Clinical trial NCT05262387
Conditions: Diabetes Mellitus, Type 1
Keywords: Lyumjev Humalog® Insulin lispro Exercise Continuous Subcutaneous Insulin Infusion Glycemic control Hypoglycemia Type 1 Diabetes
Sponsor: Eli Lilly and Company
Start date: 2022-02-14; Completion date: 2023-03-07
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will be conducted in participants with type 1 diabetes mellitus on continuous subcutaneous insulin infusion (CSII) or pump therapy to evaluate the effect of LY900014 (Lyumjev) on blood sugar levels during exercise using different approaches on basal rate reduction and following a test meal compared to insulin lispro (Humalog). The study may last up to approximately 10 weeks and may include up to 7 visits.

Detailed description:

Arms: arm 1: Period 1: Lyumjev with 50% basal rate reduction (Treatment A)

Period 2: Humalog with 100% basal rate reduction (Treatment D)

Period 3: Lyumjev with 100% basal rate reduction (Treatment B)

Period 4: Humalog with 50% basal rate reduction (Treatment C)

Participants received their assigned treatments in each of the above treatment period on Day 1 subcutaneously. arm 2: Period 1: Lyumjev with 100% basal rate reduction (Treatment B)

Period 2: Lyumjev with 50% basal rate reduction (Treatment A)

Period 3: Humalog with 50% basal rate reduction (Treatment C)

Period 4: Humalog with 100% basal rate reduction (Treatment D)

Participants received their assigned treatments in each of the above treatment period on Day 1 subcutaneously. arm 3: Period 1: Humalog with 50% basal rate reduction (Treatment C)

Period 2: Lyumjev with 100% basal rate reduction (Treatment B)

Period 3: Humalog with 100% basal rate reduction (Treatment D)

Period 4: Lyumjev with 50% basal rate reduction (Treatment A)

Participants received their assigned treatments in each of the above treatment period on Day 1 subcutaneously. arm 4: Period 1: Humalog with 100% basal rate reduction (Treatment D)

Period 2: Humalog with 50% basal rate reduction (Treatment C)

Period 3: Lyumjev with 50% basal rate reduction (Treatment A)

Period 4: Lyumjev with 100% basal rate reduction (Treatment B)

Participants received their assigned treatments in each of the above treatment period on Day 1 subcutaneously.
Interventions: intervention 1: Lyumjev with 50% basal rate reduction intervention 2: Humalog with 50% basal rate reduction intervention 3: Humalog with 100% basal rate reduction intervention 4: Lyumjev with 100% basal rate reduction
Intervention descriptions: intervention 1: Administered SC. intervention 2: Administered SC. intervention 3: Administered SC. intervention 4: Administered SC.

Protocol documents:
Prot_000.pdf: 
 
 
Protocol: I8B-MC-ITSU (b) 
 
 
EﬀecƟveness of a Basal Rate ReducƟon With LyumjevTM Versus Humalog® on the ProtecƟon From 
Exercise-Induced Hypoglycemia in Individuals With Type 1 Diabetes on ConƟnuous Subcutaneous 
Insulin Infusion 
 
 
NCT05262387 
 
 
Approval Date: 09-May-2022 


CONFIDENTIAL 
I8B-MC-ITSU(b) 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY900014, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.  
 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
 
Protocol Title: Effectiveness of a Basal Rate Reduction with LyumjevTM versus Humalog® on 
the Protection from Exercise-Induced Hypoglycemia in Individuals with Type 1 
Diabetes on Continuous Subcutaneous Insulin Infusion 
Protocol Number: I8B-MC-ITSU 
Amendment Number: I8B-MC-ITSU (b) 
Compound: LY900014 (Lyumjev) 
Brief Title: A Study to Evaluate Protection from Exercise-Induced Hypoglycemia with 
LyumjevTM Compared to Humalog® in Individuals with Type 1 Diabetes  
Study Phase: 1 
Acronym: ITSU 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Eli Lilly and Company, Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
Not Applicable  
Approval Date: Protocol Electronically Signed and Approved by Lilly on date provided below.  
Document ID: VV-CLIN-028148 
 
 
 
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Medical Monitor Name and Contact Information will be provided separately.
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I8B-MC-ITSU(b) 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment a 
09-Feb-2022 
Original Protocol 
27-Oct-2021 
Amendment (b)  
Overall Rationale for the Amendment: 
This protocol is being amended mainly to provide clarity for site implementation. Minor editorial 
changes have been done which are not reflected in the table below.  
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3.1. Overall 
schedule 
Removed row on COVID-19 
temperature screening 
Removed as this is not a study-related 
screening procedure 
Section 1.3.1. Overall 
schedule 
Reworded dosing day 
exclusion/withdrawal criteria 
as ‘eligibility 
check/additional 
exclusion/withdrawal 
criteria’; Added ‘X’ mark for 
assessment day 
Updated to align with naming of 
section 5.2.1 
Section 1.3.1. Overall 
schedule 
Removed ‘X’ on Day -1 for 
pump temporary basal rate 
reduction during prolonged 
exercise 
Basal rate reduction is done on Day 1 
and not Day -1 
Section 1.3.2. Assessment 
schedule example for in-
house visits 
Reworded dosing day 
exclusion/withdrawal criteria 
as ‘eligibility 
check/additional 
exclusion/withdrawal criteria’ 
Updated to align with section 1.3.1 
Section 1.3.2. Assessment 
schedule example for in-
house visits 
Insert venous cannula prior 
to lunch; added ‘removal of 
cannula’ at 9:00 PM 
Correction done as there are blood 
draws at 11:00 AM 
Section 4.1.2. Assessment 
day 
Insert venous cannula prior 
to lunch 
Correction done as there is glucose 
sampling at -4 hours pre-exercise 
Section 4.1.2. Assessment 
day 
Updated text on pre-
exercise glucose 
management 
To provide clarity on site 
implementation 
Section 4.1.2. Assessment 
day 
Updated text on 
hypoglycemia during 
exercise 
To provide clarity on site 
implementation 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1.2. Assessment 
day 
mM updated as mmol/L 
Updated units to ensure 
consistency 
Section 4.1.3. In-house 
visits 
Insert venous cannula prior 
to lunch 
Updated to align with 
Section 1.3.2 
Section 4.1.3. In-house 
visits 
Updated text on pre-
exercise glucose 
management 
To provide clarity on site 
implementation 
Section 4.1.3. In-house 
visits 
Updated text on 
hypoglycemia during 
exercise 
To provide clarity on site 
implementation 
Section 4.1.3. In-house 
visits 
mM updated as mmol/L 
Updated units to ensure 
consistency 
Section 4.4. End of study 
definition 
Term ‘globally’ has been 
removed 
Single site for this study 
Section 5.1. Inclusion 
criteria  
Inclusion criteria 2 – added 
fasting C-peptide value in 
pmol/L 
Added to align with laboratory 
reporting units 
Section 5.1. Inclusion 
criteria  
Inclusion criteria 2 – peak 
VO2 of ≥35 for males and 
≥32 for females 
Updated peak VO2 values  
Section 5.2. Exclusion 
criteria 
Exclusion criteria 23 – 
added details for over-the-
counter or prescription 
medications 
Clarification provided on the 
medications that should not be 
used within 14 days prior to dosing 
Section 5.2. Exclusion 
criteria 
Exclusion criteria 24 – 
added ‘basal rate 
optimization’ 
Clarification provided to avoid 
acetaminophen during basal rate 
optimization visit 
Section 5.2. Exclusion 
criteria 
Exclusion criteria 28 – in 
house visits/ periods 
replaced by study treatment 
period 
To clarify that this exclusion 
criteria is for all inpatient visits 
where study treatment is given  
Section 5.2. Exclusion 
criteria  
Separated criteria 34 into 
new Section 5.2.1.  
Separate heading added to provide 
clarity that these criteria are for 
study treatment periods 
Section 5.2.1. Additional 
exclusion criteria for study 
treatment periods 
Added statement for 
rescheduling assessment 
day in case participants 
fulfill 1 or more of the 
Clarification provided for 
participants who fulfill 1 or more 
of the additional criteria on 
assessment day and updated to be 
consistent with Section 1.3.1 
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Section # and Name 
Description of Change 
Brief Rationale 
additional criteria on 
assessment day 
Section 5.2.1. Additional 
exclusion criteria for study 
treatment periods 
Alcohol consumption 
within 24 hours prior to 
each in-house period is not 
allowed and participants 
with positive drug screen 
are not allowed 
Updated to be consistent with 
Section 5.3.2 and 1.3.1 
Section 5.2.1. Additional 
criteria for study treatment 
periods 
Sub criteria e – reference to 
exclusion criteria 22 
removed 
Updated as exclusion criteria 
includes medications which 
participants would not be taking 
based on screening criteria 
Section 5.2.1. Additional 
criteria for study treatment 
periods 
Added exclusion of 
participants who are unable 
to obtain glucose range 
 
 prior to 
initiation of exercise 
assessment 
Updated to be consistent with 
Sections 4.1.2 and 4.1.3 
Section 5.4. Screen 
failures 
Term ‘assent’ removed 
Assent is not required 
Section 6.1.1. 
Noninvestigational 
medicinal products 
mM updated as mmol/L 
Updated units to ensure 
consistency 
Section 6.5. Dose 
modification 
Clinical pharmacologist, 
clinical research scientist 
added 
Clarification provided on the 
sponsor roles 
Section 6.8. Concomitant 
therapy 
Added study periods when 
acetaminophen is to be 
avoided 
Updated to align with exclusion 
criteria 24 
Section 6.8. Concomitant 
therapy 
Clinical research scientist 
added 
Clarification provided on the 
sponsor roles 
Section 7.2. Participant 
discontinuation/withdrawal 
from the study 
Removed language on 
inadvertent enrollment 
Updated as per harmonized clinical 
protocol template 
Section 8.2.2. Vital signs 
Vital sign measurements to 
include blood pressure, 
pulse rate, heart rate, and 
body temperature 
To provide clarity on site 
implementation 
Section 8.2.7.2. Treatment 
of hyperglycemia and 
Updated text on 
hypoglycemia management  
Updated to be consistent with 
Section 4.1.3 
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Section # and Name 
Description of Change 
Brief Rationale 
hypoglycemia during in-
house periods 
Section 8.2.7.2. Treatment 
of hyperglycemia and 
hypoglycemia during in-
house periods  
mM updated as mmol/L 
Updated units to ensure 
consistency 
Appendix 7: Protocol 
amendment history 
New section added 
Summary of changes table of 
amendment a have been moved to 
this section 
 
 
 
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Table of Contents 
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................13 
1.3. 
Schedule of Activities (SoA) ..........................................................................................14 
1.3.1. 
Overall Schedule .............................................................................................................14 
1.3.2. 
Assessment Schedule Example for In-house Visits (Visits 3, 4, 5, 
6) .....................................................................................................................................19 
2. 
Introduction ...................................................................................................................23 
2.1. 
Study Rationale ...............................................................................................................23 
2.2. 
Background .....................................................................................................................23 
2.3. 
Benefit/Risk Assessment ................................................................................................24 
3. 
Objectives and Endpoints ............................................................................................26 
4. 
Study Design ..................................................................................................................28 
4.1. 
Overall Design ................................................................................................................28 
4.1.1. 
Screening Visit ................................................................................................................28 
4.1.2. 
Assessment Day ..............................................................................................................29 
4.1.3. 
In-house Visits ................................................................................................................31 
4.1.4. 
Between In-house Visits .................................................................................................34 
4.1.5. 
Follow-Up Visit ..............................................................................................................35 
4.2. 
Scientific Rationale for Study Design ............................................................................35 
4.3. 
Justification for Dose ......................................................................................................35 
4.4. 
End of Study Definition ..................................................................................................35 
5. 
Study Population ...........................................................................................................36 
5.1. 
Inclusion Criteria ............................................................................................................36 
5.2. 
Exclusion Criteria ...........................................................................................................37 
5.2.1. 
Additional criteria for study treatment periods ...............................................................39 
5.3. 
Lifestyle Considerations .................................................................................................40 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................40 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................41 
5.3.3. 
Activity ...........................................................................................................................41 
5.4. 
Screen Failures ................................................................................................................41 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................42 
6.1. 
Study Intervention(s) Administered................................................................................42 
6.1.1. 
Noninvestigational Medicinal Products ..........................................................................43 
6.1.2. 
Administration Details ....................................................................................................43 
6.1.3. 
Pump Occlusion Alarms and Accidental Infusion Set 
Discontinuations .............................................................................................................43 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................44 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................44 
6.4. 
Study Intervention Compliance ......................................................................................45 
6.5. 
Dose Modification ..........................................................................................................45 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................45 
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6.7. 
Treatment of Overdose ...................................................................................................46 
6.8. 
Concomitant Therapy .....................................................................................................46 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................48 
7.1. 
Discontinuation of Study Intervention ............................................................................48 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................48 
7.1.2. 
QTc Stopping Criteria .....................................................................................................48 
7.1.3. 
Hypoglycemia .................................................................................................................48 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................48 
7.3. 
Lost to Follow-Up ...........................................................................................................49 
8. 
Study Assessments and Procedures.............................................................................50 
8.1. 
Efficacy Assessments .....................................................................................................50 
8.2. 
Safety Assessments .........................................................................................................50 
8.2.1. 
Physical Examinations ....................................................................................................50 
8.2.2. 
Vital Signs .......................................................................................................................51 
8.2.3. 
Electrocardiograms .........................................................................................................51 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................51 
8.2.5. 
Pregnancy Testing ...........................................................................................................52 
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................52 
8.2.7. 
Safety Monitoring ...........................................................................................................52 
8.2.8. 
Rating of Perceived Exertion ..........................................................................................53 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................53 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................54 
8.3.2. 
Pregnancy ........................................................................................................................56 
8.3.3. 
Adverse Events of Special Interest .................................................................................57 
8.4. 
Pharmacokinetics ............................................................................................................57 
8.4.1. 
Bioanalysis ......................................................................................................................57 
8.5. 
Pharmacodynamics .........................................................................................................58 
8.5.1. 
Glucose Values ...............................................................................................................58 
8.5.2. 
Exploratory CGM Values ...............................................................................................58 
8.5.3. 
Exploratory Blood Ketones and Free Fatty Acids ..........................................................58 
8.6. 
Genetics ..........................................................................................................................58 
8.7. 
Biomarkers ......................................................................................................................58 
8.8. 
Immunogenicity Assessments.........................................................................................58 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................58 
9. 
Statistical Considerations .............................................................................................59 
9.1. 
Statistical Hypotheses .....................................................................................................59 
9.1.1. 
Multiplicity Adjustment ..................................................................................................59 
9.2. 
Analyses Sets ..................................................................................................................59 
9.2.1. 
Study Participant Disposition .........................................................................................59 
9.2.2. 
Study Participant Characteristics ....................................................................................59 
9.2.3. 
Treatment Compliance ....................................................................................................60 
9.3. 
Statistical Analyses .........................................................................................................60 
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9.3.1. 
General Considerations ...................................................................................................60 
9.3.2. 
Glucodynamic Analysis ..................................................................................................60 
9.3.3. 
Pharmacokinetic Analysis ...............................................................................................62 
9.3.4. 
Exploratory Analysis ......................................................................................................64 
9.3.5. 
Safety Analyses ...............................................................................................................64 
9.3.6. 
Other Analyses ................................................................................................................64 
9.4. 
Interim Analysis ..............................................................................................................65 
9.5. 
Sample Size Determination ............................................................................................65 
10. 
Supporting Documentation and Operational Considerations ..................................66 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................66 
10.1.1. Regulatory and Ethical Considerations ...........................................................................66 
10.1.2. Informed Consent Process ..............................................................................................66 
10.1.3. Data Protection................................................................................................................67 
10.1.4. Dissemination of Clinical Study Data.............................................................................67 
10.1.5. Data Quality Assurance ..................................................................................................68 
10.1.6. Source Documents ..........................................................................................................69 
10.1.7. Study and Site Start and Closure ....................................................................................70 
10.1.8. Publication Policy ...........................................................................................................70 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................71 
10.2.1. Blood Sampling Summary ..............................................................................................73 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................74 
10.3.1. Definition of AE .............................................................................................................74 
10.3.2. Definition of SAE ...........................................................................................................75 
10.3.3. Definition of Product Complaints ...................................................................................76 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................76 
10.3.5. Reporting of SAEs ..........................................................................................................78 
10.3.6. Regulatory Reporting Requirements ...............................................................................78 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................80 
10.4.1. Definitions.......................................................................................................................80 
10.4.2. Contraception Guidance..................................................................................................81 
10.5. 
Appendix 5: Provisions for Changes in Study Conduct during 
Exceptional Circumstances .............................................................................................83 
10.6. 
Appendix 6: Abbreviations and Definitions ...................................................................86 
10.7. 
Appendix 7: Protocol Amendment History ....................................................................89 
11. 
References ......................................................................................................................91 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: Effectiveness of a Basal Rate Reduction with LyumjevTM versus Humalog® on 
the Protection from Exercise-Induced Hypoglycemia in Individuals with Type 1 Diabetes on 
Continuous Subcutaneous Insulin Infusion 
Brief Title: A Study to Evaluate Protection from Exercise-Induced Hypoglycemia with 
LyumjevTM Compared to Humalog® in Individuals with Type 1 Diabetes  
Rationale: 
Study I8B-MC-ITSU (Study ITSU) will be conducted to compare the glycemic control during 
exercise achieved with LyumjevTM versus Humalog® using different approaches on basal rate 
reductions in participants with type 1 diabetes on continuous subcutaneous insulin infusion 
(CSII) therapy.  
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
 
 To compare changes in plasma 
glucose levels with Lyumjev versus 
Humalog from the start to the end of 
60 minutes of moderate-intensity 
aerobic exercise using either 50% or 
100% reduction of basal infusion 
rates, set 60 minutes or 15 minutes 
before the onset of exercise, 
respectively 
 Changes in plasma glucose from the 
start to the end of exercise 
Secondary 
 
 To compare the glucodynamic 
response with Lyumjev versus 
Humalog during a dinner MMTT 
following moderate-intensity aerobic 
exercise using either 50% or 100% 
reduction of basal infusion rates, set 
60 minutes or 15 minutes before the 
onset of exercise, respectively 
 
 
 Postprandial glucose excursion during 
the test meal (e.g., AUC0-4h) 
 
 
 
 
 
 
 
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 To compare the PK of insulin lispro 
between Lyumjev versus Humalog 
during an MMTT 
 To compare the PK of insulin lispro 
between Lyumjev versus Humalog 
during 60 minutes of moderate-
intensity aerobic exercise using either 
50% or 100% reduction of basal 
infusion rates with Lyumjev or 
Humalog, set 60 minutes or 15 minutes 
before the onset of exercise, 
respectively 
 
 Insulin lispro PK during the MMTT 
after exercise 
 
 Insulin lispro PK during the exercise 
Abbreviations: AUC0-4h = area under the plasma concentration time curve from 0 to 4 hours post-meal; MMTT = 
mixed meal tolerance test; PK = pharmacokinetics.  
Overall Design 
Study ITSU will be a single center, randomized, double-blind, 4-period, crossover Williams 
design exercise and test meal study in physically active adult patients with type 1 diabetes using 
CSII. The study will consist of 2 active treatment arms, Lyumjev and Humalog. This study will 
include a screening visit (Visit 1), visits to optimize basal rates (optional based on investigator 
decision), an assessment day (Visit 2), 4 in-house study periods with study intervention 
administration (Visits 3, 4, 5, and 6), and a follow-up visit (Visit 7). 
This is a participant- and investigator-blind study. On Day -1 of in-house period (Visit 3), 
participants will be assigned a unique number (randomization number) in ascending numerical 
order. The randomization number encodes the participant’s assignment to 1 of the 4 in-house 
study periods, according to the randomization schedule generated prior to the study by the 
statistics department at the sponsor/designee. Each participant will be dispensed blinded study 
intervention, labeled with the participant’s unique randomization number, throughout the study. 
Investigators will remain blinded to each participant’s assigned study intervention throughout the 
course of the study. To maintain this blind, an otherwise uninvolved third party, such as a 
pharmacist, will be responsible for the dispensation of all study interventions and will endeavor 
to ensure that there are no differences in time taken to dispense following randomization. 
Brief Summary: 
The purpose of this study is to measure the changes in plasma glucose levels with Lyumjev 
compared with Humalog from the start to the end of prolonged moderate-intensity aerobic 
exercise using either 50% or 100% reduction of basal infusion rates in participants with type 1 
diabetes mellitus on CSII. 
Study details include 
● The study duration will be approximately 
 weeks. 
● The treatment duration will be approximately weeks. 
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● The visit frequency during the in-house period will be 2 continuous days of stay (with 1 
overnight) in clinical research unit for a total of 4 visits with a washout period of up to 
days 
in between the visits. 
Number of Participants: 
A maximum of 
 participants will be enrolled to receive study intervention. Refer to Section 9.5 
for details. 
Intervention Groups and Duration: 
Screening (Visit 1): 
 days prior to Visit 3  
Assessment Day (Visit 2): 
 days prior to Visit 3; Humalog via standardized insulin pump.  
In-house (Visits 3, 4, 5, 6):  days of stay in clinical research unit for a total of 4 visits with 
 
 days of washout period in between visits; Lyumjev or Humalog via standardized insulin pump, 
and 2 different basal insulin reduction rates to be administered at the 4 separate in-house visits 
based on randomization.  
Follow-up (Visit 7): 
 days after Visit 6 
Data Monitoring Committee: No 
 
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1.2. 
Schema 
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1.3. 
Schedule of Activities (SoA) 
1.3.1. 
Overall Schedule 
Procedure 
Screening Period 
Study Period 
Follow-
up/ED 
Comments 
Visit Number 
1 
Optional visits 
2 
3, 4, 5, 6 
7 
 
