Conditions: Diabetes Mellitus, Type 1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 219
Healthy volunteers: no

Brief summary:
The aim of this study is to demonstrate similar efficacy and safety between MYL-1501D products produced from two manufacturing processes (Process V and Process VI) in combination with insulin lispro in patients with type 1 diabetes mellitus (T1DM).

Detailed description:
This is a multicenter, double-blind, randomized, parallel-group Phase 3 study in subjects with type 1 diabetes mellitus (T1DM) comparing the efficacy, immunogenicity, and safety of MYL-1501D products from 2 manufacturing processes (Process V and Process VI). After a 2-week screening period, all subjects will be titrated on Lantus® during a 4-week run-in period and shifted from their current mealtime insulin to insulin lispro (Humalog®). Subjects will then be randomized (stratified by time of administration of glargine \[morning and evening\]) to 1 of 2 groups:

* MYL-1501D product from Process V
* MYL-1501D product from Process VI Treatment with MYL-1501D is for 18 weeks. A follow-up visit is scheduled 2 weeks after last dose of MYL 1501D.

Arms:
arm 1: MYL-1501D (Process V Product) arm 2: MYL-1501D (Process VI Product)

Interventions: intervention 1: MYL-1501D product using manufacture process V intervention 2: MYL-1501D product using manufacture process VI
Intervention descriptions: intervention 1: MYL-1501D product using manufacture process V intervention 2: MYL-1501D product using manufacture process VI

Protocol document:
Prot_001.pdf: 
Table of Contents 
16.
Appendices ....................................................................................................................2
16.1 Study Information .........................................................................................................3 
16.1.1 Protocol and Protocol Amendments ........................................................................ 4 
Clinical Study Protocol, Version 1.0, 08 Sep 2017 ..............................................................5 
Clinical Study Protocol, Version 2.0, 11 Jan 2018 ............................................................. 69 
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16. 
Appendices 
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16.1 
Study Information 
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16.1.1 Protocol and Protocol Amendments 
Protocol Version / Amendment 
Date 
Version 1.0 
08 Sep 2017 
Version 2.0 
11 Jan 2018 
 
 
 
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MYL-1501D Protocol 18 SEP 2017 
Confidential 
 
MYL-1501D-3004 CLINICAL STUDY PROTOCOL 
Protocol Title 
A Randomized, Multi-center, Double-Blind, Parallel-Group Clinical 
Study Comparing the Efficacy and Safety of MYL-1501D Produced by 
Two Manufacturing Processes in Type 1 Diabetes Mellitus Patients 
Product 
MYL-1501D (Mylan’s Insulin Glargine)  
Protocol No. 
MYL-1501D-3004 
Study Type 
Phase 3 
Version 
Final 
Protocol Date 
08 Sep 2017 
Revision Date 
N/A 
IND No.  
IND 105279 
Sponsor 
Mylan GmbH 
Thurgauerstrasse, 40 
CH 8050 Zürich, Switzerland 
 
Confidentiality: This protocol is the confidential, intellectual property of Mylan GmbH. It 
should not be disclosed to a third party with the exception of regulatory agencies and study 
audit personnel that being Mylan employees, representatives, agents and/or contractors 
responsible for conducting the clinical study, audits. Reproduction, modification, or adaption 
in part or in total is strictly forbidden without prior written approval by Mylan GmbH  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Multi-center, Double-Blind, Parallel-Group Clinical 
Study Comparing the Efficacy and Safety of MYL-1501D Produced by 
Two Manufacturing Processes in Type 1 Diabetes Mellitus Patients 
Background 
and Rationale 
MYL-1501D is being developed as a follow-on biologic to the reference 
product Lantus® (insulin glargine). A phase 1 PK/PD study comparing 
MYL-1501D with Lantus® sourced from Europe and U.S. demonstrated 
PK and PD equivalence between the 3 products. PK/PD equivalence was 
also demonstrated with MYL-1501D product produced using two 
manufacturing processes (Process V and Process VI).  
 
The aim of this study is to demonstrate similar efficacy and safety 
between MYL-1501D products produced from two manufacturing 
processes (Process V and Process VI) in combination with insulin lispro 
in patients with type 1 diabetes mellitus (T1DM). 
Primary 
Objectives 
To test whether MYL-1501D product from Process VI once daily is 
non-inferior to MYL-1501D product from Process V once daily based on 
change in HbA1c from baseline to week 18 when administered in 
combination with mealtime insulin lispro. 
Primary 
endpoints 
The primary efficacy endpoint is change in HbA1c from baseline to week 
18 for the ITT analysis set. 
Methodology 
and 
treatments 
This is a multicenter, double-blind, randomized, parallel-group phase 3 
study in subjects with T1DM comparing the efficacy, immunogenicity 
and safety of MYL-1501D products from two manufacturing processes 
(Process V and Process VI).  
After up to 2-week screening period, all subjects will be titrated on 
Lantus® during a 4-week run-in period, and will be shifted from their 
current mealtime insulin to Humalog®. The subjects will be randomized 
(stratified by time of administration of glargine [morning and evening]); 
one group will receive MYL-1501D product from Process V, while the 
other group will receive MYL-1501D product from Process VI for 18 
weeks. A follow-up visit will be scheduled 2 weeks after last dose of 
MYL-1501D. 
The study will be conducted in the US. Approximately 110 sites will be 
included in the study. 
Inclusion/ 
exclusion 
criteria 
Inclusion criteria 
1. Written and signed informed consent needs to be provided by subjects or 
their legal representatives before starting any protocol-specific 
procedures.  
2. Male and female subjects between the ages of 18 to 65 years, both ages 
inclusive. 
3. Subjects with an established diagnosis of T1DM per ADA 2017 criteria 
who also fulfil the following criteria: 
a. Initiation of insulin treatment within 6 months of T1DM 
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diagnosis 
b. Treatment with basal-bolus insulin therapy for at least 1 year 
before screening 
c. Fasting plasma C-peptide <0.3 nmol/L at screening 
d. Subject has been on once daily Lantus® at stable dose (±15% 
variation in dose) for at least 3 months at screening 
4. Body mass index (BMI) of 18.5 to 35 kg/m2 at screening (both values 
inclusive). 
5. Stable weight, with no more than 5 kg gain or loss in the 3 months prior 
to screening, this information will be collected by subject interview 
during medical history. 
6. Glycosylated hemoglobin (HbA1c) ≤ 9.5% at screening. 
7. Hemoglobin ≥9.0 g/dL at screening. 
8. Subject has the capability of communicating appropriately with the 
investigator.  
9. Subject is able and willing to comply with the requirements of the study 
protocol including the 8-point self-monitored blood glucose (SMBG), 
completion of subject diary records and following a recommended diet 
and exercise plan for the entire duration of the study. 
10. Female subjects of childbearing potential who are willing to use oral 
contraception or two acceptable methods of contraception, (e.g., intra-
uterine device plus condom, spermicidal gel plus condom, diaphragm 
plus condom, etc.), from the time of screening and for the duration of the 
study, through study completion. 
a. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
b. Postmenopausal females must have had no regular menstrual 
bleeding for at least 1 year prior to screening.  
c. Female subjects who report surgical sterilization must have had 
the procedure at least 6 months prior to screening.  
d. All female subjects of childbearing potential must have negative 
pregnancy test results at screening and at clinic visits, as per the 
SCHEDULE OF ACTIVITIES (SOA). 
e. If female subjects have male partners who have undergone 
vasectomy, the vasectomy must have occurred more than 6 
months prior to screening 
Exclusion Criteria 
1. History or presence of a medical condition or disease that in the 
investigator’s opinion would place the subject at an unacceptable risk 
from study participation. 
2. History of hypersensitivity to any of the active or inactive ingredients of 
the insulin/insulin analogue preparations used in the study, OR history 
of significant allergic drug reactions. 
3. History of use of animal insulin within the last 3 years or use of 
approved biosimilar insulin glargine at any time prior to study entry, 
except for subject who previously participated in MYL-1501D studies 
and were compliant with the study protocols.  
4. History of use of a regular immunomodulator therapy in the 1 year prior 
to screening. 
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5. History of autoimmune disorders other than T1DM or insufficiently 
treated autoimmune thyroid disorders judged clinically relevant by the 
investigator (recorded while collecting subject history). 
6. History of ≥1 episodes of diabetic ketoacidosis or emergency room visits 
for uncontrolled diabetes leading to hospitalization within the 6 months 
prior to screening. 
7. History of clinically significant acute bacterial, viral or fungal systemic 
infections in the last 4 weeks prior to screening (recorded while 
collecting subject history). 
8. Any clinically significant abnormality in electrocardiogram (ECG) or 
safety laboratory tests (LFT, RFT, hematology or any other laboratory 
deemed clinically relevant by the investigator) conducted at screening 
and considered by the investigator to make the subject ineligible for the 
study. 
9. Serological evidence of human immunodeficiency virus (HIV), hepatitis 
B surface antigen (HbSAg) or hepatitis C antibodies (HCVAb) at 
screening. 
10. History of drug or alcohol dependence or abuse during the 1 year prior 
to screening. 
11. Receipt of another investigational drug in the 3 months prior to 
screening (or as per local regulations), or if the screening visit is within 
5 half-lives of another investigational drug received (whichever is 
longer), or scheduled to receive another investigational drug during the 
current study period. 
12. Subjects with the following secondary complications of diabetes: 
a. Active proliferative retinopathy as confirmed by a dilated 
ophthalmoscopy examination / retinal photography (performed 
by a person legally authorized to do so) within the 6 months 
prior to screening. 
b. Clinical nephrotic syndrome or diabetic nephropathy with a 
serum creatinine level >1.5 times of upper limit of reference 
range at screening 
c. History of severe form of neuropathy or cardiac autonomic 
neuropathy, recorded while collecting subject history. 
Subject’s with mild or moderate forms of neuropathy will be 
allowed. 
d. Subjects with a history of limb amputation as a complication of 
diabetes (at any time), or any vascular procedure during the 1 
year prior to screening. 
e. History of diabetic foot or diabetic ulcers in the 1 year prior to 
screening. 
13. Any elective surgery requiring hospitalization planned during the study 
period. 
14. Clinically significant major organ disorder at the time of screening 
including: 
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a. Uncontrolled hypertension, defined as stage 2 hypertension by 
Joint National Committee VII (even if therapy is ongoing, blood 
pressure ≥160 mm Hg systolic or ≥100 mm Hg diastolic). 
b. Uncontrolled hyperlipidemia (even if therapy is ongoing, LDL 
>160 mg/dL or triglycerides >500 mg/dL). 
c. Uncontrolled hyperthyroidism or hypothyroidism (subjects can 
be included if these conditions are controlled with thyroid 
hormones or anti-thyroid drugs). 
d. Impaired hepatic function (alanine transaminase [ALT] or 
aspartate transaminase [AST] value >2 times the upper limit of 
the reference range and/or serum bilirubin 1.5 times the upper 
limit of the reference range at the screening visit). Subjects with 
evidence of Gilberts disease may be included in the study if they 
have total bilirubin of <3 mg/dL with indirect bilirubin 
contributing to >80% of the total bilirubin. 
15. History of a significant medical condition, such as: 
a. Clinically significant cardiac disease like unstable angina, 
myocardial infarction, grade 3 or 4 congestive heart failure 
(CHF) according to New York Heart Association criteria, 
valvular heart disease, cardiac arrhythmia requiring treatment, 
and pulmonary hypertension; during the year prior to screening. 
b. Stroke or transient ischemic attack (TIA) in the 6 months before 
screening.  
16. Subjects with major depressive illness in the last 3 years (those who 
have well-controlled depression for 3 months on a stable dose of 
antidepressants, with no major depressive episodes in the last 3 years, 
can be included, even if they are on medication), subjects with history of 
other severe psychiatric diseases (manic depressive psychosis [MDP], 
schizophrenia), which in the opinion of the investigator precludes the 
subject from participating in the study (recorded while collecting subject 
history). 
17. History of hematological disorders that can affect the reliability of 
HbA1c estimation (hemoglobinopathies, hemolytic anemia, sickle cell 
anemia, etc.). 
18. Subjects using the following in the 3 months prior to screening: 
a. Insulin pump therapy 
b. Any anti-diabetic drugs other than the study insulins allowed by 
the protocol. 
19. Moderate insulin resistance, defined as requiring insulin of ≥1.5 
U/IU/kg/day. 
20. Subjects who have received ≥14 consecutive days of glucocorticoid 
therapy by oral, intravenous, inhaled or other routes that produce 
systemic effects within the past 1 year, or who have received steroids by 
any route (except intra-nasal, intra-ocular, and topical) within the 4 
weeks immediately preceding screening.  
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21. Subjects diagnosed as having cancer (subjects with history of basal cell 
carcinoma, carcinoma in situ or squamous cell cancer of skin, or in 
remission >5 years, will be allowed). 
22. Subjects who have donated blood or plasma in the 1 month prior to 
screening 
Sample size 
A total of 202 subjects with T1DM are planned to be randomized for this 
study and will receive either MYL-1501D Process V product or MYL-
1501D Process VI product, in a 1:1 ratio.  
The sample size estimation is based on assumptions for the change from 
baseline up to week 18 in HbA1C with either MYL-1501D product from 
Process V or Process VI. It is assumed, that true mean groups mean 
difference is 0.03 and standard deviation is equal to 0.74. To demonstrate 
non-inferiority margin of 0.4% using a 2-sided 95% confidence interval 
and a 90% power, a total of 172 subjects (86 subjects per treatment group) 
are required. To account for a maximum of 15% of subjects being not 
eligible for the per protocol analysis, a total sample size of 202 is planned 
to be randomized for this study. The true treatment difference and 
standard deviation is based on previous study MYL-GAIA-3001. 
Statistical 
Methods 
A repeated measures analysis employing a restricted maximum likelihood 
(REML)-based, mixed model repeated measures (MMRM)-effects model 
approach will be used to estimate a 95% confidence interval for the 
absolute difference between MYL-1501D Process V product and MYL-
1501D Process VI product for mean change in HbA1c at Week 18. 
Non-inferiority for primary objective will be established if the upper limit 
of a two sided 95% confidence interval for the absolute difference 
(MYL-1501D Process VI minus MYL-1501D Process V) of mean change 
from baseline for HbA1c is no greater than 0.4% at 18 weeks of 
treatment. 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .......................................................................................................... 3 
LIST OF COMMONLY USED ABBREVIATIONS.............................................................. 14 
1 
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES ............................. 15 
2 
INTRODUCTION ........................................................................................................... 19 
2.1 
Indication ................................................................................................................. 19 
2.2 
Background and Rationale ....................................................................................... 19 
2.2.1 
Rationale for Dose Selection ............................................................................... 20 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 21 
3.1 
Objectives ................................................................................................................ 21 
3.1.1 
Primary objectives ............................................................................................... 21 
3.1.2 
Other objectives ................................................................................................... 21 
3.2 
Endpoints ................................................................................................................. 21 
3.2.1 
Primary Endpoints ............................................................................................... 21 
3.2.2 
Secondary Endpoints ........................................................................................... 21 
3.2.2.1 Efficacy ......................................................................................................... 21 
3.2.2.1 Safety ............................................................................................................. 21 
4 
STUDY POPULATION .................................................................................................. 22 
4.1 
Study Population ...................................................................................................... 22 
4.2 
Inclusion and Exclusion Criteria .............................................................................. 22 
4.2.1 
Inclusion Criteria ................................................................................................. 22 
4.2.2 
Exclusion Criteria ................................................................................................ 23 
4.2.3 
Criteria for study drug termination, withdrawal from the study and study 
termination ....................................................................................................................... 25 
4.3 
Contraception ........................................................................................................... 26 
4.3.1 
Females - Non-childbearing Potential ................................................................. 26 
4.3.2 
Females - Childbearing Potential ......................................................................... 26 
4.4 
Pregnancy Testing .................................................................................................... 27 
5 
STUDY DRUG ................................................................................................................ 28 
5.1 
Investigational Drug ................................................................................................ 28 
5.1.1 
Administration of Study Drugs ............................................................................ 28 
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5.2 
Study Medication Complaints ................................................................................. 29 
5.3 
Storage, Disposition of Unused Study Drug and Drug Accountability ................... 29 
5.4 
Randomization ......................................................................................................... 30 
5.5 
Breaking the Blind ................................................................................................... 30 
5.6 
Concomitant Medications ........................................................................................ 30 
5.7 
Recommended Procedure for Subject Experiencing Adverse Effects Secondary to 
Excessive Pharmacological Effects of Study Drug ............................................................. 31 
6 
STUDY CONDUCT ........................................................................................................ 32 
6.1 
Screening Procedures ............................................................................................... 32 
6.1.1 
Screening (Visit 1 [Week -6 to Week -4]) ........................................................... 33 
6.2 
Run-in Period ........................................................................................................... 34 
6.2.1 
Visit 2 (Week -4) ................................................................................................. 34 
6.2.2 
Visit 3 (Week -3), Visit 5 (Week -1) ................................................................... 34 
6.2.3 
Visit 4 (Week -2) ................................................................................................. 34 
6.3 
Treatment phase ....................................................................................................... 35 
6.3.1 
Visit 6 (Week 0) ................................................................................................... 35 
6.3.2 
Visit 7 (Week 1), Visit 9 (Week 4), Visit 11 (Week 9) ....................................... 36 
6.3.3 
Visit 8 (Week 2), Visit 10 (Week 6) .................................................................... 36 
6.3.4 
Visit 12 (Week 12) ............................................................................................... 37 
6.3.5 
Visit 13 (Week 15) ............................................................................................... 37 
6.3.6 
Visit 14/ End of Treatment (Week 18) ................................................................ 38 
6.3.7 
Early study drug Termination (ET) visit .............................................................. 39 
6.4 
Visit 15 Follow up (Week 20) (telephone call) ....................................................... 39 
6.5 
Treatment Procedures .............................................................................................. 39 
6.5.1 
Blood Volume ...................................................................................................... 40 
6.5.2 
Safety Testing Assessments ................................................................................. 40 
6.5.2.1 Adverse Event Assessment ........................................................................... 40 
6.5.2.2 Hypoglycemia ............................................................................................... 40 
6.5.2.3 Laboratory Safety .......................................................................................... 43 
6.5.2.4 Immunogenicity Assessment......................................................................... 43 
6.5.2.5 Blood Pressure and Pulse Rate ...................................................................... 44 
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6.5.2.6 12-lead ECG .................................................................................................. 45 
6.5.2.7 General Physical Examination ...................................................................... 45 
7 
STATISTICAL ANALYSIS ........................................................................................... 46 
7.1 
Sample Size Determination ..................................................................................... 46 
7.2 
Primary Endpoints ................................................................................................... 46 
7.2.1 
Definition of Primary Endpoints .......................................................................... 46 
7.2.2 
Statistical Methodology for Primary Endpoints .................................................. 46 
7.2.3 
Primary Analysis for Primary Endpoints ............................................................. 47 
7.2.4 
Secondary/Sensitivity Analyses for Primary Endpoints ...................................... 47 
7.2.5 
Missing Data ........................................................................................................ 47 
7.2.6 
Sub-Group Analyses ............................................................................................ 47 
7.3 
Secondary Endpoints ............................................................................................... 47 
7.4 
Analysis Set Definitions .......................................................................................... 48 
7.5 
Other Safety Analyses ............................................................................................. 49 
7.5.1 
Vital Signs ............................................................................................................ 49 
7.5.2 
ECG Analyses ...................................................................................................... 49 
7.5.3 
Laboratory Data ................................................................................................... 49 
8 
ADMINISTRATIVE PROCEDURES ............................................................................ 51 
8.1 
Source Documentation Forms ................................................................................. 51 
8.2 
Access to Data/Source Documentation .................................................................... 51 
8.3 
Final Clinical Study Report and Case Report Forms (CRFs) .................................. 51 
8.4 
Adherence to Protocol ............................................................................................. 51 
8.5 
Data Handling and Record Retention ...................................................................... 52 
8.6 
Confidentiality ......................................................................................................... 52 
8.7 
Ethics and Regulatory Authorities ........................................................................... 52 
8.7.1 
Institutional Review Board/Ethics Committee .................................................... 52 
8.7.2 
Regulatory Authority ........................................................................................... 53 
8.8 
Informed Consent .................................................................................................... 53 
8.9 
Disclosure and Publication of Clinical Study Data ................................................. 53 
8.10 
End of Study ............................................................................................................ 53 
9 
ADVERSE EVENT REPORTING.................................................................................. 54 
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9.1 
Adverse events ......................................................................................................... 54 
9.2 
Definitions ............................................................................................................... 54 
9.2.1 
Adverse Events .................................................................................................... 54 
9.2.2 
Adverse Drug Reaction ........................................................................................ 54 
9.2.3 
Unexpected Adverse Event/Adverse Drug Reaction ........................................... 54 
9.2.4 
Serious Adverse Events ....................................................................................... 55 
9.3 
Management of Adverse Events .............................................................................. 56 
9.3.1 
Collection ............................................................................................................. 56 
9.3.2 
Evaluation ............................................................................................................ 56 
9.3.2.1 Severity Assessment of Adverse Events ....................................................... 56 
9.3.2.2 Action Taken ................................................................................................. 57 
9.3.2.3 Outcome at the Time of Last Observation .................................................... 57 
9.3.2.4 Causality Assessment of Adverse Events ..................................................... 58 
9.3.2.5 Documentation .............................................................................................. 59 
9.3.2.6 Treatment of Adverse Events ........................................................................ 59 
9.3.2.7 Follow-up ...................................................................................................... 60 
9.3.2.8 Notification.................................................................................................... 60 
9.3.2.9 Regulatory Reporting .................................................................................... 61 
9.4 
Special Situations ..................................................................................................... 61 
9.4.1 
Pregnancy ............................................................................................................. 61 
9.4.2 
Overdose, Medication Errors and Other Events .................................................. 62 
9.5 
Abnormal Test Findings .......................................................................................... 62 
10 REFERENCE LIST ......................................................................................................... 64 
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LIST OF TABLES 
 
Table 1: Study Schedule of Activities ..................................................................................... 16 
Table 2: List of Prohibited Medication .................................................................................... 31 
Table 3: Blood Volume ............................................................................................................ 40 
Table 4: Laboratory Safety Tests ............................................................................................. 43 
Table 5: Clinical Severity of Adverse Events .......................................................................... 57 
Table 6: Action Taken for an Adverse Event .......................................................................... 57 
Table 7: Definition of Suspected Relationship between the Events and Study Medication .... 58 
 
 
 
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LIST OF FIGURES 
Figure 1: Study Diagram .......................................................................................................... 15 
 
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LIST OF COMMONLY USED ABBREVIATIONS 
ADA 
American Diabetes Association 
 
mL 
Milliliter 
ADR 
Adverse drug reaction 
 
MMRM 
Mixed Model Repeated 
Measures 
AE 
Adverse event 
 
PD 
Pharmacodynamic 
ALT 
Alanine transaminase 
 
PK 
Pharmacokinetic 
AST 
Aspartate transaminase 
 
PP 
Per Protocol 
BMI 
Body mass index 
 
PSRM 
Product Safety and Risk 
Management 
bpm 
beats per minute 
 
SMBG 
Self-monitored blood glucose 
cm 
centimeter 
 
REML 
Restricted maximum likelihood 
CI 
Confidence interval 
 
RIPA 
Radioimmunoprecipitation assay 
CRF 
Case Report Form 
 
SAE 
Serious Adverse Event 
CRO 
Contract Research Organization 
 
SAP 
Statistical Analysis Plan 
CV 
Coefficient of Variation 
 
SD 
Standard Deviation 
ECG 
Electrocardiogram 
 
SID 
Subject Identification 
FDA 
Food and Drug Administration 
 
SMBG 
Self-monitored blood glucose 
GCP 
Good Clinical Practice 
 
SOA 
Schedule of Activities 
HbA1c 
Glycosylated hemoglobin 
 
SOP 
Standard Operating Procedure 
HbSAg  
Hepatitis B Surface Antigen  
 
T1DM 
Type 1 diabetes mellitus 
HCVAb 
Hepatitis C antibodies 
 
TEAE 
Treatment emergent adverse 
event 
HIV 
Human Immunodeficiency 
Virus 
 
US 
United States 
HR 
Heart Rate 
 
WoCBP 
Women of Child-Bearing 
Potential 
IB 
Investigator’s Brochure 
 
 
 
ICF 
Informed Consent Form 
 
 
 
ICH 
International Council for 
Harmonisation 
 
 
 
IEC 
Independent ethics committee 
 
 
 
IRB 
Institutional Review Board 
 
 
 
IVRS/IWRS 
Interactive Voice Response 
System/ Interactive Web 
Response System 
 
 
 
ITT 
Intent to treat 
 
 
 
kg 
kilogram 
 
 
 
LOCF 
Last Observation Carried 
Forward 
 
 
 
MedDRA 
Medical dictionary for 
regulatory activities 
 
 
 
mg 
Milligram 
 
 
 
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Confidential 
1 
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES 
The Schedule of Activities table provides an overview of the protocol visits and procedures. Refer to the Study Conduct Section (Section 6) for 
detailed information on each procedure and assessment required for compliance with the protocol. 
Figure 1: Study Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                              
 
Overall Study Duration- 26 Weeks 
Screening  
Run- in Period 
Treatment Period 
Follow -up 
2 weeks  
4 weeks 
18 weeks 
2 weeks 
S
C
R
E
E
N
I
N
G 
R
A
N
D
O
M
I
Z
E 
E
O
T  
F
U
P  
MYL-1501D (Process V Product) 
MYL-1501D (Process VI Product) 
Lantus 
V
1 
V
2 
V
3 
V
5 
V 
4 
V
6 
V
1
4 
V
7 
V
8 
V
9 
V 
1
0 
V
1
1 
V 
1
2 
V 
1
3 
V
1
5 
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Table 1: Study Schedule of Activities 
Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-up 
Study Visits1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
(EOT) 
V15 (FU) 
Study Week 
-6 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
6 
9 
12 
15 
18 
20 
Study Days 
-42 to -28 -28±3 -21±3 -14±3 -7±3 0±3 
7±3 
14±3 28±3 42±3 70±7 84±7 112±7 
126±7 
140±7 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
History of previous insulin usage 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated Ophthalmoscopy / retinal 
photography if not done in the last 6 
months 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard-of-care specifics2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Age, Gender, Height, Race 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight and BMI 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Pregnancy Test3 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Medical History including concomitant 
illness 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
x 
x 
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 
 
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Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-up 
Study Visits1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
(EOT) 
V15 (FU) 
Study Week 
-6 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
6 
9 
12 
15 
18 
20 
Study Days 
-42 to -28 -28±3 -21±3 -14±3 -7±3 0±3 
7±3 
14±3 28±3 42±3 70±7 84±7 112±7 
126±7 
140±7 
Physical examination 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
12-lead ECG (supine) 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
Randomization 
 
 
 
 
 
x 8 
 
 
 
 
 
 
 
 
 
Record AEs and SAEs (including local 
and systemic allergic reactions) and 
hypoglycemic events4 due to 
medication, disposable pen or needle 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record device safety information 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Fasting plasma glucose 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
HbA1c Assay 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
Fasting C-peptide, HIV, HBsAg, and 
HCVAb 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sampling for hematology, blood 
chemistry and urinalysis5 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
Fasting lipid profile 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
Sampling for immunogenicity 9 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
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Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-up 
Study Visits1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
(EOT) 
V15 (FU) 
Study Week 
-6 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
6 
9 
12 
15 
18 
20 
Study Days 
-42 to -28 -28±3 -21±3 -14±3 -7±3 0±3 
7±3 
14±3 28±3 42±3 70±7 84±7 112±7 
126±7 
140±7 
Sampling for PK6 
 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Review 8-point SMBG Profile 
performed in the week before the visit 7 
 
 
x 
x 
x 
x 
 
 
 
x 
 
x 
 
x 
 
Dose review of Lantus, MYL-1501D 
and insulin lispro and instruction 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dispense Study Medication and ancillary
supplies 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
 
 
Drug Accountability and Compliance 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Dispense subject diary 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
 
 
Review subject diary 
 
 
 
x 
 
x 
 
 
 
x 
 
x 
 
x 
 
1. 
Visits 3, 5, 7, 9 and 11 may be telephone contacts (grey columns represent telephone contacts). 
2. 
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. 
3. 
Serum pregnancy test for women of child bearing potential will be done during screening and randomization visit. During subsequent visits urine pregnancy test will be done. At the randomization visit, both urine 
and serum pregnancy tests will be done. Subject may be enrolled if the urine pregnancy test is negative. 
4. 
Non-severe hypoglycemic events (which are not consider as SAE) occurring after the EOT visit will not be recorded at the follow-up visit.  
5. 
A routine urine dipstick test will be performed by the site. A microscopic urinalysis will be performed by the central lab if the dipstick test result is abnormal. 
6. 
The PK sample will be taken during the visit, preferably prior to the daily glargine dose. The timing of study drug administration from prior day should be collected along with the time of PK sample collection.  
7. 
The 8-point SMBG profile, measurement will be done by the subject at home on 3 days (of which 2 are consecutive days) in the week before the next visit. Evaluation will be based on the measurements after 
each 6 weeks; thus during randomized period it would done at Week 6, 12 and 18, while SMBG would be done on 3 days during Weeks 5, 11 and 17. 
8. 
Prior to randomization, Investigator is required to confirm subject eligibility into the study based on the data collected during the screening period, including the labs values recorded during screening. In case 
subject does not meet the eligibility re-screening need to be confirmed by the Sponsor or designee. 
9. 
During the Randomized Comparative Treatment Period, the immunogenicity samples should be drawn immediately following the PK sample, as outlined under Footnote 6.
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2 
INTRODUCTION 
2.1 
Indication 
MYL-1501D is being developed as a follow-on biologic (US terminology) or biosimilar (EU 
terminology) to Lantus®.  
2.2 
Background and Rationale 
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 main 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. 
The Diabetes Control and Complications Trial [2] and other trials [3] provide conclusive 
evidence that maintaining tight glycemic control can prevent or delay microvascular and 
macrovascular complications in patients with T1DM. A number of different insulin regimens 
have been proposed for treatment of patients with T1DM. It is generally accepted that the so-
called basal-bolus insulin regimen (1 or 2 daily injections of long/intermediate-acting insulin 
covering basal insulin requirements in combination with 3 daily injections of short-/rapid 
acting insulin to cover meal-related insulin requirements) generally yields the best glycemic 
control in diabetes. Clear targets for plasma glucose levels have been recommended for basal-
bolus insulin regimens [4]. 
Different insulin preparations are available for management of basal insulin requirements, 
including intermediate-acting insulins (neutral protamine Hagedorn insulin) and long-acting 
insulin analogs such as insulin glargine and insulin detemir. 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. After injection of Insulin glargine into the 
subcutaneous tissue, the acidic solution is neutralized; leading to formation of micro-
precipitates from which small amounts of insulin glargine are continuously released, 
providing a smooth, peakless, predictable concentration versus time profile with a prolonged 
duration of action.  
MYL-1501D 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.  
The aim of this study is to demonstrate similar efficacy and safety between MYL-1501D 
product produced from two manufacturing processes in combination with insulin lispro in 
patients with T1DM. 
Since the two investigational products have an identical presentation of prefilled pen to be 
used by the subjects during the treatment period, the subject and the treating physician will 
remain blinded to treatment assignment. Furthermore, the evaluation of the study endpoints, 
such as analysis of immunogenicity and glycosylated hemoglobin (HbA1c), will be 
performed in a blinded manner by blinded personnel. The sponsor team as well as the CRO 
team will also be blinded to the subject assigned treatment. 
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To ensure that both treatment arms are comparable at baseline with respect to drug-induced 
immune responses and other parameters, only subjects who have been on a stable dose of 
Lantus® for at least 3 months prior to screening will be included.  
During the 4-week run-in period with Lantus® and Humalog®, the dose of insulin will be 
titrated (if required) to ensure diabetes control. The run-in period ensures comparable drug 
exposure for all subjects, and increases the likelihood of comparable immune responses at the 
start of the treatment period. An 18-week treatment period is an adequate period to detect 
differences in HbA1c of the treatment arms [5]. 
Dosing with MYL-1501D during treatment period and Lantus® during run-in period will be 
guided by self-monitored blood glucose (SMBG)-based glucose level assessments, as 
suggested in the dosing algorithm.  
Rescue criteria based on HbA1c are defined based on week 12 HbA1c measurement, so that a 
potential worsening of metabolic control in subjects during the study can be identified and 
therapy modified at the discretion of the investigator.  
A follow-up visit, 2 weeks after the end of treatment, will ensure the safety of all subjects 
after they stop the study medication and return to receiving approved medications. 
Complete information for the study medication can be found in MYL-1501D Investigator’s 
Brochure (IB). [6] 
2.2.1 
Rationale for Dose Selection 
Only subjects who have been on a stable dose of Lantus® for at least 3 months prior to 
screening will be included in the study, thus subjects would be on a stable dose at study entry. 
If required, subject dose should be adjusted during the 4-week run-in period to stabilize the 
subjects. During the treatment period, dose adjustment should be avoided but it is permitted 
to ensure subject’s stable state and safety.  
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3 
OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary objectives 
To test whether MYL-1501D product from Process VI once daily is non-inferior to 
MYL-1501D product from Process V once daily based on change in HbA1c from baseline to 
week 18 when administered in combination with mealtime insulin lispro. 
3.1.2 
Other objectives 
To compare MYL-1501D product from Process VI and Process V at week 18, when 
administered in combination with mealtime insulin lispro, with respect to: 
• Immunogenicity: incidence and change from baseline in the relative levels of 
anti-drug antibody  
• Hypoglycemic events: incidence and rate per 30 days 
• Occurrence of local reactions, systemic reactions and other adverse events 
• Device-related safety assessment 
• Change in fasting plasma glucose from baseline 
• Change in insulin dose per unit body weight (U/kg) from baseline 
• Change in 8-point SMBG profile from baseline 
 
3.2 
Endpoints 
3.2.1 
Primary Endpoints 
The primary efficacy endpoint is change in HbA1c from baseline to week 18 for the ITT 
population. 
3.2.2 
Secondary Endpoints 
3.2.2.1 Efficacy 
• Change in fasting plasma glucose from baseline 
• Change in basal insulin, meal-time, and total insulin dose per unit body weight 
(U/kg) from baseline 
• Change in 8-point SMBG profile from baseline 
 
3.2.2.1 
Safety 
• Incidence of positive antibody response and change in antibody percentage 
binding from baseline. 
• Change in hypoglycemia rate (30 day adjusted) from baseline and incidence of 
hypoglycemic events 
• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse 
events (SAEs) 
• Incidence of local reactions, systemic reactions and other adverse events 
• Incidence of device-related safety assessment 
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4 
STUDY POPULATION 
4.1 
Study Population 
A total of 202 subjects with T1DM are planned to be randomized in this study, to receive 
MYL-1501D from either Process VI or Process V with a randomization ratio of 1:1. 
A detailed description related to sample size determination is provided in Section 7. 
4.2 
Inclusion and Exclusion Criteria 
4.2.1 
Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the 
study: 
1. Written and signed informed consent needs to be provided by subjects or their legal 
representatives before starting any protocol-specific procedures.  
2. Male and female subjects between the ages of 18 to 65 years, both ages inclusive. 
3. Subjects with an established diagnosis of T1DM per American Diabetes Association 
(ADA) 2017 criteria who also fulfil the following criteria: 
a. Initiation of insulin treatment within 6 months of T1DM diagnosis 
b. Treatment with basal-bolus insulin therapy for at least 1 year before screening 
c. Fasting plasma C-peptide <0.3 nmol/L at screening 
d. Subject has been on once daily Lantus® at stable dose (±15% variation in dose) 
for at least 3 months at screening 
4. Body mass index (BMI) of 18.5 to 35 kg/m2 at screening (both values inclusive). 
5. Stable weight, with no more than 5 kg gain or loss in the 3 months prior to screening, this 
information will be collected by subject interview during medical history. 
6. HbA1c ≤9.5% at screening. 
7. Hemoglobin ≥9.0 g/dL at screening. 
8. Subject has the capability of communicating appropriately with the investigator.  
9. Subject is able and willing to comply with the requirements of the study protocol 
including the 8-point SMBG, completion of subject diary records and following a 
recommended diet and exercise plan for the entire duration of the study. 
10. Female subjects of childbearing potential who are willing to use oral contraception or two 
acceptable methods of contraception, (e.g., intra-uterine device plus condom, spermicidal 
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gel plus condom, diaphragm plus condom, etc.), from the time of screening and for the 
duration of the study, through study completion. 
a. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
b. Postmenopausal females must have had no regular menstrual bleeding for at least 
1 year prior to screening.  
c. Female subjects who report surgical sterilization must have had the procedure at 
least 6 months prior to screening.  
d. All female subjects of childbearing potential must have negative pregnancy test 
results at screening and at clinic visits, as per the SCHEDULE OF ACTIVITIES 
(SOA). 
e. If female subjects have male partners who have undergone vasectomy, the 
vasectomy must have occurred more than 6 months prior to screening 
4.2.2 
Exclusion Criteria 
Subject candidates must not be enrolled in the study if they meet any of the following criteria: 
1. History or presence of a medical condition or disease that in the investigator’s opinion 
would place the subject at an unacceptable risk from study participation. 
2. History of hypersensitivity to any of the active or inactive ingredients of the 
insulin/insulin analogue preparations used in the study, OR history of significant allergic 
drug reactions. 
3. History of use of animal insulin within the last 3 years or use of approved biosimilar 
insulin glargine at any time prior to study entry, except for subject who previously 
participated in MYL-1501D studies and were compliant with the study protocols.  
4. History of use of a regular immunomodulator therapy in the 1 year prior to screening. 
5. History of autoimmune disorders other than T1DM or insufficiently treated autoimmune 
thyroid disorders, judged clinically relevant by the investigator (recorded while collecting 
subject history). 
6. History of ≥1 episodes of diabetic ketoacidosis or emergency room visits for uncontrolled 
diabetes leading to hospitalization within the 6 months prior to screening. 
7. History of clinically significant acute bacterial, viral or fungal systemic infections in the 
last 4 weeks prior to screening (recorded while collecting subject history). 
8. Any clinically significant abnormality in electrocardiogram (ECG) or safety laboratory 
tests (LFT, RFT, hematology or any other laboratory deemed clinically relevant by the 
investigator) conducted at screening and considered by the investigator to make the 
subject ineligible for the study. 
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9. Serological evidence of human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HbSAg) or hepatitis C antibodies (HCVAb) at screening. 
10. History of drug or alcohol dependence or abuse during the 1 year prior to screening. 
11. Receipt of another investigational drug in the 3 months prior to screening (or as per local 
regulations), or if the screening visit is within 5 half-lives of another investigational drug 
received (whichever is longer), or scheduled to receive another investigational drug 
during the current study period. 
12. Subjects with the following secondary complications of diabetes: 
a. Active proliferative retinopathy as confirmed by a dilated ophthalmoscopy 
examination / retinal photography (performed by a person legally authorized to do 
so) within the 6 months prior to screening. 
b. Clinical nephrotic syndrome or diabetic nephropathy with a serum creatinine level 
>1.5 times of upper limit of reference range at screening 
c. History of severe form of neuropathy or cardiac autonomic neuropathy, recorded 
while collecting subject history. Subjects with mild or moderate forms of 
neuropathy will be allowed. 
d. Subjects with a history of limb amputation as a complication of diabetes (at any 
time), or any vascular procedure during the 1 year prior to screening. 
e. History of diabetic foot or diabetic ulcers in the 1 year prior to screening. 
13. Any elective surgery requiring hospitalization planned during the study period. 
14. Clinically significant major organ disorder at the time of screening including: 
a. Uncontrolled hypertension, defined as stage 2 hypertension by Joint National 
Committee VII (even if therapy is ongoing, blood pressure ≥160 mm Hg systolic 
or ≥100 mm Hg diastolic). 
b. Uncontrolled hyperlipidemia (even if therapy is ongoing, LDL >160 mg/dL or 
triglycerides >500 mg/dL). 
c. Uncontrolled hyperthyroidism or hypothyroidism (subjects can be included if 
these conditions are controlled with thyroid hormones or anti-thyroid drugs). 
d. Impaired hepatic function (alanine transaminase [ALT] or aspartate transaminase 
[AST] value >2 times the upper limit of the reference range and/or serum bilirubin 
1.5 times the upper limit of the reference range at the screening visit). Subjects 
with evidence of Gilberts disease may be included in the study if they have total 
bilirubin of <3 mg/dL with indirect bilirubin contributing to >80% of the total 
bilirubin. 
15. History of a significant medical condition, such as: 
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a. Clinically significant cardiac disease like unstable angina, myocardial infarction, 
grade 3 or 4 congestive heart failure (CHF) according to New York Heart 
Association criteria, valvular heart disease, cardiac arrhythmia requiring 
treatment, and pulmonary hypertension; during the year prior to screening. 
b. Stroke or transient ischemic attack (TIA) in the 6 months before screening.  
16. Subjects with major depressive illness in the last 3 years (those who have well controlled 
depression for 3 months on a stable dose of antidepressants, with no major depressive 
episodes in the last 3 years, can be included, even if they are on medication), subjects 
with history of other severe psychiatric diseases (manic depressive psychosis [MDP], 
schizophrenia), which in the opinion of the investigator precludes the subject from 
participating in the study (recorded while collecting subject history). 
17. History of hematological disorders that can affect the reliability of HbA1c estimation 
(hemoglobinopathies, hemolytic anemia, sickle cell anemia, etc.). 
18. Subjects using the following in the 3 months prior to screening: 
a. Insulin pump therapy 
b. Any anti-diabetic drugs other than the study insulins allowed by the protocol. 
19. Moderate insulin resistance, defined as requiring insulin of ≥1.5 U/IU/kg/day. 
20. Subjects who have received ≥14 consecutive days of glucocorticoid therapy by oral, 
intravenous, inhaled or other routes that produce systemic effects within the past 1 year, 
or who have received steroids by any route (except intra-nasal, intra-ocular, and topical) 
within the 4 weeks immediately preceding screening.  
21. Subjects diagnosed as having cancer (subjects with history of basal cell carcinoma, 
carcinoma in situ or squamous cell cancer of skin, or in remission >5 years, will be 
allowed). 
22. Subjects who have donated blood or plasma in the 1 month prior to screening 
4.2.3 
Criteria for study drug termination, withdrawal from the study and study 
termination 
Subjects will be free to request termination of study drug or withdrawal from the study at any 
time for any reason. 
If, for any reason, a subject discontinues the study prematurely, the subject may be followed 
up upon consent and as detailed in the following withdrawal criteria. 
Following are the withdrawal criteria:  
1. Withdrawal of consent. 
2. For female subjects, diagnosis of pregnancy or stated intention to become pregnant. 
Effort should be made by the site to obtain consent from the pregnant women, so that 
they are followed until delivery or termination. 
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3. 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 request the subject consent to follow-up as per the 
SCHEDULE OF ACTIVITIES until the Week 20 (Follow-up visit). 
4. At the investigator’s discretion (following discussion with the sponsor medical 
monitor), in certain situations such as significant illness, hospitalization for surgery, 
or an SAE which in the opinion of the investigator warrants treatment withdrawal. 
The site should request the subject consent to follow-up as per the SCHEDULE OF 
ACTIVITIES until the Week 20 (Follow-up visit).  
4.3 
Contraception 
4.3.1 
Females - Non-childbearing Potential 
Female subjects of non-childbearing potential must meet at least one of the following criteria: 
1. Postmenopausal females, defined as: 
• Females who are 45-65 years of age who have been amenorrheic for at least 1 year 
and who are known to have a serum FSH level >30 IU/L in the absence of hormone 
replacement therapy. 
2. Females who have a documented hysterectomy and/or bilateral oophorectomy. 
All other females will be considered to be of childbearing potential. 
4.3.2 
Females - Childbearing Potential 
Female subjects of child-bearing potential must use an acceptable, highly effective method of 
contraception (i.e. a method with a failure rate <1% when used consistently and correctly) 
starting from screening through to at least 7 days after the final dose of study drug. For this 
study, such methods include at least one of the following: 
• Abstinence (periodic abstinence is not acceptable). 
• Tubal ligation. 
• Intrauterine device (IUD) of intrauterine system (IUS). 
• Condom. 
o Depending on the region of study this may be with or without spermicidal 
foam/gel/film/cream/suppository. 
• Male partner who has had a vasectomy for at least 6 months. Male partners with 
vasectomies of <6 months are NOT considered protected. 
• Hormonal contraceptives (oral, injected, transdermal or implanted) with the exception 
of low dose gestagens, i.e. only containing lynestrenol or norethisterone, since they do 
not inhibit ovulation and are therefore not considered as highly-effective. The subject 
must remain on the hormonal contraceptive throughout the study and must have been 
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using hormonal contraceptives for an adequate period prior to the study to ensure 
effectiveness (e.g., 3 months). 
4.4 
Pregnancy Testing 
Serum or urinary pregnancy testing will be performed on all females of childbearing potential 
as described in the schedule of activities (results will be reviewed and must be negative prior 
to dosing). In the event of a positive test, the subject will be withdrawn from the study (or 
will not enter the study if during screening). 
Any pregnancy occurring after randomization to study drug will be followed up and reported 
to the sponsor as per Section 9.4.1. 
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5 
STUDY DRUG 
5.1 
Investigational Drug 
During Treatment period, subjects will be randomized to receive one of the following; 
MYL-1501D Product from Process V (100 U/mL) 
or 
MYL-1501D Product from Process VI (100 U/mL) 
Additional treatment drugs provided during the study which are not investigational study 
drugs are detailed below: 
During the run-in period, subject will receive Lantus® from Sanofi-Aventis sourced from the 
US (US listed drug) 100 U/mL 
All subjects will receive Humalog® (insulin lispro injection, 100 U/mL), manufactured by Eli 
Lilly throughout the study. 
MYL-1501D will be packaged and labelled according to all local legal requirements. 
Clinical Supplies will provide prepackaged supplies for each subject. A kit will be assigned at 
randomization using the Interactive Voice Response System/ Interactive Web Response 
System (IVRS/IWRS). 
A label will be attached to the outside of each kit. The text will be compliant with local 
regulatory requirements and may include some of the following information: 
• Protocol number 
• Subject number/study center number 
• Contents and quantity 
• Lot number 
• Randomization code/kit number 
• Investigator name 
• Storage instructions 
• Caution statement (for clinical study use only) 
• Expiry date 
• Mylan’s name and address 
 
