Clinical trial NCT04585776
Conditions: Type 1 Diabetes
Sponsor: Eli Lilly and Company
Start date: 2020-10-30; Completion date: 2021-05-27
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this study, participants with type 1 diabetes (T1D) will take the study drug LY900014 and insulin degludec. The reason for this study is to evaluate the amount of time with glucose values within target range.

Detailed description:

Arms: arm 1: LY900014 (100 units/milliliter (U/mL)) is a prandial insulin administered subcutaneously (SC) 0-2 minutes before meals. Insulin degludec (100 U/mL) is a basal insulin administered once daily SC. Participants received individually adjusted insulin doses during the 35-day titration period. The target glucose values were: fasting glucose 80-110 milligrams per deciliter (mg/dL), overnight glucose excursion (the difference between bedtime and prebreakfast glucose levels) \< or = +/- 30 mg/dL, postprandial glucose peak \<140 mg/dL or \<20% increase from premeal level. Following the titration period, there was an 11-day maintenance period during which the doses were kept unchanged unless for safety reasons.
Interventions: intervention 1: LY900014 intervention 2: Insulin Degludec
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Protocol: I8B-MC-ITSZ(b) 
 
 
An Exploratory Study Assessing Time in Target Glucose Range Using a New 
Titration Scheme of LY900014 and Insulin Degludec in Participants with Type 
1 Diabetes 
 
 
NCT04585776 
 
 
Approval Date: 24-Nov-2020 


CONFIDENTIAL
I8B-MC-ITSZ(b)
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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: An Exploratory Study Assessing Time in Target Glucose Range Using a New
Titration Scheme of LY900014 and Insulin Degludec in Participants with Type 1 
Diabetes
Protocol Number: I8B-MC-ITSZ
Amendment Number: (b)
Compound: LY900014
Study Phase: Phase 2
Short Title: Dose optimization study
Acronym: ITSZ
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana, USA 46285
Regulatory Agency Identifier Number(s)
IND: 127210
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 24-Nov-2020 GMT


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I8B-MC-ITSZ(b)
2
Medical Monitor Name and Contact Information will be provided separately.


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I8B-MC-ITSZ(b)
3
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment (a)
12-Jul-2020
Original protocol I8B-MC-ITSZ
08-Jun-2020
Amendment [b] 
Overall Rationale for the Amendment:
The main purpose of this protocol amendment is to modify the inclusion criteria related to the 
type of rapid-acting insulin analog and the CGM system used at study entry. 
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
(SoA), 4.1.1 Study visits
Updated language regarding use of 
personal CGM system at Visit 13
Clarification based on an update to inclusion 
criterion #12
1.3 Schedule of Activities 
(SoA), 4.1.1 Study visits
Updated the note that participants 
who enter the study on Novolog, 
Admelog, or Apidra will transition 
to Humalog at Visit 2
Clarification based on an update to inclusion 
criterion #6
5 Study population
Updated language regarding type of
rapid-acting insulin analog used
Clarification based on an update to inclusion 
criterion #6
5.1 Inclusion Criteria
Updated criterion #6 regarding the 
types of rapid-acting insulin analog
used
To update criterion to include Admelog and
Apidra as rapid-acting insulin analog used
5.1 Inclusion Criteria
Updated criterion #12 to clarify the 
use of CGM system
To update criterion to include unblinded 
personal CGM use of at least 2 months in 
the prior 6 months
8.3 Adverse events and 
serious adverse events
Removed the term ‘legally 
authorized representative’
To remove the term ‘legally authorized
representative’ as only study participants
can provide informed consent
Appendix 10.1.3
Updated section regarding informed 
consent process
To remove the term ‘legally authorized
representative’ as only study participants
can provide informed consent
Throughout
Minor editorial and document 
formatting revisions
These are minor changes; therefore, they 
have not been summarized


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I8B-MC-ITSZ(b)
4
Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.........................................................................................................................8
1.3.
Schedule of Activities (SoA) ........................................................................................9
2.
Introduction..............................................................................................................19
2.1.
Study Rationale ..........................................................................................................19
2.2.
Background ................................................................................................................20
2.3.
Benefit-Risk Assessment ............................................................................................22
2.3.1.
Risk Assessment.........................................................................................................23
2.3.2.
Benefit Assessment.....................................................................................................25
2.3.3.
Overall Benefit: Risk Conclusion................................................................................25
3.
Objectives and Endpoints.........................................................................................26
4.
Study Design .............................................................................................................28
4.1.
Overall Design............................................................................................................28
4.1.1.
Study Visits ................................................................................................................28
4.2.
Scientific Rationale for Study Design .........................................................................32
4.3.
Justification for Dose..................................................................................................32
4.3.1.
Target Glucose Values for Titration of Insulin Therapy ..............................................33
4.3.2.
LY900014 ..................................................................................................................33
4.3.3.
Insulin Degludec.........................................................................................................34
4.4.
End of Study Definition..............................................................................................34
5.
Study Population ......................................................................................................35
5.1.
Inclusion Criteria........................................................................................................35
5.2.
Exclusion Criteria.......................................................................................................37
5.3.
Lifestyle Considerations .............................................................................................39
5.3.1.
Meals and Dietary Restrictions ...................................................................................40
5.3.2.
Activity ......................................................................................................................40
5.4.
Screen Failures...........................................................................................................40
6.
Study Intervention....................................................................................................41
6.1.
Study Intervention(s) Administered ............................................................................41
6.1.1.
Medical Devices.........................................................................................................41
6.2.
Preparation/Handling/Storage/Accountability.............................................................42
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................42
6.4.
Study Intervention Compliance...................................................................................42
6.5.
Concomitant Therapy .................................................................................................42
6.6.
Dose Modification......................................................................................................43
6.7.
Intervention after the End of the Study........................................................................43
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................44
7.1.
Discontinuation of Study Intervention ........................................................................44
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................44
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................45


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I8B-MC-ITSZ(b)
5
7.3.
Lost to Follow-up .......................................................................................................45
8.
Study Assessments and Procedures .........................................................................46
8.1.
Efficacy Assessments .................................................................................................46
8.1.1.
Primary Efficacy Assessments....................................................................................46
8.1.2.
Secondary Efficacy Assessments ................................................................................46
8.2.
Safety Assessments ....................................................................................................46
8.2.1.
Physical Examinations................................................................................................46
8.2.2.
Vital Signs..................................................................................................................46
8.2.3.
Electrocardiograms.....................................................................................................47
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................47
8.2.5.
Self-monitoring of Blood Glucose ..............................................................................47
8.2.6.
Hypoglycemia ............................................................................................................47
8.2.7.
Safety Monitoring.......................................................................................................48
8.3.
Adverse Events and Serious Adverse Events ..............................................................49
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................49
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................49
8.3.3.
Follow-up of AEs and SAEs.......................................................................................49
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................50
8.3.5.
Pregnancy...................................................................................................................50
8.3.6.
Adverse Events of Special Interest..............................................................................50
8.3.7.
Product Complaints ....................................................................................................50
8.4.
Treatment of Overdose ...............................................................................................51
8.5.
Pharmacokinetics........................................................................................................51
8.6.
Pharmacodynamics.....................................................................................................51
8.7.
Genetics .....................................................................................................................51
8.8.
Biomarkers.................................................................................................................51
8.9.
Immunogenicity Assessments.....................................................................................51
8.10.
Health Economics.......................................................................................................52
9.
Statistical Considerations.........................................................................................53
9.1.
Statistical Hypotheses.................................................................................................53
9.2.
Sample Size Determination.........................................................................................53
9.3.
Populations for Analyses ............................................................................................53
9.4.
Statistical Analyses.....................................................................................................53
9.4.1.
General Considerations...............................................................................................53
9.4.2.
Primary Endpoint(s) ...................................................................................................54
9.4.3.
Secondary Endpoint(s)................................................................................................55
9.4.4.
Exploratory Endpoints................................................................................................55
9.4.5.
Other Safety Analyses ................................................................................................55
9.4.6.
Other Analyses ...........................................................................................................55
9.5.
Interim Analyses.........................................................................................................56
9.6.
Data Monitoring Committee .......................................................................................56
10.
Supporting Documentation and Operational Considerations ................................57
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................57


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I8B-MC-ITSZ(b)
6
10.1.1.
Regulatory and Ethical Considerations........................................................................57
10.1.2.
Financial Disclosure ...................................................................................................57
10.1.3.
Informed Consent Process ..........................................................................................58
10.1.4.
Data Protection...........................................................................................................58
10.1.5.
Dissemination of Clinical Study Data .........................................................................58
10.1.6.
Data Quality Assurance ..............................................................................................59
10.1.7.
Source Documents......................................................................................................60
10.1.8.
Study and Site and Closure .........................................................................................60
10.1.9.
Publication Policy.......................................................................................................61
10.1.10. Investigator Information .............................................................................................61
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................62
10.2.1.
Hypersensitivity Clinical Laboratory Tests .................................................................63
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................65
10.3.1.
Definition of AE.........................................................................................................65
10.3.2.
Definition of SAE.......................................................................................................66
10.3.3.
Recording and Follow-up of AE and/or SAE ..............................................................67
10.3.4.
Reporting of SAEs......................................................................................................69
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................70
10.5.
Appendix 5: Hepatic Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................73
10.5.1.
Hepatic Evaluation Testing.........................................................................................75
10.6.
Appendix 9: Abbreviations .........................................................................................77
10.7.
Appendix 10: Protocol Amendment History ...............................................................81
11.
References.................................................................................................................82


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I8B-MC-ITSZ(b)
7
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: An exploratory study assessing time in target glucose range using a new titration 
scheme of LY900014 and insulin degludec in participants with Type 1 Diabetes
Short Title: Dose Optimization study
Rationale: In clinical practice, prandial insulins are often titrated based on ‘next pre-meal 
glucose’. For example, clinicians use the pre-lunch blood glucose value to assess the adequacy of 
the breakfast prandial dose. This commonly used titration scheme may not be fully optimized for 
the novel time-action profile of LY900014. An alternate approach of using peak post-prandial 
glucose (PPG) values or the change from pre-meal levels may be better-suited to titrating ultra-
rapid acting prandial insulins. In particular, the ‘faster on-faster off’ profile of LY900014 might 
allow more aggressive prandial dosing that would further improve PPG without increasing the 
risk of late post-meal hypoglycemia.
The aim of this study is to evaluate the percentage of time with glucose values within target 
range (70 to 180 mg/dL, both inclusive) after 35 days of using a new titration scheme with 
LY900014 treatment and degludec.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the time that glucose values are 
within the target range 70 to 180 mg/dL from 
CGM use, after 35 days of using the study
titration scheme with LY900014 treatment and 
degludec
Percentage of time with sensor glucose 
values between 70 and 180 mg/dL (both 
inclusive), with CGM use during the 
maintenance period
Secondary
To evaluate ICR with LY900014 treatment
ICR at the end of the maintenance period
To evaluate the relationship between ICR and 
TDD with LY900014 treatment
ICR×TDD for the maintenance period
To evaluate total daily, basal, and prandial 
insulin dose with LY900014 treatment and 
degludec
Prandial: TDD ratio for the maintenance 
period
Abbreviations: CGM = continuous glucose monitoring; ICR = insulin-to-carbohydrate ratio; TDD = Total Daily 
Dose.


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I8B-MC-ITSZ(b)
8
Overall Design
Study I8B-MC-ITSZ (ITSZ) is a multicenter, single-group, open-label, Phase 2 study that will be 
conducted in participants with type 1 diabetes (T1D) currently treated with insulin degludec and 
a rapid-acting insulin analog in a multiple daily injection (MDI) regimen. The objective of the 
study is to assess the percentage of time glucose values are within the target range of 70 to 180 
mg/dL after 35 days of titration using the study titration scheme of LY900014 and insulin 
degludec in participants with type 1 diabetes.
Disclosure Statement: This is a single treatment group study with no masking.
Number of Participants
Approximately 34 participants will be assigned to study treatment intervention such that 
approximately 30 evaluable participants complete the study. 
Intervention Groups and Duration
The total duration of study participation for each participant is approximately 74 days across the 
following study periods:

Screening, up to 10 days

Lead in period, 11 days

Treatment period
o
Titration period, 35 days
o
Maintenance period, 11 days

Safety follow-up period, 7 days
Data Monitoring Committee: 
No.
1.2.
Schema
T = Telephone visits


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I8B-MC-ITSZ(b)
9
1.3.
Schedule of Activities (SoA)
Screen Lead in 
Period
-11 to 
-1
Treatment Period
Safety 
Follow-
up
ET
Titration Period
Days 0 to 35
Maintenance
Days 36 to 
46
Days 47
to 53
Day
-21 to
-12
-11
0
3
7
10
14
17
21
24
28
31
35
46
53
ET
Visit Window (days)
0
+/-3
+3 -1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
+3
+/-3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
801
ET
Telephone visits are indicated by shaded columns. Telephone visits can become office visits. Site documentation will serve as the source for telephone visits.
Informed Consent 
Signed
X
Participant eligibility 
review
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Assessments
Participant demographics
X
Medical history and 
preexisting conditions
X
Physical exam. /height
X
Body Weight
X
X
X
X
X
X
Note: Participants should be advised to remove their shoes/coats and empty their pockets before the body weight is obtained.


CONFIDENTIAL
I8B-MC-ITSZ(b)
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Screen Lead in 
Period
-11 to 
-1
Treatment Period
Safety 
Follow-
up
ET
Titration Period
Days 0 to 35
Maintenance
Days 36 to 
46
Days 47
to 53
Day
-21 to
-12
-11
0
3
7
10
14
17
21
24
28
31
35
46
53
ET
Visit Window (days)
0
+/-3
+3 -1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
+3
+/-3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
801
ET
Vital signs
blood pressure and heart 
rate
X
X
X
X
X
X
Note: Vital sign measurements should be determined after participants have been seated quietly for at least 5 minutes in a chair with 
feet on the floor. The arm used for blood pressure measurement should be supported at heart level
ECG (12-lead, local)
X
Participants must be supine for approximately 5 to 10 minutes before ECG collection and remain supine, but awake, during ECG 
collection.
Concomitant medications X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events and 
product complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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I8B-MC-ITSZ(b)
11
Screen Lead in 
Period
-11 to 
-1
Treatment Period
Safety 
Follow-
up
ET
Titration Period
Days 0 to 35
Maintenance
Days 36 to 
46
Days 47
to 53
Day
-21 to
-12
-11
0
3
7
10
14
17
21
24
28
31
35
46
53
ET
Visit Window (days)
0
+/-3
+3 -1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
+3
+/-3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
801
ET
Participant Education and Management
Diabetes education and 
nutrition counseling
X
Note: Diabetes education and nutrition counseling may be offered at additional visits if necessary. 
Confirmation of 
minimum baseline CGM 
data from SMS portal 
available before
treatment assignment
X
Note: Investigator staff should determine before Visit 3 from the participant’s Data Acceptability Report in the SMS portal that the 
participant will meet the minimum CGM requirements. The investigator should communicate to the participant whether he or she 
has met the minimum CGM requirements before treatment assignment at Visit 3. See Section 4.1.1 under Lead in period “CGM” 
for how to determine the minimum requirements.
Treatment assignment
X
Switch to morning 
administration of insulin 
degludec if applicable
X
Review ambulatory 
glucose profile using 
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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I8B-MC-ITSZ(b)
12
Screen Lead in 
Period
-11 to 
-1
Treatment Period
Safety 
Follow-
up
ET
Titration Period
Days 0 to 35
Maintenance
Days 36 to 
46
Days 47
to 53
Day
-21 to
-12
-11
0
3
7
10
14
17
21
24
28
31
35
46
53
ET
Visit Window (days)
0
+/-3
+3 -1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
+3
+/-3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
801
ET
CGM data in Clarity
Print InPen report and 
review insulin doses. 
Retain InPen report as a 
part of the participant’s 
medical chart
X
X
X
X
X
X
X
X
X
X
X
X
X
Note: The investigator should confirm the receipt of the InPen report before each study visit. 
Keep degludec insulin 
dose, ICR, ISF, and DIA
unchanged unless for 
safety reasons
X
X
X
Note: Insulin dose, ICR, ISF, and DIA should remain unchanged during the screening, lead-in, and maintenance period unless for 
safety reasons. At the end of the maintenance period (Visit 14), the investigator may adjust the participant’s ICR to the value he or 
she had at study entry. 
Adjust DIA as needed 
X
X
X
X
X
X
X
X
X
X
X
Note: The investigator is not required to adjust the DIA. However, if dose and CGM data indicate that a different duration of insulin 
action is necessary for participant safety or for optimizing glycemic control, the investigator should make the necessary changes. 
Adjust both basal and 
bolus insulin doses, ICR, 
and ISF as needed to 
achieve glucose target
X
X
X
X
X
X
X
X
X
X
X
Note: Please refer to Section 4.3 of the protocol for more details.


CONFIDENTIAL
I8B-MC-ITSZ(b)
13
Screen Lead in 
Period
-11 to 
-1
Treatment Period
Safety 
Follow-
up
ET
Titration Period
Days 0 to 35
Maintenance
Days 36 to 
46
Days 47
to 53
Day
-21 to
-12
-11
0
3
7
10
14
17
21
24
28
31
35
46
53
ET
Visit Window (days)
0
+/-3
+3 -1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
+3
+/-3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
801
ET
Start non-study rapid-
acting insulin analog
X
X
Remind participant to 
bring their personal 
CGM system to Visit 14
X
Participants return to 
their personal CGM 
device
X
X
Devices, Supplies, and IP
Dispense CGM supplies
X
X
X
Ensure that CGM mobile 
application is installed on 
participant’s smart 
phone. Ensure 
participants activate and 
set up their account
X
Grant site permission to 
access participant data
X
Note: The investigator should check the participant’s eligibility before they request access to participant data in CLARITY. 


CONFIDENTIAL
I8B-MC-ITSZ(b)
14
Screen Lead in 
Period
-11 to 
-1
Treatment Period
Safety 
Follow-
up
ET
Titration Period
Days 0 to 35
Maintenance
Days 36 to 
46
Days 47
to 53
Day
-21 to
-12
-11
0
3
7
10
14
17
21
24
28
31
35
46
53
ET
Visit Window (days)
0
+/-3
+3 -1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
+3
+/-3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
801
ET
from CLARITY
CGM training
X
Note: Additional CGM training may be performed as needed.
Start Sponsor provided 
CGM sensor session 
X
Note: See Section 4.1.1 for details. 
Dispense InPen and 
associated supplies
X
Download InPen mobile 
app on smart phone. 
Ensure participants 
activate and set up their 
InPen account
X
Note: Smartphone encompasses Android and Apple iPhone with compatible operating system.
InPen training
X
Note: Additional InPen training may be performed as needed.
All participants 
X


CONFIDENTIAL
I8B-MC-ITSZ(b)
15
Screen Lead in 
Period
-11 to 
-1
Treatment Period
Safety 
Follow-
up
ET
Titration Period
Days 0 to 35
Maintenance
Days 36 to 
46
Days 47
to 53
Day
-21 to
-12
-11
0
3
7
10
14
17
21
24
28
31
35
46
53
ET
Visit Window (days)
0
+/-3
+3 -1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
+3
+/-3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
801
ET
administer Humalog as 
rapid-acting insulin with 
the InPen during the lead 
in period
Note: Participants entering the study on Novolog, Admelog, or Apidra will transition to Humalog.
Remind participant of 
required actions and 
study procedure with 
InPen and CGM
X
X
X
X
X
X
X
X
X
X
X
X
Note: The investigator should remind the participant of the following things:

LY900014 should be administered 0-2 minutes before the start of each meal and snack (not applicable for Visit 2).