 
Screening  
Basal rate optimization  
Assessment 
In-house 
 
 
Timing 
Within 
 
days prior 
to Visit 3 
First evaluation - 
Within  days of 
screening visit 
Second evaluation - 
Within
 days of 
screening visit 
 days prior 
to Visit 3  
 
 days  
 days 
after Visit 6 
 
Day 
 
 
In-house stay 
 
 
 
X 
X 
 
 
Admission to CRU 
 
 
 
X 
 
 
 
Discharge from CRU 
 
 
 
 
X 
 
At the discretion of investigator 
Outpatient 
X 
X  
X 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
Xa 
 
 
 
Fasting 
X 
 
 
 
X 
 
 
Demographic data 
X 
 
 
 
 
 
 
Smoking and alcohol consumption 
habits 
X 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
Weight, height, BMI 
X 
 
 
Xb 
 
Xb 
 
Physical examination 
X 
 
 
X 
 
X 
 
Vital signs 
X 
 
 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
Single 
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Procedure 
Screening Period 
Study Period 
Follow-
up/ED 
Comments 
Visit Number 
1 
Optional visits 
2 
3, 4, 5, 6 
7 
 
 
Screening  
Basal rate optimization  
Assessment 
In-house 
 
 
Timing 
Within 
 
days prior 
to Visit 3 
First evaluation - 
Within days of 
screening visit 
Second evaluation - 
Within 
days of 
screening visit 
 days prior 
to Visit 3  
 
 days  
days 
after Visit 6 
 
Day 
 
 
In-house stay 
 
 
 
X 
X 
 
 
Clinical Laboratory Tests 
X 
 
 
 
 
 
See Section 10.2  
HbA1c 
X 
 
 
 
 
 
 
Fasting C-peptide 
X 
 
 
 
 
 
 
Pregnancy test (females only) 
X 
 
 
X 
 
X 
Serum test at screening; urine 
pregnancy test prior to study 
treatment and at follow-up; See 
Section 10.4.2 
Urine drug screen and ethanol 
testing 
X 
 
X 
X 
 
 
Ethanol breath test on Day -1 and 
assessment day. 
Perform pump basal rate 
assessment, review and titration if 
needed 
X 
Xc 
 
 
 
 
Collect and review the ambulatory 
glucose profile, pump settings, etc. 
Once established, these rates 
should be maintained for all study 
periods 
Dispense study diaries and 
complete training 
X 
 
 
 
 
 
 
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Procedure 
Screening Period 
Study Period 
Follow-
up/ED 
Comments 
Visit Number 
1 
Optional visits 
2 
3, 4, 5, 6 
7 
 
 
Screening  
Basal rate optimization  
Assessment 
In-house 
 
 
Timing 
Within 
 
days prior 
to Visit 3 
First evaluation - 
Within days of 
screening visit 
Second evaluation - 
Within 
 days of 
screening visit 
 days prior 
to Visit 3  
 
 days  
days 
after Visit 6 
 
Day 
 
 
In-house stay 
 
 
 
X 
X 
 
 
Collect, review, and discuss entries 
in study diaries  
 
X 
X 
X 
 
X 
 
Peak VO2, heart rate, and RPE 
assessment during progressive 
treadmill exercise test 
X 
 
 
 
 
 
RPE to be collected every 2 
minutes during the progressive 
treadmill test; refer to Section 
8.2.8 for further details 
Prolonged exercise session at 45% 
to 55% of predetermined VO2 peak 
 
 
X 
 
X 
 
Heart rate and RPE (Section 8.2.8) 
will be collected at each 17-minute 
interval (the last 2 minutes of each 
interval) over the 1-hour exercise 
period (Sections 4.1.2 and 4.1.3) 
Eligibility check/Additional 
exclusion/withdrawal criteria 
 
 
X 
X 
 
 
 
Randomization 
 
 
 
X*  
 
 
*Visit 3 only 
Study intervention administration 
 
 
Xd 
X 
X 
 
Administer study intervention 
bolus dose immediately (0-2 
minutes) before meal 
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Procedure 
Screening Period 
Study Period 
Follow-
up/ED 
Comments 
Visit Number 
1 
Optional visits 
2 
3, 4, 5, 6 
7 
 
 
Screening  
Basal rate optimization  
Assessment 
In-house 
 
 
Timing 
Within 
 
days prior 
to Visit 3 
First evaluation - 
Within  days of 
screening visit 
Second evaluation - 
Within 
 days of 
screening visit 
days prior 
to Visit 3  
 
 days  
days 
after Visit 6 
 
Day 
 
 
In-house stay 
 
 
 
X 
X 
 
 
Pump temporary basal rate 
reduction during prolonged 
exercise 
 
 
X 
 
X 
 
50% or 100% basal rate reduction 
prior and during exercise period 
MMTT 
 
 
X 
 
X 
 
 
PKe 
 
 
 
 
X 
 
 
Glucose 
 
 
Xf 
 
Xg 
 
 
Study CGM 
 
 
 
X 
X 
 
 
Blood ketones/FFAsh 
 
 
 
 
X 
 
 
Adverse events and product 
complaints 
 
 
X 
X 
X 
X 
 
Concomitant medications 
X 
 
X 
X 
X 
X 
 
Standardized lunch 
 
 
X 
 
X 
 
 
Standardized dinner 
 
 
 
X 
 
 
 
Standardized breakfast 
 
 
 
 
X 
 
 
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Abbreviations: BMI = body mass index; CGM = continuous glucose monitoring; CRU = clinical research unit; ECG = electrocardiogram; FFA = free fatty acid; 
HbA1c = glycosylated hemoglobin; MMTT = mixed meal tolerance test; PK = pharmacokinetics; RPE = rating of perceived exertion; VO2 = oxygen uptake. 
a 
Re-check of participant eligibility. 
b 
Weight only. 
c 
See Section 4.1.1 for further details. 
d 
Humalog to be administered in pump on assessment day. Refer to Section 4.1.2 for initial bolus dose selection to be administered prior to MMTT. 
e 
PK will be collected over 
 minutes after start of exercise and 
 
 
f 
Blood glucose (YSI) on assessment day at 
 minutes after start of exercise and 
 
 post-meal MMTT. 
g 
Blood glucose (YSI) will be collected at 
 pre-exercise, and 
 after 
start of exercise and 
 post-meal MMTT. 
h 
Ketones and FFAs will be collected at
 after start of exercise. 
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1.3.2. 
Assessment Schedule Example for In-house Visits (Visits 3, 4, 5, 6) 
 
Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose 
FFA/ 
Ketones 
Other 
Day -1 
 
Participant arrives at the CRU and 
continued eligibility will be checked 
 
 
 
Weight, height, BMI, physical examination, vital 
signs, urine pregnancy test, alcohol breath test, 
eligibility check/ additional exclusion/withdrawal 
criteria, AEs, concomitant medications  
 
Randomization (Visit 3 only)  
Discontinue participant’s own 
insulin pump  
Start study insulin pump with study 
intervention (participant’s usual 
basal rate) 
Insert study CGM system 
 
 
 
 
 
Standardized evening meal 
Administer individualized bolus 
dose immediately (0-2 minutes) 
before dinner meal  
 
 
 
 
 
 
 
 
 
Overnight stay in CRU with usual overnight basal 
infusion rates and glucose monitoring with CGM. 
Morning glucose target 
mmol/L 
Day 1 
 
Standardized breakfast meal  
 
 
 
The meal should be completed within 
 
 Addition of correction bolus with 
mealtime bolus is allowed, if needed 
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Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose 
FFA/ 
Ketones 
Other 
Administer individualized bolus 
dose immediately (0-2 minutes) 
before breakfast meal  
 
 
Insert venous cannula (arm/hand) 
for insulin lispro PK, glucose, 
ketones, and FFA collection prior to 
lunch 
 
 
 
 
Standardized lunch meal 
Administer individualized bolus 
dose immediately (0-2 minutes) 
before lunch meal 
Set pump to individualized single 
hourly basal rate  
X 
X 
 
The meal should be completed within 
 
 Addition of correction bolus with 
mealtime bolus is allowed, if needed. Collection of 
PK and glucose prior to meal 
 
X 
X 
X 
 
Basal rate reduction – 50% 
X 
X 
X 
For each period, either the 50% or 100% basal 
reduction will be used. Depending on the 
randomization for the participant. Sample collection 
to occur prior to basal reduction. 
 
 
 
X 
X 
X 
Basal rate reduction – 100% 
X 
X 
X 
Exercise (treadmill, brisk walking, 
or jogging at ⁓45%-55% of 
predetermined VO2 peak) x 17 
minutes x 3 with two 4-minute and 
30-second breaks 
Xa 
Xa 
Xa 
Heart rate and RPE to be recorded once within each 
17-minute interval (within the last 2 minutes of each 
interval) 
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Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose 
FFA/ 
Ketones 
Other 
Glucose sampling 
 during exercise 
period. Samples for FFAs, ketones, and PK will be 
collected 
 during exercise period 
End of exercise assessment 
Reset pump basal rate to 
participant’s usual rate (maintain 
individualized single hourly basal 
rate until the end of MMTT 
sampling) 
X 
X 
X 
Collection of glucose, PK, FFA, and ketones to occur 
prior to restart of usual basal rate 
 
Post-exercise resting period 
 
 
 
 
 
Dinner MMTT 
Administer individualized bolus 
dose immediately (0-2 minutes) 
before meal  
Xa 
Xa 
 
 
 
 
 
Xa 
Xa 
 
 
 
 
Xa 
Xa 
 
 
 
 
Xa 
Xa 
 
 
 
Following collection of PK and 
glucose samples, remove venous 
cannula, disconnect study pump, and 
remove study CGM system  
Participant resumes usual pump 
therapy 
Xa 
Xa 
 
 
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Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose 
FFA/ 
Ketones 
Other 
Discharge 
from 
CRU 
 
Participant may leave the CRU at 
the discretion of the investigator 
 
 
 
AEs, product complaints, concomitant medication 
Abbreviations: AE = adverse event; CGM = continuous glucose monitoring; CRU = clinical research unit; FFA = free fatty acids; MMTT = mixed meal 
tolerance test; PK = pharmacokinetics; RPE = rating of perceived exertion; VO2 = oxygen uptake. 
a 
Exact collection timing for PK and glucose samples is provided in footnote of table in Section 1.3.1.  
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2. 
Introduction 
LyumjevTM is a new formulation of insulin lispro developed as a more rapid-acting insulin with a 
faster onset of action and shorter duration of action compared to currently available rapid-acting 
insulin analogs, and it will more closely mimic endogenous insulin action in healthy subjects. 
2.1. 
Study Rationale 
Study I8B-MC-ITSU (Study ITSU) will be conducted to compare the glycemic control during 
exercise achieved with Lyumjev versus Humalog® using different approaches on basal rate 
reductions in participants with T1D on CSII therapy.  
2.2. 
Background 
Regular exercise in people with T1D can help in achieving targets related to their lipid profile, 
body composition, fitness, and glycemic control. It can improve the overall health and well-
being. However, people with T1D and the healthcare providers face several challenges in the 
management of different forms of physical activity. These include fear of hypoglycemia, loss of 
glycemic control, inadequate knowledge around exercise management, etc. (Riddell et al. 2017).  
Strategies for glycemic management during and after exercise include frequent glucose 
monitoring, intake of carbohydrates, and reductions in bolus and basal insulin doses. Following 
are the possible adjustment options for hypoglycemia risk reduction with prolonged 
(>30 minutes) aerobic exercise (Riddell et al. 2017): 
 Bolus insulin dose reduction up to 75% at the meal before exercise, if the exercise is up 
to 2 hours after a meal 
 Basal insulin dose reduction of approximately 20% in patients on multiple daily 
injections before exercise if the exercise is fasted or >2 to 3 hours after a meal 
 Basal rate reduction of up to 100% pre-exercise (i.e., pump suspension) in patients on 
CSII, but ideally a 50% to 80% basal rate reduction set 60 to 90 minutes before exercise 
to reduce circulating insulin levels by exercise start time (Zaharieva et al. 2019; 
McGaugh et al. 2021) 
 Basal nocturnal insulin dose reduction of approximately 20% in patients on multiple daily 
injections or CSII (for up to 6 hours in recovery) after exercise  
 Intake of additional carbohydrates before, during, and after exercise without insulin bolus 
Insulin lispro (Humalog) 
The insulin analog insulin lispro (Humalog) has been shown to be absorbed more quickly than 
regular human insulin (Humalog product monograph, 2021). In healthy volunteers given 
subcutaneous doses of Humalog ranging from 0.1 to 0.4 units (U)/kg, peak serum levels were 
seen 30 to 90 minutes after dosing ([WWW] FDA 2015). However, the consensus is that rapid-
acting insulin is still not rapid enough to match carbohydrate absorption profiles, which limit 
efficacy and dosing flexibility. An ultra-rapid-acting prandial insulin would shift the PK/GD of 
insulin analogs so that they have an even faster onset to better match carbohydrate absorption 
and also allow greater flexibility in the time of dosing relative to meals. The faster onset of 
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I8B-MC-ITSU(b) 
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action in an ultra-rapid-acting prandial insulin would also be expected to be associated with a 
faster reduction in action after its administration (i.e. less of an insulin “tail” effect), which may 
offer better protection against exercise-induced hypoglycemia in post-absorptive settings or 
when individuals on CSII perform a basal rate reduction prior to exercise. 
Lyumjev 
Lyumjev is a novel formulation of insulin lispro that contains treprostinil, sodium citrate, and 
other excipients. This formulation involves the novel use of a microdose of treprostinil as an 
excipient to enhance the absorption of insulin lispro by local vasodilatation rather than as an 
active pharmaceutical ingredient to elicit a systemic effect. Sodium citrate, an excipient that 
speeds up insulin absorption (at least in part by enhancing vascular permeability), is also 
included in the formulation to further enhance the absorption of insulin lispro. Each of the other 
excipients (such as magnesium chloride) in the Lyumjev formulation is listed in the US FDA’s 
Generally Recognized as Safe Food Additives database and in the FDA’s Inactive Ingredients in 
Approved Drugs database ([WWW] FDA 2018; [WWW] FDA 2021a). 
Lyumjev has received approval in Canada on 14 September 2021 for treatment of adult patients 
with diabetes mellitus (Lyumjev product monograph, 2021). Lyumjev also received FDA 
approval on 15 June 2020, and it was approved by the European Medicines Agency on 24 March 
2020 ([WWW] EMA 2020; [WWW] FDA 2021b).  
In the Phase 3 pivotal multiple daily injection studies, Lyumjev dosed at the start of a meal 
demonstrated noninferior overall glycemic control (HbA1c) in patients with T1D and type 2 
diabetes and consistently better postprandial glucose control, compared to Humalog (Blevins et 
al. 2020; Jinnouchi et al. 2020; Klaff et al. 2020). Additionally, improved time in range during 
daytime was observed in patients with T1D treated with Lyumjev (Malecki et al. 2020). Safety 
profile was observed to be similar between the treatment groups in these trials. Injection-site 
reactions occurred at a higher incidence with Lyumjev compared to Humalog (2.7% versus 
0.1%, respectively), but had an overall low incidence with <0.1% of patients discontinuing from 
trials due to injection site-related reactions (Lyumjev product monograph, 2021). 
Lyumjev was efficacious, providing superior postprandial glucose control and less time in 
hypoglycemia compared with Humalog when administered through CSII (Warren et al. 2021). 
The incidence of patients reporting infusion site reaction and infusion site pain was higher in the 
Lyumjev group compared with the Humalog group (19.1% versus 7.4%, and 15.8% versus 2.8%, 
respectively) (Lyumjev product monograph, 2021). Of the 215 patients treated with Lyumjev, 7 
discontinued treatment due to infusion site-related reactions (3.3%) (Lyumjev product 
monograph, 2021).  
2.3. 
Benefit/Risk Assessment 
This study will not offer any direct benefits to the participants in the study beyond the typical 
benefits derived from insulin pump use in T1D participants. The data from previous studies in 
patients with T1D on CSII therapy showed that Lyumjev was well tolerated, and overall safety 
profile was similar to that reported for Humalog (Warren et al. 2021). 
Potential risks associated with Lyumjev and Humalog 
 Hyperglycemia and/or hypoglycemia; severe or otherwise 
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 Hypokalemia  
 Lipodystrophy  
 Peripheral edema  
 Severe, life-threatening generalized allergy, including anaphylaxis, to Humalog or 
Lyumjev insulin. 
 Injection/infusion site-related reactions 
The occurrence and severity of these events are not expected to be different from routine use of 
insulin injection systems. More detailed information about the known and expected risks and 
potential AEs may be found in the Lyumjev and Humalog product monographs (Lyumjev 
product monograph, 2021, Humalog product monograph, 2021).  
Potential risks associated with CSII pump use 
 Minor skin irritation, sensitization, or localized inflammatory response can occur if skin 
contacts bioincompatible materials. 
 Pain, bruising, swelling, redness, and bleeding at the infusion set insertion site. 
The occurrence and severity of these events are not expected to be different from routine use of 
the 
 More detailed information on the use and about the 
known and expected risks and potential ADEs may be found in the manufacturer’s label and 
Instructions for Use.  
Potential risks associated with CGM use 
 Pain, bruising, swelling, redness, and bleeding at the sensor insertion site 
 Sensor breakoff where the sensor wire detaches and remains under the skin 
 Minor skin irritation, sensitization, or localized inflammatory response can occur if skin 
contacts bioincompatible materials 
 Inaccurate results due to use of meter that is out of calibration, malfunctioning, or rapidly 
changing glucose levels 
 Loss of CGM connectivity (transient and permanent)  
 Errors in the data transmitted to the software application  
 Electric shock if the device is damaged 
The occurrence and severity of these events are not expected to be different from routine use of 
CGM. More detailed information on the use and about the known and expected risks and 
potential ADEs may be found in the manufacturer’s label and Instructions for Use. 
The study includes in-house procedures during which participants will be continuously 
monitored.  
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3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
 To compare changes in plasma glucose 
levels with LyumjevTM versus Humalog® 
from the start to the end of 60 minutes of 
moderate-intensity aerobic exercise using 
either 50% or 100% reduction of basal 
infusion rates, set 60 minutes or 15 
minutes before the onset of exercise, 
respectively  
 Changes in plasma glucose from the start 
to the end of exercise 
Secondary 
 
 To compare the glucodynamic response 
with Lyumjev versus Humalog during a 
dinner MMTT following moderate-
intensity aerobic exercise using either 
50% or 100% reduction of basal infusion 
rates, set 60 minutes or 15 minutes before 
the onset of exercise, respectively 
 
 To compare the PK of insulin lispro 
between Lyumjev versus Humalog 
during an MMTT  
 
 To compare the PK of insulin lispro 
between Lyumjev versus Humalog 
during 60 minutes of moderate-intensity 
aerobic exercise using either 50% or 
100% reduction of basal infusion rates 
with Lyumjev or Humalog, set 60 
minutes or 15 minutes before the onset of 
exercise, respectively 
 Postprandial plasma glucose excursion 
during the test meal (e.g., AUC0-4h) 
 
 
 
 
 
 
 
 Insulin lispro PK during the MMTT after 
exercise 
 
 Insulin lispro PK during the exercise 
Exploratory 
 
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I8B-MC-ITSU(b) 
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Objectives 
Endpoints 
 To investigate tolerability and safety of 
Lyumjev and/or Humalog 
 
 
 To perform an exploratory comparison of 
glucose variability, time in range, 
hypoglycemia, and hyperglycemia using 
CGM profiles obtained from participants 
receiving Lyumjev and Humalog 
 
 Incidence of TEAEs, SAEs, symptomatic 
hypoglycemia 
 Blood ketone levels 
 
 Overall variability (CV and SD) 
 Time in range (70 to 180 mg/dL) during 
exercise, MMTT assessment, overnight 
period, and for the entire in-house period 
 Time in hypoglycemia (<70 and 
<54 mg/dL) and hyperglycemia (>180 
and 140 mg/dL) 
 Mean glucose levels 
Abbreviations: AUC0-4h = area under the plasma concentration time curve from 0 to 4 hours postmeal; CGM = 
continuous glucose monitoring; CV = coefficient of variation; MMTT = mixed meal tolerance test; PK = 
pharmacokinetics; SAE = serious adverse event; SD = standard deviation; TEAE = treatment-emergent adverse 
event. 
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4. 
Study Design 
4.1. 
Overall Design 
Study ITSU will be a single center, randomized, double-blind, 4-period, crossover Williams 
design exercise and test meal study in physically active adult participants with T1D using CSII. 
The study will consist of 2 active treatment arms, Lyumjev and Humalog. This study will include 
a screening visit (Visit 1), visits to optimize basal rates (optional based on investigator decision), 
an assessment day (Visit 2), 4 in-house study periods with study intervention administration 
(Visits 3, 4, 5, and 6), and a follow-up visit (Visit 7).  
4.1.1. 
Screening Visit 
Screening may occur up to 
 prior to Visit 3. Participants who are not enrolled within 28 
days of screening prior to Visit 3 may undergo an additional medical assessment and/or clinical 
measurements to confirm their eligibility. In such instances, all the screening tests and 
procedures will be repeated.  
During the screening visit, after obtaining informed consent, study participants will be assessed 
for eligibility (see Sections 5.1 and 5.2). An interview will be conducted to collect demographic 
details and medical history; examination, laboratory tests, and other assessments will be 
performed as mentioned in the SoA. Participant’s insulin requirements (i.e pump) and 
ambulatory glucose profile (i.e. CGM downloads) will be examined. Participants will receive a 
study diary to document any AEs, hypoglycemic events, insulin doses, self-monitored blood 
glucose (SMBG) values, and meals (time, units of carbohydrate equivalent).  
Prospective study participants will have their exercise capacity (i.e. peak VO2), 
 
 Section 8.2.8), and heart rates evaluated during a progressive treadmill exercise test (i.e. a 
graded 2-minute stage test that maintains a constant running or jogging speed with increase in 
grade [2.5%] every 2 minutes) until volitional fatigue, as part of the study eligibility. Prospective 
study participants on a closed-loop pump system would switch their pump to “open-loop” or 
manual mode utilizing their programmed basal rates and allowing low glucose suspend via their 
personal CGM during the screening period. These participants would also agree to maintain their 
pump in open-loop mode for the entire study period.  
For those prospective study participants who require basal rate titration based on investigator 
decision, participants will return to the CRU approximately 
 after their screening visit for 
a basal rate optimization visit. The ambulatory glucose profile from their CGM, personal pump 
data, and study diary will be reviewed. If further modification of pump settings is necessary, they 
will return to the CRU approximately a week later and their ambulatory glucose profile, personal 
pump data, and study diary will be reviewed. For those prospective study participants who are 
unable to get the basal rates optimized within this period (based on investigator decision), 
participants will not be eligible for the study. For those prospective study participants who do not 
require basal titration based on investigator decision at screening visit and are eligible for the 
study, they would return to the CRU on assessment day.  
Once basal insulin rates are set, these should be fixed for the entire study period, unless a change 
is deemed necessary by the investigator. 
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4.1.2. 
Assessment Day 
After screening, all eligible participants will have an assessment day (Visit 2) to undergo a 
prolonged exercise session at 45% to 55% of predetermined peak VO2 and to determine the 
insulin bolus dose for the MMTT to be performed in the study. 
Participants will arrive at the CRU in the morning by approximately
 (Figure ITSU.1). 
Participants will be placed on a standardized insulin pump 
 with a 
new infusion set
 After disconnecting the 
participant’s own insulin pump, the study pump reservoir will be filled with Humalog by a 
qualified CRU staff. A standard infusion set and catheter will be inserted into the abdominal 
area, as per the manufacturer’s instructions, after the region is inspected for lipodystrophy 
(Section 6.1.2). The participant’s usual basal rate settings will be programmed in the pump and 
the basal rate infusion will be started. 
A cannula will be inserted for venous access for glucose sampling prior to lunch. A standardized 
lunch will be provided 
Section 5.3.1.3) and the bolus insulin dose will 
be individualized per participant to cover the carbohydrate content. No additional bolus insulin 
injection should be administered post-meal after lunch prior to the exercise period. The basal rate 
will be set to a single hourly rate at lunch based on the participant’s usual basal rate for this time 
of day; this will be maintained until the basal rate reduction for the exercise period. The basal 
rate in the pump will be reduced by 50% at approximately 
 1 hour prior to the exercise 
assessment. A pre-exercise glucose target of 
 will need to be achieved 
 
 prior to exercise. 
 