5.1.1 
Administration of Study Drugs 
During the Run-in period, all subjects will receive Lantus® from Sanofi-Aventis sourced 
from the US (US listed drug) 100 U/mL until randomization. In addition, all subjects will be 
shifted from their current mealtime insulin to Humalog® at the start of the run-in period, and 
will continue on this for the complete study. The doses of Lantus® and Humalog® will be 
titrated (if required) during the run-in period to ensure diabetes control.  
During Treatment period, all subjects will receive one of the following treatments; 
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MYL-1501D product from Process VI or Process V. Both investigational products will be 
provided in a pre-filled disposable pen with a 3-mL cartridge. During the treatment period, 
dose titration will be kept to a minimum. 
In addition, all subjects will receive Humalog® (insulin lispro injection, 100 U/mL), 
manufactured by Eli Lilly. 
In the event of any significant dosing errors, the CRO contact person and/or CRO medical 
monitor, or Mylan study contact should be informed immediately. 
5.2 
Study Medication Complaints 
In the event the subject has a complaint/concern during study participation regarding the 
medication supplied, they should contact the site. 
In the event of a complaint/concern regarding any medication provided by Mylan for this 
study, at a minimum the following information should be sent by the site via e-mail to 
MGRG.study.medication.complaints@mylan.co.uk. 
• Study number. 
• Principal Investigator name. 
• Subject ID. 
• Date of occurrence of incident/complaint. 
• Description of incident/complaint (facts). 
• Confirmation if the complaint caused or resulted in a SAE? If “Yes”, 
confirmation that the SAE has been reported. 
 
Additional information and potentially the return of study medication may be requested by 
Mylan such that the complaint can be investigated. 
5.3 
Storage, Disposition of Unused Study Drug and Drug Accountability 
The Investigator, or an approved representative, e.g. pharmacist, will ensure that all 
investigational products are stored in a secured area under recommended storage conditions 
and in accordance with applicable regulatory requirements while at the investigator site. 
Study drug should be stored in accordance with the drug label. Storage conditions stated in 
the Investigator’s Brochure may be superseded by the label storage. 
Temperature of storage facilities should be monitored and recorded on a daily basis using 
validated devices that record maximum and minimum temperatures. Should the storage 
facility experience any excursion of temperature outside of the labelled storage condition this 
must be reported immediately to Mylan or designee. At sites where daily monitoring and 
recording is not possible on weekends, the temperature record (e.g. max/min thermometers) 
should be checked immediately for any temperature excursions on the next working day after 
the weekend. Devices used for temperature monitoring should be regularly calibrated. 
Affected material must be placed into quarantine until the impact of the excursion has been 
assessed and confirmed by Mylan.  
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the study drug. Drug accountability forms must be used. Alternatively, Mylan 
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may approve use of standard institution forms. In either case, the forms must identify the 
study drug, including batch or code numbers, and account for its disposition on a subject-by-
subject basis, including specific dates and quantities. The forms must be signed by the 
individual who dispensed the drug, and copies must be provided to Mylan or designee. 
At the end of the study, Mylan will provide instructions with regards to disposition of any 
unused investigational product. If Mylan authorizes destruction at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Mylan. Destruction must be adequately documented. 
5.4 
Randomization  
Assignment of Subject Identification number (SID), randomization number and study 
medication, as well as site drug inventory control will be managed by an automated 
IVRS/IWRS. A manual containing complete instructions for Web or telephone access and 
use will be provided to each site prior to study start. The IVRS/IWRS will assign a SID for 
each subject’s first clinic visit. Each SID will be unique and serve as the primary subject 
identifier throughout all phases of the study. The SID must appear on all case report form 
(CRF) pages, source documents, laboratory data, ECG and diary data. Subjects qualifying to 
enter the study drug treatment phase, will be assigned an additional “randomization number” 
by the IVRS/IWRS at randomization. Dynamic allocation with minimization algorithm will 
be used for treatment randomization. Randomization will be stratified by investigator and 
basal insulin (Glargine) dose time (morning or evening). 
5.5 
Breaking the Blind 
Regardless of the assigned treatment arm, all subjects in the study are provided with active 
anti-diabetic treatment, Insulin glargine. 
The blinded treatment code must not be broken except in emergency situations for which the 
identification of the study treatment of a subject is required by the Qualified Investigator to 
complete a serious adverse event report or the clinical report. In such situations, the 
randomization information will be held by designated individual(s), and the date and reason 
for breaking the blind must be recorded. If possible, the CRO project manager should be 
contacted by telephone prior to unblinding but no later than 24 hours after unblinding. The 
investigator should follow the study’s randomization procedures and should ensure that the 
code is broken only in accordance with the protocol. As the study is blinded, the investigator 
should promptly document and explain to the sponsor any premature unblinding (e.g., 
accidental unblinding, unblinding due to a serious adverse event) of the investigational 
product(s). Unblinding of treatment code for final data analysis will be done after database 
lock. Unblinding process will be performed in accordance to both sponsor’s and CRO’s 
unblinding SOPs, as detailed in the statistical analysis plan. 
5.6 
Concomitant Medications 
All concomitant medications taken during the study (from signing informed consent to post-
study follow-up) must be recorded with indication, daily dose, and start and stop dates of 
administration in the CRF. All subjects will be questioned about concomitant medication at 
each clinic visit and at follow up. 
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Medications taken within 28 days prior to screening and prior to dosing with study 
medication will be documented as a prior medication. Medications taken after dosing with 
study medication will be documented as concomitant medications. 
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) are prohibited during the study (including the run-in period and the treatment period), 
except in case of rescue medication treatment.  
A list of medications that may interfere with the effect of insulin is provided in Table 2. No 
drugs listed in this table should be started during the run-in period or treatment period. 
Table 2: List of Prohibited Medication 
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). 
 
Subjects will abstain from all prohibited medications as described in the exclusion criteria 
section of this protocol (Section 4.3.2). Use of prohibited medication during the study will be 
deemed a protocol deviation and such subjects will be assessed by Mylan or designee 
regarding the potential need to early terminate study drug (e.g. for safety reasons: see 
Section 4.3.4). 
5.7 
Recommended Procedure for Subject Experiencing Adverse Effects Secondary to 
Excessive Pharmacological Effects of Study Drug 
The following rescue criterion will be implemented to protect the safety of subjects during 
the study: 
“Worsening of HbA1c by >1.0% compared to baseline at 12 weeks post randomization”. 
If the subject meets the criterion the investigator can switch the subject to Lantus® provided 
as part of the study at week 15 (Visit 13) or earlier, and continue with the study activities and 
procedures until the end of the study. 
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6 
STUDY CONDUCT 
Subjects eligible for study recruitment will have the nature, purpose, and risks of the study 
explained to them by the investigator. They will be provided with a written copy of the 
informed consent form (ICF) for the study and given sufficient time to consider the study’s 
implications before deciding to participate. Subjects agreeing to participate in the study will 
sign the ICF and be given a duplicate copy before undergoing any screening or pre-screening 
(if required) procedures. A unique SID will be issued at the time of consent by IVRS/IWRS 
system.  
Once a subject enrolls in this study, the site will make every effort to retain the subject for the 
planned duration of the study. Clinical study site staff are responsible for developing and 
implementing support and retention plans. Elements of this plan may include the following. 
• Thorough explanation of the complete clinical study visit schedule and procedural 
requirements during the informed consent process and re-emphasis at each clinic visit. 
• A simple explanation of the key data and key time points that are critical for the 
study's successful analysis, and the importance of all the treatment groups to the 
overall success of the study. 
• Discussion at screening, and subsequent regular review of possible barriers to clinic 
visit attendance and full study participation and compliance. 
• Collection of contact information at screening (address, phone numbers, email), 
which is regularly reviewed at subsequent clinic visits. 
• Use of appropriate and timely study visit reminders. 
• Immediate and multifaceted follow-up on missed clinic visits, including the possible 
use of trained staff to complete in-person contact with subjects at their homes. 
In cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 
subject so that they can appropriately be withdrawn from the study. All contact attempts 
should be documented in the subject's medical record. Should the subject continue to be 
unreachable, then and only then will he/she be considered to have withdrawn from the study 
with a primary reason of "Lost to Follow-up." For all other subjects withdrawing from the 
study, an alternative reason for discontinuation should be recorded in the CRF. Regardless of 
site plans to support and retain subjects within the study, subjects may voluntarily withdraw 
from the study for any reason and at any time. 
For a subject that completes the study and all procedures it is anticipated that the duration of 
study would be up to 26 weeks.  
For details and timings of assessments, refer to Section 6.5. 
6.1 
Screening Procedures 
Each prospective subject must agree to participate in screening procedures by signing the 
most recent ICF before any screening procedure is initiated. The Principal Investigator or 
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Medical Sub-Investigator will review the inclusion and exclusion criteria to confirm 
eligibility of each subject prior to enrolment. 
6.1.1 
Screening (Visit 1 [Week -6 to Week -4]) 
Subjects will commence screening procedures within 6 weeks prior to randomization, to 
confirm that they meet the selection criteria for the study. If the time between screening 
procedures and potential randomization exceeds 6 weeks as a result of unexpected delays, 
then the subject will need to be discussed with Mylan or designee to consider potential for 
re-screening (if re screening is agreed, the subject will need to be re consented and assigned a 
new SID via IVRS/IWRS). Re-screening for other reasons may be possible following 
discussion with the Mylan or designee. If re screening occurs this will be clearly documented 
within the site file. 
The following will be completed in during the visit: 
• Obtain written informed consent before any study-related procedure is initiated, 
including the cessation of prohibited concomitant therapy. A copy of the signed ICF 
(including subject information sheet) will be given to the subject (and IHS-810 form 
for subjects recruited from US). 
• Check selection criteria suitability 
• Perform dilated ophthalmoscopy / retinal photography (if it was not done in the last 6 
months) to exclude active proliferative retinopathy 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject 
• Record demographic details (age, height, gender, and race) 
• Record body weight and calculate BMI  
• Record medical history, concomitant illnesses and concomitant medications  
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate)  
• Record detailed history of all previous insulin use 
• Perform and document physical examination 
• Perform 12-lead ECG (supine, after 5 minutes rest) and document results 
• Collect blood and urine samples for the following laboratory assessments: 
o Fasting C-peptide 
o Serum pregnancy test for women of childbearing potential 
o HIV, HBsAg, and HCVAb 
o Hematology 
o Blood chemistry 
o Urine analysis 
o HbA1c 
o Fasting plasma glucose 
o Fasting lipid profile 
o Immunogenicity analysis 
 
For suspected lab errors, 1 repeat of the specific test will be allowed during the 14-day 
screening period.  
After all assessments (except immunogenicity) have been performed, the investigator will 
assess the results for compliance with the inclusion and exclusion criteria. If all inclusion 
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criteria have been fulfilled and none of the exclusion criteria were met, the subject may be 
enrolled into the run-in phase. The run-in visit must be scheduled no later than 14 days after 
the start of the screening phase (date of subject signature on ICF).  
6.2 
Run-in Period  
6.2.1 
Visit 2 (Week -4) 
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate  
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit  
• Collect blood sample for fasting plasma glucose 
• Dispense subject diary to the subject and provide information regarding the 
completion requirements and necessary glucose measurements provided. 
• Review current dosing of Lantus and Humalog and if necessary provide new dosing 
instructions and document the new dose and reason for change 
• Dispense study medication and provide dose and titration instructions  
• Dispense ancillary supplies 
 
6.2.2 
Visit 3 (Week -3), Visit 5 (Week -1) 
These visits can be performed as telephone contacts if preferred by site and subject. If the 
visit is performed as a telephone contact, a time and date must be agreed in advance by both 
parties and the subject must have the completed subject diary available for discussion of the 
entries during the call.  
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit 
• Record device safety information 
• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of Lantus and Humalog and if necessary provide new dosing 
instructions and document the new dose and reason for change 
 
6.2.3 
Visit 4 (Week -2) 
During this visit the following procedures and assessments will be performed: 
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• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate  
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit  
• Record device safety information 
• Collect blood sample for fasting plasma glucose 
• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of Lantus and Humalog and if necessary provide new dosing 
instructions and document the new dose and reason for change 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided. 
 
6.3 
Treatment phase 
6.3.1 
Visit 6 (Week 0) 
After completion of the run-in phase without any major violation of the selection criteria the 
subjects will enter the randomized study treatment phase. During this visit the following 
procedures and assessments will be performed: 
• Check selection criteria suitability 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record body weight and calculate BMI  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate) 
• Perform and document physical examination 
• Perform 12-lead ECG (supine, after 5 minutes rest) and document results 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit 
• Record device safety information 
• Collect blood and urine samples for the following laboratory assessments: 
o Serum and urine pregnancy test for women of childbearing potential (only a 
negative urine test result is needed for dispensing drug) 
o Fasting plasma glucose 
o HbA1c 
o Hematology 
o Blood chemistry 
o Urine analysis 
o Fasting lipid profile 
o Immunogenicity analysis (collect blood sample prior to study drug 
administration) 
o PK analysis (collect blood sample prior to study drug administration) 
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• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of Lantus and Humalog and if necessary provide new dosing 
instructions and document the new dose and reason for change 
• Dispense study medication MYL-1501D (product from Process VI or Process V), and 
Humalog 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided. 
• Perform randomization and document result 
 
6.3.2 
Visit 7 (Week 1), Visit 9 (Week 4), Visit 11 (Week 9) 
These visits can be performed as telephone contacts if preferred by site and subject. If the 
visit is performed as a telephone contact, a time and date must be agreed in advance by both 
parties and the subject must have the completed subject diary available for discussion of the 
entries during the call.  
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit 
• Record device safety information 
• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of MYL-1501D (product from Process VI or Process V) and 
Humalog and if necessary provide new dosing instructions and document the new 
dose and reason for change 
 
6.3.3 
Visit 8 (Week 2), Visit 10 (Week 6) 
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate  
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit  
• Record device safety information 
• Collect blood and urine samples for the following laboratory assessments: 
o Serum and urine pregnancy test for women of childbearing potential (only a 
negative urine test result is needed for dispensing drug) 
o Fasting plasma glucose 
o Immunogenicity analysis (collect blood sample prior to study drug 
administration as outlined in Table 1) 
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o PK analysis (collect blood sample prior to study drug administration as 
outlined in Table 1) 
• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of MYL-1501D (product from Process VI or Process V) and 
Humalog and if necessary provide new dosing instructions and document the new 
dose and reason for change 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided. 
• Only applicable to Visit 10, Dispense study medication MYL-1501D (product from 
Process VI or Process V) and Humalog 
 
6.3.4 
Visit 12 (Week 12) 
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate) 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit 
• Record device safety information 
• Collect blood and urine samples for the following laboratory assessments: 
o Serum and urine pregnancy test for women of childbearing potential (only a 
negative urine test result is needed for dispensing drug) 
o Fasting plasma glucose 
o HbA1c 
o Fasting lipid profile 
o Immunogenicity analysis (collect blood sample prior to study drug 
administration as outlined in Table 1) 
o PK analysis (collect blood sample prior to study drug administration as 
outlined in Table 1) 
• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of MYL-1501D (product from Process VI or Process V) and 
Humalog and if necessary provide new dosing instructions and document the new 
dose and reason for change 
• Dispense study medication MYL-1501D (product from Process VI or Process V) and 
Humalog 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided 
 
6.3.5 
Visit 13 (Week 15) 
During this visit the following procedures and assessments will be performed: 
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• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate  
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit  
• Record device safety information 
• Collect blood and urine samples for the following laboratory assessments: 
o Serum and urine pregnancy test for women of childbearing potential (only a 
negative urine test result is needed for dispensing drug) 
o Fasting plasma glucose 
• Review current dosing of MYL-1501D (product from Process VI or Process V) and 
Humalog and if necessary provide new dosing instructions and document the new 
dose and reason for change 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided 
 
6.3.6 
Visit 14/ End of Treatment (Week 18) 
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record body weight and calculate BMI  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate) 
• Perform 12-lead ECG (supine, after 5 minutes rest) and document results 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit 
• Record device safety information 
• Collect blood and urine samples for the following laboratory assessments: 
o Serum and urine pregnancy test for women of childbearing potential (only a 
negative urine test result is needed for dispensing drug) 
o Fasting plasma glucose 
o HbA1c 
o Hematology 
o Blood chemistry 
o Urine analysis 
o Fasting lipid profile 
o Immunogenicity analysis (collect blood sample prior to study drug 
administration as outlined in Table 1) 
o PK analysis (collect blood sample prior to study drug administration as 
outlined in Table 1) 
• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
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• Review current dosing of MYL-1501D (product from Process VI or Process V) and 
Humalog and if necessary provide new dosing instructions and document the new 
dose and reason for change 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided 
 
6.3.7 
Early study drug Termination (ET) visit 
Subjects may request termination of study drug or withdrawal from the study at any time, or 
be required to withdraw or terminate study drug by the investigator or sponsor for reasons as 
per Section 4.3.4. If study drug is terminated or the subject withdraws or is withdrawn, the 
reason for termination/withdrawal should be established and recorded. If a subject does not 
return for a scheduled visit, every effort should be made to contact the subject. In any 
circumstance, every effort should be made to document the outcome of subject contact 
attempt, if possible. The investigator will contact Mylan or designee, if subject fails to 
complete the study or violates the protocol. 
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
Unless consent is withdrawn, subjects who prematurely terminate study drug will be asked to 
return to the clinic to conduct the ET visit as soon as possible after their last dose of study 
drug, and in case consent subject will be asked to conduct all the remaining visits according 
to study schedule table until the end of the study.  
At the ET visit the End of Treatment visit (Week 18/Visit 14), procedures should be 
completed. 
The site should explain the importance of data collection and make every effort to consent the 
subject to continue follow up per the SCHEDULE OF ACTIVITIES until Week 20 visit. 
6.4 
Visit 15 Follow up (Week 20) (telephone call) 
• Record AEs, SAEs, local and systemic allergic reactions and severe hypoglycemic 
which are classified as SAE. 
• Record concomitant medications since previous visit 
 
6.5 
Treatment Procedures 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases, the investigator or designated representative will take all 
steps necessary to ensure the safety and well-being of the subject. When a protocol required 
test cannot be performed the investigator or designated representative will document the 
reason for this and any corrective and preventive actions which he/she has taken to ensure 
that normal processes are adhered to as soon as possible. The Mylan study team will be 
informed of these incidents in a timely fashion. 
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Activities specific to this protocol are expanded upon further below. 
6.5.1 
Blood Volume 
Total blood sampling volume for an individual subject is approximately 230 mL.  
Table 3: Blood Volume 
Sample Type 
Sample Volume (mL) 
Number of Sampling 
Times 
Total 
Volume 
(mL) 
Screening 
Study Period 
Safety Labs 
30 
1 
3 
120 
PK1 
4 
 
5 
20 
Anti-drug antibody (ADA) 2 
10 
1 
5 
60 
Supplemental Immunogenicity3 
10 (baseline), 
5 (V1, V8, V10, V12, V14) 
1 
5 
35 
TOTAL 
 
 
 
235 
1 Blood samples (1 x 4 mL) will be drawn into K2EDTA plasma tubes. 
2 Blood samples (2 x 5 mL) will be drawn into serum separator tubes (SST). 
3 Blood samples (1 x 5 mL; 2 x 5 mL at baseline) will be drawn into serum separator tubes (SST). 
 
6.5.2 
Safety Testing Assessments 
Safety will be assessed through physical examinations, monitoring of vital signs, 12-lead 
electrocardiograms, laboratory analyses, and adverse event monitoring. 
6.5.2.1 
Adverse Event Assessment 
If a subject reports any symptoms after the signing of the informed consent form, they will be 
evaluated by medical staff and necessary measurements will be performed. The Principal 
Investigator or Medical Sub-Investigator will be notified before dosing to determine the 
course of action. 
Clinically relevant findings from screening procedures, e.g., laboratory tests or physical 
examinations will be recorded as medical history. Clinically significant changes from the 
screening procedures results will be recorded as adverse events. 
Subjects will be routinely queried with regard to the presence or absence of adverse events 
using open ended questions. The clinic will provide documentation of any adverse events in 
the subject’s CRF. The adverse event source documentation will minimally include the 
following information: date and time of assessment, the outcome of the response, and 
identification of the clinic staff member collecting the information. 
6.5.2.2 
Hypoglycemia 
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). In addition, nocturnal hypoglycemia rate and incidence will be analyzed in a 
same way as overall hypoglycemic episodes. 
Hypoglycemia is a state produced by a lower than normal level of glucose in the blood. This 
may develop, if for example:  
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• The subject misses or delays meals or there is a change in diet  
• The subject takes a higher dose of study drug than prescribed  
• The subject consumes alcohol  
• The subject does more intense or longer physical exercise or work than normal,  
• The subject is recovering from an injury, operation, fever or other illness, or from 
other forms of stress 
 
6.5.2.2.1 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 subject 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 subject 
goes to bed at night till the time he or she wakes up. This may include any of the above 5 
types of hypoglycemia.  
Note: A diagnosis of severe hypoglycemia as per above classification will always be 
considered as 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. 
6.5.2.2.2 Identification of Hypoglycemia 
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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. 
Subject 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 subjects on self-management of hypoglycemic episodes. 
Investigators will also instruct subjects on remedial actions to be taken during the episodes of 
severe hypoglycemia. Subject will be encouraged to call the study site if they experience 
hypoglycemia. 
6.5.2.2.3 Management of Hypoglycemia 
The following steps are recommended for managing hypoglycemic episodes:  
1. 
The subject 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 subject 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, ¾ cup of juice or regular soft drink, 4-5 glucose tablets).  
3. 
Subject 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 minutes. If the 
next meal is more than 1 hour away, subjects should follow with additional carbohydrate or a 
snack.  
4. 
If hypoglycemia persists after the second treatment, subject or companion should be 
instructed to contact the investigator.  
It is recommended that the subjects always carry some sugar lumps, sweets, biscuits, or 
sugary fruit juice.  
For an event of severe hypoglycemia the subject 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 subject 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 the different subtypes (Refer to Section 6.5.2.2.1). 
6.5.2.2.4 Reporting of hypoglycemic episodes 
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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 9.2.4) are also to be notified as SAEs to the Mylan Global 
Product Safety and Risk Management department, as described in Section 9.3.2.8; and 
entered on the SAE and AE pages. 
6.5.2.3 
Laboratory Safety 
The following safety laboratory tests will be performed at times defined in the study 
schedules in Sections 1 and Section 6. 
Table 4: Laboratory Safety Tests 
Hematology 
Chemistry 
Urinalysis 
Other  
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
Urea and Creatinine 
Glucose 
Calcium 
Sodium 
Potassium 
Chloride 
AST, ALT 
Total Bilirubin 
Direct/Indirect bilirubin 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
CRP 
C-Peptide 
Lipid Profile 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Microscopy/culturea 
Urine hCG  
HIV and HBSAg and 
HCVAb 
HbA1c 
 
a Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase. 
 
Hematology and chemistry will be analyzed by central laboratory. Urinalysis will be 
conducted by dipstick at site and if urine is positive for blood, protein, nitrites, or leukocyte 
esterase, will be analyzed via microscopy/culture by a central laboratory.  
Blood volumes to be collected and blood and urine sample handling instructions will be 
provided in the central vendor laboratory manual. The central laboratory will provide 
collection materials and directions for packaging and shipment of samples. 
Any clinically significant findings in laboratory safety data should be recorded as an AE. 
Determination of clinical significance and seriousness will be based on the Investigator's 
medical judgment. 
6.5.2.4 
Immunogenicity Assessment 
Blood samples of 5 mL each will be taken into serum separator tubes at each time point as 
outlined in Table 1. At Visits 1, 8, 10, 12, and 14, three blood samples will be drawn, 
whereas at Visit 6 (baseline) four blood samples will be drawn. The blood samples will be 
taken by direct venipuncture, and the exact times of blood sampling will be recorded in the 
CRF. Two of the samples will be used to determine the presence of anti-drug antibodies 
against insulin glargine using the approach outlined below. The other sample will be 
collected and stored in reserve for potential supplemental immunogenicity testing and/or 
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characterization. Samples collected pre-dose at the randomization visit (Visit 6) will be 
considered as baseline. Samples collected at screening and the supplemental samples 
collected at baseline may also be used for method development and validation. Sample 
handling instructions are specified in the laboratory manual. 
A conventional radioimmunoprecipitation assay (RIPA) will be employed for the assessment 
of anti-drug antibodies in clinical samples. In this assay, samples will undergo a pre-
treatment step that includes acid dissociation to release any anti-insulin antibodies complexed 
with free drug, followed by charcoal adsorption of the free insulin analog. The treated 
samples will be incubated with a fixed amount of 125I-MYL-1501D, and anti-drug antibody 
complex formation with the tracer is measured via gamma counter and expressed as a 
percentage of bound to total radioactivity (%B/T).  
The multi-tiered sample analysis recommendations for immunogenicity testing from 
published white papers [7, 8], and current regulatory guidance [9, 10], will be employed for 
the immunogenicity assessment of MYL-1501D Process V and Process VI. The antidrug 
antibody analysis methodology will be fully validated, and the sample analysis procedures 
will be documented in a Sample Analysis Protocol.  Sample handling, processing, and storage 
instructions will be detailed in a separate manual. The laboratory for immunogenicity 
analysis will be designated by the Sponsor. 
6.5.2.4.1 PK Assessment 
One blood sample of 4 mL will be taken into a K2EDTA plasma tube at each time point, as 
outlined in Table 1. The blood samples will be taken by direct venipuncture, and the exact 
times of blood sampling will be recorded in the CRF. The PK sample will be taken along 
with the immunogenicity samples. The exact time of last MYL-1501D dose prior to 
withdrawal of blood for PK will be noted. The blood samples will be analyzed for Insulin 
Glargine, Glargine M1 and M2 metabolite concentrations by Covance Laboratories Ltd. 
(Harrogate, UK) using a fully validated analytical method. Sample handling instructions are 
specified in the laboratory manual. 
The PK samples are taken as outlined in Table 1. The PK sample will be taken during the 
visit, preferably taken prior to the daily glargine dose. The timing of study drug 
administration from prior day should be collected along with the time of PK sample 
collection. 
6.5.2.5 
Blood Pressure and Pulse Rate 
Blood pressure and pulse rate will be measured at times specified in Sections 1 and Section 6. 
Additional collection times, or changes to collection times of blood pressure and pulse rate 
will be permitted, as necessary, to ensure appropriate collection of safety data. 
Supine blood pressure will be measured with the subject’s arm supported at the level of the 
heart, and recorded to the nearest mmHg after 5 minutes of rest. Where possible, the same 
arm (preferably the dominant arm) will be used throughout the study. 
The same size blood pressure cuff, which has been properly sized and calibrated, will be used 
to measure blood pressure each time. The use of automated devices for measuring blood 
pressure and pulse rate are acceptable, although, when done manually, pulse rate will be 
measured in the brachial/radial artery for at least 30 seconds. Any clinically significant 
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changes in blood pressure and pulse rate should be recorded as an AE. Determination of 
clinical significance and seriousness will be based on the Investigator's medical judgment. 
6.5.2.6 
12-lead ECG 
In this study, 12-lead ECGs will be recorded using local ECG devices and review. ECGs 
should be collected at times specified in the study schedules in Sections 1 and Section 6.  
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. 
To ensure safety of the subjects, a medically qualified individual at the site will assess ECG 
recordings and make any comparisons to baseline measurements.  
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings. Any clinically 
significant ECG abnormalities measured at screening should be assessed for their effects on 
subject eligibility of the study and recorded in medical history. ECG parameters will not be 
recorded in the CRFs, but any clinical significant changes between the screening and 
subsequent ECGs should be recorded as an AE. Determination of clinical significance and 
seriousness will be based on the Investigator's medical judgment. 
6.5.2.7 
General Physical Examination 
A full general physical examination will consist of an examination of the abdomen, 
cardiovascular system, lungs, lymph nodes, musculoskeletal and neurological systems, skin, 
extremities, head, ears, eyes, nose, and thyroid gland by trained medical personnel at the site. 
A full physical examination will be performed at Visit 1 (screening), 6 (randomization) and 
14 (EOT or ET). 
Height and weight will be assessed at Visit 1. Physical examination results will not be 
recorded in the CRFs, but any clinical significant finding at Screening (Visit 1) should be 
recorded under medical history and changes between Screening (Visit 1) and subsequent 
examinations should be recorded as an AE. Determination of clinical significance and 
seriousness will be based on the investigator's medical judgment. 
  
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7 
STATISTICAL ANALYSIS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the sponsor. This document may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. 
7.1 
Sample Size Determination 
A total of 202 subjects with T1DM are planned to be randomized for this study and will 
receive either MYL-1501D Process V product or MYL-1501D Process VI product, in a 1:1 
ratio.  
The sample size estimation is based on assumptions for the change from baseline up to week 
18 in HbA1C with either MYL-1501D product from Process V or Process VI. It is assumed, 
that true mean groups mean difference is 0.03 and standard deviation is equal to 0.74. To 
demonstrate non-inferiority margin of 0.4% using a 2-sided 95% confidence interval and a 
90% power, a total of 172 subjects (86 subjects per treatment group) are required.  
To account for a maximum of 15% of subjects being not eligible for the per protocol analysis, 
a total sample size of 202 is planned to be randomized for this study. The true treatment 
difference and standard deviation is based on previous study MYL-GAIA-3001. 
No replacement of subject will be performed if subject discontinued prematurely from the 
study. 
7.2 
Primary Endpoints 
7.2.1 
Definition of Primary Endpoints 
The change in HbA1c from baseline up to week 18 is the primary endpoint for this study. 
7.2.2 
Statistical Methodology for Primary Endpoints 
For the analysis of the primary endpoint all subjects will be taken account – irrespectively of 
their missing value pattern, which are expected to be limited to less than 5% of the subjects. 
Then the treatment effect will be estimated using a repeated measures analysis employing a 
restricted maximum likelihood (REML)-based, mixed model repeated measures (MMRM)-
effects model approach. In this model all subjects will be used for the estimation of the 95% 
confidence interval of the difference between MYL-1501D Process VI product and Process V 
product for mean change in HbA1c at week 18. The MMRM model will include the fixed, 
categorical effect of treatment group assignment, visit, treatment group-by-visit interaction 
and the other fixed effect terms investigator, basal insulin dose time, and baseline HbA1c 
value as covariates. 
Further details on the MMRM model will be provided in the SAP. Investigator pooling will 
be finalized before unblinding treatment to avoid introducing bias. The detailed method of 
investigator pooling will be documented in the SAP. 
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7.2.3 
Primary Analysis for Primary Endpoints 
For primary endpoint analysis, non-inferiority for efficacy will be established if the upper 
limit of a two sided 95% confidence interval for the absolute difference (MYL-1501D 
Process VI minus Process V) of mean change from baseline to endpoint for HbA1c is no 
greater than 0.4% at Week 18. The primary analysis will be performed on the intent to treat 
(ITT) analysis set.  
7.2.4 
Secondary/Sensitivity Analyses for Primary Endpoints 
A further robustness check will be conducted using the PP population and applying the same 
MMRM procedure as described in previous section to establish non-inferiority. Any 
differences in the conclusion will be further investigated by examining differences between 
the ITT and the PP populations. 
Other sensitivity analysis addressing missing data will be conducted in the following manner:  
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 12 and week 18 sequentially. The variables treatment, pooled investigator, and basal 
insulin dose time will be used as independent. 
In a second step, the imputed values will be corrected such that the full non-inferiority margin 
will be added for imputed values in Process VI group. All imputed datasets will be analyzed 
using the same model parameters as used in the primary analysis, and the results will be 
combined using Rubin’s rules. 
A standard last observation carried forward (LOCF) approach will be conducted such that 
missing data will be imputed by LOCF. This dataset will be analyzed for the ITT and PP 
populations using the ANCOVA model described in the protocol. 
7.2.5 
Missing Data 
The only imputed data will be performed in the sensitivity analysis as described above for 
HbA1c. Otherwise, missing data will not be imputed. 
7.2.6 
Sub-Group Analyses 
Subgroup analyses of important factors, including but not limited to factors such as age 
group, gender and race are planned for the key outcomes of HbA1c and immunogenicity 
variables. These will be conducted by adding factor and treatment-by-factor interactions to 
the MMRM model models of the main analyses. Other exploratory subgroup analyses may be 
performed, as deemed appropriate. 
7.3 
Secondary Endpoints 
The following efficacy measures (both actual and change values) will be summarized at 
baseline and scheduled visit. Similar statistical analysis approach for primary will be 
performed for continuous variables. Contrasts of LS mean at each scheduled visit will be 
used to evaluate all pairwise treatment comparisons, and 95% confidence intervals for 
treatment differences in LS means will be computed for each visit. 
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• Change in fasting plasma glucose from baseline 
• Change in basal insulin, meal-time, and total insulin dose per unit body weight (U/kg) 
from baseline 
• Change in 8-point SMBG profile from baseline. 
All above analyses will be performed on ITT set. 
The following safety measures (both actual and change values) will be summarized at 
baseline and scheduled visit. Contrasts of LS mean at each scheduled visit will be used to 
evaluate all pairwise treatment comparisons, and 95% confidence intervals for treatment 
differences in LS means will be computed for each visit. For categorical data analyses, 
Fisher’s exact test or Chi-squared test will be used. The details will be provided in the SAP.  
• Incidence of positive antibody response and change in antibody percentage binding 
from baseline. 
• Change in hypoglycemia rate (30 day adjusted) from baseline and incidence of 
hypoglycemic events 
• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) 
• Incidence of local allergic reactions, systemic allergic reactions and other adverse 
events 
• Incidence of device-related safety assessment 
 
The incidence of subjects with each of the three following criteria will be summarized 
descriptively (for categorical measures) by treatment to explore possible insulin 
neutralization effect: 
• An increase of over 10% in cross reacting antibodies from baseline 
• Increases in HbA1c of over 0.2% from baseline at any visit 
• Increase in total or basal insulin dose at any visit  
 
