 
presented by sequence group by visit for each period. The incidence of hypoglycemic 
episodes during visit time period on treatment is defined as the incidence of patients with at 
least one hypoglycemic episode occurring within that period of time. Fisher’s exact test will 
be used for sequence comparison by visit. 
Listings of hypoglycemic episodes and severe hypoglycemic episodes will be presented by 
visit for each patient. If a sufficient number of severe hypoglycemic episodes are reported, 
then incidence summaries similar to the incidence of hypoglycemic episodes will be 
included. 


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9.9.4. Adverse Event Analyses 
The evaluation of adverse events will include assessments of TEAEs and SAEs. 
The incidence of TEAEs will be summarized to include only one occurrence of a PT per 
patient per treatment period. If a patient reports multiple occurrences of the same PT and 
treatment period, then that PT will only be counted once. As with the PT, if a patient reports 
multiple TEAEs within the same SOC and treatment period, that SOC will only be counted 
once. Incidence of TEAEs will be presented by treatment sequence. The incidence of TEAE 
by severity and relation to study drug will also be summarized by treatment sequence. The 
incidence of both local and systemic allergic reaction-related TEAEs will be also 
summarized separately by SOC and treatment period for each sequence group. Fisher’s exact 
test will be used for sequence comparison by visits. 
9.9.5. Vital Signs 
Change from baseline for vital signs will be analyzed using MMRM method similar to the 
secondary efficacy variables the ANCOVA model for sequence group comparison. The 
model will include the fixed, categorical effect of region and sequence group, visit, sequence 
group-by-visit interaction and the other as fixed effect terms region, and baseline value as 
covariates.  The p-value for sequence difference and 95% confidence interval will be 
constructed using the same model for the combined periods.  The summary statistics 
including actual measurement and change from baseline will be displayed at each visit for 
each sequence group.  
9.9.6. Laboratory Measurement 
Change from baseline for laboratory evaluations will be analyzed using similar ANCOVA 
model for primary analysis for treatment sequence comparison. The summary statistics 
including actual measurement and change from baseline will be displayed at each visit for 
each sequence group.  
9.9.7. ECG 
Summary of frequency table of percentage of patients in categories such as abnormal/non-
clinically significant and abnormal/clinically significant will be presented by visit and 
sequence group.  


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9.9.8. Device Safety Assessment 
The total incidence of device-related safety events will be summarized with each sequence 
arms, per treatment arm, at each period both for device-related TEAEs and for events related 
to device complaints or failures. 
 
Subgroup Analyses 
No subgroup analysis will be planned.  
 QUALITY CONTROL AND QUALITY ASSURANCE 
This trial will be audited by the sponsor or sponsor’s designees to check compliance with 
GCP guidelines. The sponsor or designee may conduct audits on any selected trial sites, 
requiring access to patient notes, trial documentation, and facilities or laboratories used for 
the trial. 
Monitoring and auditing procedures are described in the following sections. 
 
Study Monitoring  
Before the start of the trial at a study site, an initiation visit or phone call will be conducted 
by the monitor. During the trial the monitor will visit the site to review the implementation of 
the center’s processes associated with but not limited to: 
• Completion, consistency, and accuracy of entries in the eCRFs 
• Source data verification 
• Progress of enrollment 
• Adherence to the protocol and to GCP  
• Proper storage, dispensing, and accounting of trial medication as specified in the 
protocol 
The Investigator and key site personnel must be available to assist the monitor during these 
visits. 
The Investigator must maintain source documents for each patient in the trial, as well as other 
trial documents, as specified in section 11.2. No patient identification information will leave 
the trial center. 


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In the case of electronic health records, the Investigator must give the monitor access to all 
relevant source documents to confirm consistency with the eCRF entries. Monitoring will be 
performed according to the monitoring plan for this trial.  
The Investigator (or his or her staff) is responsible for completing the eCRFs and the monitor 
is responsible for reviewing them and for clarifying and assisting in resolving any data 
queries.  
 
Audits and Inspections 
Quality assurance personnel may conduct audits to evaluate compliance with the principles 
of GCP.  
If an inspection is requested by a regulatory authority or competent authority (during the trial 
or after its completion), the Investigator must inform the sponsor immediately. 
If an audit or inspection occurs, the Investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the 
time of his/her staff to the auditor/inspector to discuss findings and any relevant issues. 
Participation as an Investigator in this trial implies acceptance of potential inspection by 
regulatory authorities. 
 DATA HANDLING AND RECORD KEEPING 
 
Electronic Case Report Forms 
Before a trial is initiated the sponsor’s representative will review the protocol and eCRF with 
the Investigators and the study staff. 
By signing the Investigator’s Agreement, the Investigator agrees to maintain accurate eCRFs 
and source documentation as part of the case histories for all patients who sign an ICF. 
Investigator sites will be provided with access to the eCRF system, which has been fully 
validated and conforms to 21 Code of Federal Regulations Part 11 requirements. The site 
staff will be trained on the use of the eCRF including trial specific details before they are 
able to enter the trial data. Investigational staff will not be given access to the eCRF until 
they have been trained and assessed as competent to use the system. 
Designated investigational staff will enter all requested information (including 
information entered into the diaries by the patients) required by the protocol into the eCRFs. 


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To ensure data accuracy, eCRF data for individual patient visits should be completed as soon 
as possible after the visit. Automated data validation software will check for data 
discrepancies in the eCRFs and, by generating appropriate error messages, allow 
modification or verification of the entered data by the investigational staff. The monitor will 
perform data verification and will document this electronically in the eCRFs. The 
Investigator or designee must certify that data are complete and accurate within the system 
by providing electronic approval of the eCRF pages. A reasonable explanation must be given 
by the Investigator or authorized staff for all missing data. Queries will be sent to the 
investigational site through the eCRF system. Designated Investigator site staff are required 
to respond to the queries and make any necessary changes to the data.  
Concomitant medications entered into the database will be coded using the WHO Drug 
Dictionary, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history or current medical conditions and AEs will be coded using MedDRA 
terminology. 
Corresponding source documentation must support all information recorded in the eCRF. 
Examples of acceptable source documentation include, but are not limited to, hospital 
records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records.  
Clinical laboratory data required by the protocol will be electronically transferred from the 
central laboratory to the sponsor or designee. Laboratory results will be provided to the trial 
site and should be retained with each patient’s source data.   
 
Record Retention 
Data on patients collected on eCRFs will be documented in an anonymous fashion and the 
patient will only be identified by the patient number. 
At the end of the trial, the Investigator will receive a copy of the data entered into the eCRF 
for his or her site. The Investigator will retain the study documents for at least 15 years or as 
per local laws (whichever is longer). At the end of that period, the Investigator shall notify 
the sponsor in writing of her/his intent to destroy all such material. The sponsor shall have 
30 days to respond to the Investigator’s notice; the sponsor may request that the site retains 


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the materials for a longer duration, at the sponsor’s expense. Source documents should be 
retained according to local laws and institution requirements.   
 
Data Confidentiality 
All data generated from the trial will be regarded as confidential. The monitor(s), the 
auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the 
patient’s original medical records for verification of trial procedures and/or data, without 
violating the confidentiality of the patient, to the extent permitted by the applicable laws and 
regulations and that, by signing a written ICF, the patient or the patient's legally acceptable 
representative will be authorizing such access. The records identifying the patient 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 trial are published, the patient's identity 
will remain confidential. All data (whether medical or laboratory) generated in the course of 
the trial will remain the property of the sponsor.  
 
Source Data Access  
Direct access to source data or documents will be permitted during trial-related monitoring, 
audits, IRB/IEC review and regulatory inspection(s). 
 
Responsibilities Related to Devices 
11.5.1. Investigator Records and Reports (See Appendix V - Letter of Approval of Pen Use 
by the Investigator) 
According to the 21 CFR 812.140 and 150 a participating Investigator shall maintain the 
following accurate, complete, and current records relating to the Investigator's participation 
in an investigation: 
• Record of receipt, use or disposition of a device that relate to: 
 The type and quantity of the device, the dates of its receipt, and the batch number 
or code mark 
 The names of all persons who received, used, or disposed of each device 
 Why and how many units of the device have been returned to the sponsor, 
repaired, or otherwise disposed of 
• Documents evidencing informed consent and, for any use of a device by the 
Investigator without informed consent, any written concurrence of a licensed 


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physician and a brief description of the circumstances justifying the failure to obtain 
informed consent. The case history for each patient shall document that informed 
consent was obtained prior to participation in the trial. 
• An Investigator shall prepare and submit the following complete, accurate, and timely 
reports: 
 An Investigator shall submit to the sponsor and to the reviewing IRB a report of 
any unanticipated adverse device effect occurring during an investigation as soon 
as possible, but in no event later than 10 working days after the Investigator first 
learns of the effect. 
 An Investigator shall report to the sponsor, within 5 working days, a withdrawal 
of approval by the reviewing IRB of the Investigator's part of an investigation. 
 If an Investigator uses a device without obtaining informed consent, the 
Investigator shall report such use to the sponsor and the reviewing IRB within 5 
working days after the use occurs. 
 An Investigator shall, upon request by a reviewing IRB or FDA, provide accurate, 
complete, and current information about any aspect of the investigation. 
Please see Appendix V for instructions regarding the prohibition of promotion and other 
practices and a format for the letter of approval of pen use by the Investigator (for US sites 
only). 
 
PROTOCOL AMENDMENTS, DEVIATIONS AND COMPLIANCE 
Investigators should ascertain that they will apply due diligence to avoid protocol deviations. 
No waivers to the protocol will be given by the sponsor.  
All significant protocol deviations will be recorded and reported in the CSR main body. 
These will include variable deviations, for example: 
1. Patient not meeting selection criteria but still included in the study 
2. Patient continued in the study despite meeting study discontinuation criteria 
3. Failure to perform tests or procedures which will impact the interpretation of key 
endpoints (e.g. safety, efficacy, immunogenicity endpoints) of the study 
4. Patient not following treatment regimen mentioned in the protocol 


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5. Patient taking medications which are prohibited by the protocol, or can have impact 
on key endpoints of the study 
6. GCP not followed. 
With respect to inadequate documentation or conduct of SMBG, the following rules will be 
followed to determine deviations: 
• In any given week, if there are missing values for SMBG AND the Investigator 
documents that the patient is non-compliant, a protocol deviation (for that visit) will 
be recorded; and listed in the main body of the CSR (as well as in the CSR 
appendices). 
• In any given week, if there are missing SMBG values without accompanying 
documentation of non-compliance by the Investigator, a protocol deviation (for that 
visit) will be recorded; but listed only in the CSR appendices, and not in the main 
body. 
Any change to the protocol can only be made in the form of a written amendment to the trial 
protocol. Depending on the local regulatory requirements, the amendment must be approved 
by the national authority and/or IEC/IRB before the amendment is implemented.  
Only amendments that are required for patient safety may be implemented prior to IEC/IRB 
approval. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any patient included in this 
trial, even if this action represents a violation of the protocol. In such cases, the sponsor 
should be notified of this action immediately. 
 ETHICS 
 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Before the start of the study, the protocol, written ICF, and/or other appropriate documents 
will be submitted to and approved by the IRB/IEC and/or the competent authorities, in 
accordance with local legal requirements. The study will not commence until written 
confirmation of their approval has been received by the sponsor or designee. No clinical 
supplies may be sent to the study sites until the relevant approvals from the IRB/IEC and 
competent authorities have been obtained. 