 
 
 
 
 prior to exercise, the assessment day will be rescheduled within the allowable time 
window mentioned in the SoA. 
Four hours after lunch 
, the participants will be instructed to walk or jog on 
the treadmill at 45% to 55% of their predetermined peak VO2 using three 17-minute intervals 
with two 4-minute and 30-second rest periods in between intervals for a total duration of 1 hour 
 During the exercise period, heart rate will be monitored 
continuously using a chest strap heart rate monitor, and participants will be asked to rate their 
perceived exertion using 
 (Section 8.2.8) during the last 2 minutes of each 
17-minute interval. Participants will be monitored for safety. If hypoglycemia ensues (plasma or 
whole blood glucose level 
), the exercise will be terminated, and the 
participant will be treated with 
of oral carbohydrates (dextrose tablets). If the glucose level 
continues to be below
 after approximately
 minutes, up to an 
additional 
 of oral carbohydrates can be provided. Repeat as necessary if glucose value 
remains below 
 mg/dL. If the exercise is terminated due to hypoglycemia during the first 
exercise interval, the assessment day will be rescheduled within the allowable time window 
mentioned in the SoA. If the exercise is terminated due to hypoglycemia during the second 
interval, the assessment day may not need to be rescheduled. If the exercise is terminated during 
the third interval, assessment day will not be rescheduled. Upon completion of the exercise 
period or once the participant recovers from hypoglycemia (blood glucose reaches 
 mg/dL or 
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 mmol/L) that occurred during the second or third interval, the pump basal rate will be 
returned to the participant’s usual basal rate for this time of the day 
 and this basal rate 
will be maintained until the end of MMTT.  
Participants will be instructed to rest for approximately 30 minutes. A standardized liquid dinner 
MMTT containing approximately 
 of carbohydrates 
 
 
will be administered approximately  hour after the exercise assessment (Section 5.3.1.1). 
Participants are expected to complete each test meal within approximately 
 minutes of starting 
the meal. This meal will be the same as the meals that will be provided during Visits 3 to 6. The 
dose-finding assessment will use Humalog administered immediately (0 to 2 minutes) before the 
dinner MMTT using 
. Selection of 
bolus dose will be as follows: 
 Initial bolus dose selection will be based on discussion between participant and 
investigator using participant’s usual dose requirements or insulin-to-carbohydrate ratio, 
insulin sensitivity index, and glycemic targets preprogrammed in their personal medical 
device along with a 25% reduction of the bolus dose to account for increased insulin 
sensitivity following exercise. 
 Postprandial glucose profile over the 4-hour post-meal period will be measured every 
 
minutes after administration of proposed insulin dose to verify that the initial bolus dose 
selected is appropriate using the following: 
The selected bolus dose will be used during subsequent liquid dinner MMTT assessments in the 
study for both Lyumjev and Humalog.  
Following completion of glucose sampling, the 
 will be 
removed and the participant’s own insulin pump will be re-introduced using a new infusion set, 
if necessary, for pump compatibility. 
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Figure ITSU.1. 
Study activities during Assessment Day (Visit 2). 
4.1.3. 
In-house Visits 
After Visit 2, all eligible participants will undergo 4 in-house study periods (Visits 3 to 6). Each 
in-house period will comprise a
day stay at the CRU. The in-house period will be separated by 
a washout period of 
 days (e.g., between Visit 3, Day 1 and Visit 4, Day 1). Each 
participant will be randomly assigned to a treatment sequence consisting of 2 treatments 
(blinded), i.e., Lyumjev and Humalog, and 2 different basal insulin reduction rates to be 
administered at the 4 separate in-house visits in 4 by 4 crossover Williams design (Figure 
ITSU.2). Randomization will take place on Day -1 of Visit 3. An example of assessment 
schedule that will be carried out during the in-house visits is presented in Section 1.3.2. 
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Figure ITSU.2. 
Assessment schedule for in-house study periods (Visits 3 to 6). 
Upon arrival at the site, participants will be placed on a standardized insulin pump 
 
 with a new infusion set 
 and a CGM 
system 
 on the evening before the exercise session (approximately 
 PM).  
After disconnecting the participant’s own insulin pump, the study pump reservoir will be filled 
with either Lyumjev or Humalog by a qualified CRU staff, and a standard infusion set and 
catheter will be inserted into the abdominal area, as per the manufacturer’s instructions, after the 
region is inspected for lipodystrophy (Section 6.1.2). The catheter should stay at the same 
catheter insertion site location for the duration of each period. However, a catheter can be 
changed to a new location on the abdomen if an occlusion is suspected up to the breakfast meal 
on Day 1 (Section 6.1.3). The participant’s usual basal rate settings will be programmed in the 
pump and the basal rate infusion will be started.  
The participants will wear the CRU-provided pump and CGM device during all in-house days. 
The study CGM device will be calibrated on the morning of the exercise day in fasted state, if 
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needed, using the plasma glucose values obtained with a glucose analyzer by CRU staff (Section 
8.5.2).  
A standardized dinner will be provided at approximately 
. On Day 1, a standardized 
breakfast 
) and lunch 
) will be provided prior to the 
scheduled exercise assessment (
 (Figure ITSU.3). Details of standardized 
meals are provided in Section 5.3.1.3. A cannula will be inserted for venous access for insulin 
lispro, glucose, FFA, and ketones sampling prior to lunch. The insulin dose for these 
standardized meals (dinner, breakfast, and lunch) before exercise will be individualized per 
participant to cover the carbohydrate content (including any correction bolus) and will be 
administered immediately prior (0 to 2 minutes) to the meal using a 
 
 No additional bolus insulin injection should be administered 
post-meal after lunch prior to the exercise period. The basal rate will be set to a single hourly rate 
at lunch 
 based on the participant’s usual basal rate for this time of day; 
this will be maintained until the basal reduction for the exercise period. A pre-exercise glucose 
target level of 
 mg/dL will need to be achieved
 minutes prior to exercise. If glucose 
level is below 90 mg/dL, ~16 g of oral carbohydrates will be administered. 
 
 
 
prior to exercise, the 
period will be rescheduled as mentioned in Section 5.2.1. 
Based on the randomization, the pump basal rate will be reduced either 60 minutes or 15 minutes 
prior to the start of exercise period, scheduled for approximately 
 in the following manner: 
 50% basal insulin reduction 60 minutes prior to exercise until end of exercise 
 
 100% basal insulin reduction 15 minutes prior to exercise until end of 
exercise 
 
Participants will begin the exercise assessment at approximately 4 hours after lunch 
They will be instructed to walk or light jog on the treadmill at 
approximately 45% to 55% of their predetermined peak VO2 using three 17-minute intervals 
with two 4-minute and 30-second rest periods in between the intervals for 1 hour. During this 
period, samples will be collected for glucose, insulin lispro, ketones and FFAs per the SoA 
(Section 1.3). Heart rate will be monitored, and participants will be asked to rate their perceived 
exertion using 6-20 Borg RPE scale (Section 8.2.8) during the last 2 minutes of each 17-minute 
interval, as per the assessment day visit. If hypoglycemia ensues (plasma or whole blood glucose 
level 
 the exercise will be terminated, and the participant will be 
treated with ~
 of oral carbohydrates. If the glucose level continues to be below 
 
 after approximately 
 minutes, up to an additional 
 of oral carbohydrates can 
be provided. Repeat as necessary if glucose value remains below 
/dL. 
Upon completion of the exercise period (or once the participant recovers from hypoglycemia 
[blood glucose reaches 
 the pump basal rate will be returned to the 
participant’s usual rate for this time of the day 
 and this basal rate will be maintained 
until the end of MMTT. Participants will be instructed to rest for approximately 30 minutes. 
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A standardized liquid dinner MMTT containing approximately 
 of carbohydrate with a fixed 
nutrient composition 
 
 will be administered approximately 1 
hour after the exercise assessment (Section 5.3.1.1). The same individualized insulin bolus dose 
determined from the dose assessment will be used for both arms (Lyumjev or Humalog) for all 4 
in-house visits, unless it is required to be changed to protect participant safety (see Section 
4.1.2). The insulin bolus dose will be administered immediately prior (0 to 2 minutes) to the 
meal using a 
 The meal is to be 
consumed within 15 minutes.  
Participants will be without further oral food intake from the start of each test meal to completion 
of blood collection 4 hours after the start of the meal (approximately 240 minutes) unless 
required to treat Level 1 hypoglycemia with symptoms or Level 2 hypoglycemia. Refer to 
Section 8.2.7.1 and 8.2.7.2 for details. If a participant’s plasma glucose concentration rises above 
 for more than  hour, 
 will be administered. 
In both situations, blood samples for plasma glucose (for safety and PD) will be taken, and PK 
samples will be collected as planned during this period per the SoA (Section 1.3). Following 
completion of study procedures, the study pump will be disconnected and the study CGM system 
will be removed. The participant’s own insulin pump will be re-introduced using a new infusion 
set, if necessary, for pump compatibility. Participants may leave the CRU at the discretion of the 
investigator. 
Appropriately trained staff must be available until the participants complete the study 
procedures. The pump can be reused after disinfection, according to the local procedure. 
Figure ITSU.3. 
Study activities during In-house Periods (Visits 3, 4, 5, and 6). 
4.1.4. 
Between In-house Visits 
During the time between visits, participants will continue their CSII therapy with their own 
pre-study insulin, pump, and CGM or FGM. Participants will be instructed 
 to perform regular blood glucose monitoring consisting of a minimum of daily 4-point 
SMBG (pre-prandial for 3 meals [that is, breakfast, lunch, and dinner] and at bedtime) 
using their own CGM and 
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 to use a diary to document any AEs, hypoglycemic events, meals (time, units of 
carbohydrate equivalent), insulin bolus doses, and basal rates, and the SMBG values.  
Upon return to the CRU, the diary will be reviewed and checked for hypoglycemic events and 
AEs. Only data related to AEs, will be entered into the eCRF. Additionally, as determined by the 
investigator, interim telephone visits may occur at any time during the outpatient periods to 
review the safety and well-being of the participant. 
4.1.5. 
Follow-Up Visit 
Participants will be required to visit CRU 3 to 7 days after Visit 6 and will undergo assessments 
as mentioned in Section 1.3.1. The diary will be reviewed and checked for hypoglycemic events 
and AEs.  
4.2. 
Scientific Rationale for Study Design 
The study has a 4-period crossover Williams design to reduce the variability of insulin PK and 
GD as each participant serves as his or her own control. The total number of participants needed 
with a crossover design is less than the number needed with a parallel group design. Williams 
design will achieve the balance and maximize the comparisons with the smaller number of 
participants and will require fewer sequences and periods. A maximum duration of 
 weeks is allowed for participants to complete all 4 assigned periods to minimize 
the risk of insulin resistance/changes in mean glycemic control during the study, provided no 
rescheduling is required.  
Randomization and blinding are used to avoid bias introduced through an association between 
allocation order of investigational medicinal product and patient characteristics. The Lilly 
clinical pharmacologist/Lilly study team will be unblinded. 
Prior to the study periods, participants will undergo an assessment day to determine an 
appropriate, individualized insulin lispro dose of Lyumjev or Humalog to be administered with 
the MMTT.  
A minimum of approximately 
 of washout between the in-house periods allows for a 
complete washout of study interventions administered with the MMTT and glucose response and 
prevents carryover effects. 
4.3. 
Justification for Dose 
The bolus dose of insulin lispro (Lyumjev or Humalog) will be individualized per participant to 
cover the carbohydrate content of both the standardized meals while in-house at the CRU and 
will be based on the participant’s individually calculated dose and/or insulin: carbohydrate ratio. 
For each participant, the individualized prandial insulin lispro dose for the dinner liquid MMTT 
and basal rates must be kept identical throughout the in-house periods.  
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA (Section 1.3) for the last participant in the trial. 
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5. 
Study Population 
Eligibility of participants for enrollment in the study will be based on the results of screening 
medical history, physical examination, vital signs, clinical laboratory tests, diabetes device 
downloads, and ECG. The nature of any conditions present at the time of the physical 
examination and any preexisting conditions will be documented.  
The inclusion and exclusion criteria used to determine eligibility should be applied at screening 
only unless otherwise specified, and not continuously throughout the trial.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be aged 18 to 55 years, inclusive, at the time of signing the informed 
consent and of an acceptable age to provide informed consent according to local law. 
Type of participant and disease characteristics 
2. Participants with a diagnosis of T1D based on medical history with a fasting C-peptide 
≤0.30 nmol/L (≤300 pmol/L) and the following: 
a. HbA1c ≤8.5% 
b. diabetes duration of at least 1 year 
c. using CSII and stable insulin regimen with a rapid-acting insulin analog for at 
least 6 months prior to inclusion into the trial 
d. currently on CSII therapy, with a total insulin dose >0.25 U/kg/day and ≤1.2 
U/kg/day 
e. have had no episodes of severe hypoglycemia in the past 6 months (severe 
hypoglycemia is defined as having neurological symptoms consistent with 
neuroglycopenia and required assistance in treatment by a second party) 
f. have clinical laboratory test results within normal reference range with acceptable 
deviations that are judged to be not clinically significant by the investigator. 
g. a peak VO2 of ≥35 for males and ≥32 for females  
h. able to undergo at least 1 hour of moderate-intensity treadmill exercise (walking 
or jogging depending on baseline fitness) 
i. exercise regularly (≥3 times per week of moderate or vigorous exercise) 
j. are using a personal CGM or FGM to self-monitor glucose 
i. are capable of, and willing, to do the following: Perform 4-point 
SMBG, prior to designated visits (participants using a personal 
CGM or FGM 
ii. keep records in participant study diaries required by this protocol  
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Weight 
3. Participants with a body mass index within the range 18.5 to 29.0 kg/m2 (inclusive). 
Sex and contraceptive/barrier requirements 
4.  Male and female 
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
a. Male participants: 
Males may participate in this trial.  
No male contraception is required except in compliance with specific local government 
study requirements. 
b. Female participants:  
1. 
Women of childbearing potential may participate in this trial as long as they 
follow the contraception guidance outlined in Section 10.4.  
2. 
Women not of childbearing potential may participate in this trial.  
Please refer to Appendix 4 (Section 10.4) for definitions and additional guidance related 
to contraception 
Informed consent 
5. Participants whom are capable of giving signed informed consent as described in 
Appendix 1 (Section 10.1), which includes compliance with the requirements and 
restrictions listed in the ICF and in this protocol. 
Other inclusions 
6. Participants who have venous access sufficient to allow for blood sampling as per 
protocol. 
7. Participants who are reliable and willing to make themselves available for the duration of 
the study and are willing to follow study procedures. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
8. Participants who are lactating.  
9. Women of childbearing potential who are not following contraception guidance as 
mentioned in Section 10.4. 
10. Participants who have known allergies to study intervention, related compounds, or any 
components of the formulation 
11. Participants who have an abnormal blood pressure and/or pulse rate as determined by the 
investigator.  
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12. Participants who have significant previous or current history of comorbidities capable of 
significantly altering the absorption, metabolism, or elimination of drugs; of constituting a 
risk when taking the investigational product; or of interfering with the interpretation of 
data  
13. Participants who have a current psychiatric disorder that may prevent them from being 
compliant with study procedures 
14. Participants who regularly use known drugs of abuse or show positive findings on drug 
screening.  
15. Participants who show evidence of human immunodeficiency virus infection and/or 
positive human immunodeficiency virus antibodies.  
16. Participants who have spontaneously cleared hepatitis C virus infection, defined as  
a. a positive hepatitis C virus antibody test and  
b. a negative hepatitis C virus RNA test. 
17. Participants who show evidence of possible chronic or active hepatitis B, including 
hepatitis B core antibody and hepatitis B surface antigen positivity or both.  
18.  Participants who have donated blood of more than 500 mL within the previous 4 weeks of 
study screening.  
19. Participants with clinically significant cardiac or pulmonary disease (e.g., angina, 
clinically significant cardiac arrhythmias, exercise-induced bronchospasm that requires 
bronchodilators or would preclude completing exercise). 
20. Participants with severe neuropathy, in particular autonomic neuropathy, as judged by the 
investigator. 
21. Participants who have had lymphoma, leukemia, or any malignancy within the past 5 
years except for basal cell or squamous epithelial carcinomas of the skin that have been 
resected with no evidence of metastatic disease for 3 years. 
Prior/concomitant therapy 
22. Participants with current use of any glucose-lowering agents other than insulin that might 
impact outcome measures: 
a. any agents that affect hepatic glucose production, including all beta-adrenergic 
agonists or antagonists, all xanthine derivatives 
b. beta blockers 
c. any noninsulin diabetes therapy, (i.e., pramlintide. etc.). 
23. Participants who intend to use over-the-counter or prescription medication including 
herbal medications and traditional medications that affect blood glucose level or the 
body’s sensitivity to insulin, or that promote weight loss within 14 days prior to dosing. 
Specific medications listed in Section 6.8, Concomitant Medications, may be allowed.  
24. Participants who intend to use acetaminophen 
 during the basal rate 
optimization, assessment day, or study periods. 
Prior/concurrent clinical study experience 
25. Participants who have previously completed or withdrawn from this study. 
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26. Participants who have participated, within the past 30 days, in a clinical study involving 
an investigational product. If the previous investigational product has a long half-life, 5 
half-lives or 30 days (whichever is longer) should have passed.  
Other exclusions 
27. Participants who have an average weekly alcohol intake that exceeds 21 units per week 
(males aged ≤55 years) and 14 units per week (females).  
28. Participants who are unwilling to stop alcohol consumption for 24 hours prior to each 
study treatment and during the study treatment periods.  
29. Participants who smoke more than 10 cigarettes per day or the equivalent including 
electronic cigarettes or are unable to abide by CRU smoking restrictions. 
30. Participants who are unwilling to comply with the dietary restrictions required for this 
study. 
31. Participants who in the opinion of the investigator or sponsor, are unsuitable for inclusion 
in the study. 
32. Participants who do not achieve the optimal basal rates, at the discretion of the 
investigator, at second evaluation of basal rate optimization visits. 
33. Individuals following a very low-carbohydrate diet, defined as ≤50 g per day of 
carbohydrates or ≤10% carbohydrates as a proportion of calories 
5.2.1. 
Additional criteria for study treatment periods 
For participants who fulfill 1 or more of the following criteria prior to the in-house periods, 
the in-house period can be rescheduled 1 to 14 days later. For the assessment day, 
rescheduling will be within the allowable time window mentioned in the SoA. Each of the 
study treatment periods can only be rescheduled once. 
a. consumption of alcohol within 24 hours prior to each in-house period, or a 
positive result for the alcohol or drug test 
b. consumption of coffee, tea, chocolate, cola, energy drinks and/or energy drinks 
containing methylxanthine within 8 hours prior to start of dosing with study 
intervention during each in-house period 
c. strenuous exercise within the past 24 hours prior to each in-house period.  
d. any medical condition or AE that could interfere with glucose metabolism, as 
judged by the investigator 
e. any use of prescription or nonprescription medication as per exclusion criteria 23 
and 24 
f. hypoglycemia 
 posing a safety problem as judged by 
the investigator, or 
g. participant is unable to obtain glucose range (
 prior to initiation 
of exercise assessment. 
 
