Conditions: Diabetes Mellitus, Type 1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 478
Healthy volunteers: no

Brief summary:
The aim of this phase III trial is to demonstrate the equivalence in the safety and efficacy profile between MYL-1601D and NovoLog® in patients with T1DM.

Detailed description:
This is a multicenter, open-label, randomized, parallel-group phase 3 study in subjects with T1DM comparing the safety and efficacy of MYL-1601D with NovoLog®.

After up to 3-week screening period, all subjects will be titrated on NovoLog® during a 4-week run-in period, and will be shifted from their current basal insulin to study insulin Lantus®. After run-in period, subjects will be randomized; one group will receive MYL-1601D, while the other group will receive NovoLog® for 24 weeks. A follow-up visit, via telephone call, will be scheduled 4 weeks after last dose of MYL-1601D.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: MYL-1601D Product intervention 2: FlexPen NovoLog®
Intervention descriptions: intervention 1: (100 U/mL) intervention 2: (100 U/mL)

Protocol document:
Prot_000.pdf: 
MYL-1601D Protocol 14 October 2019 
Confidential 
 
 
 
MYL-1601D-3001 CLINICAL STUDY PROTOCOL 
Protocol Title 
A Randomized, Multicenter, Open-Label, Parallel-Group Clinical Study 
Comparing the Safety and Efficacy of MYL-1601D with NovoLog® in 
Type 1 Diabetes Mellitus Patients 
Product 
MYL-1601D (Mylan’s Insulin Aspart)  
Protocol No. 
MYL-1601D-3001 
Study Type 
Phase 3 
Version 
5.0 
Protocol Date 
14 October 2019 
 
 
IND No.  
133571 
Sponsor 
Mylan GmbH 
Turmstrasse 24, Tower 4 
6312 Steinhausen 
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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DOCUMENT HISTORY 
 
Document 
Version, Date 
Summary of Changes 
Version 5, 14 
October 2019 
• Update immunogenicity assessment section to include the 3-tier 
approach: screening, confirmatory and titer assay in line with FDA 
January 2019 Guidance “Immunogenicity Testing of Therapeutic 
Protein Products — Developing and Validating Assays for Anti-
Drug Antibody Detection”. 
• Updated the statistical sections to include the following: use of tiered 
approach for determination of ADA status, inclusion of method of 
imputation in case of missing data, change in the proposed method 
for tipping point analysis.  
• Clarified the text in Exclusion Criteria#9, to allow the inclusion of 
subjects with confirmed inactive viral state in to the study; Exclusion 
Criteria#14c, to exclude subjects with history of impaired hepatic 
function based on investigator judgement;  
• Updated the secondary safety endpoints, to remove the evaluation of 
change in antibody titer from baseline 
• Editorial administrative changes implemented throughout the 
document 
Version 4, 04 
January 2019 
• Change in the Sponsor Address 
• Inclusion Criteria modified to allow subjects on multiple daily bolus 
injections of Humalog into study, and to exclude consent by legal 
representative  
• Exclusion criteria updated to exclude subjects with history of 
Marijuana use during 1 year prior to screening 
• Section on Patient diary and Glucometer updated to include use of 
diary in place of e-diary and provision of a user manual for the 
glucometer use to educate and train site personnel and study subjects 
• Statistical methods updated to use Wald confidence limit method for 
establishing the confidence interval of the treatment difference in 
TEAR rate and to use pattern mixture model with the complete-case 
missing values (CCMV) method (Little 1993) for imputing the 
missing values. 
• Secondary safety endpoint modified to remove measurement of 
Incidence of TEAR for cross-reactive ADA 
Version 3, 30 
August 2018 
• Updated the primary objective, endpoint, immunogenicity 
assessment and statistical sections to have immunogenicity as 
assessed by treatment emergent antibody response (TEAR) during 
the 24-week treatment period as the basis for demonstrating 
equivalence 
• Added text to suggest that TEAR rate will not be assessed in 
isolation but will be part of totality of evidence including changes in 
HbA1c, FPG, insulin dose, neutralizing antibodies and injection 
• Editorial and Administrative changes implemented throughout the 
document 


 
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Version 2, 16 
July 2018 
• Updated the visit schedule to change the frequency of scheduled 
visits to 4-weekly between Visit 9 and Visit 13 (Treatment Period) 
as per the feedback from the study sites. Previously the frequency of 
visits was 3-weekly. 
• Modified the objectives and endpoints related to Immunogenicity to 
include the Analysis of impact of Anti-Drug Antibody on 
pharmacodynamic parameters such as Fasting Plasma Glucose, 
HbA1c, and insulin dose as suggested by the Agency. Also included 
Neutralizing Antibody analysis. 
• Increased the blood volume drawn, to implement additional 
immunogenicity analysis. 
• Removal of assessment of estimated Glucose Disposal Rate (eGDR) 
as a secondary endpoint and at removal of text related to eGDR all 
the relevant sections of the protocol, as suggested by the Agency. 
• Modified the Statistical section to use the analysis of covariance 
(ANCOVA) model for analysis of study endpoints, as suggested by 
the Agency.  
• Modified statistical sections to include multiple imputations to fill in 
missing values for HbA1c prior to running the ANCOVA model, to 
minimize any bias due to missing data. 
• Editorial Administrative changes implemented throughout the 
document, including clarification on use of e-diary, and medical 
monitoring support with its contact details. 
 
 
 


 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Multicenter, Open-Label, Parallel-Group Clinical Study 
Comparing the Safety and Efficacy of MYL-1601D with NovoLog® in Type 1 
Diabetes Mellitus Patients. 
Background 
and Rationale 
Mylan’s Insulin Aspart, MYL-1601D, injection [rDNA origin] is a rapid-acting 
human insulin analog used to lower blood glucose. MYL-1601D is homologous 
with regular human insulin except for a single substitution of the amino acid 
proline by aspartic acid in position B28, and is produced by recombinant DNA 
technology utilizing Pichia pastoris (yeast). The current marketed US Insulin 
Aspart injection, NovoLog®, is homologous with regular human insulin except 
for a single substitution of the amino acid proline by aspartic acid in position 
B28, and is produced by recombinant DNA technology utilizing Saccharomyces 
cerevisiae (baker's yeast) as the production organism. 
MYL-1601D is being developed as a biosimilar to US-licensed NovoLog® and 
EU-approved NovoRapid®. 
The aim of this trial is to demonstrate the equivalence in the safety and efficacy 
profile between MYL-1601D and NovoLog® in patients with T1DM. The trial 
design is an open-label since the two products have distinct packaging. To avoid 
any bias in the evaluation of the critical endpoints, immunogenicity, 
glycosylated hemoglobin (HbA1c) and Fasting plasma glucose (FPG) will be 
analyzed at a central laboratory in a blinded manner. In addition, study personnel 
(Sponsor and select CRO staff) will be blinded to the randomized assigned 
treatment arms. 
Primary 
Objectives 
To demonstrate that immunogenicity as assessed by treatment emergent 
antibody response (TEAR) rate with MYL-1601D is equivalent to that of 
NovoLog® during 24-week treatment.  
The TEAR rate will not be assessed in isolation but will be part of totality of 
evidence including changes in HbA1c, FPG, insulin dose, neutralizing antibodies 
and injection site reactions to ensure that changes in TEAR rate, if any, are 
clinically meaningful. 
Primary 
endpoints 
The TEAR rate during 24-week treatment period is the primary endpoint for this 
study. TEAR is defined as either one of the following:  
1) subjects who are anti-drug antibody (ADA) negative at baseline and become 
positive at any timepoint post baseline  
2) Subjects who are ADA positive at baseline and demonstrate 4-fold increase in 
titer values at any timepoint post baseline visit.  
Methodology 
and 
treatments 
This is a multicenter, open-label, randomized, parallel-group phase 3 study in 
subjects with T1DM comparing the safety and efficacy of MYL-1601D with 
NovoLog®. 
After up to 3-week screening period, all subjects will be titrated on NovoLog® 
during a 4-week run-in period, and will be shifted from their current basal 
insulin to study insulin Lantus®. After run-in period, subjects will be 
randomized; one group will receive MYL-1601D, while the other group will 
receive NovoLog® for 24 weeks. A follow-up visit, via telephone call, will be 
scheduled 4 weeks after last dose of MYL-1601D. 


 
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The study will be conducted at approximately 200 sites in the United States 
(US).  
Inclusion/ 
exclusion 
criteria 
Inclusion criteria 
1. Written and signed informed consent needs to be provided by subjects 
before starting any protocol-specific procedures.  
2. Male and female subjects between the ages of 18 to 65 years, both ages 
inclusive. 
3. Clinical diagnosis of type 1 diabetes mellitus for at least 6 months prior 
to screening. 
4. Stable dose of once daily basal Lantus® or Toujeo® injection and 
multiple daily bolus NovoLog® or Humalog® injections for at least 3 
months at screening. 
5. Body mass index (BMI) of 18.5 to 35.0 kg/m2 at screening (both values 
inclusive). 
6. Stable weight, with no more than 5 kg gain or loss in the 3 months prior 
to screening (collected by subject interview during medical history). 
7. Glycosylated hemoglobin (HbA1c) 6.5-10.0% at screening. 
8. Hemoglobin ≥ 10.0 g/dL at screening. 
9. Subject has the capability of communicating appropriately with the 
Investigator.  
10. Subject is able and willing to comply with the requirements of the study 
protocol including the 7-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. 
11. 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. 


 
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3. History of use of animal insulin within the last 2 years or use of 
approved or experimental biosimilar product or any experimental insulin 
at any time prior to study entry including MYL-1501D.  
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 (However, Subjects with confirmed inactive viral state 
can be included). 
10. History of drug abuse, marijuana use, or alcohol dependence 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. 


 
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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 hyperthyroidism or hypothyroidism (subjects can 
be included if these conditions are controlled with thyroid 
hormones or anti-thyroid drugs). 
c. History of impaired hepatic function which is seen in the 
screening laboratory test and is judged by the investigator to 
be clinically significant - 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: 
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, 
and have not experienced a major depressive episode 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 total 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 3 months, 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 screening. 


 
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Sample size 
Approximately 500 subjects with type 1 diabetes will participate in this trial. The 
sample size estimation is based on primary objective – “to demonstrate that 
immunogenicity as assessed by TEAR rate with MYL-1601D is equivalent to 
that of NovoLog® during 24-week treatment” as recommended by the FDA.   
The 80% power will be achieved with 250 subjects per treatment arm to 
demonstrate that 90% confidence interval of treatment difference (MYL-1601D 
minus NovoLog®) is within prespecified ± margin (Table 5).  
Statistical 
Methods 
The 90% confidence interval of treatment difference in TEAR rate will be 
established using Wald confidence limit method. TEAR rate with ADA of MYL-
1601D is equivalent to that of NovoLog® during 24-week treatment if 90% 
confidence interval of treatment difference is within pre-specified margin, the 
specific margin will be determined by final reference drug TEAR rate as 
recommended by the agency (Table 5). For secondary continuous variables, a 
mixed model repeated measures (MMRM)-effects model will be performed. 
 
 


 
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TABLE OF CONTENTS 
DOCUMENT HISTORY ........................................................................................................... 3 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
LIST OF COMMONLY USED ABBREVIATIONS .............................................................. 16 
1 
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES ............................. 17 
2 
INTRODUCTION ........................................................................................................... 22 
2.1 
Indication ........................................................................................................................ 22 
2.2 
Background and Rationale .............................................................................................. 22 
2.2.1 
Rationale for Dose Selection ....................................................................................... 24 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 25 
3.1 
Objectives ........................................................................................................................ 25 
3.1.1 
Primary objectives ....................................................................................................... 25 
3.1.2 
Other objectives .......................................................................................................... 25 
3.2 
Endpoints ........................................................................................................................ 25 
3.2.1 
Primary Endpoints ....................................................................................................... 25 
3.2.2 
Secondary Endpoints ................................................................................................... 25 
3.2.2.1 Efficacy................................................................................................................. 26 
3.2.2.2 Safety .................................................................................................................... 26 
4 
STUDY POPULATION .................................................................................................. 27 
4.1 
Study Population ............................................................................................................. 27 
4.2 
Inclusion and Exclusion Criteria ..................................................................................... 27 
4.2.1 
Inclusion Criteria ......................................................................................................... 27 
4.2.2 
Exclusion Criteria........................................................................................................ 28 
4.2.3 
Criteria for Early Termination or Discontinuation...................................................... 30 
4.3 
Contraception .................................................................................................................. 31 
4.3.1 
Females - Non-childbearing Potential ......................................................................... 31 
4.3.2 
Females - Childbearing Potential ................................................................................ 32 
4.4 
Pregnancy Testing ........................................................................................................... 32 
5 
STUDY DRUG ................................................................................................................ 33 
5.1 
Investigational Drug ........................................................................................................ 33 
5.1.1 
Administration of Study Drugs ................................................................................... 33 


 
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5.2 
Study Medication/Device Complaints ............................................................................ 34 
5.3 
Storage, Disposition of Unused Study Drug and Drug Accountability .......................... 34 
5.4 
Randomization ................................................................................................................ 35 
5.5 
Breaking the Blind .......................................................................................................... 35 
5.6 
Concomitant Medications ............................................................................................... 35 
5.7 
Rescue Criterion .............................................................................................................. 36 
6 
STUDY CONDUCT ........................................................................................................ 37 
6.1 
Screening Procedures ...................................................................................................... 37 
6.1.1 
Screening (Visit 1 [Week -7 to Week -4]) .................................................................. 38 
6.2 
Run-in Period .................................................................................................................. 39 
6.2.1 
Visit 2 (Week -4) ......................................................................................................... 39 
6.2.2 
Visit 3 (Week -3), Visit 5 (Week -1)........................................................................... 39 
6.2.3 
Visit 4 (Week -2) ......................................................................................................... 39 
6.3 
Treatment Phase .............................................................................................................. 40 
6.3.1 
Visit 6 (Week 0) .......................................................................................................... 40 
6.3.2 
Visit 7 (Week 1), Visit 14 (Week 22) ......................................................................... 41 
6.3.3 
Visit 8 (Week 2), Visit 9 (Week 4), Visit 10 (Week 8), Visit 11 (Week 12), Visit 12 
(Week 16), Visit 13 (Week 20) ............................................................................................... 41 
6.3.4 
Visit 15/Early Termination from Treatment/Study Termination/ End of Treatment 
(EOT, Week 24) ...................................................................................................................... 42 
6.3.5 
Early Termination ....................................................................................................... 43 
6.4 
Visit 16 Follow up (Week 28) (telephone call) ............................................................... 43 
6.5 
Treatment Procedures ..................................................................................................... 44 
6.5.1 
Blood Volume ............................................................................................................. 44 
6.5.2 
Safety Testing Assessments ........................................................................................ 44 
6.5.2.1 Adverse Event Assessment................................................................................... 44 
6.5.2.2 Hypoglycemia ...................................................................................................... 45 
6.5.2.3 Laboratory Safety ................................................................................................. 47 
6.5.2.4 Immunogenicity Assessment ................................................................................ 48 
6.5.2.5 Blood Pressure and Pulse Rate ............................................................................. 49 
6.5.2.6 12-lead ECG ......................................................................................................... 50 
6.5.2.7 Diary and Glucometer .......................................................................................... 50 


 
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6.5.2.8 General Physical Examination ............................................................................. 50 
7 
STATISTICAL ANALYSIS ............................................................................................ 51 
7.1 
Sample Size Determination ............................................................................................. 51 
7.2 
Primary Endpoints ........................................................................................................... 52 
7.2.1 
Definition of Primary Endpoints ................................................................................. 52 
7.2.2 
Statistical Methodology for Primary Endpoints .......................................................... 52 
7.2.3 
Primary Analysis for Primary Endpoints .................................................................... 53 
7.2.4 
Secondary/Sensitivity Analyses for Primary Endpoints ............................................. 53 
7.2.5 
Missing Data ............................................................................................................... 54 
7.2.6 
Sub-Group Analyses ................................................................................................... 54 
7.3 
Secondary Endpoints ....................................................................................................... 54 
7.4 
Analysis Set Definitions.................................................................................................. 55 
7.5 
Other Safety Analyses ..................................................................................................... 56 
7.5.1 
Vital Signs ................................................................................................................... 56 
7.5.2 
ECG Analyses ............................................................................................................. 56 
7.5.3 
Laboratory Data .......................................................................................................... 56 
8 
ADMINISTRATIVE PROCEDURES ............................................................................ 57 
8.1 
Source Documentation Forms ......................................................................................... 57 
8.2 
Access to Data/Source Documentation ........................................................................... 57 
8.3 
Final Clinical Study Report and Case Report Forms (CRFs) ......................................... 57 
8.4 
Adherence to Protocol ..................................................................................................... 57 
8.5 
Data Handling and Record Retention ............................................................................. 58 
8.6 
Confidentiality ................................................................................................................ 58 
8.7 
Ethics and Regulatory Authorities .................................................................................. 58 
8.7.1 
Institutional Review Board/Ethics Committee............................................................ 58 
8.7.2 
Regulatory Authority .................................................................................................. 59 
8.8 
Informed Consent ............................................................................................................ 59 
8.9 
Disclosure and Publication of Clinical Study Data ......................................................... 59 
8.10 
End of Study.................................................................................................................... 59 
9 
ADVERSE EVENT REPORTING .................................................................................. 60 
9.1 
Adverse events ................................................................................................................ 60 


 
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9.2 
Definitions ....................................................................................................................... 60 
9.2.1 
Adverse Events ........................................................................................................... 60 
9.2.2 
Adverse Drug Reaction ............................................................................................... 60 
9.2.3 
Unexpected Adverse Event/Adverse Drug Reaction .................................................. 61 
9.2.4 
Serious Adverse Events............................................................................................... 61 
9.3 
Management of Adverse Events ..................................................................................... 62 
9.3.1 
Collection .................................................................................................................... 62 
9.3.2 
Evaluation ................................................................................................................... 63 
9.3.2.1 Severity Assessment of Adverse Events .............................................................. 63 
9.3.2.2 Action Taken ........................................................................................................ 63 
9.3.2.3 Outcome at the Time of Last Observation ........................................................... 64 
9.3.2.4 Causality Assessment of Adverse Events ............................................................ 64 
9.3.2.5 Documentation ..................................................................................................... 65 
9.3.2.6 Treatment of Adverse Events ............................................................................... 66 
9.3.2.7 Follow-up ............................................................................................................. 66 
9.3.2.8 Notification ........................................................................................................... 66 
9.3.2.9 Regulatory Reporting ........................................................................................... 67 
9.4 
Special Situations ............................................................................................................ 68 
9.4.1 
Pregnancy .................................................................................................................... 68 
9.4.2 
Overdose, Medication Errors and Other Events ......................................................... 69 
9.5 
Abnormal Test Findings .................................................................................................. 69 
10 REFERENCE LIST ......................................................................................................... 70 


 
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LIST OF TABLES 
 
Table 1: Study Schedule of Activities ............................................................................................. 18 
Table 2: Medication not to be started during the Run-in or Treatment period ............................... 36 
Table 3: Blood Volume ................................................................................................................... 44 
Table 4: Laboratory Safety Tests .................................................................................................... 47 
Table 5: Margins and 95% CIs with different reference TEAR event rates in 500 subjects .......... 51 
Table 6: Clinical Severity of Adverse Events ................................................................................. 63 
Table 7: Action Taken for an Adverse Event.................................................................................. 63 
Table 8: Definition of Suspected Relationship between the Events and Study Medication ........... 65 
 


 
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LIST OF FIGURES 
Figure 1: Study Diagram ................................................................................................................. 17 
 


 
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LIST OF COMMONLY USED ABBREVIATIONS 
ADA 
Anti-Drug Antibody 
 
MedDRA 
Medical dictionary for 
regulatory activities 
ADR 
Adverse drug reaction 
 
mg 
Milligram 
AE 
Adverse event 
 
mL 
Milliliter 
ALT 
Alanine transaminase 
 
MMRM 
Mixed Model Repeated 
Measures 
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 
 
RFT 
Renal Function Test 
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 
FPG 
Fasting Plasma Glucose 
 
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  
 
TEAR 
Treatment Emergent Antibody 
Response 
HCVAb 
Hepatitis C antibodies 
 
TEAE 
Treatment emergent adverse 
event 
HIV 
Human Immunodeficiency 
Virus 
 
U 
Unit 
HR 
Heart Rate 
 
US 
United States 
IB 
Investigator’s Brochure 
 
WoCBP 
Women of Child-Bearing 
Potential 
ICF 
Informed Consent Form 
 
 
 
ICH 
International Council for 
Harmonisation 
 
 
 
IEC 
Independent ethics committee 
 
 
 
IRB 
Institutional Review Board 
 
 
 
IWRS 
Interactive Web Response 
System 
 
 
 
ITT 
Intent to treat 
 
 
 
IU 
International Unit 
 
 
 
kg 
Kilogram 
 
 
 
LFT 
Liver Function Test 
 
 
 
LOCF 
Last Observation Carried 
Forward 
 
 
 


 
Protocol MYL-1601D-3001 
 
 
 