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No patient may undergo any procedure solely for determining eligibility for this trial until the 
Investigator has received written approval by the IRB/IEC and the regulatory authority. 
 
Ethical Conduct of the Study 
The trial will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subject (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2013). In addition, the trial will be conducted in accordance with the 
protocol, and applicable local regulatory requirements and laws. 
 
Patient Information and Consent 
All parties will ensure protection of patients’ personal information. Patient names will not be 
included on any forms, reports, publications, or in any other disclosures to the sponsor. 
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. The informed consent document to be used in this trial, 
and any changes made during the course of the trial, must be prospectively approved by both 
the IRB/IEC and the sponsor or designee before use.  
According to the Declaration of Helsinki, and ICH-GCP, patients must provide their written 
informed consent prior to enrollment in a clinical trial and before any protocol-specified 
procedures are performed. Patients must declare their consent by personally signing and 
dating the informed consent form (ICF).  
The patient will also be informed that if she/he wishes to withdraw (see section 6.2) at any 
time during the trial this will not have any negative consequences to further treatment at the 
investigational site. 
 DEFINITION OF END OF TRIAL 
The end of this trial is defined as the date of the last visit of the last patient participating in 
the trial (last patient out or last patient last visit). Within 90 days of the end of the clinical 
trial the sponsor or designee will notify the ECs and regulatory authorities on the completion 
/ termination of the trial as required according to law and regulation.   


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End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and have completed the trial as stated in 
the regulatory application (i.e., clinical trial application [CTA]) and ethics application in the 
Member State). Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the trial in that Member State. 
 
End of Trial in all Other Participating Countries  
End of trial in all other participating countries is defined the date and time of the last patient 
(patient) last visit.  
 SPONSOR DISCONTINUATION CRITERIA 
The sponsor is entitled to terminate the study: 
• 
In case there is evidence that the safety of the trial participants is no longer assured. 
• 
In case the 3001 study interim analysis affects the current favorable patient risk 
benefit relationship. 
Should this be necessary, the sponsor will promptly notify the Investigators; and the 
Investigators will be informed of the procedures to be followed to assure that adequate 
consideration is given to the protection of the patient’s interest.  
Pursuant to law and regulation, the sponsor or Investigator will notify IRB/IECs and 
regulatory authorities within 15 days of premature termination of the trial, clearly explaining 
the reasons for premature termination. After notification, the Investigator must contact all 
participating patients and the hospital pharmacy (if applicable) within 30 days. Trial sites 
may be asked to have all patients currently participating in the trial to complete all 
assessments for an early termination visit. As directed by the sponsor, all trial materials must 
be collected and all eCRFs completed as far as possible. 
A specific site may be terminated for unsatisfactory patient enrolment (as long as there are no 
active recruited patients), insufficient quality, or for improper data recording. 


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MYLAN CONFIDENTIAL 
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IRB/IECs and regulatory authorities may also terminate the trial prematurely for any reason 
and at any time following consultation with the sponsor. A decision to prematurely terminate 
the trial is binding on all Investigators. 
 PUBLICATION OF STUDY RESULTS 
Information generated by the trial is the property of the sponsor. Publication or other public 
presentation of data resulting from this trial requires prior review and written approval of the 
sponsor.  
 
Communication of Study Results  
This trial will be registered on ClinicalTrials.gov, the EudraCT database and in other trial 
registries as deemed appropriate. The basic results will be posted at www.clinicaltrials.gov in 
a tabular format within a year from the end of the trial (as defined in the preceding sections) 
or upon finalization of the CSR, whichever occurs later. 
The trial results will be documented in a clinical study report (CSR), in an ICH E3-compliant 
format. A copy of the final report, duly checked for correctness, completeness, integrity, and 
accurate representation of data and interpretation of trial outcome, will be issued to 
Investigators and counter-signed by the global coordinating Investigator; as per the sponsor’s 
SOPs.  
 
Publications by Investigators 
For all publications relating to the trial, institutions will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts 
Submitted 
to 
Biomedical 
Journals, http://www.icmje.org/index.html#authorship, established by the International 
Committee of Medical Journal Editors. 
Data from individual trial sites must not be published separately. It is agreed that the results 
of the trial will not be submitted for abstract, presentation, poster exhibition or publication by 
the Investigator until the sponsor has reviewed and commented on the presentation or 
manuscript for publication. Abstracts, manuscripts, and presentation materials should be 


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06-May-2016 
 
 
MYLAN CONFIDENTIAL 
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provided to the sponsor for review and approval at least 30 days prior to the relevant 
submission deadline. 
 REFERENCES 
1. de Graaff LC, Smit JW, Radder JK. Prevalence and clinical significance of 
organ-specific autoantibodies in type 1 diabetes mellitus. Neth J Med. 2007; 
65(7):235-247. 
2. Diabetes Control and Complications Trial Research Group: The effect of intensive 
treatment of diabetes on the development and progression of long-term complication 
in insulin dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986. 
3. Reichard P, Nilsson BY, Rosenqvist U. The effect of long term intensified insulin 
treatment on the development of microvascular complications of diabetes mellitus. 
N Engl J Med. 1993;329(5):304-309. 
4. American Diabetes Association. Standards of Medical Care in Diabetes-2014. 
Diabetes Care. 2014; 37(S1):S14-S80. 
5. EMEA. Annex To Guideline On Similar Biological Medicinal Products Containing 
Biotechnology-Derived Proteins As Active Substance: Non-Clinical And Clinical 
Issues: Guidance On Similar Medicinal Products Containing Recombinant Human 
Soluble Insulin (EMEA/CHMP/BMWP/32775/2005). 2006 
6. Investigator’s Brochure for Mylan’s Insulin glargine (available upon request).  
7. Lantus® US Prescribing Information. Sanofi-Aventis, 2009.  
8. Streja D. Can continuous glucose monitoring provide objective documentation of 
hypoglycemia unawareness? Endocrine Practice. 2005;11:83-90. 
9. Janssen MJ, Snoek FJ, Heine RJ. Assessing Impaired Hypoglycemia Awareness in 
Type 1 Diabetes. Diabetes Care. 2000; 23:529–532.  
10. Summary of Product Characteristics. Humalog® EPAR. Last updated on 11 May 
2011; accessed on 10 July 2013. 
(http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000088/WC500050332.pdf).  
11. Humalog® US Prescribing Information. Eli Lilly, 2013. 


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06-May-2016 
 
 
MYLAN CONFIDENTIAL 
Page 81 
 
12. Clinical trial.gov. available 
at https://clinicaltrials.gov/ct2/results?term=lantus+edition&Search=Search. Accessed 
on 23 Sep 2015. 
 


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06-May-2016 
 
 
MYLAN CONFIDENTIAL 
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APPENDICES 
Appendix 
Title 
I 
Questionnaire to Assess Hypoglycemia Unawareness 
II 
Suggested General Guidance for Insulin Dose Titration 
III 
4- and/or 8-point Glucose Estimation Time Points 
IV 
Sample Patient Diary Information 
V 
Letter of Approval of Pen Use by the Investigator (for US sites only) 
 
 


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Appendix I - Questionnaire to Assess Hypoglycemia Unawareness  
Please circle only one answer for each question.  
1. Have you lost the ability to experience symptoms such as sweating, shaking, 
palpitations, light-headedness, or nervousness when your blood sugar is low?  
 
 
No / Yes  
2. To what extent can you recognize low blood sugar based on symptoms? 
 
 
Never / Seldom / Sometimes / Often / Always ["Never," "Seldom," or 
"Sometimes" = Yes]  
3. Below which level do you feel that your blood sugar is low? 
 
 
65 / 60 / 55 / 50 / 45 [55 or below = Yes]  
4. During the past year, did you have any low blood sugar episode associated with 
confusion for which you required assistance from another person?  
 
 
No / Once / More than once ["More than once" = Yes]  
5. During the past year, did you have any low blood sugar episode for which you 
required intervention from paramedics, an emergency department visit, or an injection 
of glucagon by another person?  
No / Yes  
Diagnosis of Hypoglycemia Unawareness (HUN) 
Patients will be considered to have HUN if 3 of the 5 questions were scored "yes." 
References: [8,9]. 
 
 


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06-May-2016 
 
 
MYLAN CONFIDENTIAL 
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Appendix II - Suggested Guidance for Insulin Dose Titration 
Lowest fasting capillary blood glucose 
(pre-breakfast) value for 3 days 
Adjust basal insulin dose (U per dose) 
(Lantus® or Mylan’s insulin glargine) 
>270 mg/dL 
+ 6 U 
181-270 mg/dL 
+ 4 U 
151-180 mg/dL 
+ 2 U 
131-150 mg/dL 
+ 1 U 
71-130 mg/dL (Target level) 
Maintain Dose 
56-70 mg/dL 
-2 U 
<56 mg/dL 
-4 U 
 
Lowest post-prandial capillary blood 
glucose value (2 hour post food) for 3 days 
Adjust mealtime insulin dose (U per dose) 
(Insulin lispro) 
>270 mg/dL 
+ 6 U 
201-270 mg/dL 
+ 4 U 
180- 200 mg/dL 
+ 2 U 
< 180 mg/dL (Target level) 
Maintain Dose 
 
Comments:  
o 
Titration should be performed first for the basal insulin. For elevated fasting 
pre-breakfast glucose levels, adjust only the basal insulin dose. 
o 
Once basal insulin level has been titrated to optimum, then mealtime insulin should 
be titrated. 
o 
Post-prandial glucose levels are estimated 2 hours after the start of the respective food 
intake. 
o 
Apart from glucose levels, the dose of mealtime insulin should be guided by expected 
carbohydrate content of the next meal, and expected level of physical activity within 
next 4-6 hours. If meal is skipped, the dose should be skipped. 
o 
The target should be the lower limit of the range mentioned above, so that the final 
value will remain in the expected range.  
 


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06-May-2016 
 
 
MYLAN CONFIDENTIAL 
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Appendix III - 4-Point and/or 8-Point Glucose Estimation Time Points 
Time of the day 
Specific point (8-point) 
Specific point (4-point) 
Fasting Before breakfast 
1 
1 
2 hours after breakfast 
2 
 
Before lunch 
3 
2 
2 hours after lunch 
4 
 
Before dinner 
5 
3 
2 hours after dinner 
6 
 
Just before sleep 
7 
4 
At 3±1 AM 
8 
 
 
Comments:  
o 
Specific days on which the SMBG need to be estimated is as mentioned in the 
Assessment Schedule. 
o 
On all days in which SMBG is not mandated by protocol, patients will be advised to 
self-monitor blood glucose 4 times a day as per standard of care in type 1 diabetes. 
o 
The 8th point time can be adapted for patients on night shift (in discussion with the 
Investigator) to approximately 4 hours after going to bed. 
 