InPen reports should be sent before each visit.

Mealtime and degludec dose should be entered into the Dexcom mobile app for Days -10 to -1 and Days 36 to 45.
Dispense ancillary 
supplies
X
Dispense IP 
X
X
Dispense pharmacy cards
X
Note: Participants will use pharmacy card to obtain Humalog 3 mL cartridge for use with the InPen during the lead-in period.
Participant returns 
unused study drug 
X
X
X
X


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I8B-MC-ITSZ(b)
16
Screen Lead in 
Period
-11 to 
-1
Treatment Period
Safety 
Follow-
up
ET
Titration Period
Days 0 to 35
Maintenance
Days 36 to 
46
Days 47
to 53
Day
-21 to
-12
-11
0
3
7
10
14
17
21
24
28
31
35
46
53
ET
Visit Window (days)
0
+/-3
+3 -1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
+3
+/-3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
801
ET
Participant returns InPen 
device and associated 
supplies
X
X
Participant returns 
provided unused 
Dexcom G6 supplies to 
site
X
X
Remove access to 
participant’s CLARITY 
account and SMS portal
X
X
Note: If an investigator is the participant’s primary care provider, the investigator may discuss with the participant whether they 
would like to retain the link to the CLARITY account.
Drug accountability
X
X
X
X
X
Transfer data into eCRF
Transcribe requested 
data into eCRF from 
participant’s medical 
chart
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Note: The following data are requested: ICR, ISF, and DIA from the day before visit.
Transcribe requested 
X
X
X


CONFIDENTIAL
I8B-MC-ITSZ(b)
17
Screen Lead in 
Period
-11 to 
-1
Treatment Period
Safety 
Follow-
up
ET
Titration Period
Days 0 to 35
Maintenance
Days 36 to 
46
Days 47
to 53
Day
-21 to
-12
-11
0
3
7
10
14
17
21
24
28
31
35
46
53
ET
Visit Window (days)
0
+/-3
+3 -1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
+3
+/-3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
801
ET
data into eCRF from 
InPen pdf report from 
each day of the lead in 
period (Days -10 to -1) 
and from the 
maintenance period 
(Days 36 to 45)
Note: Individual Humalog doses from each day during the lead-in period and LY900014 doses during the maintenance period are
requested.
Laboratory Assessments
HbA1c
X
X
Fructosamine
X
X
1,5 AG
X
X
Hematology
X
Chemistry panel
X
Urinalysis
X
Serum Pregnancy test
X
Note: Serum pregnancy test must be performed in women of childbearing potential at Visit 1 and at other times at the investigator’s 


CONFIDENTIAL
I8B-MC-ITSZ(b)
18
Screen Lead in 
Period
-11 to 
-1
Treatment Period
Safety 
Follow-
up
ET
Titration Period
Days 0 to 35
Maintenance
Days 36 to 
46
Days 47
to 53
Day
-21 to
-12
-11
0
3
7
10
14
17
21
24
28
31
35
46
53
ET
Visit Window (days)
0
+/-3
+3 -1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
-1/+2
+3
+/-3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
801
ET
discretion.
Urine Pregnancy test
X
Note: A urine pregnancy test must be performed in women of childbearing potential within 24 hours before IP exposure at Visit 3 
and when required per local regulations and/or institutional guidelines, local pregnancy testing will occur at mandatory times during 
the study treatment period.
Follicle stimulating 
hormone test
X
Note: Follicle-stimulating hormone test must be performed at Visit 1 for a post-menopausal woman who is at least 40 years of age 
with an intact uterus, not on hormone therapy, and who has had cessation of menses for at least 1 year without an alternative 
medical cause.
Abbreviations: AG = anhydroglucitol; CGM = continuous glucose monitoring; DIA = Duration of Insulin Action; ECG = electrocardiogram; eCRF = electronic 
case report form; ET = Early Termination; HbA1c = hemoglobin A1c; ICR = insulin-to-carbohydrate ratio; IP = investigational product; ISF = insulin 
sensitivity factor; IWRS = interactive web-response system; SMS = Study management suite.


CONFIDENTIAL
I8B-MC-ITSZ(b)
19
2.
Introduction
LY900014 is an ultra-rapid-acting formulation of insulin lispro developed by Eli Lilly and 
Company (Lilly) for subcutaneous (SC) use and for intravenous (IV) use to improve glycemic 
control in participants with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D).
2.1.
Study Rationale
Rapid-acting insulin analogs have been shown to have a more rapid onset of action compared 
with human insulin. However, the consensus is that they are not rapid enough to match
carbohydrate absorption and many patients are unable to achieve optimal glycemic control.
An ultra-rapid-acting prandial insulin that would shift the pharmacokinetic (PK) and 
pharmacodynamic (PD) profiles of insulin to provide an even faster onset of action would better 
match carbohydrate absorption and allow for efficacious dosing immediately before meals. An 
ultra-rapid insulin would be useful in the treatment of T1D and T2D when delivered by MDI, 
continuous subcutaneous insulin infusion, or in closed loop and hybrid closed loop automated 
insulin delivery systems.
An ultra-rapid time-action profile has been achieved for LY900014 through the addition of 2 
novel excipients: microdoses of treprostinil, a prostacyclin analog that increases local capillary 
blood flow, and citrate, which enhances vascular permeability. The Phase 3 PRONTO studies in 
patients with T1D and T2D on MDI regimens demonstrated that LY900014 was noninferior to 
Humalog in hemoglobin A1c (HbA1c) reduction when administered as prandial insulin in 
combination with basal insulin for 26 weeks (Klaff et al. 2019) (Blevins et al 2019). LY900014 
also demonstrated superiority to Humalog in controlling 1-hour and 2-hour PPG excursions 
during mixed-meal tolerance tests in both patients with T1D and T2D. Improved time in range 
during daytime was observed in patients with T1D treated with LY900014.
In the PRONTO Diabetes studies, using individualized dose titration, mean bolus:basal insulin 
dose ratios at study endpoints were approximately 50:50 in both patients with T1D and T2D, 
which are typical for intensive insulin regimens. The design of the PRONTO Diabetes studies 
included an 8-week basal insulin optimization period in combination with prandial lispro before
randomization, which might have favored aggressive titration of the basal insulin and likely 
limited titration of LY900014 and Humalog during the subsequent treatment period, as the mean 
HbA1c was 7.3% at the end of the lead-in period. The PRONTO Diabetes studies provide strong 
support for the efficacy and safety of LY900014 treatment as part of an MDI regimen. Despite 
this, it is possible that patient outcomes could be further optimized with alternate dosing 
regimens.
In clinical practice, the dosing formulas currently widely used by clinicians are as follows 
(DeWitt and Hirsch 2003, Bode 2004, Pickup 2009):

Total Basal Dose (TBD)=0.5×Total Daily Dose (TDD)

Insulin-to-Carbohydrate Ratio (ICR)=450~500/TDD (“450 Rule” or “500 Rule”)

Correction Factor (CF) =1700~1800/TDD


CONFIDENTIAL
I8B-MC-ITSZ(b)
20
These formulas originated from C-peptide kinetic studies of insulin secretion and from 
retrospective reviews of pump download in ‘well-controlled’ patients, which have some 
limitations. For example, TBD=0.5 × TDD came from c-peptide kinetic studies of insulin 
secretions in healthy volunteers and assumed that the basal insulin need is flat and constant 
throughout the entire day (Kruszynska et al. 1987, Polonsky et al. 1988). Recent prospective 
insulin titration studies, including studies using structured professional continuous glucose 
monitoring (CGM), demonstrate that current dosing formulas recommend too high of a dose for 
basal insulin and too low of a dose for bolus insulin (King and Armstrong 2007a, b, King 2010, 
Kuroda et al. 2012).
Prandial insulins are often titrated based on ‘next pre-meal glucose’ (for example, using 
pre-lunch value to assess adequacy of the breakfast prandial dose). This commonly used titration 
scheme may not be optimized for the novel time-action profile of LY900014. An alternate 
approach of using peak post-prandial glucose (PPG) values or the change from pre-meal levels 
may be better-suited to titrating ultra-rapid acting prandial insulins. In particular, the ‘faster on-
faster off’ profile of LY900014 might allow more aggressive prandial dosing that would further 
improve PPG without increasing the risk of late post-meal hypoglycemia.
The aim of this study is to explore a new titration scheme of LY900014 to optimize glycemic 
control, when administered as prandial insulin, in combination with insulin degludec for 35 days. 
Insulin titration will be based on real-time Dexcom G6 CGM readings, which are approved by 
the Food and Drug Administration (FDA) for making clinical decisions.
2.2.
Background
Type 1 diabetes is an autoimmune disease mediated by a combination of genetic and 
environmental triggers resulting in lymphocytic infiltration of pancreatic islets, destruction of 
beta cells, and lifelong dependency on exogenous insulin. The prevalence of T1D is near 1 in 
300 and its incidence is steadily increasing worldwide (3% per year) (Gan et al. 2012]).
There have been many advances in the treatment of T1D in the last 20 years; however, reaching 
and maintaining glycemic goals remains challenging even under intensive insulin therapy 
regimens. Only approximately 30% of insulin requiring diabetes patients are able to reach the 
goal HbA1c target of <7% (Stark-Casagrande et al. 2013).
Recent prospective insulin titration studies using structured professional continuous glucose 
monitoring (CGM) demonstrate that current dosing formulas widely used in clinical practice
promote under-dosing of mealtime insulin (Kuroda et al. 2012) (King 2012) (King and 
Armstrong 2007a, b). Using a new titration scheme for LY900014 might further improve 
glycemic control in patients with T1D on MDI regimen. 
LY900014
LY900014 is composed of the active ingredient, insulin lispro, and 2 enabling excipients 
(treprostinil and citrate) that facilitate rapid absorption of insulin lispro into the blood stream.
This novel formulation results in earlier glucose lowering when compared with Humalog. This 
faster glucose-lowering response, as demonstrated by the PK and PD profiles of LY900014 when
compared with Humalog, more closely mimics the time-action profile of normal endogenous 
insulin secretion and may better match the speed of meal carbohydrate absorption. In previous 


CONFIDENTIAL
I8B-MC-ITSZ(b)
21
clinical pharmacology studies, LY900014 and Humalog were shown to be equipotent. In the 
completed Phase 3 studies, LY900014 and Humalog substituted generally on a unit-for-unit 
basis; LY900014 and Humalog doses at Week 26 were not statistically significantly different 
after titration. In addition, no significant difference between LY900014 and Humalog were 
observed in pump settings or bolus calculator settings in Phase 3 studies either.
The Investigator’s Brochure (IB) describes the clinical and nonclinical development of 
LY900014. 
InPen™
Companion Medical’s InPen system is an FDA-approved class II device for use with Humalog,
Novolog, or Fiasp. Lilly has determined that LY900014 is suitable for use with the InPen system
under the conditions of the current investigational study. The InPen system consists of a 
manually controlled pen injector and an app containing a logbook and a dose (bolus) calculator.
The InPen is a home-use reusable pen injector for single-patient use by people with diabetes 
aged 12 years and older for the self-injection of a desired dose of insulin. The pen injector is 
compatible with Humalog U-100 3.0 mL cartridges, which have the same dimensions to 
LY900014 cartridges, and single-use detachable and disposable pen needles. Cartridges of the 
pen injector allow the user to dial the desired dose from 0.5 to 30 units in one-half unit 
increments.
The InPen app is designed to manage with the InPen injector a wireless transfer of 

insulin dose 

insulin dose time 

mealtime carbohydrates

time of meal
The InPen app also provides a dose calculator to aid bolus insulin dose calculations. Before the 
use of the InPen app dose calculator, a health care professional (HCP) must provide the 
participant with specific target blood glucose, insulin-to-carbohydrate ratio, insulin sensitivity 
parameters, and duration of insulin action to be entered into the InPen app.
Dexcom G6
Dexcom G6 CGM System is a real time, CGM device indicated for the management of diabetes 
in individuals aged 2 years and older. Dexcom G6 System is an FDA-approved class II device 
that can replace fingerstick blood glucose testing for diabetes treatment decisions. 
Dexcom G6 CGM System has the following components:

G6 CGM sensor

G6 CGM transmitter

G6 CGM receiver

G6 System mobile app
The G6 CGM sensor continuously measures glucose concentration in interstitial fluid and can be 
worn for up to 10 days. When a new sensor is started, a code must be entered into the display 
device to use the G6 without fingerstick calibrations. Each sensor has its own code printed on the 
back of the adhesive patch. Calibration is not required if users enter a sensor code. The G6 CGM 


CONFIDENTIAL
I8B-MC-ITSZ(b)
22
transmitter contains a Bluetooth radio transceiver for communication with a compatible display 
device, either the G6 CGM receiver or a smart device. Participants in Study ITSZ will be using a 
smart device to receive data from the G6 CGM transmitter instead of the G6 CGM receiver. 
The Dexcom G6 System mobile app is for iOS and Android. The mobile app provides an 
alternative display device to the receiver for users with compatible smart devices and behaves 
similarly to the receiver. The user has the ability to manually enter insulin dose and insulin dose 
time as well as meal carbohydrates and time into the mobile app. This dosing and meal 
information can also be entered retroactively. 
2.3.
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of LY900014 may be found in the IB.


CONFIDENTIAL
I8B-MC-ITSZ(b)
23
2.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Study Intervention (s) LY900014
Hypoglycemia
Hyperglycemia
Hypersensitivity and Allergic 
reactions 
See IB Section 6.2.2.5.1
Each participant will receive Diabetes education and 
counseling on how to avoid the risks of hypoglycemia and 
hyperglycemia at Visit 2.
CGM alerts will be set up during Visit 2 for early detection 
of hypoglycemia and hyperglycemia. Participants with 
known hypersensitivity or allergy to any of the study 
medications or their excipients will be excluded from the 
study. 
Study Procedures
InPen and Mobile medical app (MMA)
Errors of LY900014 dose 
delivery
LY900014 is not approved to be used with InPen; however,
it is expected to perform similarly to Humalog due to the 
following reasons:
•
InPen is compatible with Humalog U-100 3.0 mL 
cartridges, which have the same dimensions to 
LY900014 cartridges 
•
Lilly has internal data for LY900014 supporting in use 
stability for the container closure and fluid path (that 
is, needle), which are the same as Humalog 
•
LY900014 and Humalog are shown to be equipotent in 
clinical pharmacology studies
•
LY900014 and Humalog substituted generally on a 
unit-for-unit basis in clinical pharmacology and Phase 
3 studies
•
In the pivotal study of LY900014 in adult patients with 
T1D, Study ITRM, at study endpoint of 26 weeks, 
doses of LY900014 and Humalog were not 
significantly different after titration 
•
There were no meaningful difference in safety 
observed between LY900014 and Humalog in Phase 3 
studies (that is, incidence of adverse events and 

Lilly has completed preliminary testing of InPen
supporting dose accuracy when used with LY900014. 
Definitive dose accuracy testing will be completed 
before study initiation

Real-time CGM guided insulin titration with hypo- and 
hyperglycemia alerts set up

Site selection: choose experienced primary 
investigators (PIs) and site staff with LY900014 and 
diabetes technology

Strict monitoring of patients through frequent 
interactions with investigators, who have 24/7 access to 
patient CGM data in CLARITY

Enrollment of technologically-competent and highly 
compliant patients

Carefully planned site training and patient training
Based on the medical risk assessment, potential risks of 
using InPen with LY900014 off-label can be managed 
effectively upon the implementation of risk mitigation 


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I8B-MC-ITSZ(b)
24
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
hypoglycemia)
•
There were no clinically meaningful difference 
between LY900014 and Humalog in pump settings or 
bolus calculator settings (including active insulin time) 
in Phase 3 studies
plans. Lilly Medical concluded that if InPen passes Lilly 
dose accuracy testing with LY900014, InPen can be safely 
used in Study ITSZ due to the expected similar performance 
between LY900014 and Humalog 
Abbreviations: CGM = continuous glucose monitoring; T1D = type 1 diabetes.


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I8B-MC-ITSZ(b)
25
2.3.2.
Benefit Assessment
No direct clinical benefit is anticipated from participating in this trial due to the short nature of 
this study. However, some participants may benefit from improved glycemic control as a result 
of the dose titration strategy, frequent ICR, ISF, DIA, and insulin dose adjustments, and 
increased engagement with an HCP. 
More detailed information about the known and expected benefits and risks of LY900014 along 
with its clinical and nonclinical development can be found in the IB. 
More detailed information about the known and expected benefits and risks of degludec may be 
found in the USPI (Tresiba package insert, 2015).
2.3.3.
Overall Benefit: Risk Conclusion
Considering the measures taken to minimize risk to participants involved in this study, the 
potential risks identified in association with LY900014 are justified by the potential benefits that 
may be afforded to participants with T1D.


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I8B-MC-ITSZ(b)
26
3.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the time that glucose values are 
within the target range 70 to 180 mg/dL from 
CGM use, after 35 days of using the study
titration scheme with LY900014 treatment and 
degludec
Percentage of time with sensor glucose 
values between 70 and 180 mg/dL (both 
inclusive), with CGM use during the 
maintenance period
Secondary
To evaluate ICR with LY900014 treatment
ICR at the end of the maintenance period 
To evaluate the relationship between ICR and 
TDD with LY900014 treatment
ICR×TDD for the maintenance period
To evaluate total daily, basal, and prandial 
insulin dose with LY900014 treatment and 
degludec
Prandial: TDD ratio for the maintenance 
period
Tertiary/Exploratory
To evaluate the safety of LY900014
Adverse events and vital signs 
To explore the relationship between

ICR and TDD

ISF and TDD

ICR and ISF
with LY900014 treatment

Slope of the linear regression line of 
ICR or ISF on the reciprocal of TDD

Slope of the linear regression line of 
ICR on ISF, 
for the maintenance period
To explore ISF with LY900014 treatment
ISF at the end of the maintenance period
To explore glucose profiles, obtained from 
CGM use with LY900014 treatment
Actual and change from baseline in mean 
sensor glucose with CGM use during the 
maintenance period
To explore highest PPG level within 4 hours* 
after meal(s), obtained from CGM use, with 
LY900014 treatment
Actual and change from baseline in highest 
PPG level within 4 hours after meal(s), with 
CGM use during the maintenance period 


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I8B-MC-ITSZ(b)
27
Objectives
Endpoints
To explore the time from start of meal to 
highest PPG level within 4 hours* after 
meal(s), obtained from CGM use, with 
LY900014 treatment
Actual and change from baseline in minutes 
from start of meal to highest PPG level 
within 4 hours after meal(s), with CGM use 
during the maintenance period 
To explore the percentage of time spent in 
hypoglycemic glucose ranges, obtained from 
CGM use, with LY900014 treatment
Actual and change from baseline in 
percentage of time with sensor glucose 
values <54 mg/dL, with CGM use during 
the maintenance period 
To explore percentage of time spent in 
hyperglycemic glucose ranges, obtained from 
CGM use, with LY900014 treatment
Actual and change from baseline in 
percentage of time with sensor glucose 
values >250 mg/dL, with CGM use during 
the maintenance period 
To explore within-day glucose variability, 
obtained from CGM use, with LY900014 
treatment
Actual and change from baseline in within-
day CV of sensor glucose, with CGM use 
during the maintenance period 
To explore proportion of participants achieving 
CGM-based glycemic targets, with LY900014 
treatment
The proportion of participants with 
percentage of time in 

target glucose range,
70-180 mg/dL, >70% 

hypoglycemia, <54 mg/dL, <1%

hyperglycemia, >250 mg/dL, <5%,
with CGM use during the maintenance 
period 
To explore fructosamine with LY900014 
treatment
Fructosamine at the end of the maintenance 
period compared to baseline
To explore HbA1c with LY900014 treatment
HbA1c at the end of the maintenance period
compared to baseline
To explore 1,5 Anhydroglucitol (AG) with
LY900014 treatment
1,5 AG at the end of the maintenance period
compared to baseline
Abbreviations: CGM = continuous glucose monitoring; CV = cardiovascular; HbA1c = hemoglobin A1c; ICR = 
insulin-to-carbohydrate ratio; ISF = insulin sensitivity factor; PPG = post-prandial glucose; TDD = Total Daily 
Dose.
*
Excluding the glucose data from participants who have had the next meal event before the end of time 
interval.