 
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                              
 
Figure 2: Study Diagram 
 
Overall Study Duration- 35 Weeks 
Screening  
Run- in Period 
Treatment Period 
Follow -up 
3 weeks  
4 weeks 
24 weeks 
4 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  
NovoLog® 
V
1 
V
2 
V
3 
V
5 
V 
4 
V
6 
V
1
5 
V
7 
V
8 
V
9 
V 
1
0 
V 
1
3 
V
1
6 
NovoLog® 
MYL-1601D 
V 
1
1 
V 
1
2 
Lantus® 
V
1
4 


 
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Table 1: Study Schedule of Activities 
Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-
up 
Study Visits 1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
 
V15 
(EOT) 9 
V16   
(FU) 
Study Week 
-7 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
8 
12 
16 
20 
   22 
 24 
   28 
Study Days 
-49 to -28 -28±3 -21±3 -14±3 -7±3 0±3 7±3 14±3 28±3 56±7 84±7 112±7 140±7 154±7 
168±7 
196±7 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
History of previous insulin usage 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated Ophthalmoscopy / retinal 
photography (if not done the last 6 
months) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard-of-care specifics 2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Age, Gender, Height, Race 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight and BMI 
10
 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Pregnancy Test 3 
x 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
 
x 
 
Medical History and concomitant illness 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vitals signs measurement (sitting) 
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 
Follow-
up 
Study Visits 1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
 
V15 
(EOT) 9 
V16   
(FU) 
Study Week 
-7 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
8 
12 
16 
20 
   22 
 24 
   28 
Study Days 
-49 to -28 -28±3 -21±3 -14±3 -7±3 0±3 7±3 14±3 28±3 56±7 84±7 112±7 140±7 154±7 
168±7 
196±7 
Physical examination 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
12-lead ECG (supine) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Randomization 
 
 
 
 
 
x 7 
 
 
 
 
 
 
 
 
 
 
Record AEs and SAEs (including local 
and systemic allergic reactions) and 
hypoglycemic events   
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record device complaint  
 
 
x 
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 
 
Rescue criterion evaluation 5 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
Fasting C-peptide, HIV, HBsAg, HCVAb 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sampling for hematology, blood 
chemistry and urinalysis 4 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Fasting lipid profile 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 


 
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Study Periods 
Screening 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-
up 
Study Visits 1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
 
V15 
(EOT) 9 
V16   
(FU) 
Study Week 
-7 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
8 
12 
16 
20 
   22 
 24 
   28 
Study Days 
-49 to -28 -28±3 -21±3 -14±3 -7±3 0±3 7±3 14±3 28±3 56±7 84±7 112±7 140±7 154±7 
168±7 
196±7 
Sampling for immunogenicity 8 
x 
 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Review diary, 7-point SMBG Profile and 
dose collection performed in the week 
before the visit 6 
 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Dose review of MYL-1601D, NovoLog® 
and Lantus® and dose adjust/instruction 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dispense study medication and ancillary 
supplies 
 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
 
 
 
Drug Accountability and Compliance 
 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Dispense subject diary 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
1. Visits 3, 5, 7, 14 and 16 are telephone contacts/visits, in case required an actual site visit is possible (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 childbearing potential will be done during screening and randomization visits (V1 and V6). During subsequent visits urine pregnancy test will be done, any 
positive urine test needs to be confirmed with serum test. At the randomization visit, both urine and serum pregnancy tests will be done; subject can be enrolled only if the urine pregnancy test is 
negative until serum result is provided. 
4. 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 and the Investigator deems it 
clinically significant and requests further evaluation. 
5. Rescue criterion is evaluated on V12/Week 16 based on HbA1c measurement at V11/Week 12. Sites are required to receive the V11/Week 12 results prior to V12/Week 16 subject visit to 
enable Investigator to take decision on future steps.   


 
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6. The 7-point SMBG profile recorded via glucometer and recorded  by the subject in the diary, measurement will be performed by the subject at home on 3 days (of which 2 days are consecutive) 
in the week before the visit.  
7. Prior to randomization, Investigator is required to re-confirm subject eligibility to the study based on the data collected during the screening period, including the labs values recorded during 
screening.  
8. Immunogenicity samples: At Visits 1, 6, 8, 9, 10, 11, 12, 13 and 15. At each visit, five blood samples of 5 mL each (25 ml per visit) will be drawn for ADA and NAb.   
9. V15 is regard as Early Termination from Treatment visit or Study End of Treatment visit. In case the subject discontinues treatment early, the site should explain the importance of data collection 
and make every effort to retain the subject, perform the remaining visits, off study treatment, per the SCHEDULE OF ACTIVITIES, up to the completion of Week 28/Follow-up call. 
10. BMI is calculated at screening visit, randomization visit, week 12 and week 24.  
 
 


 
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2 
INTRODUCTION 
2.1 
Indication 
MYL-1601D is being developed as a follow-on biologic (US terminology) to the US-licensed 
NovoLog®. 
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 (de Graaff LC et al, 2007). 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 and other trials (Reichard P et al, 1993) 
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 (American Diabetes 
Association 2019).  
Different insulin preparations are available for management of bolus insulin requirements, 
including; Apidra® (glulisine), Humalog® (lispro), NovoLog® (aspart). Rapid-acting insulin 
analogs have proven efficacy and offer good glucose control via regimen of 1 to 3 
dose/injections per day. Insulin aspart is a rapid-acting insulin analogue administered once to 
three times a day to cover bolus insulin requirements per day.  
MYL-1601D (Mylan insulin aspart) is a rapid-acting human insulin analog. The primary 
activity of insulin aspart is the regulation of glucose metabolism, it binds to the insulin 
receptors on muscle and fat cells, and it leads to a decrease in blood glucose by facilitating 
the cellular uptake of glucose while simultaneously inhibiting the output of glucose from the 
liver. MYL-1601D is produced by recombinant DNA technology utilizing Pichia pastoris 
(yeast). The primary structure is identical to endogenous insulin, except for replacement of a 
single proline amino acid at position 28 in the C-terminal area of the insulin B-chain with an 
aspartic acid residue. This substitution weakens the natural tendency towards self-association 
between insulin monomers, thereby inhibiting aggregation into hexamers and accelerating 
absorption after sub-cutaneous injection. 
The aim of this trial is to demonstrate the equivalence in the safety and efficacy profile 
between MYL-1601D and NovoLog® in patients with T1DM with primary focus on 
assessment of immunogenicity and its potential clinical impact on safety and efficacy.  
In case of prandial insulins like aspart, PK-PD study using an euglycemic clamp is a very 
sensitive and robust tool to assess potential differences in efficacy between biosimilar 
products versus traditional endpoints like HbA1c. This approach of using PD parameters 


 
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from euglycemic clamp as a key surrogate efficacy measure has been acknowledged by both 
FDA and EMA. In this context, the current study in T1DM patients is primarily aimed at 
addressing residual uncertainty with specific focus on assessment of immunogenicity.   
Systemic assessment of immunogenicity is a relatively new area and limited information and 
approaches are available for analyzing these data. Furthermore, the immunogenicity profile is 
highly dependent on the ADA assay format and thus data from one study cannot be easily 
extrapolated to another study especially with regards to incidence rates. The problem is 
further compounded by the fact that limited data is available from the innovator NovoLog® 
studies.  
Despite these limitations based on feedback from FDA, Mylan is proposing to use differences 
in treatment emergent antibody response (TEAR) rate as the primary endpoint for this study. 
However, given that TEAR rate is not available from innovator clinical studies and that the 
assay formats might be different, formal hypothesis testing to demonstrate that the incidence 
of specific end point falls within a predetermined equivalence margin is going to be 
challenging and a generalized equivalence margin approach suggested by FDA is proposed in 
Table 5.  
Furthermore, as discussed extensively with the agency, the clinical relevance of TEAR rate is 
still not confirmed and although the TEAR rate is the primary statistical endpoint, it will not 
be assessed in isolation but will be part of totality of evidence including changes in HbA1c, 
FPG, insulin dose, neutralizing antibodies and injection site reactions to ensure that changes 
in TEAR rate, if any, are clinically correlated and meaningful. 
The trial design is an open-label since the two products have distinct packaging. To avoid any 
bias in the evaluation of the critical endpoints, immunogenicity, glycosylated hemoglobin 
(HbA1c) and FPG will be analyzed at a central laboratory in a blinded manner. In addition, 
study personnel (Sponsor and CRO) will be blinded to the randomized assigned treatment 
arms, this will be documented to ensure transparency and proper study conduct. 
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 
multiple daily insulin injections bolus NovoLog® or Humalog® and once daily basal Lantus® 
or Toujeo® for at least 3 months prior to screening will be included. 
During the 4-week run-in period with NovoLog® and Lantus®, the dose of insulin will be 
titrated (if required) to ensure diabetes control and patients who are receiving basal insulin 
other than Lantus® will be switched to this basal-bolus combination (Lantus®-NovoLog®). 
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. The run-in 
period also serves as an approach to single transition, wherein all patients entering the run-in 
period will be receiving NovoLog® for 4 weeks and following randomization to the treatment 
period patients will receive either NovoLog® or MYL-1601D allowing for assessment of 
switch from reference, NovoLog®, to the test product, MYL-1601D. A 24-week treatment 
period is an adequate period to detect differences in HbA1c and safety parameters of the 
treatment arms (EMEA 2006). 
Dosing with NovoLog® during run-in period, and MYL-1601D and NovoLog® during 
treatment period will be guided by self-monitored blood glucose (SMBG)-based glucose 


 
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level assessments and by the Sponsor titration dose review team as detailed in the insulin 
monitoring titration plan. 
Rescue criteria based on HbA1c are defined based HbA1c measurement performed on 
V11/week 12, 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, 4 weeks after the end of treatment, will ensure the safety of all subjects 
after they stop the study medication and return to receiving market approved medications at 
the discretion of their physician. 
Complete information for the study medication can be found in MYL-1601D Investigator’s 
Brochure (IB).  
2.2.1 
Rationale for Dose Selection 
Only patients who have been on a stable multiple daily insulin injections dose of NovoLog® 
or Humalog® and once daily basal Lantus® or Toujeo® for at least 3 months prior to screening 
will be included in the study. If required, patient dose should be adjusted during the 4-week 
run-in period to stabilize the patient dose. During the treatment period, dose adjustment 
should be avoided but it is permitted to ensure patient’s stable state and safety.  


 
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3 
OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary objectives 
To demonstrate that immunogenicity as assessed by treatment emergent antibody response 
(TEAR) rate with MYL-1601D is equivalent to that of NovoLog® during 24-week treatment.  
The TEAR rate will not be assessed in isolation but will be part of totality of evidence 
including changes in HbA1c, FPG, insulin dose, neutralizing antibodies and injection site 
reactions to ensure that changes in TEAR rate, if any, are clinically meaningful. 
3.1.2 
Other objectives 
To compare MYL-1601D to NovoLog® administered in combination with Lantus®, with 
respect to: 
• 
Immunogenicity assessments: visits TEAR assessments, incidences of Anti-Drug 
Antibody (ADA), positive insulin cross-reactive ADA, and positive Neutralizing 
Antibody (NAb) 
• 
Analysis of impact of ADA on pharmacodynamic (PD) parameters such as FPG, HbA1c, 
and insulin dose.  
• 
Incidence and rate of hypoglycemic events 
• 
Occurrence of local reactions, systemic reactions and other adverse events 
• 
Safety related to hypersensitivity and immune mediated adverse events (subgroup 
analysis) 
• 
Change in HbA1c from baseline  
• 
Change in fasting plasma glucose (FPG) from baseline 
• 
Change in prandial, basal, and total daily insulin dose per unit body weight (U/kg) from 
baseline 
• 
Change in 7-point SMBG profile from baseline 
• 
Device-related safety assessment 
 
3.2 
Endpoints 
3.2.1 
Primary Endpoints 
The TEAR rate during 24-week treatment period is the primary endpoint for this study.  
TEAR is defined as either one of the following:  
1) Subjects who are ADA negative at baseline and become positive at any timepoint post 
baseline  
2) Subjects who are ADA positive at baseline and demonstrate 4-fold increase in titer 
values at any timepoint post baseline visit.  
3.2.2 
Secondary Endpoints 
The secondary endpoint points are change from baseline to week 24. 


 
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3.2.2.1 Efficacy 
• Change in HbA1c from baseline  
• Change in fasting plasma glucose from baseline 
• Change in prandial, basal and total daily insulin dose per unit body weight 
(U/kg) from baseline 
• Change in 7-point SMBG profile from baseline 
 
3.2.2.2 Safety 
• Incidence of positive antibody response and NAb  
• Impact of ADA on PD parameters, such as FPG, HbA1c, and insulin dose. 
• 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 (includes injection site reaction), systemic 
reactions. 
• Incidence of hypersensitivity and immune mediated adverse events. 
• Incidence of device-related safety assessment. 


 
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4 
STUDY POPULATION 
4.1 
Study Population 
A total of 500 subjects with T1DM are planned to be randomized in this study, to receive 
MYL-1601D or NovoLog® 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 before starting any 
protocol-specific procedures.  
2. Male and female subjects between the ages of 18 to 65 years, both ages inclusive. 
3. Clinical diagnosis of type 1 diabetes mellitus for at least 6 months or more prior to 
screening. 
 
4. Stable dose of once daily basal Lantus® or Toujeo® injection and multiple daily bolus 
NovoLog® or Humalog® injections for at least 3 months at screening. 
5. Body mass index (BMI) of 18.5 to 35.0 kg/m2 at screening (both values inclusive). 
6. Stable weight, with no more than 5 kg gain or loss in the 3 months prior to screening 
(collected by subject interview during medical history). 
7. Glycosylated hemoglobin (HbA1c) 6.5-10.0 % at screening. 
8. Hemoglobin ≥ 10.0 g/dL at screening. 
9. Subject has the capability of communicating appropriately with the Investigator.  
10. Subject is able and willing to comply with the requirements of the study protocol 
including the 7-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. 
11. 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 


 
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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 2 years or use of approved or experimental 
biosimilar product or any experimental insulin at any time prior to study entry including 
MYL-1501D.  
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 (However, Subjects 
with confirmed inactive viral state can be included). 


 
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10. History of drug abuse, marijuana use, or alcohol dependence 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 hyperthyroidism or hypothyroidism (subjects can be included if 
these conditions are controlled with thyroid hormones or anti-thyroid drugs). 
c. History of impaired hepatic function which is seen in the screening laboratory test and is 
judged by the investigator to be clinically significant -  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: 
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. 


 
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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, and  have not experienced a 
major depressive episode 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 total 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 3 
months, 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 Early Termination or Discontinuation  
Subjects can decide to discontinue entirely from the study at any time for any reason, this is 
documented as withdrawal of consent. Subjects can decide to discontinue from the study 
treatment at any time for any reason, but may choose to remain in the study for off-treatment 
study visits. Subjects can also be discontinued from the study or discontinued from the study 
treatment due to Investigator or Sponsor decision as detailed below.  
The Sponsor or their representative must be notified by the Investigator as soon as possible, 
and prior to the early termination visit, on the decision to discontinue the subject from the 
study or from study treatment and provide detailed information on the reason/event.   
In case of discontinuation of the subject from the study, an early termination visit (outlined as 
an End of Treatment visit in the Schedule of Activities) is required immediately and the site 
must complete the End of Study eCRF data. In case of the discontinuation of the subject from 
the study treatment, the subject is required to complete the End of Treatment visit, switch to 
marketed treatment (both basal and bolus treatments) and agree to proceed with the scheduled 
visits/activities.  
The reason for discontinuation should be established based on the following reasons and 
recorded.  


 
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The following are reasons for discontinuation:  
1. Withdrawal of consent. 
2. For female subjects, diagnosis of pregnancy or stated intention to become pregnant. In 
this case subjects should be discontinued from the study (early termination visit is 
done immediately). Effort should be made by the site to obtain consent from the 
pregnant women, so that they are followed until delivery or termination. 
3. At the Investigator’s discretion (following discussion with the Sponsor medical 
monitor), for safety issues such as severe hypoglycemia or hypoglycemic 
unawareness. In this case subjects can be discontinued from the study (early 
termination visit is done immediately) or discontinued from the study treatment and 
continue with the study visits and procedures with marketed treatment (no need to 
perform early termination visit as subject proceed with the scheduled visits). The site 
should request the subject consent to follow-up as per the SCHEDULE OF 
ACTIVITIES until the Week 28 (Follow-up visit). 
4. At the Investigator’s discretion (following discussion with the Sponsor medical 
monitor), in certain situations such as lack of compliance, significant illness, 
hospitalization for surgery, or an SAE. In this case subjects can be discontinued from 
the study (early termination visit is done immediately) or discontinued from the study 
treatment and continue with the study visits and procedures with marketed treatment 
(no need to perform early termination visit as subject proceed with the scheduled 
visits).   
5. Sponsor terminate the study due to safety issues. In this case subjects should be 
discontinued from the study (early termination visit is done immediately).  
Subjects who decide to discontinue from treatment and agree to remain in the study, on 
marketed treatment, are required to adhere to the study protocol, thus perform all activities 
and procedures such as SMBG measurements, completing diary entries, participating in their 
regularly scheduled study visits for completion of all assessments and procedures as outlined 
in the Schedule of Activities until the Week 28 (Follow-up visit).  
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. 
The site should explain the subject the importance of data collection and make every effort to 
consent the subject to continue follow up per the SCHEDULE OF ACTIVITIES until Week 
28 (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: 


 
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• 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 childbearing 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). 
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 urine positive test, serum test will be done to confirm the result, 
following the subject will be withdrawn from the study (or will not enter the study if during 
screening). 


 
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5 
STUDY DRUG 
5.1 
Investigational Drug 
During the Treatment period, subjects will be randomized to receive one of the following; 
MYL-1601D Product (100 U/mL) 
or 
FlexPen® NovoLog® (100 U/mL) US Listed Drug 
Additional treatment drugs provided during the study which are not investigational study 
drugs are detailed below: 
• During the run-in period, all subjects will receive FlexPen® NovoLog® manufactured 
by Novo-Nordisk for the US (US listed drug), 100 U/mL. 
• All subjects will receive Lantus® SoloSTAR® pen (insulin glargine injection, 100 
U/mL), manufactured by Sanofi-Aventis, throughout the study. 
 
Clinical Supplies will provide prepackaged supplies for each subject. A kit will be assigned at 
randomization using the Interactive Web Response System (IWRS). 
All drugs will be packaged and labeled according to US legal requirements. 
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 randomization 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 FlexPen® NovoLog® from Novo-Nordisk 
(US listed drug) 100 U/mL until randomization. In addition, all patients will be shifted from 
their current basal insulin to Lantus® SoloSTAR® at the start of the run-in period, and will 
continue this for the complete study duration. The doses of NovoLog® and Lantus® will be 
titrated (if required) during the run-in period to ensure diabetes control.  
During the Treatment period, all patients will receive one of the following treatments: 


 
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• MYL-1601D or FlexPen® NovoLog® to be taken at meal time. 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. 
• Once daily Lantus® SoloSTAR® (insulin glargine injection, 100 U/mL), manufactured 
by Sanofi-Aventis. 
In the event of any dosing errors, medication error or device complaint, the CRO contact 
person and/or CRO medical monitor and/or Mylan study contact person should be contacted 
and 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 labeled 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 or designee. 
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 
may approve use of standard institution forms. In either case, the forms must identify the 


 
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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 IWRS. A 
manual containing complete instructions for Web access and use will be provided to each site 
prior to study start. The 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 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 
The trial design is open-label since the two products, MYL-1601D and NovoLog®, have 
distinct packaging. To avoid any bias in the evaluation of the critical endpoints, a blinded 
analysis of immunogenicity and other parameters such as HbA1c and FPG is planned. In 
addition, the majority of the study personnel (Sponsor and select CRO staff) will be blinded 
to the randomized assigned treatment arms and this will be documented, listing the Sponsor 
and CRO personnel who are unblinded to ensure transparency and proper study conduct.  
As all Investigators and sites staff are not blinded to treatment, no process required for 
breaking the blind.  
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. 
Medications (except for insulin) 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 (MYL-1601D, NovoLog® and Lantus®), other insulins / other 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 


 
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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. disopyramide 
4. fibrates 
5. fluoxetine 
6. monoamine oxidase inhibitors 
7. propoxyphene 
8. pentoxifylline 
9. somatostatin analogs 
10. bromergocryptine (bromocryptine) 
11. 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). 
15. marijuana 
 
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 4.2.3). 
5.7 
Rescue Criterion 
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”. 
At the week 16 (Visit 12) study visit, if the subject meets the rescue criterion above, the 
Investigator can decide to proceed with one of the following options;  
1) continue the study with no drug change 
2) continue the study and adjust the dose of the study treatment  
3) discontinue from the study treatment and switch to study NovoLog® if the subject is 
assigned to MYL-1601D 
4) discontinue from the study treatment if the subject is already assigned to NovoLog® 
and switch to marketed treatment (both basal and bolus treatments) 
5) early termination from 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 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 visits 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 early termination 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 35 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 -7 to Week -4]) 
Subjects will commence screening procedures within up to 7 weeks prior to randomization, to 
confirm that they meet the selection criteria for the study. If the time between screening 
procedures and the run-in period exceeds 3 weeks, due to unexpected delays, drop out, or any 
other reason, the subject can be rescreened one time based on discussion between the site or 
designee and with Mylan personnel. In case re-screening is agreed, the subject will need to be 
re-consented and assigned a new SID via IWRS. If re-screening occurs, the reason and 
approval needs to be clearly documented within the site file. 
The following will be completed 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. 
• Check eligibility criteria. 
• Record detailed history of all previous insulin use (as far as the patient can remember). 
• 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 American Diabetes 
Association 2019 guidelines, self-management of diabetes and life-style modifications 
with the subject. 
• Record demographic details (age, gender, height, 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).  
• 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 Immunogenicity analysis 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
which occur after time of informed consent signature.  
 