 
 


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06-May-2016 
 
 
MYLAN CONFIDENTIAL 
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Appendix IV - Sample Patient Diary Information 
• 
Trial, site and patient identification information 
• 
Results of 8-point SMBGs performed as per protocol 
• 
Insulin dose information on days where 8-point SMBGs are performed 
• 
Details of hypoglycemic events 
• 
Details of untoward experiences (AEs)  
• 
Details of problems with the disposable pens or needles 
 
 


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06-May-2016 
 
 
MYLAN CONFIDENTIAL 
Page 87 
 
Appendix V - Letter of Approval of Pen Use by the Investigator (for US Sites only) 
Prohibition of Promotion and Other Practices 
According to the 21 CFR 812.7, an Investigator or any person acting for or on behalf of a 
sponsor or Investigator shall not: 
• Promote or test market an investigational device, until after FDA has approved the 
device for commercial distribution. 
• Commercialize an investigational device by charging the patients or investigators for 
a device a price larger than that necessary to recover costs of manufacture, research, 
development, and handling. 
• Unduly prolong an investigation. If data developed by the investigation indicate in the 
case of a class III device that premarket approval cannot be justified or in the case of 
a class II device that it will not comply with an applicable performance standard or an 
amendment to that standard, the sponsor shall promptly terminate the investigation. 
• Represent that an investigational device is safe or effective for the purposes for which 
it is being investigated. 
 
 


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06-May-2016 
 
 
MYLAN CONFIDENTIAL 
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The format below should be followed for the letter of approval.  
The protocol identification code for the study in the IND 
 
Name and address of the Investigator 
 
The name and address of the sub-Investigators who will be 
assisting the Investigator in the conduct of the study 
 
The name and address of the medical school, hospital or other 
research facility where the clinical investigations will be 
conducted 
 
 
The name and address of the clinical laboratory facilities to 
be used in the study 
 
 
The name and address of the institutional review board that is 
responsible for review and approval of the study 
 
 
1. I have gone through the protocol and agree to conduct the study as mentioned in the protocol 
2. I have sufficient education, training and experience in the clinical investigation of the drug 
using the new device. 
3. I shall maintain the following accurate, complete, and current records relating to the my 
participation in the investigation: 
• 
Record of receipt, use or disposition of a device that relate to: 
o The type and quantity of the device, the dates of its receipt, and the batch number or code 
mark. 
o The names of all persons who received, used, or disposed of each device. 
o Why and how many units of the device have been returned to the sponsor, repaired, or 
otherwise disposed of. 
• 
Documents evidencing informed consent and, for any use of a device by the Investigator 
without informed consent, any written concurrence of a licensed physician and a brief 
description of the circumstances justifying the failure to obtain informed consent. The case 
history for each individual shall document that informed consent was obtained prior to 
participation in the study. 
4. I shall prepare and submit the following complete, accurate, and timely reports: 
o I shall submit to the sponsor and to the reviewing IRB a report of any unanticipated 
adverse device effect occurring during an investigation as soon as possible, but in no 
event later than 10 working days after the Investigator first learns of the effect. 
o I shall report to the sponsor, within 5 working days, a withdrawal of approval by the 
reviewing IRB of my part of an investigation. 
o If I use a device without obtaining consent form, I shall report such use to the sponsor 
and the reviewing IRB within 5 working days after the use occurs. 
o I shall, upon request by a reviewing IRB or FDA, provide accurate, complete, and current 
information about any aspect of the investigation. 
5. I shall not: 
• 
Promote or test market an investigational device, until after FDA has approved the device for 
commercial distribution. 
• 
Commercialize an investigational device by charging the patients or Investigators for a device 
a price larger than that necessary to recover costs of manufacture, research, development, and 
handling. 
• 
Unduly prolong an investigation. If data developed by the investigation indicate in the case of 


Insulin Glargine 
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06-May-2016 
 
 
MYLAN CONFIDENTIAL 
Page 89 
 
a class III device that premarket approval cannot be justified or in the case of a class II device 
that it will not comply with an applicable performance standard or an amendment to that 
standard, the sponsor shall promptly terminate the investigation. 
• 
Represent that an investigational device is safe or effective for the purposes for which it is 
being investigated.  
 
The details of Mylan’s insulin glargine pen have been provided to me. I have gone through the 
detailed literature, label, and the user information. I am aware that the disposable pen planned for the 
study is not yet approved by FDA. I approve the use of the Mylan non-cleared, disposable pen 
injector for this study based on the device posing no significant risk to the patient. 
 
 
 
 
Signature and date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Insulin Glargine 
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Final Protocol V2.0 
06-May-2016 
 
 
MYLAN CONFIDENTIAL 
Page 90 
 
INVESTIGATOR AGREEMENT PAGE 
PROTOCOL # 
VERSION PROTOCOL TITLE 
EFFECTIVE DATE 
MYL-1501D-3003 
2.0 
An Open-label, Randomized, Multi-center, 
Parallel-Group Clinical Trial Comparing the 
Efficacy and Safety of Mylan’s Insulin Glargine 
with Lantus
® in Type 1 Diabetes Mellitus 
Patients-An Extension Study. 
06-May-2016 
I agree: 
 To assume responsibility for the proper conduct of the study at this site. 
 To conduct the study in compliance with this protocol, any future amendments, and with any 
other study conduct procedures provided by Quintiles and Mylan. 
 Not to implement any changes to the protocol without agreement from the Sponsor and 
prior review and written approval from the Competent Authority and/or Independent  Ethics 
Committee (IEC)/Institutional Review Board (IRB), as applicable, except where necessary 
to eliminate an immediate hazard to the patients. 
 That I am thoroughly familiar with the appropriate use of the investigational product(s) as 
described in this protocol, and any other information provided by the Sponsor, including 
but not limited to the following: the current Investigator’s Brochure (IB) or equivalent 
document. 
 That I will comply with the revised Declaration of Helsinki (2013), the International 
Conference on Harmonisation Guidelines on Good Clinical Practice (ICH-GCP), and other 
applicable regulations and guidelines for the conduct of clinical trials. 
 To ensure that all persons assisting me with the study are adequately informed about the 
investigational product(s) and of their study-related duties and functions as described in the 
protocol. 
 That I have been informed that certain regulatory authorities require the Sponsor to obtain 
and supply, as necessary, details about each Investigator’s proprietary interest in the Sponsor 
or the investigational product, and, more generally, about each Investigator’s financial ties with 
the Sponsor. Mylan will use and disclose the information solely to comply with regulatory 
requirements. Hence, I agree: 
• 
To supply Mylan with any necessary information regarding proprietary interest and 
financial ties (including those of my spouse and dependent children); 
• 
To promptly update this information if any relevant changes occur during the course 
of the study and for 1 year following completion of the study; and 
• 
That Mylan may disclose to regulatory authorities any information it has about such 
proprietary interests and financial ties. 
 
Investigator’s Signature 
Date 
 
Name and Title of Investigator (typed or printed) 

SAP_001.pdf: 
 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
Page 1 of 39 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
MYL-1501D-3003 
AN OPEN-LABEL, RANDOMIZED, MULTI-CENTER, PARALLEL-
GROUP CLINICAL TRIAL COMPARING THE EFFICACY AND SAFETY 
OF MYLAN’S INSULIN GLARGINE WITH LANTUS® IN TYPE 1 
DIABETES MELLITUS PATIENTS: AN EXTENSION STUDY 
 
 
 
 
 
AUTHOR: NEETU BADHONIYA AND YOGESH SONAWANE 
VERSION NUMBER AND DATE: FINAL V1.0, 27JUL2016 
 
 
 
 




 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
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MODIFICATION HISTORY 
 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant 
Changes 
from 
Previous Authorized Version 
Final V1.0 
27JUL2016 
Neetu 
Badhoniya 
and 
Yogesh Sonawane 
Not Applicable – First Version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
Page 4 of 39 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................... 8 
1. INTRODUCTION ........................................................................................................................ 10 
2. STUDY OBJECTIVES ................................................................................................................. 10 
2.1. 
Primary Objective ...................................................................................................................................... 10 
2.2. 
Secondary Objectives ................................................................................................................................ 10 
3. STUDY DESIGN .......................................................................................................................... 10 
3.1. 
General Description ................................................................................................................................... 11 
3.2. 
Schedule of Events ..................................................................................................................................... 12 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 13 
3.4. 
Not Applicable  Significant Changes from Previous Authorized Version ..................................................... 13 
4. PLANNED ANALYSES ............................................................................................................... 13 
4.1. 
Interim Analysis ......................................................................................................................................... 13 
4.2. 
Final Analysis ............................................................................................................................................. 13 
5. ANALYSIS SETS ......................................................................................................................... 13 
5.1. 
Randomized population [RND] .................................................................................................................. 14 
5.2. 
Safety population ...................................................................................................................................... 14 
5.3. 
Intent-to-treat population [ITT] ................................................................................................................. 14 
5.4. 
Modified Intent-to-treat population [mITT] ............................................................................................... 14 
5.5. 
Per Protocol population [PP] ..................................................................................................................... 14 
6. GENERAL CONSIDERATIONS ................................................................................................. 15 


 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
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6.1. 
Reference Start Date and Study Day .......................................................................................................... 15 
6.2. 
Baseline ..................................................................................................................................................... 15 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 15 
6.4. 
Windowing Conventions ............................................................................................................................ 16 
6.5. 
Statistical Tests .......................................................................................................................................... 16 
6.6. 
Common Calculations ................................................................................................................................ 16 
6.7. 
Software Version ....................................................................................................................................... 16 
7. STATISTICAL CONSIDERATIONS .......................................................................................... 16 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 16 
7.2. 
Multicenter Studies ................................................................................................................................... 16 
7.3. 
Missing data .............................................................................................................................................. 17 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 17 
7.5. 
Active-Control Study Intended to Show Equivalence ................................................................................. 17 
7.6. 
Examination of Subgroups ......................................................................................................................... 17 
8. OUTPUT PRESENTATIONS ..................................................................................................... 17 
9. DISPOSITION AND WITHDRAWALS .................................................................................... 18 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..................................... 18 
10.1. Derivations ................................................................................................................................................ 19 
10.2. Statistical tests for baseline characteristics................................................................................................ 19 
11. 
MEDICAL HISTORY ............................................................................................................... 19 
12. 
MEDICATIONS........................................................................................................................ 19 
12.1. Statistical test for concomitant medication ............................................................................................... 20 