The total incidence of Device-related safety events will be summarized for each treatment 
group and would include device-related TEAEs and events related to device complaints or 
failures. For device-related TEAEs, two categories will be summarized for each treatment: 
needle-related TEAEs such as pain, bruise, and bleeding; and other device-related TEAEs, 
such as hyperglycemia or hypoglycemia. For confirmed device-related malfunctions or 
failures, incidence will be listed and summarized for each treatment. 
All above analyses will be performed on safety set. 
7.4 
Analysis Set Definitions 
The ITT analysis set includes all randomized subjects (including subjects who receive 
incorrect treatment, do not complete the study or do not comply with the protocol or used 
prohibited medication) and have baseline (randomization visit) and at least one post-baseline 
efficacy value.  
The PP analysis set includes subjects who complete Week 18, and have HbA1c 
measurements as per the protocol, or have at least one post-baseline HbA1c data (for subjects 
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who discontinue prematurely); and do not have protocol violations that impact the primary 
outcome (as detailed in the statistical analysis plan). Subjects who meet rescue medication 
criteria and take rescue medication will be excluded from PP analysis set. The subjects 
excluded from the PP population will be identified before database lock (i.e., before 
unblinding the study team). 
The safety analysis set includes subjects who take at least one dose of the study medication 
after randomization. For safety analyses, subjects will be categorized according to the 
treatment that they actually received.  
7.5 
Other Safety Analyses 
The analysis set for safety summaries is defined as all subjects who received at least one dose 
of study medication in the randomized treatment period. Safety data from the run-in period 
will be presented in listings only.  
Treatment emergent adverse events and concomitant medications will be summarized and 
listed. All AEs that occur after the first dose of double-blind study medication through 14 
days after the last dose will be considered treatment emergent AEs. The number and 
percentage of subjects with at least one treatment emergent AE will be presented by treatment 
group and events further summarized by maximum severity and relationship to study 
medication. 
Descriptive statistics will be provided for the following safety data. No inferential analysis of 
this safety data is planned. Any ECG, blood pressure, and pulse rate abnormalities of 
potential clinical concern will be described. 
7.5.1 
Vital Signs 
Change from baseline of vital sign measurements will be analyzed using MMRM with model 
terms of pooled investigator, basal insulin dose time, treatment, visit, treatment-by-interaction 
as fixed effects, and baseline value as covariate. The descriptive statistics including actual 
measurement and change from baseline along with treatment comparison will be performed 
at scheduled visits.  
The percentage of subjects in categories such as potentially clinically significant will be 
summarized and treatment comparison will be performed using Fisher’s exact test. 
7.5.2 
ECG Analyses 
The percentage of subjects in categories such as abnormal/non-clinically significant and 
abnormal/clinically significant will be summarized and treatment comparison will be 
performed using Fisher’s exact test.  
7.5.3 
Laboratory Data 
Change from baseline of laboratory measurements will be analyzed using MMRM with 
model terms of pooled investigator, basal insulin dose time, treatment, visit, treatment-by-
visit interaction as fixed effects, and baseline value as covariate. The descriptive statistics for 
actual measurement and change from baseline along with treatment comparison will be 
performed at scheduled visits.  
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The percentage of subjects 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. 
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8 
ADMINISTRATIVE PROCEDURES 
8.1 
Source Documentation Forms 
All clinical data will be recorded by the clinical staff on raw data sheets and/or recorded 
electronically using validated software. If computerized systems are used to create, modify, 
maintain, archive, retrieve or transmit source data, they must comply with the applicable 
regulatory regulations and/or guidance. 
The nature and location of all source documents will be documented separately. Source data 
may be directly captured from devices, transferred from 3rd parties (e.g. laboratory data) or 
entered manually into CRF/database. 
8.2 
Access to Data/Source Documentation 
The Investigator or designated representative will permit full access to data and source 
documentation for the purpose of clinical monitoring, audits, IRB/IEC review and regulatory 
inspections. 
8.3 
Final Clinical Study Report and Case Report Forms (CRFs) 
A written clinical study report will be provided in accordance with the International 
Conference on Harmonization (ICH) E-3 guidelines including Annex I (Synopsis) 
documenting the clinical execution of the study. This report will include a description of any 
protocol deviations. The final report will also include reasons for withdrawals and any 
necessary treatment(s). The report will also include tables presenting demographics (separate 
summary tables for enrolled and completed subjects), and adverse events recorded during the 
study. In addition, the clinical study report will include a Quality Assurance statement, 
documenting that the report has been reviewed for completeness, accuracy, and compliance 
with the protocol and applicable local and federal regulations. For final clinical reporting 
purposes only, adverse events deemed “definite”, “probable” or “possible” will be included in 
the treatment-related summaries/listings. 
Case Report Forms containing data transcribed from subject source documents (as 
appropriate) and copies of other source documents will be supplied by the clinical site. The 
Principal Investigator must sign each subject’s CRF after completion of data entry, signifying 
that the data entered in the CRF is complete and accurate. Electronic CRFs may be provided. 
8.4 
Adherence to Protocol 
Except for an emergency situation in which proper care for the protection, safety and well-
being of the study subjects requires medical treatment, the study will be conducted as 
described in the approved protocol (and amendments, if applicable), GCP and applicable 
SOPs. In addition, the study will be conducted in accordance with the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted. Any deviation(s) from the protocol will be recorded and 
presented in the final report. 
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8.5 
Data Handling and Record Retention 
All clinical information shall be recorded, handled and stored in such a way that it can be 
accurately reported, interpreted and verified, while the confidentiality of records of the study 
subjects remains protected. 
A CRF is required to be completed for each subject receiving study medication. The CRF is 
property of the sponsor and the Investigator must review all CRFs prior to submission to the 
sponsor. 
The CRF may be consider as the source document, the investigator must seek prospective 
agreement to the sponsor in writing to use the CRF as source document prior the start of the 
study. In addition, items directly recorded in the CRF must be documented that they will be 
considered as source. 
All records pertaining to the receipt and return of study supplies (particularly study 
medication) and copies of final case report forms, worksheets, and other pertinent source 
documents must be retained in accordance with ICH-GCP and the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted. 
The investigator must obtain in writing the sponsor’s agreement to dispose of any records, 
even if the retention period has been reached. 
8.6 
Confidentiality 
Information furnished to Clinical Investigators and IRBs/Ethics Committees will be 
maintained in confidence by the Clinical Investigator and IRB/Ethics Committee. By signing 
this protocol, the Investigator affirms to the Sponsor that he/she will maintain, in confidence, 
information furnished to the IRB/Ethics Committee relevant to this study under appropriate 
understanding of confidentiality with such IRB/Ethics Committee. 
By signing the protocol, the Investigator agrees that within local regulatory restrictions and 
institutional and ethical considerations, the Sponsor may consult and/or copy source 
documents (e.g., laboratory/X-ray reports, ECG tracings, workbooks, medical records) in 
order to verify CRF data. 
8.7 
Ethics and Regulatory Authorities 
Guidelines will be followed with regard to the treatment of human subjects in the study, in 
accordance with the requirements of the Declaration of Helsinki and International Conference 
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH-E6) in addition to the regulatory requirements of the country where the study is 
being conducted as well as the country where the study will be submitted. 
8.7.1 
Institutional Review Board/Ethics Committee 
The Investigator is responsible for obtaining initial and continuing review (at intervals not 
more than once per year) of the study by an IRB/Ethics Committee, or in accordance with 
applicable government regulations of the country where the study is being conducted as well 
as the country where the study will be submitted. This study will not enroll any subjects until 
the IRB/Ethics Committee provides written approval of the protocol and the informed 
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consent to the investigator. In addition, a copy of the IRB/Ethics Committee approval 
documents must be provided to the sponsor prior to enrolling any subjects into the study. 
8.7.2 
Regulatory Authority 
This clinical study protocol, title and a list of investigational sites, IEC(s)/IRB(s) approvals, 
as well as other relevant documentation will be submitted to the local Regulatory Authorities 
for review and approval prior to study start. Upon completion, the Regulatory Authorities 
will be notified the study has ended. The study will only be undertaken in compliance with 
the local regulatory requirements. 
8.8 
Informed Consent 
A properly executed, written informed consent in compliance with current GCP guidelines 
and ICH guidelines shall be obtained from each volunteer prior to entering the study. A copy 
of the informed consent document to be used will be submitted by the investigator to an 
independent institutional review board (e.g. IRB or ethics committee) and the Sponsor and/or 
its agent for review and approval prior to the start of the study. The investigator shall provide 
a copy of the signed and dated informed consent to the subject, and a signed and dated copy 
shall be maintained in the volunteer’s medical record. 
8.9 
Disclosure and Publication of Clinical Study Data 
The disclosure and publication of clinical study data will be detailed in the clinical study 
agreement with the Investigators. 
8.10 End of Study 
The end of study is considered to be the date of last subject last visit or the date of early 
termination of the study whichever is the later. 
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9 
ADVERSE EVENT REPORTING 
9.1 
Adverse events 
All observed or subject-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 
immediate notification to Mylan. The Investigator is required to assess causality and should 
obtain sufficient information to determine the causality of all AEs. All AEs will be followed 
until 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.  
9.2 
Definitions  
9.2.1 
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 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 a TEAE if the first onset (or worsening, in the case of pre-existing 
disease) is after the first administration of MYL-1501D after randomization through follow-
up visit or 14 days after last dose [for subjects that do not have a follow-up visit].  
9.2.2 
Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose 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 study drug reported as “possible”, “probable” or 
“definite” will be considered ADRs. If the relationship to the study drug is not given, then the 
AE must be treated as if the relationship were “possible.” 
9.2.3 
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 study. For example, hepatic 
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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 MYL-1501D is the IB. For Humalog® and any 
concomitant medication, the respective SmPC or US prescribing information will be the 
reference safety document. 
9.2.4 
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 study drug during pregnancy is considered an SAE. However, a newly 
diagnosed pregnancy in a patient that has received the study drug is not 
considered an SAE unless it is suspected that the study drug interacted with a 
contraceptive method and led to the pregnancy. The patient with newly 
diagnosed pregnancy will discontinue receiving study 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 study 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). 
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 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. 
 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 study. 
9.3 
Management of Adverse Events 
AEs or SAEs will be collected from the time the subject signs the informed consent form 
until the follow-up visit or 14 days after last dose of study medication.  Pre-existing diseases 
or conditions (reported at visit 1 in medical history) will not be considered as 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 to be related to the study drug by the Investigator in consultation 
with sponsor will be reported even after the Follow-up visit if reported by subjects. 
9.3.1 
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 subject 
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?” 
Any clinically relevant observations made by the Investigator during the visit will also be 
considered AEs. 
The Subject’s diary should also be reviewed at each study visit for adverse events. At week 0 
visit when study diaries are issued, subjects will be appropriately educated by the study 
designee on what constitutes an adverse event and instructed to record adverse events in the 
study diary in a timely manner.  
9.3.2 
Evaluation 
9.3.2.1 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 study site. If an AE is not listed in the CTCAE, 
its clinical severity will be classified as follows: 
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Table 5: 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 subject's usual function. 
Grade 2 – MODERATE 
Interferes to some extent with subject's usual function. 
Grade 3 – SEVERE 
Interferes significantly with subject'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 9.3.2.8.  
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 9.2.4. 
9.3.2.2 Action Taken 
The possible actions taken for an AE are described in Table 6. 
Table 6: 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 
subject completed the treatment period. 
9.3.2.3 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 
 
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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 subject’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.  
9.3.2.4 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 study treatment(s) and record this relationship in the CRF. 
In addition, if the Investigator determines an AE or SAE is associated with study 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 study 
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 study treatment 
in accordance with the following definitions: 
Table 7: Definition of Suspected Relationship between the Events and Study 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 
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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 reasonably related 
although a causal relationship 
cannot be ruled out 
For Example: Event or laboratory test abnormality, 
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 
 
For SAEs, the relationship to the study 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. 
9.3.2.5 Documentation 
All AEs occurring within the period of observation for the study must be documented in the 
CRF with the following information; where appropriate (the period of observation for the 
study is described in Section 6): 
• 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 study medication as a result of AE. 
• Outcome. 
• Investigator’s opinion regarding the AE relationship to the study treatments. 
 
Hypoglycemic events and associated signs/symptoms will only be recorded on the 
hypoglycemic episodes page of the CRF, unless they are SAEs (i.e., a severe episode). 
9.3.2.6 Treatment of Adverse Events 
AEs that occur during the study 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 study treatment. The decision about 
whether the subject may resume the study treatment will be made by the sponsor after 
consultation with the Investigator and/or medical monitor. 
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9.3.2.7 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 subject’s medical record and recorded on the 
appropriate CRF page. 
9.3.2.8 Notification 
For SAEs, the active reporting period to Mylan, begins from the time that the subject provides 
informed consent, which is obtained prior to the subject’s participation in the study, i.e., prior 
to undergoing any study-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 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). Subject 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 
subject’s study 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 (study site and Investigator) 
• Subject’s unique identification number  
• Subject’s age 
• Investigational medicinal product 
• Date of first dose of study treatment 
• Date of last dose of study treatment, if applicable 
• SAE term 
• The seriousness criteria that were met 
• Investigator’s opinion of the relationship to the study treatment 
• Severity 
• 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 Product Safety and Risk Management department. 
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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 subject 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 
                       All SAEs must be notified within 24 hours by email (preferred) or fax to: 
Mylan Product Safety & Risk Management 
PV MAIL HUB FOR IMMEDIATE SAFETY REPORTS: 
pvclinical@mylan.com 
In the event that an electronic acknowledgment is not received within 24 hours for a SAE 
report submitted by email, please forward the report via fax to +1.304.285.6409. 
9.3.2.9 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. 
9.4 
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). 
9.4.1 
Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during 
study participation. Women should be instructed to contact the Investigator immediately if 
pregnancy occurs or is suspected. 
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Pregnancy testing will be conducted throughout the study, as detailed in the schedule of 
assessments. A woman who is found to be pregnant at the randomization visit (Visit 6 [Week 
0]), will be excluded from the study. A woman who becomes pregnant during the study will 
be immediately discontinued from study 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 Product Safety and Risk 
Management within 24 hours from the time of initial knowledge, even if beyond the closure 
of the clinical database.  
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.   
9.4.2 
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. 
9.5 
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 study drug administration or that are present at 
baseline and worsen following the administration of study 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 
• The test result requires additional diagnostic testing or medical/surgical intervention 
and/or 
• The test result leads to a change in study dosing or discontinuation from the study, 
additional concomitant drug treatment, or other therapy; and/or 
• The test result is considered to be an AE by the Investigator or sponsor. 
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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. 
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10 REFERENCE LIST 
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.  ADA 2017 criteria, Diabetes Care 2017, 40 (supplement1): S11-S24. 
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 MYL-1501D (available upon request).  
7. Mire-Sluis, A.R., et al., Recommendations for the design and optimization of immunoassays 
used in the detection of host antibodies against biotechnology products. J Immunol Methods, 
2004. 289(1-2): p. 1-16. 
8. Shankar, G., et al., Recommendations for the validation of immunoassays used for detection 
of host antibodies against biotechnology products. J Pharm Biomed Anal, 2008. 48(5): p. 
1267-81. 
9. Food and Drug Administration (FDA). Guidance for Industry: Assay Development and 
Validation for Immunogenicity Testing of Therapeutic Protein Products 2016, U.S. 
Department of Health and Human Services. 
10. 
European Medicines Agency (EMA). Guideline on Immunogenicity assessment of 
biotechnology-derived therapeutic proteins. EMEA/CHMP/BMWP/14327/2006 Rev. 1. 
2015. 
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MYL-1501D Protocol 11 JAN 2018 
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MYL-1501D-3004 CLINICAL STUDY PROTOCOL 
Protocol Title 
A Randomized, Multi-center, Double-Blind, Parallel-Group Clinical 
Study Comparing the Efficacy and Safety of MYL-1501D Produced by 
Two Manufacturing Processes in Type 1 Diabetes Mellitus Patients 
Product 
MYL-1501D (Mylan’s Insulin Glargine)  
Protocol No. 
MYL-1501D-3004 
Study Type 
Phase 3 
Version 
2.0 
Protocol Date 
11 JAN 2018 
 
 
IND No.  
IND 105279 
Sponsor 
Mylan GmbH 
Thurgauerstrasse, 40 
CH 8050 Zürich, Switzerland 
 
Confidentiality: This protocol is the confidential, intellectual property of Mylan GmbH. It 
should not be disclosed to a third party with the exception of regulatory agencies and study 
audit personnel that being Mylan employees, representatives, agents and/or contractors 
responsible for conducting the clinical study, audits. Reproduction, modification, or adaption 
in part or in total is strictly forbidden without prior written approval by Mylan GmbH  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Confidential 
DOCUMENT HISTORY 
 
Document 
Version, Date 
Summary of Changes 
Final,  
18 SEP2017 
N/A 
Version 2.0 
11 JAN 2018 
• Titration committee added to guide the dosing of MYL-1501D 
during treatment period and Lantus® during run-in period 
(Section 2.2) 
• Added option of being on stable dose for Levemir® or Toujeo® 
for at least 3 months at screening (Previously only Lantus was 
allowed as the only treatment option) (Section 4.2.1) 
• Updated the Email ID for reporting medication/device related 
complaints from 
MGRG.study.medication.complaints@mylan.co.uk to 
Clinicalbiologicscomplaints@mylan.com (Section 5.2) 
• ECGs: Updated the requirement for being in supine position 
from 10 mins to 5 mins prior to an ECG. (Section 6.5.2.6) 
• Review of results of the 8-point SMBG measurements removed 
from Visit 7 (Week 1), Visit 8 (Week 2), Visit 9 (Week 4) and 
Visit 11 (Week 9) (Section 6.3) 
• Removed fasting Plasma glucose assessment at Visit 13 (Week 
15) (Section 6.3) 
• Primary analysis to include all available outcome data from all 
randomized patients regardless of treatment discontinuation and 
use multiple imputation approach for missing data that more 
appropriately takes treatment adherence into account. (Section 
7.2.2, Section 7.2.4 and Section 7.3) 
• Primary efficacy population (ITT) to include all randomized 
subjects – irrespective of whether subjects having post-baseline 
measurement (Section 7.4) 
• Clarifications and editorial corrections to synchronize text across 
sections throughout the document 
 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Multi-center, Double-Blind, Parallel-Group Clinical 
Study Comparing the Efficacy and Safety of MYL-1501D Produced by 
Two Manufacturing Processes in Type 1 Diabetes Mellitus Patients 
Background 
and Rationale 
MYL-1501D is being developed as a follow-on biologic to the reference 
product Lantus® (insulin glargine). A phase 1 PK/PD study comparing 
MYL-1501D with Lantus® sourced from Europe and U.S. demonstrated 
PK and PD equivalence between the 3 products. PK/PD equivalence was 
also demonstrated with MYL-1501D product produced using two 
manufacturing processes (Process V and Process VI).  
 
The aim of this study is to demonstrate similar efficacy and safety 
between MYL-1501D products produced from two manufacturing 
processes (Process V and Process VI) in combination with insulin lispro 
in patients with type 1 diabetes mellitus (T1DM). 
Primary 
Objectives 
To test whether MYL-1501D product from Process VI once daily is 
non-inferior to MYL-1501D product from Process V once daily based on 
change in HbA1c from baseline to week 18 when administered in 
combination with mealtime insulin lispro. 
Primary 
endpoints 
The primary efficacy endpoint is change in HbA1c from baseline to week 
18 for the ITT analysis set. 
Methodology 
and 
treatments 
This is a multicenter, double-blind, randomized, parallel-group phase 3 
study in subjects with T1DM comparing the efficacy, immunogenicity 
and safety of MYL-1501D products from two manufacturing processes 
(Process V and Process VI).  
After up to 2-week screening period, all subjects will be titrated on 
Lantus® during a 4-week run-in period, and will be shifted from their 
current mealtime insulin to insulin lispro (Humalog®). The subjects will 
be randomized (stratified by time of administration of glargine [morning 
and evening]); one group will receive MYL-1501D product from Process 
V, while the other group will receive MYL-1501D product from Process 
VI for 18 weeks. A follow-up visit will be scheduled 2 weeks after last 
dose of MYL-1501D. 
The study will be conducted in the US. Approximately 110 sites will be 
included in the study. 
Inclusion/ 
exclusion 
criteria 
Inclusion criteria 
1. Written and signed informed consent needs to be provided by subjects or 
their legal representatives before starting any protocol-specific 
procedures.  
2. Male and female subjects between the ages of 18 to 65 years, both ages 
inclusive. 
3. Subjects with an established diagnosis of T1DM per ADA 2017 criteria 
who also fulfil the following criteria: 
a. Initiation of insulin treatment within 6 months of T1DM 
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diagnosis 
b. Treatment with basal-bolus insulin therapy for at least 1 year 
before screening 
c. Fasting plasma C-peptide <0.3 nmol/L (0.9 ng/mL) at screening 
d. Subject has been on once daily Lantus® or once daily Levemir® 
or once daily Toujeo® at stable dose (±15% variation in dose) 
for at least 3 months at screening 
4. Body mass index (BMI) of 18.5 to 35 kg/m2 at screening (both values 
inclusive). 
5. Stable weight, with no more than 5 kg gain or loss in the 3 months prior 
to screening, this information will be collected by subject interview 
during medical history. 
6. Glycosylated hemoglobin (HbA1c) ≤ 9.5% at screening. 
7. Hemoglobin ≥9.0 g/dL at screening. 
8. Subject has the capability of communicating appropriately with the 
investigator.  
9. Subject is able and willing to comply with the requirements of the study 
protocol including the 8-point self-monitored blood glucose (SMBG), 
completion of subject diary records and following a recommended diet 
and exercise plan for the entire duration of the study. 
10. Female subjects of childbearing potential who are willing to use oral 
contraception or acceptable methods of contraception, (e.g., intra-uterine 
device, spermicidal gel plus condom, diaphragm plus condom, etc.), 
from the time of screening and for the duration of the study, through 
study completion. 
a. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
b. Postmenopausal females must have had no regular menstrual 
bleeding for at least 1 year prior to screening.  
c. Female subjects who report surgical sterilization must have had 
the procedure at least 6 months prior to screening.  
d. All female subjects of childbearing potential must have negative 
pregnancy test results at screening and at clinic visits, as per the 
SCHEDULE OF ACTIVITIES (SOA). 
e. If female subjects have male partners who have undergone 
vasectomy, the vasectomy must have occurred more than 6 
months prior to screening 
Exclusion Criteria 
1. History or presence of a medical condition or disease that in the 
investigator’s opinion would place the subject at an unacceptable risk 
from study participation. 
2. History of hypersensitivity to any of the active or inactive ingredients of 
the insulin/insulin analogue preparations used in the study, OR history 
of significant allergic drug reactions. 
3. History of use of animal insulin within the last 3 years or use of 
approved biosimilar insulin glargine at any time prior to study entry, 
except for subject who previously participated in MYL-1501D studies 
and were compliant with the study protocols.  
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4. History of use of a regular immunomodulator therapy in the 1 year prior 
to screening. 
5. History of autoimmune disorders other than T1DM or insufficiently 
treated autoimmune thyroid disorders judged clinically relevant by the 
investigator (recorded while collecting subject history). 
6. History of ≥1 episodes of diabetic ketoacidosis or emergency room visits 
for uncontrolled diabetes leading to hospitalization within the 6 months 
prior to screening. 
7. History of clinically significant acute bacterial, viral or fungal systemic 
infections in the last 4 weeks prior to screening (recorded while 
collecting subject history). 
8. Any clinically significant abnormality in electrocardiogram (ECG) or 
safety laboratory tests (LFT, RFT, hematology or any other laboratory 
deemed clinically relevant by the investigator) conducted at screening 
and considered by the investigator to make the subject ineligible for the 
study. 
9. Serological evidence of human immunodeficiency virus (HIV), hepatitis 
B surface antigen (HBsAg) or hepatitis C antibodies (HCVAb) at 
screening. 
10. History of drug or alcohol dependence or abuse during the 1 year prior 
to screening. 
11. Receipt of another investigational drug in the 3 months prior to 
screening (or as per local regulations), or if the screening visit is within 
5 half-lives of another investigational drug received (whichever is 
longer), or scheduled to receive another investigational drug during the 
current study period. 
12. Subjects with the following secondary complications of diabetes: 
a. Active proliferative retinopathy as confirmed by a dilated 
ophthalmoscopy examination / retinal photography (performed 
by a person legally authorized to do so) within the 6 months 
prior to screening. 
b. Clinical nephrotic syndrome or diabetic nephropathy with a 
serum creatinine level >1.5 times of upper limit of reference 
range at screening 
c. History of severe form of neuropathy or cardiac autonomic 
neuropathy, recorded while collecting subject history. 
Subject’s with mild or moderate forms of neuropathy will be 
allowed. 
d. Subjects with a history of limb amputation as a complication of 
diabetes (at any time), or any vascular procedure during the 1 
year prior to screening. 
e. History of diabetic foot or diabetic ulcers in the 1 year prior to 
screening. 
13. Any elective surgery requiring hospitalization planned during the study 
period. 
14. Clinically significant major organ disorder at the time of screening 
including: 
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a. Uncontrolled hypertension, defined as stage 2 hypertension by 
Joint National Committee VII (even if therapy is ongoing, blood 
pressure ≥160 mm Hg systolic or ≥100 mm Hg diastolic). 
b. Uncontrolled hyperlipidemia (even if therapy is ongoing, LDL 
>160 mg/dL or triglycerides >500 mg/dL). 
c. Uncontrolled hyperthyroidism or hypothyroidism (subjects can 
be included if these conditions are controlled with thyroid 
hormones or anti-thyroid drugs). 
d. Impaired hepatic function (alanine transaminase [ALT] or 
aspartate transaminase [AST] value >2 times the upper limit of 
the reference range and/or serum bilirubin 1.5 times the upper 
limit of the reference range at the screening visit). Subjects with 
evidence of Gilberts disease may be included in the study if they 
have total bilirubin of <3 mg/dL with indirect bilirubin 
contributing to >80% of the total bilirubin. 
15. History of a significant medical condition, such as: 
a. Clinically significant cardiac disease like unstable angina, 
myocardial infarction, grade 3 or 4 congestive heart failure 
(CHF) according to New York Heart Association criteria, 
valvular heart disease, cardiac arrhythmia requiring treatment, 
and pulmonary hypertension; during the year prior to screening. 
b. Stroke or transient ischemic attack (TIA) in the 6 months before 
screening.  
16. Subjects with major depressive illness in the last 3 years (those who 
have well-controlled depression for 3 months on a stable dose of 
antidepressants, with no major depressive episodes in the last 3 years, 
can be included, even if they are on medication), subjects with history of 
other severe psychiatric diseases (manic depressive psychosis [MDP], 
schizophrenia), which in the opinion of the investigator precludes the 
subject from participating in the study (recorded while collecting subject 
history). 
17. History of hematological disorders that can affect the reliability of 
HbA1c estimation (hemoglobinopathies, hemolytic anemia, sickle cell 
anemia, etc.). 
18. Subjects using the following in the 3 months prior to screening: 
a. Insulin pump therapy 
b. Any anti-diabetic drugs other than the study insulins allowed by 
the protocol. 
19. Moderate insulin resistance, defined as requiring insulin of ≥1.5 
U/kg/day. 
20. Subjects who have received ≥14 consecutive days of glucocorticoid 
therapy by oral, intravenous, inhaled or other routes that produce 
systemic effects within the past 1 year, or who have received steroids by 
any route (except intra-nasal, intra-ocular, and topical) within the 4 
weeks immediately preceding screening.  
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21. Subjects diagnosed as having cancer (subjects with history of basal cell 
carcinoma, carcinoma in situ or squamous cell cancer of skin, or in 
remission >5 years, will be allowed). 
22. Subjects who have donated blood or plasma in the 1 month prior to 
screening 
Sample size 
A total of 202 subjects with T1DM are planned to be randomized for this 
study and will receive either MYL-1501D Process V product or MYL-
1501D Process VI product, in a 1:1 ratio.  
The sample size estimation is based on assumptions for the change from 
baseline up to week 18 in HbA1C with either MYL-1501D product from 
Process V or Process VI. It is assumed, that true mean groups mean 
difference is 0.03 and standard deviation is equal to 0.74. To demonstrate 
non-inferiority margin of 0.4% using a 2-sided 95% confidence interval 
and a 90% power, a total of 172 subjects (86 subjects per treatment group) 
are required. To account for a maximum of 15% of subjects being not 
eligible for the per protocol analysis, a total sample size of 202 is planned 
to be randomized for this study. The true treatment difference and 
standard deviation is based on previous study MYL-GAIA-3001. 
Statistical 
Methods 
A repeated measures analysis employing a restricted maximum likelihood 
(REML)-based, mixed model repeated measures (MMRM)-effects model 
approach will be used to estimate a 95% confidence interval for the 
absolute difference between MYL-1501D Process V product and MYL-
1501D Process VI product for mean change in HbA1c at Week 18. 
Non-inferiority for primary objective will be established if the upper limit 
of a two sided 95% confidence interval for the absolute difference 
(MYL-1501D Process VI minus MYL-1501D Process V) of mean change 
from baseline for HbA1c is no greater than 0.4% at 18 weeks of 
treatment. 
 
 
 
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TABLE OF CONTENTS 
DOCUMENT HISTORY........................................................................................................... 3 
PROTOCOL SYNOPSIS .......................................................................................................... 4 
LIST OF COMMONLY USED ABBREVIATIONS.............................................................. 15 
1 
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES ............................. 16 
2 
INTRODUCTION ........................................................................................................... 20 
2.1 
Indication ................................................................................................................. 20 
2.2 
Background and Rationale ....................................................................................... 20 
2.2.1 
Rationale for Dose Selection ............................................................................... 21 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 22 
3.1 
Objectives ................................................................................................................ 22 
3.1.1 
Primary objectives ............................................................................................... 22 
3.1.2 
Other objectives ................................................................................................... 22 
3.2 
Endpoints ................................................................................................................. 22 
3.2.1 
Primary Endpoints ............................................................................................... 22 
3.2.2 
Secondary Endpoints ........................................................................................... 22 
3.2.2.1 Efficacy ......................................................................................................... 22 
3.2.2.1 Safety ............................................................................................................. 22 
4 
STUDY POPULATION .................................................................................................. 23 
4.1 
Study Population ...................................................................................................... 23 
4.2 
Inclusion and Exclusion Criteria .............................................................................. 23 
4.2.1 
Inclusion Criteria ................................................................................................. 23 
4.2.2 
Exclusion Criteria ................................................................................................ 24 
4.2.3 
Criteria for study drug termination, withdrawal from the study and study 
termination ....................................................................................................................... 26 
4.3 
Contraception ........................................................................................................... 27 
4.3.1 
Females - Non-childbearing Potential ................................................................. 27 
4.3.2 
Females - Childbearing Potential ......................................................................... 27 
4.4 
Pregnancy Testing .................................................................................................... 28 
5 
STUDY DRUG ................................................................................................................ 29 
5.1 
Investigational Drug ................................................................................................ 29 
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5.1.1 
Administration of Study Drugs ............................................................................ 29 
5.2 
Study Medication/Device Complaints ..................................................................... 30 
5.3 
Storage, Disposition of Unused Study Drug and Drug Accountability ................... 30 
5.4 
Randomization ......................................................................................................... 31 
5.5 
Breaking the Blind ................................................................................................... 31 
5.6 
Concomitant Medications ........................................................................................ 31 
5.7 
Recommended Procedure for Subject Experiencing Adverse Effects Secondary to 
Excessive Pharmacological Effects of Study Drug ............................................................. 32 
6 
STUDY CONDUCT ........................................................................................................ 33 
6.1 
Screening Procedures ............................................................................................... 33 
6.1.1 
Screening (Visit 1 [Week -6 to Week -4]) ........................................................... 34 
6.2 
Run-in Period ........................................................................................................... 35 
6.2.1 
Visit 2 (Week -4) ................................................................................................. 35 
6.2.2 
Visit 3 (Week -3), Visit 5 (Week -1) ................................................................... 35 
6.2.3 
Visit 4 (Week -2) ................................................................................................. 35 
6.3 
Treatment phase ....................................................................................................... 36 
6.3.1 
Visit 6 (Week 0) ................................................................................................... 36 
6.3.2 
Visit 7 (Week 1), Visit 9 (Week 4), Visit 11 (Week 9) ....................................... 37 
6.3.3 
Visit 8 (Week 2), Visit 10 (Week 6) .................................................................... 37 
6.3.4 
Visit 12 (Week 12) ............................................................................................... 38 
6.3.5 
Visit 13 (Week 15) ............................................................................................... 38 
6.3.6 
Visit 14/ End of Treatment (Week 18) ................................................................ 39 
6.3.7 
Early study drug Termination (ET) visit .............................................................. 40 
6.4 
Visit 15 Follow up (Week 20) (telephone call) ....................................................... 40 
6.5 
Treatment Procedures .............................................................................................. 40 
6.5.1 
Blood Volume ...................................................................................................... 40 
6.5.2 
Safety Testing Assessments ................................................................................. 41 
6.5.2.1 Adverse Event Assessment ........................................................................... 41 
6.5.2.2 Hypoglycemia ............................................................................................... 41 
6.5.2.3 Laboratory Safety .......................................................................................... 44 
6.5.2.4 Immunogenicity Assessment......................................................................... 44 
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6.5.2.5 Blood Pressure and Pulse Rate ...................................................................... 45 
6.5.2.6 12-lead ECG .................................................................................................. 46 
6.5.2.7 General Physical Examination ...................................................................... 46 
7 
STATISTICAL ANALYSIS ........................................................................................... 47 
7.1 
Sample Size Determination ..................................................................................... 47 
7.2 
Primary Endpoints ................................................................................................... 47 
7.2.1 
Definition of Primary Endpoints .......................................................................... 47 
7.2.2 
Statistical Methodology for Primary Endpoints .................................................. 47 
7.2.3 
Primary Analysis for Primary Endpoints ............................................................. 48 
7.2.4 
Secondary/Sensitivity Analyses for Primary Endpoints ...................................... 48 
7.2.5 
Missing Data ........................................................................................................ 48 
7.2.6 
Sub-Group Analyses ............................................................................................ 48 
7.3 
Secondary Endpoints ............................................................................................... 48 
7.4 
Analysis Set Definitions .......................................................................................... 49 
7.5 
Other Safety Analyses ............................................................................................. 50 
7.5.1 
Vital Signs ............................................................................................................ 50 
7.5.2 
ECG Analyses ...................................................................................................... 50 
7.5.3 
Laboratory Data ................................................................................................... 50 
8 
ADMINISTRATIVE PROCEDURES ............................................................................ 52 
8.1 
Source Documentation Forms ................................................................................. 52 
8.2 
Access to Data/Source Documentation .................................................................... 52 
8.3 
Final Clinical Study Report and Case Report Forms (CRFs) .................................. 52 
8.4 
Adherence to Protocol ............................................................................................. 52 
8.5 
Data Handling and Record Retention ...................................................................... 53 
8.6 
Confidentiality ......................................................................................................... 53 
8.7 
Ethics and Regulatory Authorities ........................................................................... 53 
8.7.1 
Institutional Review Board/Ethics Committee .................................................... 53 
8.7.2 
Regulatory Authority ........................................................................................... 54 
8.8 
Informed Consent .................................................................................................... 54 
8.9 
Disclosure and Publication of Clinical Study Data ................................................. 54 
8.10 
End of Study ............................................................................................................ 54 
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9 
ADVERSE EVENT REPORTING.................................................................................. 55 
9.1 
Adverse events ......................................................................................................... 55 
9.2 
Definitions ............................................................................................................... 55 
9.2.1 
Adverse Events .................................................................................................... 55 
9.2.2 
Adverse Drug Reaction ........................................................................................ 55 
9.2.3 
Unexpected Adverse Event/Adverse Drug Reaction ........................................... 55 
9.2.4 
Serious Adverse Events ....................................................................................... 56 
9.3 
Management of Adverse Events .............................................................................. 57 
9.3.1 
Collection ............................................................................................................. 57 
9.3.2 
Evaluation ............................................................................................................ 57 
9.3.2.1 Severity Assessment of Adverse Events ....................................................... 57 
9.3.2.2 Action Taken ................................................................................................. 58 
9.3.2.3 Outcome at the Time of Last Observation .................................................... 58 
9.3.2.4 Causality Assessment of Adverse Events ..................................................... 59 
9.3.2.5 Documentation .............................................................................................. 60 
9.3.2.6 Treatment of Adverse Events ........................................................................ 60 
9.3.2.7 Follow-up ...................................................................................................... 61 
9.3.2.8 Notification.................................................................................................... 61 
9.3.2.9 Regulatory Reporting .................................................................................... 62 
9.4 
Special Situations ..................................................................................................... 62 
9.4.1 
Pregnancy ............................................................................................................. 62 
9.4.2 
Overdose, Medication Errors and Other Events .................................................. 63 
9.5 
Abnormal Test Findings .......................................................................................... 63 
10 REFERENCE LIST ......................................................................................................... 65 
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LIST OF TABLES 
 
Table 1: Study Schedule of Activities ..................................................................................... 17 
Table 2: Medication not to be started during the Run-in or Treatment period ........................ 32 
Table 3: Blood Volume ............................................................................................................ 41 
Table 4: Laboratory Safety Tests ............................................................................................. 44 
Table 5: Clinical Severity of Adverse Events .......................................................................... 58 
Table 6: Action Taken for an Adverse Event .......................................................................... 58 
Table 7: Definition of Suspected Relationship between the Events and Study Medication .... 59 
 
 
 
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LIST OF FIGURES 
Figure 1: Study Diagram .......................................................................................................... 16 
 
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LIST OF COMMONLY USED ABBREVIATIONS 
ADA 
American Diabetes Association 
 
mL 
Milliliter 
ADR 
Adverse drug reaction 
 
MMRM 
Mixed Model Repeated 
Measures 
AE 
Adverse event 
 
PD 
Pharmacodynamic 
ALT 
Alanine transaminase 
 
PK 
Pharmacokinetic 
AST 
Aspartate transaminase 
 
PP 
Per Protocol 
BMI 
Body mass index 
 
PSRM 
Product Safety and Risk 
Management 
cm 
centimeter 
 
REML 
Restricted maximum likelihood 
CI 
Confidence interval 
 
SAE 
Serious Adverse Event 
CRF 
Case Report Form 
 
SAP 
Statistical Analysis Plan 
CRO 
Contract Research Organization 
 
SD 
Standard Deviation 
CV 
Coefficient of Variation 
 
SID 
Subject Identification 
ECG 
Electrocardiogram 
 
SMBG 
Self-monitored blood glucose 
FDA 
Food and Drug Administration 
 
SOA 
Schedule of Activities 
GCP 
Good Clinical Practice 
 
SOP 
Standard Operating Procedure 
HbA1c 
Glycosylated hemoglobin 
 
T1DM 
Type 1 diabetes mellitus 
HBsAg  
Hepatitis B Surface Antigen  
 
TEAE 
Treatment emergent adverse 
event 
HCVAb 
Hepatitis C antibodies 
 
U 
Unit 
HIV 
Human Immunodeficiency 
Virus 
 
US 
United States 
HR 
Heart Rate 
 
WoCBP 
Women of Child-Bearing 
Potential 
IB 
Investigator’s Brochure 
 
 
 
ICF 
Informed Consent Form 
 
 
 
ICH 
International Council for 
Harmonisation 
 
 
 
IEC 
Independent ethics committee 
 
 
 
IRB 
Institutional Review Board 
 
 
 
S/IWRS 
Interactive Voice Response 
System/ Interactive Web 
Response System 
 
 
 
ITT 
Intent to treat 
 
 
 
IU 
International Unit 
 
 
 
kg 
kilogram 
 
 
 
LOCF 
Last Observation Carried 
Forward 
 
 
 
MedDRA 
Medical dictionary for 
regulatory activities 
 
 
 
mg 
Milligram 
 
 
 
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Confidential 
1 
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES 
The Schedule of Activities table provides an overview of the protocol visits and procedures. Refer to the Study Conduct Section (Section 6) for 
detailed information on each procedure and assessment required for compliance with the protocol. 
Figure 1: Study Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                              
 
Overall Study Duration- 26 Weeks 
Screening  
Run- in Period 
Treatment Period 
Follow -up 
2 weeks  
4 weeks 
18 weeks 
2 weeks 
S
C
R
E
E
N
I
N
G 
R
A
N
D
O
M
I
Z
E 
E
O
T  
F
U
P  
MYL-1501D (Process V Product) 
MYL-1501D (Process VI Product) 
Lantus 
V
1 
V
2 
V
3 
V
5 
V 
4 
V
6 
V
1
4 
V
7 
V
8 
V
9 
V 
1
0 
V
1
1 
V 
1
2 
V 
1
3 
V
1
5 
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Confidential 
Table 1: Study Schedule of Activities 
Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-up 
Study Visits1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
(EOT) 
V15 (FU) 
Study Week 
-6 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
6 
9 
12 
15 
18 
20 
Study Days 
-42 to -28 -28±3 -21±3 -14±3 -7±3 0±3 
7±3 
14±3 28±3 42±3 70±7 84±7 112±7 
126±7 
140±7 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
History of previous insulin usage 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated Ophthalmoscopy / retinal 
photography if not done in the last 6 
months 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard-of-care specifics2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Age, Gender, Height, Race 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight and BMI 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Pregnancy Test3 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Medical History including concomitant 
illness 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
x 
x 
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 
 
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Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-up 
Study Visits1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
(EOT) 
V15 (FU) 
Study Week 
-6 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
6 
9 
12 
15 
18 
20 
Study Days 
-42 to -28 -28±3 -21±3 -14±3 -7±3 0±3 
7±3 
14±3 28±3 42±3 70±7 84±7 112±7 
126±7 
140±7 
Physical examination 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
12-lead ECG (supine) 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
Randomization 
 
 
 
 
 
x 8 
 
 
 
 
 
 
 
 
 