After all assessments have been performed, the Investigator will assess the results for 
compliance with the inclusion and exclusion criteria. Immunogenicity results are not needed 
for eligibility. If all inclusion criteria have been fulfilled and none of the exclusion criteria 
were met, the subject may be enrolled into the run-in phase.  


 
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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 American Diabetes 
Association 2019 guidelines, self-management of diabetes and life-style modifications 
with the subject.  
• Record body weight. 
• 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 urine sample for pregnancy test. 
• Dispense subject diary and glucometer to the subject and provide information 
regarding the diary completion requirements and necessary glucose measurements 
provided, and the use and requirements of the glucometer. 
• Review current dosing of NovoLog® and Lantus® and if necessary provide new 
dosing instructions and document the new dose and reason for change (specifically for 
change from basal Toujeo® to Lantus®). 
• 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 are telephone contacts/visits, in case required an actual site visit is possible. 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 the subject diary and 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 American Diabetes 
Association 2019 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 complaint. 
• Review current dosing of NovoLog® and Lantus® 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 American Diabetes 
Association 2019 guidelines, self-management of diabetes and life-style modifications 
with the subject.  
• Record body weight. 
• 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 complaint. 
• Review the results of 7-point SMBG measurements, performed on 3 days during the 
week prior visit for the last two weeks. 
• Review current dosing of NovoLog® and Lantus® 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 and 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: 
• Re-check and re-confirm the eligibility criteria. 
• Perform randomization. 
• Discuss and check compliance to standard of care specifics as per American Diabetes 
Association 2019 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. 
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic events 
since the previous visit. 
• Record device complaint. 
• 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 


 
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o Immunogenicity analysis (collect blood sample prior to study drug 
administration) 
• Review the results of 7-point SMBG measurements, performed on 3 days during the 
week prior to the visit for the last two weeks. 
• Review current dosing of NovoLog® and Lantus® and only if necessary provide new 
dosing instructions and document the new dose and reason for change. 
• Dispense study medication MYL-1601D or NovoLog® and Lantus®. 
• Perform drug accountability and check for treatment compliance. 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided. 
 
6.3.2 
Visit 7 (Week 1), Visit 14 (Week 22) 
These visits are telephone contacts/visits, in case required an actual site visit is possible. 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 and 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 American Diabetes 
Association 2019 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 complaint. 
• Review current dosing of MYL-1601D or NovoLog® and Lantus® and only if 
necessary provide new dosing instructions and document the new dose and reason for 
change. 
• At Visit 14 (Week 22), remind subject of the date and time for Visit 15 (Week 24) .  
 
6.3.3 
Visit 8 (Week 2), Visit 9 (Week 4), Visit 10 (Week 8), Visit 11 (Week 12), Visit 
12 (Week 16), Visit 13 (Week 20) 
During this visit, the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per American Diabetes 
Association 2019 guidelines, self-management of diabetes and life-style modifications 
with the subject.  
• Record body weight and calculate BMI only at Visit 11 (Week 12). 
• 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 complaint. 
• 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), except for Visit 8. 


 
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o Fasting plasma glucose, except for Visit 8. 
o Immunogenicity analysis (collect blood sample prior to study drug 
administration). 
o HbA1c done only at Visit 11/Week 12. 
• Assess rescue criterion and record decision in case positive at Visit 12/Week 16. 
• Review the 7-point SMBG measurements, performed on 3 days during the week prior 
to the visit. 
• Review current dosing of MYL-1601D or NovoLog® and Lantus® and if necessary 
provide new dosing instructions and document the new dose and reason for change. 
• Review subject diary and provide information regarding the completion requirements 
and necessary glucose measurements provided. 
• Dispense study medication MYL-1601D or NovoLog® and Lantus®, except for Visit 
8. 
• Perform drug accountability and check for treatment compliance. 
• Dispense diary. 
 
6.3.4 
Visit 15/Early Termination from Treatment/Study Termination/ End of 
Treatment (EOT, Week 24) 
During this visit, the following procedures and assessments will be performed: 
• Discuss and check compliance to standard of care specifics as per American Diabetes 
Association 2019 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 complaint. 
• Collect blood and urine samples for the following laboratory assessments: 
o Urine pregnancy test for women of childbearing potential 
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) 
• Review diary, 7-point SMBG measurements, performed on 3 days during the week 
prior to the visit. 
• Review current dosing of MYL-1601D or NovoLog® and Lantus® . 
• Subject should be instructed on the switched to the marketed products; dosing and 
administration instructions.  


 
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• Collect all study materials for last study treatment visit (in case of Early Termination 
from Treatment/End of Treatment). In case subject is discontinued from the study 
treatment but agrees to continue and perform the study visits and procedures the 
materials will be kept until the subject last visit to the site which is visit 15.  
• Perform drug accountability and check for treatment compliance. 
 
6.3.5 
 Early Termination 
Subjects can decide to discontinue entirely from the study at any time for any reason, this is 
documented as withdrawal of consent. Subjects can decide to discontinue from the study 
treatment at any time for any reason, but may choose to remain in the study for off-treatment 
study visits. Subjects can also be discontinued from the study or discontinued from the study 
treatment due to Investigator or Sponsor decision as detailed below.  
The Sponsor or their representative must be notified by the Investigator as soon as possible, 
and prior to the early termination visit, on the decision to discontinue the subject from the 
study or from study treatment and provide detailed information on the reason/event.   
In case of discontinuation of the subject from the study, a study termination visit (outlined as 
an End of Treatment visit in the Schedule of Activities) is required immediately and the site 
must complete the End of Study eCRF data. In case of the discontinuation of the subject from 
the study treatment, the subject is required to complete the End of Treatment visit, switch to 
marketed treatment (both basal and bolus treatments) and agree to proceed with the scheduled 
visits/activities.  
The reason for discontinuation should be established based on the criteria for 
discontinuation/early termination as stated in Section 4.2.3. 
Subjects who decide to discontinue from treatment and agree to remain in the study, on 
marketed treatment, are required to adhere to the study protocol, thus perform all activities 
and procedures such as SMBG measurements, completing diary entries, participating in their 
regularly scheduled study visits for completion of all assessments and procedures as outlined 
in the Schedule of Activities until the Week 28 (Follow-up visit).  
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. 
The site should explain the subject the importance of data collection and make every effort to 
consent the subject to continue follow up per the SCHEDULE OF ACTIVITIES until 
Week 28 (Follow-up visit). 
6.4 
Visit 16 Follow up (Week 28) (telephone call) 
• Discuss and check compliance to standard of care specifics as per American Diabetes 
Association 2019 guidelines, self-management of diabetes and life-style modifications 
with the subject.  
• Record AEs, SAEs, local and systemic allergic reactions and hypoglycemic episodes  
• Record concomitant medications since previous visit 
 


 
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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 375 mL. 
Table 3: Blood Volume 
Sample Type 
Sample Volume (mL) 
Number of Sampling 
Times 
Total 
Volume 
(mL) 
Screening 
Study 
Period 
Safety Labs 
30 
1 
2 
90 
FPG, HbA1c 
5 
2 
10 
60 
Anti-drug antibody (ADA) 1 
10 
1 
8 
90 
Neutralizing antibody (NAb) 2 
5 
1 
8 
45 
Supplemental Immunogenicity3 
10 
1 
8 
90 
TOTAL 
 
 
 
375 
1 Blood samples (2 x 5 mL) will be drawn into serum separator tubes (SST). 
2 Blood samples (1 x 5 mL) will be drawn into serum separator tubes (SST). 
3 Blood samples (2 x 5 mL) 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 


 
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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 
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,  
• 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.  


 
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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 fulfills ICH criteria 
for seriousness (life-threatening, hospitalization etc.) or represent important medical events 
based on Investigator’s judgment should also be reported to the 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, 
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 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.  


 
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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 in the diary and reported 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 Section 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/culture0 
Urine/Serum 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 the 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 the central laboratory. 


 
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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. 
Per schedule of activities in Table 1 and Section 6, study conduct, samples are taken under 
fasting conditions, as described in the laboratory manual. Patients are required to adhere to 
those requirements/instruction.   
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 (5 mL each) will be taken into serum separator tubes at each time point as 
outlined in Table 3. At Visits 1, 6, 8, 9, 10, 11, 12, 13 and 15, five (5) blood samples of 5 mL 
each (25 mL total volume) will be drawn. The blood samples will be taken pre-dose 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 ADA against insulin aspart using the 
approach outlined below. One sample will be used to determine the presence of NAbs against 
insulin aspart for samples that are ADA positive. Two samples will be collected and stored in 
reserve for potential supplemental immunogenicity testing and/or characterization including 
titer assessment if needed. 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, processing, and storage instructions will be detailed in a separate laboratory 
manual. 
A conventional radioimmunoprecipitation assay (RIPA) will be employed for the assessment 
of ADA 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-1601D tracer under conditions specified for each 
tier: 
Screening Assay (Tier 1):  
• 
RIPA Assay buffer only 
Confirmatory Assay (Tier 2): 
• 
RIPA Assay buffer only 
• 
RIPA Assay buffer with excess unlabelled MYL-1601D 
• 
RIPA Assay buffer with excess unlabelled Human Insulin  
• 
RIPA Assay buffer with excess unlabelled NovoLog 
Titer assay (Tier 3) 
• RIPA Assay buffer only (multiple serial dilutions of the sample) 
 
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).  
In keeping with the multi-tiered sample analysis recommendations for immunogenicity 
testing from published white papers (Mire-Sluis AR et al, 2004; Shankar G et al, 2008), and 


 
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current regulatory guidance (FDA 2019, EMA 2017), the assay design will employ a 
screening tier (no inhibition), confirmatory tier (competitive inhibition with excess drug), 
characterization tier (competitive inhibition with excess human insulin and excess 
NovoLog®) and titration tier.  
All samples will be subjected to an initial screening assay (Tier 1), and those with %B/T 
values greater than or equal to a run-specific screening cut point will be scored as putative 
ADA positives. 
Screen positive samples would then undergo the confirmatory assay (Tier 2), and samples 
exhibiting percentage inhibition greater than the confirmatory cut point will be scored as 
confirmed positive. The cut-point for the screening assay will be based on the %B/T response 
using normal human serum from treatment naïve individuals and use a 5% false positive error 
rate. The confirmatory cut points will be determined for both ADA and insulin cross-reactive 
ADA based on the % inhibition of tracer binding using excess MYL-1601D and human 
insulin, respectively. Each confirmatory cut-point will be determined using normal human 
serum from treatment naïve individuals and employ a 1% false positive error rate. The 
percent inhibition determined using NovoLog as inhibitor would be reported for comparison 
purposes. 
All confirmed positive samples will be evaluated for titer (Tier 3) by serially diluting the 
samples (2-fold dilution steps) and estimating the titer as the interpolated dilution at the run 
specific titer cut point (determined from the screening data using normal human serum from 
treatment naïve individuals at 0.1% false positive error rate). In addition, all samples 
identified as ADA positive will be further evaluated for neutralizing antibodies using a 
separate cell-based assay. 
The labeled drug product (125I-MYL-1601D) is used as the capture reagent in the RIPA, 
which allows antibodies that arise from any insulin aspart epitope to be bound and detected. 
The specificity of capture reagent binding is confirmed by treatment with excess unlabeled 
MYL-1601D, which will interrupt binding for any of the insulin aspart epitopes. Because this 
assessment theoretically detects all antibodies that may arise due to drug exposure, it will be 
used to determine patient sample ADA status.  
Since endogenous human insulin possesses close sequence homology to insulin aspart, the 
ADA generated upon drug exposure may also cross react with human insulin. The degree of 
cross reactivity will be determined by testing the sample in the presences of excess human 
insulin. ADA that develop against epitopes common to both insulin aspart and human insulin 
will be inhibited from binding to the capture reagent.  
All samples designated for immunogenicity evaluation will be tested in a blinded manner. 
The ADA and NAb analysis methodologies will be fully validated at Celerion Switzerland 
AG (Zurich, CH) and Cirion BioPharma Research Inc. (Quebec, CA), respectively, followed 
by sample analysis. 
6.5.2.5 
Blood Pressure and Pulse Rate 
Blood pressure and pulse rate will be measured at times specified in Section 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. 


 
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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. 
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 Section 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 
Diary and Glucometer 
All subjects will receive a diary and blood glucose monitoring (glucometer) device at 
Visit 2/Week -4. The glucometer device will be used by the subject at home to monitor blood 
glucose and the diary will be used to record the 7-point SMBGs. The Investigator or designee 
will train subjects on how to use the glucometer and how to record the values and required 
information in the diary. A user manual for the glucometer is provided to each site as a tool to 
educate and train both site personnel and study subjects.  
6.5.2.8 
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 15 (EOT). 
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 
Approximately 500 subjects with type 1 diabetes will participate in this trial. The sample size 
estimation is based on primary objective - to demonstrate that immunogenicity as assessed by 
TEAR rate with MYL-1601D is equivalent to that of NovoLog® during 24-week treatment. 
The 80% power will be achieved with 250 subjects per treatment arm to demonstrate that 
90% confidence interval of treatment difference (MYL-1601D minus NovoLog®) is within 
prespecified ±margin (Table 5). (Chow SC et al, 2002; Chow S-C et al, 2003). The pre-
specified equivalent margin is dependent on the final rate of NovoLog® TEAR rate. No 
replacement of subject will be performed if subject discontinued prematurely from the study. 
An attrition rate is not considered; for the analysis an imputation of missing values will be 
done and no patient will be excluded from the primary analysis. 
Table 5: Margins and 95% CIs with different reference TEAR event rates in 500 
subjects 
Event Rate for 
Reference 
Product 
Estimated 95% 
CI for the Event 
Rate (n=250) 
Margin 
Type I error 2 
one-sided alpha 
Power 
Total N 
5% 
(2%,8%) 
5.7% 
0.05 
80% 
500 
10% 
(6%,14%) 
7.9% 
0.05 
80% 
500 
15% 
(11%,19%) 
9.3% 
0.05 
80% 
500 
20% 
(15%,25%) 
10.5% 
0.05 
80% 
500 
25% 
(20%,30%) 
11.3% 
0.05 
80% 
500 
30% 
(24%,36%) 
12.0% 
0.05 
80% 
500 
35% 
(29%,41%) 
12.5% 
0.05 
80% 
500 
40% 
(34%,46%) 
12.8% 
0.05 
80% 
500 
45% 
(39%,51%) 
13.0% 
0.05 
80% 
500 
50% 
(44%,56%) 
13.1% 
0.05 
80% 
500 
55% 
(49%,61%) 
13.0% 
0.05 
80% 
500 
60% 
(54%,66%) 
12.8% 
0.05 
80% 
500 


 
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7.2 
Primary Endpoints 
7.2.1 
Definition of Primary Endpoints 
The TEAR rate during 24-week treatment period is the primary endpoint for this study. 
TEAR criteria is defined as either one of the following:  
1) Subjects who are ADA negative at baseline and become positive at any timepoint post 
baseline.  
2) Subjects who are ADA positive at baseline and demonstrate 4-fold increase in titer 
values at any timepoint post baseline visit. 
Whether a subject sample is ADA positive or negative will be determined using screening 
and confirmatory assays in a tiered approach. Titer values will be further evaluated if a 
subject sample is confirmed ADA positive.  If the subject is ADA positive at baseline, then 
the titer values of post baseline samples will be further evaluated to determine if there is a 4-
fold increase versus baseline, indicating that the post-baseline sample(s) are treatment 
boosted ADA positives (see Section 6.5.2.4. in protocol for detailed immunogenicity 
assessment information). 
Although differences in TEAR rate is the primary endpoint for the study from a statistical 
perspective, given that immunogenicity is not a standard endpoint in clinical trials, this 
difference, even if significant, will not be assessed in isolation but will be part of totality of 
evidence including changes in HbA1c, FPG, insulin dose, neutralizing antibodies and 
injection site reactions to ensure that changes in TEAR rate, if any, are clinically correlated 
and meaningful. 
7.2.2 
Statistical Methodology for Primary Endpoints 
The 90% confidence interval of treatment difference (MYL-1601D minus NovoLog®) in 
TEAR rate will be established using Wald confidence limit method. MYL-1601D TEAR rate 
is equivalent to that of NovoLog® during 24-week treatment period if 90% confidence 
interval of treatment difference in TEAR rate is within pre-specified margin defined in 
Table 5. The pre-specified equivalent margin is dependent on the final rate of NovoLog® 
TEAR rate. 
To minimize any bias due to missing data, multiple imputation will be used to fill in missing 
values for TEAR criteria (binary response and continuous titer values) prior to deriving the 
TEAR and subsequently estimating the treatment difference and 90% confidence interval. 
The method of imputation for a subject will be dependent on the individual ADA result at 
baseline. For subjects with baseline ADA negative, post baseline binary response (positive or 
negative) will be imputed using logistic regression multiple imputation assuming missing not 
at random. For subjects with baseline positive, missing titer values (continuous values) will 
be imputed with same treatment group non-missing subjects using pattern mixture model 
with the complete-case missing values (CCMV) method (Little 1993).  
In the case where there are sufficient number of retrieved dropouts, that is, if there are 6 
retrieved dropout subjects in each treatment group, the missing values in that treatment group 
will be imputed by modelling the retrieved subgroup data. Retrieved dropout subjects are the 
subjects who discontinued assigned study treatment but still remain on the study and had their 


 
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efficacy and safety measurements captured at the planned visits. If less than 6 retrieved 
dropout subjects in each treatment group, all non-missing subjects within same treatment 
group will be used to impute missing data by multiple imputation.  
If baseline value is missing, the missing baseline value will be imputed with single 
imputation based on binomial distribution using probability of no missing baseline values 
from same treatment group.  
After imputation, the TEAR criteria will then be applied to each imputed dataset to obtain if a 
subject is TEAR positive or negative, and the treatment difference and 90% confidence 
interval will be estimated using Wald confidence limit method. The result will be combined 
over all imputations by SAS PROC MIANALYZE. 
The primary analysis will be based on the ITT analysis set. In addition, all post-
discontinuation and rescue data should be included in the analysis. Further analysis details 
analysis steps and example SAS codes will be provided in the SAP.  
7.2.3 
Primary Analysis for Primary Endpoints 
Equivalence of TEAR rate will be established if 90% confidence interval of treatment 
difference (MYL-1601D minus NovoLog®) is within ± margin indicated in Table 5. The pre-
specified equivalence margin is based on the final NovoLog® TEAR rate. The primary 
analysis will be performed on the intent to treat (ITT) analysis set.  
7.2.4 
Secondary/Sensitivity Analyses for Primary Endpoints 
• Same analysis model as the primary analysis, but without imputing missing values.  
This will be analyzed based on PP and ITT analysis set.  
• In a derived TEAR dataset, for subjects in MYL-1601D treatment group with 
missing antibody values, TEAR responder will be replaced regardless if subject is 
TEAR responder or non-responder. The TEAR rate difference between two 
treatments and 90% confidence interval will be then estimated using Wald 
confidence limit method. This will be analyzed based on ITT. 
• Tipping-point analysis using method proposed by Liublinska and Rubin (2014) will 
be performed. A graphic display (heating map) is used to indicate the tipping point 
analysis results with missing values as TEAR positive. The treatment differences 
are presented as values in the heat map. The graph will be displayed to show the 
sensitivity ranging from missing favour testing treatment to missing favour 
reference treatment.  
For tipping-point analysis, number of subjects with missing data are either 1) 
subjects who miss completely post-baseline ADA data or 2) subjects who miss 
partially ADA data that cannot be determined if subject is TEAR positive or 
negative 3) subjects who miss at baseline. If a subject with partially ADA missing 
data already meet the TEAR criteria, the subject is not considered as subject with 
missing data. 
• TEAR rate for each treatment and difference between treatments for missing data 
during treatment period will be summarized for all sensitivity analyses. 
• In addition, incidence of TEAR rate at each scheduled visits: visitwise TEAR 
(vTEAR) will be summarized at each scheduled visit by using similar TEAR 


 
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definition: ADA negative at baseline become positive at specific visit (Treatment 
Induced TEAR), and ADA positive at baseline and become 4-fold increase in titer at 
specific visit (Treatment Boosted TEAR). 
7.2.5 
Missing Data 
The only imputed data will be performed in the primary and sensitivity analyses as described 
above for TEAR rate associated with ADA and other secondary variables if deemed 
necessary. The detailed missing data imputation for other secondary variables will be 
included in SAP. 
7.2.6 
Sub-Group Analyses 
Subgroup analyses of important factors, including but not limited to factors such as age 
group, gender, race,  and ethnicity are planned for the key outcomes of TEAR rate. Wald 
confidence limit method for TEAR rate will be used for 90% confidence interval. 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. A mixed model repeated measures (MMRM)-effects model will 
be performed for continuous variables without imputing missing values. 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 value as covariates. 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. 
• Change in HbA1c from baseline. 
• Change in fasting plasma glucose from baseline. 
• Change in prandial, basal insulin and total daily insulin dose per unit body weight 
(U/kg) from baseline. 
• Change in 7-point SMBG profile from baseline. 
All above analyses will be performed on ITT set. 
A sensitivity analysis for HbA1c will be performed using multiple imputation to impute 
missing values with non-missing subjects within same treatment group using pattern mixture 
model with the complete-case missing values (CCMV) method (Little 1993). After 
imputation, treatment difference, 95% CI, and p-values will be generated using same MMRM 
model as above. 
The following safety measures (both actual and change values) will be summarized at 
baseline and scheduled visit. Similar MMRM model as efficacy analysis will be conducted 
for hypoglycemia rate. For antibody continuous variables, 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 and baseline value as covariates. 
Contrasts of LS mean at each scheduled visit will be used to evaluate all pairwise treatment 


 
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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 following analyses will also be performed and will form part of the totality of evidence 
to compare clinical efficacy and safety of two treatment groups: 
• Incidence of ADA response and positive cross-reactive ADA; and incidence of 
positive NAbs. 
• Analysis of potential impact of TEAR status on efficacy and safety parameters such as 
HbA1c, glucose control FPG,  insulin dose, hypoglycemic rate, incidence of any 
injection site allergic reactions and hypersensitivity. 
• Change in hypoglycemia rate (30 day adjusted) from baseline and incidence of 
hypoglycemic events at scheduled visits 
• Incidence of TEAEs and SAEs 
• Incidence of local allergic reactions, systemic allergic reactions and other adverse 
events 
Incidence of device-related safety assessment 
 
To explore the potential ADA impact on subject’s glucose control, the following analyses 
will be performed:  
• The incidence of subjects with meeting all three following criteria will be summarized 
descriptively (for categorical measures) by treatment, by visit, and overall: 
1) Meet the vTEAR criteria  
2) Increases in HbA1c of over 0.2% from baseline  
3) Increase in total dose from baseline  
• Scatter plots of maximum TEAR values with HbA1c, FPG and total daily insulin dose 
by treatment. 
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 device-related patient’s complaints, incidence 
will be listed and summarized for each treatment. 
All the above analyses will be performed on the safety set. 
In addition, graphical visualization of relationship between adverse events and treatment 
duration will be provided. 
The details of all safety analysis will be provided in the SAP.   
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 24 and do not have protocol 
violations that impact the primary outcome (as detailed in the statistical analysis plan). 