 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
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13. 
STUDY MEDICATION EXPOSURE ...................................................................................... 20 
13.1. Derivations ................................................................................................................................................ 20 
14. 
STUDY TREATMENT NON-COMPLIANCE ........................................................................ 20 
15. 
EFFICACY OUTCOMES .......................................................................................................... 20 
15.1. Primary Efficacy ......................................................................................................................................... 21 
15.1.1. 
Primary Efficacy Variable & Derivation ................................................................................................ 21 
15.1.2. 
Missing Data Methods for Primary Efficacy Variable ............................................................................ 21 
15.1.3. 
Primary Analysis of Primary Efficacy Variable ...................................................................................... 21 
15.1.4. 
Sensitivity Analysis of Primary Efficacy Variable(s) ............................................................................... 21 
15.2. Secondary Efficacy ..................................................................................................................................... 22 
15.2.1. 
Secondary Efficacy Variables & Derivations ......................................................................................... 23 
15.2.1.1. 
HbA1c ......................................................................................................................................... 23 
15.2.1.2. 
Fasting plasma glucose ................................................................................................................ 23 
15.2.1.3. 
Change in 8-point SMBG profile from baseline............................................................................. 23 
15.2.1.4. 
Daily insulin dose/unit body weight (daily prandial injectable, basal insulin and total) for days of 8-
point profiles ................................................................................................................................................. 24 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variables ...................................................................... 24 
15.2.3. 
Analysis of Secondary Efficacy Variables .............................................................................................. 24 
15.2.3.1. 
Analysis of change from baseline in HbA1c .................................................................................. 24 
15.2.3.2. 
Analysis of change from baseline in fasting plasma glucose ......................................................... 25 
15.2.3.3. 
Analysis of Change in 8-point SMBG profile from baseline ........................................................... 25 
15.2.3.4. 
Analysis of Change in Daily insulin dose/unit body weight (daily prandial injectable and basal 
insulin) for days of 8-point profiles. ................................................................................................................ 25 
15.2.4. 
Subgroup Analysis............................................................................................................................... 26 
16. 
QUALITY OF LIFE ANALYSIS .............................................................................................. 26 
17. 
SAFETY OUTCOMES.............................................................................................................. 26 
17.1. Adverse Events .......................................................................................................................................... 26 
17.1.1. 
All TEAEs ............................................................................................................................................. 27 
17.1.1.1. 
Severity ....................................................................................................................................... 27 
17.1.1.2. 
Relationship to Study Medication ................................................................................................ 27 
17.1.1.3. 
Adverse Drug Reaction ................................................................................................................ 27 
17.1.2. 
TEAEs Leading to Discontinuation of Study Medication ....................................................................... 28 
17.1.3. 
Serious Adverse Events ....................................................................................................................... 28 
17.1.4. 
Adverse Events Leading to Death ........................................................................................................ 28 
17.1.5. 
Local or Systemic Allergic Reaction...................................................................................................... 28 


 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
Page 7 of 39 
17.2. Laboratory Evaluations .............................................................................................................................. 28 
17.2.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ........................................................... 29 
17.3. ECG Evaluations ......................................................................................................................................... 29 
17.4. Vital Signs .................................................................................................................................................. 29 
17.4.1. 
Potential clinically significant changes ................................................................................................. 30 
17.5. Physical Examination ................................................................................................................................. 31 
17.6. Other Safety Assessments ......................................................................................................................... 31 
17.6.1. 
Device Safety Assessment ................................................................................................................... 31 
17.6.2. 
Immunogenicity Profiles Analyses ....................................................................................................... 31 
17.6.3. 
Hypoglycemia Analyses ....................................................................................................................... 32 
18. 
DATA NOT SUMMARIZED OR PRESENTED .................................................................... 33 
19. 
REFERENCES .......................................................................................................................... 34 
APPENDIX 1.PARTIAL DATE CONVENTIONS ........................................................................... 35 
Algorithm for Treatment Emergence of Adverse Events:....................................................................................... 35 
Algorithm for Prior / Concomitant Medications: ................................................................................................... 36 
APPENDIX 2.MAJOR PROTOCOL DEVIATIONS ........................................................................ 38 
 
 
 


 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
American Diabetes Association 
ADR 
Adverse Drug Reaction 
AE(s) 
Adverse Event(s) 
ALT 
Alanine Transaminase 
ANCOVA 
Analysis Of Covariance 
AST 
Aspartate Transaminase 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
DCCT 
Diabetes Control And Complications Trial 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOT 
End Of Treatment 
FDA 
Food and Drug Administration (United States) 
FPG 
Fasting Plasma Glucose 
HbA1c 
Glycosylated Hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
HCP 
Host Cell Protein 
HIV 
Human Immunodeficiency Virus 
ITT 
Intention To Treat 
IU 
International Unit 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LDL 
Low Density Lipoprotein 
LS 
LSmeans 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measures 
mITT 
Modified Intent-To-Treat 
NAb 
Neutralizing Antibody 
PP 
Per Protocol 
SAE(s) 
Serious Adverse Event(s) 
SD 
Standard Deviation 


 
 
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SMBG 
Self-Monitored Blood Glucose 
TEAE 
Treatment Emergent Adverse Event 
T1DM 
Type 1 Diabetes Mellitus 
T2DM 
Type 2 Diabetes Mellitus 
WHO 
World Health Organization 
 
 
 


 
 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy and safety 
data for Protocol MYL-1501D-3003. It describes the data to be summarized and analyzed, including the specifics of 
the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version V2.0, dated 06-MAY-2016. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective is to test whether Mylan’s insulin glargine once daily treatment sequence is equivalent to 
Lantus® once daily treatment sequence (based on change in [glycosylated hemoglobin] HbA1C from baseline at 
week 36 when administered in combination with mealtime insulin lispro.  
2.2. SECONDARY OBJECTIVES 
To compare treatment sequence group of Mylan’s insulin glargine to Lantus®, at 36 weeks, when administered in 
combination with mealtime insulin lispro with respect to: 
1. Change in basal insulin dose per unit body weight (U/Kg/day).  
2. Immunogenicity: incidence and change from baseline in the relative levels of ADA, incidence and change 
from baseline in the relative levels of anti-HCP antibodies. 
3. Rate of hypoglycemic events per 30 days; and occurrence of hypoglycemia  
4. Occurrence of local reactions, systemic reactions and other adverse events. 
5. Change in fasting plasma glucose from baseline. 
6. Change in 8-point (self-monitored blood glucose) SMBG profile from baseline  
7. Device related safety assessment.     
3. STUDY DESIGN 
Patients with an established diagnosis of T1DM per ADA 2014 criteria who were randomized to the Lantus® 
treatment arm of the MYL-GAI-3001 study, and who have completed the 52-week treatment period on Lantus® will 
be eligible to be screened for the study MYL-1501D-3003. The purpose of this study is to assess the interchangeability 
through testing equivalence between two treatment sequences with respect to the primary end point, Mylan’s 
insulin glargine and Lantus®. Eligible patients from MYL-GAI-3001 study who successfully completed 52 weeks on 


 
 
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Lantus® will be randomized 1:1 to one of the treatment sequences. Treatment sequence arm 1 - Mylan’s insulin 
glargine for 12 weeks in period 1 then switched to Lantus® for next 12 weeks in period 2 and additional switch to 
Mylan’s insulin glargine for additional 12 weeks to complete the third treatment period. Treatment sequence arm 2 
- Lantus® for 12 weeks in period 1, continue to receive Lantus® in period 2 for 12 weeks and in period 3 for another 
12 weeks.  
Twelve weeks exposure in each period is considered adequate to assess the efficacy with respect to HbA1c, as well 
as to compare the safety between the treatment sequence groups. If switching from Lantus® to Mylan’s insulin 
glargine or from Mylan’s insulin glargine to Lantus® have an impact on the efficacy or the safety, a discernible 
difference in efficacy or safety parameters is expected versus the group of patients who are continuing on Lantus® 
throughout. 
After 36 weeks of treatment, patients will resume their baseline treatment with prescribed medications and will 
have a safety follow up visit after 4 weeks resulting in a total study duration of 40 weeks.  
3.1. GENERAL DESCRIPTION 
Study Duration: 
 
The maximum possible duration of patient participation in the extension trial is 40 weeks, which includes:  
 
Treatment period 1: 12 weeks (Week 0 to Week 12). 
 
Treatment period 2: 12 weeks (Week 12 to Week 24). 
 
Treatment period 3: 12 weeks (Week 24 to Week 36). 
 
Follow-up period: 4 weeks  follow-up visit (Week 36 to Week 40) 
 
Number of Patients: 
Approximately 138 patients with type 1 diabetes who completed the 3001 study on the Lantus will participate in this 
trial. Approximately 69 patients will be randomized to one of  two sequence groups (Treatment sequence arm 1: 
Mylan’s insulin glargine switch to Lantus® sequence group and switch back to Mylan’s insulin glargine, or Treatment 
sequence arm 2: Lantus® to Lantus® to Lantus® sequence group) in a 1:1 ratio. No replacement of patients will be 
performed if a patient discontinued prematurely from the study. For the modified intent-to-treat (mITT) population, 
power to demonstrate equivalence with ±0.4% limits will be 90% with 10% patients who don’t have at least one 
baseline and one last period HbA1c data. The power is calculated assuming no true mean group difference and a 
0.61% standard deviation. This standard deviation is based on published results for clinical studies with Lantus®. 
 
Allocation to Treatment  
Patients who completed the 3001 study on Lantus® will be randomized 1:1 to receive either Mylan’s insulin glargine 
or Lantus® using an IVRS/IWRS. Change of dosing from morning to bedtime or vice versa will not be permitted. If a 
patient discontinues, the patient will not be allowed to re-enter the extension study. 
 
Blinding 
This is an open-label study. To minimize bias, treatment assignments will not be revealed to the central laboratory 
for the safety (immunogenicity) and efficacy (HbA1c) analyses.  


 
 
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Page 12 of 39 
 
Study Treatment  
The investigational products used in this trial are Mylan’s insulin glargine (test product) and Lantus® from Sanofi-
Aventis (reference product). All patients will receive insulin lispro as mealtime medication. 
Both investigational products will be provided in a pre-filled disposable pen with a 3 mL cartridge. Mylan’s insulin 
glargine formulation for injection is a, sterile, clear solution at pH 4. Each mL contains 100 units of insulin glargine 
(equivalent to 3.64 mg). The excipients of the formulation are identical to those of Lantus®. 
Humalog (insulin lispro injection, 100 IU/mL), is manufactured by Eli Lilly (administered in Humalog disposable pens).  
 
Table A: 
Study Flow Chart 
 
 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in protocol synopsis (pages 18-19) of the protocol. 
Approximately 138 MYL-GAI-3001 study 
patients receiving Lantus® till 52 week.
Randomization (1:1)
Mylan's Insulin Glargine plus 
insulin lispro (12 weeks)
Lantus® plus insulin lispro (12 
weeks)
Mylan's Insulin Glargine plus 
insulin lispro (12 weeks)
Lantus® plus insulin lispro               
(12 weeks)
Lantus® plus insulin lispro (12 weeks)
Lantus® plus insulin lispro (12 weeks)
End of Trial Visit (36 weeks)
Follow-up Visit (40 weeks)
Period 1
Period 2
Period 3
Follow up 
period 


 
 
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3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
 
An error was found for primary endpoint in Section 9.2.1 Wording “at 12 week” was deleted. 
 
The results with MMRM ANCOVA from secondary efficacy analysis will also be used to compare primary 
analysis results as robustness check. Other sensitivity analyses are added in Section 15.1.4 by using multiple 
imputation method. 
3.4. NOT APPLICABLE  SIGNIFICANT CHANGES FROM PREVIOUS AUTHORIZED 
VERSION 
Not Applicable 
4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
Final Analysis 
 
4.1. INTERIM ANALYSIS  
Not Applicable. 
4.2. FINAL ANALYSIS  
All planned analyses identified in this SAP will be performed by Quintiles Biostatistics team following sponsor 
authorization of this SAP and Database Lock. 
5. ANALYSIS SETS 
Agreement and authorization of patient included/ excluded from each analysis set will be conducted prior to the 
final database lock of the study.  
All analysis sets described below will be derived at final analysis, based on available data. 