Record AEs and SAEs (including local 
and systemic allergic reactions) and 
hypoglycemic events4 due to 
medication, disposable pen or needle 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record device safety information 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Fasting plasma glucose 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
HbA1c Assay 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
Fasting C-peptide, HIV, HBsAg, and 
HCVAb 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sampling for hematology, blood 
chemistry and urinalysis5 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
Fasting lipid profile 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
Sampling for immunogenicity 9 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
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Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-up 
Study Visits1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
(EOT) 
V15 (FU) 
Study Week 
-6 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
6 
9 
12 
15 
18 
20 
Study Days 
-42 to -28 -28±3 -21±3 -14±3 -7±3 0±3 
7±3 
14±3 28±3 42±3 70±7 84±7 112±7 
126±7 
140±7 
Sampling for PK6 
 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Review 8-point SMBG Profile 
performed in the week before the visit 7 
 
 
x 
x 
x 
x 
 
 
 
x 
 
x 
 
x 
 
Dose review of Lantus, MYL-1501D 
and insulin lispro and instruction 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dispense Study Medication and ancillary
supplies 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
 
 
Drug Accountability and Compliance 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Dispense subject diary 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
 
 
Review subject diary 
 
 
 
x 
 
x 
 
 
 
x 
 
x 
 
x 
 
1. 
Visits 3, 5, 7, 9 and 11 may be telephone contacts (grey columns represent telephone contacts). 
2. 
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. 
3. 
Serum pregnancy test for women of child bearing potential will be done during screening and randomization visit. During subsequent visits urine pregnancy test will be done. At the randomization visit, both urine 
and serum pregnancy tests will be done. Subject may be enrolled if the urine pregnancy test is negative. 
4. 
Non-severe hypoglycemic events (which are not consider as SAE) occurring after the EOT visit will not be recorded at the follow-up visit.  
5. 
A routine urine dipstick test will be performed by the site. A microscopic urinalysis will be performed by the central lab if the dipstick test result is abnormal. 
6. 
The PK sample will be taken during the visit, preferably prior to the daily glargine dose. The timing of study drug administration from prior day should be collected along with the time of PK sample collection.  
7. 
The 8-point SMBG profile, measurement will be done by the subject at home on 3 days (of which 2 are consecutive days) in the week before the next visit. Evaluation will be based on the measurements after 
each 6 weeks; thus during randomized period it would done at Week 6, 12 and 18, while SMBG would be done on 3 days during Weeks 5, 11 and 17. 
8. 
Prior to randomization, Investigator is required to confirm subject eligibility into the study based on the data collected during the screening period, including the labs values recorded during screening. In case 
subject does not meet the eligibility re-screening need to be confirmed by the Sponsor or designee. 
9. 
During the Randomized Comparative Treatment Period, the immunogenicity samples should be drawn immediately following the PK sample, as outlined under Footnote 6.
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2 
INTRODUCTION 
2.1 
Indication 
MYL-1501D is being developed as a follow-on biologic (US terminology) or biosimilar (EU 
terminology) to Lantus®.  
2.2 
Background and Rationale 
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 main 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. 
The Diabetes Control and Complications Trial [2] and other trials [3] provide conclusive 
evidence that maintaining tight glycemic control can prevent or delay microvascular and 
macrovascular complications in patients with T1DM. A number of different insulin regimens 
have been proposed for treatment of patients with T1DM. It is generally accepted that the so-
called basal-bolus insulin regimen (1 or 2 daily injections of long/intermediate-acting insulin 
covering basal insulin requirements in combination with 3 daily injections of short-/rapid 
acting insulin to cover meal-related insulin requirements) generally yields the best glycemic 
control in diabetes. Clear targets for plasma glucose levels have been recommended for basal-
bolus insulin regimens [4]. 
Different insulin preparations are available for management of basal insulin requirements, 
including intermediate-acting insulins (neutral protamine Hagedorn insulin) and long-acting 
insulin analogs such as insulin glargine and insulin detemir. 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. After injection of Insulin glargine into the 
subcutaneous tissue, the acidic solution is neutralized; leading to formation of micro-
precipitates from which small amounts of insulin glargine are continuously released, 
providing a smooth, peakless, predictable concentration versus time profile with a prolonged 
duration of action.  
MYL-1501D 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.  
The aim of this study is to demonstrate similar efficacy and safety between MYL-1501D 
product produced from two manufacturing processes in combination with insulin lispro in 
patients with T1DM. 
Since the two investigational products have an identical presentation of prefilled pen to be 
used by the subjects during the treatment period, the subject and the treating physician will 
remain blinded to treatment assignment. Furthermore, the evaluation of the study endpoints, 
such as analysis of immunogenicity and glycosylated hemoglobin (HbA1c), will be 
performed in a blinded manner by blinded personnel. The sponsor team as well as the CRO 
team will also be blinded to the subject assigned treatment. 
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To ensure that both treatment arms are comparable at baseline with respect to drug-induced 
immune responses and other parameters, only subjects who have been on a stable dose of 
Lantus® for at least 3 months prior to screening will be included.  
During the 4-week run-in period with Lantus® and Humalog®, the dose of insulin will be 
titrated (if required) to ensure diabetes control. The run-in period ensures comparable drug 
exposure for all subjects, and increases the likelihood of comparable immune responses at the 
start of the treatment period. An 18-week treatment period is an adequate period to detect 
differences in HbA1c of the treatment arms [5]. 
Dosing with MYL-1501D during treatment period and Lantus® during run-in period will be 
guided by self-monitored blood glucose (SMBG)-based glucose level assessments and by the 
titration committee as detailed in the insulin monitoring (titration committee) plan. 
Rescue criteria based on HbA1c are defined based on week 12 HbA1c measurement, so that a 
potential worsening of metabolic control in subjects during the study can be identified and 
therapy modified at the discretion of the investigator.  
A follow-up visit, 2 weeks after the end of treatment, will ensure the safety of all subjects 
after they stop the study medication and return to receiving approved medications. 
Complete information for the study medication can be found in MYL-1501D Investigator’s 
Brochure (IB). [6] 
2.2.1 
Rationale for Dose Selection 
Only subjects who have been on a stable dose of Lantus® for at least 3 months prior to 
screening will be included in the study, thus subjects would be on a stable dose at study entry. 
If required, subject dose should be adjusted during the 4-week run-in period to stabilize the 
subjects. During the treatment period, dose adjustment should be avoided but it is permitted 
to ensure subject’s stable state and safety.  
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3 
OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary objectives 
To test whether MYL-1501D product from Process VI once daily is non-inferior to 
MYL-1501D product from Process V once daily based on change in HbA1c from baseline to 
week 18 when administered in combination with mealtime insulin lispro. 
3.1.2 
Other objectives 
To compare MYL-1501D product from Process VI and Process V at week 18, when 
administered in combination with mealtime insulin lispro, with respect to: 
• Immunogenicity: incidence and change from baseline in the relative levels of 
anti-drug antibody  
• Hypoglycemic events: incidence and rate per 30 days 
• Occurrence of local reactions, systemic reactions and other adverse events 
• Device-related safety assessment 
• Change in fasting plasma glucose from baseline 
• Change in insulin dose per unit body weight (U/kg) from baseline 
• Change in 8-point SMBG profile from baseline 
 
3.2 
Endpoints 
3.2.1 
Primary Endpoints 
The primary efficacy endpoint is change in HbA1c from baseline to week 18 for the ITT 
population. 
3.2.2 
Secondary Endpoints 
3.2.2.1 Efficacy 
• Change in fasting plasma glucose from baseline 
• Change in basal insulin, meal-time, and total insulin dose per unit body weight 
(U/kg) from baseline 
• Change in 8-point SMBG profile from baseline 
 
3.2.2.1 
Safety 
• Incidence of positive antibody response and change in antibody percentage 
binding from baseline. 
• Change in hypoglycemia rate (30 day adjusted) from baseline and incidence of 
hypoglycemic events 
• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse 
events (SAEs) 
• Incidence of local reactions, systemic reactions and other adverse events 
• Incidence of device-related safety assessment 
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4 
STUDY POPULATION 
4.1 
Study Population 
A total of 202 subjects with T1DM are planned to be randomized in this study, to receive 
MYL-1501D from either Process VI or Process V with a randomization ratio of 1:1. 
A detailed description related to sample size determination is provided in Section 7. 
4.2 
Inclusion and Exclusion Criteria 
4.2.1 
Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the 
study: 
1. Written and signed informed consent needs to be provided by subjects or their legal 
representatives before starting any protocol-specific procedures.  
2. Male and female subjects between the ages of 18 to 65 years, both ages inclusive. 
3. Subjects with an established diagnosis of T1DM per American Diabetes Association 
(ADA) 2017 criteria who also fulfil the following criteria: 
a. Initiation of insulin treatment within 6 months of T1DM diagnosis 
b. Treatment with basal-bolus insulin therapy for at least 1 year before screening 
c. Fasting plasma C-peptide <0.3 nmol/L (0.9 ng/mL) at screening 
d. Subject has been on once daily Lantus® or once daily Levemir® or once daily 
Toujeo® at stable dose (±15% variation in dose) for at least 3 months at screening 
4. Body mass index (BMI) of 18.5 to 35 kg/m2 at screening (both values inclusive). 
5. Stable weight, with no more than 5 kg gain or loss in the 3 months prior to screening, this 
information will be collected by subject interview during medical history. 
6. HbA1c ≤9.5% at screening. 
7. Hemoglobin ≥9.0 g/dL at screening. 
8. Subject has the capability of communicating appropriately with the investigator.  
9. Subject is able and willing to comply with the requirements of the study protocol 
including the 8-point SMBG, completion of subject diary records and following a 
recommended diet and exercise plan for the entire duration of the study. 
10. Female subjects of childbearing potential who are willing to use oral contraception or 
acceptable methods of contraception, (e.g., intra-uterine device, spermicidal gel plus 
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condom, diaphragm plus condom, etc.), from the time of screening and for the duration of 
the study, through study completion. 
a. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
b. Postmenopausal females must have had no regular menstrual bleeding for at least 
1 year prior to screening.  
c. Female subjects who report surgical sterilization must have had the procedure at 
least 6 months prior to screening.  
d. All female subjects of childbearing potential must have negative pregnancy test 
results at screening and at clinic visits, as per the SCHEDULE OF ACTIVITIES 
(SOA). 
e. If female subjects have male partners who have undergone vasectomy, the 
vasectomy must have occurred more than 6 months prior to screening 
4.2.2 
Exclusion Criteria 
Subject candidates must not be enrolled in the study if they meet any of the following criteria: 
1. History or presence of a medical condition or disease that in the investigator’s opinion 
would place the subject at an unacceptable risk from study participation. 
2. History of hypersensitivity to any of the active or inactive ingredients of the 
insulin/insulin analogue preparations used in the study, OR history of significant allergic 
drug reactions. 
3. History of use of animal insulin within the last 3 years or use of approved biosimilar 
insulin glargine at any time prior to study entry, except for subject who previously 
participated in MYL-1501D studies and were compliant with the study protocols.  
4. History of use of a regular immunomodulator therapy in the 1 year prior to screening. 
5. History of autoimmune disorders other than T1DM or insufficiently treated autoimmune 
thyroid disorders, judged clinically relevant by the investigator (recorded while collecting 
subject history). 
6. History of ≥1 episodes of diabetic ketoacidosis or emergency room visits for uncontrolled 
diabetes leading to hospitalization within the 6 months prior to screening. 
7. History of clinically significant acute bacterial, viral or fungal systemic infections in the 
last 4 weeks prior to screening (recorded while collecting subject history). 
8. Any clinically significant abnormality in electrocardiogram (ECG) or safety laboratory 
tests (LFT, RFT, hematology or any other laboratory deemed clinically relevant by the 
investigator) conducted at screening and considered by the investigator to make the 
subject ineligible for the study. 
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9. Serological evidence of human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg) or hepatitis C antibodies (HCVAb) at screening. 
10. History of drug or alcohol dependence or abuse during the 1 year prior to screening. 
11. Receipt of another investigational drug in the 3 months prior to screening (or as per local 
regulations), or if the screening visit is within 5 half-lives of another investigational drug 
received (whichever is longer), or scheduled to receive another investigational drug 
during the current study period. 
12. Subjects with the following secondary complications of diabetes: 
a. Active proliferative retinopathy as confirmed by a dilated ophthalmoscopy 
examination / retinal photography (performed by a person legally authorized to do 
so) within the 6 months prior to screening. 
b. Clinical nephrotic syndrome or diabetic nephropathy with a serum creatinine level 
>1.5 times of upper limit of reference range at screening 
c. History of severe form of neuropathy or cardiac autonomic neuropathy, recorded 
while collecting subject history. Subjects with mild or moderate forms of 
neuropathy will be allowed. 
d. Subjects with a history of limb amputation as a complication of diabetes (at any 
time), or any vascular procedure during the 1 year prior to screening. 
e. History of diabetic foot or diabetic ulcers in the 1 year prior to screening. 
13. Any elective surgery requiring hospitalization planned during the study period. 
14. Clinically significant major organ disorder at the time of screening including: 
a. Uncontrolled hypertension, defined as stage 2 hypertension by Joint National 
Committee VII (even if therapy is ongoing, blood pressure ≥160 mm Hg systolic 
or ≥100 mm Hg diastolic). 
b. Uncontrolled hyperlipidemia (even if therapy is ongoing, LDL >160 mg/dL or 
triglycerides >500 mg/dL). 
c. Uncontrolled hyperthyroidism or hypothyroidism (subjects can be included if 
these conditions are controlled with thyroid hormones or anti-thyroid drugs). 
d. Impaired hepatic function (alanine transaminase [ALT] or aspartate transaminase 
[AST] value >2 times the upper limit of the reference range and/or serum bilirubin 
1.5 times the upper limit of the reference range at the screening visit). Subjects 
with evidence of Gilbert’s disease may be included in the study if they have total 
bilirubin of <3 mg/dL with indirect bilirubin contributing to >80% of the total 
bilirubin. 
15. History of a significant medical condition, such as: 
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a. Clinically significant cardiac disease like unstable angina, myocardial infarction, 
grade 3 or 4 congestive heart failure (CHF) according to New York Heart 
Association criteria, valvular heart disease, cardiac arrhythmia requiring 
treatment, and pulmonary hypertension; during the year prior to screening. 
b. Stroke or transient ischemic attack (TIA) in the 6 months before screening.  
16. Subjects with major depressive illness in the last 3 years (those who have well controlled 
depression for 3 months on a stable dose of antidepressants, with no major depressive 
episodes in the last 3 years, can be included, even if they are on medication), subjects 
with history of other severe psychiatric diseases (manic depressive psychosis [MDP], 
schizophrenia), which in the opinion of the investigator precludes the subject from 
participating in the study (recorded while collecting subject history). 
17. History of hematological disorders that can affect the reliability of HbA1c estimation 
(hemoglobinopathies, hemolytic anemia, sickle cell anemia, etc.). 
18. Subjects using the following in the 3 months prior to screening: 
a. Insulin pump therapy 
b. Any anti-diabetic drugs other than the study insulins allowed by the protocol. 
19. Moderate insulin resistance, defined as requiring insulin of ≥1.5 Ukg/day. 
20. Subjects who have received ≥14 consecutive days of glucocorticoid therapy by oral, 
intravenous, inhaled or other routes that produce systemic effects within the past 1 year, 
or who have received steroids by any route (except intra-nasal, intra-ocular, and topical) 
within the 4 weeks immediately preceding screening.  
21. Subjects diagnosed as having cancer (subjects with history of basal cell carcinoma, 
carcinoma in situ or squamous cell cancer of skin, or in remission >5 years, will be 
allowed). 
22. Subjects who have donated blood or plasma in the 1 month prior to screening 
4.2.3 
Criteria for study drug termination, withdrawal from the study and study 
termination 
Subjects will be free to request termination of study drug or withdrawal from the study at any 
time for any reason. 
If, for any reason, a subject discontinues the study prematurely, the subject may be followed 
up upon consent and as detailed in the following withdrawal criteria. 
Following are the withdrawal criteria:  
1. Withdrawal of consent. 
2. For female subjects, diagnosis of pregnancy or stated intention to become pregnant. 
Effort should be made by the site to obtain consent from the pregnant women, so that 
they are followed until delivery or termination. 
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3. 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 request the subject consent to follow-up as per the 
SCHEDULE OF ACTIVITIES until the Week 20 (Follow-up visit). 
4. At the investigator’s discretion (following discussion with the sponsor medical 
monitor), in certain situations such as significant illness, hospitalization for surgery, 
or an SAE which in the opinion of the investigator warrants treatment withdrawal. 
The site should request the subject consent to follow-up as per the SCHEDULE OF 
ACTIVITIES until the Week 20 (Follow-up visit).  
4.3 
Contraception 
4.3.1 
Females - Non-childbearing Potential 
Female subjects of non-childbearing potential must meet at least one of the following criteria: 
1. Postmenopausal females, defined as: 
• Females who are 45-65 years of age who have been amenorrheic for at least 1 year 
and who are known to have a serum FSH level >30 IU/L in the absence of hormone 
replacement therapy. 
2. Females who have a documented hysterectomy and/or bilateral oophorectomy. 
All other females will be considered to be of childbearing potential. 
4.3.2 
Females - Childbearing Potential 
Female subjects of child-bearing potential must use an acceptable, highly effective method of 
contraception (i.e. a method with a failure rate <1% when used consistently and correctly) 
starting from screening through to at least 7 days after the final dose of study drug. For this 
study, such methods include at least one of the following: 
• Abstinence (periodic abstinence is not acceptable). 
• Tubal ligation. 
• Intrauterine device (IUD) of intrauterine system (IUS). 
• Condom with spermicidal foam/gel/film/cream/suppository. 
• Male partner who has had a vasectomy for at least 6 months. Male partners with 
vasectomies of <6 months are NOT considered protected. 
• Hormonal contraceptives (oral, injected, transdermal or implanted) with the exception 
of low dose gestagens, i.e. only containing lynestrenol or norethisterone, since they do 
not inhibit ovulation and are therefore not considered as highly-effective. The subject 
must remain on the hormonal contraceptive throughout the study and must have been 
using hormonal contraceptives for an adequate period prior to the study to ensure 
effectiveness (e.g., 3 months). 
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4.4 
Pregnancy Testing 
Serum or urinary pregnancy testing will be performed on all females of childbearing potential 
as described in the schedule of activities (results will be reviewed and must be negative prior 
to dosing). In the event of a positive test, the subject will be withdrawn from the study (or 
will not enter the study if during screening). 
Any pregnancy occurring after randomization to study drug will be followed up and reported 
to the sponsor as per Section 9.4.1. 
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5 
STUDY DRUG 
5.1 
Investigational Drug 
During Treatment period, subjects will be randomized to receive one of the following; 
MYL-1501D Product from Process V (100 U/mL) 
or 
MYL-1501D Product from Process VI (100 U/mL) 
Additional treatment drugs provided during the study which are not investigational study 
drugs are detailed below: 
During the run-in period, subject will receive Lantus® manufactured by Sanofi-Aventis for 
the US (US listed drug), 100 U/mL. 
All subjects will receive Humalog® (insulin lispro injection, 100 U/mL), manufactured by Eli 
Lilly throughout the study. 
MYL-1501D will be packaged and labelled according to all local legal requirements. 
Clinical Supplies will provide prepackaged supplies for each subject. A kit will be assigned at 
randomization using the Interactive Voice Response System/ Interactive Web Response 
System (IVRS/IWRS). 
A label will be attached to the outside of each kit. The text will be compliant with local 
regulatory requirements and may include some of the following information: 
• Protocol number 
• Subject number/study center number 
• Contents and quantity 
• Lot number 
• Randomization code/kit number 
• Investigator name 
• Storage instructions 
• Caution statement (for clinical study use only) 
• Expiry date 
• Mylan’s name and address 
 
5.1.1 
Administration of Study Drugs 
During the Run-in period, all subjects will receive Lantus® from Sanofi-Aventis (US listed 
drug) 100 U/mL until randomization. In addition, all subjects will be shifted from their 
current mealtime insulin to Humalog® at the start of the run-in period, and will continue on 
this for the complete study. The doses of Lantus® and Humalog® will be titrated (if required) 
during the run-in period to ensure diabetes control.  
During Treatment period, all subjects will receive one of the following treatments; 
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MYL-1501D product from Process VI or Process V. Both investigational products will be 
provided in a pre-filled disposable pen with a 3-mL cartridge. During the treatment period, 
dose titration will be kept to a minimum. 
In addition, all subjects will receive Humalog® (insulin lispro injection, 100 U/mL), 
manufactured by Eli Lilly. 
In the event of any significant dosing errors, the CRO contact person and/or CRO medical 
monitor, or Mylan study contact should be informed immediately. 
5.2 
Study Medication/Device Complaints 
In the event the subject has a complaint/concern during study participation regarding the 
medication/device supplied, they should contact the site. 
In the event of a complaint/concern regarding any medication/device provided by Mylan for 
this study, at a minimum the following information should be sent by the site via e-mail to 
Clinicalbiologicscomplaints@mylan.com. 
• Study number. 
• Principal Investigator name. 
• Subject ID. 
• Date of occurrence of incident/complaint. 
• Description of incident/complaint (facts). 
• Confirmation if the complaint caused or resulted in a SAE? If “Yes”, 
confirmation that the SAE has been reported. 
 
Additional information and potentially the return of study medication may be requested by 
Mylan such that the complaint can be investigated. 
5.3 
Storage, Disposition of Unused Study Drug and Drug Accountability 
The Investigator, or an approved representative, e.g. pharmacist, will ensure that all 
investigational products are stored in a secured area under recommended storage conditions 
and in accordance with applicable regulatory requirements while at the investigator site. 
Study drug should be stored in accordance with the drug label. Storage conditions stated in 
the Investigator’s Brochure may be superseded by the label storage. 
Temperature of storage facilities should be monitored and recorded on a daily basis using 
validated devices that record maximum and minimum temperatures. Should the storage 
facility experience any excursion of temperature outside of the labelled storage condition this 
must be reported immediately to Mylan or designee. At sites where daily monitoring and 
recording is not possible on weekends, the temperature record (e.g. max/min thermometers) 
should be checked immediately for any temperature excursions on the next working day after 
the weekend. Devices used for temperature monitoring should be regularly calibrated. 
Affected material must be placed into quarantine until the impact of the excursion has been 
assessed and confirmed by Mylan. 
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the study drug. Drug accountability forms must be used. Alternatively, Mylan 
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may approve use of standard institution forms. In either case, the forms must identify the 
study drug, including batch or code numbers, and account for its disposition on a subject-by-
subject basis, including specific dates and quantities. The forms must be signed by the 
individual who dispensed the drug, and copies must be provided to Mylan or designee. 
At the end of the study, Mylan will provide instructions with regards to disposition of any 
unused investigational product. If Mylan authorizes destruction at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Mylan. Destruction must be adequately documented. 
5.4 
Randomization  
Assignment of Subject Identification number (SID), randomization number and study 
medication, as well as site drug inventory control will be managed by an automated 
IVRS/IWRS. A manual containing complete instructions for Web or telephone access and 
use will be provided to each site prior to study start. The IVRS/IWRS will assign a SID for 
each subject’s first clinic visit. Each SID will be unique and serve as the primary subject 
identifier throughout all phases of the study. The SID must appear on all case report form 
(CRF) pages, source documents, laboratory data, ECG and diary data. Subjects qualifying to 
enter the study drug treatment phase, will be assigned an additional “randomization number” 
by the IVRS/IWRS at randomization. Dynamic allocation with minimization algorithm will 
be used for treatment randomization. Randomization will be stratified by investigator and 
basal insulin (Glargine) dose time (morning or evening). 
5.5 
Breaking the Blind 
Regardless of the assigned treatment arm, all subjects in the study are provided with active 
anti-diabetic treatment, Insulin glargine. 
The blinded treatment code must not be broken except in emergency situations for which the 
identification of the study treatment of a subject is required by the Qualified Investigator to 
complete a serious adverse event report or the clinical report. In such situations, the 
randomization information will be held by designated individual(s), and the date and reason 
for breaking the blind must be recorded. If possible, the CRO project manager should be 
contacted by telephone prior to unblinding but no later than 24 hours after unblinding. The 
investigator should follow the study’s randomization procedures and should ensure that the 
code is broken only in accordance with the protocol. As the study is blinded, the investigator 
should promptly document and explain to the sponsor any premature unblinding (e.g., 
accidental unblinding, unblinding due to a serious adverse event) of the investigational 
product(s). Unblinding of treatment code for final data analysis will be done after database 
lock. Unblinding process will be performed in accordance to both sponsor’s and CRO’s 
unblinding SOPs, as detailed in the statistical analysis plan. 
5.6 
Concomitant Medications 
All concomitant medications taken during the study (from signing informed consent to post-
study follow-up) must be recorded with indication, daily dose, and start and stop dates of 
administration in the CRF. All subjects will be questioned about concomitant medication at 
each clinic visit and at follow up. 
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Medications taken within 28 days prior to screening and prior to dosing with study 
medication will be documented as a prior medication. Medications taken after dosing with 
study medication will be documented as concomitant medications. 
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) are prohibited during the study (including the run-in period and the treatment period), 
except in case of rescue medication treatment.  
A list of medications that may interfere with the effect of insulin is provided in Table 2. No 
drugs listed in this table should be started during the run-in period or treatment period. 
Table 2: Medication not to be started during the Run-in or Treatment period 
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). 
 
Subjects will abstain from all prohibited medications as described in the exclusion criteria 
section of this protocol (Section 4.2.2). Use of prohibited medication during the study will be 
deemed a protocol deviation and such subjects will be assessed by Mylan or designee 
regarding the potential need to early terminate study drug (e.g. for safety reasons: see 
Section 4.3.4). 
5.7 
Recommended Procedure for Subject Experiencing Adverse Effects Secondary to 
Excessive Pharmacological Effects of Study Drug 
The following rescue criterion will be implemented to protect the safety of subjects during 
the study: 
“Worsening of HbA1c by >1.0% compared to baseline at 12 weeks post randomization”. 
If the subject meets the criterion the investigator can switch the subject to Lantus® provided 
as part of the study at week 15 (Visit 13) or earlier, and continue with the study activities and 
procedures until the end of the study. 
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6 
STUDY CONDUCT 
Subjects eligible for study recruitment will have the nature, purpose, and risks of the study 
explained to them by the investigator. They will be provided with a written copy of the 
informed consent form (ICF) for the study and given sufficient time to consider the study’s 
implications before deciding to participate. Subjects agreeing to participate in the study will 
sign the ICF and be given a duplicate copy before undergoing any screening or pre-screening 
(if required) procedures. A unique SID will be issued at the time of consent by IVRS/IWRS 
system.  
Once a subject enrolls in this study, the site will make every effort to retain the subject for the 
planned duration of the study. Clinical study site staff are responsible for developing and 
implementing support and retention plans. Elements of this plan may include the following. 
• Thorough explanation of the complete clinical study visit schedule and procedural 
requirements during the informed consent process and re-emphasis at each clinic visit. 
• A simple explanation of the key data and key time points that are critical for the 
study's successful analysis, and the importance of all the treatment groups to the 
overall success of the study. 
• Discussion at screening, and subsequent regular review of possible barriers to clinic 
visit attendance and full study participation and compliance. 
• Collection of contact information at screening (address, phone numbers, email), 
which is regularly reviewed at subsequent clinic visits. 
• Use of appropriate and timely study visit reminders. 
• Immediate and multifaceted follow-up on missed clinic visits, including the possible 
use of trained staff to complete in-person contact with subjects at their homes. 
In cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 
subject so that they can appropriately be withdrawn from the study. All contact attempts 
should be documented in the subject's medical record. Should the subject continue to be 
unreachable, then and only then will he/she be considered to have withdrawn from the study 
with a primary reason of "Lost to Follow-up." For all other subjects withdrawing from the 
study, an alternative reason for discontinuation should be recorded in the CRF. Regardless of 
site plans to support and retain subjects within the study, subjects may voluntarily withdraw 
from the study for any reason and at any time. 
For a subject that completes the study and all procedures it is anticipated that the duration of 
study would be up to 26 weeks.  
For details and timings of assessments, refer to Section 6.5. 
6.1 
Screening Procedures 
Each prospective subject must agree to participate in screening procedures by signing the 
most recent ICF before any screening procedure is initiated. The Principal Investigator or 
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Medical Sub-Investigator will review the inclusion and exclusion criteria to confirm 
eligibility of each subject prior to enrolment. 
6.1.1 
Screening (Visit 1 [Week -6 to Week -4]) 
Subjects will commence screening procedures within 6 weeks prior to randomization, to 
confirm that they meet the selection criteria for the study. If the time between screening 
procedures and potential randomization exceeds 6 weeks as a result of unexpected delays, 
then the subject will need to be discussed with Mylan or designee to consider potential for 
re-screening (if re screening is agreed, the subject will need to be re consented and assigned a 
new SID via IVRS/IWRS). Re-screening for other reasons may be possible following 
discussion with the Mylan or designee. If re screening occurs this will be clearly documented 
within the site file. 
The following will be completed in during the visit: 
• Obtain written informed consent before any study-related procedure is initiated, 
including the cessation of prohibited concomitant therapy. A copy of the signed ICF 
(including subject information sheet) will be given to the subject (and IHS-810 form 
for subjects recruited from US). 
• Check selection criteria suitability 
• Perform dilated ophthalmoscopy / retinal photography (if it was not done in the last 6 
months) to exclude active proliferative retinopathy 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject 
• Record demographic details (age, height, gender, and race) 
• Record body weight and calculate BMI  
• Record medical history, concomitant illnesses and concomitant medications  
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate)  
• Record detailed history of all previous insulin use 
• Perform and document physical examination 
• Perform 12-lead ECG (supine, after 5 minutes rest) and document results 
• Collect blood and urine samples for the following laboratory assessments: 
o Fasting C-peptide 
o Serum pregnancy test for women of childbearing potential 
o HIV, HBsAg, and HCVAb 
o Hematology 
o Blood chemistry 
o Urine analysis 
o HbA1c 
o Fasting plasma glucose 
o Fasting lipid profile 
o Immunogenicity analysis 
 
For suspected lab errors, 1 repeat of the specific test will be allowed during the 14-day 
screening period.  
After all assessments (except immunogenicity) have been performed, the investigator will 
assess the results for compliance with the inclusion and exclusion criteria. If all inclusion 
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criteria have been fulfilled and none of the exclusion criteria were met, the subject may be 
enrolled into the run-in phase. The run-in visit must be scheduled no later than 14 days after 
the start of the screening phase (date of subject signature on ICF).  
6.2 
Run-in Period  
6.2.1 
Visit 2 (Week -4) 
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate  
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit  
• Collect blood sample for fasting plasma glucose 
• Dispense subject diary to the subject and provide information regarding the 
completion requirements and necessary glucose measurements provided. 
• Review current dosing of Lantus and Humalog and if necessary provide new dosing 
instructions and document the new dose and reason for change 
• Dispense study medication and provide dose and titration instructions  
• Dispense ancillary supplies 
 
6.2.2 
Visit 3 (Week -3), Visit 5 (Week -1) 
These visits can be performed as telephone contacts if preferred by site and subject. If the 
visit is performed as a telephone contact, a time and date must be agreed in advance by both 
parties and the subject must have the completed subject diary available for discussion of the 
entries during the call.  
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit 
• Record device safety information 
• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of Lantus and Humalog and if necessary provide new dosing 
instructions and document the new dose and reason for change 
 
6.2.3 
Visit 4 (Week -2) 
During this visit the following procedures and assessments will be performed: 
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• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate  
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit  
• Record device safety information 
• Collect blood sample for fasting plasma glucose 
• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of Lantus and Humalog and if necessary provide new dosing 
instructions and document the new dose and reason for change 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided. 
 
6.3 
Treatment phase 
6.3.1 
Visit 6 (Week 0) 
After completion of the run-in phase without any major violation of the selection criteria the 
subjects will enter the randomized study treatment phase. During this visit the following 
procedures and assessments will be performed: 
• Check selection criteria suitability 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record body weight and calculate BMI  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate) 
• Perform and document physical examination 
• Perform 12-lead ECG (supine, after 5 minutes rest) and document results 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit 
• Record device safety information 
• Collect blood and urine samples for the following laboratory assessments: 
o Serum and urine pregnancy test for women of childbearing potential (only a 
negative urine test result is needed for dispensing drug) 
o Fasting plasma glucose 
o HbA1c 
o Hematology 
o Blood chemistry 
o Urine analysis 
o Fasting lipid profile 
o Immunogenicity analysis (collect blood sample prior to study drug 
administration) 
o PK analysis (collect blood sample prior to study drug administration) 
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• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of Lantus and Humalog and if necessary provide new dosing 
instructions and document the new dose and reason for change 
• Dispense study medication MYL-1501D (product from Process VI or Process V), and 
Humalog 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided. 
• Perform randomization and document result 
 
6.3.2 
Visit 7 (Week 1), Visit 9 (Week 4), Visit 11 (Week 9) 
These visits can be performed as telephone contacts if preferred by site and subject. If the 
visit is performed as a telephone contact, a time and date must be agreed in advance by both 
parties and the subject must have the completed subject diary available for discussion of the 
entries during the call.  
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit 
• Record device safety information 
• Review current dosing of MYL-1501D (product from Process VI or Process V) and 
Humalog and if necessary provide new dosing instructions and document the new 
dose and reason for change 
 
6.3.3 
Visit 8 (Week 2), Visit 10 (Week 6) 
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate  
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit  
• Record device safety information 
• Collect blood and urine samples for the following laboratory assessments: 
o Urine pregnancy test for women of childbearing potential (only a negative 
urine test result is needed for dispensing drug) 
o Fasting plasma glucose 
o Immunogenicity analysis (collect blood sample prior to study drug 
administration as outlined in Table 1) 
o PK analysis (collect blood sample prior to study drug administration as 
outlined in Table 1) 
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• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week, only for visit 10. 
• Review current dosing of MYL-1501D (product from Process VI or Process V) and 
Humalog and if necessary provide new dosing instructions and document the new 
dose and reason for change 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided. 
• Only applicable to Visit 10, Dispense study medication MYL-1501D (product from 
Process VI or Process V) and Humalog 
 
6.3.4 
Visit 12 (Week 12) 
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate) 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit 
• Record device safety information 
• Collect blood and urine samples for the following laboratory assessments: 
o Urine pregnancy test for women of childbearing potential (only a negative 
urine test result is needed for dispensing drug) 
o Fasting plasma glucose 
o HbA1c 
o Fasting lipid profile 
o Immunogenicity analysis (collect blood sample prior to study drug 
administration as outlined in Table 1) 
o PK analysis (collect blood sample prior to study drug administration as 
outlined in Table 1) 
• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of MYL-1501D (product from Process VI or Process V) and 
Humalog and if necessary provide new dosing instructions and document the new 
dose and reason for change 
• Dispense study medication MYL-1501D (product from Process VI or Process V) and 
Humalog 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided 
 
6.3.5 
Visit 13 (Week 15) 
During this visit the following procedures and assessments will be performed: 
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• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record concomitant medications since previous visit 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit  
• Record device safety information 
• Collect blood and urine samples for the following laboratory assessments: 
o Serum and urine pregnancy test for women of childbearing potential (only a 
negative urine test result is needed for dispensing drug) 
• Review current dosing of MYL-1501D (product from Process VI or Process V) and 
Humalog and if necessary provide new dosing instructions and document the new 
dose and reason for change 
• Perform drug accountability and check for treatment compliance 
 
6.3.6 
Visit 14/ End of Treatment (Week 18) 
During this visit the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per ADA 2017 
guidelines, self-management of diabetes and life-style modifications with the subject  
• Record body weight and calculate BMI  
• Record concomitant medications since previous visit 
• Record vital signs (sitting after 5 minutes rest; pulse, blood pressure, temperature and 
respiratory rate) 
• Perform 12-lead ECG (supine, after 5 minutes rest) and document results 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit 
• Record device safety information 
• Collect blood and urine samples for the following laboratory assessments: 
o Urine pregnancy test for women of childbearing potential (only a negative 
urine test result is needed for dispensing drug) 
o Fasting plasma glucose 
o HbA1c 
o Hematology 
o Blood chemistry 
o Urine analysis 
o Fasting lipid profile 
o Immunogenicity analysis (collect blood sample prior to study drug 
administration as outlined in Table 1) 
o PK analysis (collect blood sample prior to study drug administration as 
outlined in Table 1) 
• Review the results of 8-point SMBG measurements, performed on 3 days during the 
week 
• Review current dosing of MYL-1501D (product from Process VI or Process V) and 
Humalog and if necessary provide new dosing instructions and document the new 
dose and reason for change 
• Perform drug accountability and check for treatment compliance 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided 
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6.3.7 
Early study drug Termination (ET) visit 
Subjects may request termination of study drug or withdrawal from the study at any time, or 
be required to withdraw or terminate study drug by the investigator or sponsor for reasons as 
per Section 4.3.4. If study drug is terminated or the subject withdraws or is withdrawn, the 
reason for termination/withdrawal should be established and recorded. If a subject does not 
return for a scheduled visit, every effort should be made to contact the subject. In any 
circumstance, every effort should be made to document the outcome of subject contact 
attempt, if possible. The investigator will contact Mylan or designee, if subject fails to 
complete the study or violates the protocol. 
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
Unless consent is withdrawn, subjects who prematurely terminate study drug will be asked to 
return to the clinic to conduct the ET visit as soon as possible after their last dose of study 
drug, and in case consent subject will be asked to conduct all the remaining visits according 
to study schedule table until the end of the study.  
At the ET visit the End of Treatment visit (Week 18/Visit 14), procedures should be 
completed. 
The site should explain the importance of data collection and make every effort to consent the 
subject to continue follow up per the SCHEDULE OF ACTIVITIES until Week 20 visit. 
6.4 
Visit 15 Follow up (Week 20) (telephone call) 
• Record AEs, SAEs, local and systemic allergic reactions and severe hypoglycemic 
which are classified as SAE. 
• Record concomitant medications since previous visit 
 
6.5 
Treatment Procedures 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases, the investigator or designated representative will take all 
steps necessary to ensure the safety and well-being of the subject. When a protocol required 
test cannot be performed the investigator or designated representative will document the 
reason for this and any corrective and preventive actions which he/she has taken to ensure 
that normal processes are adhered to as soon as possible. The Mylan study team will be 
informed of these incidents in a timely fashion. 
Activities specific to this protocol are expanded upon further below. 
6.5.1 
Blood Volume 
Total blood sampling volume for an individual subject is approximately 235 mL. 
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Table 3: Blood Volume 
Sample Type 
Sample Volume (mL) 
Number of Sampling 
Times 
Total 
Volume 
(mL) 
Screening 
Study Period 
Safety Labs 
30 
1 
3 
120 
PK1 
4 
 
5 
20 
Anti-drug antibody (ADA) 2 
10 
1 
5 
60 
Supplemental Immunogenicity3 
10 (baseline), 
5 (V1, V8, V10, V12, V14) 
1 
5 
35 
TOTAL 
 
 
 
235 
1 Blood samples (1 x 4 mL) will be drawn into K2EDTA plasma tubes. 
2 Blood samples (2 x 5 mL) will be drawn into serum separator tubes (SST). 
3 Blood samples (1 x 5 mL; 2 x 5 mL at baseline) will be drawn into serum separator tubes (SST). 
 
6.5.2 
Safety Testing Assessments 
Safety will be assessed through physical examinations, monitoring of vital signs, 12-lead 
electrocardiograms, laboratory analyses, and adverse event monitoring. 
6.5.2.1 
Adverse Event Assessment 
If a subject reports any symptoms after the signing of the informed consent form, they will be 
evaluated by medical staff and necessary measurements will be performed. The Principal 
Investigator or Medical Sub-Investigator will be notified before dosing to determine the 
course of action. 
Clinically relevant findings from screening procedures, e.g., laboratory tests or physical 
examinations will be recorded as medical history. Clinically significant changes from the 
screening procedures results will be recorded as adverse events. 
Subjects will be routinely queried with regard to the presence or absence of adverse events 
using open ended questions. The clinic will provide documentation of any adverse events in 
the subject’s CRF. The adverse event source documentation will minimally include the 
following information: date and time of assessment, the outcome of the response, and 
identification of the clinic staff member collecting the information. 
6.5.2.2 
Hypoglycemia 
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). In addition, nocturnal hypoglycemia rate and incidence will be analyzed in a 
same way as overall hypoglycemic episodes. 
Hypoglycemia is a state produced by a lower than normal level of glucose in the blood. This 
may develop, if for example:  
• The subject misses or delays meals or there is a change in diet  
• The subject takes a higher dose of study drug than prescribed  
• The subject consumes alcohol  
• The subject does more intense or longer physical exercise or work than normal,  
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• The subject is recovering from an injury, operation, fever or other illness, or from 
other forms of stress 
 
6.5.2.2.1 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 subject 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 subject 
goes to bed at night till the time he or she wakes up. This may include any of the above 5 
types of hypoglycemia.  
Note: A diagnosis of severe hypoglycemia as per above classification will always be 
considered as 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. 
6.5.2.2.2 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, 
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sleepiness, confusion, difficulty speaking, feeling anxious or weak. Neuroglycopenic 
manifestations may include seizure, coma, and even death. 
Subject 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 subjects on self-management of hypoglycemic episodes. 
Investigators will also instruct subjects on remedial actions to be taken during the episodes of 
severe hypoglycemia. Subject will be encouraged to call the study site if they experience 
hypoglycemia. 
6.5.2.2.3 Management of Hypoglycemia 
The following steps are recommended for managing hypoglycemic episodes:  
1. 
The subject 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 subject 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, ¾ cup of juice or regular soft drink, 4-5 glucose tablets).  
3. 
Subject 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 minutes. If the 
next meal is more than 1 hour away, subjects should follow with additional carbohydrate or a 
snack.  
4. 
If hypoglycemia persists after the second treatment, subject or companion should be 
instructed to contact the investigator.  
It is recommended that the subjects always carry some sugar lumps, sweets, biscuits, or 
sugary fruit juice.  
For an event of severe hypoglycemia, the subject 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 subject 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 the different subtypes (Refer to Section 6.5.2.2.1). 
6.5.2.2.4 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 
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seriousness criteria (Section 9.2.4) are also to be notified as SAEs to the Mylan Global 
Product Safety and Risk Management department, as described in Section 9.3.2.8; and 
entered on the SAE and AE pages. 
6.5.2.3 
Laboratory Safety 
The following safety laboratory tests will be performed at times defined in the study 
schedules in Sections 1 and Section 6. 
Table 4: Laboratory Safety Tests 
Hematology 
Chemistry 
Urinalysis 
Other  
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
Urea and Creatinine 
Glucose 
Calcium 
Sodium 
Potassium 
Chloride 
AST, ALT 
Total Bilirubin 
Direct/Indirect bilirubin 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
CRP 
C-Peptide 
Lipid Profile 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Microscopy/culturea 
Urine hCG  
HIV and HBsAg and 
HCVAb 
HbA1c 
 
a Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase. 
 