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I8B-MC-ITSZ(b)
28
4.
Study Design
4.1.
Overall Design
Study ITSZ is a multicenter, single-group, open-label, Phase 2, exploratory study that will be 
conducted in participants with T1D currently treated with insulin degludec and a rapid-acting 
insulin analog in an MDI regimen. The objective of the study is to assess the percentage of time 
glucose values are within the target range of 70 to 180 mg/dL after 35 days of titration using the 
study titration scheme.
The study will consist of the following periods:

Screening and lead-in period

Treatment period
o
Titration period
o
Maintenance period

Safety follow-up period
4.1.1.
Study Visits
Screening, Visit 1
The purpose of procedures at the screening visit is to establish eligibility for the study (see
Sections 5.1 and 5.2). Participants will continue their pre-study rapid-acting insulin analog and 
their basal insulin dose. Insulin-to-carbohydrate ratio, insulin sensitivity factor (ISF), and DIA
should not be changed unless for safety reasons during the screening period. 
Lead-in Period, Visit 2
The lead-in period starts following Visit 2. During the lead-in period, all participants will 
administer Humalog as rapid-acting insulin with the InPen Pen Injector. Participants who enter 
the study on Novolog, Admelog, or Apidra will transition to Humalog at Visit 2. The dose of 
insulin degludec and the ICR, ISF, and DIA should not be changed unless for safety reasons.
Sponsor Provided CGM Session
At Visit 2, Dexcom G6 CGM sensors and transmitter will be dispensed to all participants who 
meet study entry criteria. 
All participants will switch to a Lilly provided Dexcom G6 CGM system during Visit 2. Also, 
any participant using a personal Dexcom G6 will switch to a Lilly provided Dexcom G6 during 
Visit 2. All participants will use Dexcom G6 CGM from Visit 2 until Visit 14. Participants will 
grant permission to the site to access their CGM data.
At Visit 2, participants will insert a new Lilly provided sensor and transmitter. Between Day -11
and Day 46, participants will wear the study-provided G6 CGM system and change the sensor 
every 10 days or as needed. All participants should use the sensor code printed on the back of the 
adhesive patch to calibrate when starting a new sensor. Calibrating Dexcom G6 CGM using 
fingerstick meter values is prohibited in this study to avoid increased sensor measurement
variability across participants caused by using different brands/models of glucose meters for 
calibration. 


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I8B-MC-ITSZ(b)
29
All participants will use the Dexcom mobile app on their smart phone to view their CGM data 
during the study. Participants who enter the study using Dexcom G6 CGM will not use their 
Dexcom G6 CGM receiver to view CGM data. 
Sites will work with the participant to ensure:

the Dexcom CGM mobile app is installed on the participant’s smart phone 

participant has an active Dexcom mobile app business account

CGM device and associated Mobile medical app (MMA) is set up so that
o
all alerts and notifications are enabled
o
alert levels are adjusted, if necessary
o
location services are enabled

participant grants permission to the site to view his or her CGM data through CLARITY
and SMS
During the lead-in period from Day -10 to Day -1, participants are required to enter the following 
data into the Dexcom mobile app every day: 

meal start time for breakfast, lunch, and dinner

insulin degludec dose
Investigator staff should check CLARITY to ensure that participants are entering these data 
during the lead-in period. 
Training related to the use of Dexcom G6 CGM and its associated mobile app will be provided at 
Visit 2. Abbreviated training following Visit 2 will be made available as deemed appropriate.
Minimum CGM Requirements
The CGM data collected during the lead-in period will be used as baseline CGM. Participants 
must have at least 5 days with a minimum of 70% CGM measures per day during the lead-in 
period to be eligible for treatment assignment. These 5 days do not need to be consecutive. 
The investigator will have daily access to the SMS portal during the lead-in period and will print 
the participant’s Data Acceptability Report to determine the participant’s eligibility for treatment 
assignment. The investigator should determine before Visit 3 that the participant has met the 
minimum CGM eligibility requirements and then communicate to the participant their eligibility 
for treatment assignment. If the investigator becomes aware through SMS portal monitoring 
during the lead-in period that a participant will not meet the minimum CGM requirements before 
Visit 3, the site should advise the participant to re-schedule Visit 3 to a later date within the visit 
window. 
InPen
During Visit 2, InPen Pen Injector and associated supplies will be dispensed to all participants 
who meet study entry criteria. The InPen mobile app will be downloaded onto the participants’
smartphone. 
Sites will work with the participant to ensure:

InPen mobile app is installed on the participant’s smart phone

participant has an active InPen mobile app business account


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I8B-MC-ITSZ(b)
30

Participants have entered the following information in the InPen device and associated 
MMA:
o
Target blood glucose: this is the blood glucose value the participant is trying to 
achieve. It is prescribed by investigators and individualized for each participant in 
the study. The target blood glucose will be used by the dose calculator to calculate 
the correction bolus and is distinct from the glycemic targets used for insulin 
titration defined in Section 4.3. 
o
ICR
o
ISF
o
DIA
Participants are required to enter meal or snack carbohydrates and current CGM glucose before 
each meal/snack into the InPen mobile app in order to use the bolus dose calculator during the 
study.
Training related to the use of InPen Reusable Pen Injector and its associated mobile app will be 
provided at Visit 2. Abbreviated training following Visit 2 will be made available as deemed 
appropriate.
Transcribing Data into the eCRF at Visit 2
At Visit 2, the investigator should transcribe the following data from the day before the visit into 
the eCRF:

ICR

ISF

DIA
Diabetes Education
Initial training related to diabetes education and nutrition counseling will be provided at Visit 2
and other visits as needed. Appropriate site personnel will administer education using locally 
approved diabetes education materials and programs or by using other materials that may be 
provided by the Sponsor.
Treatment Period, Visit 3 to Visit 14
Treatment Assignment, Visit 3 (Day 0)
The investigator should determine eligibility for treatment assignment before Visit 3. There will 
be no early enrollment if a participant meets the minimum 5-day requirement of 70% CGM 
readings per day before Visit 3. 
For participants who are eligible for treatment assignment, Humalog will be discontinued, and 
LY900014 will be initiated using their current ICR, ISF, and DIA at Visit 3. All participants who 
are not currently administering insulin degludec in the morning should switch to morning 
administration with the investigator’s guidance. All participants should continue administering 
degludec in the morning throughout the treatment period. 


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Titration Period, Visit 3 through Visit 13 (Day 0 to Day 35)
Following treatment assignment at Visit 3, participants will enter a 35-day insulin titration 
period. The investigator may adjust the dose of insulin degludec, ICR, ISF, or DIA at any time 
from Visit 3 (Day 0) to Visit 13 (Day 35) to meet the glucose targets specified in Section 4.3.1. 
Participant’s ambulatory glucose profile will be reviewed using CGM data from CLARITY at 
each visit. 
Participant’s LY900014 dose will be reviewed using the InPen report. The investigator should 
confirm that the InPen report has been received before each study visit. Additionally, the 
investigator should confirm that the InPen report aligns with the clinical management of the 
participant. Based on these reports, insulin doses, ICR, ISF, and DIA will be adjusted as needed 
to reach the study specified glucose target (Sections 4.3.1 and 4.3.2).
Maintenance Period, Day 36 to Day 46
The maintenance period starts following Visit 13. Continuous glucose monitoring data collected 
during the maintenance period will be used as endpoint CGM data. 
During the maintenance period, the investigator may not adjust the dose of insulin degludec, 
ICR, ISF, or DIA unless for safety reasons. 
During the maintenance period from Day 36 to Day 45, participants are required every day to 
enter the following data into the Dexcom mobile app

meal start time for breakfast, lunch, and dinner

insulin degludec dose
Investigator staff should check CLARITY to ensure that participants are entering these data 
during the maintenance period. 
Visit 14 (Day 46)
At Visit 14, participants will return to their non-study rapid-acting insulin analog regimen. 
Participants may decide to continue to administer degludec in the morning or switch to their 
pre-study dosing schedule. The investigator will determine basal and prandial insulin doses. 
At Visit 14, participants will return to the personal CGM system that they were using before the 
study began. Participants should be reminded before Visit 14 that they will need to bring their 
personal CGM system to Visit 14. 
Transcribing Data into the eCRF from Visit 3 to Visit 14
At every visit from Visit 3 to Visit 14 inclusive, the investigator should transcribe the following 
data from the day before the visit into the eCRF:

ICR

ISF

DIA


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Transcribing Data into the eCRF for Visit 3 and Visit 14 only 
In addition to the ICR, ISF, and DIA, the investigator should transcribe the Humalog dose at 
Visit 3 (data from Day -10 to Day -1) and the LY900014 dose at Visit 14 (data from Day 36 to 
Day 45).
Safety Follow-up, Visit 801
All randomized participants who completed the treatment period should have a safety follow-up 
visit approximately 1 week after Visit 14.
Early Termination visit, ET Visit
Participants who discontinue investigational product (IP) permanently before completion of the 
treatment period for any reason will also be discontinued from the study. An (ET) visit should be 
conducted as soon as reasonably possible. After the ET visit, a safety follow-up assessment 
(Visit 801) should be conducted approximately 1 week after the ET Visit.
Transcribing Data into the eCRF at the ET Visit
At the early termination visit, the investigator should transcribe the following data from the day 
before visit into the eCRF:

ICR

ISF

DIA

LY900014 dose
4.2.
Scientific Rationale for Study Design
This study will evaluate a new titration scheme of LY900014 in participants with T1D who use 
insulin degludec for basal glucose control in an MDI regimen. The study will last up to 73 days
and include an intensive insulin titration period of 35 days followed by a 11-day maintenance 
period. The percentage of time glucose values are within the target range of 70 to 180 mg/dL 
after 35 days titration of using the study titration scheme will be evaluated. 
4.3.
Justification for Dose
In clinical practice, prandial insulins are often titrated based on the ‘next pre-meal glucose’. For 
example, clinicians use the pre-lunch blood glucose value to assess the adequacy of the breakfast 
prandial dose. This commonly used titration scheme may not be optimized for the novel time-
action profile of LY900014. An alternate approach of using peak PPG values or the change from 
pre-meal levels may be better-suited to titrating ultra-rapid acting prandial insulins. In particular, 
the ‘faster on-faster off’ profile of LY900014 might allow more aggressive prandial dosing that 
would further improve PPG without increasing the risk of late post-meal hypoglycemia.
The basal and bolus dosing of insulin in this study will be individually titrated based on real-time 
Dexcom G6 CGM readings and frequent interaction with investigators. The Dexcom G6 CGM 
system has been approved by the FDA to replace fingerstick blood glucose testing for diabetes 
treatment decisions.


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4.3.1.
Target Glucose Values for Titration of Insulin Therapy
The overall glycemic control goals for all participants enrolled in the study are generally similar 
to those recommended by the American Association of Clinical Endocrinologists (AACE)
(Bailey et al. 2016). A target for overnight glucose excursion (the difference between bedtime 
and pre-breakfast glucose levels) is also provided to guide insulin titration. 
Fasting glucose, overnight glucose excursion, and post-prandial glucose target values used to 
reach the glucose goals and for determination of titration in insulin therapy are listed as follows.
Time of Target Glucose Measurement
Glucose Target (Range)
Fasting glucose
100 mg/dL (range 80-110 mg/dL)
Overnight glucose excursion 
(the difference between bedtime and pre-breakfast 
glucose levels)
≤±30 mg/dL
Postprandial glucose peak
<140 mg/dL or <20% increase from premeal level
4.3.2.
LY900014
Participants will perform carbohydrate counting for each meal and snack throughout the study. 
Participants should use the bolus calculator function on the InPen app to determine all 
meal/snack and correction doses. Prandial insulin dose is calculated based on the estimated 
carbohydrate content of the meal and investigator prescribed ICR. Participants are allowed to eat 
snacks during the study. However, each snack should be covered by bolus insulin (if applicable). 
Participants should routinely use correction boluses as needed for hyperglycemia management 
based on the investigator-prescribed ISF. 
Treatment Period
During Visit 3, participants will receive instructions from the investigator to discontinue their 
pre-study rapid-acting insulin. LY900014 will be initiated unit-for-unit based on the pre-study 
ICR and ISF. LY900014 should be administered immediately (0 to 2 minutes) before the start of 
each meal and snack (if applicable).
During the insulin titration period (Visit 3 to Visit 13), ICR, ISF and DIA will be titrated by 
investigators based on Dexcom G6 CGM readings approximately twice per week as needed (see 
Section 1.3 SoA). Every effort should be made to reach the glycemic targets of:

Post-prandial glucose peak<140 mg/dL or

<20% rise from pre-meal level
During the maintenance period (Visit 13 to Visit 14), ICR, ISF, and DIA will remain unchanged 
unless for safety reasons. The insulin dose may be decreased at any time throughout the 
treatment period for safety reasons. 
Safety follow-up period
At Visit 14, participants will switch back to the pre-study rapid-acting insulin. The dose will be 
prescribed by the investigator. 


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4.3.3.
Insulin Degludec
Screening and lead-in period
During the screening and lead-in period, participants will continue their pre-study dose of insulin 
degludec and the dose should be kept stable unless for safety reasons such as hypoglycemia or 
unacceptable hyperglycemia. 
Treatment period
At Visit 3, participants who do not administer insulin degludec in the morning will follow the
investigator’s instructions to switch to morning dosing. All participants will administer insulin 
degludec in the morning from Visit 3 throughout the treatment period until the end of 
maintenance period, Visit 14.
During the insulin titration period (Visit 3 to Visit 13), the insulin degludec dose will be titrated 
by the investigator based on Dexcom G6 CGM readings approximately twice per week as needed
(see Section 1.3 SoA) to reach the fasting glucose target of 100 mg/dL (range 80 to 110 mg/dL).
Every effort should be made to reach the overnight glucose excursion target of ≤±30 mg/dL
during the titration period.
During the maintenance period (Visit 13 to Visit 14), the dose of insulin degludec will be kept 
unchanged unless for safety reasons. 
Safety follow-up period
During the safety follow-up period (Visit 14 to Visit 801), participants may choose to continue to
dose insulin degludec in the morning or switch to a different dosing timing. The dose of insulin 
degludec will be prescribed by the investigator. 
4.4.
End of Study Definition
The end of the study is defined as the date of the last scheduled procedure for the last participant 
shown in the Schedule of Activities.


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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. The study population will consist of 
participants with a diagnosis of T1D currently being treated with insulin degludec and a rapid-
acting insulin analog in an MDI regimen.
Eligibility of participants will be based on the results of the assessments performed at screening
as described in the Schedule of Activities (Section 1.3). 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. The nature of any 
conditions present at the time of the initial screening and any preexisting conditions will be 
documented in the eCRF.
For screen failures and rescreening activities within the screening period, see Section 5.4.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Informed Consent
1. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol
Age and Sex
2. Participant must be 18 to 65 years of age, inclusive, at the time of signing the informed 
consent.
3. Male or Female

Male: no contraception required

Female: A female participant is eligible to participate if she is not pregnant, intending 
to become pregnant, or breastfeeding, and at least one of the following conditions 
applies:

Is not a woman of childbearing potential (see Appendix 4, Section 10.4)
OR

Is a woman of childbearing potential (WOCBP) and must agree to use one 
highly effective method (less than 1% failure rate) of contraception, or a 
combination of two effective methods of contraception for the entirety of 
the study. Contraception requirements for participants are provided in 
Appendix 4 (Section 10.4).

A WOCBP must test negative for pregnancy prior to initiation of 
treatment as indicated by a negative serum pregnancy test at the screening 


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visit followed by a negative urine pregnancy text within 24 hours prior to 
exposure to investigational product (IP) at Visit 3. 
Type of Participant and Disease Characteristics
4. Have been clinically diagnosed with T1D for at least 1 year before screening, and 
continuously using intensive insulin therapy for at least 1 year. 
5. Have been on stable insulin requirements at the discretion of the investigator’s judgment 
with total daily dose (TDD) ≤1.2 U/kg/d according to the average TDD from the three 
days before Visit 1
6. Have been on the same type of rapid-acting insulin analog (Humalog U-100, Novolog, 
Admelog, or Apidra) for at least 30 consecutive days before screening 
7. Are proficient, in the opinion of the investigator, in carbohydrate counting and are willing 
to use carbohydrate counting to calculate bolus doses throughout the study
8. Routinely use correction boluses as needed for hyperglycemia with stable correction 
factor in the opinion of the investigator
9. Have been treated for at least 30 consecutive days before screening with insulin degludec 
U-100 
10. Have an HbA1c value ≥6.0 and ≤8.0%, according to the central laboratory at screening 
(Visit 1).
11. Have a body mass index (BMI) of ≤35.0 kg/m2 at screening (Visit 1).
12. CGM system

Must be using unblinded personal CGM for diabetes management with total CGM 
use of 2 months in the prior 6 months

Must be willing and able to use a study-provided Dexcom G6 CGM system,
including sensor and transmitter, during the study and must cease use of their 
personal CGM system, including Dexcom receiver if applicable

Must be willing and able to use the Dexcom mobile application and grant site 
permission to access their CGM data during the study
13. Must be willing to use InPen to inject rapid-acting insulin and share data with 
investigator via email 
14. Have access to WiFi or a cellular data plan for transmission of data
15. Have an active email account 
16. Have access to a Bluetooth enabled smart phone (either Android or iPhone) compatible 
with both the Dexcom and InPen mobile applications for transmission of the data
17. Have refrigeration in the home or have ready access to refrigeration for storage of insulin 
therapy
18. Have a regular sleep/wake cycle (for example, those who are awake during the day and 
sleep during the night)


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19. Capable of and willing to do the following:
a.
Inject insulin with the use of an insulin injection device (insulin pen) 
according to manufacturer guidelines 
b. Follow the investigator’s instructions to titrate insulin based on glucose 
targets
c.
Able to read and understand the language(s) available for devices and applications
used in the study
d. Comply with the use of the study insulin and scheduled visits
e.
Receive diabetes education
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
20. Have had more than 1 episode of severe hypoglycemia (defined as requiring assistance 
due to neurologically disabling hypoglycemia) within the last 90 days before screening
21. Have hypoglycemia unawareness as judged by the investigator
22. Have had more than 1 emergency room visit or hospitalization due to poor glucose 
control (hyperglycemia or diabetic ketoacidosis) within 6 months before screening 
(Visit 1)
23. Have a scheduled surgery or plastic surgery during the study
24. Have cardiovascular disease within the last 6 months before screening, defined as 

stroke 

decompensated heart failure New York Heart Association Class III or IV

myocardial infarction

unstable angina pectoris 

coronary arterial bypass graft
25. Gastrointestinal

Have gastroparesis before screening

Undergone gastric bypass or sleeve gastrectomy (bariatric) surgery before
screening

Undergone restrictive bariatric surgery (like Lap-Band®) before screening
26. Hepatic

Have acute or chronic hepatitis or cirrhosis


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
Have obvious clinical signs or symptoms of any other liver disease 
EXCEPT non-alcoholic fatty liver disease (NAFLD). Those with NAFLD 
are eligible.