 
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Subjects who take other fast acting insulin other than assigned study medication such as 
rescue medication will be excluded from PP analysis set. The subjects excluded from the PP 
analysis set 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.  
Run-in analysis set includes all subjects who enrolled into run-in period. 
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 summarized and listed on run-in analysis set.  
Treatment emergent adverse events and concomitant medications will be summarized and 
listed. All AEs that occur after the first dose of study treatment medication after 
randomization through follow-up visit or 14 days after last dose [for subjects that do not have 
a follow-up visit] 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. 
7.5.1 
Vital Signs 
Change from baseline of vital sign measurements will be analyzed using MMRM with model 
terms of Investigator, 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 by treatment groups. 
7.5.2 
ECG Analyses 
The percentage of subjects in categories such as normal, abnormal/non-clinically significant 
and abnormal/clinically significant will be summarized by treatment groups 
7.5.3 
Laboratory Data 
Change from baseline of laboratory measurements will be analyzed using MMRM with 
model terms of Investigator, 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.  
The percentage of subjects in categories such as normal, abnormal/non-clinically significant 
and abnormal/clinically significant will be summarized by treatment group. 
The percentage of subjects in categories such as potentially clinically significant will be 
summarized by treatment groups. The potentially clinically significant criteria will be listed 
in SAP. 


 
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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.  
o Signs, symptoms, or the clinical sequelae of a suspected drug-drug or drug-
food interaction. 
o Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study treatment or a concomitant medication. Overdose per se will not be 
reported as an AE/SAE unless this is an intentional overdose taken with 
possible suicidal/self-harming intent; this should be reported regardless of 
sequelae. 
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-1601D 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. 


 
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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 
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-1601D is the IB. For NovoLog® and Lantus® 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. 


 
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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). 
 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, and following 
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. The diary 
data is considered as source data. At week 0 visit when study diaries are issued, subjects will 


 
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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 5 or the 
latest version. 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: 
Table 6: Clinical Severity of Adverse Events 
The Investigator will use the terms defined below to describe the maximum intensity of the AE.  
Grade 1 – MILD 
Does not interfere with 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 (not applicable if using CTCAE 
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 7. 
Table 7: Action Taken for an Adverse Event 
Dose reduced  
The dose regimen was reduced by changing its frequency, strength, or 
amount. 
Dose increased 
The dose regimen was increased by changing its frequency, strength, or 
amount. 
Treatment interrupted 
The treatment was temporarily interrupted. 
Treatment withdrawn 
The treatment was permanently discontinued.  
Concomitant therapy or 
procedures 
Treatment was needed as a result of the AE (the concomitant treatment 
should be recorded on the relevant page of the CRF). 
Unknown 
Not known, not observed, not recorded, or refused. 
No action taken 
The AE did not require any intervention. 
Not applicable 
AE occurred before intake of study treatment. AE occurred after study 
medication was permanently withdrawn or subject completed the 
treatment period. 


 
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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 
 
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 assess 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: 


 
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Table 8: 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 
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, if the relationship to the study treatment(s) is considered to be unlikely or not 
related/unrelated, an alternative suspected etiology should 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. 
 


 
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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. 
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 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 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 or 14 days after last dose of study medication. 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 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) 


 
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• A brief description of the event, outcome to date, and any actions taken 
• Concomitant medication at onset of the event 
• Relevant medical 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 (preferred) or fax the written SAE report form that 
describes the SAE to the Mylan Product Safety and Risk Management department. 
The Investigator may be requested by Mylan to obtain specific additional follow-up 
information in an expedited fashion. This information collected for SAEs is more detailed 
than that captured on the AE CRF. In general, this will include a description of the SAE in 
sufficient detail to allow for a complete medical assessment of the case and independent 
determination of 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. If 
available, a death certificate should be included.  
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 of awareness by email (preferred) or fax to: 
Mylan Product Safety & Risk Management 
PV MAIL HUB FOR IMMEDIATE SAFETY REPORTS: 
pvclinical@mylan.com 
In the event 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. An email 
acknowledgement that the fax was received will be sent within 24 business hours of receipt 
of the fax. 
The Investigator or the site staff can reach out to study CRO through a 24-hour helpline for 
any emergency medical related questions at +1.919.674.5468 or +1.888.426.8801 (toll free). 
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 


 
Protocol MYL-1601D-3001 
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MYL-1601D Protocol 14 October 2019 
Confidential 
representative will also submit periodic safety reports (for e.g., Development Safety Update 
Reports) as required by international regulations. 
9.4 
Special Situations 
Any pregnancy occurring after randomization to study drug will be followed up and reported 
to the Sponsor as per Section 9.4.1 The Investigator should report the pregnancy within 24 
hours of awareness 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.  
Pregnancy testing will be conducted throughout the study, as detailed in the schedule of 
assessments. A woman who is found to be pregnant at any stage of the study will be 
discontinued immediately from the study. Early termination 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 an elective procedure and not an AE, nevertheless, Mylan requests that the 
outcome (e.g., elective termination) be reported within 24 hours of awareness and sent as a 
follow-up report on the Delivery and Infant Follow-up Form.  
If the subject consents to be followed, the Investigator will be required to follow the 
pregnancy at 3 monthly intervals until delivery or termination, informing the Sponsor about 
its outcome.   
If the study center becomes aware of a pregnancy in a female partner of a male subject, study 
personnel should contact their clinical research associate to obtain a partner pregnancy ICF. 
Consent of the pregnant partner must be obtained before any details of the pregnancy can be 
shared with Mylan or its designated representative. If the pregnant partner provides consent 
to have the pregnancy followed, the study center should collect the information specified on 
the pregnancy report form and forward the completed form to Mylan PSRM in quarterly 
intervals until the pregnancy outcome has been obtained.  
Non-exposed partner pregnancies (conception occurring prior to receipt of first dose of the 
study treatment and those occurring after the last dose of study treatment) do not need to be 
reported or followed. A male that has a partner that becomes pregnant during the study will 
not be discontinued from study treatment.  


 
Protocol MYL-1601D-3001 
Page 69 of 71 
MYL-1601D Protocol 14 October 2019 
Confidential 
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 early termination from the study, 
additional concomitant drug treatment, or other therapy; and/or 
• The test result is considered an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute 
an AE.   
Any abnormal test result determined by retest to be an error does not require reporting as an 
AE. 


 
Protocol MYL-1601D-3001 
Page 70 of 71 
MYL-1601D Protocol 14 October 2019 
Confidential 
10 REFERENCE LIST 
American Diabetes Association 2019 criteria, Diabetes Care ma , 40 (supplement1): S11-S24. 
Chow SC and Shao J. A note on statistical methods for assessing therapeutic equivalence. 
Control Clinical Trial. 2002; 23(5): 515-520. 
Chow S‐C, Shao J, Wang H. Sample size calculation in clinical research. 2003 
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. 
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. 
European Medicines Agency (EMA) 2015. Guideline on non-clinical and clinical 
development of similar biological medicinal products containing recombinant human insulin 
and insulin analogues. EMEA/CHMP/BMWP/32775/2005_Rev. 1. 2015. 
European Medicines Agency (EMA) 2017. Guideline on Immunogenicity assessment of 
therapeutic proteins. EMEA/CHMP/BMWP/14327/2006 Rev. 1. 2017. 
EMEA 2006. 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). 22 Feb 2006 
Food and Drug Administration (FDA). Guidance for Industry: Immunogenicity Testing of 
Therapeutic Protein Products – Developing and Validating Assays for Anti-Drug Antibody 
Detection. January 2019, U.S. Department of Health and Human Services.Food and Drug 
Administration (FDA) 2008. Guidance for Industry: Diabetes Mellitus: Developing Drugs 
and Therapeutic Biologics for Treatment and Prevention. Draft Guidance. 2008, U.S. 
Department of Health and Human Services. 
Hermansen K, Bohl M, Schioldan AG. Insulin Aspart in the Management of Diabetes 
Mellitus: 15 Years of Clinical Experience. Drugs. 2016; 76: 41-74.  
Investigator’s Brochure for MYL-1601D (available upon request).  
Kilpatrick ES, Rigby AS, Atkin SL. Insulin Resistance, the Metabolic Syndrome, and 
Complication Risk in Type 1 Diabetes. Diabetes Care. 2007; 30(3) 707-712. 
Little RJA. Pattern-Mixture Models for Multivariate Incomplete Data. J Am Stat Assoc. 
1993; 88 (421): 125-134. 
Liublinska V, Rubin DB. Sensitivity analysis for a partially missing binary outcome in a two-
arm randomized clinical trial. Stat Med. 2014;33(24):4170–4185. 
Mire-Sluis AR, Barrett YC, Devanarayan V, 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): 1-16. 


 
Protocol MYL-1601D-3001 
Page 71 of 71 
MYL-1601D Protocol 14 October 2019 
Confidential 
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. 
Shankar G, Devanarayan V, Amaravadi L, et al., Recommendations for the validation of 
immunoassays used for detection of host antibodies against biotechnology products. J Pharm 
Biomed Anal, 2008. 48(5): 1267-81. 
Williams KV, Erbey JR, Becker D, et al. Can clinical factors estimate insulin resistance in 
type 1 diabetes? Diabetes. 2000; 49 (4) 626-632. 

SAP_001.pdf: 
 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1301D-3001 
Version: FINAL 3.0, Date: 02 Mar 2020 
                                                Page 1 of 69 
 
Protocol Title: 
A Randomized, Multicenter, Open-Label, Parallel-Group 
Clinical Study Comparing the Safety and Efficacy of MYL-
1601D with NovoLog® in Type 1 Diabetes Mellitus Patients 
Protocol Number: 
MYL-1601D-3001 
Protocol Version, Date 
Version 5.0, 14 October 2019 
ICON ID:  
Mylan 0102/0045 
Document Version, Date: 
3.0, 02 March 2020 
 
 
 
 
 
Prepared by: 
ICON Clinical Research Services 
 
On behalf of: 
Mylan GmbH Pharmaceuticals Inc. 
 
 
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential.  
 
The recipients of the SAP must not disclose the confidential information 
contained within this document or any related information to other persons 
without the permission of the sponsor. 
 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 
 
 
 


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Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0, Date: 02 Mar 2020 
                                               Page 4 of 69   
 
REVISION HISTORY 
 
Version/Date 
Version name 
Section 
Changes implemented 
FINAL 
1.0/11JAN2019 
Final Version 1.0 
Not Applicable 
Not Applicable 
FINAL 
2.0/18OCT2019 
Final Version 2.0 
7.2.1 
 
8.1 
 
8.7.1 
8.7.2 
 
8.7.3.1 
8.7.5 
8.8.4 
8.8.5 
8.9 
 
10.1 
 
10.2 
10.3 
Updated missing data analysis method for primary analysis 
due to immunogenicity assay method changes 
Updated imputation for retests, unscheduled visits and visit 
end of treatment; updated visit window 
Updated analysis methods for primary endpoint 
Updated primary efficacy analysis method and tipping point 
analysis due to immunogenicity assay method changes 
Added sensitivity analysis for HbA1c 
Updated subgroup analysis method 
Updated the definition for relative hypoglycemia 
Updated Immunogenicity assessments 
Updated the incidence analyses for lab data, vital signs, 
physical examination and ECG  
Updated multiple imputation method SAS code, added 
multiple imputation for HbA1c  
Updated example SAS code for tipping point analysis method 
Updated SI units for laboratory category table 
FINAL 
V3.0/ 
02MAR2020 
 
6.1 
6.2 
 
6.3 
 
 
Add randomized analysis set definition. 
Modified ITT analysis set to exclude subjects who are in the 
site with GCP violation 
Modified PP analysis set to exclude subjects who are in the 
site with GCP violation and also add more clarification for PP 
analysis set. 


 
 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0, Date: 02 Mar 2020 
                                               Page 5 of 69   
 
 
6.4 
 
7.2 
 
7.3 
 
 
10.0 
Modified Safety analysis set to exclude subjects who are in 
the site with GCP violation 
Change single imputation into multiple imputations for 
missing baseline value. 
Add a section address GCP issue at one investigator site (Site 
ID: 6103) and add sensitivity analysis without inclusion of 
data from this site 
Add SAS programming flow chart per regulatory request 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020    
                                            Page 6 of 69 
 
TABLE OF CONTENTS 
 
SIGNATURE PAGE .......................................................................................................2 
REVISION HISTORY ....................................................................................................4 
TABLE OF CONTENTS .................................................................................................6 
LIST OF ABBREVIATIONS ..........................................................................................8 
1 INTRODUCTION ................................................................................................... 10 
2 STUDY OBJECTIVES ............................................................................................ 11 
2.1 Primary objective(s) ........................................................................................ 11 
2.2 Other objective(s) ............................................................................................ 11 
3 STUDY DESIGN .................................................................................................... 12 
3.1 General study design ....................................................................................... 12 
3.2 Randomization and blinding ............................................................................ 12 
3.2.1 
Randomization ..................................................................................... 12 
3.2.2 
Breaking the blinding and study team blindness .................................... 13 
3.3 Study treatments and assessments .................................................................... 13 
4 STUDY ENDPOINTS ............................................................................................. 20 
4.1 Primary efficacy endpoint(s) ............................................................................ 20 
4.2 Secondary efficacy endpoint(s) ........................................................................ 20 
4.3 Safety endpoint(s)............................................................................................ 20 
4.4 Exploratory endpoint(s) ................................................................................... 20 
5 SAMPLE SIZE AND POWER ................................................................................. 21 
6 ANALYSIS POPULATIONS................................................................................... 22 
6.1 Randomized analysis set .................................................................................. 22 
6.2 ITT analysis set ............................................................................................... 22 
6.3 PP analysis set ................................................................................................. 22 
6.4 Safety analysis set ........................................................................................... 22 
6.5 Run-in analysis set........................................................................................... 22 
6.6 Protocol deviations/violations and exclusions from analysis sets ....................... 22 
7 Statistical Considerations and analysis ...................................................................... 23 
7.1 Derived Variables............................................................................................ 23 
7.2 Handling of missing data and outliers ............................................................... 23 
7.2.1 
Missing data analysis methods .............................................................. 23 
7.2.2 
Handling of missing weight .................................................................. 25 
7.2.3 
Handling of missing or incomplete dates ............................................... 25 
7.3 Handling of site with GCP violation ................................................................. 26 
8 STATISTICAL METHODS ..................................................................................... 27 
8.1 General statistical conventions ......................................................................... 27 
8.2 Investigator pooling for secondary analyses...................................................... 28 
8.3 Subject disposition .......................................................................................... 28 
8.4 Protocol deviations .......................................................................................... 28 
8.5 Demographics and baseline characteristics ....................................................... 29 
8.5.1 
Demographics ...................................................................................... 29 
8.5.2 
Baseline and disease characteristics ...................................................... 29 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020    
                                            Page 7 of 69 
 
8.5.3 
Medical history .................................................................................... 29 
8.5.4 
Concomitant medications ..................................................................... 29 
8.6 Extent of exposure ........................................................................................... 30 
8.6.1 
Treatment duration ............................................................................... 30 
8.6.2 
Treatment compliance .......................................................................... 30 
8.7 Efficacy analyses ............................................................................................. 30 
8.7.1 
Analysis methods ................................................................................. 30 
8.7.1.1 Multiplicity .......................................................................................... 31 
8.7.1.2 Treatment by center interaction analysis (multi-center study) ................. 31 
8.7.2 
Analysis of primary efficacy endpoint(s) ............................................... 31 
8.7.2.1 Primary efficacy analysis ...................................................................... 31 
8.7.2.2 Secondary/Sensitivity analyses of the primary efficacy endpoint ............ 34 
8.7.2.3 Tipping point analysis .......................................................................... 35 
8.7.3 
Secondary endpoints............................................................................. 35 
8.7.3.1 HbA1c ................................................................................................. 36 
8.7.3.2 Fasting plasma glucose ......................................................................... 36 
8.7.3.3 Daily insulin dose per unit body weight (mealtime, basal insulin and total) 
for days of 7-Point profiles ................................................................... 37 
8.7.3.4 7-Point Self-Monitored Blood Glucose (SMBG) profile ........................ 38 
8.7.4 
Analysis of exploratory endpoint(s) ...................................................... 39 
8.7.5 
Subgroup analyses................................................................................ 39 
8.8 Safety analyses ................................................................................................ 40 
8.8.1 
Adverse events ..................................................................................... 41 
8.8.2 
Device-related Assessment include both TEAE and device complaints... 42 
8.8.3 
Hypoglycemia ...................................................................................... 43 
8.8.4 
Hypersensitivity and Immune mediated adverse events.......................... 44 
8.8.5 
Immunogenicity assessments ................................................................ 44 
8.9 Other Safety Analyses ..................................................................................... 45 
8.9.1 
Laboratory Data ................................................................................... 45 
8.9.2 
Vital signs............................................................................................ 46 
8.9.3 
Physical examinations .......................................................................... 46 
8.9.4 
Electrocardiograms (ECG).................................................................... 47 
8.10 Interim analysis ............................................................................................... 47 
9 REFERENCES ........................................................................................................ 48 
10 APPENDICES – SAS example codes ....................................................................... 49 
10.1 Multiple imputation ......................................................................................... 49 
10.1.1 Multiple imputation for binary ADA response if baseline ADA is 
negative. .............................................................................................. 51 
10.1.2 Multiple imputation for continuous ADA titer if baseline ADA positive. 56 
10.1.3 Combining the multiple imputation results to derive TEAR status .......... 58 
10.1.4 Multiple imputation for HbA1c. ............................................................ 60 
10.2 Tipping Point Analysis .................................................................................... 63 
10.3 Laboratory Category ........................................................................................ 68 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020    
                                            Page 8 of 69 
 
LIST OF ABBREVIATIONS 
The following abbreviations will be used within this SAP. 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CM 
Concomitant Medication 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria Adverse Events 
CV 
Coefficient of Variation 
DM 
Diabetes Mellitus 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated hemoglobin 
HBsAg  
Hepatitis B Surface Antigen  
HCVAb 
Hepatitis C antibodies 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
ICH 
International Council for Harmonisation 
IXRS 
Interactive Web/Voice Response System 
ITT 
Intent to treat 
IU 
International Unit 
Kg 
Kilogram 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical dictionary for regulatory activities 
mL 
Milliliter 
MMRM 
Mixed Model Repeated Measures 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020    
                                            Page 9 of 69 
 
NAb 
Neutralizing Antibody 
NCI 
National Cancer Institute 
PD 
Pharmacodynamic 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SID 
Subject Identification 
SMBG 
Self-monitored blood glucose 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
T1DM 
Type 1 diabetes mellitus 
TEAR 
Treatment Emergent Antibody Response 
TEAE 
Treatment Emergent Adverse Event 
WHODDE 
World Health Organization Drug Dictionary Enhanced 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020    
                                            Page 10 of 69 
 
