A Single-center, Single-dose, Double-blind, Randomized, Three-period, Three-treatment, Six-sequence, Crossover Study to Demonstrate Pharmacokinetic and Pharmacodynamic Similarity Between NKF-INS(A), US-NovoLog®, and EU-NovoRapid® Using the Euglycemic Clamp Technique in Healthy Male Adult Volunteers
Phase: PHASE1
Conditions: Healthy Participants
Sponsor: Xentria, Inc.

Xentria, Inc. 
2032 N. Clybourn Avenue, Chicago, Illinois 60614  | xentria.com 
Page 1 of 1 
 
 
 
25 August 2025 
 
  
Protocol: 
NKF‐INS(A)‐101 
NCT No.: 
06492226 
Subject: 
Cover Letter for Protocol 
 
 
 
Protocol V2.0 06MAY2024 for NKF‐INS(A)‐101 is attached with NCT06492226. 
 
 
  
Sincerely,  
 
 
 
 
Chris Schroth 
Clinical Project Manager | Xentria, Inc.  
 
 

Xentria, Inc. 
Protocol NKF-INS(A)-101 
NKF-INS(A) 
Version 2.0 
06-May-2024 
This document is confidential. 
Page 1 of 67 
CLINICAL STUDY PROTOCOL 
 
Xentria, Inc. 
Protocol Title: A single-center, single-dose, double-blind, randomized, three-period, 
three-treatment, six-sequence, crossover study to demonstrate pharmacokinetic and 
pharmacodynamic similarity between NKF-INS(A), US-NovoLog®, and EU-NovoRapid® using 
the euglycemic clamp technique in healthy male adult volunteers 
Protocol Number: NKF-INS(A)-101 
IND Number: 
170945  
EU Clinical Trial Number: 
Not applicable 
Name of Investigational Product: 
NKF-INS(A) (Proposed Biosimilar to Insulin Aspart) 
Phase of Development: 
Phase 1 
Indication: 
Diabetes Mellitus  
Sponsor: 
Xentria, Inc. 
2071 N. Southport Ave. 
Chicago, IL 60614 USA 
Tel: 224-443-4615 
Email: contact@xentria.com 
Protocol Version:  
2.0 
Protocol Date: 
06-May-2024 
-CONFIDENTIAL- 
This document is a confidential communication of Xentria, Inc. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from Xentria, 
Inc. except to the extent necessary to obtain informed consent from those persons to whom the drug may be administered. 
Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, and applicable 
institutional review committee and regulatory agencies to enable conduct of the study. 
 
 

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Protocol NKF-INS(A)-101 
NKF-INS(A) 
Version 2.0 
06-May-2024 
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PROTOCOL APPROVAL SIGNATURES 
Protocol Title:  
A single-center, single-dose, double-blind, randomized, three-period, 
three-treatment, six-sequence, crossover study to demonstrate 
pharmacokinetic and pharmacodynamic similarity between NKF-INS(A), 
US-NovoLog®, and EU-NovoRapid® using the euglycemic clamp technique 
in healthy male adult volunteers 
Protocol Number: 
NKF-INS(A)-101 
This study will be conducted in full conformance with the International Council for Harmonisation (ICH) E6 (R2) 
guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or all relevant laws 
and regulations of the country in which the research is conducted, whichever affords the greater protection to the 
individual. The study will comply with the requirements of the ICH E2A guideline (Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting). Studies conducted in the European Union (EU) 
or European Economic Area will comply with the EU Clinical Trial Regulation (EU-CTR). 
Sponsor Signatories: 
Tom Matthews 
Vice President, Clinical Development 
Xentria, Inc. 
Signature and Date  

Xentria, Inc. 
Protocol NKF-INS(A)-101 
NKF-INS(A) 
Version 2.0 
06-May-2024 
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Page 3 of 67 
INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A single-center, single-dose, double-blind, randomized, three-period, three-treatment, 
six-sequence, crossover study to demonstrate pharmacokinetic and pharmacodynamic 
similarity between NKF-INS(A), US-NovoLog®, and EU-NovoRapid® using the 
euglycemic clamp technique in healthy male adult volunteers 
Protocol Number: 
NKF-INS(A)-101 
This study will be conducted in full conformance with the International Council for Harmonisation (ICH) E6 (R2) 
guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or all relevant laws and 
regulations of the country in which the research is conducted, whichever affords the greater protection to the 
individual. The study will comply with the requirements of the ICH E2A guideline (Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting). Studies conducted in the European Union (EU) 
or European Economic Area will comply with the EU Clinical Trial Regulation (EU-CTR). 
• 
I, the undersigned, have reviewed this protocol including appendices, and I will conduct the study as 
described in compliance with this protocol, GCP, and relevant ICH guidelines. 
• 
I am thoroughly familiar with the appropriate use of the study treatment, as described in this protocol and 
any other information provided by Xentria, Inc. including, but not limited to, the current Investigator’s 
Brochure. 
• 
After the protocol has been approved by the Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB), I will not modify this protocol. I will submit the protocol amendments and/or any informed 
consent form modifications to Xentria, Inc. and the IEC/IRB, and approval will be obtained before any 
amendments are implemented. 
• 
I ensure that all persons or parties assisting me with the study are adequately qualified, trained, and 
informed about the Xentria, Inc. study treatment and of their delegated study-related duties and functions as 
described in the protocol. 
• 
I ensure that source documents and study records that include all pertinent observations on each of the 
site’s study participants are attributable, legible, contemporaneous, original, accurate, and complete, 
consistent, enduring, and available. 
• 
I understand that all information obtained during the conduct of the study with regard to the participants’ 
state of health will be regarded as confidential. No participants’ personal identifying information will be 
disclosed. All participants will be identified by assigned numbers on all case report forms, laboratory 
samples, or source documents forwarded to the Sponsor. Clinical information may be reviewed by the 
Sponsor or its agents or regulatory agencies. Agreement must be obtained from the participant before 
disclosure of participant information to a third party. 
• 
Information developed in this clinical study may be disclosed by Xentria, Inc. to other clinical 
Investigators, regulatory agencies, or other health authority or government agencies as required. 
 
Name: 
Title: 
Investigator Signature 
Institution: 
Date (DD-MMM-YYYY) 

Xentria, Inc. 
Protocol NKF-INS(A)-101 
NKF-INS(A) 
Version 2.0 
06-May-2024 
This document is confidential. 
Page 4 of 67 
1. 
SYNOPSIS 
Title of Study 
A single-center, single-dose, double-blind, randomized, three-period, three-treatment, 
six-sequence, crossover study to demonstrate pharmacokinetic and pharmacodynamic 
similarity between NKF-INS(A), US-NovoLog®, and EU-NovoRapid® using the 
euglycemic clamp technique in healthy male adult volunteers 
Protocol Number 
NKF-INS(A)-101 
Investigators/Study 
Sites 
This is a single-center study that will be conducted in South Africa  
Phase of 
Development 
Phase 1  
Purpose and 
Rationale 
Despite advances in diabetes mellitus care, there remains a critical unmet need for 
cost-effective insulins in many markets.  
 
Currently available mealtime insulin analogues, while associated with a lower risk of 
hypoglycemia, are expensive. Insulin aspart is a rapid-acting insulin marketed as 
NovoLog® in the United States (US) and NovoRapid® in the European Union (EU). It 
has a faster onset and a shorter duration of action, resulting in postprandial glycemic 
control by means of lowering the total glucose excursion following a meal. 
 
As a biosimilar to insulin aspart, NKF-INS(A) has the potential to address this unmet 
medical need in patients with diabetes mellitus. In order to demonstrate biosimilarity of 
NKF-INS(A) to EU-NovoRapid® and US-NovoLog®, a Phase 1 study will evaluate the 
PK and PD of NKF-INS(A) to the reference products using a euglycemic clamp 
technique in healthy male volunteers. 
Objectives 
Endpoints 
Primary 
 
• 
To compare the PK of NKF-INS(A) to 
US-approved and EU-authorized  insulin 
aspart to demonstrate PK similarity for 
insulin aspart. 
• 
Aspart concentration-time curve from 0 to 12 hours 
(AUC0-t)  
• 
Maximum observed insulin aspart concentration (Cmax) 
 
• 
To compare the PD of NKF-INS(A) to 
US-approved and EU-authorized insulin 
aspart injection by examining GIR profiles 
after a single SC dose.  
• 
Area under the GIR-time curve from 0 to 12 hours 
(AUCGIR0-t)  
• 
Maximum GIR (GIRmax) of glucose. 
 
Secondary 
 
• 
To evaluate additional PK parameters of 
NKF-INS(a) compared to US-approved and 
EU-authorized insulin aspart. 
• 
PK parameters for serum insulin aspart concentrations: 
AUC0-4h, AUC0-6h, AUC6-12h, AUC0-12h, Tmax, AUC0-∞ 
• 
Time to half-maximum before Cmax (t50%-early) 
• 
Time to half-maximum after Cmax (t50%-late)  
• 
The terminal elimination half-life (t1/2) 

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• 
To evaluate additional PD parameters of 
NKF-INS(A) compared to US-approved 
and EU-authorized insulin aspart. 
• 
AUCGIR from 0 to 4 hours (AUCGIR0-4h), from 0 to 
6 hours (AUCGIR0-6h), and from 6 hours until the end of 
clamp (AUCGIR6-last)  
• 
Time to maximum GIR (Tmax.GIR) 
• 
Time to half-maximum glucose infusion rate before 
GIRmax (tGIR,50%-early)  
• 
Time to half-maximum glucose infusion rate after GIRmax 
(tGIR,50%-late, indicator of end of duration of action) 
• 
Time from study drug administration until the blood 
glucose concentration has decreased by at least 5 mg/dL 
from baseline (onset of action) 
• 
The difference between tGIR,50%-late and the onset of 
action (duration of action) 
• 
To assess the safety of NKF-INS(A). 
• 
AE assessments (including injection site reactions), 
clinical laboratory investigations (hematology, clinical 
chemistry [including glucose], coagulation, and 
urinalysis), vital signs, physical examinations, 12-lead 
ECG, prior and concomitant medication assessments 
Exploratory 
 
• 
To assess endogenous insulin suppression 
via C-peptide measurements, which 
includes both corrected and uncorrected 
C-peptide concentrations.  
• 
Corrected and uncorrected C-peptide concentrations 
• 
If possible, i.e., if the terminal phase of serum 
concentration-time profile has sufficient data points, 
apparent terminal elimination half-life (t½.z), apparent 
terminal elimination rate constant (λz), mean residence 
time (MRT), clearance (CL/F), and volume of distribution 
(V/F) will be calculated 
Abbreviations: AE = adverse events; ECG = electrocardiogram; EU = European Union; GIR = glucose infusion rate; 
PD = pharmacodynamic; PK = pharmacokinetics; SC = subcutaneous; US = United States 

Xentria, Inc. 
Protocol NKF-INS(A)-101 
NKF-INS(A) 
Version 2.0 
06-May-2024 
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Study Design 
Study NKF-INS(A)-101 is a Phase 1, 12-hour euglycemic glucose clamp study 
conducted using a randomized, double-blind, three-period, three-treatment, six-sequence, 
crossover design. The study will compare single doses of the proposed insulin biosimilar 
(NKF-INS(A)) with respective EU- and US-reference products in healthy male 
participants.  
 
Written informed consent will be obtained from all participants, and the study will be 
conducted in accordance with the principles of Good Clinical Practice (GCP) as defined 
by the International Conference of Harmonization (ICH). 
 
The study will consist of several visits: a screening visit to obtain informed consent and 
assess eligibility for participation, three dosing visits with a washout period between 
each visit, and a follow-up visit after the last dose. 
 
Three insulin products (NKF-INS(A), EU-NovoRapid®, and US-NovoLog®) will be 
administered over three treatment periods. Upon admission to the clinical research 
unit (CRU) on Day -1, participants will be randomized to one of six treatment sequences 
in a 1:1:1:1:1:1 ratio, receiving a single subcutaneous (SC) dose of 
0.3 U/kg administration of one of the three study drugs on each dosing day.   
 
A 12-hour euglycemic glucose clamp will be conducted using a manual clamp technique, 
which will monitor the subject’s blood glucose and administer glucose infusion  (GIR) to 
maintain blood glucose close to the target blood glucose concentration. The clamp 
procedure will be initiated, maintained, and terminated, in accordance with the site 
standard operating procedures (SOPs). The participant’s blood glucose will be 
maintained within a pre-defined target window per site SOP and clinical judgment for 
the participant by manually adjusting the GIR. 
 
Blood samples will be collected at pre-specified intervals before and up to 12 hours after 
dosing for measurement of blood glucose, serum insulin, and C-peptide. 
Selection of 
Participants 
Inclusion Criteria 
Individuals must meet all of the following inclusion criteria to be included in the study: 
1. Signed and dated informed consent obtained before any trial-related activities. 
Trial-related activities are any procedures that would not have been done during 
normal management of the participant 
2. Healthy male participants 
3. Age between 18 and 50 years, both inclusive 
4. Body Mass Index between 18.5 and 29.0 kg/m2, both inclusive 
5. Body weight ≥ 50 kg 
6. Fasting plasma glucose concentration ≤ 5.5 mmol/L at screening 
7. Considered generally healthy upon completion of medical history, physical 
examination, vital signs, electrocardiogram (ECG), and analysis of laboratory 
safety variables, as judged by the Investigator 
8. Willing and able to comply with scheduled visits, treatment plan, clinical 
laboratory tests, and other study procedures including lifestyle considerations. 
9. Participants must agree to use condoms during sexual intercourse. Additionally, 
female partners of male participants should use highly effective contraception. 
All contraceptive measures apply from screening until 90 days after study 

Xentria, Inc. 
Protocol NKF-INS(A)-101 
NKF-INS(A) 
Version 2.0 
06-May-2024 
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Page 7 of 67 
treatment male participants must refrain from donating or banking sperm for 90 
days after administration of study treatment. 
10. Have competence in speaking, writing, and comprehending the local 
language(s) where the study is conducted. 
Exclusion Criteria 
Individuals will be excluded from participation if they meet any of the following criteria: 
1. Positive for human insulin antibodies at Screening 
2. Are currently enrolled in or have discontinued within 3 months or 5 half-lives 
(whichever is longer) of any investigational drug or device or are concurrently 
enrolled in any other type of medical research study and judged not to be 
scientifically or medically compatible with this study. 
3. Have known allergies to insulin, its excipients, or related drugs or have history 
of relevant allergic reactions of any origin. 
4. History of diabetes mellitus; episodes of hypoglycemia in the anamnesis; any 
history of insulin use for treatment purposes. 
5. Have known allergies to insulin, its excipients, or related drugs or have history 
of relevant allergic reactions of any origin. 
6. Have clinically relevant history of or current cardiovascular, respiratory, 
hepatic, renal, gastrointestinal, endocrine, hematological, or neurological 
disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs; of constituting a risk when taking the study drug; or of 
interfering with the interpretation of data. 
7. Increased risk of thrombosis, e.g., individuals with a history of deep leg vein 
thrombosis or family history of deep leg vein thrombosis, as judged by the 
Investigator. 
8. Clinically significant abnormal ECG at screening. 
9. Glycemia level ≥140.4 mg/dL 2 hours after the glucose load. 
10. Show evidence of significant active neuropsychiatric disease. 
11. Positive urine drug test at screening and/or evidence of current use of known 
drugs of abuse or have a history of use within the past year. 
12. Show evidence of an acute infection with fever or infectious disease at the time 
of enrollment. 
13. Show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies at screening. 
14. Have positive test results for hepatitis B surface antigen (HBsAg), 
immunoglobulin M (IgM) antibody to hepatitis B core antigen (anti-HBc), or 
hepatitis C virus (HCV) antibodies at screening. 
15. Intend to use over-the-counter medication within 7 days or prescription 
medication within 14 days prior to dosing (apart from vitamin/mineral 
supplements, occasional paracetamol, thyroid replacement). 
16. Have donated blood or had a blood loss of 450 mL 3 months prior to study 
enrollment. 
17. Have an average weekly alcohol intake that exceeds 21 units per week or is 
unwilling to stop alcohol consumption from 48 hours prior to each dosing until 
being discharged from the CRU. 
Planned Sample 
Size 
54 healthy male participants are planned to be enrolled in the study to have at least 
36 evaluable participants. 
Investigational 
Therapy 
NKF-INS(A) administered as a 0.3 U/kg single SC dose in the periumbilical area. 
Reference Therapy 
EU-NovoRapid® and US-NovoLog®, both administered as a 0.3 U/kg single SC dose in 
the periumbilical area. 