Have elevated liver enzyme measurements, as determined by the central 
laboratory at screening according to the parameters are as follows:
i. Total bilirubin ≥2 times the upper limit of normal (ULN; except 
for Gilbert’s syndrome) as defined by the central laboratory, or
ii. ALT/serum glutamic pyruvic transaminase (SGPT) ≥3 times ULN
as defined by the central laboratory, or 
iii. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic 
transaminase (SGOT) ≥3 times ULN as defined by the central 
laboratory
27. Renal

History of renal transplantation

Currently receiving renal dialysis

Serum creatinine >2.0 mg/dL (177 µmol/L) at screening as measured by 
the central laboratory
28. Cancer

Have active or untreated malignancy 

Have been in remission from clinically significant malignancy (other than 
basal cell or squamous cell skin cancer) for less than 5 years

At increased risk for developing cancer or a recurrence of cancer in the 
opinion of the investigator
29. Have any other serious disease or condition (for example, known drug or alcohol abuse 
or psychiatric disorder) that, in the opinion of the investigator, would pose a significant 
risk to the participant, preclude the participant from following and completing the 
protocol, or interfere with the interpretation of safety, efficacy, or PD data
30. Have vision or hearing loss that impairs recognition of CGM screens, alerts and alarms
31. Have experienced significant weight loss or gain (>5%) in body weight in the 3 months 
before screening
32. Have known hypersensitivity or allergy to any of the study medications or their 
excipients
33. Have had a blood transfusion or severe blood loss within 3 months before screening or 
have any hematologic condition that may interfere with HbA1c measurement (for 
example, hemoglobinopathy, hemolytic anemia, and sickle-cell disease)
Prior/Concomitant Therapy


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34. Are taking drugs that may significantly affect glycemic control (for example, niacin 
[allowed if <1.0 g/day], bile acid sequestrants)
35. Glucocorticoid therapy

Are currently receiving chronic (lasting longer than 7 consecutive days) 
systemic glucocorticoid therapy through the following preparations
i. Intravenous
ii. IM
iii. Subcutaneous
iv. Oral
v. Intra-articular

Have received such therapy within 4 weeks immediately before screening 
except for replacement therapy for adrenal insufficiency
36. Are currently taking, or have taken within the 3 months preceding screening, prescription 
or over-the-counter medications to promote weight loss
37. Are using any oral, injectable, or inhaled (except for the occasional, supplemental use of
Afrezza) medication intended for the treatment of diabetes mellitus other than an MDI 
regimen including a rapid-acting insulin analog and a basal insulin analog in the 90 days 
before screening
Prior/Concurrent Clinical Study Experience
38. Are currently enrolled in any other clinical study involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with this study
39. Have participated, within the last 30 days in a clinical trial involving an IP. If the 
previous IP has a long half-life, 3 months or 5 half-lives (whichever is longer) should 
have passed
Other Exclusions
40. Per the principal investigator’s discretion, is not technologically competent
41. Are unable and/or unwilling to provide informed consent, to make themselves available 
for the duration of the study, to comply with the use of a data collection device to directly 
record data, or to abide by study procedures
42. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted
43. Are Lilly employees or representatives (including employees, temporary contract 
workers, or designees responsible for the conduct of the study)
5.3.
Lifestyle Considerations
During the study, participants must avoid:


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40

donating blood or blood products

major changes in diet or exercise
5.3.1.
Meals and Dietary Restrictions
During the study, participants should avoid major changes in diet or exercise. Participants should 
have 3 doses of prandial insulin per day and eat 3 main meals per day (morning, midday, and 
evening) on a regular basis. Snacking is allowed if it is covered by a bolus dose of rapid-acting 
insulin (if applicable).
5.3.2.
Activity
During the study, participants should continue their usual exercise habit and avoid major changes 
in exercise. Participants should not receive an intensive exercise program with the intent of 
reducing body weight at any time during the study.
5.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be
rescreened. Individuals who were required to unexpectedly discontinue from the study during 
screening or the lead-in period (for example, due to enrollment pause related to the COVID-19 
public health emergency) will be allowed one rescreening. All participants that rescreen will 
restart at Visit 1 and complete all screening procedures.
Retesting of laboratory samples is not allowed, except for cases in which results are not available 
from the original sample.


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol.
6.1.
Study Intervention(s) Administered
Intervention Name
LY900014
Degludec
Type 
Drug
Drug
Dose Formulation
Solution
Solution
Unit Dose Strength(s)
100 units/mL
100 units/mL
Dosage Level(s)
Individualized dosing
Individualized dosing
Route of Administration
Subcutaneous
Subcutaneous
Use
Experimental prandial insulin
(0-2 minutes before start of meal or 
snack [if applicable])
Basal insulin
IMP and NIMP
IMP 
NIMP
Sourcing
Provided centrally by the Sponsor 
Provided centrally by the Sponsor
Abbreviations: IMP = Investigational Medicinal Product; NIMP = Non-Investigational Medicinal Product
6.1.1.
Medical Devices
The medical device for use in this study is the InPen.
Manufacturer instructions for use for InPen are available at www.companionmedical.com.
All device deficiencies (including malfunction, use error and inadequate labeling) shall be 
documented and reported by the investigator throughout the clinical investigation (see 
Section 8.3.7) and appropriately managed by the sponsor.


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6.2.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention 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 site staff.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (that is, receipt, reconciliation, and final disposition records).

All insulin products must be stored at the investigative site under refrigerated 
conditions (between 2°C and 8°C) in a locked and secure place. Insulin must not be 
frozen.

In-use insulin should be maintained at room temperature. In-use insulin must not be 
used after 28 days.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is a single-group, open-label study. 
6.4.
Study Intervention Compliance
Compliance for CGM will be assessed by the Clarity reports and SMS reports during all site 
visits. Compliance for prandial insulin administration will be assessed by the InPen report during 
all site visits. If the investigator deems that the participant is noncompliant with CGM or prandial 
insulin administration, the participant may be discontinued from the study.
Concomitant medication compliance and adherence to the visit window will be assessed by 
direct questioning during all site visits. If a participant is deemed noncompliant, he or she will 
receive additional diabetes education and training and the importance of compliance with the 
protocol will be reinforced. If the participant continues to be noncompliant in the opinion of the 
investigator, then the participant will be discontinued from the study.
A record of the number of LY900014 cartridges dispensed to and taken by each participant must 
be maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the CRF.
6.5.
Concomitant Therapy
The following concomitant therapies 

Are NOT allowed at any time during the study:
o
Acetaminophen dosed in quantities greater than 1 gram every 6 hours


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o
Non-study insulin (except for device failure when participants can switch to pre-existing 
rapid-acting insulin for a maximum of 48 hours)
o
Non-insulin injectables for the treatment of diabetes (for example, pramlintide, glucagon-
like peptide-1 [GLP-1] agonists)
o
Oral antidiabetic medications: dipeptidyl peptidase-4 inhibitors, Sodium-glucose 
co-transporter-2 inhibitors, GLP-1 agonists, metformin, sulfonylureas, glinides, 
alpha-glucosidase inhibitors, and so on
o
Systemic glucocorticosteroids
o
Intra-articular steroid preparations

ARE allowed at any time during the study
o
Inhaled, intranasal intraocular, and non-occlusive, limited topical steroid preparations
Lilly Medical should be contacted if there are any questions regarding concomitant or prior 
therapy.
6.6.
Dose Modification
Dosing will be individualized based on readings from the study-provided Dexcom G6 CGM and 
through frequent interactions with investigators. See Section 4.3 for details of dose modification.
6.7.
Intervention after the End of the Study
LY900014 will not be made available to participants after conclusion of the study. During the 
safety follow-up period, participants will return to the rapid-acting analog insulin regimen they 
had before the treatment period. Participants may choose to continue to dose insulin degludec in 
the morning or switch to an evening dose. The investigator will determine the dose for the rapid-
acting analog insulin and for degludec.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
Participants who need to permanently discontinue from study treatment will also be discontinued 
from the study. At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted. After the early discontinuation visit, a safety follow-up assessment 
(Visit 801) should be conducted approximately 1 week after the early termination visit.
Please see the SoA for the timing of these visits, for data to be collected at the time of study 
discontinuation and follow-up, and for any further evaluations that need to be completed.
Discontinuation is expected to be uncommon.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant will be withdrawn from the study in the following circumstances:

if he or she uses a non-study rapid-acting insulin for a period greater than 48 hours during 
the treatment period. 

if he or she loses contact with the site for more than 10 days. 

if he or she uses prohibited concomitant medication during the study as specified in 
Section 6.5.
A participant may withdraw from the study:

at any time at his or her own request 

at the request of his or her designee (for example, parents, or legal guardian)

at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons

if the participant becomes pregnant during the study

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 before introduction of the new agent

if the investigator, after consultation with the sponsor-designated medical monitor, 
determines that a systemic hypersensitivity reaction has occurred related to study drug 
administration, the participant should be permanently discontinued from the 
investigational drug. 
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 or she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records.


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7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the participant should be discontinued from study treatment unless 
there are extenuating circumstances that make it medically necessary for the participant to 
continue on study treatment. If the investigator and the sponsor clinical research physician (CRP)
agree that it is medically appropriate to continue, the investigator must obtain documented 
approval from the sponsor CRP to allow the inadvertently enrolled participant to continue in the 
study with or without treatment with investigational product.
Safety follow-up is as outlined in Section 1.3 (Schedule of Activities), Section 8.2 (Safety 
Assessments), and Section 8.3 (Adverse Events and Serious Adverse Events) of the protocol.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she loses contact with the study site for 
more than 10 days. Site personnel 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

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

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.
8.1.
Efficacy Assessments
8.1.1.
Primary Efficacy Assessments
The primary efficacy measure is the change from baseline in percentage of time with sensor 
glucose values between 70 and 180 mg/dL (both inclusive), from CGM use in the maintenance 
period.
8.1.2.
Secondary Efficacy Assessments
Secondary efficacy assessments for this study are

Change from baseline in ICR at the end of the maintenance period

ICR×TDD for the maintenance period

Prandial:TDD ratio for the maintenance period
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA Section 1.3.
The actual and change from baseline in percentage of time with sensor glucose values 
<54 mg/dL will be evaluated with CGM as an exploratory objective.
8.2.1.
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, and neurological systems. Height and weight will also be measured 
and recorded.
Investigators should pay special attention to clinical signs related to previous serious illnesses.
8.2.2.
Vital Signs
For each participant, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 1.3).


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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, and QT.
8.2.4.
Clinical Safety Laboratory Assessments
See Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. See Section 10.5 (Appendix 5) for clinical laboratory testing 
for close hepatic monitoring and see Section 10.2.1 for clinical laboratory testing for 
hypersensitivity.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the participants’ condition.
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor.
If such values do not return to normal or baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in Section 10.2 (Appendix 2) and the 
assessments described in Section 10.5 (Appendix 5) and Section 10.2.1, must be conducted in 
accordance with the laboratory manual and the SoA.
If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (for example, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.5.
Self-monitoring of Blood Glucose
Self-monitoring of blood glucose is optional in this study. Insulin titration will be guided by real-
time CGM readings from the Dexcom G6 CGM during this study. Dexcom G6 CGM has been 
approved by FDA for making clinical decisions. In case glucose alerts and readings from 
Dexcom G6 CGM do not match participant’s symptoms, the participant can use a finger stick 
blood glucose value to make treatment decisions.
All participants will wear Dexcom G6 CGM throughout the study until the end of maintenance 
period. Calibrating Dexcom G6 CGM using finger stick measurement is not allowed. All 
participants should use the sensor code printed on the back of adhesive patch to calibrate when 
starting a new sensor.
8.2.6.
Hypoglycemia
Participants will be trained about signs and symptoms of hypoglycemia, how to treat 
hypoglycemia, and how to discuss hypoglycemic events with investigators.


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Hypoglycemia will be described using the following definitions:

Level 1: Glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 mmol/L)

Level 2: Glucose <54 mg/dL (3.0 mmol/L)

Level 3: Severe hypoglycemia:
A severe event characterized by altered mental and/or physical status requiring 
assistance for treatment of hypoglycemia. Participants have altered mental status and 
cannot assist in their own care, may be semiconscious or unconscious, or experience 
coma with or without seizures, and require assistance of another person 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 blood glucose concentration to normal is considered 
sufficient evidence that the event was induced by a low blood 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.

All episodes of severe hypoglycemia must be reported as SAEs on the AE 
eCRF page and on the SAE eCRF page. 
Any events of severe hypoglycemia categorized as level 3 per the evaluation of investigators will 
be collected from ICF signing to Visit 801. 
Episodes of hypoglycemia categorized as level 1 or level 2 will be analyzed based on data from 
the CGM sensor session. Therefore, level 1 and level 2 hypoglycemic events do not need to be 
reported as an AE.
8.2.7.
Safety Monitoring
The principle investigator will monitor safety and laboratory data throughout the study and 
should discuss safety concerns with the sponsor immediately upon occurrence or awareness of 
the concern to determine whether the participant should continue or discontinue study drug.
8.2.7.1.
Hypersensitivity Reactions
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, the event will be reported as a spontaneous AE. Additional 
data describing each symptom should be provided to the sponsor in the eCRF.
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug. It is recommended that participants 
who experience a systemic hypersensitivity reaction be treated per the local standard of care.
In the case of generalized urticaria or anaphylaxis, additional blood, or urine samples should be 
collected as described in Section 10.2.1. Laboratory results are provided to the sponsor via the 
central laboratory.


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8.2.7.2.
Hepatic Monitoring
If a participant develops symptoms that warrant liver function assessment, liver function tests as 
detailed in Section 10.5 should be performed. If these tests are abnormal, clinical and laboratory 
monitoring should be initiated by the investigator. 
8.3.
Adverse Events and Serious Adverse Events
Adverse events will be reported by the participant, or when appropriate, by a caregiver or
surrogate..
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or the study (See Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs occurring after signing the ICF are recorded in the AE eCRF and assessed for serious 
criteria.
The SAE reporting to sponsor begins after the participant has signed the ICF and has received 
study drug. However, if an SAE occurs after signing the ICF, but before receiving LY900014, it 
needs to be reported ONLY if it is considered reasonably possibly related to study procedures.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3 (Appendix 3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3 (Appendix 3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits or contacts. All SAEs, and AEs of special interest (as defined in 
Section 8.3.6), will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-
up procedures is provided in Section 10.3 (Appendix 3).


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8.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards 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, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (for example, summary or listing of SAEs) from the sponsor will review and 
then file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.5.
Pregnancy
Pregnancy (maternal or paternal exposure to study treatment) does not meet the definition of an 
AE. However, to fulfill regulatory requirements, any pregnancy should be reported following the 
SAE process described in Section 10.4 (Appendix 4) to collect data on the outcome for both 
mother and fetus.
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until a period that is at least 
5 terminal half-lives after the last dose.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Section 10.4 (Appendix 4).
Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6. Adverse Events of Special Interest 
There are no adverse events of special interest (AESIs) in Study ITSZ. 
8.3.7. Product Complaints
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 
products provided in the study.
Sponsor collects product complaints on investigational products and drug delivery systems used 
in clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
Product complaints will be reported by the investigator to the sponsor per the Product Complaint 
Form.


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Note: Adverse events or SAEs that are associated with a product complaint will also follow the 
processes outlined in Section 8.3.3 and Section 10.3 (Appendix 3) of the protocol.
8.3.7.1.
Time Period for Detecting Product Complaints
Product complaints that result in an AE will be detected, documented, and reported to the 
sponsor during all periods of the study in which the drug or device is used.
If the investigator learns of any product complaint at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a drug or device
provided for the study, the investigator will promptly notify the sponsor.
8.3.7.2.
Prompt Reporting of Product Complaints to Sponsor
The Product Complaint Form will be available to the investigator on an investigator site portal
and all product complaints will be reported according to the instructions on the form. 
Additionally, the investigator will be supplied with product complaint reporting training 
materials. 
8.3.7.3.
Follow-up of Product Complaints
Follow-up applies to all participants, including those who discontinue study intervention. The 
investigator is responsible for ensuring that follow-up includes any supplemental investigations 
as indicated to elucidate the nature and/or causality of the product complaint. New or updated 
information will be recorded on the originally completed form with all changes signed and dated 
by the investigator and submitted to the sponsor.
8.4.
Treatment of Overdose
In the event of an overdose, refer to the IB for LY900014, or to the product label for degludec.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
Not applicable.
8.6.
Pharmacodynamics
Not applicable. 
8.7.
Genetics
Not applicable
8.8.
Biomarkers
Not applicable.
8.9.
Immunogenicity Assessments
Not applicable.