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5.3. 
Lifestyle Considerations 
Throughout the study, participants must adhere to lifestyle restrictions as outlined by the CRU 
and in the study procedures. Participants will be assessed for compliance with requirements 
before continuing in the study. When not resident in the CRU, participants may resume their 
regular diet. 
5.3.1. 
Meals and Dietary Restrictions 
 While resident at the CRU, participants may not consume any food or caloric drinks 
other than that provided by the CRU. While not resident at the CRU, participants may 
resume their regular diet. 
 The time of meal start and completion, the total calories, and grams of carbohydrates 
consumed in the MMTT (Section 5.3.1.1), and the standardized meals (Section 5.3.1.3) 
during the assessment day and Day 1 of in-house period will be captured in the study 
eCRF. 
5.3.1.1. 
Mixed Meal Tolerance Test 
On assessment day and on Day 1 of in-house periods, a dinner liquid MMTT will be 
administered 1 hour after the exercise assessment as mentioned in Sections 4.1.2 and 4.1.3 and as 
outlined in Section 1.3. The standardized liquid test meal will use 
 
 The macronutrient composition of the meal will contain approximately 50 g of 
carbohydrates, approximately 
 of protein, and approximately 
 of fat. Participants will be 
fasted, except for water, for 4 hours before each test meal and are required to consume the 
MMTT within approximately 
. The MMTT meals will be kept consistent across the 
assessments in the study. Participants will not be allowed to consume water for
 after 
dosing apart from fluid provided with the meal. However, water may be consumed freely after  
 post-dose. 
5.3.1.2. 
Standardized Lunch Meal 
On assessment day and on Day 1 of in-house periods, a standardized lunch will be administered 
prior to the exercise assessment as mentioned in Sections 4.1.2 and 4.1.3 and as outlined in 
Section 1.3. The macronutrient composition of the lunch should be targeted to provide 
approximately
 of the calories from carbohydrate 
, 
 of the calories from fat, 
and
 the calories from protein. The standardized lunch for each participant will be kept 
consistent for all assessment periods. Participants will consume the meal within approximately 
. 
5.3.1.3. 
Standardized Breakfast and Dinner Meals 
Participants will be provided individualized standardized meals during the in-house periods and 
assessment day, as outlined in Section 1.3. The macronutrient composition of the meals should 
be targeted to provide approximately 
 of the calories from carbohydrate, 
 of the calories 
from fat, and 
 of the calories from protein. Participants will consume each meal within 
approximately 
 minutes. Breakfast and dinner meals for each participant during the in-house 
periods will be kept consistent with regard to calories and nutrient content. 
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5.3.1.4. 
Snacks 
Snacks with 
 of carbohydrates are allowed at bedtime during in-house periods unless 
otherwise specified in the protocol. 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco 
 During the in-house period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 8 hours 
before the start of dosing with study intervention until after collection of the final PK 
sample, excluding the MMTT when 
 Plus may be given. 
 During each dosing session, participants will abstain from alcohol for 24 hours before 
the start of dosing until after collection of the final PK sample. 
 Participants who use tobacco products will be instructed to abide by the smoking 
restrictions while they are in the CRU. 
5.3.3. 
Activity 
Participants will be encouraged to maintain their regular exercise and insulin regimen adaptation 
related to exercise during the outpatient period; however, they should not undertake vigorous or 
prolonged exercise at least 24 hours before each dosing day at the CRU.  
Participants will be instructed to perform exercise on assessment day and on Day 1 of in-house 
periods as mentioned in Sections 4.1.2 and 4.1.3. On Day 1, a pre-exercise glucose target of 
 
 will need to be achieved
 prior to exercise as mentioned in Section 
4.1.3. 
5.4. 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomly assigned to study intervention.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened only once. Rescreened participants will be required to undergo all screening 
assessments and procedures. The interval between rescreening should be at least 28 days. Each 
time rescreening is performed, a new informed consent form (see Section 10.1.2 for details) must 
be signed and participants will be assigned a new identification number. 
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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.  
6.1. 
Study Intervention(s) Administered 
 
Intervention Name 
LyumjevTM 
Humalog® 
Type  
Drug 
Drug 
Dose Formulation 
10-mL vial  
10-mL vial  
Unit Dose Strength(s) 
100 U/mL 
100 U/mL 
Dosage Level(s) 
Basal and bolus infusion based 
on individual needs 
Basal and bolus infusion based 
on individual needs 
Route of 
Administration 
Subcutaneous infusion via CSII  
Subcutaneous infusion via CSII  
Use 
Experimental 
Active comparator 
IMP and NIMP 
IMP  
IMP 
Sourcing 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Packaging and 
Labeling 
The study intervention will be 
provided to the CRU in 
unblinded vials. All clinical 
study materials provided to the 
investigator will be stored in a 
secure place and allocated and 
dispensed by appropriately 
trained staff. Detailed records of 
the amounts of the study 
intervention received, dispensed, 
and remaining at the end of the 
study will be maintained. The 
study intervention will be 
The study intervention will be 
provided to the CRU in 
unblinded vials. All clinical 
study materials provided to the 
investigator will be stored in a 
secure place and allocated and 
dispensed by appropriately 
trained staff. Detailed records of 
the amounts of the study 
intervention received, dispensed, 
and remaining at the end of the 
study will be maintained. The 
study intervention will be 
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labeled according to the 
country’s regulatory requirement  
labeled according to the 
country’s regulatory requirement 
Abbreviations: CRU = clinical research unit; IMP = investigational medicinal product; NIMP = noninvestigational 
medicinal product. 
6.1.1. 
Noninvestigational Medicinal Products 
During the in-house periods, if a participant’s plasma glucose concentration rises above 
 for more than  hour during the liquid MMTT dinner, commercially 
available 
 will be administered. 
 or intravenous glucose/oral dextrose can also be 
administered during the complete in-house period outside of the MMTT procedures if required to 
treat hyperglycemia or hypoglycemia, respectively, at the discretion of the investigator. 
The doses of 
 and glucose administered during the in-house periods of the study must be 
recorded in the eCRF. 
All NIMPs will be sourced locally by the site and will be used from their original packaging. 
6.1.2. 
Administration Details 
During in-house periods (Day –1, starting prior to the administration of the standardized dinner, 
to Day 1), all study interventions will be administered using a 
 
A standardized catheter with a 
 needle length will be inserted on the day before the dinner 
meal is administered (Day –1) during each period, and the catheter site must remain the same 
until completion of study procedures on Day 1.  
For each pump, a 3-mL reservoir will be filled with 3 mL of study treatment by a qualified CRU 
staff; a 
 will be attached to the filled reservoir and the 
reservoir will be loaded into the pump. The infusion set tubing 
) will be 
primed, and a cannula fill with
 unit will be completed. 
 cannula will be 
inserted into the central abdominal area (at least 5 cm away from the umbilicus) avoiding areas 
of lipohypertrophy and surgical scars. Infusion sites will be alternated among 4 sites (that 
is, right and left upper quadrants and right and left lower quadrants) on the abdominal wall. 
Catheter insertions should be performed by a limited number of qualified and appropriately 
trained CRU staff as designated by the investigator for consistency. Whenever possible, study 
intervention administration should be carried out by the same staff. 
The insulin pump reservoir will be filled with either Lyumjev or Humalog by qualified CRU 
staff while maintaining the blinding for the investigator and participant. For each standardized 
meal and the MMTT, the doses will be administered immediately before the start of a test meal. 
The meals will be given at approximately the same time for each in-house study period. The 
actual time and dose level of all doses during the assessment day and in-house periods will be 
recorded in the participant’s eCRF. 
6.1.3. 
Pump Occlusion Alarms and Accidental Infusion Set Discontinuations 
If a pump occlusion alarm occurs during basal infusion, the infusion set tubing should be 
inspected for kinks or crimps and the basal infusion rate restarted. If the occlusion alarm persists, 
the infusion site will be discontinued, a catheter can be changed to a new location on the 
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abdomen if an occlusion is suspected up to the breakfast meal on Day 1. If a suspected occlusion 
occurs during the breakfast meal or afterwards, the period will be terminated for the participant 
and that study period will be repeated at another time. 
If a catheter occlusion alarm occurs during a bolus infusion or <5 hours after the start of the 
MMTT, the data will not be used for analysis. Data related to these events will be recorded in the 
eCRF. 
6.2. 
Preparation, Handling, Storage, and Accountability 
 
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study interventions received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention. Only authorized 
study staff may supply, prepare, or administer study intervention. All study interventions 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized study staff. 
3. The investigator or authorized study staff are responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and 
final disposition records).  
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual. 
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a participant- and investigator-blind study. Blinding will be maintained throughout the 
conduct of the study until all data are cleaned to an acceptable level of quality and locked. The 
details are included in the blinding/unblinding plan. 
To preserve the blinding of the study, only a minimum number of staff at the CRU will see the 
randomization table and codes before the study is complete. Those individuals with access to the 
randomization table and codes will not be involved in the conduct of the study or subject care. 
On Day -1 of in-house period (Visit 3), participants will be assigned a unique number 
(randomization number) in ascending numerical order. The randomization number encodes the 
participant’s assignment to 1 of the 4 sequences for the in-house study periods, according to the 
randomization schedule generated prior to the study by the statistics department at the 
sponsor/designee. Each participant will be dispensed blinded study intervention, labeled with the 
participant’s unique randomization number, throughout the study. 
Participants will be randomly assigned in a 1:1 ratio to receive study intervention. Investigators 
will remain blinded to each participant’s assigned study intervention throughout the course of the 
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study. To maintain this blind, an otherwise uninvolved third party, such as a pharmacist, will be 
responsible for the dispensation of all study interventions and will endeavor to ensure that there 
are no differences in time taken to dispense following randomization. 
This third party will instruct the participant to avoid discussing dosing frequency, or packaging 
of the study intervention with the investigator. 
In the event of a quality assurance audit, the auditor(s) will be allowed access to unblinded study 
intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately. 
Emergency codes will be available to the pharmacy. A code, which reveals the study intervention 
for a specific study participant, may be opened during the study only if the participant’s well-
being requires knowledge of the participant’s treatment assignment. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event. The 
participant’s safety must always be the first consideration in making such a determination. 
Where feasible and when timing of the emergent situation permits, the investigator should 
attempt to contact the Lilly medical monitor before unblinding a participant’s treatment 
assignment. If the investigator decides that unblinding is warranted, it is the responsibility of the 
investigator to promptly document the decision and rationale and notify Lilly as soon as possible. 
If an investigator, site staff performing assessments, or participant is unblinded, the participant 
must be discontinued from the study. In cases where there are ethical reasons to have the 
participant remain in the study, the investigator must obtain specific approval from Lilly clinical 
pharmacologist or CRP for the participant to continue in the study. During the study, emergency 
unblinding should occur only by accessing the study participant’s emergency code.  
Upon completion of the study, all codes must be returned to Lilly or its designee. 
6.4. 
Study Intervention Compliance 
When the individual dose for a participant is prepared from a bulk supply, the preparation of the 
dose will be confirmed by a second member of the CRU staff.  
Study intervention will be administered under medical supervision by the investigator or 
designee. The dose of study intervention and study participant identification will be confirmed 
prior to the time of dosing. The date and time of each dose administered will be recorded in the 
source documents and in the eCRF.  
6.5. 
Dose Modification 
For the in-house period, there will be no dose modifications of insulin lispro for the MMTT and 
basal rates unless medically indicated and confirmed between the sponsor clinical 
pharmacologist/CRP/CRS and the investigator. 
 
6.6. 
Continued Access to Study Intervention after the End of the Study 
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Study completion will occur following the final analysis of primary and secondary objectives, as 
determined by Lilly. Investigators will continue to follow SoA (Section 1.3) for all participants 
until notified by Lilly that study completion has occurred.   
No intervention is allowed following the end of the trial. Participants will return to their 
pre-study interventions and devices. 
6.7. 
Treatment of Overdose 
In the event of an overdose, refer to the Humalog or Lyumjev package insert. 
Excess insulin administration may cause hypoglycemia and hypokalemia.  
Mild episodes of hypoglycemia can usually be treated with oral glucose. Adjustments in drug 
dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or 
neurologic impairment may be treated with intramuscular or subcutaneous glucagon or 
concentrated intravenous glucose. Sustained carbohydrate intake and observation may be 
necessary because hypoglycemia may recur after apparent clinical recovery.  
Hypokalemia must be corrected appropriately. 
6.8. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) other than study intervention that the participant is receiving at the 
time of enrollment or receives during the study must be recorded along with 
● reason for use 
● dates of administration including start and end dates 
● dosage information including dose and frequency for concomitant therapy of 
special interest 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study. Participants will continue their basal insulin 
infusion rate during the entire study except when presenting safety issues and prior to and during 
the exercise assessment period when the basal insulin rate is reduced as defined in Section 4.1.3. 
In case of safety-driven indications for a basal rate adaptation, the investigator will discuss a 
change of the regimen of insulin basal rate to prevent any medical problems. Any change in the 
basal rate will be captured in the participant diary and eCRF. 
Participants should not use over-the-counter or prescription medication (other than their current 
regimen of insulin therapy and concomitant medication [e.g., antihypertensives, lipid-lowering 
agents] at enrollment) or nutritional supplements that affect blood glucose level or the body’s 
sensitivity to insulin or that promote weight loss within 14 days before dosing (apart from 
vitamin/mineral supplements, ibuprofen, hormone/thyroid-replacement therapy, or hormonal 
contraceptives) or throughout the study.  
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Participants should not use over-the-counter or prescription medications containing 
acetaminophen (paracetamol) during the basal rate optimization, assessment day, or study 
periods because it is known to interfere with CGM sensing, impacting the accuracy of the 
 
Participants should not apply any creams or lotions to the abdominal skin on the morning of the 
catheter insertion or during the in-house study procedure. 
If the need for concomitant medication arises (e.g., to treat an AE or infusion-site pain), 
inclusion or continuation of the patient may be at the discretion of the investigator, preferably 
after consultation with a Lilly clinical pharmacologist or CRS/CRP. Any additional medication 
used during the course of the study must be documented. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, for any 
reason, participants should report AEs and product complaints and complete other safety follow-
up at exit visit, in accordance with this protocol. Safety follow-up should be performed as 
outlined in Sections 1.3 and 8.3.  
The sponsor shall be notified of any instance of participant withdrawal or discontinuation. Any 
data collected up to the point of withdrawal or discontinuation may be used in the study. 
See the SoA (Section 1.3) for data to be collected at the time of discontinuation of study 
intervention and for any further evaluations that need to be completed. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Not applicable. 
7.1.2. 
QTc Stopping Criteria 
Not applicable. 
7.1.3. 
Hypoglycemia  
Discontinuation of the study intervention should be considered by the investigator for 
participants with severe hypoglycemia (Level 3 according to Section 8.2.7.1) or persistent 
hypoglycemic events (Level 2). 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study 
● at any time at the participant’s own request 
● at the request of the participant’s designee (e.g., parents or legal guardian) 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
● if enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
● if the participant, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent. 
Discontinuation is expected to be uncommon. 
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At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. The 
participant will be permanently discontinued from both the study intervention and the study at 
that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, he/she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records. 
Participants will be discontinued under the following circumstances: 
 enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study 
 participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws and regulations 
 the investigator decides that the participants should be discontinued from the study  
 participant becomes pregnant during the course of the study 
 participant did not meet the enrollment criteria and was inadvertently enrolled 
 any episode of diabetic ketoacidosis occurring in the past 6 months 
 any episode of severe hypoglycemia occurring in the past 6 months, and 
 the study is discontinued. 
Participants discontinuing from the study prematurely for any reason should return to the CRU. 
Concomitant medications, AEs, and product complaints will be reviewed. CRU staff should 
document details regarding the reason for discontinuation when available. Participants will return 
all appropriate sponsor-provided study materials per sponsor instructions. A point-of-care 
HbA1c measurement will be taken that may be used to inform decision making for end-of-study 
insulin regimen. Participants will begin non-study insulin. 
Lilly shall be notified of any instance of participant withdrawal or discontinuation. Any data 
collected up to the point of withdrawal or discontinuation may be used in the study. 
 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the CRU. CRU staff or designee are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.  
 
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8. 
Study Assessments and Procedures 
 
● Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
● Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
● All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
Section 1.3 lists the SoA, detailing the study procedures and their timing (including tolerance 
limits for timing). The specifications in this protocol for the timings of safety and sample 
collection are given as targets to be achieved within reasonable limits. Modifications may be 
made to the time points based upon emerging clinical information. The scheduled time points 
may be subject to minor alterations; however, the actual time must be correctly recorded in the 
eCRF.  
Section 10.2 (Appendix 2) lists the laboratory tests that will be performed for this study. 
Section 10.2.1 provides a summary of the maximum number and volume of invasive samples, 
for all sampling, during the study. 
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test results. Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards. 
8.1. 
Efficacy Assessments 
There are no efficacy assessments within this study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
● A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and peripheral neurological systems. 
Height and weight will also be measured and recorded. 
● Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
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8.2.2. 
Vital Signs 
● For each participant, vital sign measurements (blood pressure, pulse rate, heart 
rate, and body temperature) should be conducted according to the SoA (Section 
1.3) and following the study-specific recommendations included in Manual of 
Operations for the study.   
 Blood pressure and pulse rate should be measured after at least 5 minutes in supine 
position.  
 If orthostatic measurements are required, participants should be supine for at least 
5 minutes and stand for at least 3 minutes.  
 If the participant feels unable to stand, supine vital signs only will be recorded.  
 Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of 
dizziness or posture-induced symptoms. Additional vital signs may be measured during 
each study period if warranted. 
 
8.2.3. 
Electrocardiograms 
● Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) 
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and corrected QT intervals.  
 ECGs must be recorded before collecting any blood samples. Participants must be supine 
for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection. ECGs may be obtained at additional times, when deemed 
clinically necessary. All ECGs recorded should be stored at the CRU. 
 ECGs will be interpreted by a qualified physician (the investigator or qualified designee) 
as soon after the time of ECG collection as possible, and ideally while the participant is 
still present, to determine whether the participant meets entry criteria at screening visit 
and for immediate participant management, should any clinically relevant findings be 
identified.   
 If a clinically significant finding is identified the investigator will determine if the 
participant can be enrolled in the study.  
8.2.4. 
Clinical Safety Laboratory Tests 
● See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be 
performed and the SoA for the timing and frequency. 
● The investigator must review the laboratory results, document this review, and 
report any clinically relevant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
participant's condition. 
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 All protocol-required laboratory assessments, as defined in Appendix 2 (Section 
10.2), must be conducted in accordance with the SoA, standard collection 
requirements, and laboratory manual. 
● If laboratory values from non-protocol specified laboratory assessments 
performed at an investigator-designated local laboratory require a change in 
participant management or are considered clinically significant by the investigator 
(e.g., SAE or AE or dose modification), then report the information as an AE.  
If a central vendor is used for the study, Lilly or its designee will provide the investigator with 
the results of laboratory tests analyzed by a central vendor, unless the safety laboratory test 
results may unblind the study. 
8.2.5. 
Pregnancy Testing  
Pregnancy test will be carried out as outlined in SoA (Section 1.3). 
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring 
Not applicable. 
8.2.7. 
Safety Monitoring 
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study. 
8.2.7.1. 
Hypoglycemia 
Glucose level will be monitored for safety throughout the study according to the SoA using YSI 
and using CGM. Participants will be trained by CRU staff about signs and symptoms of 
hypoglycemia and the manner of treating hypoglycemia. Investigators should use the following 
classification of hypoglycemia: 
 Level 1 hypoglycemia (glucose 
 - 
It can alert a person to take action, such as treatment with fast-acting carbohydrates. 
Providers should continue to counsel participants to treat hypoglycemia at this glucose 
alert value. 
 Level 2 hypoglycemia (glucose 
 - This is also referred to as 
documented or blood glucose confirmed hypoglycemia with glucose 
 