Xentria, Inc. 
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NKF-INS(A) 
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Treatment Duration 
The study will consist of a screening period of up to 4 weeks (Days -28 to -1), three 
treatment periods each consisting of 1-day dose administrations and euglycemic clamp 
periods (periods 1, 2, and 3) separated by a washout period of 3-14 calendar days 
between treatment periods 1 and 2, and a washout period of 5-21 calendar days between 
treatment periods 2 and 3, and a follow-up period of 2-11 days. The entire study duration 
will be a maximum of 11 weeks. 
Pharmacokinetics 
Insulin (serum) samples will be collected at 60, 30, 0 minutes pre-dose and 5, 10, 20, 30, 
40, 50, 60, 75, 90, 105, 120, 135, 150, 180, 210, 240, 300, 600, and 720 minutes 
post-dose. 
Pharmacodynamics 
C-peptide (serum) 60, 30, 0 minutes pre-dose and 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 
120, 135, 150, 180, 210, 240, 300, 600, and 720 minutes post-dose. 
Blood glucose values will be analyzed pre-dose, every 3 minutes from 0 to 120 minutes, 
every 5 from 120 to 240 minutes, and every 10 minutes from 240 to 720 minutes 
post-dose.   
Immunogenicity 
Not applicable 
Safety 
Safety assessments include vital signs, physical examinations, ECG recordings, clinical 
laboratory assessments (hematology, clinical chemistry [including glucose], coagulation, 
and urinalysis), AE monitoring (including injection site reactions). 
 
AEs will be coded by using the Medical Dictionary for Regulatory Activities dictionary. 
All treatment-emergent AEs (TEAEs) will be summarized by insulin product 
(NKF-INS(A), US-NovoLog®, EU-NovoRapid®) as follows: 
• 
All AEs 
• 
Grade ≥3 AEs 
• 
AEs related to study treatment, including related Grade ≥3 AEs 
• 
All adverse reactions 
• 
Serious AEs (SAEs) 
All AE data will be defined in the listing (onset, stop date, severity, etc.). 
 
The original results and change from baseline values for clinical laboratory assessments, 
vital signs, and ECG parameters, will be summarized by insulin product and scheduled 
visits. Potential clinically significant values will also be flagged and summarized. 
Significant changes in physical examination findings will be listed as AEs. 
Injection site reactions will be summarized by treatment group and scheduled visits. The 
number and percentage of participants having reactions at each assessment timepoint, 
overall and by specific reaction subtype, will be presented. 
Other Assessments 
Not applicable  
Statistical Methods 
and Planned 
Analyses 
The statistical evaluation will be performed using R version 4.0 or higher. All data will 
be listed, and summary tables and figures will be provided. Summary statistics will be 
presented by treatment group, to the extent possible. For continuous variables, data will 
be summarized with the number of participants (N), arithmetic mean, standard 
deviation (SD), median, minimum, and maximum by treatment group. Geometric mean 
and coefficient of variation (CV%) will be presented as appropriate, by treatment group. 
For categorical variables, data will be tabulated with the number and proportion of 
participants for each category by treatment group. 
Interim Analysis 
Not applicable. 

Xentria, Inc. 
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Data Monitoring 
Committee 
Not applicable. 
 
 

Xentria, Inc. 
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NKF-INS(A) 
Version 2.0 
06-May-2024 
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2. 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS ...........................................................................................10 
3. 
LIST OF ABBREVIATIONS.....................................................................................15 
4. 
INTRODUCTION ......................................................................................................17 
4.1. 
Background on NKF-INS(A) .....................................................................................17 
4.1.1. 
Preliminary Analytical Similarity Study for Program Feasibility ..............................17 
4.2. 
Clinical Benefits/Risks of NKF-INS(A) .....................................................................18 
4.3. 
Study Rationale ...........................................................................................................18 
4.4. 
Dose Rationale ............................................................................................................18 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................19 
6. 
INVESTIGATIONAL PLAN .....................................................................................21 
6.1. 
Description of Overall Study Design and Plan ...........................................................21 
6.2. 
Discussion of Study Design ........................................................................................22 
6.3. 
End of Study ...............................................................................................................23 
6.4. 
Criteria for Early Study Termination ..........................................................................23 
7. 
SELECTION OF STUDY POPULATION ................................................................24 
7.1. 
Inclusion Criteria ........................................................................................................24 
7.2. 
Exclusion Criteria .......................................................................................................24 
7.3. 
Rescreening .................................................................................................................25 
7.4. 
Study Withdrawal, Removal, and Replacement of Participants .................................26 
7.4.1. 
Replacement of Participants .......................................................................................26 
8. 
TREATMENTS ..........................................................................................................27 
8.1. 
Study Treatment Description ......................................................................................27 
8.1.1. 
Preparation, Handling, and Disposal ..........................................................................28 
8.1.2. 
Product Labeling and Packaging ................................................................................28 
8.1.3. 
Administration ............................................................................................................28 
8.1.4. 
Storage ........................................................................................................................28 
8.2. 
Dosage Schedule .........................................................................................................29 
8.3. 
Measures to Minimize Bias: Study Treatment Assignment and Blinding .................29 
8.3.1. 
Method of Study Treatment Assignment ....................................................................29 

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8.3.2. 
Blinding ......................................................................................................................29 
8.4. 
Treatment Modifications and Discontinuations ..........................................................30 
8.5. 
Treatment Accountability and Compliance ................................................................31 
8.6. 
Prior and Concomitant Therapy and Other Restrictions During the Study ................31 
8.6.1. 
Prior and Concomitant Medications ...........................................................................31 
8.6.1.1. 
Permitted Concomitant Medications and Therapies ...................................................32 
8.6.1.2. 
Prohibited Concomitant Medications and Therapies ..................................................32 
8.6.1.3. 
Advisory on COVID-19 Vaccination and Risk Assessment ......................................32 
8.6.2. 
Other Restrictions During the Study...........................................................................33 
8.6.2.1. 
Meals and Dietary Restrictions ...................................................................................33 
8.6.2.2. 
Caffeine, Alcohol and Tobacco ..................................................................................33 
8.6.2.3. 
Activity .......................................................................................................................33 
9. 
STUDY PROCEDURES ............................................................................................34 
9.1. 
Screening and Baseline Assessments .........................................................................39 
9.1.1. 
Informed Consent .......................................................................................................39 
9.1.2. 
Demographics .............................................................................................................39 
9.1.3. 
Medical History ..........................................................................................................39 
9.1.4. 
Eligibility Review .......................................................................................................40 
9.1.5. 
Drug and Alcohol Screening ......................................................................................40 
9.1.6. 
Serology Testing .........................................................................................................40 
9.1.7. 
Prior and Concomitant Medication .............................................................................40 
9.1.8. 
Other Screening Assessments .....................................................................................40 
10. 
PHARMACOKINETICS ...........................................................................................41 
10.1. 
Pharmacokinetic Sampling .........................................................................................41 
10.1.1. 
Blood Samples ............................................................................................................41 
10.1.2. 
Pharmacokinetic Evaluation .......................................................................................41 
10.2. 
Pharmacokinetic Analytical Methodology .................................................................41 
11. 
PHARMACODYNAMICS ........................................................................................42 
11.1. 
Pharmacodynamic Sampling ......................................................................................42 
11.1.1. 
Blood Samples ............................................................................................................42 
11.1.2. 
Pharmacodynamic Evaluation ....................................................................................42 
11.1.3. 
Pharmacodynamic Analytical Methodology ..............................................................43 
12. 
SAFETY ASSESSMENTS ........................................................................................44 

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12.1. 
Vital Signs ..................................................................................................................44 
12.2. 
Physical Examination .................................................................................................44 
12.3. 
Electrocardiograms .....................................................................................................44 
12.4. 
Laboratory Assessments .............................................................................................45 
12.5. 
Injection Site Assessment ...........................................................................................45 
12.6. 
Adverse Events ...........................................................................................................46 
12.6.1. 
Definitions ..................................................................................................................46 
12.6.1.1. 
Adverse Event .............................................................................................................46 
12.6.1.2. 
Adverse Reaction ........................................................................................................46 
12.6.1.3. 
Serious Adverse Event ................................................................................................46 
12.6.1.4. 
Pre-treatment Adverse Event ......................................................................................47 
12.6.1.5. 
Treatment-Emergent Adverse Event ..........................................................................47 
12.6.1.6. 
Unexpected Adverse Reaction ....................................................................................47 
12.6.2. 
Adverse Event Collection, Assessment and Reporting ..............................................47 
12.6.2.1. 
Observation Period for Assessment of Adverse Events .............................................47 
12.6.2.2. 
Parameters for Adverse Events Collection .................................................................47 
12.6.3. 
Assessment of Event Severity ....................................................................................48 
12.6.4. 
Relationship to Study Treatment ................................................................................49 
12.6.5. 
Serious Adverse Event Reporting ...............................................................................49 
12.7. 
Drug-Induced Liver Injury Monitoring ......................................................................50 
12.7.1. 
Pregnancy ...................................................................................................................50 
12.7.2. 
Accidental Overdose, Medication Error, or Drug Misuse ..........................................51 
13. 
OTHER ASSESSMENTS ..........................................................................................52 
13.1. 
Euglycemic Clamp Procedure ....................................................................................52 
14. 
STATISTICAL ANALYSIS ......................................................................................53 
14.1. 
Determination of Sample Size ....................................................................................53 
14.2. 
Analysis Populations ..................................................................................................53 
14.3. 
Pharmacokinetic Analysis ..........................................................................................54 
14.4. 
Pharmacodynamic Analysis........................................................................................55 
14.5. 
Safety Analysis ...........................................................................................................55 
14.6. 
Other Analyses ............................................................................................................56 
14.7. 
Interim Analysis ..........................................................................................................56 
14.8. 
Data Monitoring Committee .......................................................................................56 

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15. 
STUDY MANAGEMENT .........................................................................................57 
15.1. 
Approval and Consent ................................................................................................57 
15.1.1. 
Compliance with Laws and Regulations ....................................................................57 
15.1.2. 
Institutional Review Board/Independent Ethics Committee ......................................57 
15.1.3. 
Informed Consent Process ..........................................................................................57 
15.1.3.1. 
Consent and Other Informational Documents Provided to Participants .....................57 
15.1.3.2. 
Consent Procedures and Documentation ....................................................................57 
15.2. 
Study Discontinuation and Closure ............................................................................58 
15.3. 
Confidentiality and Privacy ........................................................................................58 
15.4. 
Future Use of Stored Specimens and Data .................................................................59 
15.5. 
Safety Oversight .........................................................................................................59 
15.6. 
Clinical Monitoring ....................................................................................................59 
15.7. 
Quality Assurance and Quality Control ......................................................................59 
15.8. 
Data Handling and Record Keeping ...........................................................................60 
15.8.1. 
Data Collection and Management Responsibilities ....................................................60 
15.8.2. 
Study Records Retention ............................................................................................60 
15.9. 
Protocol Amendment and Protocol Deviation ............................................................60 
15.9.1. 
Protocol Amendment ..................................................................................................60 
15.9.2. 
Protocol Deviations ....................................................................................................61 
15.10. 
Ethical Considerations ................................................................................................61 
15.11. 
Financing and Insurance .............................................................................................61 
15.12. 
Publication Policy .......................................................................................................61 
15.13. 
Conflict of Interest Policy ...........................................................................................62 
16. 
REFERENCES ...........................................................................................................63 
17. 
APPENDICES ............................................................................................................64 
APPENDIX 1. CONTRACEPTION DEFINITIONS AND REQUIREMENTS .......................65 
APPENDIX 2. PROTOCOL AMENDMENTS .........................................................................67 
 
 

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LIST OF TABLES 
Table 1. 
Objectives and Endpoints ...........................................................................................19 
Table 2 
Study Treatments ........................................................................................................27 
Table 3. 
Schedule of Assessments ............................................................................................35 
Table 4. 
Pharmacokinetic, Pharmacodynamic, C-Peptide, and Glucose Sampling 
Schedule ......................................................................................................................38 
Table 5 
Pharmacokinetic Parameters .......................................................................................41 
Table 6 
Pharmacodynamic Parameters ....................................................................................42 
Table 7 
Laboratory Assessments .............................................................................................45 
Table 8 
Classification of Adverse Events by Relationship to Study Treatment ......................49 
Table 9. 
Studies Referenced for Sample Size Assumptions .....................................................53 
 
LIST OF FIGURES 
Figure 1. 
Study Design ...............................................................................................................22 
Figure 2 
Investigational Product Description ...........................................................................27 
Figure 3 
Control Treatment .......................................................................................................28 
 
 

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3. 
LIST OF ABBREVIATIONS 
Abbreviation 
Expanded Term 
AE 
adverse event 
ADL 
activities of daily living 
ALT 
alanine aminotransferase 
Anti-HBc 
antibody to hepatitis B core antigen 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
clearance 
CMP 
Clinical Monitoring Plan 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract Research Organization 
CRU 
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTR 
Clinical Trial Regulation 
CV 
coefficient of variance 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
end of study 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GIR 
glucose infusion rate 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
ID 
identification 
IgM 
immunoglobulin M 
INR 
international normal ratio 
IRB 
Institutional Review Board 
MRT 
mean residence time 
NCI 
National Cancer Institute 
PD 
pharmacodynamic 
PI 
Principal Investigator 
PK 
pharmacokinetic 
QC 
Quality Control 
QTcF 
QT-interval corrected by Fridericia’s formula 

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SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
SD 
standard deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
t½.z 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse events 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
V/F 
volume of distribution 
λz 
apparent terminal elimination rate constant 
Note: Definitions of pharmacokinetic (PK) and pharmacodynamic (PD) parameters are provided in 
Section 10.1.2 and Section 11.1.2. 
 