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8.10.
Health Economics
Not applicable.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
As an exploratory pilot dose optimization study, the primary objective of Study ITSZ is to
evaluate the percentage of time with glucose values within target range (70 to 180 mg/dL, both 
inclusive) after 35 days of using the study titration scheme with LY900014 treatment and 
degludec.
The study will investigate if a more aggressive ICR is needed with LY900014 treatment for
participants to reach the study-specific glucose target, compared to the “500 Rule” that is 
currently used in clinical practice.
9.2.
Sample Size Determination
Approximately 34 participants will be assigned to study treatment such that 30 evaluable 
participants will complete the maintenance period, assuming a 10% dropout rate.
The study is not strictly powered to demonstrate a statistically significant change from baseline
in the primary endpoint (percentage of time with glucose within 70 to 180 mg/dL) because of the
exploratory nature of the study. 
Using a standard deviation of 12%, the sample will provide approximately 80% coverage 
probability that the half-width of the 95% confidence interval of the change from baseline in the 
primary endpoint falls within 4.93%.
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Entered
All participants who give informed consent
Enrolled
All participants who continue the study after Visit 2
Treated
All assigned participants who receive at least 1 dose of the assigned study treatment after 
Visit 3
9.4.
Statistical Analyses
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
statistical analysis plan (SAP) or the clinical study report. Additional exploratory analyses of 
data will be conducted, as deemed appropriate.
9.4.1. General Considerations
Unless otherwise specified, all efficacy and safety analyses will be conducted on the Treated 
Population. Unless otherwise noted, all tests will be conducted at a 2-sided alpha level of 0.05, 
and confidence intervals will be calculated at 95%, 2-sided. Comparison between baseline and 


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endpoints will be performed at the full significance level of 0.05. No multiplicity adjustment will 
be made. Baseline is defined as the last non-missing measurement at or before the treatment 
assignment (Visit 3) unless otherwise specified.
An analysis of covariance (ANCOVA) will be used to analyze continuous variables that are 
planned to be collected only for baseline and endpoint. The model will include baseline as a 
covariate.
A restricted-maximum-likelihood-based, mixed model repeated measures (MMRM) analysis will 
be used to analyze continuous longitudinal variables collected only at baseline and more than one 
scheduled post-baseline visits according to SoA in Section 1.3. All the longitudinal observations 
at each scheduled post-baseline visit will be included in the analysis. The model for the analysis 
of the primary efficacy endpoint will include the fixed class effect of visit, and the random effect 
of patient. An unstructured covariance structure will be used to model the within-patient errors. 
Significance tests will be based on least-squares (LS) means and Type III tests. SAS PROC 
MIXED will be used to perform the analysis. If this analysis fails to converge, the following 
covariance structures will be tested in order:

Toeplitz with heterogeneity

Autoregressive with heterogeneity

Compound symmetry with heterogeneous variances

Toeplitz

Autoregressive

Compound symmetry without heterogeneous variances
The first covariance structure that converges will be used. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom. If the analysis still does not converge 
with Compound symmetry without heterogeneous variances, only summary statistics will be 
provided.
For continuous measures, summary statistics will include sample size, mean, standard deviation, 
median, minimum, and maximum for both the actual and the change from baseline 
measurements. Least-square (LS) means and standard errors derived from the analysis models 
will also be displayed for the actual and the change from baseline measurements.
For categorical measures, summary statistics will include sample size, frequency, and 
percentages. No statistical analyses will be conducted for baseline and endpoint comparison.
All CGM outcome variables will only be derived for Visit 3 (baseline) and Visit 14 (endpoint)
based upon the CGM data collected from valid CGM days, excluding data (if any) that are 
collected while patients are temporarily off Humalog during the lead-in period or temporarily off 
IP during the maintenance period. A valid CGM day to be counted into the calculation for a visit
must have at least 70% of the total measures that are supposed to be obtained.
9.4.2.
Primary Endpoint(s)
The primary objective of this study is to evaluate the percentage of time with glucose values 
within target range (70 to 180 mg/dL, both inclusive) after 35 days of using the study titration 


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scheme with LY900014 treatment and degludec. Both actual and change from baseline will be 
derived and analyzed by the ANCOVA model as described in Section 9.4.1.
The primary analyses will be conducted based upon the CGM data collected for Visit 3 
(baseline) and Visit 14 (endpoint), excluding data (if any) that are collected while patients are
temporarily off Humalog during the lead-in period or temporarily off IP during the maintenance 
period.
9.4.3.
Secondary Endpoint(s)
Additional continuous secondary efficacy variables, as well as the change from baseline for these 
variables, will be analyzed by the MMRM or ANCOVA model as described in Section 9.4.1.
Relationships between ICR and TDD will be evaluated through regression lines (ICR versus 
1/TDD) and compared with the “500 Rule,” which is currently used in clinical practice where 
ICR = 500/TDD (Section 2.1).
9.4.4.
Exploratory Endpoints
Additional continuous exploratory efficacy variables, as well as the change from baseline for
these variables, will be analyzed by the MMRM or ANCOVA model described in Section 9.4.1, 
unless otherwise specified.
Relationships between the following endpoints will be explored through regression lines (King et 
al. 2007a, 2007b).

ISF and 1/TDD

ICR and ISF 

TBD and weight 
9.4.5.
Other Safety Analyses
Safety measures will include AEs, vital signs, and treatment exposure. Events that are newly 
reported after the first dose of IP used or reported to worsen in severity from baseline (details 
will be described in SAP) will be considered TEAEs. 
Analyses of AEs will be descriptive and include all data collected during the treatment period. 
AEs during the lead-in period and the safety follow-up period will be provided in a listing.
Serious AEs, AEs reported as the reason for discontinuation from the IP or study, and TEAEs 
will be summarized in tables using the Medical Dictionary for Regulatory Activities (MedDRA) 
Preferred Term sorted by decreasing frequency. Treatment-emergent AEs will also be 
summarized by preferred term sorted by decreasing frequency within the SOC for all TEAEs and 
by maximum severity. For events that are gender-specific (as defined by MedDRA), the 
denominator and computation of the percentage will include only patients from the given gender. 
The number and proportion of patients with at least 1 event for each type of event will also be
summarized.
In addition, time in hypoglycemic ranges will be assessed by CGM analyses. 
9.4.6.
Other Analyses 
Analysis details for additional exploratory endpoints will be described in the SAP.


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9.5.
Interim Analyses 
No interim analyses are planned for this study. If an unplanned interim analysis is deemed
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.
9.6.
Data Monitoring Committee
No Data Monitoring Committee is planned for this study. 


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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 (CIOMS) International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(for example, 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.
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 the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), 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.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the study and for 1 year after 
completion of the study.


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10.1.3.
Informed Consent Process
The investigator or his or her representative will explain the nature of the study, including the 
risks and benefits, to the participant and answer all questions regarding the study.
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
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 re-consented 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 participant and is kept on file.
10.1.4.
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 which would make the participant identifiable will not be transferred.
The participant must be informed that his or her 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 his or her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5.
Dissemination of Clinical Study Data
Reports
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available website where required by local law or regulation. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK or genetic data. Data are available to request 6 months 
after the indication studied has been approved in the United States (US) and European Union 
(EU) and after the primary publication acceptance, whichever is later. No expiration date of data 
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement. Data and 
documents, including the study protocol, statistical analysis plan, clinical study report, blank, or 
annotated case report forms, will be provided in a secure data sharing environment for up to 2 
years per proposal. 


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For details on submitting a request, see the instructions provided at 
www.clnicalstudydatarequest.com. 
10.1.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (for example, 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.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (for example, 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 (for 
example, Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel 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.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the period outlined in the Clinical Trial 
Agreement (CTA) 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, Sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study may be 
audited by Sponsor or its representatives, and/or regulatory agencies at any time. 
Investigators will be given notice before an audit occurs.


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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 (EDC) 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 EDC 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 will be stored at a single third-party. 
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system. Before decommissioning, the investigator will 
receive 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 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 Sponsor will be encoded and stored in the global 
product complaint management system.
10.1.7.
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 the CRF or entered in the eCRF that 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 Section 10.1.6.
10.1.8.
Study and Site and Closure
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:

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


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
Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
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.
10.1.9.
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.
10.1.10.
Investigator Information
Physicians with a specialty in endocrinology or primary care physicians specializing in 
endocrinology or internal medicine will participate as investigators in this clinical trial.


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10.2.
Appendix 2: Clinical Laboratory Tests
The tests detailed below will be performed by the central laboratory except where indicated. 
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. Investigators must document their 
review of each laboratory safety report.
For the timing and frequency of the tests refer to the Schedule of Activities in Section 1.3.
Clinical Laboratory Testsa
Hematology
Clinical Chemistry (Serum Concentrations of)
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Total bilirubin
Mean cell volume
Direct bilirubin
Mean cell hemoglobin concentration
Alkaline phosphatase
Leukocytes (WBC)
Chloride
Neutrophils, segmented
Blood urea nitrogen (BUN)
Lymphocytes
Creatinine
Monocytes
Glucose
Eosinophils
Alanine aminotransferase (ALT)
Basophils
Aspartate aminotransferase (AST)
Platelets
Magnesium
Uric acid
Pregnancy Test (females only)b
Total protein
Follicle-stimulating hormonec
Albumin
Calcium
Urinalysis
Creatine kinase (CK)
Specific gravity
1,5 Anhydroglucitol
pH
Fructosamine
Protein
Glucose
HbA1c
Ketones
Blood
Urine leukocyte esterase
Bilirubin
Nitrite
a
All laboratory tests will be assayed by a Lilly-designated central laboratory, unless otherwise noted.
b
Serum pregnancy test must be performed in women of childbearing potential at Visit 1 followed by a urine 
pregnancy test within 24 hours before IP exposure at randomization and at other times at the investigator’s 
discretion.
c
Follicle-stimulating hormone test must be performed at Visit 1 for women at least 40 years of age with an intact 
uterus, not on hormone therapy, and who has had cessation of menses for at least 1 year without an alternative 
medical cause.


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10.2.1.
Hypersensitivity Clinical Laboratory Tests
Laboratory testing should be performed at the time of a Systemic Hypersensitivity Event. 
Important information about why, when, and what to test for are provided as follows. The 
management of the AE may warrant laboratory testing beyond that described below and should 
be performed as clinically indicated.
Laboratory testing during a Systemic Hypersensitivity Event is not performed for diagnostic 
purposes. Its intent is several fold:

To help characterize and classify systemic hypersensitivity reactions

To meet regulatory expectations

To improve subsequent clinical management by helping to distinguish between the 
various mechanistic bases of anaphylaxis
When should labs be obtained?

In the presence of generalized urticaria or if anaphylaxis is suspected

After the subject has been stabilized, obtain a sample within 1 to 2 hours of the event;
however, samples may be obtained as late as 12 hours after the event as analytes can 
remain altered for an extended period of time. Record the time at which the sample was 
collected.

Obtain a follow-up sample at the next regularly scheduled visit or after 4 weeks, 
whichever is later.
What labs* should be obtained?

Tryptase**

ADA and LY concentration (PK)
o
ADA testing should include drug-specific immunoglobulin E (IgE) or the 
basophil activation test (BAT)#. These tests are not routinely available and need 
to be developed for individual molecules based on their evolving safety profile. 
Samples are collected, and testing conducted once the assay is available, as 
appropriate. Please consult an immunologist within GPS for further guidance.

Complement
o
C3, C3a, and C5a

Cytokines
o
Interleukin (IL)‐6, IL‐1β, IL‐10 (or any cytokine panel that includes these 
3 cytokines)
*
These laboratories are bundled in the Clinical Laboratory Operations Hypersensitivity 
Lab Testing Kit 
** If a tryptase sample is obtained more than 2 hours after the event (that is, within 2 to 
12 hours), or is not obtained because more than 12 hours have lapsed since the event, obtain 
urine for N-methylhistamine (NMH) testing. Note that for tryptase serum samples obtained 
within 2 to 12 hours of the event, urine NMH testing is performed in addition to tryptase 
testing. Collect the first void urine following the event. Obtain a follow-up urine for NMH 
testing at the next regularly scheduled visit or after 4 weeks, whichever is later.


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#
The BAT is an in vitro cell based assay that only requires a serum sample. It is a 
surrogate assay for drug-specific IgE but is not specific for IgE.


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10.3.
Appendix 3: 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 patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: Therefore, an AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (that is, ECG, radiological scans, and 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 pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions 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.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as 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.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. Such a 
finding includes an episode considered to be related to hypoglycemia categorized as 
either level 1 or level 2 based on plasma glucose levels.
o
Level 1: <70 mg/dL (3.9 mmol/L) and glucose ≥54 mg/dL (3.0 mmol/L)
o
Level 2: <54 mg/dL (3.0 mmol/L)

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.

Medical or surgical procedure (for example, endoscopy and 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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (for example, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Is categorized as level 3 hypoglycemia: a severe event characterized by altered 
mental and/or physical status requiring assistance
b.
Results in death
c.
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.
d.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to hospital
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 pre-existing condition that did not worsen 
from baseline is not considered an AE.


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e.
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 (for example, sprained ankle), which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
f.
Is a congenital anomaly/birth defect
g.
Other situations:

Medical or scientific judgment should be exercised 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 one 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.
Recording and Follow-up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participants’
medical records to Sponsor or designee in lieu of completion of the AE/SAE CRF 
page.

There may be instances when copies of medical records for certain cases are requested 
by 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 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.


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Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a 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.

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.

The investigator will use clinical judgment to determine the relationship.

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.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in his or her assessment.

For each AE/SAE, the investigator must document in the medical notes that he or 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 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 Sponsor or designee.

The investigator may change his or her 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 one of the criteria used when determining regulatory 
reporting requirements.


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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 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.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to Sponsor or designee within 24 
hours of receipt of the information.
10.3.4.
Reporting of SAEs
SAE Reporting via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE will be the electronic data collection 
tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form (see next 
section) or to Lilly Medical by telephone.

Contacts for SAE reporting can be found at 1.800.LillyRx.
SAE Reporting via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to Lilly Medical.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found at 1.800.LillyRx.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. If fertility is unclear (for example, amenorrhea in adolescents or athletes) 
and a menstrual cycle cannot be confirmed before first dose of study intervention, additional 
evaluation should be considered.
Women not of childbearing potential 
1. Premenarchal
2. Premenopausal female with one of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (for example, Mullerian agenesis and androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female is defined as, women with:

12 months amenorrhea for women aged >55 years, with no need for follicle 
stimulating hormone (FSH)

12 months of amenorrhea for women >40 years old with FSH ≥40 mIU/mL and 
no other medical condition such as anorexia nervosa and not taking medications 
during the amenorrhea (for example, oral contraceptives, hormones, 
gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor 
modulators, or chemotherapy that induced amenorrhea)
Contraception Guidance
Male Participants
No male contraception required.
Female Participants
A female participant is eligible to participate if she is not pregnant, intending to become 
pregnant, or breastfeeding, and at least one of the following conditions applies:

Is not a woman of childbearing potential
OR

Is a WOBCP with the following study requirements:

A WOCBP must test negative for pregnancy prior to initiation of treatment as 
indicated by a negative serum pregnancy test at the screening visit followed by a 


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negative urine pregnancy text within 24 hours prior to exposure to investigational 
product (IP) at Visit 3.

WOCBP who are abstinent (if this is complete abstinence, as their preferred and 
usual lifestyle) or in a same-sex relationship (as part of their preferred and usual 
lifestyle) must agree to either remain abstinent or stay in a same-sex relationship 
without sexual relationships with males. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence just 
for the duration of a trial, and withdrawal are not acceptable methods of 
contraception.

WOCBP (who are not abstinent or in a same-sex relationship) must agree to use 
one highly effective method (less than 1% failure rate) of contraception, or a 
combination of two effective methods of contraception for the entirety of the 
study.
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly effective methods of contraception 

Combined oral contraceptive pill and mini-pill

NuvaRing

Implantable contraceptives

Injectable contraceptives (such as Depo-Provera®)

Intrauterine device (such as Mirena® and ParaGard)

Contraceptive patch – ONLY women <198 pounds or 90Kg

Total Abstinence

Vasectomy

Fallopian tube implants (Essure) [if confirmed by hysterosalpingogram]
Effective methods of contraception (must use two forms combined)a

Male condom with spermicideb

Female condom with spermicideb

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide
a
Participants may choose to use a double-barrier method of contraception. Barrier protection methods without 
concomitant use of a spermicide are not a reliable or acceptable method. Thus, each barrier method must include 
use of a spermicide.
b
Male and female condoms should not be used in combination as a double barrier method due to the high failure 
rate when these methods are combined.


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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 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.

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. 

A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring 
at >20 weeks gestational age) is always considered to be an SAE and will be reported as 
such. 

Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 10.3.4. 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 from study intervention and from the study.


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10.5.
Appendix 5: Hepatic Safety: Suggested Actions and Follow-up 
Assessments 
Close Hepatic Monitoring
Laboratory tests including ALT, AST, ALP, TBL, D. Bil, GGT, and CK, should be repeated 
within 48 to 72 hours to confirm the abnormality and to determine if it is increasing or 
decreasing, if one or more of these conditions occur. 
If a participant with baseline 
results of ... 
Develops the following elevations:
ALT or AST <1.5x ULN
ALT or AST ≥3x ULN
ALP <1.5x ULN
ALP ≥2x ULN
TBL <1.5x ULN
TBL ≥2x ULN (except for participants with Gilbert’s syndrome)
ALT or AST ≥1.5x ULN
ALT or AST ≥2x baseline
ALP ≥1.5x ULN
ALP ≥2x baseline
TBL ≥1.5x ULN
TBL ≥2x baseline (except for participants with Gilbert’s 
syndrome)
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse.
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels.


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Comprehensive Hepatic Evaluation
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur:
If a participant with baseline 
results of... 
Develops the following elevations:
ALT or AST <1.5x ULN
ALT or AST ≥3x ULN with hepatic signs/symptoms,* or
ALT or AST ≥5x ULN
ALP <1.5x ULN
ALP ≥3x ULN
TBL <1.5x ULN
TBL ≥2x ULN (except for participants with Gilbert’s 
syndrome)
ALT or AST ≥1.5x ULN
ALT or AST ≥2x baseline with hepatic signs/symptoms,* or
ALT or AST ≥3x baseline
ALP ≥1.5x ULN
ALP ≥2x baseline
TBL ≥1.5x ULN
TBL ≥1.5x baseline (except for participants with Gilbert’s 
syndrome) 
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, 
rash, and/or eosinophilia >5%.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR; tests for viral hepatitis A, B, C, or E; tests 
for autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT scan). 
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus 
(HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, 
acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, 
urinary ethyl glucuronide, and serum phosphatidylethanol. Based on the circumstances and the 
investigator’s assessment of the participant’s clinical condition, the investigator should consider 
referring the participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), 
cardiac echocardiogram, or a liver biopsy.
Additional hepatic data collection in study participants who have abnormal liver tests 
during the study
Additional hepatic safety data collection in hepatic safety case report forms (CRF) should be 
performed in study participants who meet one or more of the following 5 conditions:
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN)

In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline
on 2 or more consecutive tests
2. Elevated TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome)


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
In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN)

In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline 
on 2 or more consecutive blood tests
4. Hepatic event considered to be a serious adverse event (SAE)
5. Discontinuation of study drug due to a hepatic event 
Note: the interval between the two consecutive blood tests should be at least 2 days.
10.5.1.
Hepatic Evaluation Testing
If the investigator has confirmed liver test abnormality, he or she should select further
appropriate tests. For the selected testing, analysis is required to be completed by the Lilly 
designated central laboratory except for microbiology.
Local testing may be performed in addition to central testing when required for immediate 
participant management.
Results will be reported if a validated test or calculation is available.