Hematology and chemistry will be analyzed by central laboratory. Urinalysis will be 
conducted by dipstick at site and if urine is positive for blood, protein, nitrites, or leukocyte 
esterase, will be analyzed via microscopy/culture by a central laboratory. 
Blood volumes to be collected and blood and urine sample handling instructions will be 
provided in the central vendor laboratory manual. The central laboratory will provide 
collection materials and directions for packaging and shipment of samples. 
Any clinically significant findings in laboratory safety data should be recorded as an AE. 
Determination of clinical significance and seriousness will be based on the Investigator's 
medical judgment. 
6.5.2.4 
Immunogenicity Assessment 
Blood samples of 5 mL each will be taken into serum separator tubes at each time point as 
outlined in Table 1. At Visits 1, 8, 10, 12, and 14, three blood samples will be drawn, 
whereas at Visit 6 (baseline) four blood samples will be drawn. The blood samples will be 
taken by direct venipuncture, and the exact times of blood sampling will be recorded in the 
CRF. Two of the samples will be used to determine the presence of anti-drug antibodies 
against insulin glargine using the approach outlined below. The other sample will be 
collected and stored in reserve for potential supplemental immunogenicity testing and/or 
characterization. Samples collected pre-dose at the randomization visit (Visit 6) will be 
considered as baseline. Samples collected at screening and the supplemental samples 
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collected at baseline may also be used for method development and validation. Sample 
handling instructions are specified in the laboratory manual. 
A conventional radioimmunoprecipitation assay will be employed for the assessment of anti-
drug antibodies in clinical samples. In this assay, samples will undergo a pre-treatment step 
that includes acid dissociation to release any anti-insulin antibodies complexed with free 
drug, followed by charcoal adsorption of the free insulin analog. The treated samples will be 
incubated with a fixed amount of 125I-MYL-1501D, and anti-drug antibody complex 
formation with the tracer is measured via gamma counter and expressed as a percentage of 
bound to total radioactivity (%B/T).  
The multi-tiered sample analysis recommendations for immunogenicity testing from 
published white papers [7, 8], and current regulatory guidance [9, 10], will be employed for 
the immunogenicity assessment of MYL-1501D Process V and Process VI. The antidrug 
antibody analysis methodology will be fully validated, and the sample analysis procedures 
will be documented in a Sample Analysis Protocol.  Sample handling, processing, and storage 
instructions will be detailed in a separate manual. The laboratory for immunogenicity 
analysis will be designated by the Sponsor. 
6.5.2.4.1 PK Assessment 
One blood sample of 4 mL will be taken into a K2EDTA plasma tube at each time point, as 
outlined in Table 1. The blood samples will be taken by direct venipuncture, and the exact 
times of blood sampling will be recorded in the CRF. The PK sample will be taken along 
with the immunogenicity samples. The exact time of last MYL-1501D dose prior to 
withdrawal of blood for PK will be noted. The blood samples will be analyzed for Insulin 
Glargine, Glargine M1 and M2 metabolite concentrations by Covance Laboratories Ltd. 
(Harrogate, UK) using a fully validated analytical method. Sample handling instructions are 
specified in the laboratory manual. 
The PK samples are taken as outlined in Table 1. The PK sample will be taken during the 
visit, preferably taken prior to the daily glargine dose. The timing of study drug 
administration from prior day should be collected along with the time of PK sample 
collection. 
6.5.2.5 
Blood Pressure and Pulse Rate 
Blood pressure and pulse rate will be measured at times specified in Sections 1 and Section 6. 
Additional collection times, or changes to collection times of blood pressure and pulse rate 
will be permitted, as necessary, to ensure appropriate collection of safety data. 
Blood pressure will be measured at sitting position, after 5 minutes rest. 
The same size blood pressure cuff, which has been properly sized and calibrated, will be used 
to measure blood pressure each time. The use of automated devices for measuring blood 
pressure and pulse rate are acceptable, although, when done manually, pulse rate will be 
measured in the brachial/radial artery for at least 30 seconds. Any clinically significant 
changes in blood pressure and pulse rate should be recorded as an AE. Determination of 
clinical significance and seriousness will be based on the Investigator's medical judgment. 
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6.5.2.6 
12-lead ECG 
In this study, 12-lead ECGs will be recorded using local ECG devices and review. ECGs 
should be collected at times specified in the study schedules in Sections 1 and Section 6.  
All scheduled ECGs should be performed after the subject has rested quietly for at least 
5 minutes in a supine position. 
To ensure safety of the subjects, a medically qualified individual at the site will assess ECG 
recordings and make any comparisons to baseline measurements.  
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings. Any clinically 
significant ECG abnormalities measured at screening should be assessed for their effects on 
subject eligibility of the study and recorded in medical history. ECG parameters will not be 
recorded in the CRFs, but any clinical significant changes between the screening and 
subsequent ECGs should be recorded as an AE. Determination of clinical significance and 
seriousness will be based on the Investigator's medical judgment. 
6.5.2.7 
General Physical Examination 
A full general physical examination will consist of an examination of the abdomen, 
cardiovascular system, lungs, lymph nodes, musculoskeletal and neurological systems, skin, 
extremities, head, ears, eyes, nose, and thyroid gland by trained medical personnel at the site. 
A full physical examination will be performed at Visit 1 (screening), Visit 6 (randomization) 
and Visit 14 (EOT or ET). 
Height and weight will be assessed at Visit 1. Physical examination results will not be 
recorded in the CRFs, but any clinical significant finding at Screening (Visit 1) should be 
recorded under medical history and changes between Screening (Visit 1) and subsequent 
examinations should be recorded as an AE. Determination of clinical significance and 
seriousness will be based on the investigator's medical judgment. 
  
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7 
STATISTICAL ANALYSIS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the sponsor. This document may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. 
7.1 
Sample Size Determination 
A total of 202 subjects with T1DM are planned to be randomized for this study and will 
receive either MYL-1501D Process V product or MYL-1501D Process VI product, in a 1:1 
ratio. 
The sample size estimation is based on assumptions for the change from baseline up to week 
18 in HbA1C with either MYL-1501D product from Process V or Process VI. It is assumed, 
that true mean groups mean difference is 0.03 and standard deviation is equal to 0.74. To 
demonstrate non-inferiority margin of 0.4% using a 2-sided 95% confidence interval and a 
90% power, a total of 172 subjects (86 subjects per treatment group) are required. 
To account for a maximum of 15% of subjects being not eligible for the per protocol analysis, 
a total sample size of 202 is planned to be randomized for this study. The true treatment 
difference and standard deviation is based on previous study MYL-GAIA-3001. 
No replacement of subject will be performed if subject discontinued prematurely from the 
study. 
7.2 
Primary Endpoints 
7.2.1 
Definition of Primary Endpoints 
The change in HbA1c from baseline up to week 18 is the primary endpoint for this study. 
7.2.2 
Statistical Methodology for Primary Endpoints 
For the analysis of the primary endpoint all randomized subjects will be taken account – 
irrespective of whether subjects having post-baseline measurement. All scheduled 
non-missing data combined together with imputed missing data will be performed for 
primary analysis. 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 12 and week 18 sequentially. The variables treatment, pooled 
investigator, and basal insulin dose time will be used as independent variables. 
Then the treatment effect will be estimated using a repeated measures analysis employing a 
restricted maximum likelihood (REML)-based, mixed model repeated measures (MMRM)-
effects model approach. In this model all subjects will be used for the estimation of the 95% 
confidence interval of the difference between MYL-1501D Process VI product and Process V 
product for mean change in HbA1c at week 18. The MMRM model will include the fixed, 
categorical effect of treatment group assignment, visit, treatment group-by-visit interaction 
and the other fixed effect terms investigator, basal insulin dose time, and baseline HbA1c 
value as covariates. 
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Further details on the MMRM model will be provided in the SAP. Investigator pooling will 
be finalized before unblinding treatment to avoid introducing bias. The detailed method of 
investigator pooling will be documented in the SAP. 
7.2.3 
Primary Analysis for Primary Endpoints 
For primary endpoint analysis, non-inferiority for efficacy will be established if the upper 
limit of a two sided 95% confidence interval for the absolute difference (MYL-1501D 
Process VI minus Process V) of mean change from baseline to endpoint for HbA1c is no 
greater than 0.4% at Week 18. The primary analysis will be performed on the intent to treat 
(ITT) analysis set.  
7.2.4 
Secondary/Sensitivity Analyses for Primary Endpoints 
A further robustness check will be conducted using the PP population and applying the same 
MMRM procedure as described in previous section to establish non-inferiority. Any 
differences in the conclusion will be further investigated by examining differences between 
the ITT and the PP populations. 
Other sensitivity analysis addressing missing data will be conducted in the following manner:  
Same analysis approach as primary analysis without imputing missing values. 
In another method, the imputed values will be corrected such that the full non-inferiority 
margin will be added for imputed values in Process VI group. All imputed datasets will be 
analyzed using the same model parameters as used in the primary analysis, and the results 
will be combined using Rubin’s rules. 
A standard last observation carried forward (LOCF) approach will be conducted such that 
missing data will be imputed by LOCF. This dataset will be analyzed for the ITT and PP 
populations using the ANCOVA model for which details will be described in the SAP. 
7.2.5 
Missing Data 
The only imputed data will be performed in the primary and sensitivity analyses as described 
above for HbA1c. Otherwise, missing data will not be imputed. 
7.2.6 
Sub-Group Analyses 
Subgroup analyses of important factors, including but not limited to factors such as age 
group, gender and race are planned for the key outcomes of HbA1c and immunogenicity 
variables. These will be conducted by adding factor and treatment-by-factor interactions to 
the MMRM model models of the main analyses. Other exploratory subgroup analyses may be 
performed, as deemed appropriate. 
7.3 
Secondary Endpoints 
The following efficacy measures (both actual and change values) will be summarized at 
baseline and scheduled visit. Similar statistical analysis approach for primary will be 
performed for continuous variables without imputing missing values. Contrasts of LS mean at 
each scheduled visit will be used to evaluate all pairwise treatment comparisons, and 95% 
confidence intervals for treatment differences in LS means will be computed for each visit. 
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• Change in fasting plasma glucose from baseline 
• Change in basal insulin, meal-time, and total insulin dose per unit body weight (U/kg) 
from baseline 
• Change in 8-point SMBG profile from baseline. 
All above analyses will be performed on ITT set. 
The following safety measures (both actual and change values) will be summarized at 
baseline and scheduled visit. Contrasts of LS mean at each scheduled visit will be used to 
evaluate all pairwise treatment comparisons, and 95% confidence intervals for treatment 
differences in LS means will be computed for each visit. For categorical data analyses, 
Fisher’s exact test or Chi-squared test will be used. The details will be provided in the SAP.  
• Incidence of positive antibody response and change in antibody percentage binding 
from baseline. 
• Change in hypoglycemia rate (30 day adjusted) from baseline and incidence of 
hypoglycemic events 
• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) 
• Incidence of local allergic reactions, systemic allergic reactions and other adverse 
events 
• Incidence of device-related safety assessment 
 
The incidence of subjects with each of the three following criteria will be summarized 
descriptively (for categorical measures) by treatment to explore possible insulin 
neutralization effect: 
• An increase of over 10% in cross reacting antibodies from baseline 
• Increases in HbA1c of over 0.2% from baseline at any visit 
• Increase in total or basal insulin dose at any visit  
 
The total incidence of Device-related safety events will be summarized for each treatment 
group and would include device-related TEAEs and events related to device complaints or 
failures. For device-related TEAEs, two categories will be summarized for each treatment: 
needle-related TEAEs such as pain, bruise, and bleeding; and other device-related TEAEs, 
such as hyperglycemia or hypoglycemia. For confirmed device-related malfunctions or 
failures, incidence will be listed and summarized for each treatment. 
All above analyses will be performed on safety set. 
7.4 
Analysis Set Definitions 
The ITT analysis set includes all randomized subjects (including subjects who receive 
incorrect treatment, do not complete the study or do not comply with the protocol or used 
prohibited medication). 
The PP analysis set includes subjects who complete Week 18, and have HbA1c 
measurements as per the protocol, or have at least one post-baseline HbA1c data (for subjects 
who discontinue prematurely); and do not have protocol violations that impact the primary 
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outcome (as detailed in the statistical analysis plan). Subjects who meet rescue medication 
criteria and take rescue medication will be excluded from PP analysis set. The subjects 
excluded from the PP population will be identified before database lock (i.e., before 
unblinding the study team). 
The safety analysis set includes subjects who take at least one dose of the study medication 
after randomization. For safety analyses, subjects will be categorized according to the 
treatment that they actually received.  
7.5 
Other Safety Analyses 
The analysis set for safety summaries is defined as all subjects who received at least one dose 
of study medication in the randomized treatment period. Safety data from the run-in period 
will be presented in listings only.  
Treatment emergent adverse events and concomitant medications will be summarized and 
listed. All AEs that occur after the first dose of double-blind study medication through 14 
days after the last dose will be considered treatment emergent AEs. The number and 
percentage of subjects with at least one treatment emergent AE will be presented by treatment 
group and events further summarized by maximum severity and relationship to study 
medication. 
Descriptive statistics will be provided for the following safety data. No inferential analysis of 
this safety data is planned. Any ECG, blood pressure, and pulse rate abnormalities of 
potential clinical concern will be described. 
7.5.1 
Vital Signs 
Change from baseline of vital sign measurements will be analyzed using MMRM with model 
terms of pooled investigator, basal insulin dose time, treatment, visit, treatment-by-interaction 
as fixed effects, and baseline value as covariate. The descriptive statistics including actual 
measurement and change from baseline along with treatment comparison will be performed 
at scheduled visits.  
The percentage of subjects in categories such as potentially clinically significant will be 
summarized and treatment comparison will be performed using Fisher’s exact test. 
7.5.2 
ECG Analyses 
The percentage of subjects in categories such as abnormal/non-clinically significant and 
abnormal/clinically significant will be summarized and treatment comparison will be 
performed using Fisher’s exact test.  
7.5.3 
Laboratory Data 
Change from baseline of laboratory measurements will be analyzed using MMRM with 
model terms of pooled investigator, basal insulin dose time, treatment, visit, treatment-by-
visit interaction as fixed effects, and baseline value as covariate. The descriptive statistics for 
actual measurement and change from baseline along with treatment comparison will be 
performed at scheduled visits.  
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The percentage of subjects 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. 
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8 
ADMINISTRATIVE PROCEDURES 
8.1 
Source Documentation Forms 
All clinical data will be recorded by the clinical staff on raw data sheets and/or recorded 
electronically using validated software. If computerized systems are used to create, modify, 
maintain, archive, retrieve or transmit source data, they must comply with the applicable 
regulatory regulations and/or guidance. 
The nature and location of all source documents will be documented separately. Source data 
may be directly captured from devices, transferred from 3rd parties (e.g. laboratory data) or 
entered manually into CRF/database. 
8.2 
Access to Data/Source Documentation 
The Investigator or designated representative will permit full access to data and source 
documentation for the purpose of clinical monitoring, audits, IRB/IEC review and regulatory 
inspections. 
8.3 
Final Clinical Study Report and Case Report Forms (CRFs) 
A written clinical study report will be provided in accordance with the International 
Conference on Harmonization (ICH) E-3 guidelines including Annex I (Synopsis) 
documenting the clinical execution of the study. This report will include a description of any 
protocol deviations. The final report will also include reasons for withdrawals and any 
necessary treatment(s). The report will also include tables presenting demographics (separate 
summary tables for enrolled and completed subjects), and adverse events recorded during the 
study. In addition, the clinical study report will include a Quality Assurance statement, 
documenting that the report has been reviewed for completeness, accuracy, and compliance 
with the protocol and applicable local and federal regulations. For final clinical reporting 
purposes only, adverse events deemed “definite”, “probable” or “possible” will be included in 
the treatment-related summaries/listings. 
Case Report Forms containing data transcribed from subject source documents (as 
appropriate) and copies of other source documents will be supplied by the clinical site. The 
Principal Investigator must sign each subject’s CRF after completion of data entry, signifying 
that the data entered in the CRF is complete and accurate. Electronic CRFs may be provided. 
8.4 
Adherence to Protocol 
Except for an emergency situation in which proper care for the protection, safety and well-
being of the study subjects requires medical treatment, the study will be conducted as 
described in the approved protocol (and amendments, if applicable), GCP and applicable 
SOPs. In addition, the study will be conducted in accordance with the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted. Any deviation(s) from the protocol will be recorded and 
presented in the final report. 
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8.5 
Data Handling and Record Retention 
All clinical information shall be recorded, handled and stored in such a way that it can be 
accurately reported, interpreted and verified, while the confidentiality of records of the study 
subjects remains protected. 
A CRF is required to be completed for each subject receiving study medication. The CRF is 
property of the sponsor and the Investigator must review all CRFs prior to submission to the 
sponsor. 
The CRF may be consider as the source document, the investigator must seek prospective 
agreement to the sponsor in writing to use the CRF as source document prior the start of the 
study. In addition, items directly recorded in the CRF must be documented that they will be 
considered as source. 
All records pertaining to the receipt and return of study supplies (particularly study 
medication) and copies of final case report forms, worksheets, and other pertinent source 
documents must be retained in accordance with ICH-GCP and the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted. 
The investigator must obtain in writing the sponsor’s agreement to dispose of any records, 
even if the retention period has been reached. 
8.6 
Confidentiality 
Information furnished to Clinical Investigators and IRBs/Ethics Committees will be 
maintained in confidence by the Clinical Investigator and IRB/Ethics Committee. By signing 
this protocol, the Investigator affirms to the Sponsor that he/she will maintain, in confidence, 
information furnished to the IRB/Ethics Committee relevant to this study under appropriate 
understanding of confidentiality with such IRB/Ethics Committee. 
By signing the protocol, the Investigator agrees that within local regulatory restrictions and 
institutional and ethical considerations, the Sponsor may consult and/or copy source 
documents (e.g., laboratory/X-ray reports, ECG tracings, workbooks, medical records) in 
order to verify CRF data. 
8.7 
Ethics and Regulatory Authorities 
Guidelines will be followed with regard to the treatment of human subjects in the study, in 
accordance with the requirements of the Declaration of Helsinki and International Conference 
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH-E6) in addition to the regulatory requirements of the country where the study is 
being conducted as well as the country where the study will be submitted. 
8.7.1 
Institutional Review Board/Ethics Committee 
The Investigator is responsible for obtaining initial and continuing review (at intervals not 
more than once per year) of the study by an IRB/Ethics Committee, or in accordance with 
applicable government regulations of the country where the study is being conducted as well 
as the country where the study will be submitted. This study will not enroll any subjects until 
the IRB/Ethics Committee provides written approval of the protocol and the informed 
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consent to the investigator. In addition, a copy of the IRB/Ethics Committee approval 
documents must be provided to the sponsor prior to enrolling any subjects into the study. 
8.7.2 
Regulatory Authority 
This clinical study protocol, title and a list of investigational sites, IEC(s)/IRB(s) approvals, 
as well as other relevant documentation will be submitted to the local Regulatory Authorities 
for review and approval prior to study start. Upon completion, the Regulatory Authorities 
will be notified the study has ended. The study will only be undertaken in compliance with 
the local regulatory requirements. 
8.8 
Informed Consent 
A properly executed, written informed consent in compliance with current GCP guidelines 
and ICH guidelines shall be obtained from each volunteer prior to entering the study. A copy 
of the informed consent document to be used will be submitted by the investigator to an 
independent institutional review board (e.g. IRB or ethics committee) and the Sponsor and/or 
its agent for review and approval prior to the start of the study. The investigator shall provide 
a copy of the signed and dated informed consent to the subject, and a signed and dated copy 
shall be maintained in the volunteer’s medical record. 
8.9 
Disclosure and Publication of Clinical Study Data 
The disclosure and publication of clinical study data will be detailed in the clinical study 
agreement with the Investigators. 
8.10 End of Study 
The end of study is considered to be the date of last subject last visit or the date of early 
termination of the study whichever is the later. 
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9 
ADVERSE EVENT REPORTING 
9.1 
Adverse events 
All observed or subject-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 
immediate notification to Mylan. The Investigator is required to assess causality and should 
obtain sufficient information to determine the causality of all AEs. All AEs will be followed 
until 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.  
9.2 
Definitions  
9.2.1 
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 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 a TEAE if the first onset (or worsening, in the case of pre-existing 
disease) is after the first administration of MYL-1501D after randomization through follow-
up visit or 14 days after last dose [for subjects that do not have a follow-up visit].  
9.2.2 
Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose 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 study drug reported as “possible”, “probable” or 
“definite” will be considered ADRs. If the relationship to the study drug is not given, then the 
AE must be treated as if the relationship were “possible.” 
9.2.3 
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 study. For example, hepatic 
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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 MYL-1501D is the IB. For Humalog® and any 
concomitant medication, the respective SmPC or US prescribing information will be the 
reference safety document. 
9.2.4 
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 study drug during pregnancy is considered an SAE. However, a newly 
diagnosed pregnancy in a patient that has received the study drug is not 
considered an SAE unless it is suspected that the study drug interacted with a 
contraceptive method and led to the pregnancy. The patient with newly 
diagnosed pregnancy will discontinue receiving study 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 study 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). 
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 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. 
 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 study. 
9.3 
Management of Adverse Events 
AEs or SAEs will be collected from the time the subject signs the informed consent form 
until the follow-up visit or 14 days after last dose of study medication.  Pre-existing diseases 
or conditions (reported at visit 1 in medical history) will not be considered as 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 to be related to the study drug by the Investigator in consultation 
with sponsor will be reported even after the Follow-up visit if reported by subjects. 
9.3.1 
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 subject 
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?” 
Any clinically relevant observations made by the Investigator during the visit will also be 
considered AEs. 
The Subject’s diary should also be reviewed at each study visit for adverse events. At week 0 
visit when study diaries are issued, subjects will be appropriately educated by the study 
designee on what constitutes an adverse event and instructed to record adverse events in the 
study diary in a timely manner.  
9.3.2 
Evaluation 
9.3.2.1 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 study site. If an AE is not listed in the CTCAE, 
its clinical severity will be classified as follows: 
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Table 5: 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 subject's usual function. 
Grade 2 – MODERATE 
Interferes to some extent with subject's usual function. 
Grade 3 – SEVERE 
Interferes significantly with subject'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 9.3.2.8.  
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 9.2.4. 
9.3.2.2 Action Taken 
The possible actions taken for an AE are described in Table 6. 
Table 6: 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 
subject completed the treatment period. 
9.3.2.3 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 
 
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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 subject’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.  
9.3.2.4 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 study treatment(s) and record this relationship in the CRF. 
In addition, if the Investigator determines an AE or SAE is associated with study 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 study 
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 study treatment 
in accordance with the following definitions: 
Table 7: Definition of Suspected Relationship between the Events and Study 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 
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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 reasonably related 
although a causal relationship 
cannot be ruled out 
For Example: Event or laboratory test abnormality, 
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 
 
For SAEs, the relationship to the study 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. 
9.3.2.5 Documentation 
All AEs occurring within the period of observation for the study must be documented in the 
CRF with the following information; where appropriate (the period of observation for the 
study is described in Section 6): 
• 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 study medication as a result of AE. 
• Outcome. 
• Investigator’s opinion regarding the AE relationship to the study treatments. 
 
Hypoglycemic events and associated signs/symptoms will only be recorded on the 
hypoglycemic episodes page of the CRF, unless they are SAEs (i.e., a severe episode). 
9.3.2.6 Treatment of Adverse Events 
AEs that occur during the study 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 study treatment. The decision about 
whether the subject may resume the study treatment will be made by the sponsor after 
consultation with the Investigator and/or medical monitor. 
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9.3.2.7 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 subject’s medical record and recorded on the 
appropriate CRF page. 
9.3.2.8 Notification 
For SAEs, the active reporting period to Mylan, begins from the time that the subject provides 
informed consent, which is obtained prior to the subject’s participation in the study, i.e., prior 
to undergoing any study-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 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). Subject 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 
subject’s study 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 (study site and Investigator) 
• Subject’s unique identification number  
• Subject’s age 
• Investigational medicinal product 
• Date of first dose of study treatment 
• Date of last dose of study treatment, if applicable 
• SAE term 
• The seriousness criteria that were met 
• Investigator’s opinion of the relationship to the study treatment 
• Severity 
• 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 Product Safety and Risk Management department. 
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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 subject 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 
                       All SAEs must be notified within 24 hours by email (preferred) or fax to: 
Mylan Product Safety & Risk Management 
PV MAIL HUB FOR IMMEDIATE SAFETY REPORTS: 
pvclinical@mylan.com 
In the event that an electronic acknowledgment is not received within 24 hours for a SAE 
report submitted by email, please forward the report via fax to +1.304.285.6409. 
9.3.2.9 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. 
9.4 
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). 
9.4.1 
Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during 
study participation. Women should be instructed to contact the Investigator immediately if 
pregnancy occurs or is suspected. 
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Pregnancy testing will be conducted throughout the study, as detailed in the schedule of 
assessments. A woman who is found to be pregnant at the randomization visit (Visit 6 [Week 
0]), will be excluded from the study. A woman who becomes pregnant during the study will 
be immediately discontinued from study 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 Product Safety and Risk 
Management within 24 hours from the time of initial knowledge, even if beyond the closure 
of the clinical database.  
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.   
9.4.2 
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. 
9.5 
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 study drug administration or that are present at 
baseline and worsen following the administration of study 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 
• The test result requires additional diagnostic testing or medical/surgical intervention 
and/or 
• The test result leads to a change in study dosing or discontinuation from the study, 
additional concomitant drug treatment, or other therapy; and/or 
• The test result is considered to be an AE by the Investigator or sponsor. 
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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. 
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10 REFERENCE LIST 
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.  ADA 2017 criteria, Diabetes Care 2017, 40 (supplement1): S11-S24. 
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 MYL-1501D (available upon request).  
7. Mire-Sluis, A.R., et al., Recommendations for the design and optimization of immunoassays 
used in the detection of host antibodies against biotechnology products. J Immunol Methods, 
2004. 289(1-2): p. 1-16. 
8. Shankar, G., et al., Recommendations for the validation of immunoassays used for detection 
of host antibodies against biotechnology products. J Pharm Biomed Anal, 2008. 48(5): p. 
1267-81. 
9. Food and Drug Administration (FDA). Guidance for Industry: Assay Development and 
Validation for Immunogenicity Testing of Therapeutic Protein Products 2016, U.S. 
Department of Health and Human Services. 
10. 
European Medicines Agency (EMA). Guideline on Immunogenicity assessment of 
biotechnology-derived therapeutic proteins. EMEA/CHMP/BMWP/14327/2006 Rev. 1. 
2015. 
 
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SAP_000.pdf: 
Table of Contents 
16.1.9 Documentation of Statistical Methods ..........................................................................2 
Statistical Analysis Plan V1.0, 04 May 2018 ...........................................................................3 
Statistical Analysis Plan V2.0, 18 October 2018 ......................................................................49 
 
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16.1.9 
Documentation of statistical methods 
Statistical Analysis Plan V1.0, 04 May 2018 
Statistical Analysis Plan V2.0, 18 October 2018 
 
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Analysis Plan Template 
Mylan GmbH 
PROTOCOL MYL-1501D-3004 
Page 1 of 46
Document: 
\sasdata\Mylan\Insulin_glargine\SYA22825\Biostatistics\Documentation\Protocol\MYL-
1501D3003_SAP_V1_MAY2018 
Author: 
Irene Dehem 
Version Number: 
1.0 
Version Date:
04MAY2018
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
STATISTICAL ANALYSIS PLAN 
MYL‐1501D‐3004 
A  RANDOMIZED,  MULTI‐CENTER,  DOUBLE‐BLIND,  PARALLEL‐GROUP  CLINICAL 
STUDY COMPARING THE EFFICACY AND SAFETY OF MYL‐1501D PRODUCED BY TWO 
MANUFACTURING PROCESSES IN TYPE 1 DIABETES MELLITUS PATIENTS. 
AUTHOR: IRENE DEHEM 
VERSION NUMBER AND DATE: V1.0 04MAY2018 
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Document: 
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Version Number: 
1.0 
 
 
Version Date: 
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Effective Date: 01Apr2016 
 
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MODIFICATION HISTORY 
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized 
Version 
1.0  
04MAY2018 
Irene 
Dehem 
Not Applicable – First 
Version 
 
 
 
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Document: 
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Author: 
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Effective Date: 01Apr2016 
 
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reproduction is strictly prohibited. 
TABLE OF CONTENTS 
1.  LIST OF ABBREVIATIONS .............................................................................................................. 9 
2.  INTRODUCTION ............................................................................................................................ 10 
3.  STUDY OBJECTIVES ...................................................................................................................... 10 
3.1. 
Other Objectives .................................................................................................................................... 10 
4.  STUDY DESIGN ............................................................................................................................... 11 
4.1. 
General Description ................................................................................................................................ 11 
4.2. 
Schedule of Events ................................................................................................................................. 12 
4.3. 
Changes to Analysis from Protocol .......................................................................................................... 13 
5.  PLANNED ANALYSES ................................................................................................................... 14 
5.1. 
Data Monitoring Committee (DMC) ........................................................................................................ 14 
5.2. 
Final Analysis ......................................................................................................................................... 14 
6.  ANALYSIS SETS .............................................................................................................................. 14 
6.1. 
All Patients Screened .............................................................................................................................. 14 
6.2. 
Run‐in Population .................................................................................................................................. 14 
6.3. 
All Patients Randomized Population [RND] ............................................................................................. 14 
6.4. 
Intent‐to‐Treat Population [ITT] ............................................................................................................. 15 
6.5. 
Safety Population [SAF] .......................................................................................................................... 15 
6.6. 
Per Protocol Population [PP] .................................................................................................................. 15 
7.  GENERAL CONSIDERATIONS .................................................................................................... 15 
7.1. 
Reference Start Date and Study Day ....................................................................................................... 15 
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7.2. 
Baseline ................................................................................................................................................. 16 
7.3. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 16 
7.4. 
Windowing Conventions ........................................................................................................................ 16 
7.5. 
Statistical Tests ...................................................................................................................................... 16 
7.6. 
Common Calculations ............................................................................................................................. 17 
7.7. 
Software Version .................................................................................................................................... 17 
8.  STATISTICAL CONSIDERATIONS ............................................................................................. 17 
8.1. 
Adjustments for Covariates and Factors to be Included in Analyses ......................................................... 17 
8.2. 
Multicenter Studies ................................................................................................................................ 17 
8.3. 
Missing data ........................................................................................................................................... 18 
8.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................ 18 
8.5. 
Active‐Control Studies Intended to Show Non‐inferiority or Equivalence ................................................ 18 
8.6. 
Examination of Subgroups ...................................................................................................................... 18 
9.  OUTPUT PRESENTATIONS ........................................................................................................ 19 
10. DISPOSITION AND WITHDRAWALS ....................................................................................... 19 
11. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................................... 20 
11.1. 
Derivations ......................................................................................................................................... 21 
12. MEDICAL HISTORY ....................................................................................................................... 21 
13. MEDICATIONS ................................................................................................................................ 21 
14. STUDY MEDICATION EXPOSURE ............................................................................................. 21 
14.1. 
Derivations ......................................................................................................................................... 22 
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15. STUDY TREATMENT NON‐COMPLIANCE .............................................................................. 22 
16. EFFICACY OUTCOMES ................................................................................................................. 22 
16.1. 
Primary Efficacy .................................................................................................................................. 22 
16.1.1. 
Primary Efficacy Variable ..........................................................................................................................22 
16.1.2. 
Missing Data Method for Primary Efficacy Variable .................................................................................23 
16.1.3. 
Primary Analysis of Primary Efficacy Variable ..........................................................................................23 
16.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .......................................................................................24 
16.2. 
Secondary Efficacy .............................................................................................................................. 25 
16.2.1. 
Secondary Efficacy Variables & Derivations .............................................................................................25 
16.2.1.1. 
Fasting plasma glucose .....................................................................................................................25 
16.2.1.2. 
Daily insulin dose per unit body weight (mealtime, basal insulin and total) for days of 8‐point 
profiles 
25 
16.2.1.3. 
8‐point Self‐Monitored Blood Glucose (SMBG) profile ....................................................................26 
16.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .......................................................................28 
16.2.3. 
Analysis of Secondary Efficacy Variables ..................................................................................................28 
16.2.3.1. 
Analysis of change from baseline in HbA1c at scheduled visits ........................................................28 
16.2.3.2. 
Analysis of change from baseline in fasting plasma glucose ............................................................28 
16.2.3.3. 
Analysis of Change in Daily insulin dose per unit body weight (mealtime, basal insulin and total) for 
days of 8‐point profiles. ........................................................................................................................................28 
16.2.3.4. 
Analysis of Change in 8‐point SMBG profile from baseline ..............................................................29 
16.2.4. 
Subgroup Analysis .....................................................................................................................................29 
16.3. 
Exploratory PK Analysis ...................................................................................................................... 29 
17. QUALITY OF LIFE ANALYSIS ..................................................................................................... 30 
18. SAFETY OUTCOMES ..................................................................................................................... 30 
18.1. 
Adverse Events ................................................................................................................................... 30 
18.1.1. 
All TEAEs ...................................................................................................................................................31 
18.1.1.1. 
Severity .............................................................................................................................................31 
18.1.1.2. 
Adverse Drug Reaction (Relationship to Study Medication) ............................................................31 
18.1.2. 
TEAEs Leading to Discontinuation of Study Medication ...........................................................................31 
18.1.3. 
Serious Adverse Events .............................................................................................................................31 
18.1.4. 
Adverse Events Leading to Death .............................................................................................................32 
18.1.5. 
Local or Systemic Allergic Reaction ..........................................................................................................32 
18.1.6. 
Device‐related Assessment .......................................................................................................................32 
18.1.7. 
Non TEAEs .................................................................................................................................................32 
18.2. 
Laboratory Evaluations ....................................................................................................................... 32 
18.2.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ..............................................................33 
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18.3. 
ECG Evaluations .................................................................................................................................. 35 
18.4. 
Vital Signs ........................................................................................................................................... 35 
18.4.1. 
Potential Clinically Significant Changes ....................................................................................................35 
18.5. 
Physical Examination .......................................................................................................................... 36 
18.6. 
Other Safety Assessments .................................................................................................................. 36 
18.6.1. 
Immunogenicity profiles analyses ............................................................................................................36 
18.6.2. 
Hypoglycemia Analyses ............................................................................................................................37 
19. STUDY DATA TECHNICAL CONFORMANCE .......................................................................... 38 
20. DATA NOT SUMMARIZED OR PRESENTED .......................................................................... 38 
21. REFERENCES .................................................................................................................................. 39 
APPENDIX 1.  REPORTING CONVENTIONS .................................................................................. 40 
APPENDIX 2.  PARTIAL DATE CONVENTIONS ............................................................................ 41 
Algorithm for Treatment Emergence of Adverse Events: .................................................................................... 41 
Algorithm for Prior / Concomitant Medications: ................................................................................................ 42 
APPENDIX 3.  SAS CODE EXAMPLE FOR MULTIPLE IMPUTATION ...................................... 44 
APPENDIX 4.  SAS CODE EXAMPLE FOR TIPPING POINT ........................................................ 46 
 
 
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Version Date: 
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Template No:  CS_TP_BS016  Revision 4 
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Effective Date: 01Apr2016 
 
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reproduction is strictly prohibited. 
1. LIST OF ABBREVIATIONS 
 AE  
adverse event 
ANOVA 
analysis of variance 
ATC 
Anatomical Therapeutic Chemical (class) 
BDR 
blind data review 
BMI 
Body Mass Index 
CRF 
case report form 
CRO 
contract research organization 
DMC 
data monitoring committee 
HLGT 
High Level Group Term 
HLT 
High Level Term 
ICH 
International Conference of Harmonization 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
MAR 
missing at random 
MCMC 
Markov chain Monte Carlo 
MedDRA Medical Dictionary for Regulatory Activities 
MI  
Multiple Imputation 
MMRM 
mixed model for repeated measures 
PP  
Per Protocol 
PT  
Preferred Term 
RND 
randomized population 
SAE 
serious adverse event 
SAF 
Safety 
SAP 
statistical analysis plan 
SE  
standard error 
SMBG 
Self Monitored Blood Glucose 
SOC 
System Organ Class 
TEAE 
treatment emergent adverse event 
T1DM 
type 1 diabetes mellitus 
WHO-DD World Health Organization – Drug Dictionary (enhanced) 
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Template No:  CS_TP_BS016  Revision 4 
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reproduction is strictly prohibited. 
2. 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-3004. It describes the data to be summarized and 
analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol amendment 1 (dated 11JAN2018). 
3. STUDY OBJECTIVES 
The primary objective is to test whether MYL-1501D product from Process VI once daily is non-
inferior to MYL-1501D product from Process V once daily based on the change in HbA1c from 
baseline to week 18 when administered in combination with mealtime insulin lispro. 
3.1. OTHER OBJECTIVES 
The other objectives are to compare MYL-1501D product from Process VI and Process V at week 
18, when administered in combination with mealtime insulin lispro, with respect to: 
- 
Immunogenicity: incidence and change from baseline in the relative levels of anti-drug 
antibody 
- 
Hypoglycemic events: incidence and rate per 30 days 
- 
Occurrence of local reactions, systemic reactions and other adverse events 
- 
Device-related safety assessment 
- 
Change in fasting plasma glucose from baseline 
- 
Change in insulin dose per unit body weight (U/kg) from baseline 
- 
Change in 8-point Self-Monitored Blood Glucose (SMBG) profile from baseline 
 
 
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reproduction is strictly prohibited. 
4. STUDY DESIGN 
 
4.1. GENERAL DESCRIPTION 
This is a multicenter, double-blind, randomized, parallel-group phase 3 study in patients with type 1 
diabetes mellitus (T1DM) comparing the efficacy, immunogenicity and safety of MYL-1501D 
products from two manufacturing processes (Process V and Process VI).  A total of 202 patients 
with T1DM are planned to be randomized in a 1:1 ratio between MYL-1501D Process V and MYL-
1501D Process VI.  Approximately 110 sites will be included in the study. 
After up to 2-week screening period, all patients will be titrated on Lantus® during a 4-week run-in 
period, and will be shifted from their current mealtime insulin to Humalog®.  The patients will be 
randomized (stratified by investigational site and time of administration of glargine [morning and 
evening]); one group will receive MYL-1501D product from Process V, while the other group will 
receive MYL-1501D product from Process VI for 18 weeks.  A follow-up visit will be scheduled 2 
weeks after last dose of MYL-1501D. 
The none-hypothesis is that the upper bound of treatment difference (Process VI minus Process V)  
is over 0.4 and alternative hypothesis is that upper bound of treatment difference is less than or 
equal to 0.4.  
Patients will remain blinded until the database is locked, then an unblinding request form will be 
sent to the IVR provider in order to get the randomization code.  Any analyses done prior to 
database lock will use dummy treatments. 
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reproduction is strictly prohibited. 
4.2. SCHEDULE OF EVENTS 
Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
F-U 
Study Visits1 
V1 
V2 
V3 
V4 
V5
V6
V7 V8
V9 V10 V11 V12 V13
V14
(EOT)
V15 
(FU)
Study Week 
-6 to -4 
-4 
-3
-2
-1
0
1
2
4
6
9 
12 
15
18
20
Study Days 
-42 to -28 -28±3 -21±3 -14±3 -7±3 0±3 7±3 14±3 28±3 42±3 70±7 84±7 112±7 126±7 140±7
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria Review 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
History of previous 
insulin usage 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated 
Ophthalmoscopy / 
retinal photography if 
not done in the last 6 
months 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard-of-care 
specifics2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Age, Gender, Height, 
Race 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight and 
BMI 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Pregnancy Test3 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Medical History 
including concomitant
illness 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
x 
x 
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 
 
Physical examination 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
12-lead ECG (supine) 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
Randomization 
 
 
 
 
 
x 8 
 
 
 
 
 
 
 
 
 
Record AEs and 
SAEs (including local
and systemic allergic 
reactions) and 
hypoglycemic events4
due to medication, 
disposable pen or 
needle 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record device safety 
information 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
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Version Date: 
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Template No:  CS_TP_BS016  Revision 4 
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Effective Date: 01Apr2016 
 
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reproduction is strictly prohibited. 
Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
F-U 
Study Visits1 
V1 
V2 
V3 
V4 
V5
V6
V7 V8
V9 V10 V11 V12 V13
V14
(EOT)
V15 
(FU)
Study Week 
-6 to -4 
-4 
-3
-2
-1
0
1
2
4
6
9 
12 
15
18
20
Study Days 
-42 to -28 -28±3 -21±3 -14±3 -7±3 0±3 7±3 14±3 28±3 42±3 70±7 84±7 112±7 126±7 140±7
Fasting plasma 
glucose 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
HbA1c Assay 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
Fasting C-peptide, 
HIV, HBsAg, and 
HCVAb 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sampling for 
hematology, blood 
chemistry and 
urinalysis5 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
Fasting lipid profile 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
Sampling for 
immunogenicity 9 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Sampling for PK6 
 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Review 8-point 
SMBG Profile 
performed in the 
week before the visit 7
 
 
x 
x 
x 
x 
 
 
 
x 
 
x 
 
x 
 
Dose review of 
Lantus, MYL-1501D 
and insulin lispro and 
instruction 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dispense Study 
Medication and 
ancillary supplies 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
 
 
Drug Accountability 
and Compliance 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Dispense subject 
diary 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
 
 
Review subject diary 
 
 
 
x 
 
x 
 
 
 
x 
 
x 
 
x 
 
 
4.3. CHANGES TO ANALYSIS FROM PROTOCOL 
No changes. 
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reproduction is strictly prohibited. 
5. PLANNED ANALYSES 
The following analyses will be performed for this study: 
 
Final Analysis  
5.1. DATA MONITORING COMMITTEE (DMC)  
There will be no DMC or interim analysis for this study. 
5.2. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following 
Sponsor Authorization of this SAP, Sponsor Authorization of Analysis Sets, Database Lock and 
Unblinding of Treatment.  
6. ANALYSIS SETS 
Agreement and authorization of patients included/ excluded from each analysis set will be 
conducted prior to the unblinding of the study.  
6.1. ALL PATIENTS SCREENED 
The all patients screened population is defined as all patients who consent for the study. 
6.2. RUN‐IN POPULATION  
The run-in population is defined as all patients who consent for the study and entered into the run-
in phase. The patients in this population will be summarized under the total number of patients.  
Run-in failure patients will be summarized under the category of “run-in failure”. 
6.3. ALL PATIENTS RANDOMIZED POPULATION [RND] 
The all patient randomized (RND) population will contain all patients got randomized to study 
medication.  The patients who discontinue the study during run-in period will not be included in the 
randomized population. 
For analyses and displays based on RND, patients will be classified according to randomized 
treatment.  
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6.4. INTENT‐TO‐TREAT POPULATION [ITT] 
The Intent-to-Treat (ITT) population includes all randomized patients (including patients who 
receive incorrect treatment, do not complete the trial or do not comply with the protocol).   
The patients under the ITT population will be analyzed according to the planned treatment group. 
All primary and secondary efficacy analysis will be based on the ITT population. 
6.5. SAFETY POPULATION [SAF] 
The safety population (SAF) will contain all patients who are randomized and take at least one 
dose of study drug. 
The safety analysis will be conducted according to the treatment received.  If there is any doubt 
whether a patient was treated or not, they will be assumed treated for the purpose of the analysis.  
6.6. PER PROTOCOL POPULATION [PP] 
The per-protocol population (PP) will contain all patients who complete week 18 and have HbA1c3 
measurements as per the protocol, or have at least one post-baseline HbA1c data for patients who 
discontinue prematurely, and do not have protocol deviation that impact the primary outcome.  
Patients who meet rescue medication criteria and take rescue medication will be excluded from the 
PP.  The list of deviations leading to exclusion from the PP population will be identified, reviewed 
and documented prior to DB lock and determined in the blind data review meeting and documented 
in the blind data review report prior to the database lock. The subjects who are excluded from PP 
population and reason for exclusion will be listed. 
7. GENERAL CONSIDERATIONS 
7.1. 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 randomization, (Day 1 is the day of randomization).  
 