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4. 
INTRODUCTION 
Insulin therapy is essential for the treatment of diabetes mellitus Type 1 and is sometimes used in 
diabetes mellitus Type 2. Insulin aspart is a short-acting insulin. The onset of action is 
approximately fifteen minutes, the peak action is reached in 45–90 minutes, and the duration is 
3–5 hours.   
Currently available mealtime insulin analogues, while associated with a lower risk of 
hypoglycemia, are expensive (Ampudia Blasco, 2020). Insulin aspart is a rapid-acting insulin 
marketed as NovoLog® in the United States (US) and NovoRapid® in the European Union (EU). 
It has a faster onset and a shorter duration of action, resulting in postprandial glycemic control by 
means of lowering the total glucose excursion following a meal. 
Biosimilar insulins should offer the advantages of insulin analogues at reduced costs.  
4.1. 
Background on NKF-INS(A)  
As a proposed biosimilar to insulin aspart, NKF-INS(A) has the potential to address the critical 
unmet need for cost-effective insulins, in patients with diabetes. 
To demonstrate biosimilarity compared to US-approved and EU-authorized insulin aspart, a 
comparative clinical pharmacology study between the proposed insulin aspart test product 
(NKF-INS(A)) and both US-NovoLog® and EU-NovoRapid® reference products is required. 
This study should provide a time-concentration profile and a time-action profile over the 
duration of action of each product based on reliable measures of systemic exposure and glucose 
response. 
As a proposed biosimilar to insulin aspart, NKF-INS(A) has the same amino acid sequence as 
NovoLog® and NovoRapid®. Insulin aspart is homologues with regular human insulin with the 
exception of a single substitution of the amino acid proline by aspartic acid in position B28. 
NKF-INS(A) is produced by recombinant DNA technology utilizing Escherichia coli whereas 
NovoLog® and NovoRapid® are produced in Saccharomyces cerevisiae by recombinant DNA 
technology. NKF-INS(A) has the empirical formula of C256H381N65O79S6 and has a molecular 
weight of 5822.6 Da. 
As in human insulin, insulin aspart contains two interchain disulfide bonds, and one intrachain 
disulfide bond. 
The primary activity of insulin aspart is the regulation of glucose metabolism. Insulins, including 
insulin aspart, bind to the insulin receptors on muscle and fat cells and lower blood glucose by 
facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose 
from the liver.  
This is the first clinical study of NKF-INS(A) drug product. 
4.1.1. 
Preliminary Analytical Similarity Study for Program Feasibility 
To confirm the feasibility with the Food and Drug Administration (FDA) for the licensure in the 
US of insulin aspart as a biosimilar to US-licensed US-NovoLog® through the 351(k) pathway, a 
preliminary analytical similarity study was conducted between the reference product and 
US-insulin aspart early development drug substance lots, utilizing a subset of quality attributes to 
be included in the full analytical similarity test panel. Three lots of US-licensed NovoLog® were 

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included and three insulin aspart early development drug substance lots were included in this 
similarity study. The most critical quality attributes that were not likely to be significantly 
impacted by the drug product fill/finish process and container closure were included in this 
study. 
The preliminary analytical similarity study results demonstrated that insulin aspart is highly 
similar to the US-reference product in both physicochemical and biological characteristics, 
therefore further development of insulin aspart as a biosimilar to US-NovoLog® is feasible. 
No other nonclinical animal studies or clinical studies have been completed for insulin aspart. 
4.2. 
Clinical Benefits/Risks of NKF-INS(A)  
The safety profile of NKF-INS(A) has not been evaluated in humans. Based on currently 
approved insulin aspart products, side effects include allergic reactions, hypoglycemia, 
hypokalemia, and weight gain. Recognizing that NKF-INS(A) is a biosimilar product, no 
additional risks are expected; however, participants will be closely monitored throughout the 
study for side effects. 
Details regarding known or anticipated benefits and risks, as well as reasonably anticipated 
adverse events (AEs) for NKF-INS(A) are provided in the Investigator’s Brochure.  
4.3. 
Study Rationale 
Despite advances in diabetes mellitus care, there remains a critical unmet need for cost-effective 
insulins in many markets.  
As a biosimilar to insulin aspart, NKF-INS(A) has the potential to address this unmet medical 
need in patients with diabetes mellitus. In order to demonstrate biosimilarity of NKF-INS(A) to 
EU-NovoRapid® and US-NovoLog®, a Phase 1 study will evaluate the PK and PD of NKF-
INS(A) to the reference products using a euglycemic clamp technique in healthy male 
volunteers.  
4.4. 
Dose Rationale 
NKF-INS(A), EU-NovoRapid® and US-NovoLog® will be administered as a 0.3 U/kg single 
subcutaneous (SC) dose in the periumbilical area. US-NovoLog® and EU-NovoRapid® are dosed 
between 0.5 U/kg/day and 1.0 U/k/day to patients with diabetes mellitus (Novolog US 
Prescribing Information [PI], 2008). Given this study will recruit healthy male participants, a 
dose of 0.3 U/kg was selected and aligned with similar trials of aspart analogues (Chen et al, 
2023; Drai et al, 2022; Hövelmann et al, 2021). 
NKF-INS(A) dosage is individualized based on the route of administration, and the participant’s 
metabolic needs, blood glucose monitoring results, and glycemic control goal. For the purposes 
of the clinical study, the participant will receive a single dose of 0.3 U/kg SC by injection in the 
periumbilical area in three treatment sequences.   
 

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5. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives and related endpoints are described in Table 1. 
Table 1. 
Objectives and Endpoints 
Objectives 
 
Primary 
 
• 
To compare the PK of NKF-INS(A) to 
US-approved and EU-authorized insulin 
aspart to demonstrate PK similarity for 
insulin aspart.  
• 
Aspart concentration-time curve from 0 to 
12 hours (AUC0-t)  
• 
Maximum observed insulin aspart 
concentration (Cmax) 
• 
To compare the PD of NKF-INS(A) to 
US-approved and EU-authorized insulin 
aspart injection by examining GIR profiles 
after a single SC dose.  
• 
Area under the GIR-time curve from 0 to 12 
hours (AUCGIR0-t)  
• 
Maximum GIR (GIRmax) of glucose 
 
Secondary 
 
• 
To evaluate additional PK parameters of 
NKF-INS(A) compared to US-approved and 
EU-authorized insulin aspart.  
• 
PK parameters for serum insulin aspart 
concentrations: AUC0-4h, AUC0-6h, AUC6-12h, 
AUC0-12h, Tmax, AUC0-∞ 
• 
Time to half-maximum before Cmax 
(t50%-early) 
• 
Time to half-maximum after Cmax (t50%-late)  
• 
The terminal elimination half-life (t1/2) 
• 
To evaluate additional PD parameters of 
NKF-INS(A) compared to US-approved and 
EU-authorized insulin aspart. 
• 
AUCGIR from 0 to 4 hours (AUCGIR0-4h), 
from 0 to 6 hours (AUCGIR0-6h), and from 
6 hours until the end of clamp (AUCGIR6-last)  
• 
Time to maximum glucose infusion rate 
(Tmax.GIR) 
• 
Time to half-maximum glucose infusion rate 
before GIRmax (tGIR,50%-early)  
• 
Time to half-maximum glucose infusion rate 
after GIRmax (tGIR,50%-late, indicator of end 
of duration of action) 
• 
Time from study drug administration until the 
blood glucose concentration has decreased by 
at least 5 mg/dL from baseline (onset of action) 
• 
The difference between tGIR,50%-late and the 
onset of action (duration of action) 

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Objectives 
 
• 
To assess the safety of NKF-INS(A). 
• 
AE assessments, (including injection site 
reactions), clinical laboratory investigations 
(hematology, clinical chemistry [including 
glucose], coagulation, and urinalysis), vital 
signs, physical examinations, 12-lead ECG, 
prior and concomitant medication assessments 
Exploratory  
 
• 
To assess endogenous insulin suppression 
via C-peptide measurements, which includes 
both corrected and uncorrected C-peptide 
concentrations.  
• 
Corrected and uncorrected C-peptide 
concentrations 
• 
If possible, i.e., if the terminal phase of serum 
concentration-time profile has sufficient data 
points, apparent terminal elimination half-life 
(t½.z), apparent terminal elimination rate 
constant (λz), mean residence time (MRT), 
clearance (CL/F), and volume of distribution 
(V/F) will be calculated 
Abbreviations: AE = adverse events; ECG = electrocardiogram; EU = European Union; GIR = glucose infusion rate; 
PD = pharmacodynamic; PK = pharmacokinetics; SC = subcutaneous; US = United States 

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6. 
INVESTIGATIONAL PLAN 
6.1. 
Description of Overall Study Design and Plan 
The NKF-INS(A) clinical program is designed to demonstrate biosimilarity to the US and 
EU-insulin aspart (EU-NovoRapid®, and US-NovoLog®) by comparing the PK and PD of 
NKF-INS(A) to the reference products after a single SC dose. 
Study NKF-INS(A)-101 is a Phase 1, 12-hour euglycemic glucose clamp study conducted using 
a randomized, double-blind, three-period, three-treatment, six-sequence, crossover design. The 
study will compare single doses of the proposed insulin biosimilar (NKF-INS(A)) with 
respective EU- and US-reference products in healthy male participants.  
Written informed consent will be obtained from all participants, and the study will be conducted 
in accordance with the principles of Good Clinical Practice (GCP) as defined by the International 
Conference of Harmonization (ICH). 
The study will consist of: 
• a screening period of up to 4 weeks (Days -28 to -1),  
• three treatment periods each consisting of 1-day dose administrations and euglycemic 
clamp periods (periods 1, 2, and 3) separated by a washout period of 3-14 calendar 
days between treatment periods 1 and 2, and a washout period of 5-21 calendar days 
between treatment periods 2 and 3, and  
• a follow-up period of 2-11 days after last dose.  
The entire study duration will be a maximum of 11 weeks. 
Three insulin products (NKF-INS(A), EU-NovoRapid®, and US-NovoLog®) will be 
administered over three treatment periods. Upon admission to the clinical research unit (CRU) on 
Day -1, participants will be randomized to one of six treatment sequences in a 1:1:1:1:1:1 ratio, 
receiving a single SC dose of 0.3 U/kg administration of one of the three study drugs on each 
dosing day.   
A 12-hour euglycemic glucose clamp will be conducted using a manual clamp technique, which 
will monitor the subject’s blood glucose and administer glucose infusion rate (GIR) to maintain 
blood glucose close to the target blood glucose concentration. The clamp procedure will be 
initiated, maintained, and terminated, in accordance with the site standard operating procedures 
(SOPs). The participant’s blood glucose will be maintained within a pre-defined target window 
per site SOP and clinical judgment for the participant by manually adjusting the GIR. 
Blood samples will be collected at pre-specified intervals before and up to 12 hours after dosing 
for measurement of blood glucose, serum insulin, and C-peptide. 
Fifty-four healthy male participants are planned to be enrolled in the study to have at least 
36 evaluable participants. 

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The following steps will be taken to minimize variability:  
• Prior to each dosing, participants will have been fasting for 10-12 hours 
• Individual participants will be dosed at about the same time of day within each treatment 
period 
• The injection site and technique will be standardized between treatment periods 
• Any occurrence of a drop in glucose below 3.3 mmol/L will be recorded as this may 
induce counter-regulatory hormones 
The study design schema is provided in Figure 1.  
Figure 1. 
Study Design 
 
Abbreviations: EU = European Union; US = United States 
6.2. 
Discussion of Study Design 
Congruent to Draft Guidance “Clinical Immunogenicity Considerations for Biosimilar and 
Interchangeable Insulin Products”, the Sponsor believes the aforementioned comparative 
analytical assessment demonstrates NKF-INS(A) is highly similar to EU-NovoRapid®, and 
US-NovoLog® and there is no residual uncertainty regarding immunogenicity. Therefore, in 
addition to the comparative analytical assessments, the Sponsor plans to conduct one Phase 1 study 
to demonstrate PK similarity to reference products to provide a totality of evidence for 
biosimilarity for licensure. 
The design of the study was chosen as both FDA and European Medicines Agency recognize the 
clamp technique as the most reliable method for qualifying the PK and PD proprieties of a novel 
biosimilar. Clamp technique is used to rapidly attain the required blood glucose levels and 
maintain it at target levels (Heinemann et al, 2023).  
EOS Visit 
Within 2-11 days after last 
administration of study drug 

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6.3. 
End of Study 
A participant will have fulfilled the requirements for study completion if/when the participant 
has completed all three treatment periods and the end of study (EOS) visit within 2-11 days after 
last administration of the study drug. 
The EOS is defined as the date of the last visit for the last participant in the study/last scheduled 
procedure shown in the schedule of assessments (Table 3). 
6.4. 
Criteria for Early Study Termination 
The Sponsor reserves the right to close a study site or terminate the study at any time for any 
reason. Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study site closure visit has 
been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, requirements of the Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) or local health authorities, the 
Sponsor’s procedures, or ICH GCP guidelines, or contractual agreement. 
• Inadequate recruitment of participants by the Investigator. 
• Discontinuation of further development of NKF-INS(A).  
The IRB/IEC and regulatory authorities will be informed about the reason and time of the 
termination according to applicable laws and regulations. If the study is terminated prematurely, 
Investigators will inform their participants. 

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7. 
SELECTION OF STUDY POPULATION 
7.1. 
Inclusion Criteria 
Individuals must meet all of the following inclusion criteria to be included in the study: 
1. Signed and dated informed consent obtained before any trial-related activities. Trial-related 
activities are any procedures that would not have been done during normal management of 
the participant. 
2. Healthy male participants. 
3. Age between 18 and 50 years, both inclusive. 
4. Body Mass Index between 18.5 and 29.0 kg/m2, both inclusive. 
5. Body weight ≥ 50 kg. 
6. Fasting plasma glucose concentration ≤ 5.5 mmol/L at screening. 
7. Considered generally healthy upon completion of medical history, physical examination, 
vital signs, ECG, and analysis of laboratory safety variables, as judged by the Investigator. 
8. Willing and able to comply with scheduled visits, treatment plan, clinical laboratory tests, 
and other study procedures including lifestyle considerations. 
9. Participants must agree to use condoms during sexual intercourse. Additionally, female 
partners of male participants should use highly effective contraception. All contraceptive 
measures apply from screening until 90 days after study treatment. Male participants must 
refrain from donating or banking sperm for 90 days after administration of study treatment. 
10. Have competence in speaking, writing, and comprehending the local language(s) where the 
study is conducted. 
7.2. 
Exclusion Criteria 
Individuals will be excluded from participation if they meet any of the following criteria: 
1. Positive for human insulin antibodies at Screening. 
2. Are currently enrolled in or have discontinued within 3 months or 5 half-lives (whichever is 
longer) of any investigational drug or device or are concurrently enrolled in any other type of 
medical research study and judged not to be scientifically or medically compatible with this 
study. 
3. Have known allergies to insulin, its excipients, or related drugs or have history of relevant 
allergic reactions of any origin. 
4. History of diabetes mellitus; episodes of hypoglycemia in the anamnesis; any history of 
insulin use for treatment purposes. 