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Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - Red Blood Cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - White Blood Cells) 
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
    Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
    Lymphocytes
Creatine kinase (CK)
    Monocytes
Other Chemistry  
    Basophils
Acetaminophen
    Eosinophils
Acetaminophen Protein Adducts
Platelets
Alkaline Phosphatase Isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Ethyl Alcohol (EtOH)
Prothrombin Time, INR (PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (Quantitative)
Hepatitis A Virus (HAV) Testing:
Immunoglobulin IgG (Quantitative)
    HAV Total Antibody
Immunoglobulin IgM (Quantitative)
    HAV IgM Antibody
Phosphatidylethanol (PEth)
Hepatis B Virus (HBV) Testing:
Urine Chemistry
    Hepatitis B surface antigen (HBsAg)
Drug Screen
    Hepatitis B surface antibody (Anti-HBs) 
Ethyl glucuronide (EtG)
    Hepatitis B core total antibody (Anti-HBc)
Other Serology
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA)
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a
    HBV DNA d
Anti-actin antibody b
Hepatis C Virus (HCV) Testing:
Epstein-Barr Virus (EBV) Testing:
    HCV antibody
    EBV antibody
    HCV RNA d
    EBV DNA d
Hepatitis D Virus (HDV) Testing:
Cytomegalovirus (CMV) Testing:
    HDV antibody
    CMV antibody
Hepatitis E Virus (HEV) Testing:
    CMV DNA d
    HEV IgG antibody
Herpes Simplex Virus (HSV) Testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody
    HEV RNA d
    HSV (Type 1 and 2) DNA d
Microbiology c
Liver Kidney Microsomal Type 1 (LKM-1) Antibody
Culture:
    Blood
    Urine
a
This is not required if Anti-Actin Antibody is tested.
b
This is not required if Anti-smooth muscle antibody (ASMA) is tested.
c
Assayed by Investigator-designated local laboratory ONLY; no Central Testing available.
d
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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10.6.
Appendix 9: Abbreviations
Term
Definition
AACE
American Association of Clinical Endocrinologists
ADA
Anti-drug Antibodies
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BAT
basophil activation test
CF
Correction Factor
CFR
Code of Federal Regulations
CGM
continuous glucose monitoring
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CMV
cytomegalovirus
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.
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.
CT
computed tomography
D. Bill
direct bilirubin
Device Deficiencies
Equivalent to product complaint
DIA
Duration of Insulin Action
DMC
data monitoring committee
EBV
Epstein-Barr virus


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ECG
electrocardiogram
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.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
ERCP
endoscopic retrograde cholangiopancreatography
FSH
follicle stimulating hormone
GCP
good clinical practice
gestational age
The estimated age of the fetus calculated from the first day of the last menstrual period 
to the delivery of the fetus. It is expressed in the number of completed weeks. This is 
based on 40 weeks or 10 months.
GGT
Gamma-glutamyltransferase
GLP-1
glucagon-like peptide 1
HCP
health care professional
HDV
Hepatitis D virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICR
insulin-to-carbohydrate ratio
IEC
Independent Ethics Committees
IgE
immunoglobulin E
IL
interleukin
IMP
Investigational Medicinal Product
Informed consent
A process by which a participant voluntarily confirms his or her 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.
INR
international normalized ratio
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.


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investigational 
product (IP)
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 Boards
ISF
insulin sensitivity factor
ITT
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, 
the planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to 
the planned course of treatment.
IV
intravenous
IWRS
interactive web-response system
MedDRA
Medical Dictionary for Regulatory Activities
MDI
multiple daily injections
MMA
mobile medical app
MMRM
mixed model repeated measures
MRCP
magnetic resonance cholangiopancreatography
NAFLD
non-alcoholic fatty liver disease
NIMP
Non-investigational Medicinal Product
NMH
N-methylhistamine
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
PIs
primary investigators 
PK/PD
pharmacokinetics/pharmacodynamics
PT
prothrombin time
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
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. 


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SMS
Study management suite
T1D
type 1 diabetes
T2D
type 2 diabetes
TBL
total bilirubin
TBD
Total Basal Dose
TDD
Total Daily Dose
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.
ULN
upper limit of normal
USPI
United States Prescribing Information
WOCBP
woman of childbearing potential


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10.7. Appendix 10: Protocol Amendment History
Amendment [a] 
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities (SoA)
Removal of Visit 7 for 
investigational product (IP) 
dispensing
Study IP will not be dispensed at 
Visit 7. IP will be dispensed at Visits 
3 and 11. 
1.3. Schedule of 
Activities (SoA), 4.1.1. 
Study Visits
Addition of language to 
clarify data capture on insulin 
dosing
Clarification for transcribing data 
into eCRF for insulin dosing at Visit 
3 and Visit 14
5.1. Inclusion Criteria
Addition of language to align 
with Lilly guidance
Clarification of inclusion criteria for 
females regarding pregnancy, 
breastfeeding and contraceptive 
guidance 
9.4.1. General 
Considerations
Add analysis details if mixed 
model repeated measures 
(MMRM) does not converge
Clarification of analysis details if 
MMRM does not converge
Addition of language for 
continuous glucose 
monitoring (CGM) data 
analysis for Visit 3 and 
Visit 14
Clarification of study interventions 
data during study periods
9.4.2. Primary 
Endpoint(s)
Replace analysis method with 
analysis of covariance 
(ANCOVA)
Change was made because CGM 
data will only be derived for Visit 3 
and Visit 14
Addition of language for 
CGM data analysis for Visit 3 
and Visit 14
Clarification of study interventions 
data during study periods
10.4. Appendix 4: 
Contraceptive Guidance 
and Collection of 
Pregnancy Information
Addition of language to align 
with Lilly guidance
Clarification of contraceptive 
guidance 
Throughout
Minor editorial and document 
formatting revisions
These are minor changes; therefore, 
they have not been summarized


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11.
References
Bailey TS, Grunberger G, Bode BW, Handelsman Y, Hirsch IB, Jovanovič L, Roberts VL, 
Rodbard D, Tamborlane WV, Walsh J. American Association of Clinical Endocrinologists and 
American College of Endocrinology 2016 Outpatient Glucose Monitoring Consensus Statement. 
Endocrine Practice. 2016; 22(2): 231-261. 
Blevins T, Zhang Q, Frias JP, Jinnouchi H, Chang AM. Ultra Rapid Lispro (URLi) Improves 
Postprandial Glucose (PPG) Control vs. Humalog (Lispro) in Patients with Type 2 Diabetes 
(T2D): PRONTO-T2D [abstract]. In: American Diabetes Association 4 June 2019; 68(1).
Bode BW. Insulin pump therapy in Therapy for Diabetes Mellitus and related disorders, Fourth 
edition. In: Lebovitz HE, editor. American Diabetes Association; 2004.
DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes. JAMA. 
2003;289:2254-2264.
Gan MJ, Albanese-O’Neill A, Haller MJ. Type 1 diabetes: current concepts in epidemiology, 
pathophysiology, clinical care, and research. Curr Probl Pediatr Adolesc Health Care. 
2012;42(10):269-291
Insulin pump therapy and continuous glucose monitoring. Pickup J, editor. London: Oxford 
University Press; 2009.
King AB, Armstrong DU. A prospective evaluation of insulin dosing recommendations in 
patients with type 1 diabetes at near normal glucose control: basal dosing. J Diabetes Sci 
Technol. 2007a;1(1):42-46.
King AB, Armstrong DU. A prospective evaluation of insulin dosing recommendations in 
patients with Type 1 Diabetes at near normal glucose control: bolus dosing. J Diabetes Sci 
Technol. 2007b;1(1):42-46.
Allen King. How Much Do I Give? Reevaluation of Insulin Dosing Estimation Formulas Using 
Continuous Glucose Monitoring. Endocrine Practice. 2010;16(3):428-432.
King AB. Continuous glucose monitoring-guided insulin dosing in pump-treated patients with 
type 1 diabetes: a clinical guide. J Diabetes Sci Technol. 2012;16(3):191-203.
Klaff L, Cao D, Dellva MA, Tobian J, Miura J, Dahl D, Bue-Valleskey JM. Ultra Rapid Lispro 
(URLi) Improves Postprandial Glucose (PPG) Control vs. Humalog (Lispro) in T1D: PRONTO 
T1D Study [abstract]. In: American Diabetes Association; 4 June 2019; 68(1).
Kruszynska YT, Home PD, Hanning I, Alberti KGMM. Basal and 24-hour C-peptide and insulin 
secretion rate in normal man. Diabetologia. 1987;30:16-21.
Kuroda A, Yasuda T, Takahara M, Sakamoto F, Kasami R, Miyashita K, Yoshida S, Kondo E, 
Aihara K, Endon I, Matsuoka T, Kaneto H, Matsumoto T, Shimomura I, Matsuhisa M. 300–400 
Divided by total daily insulin dose in type 1 diabetes patients who use the insulin pump. 
Diabetes Technol Ther. 2012;14(11):1077-1080.
Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of 
insulin secretion in normal and obese subjects. J Clin Invest. 1988;81:442-448.


CONFIDENTIAL
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83
Stark-Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting 
A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care. 
2013;36(8):2271-2279.
Tresiba [package insert]. DK-2880 Bagsvaerd, Denmark, Novo Nordisk A/S; 2015.


Leo Document ID = 3dbe4b3d-88ac-475e-bbbb-827b6db38ce9
Approver: 
Approval Date & Time: 24-Nov-2020 13:51:42 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 24-Nov-2020 14:04:12 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan: I8B-MC-ITSZ (Version 1) 
 
 
An Exploratory Study Assessing Time in Target Glucose Range Using a New 
Titration Scheme of LY900014 and Insulin Degludec in Participants with Type 
1 Diabetes 
 
 
NCT04585776 
 
 
Approval Date: 05-Oct-2020 


I8B-MC-ITSZ Statistical Analysis Plan Version 1
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1.
Statistical Analysis Plan:  
I8B-MC-ITSZ:  An Exploratory Study Assessing Time in 
Target Glucose Range Using a New Titration Scheme of 
LY900014 and Insulin Degludec in Participants with Type 
1 Diabetes
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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.
LY900014
Study I8B-MC-ITSZ (ITSZ) is a multicenter, single-group, open-label, Phase 2 study that 
will be conducted in participants with type 1 diabetes (T1D) currently treated with insulin 
degludec and a rapid-acting insulin analog in a multiple daily injection (MDI) regimen.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8B-MC-ITSZ
Phase 2
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 05-Oct-2020 GMT


I8B-MC-ITSZ Statistical Analysis Plan Version 1
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I8B-MC-ITSZ:  An Exploratory Study 
Assessing Time in Target Glucose Range Using a New Titration 
Scheme of LY900014 and Insulin Degludec in Participants with 
Type 1 Diabetes ..................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
5.
Study Design.....................................................................................................................10
5.1.
Summary of Study Design............................................................................................10
5.2.
Determination of Sample Size ......................................................................................10
5.3.
Method of Treatment Assignment ................................................................................11
6.
A Priori Statistical Methods ..............................................................................................12
6.1.
General Considerations ................................................................................................12
6.2.
Adjustments for Covariates ..........................................................................................15
6.3.
Handling of Dropouts or Missing Data.........................................................................15
6.4.
Multiple Comparisons/Multiplicity...............................................................................15
6.5.
Patient Disposition .......................................................................................................15
6.6.
Patient Characteristics ..................................................................................................16
6.7.
Treatment Compliance .................................................................................................16
6.8.
Concomitant Therapy...................................................................................................16
6.9.
Efficacy Analyses ........................................................................................................17
6.9.1.
Primary Outcome and Methodology.....................................................................17
6.9.2.
Other Secondary Efficacy Analyses .....................................................................17
6.9.3.
Exploratory Efficacy Analyses .............................................................................18
6.10. Safety Analyses............................................................................................................18
6.10.1.
Extent of Exposure...............................................................................................18
6.10.2.
Adverse Events ....................................................................................................19
6.10.3.
Hypoglycemic Events and Other Adverse Events.................................................20
6.10.3.1.
Hypoglycemia ................................................................................................20
6.10.3.2.
Injection Site Reaction....................................................................................21
6.10.4.
Clinical Laboratory Evaluation.............................................................................21
6.10.5.
Vital Signs and Other Physical Findings...............................................................21
6.10.6.
Patient Narratives.................................................................................................22
6.11. Important Protocol Deviations......................................................................................22
6.12. Interim Analyses and Data Monitoring.........................................................................22


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6.13. CGM Analyses.............................................................................................................22
6.14. Clinical Trial Registry Analyses...................................................................................25
7.
Unblinding Plan................................................................................................................27
8.
References ........................................................................................................................28
9.
Appendices .......................................................................................................................29


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Table of Contents
Table
Page
Table ITSZ.4.1.
Objectives and Endpoints............................................................................8
Table ITSZ.6.1.
Patient Populations ...................................................................................12
Table ITSZ.6.2.
Baseline and Post-Baseline Definitions and Patient Population by Study 
Period and Type of Analysis..............................................................................................14
Table ITSZ.6.3.
Adverse Event Analysis Periods ...............................................................20
Table ITSZ.6.4.
Summary of Analyses for Severe Hypoglycemia.......................................21
Table ITSZ.6.5.
Outcome Measures of CGM Data .............................................................23
Table ITSZ.6.6.
Guidance Recommended CGM Targets of Glycemic Control ...................24


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Table of Contents
Figure
Page
Figure ITSZ.5.1.
Illustration of study design for Clinical Protocol I8B-MC-ITSZ................10


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Table of Contents
Appendix
Page
Appendix 1.
Derivation of CGM Variables.........................................................................30


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3.
Revision History
This statistical analysis plan (SAP) is the first version and is based on the protocol of I8B-MC-
ITSZ approved on 08 June 2020 and the amendments (a) approved on 12 July 2020. SAP 
Version 1 was approved prior to the first visit when a subject receives study drug or any other 
protocol intervention.


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4.
Study Objectives
Table ITSZ.4.1 shows the objectives and endpoints of the study.
Table ITSZ.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the time that glucose values are within the 
target range 70 to 180 mg/dL from CGM use, after 35 
days of using the study titration scheme with LY900014 
treatment and degludec
Percentage of time with sensor glucose values 
between 70 and 180 mg/dL (both inclusive), with 
CGM use during the maintenance period 
Secondary
To evaluate ICR with LY900014 treatment
ICR at the end of the maintenance period 
To evaluate the relationship between ICR and TDD with 
LY900014 treatment
ICR×TDD for the maintenance period
To evaluate total daily, basal, and prandial insulin dose 
with LY900014 treatment and degludec
Prandial: TDD ratio for the maintenance period
Tertiary/Exploratory
To evaluate the safety of LY900014
Adverse events and vital signs 
To explore the relationship between

ICR and TDD

ISF and TDD

ICR and ISF
with LY900014 treatment

Slope of the linear regression line of ICR or 
ISF on the reciprocal of TDD

Slope of the linear regression line of ICR on 
ISF, 
for the maintenance period
To explore ISF with LY900014 treatment
ISF at the end of the maintenance period
To explore glucose profiles, obtained from CGM use 
with LY900014 treatment
Actual and change from baseline in mean sensor 
glucose with CGM use during the maintenance 
period
To explore highest PPG level within 4 hours* after 
meal(s), obtained from CGM use, with LY900014 
treatment
Actual and change from baseline in highest PPG 
level within 4 hours after meal(s), with CGM use 
during the maintenance period 


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Objectives
Endpoints
To explore the time from start of meal to highest PPG 
level within 4 hours* after meal(s), obtained from CGM 
use, with LY900014 treatment
Actual and change from baseline in minutes from 
start of meal to highest PPG level within 4 hours after 
meal(s), with CGM use during the maintenance 
period 
To explore the percentage of time spent in hypoglycemic 
glucose ranges, obtained from CGM use, with LY900014 
treatment
Actual and change from baseline in percentage of 
time with sensor glucose values <54 mg/dL, with
CGM use during the maintenance period 
To explore percentage of time spent in hyperglycemic 
glucose ranges, obtained from CGM use, with LY900014 
treatment
Actual and change from baseline in percentage of 
time with sensor glucose values >250 mg/dL, with 
CGM use during the maintenance period 
To explore within-day glucose variability, obtained from 
CGM use, with LY900014 treatment
Actual and change from baseline in within-day CV of 
sensor glucose, with CGM use during the 
maintenance period 
To explore proportion of participants achieving CGM-
based glycemic targets, with LY900014 treatment
The proportion of participants with percentage of 
time in 

target glucose range,
70-180 mg/dL, >70% 

hypoglycemia, <54 mg/dL, <1%

hyperglycemia, >250 mg/dL, <5%, 
with CGM use during the maintenance period 
To explore fructosamine with LY900014 treatment
Fructosamine at the end of the maintenance period 
compared to baseline
To explore HbA1c with LY900014 treatment
HbA1c at the end of the maintenance period 
compared to baseline
To explore 1,5 Anhydroglucitol (AG) with LY900014 
treatment
1,5 AG at the end of the maintenance period 
compared to baseline
Abbreviations: CGM = continuous glucose monitoring; CV = cardiovascular; HbA1c = hemoglobin A1c; ICR = 
insulin-to-carbohydrate ratio; ISF = insulin sensitivity factor; PPG = post-prandial glucose; TDD = Total Daily 
Dose.
*Excluding the glucose data from participants who have had the next meal event before the end of time interval.


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5.
Study Design
5.1.
Summary of Study Design
Study I8B-MC-ITSZ (ITSZ) is a multicenter, single-group, open-label, Phase 2 study that will be 
conducted in participants with type 1 diabetes (T1D) currently treated with insulin degludec and 
a rapid-acting insulin analog in a multiple daily injection (MDI) regimen. The objective of the 
study is to assess the percentage of time glucose values are within the target range of 70 to 180 
mg/dL after 35 days of titration using the study titration scheme of LY900014 and insulin 
degludec in participants with T1D.
The total duration of study participation for each participant is approximately 74 days across the 
following study periods:

Screening, up to 10 days

Lead in period, 11 days

Treatment period
o
Titration period, 35 days
o
Maintenance period, 11 days

Safety follow-up period, 7 days
Figure ITSZ.5.1 illustrates the study design.
Figure ITSZ.5.1.
Illustration of study design for Clinical Protocol I8B-MC-ITSZ.
5.2.
Determination of Sample Size
Approximately 34 participants will be assigned to study treatment such that 30 evaluable 
participants will complete the maintenance period, assuming a 10% dropout rate.
The study is not strictly powered to demonstrate a statistically significant change from baseline 
in the primary endpoint (percentage of time with glucose within 70 to 180 mg/dL) because of the 
exploratory nature of the study. 


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Using a standard deviation of 12%, the sample will provide approximately 80% coverage 
probability that the half-width of the 95% confidence interval (CI) of the change from baseline in 
the primary endpoint falls within 4.93%. 
5.3.
Method of Treatment Assignment
The investigator should determine eligibility for treatment assignment before Visit 3. There will 
be no early enrollment if a participant meets the minimum 5-day requirement of 70% CGM 
readings per day before Visit 3. 
For participants who are eligible for treatment assignment, Humalog will be discontinued, and 
LY900014 will be initiated using their current ICR, ISF, and DIA at Visit 3. All participants 
who are not currently administering insulin degludec in the morning should switch to morning 
administration with the investigator’s guidance. All participants should continue administering 
degludec in the morning throughout the treatment period.