 
 
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5.1. RANDOMIZED POPULATION [RND] 
The Randomized (RND) population will contain all patients who are enrolled and randomized to study medication.  
For analyses and displays based on RND, patients will be classified according to randomized treatment sequence 
group.  
5.2. SAFETY POPULATION 
The safety population includes patients who are randomized and take at least one dose of the trial drug. Safety 
population will be mainly used for safety analyses. 
If there is any doubt whether a patient was treated or not, they will be assumed treated for the purposes of analysis.  
5.3. INTENT-TO-TREAT POPULATION [ITT] 
The ITT population includes all randomized patients (including patients who receive incorrect treatment sequence, 
do not complete the trial or do not comply with the protocol or used prohibited medication) and have baseline (week 
0 visit) and at least one post-baseline visit. The patients under ITT population will be analyzed according to the 
planned treatment sequence. ITT population will be used for secondary variable analyses. 
The sensitivity analysis to check the robustness of primary analysis will be based on the ITT population. All secondary 
efficacy analyses will be based on the ITT population. 
5.4. MODIFIED INTENT-TO-TREAT POPULATION [MITT] 
The mITT population includes all randomized patients (including patients who receive incorrect treatment sequence, 
do not complete the trial or do not comply with the protocol or used prohibited medication) and have at least one 
baseline (week 0 visit) HbA1c value and one post-baseline HbA1c value at treatment period 3 (24 < Week ≤ 36). The 
mITT will be used for primary analysis. 
5.5. PER PROTOCOL POPULATION [PP] 
The PP population includes patients who have at least one baseline and one period 3 value and do not have protocol 
violations that impact the primary outcome. The patients excluded from the PP population will be identified before 
database lock (i.e., before unblinding the study team). All protocol deviations and the deviations impacting the 
primary outcome variable will be documented separately and will be signed off prior to the database lock (i.e., before 
unblinding the study team).  PP population will be used for sensitivity analysis for primary variable. 


 
 
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6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/ stop day of assessments 
and events.  
Reference start date is defined as the day of first dose of study medication (Day 1 is the day of the first dose of study 
medication in extension study), and will appear in every listing where an assessment date or event date appears.  
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations will appear 
partial or missing in the listings. 
6.2. BASELINE 
Unless otherwise specified, baseline is visit 1, which includes the post study measurements from week 52 of the 
main study MYL-GAI-3001 and assessment prior to receiving randomized treatment sequence group (including 
unscheduled assessments) in extension study. In the case where the last non-missing measurement and the 
randomized treatment sequence group start date coincide, that measurement will be considered pre-baseline, but 
Adverse Events (AEs) and medications commencing on the randomized treatment sequence group start date will be 
considered post-baseline.  
6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled measurements 
will not be included in by-visit summaries, but will contribute to the best/ worst case value where required (e.g. shift 
table).  
In the case of a retest (same visit number assigned), the earliest available measurement for that visit will be used for 
by-visit summaries.  
Early termination data will be mapped to the next available visit number for by-visit summaries. 
Listings will include scheduled, unscheduled, retest, and early discontinuation data. 


 
 
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6.4. WINDOWING CONVENTIONS  
Allowed time window for each visit will performed as mentioned in protocol Schedule of 
Activities (page numbers 18 and 19).  
6.5. STATISTICAL TESTS 
All tests of treatment effects will be conducted at a two-sided alpha level of 0.05 or with 2-sided 95% confidence 
intervals, unless otherwise specified. 
6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: Test Value at Visit X – Baseline Value 
6.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.2 or higher. 
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES 
The following covariates and factors are used in the analyses. For details of their inclusion in the models, see the 
specific analysis section. 
 
Geographical Region (Categories North America/ Europe)  
 
Baseline value (Continuous Variable) 
7.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers globally. Randomization to treatment 
sequence arms is stratified by region.   
Geographical region will be categorized as follows: 
Geographic Region 
Country 
North America 
United States of America, Canada 


 
 
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Europe 
Latvia, Estonia, Slovakia, Czech Republic, Hungry, 
Germany 
 
A term for treatment by region interaction will not be included in the primary analysis model, however, a sensitivity 
analysis, based on the primary model but including a term for treatment sequence by region interaction, will be 
performed.   
7.3. MISSING DATA 
Missing primary and secondary efficacy and safety analysis data will be not imputed except when week 36 HbA1c 
data is missing due to early discontinuation, exit measurement of that period will be used for endpoint. In addition, 
for sensitivity analysis of multiple imputation method, if missing values occur in more than 10% of the patients for 
HbA1C values, then monotone regression for multiple imputations will be used. 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
No adjustment for multiplicity will be performed. 
7.5. ACTIVE-CONTROL STUDY INTENDED TO SHOW EQUIVALENCE  
For primary endpoint analysis, equivalence for efficacy will be supported if the two sided 95% confidence interval 
for the difference of mean change from baseline between two sequence groups for HbA1c is within ±0.4%. 
Two-sided 95% CI will be derived using ANCOVA model which includes region, treatment sequence as fixed effects, 
and baseline HbA1c as a covariate. 
7.6. EXAMINATION OF SUBGROUPS 
No subgroup analysis is planned. 
8. OUTPUT PRESENTATIONS 
For safety and efficacy presentations, the order and naming of the treatment sequence group will be as follows. 
 
MYL-IG Seq (to Mylan’s insulin glargine  to Lantus® to Mylan’s insulin glargine )  
 
Lantus® Seq ( to Lantus® to Lantus® to Lantus® sequence group) 
All descriptive safety and efficacy summaries will be presented by treatment sequence group and be broken down   
by visit for each period.  


 
 
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9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study.  
The frequency and percentage of randomized patients who completed the trial or discontinue early will be 
summarized for each treatment sequence group. The comparison of patient discontinuations across treatment 
sequence groups will be performed using the Fisher’s exact test. Reason for discontinuation from the study will also 
be summarized.  
The number and proportion of patients withdrawing from the study during screening will be presented in a table. 
Additionally, the number and proportion of patients in each population will be summarized. 
A listing of patients who did not meet the inclusion/exclusion criteria will be produced.  
A list of significant protocol violations will be provided. A summary of significant protocol violations will also be 
provided as frequency and percentages, and treatment sequence group comparisons will be performed using the 
Fisher’s exact test. Refer Appendix 2 for significant protocol violation. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the randomized population. 
Patient characteristics will be recorded prior to randomization or already collected in the MYL-GAI-3001 trial and 
will be listed and summarized by treatment sequence group. Overall summaries will include descriptive statistics for 
continuous measures (n, mean, standard deviation, median, minimum and maximum) and for categorical measures 
(n, frequency, and percent).  
The following demographic and other baseline characteristics will be reported for this study: 
 
Age (years) - calculated relative to date of randomization 
 
Gender 
 
Race  
 
Weight (kg) 
 
Height (cm) 
 
Body Mass Index (BMI) (kg/m2) 
 
Duration of diabetes (years) 
 
Basal insulin timings (Morning/Evening) 
 
Baseline fasting plasma blood glucose 
 
Baseline HbA1c 
 
Fasting C-peptide, HIV, HBsAg, and HCVAb 
 
Region  


 
 
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10.1. DERIVATIONS 
 
BMI (kg/ m2) = weight (kg)/ height (m)2 
 
Duration of diabetes (years) = (Date of screening – date of onset of diabetes+1) /365.25 
10.2. STATISTICAL TESTS FOR BASELINE CHARACTERISTICS  
Treatment sequence groups will be compared by using t-tests for quantitative measures and the Fisher’s exact test 
or the chi-squared test for categorical measures to investigate if there are any significant differences in baseline 
characteristics. The p-value for the corresponding two-sided test will be presented. 
11. MEDICAL HISTORY 
Medical History information will be presented for the safety population, and coded using Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary Version 18.1. 
Medical history will be recorded at screening and will include pre-existing diseases or conditions reported at time of 
screening, which are resolved/stopped stop prior randomization, other than the study condition. 
Frequency and percentage of Medical History conditions will be presented by treatment sequence groups and 
preferred term. 
12. MEDICATIONS 
Medications will be presented for the safety population and coded using WHO Drug dictionary 1DEC2015. 
Prior and concomitant medications at enrollment will be summarized using ATC level 3 coding. 
 
‘Prior’ medications are medications which started and stopped prior to the first dose of randomized study 
medication.  
 
‘Concomitant’ medications are medications which:  
o started prior to, on or after the first dose of randomized study medication,  
o AND ended after the dose of randomized study medication or were ongoing at the end of the study. 
 
See Appendix 1 for handling of partial dates for medications, in the case where it is not possible to define a 
medication as prior, concomitant, or post treatment, the medication will be classified by the worst case; i.e. 
concomitant. 
 
Percentage of patients with at least 10% and overall concomitant medications will be summarized for each treatment 
period by treatment sequence groups as counts and percentages. 


 
 
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12.1. STATISTICAL TEST FOR CONCOMITANT MEDICATION 
Treatment sequence groups for percentages of patients with at least 10% and overall concomitant medications will 
be compared using Chi-square test. P-value for the corresponding two-sided test will be presented. 
13. STUDY MEDICATION EXPOSURE 
Total treatment duration (in days) will be summarized for each treatment sequence and by period.  The sequence 
group will be compared using t-test. Descriptive statistics for continuous measures will be presented along with 
the p-value for treatment sequence comparison. 
 
Interruptions, compliance, and dose changes are not taken into account for duration of exposure.  
13.1. DERIVATIONS 
Total treatment duration = date of last intake of study medication prior to the scheduled visit (Week 36) – date of 
first intake of study medication + 1. 
It will be presented in days. 
14. STUDY TREATMENT NON-COMPLIANCE  
Patient will be identified as study treatment non-compliant if the patient meets any following criteria: 
 
Missing either total meal time insulin or basal insulin doses for 5 consecutive days. 
 
Missing either total meal time insulin or basal insulin doses for more than 30 accumulative days for 
completer or more than 20% treatment days for drop-out. 
 
Taking more than one administration of basal insulin (If multiple injections are required to deliver the 
required quantity of drug due to logistic reasons, then it is considered as one administration) for 10 days 
cumulative. 
 
Taking more than the prescribed basal insulin dose for more than 30 days cumulative. 
Number and proportion of patients with noncompliance will summarized along with individual reasons for non-
compliance. 
15. EFFICACY OUTCOMES  
Summaries will include descriptive statistics for continuous measures (n, mean, standard deviation, median, 
minimum and maximum) and for categorical measures (n, frequency, and percent). 