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5. Have known allergies to insulin, its excipients, or related drugs or have history of relevant 
allergic reactions of any origin. 
6. Have clinically relevant history of current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly 
altering the absorption, metabolism, or elimination of drugs; of constituting a risk when 
taking the study drug; or of interfering with the interpretation of data. 
7. Increased risk of thrombosis, e.g., individuals with a history of deep leg vein thrombosis or 
family history of deep leg vein thrombosis, as judged by the Investigator. 
8. Clinically significant abnormal ECG at screening. 
9. Glycemia level ≥140.4 mg/dL 2 hours after the glucose load. 
10. Show evidence of significant active neuropsychiatric disease. 
11. Positive urine drug test at screening and/or evidence of current use of known drugs of abuse 
or have a history of use within the past year. 
12. Show evidence of an acute infection with fever or infectious disease at the time of 
enrollment. 
13. Show evidence of human immunodeficiency virus (HIV) infection and/or positive human 
HIV antibodies at screening. 
14. Have positive test results for hepatitis B surface antigen (HBsAg), immunoglobulin M (IgM) 
antibody to hepatitis B core antigen (anti-HBc), or hepatitis C virus (HCV) antibodies at 
screening. 
15. Intend to use over-the-counter medication within 7 days or prescription medication within 
14 days prior to dosing (apart from vitamin/mineral supplements, occasional paracetamol, 
thyroid replacement). 
16. Have donated blood or had a blood loss of 450 mL 3 months prior to study enrollment. 
17. Have an average weekly alcohol intake that exceeds 21 units per week or is unwilling to stop 
alcohol consumption from 48 hours prior to each dosing until being discharged from the 
CRU. 
7.3. 
Rescreening 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered into the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened only once, at the discretion of the Investigator.  

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The participant must be reconsented and a new screening number will be assigned. Also, a new 
informed consent form (ICF) must be signed if updates have been made since signing of the first 
ICF. 
7.4. 
Study Withdrawal, Removal, and Replacement of Participants 
Participants may withdraw from the study at any time with or without reason. The Investigator 
also has the right to discontinue or terminate participants from the study in the event of 
concomitant disease, AEs, or any reason that would benefit the participant (see Section 8.4). 
If a participant withdraws from the study for any reason, the study site must immediately notify 
the clinical monitor. The date and the reason for study discontinuation must be recorded in the 
electronic case report form (eCRF). Participants who discontinue early, irrespective of the reason 
for discontinuation from the study, will be asked to complete the EOS assessments at the time of 
the participant’s withdrawal, as outlined in the schedule of assessments (Table 3). 
If a participant withdraws from the study, he may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
Additionally (as described in Section 6.4), the Sponsor may stop the study at any time for safety, 
regulatory, legal, or other reasons aligned with GCP. This study may be terminated at the 
discretion of the Sponsor or any regulatory agency. An Investigator may elect to discontinue or 
stop the study at his or her study site for any reason, including safety or low enrollment. 
7.4.1. 
Replacement of Participants 
Participants who sign the ICF and are randomized but not treated may be replaced at the 
discretion of the Sponsor. 

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8. 
TREATMENTS 
A list of study treatments used in this study is provided in Table 2. 
Table 2 
Study Treatments 
Agent 
Use 
NKF-INS(A)  
Investigational agent 
US-NovoLog®, and 
EU-NovoRapid® Flex 
Pen 
Indicated to improve glycemic control in adults and children with diabetes 
mellitus 
Source: NovoLog United States Prescribing Information (USPI); NovoRapid Summary of Product Characteristics 
8.1. 
Study Treatment Description 
NKF-INS(A), US-NovoLog® and EU-NovoRapid® is intended to be administered as a 0.3 U/kg 
single dose SC in the periumbilical area.  
US-NovoLog® and EU-NovoRapid® will be supplied by Novo Nordisk, Plainsboro, NJ, US. 
NKF-INS(A) is a clear and colorless solution.  
NKF-INS(A) is supplied in a disposable pen (with cartridge) containing 300 U/3mL; 1 mL 
solution contains 100 units of NKF-INS(A), equivalent to 3.5 mg. The disposable pen syringe 
device is a BD Vystra Disposable Pen sourced commercially (Figure 2).  
Figure 2 
Investigational Product Description 
 
US-NovoLog® and EU-NovoRapid® is supplied in a disposable pen syringe containing 
300 U/3mL (NovoLogâ United States Prescribing Information (USPI); NovoRapid Summary of 
Product Characteristics[SmPC]); 1 mL solution contains 100 units of insulin aspart equivalent to 
3.5 mg. The disposable pen is a proprietary device with a NovoFine needle (Figure 3).  

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Figure 3 
Control Treatment 
 
8.1.1. 
Preparation, Handling, and Disposal 
The preparation of NKF-INS(A), US-NovoLog® and EU-NovoRapid® will be conducted in 
accordance with the Pharmacy Manual. 
Procedures for proper handling and disposal should be followed in compliance with the SOPs of 
the site. 
8.1.2. 
Product Labeling and Packaging 
NKF-INS(A), US-NovoLog® and EU-NovoRapid® will be labeled to meet country-specific 
regulatory requirements.  
Refer to the Pharmacy Manual for packaging and labeling information. 
8.1.3. 
Administration 
NKF-INS(A), US-NovoLog® and EU-NovoRapid® will be administered as a single dose via the 
SC route (refer to Section 8.2). Device-related events or complaints should be reported to the 
Sponsor in accordance with the Pharmacy Manual. 
8.1.4. 
Storage 
Refer to the Pharmacy Manual for information regarding storage, handling, and administration of 
NKF-INS(A), US-NovoLog® and EU-NovoRapid®. 
Before opening (unpunctured), NKF-INS(A) should be stored at 2 °C to 8 °C (36 °F to 46 °F) 
and protected from heat and light until the time of use. The drug product must not be frozen or 
placed adjacent to the refrigerator cooling element.  
During use (punctured), NKF-INS(A) should be stored below 30 °C (86 °F) for up to 28 days 
and should not be exposed to excessive heat or sunlight. Do not freeze and do not draw into a 
syringe for later use. Pen cap should be kept on the pen in order to protect from light.  

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Always remove and discard the needle after each injection of NKF-INS(A) pen. Pens are 
considered single use. 
The shelf life during use for US-NovoLog® and EU-NovoRapid® is 28 days when stored below 
30 °C (86 °F). The unpunctured disposable pen can be used until their expiry date if stored at 
2 °C to 8 °C (36 °F to 46 °F). NKF-INS(A) is being studied on an ongoing stability program and 
is tested at regular intervals to establish shelf life.  
8.2. 
Dosage Schedule 
Upon admission to the CRU on Day -1, participants will be randomized on Day 1 to one of six 
treatment sequences in a 1:1:1:1:1:1 ratio, receiving a single SC dose of 0.3 U/kg administration 
of one of the three study drugs on each dosing day.   
The insulin products will be administered using an euglycemic glucose clamp at a targeted blood 
glucose concentration. The euglycemic glucose clamp will be conducted using a clamp 
technique. The glucose clamp device will manually adjust the infused GIR to maintain the target 
blood glucose concentration based on the actual measured blood glucose concentration and the 
degree of variability in the previous minute.  
Blood samples will be collected at pre-specified intervals before and up to 12 hours after dosing 
for measurement of blood glucose, serum insulin, and C-peptide. 
Participants will visit the study site for 3 single-dose periods with specified washouts (3-14 days 
between treatment periods 1 and 2; and 5-21 days between treatment periods 2 and 3). The entire 
duration of the study will be a maximum of 11 weeks.  
8.3. 
Measures to Minimize Bias: Study Treatment Assignment and 
Blinding 
8.3.1. 
Method of Study Treatment Assignment 
Participants will be assigned a screening identification (ID) number when providing informed 
consent. A participant ID will be provided on Day -1. A participant ID consists of a site ID and a 
participant number that uniquely identifies each participant.  
On Day 1, participants will be randomly allocated to study treatment sequence according to a 
pre-specified randomization scheme prepared by an independent statistician (refer to 
Section 8.2). 
8.3.2. 
Blinding 
All participants, Investigators, and study personnel involved in the conduct of the study will be 
blinded to treatment assignment with the exception of unblinded statistician, programmer, 
pharmacists, and drug administrator.  
Because study drug and comparator differ slightly in appearance, the study drug will be prepared 
by an unblinded pharmacist and administered by an unblinded administrator, while the 
participant is blindfolded. The used pen will be returned to the packaging and reconciliation will 
be completed by the unblinded pharmacist.  

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The unblinded study personnel will not participate in study procedures or data analysis prior to 
unblinding of the study data. 
The following controls will be employed to maintain the double-blind status of the study: 
The randomization list will be kept within the Clinical Data Management System and role-based 
access will prevent any unauthorized personnel from accessing the blinded information. The 
pharmacist will have access to the randomization list for dispensing purposes. 
• To manage the participant’s condition in case of a medical emergency, the 
Investigator will be able to break the blind for a specific participant, using the 
Clinical Data Management System, to know whether a participant received 
NKF-INS(A), US-NovoLog® and EU-NovoRapid®. In order to break the blind, the 
Investigator will have to provide a reason for doing so. All relevant data including the 
responsible individual, the date, the time, and the reason for breaking the blind will be 
captured electronically within audit trail of the Clinical Data Management System. 
The Sponsor will be informed in case of unblinding. 
• Extra measures (where relevant) will be put in place to maintain the blind during 
dosing, e.g., blindfolding of participants, presenting the study treatments as identical 
in appearance where possible, double-blind labelling, unblinded personnel to 
administer study treatment.  
8.4. 
Treatment Modifications and Discontinuations 
Dose reductions and adjustments are not permitted; any dose reductions and adjustments that 
occur will be recorded and considered protocol deviations. 
Delays and omissions of study treatment administration because of medical or nonmedical 
reasons are not permitted. All delays and omissions of study treatment that occur during the 
study will be recorded and considered protocol deviations. 
A participant may be discontinued from the study at any time for reasons including, but not 
limited to, the following: 
• AE and/or SAEs in the judgment of the Investigator that may prevent the participant 
from continuing participation in the study. 
• Participant withdrawal of consent (at any time, a participant’s participation in the 
study may be terminated at their request). 
• On the basis of the Investigator’s clinical judgment. 
• General or specific changes in the participant’s condition that render them ineligible 
for further treatment according to the inclusion/exclusion criteria. 
• Participant fails to adhere to the protocol requirements (e.g., study treatment 
noncompliance). 
• Lost to follow up: the participant stopped coming for visits and study personnel were 
unable to contact the participant. 

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Note: In cases in which the participant is deemed lost to follow up, prior to this designation, 
the Investigator (or designee) must make every effort to make contact with the participant 
(e.g., telephone calls, certified letter to the participant’s last known mailing address, or local 
equivalent methods, and efforts to reach the participant’s emergency contact). The site will 
make 3 attempts to regain contact with the participant. These contact attempts must be 
documented in the participant’s medical records. 
Any participant who discontinues from the study will be asked to return to the clinic for an EOS 
visit that includes the assessments as shown in the schedule of assessments (Table 3). The reason 
and date for the participant’s discontinuation from the study must be recorded in the eCRF. 
8.5. 
Treatment Accountability and Compliance 
The pharmacist or other designated individual will maintain records of study drug delivered to 
the study site, the inventory at the study site, the distribution to and use by each participant, and 
the return of materials to the Sponsor for storage or disposal/destruction of materials at the study 
site. These records must include dates, quantities, lot/batch/serial numbers, expiration dates, 
storage temperature log, and unique code numbers assigned to the study drug and study 
participants. 
Investigators/designee will maintain records that adequately document that the participants were 
provided with the correct study treatment and reconcile the products received from the drug 
dispensing center. Investigational product will not be returned to the Sponsor or disposed of until 
accountability has been fully monitored. 
Administration of the study treatment will be supervised by unblinded study site personnel to 
ensure compliance. An unblinded monitor will periodically review the study records to ensure 
compliance. Discontinuation for noncompliance is at the Investigator’s discretion and is to be 
noted in the eCRF. 
Cases of accidental overdose or medication error, along with any associated AEs, should be 
reported as described in Section 12.6.2. 
8.6. 
Prior and Concomitant Therapy and Other Restrictions During the 
Study 
8.6.1. 
Prior and Concomitant Medications 
Medications taken by or administered to the participant for the period before screening will be 
recorded in the eCRF as prior medications. Restricted prior therapies include over-the-counter 
medication within 7 days or prescription medication within 14 days prior to dosing (apart from 
vitamin/mineral supplements, occasional paracetamol, thyroid replacement, or birth control 
methods). 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) other than NKF-INS(A), US-NovoLog® and EU-NovoRapid® that 
the participant is receiving at the time of enrollment, or receives during the study, must be 
recorded in the eCRF as concomitant medications along with: 
• Reason for use 

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• Dates of administration including start and end dates 
• Dosage information including dose, regimen, route, and frequency 
The participant must be told to notify the investigational site about any new medications taken 
after administration of the study treatment. 
All previous and on study Coronavirus disease 2019 (COVID-19) vaccinations should be 
recorded in the eCRF. 
The Medical Monitor should be contacted if there are any questions regarding prior or 
concomitant therapy. 
8.6.1.1. 
Permitted Concomitant Medications and Therapies 
Other than those medications explicitly prohibited (Section 8.6.1), concomitant medication 
decisions will be left to the discretion of the Investigator. 
8.6.1.2. 
Prohibited Concomitant Medications and Therapies 
Participants must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator. 
If the participant has received any other investigational drug within 3 months before the 
administration of study treatment, he will not be eligible for this study. 
No prophylactic medication, treatments, or procedures will be administered during the study 
period, unless at the discretion of the Investigator. 
8.6.1.3. 
Advisory on COVID-19 Vaccination and Risk Assessment 
The COVID-19 pandemic is an ongoing pandemic with varying impact at any time in different 
geographies worldwide (World ). It is recommended that participants and their investigators 
discuss on an individual basis the benefits and risks of COVID-19 vaccination in the context of 
their prior vaccination history and consider the vaccinations approved by national regulatory 
agencies, as well as COVID-19 vaccination guidance from scientific and medical associations. 
The following recommendations should be considered for the study: 
• Participants with prior COVID-19 vaccination may be allowed to enter the study with 
a washout period of at least 7 days since the last COVID-19 vaccine dose. 
• Administration of a COVID-19 vaccine during participation in the study should be 
documented as a concomitant medication (Section 8.6.1). 
• Previous administration(s) of COVID-19 vaccine should be documented in the prior 
and concomitant medication form. 

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8.6.2. 
Other Restrictions During the Study 
8.6.2.1. 
Meals and Dietary Restrictions 
For all treatment periods, participants will fast for 10-12 hours prior to dosing and until the 
glucose clamp procedure is completed, after which participants will receive a meal. There is no 
restriction on water during the fasting periods of the study. When not in CRU subjects will be 
encouraged to follow their normal diets. Grapefruit juice is an inhibitor of the CYP3A4 enzyme 
but CYP3A4 does not play a role in the metabolism of insulin aspart thus it is not mentioned. 
8.6.2.2. 
Caffeine, Alcohol and Tobacco 
No alcohol will be allowed 48 hours before each dose and for the duration of each CRU visit. 
Participants should refrain from caffeine-containing food/beverages for at least 24 hours before 
each dose and through the duration of visit. 
Smoking of tobacco products, nicotine replacements etc., will not be permitted during the 
confinement period.  
8.6.2.3. 
Activity 
Participants are encouraged to maintain their regular exercise habits; however, they should not 
undertake vigorous or prolonged exercise within 48 hours prior to dosing. Strenuous exercise is 
not allowed throughout the entire study. 

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9. 
STUDY PROCEDURES 
Assessments and their timing to be performed are outlined in the schedule of 
assessments (Table 3). 
See Sections 10, 11, 12, and 13 for additional details regarding PK, PD, safety, and other 
assessments, respectively. 
The Investigator may, at his or her discretion, arrange for a participant to have an unscheduled 
assessment, especially in the case of AEs that require follow up or are considered by the 
Investigator to be possibly related to the use of study treatment. The unscheduled visit page in 
the eCRF must be completed for all unscheduled assessments. 
 