. This glucose threshold is clinically relevant regardless of the presence of 
absence of symptoms of hypoglycemia. 
 Level 3 hypoglycemia (severe hypoglycemia [in adults]) - A severe event characterized 
by altered mental and/or physical status requiring assistance for treatment of 
hypoglycemia. For example, participants had altered mental status, and could not assist in 
their own care, or were semiconscious or unconscious, or experienced coma with or 
without seizures, and the assistance of another person was needed to actively administer 
carbohydrate, glucagon, or other resuscitative actions. Glucose measurements may not be 
available during such an event, but neurological recovery attributable to the restoration of 
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glucose concentration to normal is considered sufficient evidence that the event was 
induced by a low glucose concentration. 
The determination of a hypoglycemic event as an episode of severe hypoglycemia, as defined 
above, is made by the investigator based on the medical need of the participant to have required 
assistance and is not predicated on the report of a participant simply having received assistance. 
If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator must record 
the event as serious on the AE eCRF and report it to Lilly as an SAE. 
Nocturnal hypoglycemia is a hypoglycemic event (including severe hypoglycemia) that occurs at 
night and presumably during sleep. 
8.2.7.2. 
Treatment of Hyperglycemia and Hypoglycemia during In-house Periods 
Hypoglycemia during MMTT: 
Participants will be without food intake from the start of the MMTT to completion of blood 
collection (approximately 240 minutes) unless required to treat Level 1 hypoglycemia with 
symptoms or Level 2 hypoglycemia. If it occurs, treatment is to be done with either rapidly 
absorbable oral carbohydrates or intravenous glucose. 
Hypoglycemia during Exercise: 
If hypoglycemia ensues 
, the exercise will be terminated, and 
the participant will be treated initially with ~
 of oral carbohydrates. If the glucose level 
continues to be below 
 after approximately 
 minutes, up to an 
additional 
 of oral carbohydrates can be provided. Repeat as necessary if glucose value 
remains below 
mg/dL. The same approach should be used if hypoglycemia ensues after 
completion of the exercise prior to the MMTT. The administration of the MMTT could be given 
 minutes earlier to prevent hypoglycemia at the discretion of the investigator.  
If carbohydrates are administered and consumed during the in-house periods, it must be captured 
in the eCRF.  
If a patient is experiencing hyperglycemia (glucose level 
 for more 
than  hour, insulin glulisine will be administered intravenously. 
In cases where treatment of either hypo- or hyperglycemia require intervention, samples for 
glucose will be taken and PK samples will be collected as planned. 
8.2.8. 
Rating of Perceived Exertion 
The RPE scale will be used during each of the exercise periods as outlined in the SoA  
(Section 1.3). The
 is a well-validated tool 
 to 
assess perceived physical effort during exercise; it is presented as a scale 
 anchored by 
verbal descriptors. This scale describes different efforts: is no exertion at all and 
 the 
maximal exertion or hardest possible effort. Participants will be asked to point to a number that 
best describes their feelings of the exercise at that moment. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Appendix 3 (Section 10.3): 
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 AEs 
 SAEs, and 
 product complaints 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study (see Section 7). 
Care will be taken not to introduce bias while detecting events. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow up each participant at 
subsequent visits/contacts. All SAEs will be followed up until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). For 
product complaints, the investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality. Further 
information on follow-up procedures is provided in Appendix 3 (Section 10.3).  
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant.  
The investigator is responsible for the appropriate medical care of participants during the study. 
8.3.1. 
Timing and Mechanism for Collecting Events 
This table describes the timing, deadlines, and mechanism for collecting events.
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the ICF 
The follow-
up visit  
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
with study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE* – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
 
 
 
After the 
start of study 
intervention 
10 hours after 
the last dose 
Within 24 hours of 
learning of the 
pregnancy (see Section 
8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End-of-study 
intervention 
Within 24 hours of 
awareness 
Product Complaint 
form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End- of-study 
intervention 
Within 1 business day 
of awareness 
Product Complaint 
form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed Product 
Complaint form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
Product Complaint 
form 
 
Abbreviations: AE = adverse event; CRF = case report form; ICF = informed consent form; N/A = not applicable; 
PC = product complaint; SAE = serious adverse event. 
* SAEs should not be reported unless the investigator deems them to be possibly related to study treatment or study 
participation. 
8.3.2. 
Pregnancy 
Collection of pregnancy information 
Female participants who become pregnant 
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 24 
hours of learning of a participant’s pregnancy.  
● The participant will be followed up to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the sponsor. Generally, follow-
up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 
date. Any termination of pregnancy will be reported, regardless of gestational age, 
fetal status (presence or absence of anomalies) or indication for the procedure. 
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● While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
● Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.1. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
● Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention. If the participant is discontinued from the 
study, follow the standard discontinuation process and continue directly to the 
follow-up phase. The follow-up on the pregnancy outcome should continue 
independent of intervention or study discontinuation.  
8.3.3. 
Adverse Events of Special Interest  
Not applicable. 
 
8.4. 
Pharmacokinetics 
At the visits and times specified in the SoA (Section 1.3), venous samples will be 
collected to determine the serum concentrations of insulin lispro. Instructions for the 
collection and handling of blood samples will be provided by the sponsor. The actual date 
and time (24-hour clock time) of each sampling will be recorded. 
Samples collected for analyses of insulin lispro concentration may also be used to 
evaluate safety or pharmacology aspects related to concerns arising during the study. 
Drug concentration information that would unblind the study will not be reported to CRU or 
blinded staff until the study has been unblinded. 
8.4.1. 
Bioanalysis 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.  
Concentrations of insulin lispro will be assayed using a validated enzyme-linked immunosorbent 
assay method specific for insulin lispro at a laboratory approved by the sponsor. Serum 
remaining may be used for other analyses on insulin lispro 
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last participant visit for the study.  
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8.5. 
Pharmacodynamics 
8.5.1. 
Glucose Values 
Blood will be collected for glucose values via 
 at visits and times specified 
in the SoA (Section 1.3). These values will be used in statistical analyses, and the actual date and 
time (24-hour clock time) of each sampling will be recorded in the eCRF. 
8.5.2. 
Exploratory CGM Values 
For the CGM, a standard system (e.g., 
) will be used in this study. The study 
CGM sensor will be inserted by qualified CRU staff, and the participants will be instructed to 
always carry the receiver with them. The CGM device will be calibrated, if required, using the 
plasma glucose values obtained with the 
 by qualified CRU staff. 
Participants will not be allowed to view their glucose levels during the exercise or the liquid 
MMTT assessments. The participants will wear this device before the start of a standardized 
dinner (at 
 on Day -1 until completion of MMTT assessment on Day 1 for 
each in-house period. The monitor will record continuous glucose measurements. At the end of 
the recording, the study CGM sensor will be removed, and the receiver will be used to download 
the glucose data. 
8.5.3. 
Exploratory Blood Ketones and Free Fatty Acids 
Blood will be collected for ketones via
 at visits and times specified in the 
SoA (Section 1.3). The actual date and time (24-hour clock time) of each sampling will be 
recorded in the eCRF. 
Blood will be collected to determine concentration of free fatty acid levels at visits and times 
specified in the SoA (Section 1.3) using a validated method. The actual date and time (24-hour 
clock time) of each sampling will be recorded in the eCRF. Instructions for the collection and 
handling of these samples will be provided by the sponsor. 
8.6. 
Genetics 
Genetics are not evaluated in this study. 
8.7. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Not applicable. 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics 
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
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9. 
Statistical Considerations 
The SAP will be finalized prior to the first participant first visit, and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints, including 
primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses 
This study will evaluate if there is a significant difference in the change in plasma glucose level 
during exercise between Lyumjev and Humalog using either 50% or 100% reduction of basal 
infusion rates. 
9.1.1. 
Multiplicity Adjustment 
There is no multiplicity adjustment in this study.  
9.2. 
Analyses Sets 
Participant Analysis Set 
Description 
Full analysis set 
Participants who receive at least 1 dose of IP and have completed at 
least 1 MMTT procedure will be included in the analysis set for the 
PD analyses. Participants who receive at least 1 dose of insulin 
during the in-house period and have measurable insulin lispro 
concentrations will be included in the PK analysis dataset 
Modified full analysis set 
All participants who receive both treatments (Lyumjev and 
Humalog) for at least 1 basal rate reduction (either 50% or 100%) 
and receive the same dose and meal consumption. Participants who 
do not keep identical insulin lispro doses for Lyumjev and Humalog 
or have difference in the consumption of the meal for each 
visit/period will be excluded from the statistical analysis of the PK* 
and glucodynamic parameters 
Safety analysis set 
All participants who are exposed to at least 1 dose of IP. Participants 
will be analyzed according to the intervention they actually received 
Abbreviations: IP = investigational product; MMTT = mixed meal tolerance test; PD = 
pharmacodynamics; PK = pharmacokinetics.  
*For the MMTT PK parameters analysis, all participants who receive both treatments with an identical insulin lispro 
doses for Lyumjev and Humalog will be included. 
9.2.1. 
Study Participant Disposition 
A detailed description of the participant’s disposition will be provided.  
9.2.2. 
Study Participant Characteristics 
The participant’s age, sex, weight, body mass index, height, race/subrace, duration of diabetes, 
smoking habits, or other demographic characteristics will be recorded. 
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9.2.3. 
Treatment Compliance 
Every attempt will be made to select participants who have the ability to understand and comply 
with instructions. Noncompliant participants may be discontinued from the study. The time and 
day of drug administration will be recorded. Drug accountability records will be maintained by 
the CRU. 
The specifications in this protocol for the timings of safety, PK, and PD sampling are given as 
targets, to be achieved within the time windows described in the study specific CRF completion 
guidelines. Modifications may be made to the time points based upon the safety and PK 
information obtained. The scheduled time points may be subject to minor alterations; however, 
the actual time must be correctly recorded in the eCRF. Failure to obtain samples and perform 
protocol-specific procedures outside the allowable time window because of clinical issues, such 
as problems with venous access, technical problems with equipment, or problems with 
participant no-show for scheduled procedures, will not be considered a protocol deviation but the 
site will still be required to notify the sponsor in writing. Written documentation (e.g., a note-to-
file) will have to be provided to the sponsor for all missing or delayed samples and procedures 
(regardless of reasons) to facilitate data reconciliation before study completion. 
Any major modifications that might affect the conduct of the study, participant safety, and/or 
data integrity will be detailed in a protocol amendment. 
9.3. 
Statistical Analyses 
9.3.1. General Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designee. Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol. Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
SAP or the CSR. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. Analyses 
will be fully detailed in the SAP.  
Insulin lispro concentration will be used for population PK analysis. Additionally, the study 
results may be pooled with the results of other studies for population PK analysis. This analysis 
and output will not be captured in the final CSR.  
Insulin lispro concentration may be pooled with the results of other studies for population PK 
analysis purposes. This analysis and output will not be captured in the final CSR. 
9.3.2. 
Glucodynamic Analysis 
9.3.2.1. 
Glucodynamic Parameter Estimation 
Participants who receive at least 1 dose of study intervention and have completed at least 1 
MMTT procedure will be included in the analysis set for the PD analyses. 
Data will be analyzed for the participants during each exercise and MMTT assessment.  
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During the exercise period, the change from baseline values
 
for each participant will be 
calculated to derive the change in plasma glucose level from start to end of exercise. 
The rate of plasma glucose during the exercise, the nadir plasma glucose, decremental AUC, for 
each exercise assessments will be calculated. 
During the MMTT, the change from baseline values
 
for each participant will 
be calculated. The area under the baseline subtracted plasma glucose concentration versus time 
curve (incremental) (iAUC) will be calculated during the MMTT for each in-house period. 
 The AUC from time zero to 30 minutes postmeal (iAUC0-30min) 
 The AUC from time zero to 1-hour postmeal (iAUC0-1hour) 
 The AUC from time zero to 2 hours postmeal (iAUC0-2hours) 
 The AUC from time zero to 3 hours postmeal (iAUC0-3hours) 
 The AUC from time zero to 4 hours postmeal (iAUC0-4hours) 
In addition, the change from baseline maximum plasma glucose observed during the 4 hours 
postmeal (∆PGmax) and change from baseline 1-hour plasma glucose (∆PG1h and 2-hour 
plasma glucose after the start of the meal (∆PG2h) will be calculated. Other partial iAUCs may 
be calculated, as deemed appropriate. 
The mean data will be presented by summary statistics and presented by treatment for those 
participants who received both treatments (Lyumjev and Humalog) with the same insulin dose 
(bolus dose for the MMTT or basal reduction) and meal consumption. 
9.3.2.2. 
Glucodynamic Statistical Inference 
Statistical analyses comparing PD parameters (described in Section 9.3.2.1) of Lyumjev versus 
Humalog during exercise with a basal reduction of either 50% or 100% and after the MMTT will 
be conducted on the modified full analysis set. The exercise and MMTT will be analyzed 
separately.  
9.3.2.2.1. Statistical Analysis of the Primary Endpoint Change in Plasma Glucose during 
Exercise 
Changes in plasma glucose will be compared between Lyumjev versus Humalog from the start to 
the end of exercise during either 50% or 100% reduction of basal infusion rates. 
For the primary endpoint, the change in plasma glucose will be analyzed using a mixed-effect 
model that includes treatment (Lyumjev, Humalog), sequence, period, and treatment as fixed 
effects and participant within sequence as a random effect. LSmeans, treatment differences in 
LSmeans, and the corresponding 90% CIs for the treatment differences will be estimated from 
the model. The p-value on the difference between LSmeans will be used to determine statistical 
significance.  
9.3.2.2.2. Statistical Analysis of the Secondary GD Endpoints  
Changes in GD parameters during exercise and MMTT will be compared between Lyumjev 
versus Humalog during exercise with either 50% or 100% reduction of basal infusion rates.  
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Log-transformed iAUCs, ∆PGmax, ∆PG1h, and ∆PG2h will be evaluated to estimate geometric 
means, ratios of geometric means of insulin lispro within Lyumjev to Humalog, and their 
corresponding 90% CIs of the ratios using the mixed-effects model that includes treatment 
(Lyumjev, Humalog), sequence, period, and treatment as fixed effects and subject as a random 
effect. Analysis of iAUCs during the MMTT and AUCs during exercise will be based on 
untransformed endpoints, if negative values occurred. In this case, LSmeans, treatment 
differences in LSmeans, and corresponding 90% CIs for the treatment differences will be 
estimated from the model. The p-value on the difference between LSmeans will be used to 
determine statistical significance. The treatment ratios and 90% CIs for the ratios will be 
calculated using Fieller’s theorem. Additionally, treatment differences in LSmeans, and 
corresponding 90% CIs may be estimated from the model for ∆PGmax , ∆PG1h , and ∆PG2h 
based on untransformed data. 
The same model without log transformation will be used for the analysis of the rate of change in 
PG during the exercise period and exploratory GD time parameters. LSmeans, treatment 
differences in LSmeans, and the corresponding 90% CIs for the treatment differences will be 
estimated from the model. The p-value on the difference between LSmeans will be used to 
determine statistical significance. The treatment ratios and 90% CIs for the ratios will be 
calculated using the Fieller’s theorem (Chow and Liu 2009). 
Additionally, exploratory analysis may be conducted and will be defined in the SAP. 
9.3.3. 
Pharmacokinetic Analysis 
9.3.3.1. 
Pharmacokinetic Parameter Estimation 
Participants who receive at least 1 dose of insulin during the in-house period and have 
measurable insulin lispro concentrations will be included in the PK analysis dataset.  
Pharmacokinetic analyses will be conducted using standard noncompartmental methods of 
 on a computer 
that meets or exceeds the minimum system requirements for these programs. The version of any 
software used for the analysis will be documented, and the program will meet the Lilly 
requirements of software validation. It is possible that other validated equivalent PK software 
programs may be utilized if appropriate, warranted, and approved by global PK management. 
Free serum insulin lispro concentrations will be used to calculate several PK parameters 
following the meal bolus for the MMTT, including time to early half-maximal drug 
concentration (early 50% tmax), time to late half-maximal drug concentration (late 50% tmax), 
maximum observed drug concentration (Cmax), time of maximum observed drug concentration 
(tmax), and area under the plasma concentration time curve (AUC) from zero to 15 minutes 
(AUC[0-15min]), AUC from time zero to 30 minutes (AUC[0-30min]), AUC from time zero to 1 
hour (AUC[0-1h]), AUC from time zero to 4 hours (AUC[0-4h]), and AUC from time zero to 
infinity (AUC[0-∞]). Other parameters may be calculated as deemed appropriate. Additional 
partial AUCs may be computed as necessary. If the pre-bolus insulin lispro concentrations differ 
between Lyumjev and Humalog, the average of the two samples collected immediately prior to 
the correction bolus will represent as the 0-hour time point for each subject and will be used to 
subtracting the baseline value from all post-dose insulin lispro measurements to calculate the PK 
parameters. 
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Additionally, an analysis will be conducted to assess the insulin lispro PK during the basal 
insulin suspension period. PK parameters that were used included the terminal half-life (t1/2), 
time of the last concentration prior to dose (tlast) and AUC from time of suspension to the time of 
the last detectable concentration (AUC[0-tlast]). The insulin lispro concentration versus time 
profile will be compared between Lyumjev and Humalog during this time. 
Although attempts will be made to adhere to the scheduled collection times (Section 1.3), failure 
to collect PK samples due to legitimate clinical issues will not be considered as protocol 
deviations.  
Parameters will be individually calculated for each participant based on actual collection times. 
The mean data will be presented by summary statistics and presented by treatment for those 
participants who received both treatments (Lyumjev and Humalog) with the same insulin dose 
(bolus dose for the MMTT or basal reduction) and meal consumption. 
9.3.3.2. 
Pharmacokinetic Statistical Inference 
The statistical analyses comparing PK parameters (described in Section 9.3.3.1) following 
Lyumjev and Humalog for the exercise period and MMTT for test condition of either 50% or 
100% reduction of basal infusion rates during exercise will be conducted on the modified full 
analysis set. The statistical analyses of the PK parameters for the MMTT will be conducted on 
those participants who receive both treatments with an identical insulin lispro doses for Lyumjev 
and Humalog. The exercise and MMTT will be analyzed separately. 
9.3.3.2.1. Statistical Analysis of the Secondary PK Endpoints during MMTT 
Log-transformed AUCs and Cmax for insulin lispro were evaluated to estimate geometric means, 
ratios of geometric means of insulin lispro within Lyumjev to Humalog, and their corresponding 
90% CIs of the ratios using the mixed-effects model that includes treatment (Lyumjev, Humalog) 
and period as fixed effects and participant as a random effect.  
The same model without log transformation was used for the analysis of the PK time parameters 
(early 50% tmax, late 50% tmax, and tmax). LSmeans, treatment differences in LSmeans, and the 
corresponding 90% CIs for the treatment differences were estimated from the model. The 2-sided 
p-value on the difference between LSmeans was used to determine statistical significance. The 
treatment ratios and 90% CIs for the ratios were calculated using the Fieller’s theorem (Chow 
and Liu 2009).  
9.3.3.2.2. Statistical Analysis of the Secondary PK Endpoints during Exercise  
A mixed-effects model without log transformation that includes treatment (Lyumjev, Humalog), 
sequence, period, and treatment as fixed effects and subject as a random effect may be used for 
the exploratory PK endpoints during the exercise period. LSmeans, treatment differences in 
LSmeans, and the corresponding 90% CIs for the treatment differences will be estimated from 
the model. The p-value on the difference between LSmeans will be used to determine statistical 
significance. The treatment ratios and 90% CIs for the ratios will be calculated using the Fieller’s 
theorem (Chow and Liu 2009). 
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9.3.4. 
Exploratory Analysis 
9.3.4.1. 
Exploratory CGM Parameter Estimation 
The following variables will be derived from the CGM for each participant for the analysis 
periods during the exercise, test meal assessments, overnight periods (Day -1 from 
 
on Day 1), as duration (in minutes) and percentage of time with glucose values between 70 and 
180 mg/dL (3.9 and 10.0 mmol/L) (both inclusive). 
 duration (in minutes) and percentage of time with glucose values <54 and 70 mg/dL 
(3.0 and 3.9 mmol/L)  
 duration (in minutes) and percentage of time with glucose values >180 and >250 mg/dL 
(10.0 and 13.9 mmol/L) 
 mean glucose 
 overall variability (coefficient of variation and standard deviation). 
9.3.4.2. 
CGM Statistical Inference 
Statistical analyses comparing of CGM parameters (described in Section 9.3.4.1) of Lyumjev 
and Humalog for test condition of either 50% or 100% reduction of basal infusion rates will be 
conducted on the modified full analysis set for the analysis periods of exercise, test meal 
assessments, overnight periods, and for the duration of in-house period. The same model as 
described in Section 9.3.2.2.1 is used for the CGM parameter analysis. 
9.3.5. 
Safety Analyses 
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data (including hypoglycemic events) will be summarized using descriptive 
methodology. 
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator. Symptoms reported to occur prior 
to enrollment will be distinguished from those reported as new or increased in severity during the 
study. Each symptom will be classified by the most suitable term from the Medical Dictionary 
for Regulatory Activities. 
The number of investigational product-related SAEs will be reported. 
9.3.5.1. 
Statistical Evaluation of Safety 
Safety parameters that will be assessed include safety laboratory parameters and vital signs. The 
parameters will be listed and may be summarized using standard descriptive statistics. Additional 
analysis will be performed if warranted upon review of the data. 
9.3.6. 
Other Analyses 
Other analyses will be provided in the SAP.  
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9.4. 
Interim Analysis 
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP, investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol. 
The Lilly clinical pharmacologist/CRP/Lilly study team is unblinded. Data may be accessed and 
analyzed while the trial is ongoing, but no changes to the study design are planned. The results 
may help Lilly expedite final delivery and enable planning of future studies. Information that 
may unblind the study during the analyses will not be reported to the CRU until the study has 
been unblinded. An assessment committee will not be formed. 
9.5. 
Sample Size Determination 
Approximately 
 participants may be enrolled to ensure that at least 
 participants complete 
the study. 
This sample size will provide approximately 
 power to demonstrate a 
 mg/dL difference in 
the change in plasma glucose level from start to the end of the exercise between Lyumjev and 
Humalog, assuming no true difference in the change in plasma glucose level between Lyumjev 
and Humalog and a standard deviation of
mg/dL with a 2-sided alpha-level of 0.1. 
Discontinued participants may be replaced to ensure that 
subjects complete the trial. A 
replacement participant will be assigned to the same treatment sequence as the participant being 
replaced. 
 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
● This study will be conducted in accordance with the protocol and with the 
following: 
○ consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines 
○ applicable ICH GCP guidelines 
○ applicable laws and regulations 
● The protocol, protocol amendments, ICF, Investigator’s Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations, ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
● Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
10.1.2. 
Informed Consent Process 
● The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participant and answer all questions 
regarding the study. 
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● Participants must be informed that their participation is voluntary. Participant will 
be required to sign a statement of informed consent that meets the requirements of 
21 Code of Federal Regulations 50, local regulations, ICH guidelines, privacy and 
data protection requirements, where applicable, and the IRB/IEC or study center. 
● The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
● A copy of the ICF(s) must be provided to the and is kept on file. 
Participants who are rescreened are required to sign a new ICF. 
10.1.3. 
Data Protection 
● Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets, or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information that would make the 
participant identifiable will not be transferred. 
● The participant must be informed that the participant’s personal study-related data 
will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who will be required 
to give consent for their data to be used as described in the informed consent.  
● The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized staff appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
● The sponsor has processes in place to ensure data protection, information security, 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach. 
10.1.4. 
Dissemination of Clinical Study Data 
Communication of suspended or terminated dosing  
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (e.g., through phone and/or email) as 
soon as possible. It will be a requirement that investigators respond upon receipt to confirm that 
they understand the communication and have taken the appropriate action prior to further dosing 
any participants with study intervention. Any investigator not responding will be followed up by 
Lilly staff prior to any further planned dosing. If a dose is planned imminently, Lilly staff will 
immediately, and continually, use all efforts to reach investigators until contact is made and 
instructions verified.  
 