 
 
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Version Number:
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Effective Date: 01May2012
 
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15.1. PRIMARY EFFICACY 
15.1.1. 
PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy outcome is change in HbA1c from baseline at week 36.  . 
15.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
The imputation will not be applied. If week 36 HbA1c is missing then last non-missing values from period 3 will be 
used. 
15.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary objective of this study is to test the equivalence of changes in HbA1C between two treatment sequence 
groups at week 36. 
The primary efficacy analysis will be performed for the mITT population. 
ANCOVA will be performed on the primary outcome variable and the model will include region and sequence group 
as fixed effect and baseline value (52 weeks in MYL-GAI-3001) as covariate using mITT population. A 95% confidence 
interval for the difference between two treatment sequence groups for mean change from baseline HbA1c at 
endpoint will be produced using the ANCOVA method. Equivalence of Mylan’s insulin glargine sequence group to 
Lantus® sequence group will be established if the 95% confidence interval is within ±0.4% equivalence limits. 
The Least Square (LS) means for each treatment sequence group and associated standard errors will be derived. 
Differences in LS means will be calculated and associated 2-sided 95% confidence intervals will be provided. 
15.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
A further robustness check will be conducted using the PP population and applying the same ANCOVA procedure as 
described in Section 15.1.3. Any differences in the conclusion will be further investigated by examining differences 
between the mITT and the PP populations. 
Additional sensitivity analysis will be performed based on MMRM ANCOVA from secondary efficacy analysis. A 
repeated measures analysis employing a restricted maximum likelihood (REML)-based, mixed-effects model 
approach (MMRM) will be used to produce a 95% confidence interval for the difference between Mylan’s insulin 
glargine sequence and Lantus® sequence for mean change of HbA1c at week 36. The MMRM model will include the 
fixed, categorical effect of treatment sequence group, region, visit, treatment sequence-by-visit interaction and 
baseline value (52 weeks in MYL-GAI-3001) as covariates. 
A further robustness check will be done using the PP population and applying the same MMRM procedure as 
described in Section 15.1.3 to establish equivalence. Any differences in conclusions will be further investigated by 
examining differences in the ITT and the PP populations. 
Other sensitivity analysis addressing missing data be conducted as following 


 
 
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Multiple imputed datasets will be generated based on the assumption of a monotone missing data pattern. The 
imputation will be performed using the monotone regression method for week 24 and week 36 sequentially. The 
variables treatment region, previous exposure to insulin and basal insulin dosing time will be used as independent 
variables. 
An example of the SAS code using monotone regression for multiple imputation for week 36 (visit 13). 
PROC MI DATA=XXX OUT=OXXX NIMPUTE=100 SEED=1122015; 
         VAR Baseline VISIT13 VISIT9 VISIT5 ARMCD PSTRTRGN;  
         CLASS ARMCD PSTRTRGN; 
         MONOTONE REG (VISIT5 = BASELINE ARMCD PSTRTRGN); 
         MONOTONE REG (VISIT9 = BASELINE VISIT5 ARMCD PSTRTRGN);  
         MONOTONE REG (VISIT13 = BASELINE VISIT9 VISIT5 ARMCD PSTRTRGN);  
RUN; 
Imputation for the week 36 will be performed using the set with values imputed. In case non-monotone missing data 
(usually relatively infrequent) will be imputed using the Markov Chain Monte Carlo (MCMC) option prior to the above 
regression approach.  
All imputed datasets will be analyzed using the same model parameters as used in the additional sensitivity analysis, 
and the results will be combined using Rubin’s rules 
An example of the SAS code for combining results using Rubin’s rules with PROC MIANALYZE is given below: 
ODS OUTPUT PARAMETERESTIMATES=MIESTDIFF ; 
PROC MIANALYZE DATA=LSDIFF; 
       MODELEFFECTS LSMEANSDIFF; 
                        STDERR STDERR; 
RUN; 
 This approach will be performed for the ITT and the PP populations. 
15.2. SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the ITT population. 
A repeated measures analysis employing a restricted maximum likelihood (REML)-based, mixed-effects model 
approach (MMRM) will be used to compare treatment sequence diffference at scheduled visits. The MMRM model 
will include the fixed, categorical effect of treatment sequence group, region, visit,  treatment sequence-by-visit 
interaction and baseline value (52 weeks in MYL-GAI-3001) as covariates. The data collected at Baseline,  all schedule 
visits will be used in the MMRM model for the purpose of analysis. For the drop-out patients, if the last post baseline 
data is not falling at the scheduled visit, then it will be mapped to the next scheduled visit and this data will also be 
included in the analysis.  
An unstructured covariance matrix will be used to model the within-patient errors. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom.  If the model for unstructured covariance 
matrix fails to converge, the heterogeneous Toeplits covariance structure, followed by heterogeneous auto 
regressive covariance structure, will be used. If a structured covariance matrix is used because of the convergence 


 
 
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problem, an analysis will be conducted where a sandwich estimator will be used for the fixed effects parameters to 
take account of possible misspecification of the true covariance matrix. 
Above mentioned statistical analysis approach will be performed for all secondary continuous efficacy variables.  
Contrasts of LS mean at each scheduled visit will be used to evaluate all pairwise treatment sequence group 
comparisons, and 95% confidence intervals for treatment sequence group differences in LS means will be computed 
for each visit. 
Following efficacy measures (both actual and change values) will be summarized at baseline (week 52 in MYL-GAI-
3001) and scheduled visits.  
15.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
Change from baseline calculation will be done as defined in Section 6.6. 
15.2.1.1. 
HbA1c  
The measurement will be performed by the central laboratory for efficacy and safety samples. 
15.2.1.2. 
Fasting plasma glucose  
The measurement of fasting plasma glucose will be performed by the central laboratory for efficacy and safety 
samples. ‘Fasting’ is defined as no intake of food or drink (except water) for at least 10 hours. 
15.2.1.3. 
Change in 8-point SMBG profile from baseline 
8-point SMBG profile measurements will be performed by the patient at home and recorded in the patient diary, A 
single 8-point SMBG profile set includes measurements of SMBG values on 3 days, performed in the week preceding 
the next visit (of the three days, 2 should be consecutive). The patient should document the 3 pre-visit 
measurements in the diary, and will be advised to similarly document any additional estimations.  
Individual pre-meal, individual post-meal, individual 2-hour excursion after meal, bedtime, overall (average) pre-
meal, overall post-meal, overall excursion, 4-point average (pre-meal + bedtime), and daily average at scheduled 
visits will be computed. 
For overall mean of blood glucose (BG), values for the SMBG profiles will be averaged over the specific time points 
in a day. Then this averaged value per day will be averaged across three days. The missing values will not be imputed. 
The daily average SMBG will not be computed for a day if the SMBG measurement was missing for more than 3 time 
points on a particular day. The SMBG overall average will be kept missing if the daily average is missing for all three 
days. If SMBG average is missing for one or two days, the SMBG average of the remaining days will be considered 
for the computation. 
The average SMBG value across the three days at a particular visit and time point will be considered for the SMBG 
values at specific time points. For individual pre-meal, the average of pre-breakfast, pre-lunch and pre-dinner 
measurements within a day will be considered. The individual pre-meal values will be averaged across three days for 
overall average of pre-meal values. The individual post meal and overall post meal values will be computed in the 
same manner. 
SMBG individual excursion values will be obtained by subtracting post-meal values with pre-meal values, it will be 


 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
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applicable for morning excursion, noon excursion and evening excursion on the respective days. For overall excursion 
at morning, afternoon and evening, the individual excursion values obtained on each day will be averaged across 
three days.   
For 4-point average, pre-meal and bedtime SMBG measurements will be averaged for a particular day and then this 
average value will be averaged across three days. 
15.2.1.4. 
Daily insulin dose/unit body weight (daily prandial injectable, basal insulin and total) for 
days of 8-point profiles  
Patients will be asked to document the dose of Mylan’s insulin glargine/Lantus® and insulin lispro taken on the days 
when they perform 8-point SMBG profiles (from week 0 to week 36). Doses will be recorded in the patient diary. 
This data will be transcribed to the eCRF after the patient diary is collected, by the investigator or designee at 
scheduled visits. The patient should document the 3 pre-visit estimations in the diary; and will be advised to 
document any additional estimations. 
There will be three dose variables – daily prandial insulin, basal insulin dose and total insulin dose. 
Daily prandial insulin dose (meal time insulin dose) per day is the sum of all the daily prandial insulin dose for a day 
and then averages for number of days measured. 
Basal insulin dose is the average of the insulin glargine or insulin Lantus dose over days measured. If the basal insulin 
dose is missing for a particular day of collection, total insulin dose will not be computed for that day. The total insulin 
dose will be computed for the remaining days were basal insulin dose is collected. The total insulin dose available at 
the remaining days will be used for the computation of average total insulin dose. For the computation of total daily 
prandial doses, the patients with at least three daily prandial doses at a particular day are considered. Total daily 
prandial dose will not be computed for a day if the daily prandial dose is recorded less than 3 times in a day and the 
total daily prandial dose computed at the remaining days will be used for the computation of average total daily 
prandial dose across the days. 
Total insulin is the sum of daily prandial and basal insulin and then averaged for days measured. The missing insulin 
doses will not be considered for the average computation. All dose will be divided by total body weight (kg) to 
convert to daily insulin dose (U)/unit body weight (kg). 
15.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLES 
Not applicable.  
15.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
15.2.3.1. 
Analysis of change from baseline in HbA1c  
Descriptive statistics for HbA1c will be presented by treatment sequence group for actual and change from baseline 
(week 52 result from MYL-GAI-3001) to scheduled visits. 
Treatment sequence group comparison will be done using the MMRM model, including treatment sequence, visit, 
treatment sequence-by-visit interaction, region as fixed effects, and baseline values as covariates. 


 
 
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reproduction is strictly prohibited. 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
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LS means for each treatment sequence group and associated standard errors will be derived. Differences in LS means 
will be calculated and associated 2-sided 95% confidence intervals (p-value, as required) will be provided. These will 
be derived from the calculation of Type III sum-of –square and LS means from MMRM model. 
For graphical display at each visit, LS means and 95% CI will be generated from the MMRM model including 
treatment sequence group, visit, treatment- sequence group by-visit interaction, region as fixed effects, and baseline 
values as covariates. In addition, mean (± SD) plot will be prepared for actual HbA1c measurements by visit. 
15.2.3.2. 
Analysis of change from baseline in fasting plasma glucose 
Descriptive statistics will be presented by treatment sequence group for actual and change from baseline (week 52 
result from MYL-GAI-3001) to scheduled visits for fasting plasma glucose.  
Treatment sequence group comparison will be done using the MMRM model, including treatment sequence group, 
visit, treatment sequence group-by-visit interaction, region, as fixed effects, and baseline values as covariates. 
LS means for each treatment sequence group and associated standard errors will be derived. Differences in LS means 
will be calculated and associated 2-sided 95% confidence intervals (p-value, as required) will be provided. These will 
be derived from the calculation of Type III sum-of –square and LS means from MMRM model. 
15.2.3.3. 
Analysis of Change in 8-point SMBG profile from baseline 
 
8-point SMBG profile at a visit will be calculated using available pre-visit measurements in the diary (performed in 
the week preceding the visit), as defined in Section 15.2.1.3. 
 