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Table 3. 
Schedule of Assessments 
Assessment 
Screening 
Euglycemic Clamp Procedure Treatment Periods 1-31 
EOS Visit 
-28 to -1 Days Priorto 
Treatment Period 1 
Day -1 
Clamp Procedure 
Starting the Morning of Day 1 for 
12 Hours2 
Post- 
Clamp 
(Day 2) 
Within 2-11 Days 
After Last 
Administration of 
Study Drug 
Informed consent 
X 
Demographic data3 
X 
Alcohol and tobacco 
consumption patterns 
X 
Medical and medications 
history4 
X 
X 
Inclusion/exclusion criteria 
X 
X 
Admission to CRU5 
X 
Randomization 
 
X6 
 
Discharge from CRU 
X 
 
Height/weight7 
X 
X 
Physical examination8 
X 
X 
Vital signs9 
X 
X 
X 
X 
12-lead ECG 
X 
X 
Hematology10 
X 
X 
Clinical chemistry11 
X 
X 
Blood coagulation12 
X 
Serology tests  
(HBsAg, IgM anti-HBc, HCV, 
HIV)
13 
X 
Urinalysis
14 
X 
Urine screen for drugs of 
abuse15 
X 
X 
Alcohol breath test16 
X 
X 
Human insulin antibodies 
X 
Oral glucose tolerance test17 
X 
Study drug administration18 
Day 1 at time = 0 hours/0 min 
Injection site assessment19 
X 
X 
GIR 
X 
Adverse events 

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Assessment 
Screening 
Euglycemic Clamp Procedure Treatment Periods 1-31 
EOS Visit 
-28 to -1 Days Priorto 
Treatment Period 1 
Day -1 
Clamp Procedure 
Starting the Morning of Day 1 for 
12 Hours2 
Post- 
Clamp 
(Day 2) 
Within 2-11 Days 
After Last 
Administration of 
Study Drug 
Concomitant medications 
PK, PD, C-peptide, and glucose sampling (see Table 4) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; anti-HBc = antibody to hepatitis B core antigen; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; CRU = clinical research unit; ECG = electrocardiogram; EOS = end of study; GGT = gamma-glutamyl transferase; GIR = glucose infusion rate; 
Hb = hemoglobin; HBsAg = hepatitis B surface antigen; HCT = hematocrit; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IgM = immunoglobulin M; 
INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; PD = pharmacodynamic; PK = pharmacokinetic; 
PT = prothrombin time; RBC = red blood cell; WBC = white blood cell 
1 There will be a washout period of 3-14 calendar days between treatment period 1 and 2, and a washout period of 5-21 calendar days between treatment periods 2 and 3. 
2 The clamp procedure will be considered as ended if the 20% GIR is on zero (0) and the infusion pump has been stopped or the 12-hour mark is reached. Blood glucose 
concentration will be measured for 3 consecutive times for safety reasons, after the infusion pump is on zero (0). 
3 Sex, race, year of birth, age, and ethnicity. 
4 The recorded medical history will be updated, if necessary, at admission to treatment period 1. 
5 Participants will be admitted to the CRU approximately 12 hours prior to dosing on Day -1. 
6 Randomization will only be done on first sequence. 
7 Body weight will be recorded at screening and on Day -1 of all treatment periods. The weight measured on Day -1 of treatment period 1 will be used for dosage calculations of 
insulin. Height will be recorded at screening only. 8 A full physical examination will include the following: Evaluation for jaundice, pallor (anemia), cyanosis, clubbing, edema 
and lymphadenopathy; skin evaluation; fundoscopy; ear, nose and throat; cardiovascular assessment; respiratory assessment; abdominal evaluation; musculoskeletal assessment; 
neurological assessment; other evaluations may be performed as deemed necessary by the Investigator. A full physical exam should be done at screening. A limited symptom-
based physical exam may be done at timepoints thereafter. 
9 Supine systolic and diastolic blood pressure, pulse, and respiratory rate will be recorded at screening, before administration of the study drug, at the end of the clamp (before 
discharge from the study center) and at the EOS visit. Body temperature (temporal or ear) will be recorded at screening and before administration of study drug (either standing or 
supine). All vital signs will be measured after the participant has been resting in a supine position for at least 5 minutes. 
10 Hematology (ethylenediaminetetraacetic acid tubes): full and differential blood count, WBC count, RBC count, Hb, HCT, MCV, MCH, MCH concentration, absolute 
differential count (neutrophils, lymphocytes, monocytes, eosinophils and basophils), and platelets. 
11 Clinical chemistry (serum separator tubes): potassium, sodium, urea, chloride, phosphorus, creatinine, calcium, albumin, total and direct bilirubin, creatine kinase, ALP, GGT, 
AST, ALT, lactate dehydrogenase, total cholesterol, triglycerides, and glucose. 
12 Blood coagulation tests (citrated tubes): PT, aPTT, and INR. 
13 Tests for HIV, HBsAg, IgM anti-HBc, and HCV, performed using commercially available test kits. Pre- and post-test counseling will be provided as appropriate. 
14 Urinalysis (dipstick): appearance, bilirubin, glucose, ketone, specific gravity, blood, pH, protein, urobilinogen, nitrite, leucocytes. Abnormal urinalysis results may be repeated 
at the discretion of the Investigator. 

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15 A rapid, one-step screening test for simultaneous, qualitative detection of multiple drugs and drug metabolites will be used. Subjects with alleged false positive test results will 
be excluded from the study. However, a positive test may be repeated once at the discretion of the Investigator. 
16 Alcohol breath test using a portable breath alcohol measuring device. The test will be performed at screening, at admission to each treatment period and at random. If any of 
these tests are positive, the subject will not be allowed further participation in the study. 
17 Oral glucose tolerance test may be completed after all other eligibility has been determined. For participants who re-screen, oral glucose tolerance test does not need to be 
repeated if completed within the last 6 months. 
18 From 1 hour before study drug administration until 3 hours post-dose, the injection site will be kept at a constant temperature. The time of injection is defined as time 
zero (0 hour/0 min) and marks the start of the clamp period, which will continue for up to 12 hours or until the GIR is 0 and blood glucose remains stable. 
19 The injection site will be assessed at 1 min and 15 min post-dose on Day 1 and at the EOS visit. Reactions to the study drug injection will be documented using a numerical 
scoring system. 
 
 

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Table 4. 
Pharmacokinetic, Pharmacodynamic, C-Peptide, and Glucose Sampling Schedule 
Sample 
Pre-dose 
(minutes) 
Post-dose (minutes) 
60 
30 
0 
5 
10 
20 
30 
40 
50 
60 
75 
90 
105 
120 
135 
150 
180 
210 
240 
300 
600 
720 
(12 hours) 
Insulin (serum) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-peptide (serum) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood glucose 
 
 
Every 3 minutes 
 
Every 5 minutes 
 
Every 10 minutes 
 
 

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9.1. 
Screening and Baseline Assessments 
Standard study procedures will be performed at the timepoints indicated in the schedule of 
assessments (Table 3). A description of the study procedures is provided in the sections 
below. 
9.1.1. 
Informed Consent 
Before performing any study-related procedures, the Investigator (or designee) will obtain 
written informed consent from the participant according to national legal regulations (see 
Section 15.1.3). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened only once. Participants may be rescreened at the Investigator’s discretion. The 
participant must be reconsented and a new screening number will be assigned. Also, a new 
ICF must be signed if updates have been made since signing of the first ICF. 
To give the participant sufficient time to consider study participation, informed consent can 
be obtained before the screening visit. However, if the informed consent is obtained on the 
day of screening, then the time must be documented in the participant’s chart to provide proof 
that consent was given before the first study-related screening procedure. 
• The Investigator or their authorized representative will explain the nature of the 
study to the participant and answer all questions regarding the study. 
• Participants will be informed that their participation is voluntary and will be 
required to sign a statement of informed consent that meets the requirements of 
the local regulations, the ICH guidelines, the IEC/IRB, or study site. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date (and time, if 
obtained on the day of screening) when the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
• Participants must give new consent to each updated version of the ICF during 
their participation in the study. 
• Each ICF must be personally dated and signed by the participant as well as by the 
Investigator (or designee). 
• A copy of the ICF (or second original ICF per local regulations) must be provided 
to the participant. If the ICF is not taken by the participant, it will be archived with 
the participant’s study documents.  
9.1.2. 
Demographics 
Date of birth and/or age, sex at birth, race, ethnicity, and country will be recorded at 
screening in the eCRF. 
9.1.3. 
Medical History 
Medical history will be recorded at screening. The recorded medical history will be updated, 
if necessary, at admission to treatment period 1. Investigators should document the 
occurrence, signs, and symptoms of the participant’s preexisting conditions, including all 
prior significant illnesses. Medical history will include alcohol consumption and smoking 
history, if applicable. 

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Illnesses first occurring or detected during the study and/or worsening of a concomitant 
illness during the study are to be documented as AEs in the eCRF in accordance with 
Section 12.5. All changes that are not present at baseline or described in the medical history 
and identified as clinically noteworthy must be recorded as AEs. 
9.1.4. 
Eligibility Review 
Participant eligibility will be reviewed per the inclusion criteria (Section 7.1) and exclusion 
criteria (Section 7.2) at the timepoints specified in the schedule of assessments (Table 3). 
Before randomization on Day 1, the eligibility review must be completed. 
9.1.5. 
Drug and Alcohol Screening 
A urine drug test for prohibited substances, using a rapid, one-step screening test for 
simultaneous, qualitative detection of multiple drugs and drug metabolites will be performed 
at the timepoints specified in the schedule of assessments (Table 3). Results must be negative 
for study eligibility. However, if a participant has a positive result for a medically indicated 
substance such as benzodiazepines, and the Investigator determines that the participant was 
not abusing the substance, the positive result will not be exclusionary, provided that the 
Investigator consults with the Medical Monitor before enrolling or randomizing/dosing the 
participant. 
An alcohol breath test using a portable breath alcohol measuring device will be performed. 
The test will be performed at screening, at admission to each treatment period and at random. 
If any of these tests are positive, the subject will not be allowed further participation in the 
study. 
9.1.6. 
Serology Testing 
Serum testing for HBsAg, IgM anti-HBc, HCV, and HIV will be performed at the timepoints 
specified in the schedule of assessments (Table 3). 
9.1.7. 
Prior and Concomitant Medication 
Any medication or therapy other than NKF-INS(A), US-NovoLog® and EU-NovoRapid® is 
considered concomitant medication (see Section 8.6.1) and should be recorded in the eCRF. 
Relevant prior concomitant medication given within 3 weeks before screening and all 
medication given from screening until the EOS visit (within 2-11 days after last 
administration of the study drug) must be recorded. 
All previous and on study COVID-19 vaccinations should be recorded in the eCRF. 
9.1.8. 
Other Screening Assessments 
Other screening assessments include physical examination, height and weight, vital signs, 
12-lead ECG, and safety laboratory assessments.  
An oral glucose tolerance test will be conducted per site SOP. Oral glucose tolerance test may 
be completed after all other eligibility has been determined. For participants who re-screen, 
oral glucose tolerance test does not need to be repeated if completed within the last 6 months. 
These assessments are also conducted at other timepoints as detailed in the schedule of 
assessments (Table 3).  

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10. 
PHARMACOKINETICS 
10.1. 
Pharmacokinetic Sampling 
10.1.1. 
Blood Samples 
Blood samples for PK analysis of NKF-INS(A), US-NovoLog® and EU-NovoRapid® will be 
collected at the timepoints indicated in Table 4. The actual date and time of each blood 
sample collection will be recorded. Actual time will be used for derivation of PK parameters. 
Details of PK blood sample collection, processing, storage, and shipping procedures are 
provided in a separate laboratory manual. 
10.1.2. 
Pharmacokinetic Evaluation 
The PK parameters will be derived for NKF-INS(A), US-NovoLog® and EU-NovoRapid® from 
serum concentrations by a validated PK analysis platform using standard noncompartmental 
methods (where data allow). A description of the PK parameters is provided in Table 5. A 
complete list of PK parameters will be provided in the statistical analysis plan (SAP). 
Table 5 
Pharmacokinetic Parameters 
PK Parameter 
Description 
AUC0-4h 
concentration-time curve from 0 to 4 hours 
AUC0-6h 
concentration-time curve from 0 to 6 hours 
AUC6-12h 
concentration-time curve from 6 to 12 hours 
AUC0-12h 
concentration-time curve from 0 to 12 hours/end of clamp 
AUC0-t 
concentration-time curve from 0 hour to the last quantifiable concentration 
time 
AUC0-∞ 
concentration-time curve from 0 hour to infinity 
Tmax 
time to maximum serum concentration 
Cmax 
maximum observed insulin aspart concentration 
t50%-early 
time to half-maximum before Cmax 
t50%-late 
time to half-maximum after Cmax 
t1/2 
terminal elimination half-life 
PK parameters will be estimated using noncompartmental methods. Estimates of PK 
parameters will be listed and summarized (N, arithmetic and geometric mean, standard 
deviation [SD], coefficient of variation [CV%], median, minimum, and maximum) by 
treatment group), descriptively and graphically. The full analysis will be described in the 
prospective SAP that will be finalized prior to database lock. 
10.2. 
Pharmacokinetic Analytical Methodology 
The concentration of NKF-INS(A), US-NovoLog® and EU-NovoRapid® will be determined 
from the serum samples using a validated analytical method. Details of the method validation 
and sample analysis will be included with the final clinical study report. 

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11. 
PHARMACODYNAMICS 
11.1. 
Pharmacodynamic Sampling 
11.1.1. 
Blood Samples 
Blood samples for NKF-INS(A), US-NovoLog®, and EU-NovoRapid® in serum will be 
collected at the timepoints indicated in the sample schedule shown in Table 4. The actual date 
and time of each blood sample collection will be recorded. Actual time will be used for 
derivation of PD parameters. 
Details of PD blood sample collection, processing, storage, and shipping procedures are 
provided in a separate laboratory manual. 
11.1.2. 
Pharmacodynamic Evaluation 
The following PD parameters will be derived for NKF-INS(A), EU-NovoRapid®, and 
US-NovoLog® from serum concentrations by a validated PK analysis program using standard 
noncompartmental methods (where data allow): 
The PD similarity will be assessed using the parameters provided in Table 6, and by 
assessing: 
• 
Time from study drug administration until the blood glucose concentration has decreased 
by at least 5 mg/dL from baseline (onset of action) 
• 
The difference between tGIR,50%-late and the onset of action (duration of action) 
• 
Total amount of glucose infused during clamp procedure (Gtot) 
A complete list of PD parameters will be provided in the SAP.   
Table 6 
Pharmacodynamic Parameters 
PD Parameter 
Description 
AUCGIR0-12h 
Area under the GIR-time curve from 0 to 12 hours 
GIRmax 
The maximum GIR of glucose 
AUCGIR0-4h 
Area under the GIR-time curve from 0 to 4 hours 
AUCGIR0-6h 
Area under the GIR-time curve from 0 to 6 hours 
AUCGIR6-last 
Area under the GIR-time curve from 6 hours until the end of clamp 
AUCGIR0-t 
Area under the GIR-time curve from 0 hours to the last quantifiable 
concentration time 
AUCGIR0-∞ 
Area under the GIR-time curve from 0 hours to the last quantifiable 
concentration time with extrapolation to infinity 
AUCGIR0-end of clamp 
Area under the GIR-time curve from 0 hours to end of clamp 
Tmax.GIR 
Time to maximum GIR 
tGIR,50%-early 
Time to half-maximum GIR before GIRmax 
tGIR,50%-late 
Time to half-maximum GIRe after GIRmax (indicator of end of 
duration of action) 
Abbreviation: GIR = glucose infusion rate 

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Estimates of PD parameters will be listed and summarized (N, arithmetic and geometric 
mean, SD, CV%, median, minimum, and maximum) by treatment group, descriptively and 
graphically. 
Endogenous insulin suppression via C-peptide measurements will also be explored. These 
values include corrected and uncorrected C-peptide concentrations. C-peptide corrected 
estimates of exogenous insulin will be calculated using Owen’s method (Plum-Mörschel, 
2022). If terminal phase of serum concentration-time profile has sufficient data points, 
apparent terminal elimination half-life (t½.z), apparent terminal elimination rate constant 
(λz), mean residence time (MRT), clearance (CL/F), and volume of distribution (V/F) will be 
calculated. 
11.1.3. 
Pharmacodynamic Analytical Methodology 
The concentration of C-peptide, NKF-INS(A), US-NovoLog® and EU-NovoRapid® will be 
determined from the serum samples using a validated analytical method. Details of the 
method validation and sample analysis will be included with the final clinical study report. 