1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for study protocol MYL-1601D-3001 
Version 5.0 “A Randomized, Multicenter, Open-Label, Parallel-Group Clinical Study 
Comparing the Safety and Efficacy of MYL-1601D with NovoLog® in Type 1 Diabetes 
Mellitus Patients” dated 14 October 2019 for Clinical Study Report (CSR) analysis and 
interim analyzes, if any. The table of contents and templates for the tables, figures and 
listings (TFLs) will be produced in a separate document. 
Any deviations from this SAP will be described and justified in the CSR. 
The preparation of this SAP has been based on International Conference on Harmonisation 
(ICH) E9 guidelines. 
All data analyzes and generation of TFLs will be performed using SAS 9.3® or higher. 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020    
                                            Page 11 of 69 
 
2 
STUDY OBJECTIVES 
2.1 
Primary objective(s) 
The primary objectives of the study are as follows: 
To demonstrate that immunogenicity as assessed by treatment emergent antibody response 
(TEAR) rate with MYL-1601D is equivalent to that of NovoLog® during 24-week 
treatment. The TEAR rate will not be assessed in isolation but will be part of totality of 
evidence including changes in HbA1c, fasting plasma glucose (FPG), insulin dose, 
neutralizing antibodies and injection site reactions to ensure that changes in TEAR rate, if 
any, are clinically meaningful. 
2.2 
Other objective(s) 
The other objectives of the study is to compare MYL-1601D to NovoLog® administered in 
combination with Lantus®, with respect to: 
• Immunogenicity assessments: visits TEAR assessments, incidences of Anti-Drug 
Antibody (ADA) and positive Cross-reactive ADA, and positive Neutralizing 
Antibody (NAb) 
• Analysis of impact of ADA on pharmacodynamic (PD) parameters such as FPG, 
HbA1c, and insulin dose.  
• Incidence and rate of hypoglycemic events 
• Occurrence of local reactions, systemic reactions and other adverse events 
• Safety related to hypersensitivity and immune mediated adverse events (subgroup 
analysis) 
• Change in HbA1c from baseline 
• Change in fasting plasma glucose (FPG) from baseline 
• Change in prandial, basal, and total daily insulin dose per unit body weight (U/kg) 
from baseline 
• Change in 7-point SMBG profile from baseline 
• Device-related safety assessment 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020    
                                            Page 12 of 69 
 
3 
STUDY DESIGN 
3.1 
General study design 
This is a multicenter, open-label, randomized, parallel-group phase 3 study in subjects with 
Type 1 Diabetes Mellitus (T1DM) comparing the safety and efficacy of MYL-1601D with 
NovoLog®. 
After up to 3-week screening period, all subjects will be titrated on NovoLog® during a 
4-week run-in period, and will be shifted from their current basal insulin to study insulin 
Lantus®. After run-in period, subjects will be randomized; one group will receive MYL-
1601D, while the other group will receive NovoLog® for 24 weeks. A follow-up visit, via 
telephone call, will be scheduled 4 weeks after last dose of MYL-1601D. 
The study will be conducted at approximately 200 sites in the United States (US).   
The Study Flow Chart is presented in Figure 1. 
Figure 1: Study Flow Chart 
 
Abbreviations: V=Visit; EOT=End of Treatment; FUP=Follow-up; 
3.2 
Randomization and blinding 
3.2.1 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 IWRS. 
A manual containing complete instructions for Web or telephone access and use will be 
provided to each site prior to study start. The IWRS will assign a SID for each subject’s 
first clinic visit. Each SID will be unique and serve as the primary subject identifier 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020    
                                            Page 13 of 69 
 
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 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). 
3.2.2 Breaking the blinding and study team blindness 
The trial design is open-label since the two products, MYL-1601D and NovoLog®, have 
distinct packaging. To avoid any bias in the evaluation of the critical endpoints, a blinded 
analysis of immunogenicity and other parameters such as HbA1c and FPG is planned.  In 
addition, most of the study personnel (Sponsor and CRO teams) will be blinded to the 
randomized assigned treatment arms. This will be detailed in separate document, listing the 
Sponsor and CRO personnel who are unblinded to ensure transparency and proper study 
conduct. As all investigators and sites staff are not blinded to treatment, no process is 
required for breaking the blind. 
3.3 
Study treatments and assessments 
During the Run-in period, all subjects will receive FlexPen NovoLog® from Novo-
Nordisk (US listed drug) 100 U/mL until randomization. In addition, all patients will be 
shifted from their current basal insulin to Lantus® SoloSTAR® at the start of the run-in 
period, and will continue this for the complete study duration. The doses of NovoLog® 
and Lantus® will be titrated (if required) during the run-in period to ensure diabetes 
control.  
During the Treatment period, all patients will receive one of the following treatments: 
• MYL-1601D or FlexPen NovoLog® to be taken at meal time. 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. 
• Once daily Lantus® SoloSTAR® (insulin glargine injection, 100 U/mL), 
manufactured by Sanofi-Aventis. 
A detailed description of procedures and assessments to be conducted during this study is 
summarized in the Scheduled of Study Assessments in Table 1 below. 
 
 
 
 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020 
                                            Page 14 of 69 
 
Table 1: Schedule of Study Assessments 
Study Periods 
Screenin
g 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-
up 
Study Visits 1 
V1 
V2 
V3 
V4 
V5 V6 V7 
V8 
V9 V10 V11 V12 V13 V14 
 
V15 
(EOT) 10 
V16   
(FU) 
Study Week 
-7 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
8 
12 
16 
20    22 
 24 
   28 
Study Days 
-49 to -28 -28±3-21±3-14±3 -7±3 0±3 7±3 14±3 28±3 56±7 84±7 112±
7 
140±
7 
154±7 168±7 196±7 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
History of previous insulin usage 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated Ophthalmoscopy / retinal 
photography (if not done the last 6 
months) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard-of-care specifics 2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Age, Gender, Height, Race 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020 
                                            Page 15 of 69 
 
Study Periods 
Screenin
g 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-
up 
Study Visits 1 
V1 
V2 
V3 
V4 
V5 V6 V7 
V8 
V9 V10 V11 V12 V13 V14 
 
V15 
(EOT) 10 
V16   
(FU) 
Study Week 
-7 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
8 
12 
16 
20    22 
 24 
   28 
Study Days 
-49 to -28 -28±3-21±3-14±3 -7±3 0±3 7±3 14±3 28±3 56±7 84±7 112±
7 
140±
7 
154±7 168±7 196±7 
Body Weight and BMI 11 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Pregnancy Test 3 
x 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
 
x 
 
Medical History and concomitant 
illness 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vitals signs measurement (sitting) 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Physical examination 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
12-lead ECG (supine) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020 
                                            Page 16 of 69 
 
Study Periods 
Screenin
g 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-
up 
Study Visits 1 
V1 
V2 
V3 
V4 
V5 V6 V7 
V8 
V9 V10 V11 V12 V13 V14 
 
V15 
(EOT) 10 
V16   
(FU) 
Study Week 
-7 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
8 
12 
16 
20    22 
 24 
   28 
Study Days 
-49 to -28 -28±3-21±3-14±3 -7±3 0±3 7±3 14±3 28±3 56±7 84±7 112±
7 
140±
7 
154±7 168±7 196±7 
Randomization 
 
 
 
 
 
x 8 
 
 
 
 
 
 
 
 
 
 
Record AEs and SAEs (including local 
and systemic allergic reactions) and 
hypoglycemic events 4 due to 
medication, disposable pen or needle 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record device complaint  
 
 
x 
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 
 
Rescue criterion evaluation 6 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020 
                                            Page 17 of 69 
 
Study Periods 
Screenin
g 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-
up 
Study Visits 1 
V1 
V2 
V3 
V4 
V5 V6 V7 
V8 
V9 V10 V11 V12 V13 V14 
 
V15 
(EOT) 10 
V16   
(FU) 
Study Week 
-7 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
8 
12 
16 
20    22 
 24 
   28 
Study Days 
-49 to -28 -28±3-21±3-14±3 -7±3 0±3 7±3 14±3 28±3 56±7 84±7 112±
7 
140±
7 
154±7 168±7 196±7 
Fasting C-peptide, HIV, HBsAg, 
HCVAb 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sampling for hematology, blood 
chemistry and urinalysis 5 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Fasting lipid profile 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Sampling for immunogenicity 9 
x 
 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Review diary, 7-point SMBG Profile 
and dose collection performed in the 
week before the visit 7 
 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Dose review of MYL-1601D, 
NovoLog® and Lantus® and dose 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020 
                                            Page 18 of 69 
 
Study Periods 
Screenin
g 
Run-in Period 
Randomized Comparative Treatment Period 
Follow-
up 
Study Visits 1 
V1 
V2 
V3 
V4 
V5 V6 V7 
V8 
V9 V10 V11 V12 V13 V14 
 
V15 
(EOT) 10 
V16   
(FU) 
Study Week 
-7 to -4 
-4 
-3 
-2 
-1 
0 
1 
2 
4 
8 
12 
16 
20    22 
 24 
   28 
Study Days 
-49 to -28 -28±3-21±3-14±3 -7±3 0±3 7±3 14±3 28±3 56±7 84±7 112±
7 
140±
7 
154±7 168±7 196±7 
adjust/instruction 
Dispense study medication and 
ancillary supplies 
 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
 
 
 
Drug Accountability and Compliance 
 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Dispense subject diary 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020 
                                            Page 19 of 69 
 
1. Visits 3, 5, 7 14 and 16 may be telephone contacts/visits, in case required an actual site visit is possible (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 visits (V1 and V6). During subsequent 
visits urine pregnancy test will be done, any positive urine test needs to be confirmed with serum test. At the randomization visit, both urine and serum 
pregnancy tests will be done, subject can be enrolled only if the urine pregnancy test is negative until serum result is provided. 
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 and the Investigator deems it clinically significant and requests further evaluation. 
6. Rescue criterion is evaluated on V12/Week 16 based on HbA1c measurement at V11/Week 12. Sites are required to receive the V11/Week 12 results 
prior to V12/Week 16 subject visit to enable Investigator to take decision on future steps.   
7. The 7-point SMBG profile recorded via glucometer and recorded by the subject in the diary, measurement will be performed by the subject at 
home on 3 days (of which 2 days are consecutive) in the week before the visit.  
8. Prior to randomization, Investigator is required to re-confirm subject eligibility to the study based on the data collected during the screening 
period, including the labs values recorded during screening.  
9. Immunogenicity samples: At Visits 1, 6, 8, 9, 10, 11, 12, 13 and 15. At each visit, five blood samples of 5 mL each (25 ml per visit) will be drawn for 
ADA and NAb.   
10. In case the subject discontinues treatment early, the site should explain the importance of data collection and make every effort to retain the 
subject, perform the remaining visits, off study treatment, per the Schedule of Study Assessments, up to the completion of Week 28/Follow-up call. 
BMI is calculated at screening visit, randomization visit, week 12 and week 24.


 
 
Statistical Analysis Plan 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 20 of 69 
 
4 
STUDY ENDPOINTS 
4.1 
Primary efficacy endpoint(s) 
The TEAR rate during 24-week treatment period is the primary endpoint for this study.  
TEAR is defined as either one of the following:  
1) Subjects who are ADA negative at baseline and become positive at any timepoint post 
baseline  
2) Subjects who are ADA positive at baseline and demonstrate 4-fold increase in titer values 
at any timepoint post baseline visit. 
4.2 
Secondary efficacy endpoint(s) 
The secondary endpoint points are change from baseline to week 24 for the ITT population. 
• Change in HbA1c from baseline 
• Change in fasting plasma glucose from baseline 
• Change in prandial, basal and total daily insulin dose per unit body weight 
(U/kg) from baseline 
• Change in 7-point SMBG profile from baseline 
4.3 
Safety endpoint(s) 
• Incidence of positive antibody response and NAb and change in antibody 
percentage binding from baseline. 
• Impact of ADA on PD parameters, such as FPG, HbA1c, and insulin dose. 
• 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 (includes injection site reaction), systemic 
reactions. 
• Incidence of hypersensitivity and immune mediated adverse events. 
• Incidence of device-related safety assessment. 
4.4 
Exploratory endpoint(s) 
Not Applicable. 


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 21 of 69 
 
5 
SAMPLE SIZE AND POWER 
Approximately 500 subjects with type 1 diabetes will participate in this trial. The sample 
size estimation is based on primary objective - to demonstrate that immunogenicity as 
assessed by TEAR rate with MYL-1601D is equivalent to that of NovoLog® during 24-
week treatment. The 80% power will be achieved with 250 subjects per treatment arm to 
demonstrate that 90% confidence interval of treatment difference (MYL-1601D minus 
NovoLog®) is within prespecified ±margin (Table 2 of the SAP) (Chow SC et al, 2002; 
Chow S-C et al 2003). The pre-specified equivalent margin is dependent on the final rate of 
NovoLog® TEAR rate. No replacement of subject will be performed if subject discontinued 
prematurely from the study.  
Table 2: Margins and 95% CIs with different reference TEAR event rates in 500 
subjects 
Event Rate 
for Reference 
Product 
Estimated 
95% CI for 
the Event 
Rate (n=250) 
Margin 
Type I error 2 
one-sided 
alpha 
Power 
Total N 
5% 
(2%,8%) 
5.7% 
0.05 
80% 
500 
10% 
(6%,14%) 
7.9% 
0.05 
80% 
500 
15% 
(11%,19%) 
9.3% 
0.05 
80% 
500 
20% 
(15%,25%) 
10.5% 
0.05 
80% 
500 
25% 
(20%,30%) 
11.3% 
0.05 
80% 
500 
30% 
(24%,36%) 
12.0% 
0.05 
80% 
500 
35% 
(29%,41%) 
12.5% 
0.05 
80% 
500 
40% 
(34%,46%) 
12.8% 
0.05 
80% 
500 
45% 
(39%,51%) 
13.0% 
0.05 
80% 
500 
50% 
(44%,56%) 
13.1% 
0.05 
80% 
500 
55% 
(49%,61%) 
13.0% 
0.05 
80% 
500 
60% 
(54%,66%) 
12.8% 
0.05 
80% 
500 


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 22 of 69 
 
6 
ANALYSIS POPULATIONS 
6.1 
Randomized analysis set 
Randomized analysis set include all subjects who are randomized into the study.   
6.2 
ITT analysis set 
The ITT analysis set includes all randomized subjects without being in the site with GCP 
violation (including subjects who receive incorrect treatment, do not complete the study or 
do not comply with the protocol or used prohibited medication, randomized but do not take 
any study drug). The subjects who are in the site with GCP violation will be excluded from 
ITT analysis set. 
6.3 
PP analysis set 
The PP analysis set includes subjects who complete Week 24, and do not have protocol 
violations that impact the primary outcome (as detailed in the blind data review (BDR) plan). 
Subjects who take other fast acting insulin other than assigned study medication such as 
rescue medication or subject’s own insulin will be excluded from PP analysis set. Subjects 
who are in the site with GCP violation will also be excluded from PP analysis set. The 
subjects excluded from the PP population will be determined during the blind data review 
meeting and summarized in the blind data review report.  
6.4 
Safety analysis set 
The safety analysis set includes subjects who take at least one dose of the study medication 
after randomization and who aren't in the site with GCP violation. For safety analyses, 
subjects will be categorized according to the treatment that they actually received.  
6.5 
Run-in analysis set 
Run-in analysis set includes all subjects who enrolled into run-in period. 
6.6 
Protocol deviations/violations and exclusions from analysis sets 
All violations and exclusions of subjects from analysis sets will be identified at the 
Classification Meeting just prior to study unblinding, through clinical review input provided 
by Sponsor, using the following sources of information: 
• Supportive subject listings, provided by the ICON lead statistician ahead of the 
Classification Meeting, based on data recorded on the electronic case report form 
(eCRF).  
• Protocol Deviation Logs, provided by ICON Medical. 
Further, deviations from the protocol will be classified as major or minor. 
 
 


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 23 of 69 
 
7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
7.1 
Derived Variables 
The below table provides the list of derived variables for Demographic and baseline 
characteristics, various duration derivations, drug compliance, baseline derivations and other 
important derivations applicable for this study. 
 
Table 3. 
Variables 
Formula 
Demographic and Baseline characteristics 
Body mass index (BMI) 
(kg/m2)   
weight (kg) / [height (m)]^2 
Derivation of Duration 
Study day at any visit 
Date of interest – date of first dose of study drug. One 
day is added if this difference is ≥ 0 
Extent of Exposure (Days) 
Date of last randomized study medication intake – Date 
of first randomized study medication intake + 1 
Extent of Exposure (Weeks)   
Extent of exposure (days)/7 
Baseline Derivations 
Baseline 
Last non-missing value collected prior to the first dose of 
study medication in treatment period. 
Change from baseline 
Post baseline value – Baseline 
SMBG Derivations 
 
SMBG excursion 
Post-meal blood glucose – Pre-meal blood glucose 
Mean SMBG 
All BG/7 and average over 3 days 
Mean excursion 
All excursion values average over 3 days 
 
7.2 
Handling of missing data and outliers 
7.2.1 Missing data analysis methods 
Missing data will only be imputed in the primary and sensitivity analyses for TEAR rate 
associated with ADA and other secondary variables that are mentioned in this document. 
Otherwise, missing data will not be imputed. 
Subjects with missing data are either 1) subjects who completely miss post-baseline ADA 
data or 2) subjects who miss a portion of ADA data and for whom the TEAR positive or 
negative status cannot be determined. If a subject with partially missing ADA data already 


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 24 of 69 
 
meets the TEAR criteria, the subject is not considered to be a subject with missing data. 
To minimize any bias due to missing data, multiple imputation will be used to fill in 
missing values according to either of two TEAR criteria (binary response and continuous 
titer values) prior to deriving the TEAR and subsequently estimating the treatment 
difference and 90% confidence interval. Two imputation processes will be used for each of 
two TEAR criteria among the missing data.  For baseline ADA negative subjects, post 
baseline binary response (positive or negative) will be imputed using logistic regression 
multiple imputation assuming missing not at random. For baseline positive subjects, 
missing titer values (continuous values) will be imputed with same treatment group non-
missing subjects using pattern mixture model with the complete-case missing values 
(CCMV) method (Little 1993).  In the case where there are sufficient number of retrieved 
dropouts, that is, if there are 6 retrieved dropout subjects in each treatment group, the 
missing values in that treatment group will be imputed by modelling the retrieved 
subgroup data. Retrieved dropout subjects are the subjects who discontinued assigned 
study treatment but still remain on the study and had their efficacy and safety 
measurements captured at the planned visits. If less than 6 retrieved dropout subjects in 
each treatment group, all non-missing subjects within same treatment group will be used to 
impute missing data by multiple imputation.  
If baseline value is missing, the missing baseline value will be imputed with multiple 
imputations (6 imputations) using no missing baseline values from same treatment group.  
After imputation, the TEAR criteria will then be applied to each imputed dataset to obtain 
if a subject is TEAR positive or negative, and the treatment difference and 90% confidence 
interval will be estimated using Wald confidence limit method. The result will be 
combined over all imputations by SAS PROC MIANALYZE.  
Tipping-point analysis will be performed via the method proposed by Liublinska and 
Rubin (2014).  This will include a graphic display to indicate the tipping point analysis for 
the TEAR status binary outcome. A graphic display (heating map) is used to indicate the 
tipping point analysis results with missing values as TEAR positive. The treatment 
differences are presented as values in the heat map. The graph will be displayed to show 
the sensitivity ranging from missing favour testing treatment to missing favour reference 
treatment.  
For tipping-point analysis, the number of subjects with missing data include 1) subjects 
who are missing all post-baseline ADA data, 2) subjects with partially missing ADA data 
whose TEAR status cannot be determined as positive or negative, and 3) subjects who are 
missing ADA data at baseline. If a subject with partially missing ADA data already meets 
the TEAR criteria, the subject is not considered as a subject with missing data. 


 
 
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Protocol Number: MYL-1601D-3001 
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7.2.2 Handling of missing weight 
In the secondary efficacy data, the body weight used to calculate prandial, basal and total 
daily insulin dose per unit body weight (U/kg). If the body weight value is missing, the 
body weight in previous visit will be used. It means the body weight will do LOCF. 
7.2.3 Handling of missing or incomplete dates 
Imputation rules for missing or partial AE start dates are defined below: 
If only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date, then: 
• If the full (or partial) AE end date is NOT before the first dose date or AE end date 
is missing, then impute the AE start day as the day of first dose date;  
• Otherwise, impute the AE start day as 1. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year, then: 
• If the full (or partial) AE end date is NOT before the first dose date or AE end date 
is missing, then impute the AE start Month and Day as the Month and Day of first 
dose date 
• Otherwise, impute the AE start MONTH as January and the DAY as 1. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing, then query site and 
leave as missing.  
For missing and partial adverse event end dates, imputation will be performed as follows: 
If only the day of the month is missing, the last day of the month will be used to replace the 
missing day. If the day and month are missing or a date is completely missing, it will be 
considered as missing. 
For the purpose of the derivation of adverse event duration, the following rules will be 
applied for missing/invalid onset/resolution time: 
If onset time is collected and missing/invalid, onset time will be temporarily set to 00:00:01 
If resolution time is collected and missing/invalid, resolution time will be temporarily set to 
23:59:59 
Imputation rules for missing or partial AE stop dates and the “continuing” variable indicated 
as “no” are defined below: 
• Year is missing – date left missing. 
• Month is missing – impute December. 
• Day is missing – impute last date of that month. 