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6.
A Priori Statistical Methods
6.1.
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 clinical study report. Additional exploratory analyses of data will be conducted, as 
deemed appropriate.
The following populations are defined in Table ITSZ.6.1.
Table ITSZ.6.1.
Patient Populations
Population
Description
Entered
All participants who give informed consent
Enrolled
All participants who continue the study after Visit 2
Treated
All assigned participants who receive at least 1 dose of the assigned study treatment after Visit 3
Unless otherwise specified, all efficacy and safety analyses will be conducted on the Treated 
Population. Unless otherwise noted, all tests will be conducted at a 2-sided alpha level of 0.05, 
and CIs will be calculated at 95%, 2-sided. Comparison between baseline and endpoints will be 
performed at the full significance level of 0.05. No multiplicity adjustment will be made.
The definitions of baseline and post-baseline for the safety and efficacy analyses depend on 
which analysis period is being used.  The following analysis periods will be used:

Lead-in Period – from Day -11 to Day -1

Treatment Period – from first dose to Day 46 (Visit 14) while on investigational product 
(IP) and from first dose to Day 46 (Visit 14) including all data regardless of IP use

Treatment Period and Safety Follow-up Period – from first dose to Visit 801 including all 
data regardless of IP use
Table ITSZ.6.2 describes the rules for determining the patient population, baseline, and 
postbaseline observations for the different analysis periods.  
The data on IP is defined based on the following rules:

for data only measured at an office visit (eg, HbA1c and 1,5 Anhydroglucitol [1,5-AG]), 
if the office visit date (or laboratory sample collection date) is within 14 days of the date 
of last study drug dose of the current treatment period (treatment period), then 
postbaseline data measured at or prior to that office visit will be considered as data on IP 
for the current treatment period (treatment period).

for data collected as running records with an exact date such as adverse events (AEs) 
where the date of the measures is not tied with the date of an office visit, postbaseline 


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data with date ≤ (last study drug dose date) will be considered as data on IP for the 
treatment period.
An analysis of covariance (ANCOVA) will be used to analyze continuous variables that are 
planned to be collected only for baseline and endpoint. The model will include baseline as a 
covariate. 
A restricted maximum likelihood based, mixed model repeated measures (MMRM) analysis will 
be used to analyze continuous longitudinal variables collected only at baseline and more than one 
scheduled post-baseline visits according to SoA in Section 1.3.  All the longitudinal observations 
at each scheduled post-baseline visit will be included in the analysis.  The model for the analysis 
of the primary efficacy endpoint will include the fixed class effect of visit, and the random effect 
of patient. An unstructured covariance structure will be used to model the within patient errors.  
Significance tests will be based on least squares (LS) means and Type III tests. SAS PROC 
MIXED will be used to perform the analysis. If this analysis fails to converge, the following 
covariance structures will be tested in order:
•
Toeplitz with heterogeneity
•
Autoregressive with heterogeneity
•
Compound symmetry with heterogeneous variances
•
Toeplitz
•
Autoregressive
•
Compound symmetry without heterogeneous variances
The first covariance structure that converges will be used.  The Kenward Roger approximation 
will be used to estimate denominator degrees of freedom.  If the analysis still does not converge 
with Compound symmetry without heterogeneous variances, only summary statistics will be 
provided.
For continuous measures, summary statistics will include sample size, mean, standard deviation, 
median, minimum, and maximum for both the actual and the change from baseline 
measurements.  Least square (LS) means and standard errors derived from the analysis models 
will also be displayed for the actual and the change from baseline measurements.
For categorical measures, summary statistics will include sample size, frequency, and 
percentages.  No statistical analyses will be conducted for baseline and endpoint comparison. 
All CGM outcome variables will only be derived for Visit 3 (baseline) and Visit 14 (endpoint) 
based upon the CGM data collected from valid CGM days, excluding data (if any) that are 
collected while patients are temporarily off IP.  A valid CGM day to be counted into the 
calculation for a visit must have at least 70% of the total measures that are supposed to be 
obtained.
For laboratory values, both conventional (CN) and Systeme International (SI) units will be 
presented.  Therefore, both % and mmol/mol will be presented for HbA1c and both mg/dL and 
mmol/L will be presented for glucose measurements. 


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Table ITSZ.6.2.
Baseline and Post-Baseline Definitions and Patient Population by 
Study Period and Type of Analysis
Baseline and Post-Baseline Definitions and Patient Population by Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline 
Observations
Lead-In Period 
AEs
Enrolled Population
Prior to first dose of open-
label Humalog (or Visit 2 
date if the dose date is 
missing) 
The entire lead-in period 
after first dose of open-
label Humalog and prior to 
first dose of IP (or Visit 3 
date if the dose date is 
missing)
Treatment Period (including Titration and Maintenance periods) and Safety Follow-Up Visit where 
applicable
TEAEs 
All patients in the 
Treated Population 
Prior to first dose of IP (or 
Visit 3 if the dose date is 
missing)
From first dose of IP to last
dose of IP
AND
From first dose of IP to 
Visit 801 
Weight and vital signs
All patients in the 
Treated Population with 
a baseline and a post-
baseline observation
Last of Visits 1 and 3 
Visits 7, 11, 14 while on IP
AND
Visits 7, 11, 14 and 801 
regardless of IP use
Basal, bolus, and total 
insulin doses, and 
bolus/total insulin dose 
ratios continuous 
analysisa
All Randomized Patients
Visits 3
Visit 14 
ICR, ISF, and DIA
All patients in the 
Treated Population with 
a baseline and at least 
one post-baseline 
observation
Last value of Visits 2-3 prior 
to or on the date of the first 
dose of IP
Visit 4-14 while on IP
CGM outcome variables 
All patients in the 
Treated Population with 
a baseline and a post-
baseline observation
Based upon the CGM data 
collected for Visit 3 
(baseline), excluding data (if 
any) that are collected while 
patients are temporarily off 
IP Humalog during the lead-
in period 
Based upon the CGM data 
collected for Visit 14 
(endpoint), excluding data 
(if any) that are collected 
while patients are 
temporarily off IP during 
the maintenance period.  
HbA1c 
All Patients in the 
Treated Population with 
a baseline and a post-
baseline observation
Visit 1 
Visits 14 while on IP
Fructosamine
All Patients in the 
Treated Population with 
a baseline and a post-
baseline observation
Visit 1 
Visits 14 while on IP


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1,5-AG
All Patients in the 
Treated Population with 
a baseline and a post-
baseline observation
Visit 1 
Visits 14 while on IP
Abbreviations:  1,5-AG = 1,5-Anhydroglucitol; CGM = continuous glucose monitoring; ICR = 
insulin-to-carbohydrate ratio; eCRFs = electronic case report forms; HbA1c = hemoglobin A1c; 
IP = investigational product; ISF = insulin sensitivity factor; DIA = Duration of Insulin Action; 
TEAE = treatment-emergent adverse event.
a
The investigator will transcribe the LY900014 Humalog dose at Visit 3 (data from Day -10 to Day -1) and the 
LY900014 dose at Visit 14 (data from Day 36 to Day 45) to eCRF.  These data will be used for summary and 
analyses of mean total daily basal dose, mean total daily bolus dose, mean total daily insulin dose, and the ratio 
of mean total daily bolus dose to mean total daily insulin dose.  
6.2.
Adjustments for Covariates
The MMRM model for the analysis of the primary efficacy endpoint will include the fixed class 
effect of visit, and the random effect of patient, as noted in Sections 6.9.
The ANCOVA model will include baseline as a covariate, as noted in Sections 6.9 to 6.10.
6.3.
Handling of Dropouts or Missing Data
For CGM outcome variables only derived for Visit 3 (baseline) and Visit 14 (endpoint) based 
upon the CGM data, missing data will not be addressed.  Only completers will be included in 
ANCOVA analysis. 
For continuous variables collected at baseline and at Visit 14, missing data will not be addressed.  
Only completers will be included in ANCOVA analysis. 
For continuous longitudinal variables collected at baseline and more than one scheduled post-
baseline visits according to SoA in Section 1.3, missing data will be addressed by using a 
MMRM analysis.  The MMRM model provides consistent estimator when data is missing at 
random.  The model implicitly adjusts for missing data through a variance-covariance structure.  
6.4.
Multiple Comparisons/Multiplicity
Comparison between baseline and endpoints will be performed at the full significance level of 
0.05.  No multiplicity adjustment will be made.
6.5.
Patient Disposition
Patient disposition will be displayed in a flowchart showing the number of patients entered, 
enrolled, treated, and discontinued across all study periods.
Frequency counts and percentages of the Treated Population completing and discontinuing from 
the study will be presented.  Reasons for discontinuation from the study and study treatment will 
be summarized.
Frequency counts and percentages of all patients entered, enrolled, and discontinued from the 
study during the lead-in period will be summarized.  Reasons for discontinuation during 


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screening will be summarized for the Entered Population.  Reasons for discontinuation from the 
study during the lead-in period will be summarized for the Enrolled Population.
A listing of the primary reason for study/treatment discontinuation will be generated for the 
Enrolled Population.
A listing will be generated for the Treated Population, including the following variables but not 
limited to:  investigator ID, patient ID, date of signature of informed consent form, first and last 
dose date of Humalog in the lead in period, study treatment assignment date, first and last dose 
date of LY900014 in the treatment period (titration and maintenance periods). 
6.6.
Patient Characteristics
A summary table will be generated for patient characteristics at study entry using the Treated 
Population.  The following variables will be included but not limited to:  age, age groups (<40 
and ≥40 years, and <65, ≥65 years), sex, ethnicity, race, height, weight, body mass index (BMI), 
BMI groups (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2).  For continuous variables, the 
following statistics will be provided:  mean, SD, minimum, maximum, and median.  For 
categorical variables, summary statistics will include sample size, frequency, and percentage.  A 
listing of patient characteristics at baseline will be provided.
A similar summary of diabetes characteristics will also be generated.  The following variables 
will be included but not limited to:  duration of diabetes, percentage of time with CGM values 
from 70 to 180 mg/dL over the lead in period, HbA1c at study entry.
For the Treated Population, the number and percentage of patients with historical conditions will 
be summarized using Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term 
(PT) (without regard to System Organ Class [SOC]), and the number and percentage of patients 
with preexisting conditions will also be summarized using MedDRA PT (without regard to 
SOC).  Historical conditions are conditions that end prior to informed consent and preexisting 
conditions are conditions that are still ongoing at informed consent.  Events will be ordered by 
decreasing frequency. 
6.7.
Treatment Compliance
No analysis for treatment compliance is planned for this study.
6.8.
Concomitant Therapy
Concomitant medications will be summarized for the Treated Population for Titration and 
Maintenance periods combined.  The percentages of patients receiving each concomitant 
medication will be summarized by treatment using PT nested within Anatomical Therapeutic 
Chemical (ATC) Level 3 code.  Medications will be ordered by decreasing frequency within 
ATC level.  Concomitant medication used during the lead-in period will also be summarized for 
the Enrolled Population.  


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6.9.
Efficacy Analyses
6.9.1. Primary Outcome and Methodology
The primary objective of this study is to evaluate the percentage of time with glucose values 
within target range (70 to 180 mg/dL, both inclusive) after 35 days of using the study titration 
scheme with LY900014 treatment and degludec.  Both actual and change from baseline will be 
derived and analyzed by the ANCOVA model as described in Section 6.1. 
The primary analyses will be conducted on the Treated Population based upon the CGM data 
collected for Visit 3 (baseline) and Visit 14 (endpoint), excluding data (if any) that are collected 
while patients are temporarily off Humalog during the lead-in period or temporarily off IP during 
the maintenance period.  Comparison between baseline and endpoints will be performed at the 
full significance level of 0.05.
Derivation and analysis of primary endpoint (derived for 24-hour, daytime and nighttime and by-
meal) and other CGM endpoints are described in Section 6.13.  
6.9.2. Other Secondary Efficacy Analyses
The analyses described in Section 6.9.2 will include data collected from the Treated Population.  
Details for the CGM analyses are described in Section 6.13.  Continuous secondary efficacy 
variables, as well as the change from baseline for these variables, will be analyzed by the 
MMRM or ANCOVA model as described in Section 6.1.
The ICR data from the day before a scheduled visit will be transcribed in eCRF at Visit 2, Visit 3 
through Visit 14 and ET Visit,  respectively.  Any changes and associated to meals for ICR 
during the Treatment period will be captured.  A listing will be provided to include ICR data 
collected at Visit 2, changes in ICR by meal captured during Treatment period in the eCRF.  An 
MMRM model similar to that for the primary endpoint will be used to analyze actual and change 
from baseline in ICR. 
For the following secondary efficacy endpoints data collected for Visit 3 (baseline) and Visit 14 
(endpoint), an ANCOVA model as described in Section 6.1 will be used:

actual and change from baseline in insulin doses, including mean total daily basal (U/day, 
U/kg/day), mean total daily bolus (U/day, U/kg/day), and mean total daily insulin dose 
(U/day, U/kg/day) and mean total daily bolus / total daily insulin dose ratios (%)
The investigator will transcribe the Humalog dose at Visit 3 (data from Day -10 to Day -1) and 
LY900014 dose at Visit 14 (data from Day 36 to Day 45) to eCRF.  To assess the insulin doses 
over the course of 10 days for each visit, the mean total daily basal dose will be derived based on 
CGM data collected during lead in period (data from Day -10 to Day -1) and maintenance period 
(data from Day 36 to Day 45), and mean total bolus doses will be derived based upon the eCRF 
data collected at Visit 3 and Visit 14.  
Relationships between ICR and TDD will be evaluated through regression lines (ICR versus 
1/TDD) and compared with the “500 Rule,” which is currently used in clinical practice where 


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ICR = 500/TDD (Section 2.1 in study protocol) by visit.  Regression lines with and without 
intercept will be analyzed.  The analyses will be conducted based upon ICR and mean total daily 
insulin dose (U/day) collected for Visit 3 and Visit 14, separately. 
6.9.3. Exploratory Efficacy Analyses
Continuous exploratory efficacy variables, as well as the change from baseline for these 
variables, will be analyzed by the MMRM or ANCOVA model as described in Section 6.1, 
unless otherwise specified.
The following analyses will be conducted based upon ISF (mg/dL per insulin unit), mean total 
daily basal dose (U/day), mean total daily insulin dose (U/day), and weight (kg) collected for 
Visit 3 and Visit 14, separately.  Relationships between the following endpoints will be explored 
through regression lines (King et al. 2007a, 2007b) by visit, separately.  Regression lines with 
and without intercept will be analyzed.  

ISF and 1/TDD  

TBD and weight 
The ICR (grams per insulin unit) and ISF (mg/dL per insulin unit) data from the day before a 
scheduled visit will be transcribed in eCRF at Visit 2, Visit 3 through Visit 14 and ET Visit,  
respectively.  Relationships between ICR and ISF will be explored through regression lines with 
and without intercept by scheduled visit, separately. 
The ISF and DIA data from the day before a scheduled visit will be transcribed in eCRF at Visit 
2, Visit 3 through Visit 14 and ET Visit,  respectively.  Any changes  for ISF and DIA during the 
Treatment period will be captured.  A listing will be provided to include ISF and DIA data 
collected at Visit 2, changes in ISF and DIA by meal captured during treatment period in the 
eCRF.  An MMRM model similar to that for the primary endpoint will be used to analyze actual 
and change from baseline in ISF and DIA, respectively.
Actual and change from baseline in fructosamine, HbA1c and 1,5-AG will be summarized and 
analyzed by ANCOVA. 
In addition, CGM outcomes that are not included in the primary and secondary efficacy 
endpoints will be analyzed as exploratory efficacy endpoints.  Details for the CGM analyses can 
be found in Section 6.13.  
6.10. Safety Analyses
6.10.1. Extent of Exposure
Duration of exposure to study drug will be summarized based upon eCRF data.  The following 
summary statistics will be provided:  n, mean, SD, median, minimum, maximum, and sum (that 
is, total patient-years of exposure).  The number and proportion of patients falling into the 
following different exposure categories will also be summarized:  <14 days (>0 and <14 days), 
≥14 and <35 days , ≥35 and <46 days, and ≥46 days. 


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Patients who complete the study treatment period are required to complete a safety follow-up 
visit without study drug; and patients who discontinue the IP unplanned are required to 
discontinue from the study (ITSZ Protocol 7.1).  
6.10.2. Adverse Events
Events that are newly reported after the first dose of IP or reported to worsen in severity from 
baseline will be considered TEAEs.  Events that continue during more than 1 study period (lead-
in, Treatment, and safety follow-up period) with the same severity will only be counted once for 
the first study period.  
Analyses of AEs will be descriptive and include all data collected during the treatment period.  
Adverse events during the lead-in period and the safety follow-up period will be provided in a 
listing.
The MedDRA lowest level term (LLT) will be used in the treatment-emergent assessment.  The 
maximum severity for each LLT during the baseline period will be used as baseline severity.
In an overview table, the number and percentage of patients who experienced a TEAE, 
experienced a serious adverse event (SAE), died due to an AE, and discontinued from study due 
to an AE will be summarized.
The number and percentage of patients with SAEs and who discontinued from the study due to 
an AE will be summarized using MedDRA PT nested within SOC if any such events occurred.  
The number and percentage of patients with TEAEs will be summarized using MedDRA PT 
nested within SOC.  Events will be ordered by decreasing frequency within SOC.  
The number and percentage of patients who experienced a SAE including deaths and SAEs 
temporally associated or preceding deaths will be summarized using MedDRA PT (without 
regard to SOC).  Events will be ordered by decreasing frequency within SOC.  A listing of all 
SAEs (including data collected during lead in and the safety follow-up period) will also be 
provided.
The number and percentage of patients who discontinued from study in Treatment period due to 
an AE will be summarized using MedDRA PT (without regard to SOC).  Events will be ordered 
by decreasing frequency.  A listing of all AEs as reason for study discontinuation will also be 
provided. 
For events that are gender-specific (as defined by MedDRA), the denominator and computation 
of the percentage will include only patients from the given gender.  The number and proportion 
of patients with at least 1 event for each type of event will also be summarized. 
Table ITSZ.6.3 summarizes the planned analyses and the requirement of analysis data for 
different analysis periods. 


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Table ITSZ.6.3.
Adverse Event Analysis Periods
Analysis Period
Analysis Population
Analysis
IP USE
Treatment
Lead-in Period
Enrolled Population
Listing: All AE 
including SAEs and 
discontinuation due to 
AE
N/A
Humalog
Treatment Period 
(Titration and 
Maintenance
periods)
Treated Population
AE overview; TEAE by 
SOC and by PT;; SAE; 
discontinuation due to 
AE
Yes
LY900014
Treatment Period 
(Titration and 
Maintenance
periods) and Safety 
Follow-up Period
Treated Population
AE overview; TEAE by
SOC; SAE; 
discontinuation
from study due to AE;
All data regardless 
of IP use
LY900014
Abbreviations:  AE = adverse event; IP = investigational product; N/A = not applicable/available; PT = preferred 
term; SAE = serious adverse event; SOC = system organ class; TEAE = treatment-emergent adverse event.
6.10.3. Hypoglycemic Events and Other Adverse Events
The analysis plans for the following AEs are discussed in Section 6.10.3.1:

hypoglycemia 

injection site reaction
These AE analyses will be similar to the TEAE analyses, refer to Table ITSZ.6.3 for the 
requirement of analysis data for a specific analysis period. 
6.10.3.1. Hypoglycemia
Hypoglycemia will be described using the following definitions:

Level 1: Glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 mmol/L) 

Level 2: Glucose <54 mg/dL (3.0 mmol/L)

Level 3: Severe hypoglycemia:
Participants have altered mental status and cannot assist in their own care, may be 
semiconscious or unconscious, or experience coma with or without seizures, and 
require assistance of another person 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 blood glucose 
concentration to normal is considered sufficient evidence that the event was induced 
by a low blood 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.

All episodes of severe hypoglycemia must be reported as SAEs on the AE 
eCRF page and on the SAE eCRF page. 