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12. 
SAFETY ASSESSMENTS 
Safety assessments (vital signs, physical examinations, ECG recordings, clinical laboratory 
assessments [hematology, clinical chemistry (including glucose), coagulation, and urinalysis], 
AE monitoring [including injection site reactions]) are to be performed as outlined in the 
schedule of assessments (Table 3). 
12.1. 
Vital Signs 
Vital signs (heart rate, respiratory rate, systolic and diastolic blood pressure, and temporal or 
ear temperature measurements) will be evaluated at the timepoints indicated in the schedule 
of assessments (Table 3). All vital signs will be measured after the participant has been 
resting in a supine position for at least 5 minutes. Height (without shoes) will be recorded at 
screening. Weight will be recorded at screening and on Day -1.  
Vital sign measurements will be repeated if clinically significant abnormal or 
machine/equipment errors occur. Out-of-range blood pressure, respiratory rate, or heart rate 
measurements will be repeated at the Investigator’s discretion. Any confirmed, clinically 
significant abnormal vital sign measurements must be recorded as AEs. 
12.2. 
Physical Examination 
A complete physical examination will be performed at screening (Visit 1). Physical 
examinations will be performed by a physician. 
A full physical examination will include the following: evaluation for jaundice, 
pallor (anemia), cyanosis, clubbing, edema and lymphadenopathy; skin evaluation; 
fundoscopy; ear, nose and throat; cardiovascular assessment; respiratory assessment; 
abdominal evaluation; musculoskeletal assessment; neurological assessment. Other 
evaluations may be performed as deemed necessary by the Investigator. 
A limited physical or symptom-driven examination to verify continued participant eligibility 
and to follow up regarding any change in medical history will be performed at the timepoints 
indicated in the schedule of assessments (Table 3) or at the Investigator’s discretion. 
Symptom-driven, limited physical examinations may be performed as clinically indicated or 
at the discretion of the Investigator at any study visit. Clinically significant findings must be 
recorded as AEs. 
12.3. 
Electrocardiograms 
A 12-lead, resting ECG will be obtained at the timepoints indicated in the schedule of 
assessments (Table 3). ECG should always be performed after the participant has been resting 
in a supine position for at least 5 minutes. 
At screening, the Investigator will examine the ECG traces for signs of cardiac disease that 
could exclude the participant from the study. An assessment of normal, clinically significant, 
or abnormal not clinically significant will be recorded; if the ECG is considered abnormal, 
the abnormality will be documented in the eCRF. ECGs will be repeated if clinically 
significant abnormalities are observed, or artifacts are present. Any confirmed, clinically 
significant abnormal ECG findings must be recorded as AEs. 

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12.4. 
Laboratory Assessments 
Laboratory assessment samples (Table 7) are to be obtained at designated timepoints as 
detailed in the schedule of assessments (Table 3). 
Table 7 
Laboratory Assessments 
Hematology: 
Clinical Chemistry: 
Urinalysis (Dipstick): 
Full and differential blood count 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
  concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
White blood cell count with 
  Differential (absolute values): 
    Basophils 
    Eosinophils 
    Lymphocytes 
    Monocytes 
    Neutrophils 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bilirubin (direct and total) 
Urea 
Creatine kinase* 
Creatinine 
Electrolytes (calcium, chloride, 
  phosphorus, potassium, 
  sodium) 
Gamma-glutamyl transferase 
Glucose 
Lactate dehydrogenase 
Total cholesterol 
Triglycerides 
Oral glucose tolerance test 
Appearance 
Glucose 
Blood 
Leucocytes 
Ketone bodies 
pH 
Protein 
Specific gravity 
Urobilinogen 
Bilirubin 
Nitrite 
Coagulation: 
Other: 
Serology: 
PT 
aPTT 
INR 
 
Urine drug  
Human insulin antibodies 
HBsAg 
IgM anti-HBc 
HCV 
HIV 
Abbreviations: anti-HBc = hepatitis B core antigen; aPTT = activated partial thromboplastin time; 
CK-MB = creatine kinase MB; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; IgM = immunoglobulin M; INR = international normalized ratio; PT = prothrombin 
time.  
Vitamin D retest is allowed once. 
* In case of elevated creatine kinase, CK-MB may be performed, at the discretion of the Investigator 
 
The tests detailed in Table 7 will be performed. All laboratory reports must be reviewed, 
signed, and dated by the Investigator. A legible copy of all reports must be filed with the 
participant’s medical record (source document) for that visit. Any laboratory test result 
considered by the Investigator to be clinically significant should be considered an AE 
(clinically significant AEs include those that require an intervention). Clinically significant 
abnormal values occurring during the study will be followed up until repeat test results return 
to normal, stabilize, or are no longer clinically significant. 
Further laboratory assessments outside the protocol-defined schedule may be obtained at the 
discretion of the Investigator and used for other clinical treatment decisions. 
12.5. 
Injection Site Assessment 
The injection site and surrounding area will be assessed by the investigator at 1 min and 
15 min post-dose on Day 1 and at the EOS visit. Reactions to the study drug injection will be 
documented using a numerical scoring system. 

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12.6. 
Adverse Events 
12.6.1. 
Definitions  
12.6.1.1. Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
an investigational product which does not necessarily have to have a causal relationship with 
this treatment. An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with 
the use of an investigational product, whether or not considered related to the investigational 
product. 
12.6.1.2. Adverse Reaction 
A response to a medicine in humans which is noxious and unintended, and which occurs at 
any dose, and which can also result from overdose, misuse, or abuse of a medicine. Response 
to a medicinal product in this context means that a causal relationship between the medicinal 
product and an AE is at least a reasonable possibility. 
12.6.1.3. Serious Adverse Event 
Any untoward medical occurrence, in the view of either the Investigator or Sponsor, that: 
• Results in death 
• Is life-threatening 
− An AE is life-threatening if the participant was at immediate risk of death 
from the event as it occurred (i.e., it does not include a reaction that might 
have caused death if it had occurred in a more serious form). 
• Requires or prolongs inpatient hospitalization 
− A hospitalization is defined as ≥24 hours in hospital or an overnight stay. 
Complications occurring during hospitalization are AEs and SAEs if they 
cause prolongation of the current hospitalization. Hospitalization for elective 
treatment of a preexisting, non-worsening condition is not, however, 
considered an AE. The details of such hospitalizations must be recorded in the 
medical history/procedures or physical examination page of the eCRF. 
• Results in persistent or significant disability/incapacity 
- 
An AE is incapacitating or disabling if it results in a substantial and/or 
permanent disruption of the participant’s ability to carry out normal life 
functions. 
• Results in a congenital anomaly/birth defect 
• Is another medically important event 
In addition, medical and scientific judgment is required to decide if prompt notification is 
required in situations other than those defined for SAEs. This may include any event that the 
Investigator regards as serious that did not strictly meet the criteria above but may have 
jeopardized the participant or required intervention to prevent one of the outcomes listed 

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above, or that would suggest any significant hazard, contraindication, AE, or precaution that 
may be associated with the use of the study treatment. 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization, based upon appropriate medical judgment, are considered SAEs if 
they are thought to jeopardize the participant and/or require medical or surgical intervention 
to prevent one of the outcomes defining an SAE. SAEs are critically important for the 
identification of significant safety problems; therefore, it is important to consider both the 
Investigator’s and the Sponsor’s assessment. 
12.6.1.4. Pre-treatment Adverse Event 
An AE with a start date and time before the first dose of study drug. 
12.6.1.5. Treatment-Emergent Adverse Event 
An AE with a start date and time on or after the first dose of study drug. 
12.6.1.6. Unexpected Adverse Reaction 
An adverse reaction in which the nature, specificity, severity, and outcome is not consistent 
with the referenced safety information. 
12.6.2. 
Adverse Event Collection, Assessment and Reporting 
12.6.2.1. Observation Period for Assessment of Adverse Events 
For the purposes of this study, the period of observation for collection of AEs (including 
nonserious AEs and SAEs) extends from the time the participant begins study 
treatment (Day 1) until the EOS visit (within 2-11 days after last administration of the study 
drug). If a participant withdraws or is discontinued from the study by the Investigator, AEs 
should be collected from the time the participant begins study treatment (Day 1) up to the 
completion of EOS assessments. 
12.6.2.2. Parameters for Adverse Events Collection 
All nonserious AEs and SAEs will be recorded on the AE eCRF. SAEs will also be 
immediately reported to the Sponsor safety representative in accordance with Section 12.5.5. 
Nonserious and SAEs will be documented in the clinical database with the highest severity 
documented during the duration of each serious or nonserious episode. Each AE is to be 
documented in the eCRF with reference to date of onset, severity, relationship to study drug, 
treatment of event, and outcome.  
All AEs are to be followed up until resolution or a stable clinical endpoint is reached, as 
determined by the Investigator. Changes in AEs and resolution dates are to be documented in 
the eCRF. 
Participants will be instructed by the Investigator to report AEs at each study visit. All 
volunteered, elicited, and observed AEs are to be recorded. A consistent methodology of 
nondirective questioning should be adopted for eliciting AE information at all participant 
evaluation timepoints. Examples of nondirective questions include the following: 
• “How are you feeling?” 
• “How have you felt since your last clinic visit?” 

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• “Have you had any new or changed health problems since you were last here?” 
• “Have you taken any new medications since your last visit?” 
The following considerations should also be made regarding AE and SAE reporting: 
• All medical and psychiatric conditions present at screening (i.e., conditions 
present before the AE reporting period) will be considered preexisting conditions 
and documented in the medical history eCRF. A preexisting condition is not to be 
reported as an AE. If a preexisting condition worsens during the study treatment 
period, the event should be reported as an AE. Planned hospitalization for a 
preexisting condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered an SAE. 
• Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, 
should not be reported as AEs. A medical condition for which an unscheduled 
procedure was performed, should however be reported if it meets the definition of 
an AE. For example, an acute appendicitis, and not the appendectomy, should be 
reported as the AE. 
• Clinically significant abnormal laboratory findings (e.g., hematology, clinical 
chemistry [including glucose], coagulation, and urinalysis) or other abnormal 
assessments (e.g., in ECG results and vital signs), meeting the definition of an AE 
or SAE, that are detected during the study or are present at baseline and 
significantly worsen following the start of the study will be reported as AEs or 
SAEs. The Investigator will exercise his/her medical and scientific judgment in 
deciding whether an abnormal laboratory finding, or other abnormal assessment is 
clinically significant. 
Special situations are non-standard medical conditions that provide valuable information 
(e.g., clinical, safety) about a medicinal product, even when special situations do not occur in 
association with an AE or medical condition. Special situations, defined in this protocol as 
events of accidental overdose, medication error, and drug misuse, are not in and of 
themselves AEs but may result in AEs. Each AE associated with a special situation should be 
recorded in the AE eCRF. If the associated AE fulfills seriousness criteria, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event).  
In the event of an accidental overdose, medication error or drug misuse special situation, the 
Investigator should: 
• Inform the Medical Monitor immediately. 
• Closely monitor the participant for an AE/SAE and laboratory abnormalities. 
• In the event of an accidental overdose: document the quantity of excess dose in 
the eCRF. 
12.6.3. 
Assessment of Event Severity 
The Investigator will use the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 to describe the severity of AEs. AEs not listed in 
the CTCAE will be graded as follows: 

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Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age‑appropriate instrumental activities of daily living (ADL). ADL refers to 
preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
Grade 3 
Severe or medically significant but not immediately life‑threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. Self-care ADL refers to bathing, dressing & undressing, 
feeding self, using the toilet, taking medications, and not bedridden. 
Grade 4 
Life‑threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to the AE. 
12.6.4. 
Relationship to Study Treatment 
Specific guidelines for classifying AEs by relationship to study treatment are given in 
Table 8. 
Table 8 
Classification of Adverse Events by Relationship to Study Treatment 
NOT RELATED: There is not a reasonable possibility that the administration of the study intervention caused 
the event, there is no temporal relationship between the study intervention and event onset, or an alternate 
etiology has been established.  
RELATED: The AE is known to occur with the study intervention, there is a reasonable possibility that the 
study intervention caused the AE, or there is a temporal relationship between the study intervention and event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the study 
intervention and the AE. 
 