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 26 of 69 
 
If imputed AE stop date is before AE start date, AE stop date will be set to AE start date. 
Imputation rules for missing or partial medication start dates are defined below: 
If only Day of CM start date is missing:  
If the CM start year and month are the same as that for the first dose date, then: 
• If the full (or partial) CM end date is NOT before the first dose date or CM end date 
is missing, then impute the CM start day as the day of first dose date;  
• Otherwise, impute the CM start day as 1. 
If Day and Month of CM start date are missing: 
If CM start year = first dose year, then: 
• If the full (or partial) CM end date is NOT before the first dose date or CM end date 
is missing, then impute the CM start Month and Day as the Month and Day of first 
dose date 
• Otherwise, impute the CM start MONTH as January and the DAY as 1. 
If Year of CM start date is missing: 
If the year of CM start is missing or CM start date is completely missing, then query site and 
leave as missing.  
If the stop date for CM is missing or partially missing and the “ongoing” variable is indicated 
as “no”, the imputation rule is applied in the following order: 
• Year is missing – Date is left missing. 
• Month is missing – impute December. 
• Day is missing – impute last date of that month. 
 
7.3 
Handling of site with GCP violation 
During routine monitoring of this study, it was observed that one site (Site ID: 6103) had 
GCP compliance issues, which raised doubts on the study conduct.  The blinded ADA results 
from the site also confirmed the need to exclude the site from results reporting. Mylan 
decided to conduct statistical analyses to exclude this site from ITT, Safety, and PP analysis 
sets. Additional sensitivity analysis to include this site (Randomized analysis set) for major 
baseline findings, efficacy and safety analysis will be performed. The purpose of the 
sensitivity analysis is to determine if major efficacy and safety analyses remain consistent 
with inclusion data from this site.   


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 27 of 69 
 
8 
STATISTICAL METHODS 
8.1 
General statistical conventions 
All statistical procedures will be completed using SAS version 9.3 or higher. 
Unless otherwise stated, all statistical testing will be two-sided and will be performed using 
a significance (alpha) level of 0.05. Two-sided 95 % confidence intervals (CI) will be 
provided when relevant. 4 digits after decimal point will be used for all p-values. 
All quantitative endpoints will be summarized using an 8-number summary (n, mean, 
standard deviation, median, 25th quartile, 75th quartile, minimum and maximum values). 
Unless otherwise specified, minimum and maximum will be presented with same number of 
decimal places as reported/collected, one additional decimal place for mean, median, 25th 
quartile and 75th quartile, and two additional decimal places for standard deviation. All 
qualitative endpoints will be summarized by the number of subjects meeting the endpoint 
and the percentage of subjects out of the appropriate population. The denominator will be 
displayed when needed. 
For retests, unscheduled visits and visit end of treatment, 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. The same principle will be applied to the visit end of treatment data.  
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 11. 
All subject data, including those derived, will be presented in individual subject data listings. 
Unless otherwise stated, unscheduled visit results will be included in date/time chronological 
order, within subject listings only. All listings will be sorted by investigational site, patient 
number, date/time and visit. The treatment group as well as patient’s sex and age will be 
stated on each listing. Unless otherwise stated, data listings will be based on all subjects 
randomized.  
The visit schedules and window are shown below. If multiple records in the same visit, 
please use the latest one for analysis. 
Study Periods 
Screening 
Run-in Period 
Treatment Period 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Study Week 
-7 to -4 
-4 
-3 
-2 
-1 
0 
1 
Study Day 
-49 to -28 
-28+/-3 
-21+/-3 
-14+/-3 
-7+/-3 
0+/-3 
7+/-3 
Study 
Day 
Range 
[-49, -28] 
[-27, -
25] 
[-24, -
18] 
[-17,-
11] 
[-10, -
4] 
[-3, 3] 
[4,10] 


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 28 of 69 
 
 
Study 
Periods 
Treatment Period (continue to upward table) 
Foll
ow-
up 
Visit 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
Study 
Week 
2 
4 
8 
12 
16 
20 
22 
24 
28 
Study 
Day 
14+/-3 
28+/-3 
56+/-7 
84+/-
7 
112+/-7 
140+/-
7 
154+/-7 
168+
/-7 
196
+/-7 
Study 
Day 
Range 
[11, 
20] 
[21, 
40] 
[41, 
70] 
[71,9
8] 
[99,126
] 
[127,1
47] 
[148,16
1] 
[162, 
182] 
[183
, 
203] 
 
8.2 
Investigator pooling for secondary analyses 
Investigator pooling will be done for secondary analyses where model contain investigator 
effect. 
Pooling will be based on: 
1) sites with less than 16 subject within each state will be pooled together geographically 
but can’t over 40 subjects;   
2) if a state with more than 40 subjects, sites within the state can be pooled geographically 
or sites will be pooled with neighbor state(s) geographically;  
3) if a state with less 16 total subjects, then the sites will be pooled with other state (but 
can’t be exceeded 40 subjects) geographically. 
Pooling will be done prior to database lock and will be documented in the final BDR 
report. 
8.3 
Subject disposition 
The number of patients screened, run-in, randomized, and included in each analysis 
population, along with study completion status, will be summarized by treatment group as 
well as overall. In addition, the number of patients who discontinue from the study and from 
IMP will be summarized by discontinuation reason. And the number of patients who 
discontinue from the run-in period will be summarized by discontinuation reason too. 
The denominator used for the calculation of percentages will be the number of subjects 
randomized. 
8.4 
Protocol deviations 
All protocol deviations identified will be summarized by treatment group and overall and by 
classification, i.e., major and minor. 


 
 
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Summaries will be conducted on all subjects that were randomized. 
8.5 
Demographics and baseline characteristics 
No statistical testing will be performed for the comparison between treatment groups on 
demographics and baseline characteristics. 
8.5.1 Demographics 
Subject demographics will be summarized by randomized treatment group, as well as overall 
for all subjects in the ITT analysis population. Age, height, weight and BMI at baseline will 
be summarized using an 8-number summary (n, mean, standard deviation, median, 25th 
quartile, 75th quartile, minimum and maximum values). Qualitative variables such as 
gender, child-bearing potential status, ethnicity and race will be summarized using count and 
percentage.    
A by-subject listing will be provided. 
8.5.2 Baseline and disease characteristics 
The categorical baseline characteristics such as duration of DM, time of basal dose, TEAR, 
HbA1c, FPG, insulin used prior to screening, baseline ECG and other baseline lab 
parameters will be summarized using frequency counts for the ITT analysis population.  
A by-subject listing will be provided.  
8.5.3 Medical history 
A summary of medical history will be summarized by treatment group, as well as overall,  
by system organ class (SOC) and preferred term (PT) using latest version of Medical 
Dictionary for Regulatory Activities® (MedDRA) for the ITT analysis population. 
A by-subject listing will be provided. 
8.5.4 Concomitant medications 
Medications used in this study will be coded by using the latest available version of the 
World Health Organization Drug Dictionary Enhanced (WHODDE).  
Prior medications: are defined as medications taken within 28 days prior to screening and 
prior to dosing with study medication.   
Concomitant medications: are defined as medications that were ongoing at the time of first 
dose of study medication or new medications that started after first dose of study medication 
and within 28 days following the date of the last dose of study medication. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by anatomical therapeutic chemical (ATC) class and preferred name by 
treatment group, as well as overall on the ITT analysis population.  
A by-subject listing will be provided.  


 
 
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Details for imputing missing or partial start and/or stop dates of medication are described in 
Section 7.2.3. 
8.6 
Extent of exposure 
8.6.1 Treatment duration 
Duration of study drug (in days) will be calculated as: last dose date – first dose date + 1 day, 
regardless of study drug interruption. 
Study drug exposure will be summarised by treatment group as well as overall on the ITT 
analysis set using descriptive statistics for run-in period and treatment period. 
8.6.2 Treatment compliance 
Patient will be identified as study treatment non-compliant if the patient meets any following 
criteria: 
• Missing total meal time insulin daily  
• Missing basal insulin daily  
• Took two times more basal insulin daily  
• Took less or more than prescribed basal insulin dose units daily  
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 divided 
by 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. 
Treatment compliance will be summarized on the ITT analysis set. 
8.7 
Efficacy analyses 
This section addresses separately the analyses to be conducted on the primary and secondary 
efficacy variables. The primary analysis population for efficacy analyses will be the ITT 
population, although some analyses may be repeated for other analysis sets as indicated. 
8.7.1 Analysis methods 
Definition of Primary Endpoints  
The TEAR rate during 24-week treatment period is the primary endpoint for this study. 
TEAR is defined as either one of the following:  
1) Subjects who are ADA negative at baseline and become positive at any timepoint post 
baseline.  
2) Subjects who are ADA positive at baseline and demonstrate 4-fold increase in titer values 
at any timepoint post baseline visit. 


 
 
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Although differences in TEAR rate is the primary endpoint for the study from a statistical 
perspective, given that immunogenicity is not a standard endpoint in clinical trials, this 
difference, even if significant, will not be assessed in isolation but will be part of totality of 
evidence including changes in HbA1c, FBG, insulin dose, neutralizing antibodies and 
injection site reactions to ensure that changes in TEAR rate, if any, are clinically correlated 
and meaningful. 
Statistical Methodology for Primary Endpoint 
The 90% confidence interval of the treatment difference (MYL-1601D minus NovoLog®) in 
the TEAR rate will be established using the Wald confidence limit method with multiple 
imputation (Section 8.7.2.1).  The MYL-1601D TEAR rate will be declared equivalent to 
that of NovoLog® during the 24-week treatment period if the 90% confidence interval of 
the treatment difference in TEAR rate is within the pre-specified margin as displayed in 
Table 2 of the study SAP, as suggested by Chow et al. (2002; 2003). For specific reference 
drug rate–based margin calculation, please refer to the SAS example code in Section 10 
(Appendices – SAS Example Codes). 
The primary analysis will be based on the ITT population. In addition, all post-
discontinuation and rescue data will be included in the analysis. 
8.7.1.1 Multiplicity 
No adjustment will be made for multiple comparisons. 
8.7.1.2 Treatment by center interaction analysis (multi-center study) 
No analysis will be made to assess the treatment-by-center interaction. 
8.7.2 Analysis of primary efficacy endpoint(s) 
The primary objective of the study is to assess whether MYL-1601D is equivalent to 
NovoLog in immunogenicity, as assessed by the rate of treatment emergent antibody 
response (TEAR) during 24 weeks of treatment. The primary efficacy endpoint is the TEAR 
rate at Week 24. TEAR is defined as either one of the following: 
1) Subjects who are ADA negative at baseline and become positive at any timepoint 
post baseline  
2) Subjects who are ADA positive at baseline and demonstrate 4-fold increase in titer 
values at any timepoint post baseline visit.  
8.7.2.1 Primary efficacy analysis 
The primary efficacy analysis will be a test of equivalence for the MYL-1601D and 
NovoLog groups in the TEAR rate at Week 24. The null hypothesis is non-equivalence, 
expressed by 
𝐻𝐻0:  |𝑝𝑝𝑀𝑀−𝑝𝑝𝑁𝑁| ≥𝛿𝛿,   𝛿𝛿> 0 


 
 
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where 𝑝𝑝𝑀𝑀 and 𝑝𝑝𝑁𝑁 are the (true) proportions of subjects with TEAR in the MYL-1601D and 
NovoLog groups, respectively, and 𝛿𝛿 is the equivalence margin. The null will be rejected 
in favor of equivalence if the 90% confidence interval of the treatment difference is within 
the range (−𝛿𝛿, 𝛿𝛿). The confidence interval as defined by Chow and Shao (2002) is 
constructed as  
CI2𝛼𝛼= [𝑝𝑝̂ 𝑀𝑀−𝑝𝑝̂ 𝑁𝑁−𝑡𝑡𝛼𝛼𝜎𝜎ො,   𝑝𝑝̂𝑀𝑀−𝑝𝑝̂𝑁𝑁+ 𝑡𝑡𝛼𝛼𝜎𝜎ො] 
where 𝑝𝑝̂𝑗𝑗 is the estimate of the TEAR rate 𝑝𝑝𝑗𝑗 in each treatment group, 𝑗𝑗∈{𝑀𝑀, 𝑁𝑁} ,  𝜎𝜎ො is the 
sample estimate of the standard error of the mean, and 𝑡𝑡𝛼𝛼 the 0.05 quantile of the t 
distribution with (𝑁𝑁−2) degrees of freedom with 𝑁𝑁 being the pooled number of subjects 
in the analysis. That is, 𝐻𝐻0 will be rejected if neither – 𝛿𝛿 nor 𝛿𝛿 is contained within the 90% 
confidence interval. 
To minimize any bias due to missing data, the primary efficacy analysis will use multiple 
imputation to fill in missing ADA values. Multiple imputation (MI) will be applied to two 
measured variables: ADA binary response (positive/negative) and ADA continuous titer 
values. Multiple imputation will be done for each variable separately, then the two sets of 
imputed datasets will be merged in order to generate the imputed TEAR status. For subjects 
who are ADA negative at baseline, post-baseline missing values will be imputed using the 
binary response values obtained from logistic regression MI. Missing post-baseline values 
for subjects who are ADA positive at baseline will be derived from the continuous MI model. 
The primary efficacy analysis is based on the Week 24 (Visit 15) value. Subjects who 
discontinue treatment prematurely will be classified based on whether ADA values were 
obtained for the visits after treatment discontinuation (retrieved dropouts) or not.  
For continuous-valued ADA titer, missing values prior to the last observed visit will be filled 
in with MCMC imputation 
to make the dataset monotone. Missing values after 
discontinuation will be imputed by regression imputation of the monotone missing dataset. 
If there are at least 6 retrieved dropouts in each treatment arm, then a pattern mixture model 
estimated from the retrieved values will be used for regression imputation of missing values. 
Otherwise, the complete case missing values method will be used. Missing values for the 
binary response variable will be imputed using a logistic regression multiple imputation 
model. A monotone missingness pattern will be created by taking a random draw from the 
binomial distribution with the same probability as the observed responses from the same 
treatment group at the same visit. 
Pattern mixture models will be fit separately for ADA binary response and for ADA titer. 
Binary response will be imputed using a logistic regression imputation model, while ADA 
titer will use a continuous-valued regression. Independent variables in the regression will 
include the values at all prior visits. Each imputation will be repeated 30 times with a seed 
of 40872021 for ADA binary response and a seed of 41671703 for ADA titer. Code for the 
multiple imputation analyses is presented in Appendix 10.1. 


 
 
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If baseline value is missing, the missing baseline value will be imputed with six imputations 
based on binomial distribution using probability of no missing baseline values from same 
treatment group. 
After imputation, the dataset containing the imputed visitwise TEAR positive or negative 
status binary response and the dataset containing the imputed ADA titer values will be 
merged by subject, visit, and imputation number.  The Week 24 values will then be used to 
assign the status of TEAR positive or negative, as follows:  
If the subject was ADA negative at baseline, then this subject will be considered TEAR 
positive if any post-baseline observed or imputed value was ADA positive; otherwise, the 
subject will be considered TEAR negative. The imputed titer values will not be considered 
in subjects who are ADA negative at baseline. 
If the subject was ADA positive at baseline, then the imputed titer values will be used. The 
subject will be considered TEAR positive if the ADA titer at any post-baseline visit was ≥ 
4× the baseline titer. If none of the post-baseline titer values reached 4 times the baseline 
titer, then the subject will be classified as TEAR negative. 
For each imputation, the proportion of responders, along with standard errors, will be 
estimated for each treatment group, and the estimate and standard error of the risk difference 
will be computed. These values will be combined across imputations using PROC 
MIANALYZE. Subsequently, the 90% confidence interval for the risk difference will be 
computed using the Wald confidence limit method.  
An equivalence margin will be established as a function of the TEAR rate among the 
Novolog subjects. Under the null hypothesis of equivalence (i.e., 𝐻𝐻0: 𝑝𝑝𝑀𝑀= 𝑝𝑝𝑁𝑁), the margin 
can be obtained as a function of the TEAR rate in the Novolog group using the following 
expression (Chow S-C et al., 2003, p. 91). 
 
𝛿𝛿= ൫𝑧𝑧𝛼𝛼+ 𝑧𝑧𝛽𝛽൯ඨ2𝑝𝑝𝑁𝑁(1 −𝑝𝑝𝑁𝑁)
𝑛𝑛𝑁𝑁
 
Selected values for 𝛿𝛿 are provided in Table 2 of Section 5 above. If the margin falls within 
the 90% confidence interval for the risk difference, then equivalence of MYL1601-D and 
Novolog will be declared. 
 
These steps can be executed using code similar to the following: 


 
 
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proc freq data=simdata ; 
title "90% Wald confidence interval”; 
by _imputation_; 
ods output riskdiffcol2=rdiff1; 
table group*resp / riskdiff (CL=WALD column=2)  alpha=0.1; 
weight count; 
run; 
 
data rdiff1; set rdiff1; 
keep _imputation_ row risk ase lowercl uppercl; 
if row='Difference'; 
run; 
 
proc mianalyze data=rdiff1; 
modeleffects risk; 
stderr ase; 
ods output ParameterEstimates=mirisk1; 
run; 
 
ods listing; 
data parms1; 
set mirisk1; 
lowercl = estimate - (1.645*stderr); 
uppercl = estimate + (1.645*stderr) ; 
run; 
proc print data=parms1; 
var estimate stderr lowercl uppercl; 
run; 
 
8.7.2.2 Secondary/Sensitivity analyses of the primary efficacy endpoint 
Several sensitivity analyses will be conducted on the primary efficacy analysis: 
1) The primary efficacy analysis will be repeated using observed data without 
imputation. This analysis will be conducted on both the ITT and the PP populations. 
2) Subjects in the MYL-1601D group who are missing ADA values, and thus a TEAR 
assessment, will have their TEAR status at Week 24 imputed as positive. No 
imputation will be done for missing values in the NovoLog group. 
3) A tipping point analysis will be implemented following Liublinska and Rubin (2014). 
See below. 
The ADA TEAR rate for each treatment group, and the difference between treatments, for 


 
 
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subjects who are missing data during the treatment period will be summarized for all 
sensitivity analyses. 
The number and percent of subjects with TEAR will be summarized by treatment for each 
study visit during the treatment period by using similar TEAR definition: ADA negative at 
baseline become positive at specific visit, and ADA positive at baseline and become 4-fold 
increase in titer at specific visit.  
A by-subject listing will be provided for observed and derived variables. 
8.7.2.3 Tipping point analysis 
A tipping point analysis will be used to estimate the point at which the equivalence boundary 
is crossed and the results fail to reject non-equivalence; that is, where 
|𝑝𝑝̂𝑀𝑀−𝑝𝑝̂ 𝑁𝑁| ≥𝛿𝛿,   𝛿𝛿> 0 
The tipping point analysis will consider all possible counts of TEAR positive subjects that 
could result if TEAR status could be observed for each missing value. This will range from 
all missing values being imputed as positive to all missing values imputed as negative. 
Following Liublinska and Rubin (2014), a graphical display (heat map) is used to indicate 
the tipping point analysis results for each combination of imputed missing values. The risk 
difference in TEAR rate across the treatment arms is presented for each combination in the 
heat map. The graph will display the sensitivity across the range of missing values as a color 
gradient from most favorable for the test treatment arm to the most favorable for the 
reference treatment. 
In addition, the TEAR rate at each scheduled visit (visitwise TEAR [vTEAR]) will be 
summarized at each scheduled visit by using the following criteria: Subjects who are ADA 
negative at baseline and become positive at a specific visit (Treatment Induced TEAR), and 
subjects who are ADA positive at baseline and obtain a 4-fold increase in titer at a specific 
visit (Treatment Boosted TEAR), will each be counted as TEAR positive at the specified 
visit. 
8.7.3 Secondary endpoints 
The following efficacy measures (both actual and change values) will be summarized at 
baseline and each scheduled visit.  
• Change in HbA1c from baseline. 
• Change in fasting plasma glucose from baseline. 
• Change in prandial, basal insulin and total daily insulin dose per unit body weight 
(U/kg) from baseline. 
• Change in 7-point self-monitored blood glucose (SMBG) profile from baseline. 
A mixed model for repeated measures (MMRM) will be performed for continuous variables 
without imputing missing values. The MMRM model will include the fixed, categorical 


 
 
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effects of treatment group assignment, visit, treatment group-by-visit interaction, basal 
insulin dose time (AM/PM), and investigative site, as well as the baseline value as a 
continuous covariate.  
The MMRM model results will be presented along with Least Squares (LS) means for the 
difference between the MYL1601-D and NovoLog groups, standard errors, and two-sided 
95% CIs for the difference between treatment groups. Contrasts of LS means 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. 
The interaction of time points and treatment groups will also be presented. An unstructured 
covariance matrix will be assumed for within-subject error. The denominator degrees of 
freedom will be calculated according to the Kenward-Roger method. 
In case of non-convergence of the above model using an unstructured covariance matrix, the 
following variance structures will be tested, and based on Akaike’s information criteria the 
best fitting model will be chosen. The variance structures that will be considered for the 
within-subject variation in case of non-convergence are in this order: Heterogeneous 
Toeplitz, Toeplitz, and Compound Symmetry.  
If convergence is still not obtained, the model may be revised to remove investigative site 
from the list of covariates. 
All of the above analyses will be performed on the ITT set. 
8.7.3.1 HbA1c 
HbA1c is collected at week -7 to -4 (visit 1), baseline, week 12 (visit 11), and week 24 (visit 
15). The measurements are performed by the central laboratory. 
Actual values and changes from baseline at each time point will be computed and 
summarized by treatment group. Treatment difference and 95% confidence interval will be 
displayed along with p-values. 
A sensitivity analysis for HbA1c will be performed using multiple imputation to impute 
missing values with non-missing subjects within the same treatment group using a pattern 
mixture model with the complete-case missing values (CCMV) method (Little 1993). After 
imputation, treatment difference, 95% CI, and p-values will be generated using same 
MMRM model as above. Sample imputation code is provided in Appendix 10.1.4.  
8.7.3.2 Fasting plasma glucose 
The fasting plasma glucose is collected at week -7 to -4 (visit 1), baseline, week 4 (visit 9), 
week 8 (visit 10), week 12 (visit 11), week 16 (visit 12), week 20 (visit 13), and week 24 
(visit 15, End of Treatment).  The measurements are performed by the central laboratory. 
Actual values and changes from baseline at each time point will be computed and 
summarized by treatment group. 