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Reports  
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation.  
Data 
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected. 
10.1.5. 
Data Quality Assurance 
● All participant data relating to the study will be recorded on printed or eCRFs 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). 
The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 
● The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. Source data may include laboratory 
tests, medical records, and clinical notes.  
● The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
● Quality tolerance limits will be predefined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These predefined 
parameters will be monitored during the study and important excursions from the 
quality tolerance limits and remedial actions taken will be summarized in the 
CSR. 
● Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as risk management and mitigation strategies and analytical risk-
based monitoring), methods, responsibilities, and requirements, including 
handling of noncompliance issues and monitoring techniques are provided in the 
Monitoring Plan. 
● The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
● The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations). 
● Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site staff are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
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● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 
clinical trial agreement unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
● In addition, the sponsor or its representatives will periodically check a sample of 
the participant data recorded against source documents at the CRU. The study 
may be audited by the sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data capture system 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture system will be used in this study for the collection of CRF data. The 
investigator maintains a separate source for the data entered by the investigator or designee into 
the sponsor-provided electronic data capture  system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Data collected via the sponsor-provided data capture system(s) will be stored at third party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system(s). Prior to decommissioning, the investigator will receive or access 
an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the sponsor data warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.6. 
Source Documents 
● Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
● Data reported on or entered in the CRF and are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
● Definition of what constitutes source data can be found in 10.1.5.
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10.1.7. 
Study and Site Start and Closure 
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or site termination 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. 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 
For study termination: 
● 
Discontinuation of further study intervention development 
For site termination: 
● Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
● Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
● Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.8. 
Publication Policy 
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance.
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10.2. 
Appendix 2: Clinical Laboratory Tests 
● The tests detailed in the following table will be performed by the local laboratory. 
● Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
● Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
 Pregnancy testing will occur as indicated in the SoA (Section 1.3). 
Investigators must document their review of the laboratory safety results.  
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded staff. 
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Safety Laboratory Tests at Screening 
Hematology 
Clinical Chemistry 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate  
Mean cell volume  
Chloride  
Mean cell hemoglobin  
Calcium (ionized/total)  
Mean cell hemoglobin concentration  
Phosphorus/Phosphate  
Leukocytes (WBC)  
Magnesium  
 
Glucose, fasting 
Absolute counts of: 
Blood urea nitrogen (BUN) 
Neutrophils 
Creatinine  
Uric acid 
Lymphocytes 
Total cholesterol 
Monocytes 
Total protein 
Eosinophils 
Albumin 
Basophils 
Total bilirubin 
 
Alkaline phosphatase (ALP) 
Urinalysis 
Aspartate aminotransferase (AST) 
Specific gravity 
Alanine aminotransferase (ALT) 
pH 
 
Protein 
Glucose 
 
Ketones 
Ethanol testinga 
Bilirubin 
Urine drug screena 
Urobilinogen 
Hepatitis B surface antigenb 
Blood 
Hepatitis C antibodyb 
Nitrite 
HIVb 
Pregnancy test  
 
FSHc  
 
HbA1c, C-peptide 
Abbreviations: FSH = follicle-stimulating hormone; HbA1c = glycated hemoglobin; HIV = human 
immunodeficiency virus; RBC = red blood cell; WBC = white blood cell. 
Note: Results of these assays will be validated by the local laboratory at the time of testing. Additional tests may be 
performed or auto calculated by the laboratory as part of its standard panel that cannot be removed. Some of the 
above parameters are calculated from measured values. Omission of calculated values will not be considered as a 
protocol violation. 
a Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit and at other 
times indicated in the schedule of activities.  
b 
These tests may be waived if performed within 6 months prior to screening, and if test results are available for 
“review” for hepatitis B and C and HIV. 
c Follicle-stimulating hormone test must be performed at screening for a woman who is aged less than 55 years 
with an intact uterus, not on hormone therapy and has had 12 months of spontaneous amenorrhea. 
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10.2.1. 
Blood Sampling Summary 
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study. 
Protocol I8B-MC-ITSU Sampling Summary 
 
Purpose 
Blood Volume per 
Sample (mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening testsa 
Pharmacokinetics  
Ketones 
FFAs 
Blood discard for cannula patency 
Total 
 
 
492.1 
Total for clinical purposes (rounded up to nearest 10 mL) 
500 
a Additional samples may be drawn if needed for safety purposes. 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
10.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (that is, not related to progression 
of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.  
 The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as an AE or SAE if they fulfill the definition of an AE or SAE. Also, lack of 
efficacy or failure of expected pharmacological action also constitutes an AE or SAE.  
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
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 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.2. 
Definition of SAE 
 
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
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f. 
Other situations: 
 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
10.3.3. 
Definition of Product Complaints 
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected to 
ensure the safety of participants, monitor quality, and to facilitate process and product 
improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints 
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/product complaint information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice. AE/SAE information is reported on the appropriate CRF page and 
product complaint information is reported on the Product Complaint Form. 
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Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the CRF page for AE/SAE 
and the Product Complaint Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested 
by the sponsor or designee. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.  
Assessment of intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:  
 Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.  
 
Assessment of causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship/ 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
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 The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the sponsor or designee. 
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the sponsor 
or designee. 
 The investigator may change their opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
or designee to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
10.3.5. 
Reporting of SAEs 
SAE reporting via SAE report 
 Facsimile transmission of the SAE report is the preferred method to transmit this 
information to the sponsor or designee.  
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE report within the designated reporting time frames. 
 Contacts for SAE reporting can be found in SAE report.  
10.3.6. 
Regulatory Reporting Requirements 
SAE regulatory reporting 
Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities toward the safety of participants 
and the safety of a study intervention under clinical investigation are met. 
● The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators. 
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● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.  
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Word/Phrase 
Definition 
Women of 
childbearing 
potential 
Females are considered women of childbearing potential if 
 
they have had at least 1 cycle of menses, or 
 
they have Tanner 4 breast development. 
 
Any amount of spotting should be considered menarche. If Tanner staging of 
breasts is performed as part of study procedures, please refer to the Reproductive, 
Pregnancy and Pediatrics Safety Committee Safety Guidance for Children in 
Clinical Trial regarding Tanner staging. 
Women not of 
childbearing 
potential 
Females are considered women not of childbearing potential if 
 
they have a congenital anomaly such as Mullerian agenesis 
 
they are infertile due to surgical sterilization, or  
 
they are postmenopausal. 
 
Examples of surgical sterilization include hysterectomy, bilateral oophorectomy, 
tubal ligation. 
Postmenopausal 
state 
The postmenopausal state should be defined as 
1. a woman at any age at least 6 weeks postsurgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or  
2. a woman aged at least 40 years and up to 55 years with an intact uterus, 
not on hormone therapy*, who has had cessation of menses for at least 12 
consecutive months without an alternative medical cause, AND  
With a follicle-stimulating hormone >40 mIU/mL; or  
3. A woman aged 55 years or above not on hormone therapy, who has had at 
least 12 months of spontaneous amenorrhea, or 
4. A woman aged at least 55 years with a diagnosis of menopause prior to 
starting hormone replacement therapy 
 
* Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, 
selective estrogen receptor modulators, or chemotherapy that could induce 
transient amenorrhea. 
Reproductive 
toxicology 
studies 
Embryo-fetal studies are toxicity studies in pregnant animals designed to identify 
abnormalities in the development of fetuses, which could indicate potential for 
teratogenicity in humans. The relevant dosing period is during organogenesis. 
 
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10.4.2. 
Contraception Guidance 
WOCBPs who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle 
Must… 
Must not… 
agree to either remain abstinent, or 
 
use periodic abstinence methods 
o calendar  
o ovulation  
o symptothermal, or 
o post-ovulation  
 
declare abstinence just for the duration of 
a trial, or 
stay in a same-sex relationship without sexual 
relationships with males 
 
use the withdrawal method 
 
 
WOCBPs who are NOT completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle 
Topic 
Explanation 
Pregnancy testing 
Negative serum result at screening followed by a 
negative urine result prior to study treatment and 
at follow-up. 
Note: subsequent pregnancy testing is compound 
specific 
Contraception 
Agree to use 2 forms of effective contraception, 
where at least 1 form must be highly effective 
(less than 1% failure rate) 
 
Examples of different forms of contraception:  
Methods 
Examples 
Highly effective contraception  
 
combination oral contraceptive pill and 
mini pill 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 
pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices 
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Effective contraception  
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical 
sponges 
 
barrier method with use of a spermicide 
o condom with spermicide 
o  diaphragm with spermicide, or 
o female condom with spermicide 
 
Note: The barrier method must include use of a 
spermicide (i.e., condom with spermicide, 
diaphragm with spermicide, female condom with 
spermicide) to be considered effective. 
Ineffective forms of contraception 
 
spermicide alone  
 
immunocontraceptives 
 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, combination of 
above 2, cervical mucus, symptothermal) 
 
withdrawal 
 
post-coital douche 
 
lactational amenorrhea 
 
 
 
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10.5. 
Appendix 5: Provisions for Changes in Study Conduct during 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local ethical review boards, regulatory bodies, and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (e.g., upon implementation and suspension of changes). All approvals and 
notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study.  
Informed consent 
Additional consent from the participant will be obtained, if required, for 
 participation in remote visits, as defined below in “Remote visits” 
 a change in the method of study intervention administration 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
 
 
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Remote visits  
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable only for 
optional basal optimization visits or follow-up visit to complete appropriate assessments. 
Assessments to be completed in this manner include, but are not limited to, concomitant 
medications, safety monitoring, etc. 
Data capture 
In source documents and the CRF, the CRU should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged.  
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the CRU staff. 
Screening period guidance  
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening visit are valid for a maximum of 42 days. The following rules will be applied for 
active, nonrandomized participants whose participation in the study must be paused due to 
exceptional circumstances: 
 If screening is paused for less than 42 days from screening to randomization visit: the 
participant will proceed to the next study visit per the usual SoA, provided that 
randomization visit must be conducted within 42 days from screening visit.  
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 42 days from screening visit to randomization 
visit: the participant must undergo an additional medical assessment and/or clinical 
measurements to confirm their eligibility. The screening procedures per the usual 
SoA should be followed, starting at the screening visit to ensure participant eligibility 
by the randomization visit. 
Adjustments to visit windows  
Adjustments to visit windows will not be considered protocol deviations. Missing data will be 
captured as protocol deviations. 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
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on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
 
Trial Period 
Screening Period 
Study Period 
Follow-
up 
Visit 
Interval 
Tolerance 
Visit no. 
1 
Optional visits 
2 
3, 4, 5, 6 
7 
 
Timing 
 
Within 
 days 
prior to 
Visit 3 
First evaluation - Within  
days of screening visit 
Second evaluation - Within 
 
days of screening visit 
days 
prior to 
Visit 3 
 
 
days 
after 
Visit 6 
 
Day 
 
 
 
 
 
 
 
In-house stay 
 
 
 
X 
X 
 
 
 
On-
site 
only 
On-site 
On-site 
only 
On-
site 
only 
On-
site 
only 
Televisit 
Same as 
shown in 
SoA, but 
flexibility 
can be 
considered 
following 
consultation 
with, land 
with prior 
approval by, 
the sponsor 
Abbreviations: no. = number; SoA = schedule of activities. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the CRU should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner.  
 
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10.6. 
Appendix 6: Abbreviations and Definitions 
 
Term 
Definition 
ADE 
adverse device effect 
AE 
adverse event 
AUC 
area under the plasma concentration time curve 
blinding/masking 
A single-blind study is one in which the investigator and/or the investigator’s staff are 
aware of the treatment, but the participant is not, or vice versa, or when the sponsor is 
aware of the treatment, but the investigator and/the investigator’s staff and the 
participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received. 
CGM 
continuous glucose monitoring 
CI 
confidence interval 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CRF 
case report form: a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
CRP 
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 
CRS 
clinical research scientist 
CRU 
clinical research unit 
CSII 
continuous subcutaneous insulin infusion 
CSR 
clinical study report 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
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enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
FGM 
flash glucose monitoring 
GCP 
good clinical practice 
GD 
glucodynamics 
HbA1c 
glycosylated hemoglobin 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
institutional ethics committee 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate in 
a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed, and dated informed consent form. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IRB 
institutional review board 
LSmean 
least-square mean 
MMTT 
mixed meal tolerance test 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PK/PD 
pharmacokinetics/pharmacodynamics 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMBG 
self-monitored blood glucose 
SoA 
schedule of activities 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
T1D 
type 1 diabetes 
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TEAE 
treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
VO2 
oxygen uptake 
 
 
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10.7. 
Appendix 7: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment a: 09 February 2022 
Overall Rationale for the Amendment 
This protocol is being amended mainly to clarify the language related to pregnancy testing. 
Minor editorial changes have been done and are not provided in the table below. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3.1. 
Overall 
Schedule 
Added pregnancy testing on 
assessment day; serum test at 
screening; urine pregnancy test 
prior to study treatment and at 
follow-up 
For clarification, updated timing and 
type of pregnancy testing 
Section 1.3.1. 
Overall 
Schedule 
Added urine drug screen and 
ethanol breath testing on 
assessment day 
For clarification, updated timing of 
urine drug screen and ethanol testing 
Section 1.3.1. 
Overall 
Schedule 
CGM mentioned as ‘study 
CGM’ and removed ‘X’ from 
assessment day for study CGM 
Clarified that CGM will be study CGM; 
participant will be placed on study CGM 
during in-house period 
Section 1.3.1. 
Overall 
Schedule, 
footnote 
Footnotes e, f, g, and h updated 
Clarification on timings provided and 
correction done to be consistent with 
collections in Section 1.3.2 
Section 1.3.2. 
Assessment 
Schedule 
Example for In-
house Visits 
CGM mentioned as ‘study 
CGM’ 
Clarified that CGM will be study CGM 
Section 1.3.2. 
Assessment 
Schedule 
Example for In-
house Visits  
Clarified timing of sample 
collection, updated nominal 
timing as -4 hours at 11:00 AM 
Clarified the timing of the samples 
relative to the study activities and made 
nominal timing consistent between 
Sections 1.3.1 and 1.3.2 
Section 4.1.3. 
In-house Visits 
 
Corrected typo.  Platinum is not part of 
the name of CGM. 
Section 4.1.3. 
In-house Visits 
CGM mentioned as ‘study 
CGM’ 
Clarified that CGM will be study CGM 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.3.1.4. 
Snacks 
Removed the term “uncovered’ 
Removed due to lack of clarity 
Section 5.3.2. 
Substance Use: 
Caffeine, 
Alcohol, and 
Tobacco 
Added the following text to the 
first bullet point excluding the 
MMTT when chocolate-flavored 
Ensure® Plus may be given 
Clarification provided regarding the use 
of chocolate-flavored Ensure® Plus in 
the MMTT 
Section 6.3. 
Measures to 
Minimize Bias: 
Randomization 
and Blinding 
Added 1 of the 4 ‘sequences for 
the’ in-house study periods 
Clarified that participants will be 
assigned to 1 of the 4 ‘sequences for 
the’ in-house study periods 
Section 6.8. 
Concomitant 
therapy 
Medications mentioned should 
not be used within 14 days prior 
to dosing  
Correction done to be consistent with 
Exclusion Criteria Number 23  
Section 8.5.2. 
Exploratory 
CGM Values 
 
Correction done. Platinum is not part of 
the name of CGM 
Section 8.5.2. 
Exploratory 
CGM Values 
CGM mentioned as ‘study 
CGM’ 
Clarified that CGM will be study CGM 
Section 9.3.2.1. 
Glucodynamic 
Parameter 
Estimation 
The change from baseline values 
is the average of -15 minutes 
and 0 minute 
Corrected typo of -10 minutes to -15 
minutes to be consistent with schedule 
of activities (Section 1.3.2)  
Section 9.3.3.1. 
Pharmacokinetic 
parameter 
estimation 
LY900014 replaced as Lyumjev 
Correction done to be consistent with 
document (LY900014 and Lyumjev 
refer to the same product) 
Section 10.4.2. 
Contraception 
guidance 
Negative serum result at 
screening followed by a  
negative urine result prior to 
study treatment and at follow-up 
Updated language on pregnancy testing 
in women of childbearing potential who 
are not completely abstinent or in a 
same-sex relationship to be consistent 
with schedule of activities  
Section 10.2.1 
Updated number of blood 
samples for glucose and 
pharmacokinetics and updated 
total blood volume 
Corrected table to be consistent with 
Sections 1.3.1 and 1.3.2 for glucose and 
pharmacokinetic samples 
 
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91 
11. 
References 
Blevins T, Zhang Q, Frias JP, et al.; PRONTO-T2D Investigators. Randomized double-blind 
clinical trial comparing ultra rapid lispro with lispro in a basal-bolus regimen in patients with 
type 2 diabetes: PRONTO-T2D. Diabetes Care. 2020;43(12):2991-2998. doi:10.2337/dc19-
2550 
Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. 3rd ed. 
Taylor and Francis Group, LLC; 2009:p 88-90. 
[EMA] European Medicines Agency. Lyumjev (previously Liumjev). Published April 16, 2020. 
Updated July 02, 2021. Accessed October 05, 2021. 
https://www.ema.europa.eu/en/medicines/human/EPAR/lyumjev-previously-liumjev 
[FDA] US Food and Drug Administration. GRAS Substances (SCOGS) Database. March 28, 
2018. Accessed October 05, 2021. https://www.fda.gov/food/generally-recognized-safe-
gras/gras-substances-scogs-database 
[FDA] US Food and Drug Administration. Inactive ingredient search for approved drug 
products. Updated October 21, 2021a. Accessed October 26, 2021. 
https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm 
[FDA] US Food and Drug Administration. Drug approval package: Lyumjev. Published May 18, 
2021b. Accessed October 05, 2021. 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761109Orig1s000TOC.cfm 
[FDA] US Food and Drug Administration. Humalog® Mix50/50TM. Revised February 2015. 
Accessed October 22, 2021. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021018s100lbl.pdf 
Humalog [product monograph]. Toronto, Ontario, Canada: Eli Lilly Canada Inc. revision April 
12, 2021. Accessed October 26, 2021. http://pi.lilly.com/ca/humalog-ca-
pm.pdf#:~:text=PRODUCT%20MONOGRAPH%20HUMALOG%C2%AE%20%28insulin%
20lispro%20injection%29%20Solution%20for,Injection%2C%20200units%2FmL%2C%20Lil
ly%20Standard%20ATC%20Code%3A%20A10AB04%20fast-acting 
Jinnouchi H, Imori M, Nishiyama H, Imaoka T. Ultra-rapid lispro efficacy and safety compared 
to Humalog® in Japanese patients with type 2 diabetes: PRONTO-T2D subpopulation 
analysis. Diabetes Ther. 2020;11(9):2075-2088. doi:10.1007/s13300-020-00890-2 
Klaff L, Cao D, Dellva MA, et al. Ultra rapid lispro improves postprandial glucose control 
compared with lispro in patients with type 1 diabetes: results from the 26-week PRONTO-T1D 
study. Diabetes Obes Metab. 2020;22(10):1799-1807. doi:10.1111/dom.14100 
Lyumjev [prescribing information]. Indianapolis, IN: Eli Lilly and Company. 2020. Revised 
August 2021. Accessed October 22, 2021. http://pi.lilly.com/us/lyumjev-uspi.pdf 
Approved on 09 May 2022 GMT
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92 
Lyumjev [product monograph]. Indianapolis, IN: Eli Lilly and Company. Published 2021. 
September 14, 2021. Accessed October 22, 2021. https://pdf.hres.ca/dpd_pm/00062901.PDF 
Lyumjev [summary of product characteristics]. Annex I. Utrecht, The Netherlands: Eli Lilly 
Nederland B.V. Accessed October 22, 2021. 
https://www.ema.europa.eu/en/documents/product-information/lyumjev-previously-liumjev-
epar-product-information_en.pdf 
Malecki MT, Cao D, Liu R, et al. Ultra-Rapid Lispro Improves Postprandial Glucose Control 
and Time in Range in Type 1 Diabetes Compared to Lispro: PRONTO-T1D Continuous 
Glucose Monitoring Substudy. Diabetes Technol Ther. 2020;22(11):853-860. 
doi:10.1089/dia.2020.0129 
McGaugh SM, Zaharieva DP, Pooni R, et al. Carbohydrate requirements for prolonged, fasted 
exercise with and without basal rate reductions in adults with type 1 diabetes on continuous 
subcutaneous insulin infusion. Diabetes Care. 2021;44(2):610-613. doi:10.2337/dc20-1554 
Riddell MC, Gallen IW, Smart CE, et al. Exercise management in type 1 diabetes: a consensus 
statement [published correction appears in Lancet Diabetes Endocrinol. 2017;5(5):e3]. Lancet 
Diabetes Endocrinol. 2017;5(5):377-390. doi:10.1016/S2213-8587(17)30014-1 
Warren M, Bode B, Cho JI, et al. Improved postprandial glucose control with ultra rapid lispro 
versus lispro with continuous subcutaneous insulin infusion in type 1 diabetes: PRONTO-
Pump-2. Diabetes Obes Metab. 2021;23(7):1552-1561. doi:10.1111/dom.14368 
Zaharieva DP, McGaugh S, Pooni R, et al. Improved open-loop glucose control with basal 
insulin reduction 90 minutes before aerobic exercise in patients with type 1 diabetes on 
continuous subcutaneous insulin infusion. Diabetes Care. 2019;42(5):824-831. 
doi:10.2337/dc18-2204 
Approved on 09 May 2022 GMT