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:  
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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. 
7.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to 
receiving randomized treatment reference (day of randomization) start date (including unscheduled 
assessments). In the case where the last non-missing measurement and the randomized treatment 
start date coincide, that measurement will be considered pre-baseline, but Adverse Events (AEs) 
and medications commencing on the randomized treatment start date will be considered post-
baseline. 
For insulin (mealtime, basal and total) levels, baseline is the value collected at Visit 6 (Week 0) 
which correspond to values collected prior injection of study medication. 
7.3. 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 
scheduled visit if scheduled visit value is missing or the Last Observation Carried Forward (LOCF) 
value in case primary sensitivity analysis, or best/ worst case value where required (e.g. shift table) 
in safety analysis.  
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 entered under the Visit 14 (week 18), but for summary tables it will be 
mapped to the next available planned visit number after their last scheduled visit.  For example, 
should a patient discontinue at Visit 9, the Early Termination visit will have their Fasting plasma 
glucose and their HbA1c assay taken.  The fasting plasma glucose would then be summarized 
under Visit 10 and the HbA1c under Visit 12. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
7.4. WINDOWING CONVENTIONS  
No visit windowing will be performed for this study. 
7.5. STATISTICAL TESTS 
The default significant level will be (5%); confidence intervals will be 95% and all tests will be two-
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sided, unless otherwise specified in the description of the analyses. 
Non-inferiority will be tested at 2.5% (one-sided) level of significance. 
7.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as:  
 
Test Value at Visit X – Baseline Value 
7.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher.  
8. STATISTICAL CONSIDERATIONS 
8.1. 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. 
 
Pooled sites 
 
Time of Glargine administration (morning, evening), stratification factor. 
 
Baseline HbA1c (continuous variable) 
8.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers in the USA.   
When specified, statistical analysis will be adjusted for pooled sites based on US census regions.   
All sites within a US census region (northeast, midwest, south, west, pacific) with fewer than 8 
randomized patients will be combined into a single pooled site for analysis purposes. 
The pooled method will be as follow (performed manually): 
Step 1: All sites within a US census region with fewer than 8 patients will be combined into a single 
pooled site.  If the resulting pooled site still has fewer than 8 patients, then proceed to the next 
step. 
Step 2: The pooled site (<8) will be further combined with the smallest unpooled site within that 
region.  If there is not another unpooled site within that region, then proceed to the next step. 
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If several unpooled sites within the region have the smallest patients, the preference is to select the 
unpooled site that is the closest to the site in distance. 
If there are still more than one unpooled site within the region after evaluating the distance, an 
unpooled site will be selected randomly to combine with the pooled site (<8) from Step 1. 
Step 3: The pooled site will be combined with the smallest pooled site from another region (that is 
the closest in distance). 
The treatment by pooled-site interaction will be tested in the primary efficacy model.  Where there 
is evidence of an interaction (p<0.10), graphical inspection of descriptive statistics will be used to 
assess whether the interaction is quantitative (i.e. the treatment effect is consistent in direction but 
not size of effect) or qualitative (i.e. the treatment is beneficial for some but not other regions).  
8.3. MISSING DATA 
After having mapped data captured at unscheduled and/or early termination visits (if any) to 
schedule missing visits using visit windows technique (refer to section 7.4), missing primary data 
will be imputed by using the multiple imputation (MI) technique (see section 16.1.3).   
As another sensitivity analysis, the imputed values by MI will be corrected such that the full non-
inferiority margin will be added for imputed values in Process VI group. 
A sensitivity analysis using Last Observation Carried Forward (LOCF) will also be performed on the 
primary efficacy parameter. 
In the secondary efficacy data, the weight used in the daily total insulin will be imputed by the 
weight of the previous visit value if current weight value is missing. 
8.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
No adjustment for multiplicity will be performed. 
8.5. ACTIVE‐CONTROL STUDIES INTENDED TO SHOW NON‐INFERIORITY OR 
EQUIVALENCE 
Non-inferiority will be established if the upper bound of a two-sided 95% confidence interval (CI) for 
the absolute difference (MYL-1501D Process VI minus Process V) of mean change from baseline 
to week 18 for HbA1c is less than or equal 0.4%. 
8.6. EXAMINATION OF SUBGROUPS 
Subgroup analyses will be conducted as stated in the exploratory analysis sections. It should be 
noted that the study was not designed to detect treatment differences with high statistical power 
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within subgroups. 
The following subgroups will be assessed and described within the subgroup analysis sections 
(16.2.4).  A minimum of 8 subjects/arm in each subgroup is needed.  For subgroup with less than 8 
subjects/arm, this subgroup will be pooled with the other ones having less than 8 subjects/arm 
together and the subgroup will be named “other” if there are other subgroups with less than 8 
subjects/arm exist.   
 
Gender:  
o 
Female 
o 
Male 
 
Age (years): 
o 
≤ 21  
o 
> 21 to <65  
o 
 ≥65 
 
Race in 5 categories: 
o 
American Indian or Alaska Native 
o 
Asian 
o 
Black or African American 
o 
Native Hawaiian or Other Pacific Islander 
o 
White 
 
Ethnicity in 2 categories: 
o 
Hispanic or Latino 
o 
Not Hispanic or Latino 
o 
Not reported or Unknown 
9. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the 
format and content of the summary tables, figures and listings to be provided by IQVIA 
Biostatistics. 
10. 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 week 18 or discontinued 
early as well as completed the trial will be summarized for each treatment group.  Reason for 
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discontinuation during week 18 will be summarized.  The summary of reason for discontinuation 
from the study will also be presented.   
The number and proportion of patients withdrawing the study during the run-in phase will be 
presented.  The number and proportion of patients in each population will also be summarized. 
A listing of patients who fail the inclusion/exclusion criteria will be produced. 
A summary of major protocol deviations will be provided as frequency and percentages.  Protocol 
deviations in the run-in phase will be summarized separately.  A list of all major protocol deviations 
will also be provided. 
11. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the RND and SAF 
populations. 
The continuous demographic/baseline variables will be summarized using the mean, median, 
standard deviation, minimum, and maximum values.  For categorical (nominal) variables, the 
number and percentage of patients will be used. No statistical testing will be carried out for 
demographic or other baseline characteristics.  All demographic and baseline characteristics will be 
presented in a listing. 
The following demographic and other baseline characteristics will be reported for this study: 
 
Age (years) ‐ calculated relative to date of informed consent 
 
Gender  
 
Race  
 
Ethnicity 
 
Weight (kg) 
 
Height (cm) 
 
BMI (kg/m2) 
 
Duration of diabetes (years) 
 
Time of glargine administration (morning, evening) 
 
Baseline fasting plasma glucose (mmol/L) 
 
Baseline HbA1c (%) 
 
Insulin use prior to screening (yes, no) 
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 
Fasting C‐Peptide, HIV, HBsAg and HCVAb (positive, negative) 
11.1. DERIVATIONS 
 
BMI (kg/ m2) = weight (kg)/ height (m)2 
 
Duration of diabetes (years) = ((date of screening – date of onset of diabetes) + 1)/365.25 
12. MEDICAL HISTORY 
Medical History information will be presented for the SAF and coded using Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary version 20.  Coded medical history terms will be 
summarized by System Organ Class (SOC) and Preferred Term (PT), by treatment group.  Multiple 
entries for an individual patient under same SOC/PT will only be counted once. 
13. MEDICATIONS 
Medications will be presented for the SAF and coded using WHO Drug dictionary 01SEP2017. 
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible to 
define a medication as prior or concomitant, the medication will be classified by the worst case; i.e. 
concomitant.  
 
‘Prior’ medications are medications which started and stopped prior to the reference start date.  
 
Insulin use prior first dose are any insulin medication used prior to screening visit. 
 
‘Concomitant’ medications are medications which:  
o 
started prior to, on or after the randomization date  
o 
AND ended on or after the randomization date of study medication or were ongoing at the end of 
the study. 
Prior and concomitant medication will be summarized by treatment group.  The number of patients 
taking each medication will be presented by Anatomical Therapeutic Chemical (ATC) names (levels 
1, 2, 3).  Each patient taking the same therapy more than once will be counted once within each 
ATC code level.  All prior and concomitant medications will be presented in data listing.  A separate 
listing on prohibited medications will also be provided. 
14. STUDY MEDICATION EXPOSURE 
Exposure to study medication in days will be presented for the SAF. 
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The exposure will be summarized for each treatment group using the mean, standard deviation, 
median, minimum and maximum.  Interruptions, compliance, and dose changes are not taken into 
account for duration of exposure. 
14.1. DERIVATIONS 
Duration of exposure days = date of last study medication administration minus the date of 
reference day + 1.  
Where the reference start date is defined in section 6.1 and the date of last study medication will be 
taken from the “End of Treatment” form. 
15. STUDY TREATMENT NON‐COMPLIANCE  
Patient will be identified as study treatment non-compliant if the patient meets any following criteria: 
 
Missing total meal time insulin daily since last visit 
 
Missing basal insulin daily since last visit 
 
Took two times more basal insulin daily since last visit 
 
Took less or more than prescribed basal insulin dose units daily since last visit 
Number and proportion of patients with non-compliance will be summarized along with individual 
categories of non-compliance for each category. 
The non compliance proportion is defined as total accumulative non-compliant days/duration of 
treatment exposure in days. Summary of non-compliance proportion will be performed by each 
non-compliance category for each treatment group. The treatment groups will be compared by 
using an ANOVA model which will include treatment and pooled-site. 
16. EFFICACY OUTCOMES  
16.1. PRIMARY EFFICACY 
16.1.1. 
PRIMARY EFFICACY VARIABLE 
The primary efficacy variable is change in HbA1c from baseline to week 18 for the ITT population. 
The HbA1c is collected by central laboratory Q2Solutions. 
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16.1.2. 
MISSING DATA METHOD FOR PRIMARY EFFICACY VARIABLE 
After having mapped data captured at unscheduled and/or early termination visits (if any) to 
schedule missing visits using visit windows technique (refer to section 7.4), MI will be used for the 
primary efficacy analysis.  Refer to section 16.1.3 for more details. 
If subjects initiate rescue medication after Week 12, HbA1c value at Week 18 will be considered as 
missing and imputed as described above i.e., first remapped data collected at unscheduled/early 
termination visits (if any) to Week 18 and then, use MI to impute remaining Week 18 data. 
16.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
Descriptive statistics will be tabulated by treatment and by time point of the actual HbA1c value and 
the changes from baseline. 
The primary objective of this study is to test the hypothesis that MYL-1501D product from Process 
VI is non-inferior to MYL-1501D product from Process V based on change in HbA1c from baseline 
to week 18. 
The primary efficacy analysis will be performed for the ITT analysis set.  
Mean changes from baseline in HbA1c will be analyzed based on all observed data of schedule 
visits as well as data imputed using the unscheduled/early termination data (if collected) or MI 
methodology for schedule visits at which no value is captured (refer to section 16.1.2). 
MI will be performed under the assumption of missing-at-random (MAR) and will be implemented in 
two steps. 
First, partial imputation assuming MAR will be carried out to impute intermittent (non-monotone) 
missing data based on multivariate joint Gaussian imputation model using the Markov chain Monte 
Carlo (MCMC) method.  A separate model will be used for each treatment group.  The imputation 
model will include the pooled investigator sites and basal insulin dose time (morning vs. evening) as 
fixed covariate and observed HbA1c values at baseline (visit 6), week 12 (visit 12) and week 18 (visit 
14).  The MCMC method in the MI procedure in SAS will be used with multiple chains, 200 burn-in 
iterations, and a non-informative prior.  In case of non-convergence or non-estimability issues, a 
ridge prior and single model will be considered with treatment group added as explanatory variable 
to model. 
Then, the remaining monotone missing data will be imputed using sequential regression multiple 
imputation, where a separate regression model is estimated for imputation of each variable (i.e., 
measurement at each visit) one after the other including the observed values and the values just 
imputed from the previous visit.  Each regression model will include explanatory variables for pooled 
investigational sites, basal insulin dose time (morning vs. evening), treatment group and all previous 
(baseline (visit 6), week 12 (visit 12) and week 18 (visit 14)) values of HbA1c. 
No rounding or range restrictions will be applied. 
Imputed data will consist of 100 imputed datasets.  The random seed number for the partial 
imputation with the MCMC method will be 20171220, and the random seed number for the sequential 
regression MI will be 171016. 
Each of the 100 imputed datasets will be analyzed using the following analysis method. Change from 
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baseline in HbA1c to each post-baseline visit will be calculated based on observed and imputed 
data.  Mean changes from baseline in HbA1c values will be analyzed using a mixed model for 
repeated measures (MMRM) approach.  Restricted maximum likelihood (ReML) estimation will be 
used.  The MMRM model will include the changes from baseline in HbA1c values as dependent 
variables, the baseline HbA1c values as fixed covariate, pooled investigational sites, basal insulin 
dose time (morning vs evening), treatment group (MYL 1501D Process V and MYL 1501D Process 
VI), visit (week 12 and week 18), and treatment group by visit interaction as fixed effects, and 
subjects as random effect.  An unstructured covariance structure will be used to model the within-
subject error and the Kenward-Roger approximation will be used to estimate the degrees of freedom.  
If this analysis fails to converge, the following covariance structures will be tested: AR(1), ARH(1), 
CS, CSH, TOEP, TOEPH.  The covariance structure converging to the best fit, as determined by 
Akaike’s information criteria (AIC) will be used as the primary analysis. 
Treatment group comparison at week 18 will be based on the least square mean (LS mean) 
difference between treatment groups (i.e., MYL 1501D Process VI – MYL 1501D Process V) in 
change from baseline in HbA1c estimated by the model in each imputed datasets.  Results from 
analysis of each imputed dataset i.e., LS mean differences and their standard error (SE), will be 
combined using the Rubin’s imputation rules to produced pooled LS mean estimate of treatment 
difference and its 2-sided 95% confidence interval (CI). 
Non-inferiority will be established if the upper limit of the two sided 95%CI for the difference (MYL-
1501D Process VI minus Process V) of mean change from baseline to endpoint for HbA1c is not 
greater than 0.4% at week 18. 
Refer to APPENDIX 3 for SAS code example. 
For graphical display at scheduled visits, the LS Means and 2-sided 95% CI for the changes from 
baseline in HbA1c to week 12 and week 18 obtained from the MMRM model will be presented by 
treatment group.  Similar graphical display will be presented for the mean actual HbA1c values and 
SD over time by treatment group. 
16.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
 
Sensitivity to analysis set: the PP population will be used with the same MMRM model 
described above to establish non-inferiority.   
 
Sensitivity to missing data assumptions:  
o 
Same analysis approach as the primary analysis, but without imputing missing values.  
This will be analyzed based in ITT. 
o 
In another method, the same analysis approach as the primary analysis will be 
performed, but the imputed values will be corrected such that the full non-inferiority 
margin will be added for imputed values in Process VI group.  This will be analysed 
based on ITT. 
o 
In a third sensitivity analysis, tipping-point analysis will be performed using an algorithm 
proposed by Yan et al (2009) to explore the robustness of the results with regard to a 
bias against the Process VI treatment arm and in favour of the Process V treatment 
arm.  In order to quantify the bias (k), scenario 2 of the Yan et al (2009) algorithm will 
be used.  Missing Week 18 values will have the value k (positive) added to the Process 
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VI arm (worsening results) and subtracted from the Process V arm (improving results).  
The value for k is determined by adjusting the bias in an MNAR version of starting with 
a value of 0.01 and increasing it until the MNAR version of the MI method described in 
Appendix 4 meets or surpasses the non-inferiority margin. That is the upper limit of 95% 
interval of treatment difference is > =0.4 (p-value for test non-interiority is >=0.05). The 
seed and code for this process are detailed in Appendix 4.  The shift parameter as well 
as summary statistics for the MI model with the tipping point adjustment of k will be 
reported. 
o 
As a final sensitivity analysis, missing data will be imputed by using LOCF.  An 
ANCOVA model will be used on the change from baseline in HbA1c to month 18.  The 
model will include treatment (2 levels: MYL-1501D Process V and MYL-1501D Process 
VI) as fixed effect, the baseline HbA1c as covariate, and patient as random effect.  The 
pooled sites and basal insulin dose time (morning or event) will also be included in the 
model as fixed effects.  This will be analyzed on ITT and PP. 
o 
In addition, the means for each treatment and difference between treatments for 
missing data at Week 18 will be summarized for all sensitivity analyses. 
16.2. SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the ITT population. 
16.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
16.2.1.1. Fasting plasma glucose 
The fasting plasma glucose is collected at baseline, week 2 (visit 8), week 6 (visit 10), week 12 
(visit 12) and week 18 (visit 14, End of Treatment).  The measurements are performed by the 
central laboratory Q2. 
Actual values and changes from baseline at each time point will be computed and summarized by 
treatment group. 
A separate analysis will be performed excluding patients with no fasting status. 
16.2.1.2. Daily insulin dose per unit body weight (mealtime, basal insulin and total) for days of 8‐point 
profiles 
Patients will be asked to document the dose of insulin taken on the same day they will perform the 
8-point SMBG profiles (from week -3 to week 18).  The measurements are taken the week prior to 
the visits, so the week prior to: 
- 
Week -3 (Visit 3) 
- 
Week -2 (Visit 4) 
- 
Week -1 (Visit 5) 
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- 
Week 0 (Visit 6) 
- 
Week 6 (Visit 10) 
- 
Week 12 (Visit 12) 
- 
Week 18 (Visit 14) 
Doses will be recorded in the patient’s 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 doses variables: meal time insulin dose, basal insulin and total insulin dose. 
Daily Meal time insulin dose: is the sum of all the total daily meal time insulin (Humalog) dose over 
the double-blind treatment period divided by the number of days measured.  For the computation of 
total daily mealtime doses, only the patients with at least three mealtime doses at a particular day 
are considered.  That is, total daily mealtime dose will not be computed for a day if the mealtime 
dose is recorded less than 3 times for that day. 
Daily Basal insulin dose:  is the average of the insulin dose over days measured during the double-
blind period. 
Daily Total insulin: is the sum of all total daily meal time doses and all basal insulin doses over the 
double-blind treatment period divided by the number of days measured.  Similarly to total daily 
mealtime dose for which less than 3 mealtime doses are recorded, the missing insulin doses will 
not be considered for the average computation.  That is, if either the mealtime doses are recorded 
less than 3 times or the basal insulin dose is missing for a particular day of collection, total insulin 
dose will not be computed.  The total insulin dose will be computed for the remaining days where 
basal insulin dose and at least 3 mealtime doses are collected.  
All doses will be divided by total body weight (kg) to convert to daily insulin dose (U) per unit body 
weight (kg).  If body weight at that visit is missing, the weight from previous visit will be used. 
16.2.1.3. 8‐point Self‐Monitored Blood Glucose (SMBG) profile 
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 3 days, 2 should be consecutive).  The 
patient should document the 3 pre-visit measurements in the diary.  
The following summaries will be summarized at week 6, 12, and week 18: 
Individual 8-points SMBG: 
The over 3 day averages will be performed for the measures taken at: 
- 
Before breakfast 
- 
Two hours after breakfast 
- 
Before lunch 
- 
Two hours after lunch 
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- 
Before dinner 
- 
Two hours after dinner 
- 
Just before sleep 
- 
At 3:00 AM 
Averages will be performed at each visit. 
 
Excursions and averages in SMBG: 
The following averages will be computed: 
- 
Morning excursion 
- 
Noon excursion 
- 
Evening excursion 
- 
Overall excursion 
- 
Pre-meal average 
- 
Post-meal average 
- 
(4-point average) pre-meal and bedtime average 
- 
Overall average 
The individual excursion values will be obtained by subtracting post-meal values with pre-meal 
values, it will be applicable for morning excursion, noon excursion and evening excursion on the 
respective days.  For the overall excursion at morning, afternoon and evening, the individual 
excursion values obtained on each day will be averaged across the three days. 
To compute the overall excursion, first the average of the morning, noon and evening excursion 
within a day will be computed, then the average will be done across the 3 days. 
The pre-meal average will be the average of the following timepoints: before breakfast, before 
lunch, before dinner on each day, then the average will be done over the 3 days. 
The post-meal average will be the average of the following timepoints: two hours after breakfast, 
two hours after lunch, two hours after dinner on each day, then the average will be done over the 3 
days. 
The pre-meal and bedtime average will be the average of the following timepoints: before 
breakfast, before lunch, before dinner, just before sleep, then the average will be done over the 3 
days. 
The overall average will be the average of all the 8 timepoints during a day.  The daily average will 
not be computed for a day if more than 3 timepoints are missing on a particular day.  The overall 
average will be kept missing if the daily average is missing for all three days.  If the average is 
missing for one or two days, the average of the remaining days will be considered for the 
computation. 
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16.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
Imputation will be performed for the SMBG and weight for dose calculation as described in section 
16.2.1. 
16.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
16.2.3.1. Analysis of change from baseline in HbA1c at scheduled visits 
Descriptive statistics will be presented for actual and change from baseline to scheduled visits for 
HbA1c. 
Treatment group comparison will be done using the MMRM model as used for the primary endpoint 
(without imputing the missing values), including treatment, visit, treatment-by-visit interaction, 
pooled-investigator, basal insulin dosing time, as fixed effects, baseline values as covariate and 
subjects as random effect. 
LSMeans for each treatment group, as well as associated SE and 2-sided 95% CI will be provided 
by visit.  Differences in LSMeans will be calculated and associated 2-sided 95% confidence 
intervals and p-values will be provided for each visit.   
16.2.3.2. Analysis of change from baseline in fasting plasma glucose 
Descriptive statistics will be presented for actual and change from baseline to scheduled visits for 
fasting plasma glucose.  A separate analysis will be done with excluding data with non-fasting 
status. 
Treatment group comparison will be done using the MMRM model as used for the primary endpoint 
(without imputing missing values), including treatment, visit, treatment-by-visit interaction, pooled-
site, basal insulin dosing time, as fixed effects, baseline values as covariate and subjects as 
random effect. 
LSMeans for each treatment group, as well as associated SE and 2-sided 95% CI will be provided 
by visit.  Differences in LSMeans will be calculated and associated 2-sided 95% confidence 
intervals and p-values will be provided for each visit.   
For graphical display at scheduled visits the mean and SD plot will be prepared for the actual 
plasma glucose measurement by visit and treatment group; LSMeans and 2-sided 95% CI from the 
same MMRM model will similarly be displayed graphically. 
16.2.3.3. Analysis of Change in Daily insulin dose per unit body weight (mealtime, basal insulin and 
total) for days of 8‐point profiles.  
Descriptive statistics will be tabulated by treatment and by timepoint.  Change from baseline to 
post-baseline timepoints will also be presented for insulin dose including daily basal insulin dose, 
daily meal time insulin dose, and daily total insulin dose. 
These secondary efficacy parameters will be analyzed using the same MMRM model as the 
primary efficacy analysis (without imputing missing values).  Estimates of the means, LSMeans (2-
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sided 95% CIs) as well as treatment difference at each visit will be presented. 
A graphical display at scheduled visits with the mean and SD plot will be prepared for each of these 
secondary efficacy endpoints by visit and treatment group; LSMeans and 2-sided 95% CI from the 
same MMRM model will similarly be displayed graphically. 
16.2.3.4. 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). 
Descriptive statistics will be presented for the actual and change from baseline to scheduled visits 
for SMBG profile. 
Treatment group comparison will be done using the same MMRM model as the primary efficacy 
analysis (without imputing missing values).  Estimates of the means, LSMeans (2-sided 95% CIs) 
as well as treatment difference at each visit will be presented. 
For graphical display at scheduled visits the mean and SD plot will be prepared for the actual 
Overall SMBG average measurement by visit, LSMeans and 95% CI from the same MMRM model 
will similarly be displayed graphically. 
16.2.4. 
SUBGROUP ANALYSIS 
The effect of subgroups mentioned in section 8.6 on the change from baseline HbA1c at week 18 
will be examined by employing a MMRM model.  The subgroups will be included in the model along 
with the treatment group.  Additionally separate subgroup analysis within each subgroup mentioned 
in section 8.6 will be performed same MMRM model for treatment comparison within each 
subgroups. 
The similar subgroups will also be examined for the immunogenicity parameters for the percent 
binding and the incidence analysis of cross reactive antibody.  Besides examine subgroup by 
treatment interaction for percent binding. Separate analysis for both percent binding and incidence 
will be performed for treatment comparison within each subgroup. 
16.3. EXPLORATORY PK ANALYSIS 
Exploratory PK analysis will be performed by Mylan PK/DM department. 
Descriptive statistics of PK concentration values will be presented for each scheduled visits by 
treatment group. 
Treatment group comparison will be done using the GLM model on log-transformed PK 
concentration values including treatment, visit, treatment-by-visit interaction, time of administration 
of glargine [morning and evening], all as fixed effects. If treatment-by-visit interaction is not 
significant, this term will be dropped from the model, the reduced model will be performed to 
produce the final analysis. If treatment-by-visit interaction is significant, then this interaction term 
and visit term will be drop from the model and final model will be performed by visit with only 
treatment and time of administration in the model. 
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LSMeans for each treatment group and Geometric Mean Ratio between the treatment groups will 
be calculated. 2-sided 90% confidence intervals for the log transformed treatment difference and p-
values will be provided.   
17. QUALITY OF LIFE ANALYSIS  
Not applicable. 
18. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the Safety Analysis Set. Percentages will be 
computed on the total number of subjects in each treatment group. 
18.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, Version 20.1. 
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. 
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. 
Events occurring in patients treated with the active comparator are also considered AEs. 
An AE will be defined as treatment emergent (TEAE) if the first onset (or worsening in the case of 
pre-existing disease) is after randomization through follow-up visit or 14 days after last dose [for 
patients that do not have a follow-up visit]. 
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 within each of the categories described in the sub-
sections below, will be provided as specified in the templates. 
Treatment group comparison will be performed using Fisher’s exact test.  P-value for the 
corresponding two-sided test will be presented. 
Listings will include TEAEs and Non-TEAEs. 
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18.1.1. 
ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and 
also broken down further by maximum severity and relationship to study medication.  The number 
of events will also be presented. 
18.1.1.1. Severity 
Severity is classed as mild/ moderate/ severe/ life-threatening/ death (increasing severity). TEAEs 
starting on or after the first dose of study medication with a missing severity will be classified as 
severe. If a patient reports a TEAE more than once within that SOC/ PT, the AE with the worst case 
severity will be used in the corresponding severity summaries. 
18.1.1.2. Adverse Drug Reaction (Relationship to Study Medication) 
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 study medication will be used in the corresponding relationship summaries. 
Frequency and percentage of patients having adverse drug reaction will be presented by treatment, 
SOC and PT. 
18.1.2. 
TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
TEAEs leading to permanent discontinuation of study medication will be identified by using the 
Treatment withdrawn field in the CRF under “Action taken with study medication”.  
For TEAEs leading to discontinuation of study medication, summaries of incidence rates 
(frequencies and percentages) by SOC and PT will be prepared. 
18.1.3. 
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. 
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18.1.4. 
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. 
18.1.5. 
LOCAL OR SYSTEMIC ALLERGIC REACTION 
The local and systemic allergic reactions are recorded on the adverse events page of the eCRF. 
TEAE incidence of both local and systemic allergic reaction will be summarized by SOC and 
treatment group.  A separate listing will also be produced which include only events of local or 
systemic allergic reaction. 
18.1.6. 
DEVICE‐RELATED ASSESSMENT 
The relationship to the insulin glargine pen/needle and to the Humalog pen/needle are recorded on 
the adverse events page of the eCRF. 
TEAE incidence will be summarized by SOC and treatment group for the insulin glargine 
pen/needle relationship and for the humalog pen/needle relationship and for both. 
The incidence of device problems (even if not leading to an AE) will be summarized for each 
treatment group. 
18.1.7. 
NON TEAES 
The non-TEAEs, the events occurred during the run-in phase before randomization, will be 
summarized separately.  The frequency and percentage of patients experiencing non-TEAEs, 
serious non-TEAE, withdrawing during the run-in phase due to non-TEAE during run-in phase, 
Deaths before the active treatment start will be summarized.  All enrolled patients who enter into 
the run-in period will be considered for this summary. 
18.2. LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for Hematology, 
Blood Chemistry and Urinalysis.  A list of laboratory assessments to be included in the outputs is 
included in the protocol section 6.5.2.3.  
Presentations will use SI Units as provided by the central laboratory Q2. 
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. 
The following summaries will be provided for laboratory data: 
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 
Actual and change from baseline by visit (for quantitative measurements).  Descriptive summaries will be 
presented for the actual and the changes from baseline at each visit.  Changes from baseline will be 
analyzed using the same MMRM model then the primary efficacy variable, but without any imputation.  
LSMeans for each treatment group and associated SE/2‐sided 95% CI will be presented.  Differences in 
LSMeans will also be calculated with the SE, 2‐sided 95% CI and p‐value.   
 
Incidence of markedly abnormal laboratory criteria.  The number of patients and percentages will be 
provided for each treatment group at each visit for each markedly abnormal criteria. 
 
Shift from baseline according to normal range criteria (for quantitative measurements and categorical 
measurements) 
18.2.1. 
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. 
The markedly abnormal criteria are defined in the table below: 
Laboratory Category 
Parameter (unit) 
Markedly Abnormal Low 
Markedly Abnormal High 
Hematology 
WBC(X10E3 cells/µl) 
<2.0 
>20.0 
 
Neutrophil count (X10E3 
cells/µl) 
<1.0 
NA 
 
Hemoglobin (g/dL) 
<8.0 
>20 
 
Platelets(cells/µl) 
<50 
>999 
Biochemistry 
ALT 
NA 
>3XULN 
 
AST 
NA 
>3XULN 
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Laboratory Category 
Parameter (unit) 
Markedly Abnormal Low 
Markedly Abnormal High 
 
ALK phosphatase 
 NA 
>3XULN 
 
Total Bilirubin 
NA 
>2XULN 
 
LDH (IU/L) 
NA 
>800 
 
Glucose (mg/dL) 
<55 
>270 
 
Creatinine  
NA 
>1.5XULN 
 
BUN (mg/dL) 
NA 
>60 
 
CPK(U/L) 
NA 
>850 
 
Sodium (mEq/L) 
<130 
>155 
 
Potassium(mEq/L) 
<3.0 
>6.0 
 
Total Protein(g/dL) 
NA 
>9.5 
 
Albumin(g/dL) 
<2.0 
NA 
 
Calcium (mg/dL) 
<7.0 
>12.5 
 
Lipase(U/L) 
NA 
>180 
Lipids 
Triglycerides (mg/dL) 
<10 
>900 
 
Total Cholesterol (mg/dL) 
<20 
>400 
 
LDL Cholesterol (mg/dL) 
<20 
>350 
 
HDL Cholesterol (mg/dL) 
<20 
NA 
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18.3. ECG EVALUATIONS 
Results from the central ECG (Electrocardiogram) Reading Centre will be included in the reporting 
of this study.  
Frequency and percentage of overall assessment of ECG (investigator’s judgment) will be 
presented i.e. the percentage of patients in categories such as normal, abnormal/not clinically 
significant and abnormal/clinically significant will be summarized.  A Fisher’s exact test will be 
performed between the treatment groups. 
18.4. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
 
Sitting Systolic Blood Pressure (mmHg) 
 
Sitting Diastolic Blood Pressure (mmHg) 
 
Pulse Rate (bpm) 
 
Respiratory Rate (breaths/min) 
 
Temperature (⁰C) 
 
Weight (kg) 
The following summaries will be provided for vital signs data: 
 
Actual and change from baseline by visit.  Descriptive summaries will be presented for the actual and the 
changes from baseline at each visit.  Changes from baseline will be analyzed using the same MMRM model 
than the primary efficacy variable, but without any imputation.  LSMeans for each treatment group and 
associated SE/2‐sided 95% CI will be derived.  Differences in LSMeans will be calculated with the SE, 95% CI 
and p‐value. 
 
Incidence of potentially clinically significant vital signs.  The number of patients and percentages will be 
provided for each treatment group at each visit and overall visit (patient will be counted as clinically 
significant if at least one clinically significant occurred in all the visits.  Fisher exact test will be performed 
between the treatment groups. 
 
Listing of patients meeting markedly abnormal criteria  
18.4.1. 
POTENTIAL CLINICALLY SIGNIFICANT CHANGES 
Potential clinically significant Vital Signs measurements will be identified in accordance with the 
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following predefined markedly abnormal criteria: 
Variable 
Unit 
Low 
High 
SBP 
mm
Hg 
≤ 90 mmHg AND  
change from baseline 
≤ -20 mmHg 
≥ 180 mmHg AND 
change from baseline 
≥ 20 mmHg 
DBP 
mm
Hg 
≤ 50 mmHg AND 
change from ≤ -15 mmHg 
≥ 105 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 
Body 
tempera
ture 
°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 % 
18.5. PHYSICAL EXAMINATION  
Physical examination will not be recorded in the CRF, any findings will appear in medical history or 
adverse events.  The date of physical examination will be listed in a listing.  
18.6. OTHER SAFETY ASSESSMENTS 
18.6.1. 
IMMUNOGENICITY PROFILES ANALYSES 
The following parameter will be summarized for immunogenicity: 
1) Total Insulin Antibodies 
o 
Percent Binding (% B/T) 
o 
Positive/Negative 
2) Cross Reactive Insulin Antibodies 
o 
Percent Binding (% B/T) 
o 
Positive/Negative 
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3) Insulin (Drug), Specific Antibodies 
o 
Percent Binding (% B/T) 
Descriptive statistics will be tabulated by treatment and by timepoint for the continuous variables.  
Change from baseline to post-baseline timepoints will also be presented.  The same MMRM model 
as the primary efficacy analysis (without imputing missing data  and excluding the basal insulin 
dosing time)) will be used.  Estimates of the means, LSMeans (SE and 2-sided 95% CIs) as well as 
treatment difference at each visit will be presented.  Analyses will be done on the Safety 
Population. 
The dichotomous outcomes will be summarized with frequency and percentage at scheduled visits. 
Treatment comparison will be performed using Fisher’s exact test.  P-value for the two-sided test 
will be presented.   
Potential immunogenicity effect on local and systematic allergic reaction, hypersensitivity, and 
severe hypoglycaemia will be explored by summarizing those incidences between the treatment 
groups among subjects with post-baseline positive response of cross reactive antibodies.   The 
local and system allergic reactions as well as the hypoglycaemia are found directly on the CRF, the 
hypersensitivity events will be found in the coded adverse events with the following specifications: 
- 
System Organ Class (SOC):  Immune system disorders 
- 
High Level Group Term (HLGT): Allergic conditions 
- 
High Level Term (HLT): Allergies to foods, food additives, drugs and other 
- 
Preferred Term (PT): Drug hypersensitivity 
- 
Lower level term (LLT): Drug hypersensitivity 
 
The possible insulin neutralization effect will also be explored by presenting:  
- 
The incidence of patients with increase over 10% in cross reacting antibody from baseline at 
any visit 
- 
The incidence of patients with increases of HbA1c over 0.2% increase from baseline at any 
visit 
- 
The incidence of patients with increase in total or basal insulin dose at any visit.  
Treatment group comparisons will be performed by using a Chi-Square test, if 80% of the cells 
have an expected frequency >=5 otherwise Fisher’s exact test will be used. 
18.6.2. 
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, nocturnal hypoglycemia. Patients will be instructed to record all 
hypoglycemic events in the patient’s 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. 
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The classification will be derived as follows: 
- 
Severe: the patients entered in the eCRF: “severe (external assistance required to resolve 
event)” 
- 
Documented Symptomatic Hypoglycemia: the patient entered in the eCRF: symptomatic and 
checked the “glucose value was less than or equal to 70 mg/dL”. 
- 
Asymptomatic Hypoglycemia: the patient entered in the eCRF: asymptomatic (symptoms of 
hypoglycemia not present) and checked the “glucose value was less than or equal to 70 
mg/dL”. 
- 
Probable Symptomatic Hypoglycemia: the patient entered in the eCRF: symptomatic and 
checked the “glucose was not measured”. 
- 
Relative Hypoglycemia: the patient entered in the eCRF: asymptomatic or symptomatic and 
checked the “glucose value was over 70 mg/dL”. 
- 
Nocturnal Hypoglycemia: the patient has any of the 5 types above and also checked the 
“Nocturnal” time of the event. 
Hypoglycemia event 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 event rate per patient per 30 days will be analyzed using the same MMRM model as 
for the primary efficacy parameter (without imputing any missing data). 
For change from baseline of hypoglycemia rate, a graphical display at scheduled visits, of 
LSMeans and 2-sided 95% CI will be generated from the MMRM model.  Additionally, mean (+/- 
SD) for actual measurements by visit will also be presented. 
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. 
19. STUDY DATA TECHNICAL CONFORMANCE 
The data will be submitted using the Clinical Data Interchange Standards Consortium (CDISC).  
The Study Data Tabulation Model (SDTM) data will use version 1.4 (SDTMIG).  The derived 
datasets will follow the Analysis Data Model (ADAM) and will use version 1.1 (ADAMIG). 
20. DATA NOT SUMMARIZED OR PRESENTED 
Not applicable. 
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21. REFERENCES  
Yan, X., Lee, S., and Li, N. (2009), “Missing Data Handling Methods in Medical Device Clinical Trials,” Journal of 
Biopharmaceutical Statistics, 19, 1085–1098. [392] 
 
 
 
 
 
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reproduction is strictly prohibited. 
APPENDIX 1. REPORTING CONVENTIONS 
Page Layout: 
The Section 14 tables and Appendix 16 listings should be in landscape orientation by default. 
The output in Section 14 and Appendix 16 will be in RTF file formal using Courier New font with 8 
point size. 
 