 
 
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A separate analysis will be performed excluding patients with no fasting status. 
8.7.3.3 Daily insulin dose per unit body weight (mealtime, basal insulin and total) for 
days of 7-Point profiles 
Patients will be asked to document the dose of insulin taken on the same day they will 
perform the 7-Point SMBG profiles (from week -2 to week 24).  The measurements are taken 
the week prior to the visits, so the week prior to: 
- 
Week -2 (Visit 4) 
- 
Week 0 (Visit 6)  
- 
Week 2 (Visit 8) 
- 
Week 4 (Visit 9) 
- 
Week 8 (Visit 10) 
- 
Week 12 (Visit 11) 
- 
Week 16 (Visit 12)  
- 
Week 20 (Visit 13) 
- 
Week 24 (Visit 15) 
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.  


 
 
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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. 
8.7.3.4 7-Point Self-Monitored Blood Glucose (SMBG) profile 
The 7-point SMBG profile recorded via glucometer and transferred by the subject to the 
diary, measurement will be performed by the subject at home on 3 days (of which 2 days are 
consecutive) in the week before the visit 
The following summaries will be summarized at week 2, 4, 8, 12, 16, 20 and week 24: 
Individual 7-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 
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. 


 
 
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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 7 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. 
8.7.4 Analysis of exploratory endpoint(s) 
Not Applicable. 
8.7.5 Subgroup analyses 
Subgroup analyses of important factors, including but not limited to factors such as age 
group, gender, race, and ethnicity are planned for the key outcomes of TEAR rate and 
immunogenicity variables. Wald confidence limit method for TEAR rate will be used for 
90% confidence interval. Other exploratory subgroup analyses may be performed, as deemed 
appropriate. 
The following subgroups will be assessed and described within the subgroup analysis.  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: 


 
 
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o 
American Indian or Alaska Native 
o 
Asian 
o 
Black or African American 
o 
Native Hawaiian or Other Pacific Islander 
o 
White 
• Ethnicity: 
o 
Hispanic or Latino 
o 
Not Hispanic or Latino 
o 
Not reported or Unknown 
8.8 
Safety analyses 
Safety data from the run-in period will be summarized and listed on run-in analysis set.  
Descriptive statistics will be provided for the following safety data. No inferential analysis 
of this safety data is planned. Any Vital signs, ECG, and Laboratory abnormalities of 
potential clinical concern will be described. 
For the continuous safety measures, both actual and change values will be summarized at 
baseline and scheduled visit. Similar MMRM model as efficacy analysis will be conducted 
for hypoglycemia rate. For antibody continuous variables, 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 and baseline value as covariates. 
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 following analyses will also be performed. 
• Incidence of ADA response, incidence of positive cross-reactive ADA, and 
incidence of positive NAbs 
• Analysis of potential impact of TEAR status on efficacy and safety parameters such 
as HbA1c, FPG, insulin dose hypoglycemic rate, and incidence of any injection site 
allergic reactions and hypersensitivity 
• Change in hypoglycemia rate (30 day adjusted) from baseline and incidence of 
hypoglycemic events at scheduled visits 
• Incidence of TEAEs and SAEs 
• Incidence of local allergic reactions, systemic allergic reactions and other adverse 
events 
• Incidence of device-related safety assessment 
To explore the potential ADA impact on subject’s glucose control, the following analyses 
will be performed: 


 
 
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• The incidence of subjects with each of the three following criteria will be 
summarized descriptively (for categorical measures) by treatment: 
1) Meet TEAR criteria 
2) Increases in HbA1c of over 0.2% from baseline  
3) Increase in total dose from baseline  
• Scatter plots of maximum tear values with HbA1c FPG and total daily insulin dose 
by treatment. 
All the above analyses will be performed on the safety set. 
In addition, graphical visualization of relationship between adverse events and treatment 
duration will be provided. 
8.8.1 Adverse events 
The frequency of AEs, SAEs, and AEs leading to discontinuation through Week 24 will be 
summarized based on safety analysis set or run-in analysis set. 
All Adverse Events (AEs) will be classified by Primary System Organ Class (SOC) and 
Preferred Term (PT) according to the Medical Dictionary for Regulatory Activities 
(MedDRA) Version latest version. All subjects in the safety analysis set will be included in 
the summaries.  
AEs will be classified as treatment emergent adverse events (TEAEs) are defined as follows:  
TEAE: All AEs that occur after the first dose of study treatment medication after 
randomization through follow-up visit or 14 days after last dose [for subjects that do not 
have a follow-up visit] will be considered treatment emergent AEs. 
Treatment-Related AEs: AE will be defined as related if causality is either definitely, 
probably or possible. AE will be defined as unrelated if causality is unlikely or not related.  
AEs where the causality is missing will be assumed to have “Reasonable possibility of 
relatedness.” 
Grade AEs:  
Grade AEs (serious and non-serious) in accordance with the NCI/CTCAE scale (available 
at  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/) as presented below: 
• Mild (Grade 1) asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
• Moderate (Grade 2) minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• Severe (Grade 3) Severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living 


 
 
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• Life-threatening (Grade 4) Life-threatening consequences; urgent intervention 
indicated 
• Death (Grade 5) Death related to the AE. 
Details for imputing missing or partial start dates of adverse events are described in Section 
7.2.2. Imputed Adverse Event dates will be used for determining treatment-emergence. 
Summaries of AEs will include the following: 
• Treatment-emergent AEs 
• Treatment-emergent treatment-related AEs 
• Treatment-emergent AEs leading to study drug discontinuation 
• SAEs 
• Treatment-related SAEs 
• AEs leading to death 
• TEAE with the local and systemic allergic reactions 
All TEAEs will be summarized by SOC, PT and treatment group as well as overall using 
frequency counts and percentages. In addition, an overall summary for the categories above 
will be prepared by treatment group and overall.  
The number and percentage of subjects with at least one treatment emergent AE will be 
presented by treatment group as well as overall and events further summarized by maximum 
severity and relationship to study medication. 
Where a subject has the same adverse event, based on preferred terminology, reported 
multiple times in the treatment period, the subject will only be counted once at the preferred 
terminology level in adverse event frequency tables. 
Where a subject has multiple adverse events within the same system organ class in the 
treatment period, the subject will only be counted once at the system organ class level in 
adverse event frequency tables. 
When reporting adverse events by severity, in addition to providing a summary table based 
on the event selection criteria detailed above, summary table will also be provided based on 
the most severe event during the treatment period - independent of relationship to study 
treatment. 
Graphical visualization of relationship between adverse events and treatment duration will 
be provided. There are 2 graphs which are Time to AE Occurrence and Most Frequent On-
Therapy AE Sorted by Risk Difference. 
For run-in period, AEs and SAEs will also be summarized for run-in analysis set. 
8.8.2 Device-related Assessment include both TEAE and device complaints 
The total incidence of Device-related safety events will be summarized for each treatment 
group as well as overall and would include device-related TEAEs and events related to 


 
 
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device complaints or failures. For device-related TEAEs, two categories will be summarized 
for each treatment as well as overall: needle-related TEAEs such as pain, bruise, and 
bleeding; and other device-related TEAEs, such as hyperglycemia or hypoglycemia. For 
device-related patient’s complaints, incidence will be listed and summarized for each 
treatment and overall. Observed values and change from baseline will also be presented. 
All the above analyses will be performed on the safety set for treatment period and run-in 
period. 
8.8.3 Hypoglycemia 
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: 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). 


 
 
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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. 
8.8.4 Hypersensitivity and Immune mediated adverse events 
Incidence of hypersensitivity and immune mediated adverse events will be presented for 
treatment groups as well as overall. 
8.8.5 Immunogenicity assessments 
For antibody continuous variables, 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 and baseline value as covariates. 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 following analyses will also be performed. 
• Incidence of ADA by visit, incidence of positive cross-reactive ADA by ADA 
status and by visit, and incidence of NAbs. 
• Analysis of potential impact of TEAR status on efficacy and safety parameters such 
as HbA1c, glucose control FPG, insulin dose, hypoglycemic rate, and Incidence of 
any injection site allergic reactions and hypersensitivity. 
To explore the potential ADA impact on the subjects’ glucose control, scatter plots of 
maximum TEAR values with HbA1c, FPG and total daily insulin dose will be 
displayed by treatment. In addition, the following analyses will be performed: 
• TEAR effect on Efficacy will be assessed using the following: 
1) HbA1c and total insulin dose values by TEAR status and treatment group. 
2) A summary of subjects who experience meet vTEAR criteria, an increase in 
A1c of at least 0.2% from baseline, and an increase in the total dose from 
baseline at a protocol scheduled visit (where immunogenicity, A1c and dose all 
measured). This summary will be provided by visit, by treatment group, and 
overall. 
• TEAR effect on Safety will be assessed using the following: 


 
 
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1) Hypoglycemic rate by treatment group and TEAR status. 
2) Incidence of injection site allergic reactions and incidence of hypersensitivity in 
TEAR positive subjects. 
3) Incidence of positive NAb by TEAR status and treatment group. 
All the above analyses will be performed on the safety set. 
The NAb actual assay results will not be available at the time of database lock (EDC database 
lock) for the analysis.  However, the treatment will remain blinded during the laboratory 
assay.  These data will be sent later from assay lab and statistical analysis will be performed 
according to pre-specified method in this SAP. 
8.9 
Other Safety Analyses 
8.9.1 Laboratory Data 
Change from baseline of laboratory measurements will be analyzed using MMRM with 
model terms of investigator, 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.  
The percentage of subjects in categories such as normal, abnormal/non-clinically significant 
and abnormal/clinically significant will be summarized by treatment.  
The percentage of subjects who meet potentially clinically significant criteria will be 
summarized by treatment groups. 
The criteria for the Potential Clinically Significant Lab is listed in Appendix 10.3. 
The following safety laboratory tests will be performed at times defined in the study 
schedules in Table 1. 
 
Table 4: Laboratory Safety Tests 


 
 
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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/Serum hCG  
HIV and HBsAg 
and HCVAb 
HbA1c 
 
a Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase. 
Hematology, chemistry, urinalysis and other (parameters in last column of Table 4) will be 
summarized for treatment groups as well as overall by visits and parameters in each category.  
8.9.2 Vital signs 
Change from baseline of vital sign measurements will be analyzed using MMRM with model 
terms of investigator, 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 who meet potentially clinically significant criteria will be 
summarized by treatment groups. 
8.9.3 Physical examinations 
A full physical examination will be performed at Visit 1 (screening), Visit 6 (randomization) 
and Visit 15 (EOT or ET). Height and weight will be assessed at Visit 1. The percentage of 
subjects in 
categories such as normal, 
abnormal/non-clinically 
significant 
and 
abnormal/clinically significant will be summarized at scheduled visits. But clinically 
significant changes from the screening procedures results will be recorded as adverse events. 
Physical examinations will be summarized for the safety analysis set. 


 
 
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8.9.4 Electrocardiograms (ECG) 
The percentage of subjects in categories such as normal, abnormal/non-clinically significant 
and abnormal/clinically significant will be summarized by treatment group at screening and 
EOT.  
8.10 Interim analysis 
No interim analysis is planned for this study. 
 


 
 
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9 
REFERENCES 
1) 
ICH Topic E3: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95- 
adopted December 1995). 
2) 
Dong and Peng. Principled missing data methods for researchers. SpringerPlus, 
2013, 2:222.  
3) 
Chow S-C and Shao J. A note on statistical methods for assessing therapeutic 
equivalence. Controlled Clinical Trials, 2002; 23: 515–520. 
4) 
Chow S-C, Shao J, Wang H. Sample Size Calculations in Clinical Research. New 
York: Marcel Dekker, 2003. 
5) 
Liublinska and Rubin. Sensitivity analysis for a partially missing binary outcome in 
a two-arm randomized clinical trial. Stat Med. 2014; 33(24) 4170-4185. 
6) 
Roderick J. A. Little. Pattern-Mixture Models for Multivariate Incomplete Data. 
Journal of the American Statistical Association. 1993: 88: 125-134. 
 
 
 


 
 
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10 
APPENDICES – SAS EXAMPLE CODES 
10.1 Multiple imputation 
Multiple imputation will be applied to fill in missing values for ADA binary response and 
for ADA titer. 
For binary ADA response, if baseline ADA value is missing, the missing baseline value 
will be imputed (6 imputations) based on binomial distribution using probability of no 
missing baseline values form the same treatment group. After imputations, for subjects 
with negative baseline ADA (Section 10.1.1) missing post-baseline binary response 
(positive or negative) will be imputed using logistic regression multiple imputation. For 
subjects who are ADA positive at baseline (Section 10.1.2), missing post-baseline ADA 
continuous titer values will be imputed with same treatment group non-missing subjects 
using continuous MI model. 
The steps are summarised below: 


 
 
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Create a dataset with one record per subject, 
containing all values of ADA Response for 
Baseline, Weeks 2, 4, 8, 12, 16, 20, 24 
(variables RESP6, RESP8 - RESP13, and 
RESP15).
Create a dataset with one record per subject, 
containing all values of ADA Titer for Baseline, 
Weeks 2, 4, 8, 12, 16, 20, 24 
(variables ADA6, ADA8 - ADA13, and ADA15).
Add visit-level variables EMPTYx for each subject.
Run 6 MCMC imputations .
Multiple Imputation
to fill in missing ADA values
ADA Binary Response 
(Positive/Negative)
ADA Titer 
(continuous values )
Non-missing 
value for any 
visit after Week 
x
Fill in RESPx with a randomly generated 0 or 1.
Run 6 imputations by drawing random Response 
values from the binomial distribution based on the 
Response frequencies for the given visit within 
treatment group.
Step 1
Step 2
EMPTYx=0
EMPTYx=1
MYL-1601D
RESPx = 
ranbin(86537043,
1,&mylrate)
NovoLog
RESPx = 
ranbin(48010557,
1,&novrate)
Step 3
Run a pattern mixture model logistic regression 
to produce 5 imputations for each record from 
Step 2. 
≥  6 retrieved 
subjects per arm 
Impute missing 
values by modelling 
the retrieved 
subgroup data
<  6 retrieved 
subjects per arm 
Impute missing 
values using 
CCMV method
Run a pattern mixture model regression to produce 
5 imputations for each record from Step 2. 
Step 4
Combining the multiple 
imputation results and derive 
TEAR status.
≥  6 retrieved 
subjects per arm 
Impute missing 
values by modelling 
the retrieved 
subgroup data
<  6 retrieved 
subjects per arm 
Impute missing 
values using 
CCMV method
No non-missing 
values for any visit 
after Week x


 
 
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Section 10.1.1 describes the methodology for imputation of binary response, while Section 
10.1.2 covers the imputation of continuous ADA titer, and Section 10.1.3 puts them 
together. 
10.1.1 Multiple imputation for binary ADA response if baseline ADA is negative. 
For purposes of these specifications, let RESPx represent the binary value (0 or 1) at 
Visit x, where x takes the values 0 (for Baseline) or 8–15. The seed that will be used in the 
multiple imputation of ADA binary response will be 40872021.  
Missing values will be obtained from logistic regression imputation on the observed values 
of binary response. A fully conditional specification (FCS) method will be used to impute 
values from a non-monotone missing data pattern.  
There are 3 steps to this process: 
1. Create a dataset with one record per subject, containing all values of RESP for all 
weeks (Baseline and Weeks 2–24 on one record); that is, each record would contain 
variables for RESP0 and RESP8–RESP15. The subject-level RETRIEVED variable 
described in Section 8.7.2.1 can also be generated at this time for subjects who 
discontinued treatment, based on whether values after treatment discontinuation 
MI of 
ADA Binary Response
MI 
of ADA Titer
Generate Visitwise TEAR 
Responder Status
(using observed and imputed 
values)
Combining the multiple 
imputation results by Subject, 
Visit, and _imputation_
ADA Negative 
at Baseline
TEAR=0
TEAR=1
Any RESPx is 
positive?
YES
NO
ADA Positive
at Baseline
TEAR=1
Any Ratio 
ADAx/ADA at 
Baseline >=4?
NO
YES
Generate TEAR Responder Status 
based on Week 24 values
Combine the 30 CIs to generate 
one summary CI 
(PROC MIANALYZE)
Run the primary efficacy analysis: 
Create the 90% CI interval using 
Wald CI method within each 
imputation.


 
 
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were retrieved (set retrieved=1) or remain missing (set retrieved=0). 
2. Fill in missing values to make a monotone missing data pattern, by drawing random 
TEAR values from the binomial distribution based on the TEAR frequencies for the 
given visit within treatment group. 
3. Run a pattern mixture model logistic regression to impute missing values to 
generate 30 imputed datasets. This will generate a single pooled dataset containing 
one observation per subject per imputation. All missing values will have been filled 
in for each subject. 
Step 1. 
The dataset for this imputation has to put the values for all weeks onto one record. That is, 
the dataset would have one record per subject, with 8 values for RESP0 and RESP8–
RESP15. One way this can be accomplished is the following: 
data analysis (keep=usubjid RESP0 RESP8-RESP14); 
set indata; 
by usubjid avisitn; 
array R {9} RESP0 RESP8-RESP15; 
retain RESP0 RESP8-RESP15; 
if first.usubjid then do; 
   resp0 = base; 
   do visit = 8 to 15; 
      R{visit} = .; 
   end; 
end; 
do visit = 8 to 15; 
   if avisit = visit then R{visit} = aval; 
end; 
if last.usubjid then output; 
run; 
 
STEP 2. 
First a flag needs to be created to indicate which missing values need to be filled in. This is 
a visit-level variable for each subject. For explanatory purposes, this variable will be 
referred to as EMPTYx for Visit x. For each visit where a subject has a missing value, use 
the logic below: 
• If there is a non-missing value for any visit AFTER Visit x, then EMPTYx=0; 
• Else if there are no non-missing values for any of the remaining visits, then 
EMPTYx=1; 


 
 
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Then all records with EMPTYx=1 have to have their RESPx value filled in with a 
randomly generated 0 or 1. One way this can be accomplished is the following: 
/*** step 2: Make missingness monotone ***/ 
%global mylrate novrate; 
 
%macro getrate(visnum); 
 
proc sort data=indata; 
by trtgroup; 
run; 
ods exclude all; 
proc freq data=indata; 
by trtgroup; 
table RESP&visnum; 
ods output onewayfreqs=pct; 
run; 
ods exclude none; 
 
data binom; 
set pct (where=(RESP&visnum=1)); 
probresp = percent/100; 
if trtgroup=”MYL-1601D” then call 
symput("mylrate",probresp); 
else if trtgroup=”NOVOLOG” then call 
symput("novrate",probresp); 
run; 
 
%mend getrate; 
 
 
%macro fillin (visit); 
 
%getrate(&visit); 
 
data indata; 
set indata; 
if empty&visit=1 then do; 
   if trtgroup=”MYL-1601D” then  
RESP&visit=ranbin(86537043,1,&mylrate); 
   else if trtgroup=”NOVOLOG” then  
RESP&visit=ranbin(48010557,1,&novrate); 


 
 
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end; 
run; 
 
%mend fillin; 
 
 
%macro monotone; 
%do vis=8 %to 13; 
   %fillin(&vis); 
%end; 
%mend monotone; 
 
%monotone; 
 
STEP 3. 
Since SAS will not accept a binary variable as an independent variable in a logistic 
imputation model, continuous versions of the binary RESP variables. Both the continuous 
and categorical variables will be used during the regression. In the code below, the logistic 
regression code is different If there are <6 retrieved dropouts per group versus ≥6. 
 