Descriptive statistics will be presented by treatment sequence group for actual and change from baseline (week 52 
result from MYL-GAI-3001) to scheduled visits for SMBG profile.  
Treatment sequence group comparison will be done using the MMRM model, including treatment sequence group, 
visit, treatment sequence group-by-visit interaction, region, as fixed effects, and baseline values as covariates. 
LS means for each treatment sequence group and associated standard errors will be derived. Differences in LS means 
will be calculated and associated 2-sided 95% confidence intervals (p-value, as required) will be provided. These will 
be derived from the calculation of Type III sum-of –square and LS means from MMRM model. 
For graphical display at each period, LS means and 95% CI for daily mean of SMBG will be generated from the MMRM 
model including treatment sequence group, treatment sequence group -by-visit interaction, region, as fixed effects, 
and baseline values as covariates. In addition, mean (± SD) plot for daily mean of SMBG will be prepared for actual 
measurements by visit. 
15.2.3.4. 
Analysis of Change in Daily insulin dose/unit body weight (daily prandial injectable and 
basal insulin) for days of 8-point profiles. 
Descriptive statistics will be presented by treatment sequence group for actual and change from baseline (week 52 
result from MYL-GAI-3001) to scheduled visits for insulin dose including basal insulin dose, daily prandial insulin dose, 
and total insulin dose.  
Treatment sequence group comparison will be done using the MMRM model, including treatment sequence group, 
visit, treatment sequence group by-visit interaction, region, as fixed effects, and baseline values as covariates. 


 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
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LS means for each treatment sequence group and associated standard errors will be derived. Differences in LS means 
will be calculated and associated 2-sided 95% confidence intervals (p-value, as required) will be provided. These will 
be derived from the calculation of Type III sum-of-square and LS means from MMRM model. 
For graphical display at scheduled visits , LS means and 95% CI for total daily insulin dose (meal time +basal) will be 
generated from the MMRM model including treatment sequence group, visit treatment sequence group-by-visit 
interaction, region, as fixed effects, and baseline values as covariates. In addition, mean (± SD) plot total daily insulin 
dose will be prepared for actual measurements by schedule visit. 
15.2.4. 
SUBGROUP ANALYSIS 
Not applicable.   
16. QUALITY OF LIFE ANALYSIS  
Not applicable. 
17. SAFETY OUTCOMES  
All outputs for safety outcomes will be based on the Safety Analysis Set. All safety output will be presented by 
treatment sequence group at each treatment period. 
17.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using most updated MedDRA central coding dictionary, when it is available at 
time of analysis is conducted. 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product that does not necessarily have a causal relationship with the product. An AE can therefore 
be any unfavorable and unintended sign (including a new, clinically important abnormal laboratory finding), 
symptom, or disease, temporally associated with drug administration, whether or not related to the product. 
The above definition covers also cases of  
 
Exacerbation of pre-existing diseases or conditions. 
o 
Pre-existing diseases or conditions (reported at time of screening in medical history) will not be 
considered AEs unless there is an increase in the frequency or severity, or a change in the quality 
of the disease or condition.  
An AE will be defined as treatment emergent (TEAE) if the first onset (or worsening in the case of pre-existing disease) 
is after the first administration of Mylan’s insulin glargine sequence group or Lantus®  sequence group (i.e. after the 
randomization) through 28 days after the last dose. 


 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
Page 27 of 39 
See Appendix 1 for handling of partial dates for AEs.  In the case where it is not possible to define an AE as treatment 
emergent or not, the AE will be classified by the worst case; i.e. treatment emergent.  
An overall summary of number of patients for each treatment period within each of the categories described in the 
sub-section below, will be provided as specified in the templates.  
Treatment sequence group comparison will be performed using Fisher’s exact test for each treatment period. P-
value for the corresponding two-sided test will be presented. 
Listings will include TEAEs and Non-TEAEs. 
17.1.1. 
ALL TEAES  
Incidence of TEAEs will be presented for each treatment period by System Organ Class (SOC) and Preferred Term 
(PT) and also broken down further by maximum severity and relationship to study medication.   
17.1.1.1. 
Severity 
Severity is classed according to CTCAE v4.03 - Grade 1/mild, Grade 2/moderate, Grade 3/severe, Grade 4/ life-
threatening, or Grade 5/Fatal. TEAEs starting after the first dose of study medication with a missing severity will be 
classified as Grade3/severe. If a patient reports a TEAE more than once within that SOC/ PT/Treatment period, the 
AE with the highest severity grade will be used in the corresponding severity summaries. 
17.1.1.2. 
Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as ” Unrelated/not related”, “Unlikely related” “possibly 
related”, “probably related” and “definitely related” (increasing severity of relationship). A “related” TEAE is defined 
as a TEAE with a relationship to study medication as “possibly related”, “probably related” and “definitely related” 
to study medication. TEAEs with a missing relationship to study medication will be regarded as “possible related” to 
study medication. If a patient reports the same AE more than once within that SOC/ PT/Treatment period, the AE 
with the worst case relationship to study medication will be used in the corresponding relationship summaries.  
All AEs, with the causal relationship to the trial drug reported as “possible”, “probable” or “definite” will be 
considered ADRs. If the relationship to the trial drug is not given, then the AE must be treated as if the relationship 
were “possible.” 
17.1.1.3. 
Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose of the investigation products 
should be considered adverse drug reactions (ADRs). The phrase “responses to an investigational product” means 
that a causal relationship between an investigational product and an AE is at least a reasonable possibility. All AEs 
judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to an 
investigational product will be designated as ADRs. 
All AEs, with the causal relationship to the trial drug reported as “possible”, “probable” or “definite” will be 
considered ADRs. If the relationship to the trial drug is not given, then the AE must be treated as if the relationship 
were “possible.” 
If a patient reports the same AE more than once within that SOC/ PT, the AE with the worst case relationship to 


 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
Page 28 of 39 
study medication will be used in the corresponding relationship summaries. 
Frequency and percentage of patients having adverse drug reactions will be presented by treatment sequence 
group, treatment period, SOC and PT. 
17.1.2. 
TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
TEAEs leading to permanent discontinuation of study medication will be identified by using the Treatment sequence 
group withdrawn field in the CRF under “Action taken with IMP/ study medication” or  recorded as “Yes” in the CRF 
under “Did the AE cause the subject to discontinue from the study?”. 
For TEAEs leading to discontinuation of study medication, summaries of incidence rates (frequencies and 
percentages) by SOC and PT will be prepared for each treatment period. 
17.1.3. 
SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events page of the (e) CRF. A 
summary of serious TEAEs by SOC and PT will be prepared for each treatment period. 
17.1.4. 
ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to death are those events which are recorded as ”Fatal” on the Adverse Events page of the (e) CRF. A 
summary of TEAEs leading to death by SOC and PT will be prepared for each treatment period. 
17.1.5. 
LOCAL OR SYSTEMIC ALLERGIC REACTION  
TEAE incidence of both local and systemic allergic reaction will be summarized by SOC and treatment sequence 
group for each treatment period. A separate listing will also be produced which include only events of local or 
systemic allergic reaction. 
17.2. LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for Hematology, Blood Chemistry, 
lipid profile and Urinalysis. A list of laboratory assessments to be included in the outputs is included in the protocol.  
Presentations will use SI Units provided the conversion factors and SI Units are shared by sponsor.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or “> X”, 
i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative summaries, 
but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
Week 52 result from MYL-GAI-3001 trial will be considered as baseline. 
The following summaries (descriptive statistics for quantitative measurements and frequency and percentage for 
qualitative measurements) will be provided for laboratory data: 


 
 
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Page 29 of 39 
 
Actual and change from baseline by visit (for quantitative measurements). 
 
Incidence of abnormal values according to normal range criteria. 
 
Shift from baseline according to normal range criteria (for quantitative measurements and/or categorical 
measurements). 
 
Shift from baseline according to markedly abnormal criteria (for quantitative measurements and/or 
categorical measurements). 
 
Listing of patients meeting markedly abnormal criteria. 
 
Change from baseline of laboratory measurements will be analyzed using MMRM with model terms of 
region, treatment sequence group, visit, treatment sequence group-by-visit interaction as fixed effects, and 
baseline value as covariate. The descriptive statistics for actual measurement and change from baseline 
along with treatment sequence group comparison will be performed at scheduled visits. LS means for each 
treatment sequence group and associated standard errors will be derived. Differences in LS means will be 
calculated and associated 2-sided 95% confidence intervals (p-value, as required) will be provided. These 
will be derived from the calculation of Type III sum-of-square and LS Means from MMRM model.  
 
The percentage of patients in categories such as abnormal/non-clinically significant and abnormal/clinically 
significant will be analyzed using Fisher’s exact test. P-value for the two-sided test will be presented. 
17.2.1. 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI units 
and categorized as: 
 
Low: Below the lower limit of the laboratory reference range.  
 
Normal: Within the laboratory reference range (upper and lower limit included). 
 
High: Above the upper limit of the laboratory reference range. 
17.3. ECG EVALUATIONS 
Results from the central ECG (Electrocardiogram) Reading Centre will be included in the reporting of this study.  
Week 52 result from MYL-GAI-3001 trial will be considered as baseline. 
Frequency and percentage of overall assessment of ECG (investigator’s judgment) will be presented. 
The percentage of patients in categories such as abnormal/non-clinically significant and abnormal/clinically 
significant will be summarized and treatment sequence group comparison will be performed using Fisher’s exact 
test. The p-value will be presented for the same. 
17.4. VITAL SIGNS  
The following vital signs measurements will be reported for this study: 


 
 
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 
Sitting Systolic Blood Pressure (mmHg) 
 
Sitting Diastolic Blood Pressure (mmHg) 
 
Sitting Pulse Rate (bpm) 
 
Respiratory Rate (breaths/min) 
 
Temperature (⁰C) 
 
Weight (kg) 
The following summaries will be provided for all above vital signs parameters data: 
 
Actual and change from baseline by visit  
 
Incidence of markedly abnormal values  
 
Listing of patients meeting markedly abnormal criteria  
Change from baseline (week 52 result from MYL-GAI-3001 trial) of vital sign measurements will be analyzed using 
MMRM with model terms of region, treatment sequence group, visit, treatment sequence group-by-visit interaction 
as fixed effects, and baseline value as covariate. The descriptive statistics including actual measurement and change 
from baseline along with treatment sequence group comparison will be performed at scheduled visits for each 
period. LS means for each treatment sequence group and associated standard errors will be derived. Differences in 
LS means will be calculated and associated 2-sided 95% confidence intervals (p-value, as required) will be provided. 
These will be derived from the calculation of Type III sum-of-square and LS Means from MMRM model.  
 