Signature Page for VV-CLIN-028148 v1.0
Signature Page for VV-CLIN-028148 v1.0
Approval
or
06-May-2022 13:09:41 GMT+0000
Approval
09-May-2022 07:32:37 GMT+0000
Approved on 09 May 2022 GMT
PPD
PPD

SAP_001.pdf: 
 
 
I8B-MC-ITSU (b) StaƟsƟcal Analysis Plan Version: 2.0 
 
 
EﬀecƟveness of a Basal Rate ReducƟon With LyumjevTM Versus Humalog® on the ProtecƟon From 
Exercise-Induced Hypoglycemia in Individuals With Type 1 Diabetes on ConƟnuous Subcutaneous 
Insulin Infusion 
 
 
NCT05262387 
 
 
Approval Date: 05-Apr-2023 


 
Final Version 2.0, 31MAR2023 
 
             Page 1 of 27 
STATISTICAL ANALYSIS PLAN 
Effectiveness of a Basal Rate Reduction with LyumjevTM versus Humalog® on the 
Protection from Exercise-Induced Hypoglycemia in Individuals with Type 1 Diabetes on 
Continuous Subcutaneous Insulin Infusion 
Statistical Analysis Plan Status:  Final 
Statistical Analysis Plan Version:  2.0 
Statistical Analysis Plan Date:  31-March-2023 
Investigational Medicinal Product:  LY900014 (Lyumjev) 
Protocol Reference:  I8B-MC-ITSU  
Labcorp Drug Development Study:  8479939 
Clinical Phase I 
 
 
 


 
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Statistical Analysis Plan  
 
CONFIDENTIAL 
Labcorp Drug Development Study: 8479939  
Protocol Reference: I8B-MC-ITSU 
1. TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ................................................................................................... 2 
2. 
ABBREVIATIONS ............................................................................................................ 4 
3. 
INTRODUCTION .............................................................................................................. 6 
4. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 6 
4.1 
Primary Objective and Endpoint ................................................................................. 6 
4.2 
Secondary Objectives and Endpoints .......................................................................... 6 
4.3 
Exploratory Objectives and Endpoints ........................................................................ 7 
5. 
STUDY DESIGN ............................................................................................................... 7 
6. 
TREATMENTS ................................................................................................................ 13 
7. 
SAMPLE SIZE JUSTIFICATION ................................................................................... 14 
8. 
DEFINITION OF ANALYSIS POPULATIONS ............................................................ 14 
9. 
STATISTICAL METHODOLOGY ................................................................................. 15 
9.1 
General ....................................................................................................................... 15 
9.2 
Demographics and Participant Disposition ............................................................... 15 
9.3 
Pharmacokinetic Assessment ..................................................................................... 15 
9.3.1 
Pharmacokinetic Parameter Estimation ............................................................ 15 
9.3.2 
Pharmacokinetic Statistical Methodology ........................................................ 16 
9.4 
Pharmacodynamic Assessment .................................................................................. 18 
9.4.1 
Pharmacodynamic Analysis ............................................................................. 18 
9.4.2 
Pharmacodynamic Statistical Methodology ..................................................... 19 
9.5 
Exploratory PD Analysis ........................................................................................... 20 
9.5.1 
Continuous Glucose Monitoring ...................................................................... 20 
9.5.2 
Free Fatty Acids and Ketones .......................................................................... 21 
9.6 
Safety and Tolerability Assessments ......................................................................... 21 
9.6.1 
Adverse events ................................................................................................. 21 
9.6.2 
Glucose Monitoring and Hypoglycemia .......................................................... 22 
9.6.3 
Concomitant medication ................................................................................... 23 
9.6.4 
Clinical laboratory parameters ......................................................................... 23 
9.6.5 
Vital signs ......................................................................................................... 23 
9.6.6 
Electrocardiogram (ECG) ................................................................................. 23 
9.6.7 
Perceived Exertion during Exercise ................................................................. 23 
9.6.8 
Other assessments ............................................................................................. 24 
9.6.9 
Safety and Tolerability Statistical Methodology .............................................. 24 


 
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Protocol Reference: I8B-MC-ITSU 
10. INTERIM ANALYSES .................................................................................................... 24 
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ....... 24 
12. REFERENCES ................................................................................................................. 24 
13. DATA PRESENTATION ................................................................................................ 24 
13.1 Derived Parameters .................................................................................................... 24 
13.2 Missing Data .............................................................................................................. 25 
13.3 Insufficient Data for Presentation .............................................................................. 25 
14. APPENDICES .................................................................................................................. 26 
Appendix 1: Document History .......................................................................................... 26 
Appendix 2: Supplementary material ................................................................................. 27 
 


 
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Labcorp Drug Development Study: 8479939  
Protocol Reference: I8B-MC-ITSU 
2. ABBREVIATIONS  
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).  
AE 
Adverse event 
AUC 
Area under the plasma concentration versus time curve 
AUC(0-15min) 
Area under the plasma concentration time curve from time zero to 15 
minutes 
AUC(0-1h) 
Area under the plasma concentration time curve from time zero to 1 
hour 
AUC(0-30min) 
Area under the plasma concentration time curve from time zero to 30 
minutes 
AUC(0-4h) 
Area under the plasma concentration time curve from time zero to 4 
hours 
AUC(0-∞) 
Area under the plasma concentration versus time curve from zero to 
infinity 
AUC(0-tlast) 
Area under the plasma concentration versus time curve from time of 
suspension to the time of last detectable concentration 
CGM 
Continuous glucose monitoring 
CI 
Confidence interval 
Cmax 
Maximum observed drug concentration 
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
early 50% tmax 
Time to early half-maximal drug concentration 
ECG 
Electrocardiogram 
FFA 
Free fatty acids 
iAUC 
Incremental area under the plasma concentration versus time curve 
ICH 
International Conference on Harmonisation 
IP 
Investigational product 
late 50% tmax 
Time to late half-maximal drug concentration 
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
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MMTT 
Mixed-meal tolerance test 
NA 
Not applicable 
PD 
Pharmacodynamic 
PG 
Plasma Glucose 
PK 
Pharmacokinetic 
RPE 
Rating of perceived exertion 
SAE 
Serious adverse events 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation  
t1/2 
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis 
TEAE 
Treatment emergent adverse events 
TFLs 
Tables, Figures, and Listings 
tlast 
Time of the last concentration prior to dose 
tmax 
Time of maximum observed drug concentration 
VO2 
Peak oxygen uptake 
WHO 
World Health Organization 
ΔPG1h 
Change from baseline 1-hour plasma glucose 
ΔPG2h 
Change from baseline 2-hour plasma glucose 
ΔPGmax 
Change from baseline maximum plasma glucose observed during the 
4 hours postmeal 


 
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CONFIDENTIAL 
Labcorp Drug Development Study: 8479939  
Protocol Reference: I8B-MC-ITSU 
3. INTRODUCTION  
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
27 October 2021). 
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK), and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document. 
The intent of this document is to provide guidance for the statistical and PK/PD analyses of data. 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Eli Lilly and Company. A limited amount of information 
concerning this study (e.g., objectives, study design) is given to help the reader’s interpretation. 
When the SAP and TFL shells are agreed upon and finalized, they will serve as the template for 
this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with 
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry:  Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry:  
Structure and Content of Clinical Study Reports2. 
4. STUDY OBJECTIVES AND ENDPOINTS  
4.1 
Primary Objective and Endpoint  
The primary objective of the study is: 
 To compare changes in plasma glucose (PG) levels with LyumjevTM versus Humalog® 
from the start to the end of 60 minutes of moderate-intensity aerobic exercise using either 
50% or 100% reduction of basal infusion rates, set 60 minutes or 15 minutes before the 
onset of exercise, respectively. 
The primary endpoint of the study is: 
 Changes in PG from the start to the end of exercise. 
4.2 
Secondary Objectives and Endpoints  
The secondary objectives of the study are: 


 
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 To compare the glucodynamic response with Lyumjev versus Humalog during a dinner 
mixed-meal tolerance test (MMTT) following moderate-intensity aerobic exercise using 
either 50% or 100% reduction of basal infusion rates, set 60 minutes or 15 minutes before 
the onset of exercise, respectively 
 To compare the PK of insulin lispro between Lyumjev versus Humalog during an MMTT 
 To compare the PK of insulin lispro between Lyumjev versus Humalog during 
60 minutes of moderate-intensity aerobic exercise using either 50% or 100% reduction of 
basal infusion rates with Lyumjev or Humalog, set 60 minutes or 15 minutes before the 
onset of exercise, respectively. 
The secondary endpoints of the study are: 
 Postprandial PG excursion during the test meal (e.g., area under the plasma concentration 
versus time curve [AUC] from time 0 to 4 hours [AUC{0-4h}]) 
 Insulin lispro PK during the MMTT after exercise 
 Insulin lispro PK during the exercise. 
4.3 
Exploratory Objectives and Endpoints  
The exploratory objectives of the study are: 
 To investigate tolerability and safety of Lyumjev and/or Humalog 
 To perform an exploratory comparison of glucose variability, time in range, 
hypoglycemia, and hyperglycemia using continuous glucose monitoring (CGM) profiles 
obtained from participants receiving Lyumjev and Humalog. 
The exploratory endpoints of the study are: 
 Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), 
symptomatic hypoglycemia 
 Blood ketone levels 
 Overall variability (coefficient of variation [CV] and standard deviation [SD]) 
 Time in range (70 to 180 mg/dL) during exercise, MMTT assessment, overnight period, 
and for the entire in-house period 
 Time in hypoglycemia (<70 and <54 mg/dL) and hyperglycemia (>180 and 140 mg/dL) 
 Mean glucose levels. 
5. STUDY DESIGN  
Study ITSU will be a single center, randomized, double-blind, 4-period, crossover Williams 
design exercise and test meal study in physically active adult participants with type 1 diabetes 
using continuous subcutaneous insulin infusion. The study will consist of 2 active treatment 
arms, Lyumjev and Humalog. This study will include a screening visit (Visit 1), visits to 
optimize basal rates (optional based on investigator decision), an assessment day (Visit 2), 4 
in-house study periods with study intervention administration (Visits 3, 4, 5, and 6), and a 
follow-up visit (Visit 7). 


 
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Assessment Day (Visit 2) 
After screening, all eligible participants will have an assessment day (Visit 2) to undergo a 
prolonged exercise session at 45% to 55% of predetermined peak oxygen uptake (VO2) and to 
determine the insulin bolus dose for the MMTT to be performed in the study. 
Participants will be placed on a standardized insulin pump 
 with a 
new infusion set 
 After disconnecting the 
participant’s own insulin pump, the study pump reservoir will be filled with Humalog by a 
qualified Clinical Research Unit (CRU) staff. A standard infusion set and catheter will be 
inserted into the abdominal area, as per the manufacturer’s instructions, after the region is 
inspected for lipodystrophy. The participant’s usual basal rate settings will be programmed in the 
pump and the basal rate infusion will be started. 
A standardized lunch will be provided 
 and the bolus insulin dose will be 
individualized per participant to cover the carbohydrate content. No additional bolus insulin 
injection should be administered postmeal after lunch prior to the exercise period. The basal rate 
will be set to a single hourly rate at lunch based on the participant’s usual basal rate for this time 
of day; this will be maintained until the basal rate reduction for the exercise period. A cannula 
will be inserted for venous access for glucose sampling at around 
 The basal rate in the 
pump will be reduced by 50% at approximately 
 1 hour prior to the exercise assessment. A 
pre-exercise glucose target of 
 will need to be achieved 
 minutes prior to 
exercise. 
 
 
 
Four hours after lunch 
 the participants will be instructed to walk or jog on 
the treadmill at 45% to 55% of their predetermined peak VO2 using three 17-minute intervals 
with two 4-minute and 30-second rest periods in between intervals for a total duration of 1 hour 
(i.e. 
). During the exercise period, heart rate will be monitored 
continuously using a chest strap heart rate monitor, and participants will be asked to rate their 
perceived exertion using 
 Borg rating of perceived exertion (RPE) scale during the last 
2 minutes of each 17-minute interval. Participants will be monitored for safety. If hypoglycemia 
ensues (plasma or whole blood glucose level 
 the exercise will be terminated, and 
the participant will be treated with 
 of oral carbohydrates (dextrose tablets). Upon 
completion of the exercise period, the pump basal rate will be returned to the participant’s usual 
basal rate for this time of the day and this basal rate will be maintained until the end of MMTT. 
Participants will be instructed to rest for approximately 30 minutes. A standardized liquid dinner 
MMTT containing approximately 
 of carbohydrates 
 
will be administered approximately hour after the exercise assessment. Participants are 
expected to complete each test meal within approximately 
minutes of starting the meal. This 
meal will be the same as the meals that will be provided during Visits 3 to 6. The dose-finding 
assessment will use Humalog administered immediately (0 to 2 minutes) before the dinner 
MMTT using 
. Selection of bolus 
dose will be as follows: 
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 Initial bolus dose selection will be based on discussion between participant and 
investigator using participant’s usual dose requirements or insulin-to-carbohydrate ratio, 
insulin sensitivity index, and glycemic targets preprogrammed in their personal medical 
device along with a 25% reduction of the bolus dose to account for increased insulin 
sensitivity following exercise. 
 Postprandial glucose profile over the 4-hour postmeal period will be measured every 
 minutes after administration of proposed insulin dose to verify that the initial bolus 
dose selected is appropriate using the following: 
The selected bolus dose will be used during subsequent liquid dinner MMTT assessments in the 
study for both Lyumjev and Humalog. 
Following completion of glucose sampling, the 
 will be 
removed and the participant’s own insulin pump will be re-introduced using a new infusion set, 
if necessary, for pump compatibility. 
 
Figure 1: Study activities during Assessment day (Visit 2)  
In-house Visits (Visits 3, 4, 5, and 6) 
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After Visit 2, all eligible participants will undergo 4 in-house study periods (Visits 3 to 6). Each 
in-house period will comprise a 2-day stay at the CRU. The in-house period will be separated by 
a washout period of 
 (e.g., between Visit 3, Day 1 and Visit 4, Day 1). Each 
participant will be randomly assigned to a treatment sequence consisting of 2 treatments 
(blinded), i.e., Lyumjev and Humalog, and 2 different basal insulin reduction rates to be 
administered at the 4 separate in-house visits in 4 by 4 crossover Williams design. 
Randomization will take place on Day -1 of Visit 3.  
Upon arrival at the site, participants will be placed on a standardized insulin pump 
 
 with a new infusion set
 and a CGM 
system 
 on the evening before the exercise session 
 
 
After disconnecting the participant’s own insulin pump, the study pump reservoir will be filled 
with either Lyumjev or Humalog by a qualified CRU staff, and a standard infusion set and 
catheter will be inserted into the abdominal area, as per the manufacturer’s instructions, after the 
region is inspected for lipodystrophy. The catheter should stay at the same catheter insertion site 
location for the duration of each period. However, a catheter can be changed to a new location on 
the abdomen if an occlusion is suspected up to the breakfast meal on Day 1. The participant’s 
usual basal rate settings will be programmed in the pump and the basal rate infusion will be 
started. 
The participants will wear the CRU-provided pump and CGM device during all in-house days. 
The CGM device will be calibrated on the morning of the exercise day in fasted state, if needed, 
using the PG values obtained with a glucose analyzer by CRU staff. 
A standardized dinner will be provided at approximately 
 On Day 1, a standardized 
breakfast (
) and lunch (
) will be provided prior to the 
scheduled exercise assessment (
 The insulin dose for these standardized 
meals (dinner, breakfast, and lunch) before exercise will be individualized per participant to 
cover the carbohydrate content (including any correction bolus) and will be administered 
immediately prior (0 to 2 minutes) to the meal using a 
 
 No additional bolus insulin injection should be administered postmeal after 
lunch prior to the exercise period. The basal rate will be set to a single hourly rate at lunch 
 based on the participant’s usual basal rate for this time of day; this will 
be maintained until the basal reduction for the exercise period.
 
 
 
A cannula will be inserted for venous access for insulin lispro, glucose, free fatty acids (FFA) 
and ketones sampling at around
 Based on the randomization, the pump basal rate will be 
reduced either 60 minutes or 15 minutes prior to the start of exercise period, scheduled for 
, in the following manner: 
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 50% basal insulin reduction 60 minutes prior to exercise until end of exercise 
  
 100% basal insulin reduction 15 minutes prior to exercise until end of exercise 
 
Participants will begin the exercise assessment at approximately 4 hours after lunch 
(approximately 3 PM). They will be instructed to walk or light jog on the treadmill at 
approximately 45% to 55% of their predetermined peak VO2 using three 17-minute intervals 
with two 4-minute and 30-second rest periods in between the intervals for 1 hour. During this 
period, samples will be collected for glucose, insulin lispro, ketones and FFAs. Heart rate will be 
monitored, and participants will be asked to rate their perceived exertion using 
 
scale during the last 2 minutes of each 17-minute interval, as per the assessment day visit. If 
hypoglycemia ensues (plasma or whole blood glucose level 
 the exercise will be 
terminated, and the participant will be treated with 
 of oral dextrose. 
Upon completion of the exercise period, the pump basal rate will be returned to the participant’s 
usual rate for this time of the day and this basal rate will be maintained until the end of MMTT. 
Participants will be instructed to rest for approximately 30 minutes. 
A standardized liquid dinner MMTT containing approximately 
 of carbohydrate with a fixed 
nutrient composition 
 will be administered approximately 
 hour after the exercise assessment. The same individualized insulin bolus dose determined 
from the dose assessment will be used for both arms (Lyumjev or Humalog) for all 4 in-house 
visits, unless it is required to be changed to protect participant safety. The insulin bolus dose will 
be administered immediately prior (0 to 2 minutes) to the meal using a 
 
 The meal is to be consumed within 
 minutes. 
Participants will be without further oral food intake from the start of each test meal to completion 
of blood collection 4 hours after the start of the meal (approximately 240 minutes) unless 
required to treat Level 1 hypoglycemia with symptoms or Level 2 hypoglycemia. If a 
participant’s PG concentration rises above 
 for more than  hour, insulin 
glulisine 
 will be administered. In both situations, blood samples for PG (for safety 
and PD) will be taken, and PK samples will be collected as planned during this period. Following 
completion of study procedures, the study pump will be disconnected and the CGM system will 
be removed. The participant’s own insulin pump will be re-introduced using a new infusion set, 
if necessary, for pump compatibility. Participants may leave the CRU at the discretion of the 
investigator. 
Appropriately trained staff must be available until the participants complete the study 
procedures. The pump can be reused after disinfection, according to the local procedure. 
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Figure 2: Study activities during in-house periods (Visits 3, 4, 5, and 6)  
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Abbreviations: ED = early discontinuation; R = randomization; T1D = type 1 diabetes mellitus. Randomization on Day -1 of 
Visit 3 only. Participants will be blinded to study intervention during the in-house periods. 
Figure 3: Treatment schedule for in-house study periods (Visits 3 to 6)  
6. TREATMENTS  
The following is a list of the study treatment abbreviations that will be used in the TFLs. 
Study Treatment Name 
Abbreviation 
Treatment 
order in TFL 
Lyumjev with 50% basal rate reduction  
Treatment A 
1 
Lyumjev with 100% basal rate reduction  
Treatment B 
2 
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Humalog with 50% basal rate reduction  
Treatment C 
3 
Humalog with 100% basal rate reduction  
Treatment D 
 