Statistical conventions: 
The patient percentages (%) should be rounded to a whole number, with SAS rounding options 
used to obtain the values. 
Percentages for values in the tables that are less than <1 should be presented as “<1”. 
If “%” is part of the column heading, do not repeat the “%” sign in the body of the table. 
If a value is zero (0), then do not use 0% and leave the corresponding percentage blank. 
The format for range should always be “Min, Max”. 
If there are missing data, then a missing row will be added to keep track of all patients.  If there are 
no missing data, then delete the missing row.  Percentages will not be presented on the missing 
category row. 
Standard Deviation should be abbreviated as “SD”, and Standard Error should be abbreviated as 
“SE”; it is presented within parenthesis next to the mean value, without any +/- sign.  The Standard 
Deviation or Standard Error should have one additional decimal point beyond that of the mean (for 
example, if the mean has one decimal point, SD/SE should have two decimal points).  Mean and 
medican should have one additional decimal point beyond that of the data being summarized. 
“N” will represent the entire treatment group, while “n” will represent a subset of the treatment 
group.  For tables with population designated as a row heading, “N” should be used (i.e. tables 
where all the participant data is not available for every variable within a treatment group).  As a 
guideline, if the number is used in denominator that it should be presented as “N”.  If the number is 
used in numerator it should be presented as “n”. 
P-values will be presented with 4 decimals. 
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APPENDIX 2. 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 
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START DATE 
STOP 
DATE 
ACTION 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
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 
 
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 
 
 
 
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START 
DATE 
STOP 
DATE 
ACTION 
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 
 
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 3. SAS CODE EXAMPLE FOR MULTIPLE IMPUTATION 
/* First, generate enough data to produce a monotone missing data pattern */ 
/* MCMC does not work with class statement. Pooled investigator sites and */ 
/* baseline insulin dose time have been converted to indicator variables  */ 
/* For pooled investigator sites, let say that x is the total number of   */ 
/* pooled investigator sites.  Then, for pooled investigator sites #1,    */ 
/* inv01=1, inv02=0, …, inv0[x-1]=0                                       */ 
/* For pooled investigator sites #2, inv01=0, inv02=1, …, inv0[x-1]=0     */ 
/* For pooled investigator sites #[x-1], inv01=0, inv02=0, …, inv0[x-1]=1 */ 
/* For pooled investigator sites #x, inv01=0, inv02=0, …, inv0[x-1]=0     */ 
/* For baseline insulin dose time= morning, binstime=1                    */ 
/* For baseline insulin dose time= evening, binstime=0                    */ 
/* No rounding or range is applied for any variable                       */ 
/* Non-informative prior is proc mi default MCMC prior information        */ 
/* 200 is proc mi default number of burn-in iterations                    */ 
proc mi data = <<insert input dataset name>> out = datamono 
seed =20171220  
NIMPUTE=100; 
by trt; 
var inv01 inv02 … inv0[x-1] binstime HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
mcmc impute = monotone chain= multiple; 
run; 
 
 
/* Then, do full imputation based on sequential regression models          */ 
/* assuming monotone missing pattern.                                      */ 
proc mi data = datamono seed = 171016 out = datami NIMPUTE = 1; 
by _imputation_; 
class inv01 inv02 … inv0[x-1] binstime trt; 
var inv01 inv02 … inv0[x-1] binstime trt HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
monotone regression; 
run; 
 
 
/* Compute Changes from Baseline and create one categorical variables for  */ 
/* the pooled investigational sites based on the [x-1] indicator pooled    */ 
/* investigational site variables                                          */ 
data datmichg; 
set datami (in=a drop = HbA1c_WK18 rename = (HbAc1_WK12 = result)) 
    datami (in=b drop = HbA1c_WK12 rename = (HbAc1_WK18 = result)); 
 
* Visit; 
if a then visit = “Week 12”; 
else if b then visit = “Week 18”; 
 
* Change from baseline; 
change = result – HbA1c_BASE; 
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* Pooled investigational sites as 1 categorical variable; 
if inv01 = 1 then psites = 1; 
 
else if inv02 = 1 then psites = 2; 
 
… 
 
else if inv0[x-1] = 1 then psites = [x-1]; 
 
else psites = x; 
run; 
 
/* MMRM Analysis by _imputation_ */ 
proc sort data=datmichg; 
by _imputation_ psites binstime trt visit subject; 
run; 
 
proc mixed data = datmichg method = REML; 
by _imputation_; 
class psites binstime trt visit subject; 
model change = HbA1c_BASE psites binstime trt visit trt*visit / DDFM = KR; 
random subject; 
repeated visit / type = UN subject = subject; 
lsmeans trt*visit /diff cl;  
ods output diff = lsdiffs(where=(trt= ‘Process IV’ and _trt=’Process V’ and 
visit=_visit)); 
run; 
 
/* Combine LSmean Differences for Visit ‘Week 12’ */ 
proc mianalyze parms(classvar = full) = lsdiffs (where = (visit = ‘Week 12’)); 
class trt*visit; 
modeleffects trt*visit; 
run; 
 
/* Combine LSmean Differences for Visit ‘Week 18’ */ 
proc mianalyze parms(classvar = full) = lsdiffs (where = (visit = ‘Week 18’)); 
class trt*visit; 
modeleffects trt*visit; 
run; 
 
Note to programmers: In case of non-convergence or non-estimability issues for the generation of 
enough data to produce a monotone missing data pattern, replace the two proc mi by the following: 
 
proc mi data = <<insert input dataset name>> out = datamono 
seed =20171220  
NIMPUTE=100  
round = 1 1 1 … 1 1 . min = 0 0 0 … 0 0 . max = 1 1 1 … 1 1 . ; 
var trt inv01 inv02 … inv0[x-1] binstime HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
mcmc impute = monotone chain= multiple prior=ridge=p; 
run; 
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PROTOCOL MYL-1501D-3004 
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Document: 
\sasdata\Mylan\Insulin_glargine\SYA22825\Biostatistics\Documentation\Protocol\MYL-
1501D3003_SAP_V1_MAY2018 
Author: 
Irene Dehem 
Version Number: 
1.0 
 
 
Version Date: 
04MAY2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
 
proc mi data = datamono seed = 171016 out = datami NIMPUTE = 1; 
by _imputation_; 
class trt inv01 inv02 … inv0[x-1] binstime; 
var trt inv01 inv02 … inv0[x-1] binstime HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
monotone regression; 
run; 
 
APPENDIX 4. SAS CODE EXAMPLE FOR TIPPING POINT 
/*An MNAR version of the MI procedure from Appendix 3 will be used. 
  The SHIFT value will start at 0.01 and be incremented until the critical 
value for non-inferiority of 0.4 is surpassed.  In particular, the upper limit 
of the 95% confidence interval of the treatment difference will be calculated 
for each iteration of the 0.01 increase to the MNAR adjustment and once it 
surpasses 0.4, we take that MNAR adjustment value as k. 
 
Note: Code assumes TRT=1 is Process VI (Test) and TRT=2 is Process V 
(Control). 
 
The code for the MNAR MI proc which differs from the MAR MI proc in Appendix 3 
is shown below. 
 
 
proc mi data = <<insert input dataset name>> out = datamono 
seed =20171220  
NIMPUTE=100; 
by trt; 
   MNAR 
Adjust (<Week18VariablefromTranspose>/SHIFT= +Kprime 
 
ADJUSTOBS=(TRT=’1’)) 
 
 
Adjust (<Week18VariablefromTranspose>/SHIFT= -Kprime  
 
ADJUSTOBS=(TRT=’2’)); 
 
var inv01 inv02 … inv0[x-1] binstime HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
mcmc impute = monotone chain= multiple; 
run; 
 
 
Where Kprime is the shift value starting at 0.01 and ending at k. 
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Version Number: 
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Version Date: 
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Effective Date: 01Apr2016 
 
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reproduction is strictly prohibited. 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
MYL-1501D-3004 
A RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, PARALLEL-GROUP CLINICAL 
STUDY COMPARING THE EFFICACY AND SAFETY OF MYL-1501D PRODUCED BY TWO 
MANUFACTURING PROCESSES IN TYPE 1 DIABETES MELLITUS PATIENTS. 
 
 
AUTHOR: IRENE DEHEM 
 
 
VERSION NUMBER AND DATE: V2.0 18OCT2018 
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#riiVlx
Analysis Plan Template
Mylan GmbH
PROTOCOL MYL1 501 D-3004
Page 2 of49
SrnNsncAL ANALYSIS PTAN Srcr*nrunE PA6E
$tatisticalAnalysis Flan V2.0 (Dated 18OCT2S18) for Protocol MYL-1501D-3004 V2.
Name
lrene Dehem
Siatistical Scientist
IOVIA
$ignalure
Date
Upon review of this document, the undersigned approv€$ this version of the StatisticalAnalysis Plan,
authorizing that the conteflt is acceptabla for the reporting of this study.
Nama
Approvad By: 
Edith
SimeonJsenior
Reviewer
\Bcrcrzc>rg
Signalure 
Date
fA?W^
l*a***brg
,tr#*?.*rB
Author:
Posltion:
Company:
Position:
Company:
Approved By:
Position:
Company:
Manager Biostatislics
IOVIA
8in Sun
Principal Biostatistician
M$an
Oocuffisnt lsasdah\Mylan\lnsulinglaqinelSYA2202$\BiostatlsllcslDacumenta$onl$APl\MYt-1501n-
3004'SAP*F inal*Z;0 clean.doc
Aulhor: 
lrene Dsham
2.0
180CT2018
Rafgrsnee; CS-"UVl_BSms
Unauttorized use, disclosure cr
Vorsisn Number:
Version Date:
IBmplato No: C$*TP*E$o1S Reylsion 4
Effective Date: 01Apr2016
Copytight @ 200S, 20.10, 201?, 2018 Quintiles Transnallonal Sorp. Ali righis reseryed.
The conients of thi$ document are confdential end propriotary to Quintiles Transnational Corp
repmductlon is stricuy prohibited.
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.!!!!!srrr\lr r,' 
MYlan GmbH
:i.:= I \r/ v I /-\ 
PROTOCOL MyL-1S01D-,0M
Analysis P-lBa T,smpfgte 
Page 3 of 49
Ourpur TcMPLATES StenerunE PAGE
outpuiTemplates v2.0 (Dated 1socr2018) for Protocot MyL-1s0rD-8004 v2.
Name
lrene Dehem
Name
Approved By: 
Edith
$imeonlSenior
Reviewer
Fositian:
Manager Biostatistics
Company: 
IQVIA
Approved By: 
Bin Su*
Posiiion: 
Princlpal Bioetaiislician
Company: 
Mylan
$ignaiure
Date
Authar:
Position: 
$talistical$cientist
Company: 
IQVIA
Upon review of this document,,lhe undersigned approves this version of the Output Templates Plan,
authorizing thal the content is acceptable for the reporting of this study.
H'rg,oci2o\e
Date
l$"s#" ?plfl
r8**l-*zo8
$lgnature
&rtffi,i**
W4,SAP-Finel2;0 dsrn.doc
Author: 
irenE $ehem 
Version Number: 
2.0
Vercion Dale: 
18OCT201S
Tsrplal* No: C$JP_8SOf S Flevision 4 
Refrrsncs; CS*WJBS005
Efieclivs Oala: 01Apr20 1 S
Copyrighl S 200q 2010. 2012, 2016 Qulntlles Tranrnailsnat Corp. A& rights re$orvsd,
The contents ol thls docir.fisnt sre cor*denliel ard prcpietary to Quintiles Transnallonal Corp. Unauthorized u$e, di$donurs or
roprodrrtion is stricijy pmhibiied.
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Document: 
\sasdata\Mylan\Insulin_glargine\SYA22825\Biostatistics\Documentation\SAP\\MYL-1501D-
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Author: 
Irene Dehem 
Version Number: 
2.0 
 
 
Version Date: 
18OCT2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0  
04MAY2018 
Irene Dehem 
Not Applicable – First Version 
2.0 
16OCT2018 
Irene Dehem 
Adding footnote to Schedule of Events in 
section 4.2. 
Added visit windows in section 7.4 for 
mapping the unscheduled visit if scheduled 
visit is missing for HbA1c data. 
Updated site pooling information in section 
8.2 to detail site pooling information. 
Added clarification for sensitivity analysis in 
section 16.1.2 and 16.1.4 to handle subjects 
who switch to their own insulin Lantus. 
Added clarification for immunogenicity data 
and PK analysis in sections 16.3 and 18.6.1 
for excluding immunogenicity data and PK 
data from database lock. 
Added clarification on definition of baseline 
hypoglycemia period in section 18.6.2. 
 
 
 
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Author: 
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Version Number: 
2.0 
 
 
Version Date: 
18OCT2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS .............................................................................................................. 9 
2. INTRODUCTION ............................................................................................................................ 10 
3. STUDY OBJECTIVES ...................................................................................................................... 10 
3.1. 
Other Objectives ........................................................................................................................................ 10 
4. STUDY DESIGN ............................................................................................................................... 11 
4.1. 
General Description ................................................................................................................................... 11 
4.2. 
Schedule of Events..................................................................................................................................... 12 
4.3. 
Changes to Analysis from Protocol ............................................................................................................ 14 
5. PLANNED ANALYSES ................................................................................................................... 14 
5.1. 
Data Monitoring Committee (DMC) ........................................................................................................... 14 
5.2. 
Final Analysis ............................................................................................................................................. 14 
6. ANALYSIS SETS .............................................................................................................................. 14 
6.1. 
All Patients Screened ................................................................................................................................. 14 
6.2. 
Run-in Population ...................................................................................................................................... 15 
6.3. 
All Patients Randomized Population [RND] ............................................................................................... 15 
6.4. 
Intent-to-Treat Population [ITT] ................................................................................................................ 15 
6.5. 
Safety Population [SAF] ............................................................................................................................. 15 
6.6. 
Per Protocol Population [PP] ..................................................................................................................... 15 
7. GENERAL CONSIDERATIONS .................................................................................................... 16 
7.1. 
Reference Start Date and Study Day .......................................................................................................... 16 
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Document: 
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Author: 
Irene Dehem 
Version Number: 
2.0 
 
 
Version Date: 
18OCT2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
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reproduction is strictly prohibited. 
7.2. 
Baseline ..................................................................................................................................................... 16 
7.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 16 
7.4. 
Windowing Conventions ............................................................................................................................ 17 
7.5. 
Statistical Tests .......................................................................................................................................... 17 
7.6. 
Common Calculations ................................................................................................................................ 18 
7.7. 
Software Version ....................................................................................................................................... 18 
8. STATISTICAL CONSIDERATIONS ............................................................................................. 18 
8.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 18 
8.2. 
Multicenter Studies ................................................................................................................................... 18 
8.3. 
Missing data .............................................................................................................................................. 19 
8.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 20 
8.5. 
Active-Control Studies Intended to Show Non-inferiority or Equivalence .................................................. 20 
8.6. 
Examination of Subgroups ......................................................................................................................... 20 
9. OUTPUT PRESENTATIONS ........................................................................................................ 21 
10. DISPOSITION AND WITHDRAWALS ....................................................................................... 21 
11. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................................... 21 
11.1. 
Derivations ............................................................................................................................................ 22 
12. MEDICAL HISTORY ....................................................................................................................... 22 
13. MEDICATIONS ................................................................................................................................ 22 
14. STUDY MEDICATION EXPOSURE ............................................................................................. 23 
14.1. 
Derivations ............................................................................................................................................ 23 
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Author: 
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Version Number: 
2.0 
 
 
Version Date: 
18OCT2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
15. STUDY TREATMENT NON-COMPLIANCE .............................................................................. 23 
16. EFFICACY OUTCOMES ................................................................................................................. 24 
16.1. 
Primary Efficacy ..................................................................................................................................... 24 
16.1.1. 
Primary Efficacy Variable ..........................................................................................................................24 
16.1.2. 
Missing Data Method And Data Observed Under Rescue Medication for Primary Efficacy Variable ......24 
16.1.3. 
Primary Analysis of Primary Efficacy Variable ..........................................................................................24 
16.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .......................................................................................26 
16.2. 
Secondary Efficacy ................................................................................................................................. 26 
16.2.1. 
Secondary Efficacy Variables & Derivations .............................................................................................26 
16.2.1.1. 
Fasting plasma glucose .....................................................................................................................26 
16.2.1.2. 
Daily insulin dose per unit body weight (mealtime, basal insulin and total) for days of 8-point 
profiles 
27 
16.2.1.3. 
8-point Self-Monitored Blood Glucose (SMBG) profile ....................................................................28 
16.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .......................................................................29 
16.2.3. 
Analysis of Secondary Efficacy Variables ..................................................................................................29 
16.2.3.1. 
Analysis of change from baseline in HbA1c at scheduled visits ........................................................29 
16.2.3.2. 
Analysis of change from baseline in fasting plasma glucose ............................................................29 
16.2.3.3. 
Analysis of Change in Daily insulin dose per unit body weight (mealtime, basal insulin and total) for 
days of 8-point profiles. ........................................................................................................................................30 
16.2.3.4. 
Analysis of Change in 8-point SMBG profile from baseline ..............................................................30 
16.2.4. 
Subgroup Analysis .....................................................................................................................................30 
16.3. 
Exploratory PK Analysis ......................................................................................................................... 31 
17. QUALITY OF LIFE ANALYSIS ..................................................................................................... 31 
18. SAFETY OUTCOMES ..................................................................................................................... 31 
18.1. 
Adverse Events ...................................................................................................................................... 31 
18.1.1. 
All TEAEs ...................................................................................................................................................32 
18.1.1.1. 
Severity .............................................................................................................................................32 
18.1.1.2. 
Adverse Drug Reaction (Relationship to Study Medication) ............................................................32 
18.1.2. 
TEAEs Leading to Discontinuation of Study Medication ...........................................................................33 
18.1.3. 
Serious Adverse Events .............................................................................................................................33 
18.1.4. 
Adverse Events Leading to Death .............................................................................................................33 
18.1.5. 
Local or Systemic Allergic Reaction ..........................................................................................................33 
18.1.6. 
Device-related Assessment.......................................................................................................................33 
18.1.7. 
Non TEAEs .................................................................................................................................................33 
18.2. 
Laboratory Evaluations .......................................................................................................................... 34 
18.2.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ..............................................................34 
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Author: 
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Version Number: 
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Version Date: 
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Template No:  CS_TP_BS016  Revision 4 
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Effective Date: 01Apr2016 
 
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reproduction is strictly prohibited. 
18.3. 
ECG Evaluations ..................................................................................................................................... 36 
18.4. 
Vital Signs .............................................................................................................................................. 36 
18.4.1. 
Potential Clinically Significant Changes ....................................................................................................37 
18.5. 
Physical Examination ............................................................................................................................. 38 
18.6. 
Other Safety Assessments ..................................................................................................................... 38 
18.6.1. 
Immunogenicity profiles analyses ............................................................................................................38 
18.6.2. 
Hypoglycemia Analyses ............................................................................................................................39 
19. STUDY DATA TECHNICAL CONFORMANCE .......................................................................... 40 
20. DATA NOT SUMMARIZED OR PRESENTED .......................................................................... 40 
21. REFERENCES .................................................................................................................................. 41 
APPENDIX 1. REPORTING CONVENTIONS .................................................................................. 42 
APPENDIX 2. PARTIAL DATE CONVENTIONS ............................................................................ 43 
Algorithm for Treatment Emergence of Adverse Events: ...................................................................................... 43 
Algorithm for Prior / Concomitant Medications: ................................................................................................... 44 
APPENDIX 3. SAS CODE EXAMPLE FOR MULTIPLE IMPUTATION ...................................... 46 
APPENDIX 4. SAS CODE EXAMPLE FOR TIPPING POINT ........................................................ 48 
 
 
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Version Date: 
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Template No:  CS_TP_BS016  Revision 4 
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Effective Date: 01Apr2016 
 
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reproduction is strictly prohibited. 
1. LIST OF ABBREVIATIONS 
 AE 
 
adverse event 
ANOVA 
analysis of variance 
ATC 
Anatomical Therapeutic Chemical (class) 
BDR 
blind data review 
BMI 
Body Mass Index 
CRF 
case report form 
CRO 
contract research organization 
DMC 
data monitoring committee 
HLGT 
High Level Group Term 
HLT 
High Level Term 
ICH 
International Conference of Harmonization 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
MAR 
missing at random 
MCMC 
Markov chain Monte Carlo 
MedDRA Medical Dictionary for Regulatory Activities 
MI  
Multiple Imputation 
MMRM 
mixed model for repeated measures 
PP  
Per Protocol 
PT  
Preferred Term 
RND 
randomized population 
SAE 
serious adverse event 
SAF 
Safety 
SAP 
statistical analysis plan 
SE  
standard error 
SMBG 
Self Monitored Blood Glucose 
SOC 
System Organ Class 
TEAE 
treatment emergent adverse event 
T1DM 
type 1 diabetes mellitus 
WHO-DD World Health Organization – Drug Dictionary (enhanced) 
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Author: 
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Version Number: 
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Version Date: 
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reproduction is strictly prohibited. 
2. 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-3004. It describes the data to be summarized and 
analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol amendment 1 (dated 11JAN2018). 
3. STUDY OBJECTIVES 
The primary objective is to test whether MYL-1501D product from Process VI once daily is non-
inferior to MYL-1501D product from Process V once daily based on the change in HbA1c from 
baseline to week 18 when administered in combination with mealtime insulin lispro. 
3.1. OTHER OBJECTIVES 
The other objectives are to compare MYL-1501D product from Process VI and Process V at week 
18, when administered in combination with mealtime insulin lispro, with respect to: 
- 
Immunogenicity: incidence and change from baseline in the relative levels of anti-drug antibody 
- 
Hypoglycemic events: incidence and rate per 30 days 
- 
Occurrence of local reactions, systemic reactions and other adverse events 
- 
Device-related safety assessment 
- 
Change in fasting plasma glucose from baseline 
- 
Change in insulin dose per unit body weight (U/kg) from baseline 
- 
Change in 8-point Self-Monitored Blood Glucose (SMBG) profile from baseline 
 
 
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Version Date: 
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reproduction is strictly prohibited. 
4. STUDY DESIGN 
 
4.1. GENERAL DESCRIPTION 
This is a multicenter, double-blind, randomized, parallel-group phase 3 study in patients with type 1 
diabetes mellitus (T1DM) comparing the efficacy, immunogenicity and safety of MYL-1501D products 
from two manufacturing processes (Process V and Process VI).  A total of 202 patients with T1DM 
are planned to be randomized in a 1:1 ratio between MYL-1501D Process V and MYL-1501D 
Process VI.  Approximately 110 sites will be included in the study. 
After up to 2-week screening period, all patients will be titrated on Lantus® during a 4-week run-in 
period, and will be shifted from their current mealtime insulin to Humalog®.  The patients will be 
randomized (stratified by investigational site and time of administration of glargine [morning and 
evening]); one group will receive MYL-1501D product from Process V, while the other group will 
receive MYL-1501D product from Process VI for 18 weeks.  A follow-up visit will be scheduled 2 
weeks after last dose of MYL-1501D. 
The none hypothesis is that the upper bound of treatment difference (Process VI minus Process V) 
is over 0.4 and alternative hypothesis is that upper bound of treatment difference is less than or equal 
to 0.4. 
Patients will remain blinded until the database is locked, then an unblinding request form will be sent 
to the IVR provider in order to get the randomization code.  Any analyses done prior to database lock 
will use dummy treatments. 
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4.2. SCHEDULE OF EVENTS 
Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
F-U 
Study Visits1 
V1 
V2 
V3 
V4 
V5 V6 V7 V8 V9 V10 V11 V12 V13 
V14 
(EOT) 
V15 
(FU) 
Study Week 
-6 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
6 
9 
12 
15 
18 
20 
Study Days 
-42 to -28 -28±3 -21±3 -14±3 -7±3 0±3 7±3 14±3 28±3 42±3 70±7 84±7 112±7 126±7 140±7
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria Review 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
History of previous 
insulin usage 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated 
Ophthalmoscopy / 
retinal photography if 
not done in the last 6 
months 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard-of-care 
specifics2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Age, Gender, Height, 
Race 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight and 
BMI 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Pregnancy Test3 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Medical History 
including concomitant
illness 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
x 
x 
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 
 
Physical examination 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
12-lead ECG (supine) 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
Randomization 
 
 
 
 
 
x 8 
 
 
 
 
 
 
 
 
 
Record AEs and 
SAEs (including local
and systemic allergic 
reactions) and 
hypoglycemic events4
due to medication, 
disposable pen or 
needle 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record device safety 
information 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
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Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
F-U 
Study Visits1 
V1 
V2 
V3 
V4 
V5 V6 V7 V8 V9 V10 V11 V12 V13 
V14 
(EOT) 
V15 
(FU) 
Study Week 
-6 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
6 
9 
12 
15 
18 
20 
Study Days 
-42 to -28 -28±3 -21±3 -14±3 -7±3 0±3 7±3 14±3 28±3 42±3 70±7 84±7 112±7 126±7 140±7
Fasting plasma 
glucose 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
HbA1c Assay 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
Fasting C-peptide, 
HIV, HBsAg, and 
HCVAb 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sampling for 
hematology, blood 
chemistry and 
urinalysis5 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
Fasting lipid profile 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
Sampling for 
immunogenicity 9 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Sampling for PK6 
 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Review 8-point 
SMBG Profile 
performed in the 
week before the visit 7
 
 
x 
x 
x 
x 
 
 
 
x 
 
x 
 
x 
 
Dose review of 
Lantus, MYL-1501D 
and insulin lispro and 
instruction 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dispense Study 
Medication and 
ancillary supplies 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
 
 
Drug Accountability 
and Compliance 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Dispense subject 
diary 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
 
 
Review subject diary 
 
 
 
x 
 
x 
 
 
 
x 
 
x 
 
x 
 
1. Visits 3, 5, 7, 9 and 11 may be telephone contacts (grey columns represent telephone contacts).  
2. 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.  
3. Serum pregnancy test for women of child bearing potential will be done during screening and randomization visit. During 
subsequent visits urine pregnancy test will be done. At the randomization visit, both urine and serum pregnancy tests will be done. 
Subject may be enrolled if the urine pregnancy test is negative.  
4. Non-severe hypoglycemic events (which are not consider as SAE) occurring after the EOT visit will not be recorded at the 
follow-up visit.  
5. A routine urine dipstick test will be performed by the site. A microscopic urinalysis will be performed by the central lab if the 
dipstick test result is abnormal.  
6. The PK sample will be taken during the visit, preferably prior to the daily glargine dose. The timing of study drug 
administration from prior day should be collected along with the time of PK sample collection.  
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7. The 8-point SMBG profile, measurement will be done by the subject at home on 3 days (of which 2 are consecutive days) in 
the week before the next visit. Evaluation will be based on the measurements after each 6 weeks; thus during randomized period it 
would done at Week 6, 12 and 18, while SMBG would be done on 3 days during Weeks 5, 11 and 17.  
8. Prior to randomization, Investigator is required to confirm subject eligibility into the study based on the data collected during 
the screening period, including the labs values recorded during screening. In case subject does not meet the eligibility re-screening 
need to be confirmed by the Sponsor or designee.  
9. During the Randomized Comparative Treatment Period, the immunogenicity samples should be drawn immediately following 
the PK sample, as outlined under Footnote 6. 
4.3. CHANGES TO ANALYSIS FROM PROTOCOL 
No changes. 
5. PLANNED ANALYSES 
The following analyses will be performed for this study: 
• 
Final Analysis  
5.1. DATA MONITORING COMMITTEE (DMC)  
There will be no DMC or interim analysis for this study. 
5.2. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following 
Sponsor Authorization of this SAP, Sponsor Authorization of Analysis Sets, Database Lock and 
Unblinding of Treatment.  
6. ANALYSIS SETS 
Agreement and authorization of patients included/ excluded from each analysis set will be conducted 
prior to the unblinding of the study.  
6.1. ALL PATIENTS SCREENED 
The all patients screened population is defined as all patients who consent for the study. 
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6.2. RUN-IN POPULATION  
The run-in population is defined as all patients who consent for the study and entered into the run-in 
phase. The patients in this population will be summarized under the total number of patients.  Run-
in failure patients will be summarized under the category of “run-in failure”. 
6.3. ALL PATIENTS RANDOMIZED POPULATION [RND] 
The all patient randomized (RND) population will contain all patients got randomized to study 
medication.  The patients who discontinue the study during run-in period will not be included in the 
randomized population. 
For analyses and displays based on RND, patients will be classified according to randomized 
treatment.  
6.4. INTENT-TO-TREAT POPULATION [ITT] 
The Intent-to-Treat (ITT) population includes all randomized patients (including patients who receive 
incorrect treatment, do not complete the trial or do not comply with the protocol).   
The patients under the ITT population will be analyzed according to the planned treatment group. 
All primary and secondary efficacy analysis will be based on the ITT population. 
6.5. SAFETY POPULATION [SAF] 
The safety population (SAF) will contain all patients who are randomized and take at least one dose 
of study drug. 
The safety analysis will be conducted according to the treatment received.  If there is any doubt 
whether a patient was treated or not, they will be assumed treated for the purpose of the analysis.  
6.6. PER PROTOCOL POPULATION [PP] 
The per-protocol population (PP) will contain all patients who complete week 18 and have HbA1c3 
measurements as per the protocol, or have at least one post-baseline HbA1c data for patients who 
discontinue prematurely, and do not have major protocol deviation that impact the primary outcome.  
Patients who meet rescue medication criteria and take rescue medication will be excluded from the 
PP.  The list of deviations leading to exclusion from the PP population will be identified, reviewed and 
documented prior to DB lock and determined in the blind data review meeting and documented in 
the blind data review report prior to the database lock. The subjects who are excluded from PP 
population and reason for exclusion will be listed. 
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7. GENERAL CONSIDERATIONS 
7.1. 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 randomization, (Day 1 is the day of randomization).  
• 
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. 
7.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to 
receiving randomized treatment reference (day of randomization) start date (including unscheduled 
assessments). In the case where the last non-missing measurement and the randomized treatment 
start date coincide, that measurement will be considered pre-baseline, but Adverse Events (AEs) 
and medications commencing on the randomized treatment start date will be considered post-
baseline. 
For insulin (mealtime, basal and total) levels, baseline is the value collected at Visit 6 (Week 0) which 
correspond to values collected prior injection of study medication. 
7.3. 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 scheduled visit if 
scheduled visit value is missing or the Last Observation Carried Forward (LOCF) value in case 
primary sensitivity analysis, or best/ worst case value where required (e.g. shift table) in safety 
analysis.  
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 entered under the Visit 14 (week 18), but for summary tables it will be 
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mapped to the next available planned visit number after their last scheduled visit.  For example, 
should a patient discontinue at Visit 9, the Early Termination visit will have their Fasting plasma 
glucose and their HbA1c assay taken.  The fasting plasma glucose would then be summarized under 
Visit 10 and the HbA1c under Visit 12. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
7.4. WINDOWING CONVENTIONS  
Visit windowing will be performed only on HbA1c data.  Should a visit have a missing value, the 
unscheduled visit will be used and mapped by using the following algorithm. 
 
Days to first dose of 
unscheduled measurement 
Mapped Visit 
-42 to -28 days 
Visit 1 (Week -6 to -4) 
-27 to -25 days 
Visit 2 (Week -4) 
-24 to -18 days 
Visit 3 (Week -3) 
-17 to -11 days 
Visit 4 (Week -2) 
-10 to -4 days 
Visit 5 (Week -1) 
-3 to 3 days 
Visit 6 (Week 0) 
4 to 10 days 
Visit 7 (Week 1) 
11 to 17 days 
Visit 8 (Week 2) 
25 to 31 days 
Visit 9 (Week 4) 
39 to 45 days 
Visit 10 (Week 6) 
63 to 75 days 
Visit 11 (Week 9) 
76 to 91 days 
Visit 12 (Week 12) 
105 to 119 days 
Visit 13 (Week 15) 
121 to 133 days 
Visit 14 (Week 18) 
134 to 147 days 
Visit 15 (Week 20) 
 
For subjects who discontinue the study, their early termination HbA1c value will be remapped to their 
actual visit using the same time window as desctibed above. 
7.5. STATISTICAL TESTS 
The default significant level will be (5%); confidence intervals will be 95% and all tests will be two-
sided, unless otherwise specified in the description of the analyses. 
Non-inferiority will be tested at 2.5% (one-sided) level of significance. 
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7.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as:  
• 
Test Value at Visit X – Baseline Value 
7.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher.  
8. STATISTICAL CONSIDERATIONS 
8.1. 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. 
• 
Pooled sites 
• 
Time of Glargine administration (morning, evening), stratification factor. 
• 
Baseline HbA1c (continuous variable) 
8.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers in the USA.   
When specified, statistical analysis will be adjusted for pooled sites based on US census regions.   
All sites are grouped by state. 
All states within a US census region (Northeast, Midwest, South, West, Pacific) with fewer than 8 
randomized patients will be combined into a single pooled site for analysis purposes.  The maximum 
number of subjects can not exceed 40 per site. 
The pooled method will be as follow (performed manually): 
Sites within a census region (New England, Midwest, South, West) with less than 8 randomized 
patients will be pooled with the closest’ sites within the same census region until they reach at least 
8 subjects. 
 
 
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Pooled Site Group  
Site ID (number of subjects per site) 
Total Number 
of Subjects 
Pool_1 (Midwest_1) 
40016 (2), 40029 (2), 40038 (1), 40059 (2), 40074 (1), 
40097 (2), 40098 (2), 40100 (1) 
13 
Pool_2 (Midwest_2) 
40083 (3), 40086 (1), 40095 (5) 
9 
Pool_3 (North_1) 
40040 (3), 40051 (2), 40062 (2), 40087 (3), 40096 (2), 
40103 (1) 
13 
Pool_4 (South_1) 
40009 (2), 40019 (1), 40026 (1), 40027 (1), 40035 (3), 
40048 (4), 40057 (3), 40077 (4) 
19 
Pool_5 (South_2) 
40012 (5), 40024(1), 40050 (4), 40078 (6) 
16 
Pool_6 (South_3) 
40047 (4), 40075 (2), 40084 (1), 40106 (2) 
9 
Pool_7 (South_4) 
40018 (2), 40030 (3), 40042 (1), 40054 (3), 40107 (1) 
10 
Pool_8 (South_5) 
40025 (2), 40036 (3), 40037 (4), 40056 (2), 40108 (1) 
12 
Pool_9 (South_6) 
40001 (4), 40004 (8), 40017 (3), 40033 (2), 40045 (3), 
40046 (4), 40070 (3), 40088 (1), 40111(1) 
29 
Pool_10 (West_1) 
40003 (3), 40005 (2), 40008 (6), 40014 (2), 40022 (1), 
40049 (2), 40060 (3), 40061 (2), 40064 (2), 40071 (6), 
40081 (3), 40082 (2), 40090 (3) 
37 
Pool_11 (West_2) 
40021 (3), 40043 (2), 40079 (2), 40091 (6) 
13 
Pool_12 (West_3) 
40020 (5), 40053 (3) 
8 
Pool_13 (West_4) 
40011 (13), 40015 (6), 40092 (4) 
23 
Pool_14 (West_5) 
40089 (4), 40093 (4) 
8 
 