/*** setup: create numeric versions of binary variables 
***/ 
data indata; 
set indata; 
array resps {7) resp0 resp8-resp14; 
array respns {7) respn0 respn8-respn14; 
do i=1 to 7; 
   respns{i} = resps{i}; 
end; 
run; 
 


 
 
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/*** step 3: Perform logistic regression imputation ***/ 
 
/*** Code to use if >=6 retrieved subjects per arm ***/ 
proc mi data=indata nimpute=30 seed=40872021 
out=outdata; 
class resp8-resp15; 
var resp0n resp8 resp8n resp9 resp9n resp10 resp10n 
resp11 
resp11n resp12 resp12n resp13 resp13n resp14 resp14n 
resp15; 
monotone logistic (resp8= resp0n) ; 
monotone logistic (resp9= resp0n resp8n) ; 
monotone logistic (resp10= resp0n resp8n resp9n) ; 
monotone logistic (resp11= resp0n resp8n resp9n resp10n) 
; 
monotone logistic (resp12= resp0n resp8n resp9n resp10n 
resp11n) ; 
monotone logistic (resp13=  
resp0n resp8n resp9n resp10n resp11n resp12n) ; 
monotone logistic (resp14=  
resp0n resp8n resp9n resp10n resp11n resp12n resp13n) 
; 
monotone logistic (resp15=  
resp0n resp8n resp9n resp10n resp11n resp12n resp13n 
resp14n) ; 
mnar model (resp8-resp15 / modelobs=(retrieved=1)); 
run; 
 


 
 
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/*** Code to use if <6 retrieved subjects per arm ***/ 
proc mi data=indata nimpute=30 seed=40872021 
out=outdata; 
by trtgroup; 
class resp8-resp15; 
var resp0n resp8 resp8n resp9 resp9n resp10 resp10n 
resp11 
resp11n resp12 resp12n resp13 resp13n resp14 resp14n 
resp15; 
monotone logistic (resp8= resp0n) ; 
monotone logistic (resp9= resp0n resp8n) ; 
monotone logistic (resp10= resp0n resp8n resp9n) ; 
monotone logistic (resp11= resp0n resp8n resp9n resp10n) 
; 
monotone logistic (resp12= resp0n resp8n resp9n resp10n 
resp11n) ; 
monotone logistic (resp13=  
resp0n resp8n resp9n resp10n resp11n resp12n) ; 
monotone logistic (resp14=  
resp0n resp8n resp9n resp10n resp11n resp12n resp13n) 
; 
monotone logistic (resp15=  
resp0n resp8n resp9n resp10n resp11n resp12n resp13n 
resp14n) ; 
mnar model (resp8-resp15 / modelobs=ccmv(k=1)); 
run; 
 
10.1.2 Multiple imputation for continuous ADA titer if baseline ADA positive. 
For purposes of these  specifications, let ADAx represent the continuous value for ADA 
titer at Visit x, where x takes the values 0 (for Baseline) or 8–15. The seed that will be used 
in the multiple imputation of ADA titer will be 41671703.  
There are 3 steps to this process: 
1. Create a dataset with one record per subject, containing all values of ADA for all 
weeks (Baseline and Weeks 2–24 on one record); that is, each record would contain 
variables for ADA0 and ADA8–ADA15. The subject-level RETRIEVED variable 
described in Section 8.7.2.1 can also be generated at this time for subjects who 
discontinued treatment, based on whether values after treatment discontinuation 
were retrieved (set retrieved=1) or remain missing (set retrieved=0). 
2. Run 30 Markov Chain Monte Carlo (MCMC) imputations to make the missing 


 
 
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values in the dataset have a monotone missingness pattern. This will produce a 
dataset with an index variable _imputation_ and otherwise the same variables 
as the input dataset. It will have one record per imputation per subject. 
3. Run a pattern mixture model regression imputation on each imputed dataset from 
Step 2. This will generate a dataset with the same structure as the input dataset, but 
will have the missing values filled in. 
Step 1. 
The dataset for this imputation has to put the values for all weeks onto one record. That is, 
the dataset would have one record per subject, with 8 values for ADA0 and ADA8–
ADA15. One way this can be accomplished is the following: 
data analysis (keep=usubjid trtp ADA0 ADA8-ADA15); 
set indata; 
by usubjid avisitn; 
array y {9} ADA0 ADA8-ADA15; 
retain ADA0 ADA8-ADA15; 
if first.usubjid then do; 
   ada0 = base; 
   do visit = 8 to 15; 
      y{visit} = .; 
   end; 
end; 
do visit = 8 to 15; 
   if avisit = visit then y{visit} = aval; 
end; 
if last.usubjid then output; 
run; 
Step 2. 
/*** step 2: Create monotone missingness using MCMC 
imputation ***/ 
proc mi data=analysis seed=41671703 nimpute=1 
out=outdata1; 
mcmc impute=monotone; 
var ada0 ada8-ada15; 
run; 


 
 
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Step 3. 
/*** step 3: Perform PMM regression imputation ***/ 
proc sort data=outdata1; 
run; 
 
/*** Code to use if >=6 retrieved subjects per arm ***/ 
proc mi data=outdata1 seed=41671703 nimpute=30 
out=outdata2; 
class retrieved; 
monotone reg(ada8-ada15 / details); 
mnar model (ada8-ada15 / modelobs=(retrieved=1)); 
var ada0 ada8-ada15; 
run; 
 
/*** Code to use if <6 retrieved subjects per arm ***/ 
proc mi data=outdata1 seed=41671703 nimpute=30 
out=outdata2; 
by treatment; 
monotone reg(ada8-ada15 / details); 
mnar model (ada8-ada15 / modelobs=ccmv(k=1)); 
var ada0 ada8-ada15; 
run; 
10.1.3 Combining the multiple imputation results to derive TEAR status 
At this point there should be two sets of imputed data, each containing 30 records per 
subject, with all visits on the same record. These will need to be merged by subject and 
imputation. Then the TEAR values will be computed for each subject and analyzed. There 
are 3 steps:  
1. Merge the imputed ADA binary response dataset with the imputed ADA titer 
dataset, by usubjid avisitn _imputation_. Then generate TEAR 
responder status based on the Week 24 (Visit 15) ADA values using the same 
algorithm as was used for the original data. This dataset will have one record per 
imputation per subject, but the TEAR values will be non-missing for all subject 
visits. Note that the variable TEAR may vary from imputation to imputation for the 
same subject. That is supposed to happen. 
2. Run the primary efficacy analysis to create the 90% confidence interval using the 
Wald confidence limit method within each imputation. That will result in 30 
confidence intervals, one for each imputation.  
3. Combine the 30 confidence intervals to generate one summary confidence interval 
to be presented in the table. 


 
 
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Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 59 of 69 
 
 
Step 1. 
Merge the imputed titer values by usubjid avisitn _imputation_ to make a 
single dataset. Then create a new variable for TEAR status by following the ADaM specs 
for the definition of TEAR events, but using the new imputed ADA data. Again, the 
dataset will contain one record per imputation per subject, with a new response variable 
added to every record. For the purposes of the next steps below, this new response variable 
will be called TEAR.  
a. If the subject was ADA negative at baseline then do: 
i. If any of RESP8–RESP15 is positive, then TEAR=1 for that 
imputation for that subject 
ii. Else TEAR=0 for that imputation for that subject 
b. Else if subject was ADA positive at baseline then do: 
i. If ADAx / ADA0 >=4 for any visit, where x is in 8–15, then TEAR 
= 1; 
ii. else TEAR=0 
Step 2. 
Use code similar to what was used to analyze the primary efficacy endpoint, but run the 
code by _imputation_. For example, 
/*** step 2: Analyze the imputed datasets ***/ 
proc freq data=imputed; 
by _imputation_; 
table trt*tear / alpha=0.10 riskdiff (cl= wald column=2) 
; 
output=outmi riskdiff; 
run; 
Step 3. 
Combine the 30 estimated statistics into one using PROC MIANALYZE. 
proc mianalyze data=outmi; 
modeleffects _rdif1_ ; 
stderr e_rdif1; 
ods output parameterestimates=parms; 
run; 
 
proc print data=parms; 
var estimate stderr lclmean uclmean probt; 


 
 
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Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 60 of 69 
 
run; 
 
10.1.4 Multiple imputation for HbA1c. 
HbA1c is measured at baseline and at Weeks 12 and 24 (visits 11 and 15). For purposes of 
these specifications, let HBx represent the continuous value for HbA1c value at Visit x, 
where x takes the values 0 (for Baseline) or 11 or 15. The seed that will be used in the 
multiple imputation of ADA titer will be 24637883. The imputations will be combined 
using a mixed model for repeated measures. 
There are 6 steps to this process: 
1. Create a dataset with one record per subject, containing all values of HbA1c for all 
weeks (Baseline and Weeks 12 and 24 on one record); that is, each record would 
contain variables for HB0, HB11, and HB15.  
2. Run 30 Markov Chain Monte Carlo (MCMC) imputations to make the missing 
values in the dataset have a monotone missingness pattern. This will produce a 
dataset with an index variable _imputation_ and otherwise the same variables 
as the input dataset. It will have one record per imputation per subject. 
3. Run a pattern mixture model regression imputation on each imputed dataset from 
Step 2. This will generate a dataset with the same structure as the input dataset, but 
will have the missing values filled in. 
4. Transform the dataset back into one record per subject per visit, with imputation 
number retained on each record. 
5. Run a mixed model for repeated measures on the imputed datasets. 
6. Combine the imputations to provide summary statistics. 
Step 1. 
The dataset for this imputation has to put the values for all weeks onto one record. That is, 
the dataset would have one record per subject, with 3 values for HB0, HB11, and HB15. 
One way this can be accomplished is the following: 
data analysis (keep=usubjid trtp HB0 HB11 HB15); 
set indata; 
by usubjid avisitn; 
array y {3} HB0 HB11 HB15; 
retain HB0 HB11 HB15; 
if first.usubjid then do; 
   hb0 = base; 
   hb11 = .; 
   hb15 = .; 
end; 


 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 61 of 69 
 
if avisit = 11 then hb11 = aval; 
if avisit = 15 then hb15 = aval; 
if last.usubjid then output; 
run; 
Step 2. 
/*** step 2: Create monotone missingness using MCMC 
imputation ***/ 
proc mi data=analysis seed=24637883 nimpute=1 
out=outdata1; 
mcmc impute=monotone; 
var hb0 hb11 hb15; 
run; 
Step 3. 
/*** step 3: Perform PMM regression imputation ***/ 
proc sort data=outdata1; 
run; 
 
proc mi data=outdata1 seed=24637883 nimpute=30 
out=outdata2; 
by treatment; 
monotone reg(hb11 hb15 / details); 
mnar model (hb11 hb15 / modelobs=ccmv(k=1)); 
var hb0 hb11 hb15; 
run; 
Step 4. 
Reverse the process from Step 1, creating one record per subject visit, retaining the 
imputation number on each record.  
Step 5. 
Use code similar to what was used to analyze the primary efficacy endpoint, but run the 
code by _imputation_. For example, 
/*** step 5: Analyze the imputed datasets ***/ 
proc sort data=imputed; 
by _imputation_ subjid avisitn; 
run; 
 
proc mixed data=imputed; 
by _imputation_; 


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 62 of 69 
 
class trt avisitn dosetime site; 
model chg = trt avisitn dosetime site trt*avisitn base / 
ddfm=kr s; 
repeated avisitn / type=un; 
lsmeans trt*avisitn / diff cl; 
ods output ConvergenceStatus=converge; 
ods output diffs=trtdiff; 
run; 
Convergence status is assessed by the condition that: 
 
if pdg=1 and pdh=1 and status=0 
in the dataset converge above, then model has converged. In the above code, if the 
model does not converge, replace the type=un option by each of the following: 
type=toeph, type=toep,and type=cs. You will also need to replace ddfm=kr 
with ddfm=bw. Choose the best fit model by checking the AIC and selecting the model 
with the lowest one. Please contact the statistician if this step is necessary. 
Step 6. 
Combine the 30 estimated statistics into one using PROC MIANALYZE. 
data trtdiff; 
set trtdiff (where=(avisitn=_avisitn)); 
run; 
 
proc sort data=trtdiff; 
by avisitn _imputation_; 
run; 
 
proc mianalyze data=trtdiff; 
by avisitn; 
modeleffects estimate ; 
stderr stderr; 
ods output parameterestimates=parms; 
run; 
 
proc print data=parms; 
var avisitn estimate stderr lclmean uclmean probt; 
run; 
 
 


 
 
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Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 63 of 69 
 
10.2 Tipping Point Analysis 
The tipping point analysis will create a type of figure called a heat map. It will not impute 
data at the subject level, but rather will be based on the observed total counts of TEAR 
status and number of missing values per group. 
The steps are summarised below: 
 
 
 
ADSL
where ITTFL=‘Y‘
ADTEAR 
where ITTFL=‘Y’and 
PARAMCD=‘TEAR‘ and DTYPE = ‘ ’
X=Mm+1, Y=Mn+1, 
Risk Difference, and Color Gradient for 
all possible combinations based on 
number of subjects with unconfirmed 
TEAR status
HEATMAP Datatset
Nm
Total # of 
Subjects in 
MYL-1601D 
Group
AVALC is missing 
or Unconfirmed
AVALC=Positive
HEAT MAP Figure
Nn
Total # of 
Subjects in 
NovoLog 
Group
Mm
# of Subjects in 
MYL-1601D 
Group
Mn
# of Subjects 
in NovoLog 
Group
TEARm
# of Subjects in 
MYL-1601D 
Group
TEARn
# of Subjects 
in NovoLog 
Group
Append asterix ‘*‘ 
to Risk Difference if Risk Difference lies 
outside the margin.
Margin
(quantile('NORMAL',0.95) + 
quantile('NORMAL',0.90))*
√ (2*pn*(1-pn)/Nn)
where pn=Y/nN


 
 
Statistical Analysis Plan 
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Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 64 of 69 
 
For purposes of the code below, set 
Nm = Total # of subjects randomized to MYL-1601D group 
Nn = Total # of subjects randomized to Novolog group 
Mm = # of subjects missing TEAR status in MYL-1601D 
group  
Mn = # of subjects missing TEAR status in Novolog group  
TEARm = # of subjects in MYL-1601D group who are TEAR 
positive 
TEARn = # of subjects in Novolog group who are TEAR 
positive 
Then run code similar to the following. The code below assumes that the above variables 
have been created as global variables. 
 
%macro heat; 
 
data heatmap; 
do i = 0 to &mn; 
   do j = 0 to &mm; 
      y = &tearn + i; 
      x = &tearm + j; 
     pn = y/&nn; 
 
   pm = x/&nm; 
 
   riskdiff = pm - pn; 
margin = (quantile('NORMAL',0.95) + 
quantile('NORMAL',0.90))*     
   sqrt(2*pn*(1-pn)/&nn); 
      output; 
   end; 
end; 
run; 
 
%do i = 0 %to &mn; 
   %do j = 0 %to &mm; 
 
   data imputed; 
   length group $8; 
   group="NOVOLOG"; 
   status=1; 
   count=%eval(&tearn+&i); 
   output; 
   status=0; 
   count=%eval(&nn - (&tearn+&i)); 
   output; 


 
 
Statistical Analysis Plan 
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Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 65 of 69 
 
   group="MYL-1601D"; 
   status=1; 
   count=%eval(&tearm+&j); 
   output; 
   status=0; 
   count=%eval(&nm - (&tearm+&j)); 
   output; 
   run; 
 
   ods exclude all; 
   proc freq data=imputed; 
   table group * status / riskdiff (cl=WALD column=2) 
alpha=0.1; 
   weight count; 
   ods output riskdiffcol2=rdiff1; 
   run; 
   ods exclude none; 
   data ci; 
   set rdiff1 (where=(row="Difference")); 
      y = &tearn + &i; 
      x = &tearm + &j; 
   run; 
 
   data heatmap; 
   merge heatmap 
      ci (keep=x y risk ase lowercl uppercl) 
   ; 
   by x y; 
length color $8 digits $16 a1-a6 asterisk $1; 
if -0.0000001 <riskdiff < 0.0000001 then do; 
   red=255; 
   green=255; 
   blue=255; 
end; 
else if riskdiff > 0 then do; 
   if riskdiff >= 0.16 then do; 
      red = round(484 - (1435*riskdiff)); 
   green = 0; 
      blue = 0; 
      end; 
      else do; 
         red = 254; 
         green = round(255/(1+exp(-32.96*(0.1149-
abs(riskdiff))))); 
         blue = round(255/(1+exp(-21.58*(0.0793-
abs(riskdiff))))); 


 
 
Statistical Analysis Plan 
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Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 66 of 69 
 
      end; 
else if . < riskdiff < 0 then do; 
   red = round(255/ (1+exp(-18.51*(0.1108-
abs(riskdiff))))); 
   green = round(255/ (1+exp(-27.85*(0.1699-
abs(riskdiff))))); 
   blue = round(255/ (1+exp(-20.10*(0.1024-
abs(riskdiff))))); 
end; 
 
   digits = "0123456789ABCDEF"; 
   n1 = floor(red/16); 
   n2 = red - (n1*16); 
   a1 = substr(digits,n1+1,1); 
   a2 = substr(digits,n2+1,1); 
   n3 = floor(green/16); 
   n4 = green - (n3*16); 
   a3 = substr(digits,n3+1,1); 
   a4 = substr(digits,n4+1,1); 
   n5 = floor(blue/16); 
   n6 = blue - (n5*16); 
   a5 = substr(digits,n5+1,1); 
   a6 = substr(digits,n6+1,1); 
   color = compress("CX"||a1||a2||a3||a4||a5||a6); 
 
if (lowercl < (margin) < uppercl) and  
(lowercl < (-margin) < uppercl) then asterisk=" "; 
else asterisk="*"; 
 
   run; 
 
   %end; 
%end; 
%mend heat; 
 
%heat; 
 
This code will create a dataset called HEATMAP that contains the X and Y variables, risk 
difference, and color to use for the plot. There will be (Mm+1) values on the x-axis and 
(Mn+1) values on the y-axis. These will be the number of subjects with TEAR=1 in the 
MYL-1601D (x-axis) and Novolog (y-axis) groups, respectively, based on all possible 
counts that could be observed if the missing TEAR values were known. The HEATMAP 
dataset provides these counts as variables x and y for each row.  
The heat map figure will consist of a grid with dimensions (Mm+1) × (Mn+1). The x-axis 


 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 67 of 69 
 
will be labeled with the range of values of the variable x in the HEATMAP dataset, and the 
y-axis will be labeled with the range of y values. Each row in the HEATMAP dataset 
corresponds to one rectangle on the grid. Within that one rectangle should be printed the 
value of the variable RISKDIFF. If the value of RISKDIFF lies outside the margin, then 
an asterisk should be appended to the numeric value of RISKDIFF. A variable 
ASTERISK has been created in the sample code for this purpose. 
The rectangle itself should be filled with color, which will be generated based on the value 
of RISKDIFF. Shades of red color will indicate that the TEAR rate is higher in the MYL-
1601D group, while green shades will indicate a higher TEAR rate in the Novolog group. 
The color intensity will increase as the magnitude of RISKDIFF becomes more extreme. 
Colors will be programmatically assigned and will be captured in hexadecimal format in 
the variable COLOR in the HEATMAP dataset. This hexadecimal value can be supplied to 
the SAS graphics procedure.  
The heat map will display the number of TEAR events in the MYL-1601D group in 
descending order on the x-axis and number of TEAR events in the Novolog group in 
descending order on the y-axis. An example is provided in the figure shells. 
 
 
 


 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 68 of 69 
 
10.3 Laboratory Category 
 
Laboratory 
Category 
Parameter (SI unit) 
Potentially 
Clinically 
Significant Low 
Potentially 
Clinically 
Significant High 
Hematology 
WBC (109 L−1) 
<2.0 
>20.0 
 
Neutrophil count (109 
L−1) 
<1.0 
NA 
 
Hemoglobin (g/L) 
<80 
>200 
 
Platelets (109 L−1) 
<50 
>999 
Biochemistry 
ALT (U/L) 
NA 
>3XULN 
 
AST (U/L) 
NA 
>3XULN 
 
ALK phosphatase (IU/L) 
 NA 
>3XULN 
 
Total Bilirubin (umol/L) 
NA 
>2XULN 
 
Glucose (mmol/L) 
<3.1 
>15.0 
 
Creatinine (umol/L) 
NA 
>1.5XULN 
 
BUN (mmol/L) 
NA 
>21.4 
 
Sodium (mmol/L) 
<130 
>155 
 
Potassium(mmol/L) 
<3.0 
>6.0 
 
Total Protein(g/L) 
NA 
>95 
 
Albumin(g/L) 
<20 
NA 


 
 
Statistical Analysis Plan 
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Statistical Analysis Plan 
Protocol Number: MYL-1601D-3001 
Version: FINAL 3.0 Date: 02 Mar 2020   
                                            Page 69 of 69 
 
Laboratory 
Category 
Parameter (SI unit) 
Potentially 
Clinically 
Significant Low 
Potentially 
Clinically 
Significant High 
 
Calcium (mmol/L) 
<1.8 
>3.1 
Lipids 
Triglycerides (mmol/L) 
<0.1 
>10.2 
 
Total Cholesterol 
(mmol/L) 
<0.5 
>10.3 
 
LDL Cholesterol 
(mmol/L) 
<0.5 
>9.0 
 
HDL Cholesterol 
(mmol/L) 
<0.5 
NA 
 
 
 
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 %