The percentage of patients in categories such as potentially clinically significant will be analyzed using Fisher’s exact 
test. P-value for the two-sided test will be presented. Descriptive statistics will also be provided as summary tables. 
17.4.1. 
POTENTIAL CLINICALLY SIGNIFICANT CHANGES 
Potential clinically significant changes in vital signs measurements will be identified in accordance with the following 
predefined markedly abnormal criteria  
 
Variable 
Unit 
Low 
High 
SBP 
mmHg 
≤ 90 mmHg AND  
change from baseline ≤ -20 mmHg 
≥ 160 mmHg AND 
change from baseline ≥ 20 mmHg 
DBP 
mmHg 
≤ 50 mmHg AND 
change from ≤ -15 mmHg 
≥ 100 mmHg AND 
change from baseline ≥ 15 mmHg 
Heart rate 
Bpm 
≤ 50 bpm AND 
change from baseline ≤ -15 bpm 
≥ 120 bpm AND 
change from baseline ≥ 15 bpm 


 
 
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Variable 
Unit 
Low 
High 
Body 
temperature 
˚C 
NA 
≥ 38.3 ˚C AND 
change from baseline ≥ 1.1 ˚C 
Weight 
Kg 
percentage change from baseline ≤ -
7.0 % 
percentage change from baseline ≥ 
7.0 % 
17.5. PHYSICAL EXAMINATION  
Listings will be generated for all physical examination tests.  
17.6. OTHER SAFETY ASSESSMENTS 
17.6.1. 
DEVICE SAFETY ASSESSMENT 
The device safety assessment will use responses to investigator-administered device questionnaires, and incidence 
of device-related AEs. 
The total incidence of device-related safety events will be summarized with each treatment sequence group both 
for device-related TEAEs and for events related to device complaints or failures. For device-related TEAEs, two 
categories will be summarized for each treatment sequence group: needle-related TEAEs such as pain, bruise, and 
bleeding; and other device-related TEAEs, such as hyperglycemia or hypoglycemia. For confirmed device-related 
malfunction or failures, incidence will be listed and summarized for each treatment sequence group. 
If there are sufficient events of any category, a Fisher exact test will be performed for treatment sequence group 
comparison. The p-value for the corresponding two-sided test will be presented. 
Number and percentage of subjects with device complaints, device complaints leading to dosing error and device 
complaints leading to an adverse event will be presented. 
. 
17.6.2. 
IMMUNOGENICITY PROFILES ANALYSES 
Following parameters will be summarized for immunogenicity. 
 
Total Insulin Antibodies  
o 
Percent Binding (%B/T,  Continuous outcome) 
o 
Positive/Negative (Categorical outcome) 
 
Cross Reactive Insulin Antibodies 
o 
Percent Binding (%B/T,  Continuous outcome) 
o 
Positive/Negative (Categorical outcome) 


 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL MYL-1501D-3003   
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 
Insulin(Drug) Specific Antibody 
o 
Percent Binding (%B/T,  Continuous outcome) 
 
Anti-HCP 
o Positive/Negative (Categorical outcome) 
 
Immunogenicity profiles with continuous variables (% binding) will be analyzed using the MMRM method for each 
assay, similar to change from baseline efficacy analyses. The model will include the terms region, treatment 
sequence group, visit, treatment sequence group-by-visit as fixed effects, and baseline value as covariate. The 
treatment sequence group difference and 95% confidence intervals will be constructed using the model at scheduled 
visits. In case the normal distribution assumption is severely violated, then non-parametric analysis will be 
performed using Wilcoxon rank-sum test for treatment sequence group comparison, Hodges Lehmann's estimator 
will be used to compute the median difference between the treatment sequence groups and the corresponding 95% 
confidence interval. Safety population will be used for ADA continuous variables. Immunogenicity profiles with 
dichotomous outcomes will be summarized with frequency and percentage at scheduled visits for each assay. 
Treatment sequence group comparison will be performed using Fisher’s exact test. P-value for the two-sided test 
will be presented.  
Correlation analyses of insulin cross-reactive antibodies with clinical factors such as HbA1c and insulin doses will be 
performed by treatment sequence group along with graphics to explore relationship of insulin antibodies with such 
factors for each assay method used. Additionally, mean (±SD) and median (IQR) for actual measurements by visit will 
also be presented. 
Regression plots will be produced to assess the consistency of results obtained between the two assay types, and 
the regression plots will be produced for Total Insulin Antibody, Cross Reactive Insulin Antibody and Insulin (Drug) 
Specific Antibody by treatment sequence group. 
 
The incidence of patients with increase over 10% cross reacting antibody increase in both assays, of HbA1c over 0.2% 
increase and insulin dose increase at any visit will also be summarized descriptively (for categorical measures) 
together to explore treatment sequence group difference. 
 
An individual data listing will be provided for the patients with increase over 10% cross reacting antibody increase 
in both assays, of HbA1c over 0.2% increase and insulin dose increase at Week 12, 24 and 36. 
The observed and Change values of HbA1c, Insulin dose, Cross reactive antibodies (Both assays) Fasting blood 
glucose, Subject's age, Duration of diabetes and Adverse events reported will be presented in the listing. 
 
Presence of anti-HCP antibodies in samples from patients will be assessed using a validated immunoassay method. 
The results will be presented as positive or negative from anti-HCP antibodies based on the samples that HCP assay 
was done. Frequency and percentage of presence of anti-HCP antibodies will be presented at scheduled visits by 
treatment sequence group. The p-value from Fisher’s exact test will be presented to test the difference between the 
treatment sequence groups for scheduled visits. 
17.6.3. 
HYPOGLYCEMIA ANALYSES 
Hypoglycemia is a state produced by a lower than normal level of glucose in the blood. Hypoglycemia is classified as 
severe, documented symptomatic, asymptomatic, probable symptomatic, relative, or nocturnal hypoglycemia. The 
details of Classification can be found in protocol Sections 7.4.8 and 7.5.6.1. 


 
 
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Patients will be instructed to record all hypoglycemic events in the patient diary from visit 2 until the EOT visit. The 
hypoglycemic events will be reviewed by the investigator and transcribed into the eCRF by the investigator or 
designee after the diary has been collected. 
Hypoglycemia rate per patient per 30 days calculated between two visits is defined as total number of episodes 
between two visits divided by the number of days between the visits, multiplied by 30 days. This rate will also be 
calculated per patient for nocturnal hypoglycemia episodes.   
Hypoglycemia rate per patient per 30 days will be analyzed at all scheduled visit using MMRM method similar to the 
continuous efficacy variables at scheduled visits. The model will include the terms region, treatment sequence group, 
visit, visit-by-treatment sequence group as fixed effects, and baseline value as covariates. The rate per patient per 
30 days calculated between two visits is defined as total number of episodes between two visits divided by the 
number of days between the visits, multiplied by 30 days. This rate will also be calculated per patient for nocturnal 
hypoglycemia episodes. In case the normal distribution assumption is severely violated, then non-parametric 
analysis will be performed using Wilcoxon rank-sum test for treatment sequence group comparison, Hodges 
Lehmann's estimator will be used to compute the median difference between the treatment sequence groups and 
the corresponding 95% confidence interval. 
Due to the uneven visit intervals for scheduled visits, additional exploratory analyses for hypoglycemia rate per 
patient per 30 days based only on the SMBG week (during the week the SMBG is done) for each visit will be 
performed using same method as above. 
The similar analysis will be done for asymptomatic hypoglycemia rate separately based only on SMBG week and 
none SMBG week. 
For change from baseline of hypoglycemia rate, for graphical display at scheduled visits, LS means and 95% CI will 
be generated from the MMRM model.  Additionally, mean (±SD) and median (IQR) for actual measurements by visit 
will also be presented.   
The incidence of hypoglycemic episodes during a time period on treatment is defined as the incidence of patients 
with at least one hypoglycemic episode occurring within that period of time. Incidence of hypoglycemic episodes 
will be presented by treatment sequence group, visit and overall. Incidence of hypoglycemic episodes will also be 
summarized by category (Severe Hypoglycemia, Documented Symptomatic Hypoglycemia, Asymptomatic 
Hypoglycemia, Probable Symptomatic Hypoglycemia, Relative Hypoglycemia and Nocturnal Hypoglycemia). The 
detailed definition of each type of hypoglycemic event is mentioned in the protocol Section 7.5.6.1. 
In addition, nocturnal hypoglycemia rate and incidence will be analyzed in a same way as overall hypoglycemic 
episodes 
Listings of hypoglycemic episodes and severe hypoglycemic episodes will be presented by visit for each patient. If a 
sufficient number of severe hypoglycemic episodes are reported, then incidence summaries similar to the incidence 
of hypoglycemic episodes will be included. 
18. DATA NOT SUMMARIZED OR PRESENTED 
Not Applicable 
 
 


 
 
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19. REFERENCES  
Dobson, A. J. (2002). An introduction to generalized linear models, 2nd ed. Chapman & Hall/CRC. 
Little, R., & Yau, L. (1996). Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs. Biometrics , vol 52, 
1324-1333. 
 
 
 
 


 
 
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Page 35 of 39 
APPENDIX 1. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, 
but 
known 
components show that it 
cannot be on or after study 
med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
study med start date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 


 
 
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START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant  
If stop date >= study med start date and start date > end of treatment, 
assign as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 


 
 
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START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 
 
 


 
 
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APPENDIX 2. 
MAJOR PROTOCOL DEVIATIONS 
The major protocol deviations are defined in the following table: 
 
PD header as per 
Protocol 
Specific example database
Patient not meeting the 
following selection 
criteria (inclusion and 
exclusion) at screening 
but still included in the 
study 
Patients recruited in to the study violating the selection criteria 
Insulin was initiated only after 6 months of T1DM diagnosis 
Patient was on basal-bolus insulin therapy for at least 1 year before 
screening 
Patient was on once daily Lantus® at stable dose 
Lab criteria 
Efficacy criteria - HbA1c  
Safety criteria - ECG, Eye testing, Safety lab tests, Hb, LDL, TG, ALT, AST, 
Creatinine, Vital signs, HT  
Other criteria - C peptide, BMI, infectious samples, drug abuse,   
Insulin resistance, age 
Patient continued in the 
study despite meeting 
study discontinuation 
criteria 
Protocol specified withdrawal criteria 
Withdrawal of consent 
Use of prohibited medications [insulin, insulin analogs and other 
anti-diabetes medications as well as glucocorticoid therapy (oral, 
intravenous, inhaled or other routes that produce systemic effects)] 
For female patients, diagnosis of pregnancy or a stated intention to 
become pregnant. 
Repeated non-compliance as determined by the investigator in a 
consolidated overall evaluation of compliance 
At the investigator’s discretion, for safety issues such as severe 
hypoglycemia or hypoglycemic unawareness. 
At the investigator’s discretion, in certain situations such as 
significant intercurrent illness, hospitalization for surgery, or an SAE 
which in the opinion of the investigator warrants withdrawal. 
Failure to perform tests 
or procedures which will 
impact the 
interpretation of key 
endpoints of the study 
HbA1c not tested at screening, randomization, 12th  and 24th week visit (all 
missed) 
Patient not following 
treatment regimen 
mentioned in the 
protocol 
Patient was not given the assigned IP (instead of test medication, 
comparator medication was given) 
Using insulin Glargine that is not IMP and part of the study during the study 
period 
Study procedure issue 
Study completed without signing ICF 
Sponsor unapproved IP used (temperature or humidity excursion prove. 
For a patient recruited from Germany, Name, date of birth, or information 


 
 
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revealing patient identify was captured and it is not acceptable as per the 
German law