12.6.5. 
Serious Adverse Event Reporting 
Any SAE occurring during the course of the study within the defined AE reporting window, 
must be immediately reported to the appropriate Sponsor safety representative 
(PrimeVigilance) within 1 calendar day (i.e., within 24 hours) of the investigational site’s 
initial awareness of the event. The study SAE Report Form, provided by the Sponsor, will be 
utilized for reporting safety information to the Sponsor safety representative and completed in 
English. For fatal or life-threatening treatment-emergent SAEs, where important or relevant 
information is missing, active follow up will be undertaken immediately by the Investigator.  
A post-study AE or SAE is defined as any event that occurs outside of the AE/SAE 
monitoring period. Investigators are not obligated to actively monitor AEs or SAEs of such 
study participants. However, if the Investigator learns of any AE or SAE, including a death, 
at any time after a participant has completed the study, and it is considered reasonably related 
to the study treatment, the Investigator should promptly notify the Sponsor safety 
representative within 24 hours of becoming aware of the event. 
Investigators or other site personnel will inform the Sponsor safety representative of any 
follow-up information on a previously reported SAE within 1 calendar day (i.e., within 
24 hours) of the investigational site’s awareness of the new information. All SAEs will be 
followed until satisfactory resolution, until the Investigator deems the event to be chronic, or 

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the participant is stable. Other supporting documentation of the event may be requested by 
the Sponsor or Sponsor safety representative and should be provided by the Investigator as 
soon as possible. 
The Sponsor will notify regulatory authorities and participating Investigators of any 
reportable SAEs for NKF-INS(A), US-NovoLog®, and EU-NovoRapid®) in an expedited 
fashion in accordance with local requirements. Where required and in accordance with local 
requirements, the Sponsor will ensure unblinding of subject treatment assignment for the 
purposes of reporting the event to regulatory authorities. IRBs/IECs will be promptly 
notified, in accordance with local regulations, of all reportable SAEs involving risk to human 
participants. Where reportable SAEs are identified for referenced products, i.e., 
US-NovoLog® and EU-NovoRapid®, the Sponsor will ensure the product manufacturer is 
notified within the same expedited timelines as regulatory authorities. 
For further guidance on the definition of an SAE, see Section 12.5.1.3. 
12.7. 
Drug-Induced Liver Injury Monitoring 
For new elevations in transaminases greater than 2 × the upper limit of normal (ULN) in 
participants with normal baseline values, repeat measurement will be performed within 
48 hours. If elevations persist, participants will be evaluated for other causes of transaminase 
elevations and with tests of hepatic function. If no other cause is found, then the participants 
will be monitored closely and the drug discontinued as per the recommendations in the FDA 
Guidance for Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation (US 
FDA, 2009). 
The participant should be followed until resolution of symptoms or signs in the following 
situations: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × ULN. 
• ALT or AST >5 × ULN for more than 4 days during the 7-day treatment period. 
• ALT or AST >3 × ULN (and total bilirubin >2 × ULN or international normalized 
ratio [INR] >1.5). 
• ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
12.7.1. 
Pregnancy 
After administration of study treatment, any known cases of pregnancy in female partners of 
male study participants will be reported until the male participant completes or withdraws 
from the study and within 90 days of their exposure to study treatment. The Investigator may 
arrange counseling for pregnant female partners of male study participants by a specialist to 
discuss the risks of continuing with the pregnancy and the possible effects on the fetus. The 
pregnancy will be reported immediately by faxing/emailing a completed pregnancy report to 
the Sponsor safety representative (or designee) within 24 hours of knowledge of the event. 
The pregnancy will not be processed as an AE/SAE; however, the Investigator must follow 
up with female partners of male study participants until completion of the pregnancy, and 
must assess the outcome in the shortest possible time, but not more than 30 days, after 
completion of the pregnancy. The Investigator should notify the Sponsor (or designee) of the 
pregnancy outcome by submitting a follow-up pregnancy report. If the outcome of the 
pregnancy involved spontaneous or therapeutic abortion (any congenital anomaly detected in 

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an aborted fetus is to be documented as an SAE), stillbirth, neonatal death, or congenital 
anomaly, the Investigator will report the SAE by faxing/emailing a completed pregnancy 
report form to the Sponsor safety representative (or designee) within 24 hours of knowledge 
of the event. Any pregnancy in female partners of male study participants will be followed to 
term, and the status of the mother and child will be reported to the Sponsor after delivery. 
Contraception guidance is provided in Appendix 1. 
12.7.2. 
Accidental Overdose, Medication Error, or Drug Misuse 
Accidental overdose, medication error, and drug misuse, hereafter collectively referred to as 
“special situations,” are defined as follows: 
• Accidental overdose: accidental administration of a drug in a quantity that is 
higher than the assigned dose. 
• Medication error: accidental deviation in the administration of a drug. In some 
cases, a medication error may be intercepted before administration of the drug. 
• Drug misuse: intentional deviation in the administration of a drug that does not 
qualify as drug abuse. 
Cases of accidental overdose, drug misuse, or medication error without manifested signs or 
symptoms are not considered AEs. Adverse events associated with an overdose will be 
documented according to Section 12.5.5. SAEs associated with overdose should be reported 
according to the procedure outlined in Section 12.6.2. All cases of overdose (with or without 
associated AEs) will be documented on the eCRF. 

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13. 
OTHER ASSESSMENTS 
13.1. 
Euglycemic Clamp Procedure  
NKF-INS(A), US-NovoLog® and EU-NovoRapid® will be administered using a euglycemic 
glucose clamp at targeted blood glucose concentrations. The euglycemic glucose clamp will 
be conducted using a manual clamp technique, which will continuously monitor the subject’s 
blood glucose and administer GIR to maintain blood glucose close to the target blood glucose 
concentration. The clamp procedure will be initiated, maintained, and terminated, in 
accordance with the site SOPs. The participant’s blood glucose will be maintained within a 
pre-defined target window per site SOP and clinical judgment for the participant by manually 
adjusting the GIR. 
Blood samples will be collected at pre-specified intervals before and up to 12 hours after 
dosing for measurement of blood glucose, serum insulin, and C-peptide as shown in the 
schedule of assessments (Table 3). 

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14. 
STATISTICAL ANALYSIS 
An SAP will be prepared after the protocol is approved. The SAP will provide further details 
regarding the definition of analysis variables and analysis methodology to address all study 
objectives. The SAP will serve as a complement to the protocol and supersedes it in case of 
differences. 
The statistical evaluation will be performed using R version 4.0 or higher. All data will be 
listed, and summary tables and figures will be provided. Summary statistics will be presented 
by treatment group, to the extent possible. For continuous variables, data will be summarized 
with the number of participants (N), arithmetic mean, SD, median, minimum, and maximum 
by treatment group. Geometric mean and CV% will be presented as appropriate, by treatment 
group. For categorical variables, data will be tabulated with the number and proportion of 
participants for each category by treatment group. 
14.1. 
Determination of Sample Size 
A literature review of similar studies was conducted in order to inform the assumptions for 
the sample size, for the primary endpoints of AUC0-∞ and Cmax (see Table 9).  
Table 9. 
Studies Referenced for Sample Size Assumptions 
Program  
AUC0-t 
AUC0-∞ 
Cmax 
GIRmax 
AUCGIR 
Median 
Sample 
Size 
Innovator 
[NovoLog 
USPI] 
 
9.8% 
25.30% 
18.0% 
17.6% 
 
24 
Mylan (HV) 
[Hovelmann, 
2021] 
32.0% 
32.0% 
30.90% 
18.5% 
17.5% 
 
71 
Sanofi (T1DM) 
[Kapitza, 2020] 
16.0% 
15.7% 
30.75% 
30.8% 
30.0% 
 
30 
Yichang HEC 
Changjiang 
Pharmaceutical 
Co., Ltd (HV) 
[Liu, 2021] 
17.0% 
16.5% 
31.0% 
22.0% 
27.0% 
 
30 
Mean 
21.7% 
18.5% 
29.5% 
22.3% 
23.0% 
22.3% 
 
Median 
17.0% 
16.1% 
30.8% 
20.3% 
22.3% 
 
 
Abbreviation: GIR = glucose infusion rate; HV = healthy volunteers; T1DM = type 1 diabetes mellites 
 
The CV value ranged from 23.8% to 30.8%, with a mean value of 25.4%. The CV of the 
Innovator study was 25.3%. Based on the above data, the CV value is selected as 26%. 
The sample size is calculated using PASS software with following parameters including 90% 
power, drop rate 20%, α=0.05, 90% confidence interval (CI), assumed actual ratio 0.95 
within 80-125%, N=40; taking account of 20% dropout, the sample size is determined as 
N=54 to have at least 36 evaluable participants. 
14.2. 
Analysis Populations 
The following analysis populations are planned for this study: 

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Screening Population 
All individuals who provide informed consent and provide demographic and/or baseline 
screening assessments, regardless of the participant’s randomization status. 
Enrolled Population 
The Enrolled Population will include all individuals who sign the ICF. 
Safety Population 
The Safety Population will include all participants who receive any amount of study 
treatment. This population will be used for the analysis of safety. 
Pharmacokinetic Concentration Population 
The PK Concentration Population will include all participants in the Safety Population who 
received any amount of study treatment and have at least 1 post-baseline reportable PK result. 
Pharmacokinetic Parameter Population 
The PK Parameter Population will include all participants in the PK Concentration 
Population who have at least 1 PK parameter derived. 
Pharmacodynamic Parameter Population 
The PD Parameter Population will include all participants in the Safety Population who have 
at least 1 PD parameter derived. 
14.3. 
Pharmacokinetic Analysis 
The primary PK objective is to compare the PK of NKF-INS(A) to US-approved and 
EU-authorized insulin aspart to demonstrate PK similarity for insulin aspart. The secondary 
PK objective is to evaluate additional PK parameters of NKF-INS(A) compared to 
US-approved and EU-authorized insulin aspart. Details on the endpoints are provided in 
Table 1. 
PK concentrations and parameter data will be listed and summarized descriptively (N, 
arithmetic and geometric mean, SD, CV%, median, minimum, and maximum) by treatment 
group and graphically. 
Biosimilarity between the test product and the US-approved and EU-authorized insulin aspart 
will be considered separately, i.e., test product vs US-approved product and test product vs 
EU-authorized product. Biosimilarity of the test and reference products will be assessed on 
the basis of the 90% Cis for estimates of the geometric mean ratios between the primary PK 
parameters of the test and reference products in relation to the conventional bioequivalence 
range of 80% to 125%. The test product will be compared to the reference product by means 
of statistical analysis with respect to the primary PK parameters using an analysis of variance 
after logarithmic transformation of the data. Point estimates and 90% Cis for the 
“test/reference” geometric mean ratios of these parameters will be provided. The primary PK 
parameters that will be used for the bioequivalence assessment are Cmax and AUC0-t. All other 
PK-related assessments of equivalence will be considered secondary. 
Any missing samples or non-reportable concentration values will be disregarded in the PK 
analysis. 
Refer to the SAP for full details. 

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14.4. 
Pharmacodynamic Analysis 
The primary PD objective is to compare the PD of NKF-INS(A) to US-approved and 
EU-authorized insulin aspart injection by examining GIR profiles after a single SC dose. The 
secondary PD objective is to evaluate the additional parameters NKF-INS(A) compared to 
US-approved and EU-authorized insulin aspart. Details on the endpoints are provided in 
Table 1. PD concentrations and parameter data will be listed and summarized descriptively 
(N, arithmetic and geometric mean, SD, CV%, median, minimum, and maximum) by 
treatment group and graphically. 
As for PK similarity, biosimilarity between the test product and the US-approved and 
EU-authorized insulin aspart will be considered separately, i.e., test product vs US-approved 
product and test product vs EU-authorized product. Biosimilarity of the test and reference 
products will be assessed on the basis of the 95% Cis for estimates of the geometric mean 
ratios between the primary PK parameters of the test and reference products in relation to the 
conventional bioequivalence range of 80% to 125%. The test product will be compared to the 
reference product by means of statistical analysis with respect to the primary PD parameters 
using an analysis of variance after logarithmic transformation of the data. Point estimates and 
90% and 95% Cis for the “test/reference” geometric mean ratios of these parameters will be 
provided. The primary PD parameters that will be used for the bioequivalence assessment are 
GIRmax and AUCGIR0-t. All other PD-related assessments of equivalence will be considered 
secondary. 
All PD analyses will be based on the PD Parameter Population. Refer to the SAP for full 
details. 
14.5. 
Safety Analysis 
All analyses of safety will be conducted on the Safety Population unless otherwise specified 
in the SAP. 
All reported AEs will be graded using NCI CTCAE version 5.0 and will be coded using the 
Medical Dictionary for Regulatory Activities, version 26.0. The incidence of treatment-
emergent AEs (TEAEs) will be included in incidence tables. Events with missing onset dates 
will be included as treatment-emergent. If a participant experiences more than 1 occurrence 
of the same AE, the occurrence with the greatest severity and the closest association with the 
study treatment will be used in the summary tables. All TEAEs will be summarized by 
treatment group (NKF-INS(A), US-NovoLog®, and EU-NovoRapid®) as follows: 
• All AEs 
• Grade ≥3 AEs 
• AEs related to study treatment, including related Grade ≥3 AEs 
• All adverse reactions 
• SAEs 
All AEs will be listed by participant, along with information regarding onset, duration, 
relationship and severity to study treatment, action taken with study treatment, treatment of 
event, and outcome. 
Clinical laboratory data (hematology, clinical chemistry [including glucose], coagulation, and 
urinalysis) and vital signs (heart rate, respiratory rate, systolic and diastolic blood pressure, 
and temporal or ear temperature measurements) will be summarized by treatment group and 

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scheduled visits using descriptive statistics, including mean values and mean change from 
screening values, as well as numbers of participants with values outside limits of the normal 
range at each timepoint. Shift tables will be provided presenting change from screening 
values to the last EOS visit. 
The frequency of ECG abnormalities (e.g., heart rate, PR interval, QRS complex, and QT-
interval corrected by Fridericia’s formula [Fridericia’s corrected QT]) will be summarized by 
treatment group and scheduled visits using counts and percentages.  
Participant ECG status (normal, abnormal clinically significant, or abnormal not clinically 
significant) may be summarized for each scheduled ECG and shifts from screening may be 
tabulated. 
Injection site reactions will be summarized by treatment group and scheduled visits. The 
number and percentage of participants having reactions at each assessment timepoint, overall 
and by specific reaction subtype, will be presented. 
Summary tables will be provided for concomitant medications initiated during the study 
period. 
Clinically significant changes in physical examination findings and laboratory abnormalities 
will be listed as AEs. 
14.6. 
Other Analyses 
All other safety variables will be listed. 
14.7. 
Interim Analysis 
No interim analysis is planned. 
14.8. 
Data Monitoring Committee 
Not applicable. 

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15. 
STUDY MANAGEMENT 
15.1. 
Approval and Consent 
15.1.1. 
Compliance with Laws and Regulations 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and the 
principles of the Declaration of Helsinki or all relevant laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the individual. 
The study will comply with the requirements of the ICH E2A guideline (Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting). Studies conducted in the 
EU or European Economic Area will comply with the EU Clinical Trial Regulation (CTR). 
15.1.2. 
Institutional Review Board/Independent Ethics Committee 
This protocol, protocol amendments (if applicable), Investigator’s Brochure, the ICFs, 
recruitment material and participant information sheets, any information to be given to the 
participant, and relevant supporting information must be submitted to the IEC/IRB by the 
Principal Investigator (PI) and reviewed and approved by the IEC/IRB before the study is 
initiated; no participant may undergo any procedure for determining eligibility for this study 
until IEC/IRB approval is obtained. 
The PI is responsible for providing written summaries of the status of the study to the 
IEC/IRB annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IEC/IRB. Investigators are also responsible for promptly 
informing the IEC/IRB of any protocol amendments. The PI must receive 
approval/acknowledgement from the IEC/IRB before implementation of the amendment. 
In addition to the requirements for reporting all AEs to the Sponsor, Investigators must 
comply with requirements for reporting SAEs to the local health authority and IEC/IRB. 
Investigators may receive written investigational new drug safety reports or other safety-
related communications from the Sponsor. Investigators are responsible for ensuring that 
such reports are reviewed and processed in accordance with health authority requirements 
and the policies and procedures established by their IEC/IRB and archived in the site’s study 
file. 
15.1.3. 
Informed Consent Process 
15.1.3.1. Consent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant and written documentation of informed consent is required before 
protocol-specific procedures are performed. 
15.1.3.2. Consent Procedures and Documentation 
Informed consent is a process that is initiated before the participant’s agreeing to participate 
in the study and continues throughout the study participation. Consent forms will be 
IRB-approved, and the participant will be asked to read and review the document. The 
Investigator will explain the research study to the participant and answer any questions that 
may arise. A verbal explanation will be provided in terms suited to the participant’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights 
as research participants. Participants will have the opportunity to carefully review the written 

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consent form and ask questions before signing. The participants should have the opportunity 
to discuss the study with their family or surrogates or think about it before agreeing to 
participate. The participant will sign the informed consent document before any procedures 
being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy 
of the informed consent document will be given to the participants for their records. The 
informed consent process will be conducted and documented in the source document 
(including the date), and the form signed, before the participant undergoes any study-specific 
procedures. The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
15.2. 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated at any time by the 
Sponsor, IEC/IRB and/or regulatory authorities if there is sufficient reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be provided by 
the Sponsor to Investigators, the IRBs/IECs and regulatory authorities, as well as to any 
contract research organizations used in the study and provide the reason for termination. If 
the study is prematurely terminated or suspended, the PI will promptly inform study 
participants and the IRBs/IECs. Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. 
15.3. 
Confidentiality and Privacy 
Participant confidentiality and privacy are strictly held in trust by the participating 
Investigators, their staff, and the Sponsor. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study, or the data 
will be released to any unauthorized third party without prior written approval of the Sponsor. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the Sponsor, representatives of the 
IRB, regulatory agencies may inspect all documents and records required to be maintained by 
the Investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access 
to such records. 
The study participants’ contact information will be securely stored at each CRU for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, institutional policies, or 
Sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the data management company responsible for 
data management, analysis, and reporting. This will not include the participants’ contact or 
identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study 
management systems used by CRUs and by data management research staff will be secured 
and password protected. At the end of the study, all study databases will be de-identified and 
archived by the Sponsor. 