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Any events of severe hypoglycemia categorized as level 3 per the evaluation of investigators will 
be collected from ICF signing to Visit 801. 
Level 1 and level 2 hypoglycemia will be analyzed based on glucose data from the CGM sensor 
session.  Derivation and analysis of Level 1 and Level 2 hypoglycemia (derived for duration (in 
minutes) and percentage of time in Level 1 or Level 2) and other CGM endpoints are described 
in Section 6.13.  
Severe hypoglycemia will be collected as AEs in eCRF and all episodes of severe hypoglycemia 
will be considered as SAEs.  Table ITSZ.6.4 provides detailed statistical methods for severe
hypoglycemia.  Summary statistics will be provided for severe hypoglycemia events from first 
dose to last dose of IP.  
A listing of patients with at least 1 severe hypoglycemia reported (as SAE) from Visit 3 through  
Visit 801 will be provided.
A list of MedDRA PTs will be used for the narrow search of potential severe hypoglycemia in 
spontaneously reported AEs.  The events identified through the search strategy that are also 
reported as SAEs will be summarized.  
Table ITSZ.6.4.
Summary of Analyses for Severe Hypoglycemia
Endpoint
Analysis Period
Statistical Method
Rate of severe hypoglycemic events 
(per patient per year / 100 years)
Treatment Period
Summary statistics for exposure adjusted rate 
per year / 100 years (calculated for each patient 
by total number of events divided by total 
exposure) will be provided 
Incidence of severe hypoglycemic 
events
Treatment Period
Summary statistics for proportion of patients 
with severe hypoglycemia will be reported.  
6.10.3.2. Injection Site Reaction
The injection site reactions will be searched by MedDRA PTs from all TEAEs.  The 
number and percentage of patients experiencing treatment-emergent injection site 
reaction will be summarized.
6.10.4. Clinical Laboratory Evaluation
The data from safety laboratory measures will be only collected at Visit 1 for patient eligibility 
and safety.  Therefore, no summary will be provided.  
6.10.5. Vital Signs and Other Physical Findings
Post-baseline measurements and change from baseline to post-baseline for vital signs (systolic 
blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and physical characteristics 
(weight, BMI) at the scheduled visits will be summarized for patients who have both baseline 
and at least 1 post-baseline result.  
The measurements during the treatment period will be analyzed by MMRM model similar to that 
for the primary endpoint, i.e., with baseline value of the response variable, visit as fixed factors 
and patient as the random factor.  


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6.10.6. Patient Narratives
Patient narratives will be provided for all patients in the study who experience any of the 
following “notable” events prior to data cutoff for the submission, if any occur during the study:

deaths

SAEs

discontinuations from study (or study drug) due to AEs

pregnancy
A list of patients who meet the criteria for narratives will be provided.
6.11. Important Protocol Deviations
Important protocol deviations, as defined in the Trial Issue Management Plan (TIMP), will be 
summarized for the Treated Population.  The listing of important protocol deviations for the 
Treated Population during the entire study, will be provided in the CSR.  No per-protocol 
population is planned for any analyses. 
6.12. Interim Analyses and Data Monitoring 
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.
6.13. CGM Analyses
The analyses described in Section 6.13 will include data collected from first dose of Humalog 
used during the lead-in period to the last IP used during the treatment period, excluding data (if 
any) that are collected while patients are temporarily off Humalog or IP.
All CGM outcome variables will only be derived for Visit 3 (baseline) and Visit 14 (endpoint) 
based upon the CGM data collected from valid CGM days, excluding data (if any) that are 
collected while patients are temporarily off Humalog during the lead-in period or temporarily off 
IP during the maintenance period.  A valid CGM day to be counted into the calculation for a visit 
must have at least 70% of the total measures that are supposed to be obtained.
Table ITSZ.6.5 lists all numerical measures for CGM data.  
To ensure that the CGM outcome variables are only calculated from CGM session days with 
sufficient data within the 24-hour, daytime (0600 hours to midnight), or nighttime (midnight to 
0600 hours) periods, the following criteria will be used to determine a valid CGM session day to 
be counted into the calculation for a visit:  minimum number of measures per day – at least 70% 
of the total measures that are supposed to be obtained, i.e., 70% of the 288 measures for the 24-
hour period;.
Similarly, for the by-meal outcome variables, the following criteria will be used to determine a 
valid CGM session day for a visit:  minimum number of measures per day – at least 70% of the 


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total measures that are supposed to be obtained.  For example, 70% of the 24 measures for the 
iAUC0-2hr after breakfast. 
The definition and derivation of these variables are described in detail in Appendix 1.
Table ITSZ.6.5.
Outcome Measures of CGM Data
Category
Endpoints
24-Hour
Daytimea
Nighttimeb
By Mealc
Efficacy Endpoint:  Glucose in the Target Ranges 
Duration (in minutes) and percentage of 
time with sensor glucose values within 
target range 70 to 180 mg/dL [3.9 and 
10.0 mmol/L], both inclusive (Primary 
Efficacy Endpoint)
X
X
X
Efficacy Endpoint:  Incremental AUCs (iAUCs) (after the start of meals)
iAUC0-1hr
X
iAUC0-2hr
X
iAUC0-3hr
X
iAUC0-4hr
X
Efficacy Endpoint:  Mean Glucose Excursions (after the start of meals) d
mean sensor glucose excursions 0 to 
1 hour
X
mean sensor glucose excursions 0 to 
2 hour
X
mean sensor glucose excursions 0 to 
3 hour
X
mean sensor glucose excursions 0 to 
4 hour
X
Efficacy Endpoint:  Hyperglycemia
Duration (in minutes) and percentage of 
time with glucose values >180, 181-250  
and >250 mg/dL [10.0, 10.1-13.9 and 
13.9 mmol/L] 
X
X
X
Efficacy Endpoint:  Daily CGM Data Summary
Mean sensor glucose
X
X
X
Median sensor glucose
X
X
X
Efficacy Endpoint:  Glucose Variability and Risk Assessment
Within-Day
CV
X
X
X
SD
X
X
X
IQR
X
X
X
Between-Day
CV
X
X
X
SD
X
X
X
Overalle
CV
X
X
X
SD
X
X
X
IQR
X
X
X


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Efficacy Endpoint:  Highest Postprandial Glucose
Time from start of meal to the highest 
postprandial glucose level (minutes) 
within 4 hours after meal(s) 
X
Highest postprandial glucose level 
within 4 hours after meal(s)
X
Highest postprandial glucose excursion 
level within 4 hours after meal(s)
X
Safety Endpoint:  Hypoglycemiaf
Duration (in minutes) and percentage of 
time with sensor glucose values <54, 54-
69 and <70 mg/dL [3.0, 3.0-3.8  and 3.9 
mmol/L]
X
X
X
X
Abbreviations:  AUC = area under curve; CGM = continuous glucose monitoring; CV = coefficient of variation; hr 
= hour; IQR = interquartile range;  SD = Standard deviation.
a
Daytime:  0600 hours to midnight (06:00:00-23:59:59 on the 24-hour clock).
b
Nighttime:  midnight to 0600 hours (00:00:00-05:59:59 on the 24-hour clock).
c
By meals:  for morning (breakfast), midday (lunch) and evening (dinner) meals and overall (average across all 
meals).  The start time of morning, midday and evening meals are determined as the first entry in the CGM data 
during [04:00:00, 11:00:00], (11:00:00, 15:00:00] and [17:00:00, 21:00:00], respectively.  When calculating time 
in ranges (target, hypo, hyper) for meals (0 to 1 hour, 0 to 2 hours, 0 to 3 hours and 0 to 4 hours), any data that 
are collected after the next meal event will be excluded.
d
Mean sensor glucose measured at different time points (1, 2, 3 or 4 hours) after the start of the meal minus mean 
sensor glucose at the start of meal
e
Overall variability refers to the variability calculated based upon all the CGM measurements collected across all 
valid days for each derivation period
f
In addition, postprandial hypoglycemia during the following time interval after each meal and overall will also be 
derived:  0 to 1 hour, 0 to 2 hours, 2 to 4 hours, 0 to 4 hours.  The calculation will exclude the data from patients 
who have had the next meal event before the end of time interval. 
The proportion of patients who have achieved the guidance (Battelino 2019) recommended CGM 
targets of glycemic control (Table ITSZ.6.6) during the lead in period (baseline) and the 
maintenance period (endpoint) will be summarized.
Table ITSZ.6.6.
Guidance Recommended CGM Targets of Glycemic Control
Percentage of time with sensor glucose (24-hour)
Guidance Recommendation
target range
         70-180 mg/d.L (3.9-10.0 mmol/L, both inclusive
>70%
hypoglycemia range
        <54 mg/dL (3.0 mmol/L)
<1%
hyperglycemia range
     >250 mg/dL (13.9 mmol/L)
<5%


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Other than that, all continuous variables (actual and change from baseline, if applicable) will be 
analyzed by sing the ANCOVA defined in Section 6.1.
In addition, the following standardized glucose summary reports from the ambulatory glucose 
profile (AGP) will be generated, based upon all the observed CGM data during the lead in period 
and the maintenance period, regardless of whether they are collected on valid CGM days:

24-hour period at individual patient level 

24-hour period at the treatment level

0 to 4 hours relative to meal starting time, excluding data collected after the next 
meal event (if any is captured within the interval) at the treatment level

0 to 4 hours relative to meal starting time, by meal (breakfast, lunch, and dinner) 
and by infusion set wear day excluding data collected after the next meal event
6.14. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:

Summary of AEs, provided as a dataset which will be converted to an XML file. 
Both SAEs and ‘Other’ Non-SAEs are summarized by MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

For each SAE, these additional terms are provided for EudraCT:
o
the total number of occurrences causally related to treatment
o
the total number of deaths
o
the total number of deaths causally related to treatment.  

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in 
fewer than 5% of patients/subjects in every treatment may be excluded if a 5% 
threshold is chosen.  Allowable thresholds include 0% (all events), 1%, 2%, 3%, 
4%, and 5%.  


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
AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 


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7.
Unblinding Plan 
Not applicable as this is an open label study.


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8.
References 
Baghurst PA. Calculating the mean amplitude of glycemic excursion from continuous glucose 
monitoring data: an automated algorithm. Diabetes Technol Ther. 2011;13(3):296-302.
Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, et al. Clinical targets for 
continuous glucose monitoring data interpretation: Recommendations from the International 
Consensus on Time in Range. Diabetes Care. 2019; pii: dci190028. 
Clarke W, Kovatchev B. Statistical tools to analyze continuous glucose monitor data. Diabetes 
Technol Ther. 
Hirsch IB. Glycemic variability: It’s not just about A1c anymore! Diabetes Technol Ther. 
2005;7(5):780-783.
Kovatchev BP, Clarke WL, Breton M, Brayman K, McCall A. Quantifying temporal glucose 
variability in diabetes via continuous glucose monitoring: mathematical methods and clinical 
application. Diabetes Technol Ther. 2005;7(6):849-862.
King AB, Armstrong DU. A prospective evaluation of insulin dosing recommendations in 
patients with type 1 diabetes at near normal glucose control: basal dosing. J Diabetes Sci 
Technol. 2007a;1(1):42-46.
King AB, Armstrong DU. A prospective evaluation of insulin dosing recommendations in 
patients with Type 1 Diabetes at near normal glucose control: bolus dosing. J Diabetes Sci 
Technol. 2007b;1(1):42-46.
Mazze RS, Strock E, Wesley D, Borgman S, Morgan B, Bergenstal R, Cuddihy R. 
Characterizing glucose exposure for individuals with normal glucose tolerance using 
continuous glucose monitoring and ambulatory glucose profile analysis. Diabetes Technol 
Ther. 2008;10(3):149-159.
Rodbard D. Interpretation of continuous glucose monitoring data: glycemic variability and 
quality of glycemic control. Diabetes Technol Ther. 2009;11(suppl 1):S55-S67.
Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean amplitude 
of glycemic excursions, a measure of diabetic instability. Diabetes. 1970;19(9):644–655.
Service FJ, O’Brien PC, Rizza RA. Measurements of glucose control. Diabetes Care. 
1987;10(2):225-237.


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9.
Appendices


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Appendix 1.
Derivation of CGM Variables
9.1.
General Derivation Specifications
All CGM outcome variables will only be analyzed for each patient at Visit 3 (baseline) and Visit 
14 (endpoint) based upon the CGM data collected from valid CGM days, excluding data (if any) 
that are collected while patients are temporarily off Humalog during the lead-in period or 
temporarily off IP during the maintenance period. A valid CGM day to be counted into the 
calculation for a visit must have at least 70% of the total measures that are supposed to be 
obtained (Section 6.13).  
No missing CGM values will be imputed.
Since the CGM values may not be measured at the exact same time for each day for a specific 
individual patient, due to device changes or gaps in usage, non-overlapping intervals (‘buckets’) 
of 5 minutes over 00:00:00 to 23:59:59 (00:00:00 to 00:04:59, 00:05:00 to 00:09:59, etc.) will be 
used for any derivations requiring time-matched measurements across days within a visit. 
All CGM parameters will be estimated to precision of 1 decimal place, unless stated otherwise.  
All CGM glucose derivations will be conducted in units of mg/dL and mmol/L. 
Only readings collected from valid CGM days while patients are on Humalog in the lead-in 
period or on IP during the treatment period, will be included in the derived.
9.2.
Glucose in Target Ranges, Hypoglycemia or Hyperglycemia
Glucose in target range, hypoglycemia or hyperglycemia will be calculated as the average value 
of percentage of time within a glucose range (target, hypo- or hyperglycemia ranges) on all valid 
CGM days during that visit. 
The percentage of time within a glucose range (target, hypo- or hyperglycemia ranges) will be 
calculated as the number of observations within the specified range divided by the number of 
observations in the time interval (eg, 24-hour period).  The duration (in minutes) within the 
glucose range will then be calculated as the percentage of time within the glucose range times the 
length of the period (24 hour, 18 hour, and 6 hour, for the periods of 24-hour, daytime or 
nighttime, respectively). 
For example, if a patient had a total of 15 observations with glucose values <70 mg/dL 
(3.9 mmol/L) out of a total of 288 observations recorded during the 24-hour period in a valid 
CGM day at Visit 3, the percentage of time spent in hypoglycemia during the 24-hour period for 
this patient at that valid CGM day at Visit 3 will be calculated as 15/288 = 5.2%.  The duration 
(in minutes) with hypoglycemia (glucose value <70 mg/dL [3.9 mmol/L]) during the 24-hour 
period for this patient at that valid CGM day at Visit 3 will be calculated as the percentage times 
1440, (ie, 15/288*1440 = 75.0 minutes). Then derive the CGM outcome for each visit by 
averaging across all valid CGM days at that visit.


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The percentage and duration in ranges within 0 to 1 hour, 0 to 2 hours, 0 to 3 hours, and 0 to 4 
hours after meals will also be derived.
9.3.
Incremental Area under the Glucose Curve (iAUC)
iAUC0-T will be calculated as the average value of iAUC on all valid CGM days during that visit 
with sufficient data to calculate the iAUC0-T (Section 6.13).  For each day, iAUC0-T will be 
calculated as the sum of areas of all individual trapezoids within the time frame according to the 
formula:
݅AUC଴ି୘ൌ෍ܣ݅
௞
௜ୀଵ
ൌ෍
ሺܩ௜െܩ଴ሻ൅ሺܩ௜ିଵെܩ଴ሻ
2
∆࢚࢏
௞
௜ୀଵ
where Ai is area of the respective trapezoid, Gi is glucose concentration at a particular time, G0 is 
the starting glucose concentration before the start of the meal, is the time interval between 
consecutive CGM values, which should be always 5 minutes unless missing data occur, and k is 
the total number of intervals within the time frame 0-T.  If the intermediate time points are 
missing, the next available time point will be used in calculating the trapezoid area.  Also since it 
is possible that Gi < G0 or Gi-1 < G0, Ai could also be negative.  G0, the starting glucose 
concentration, will be calculated as the average of the CGM values in the time window [-19, 0] 
mins relative to the start of the meal (at most 3 CGM values); Gk, the last glucose concentration, 
is defined as the average of the CGM values in the window [0, +14] minutes relative to the last 
time point of the time frame (at most 2 CGM values).  For example, to calculate iAUC0-2hr after 
the start of breakfast, Gk will be the average of the CGM values in the window [0, +14] minutes 
relative to the 2 hours after the start of breakfast.  The derivation of each iAUC0-T will require 
that G0 and Gk values are both available.  The derivation iAUC0-T on a specific infusion set wear 
day, requires that time 0 and time T fall on the same infusion set wear day,but it is acceptable 
that the CGM measures in the window [-19,0] for G0 and [0+14] for GT fall on the previous or 
the next infusion set wear day. 
9.4.
Mean Sensor Glucose Excursions
Mean sensor glucose excursions in a postmeal time interval (0-1 hr, 0-2 hr, 0-3 hr or 0-4 hr) will 
be calculated by averaging all excursion values within the time interval.  Excursions will be 
derived by subtracting glucose values by the starting glucose concentration, which is the average 
of the CGM values in the time window [-19, 0] mins relative to the start of the meal (at most 3 
interstatial glucose measures).
9.5.
Glucose Variability 
Glycemic variability will be evaluated using the notation below:
i represents a time point within a time period (a 24-hour period, daytime or nighttime)
n represents the number of time points within the time period 
k represents a day within a visit


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m represents number of days CGM is performed at a visit 
i
k,
BG
represents the glucose value at time point i on day k.
9.5.1.Within-Day Variability
For variables assessing within-day variability, first determine the variability within each day, 
then average across days within a visit. 
Within-day glucose standard deviation (SD) (Hirsch 2005; Rodbard 2009):
Within-day glucose coefficient of variation (CV) (Clarke 2009): 
Inter-quartile range (IQR) (Mazze et al. 2008):
                  






m
k
m
k
k
m
IQR
m
IQR
1
1
k)
day 
on 
BG values
all
of
percentile
25th 
  -
(75th 
1
1
9.5.2.Between-Day Variability
For variables assessing between-day variability, first determine the variability for each time 
points across days within a visit then average across all time points. 
Between-day glucose standard deviation (SD) (Rodbard 2009):
Between-day glucose coefficient of variation (CV):



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i
k
m
k
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m
m
SD
1
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1
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,
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1
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,
1
1
)
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BG
(BG
1
SD
1

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
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

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
m
k
i
k
k
m
k
k
SD
m
CV
m
CV
1
n
1
i
,
1
100
)
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BG
(
1
1
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1
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k,
m
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k
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n
1
i
i
1
m
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(BG
n
1
n
1
SD


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9.5.3.Overall Variability
The CV, SD and IQR will be calculated using the standard formulas across collected across all 
valid days for time interval in each randomized treatment period. 
9.6.
Daily CGM Data Summary
For daily CGM summary variables, first determine the values within each day, then average 
across days within a visit.  The hourly mean glucose will be calculated as the mean across all 
CGM values collected, based on actual local time for the subject.
9.7.
AUC
Area under the curve (AUC) during a period (24-hour, daytime, or nighttime) will be calculated 
using the standard linear trapezoidal method as defined previously in Section 9.3, by multiplying 
the sum of trapezoids by (the length of the period)/(the length of the period - total length of gaps 
that are not counted into the calculation of the AUC).
9.8.
Highest Postprandial Glucose
9.8.1. Time to the highest postprandial glucose within 4 hours after 
Meals
Time from start of meal to the highest postprandial glucose level will be calculated as the time 
from start of meal to the maximum glucose value within 4 hours after meals, excluding the data 
from patients who have had the next meal event. If there are multiple time points with the 
maximum glucose value, then the earliest time will be used. 
9.8.2. Highest Postprandial Glucose Level within 4 hours after Meals
Highest postprandial glucose level excursions within 4 hours after meals, will be calculated as 
the maximum glucose value during 0 to 4 hours after start of meal, excluding the data from 
patients who have had the next meal event.
9.9.
Other
The duration of each episode of hypoglycemia will be calculated as stop time – start time. 





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m
k
k
i
m
n
CV
n
CV
1
1
i,
n
1
i
i
100
BG
SD
1
1


Leo Document ID = 2af4a1db-2508-40af-a5a4-6ab4e66add38
Approver: 
Approval Date & Time: 05-Oct-2020 13:39:47 GMT
Signature meaning: Approved
PPD