4 
The following is a list of the study treatment sequences that will be used in the demographics and 
vital signs TFLs. 
Study Treatment Sequence 
Abbreviation 
Treatment 
order in 
TFL 
Treatment A/ Treatment D/ Treatment B/ Treatment C 
A/D/B/C 
1 
Treatment B/ Treatment A/ Treatment C/ Treatment D 
B/A/C/D 
2 
Treatment C/ Treatment B/ Treatment D/ Treatment A 
C/B/D/A 
3 
Treatment D/ Treatment C/ Treatment A/ Treatment B 
D/C/A/B 
4 
7. SAMPLE SIZE JUSTIFICATION  
Approximately 32 participants may be enrolled to ensure that at least 28 participants complete 
the study. 
This sample size will provide approximately 80% power to demonstrate a 14-mg/dL difference 
in the change in PG level from start to the end of the exercise between Lyumjev and Humalog, 
assuming no true difference in the change in PG level between Lyumjev and Humalog and a SD 
of 27.9 mg/dL with a 2-sided alpha-level of 0.1. Discontinued participants may be replaced to 
ensure that 28 participants complete the trial. A replacement participant will be assigned to the 
same treatment sequence as the participant being replaced. 
8. DEFINITION OF ANALYSIS POPULATIONS  
The “Safety analysis” population will consist of all participants who are exposed to at least 1 
dose of investigational product (IP). Participants will be analyzed according to the intervention 
they actually received. 
The “Full analysis” population will consist of participants who receive at least 1 dose of IP and 
have completed at least 1 MMTT procedure will be included in the analysis set for the PD 
analyses. Participants who receive at least 1 dose of insulin during the in-house period and have 
measurable insulin lispro concentrations will be included in the PK analysis dataset. 
The “Modified full analysis” population will consist of all participants who receive both 
treatments (Lyumjev and Humalog) for at least 1 basal rate reduction (either 50% or 100%) and 
receive the same dose and meal consumption. Participants who do not keep identical insulin 
lispro doses for Lyumjev and Humalog or have difference in the consumption of the meal for 
each visit/period will be excluded from the statistical analysis of the PK and glucodynamic 
parameters. All participants who receive both treatments with an identical insulin lispro dose for 
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All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when participants are assigned to analysis populations. 
9. STATISTICAL METHODOLOGY  
9.1 
General  
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic SD, median, min, max and n; for 
log-normal data (e.g. the PK parameters: AUCs and maximum observed drug concentration 
[Cmax]) the geometric mean and geometric CV% will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all 
participants up to the point of withdrawal, with any participants excluded from the relevant 
population highlighted. Summary statistics and statistical analyses will generally only be 
performed for participants included in the relevant analysis population. For the calculation of 
summary statistics and statistical analysis, unrounded data will be used.  
Mean change from baseline is the mean of all individual participants’ change from baseline 
values. Each individual change from baseline will be calculated by subtracting the individual 
participant’s baseline value from the value at the timepoint. The individual participant’s change 
from baseline values will be used to calculate the mean change from baseline using a SAS 
procedure such as Proc Univariate. 
Data analysis will be performed using SAS® Version 9.4 or greater. 
9.2 
Demographics and Participant Disposition  
Participant disposition will be summarized and listed. The demographic variables age, sex, race, 
ethnicity, duration of diabetes (years), screening glycated hemoglobin (%), screening C-peptide, 
smoking & alcohol habits, insulin therapy, VO2 max, body weight, height and body mass index 
will be summarized and listed. All other demographic variables will be listed only. 
9.3 
Pharmacokinetic Assessment  
9.3.1 
Pharmacokinetic Parameter Estimation  
The PK analyses will be conducted using standard noncompartmental methods of analysis 
 on a computer that 
meets or exceeds the minimum system requirements for these programs. The version of any 
software used for the analysis will be documented, and the program will meet the Lilly 
requirements of software validation. It is possible that other validated equivalent PK software 
programs may be utilized if appropriate, warranted, and approved by global PK management. 
Free serum insulin lispro concentrations will be used to calculate several PK parameters 
following the meal bolus for the MMTT, including: 
 time to early half-maximal drug concentration (early 50% tmax), 
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  time to late half-maximal drug concentration (late 50% tmax),  
 maximum observed drug concentration (Cmax), 
  time of maximum observed drug concentration (tmax),  
 AUC from zero to 15 minutes (AUC[0-15min]),  
 AUC from time zero to 30 minutes (AUC[0-30min]),  
 AUC from time zero to 1 hour (AUC[0-1h]),  
 AUC from time zero to 4 hours (AUC[0-4h]),  
 AUC from time zero to infinity (AUC[0-∞]).  
Other parameters may be calculated as deemed appropriate. Additional partial AUCs may be 
computed as necessary. If the prebolus insulin lispro concentrations differ between Lyumjev and 
Humalog prior to the MMTT, the change from baseline values
 
will be used to subtracting the baseline value from all post-dose insulin lispro 
measurements to calculate the PK parameters. Similarly, the prebolus insulin lispro 
concentrations differ between Lyumjev and Humalog prior to the lunch before the exercise 
period, the PK sample collected immediately prior to the bolus will represent as the 0-hour time 
point for each participant and will be used to subtracting the baseline value from all post-dose 
insulin lispro measurements to calculate the PK parameters. Other baseline normalization 
approaches may be explored for assessing the insulin lispro concentrations during the basal 
reduction. The approach used will be documented in the CSR. 
Additionally, an analysis will be conducted to assess the insulin lispro PK during the basal 
insulin suspension period. PK parameters that were used included the terminal half-life (t1/2), 
time of the last concentration prior to dose (tlast) and AUC from time of suspension to the time of 
the last detectable concentration (AUC[0-tlast]). The insulin lispro concentration versus time 
profile will be compared between Lyumjev and Humalog during this time. 
Although attempts will be made to adhere to the scheduled collection times, failure to collect PK 
samples due to legitimate clinical issues will not be considered as protocol deviations. 
Parameters will be individually calculated for each participant based on actual collection times. 
The mean data will be presented by summary statistics and presented by treatment for those 
participants who received both treatments (Lyumjev and Humalog) with the same insulin dose 
(bolus dose for the MMTT or basal reduction) and meal consumption. 
PK analysis is the responsibility of Eli Lilly and Company. 
9.3.2 
Pharmacokinetic Statistical Methodology  
The modified full analysis population will be used for these analyses. The PK parameters for the 
MMTT and during exercise will be analyzed separately. 
During the MMTT 
Log-transformed PK parameters AUCs, and Cmax from insulin lispro during the MMTT will be 
statistically analyzed using a mixed-effect model. The model will include treatment (Lyumjev or 
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Humalog) and period as fixed effects, and participant as a random effect. The least squares (LS) 
means will be back-transformed to produce the treatment geometric LS means, ratio of geometric 
LS means of Lyumjev to Humalog, and corresponding 90% CIs, as well as the p-value, will be 
reported. 
Example of the SAS code is as follows: 
proc mixed data=xxx; 
class treat period usubjid; 
model logPK = treat period /residual ddfm=kr; 
random usubjid; 
lsmeans treat / cl pdiff alpha=0.1; 
estimate ‘Lyumjev vs Humalog' treat 1 -1/ CL alpha=0.1; 
ods output lsmeans=lsm diffs=estims; 
run; 
The same analysis without log transformation will be performed on the PK time parameters 
(early 50% tmax, late 50% tmax, and tmax ) during the MMTT. The treatment LS means, treatment 
difference in LS means between Lyumjev and Humalog, and corresponding 90% CIs, as well as 
the 2-sided p-value, will be reported. The treatment ratios and 90% CIs for the ratios will be 
calculated using the Fieller’s theorem3, see Appendix 2 for further details on this calculation. 
Statistical significance will be achieved when the p-value for a test is less than 0.10. 
During exercise 
A mixed-effects model without log transformation that includes treatment (Lyumjev with 50% 
basal reduction, Lyumjev with 100% basal reduction, Humalog with 50% basal reduction, and 
Humalog with 100% basal reduction), sequence, and period as fixed effects and participant-
within-sequence as a random effect may be used for the exploratory PK endpoints during the 
exercise period. LS means, treatment differences in LS means, and the corresponding 90% CIs 
for the treatment differences will be estimated from the model. The p-value on the difference 
between LS means will be used to determine statistical significance. The treatment ratios and 
90% CIs for the ratios will be calculated using the Fieller’s theorem (Chow and Liu 2009). 
Additionally, exploratory analysis may be conducted if deemed necessary upon review of the 
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9.4 
Pharmacodynamic Assessment  
9.4.1 
Pharmacodynamic Analysis  
Blood Ketones and Free Fatty Acids 
Blood ketones and free fatty acids data will be summarized by timepoint and treatment, and 
listed. 
Glucodynamic Parameter Estimation 
Glucodynamic data will be determined from the plasma glucose (PG) reported from the YSI 
glucose analyzer during the exercise and MMTT assessment. 
Glucodynamic data will be analyzed for the participants during each exercise and MMTT 
assessment. During the exercise period, the change from baseline value (the 0-hour time point 
prior to the start of exercise) for each participant will be calculated to derive the change in PG 
level from start to end of exercise.  
The rate of PG during the exercise, the nadir PG, decremental AUC, for each exercise 
assessments will be calculated. 
During the MMTT, the change from baseline values
 
for each participant will be calculated. The approach used will be documented in the CSR. 
The area under the baseline subtracted PG concentration versus time curve (incremental) (iAUC) 
will be calculated during the MMTT for each in-house periods; the list of derived iAUCs are: 
 The incremental AUC from time zero to 30 minutes postmeal (iAUC0-30min) 
 The incremental AUC from time zero to 1-hour postmeal (iAUC0-1hour) 
 The incremental AUC from time zero to 2-hours postmeal (iAUC0-2hour) 
 The incremental AUC from time zero to 3-hours postmeal (iAUC0-3hour) 
 The incremental AUC from time zero to 4-hours postmeal (iAUC0-4hour) 
In addition, the change from baseline maximum PG observed during the 4 hours postmeal 
(ΔPGmax) and change from baseline 1-hour plasma glucose (ΔPG1h) and 2-hour plasma glucose 
after the start of the meal (ΔPG2h) will be calculated. Other partial iAUCs may be calculated, as 
deemed appropriate. 
The mean data will be presented by summary statistics and presented by treatment for those 
participants who received both treatments (Lyumjev and Humalog) with the same insulin dose 
(bolus dose for the MMTT or basal reduction) and meal consumption. The data will also be 
listed. 
This will be the responsibility of Eli Lilly and Company. 
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9.4.2 
Pharmacodynamic Statistical Methodology  
Primary glucodynamic endpoint 
Changes in PG from the start to end of exercise will be statistically analyzed using a mixed–
effect model. The model will include treatment (Lyumjev with 50% basal reduction, Lyumjev 
with 100% basal reduction, Humalog with 50% basal reduction, and Humalog with 100% basal 
reduction), sequence, period, timepoint, treatment-by-timepoint interaction as fixed effects, and 
participant-within-sequence as a random effect. Baseline (0 min timepoint) will be included as a 
covariate. The LS means, difference LS means between Lyumjev and Humalog for 
corresponding basal rate reduction, and corresponding 90% CIs, as well as the p-value, will be 
reported. 
The p-value on the difference between LS means will be used to determine statistical 
significance. 
Secondary glucodynamic endpoints 
For the derived glucodynamic parameters iAUCs  ΔPGmax, ΔPG1h, and ΔPG2h, a statistical 
analysis will be performed during exercise with a basal reduction, and after the MMTT 
independently. The modified full analysis population will be used for this analysis.  
The parameters iAUCs during the MMTT and AUCs during exercise will be log-transformed 
before the statistical analysis. If negative values occur, the analysis will be performed on 
untransformed parameters. A mixed effects model will be used for this analysis. The model will 
include treatment (Lyumjev with 50% basal reduction, Lyumjev with 100% basal reduction, 
Humalog with 50% basal reduction, and Humalog with 100% basal reduction), sequence, and 
period as fixed effects, and participant-within-sequence will be included as a random effect. The 
LS means will be back-transformed to produce geometric means. The treatment geometric LS 
mean of each treatment, ratio of geometric means between Lyumjev and Humalog for 
corresponding basal rate reduction, and corresponding 90% CIs will be reported. The p-value 
will also be reported for the ratios. If the analysis is done on the untransformed parameters, the 
treatment LS means, difference in LS means between Lyumjev and Humalog for corresponding 
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basal rate reduction, and corresponding 90% CIs, as well as the p-value, will instead be reported.  
The treatment ratios and 90% CIs for the ratios will be calculated using the Fieller’s theorem. 
The rate of change in PG during exercise period and exploratory GD time parameters will also be 
statistically analyzed. A mixed effect model will be used, identical to the one above, on the 
actual values of the parameters. The LS means, difference in LS means between Lyumjev and 
Humalog for corresponding basal rate reduction, and corresponding 90% CIs, as well as the 
p-value, will be reported. The treatment ratios and 90% CIs will be reported using Fieller’s 
theorem. 
Additionally, exploratory analysis may be conducted if deemed necessary upon review of the 
data. 
9.5 
Exploratory PD Analysis  
9.5.1 
Continuous Glucose Monitoring  
Continuous glucose monitoring data will be collected during the exercise, test meal assessments, 
and overnight periods (Day -1 from 
 on Day 1) as both duration (in minutes and 
percentage of time in range with glucose values between 70 and 180 mg/dL (3.9 and 10.0 
mmol/L), inclusive. The parameters to be derived from the CGM data are: 
 duration (in minutes) and percentage of time of hypoglycemia with glucose values <54 
and <70 mg/dL (3.0 and 3.9 mmol/L) 
 duration (in minutes) and percentage of time of hyperglycemia with glucose values >180 
and >250 mg/dL (10.0 and 13.9 mmol/L) 
 mean glucose 
 overall variability (CV and SD) 
The parameters will be summarized by treatment and test period (exercise, test meal, in-house 
period, or overnight), and listed. 
The derived CGM parameters will be statistically analyzed for each test period independently 
using a mixed-effect model. The modified full analysis population will be used for the analysis. 
The model will include treatment, sequence, and period as fixed effects, and 
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participant-within-sequence as a random effect. For the in-house and overnight time periods, the 
categorical variable treatment will have two levels, Lyumjev and Humalog, whereas the exercise 
and test meal periods will have four levels, Lyumjev with 50% basal reduction, Lyumjev with 
100% basal reduction, Humalog with 50% basal reduction, and Humalog with 100% basal 
reduction. The LS means, difference LS means between Lyumjev and Humalog for 
corresponding basal rate reduction (test meal and exercise time periods only), difference in LS 
means between Lyumjev and Humalog (in-house and overnight time periods only), and 
corresponding 90% CIs, as well as the p-value, will be reported.  
If appropriate, the treatment variable for the in-house time period will be changed to use four 
factors, using the same factors as the test meal and exercise time periods. 
9.5.2 
Free Fatty Acids and Ketones  
Ketone and FFAs levels will be analyzed for the participants during each exercise and MMTT 
assessment.  The mean data will be presented by summary statistics and presented by treatment 
for those participants who received both treatments (Lyumjev and Humalog) with the same 
insulin dose (bolus dose for the MMTT or basal reduction) and meal consumption. The data may 
be presented graphically. A statistical analysis may be conducted upon review of the data. If a 
statistical analysis is conducted the same or similar model will be used as presented for the 
glucodynamic endpoints. 
9.6 
Safety and Tolerability Assessments  
9.6.1 
Adverse events  
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as a condition that starts before the 
participant has provided written informed consent and is ongoing at consent. A non-treatment 
emergent AE is defined as an AE which starts after informed consent but prior to dosing. A 
TEAE is defined as an AE which occurs postdose or which is present prior to dosing and 
becomes more severe postdose.  
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All AEs will be listed. Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of participants 
experiencing an AE and the percentage of participants experiencing an AE) of 
treatment-emergent AEs will be summarized by treatment, Medical Dictionary for Regulatory 
Activities (MedDRA) version 24.1 system organ class and preferred term. The summary and 
frequency AE tables will be presented for all causalities and those considered related to the study 
drug by the investigator. Any serious AEs will be listed. 
Discontinuations due to AEs will be listed. 
9.6.2 
Glucose Monitoring and Hypoglycemia  
During the study, blood glucose concentrations will be monitored for safety assessments using 
YSI and CGM (see Section 9.5.9 for further information).  
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
any treatments administered. Each category of hypoglycemic events (defined below) will be 
listed and summarized by treatment. Hypoglycemia is defined as follows:  
 Level 1 hypoglycemia:  
Glucose 
   
o Can alert a person to take action such as treatment with fast-acting carbohydrates. 
Providers should continue to counsel participants to treat hypoglycemia at this 
glucose alert value. 
 Level 2 hypoglycemia: 
Glucose 
   
o Also referred to as documented or blood glucose confirmed hypoglycemia with 
glucose 
 This glucose threshold is clinically relevant 
regardless of the presence or absence of symptoms of hypoglycemia. 
 Level 3 hypoglycemia: 
Severe hypoglycemia (in adults): A severe event characterized by altered mental and/or 
physical status requiring assistance for treatment of hypoglycemia. For example, 
participants had altered mental status, and could not assist in their own care, or were 
semiconscious or unconscious, or experienced coma with or without seizures, and the 
assistance of another person was needed to actively administer carbohydrate, glucagon, or 
other resuscitative actions. Glucose measurements may not be available during such an 
event, but neurological recovery attributable to the restoration of glucose concentration to 
normal is considered sufficient evidence that the event was induced by a low glucose 
concentration. 
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The determination of a hypoglycemic event as an episode of severe hypoglycemia, as defined 
above, is made by the investigator based on the medical need of the participant to have required 
assistance and is not predicated on the report of a participant simply having received assistance. 
If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator must record 
the event as serious on the AE CRF and report it to Lilly as an SAE. 
 Other hypoglycemia: 
o Nocturnal hypoglycemia: A hypoglycemia event (including severe 
hypoglycemia) that occurs at night and presumably during sleep 
Investigator’s review of glucose results clinically indicative of hypoglycemia will be required. 
Participants that are administered and consume carbohydrates during the in-house period will be 
listed. 
9.6.3 
Concomitant medication  
Concomitant medication will be coded using the WHO drug dictionary (Version 
September 2021). Concomitant medication will be listed. 
9.6.4 
Clinical laboratory parameters  
Clinical laboratory data are collected at screening only and, with the exception of those reported 
in the demographics, will not be presented.   
9.6.5 
Vital signs  
Vital signs data will be listed for individual participants. 
9.6.6 
Electrocardiogram (ECG)  
ECGs will be performed for screening and will not be presented. 
9.6.7 
Perceived Exertion during Exercise  
The 
 scale is a well-validated tool4 to assess perceived physical effort during 
exercise; it is presented as a scale 
 anchored by verbal descriptors. This scale describes 
different efforts:  is no exertion at all and 
 the maximal exertion or hardest possible effort. 
Participants will be asked to point to a number that best describes their feelings of the exercise at 
that moment. 
During screening, prospective study participants will have their exercise capacity assessed during 
a progressive treadmill exercise test until volitional fatigue, as part of the study eligibility. As 
part of this assessment, the RPE score will be collected every 2 minutes.  The data will be listed 
for those participants who are then enrolled into the study. 
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During each exercise period, participants will record their perceived physical effort using the 
RPE score the last 2 minutes of each exercise interval over the 1-hour exercise period. The data 
will be listed and summarized by assessment day (Visit 2-Humalog) and in-house visit (Visit 
3,4,5,6) and by treatment (Lyumjev vs Humalog for the corresponding basal rate reduction). 
9.6.8 
Other assessments  
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.6.9 
Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned. 
10. 
INTERIM ANALYSES  
No interim statistical analyses are planned. 
11. 
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES  
There were no changes from the protocol specified statistical analyses. 
12. 
REFERENCES  
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
3. Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. 3rd 
ed. Taylor and Francis Group, LLC; 2009:p 88-90. 
5. September 17, 2020. Accessed October 22, 2021. 
13. 
DATA PRESENTATION  
13.1 
Derived Parameters  
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values. 
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13.2 
Missing Data  
Missing data will not be displayed in listings. 
13.3 
Insufficient Data for Presentation  
Some of the TFLs may not have sufficient numbers of participants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, “No serious adverse events occurred for this study.” 
 
 


 
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14. 
APPENDICES  
Appendix 1: Document History  
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
Final Version 2.0 
31MAR2023 
Update to primary analysis 
NA = not applicable 
 
 


 
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Appendix 2: Supplementary material  
To find the CIs associated with the treatment ratio 𝜇𝑇𝜇𝑅
⁄
, Fieller’s theorem will be used, the 
equations to calculate the lower and upper interval values as follows: 
𝐿1−∝2
⁄ =
1
1−𝐺{(𝑌𝑇
̅̅̅
𝑌𝑅
̅̅̅
⁄
−𝐺 𝑆𝑅𝑅
𝑆𝑅𝑅
2
⁄
) −[𝑡(∝2
⁄ , 𝑛1 + 𝑛2 −2) √𝜔𝑆𝑅𝑅
2
𝑌𝑅
̅̅̅
⁄
 𝐺∗]}, 
𝑈1−∝2
⁄ =
1
1−𝐺{(𝑌𝑇
̅̅̅
𝑌𝑅
̅̅̅
⁄
−𝐺 𝑆𝑅𝑅
𝑆𝑅𝑅
2
⁄
) + [𝑡(∝2
⁄ , 𝑛1 + 𝑛2 −2) √𝜔𝑆𝑅𝑅
2
𝑌𝑅
̅̅̅
⁄
 𝐺∗]}, 
where 
𝐺= [𝑡(∝2
⁄ , 𝑛1 + 𝑛2 −2)]
2 (𝜔𝑆𝑅𝑅
2
𝑌𝑅
2
̅̅̅
⁄
), 
𝐺∗= (𝑌𝑇
̅̅̅
𝑌𝑅
̅̅̅
⁄ )
2
+ 𝑆𝑇𝑇
2
𝑆𝑅𝑅
2
⁄
(1 −𝐺) + 𝑆𝑇𝑅
𝑆𝑅𝑅
2
⁄
(𝐺𝑆𝑇𝑅
𝑆𝑅𝑅
2
⁄
−2 𝑌𝑇
̅̅̅
𝑌𝑅
̅̅̅
⁄ ), 
𝜔= 1 4
⁄ (1 𝑛1
⁄
+ 1 𝑛2
⁄
), 
𝑌𝑅
̅̅̅ is the LSM estimate of the reference mean, 𝑌𝑇
̅̅̅ is the LSM estimate of the treatment mean, and 
t(a,q) is the value of the student’s t-distribution pdf at the ath percentile with q degrees of 
freedom. 


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Approval
31-Mar-2023 16:22:24 GMT+0000
Approval
03-Apr-2023 09:21:09 GMT+0000
Approval
05-Apr-2023 03:13:35 GMT+0000
Approved on 05 Apr 2023 GMT
PPD
PPD
PPD