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All information generated in this study must be considered highly confidential and must not 
be disclosed to any people not directly concerned with the study without written prior 
permission from the Sponsor. Authorized regulatory officials and Sponsor personnel (or their 
representatives) will be allowed full access to inspect and copy the records. All study 
investigational products, participant bodily fluids, and/or other materials collected shall be 
used solely in accordance with this protocol, unless otherwise agreed to in writing by the 
Sponsor. Participants will only be identified by unique participant numbers in eCRFs. 
Every participant will be given a copy of each version of the ICF that he signs before and 
during the study. Each ICF may also include authorization allowing the institution, 
Investigator, and Sponsor to use and disclose personal health information in compliance with 
the Health Insurance Portability and Accountability Act of 1996. 
15.4. 
Future Use of Stored Specimens and Data 
No future use of stored specimens is planned.  
Once samples have been analyzed, specimens will be destroyed. If no analyses have been 
completed within 5 years following EOS, samples will be destroyed. 
15.5. 
Safety Oversight 
Safety oversight will be under the direction of the Medical Monitor in concert with the 
Sponsor Medical Director as outlined in the Safety Management Plan and Medical 
Monitoring Plan. 
15.6. 
Clinical Monitoring 
CRU monitoring is conducted to ensure that the rights and well-being of study participants 
are protected. Study monitors will perform ongoing source data verification to confirm that 
the reported study data are accurate, complete, and verifiable from source documents, and 
that the conduct of the study is in compliance with the currently approved 
protocol/amendment(s), with ICH GCP, and with applicable regulatory requirement(s). 
Monitoring for this study will be performed by a Sponsor-contracted Contract Research 
Organization (CRO).  
Details of CRU monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP 
describes in detail who will conduct the monitoring, at what frequency monitoring will be 
done, at what level of detail monitoring will be performed, and the distribution of monitoring 
reports. 
Independent audits will be conducted by a Sponsor-designated, qualified person to ensure 
monitoring practices are performed consistently across all participating sites and that 
monitors are following the CMP. 
15.7. 
Quality Assurance and Quality Control 
Quality control (QC) procedures will be implemented beginning with the data entry system 
and data QC checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the site for clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical study is conducted, data are 
generated, and biological specimens are collected, documented (recorded), and reported in 

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compliance with the protocol, ICH GCP, and applicable regulatory requirements (e.g., Good 
Laboratory Practices, Good Manufacturing Practices). 
The investigational site will provide direct access to all study-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor, and 
inspection by local and regulatory authorities. 
15.8. 
Data Handling and Record Keeping 
15.8.1. 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical study staff at the CRU under the 
supervision of the site Investigator. The Investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
Data recorded in the eCRF derived from source documents should be consistent with the data 
recorded in the source documents. 
Clinical data (including AEs, concomitant medications, and adverse reactions data) and 
clinical laboratory data will be entered into a 21 Code of Federal Regulations (CFR) 
Part 11-compliant data capture system provided by the CRO. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify 
data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly 
from the source documents as outlined in the Case Report Form Completion Guidelines. 
15.8.2. 
Study Records Retention 
The Investigator shall retain and preserve a copy of all records and data generated in the 
course of the study, specifically those defined by ICH GCP E6 as essential until:  
• A minimum of 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an 
ICH region, or 
• A least 2 years have elapsed since the formal discontinuation of clinical 
development of the study drug. 
These documents should be retained for a longer period, however, if required by local 
regulations or requested by the Sponsor. No records will be destroyed without the written 
consent of the Sponsor. It is the responsibility of the Sponsor to inform the Investigator when 
these documents no longer need to be retained. 
At the end of the retention period, the Investigator shall notify the Sponsor in writing of 
her/his intent to destroy such material. The Sponsor shall have 30 days to respond to the 
Investigator's notice and shall have further opportunity to retain such materials. 
15.9. 
Protocol Amendment and Protocol Deviation 
15.9.1. 
Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect 
on the safety of participants, or the conduct of the study will be classed as administrative 

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amendments. The Sponsor will ensure that acknowledgement is received, filed, and submitted 
according to local regulations.  
Amendments that are classed as substantial amendments must be submitted by the PI to the 
appropriate regulatory authorities and the IECs/IRBs for approval, and will not be 
implemented at sites until such approvals are received other than in the case of an urgent 
safety measure. 
15.9.2. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, ICH GCP, or 
applicable SOPs and site manuals. In addition, the study will be conducted in accordance 
with the applicable regulatory requirements of the country where the study is being 
conducted. The noncompliance may be either on the part of the participant, the Investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by the 
site and implemented promptly. 
It is the responsibility of the site Investigator to use continuous vigilance to identify and 
report deviations as soon as possible. All deviations must be addressed in study source 
documents and must be sent to the reviewing IRB/IEC, per their SOPs. The site Investigator 
is responsible for knowing and adhering to the reviewing IRB/IEC requirements. Further 
details about the handling of protocol deviations will be included in the Protocol Deviation 
Plan, Data and Medical Management Plans, and SAP. 
The study will be conducted as described in this protocol, except for an emergency situation 
in which the protection, safety, and well-being of the participant requires immediate 
intervention, based on the judgment of the Investigator (or a responsible, appropriately 
trained professional designated by the Investigator). In the event of a significant deviation 
from the protocol due to an emergency, accident, or mistake, the Investigator (or designee) 
must contact the Medical Monitor and the Sponsor at the earliest possible time by telephone. 
This will allow an early joint decision regarding the participant’s continuation in the study. 
This decision will be documented by the Investigator and the Medical Monitor. 
15.10. 
Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 
312, Subpart D, of Title 21 of the CFR and EU 536/2014, Annex 1, D, 17 (a); and in 
compliance with ICH GCP guidelines, as well as local regulatory requirements in 
countries/regions where the study is being conducted. 
IECs/IRBs will review and approve this protocol and the ICF. All participants are required to 
give written informed consent before participation in the study. 
15.11. 
Financing and Insurance 
Details on finance and insurance will be provided in a separate agreement between the 
Investigator and the Sponsor.   
15.12. 
Publication Policy 
This study will be registered at ClinicalTrials.gov, and results information from this study 
will be submitted to ClinicalTrials.gov and local registries as required by local regulation. 

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Any publication proposed to be published by Investigator shall be provided to Sponsor prior 
to publication or other disclosure. Due regard shall be given to, and adjustments to 
publication content and timing shall be made, based upon Sponsor’s legitimate interests in 
publication review, e.g., ensuring compliance with the statistical analyses for the primary 
endpoints of the study according to, and consistent with, the Protocol; identifying any 
inaccuracies or errors in data analyses; obtaining patent protection; coordinating and 
maintaining the proprietary nature of submissions to health authorities; and protection of 
Confidential Information.  In order to ensure that all publications related to Sponsor studies 
are responsible, ethical, timely, legally compliant, and scientifically fair and balanced, all 
publications contemplated hereunder will follow prevailing industry guidelines for good 
publication practices, including, but not limited to guidelines published by the International 
Committee of Medical Journal Editors and the position statements and guidelines published 
by the International Society for Medical Publication Professionals regarding good publication 
practices 
In the event that Institution or Investigator proposes to publish or otherwise disclose (whether 
orally or in writing) any findings, data, or results regarding the study, a draft thereof shall be 
submitted to Sponsor at least forty-five (45) days prior to submission for publication or other 
disclosure. Procedures set forth shall apply to publication of research and data derived from 
the study even when the study is terminated early or suspended for any reason. Results from 
the study shall not be made available to any third party by the Institution, Investigator, or any 
Study Site Team Participant outside of the publication procedures set out above. 
15.13. 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual, perceived, or potential conflict of 
interest of persons who have a role in the design, conduct, analysis, publication, or any aspect 
of this trial will be disclosed and managed. Furthermore, persons who have an actual, 
perceived, or potential conflict of interest will be required to have such conflicts managed in 
a way that is appropriate to their participation in the design and conduct of this trial. The 
study leadership has established policies and procedures for all study group members to 
disclose all actual, perceived, or potential conflicts of interest and will establish a mechanism 
for the management of all reported conflicts of interest. 

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16. 
REFERENCES 
Ampudia Blasco FJ. Biosimilars and novel insulins. Am J ther. 202;27(1):e52-e61. 
Chen W, Lu J, Plum-Mörschel L, Andersen G, Zijlstra E, He A, et al. Pharmacokinetic and 
pharmacodynamic bioequivalence of Gan & Lee insulin analogues aspart (rapilin), lispro 
(prandilin) and glargine (basalin®) with EU- and US-sourced reference insulins. Diabetes 
Obes Metab. 2023;1-9. 
Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy 
testing in clinical trials. 2014. Accessed at: 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
Drai RV, Karonova TL, Mayorov AY, Makarenko IE, Dorotenko AR, Kulesh VS, et al. 
Clinical pharmacology of insulin aspart biosimilar comparability in hyperinsulinemic 
euglycemic clamp procedure. Clinical Pharmacology in Drug Development. 2022;11(8):922-
929 
Heinemann L, Davies M, Home P, Forst T, Vilsbøll T, Schnell O. Understanding Biosimilar 
Insulins - Development, Manufacturing, and Clinical Trials. J Diabetes Sci Technol. 2023 
Nov;17(6):1649-1661.  
Hövelmann U, Raiter Y, Chullikana A, Liu M, Donnelly C, Lawrence T, et al. 
Pharmacokinetic and pharmacodynamic bioequivalence of biosimilar MYL-1601D with US 
and European insulin aspart in healthy volunteers: a randomized, double-blind, crossover, 
euglycaemic glucose clamp study. Diabetes Obes Metab. 2021;23:2670-2678. 
Kapitza C, Nosek L, Schmider W, Teichert L, Nowotny I. Single-Dose Euglycemic Clamp 
Study Demonstrating Pharmacokinetic and Pharmacodynamic Similarity Between 
SAR341402 Insulin Aspart and US- and EU-Approved Versions of Insulin Aspart in Subjects 
with Type 1 Diabetes. Diabetes Technol Ther. 2020 Apr;22(4):278-284.  
Liu H, Yu H, Sun L, Qiao J, Wan S, Li S, Li J, Tan H, Yu Y. Similar pharmacokinetics and 
pharmacodynamics of a new biosimilar and reference insulin aspart in healthy Chinese males. 
Sci Rep. 2021 May 4;11(1):9495.  
NovoLog (insulin aspart) United States Prescribing Information. 2023. Novo Nordisk Inc, 
DK-2880 Bagsvaerd, Denmark. 
NovoRapid Summary of Product Characteristics. 2021. Novo Nordisk Limited, Gatwick, 
West Sussex, RH6 0PA, UK. 
Plum-Mörschel L, Singh G, Murugesan SNM, Marwah A, Panda J, Loganathan S, et al. 
Pharmacokinetic and pharmacodynamic equivalence of Biocon’s biosimilar insulin-R with 
the US-licensed Humulin R formulation in healthy subjects: results from the RHINE-1 
(Recombinant Human Insulin Equivalence-1) study. Diabetes Obes Metab. 2022;24:713-721. 
World Health Organization. Coronavirus disease (COVID-19) pandemic. Accessed at: 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019 

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17. 
APPENDICES 
Appendix 1 describes the contraception definitions and requirements applicable for this 
study. 

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Appendix 1. 
Contraception Definitions and Requirements 
Definitions (CTFG, 2014) 
Male participants who can father a child with a female partner of childbearing potential must 
agree to use birth control (2 highly effective methods of contraception including 1 barrier 
method) during the study period and 90 days after administration of study treatment. Male 
participants must refrain from donating or banking sperm for 90 days after administration of 
study treatment. Additionally, female partners of male participants should use highly 
effective contraception. 
A man is considered fertile after puberty unless permanently sterile by bilateral vasectomy 
with documented aspermia or a bilateral orchiectomy. 
Highly Effective Methods of Contraception 
Highly effective methods of contraception are those that have a failure rate of <1% (when 
implemented consistently and correctly) and include: 
• Combined (containing estrogen and progestogen) hormonal contraception 
associated with inhibition of ovulation (administration may be oral, intravaginal, 
or transdermal) initiated at least 3 months before the first dose of study treatment; 
and used in conjunction with a barrier method (e.g., male condom). 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable) initiated at least 3 months 
before the first dose of study treatment; and used in conjunction with a barrier 
method (e.g., male condom). 
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal ligation   
• Vasectomy (provided that the male participant has received medical assessment of 
surgical success [i.e., azoospermia]). 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment[s]); the reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the participant initiated at least 
1 month before the first dose of study treatment. 
Acceptable Methods of Contraception That Are Not Considered Highly Effective 
Acceptable methods of contraception that result in a failure rate of >1% per year include: 
• Progestogen-only hormonal contraception, where inhibition of ovulation is not the 
primary mode of action. 
• Male or female condom with or without spermicide. 
• Cap, diaphragm, or sponge with spermicide. 
• Double-barrier method (i.e., male condom with either cap, diaphragm, or sponge 
with spermicide). 

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Unacceptable Methods of Contraception 
Unacceptable methods of contraception include: 
• Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods). 
• Withdrawal (i.e., coitus interruptus). 
• Spermicides only. 
• Lactational amenorrhea. 
• Use of female and male condoms together. 
• No method at all. 
• Cap, diaphragm/sponge without spermicide and without male condom. 
 

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Appendix 2. 
Protocol Amendments 
Protocol Amendment # 1 
Date of Amendment: May 6, 2024 
The following updates were made based on regulatory feedback: 
Section 
Summary of Change 
Justification  
Section 5. 
Study 
Objectives and 
Endpoints 
Added injection site reactions and 
coagulation to safety endpoint, and 
specifically mentioned glucose as a 
clinical chemistry parameter of interest 
SAPHRA Recommendation  
Section 8.6.2.1. 
Meals and 
Dietary 
Restrictions 
Added confirmation that grapefruit juice 
does not impact the metabolism of 
insulin aspart 
SAPHRA Recommendation 
Section 8.6.2.3. 
Activity 
Adjusted prohibition of strenuous 
exercise to the entire duration of the 
study 
SAPHRA Recommendation 
Section 9. 
Study 
Procedures 
Added Injection Site Assessment to the 
EOS visit 
SAPHRA Recommendation 
Section 12. 
Safety 
Assessments 
Updated for consistency with safety 
endpoints 
SAPHRA Recommendation 
Section 12.5. 
Injection Site 
Assessment 
Provided additional clarity on Injection 
Site Assessment 
SAPHRA Recommendation