 
8.3. MISSING DATA 
After having mapped data captured at unscheduled and/or early termination visits (if any) to schedule 
missing visits using visit windows technique (refer to section 7.4), missing primary data will be 
imputed by using the multiple imputation (MI) technique (see section 16.1.3).   
As another sensitivity analysis, the imputed values by MI will be corrected such that the full non-
inferiority margin will be added for imputed values in Process VI group. 
A sensitivity analysis using Last Observation Carried Forward (LOCF) will also be performed on the 
primary efficacy parameter. 
In the secondary efficacy data, the weight used in the daily total insulin will be imputed by the weight 
of the previous visit value if current weight value is missing. 
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8.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
No adjustment for multiplicity will be performed. 
8.5. ACTIVE-CONTROL STUDIES INTENDED TO SHOW NON-INFERIORITY OR 
EQUIVALENCE 
Non-inferiority will be established if the upper bound of a two-sided 95% confidence interval (CI) for 
the absolute difference (MYL-1501D Process VI minus Process V) of mean change from baseline to 
week 18 for HbA1c is less than or equal 0.4%. 
8.6. EXAMINATION OF SUBGROUPS 
Subgroup analyses will be conducted as stated in the exploratory analysis sections. It should be 
noted that the study was not designed to detect treatment differences with high statistical power 
within subgroups. 
The following subgroups will be assessed and described within the subgroup analysis sections 
(16.2.4).  A minimum of 8 subjects/arm in each subgroup is needed.  For subgroup with less than 8 
subjects/arm, this subgroup will be pooled with the other ones having less than 8 subjects/arm 
together and the subgroup will be named “other” if there are other subgroups with less than 8 
subjects/arm exist.   
• 
Gender:  
o 
Female 
o 
Male 
• 
Age (years): 
o 
≤ 21  
o 
> 21 to <65  
o 
 ≥65 
• 
Race in 5 categories: 
o 
American Indian or Alaska Native 
o 
Asian 
o 
Black or African American 
o 
Native Hawaiian or Other Pacific Islander 
o 
White 
• 
Ethnicity in 2 categories: 
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o 
Hispanic or Latino 
o 
Not Hispanic or Latino 
o 
Not reported or Unknown 
9. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the 
format and content of the summary tables, figures and listings to be provided by IQVIA Biostatistics. 
10. 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 week 18 or discontinued early 
as well as completed the trial will be summarized for each treatment group.  Reason for 
discontinuation during week 18 will be summarized.  The summary of reason for discontinuation from 
the study will also be presented.   
The number and proportion of patients withdrawing the study during the run-in phase will be 
presented.  The number and proportion of patients in each population will also be summarized. 
A listing of patients who fail the inclusion/exclusion criteria will be produced. 
A summary of major protocol deviations will be provided as frequency and percentages.  Protocol 
deviations in the run-in phase will be summarized separately.  A list of all major protocol deviations 
will also be provided. 
11. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the RND and SAF 
populations. 
The continuous demographic/baseline variables will be summarized using the mean, median, 
standard deviation, minimum, and maximum values.  For categorical (nominal) variables, the number 
and percentage of patients will be used. No statistical testing will be carried out for demographic or 
other baseline characteristics.  All demographic and baseline characteristics will be presented in a 
listing. 
The following demographic and other baseline characteristics will be reported for this study: 
• 
Age (years) - calculated relative to date of informed consent 
• 
Gender  
• 
Race  
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• 
Ethnicity 
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2) 
• 
Duration of diabetes (years) 
• 
Time of glargine administration (morning, evening) 
• 
Baseline fasting plasma glucose (mmol/L) 
• 
Baseline HbA1c (%) 
• 
Insulin use prior to screening (yes, no) 
• 
Fasting C-Peptide, HIV, HBsAg and HCVAb (positive, negative) 
11.1. DERIVATIONS 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
• 
Duration of diabetes (years) = ((date of screening – date of onset of diabetes) + 1)/365.25 
12. MEDICAL HISTORY 
Medical History information will be presented for the SAF and coded using Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary version 20.  Coded medical history terms will be 
summarized by System Organ Class (SOC) and Preferred Term (PT), by treatment group.  Multiple 
entries for an individual patient under same SOC/PT will only be counted once. 
13. MEDICATIONS 
Medications will be presented for the SAF and coded using WHO Drug dictionary 01SEP2017. 
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible to 
define a medication as prior or concomitant, the medication will be classified by the worst case; i.e. 
concomitant.  
• 
‘Prior’ medications are medications which started and stopped prior to the reference start date.  
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• 
Insulin use prior first dose are any insulin medication used prior to screening visit. 
• 
‘Concomitant’ medications are medications which:  
o 
started prior to, on or after the randomization date  
o 
AND ended on or after the randomization date of study medication or were ongoing at the end of 
the study. 
Prior and concomitant medication will be summarized by treatment group.  The number of patients 
taking each medication will be presented by Anatomical Therapeutic Chemical (ATC) names (levels 
1, 2, 3).  Each patient taking the same therapy more than once will be counted once within each ATC 
code level.  All prior and concomitant medications will be presented in data listing.  A separate listing 
on prohibited medications will also be provided. 
14. STUDY MEDICATION EXPOSURE 
Exposure to study medication in days will be presented for the SAF. 
The exposure will be summarized for each treatment group using the mean, standard deviation, 
median, minimum and maximum.  Interruptions, compliance, and dose changes are not taken into 
account for duration of exposure. 
14.1. DERIVATIONS 
Duration of exposure days = date of last study medication administration minus the date of reference 
day + 1.  
Where the reference start date is defined in section 6.1 and the date of last study medication will be 
taken from the “End of Treatment” form. 
15. STUDY TREATMENT NON-COMPLIANCE  
Patient will be identified as study treatment non-compliant if the patient meets any following criteria: 
• 
Missing total meal time insulin daily since last visit 
• 
Missing basal insulin daily since last visit 
• 
Took two times more basal insulin daily since last visit 
• 
Took less or more than prescribed basal insulin dose units daily since last visit 
Number and proportion of patients with non-compliance will be summarized along with individual 
categories of non-compliance for each category. 
The non compliance proportion is defined as total accumulative non-compliant days/duration of 
treatment exposure in days. Summary of non-compliance proportion will be performed by each non-
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compliance category for each treatment group. The treatment groups will be compared by using an 
ANOVA model which will include treatment and pooled-site. 
16. EFFICACY OUTCOMES  
16.1. PRIMARY EFFICACY 
16.1.1. 
PRIMARY EFFICACY VARIABLE 
The primary efficacy variable is change in HbA1c from baseline to week 18 for the ITT population. 
The HbA1c is analyzed by central laboratory Q2Solutions. 
16.1.2. 
MISSING DATA METHOD AND DATA OBSERVED UNDER RESCUE MEDICATION FOR PRIMARY EFFICACY 
VARIABLE 
After having mapped data captured at unscheduled and/or early termination visits (if any) to schedule 
missing visits using visit windows technique (refer to section 7.4), MI will be used for the primary 
efficacy analysis.  Refer to section 16.1.3 for more details. 
If subjects initiate rescue medication after Week 12, HbA1c value at Week 18  or subjects who switch 
to their own insulin Lantus, will be considered as missing and imputed as described above i.e., first 
remapped data collected at unscheduled/early termination visits (if any) to Week 18 and then, use 
MI to impute remaining Week 18 data. 
16.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
Descriptive statistics will be tabulated by treatment and by time point of the actual HbA1c value and 
the changes from baseline. 
The primary objective of this study is to test the hypothesis that MYL-1501D product from Process 
VI is non-inferior to MYL-1501D product from Process V based on change in HbA1c from baseline 
to week 18. 
The primary efficacy analysis will be performed for the ITT analysis set.  
Mean changes from baseline in HbA1c will be analyzed based on all observed data of schedule 
visits as well as data imputed using the unscheduled/early termination data (if collected) or MI 
methodology for schedule visits at which no value is captured (refer to section 16.1.2). 
MI will be performed under the assumption of missing-at-random (MAR) and will be implemented in 
two steps. 
First, partial imputation assuming MAR will be carried out to impute intermittent (non-monotone) 
missing data based on multivariate joint Gaussian imputation model using the Markov chain Monte 
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Carlo (MCMC) method.  A separate model will be used for each treatment group.  The imputation 
model will include the pooled investigator sites and basal insulin dose time (morning vs. evening) as 
fixed covariate and observed HbA1c values at baseline (visit 6), week 12 (visit 12) and week 18 (visit 
14).  The MCMC method in the MI procedure in SAS will be used with multiple chains, 200 burn-in 
iterations, and a non-informative prior.  In case of non-convergence or non-estimability issues, a 
ridge prior and single model will be considered with treatment group added as explanatory variable 
to model. 
Then, the remaining monotone missing data will be imputed using sequential regression multiple 
imputation, where a separate regression model is estimated for imputation of each variable (i.e., 
measurement at each visit) one after the other including the observed values and the values just 
imputed from the previous visit.  Each regression model will include explanatory variables for pooled 
investigational sites, basal insulin dose time (morning vs. evening), treatment group and all previous 
(baseline (visit 6), week 12 (visit 12) and week 18 (visit 14)) values of HbA1c. 
No rounding or range restrictions will be applied. 
Imputed data will consist of 100 imputed datasets.  The random seed number for the partial 
imputation with the MCMC method will be 20171220, and the random seed number for the sequential 
regression MI will be 171016. 
Each of the 100 imputed datasets will be analyzed using the following analysis method. Change from 
baseline in HbA1c to each post-baseline visit will be calculated based on observed and imputed 
data.  Mean changes from baseline in HbA1c values will be analyzed using a mixed model for 
repeated measures (MMRM) approach.  Restricted maximum likelihood (ReML) estimation will be 
used.  The MMRM model will include the changes from baseline in HbA1c values as dependent 
variables, the baseline HbA1c values as fixed covariate, pooled investigational sites, basal insulin 
dose time (morning vs evening), treatment group (MYL 1501D Process V and MYL 1501D Process 
VI), visit (week 12 and week 18), and treatment group by visit interaction as fixed effects, and 
subjects as random effect.  An unstructured covariance structure will be used to model the within-
subject error and the Kenward-Roger approximation will be used to estimate the degrees of freedom.  
If this analysis fails to converge, the following covariance structures will be tested: AR(1), ARH(1), 
CS, CSH, TOEP, TOEPH.  The covariance structure converging to the best fit, as determined by 
Akaike’s information criteria (AIC) will be used as the primary analysis. 
Treatment group comparison at week 18 will be based on the least square mean (LS mean) 
difference between treatment groups (i.e., MYL 1501D Process VI – MYL 1501D Process V) in 
change from baseline in HbA1c estimated by the model in each imputed datasets.  Results from 
analysis of each imputed dataset i.e., LS mean differences and their standard error (SE), will be 
combined using the Rubin’s imputation rules to produced pooled LS mean estimate of treatment 
difference and its 2-sided 95% confidence interval (CI). 
Non-inferiority will be established if the upper limit of the two sided 95%CI for the difference (MYL-
1501D Process VI minus Process V) of mean change from baseline to endpoint for HbA1c is not 
greater than 0.4% at week 18. 
Refer to APPENDIX 3 for SAS code example. 
For graphical display at scheduled visits, the LS Means and 2-sided 95% CI for the changes from 
baseline in HbA1c to week 12 and week 18 obtained from the MMRM model will be presented by 
treatment group.  Similar graphical display will be presented for the mean actual HbA1c values and 
SD over time by treatment group. 
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16.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
• 
Sensitivity to analysis set: the PP population will be used with the same MMRM model described 
above to establish non-inferiority.  For sensitivity analysis, all non-missing HbA1c data will be 
used regardless if subject switched their assigned study medication. 
• 
Sensitivity to missing data assumptions:  
o 
Same analysis approach as the primary analysis, but without imputing missing values.  
This will be analyzed based in ITT. 
o 
In another method, the same analysis approach as the primary analysis will be 
performed, but the imputed values will be corrected such that the full non-inferiority 
margin will be added for imputed values in Process VI group.  This will be analysed based 
on ITT. 
o 
In a third sensitivity analysis, tipping-point analysis will be performed using an algorithm 
proposed by Yan et al (2009) to explore the robustness of the results with regard to a 
bias against the Process VI treatment arm and in favour of the Process V treatment arm.  
In order to quantify the bias (k), scenario 2 of the Yan et al (2009) algorithm will be used.  
Missing Week 18 values will have the value k (positive) added to the Process VI arm 
(worsening results) and subtracted from the Process V arm (improving results).  The 
value for k is determined by adjusting the bias in an MNAR version of starting with a value 
of 0.01 and increasing it until the MNAR version of the MI method described in Appendix 
4 meets or surpasses the non-inferiority margin. That is the upper limit of 95% interval of 
treatment difference is > =0.4 (p-value for test non-interiority is >=0.05). The seed and 
code for this process are detailed in Appendix 4.  The shift parameter as well as summary 
statistics for the MI model with the tipping point adjustment of k will be reported. 
o 
As a final sensitivity analysis, missing data will be imputed by using LOCF.  An ANCOVA 
model will be used on the change from baseline in HbA1c to month 18.  The model will 
include treatment (2 levels: MYL-1501D Process V and MYL-1501D Process VI) as fixed 
effect, the baseline HbA1c as covariate, and patient as random effect.  The pooled sites 
and basal insulin dose time (morning or event) will also be included in the model as fixed 
effects.  This will be analyzed on ITT and PP. 
o 
In addition, the means for each treatment and difference between treatments for missing 
data at Week 18 will be summarized for all sensitivity analyses. 
16.2. SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the ITT population. 
16.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
16.2.1.1. Fasting plasma glucose 
The fasting plasma glucose is collected at baseline, week 2 (visit 8), week 6 (visit 10), week 12 (visit 
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12) and week 18 (visit 14, End of Treatment).  The measurements are performed by the central 
laboratory Q2. 
Actual values and changes from baseline at each time point will be computed and summarized by 
treatment group. 
A separate analysis will be performed excluding patients with no fasting status. 
16.2.1.2. Daily insulin dose per unit body weight (mealtime, basal insulin and total) for days of 8-point 
profiles 
Patients will be asked to document the dose of insulin taken on the same day they will perform the 
8-point SMBG profiles (from week -3 to week 18).  The measurements are taken the week prior to 
the visits, so the week prior to: 
- 
Week -3 (Visit 3) 
- 
Week -2 (Visit 4) 
- 
Week -1 (Visit 5) 
- 
Week 0 (Visit 6) 
- 
Week 6 (Visit 10) 
- 
Week 12 (Visit 12) 
- 
Week 18 (Visit 14) 
Doses will be recorded in the patient’s 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 doses variables: meal time insulin dose, basal insulin and total insulin dose. 
Daily Meal time insulin dose: is the sum of all the total daily meal time insulin (Humalog) dose over 
the double-blind treatment period divided by the number of days measured.  For the computation of 
total daily mealtime doses, only the patients with at least three mealtime doses at a particular day 
are considered.  That is, total daily mealtime dose will not be computed for a day if the mealtime dose 
is recorded less than 3 times for that day. 
Daily Basal insulin dose:  is the average of the insulin dose over days measured during the double-
blind period. 
Daily Total insulin: is the sum of all total daily meal time doses and all basal insulin doses over the 
double-blind treatment period divided by the number of days measured.  Similarly to total daily 
mealtime dose for which less than 3 mealtime doses are recorded, the missing insulin doses will not 
be considered for the average computation.  That is, if either the mealtime doses are recorded less 
than 3 times or the basal insulin dose is missing for a particular day of collection, total insulin dose 
will not be computed.  The total insulin dose will be computed for the remaining days where basal 
insulin dose and at least 3 mealtime doses are collected.  
All doses will be divided by total body weight (kg) to convert to daily insulin dose (U) per unit body 
weight (kg).  If body weight at that visit is missing, the weight from previous visit will be used. 
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16.2.1.3. 8-point Self-Monitored Blood Glucose (SMBG) profile 
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 3 days, 2 should be consecutive).  The patient 
should document the 3 pre-visit measurements in the diary.  
The following summaries will be summarized at week 6, 12, and week 18: 
Individual 8-points SMBG: 
The over 3 day averages will be performed for the measures taken at: 
- 
Before breakfast 
- 
Two hours after breakfast 
- 
Before lunch 
- 
Two hours after lunch 
- 
Before dinner 
- 
Two hours after dinner 
- 
Just before sleep 
- 
At 3:00 AM 
Averages will be performed at each visit. 
 
Excursions and averages in SMBG: 
The following averages will be computed: 
- 
Morning excursion 
- 
Noon excursion 
- 
Evening excursion 
- 
Overall excursion 
- 
Pre-meal average 
- 
Post-meal average 
- 
(4-point average) pre-meal and bedtime average 
- 
Overall average 
The individual excursion values will be obtained by subtracting post-meal values with pre-meal 
values, it will be applicable for morning excursion, noon excursion and evening excursion on the 
respective days.  For the overall excursion at morning, afternoon and evening, the individual 
excursion values obtained on each day will be averaged across the three days. 
To compute the overall excursion, first the average of the morning, noon and evening excursion 
within a day will be computed, then the average will be done across the 3 days. 
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The pre-meal average will be the average of the following timepoints: before breakfast, before lunch, 
before dinner on each day, then the average will be done over the 3 days. 
The post-meal average will be the average of the following timepoints: two hours after breakfast, two 
hours after lunch, two hours after dinner on each day, then the average will be done over the 3 days. 
The pre-meal and bedtime average will be the average of the following timepoints: before breakfast, 
before lunch, before dinner, just before sleep, then the average will be done over the 3 days. 
The overall average will be the average of all the 8 timepoints during a day.  The daily average will 
not be computed for a day if more than 3 timepoints are missing on a particular day.  The overall 
average will be kept missing if the daily average is missing for all three days.  If the average is missing 
for one or two days, the average of the remaining days will be considered for the computation. 
16.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
Imputation will be performed for the SMBG and weight for dose calculation as described in section 
16.2.1. 
16.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
16.2.3.1. Analysis of change from baseline in HbA1c at scheduled visits 
Descriptive statistics will be presented for actual and change from baseline to scheduled visits for 
HbA1c. 
Treatment group comparison will be done using the MMRM model as used for the primary endpoint 
(without imputing the missing values), including treatment, visit, treatment-by-visit interaction, 
pooled-investigator, basal insulin dosing time, as fixed effects, baseline values as covariate and 
subjects as random effect. 
LSMeans for each treatment group, as well as associated SE and 2-sided 95% CI will be provided 
by visit.  Differences in LSMeans will be calculated and associated 2-sided 95% confidence intervals 
and p-values will be provided for each visit.   
16.2.3.2. Analysis of change from baseline in fasting plasma glucose 
Descriptive statistics will be presented for actual and change from baseline to scheduled visits for 
fasting plasma glucose.  A separate analysis will be done with excluding data with non-fasting status. 
Treatment group comparison will be done using the MMRM model as used for the primary endpoint 
(without imputing missing values), including treatment, visit, treatment-by-visit interaction, pooled-
site, basal insulin dosing time, as fixed effects, baseline values as covariate and subjects as random 
effect. 
LSMeans for each treatment group, as well as associated SE and 2-sided 95% CI will be provided 
by visit.  Differences in LSMeans will be calculated and associated 2-sided 95% confidence intervals 
and p-values will be provided for each visit.   
For graphical display at scheduled visits the mean and SD plot will be prepared for the actual plasma 
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glucose measurement by visit and treatment group; LSMeans and 2-sided 95% CI from the same 
MMRM model will similarly be displayed graphically. 
16.2.3.3. Analysis of Change in Daily insulin dose per unit body weight (mealtime, basal insulin and 
total) for days of 8-point profiles.  
Descriptive statistics will be tabulated by treatment and by timepoint.  Change from baseline to post-
baseline timepoints will also be presented for insulin dose including daily basal insulin dose, daily 
meal time insulin dose, and daily total insulin dose. 
These secondary efficacy parameters will be analyzed using the same MMRM model as the primary 
efficacy analysis (without imputing missing values).  Estimates of the means, LSMeans (2-sided 95% 
CIs) as well as treatment difference at each visit will be presented. 
A graphical display at scheduled visits with the mean and SD plot will be prepared for each of these 
secondary efficacy endpoints by visit and treatment group; LSMeans and 2-sided 95% CI from the 
same MMRM model will similarly be displayed graphically. 
16.2.3.4. 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). 
Descriptive statistics will be presented for the actual and change from baseline to scheduled visits 
for SMBG profile. 
Treatment group comparison will be done using the same MMRM model as the primary efficacy 
analysis (without imputing missing values).  Estimates of the means, LSMeans (2-sided 95% CIs) as 
well as treatment difference at each visit will be presented. 
For graphical display at scheduled visits the mean and SD plot will be prepared for the actual Overall 
SMBG average measurement by visit, LSMeans and 95% CI from the same MMRM model will 
similarly be displayed graphically. 
16.2.4. 
SUBGROUP ANALYSIS 
The effect of subgroups mentioned in section 8.6 on the change from baseline HbA1c at week 18 
will be examined by employing a MMRM model.  The subgroups will be included in the model along 
with the treatment group.  Additionally separate subgroup analysis within each subgroup mentioned 
in section 8.6 will be performed same MMRM model for treatment comparison within each subgroups. 
The similar subgroups will also be examined for the immunogenicity parameters for the percent 
binding and the incidence analysis of cross reactive antibody.  Besides examine subgroup by 
treatment interaction for percent binding. Separate analysis for both percent binding and incidence 
will be performed for treatment comparison within each subgroup. 
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16.3. EXPLORATORY PK ANALYSIS 
Exploratory PK analysis will be performed by Mylan PK/DM department. 
Descriptive statistics of PK concentration values will be presented for each scheduled visits by 
treatment group. 
Treatment group comparison will be done using the GLM model on log-transformed PK concentration 
values including treatment, visit, treatment-by-visit interaction, time of administration of glargine 
[morning and evening], all as fixed effects. If treatment-by-visit interaction is not significant, this term 
will be dropped from the model, the reduced model will be performed to produce the final analysis. If 
treatment-by-visit interaction is significant, then this interaction term and visit term will be drop from 
the model and final model will be performed by visit with only treatment and time of administration in 
the model. 
LSMeans for each treatment group and Geometric Mean Ratio between the treatment groups will be 
calculated. 2-sided 90% confidence intervals for the log transformed treatment difference and p-
values will be provided. 
The PK data will not be available at the time of database lock for the analysis.  However the treatment 
will remain blinded during the laboratory assay.  These data will be locked later and statistical analysis 
will be performed according to pre-specified method in this SAP 
17. QUALITY OF LIFE ANALYSIS  
Not applicable. 
18. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the Safety Analysis Set. Percentages will be 
computed on the total number of subjects in each treatment group. 
18.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, Version 20.1. 
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. 
Pre-existing diseases or conditions (reported at time of screening in medical history) will not be 
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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 treatment emergent (TEAE) if the first onset (or worsening in the case of 
pre-existing disease) is after randomization through follow-up visit or 14 days after last dose [for 
patients that do not have a follow-up visit]. 
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 within each of the categories described in the sub-sections 
below, will be provided as specified in the templates. 
Treatment group comparison will be performed using Fisher’s exact test.  P-value for the 
corresponding two-sided test will be presented. 
Listings will include TEAEs and Non-TEAEs. 
18.1.1. 
ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and 
also broken down further by maximum severity and relationship to study medication.  The number of 
events will also be presented. 
18.1.1.1. Severity 
Severity is classed as mild/ moderate/ severe/ life-threatening/ death (increasing severity). TEAEs 
starting on or after the first dose of study medication with a missing severity will be classified as 
severe. If a patient reports a TEAE more than once within that SOC/ PT, the AE with the worst case 
severity will be used in the corresponding severity summaries. 
18.1.1.2. Adverse Drug Reaction (Relationship to Study Medication) 
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 study medication will be used in the corresponding relationship summaries. 
Frequency and percentage of patients having adverse drug reaction will be presented by treatment, 
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SOC and PT. 
18.1.2. 
TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
TEAEs leading to permanent discontinuation of study medication will be identified by using the 
Treatment withdrawn field in the CRF under “Action taken with study medication”.  
For TEAEs leading to discontinuation of study medication, summaries of incidence rates (frequencies 
and percentages) by SOC and PT will be prepared. 
18.1.3. 
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. 
18.1.4. 
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. 
18.1.5. 
LOCAL OR SYSTEMIC ALLERGIC REACTION 
The local and systemic allergic reactions are recorded on the adverse events page of the eCRF. 
TEAE incidence of both local and systemic allergic reaction will be summarized by SOC and 
treatment group.  A separate listing will also be produced which include only events of local or 
systemic allergic reaction. 
18.1.6. 
DEVICE-RELATED ASSESSMENT 
The relationship to the insulin glargine pen/needle and to the Humalog pen/needle are recorded on 
the adverse events page of the eCRF. 
TEAE incidence will be summarized by SOC and treatment group for the insulin glargine pen/needle 
relationship and for the humalog pen/needle relationship and for both. 
The incidence of device problems (even if not leading to an AE) will be summarized for each 
treatment group. 
18.1.7. 
NON TEAES 
The non-TEAEs, the events occurred during the run-in phase before randomization, will be 
summarized separately.  The frequency and percentage of patients experiencing non-TEAEs, 
serious non-TEAE, withdrawing during the run-in phase due to non-TEAE during run-in phase, 
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Deaths before the active treatment start will be summarized.  All enrolled patients who enter into the 
run-in period will be considered for this summary. 
18.2. LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for Hematology, 
Blood Chemistry and Urinalysis.  A list of laboratory assessments to be included in the outputs is 
included in the protocol section 6.5.2.3.  
Presentations will use SI Units as provided by the central laboratory Q2. 
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. 
The following summaries will be provided for laboratory data: 
• 
Actual and change from baseline by visit (for quantitative measurements).  Descriptive summaries will be 
presented for the actual and the changes from baseline at each visit.  Changes from baseline will be 
analyzed using the same MMRM model then the primary efficacy variable, but without any imputation.  
LSMeans for each treatment group and associated SE/2-sided 95% CI will be presented.  Differences in 
LSMeans will also be calculated with the SE, 2-sided 95% CI and p-value.   
• 
Incidence of markedly abnormal laboratory criteria.  The number of patients and percentages will be 
provided for each treatment group at each visit for each markedly abnormal criteria. 
• 
Shift from baseline according to normal range criteria (for quantitative measurements and categorical 
measurements) 
18.2.1. 
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. 
The markedly abnormal criteria are defined in the table below: 
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Laboratory Category 
Parameter (unit) 
Markedly Abnormal Low 
Markedly Abnormal High 
Hematology 
WBC(X10E3 cells/µl) 
<2.0 
>20.0 
 
Neutrophil count (X10E3 
cells/µl) 
<1.0 
NA 
 
Hemoglobin (g/dL) 
<8.0 
>20 
 
Platelets(cells/µl) 
<50 
>999 
Biochemistry 
ALT 
NA 
>3XULN 
 
AST 
NA 
>3XULN 
 
ALK phosphatase 
 NA 
>3XULN 
 
Total Bilirubin 
NA 
>2XULN 
 
LDH (IU/L) 
NA 
>800 
 
Glucose (mg/dL) 
<55 
>270 
 
Creatinine  
NA 
>1.5XULN 
 
BUN (mg/dL) 
NA 
>60 
 
CPK(U/L) 
NA 
>850 
 
Sodium (mEq/L) 
<130 
>155 
 
Potassium(mEq/L) 
<3.0 
>6.0 
 
Total Protein(g/dL) 
NA 
>9.5 
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Laboratory Category 
Parameter (unit) 
Markedly Abnormal Low 
Markedly Abnormal High 
 
Albumin(g/dL) 
<2.0 
NA 
 
Calcium (mg/dL) 
<7.0 
>12.5 
 
Lipase(U/L) 
NA 
>180 
Lipids 
Triglycerides (mg/dL) 
<10 
>900 
 
Total Cholesterol (mg/dL) 
<20 
>400 
 
LDL Cholesterol (mg/dL) 
<20 
>350 
 
HDL Cholesterol (mg/dL) 
<20 
NA 
18.3. ECG EVALUATIONS 
Results from the central ECG (Electrocardiogram) Reading Centre will be included in the reporting 
of this study.  
Frequency and percentage of overall assessment of ECG (investigator’s judgment) will be presented 
i.e. the percentage of patients in categories such as normal, abnormal/not clinically significant and 
abnormal/clinically significant will be summarized.  A Fisher’s exact test will be performed between 
the treatment groups. 
18.4. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
• 
Sitting Systolic Blood Pressure (mmHg) 
• 
Sitting Diastolic Blood Pressure (mmHg) 
• 
Pulse Rate (bpm) 
• 
Respiratory Rate (breaths/min) 
• 
Temperature (⁰C) 
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• 
Weight (kg) 
The following summaries will be provided for vital signs data: 
• 
Actual and change from baseline by visit.  Descriptive summaries will be presented for the actual and the 
changes from baseline at each visit.  Changes from baseline will be analyzed using the same MMRM model 
than the primary efficacy variable, but without any imputation.  LSMeans for each treatment group and 
associated SE/2-sided 95% CI will be derived.  Differences in LSMeans will be calculated with the SE, 95% CI 
and p-value. 
• 
Incidence of potentially clinically significant vital signs.  The number of patients and percentages will be 
provided for each treatment group at each visit and overall visit (patient will be counted as clinically 
significant if at least one clinically significant occurred in all the visits.  Fisher exact test will be performed 
between the treatment groups. 
• 
Listing of patients meeting markedly abnormal criteria  
18.4.1. 
POTENTIAL CLINICALLY SIGNIFICANT CHANGES 
Potential clinically significant Vital Signs measurements will be identified in accordance with the 
following predefined markedly abnormal criteria: 
Variable 
Unit 
Low 
High 
SBP 
mm
Hg 
≤ 90 mmHg AND  
change 
from 
baseline 
≤ -20 mmHg 
≥ 180 mmHg AND 
change 
from 
baseline 
≥ 20 mmHg 
DBP 
mm
Hg 
≤ 50 mmHg AND 
change from ≤ -15 mmHg 
≥ 105 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 
Body 
tempera
ture 
˚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 % 
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18.5. PHYSICAL EXAMINATION  
Physical examination will not be recorded in the CRF, any findings will appear in medical history or 
adverse events.  The date of physical examination will be listed in a listing.  
18.6. OTHER SAFETY ASSESSMENTS 
18.6.1. 
IMMUNOGENICITY PROFILES ANALYSES 
The following parameter will be summarized for immunogenicity: 
1) Total Insulin Antibodies 
o 
Percent Binding (% B/T) 
o 
Positive/Negative 
2) Cross Reactive Insulin Antibodies 
o 
Percent Binding (% B/T) 
o 
Positive/Negative 
3) Insulin (Drug), Specific Antibodies 
o 
Percent Binding (% B/T) 
Descriptive statistics will be tabulated by treatment and by timepoint for the continuous variables.  
Change from baseline to post-baseline timepoints will also be presented.  The same MMRM model 
as the primary efficacy analysis (without imputing missing data  and excluding the basal insulin 
dosing time)) will be used.  Estimates of the means, LSMeans (SE and 2-sided 95% CIs) as well as 
treatment difference at each visit will be presented.  Analyses will be done on the Safety Population. 
The dichotomous outcomes will be summarized with frequency and percentage at scheduled visits. 
Treatment comparison will be performed using Fisher’s exact test.  P-value for the two-sided test will 
be presented.   
Potential immunogenicity effect on local and systematic allergic reaction, hypersensitivity, and severe 
hypoglycaemia will be explored by summarizing those incidences between the treatment groups 
among subjects with post-baseline positive response of cross reactive antibodies.   The local and 
system allergic reactions as well as the hypoglycaemia are found directly on the CRF, the 
hypersensitivity events will be found in the coded adverse events with the following specifications: 
- 
System Organ Class (SOC):  Immune system disorders 
- 
High Level Group Term (HLGT): Allergic conditions 
- 
High Level Term (HLT): Allergies to foods, food additives, drugs and other 
- 
Preferred Term (PT): Drug hypersensitivity 
- 
Lower level term (LLT): Drug hypersensitivity 
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The possible insulin neutralization effect will also be explored by presenting:  
- 
The incidence of patients with increase over 10% in cross reacting antibody from baseline at 
any visit 
- 
The incidence of patients with increases of HbA1c over 0.2% increase from baseline at any visit 
- 
The incidence of patients with increase in total or basal insulin dose at any visit.  
Treatment group comparisons will be performed by using a Chi-Square test, if 80% of the cells have 
an expected frequency >=5 otherwise Fisher’s exact test will be used. 
The immunogenicity and PK data will not be available at the time of database lock for the analysis.  
However the treatment will remain blinded during the laboratory assay.  These data will be locked 
later and statistical analysis will be performed according to pre-specified method in this SAP. 
18.6.2. 
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, 
nocturnal hypoglycemia. Patients will be instructed to record all hypoglycemic events in the patient’s 
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. 
The classification will be derived as follows: 
- 
Severe: the patients entered in the eCRF: “severe (external assistance required to resolve 
event)” 
- 
Documented Symptomatic Hypoglycemia: the patient entered in the eCRF: symptomatic and 
checked the “glucose value was less than or equal to 70 mg/dL”. 
- 
Asymptomatic Hypoglycemia: the patient entered in the eCRF: asymptomatic (symptoms of 
hypoglycemia not present) and checked the “glucose value was less than or equal to 70 mg/dL”. 
- 
Probable Symptomatic Hypoglycemia: the patient entered in the eCRF: symptomatic and 
checked the “glucose was not measured”. 
- 
Relative Hypoglycemia: the patient entered in the eCRF: asymptomatic or symptomatic and 
checked the “glucose value was over 70 mg/dL”. 
- 
Nocturnal Hypoglycemia: the patient has any of the 5 types above and also checked the 
“Nocturnal” time of the event. 
Hypoglycemia event 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.  The baseline hypoglycemia period is defined from the run-in period until randomization 
day.  This rate will also be calculated per patient for nocturnal hypoglycemia episodes. 
Hypoglycemia event rate per patient per 30 days will be analyzed using the same MMRM model as 
for the primary efficacy parameter (without imputing any missing data). 
For change from baseline of hypoglycemia rate, a graphical display at scheduled visits, of LSMeans 
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and 2-sided 95% CI will be generated from the MMRM model.  Additionally, mean (+/- SD) for actual 
measurements by visit will also be presented. 
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. 
19. STUDY DATA TECHNICAL CONFORMANCE 
The data will be submitted using the Clinical Data Interchange Standards Consortium (CDISC).  The 
Study Data Tabulation Model (SDTM) data will use version 1.4 (SDTMIG).  The derived datasets will 
follow the Analysis Data Model (ADAM) and will use version 1.1 (ADAMIG). 
20. DATA NOT SUMMARIZED OR PRESENTED 
Not applicable. 
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21. REFERENCES  
Yan, X., Lee, S., and Li, N. (2009), “Missing Data Handling Methods in Medical Device Clinical Trials,” Journal of 
Biopharmaceutical Statistics, 19, 1085–1098. [392] 
 
 
 
 
 
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APPENDIX 1. REPORTING CONVENTIONS 
Page Layout: 
The Section 14 tables and Appendix 16 listings should be in landscape orientation by default. 
The output in Section 14 and Appendix 16 will be in RTF file formal using Courier New font with 8 
point size. 
 
Statistical conventions: 
The patient percentages (%) should be rounded to a whole number, with SAS rounding options used 
to obtain the values. 
Percentages for values in the tables that are less than <1 should be presented as “<1”. 
If “%” is part of the column heading, do not repeat the “%” sign in the body of the table. 
If a value is zero (0), then do not use 0% and leave the corresponding percentage blank. 
The format for range should always be “Min, Max”. 
If there are missing data, then a missing row will be added to keep track of all patients.  If there are 
no missing data, then delete the missing row.  Percentages will not be presented on the missing 
category row. 
Standard Deviation should be abbreviated as “SD”, and Standard Error should be abbreviated as 
“SE”; it is presented within parenthesis next to the mean value, without any +/- sign.  The Standard 
Deviation or Standard Error should have one additional decimal point beyond that of the mean (for 
example, if the mean has one decimal point, SD/SE should have two decimal points).  Mean and 
median should have one additional decimal point beyond that of the data being summarized. 
“N” will represent the entire treatment group, while “n” will represent a subset of the treatment group.  
For tables with population designated as a row heading, “N” should be used (i.e. tables where all the 
participant data is not available for every variable within a treatment group).  As a guideline, if the 
number is used in denominator that it should be presented as “N”.  If the number is used in numerator 
it should be presented as “n”. 
P-values will be presented with 4 decimals. 
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APPENDIX 2. 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 
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START DATE 
STOP 
DATE 
ACTION 
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 
 
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 
Mylan 
MYL-1501D-3004
Final 
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Analysis Plan Template 
Mylan GmbH  
PROTOCOL MYL-1501D-3004 
Page 45 of 49 
 
Document: 
\sasdata\Mylan\Insulin_glargine\SYA22825\Biostatistics\Documentation\SAP\\MYL-1501D-
3004_SAP_Final_2_0 clean.doc 
Author: 
Irene Dehem 
Version Number: 
2.0 
 
 
Version Date: 
18OCT2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
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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Final 
08 January 2019
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Analysis Plan Template 
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PROTOCOL MYL-1501D-3004 
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Document: 
\sasdata\Mylan\Insulin_glargine\SYA22825\Biostatistics\Documentation\SAP\\MYL-1501D-
3004_SAP_Final_2_0 clean.doc 
Author: 
Irene Dehem 
Version Number: 
2.0 
 
 
Version Date: 
18OCT2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
APPENDIX 3. SAS CODE EXAMPLE FOR MULTIPLE IMPUTATION 
/* First, generate enough data to produce a monotone missing data pattern */ 
/* MCMC does not work with class statement. Pooled investigator sites and */ 
/* baseline insulin dose time have been converted to indicator variables  */ 
/* For pooled investigator sites (sitegr1n),                              */ 
/* let say that x is the total number of                                  */ 
/* pooled investigator sites.  Then, for pooled investigator sites #1,    */ 
/* inv01=1, inv02=0, …, inv0[x-1]=0                                       */ 
/* For pooled investigator sites #2, inv01=0, inv02=1, …, inv0[x-1]=0     */ 
/* For pooled investigator sites #[x-1], inv01=0, inv02=0, …, inv0[x-1]=1 */ 
/* For pooled investigator sites #x, inv01=0, inv02=0, …, inv0[x-1]=0     */ 
/* For baseline insulin dose (strata) time= morning, binstime=1           */ 
/* For baseline insulin dose time= evening, binstime=0                    */ 
/* No rounding or range is applied for any variable                       */ 
/* Non-informative prior is proc mi default MCMC prior information        */ 
/* 200 is proc mi default number of burn-in iterations                    */ 
 
proc mi data = <<insert input dataset name>> out = datamono 
seed =20171220  
NIMPUTE=100; 
by trtpn; 
var inv01 inv02 … inv0[x-1] binstime HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
mcmc impute = monotone chain= multiple; 
run; 
 
 
/* Then, do full imputation based on sequential regression models          */ 
/* assuming monotone missing pattern.                                      */ 
proc mi data = datamono seed = 171016 out = datami NIMPUTE = 1; 
by _imputation_; 
class trtp strata sitegr1; 
var trtp strata sitegr1 HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
monotone regression; 
run; 
 
 
/* Compute Changes from Baseline and create one categorical variables for  */ 
/* the pooled investigational sites based on the [x-1] indicator pooled    */ 
/* investigational site variables                                          */ 
data datmichg; 
set datami (in=a drop = HbA1c_WK18 rename = (HbAc1_WK12 = result)) 
    datami (in=b drop = HbA1c_WK12 rename = (HbAc1_WK18 = result)); 
 
* Visit; 
if a then visit = “Week 12”; 
else if b then visit = “Week 18”; 
 
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Author: 
Irene Dehem 
Version Number: 
2.0 
 
 
Version Date: 
18OCT2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
* Change from baseline; 
change = result – HbA1c_BASE; 
 
run; 
 
/* MMRM Analysis by _imputation_ */ 
 
proc sort data=datmichg; 
by _imputation_; 
run; 
 
proc mixed data = datmichg method = REML order=internal; 
by _imputation_; 
class trtp(ref=”Process V”) strata sitegr1 avisit usubjid; 
model change = HbA1c_BASE trtp strata avisit sitegr1 trtp*avisit / DDFM = 
KR; 
repeated avisit / type = UN subject = usubjid; 
lsmeans trtp*avisit /diff cl;  
ods output diff = lsdiffs(where=(trt= ‘Process IV’ and _trt=’Process V’ and 
visit=_visit)); 
run; 
 
/* Combine LSmean Differences for Visit ‘Week 12’ */ 
proc mianalyze parms(classvar = full) = lsdiffs (where = (visit = ‘Week 12’)); 
class trtp*avisit; 
modeleffects trtp*pvisit; 
run; 
 
/* Combine LSmean Differences for Visit ‘Week 18’ */ 
proc mianalyze parms(classvar = full) = lsdiffs (where = (visit = ‘Week 18’)); 
class trtp*avisit; 
modeleffects trtp*avisit; 
run; 
 
Note to programmers: In case of non-convergence or non-estimability issues for the generation of 
enough data to produce a monotone missing data pattern, replace the two proc mi by the following: 
 
proc mi data = impute3 out = datamono seed =20171220 NIMPUTE=100 
  round = 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1   
  min   = 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 
  max   = 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1; 
  var trtpn  binstime inv01 inv02 inv03 inv04 inv05 inv06 inv07 inv08 inv09 
inv10 inv11 inv12 inv13 HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
  mcmc impute = monotone chain= multiple /*prior=ridge=p*/; 
run; 
 
 
 
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08 January 2019
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Analysis Plan Template 
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PROTOCOL MYL-1501D-3004 
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Document: 
\sasdata\Mylan\Insulin_glargine\SYA22825\Biostatistics\Documentation\SAP\\MYL-1501D-
3004_SAP_Final_2_0 clean.doc 
Author: 
Irene Dehem 
Version Number: 
2.0 
 
 
Version Date: 
18OCT2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
proc mi data = datamono seed = 171016 out = datami NIMPUTE = 1; 
  by _imputation_; 
  class trtp strata sitegr1; 
  var trtp strata sitegr1 HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
  monotone regression; 
run; 
 
 
APPENDIX 4. SAS CODE EXAMPLE FOR TIPPING POINT 
/*An MNAR version of the MI procedure from Appendix 3 will be used. 
  The SHIFT value will start at 0.01 and be incremented until the critical 
value for non-inferiority of 0.4 is surpassed.  In particular, the upper limit 
of the 95% confidence interval of the treatment difference will be calculated 
for each iteration of the 0.01 increase to the MNAR adjustment and once it 
surpasses 0.4, we take that MNAR adjustment value as k.    */ 
 
 
/* The first part gives a monotone patern to the data                    */ 
/* It imputes the holes in the data but leave empty the missings at the  */ 
/* end for discontinued patients                                         */ 
 
Proc mi data= <<insert input dataset name>> out=datamono  
        seed=20171220 
        NIMPUTE=100; 
    by trtp; 
    var inv01 inv02 … inv13 binstime HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
    mcmc impute = monotone chain= multiple; 
run; 
 
/* This part gives the imputation at the end of data                 */ 
/* Experimental treatment is trtpn=2, control treatment is trtpn=1   */ 
/* The shifts are done on AVAL not the CHG therefore we substract    */ 
/* a positive shift to the control making it harder to obtain        */ 
/* non-inferiority and at the same time add a positive shift to the  */ 
/* experimental treatment                                            */ 
 
 
proc sort data=datamono; 
  by _imputation_; 
run; 
 
 
 
 
 
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Analysis Plan Template 
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PROTOCOL MYL-1501D-3004 
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Document: 
\sasdata\Mylan\Insulin_glargine\SYA22825\Biostatistics\Documentation\SAP\\MYL-1501D-
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Author: 
Irene Dehem 
Version Number: 
2.0 
 
 
Version Date: 
18OCT2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
proc mi data = datamono out = datamono2 
seed =20171220  
NIMPUTE=1; 
by _imputation_; 
   class trtpn strata sitegr1; 
   monotone reg; 
    MNAR 
Adjust (<HbA1c_WK18>/SHIFT= +Kprime ADJUSTOBS=(trtpn=’2’)) 
 
 
Adjust (<HbA1c_WK18>/SHIFT= -Kprime  ADJUSTOBS=(trtpn=’1’)); 
 
Var trtpn strata sitegr1 HbA1c_BASE HbA1c_WK12 HbA1c_WK18; 
; 
run; 
 
 
Where Kprime is the shift value starting at 0.01 and ending at k. 
 
 
proc mixed data= <<dataset>> method=REML order=internal; 
   by shift_imputation_; 
   class trtp(ref=”Process V”) strata sitegr1 avisit usubjid; 
   model change= HbA1c_BASE trtp strata avisit sitegr1 trtp*avisit/DDFM=KR; 
   repeated avisit/type=UN subject=usubjid; 
   lsmeans trtp*avisit/diffcl; 
run; 
Mylan 
MYL-1501D-3004
Final 
08 January 2019
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