Conditions: Type 2 Diabetes
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 187
Healthy volunteers: no

Brief summary:
This study is being done to evaluate glycemic control in participants with type 2 diabetes who are taking mealtime insulin LY900014 in combination with long-acting insulin glargine. Participants will use continuous glucose monitoring (CGM) (Freestyle Libre 14-day system) during the study.

Detailed description:

Arms:
arm 1: LY900014 (100 units/milliliter (U/mL)) is a mealtime insulin administered subcutaneously (SC) 0-2 minutes prior to each meal in combination with insulin glargine (100 U/mL) SC as long-acting insulin. Mealtime (bolus) and long-acting (basal) insulin doses were titrated to achieve glucose targets during the study.

Interventions: intervention 1: LY900014 intervention 2: Insulin Glargine
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol document:
Prot_000.pdf: 
 
 
 
Protocol I8B-MC-ITSW(a) 
 
 
A Study of LY900014 in Participants with Type 2 Diabetes using 
Continuous Glucose Monitoring 
 
 
NCT04605991 
 
 
Approval Date: 13-Jul-2020 


CONFIDENTIAL
I8B-MC-ITSW(a)
1
Title Page
Confidential Information
the information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of Eli 
Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical investigation 
of LY900014, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title: A Study of LY900014 in Participants with Type 2 Diabetes using Continuous 
Glucose Monitoring
Protocol Number: I8B-MC-ITSW
Amendment Number: (a)
Compound: LY900014
Study Phase: 3b
Short Title: PRONTO-Time in Range
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA 46285
Regulatory Agency Identifier Number
IND: 127210
Approval Date: Protocol Electronically Signed and Approved by Lilly: 21 April 2020 GMT
Protocol Amendment (a) Electronically Signed and Approved on date provided below.
Approval Date: 13-Jul-2020 GMT


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


CONFIDENTIAL
I8B-MC-ITSW(a)
3
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Protocol I8B-MC-ITSW
21-Apr-2020
Amendment [a] 
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
5.1. Inclusion Criteria
Addition of language to align 
with Lilly guidance  
Clarification of inclusion criteria for 
females regarding pregnancy,
breastfeeding, and contraceptive 
guidance 
5.2 Exclusion Criteria
Renumbering of exclusion 
criteria
Renumbering was completed to 
align with Lilly guidance
8.2.5. Hypoglycemia
Addition of language to align 
with classifications 
Clarification of standard 
classifications for hypoglycemia
10.1.1. Regulatory and 
Ethical Considerations
Addition of language to align 
with Lilly template
Clarification of regulatory 
information for investigator sites 
10.2. Appendix 2: 
Clinical Laboratory 
Tests
Complement laboratory 
testing updated
Complement laboratory tests were 
updated to align with current 
evaluations 
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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I8B-MC-ITSW(a)
4
Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.......................................................................................................................10
1.3.
Schedule of Activities (SoA) ......................................................................................11
2.
Introduction..............................................................................................................14
2.1.
Study Rationale ..........................................................................................................14
2.2.
Background ................................................................................................................14
2.3.
Benefit/Risk Assessment ............................................................................................15
3.
Objectives and Endpoints.........................................................................................16
4.
Study Design .............................................................................................................19
4.1.
Overall Design............................................................................................................19
4.2.
Scientific Rationale for Study Design .........................................................................19
4.2.1.
Participant Input into Study Design.............................................................................19
4.3.
Justification for Dose..................................................................................................19
4.4.
End of Study Definition..............................................................................................19
5.
Study Population ......................................................................................................20
5.1.
Inclusion Criteria........................................................................................................20
5.2.
Exclusion Criteria.......................................................................................................21
5.3.
Lifestyle Considerations .............................................................................................23
5.4.
Screen Failures...........................................................................................................24
6.
Study Intervention....................................................................................................25
6.1.
Study Interventions.....................................................................................................25
6.1.1.
Medical Devices.........................................................................................................25
6.2.
Preparation/Handling/Storage/Accountability.............................................................25
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................26
6.4.
Study Intervention Compliance...................................................................................26
6.5.
Concomitant Therapy .................................................................................................26
6.5.1.
Management of Oral Antihyperglycemic Medications and 
Injectable GLP-1 Agonist ...........................................................................................26
6.6.
Dose Modification......................................................................................................27
6.6.1.
Target Glucose Values for Titration of Insulin Therapy ..............................................27
6.6.2.
Basal Insulin Therapy and Titration............................................................................27
6.6.3.
Study Prandial Insulin Therapy and Titration..............................................................29
6.6.4.
Transitioning off Study Prandial Insulin Therapy........................................................31
6.7.
Intervention after the End of the Study........................................................................31
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................32
7.1.
Discontinuation of Study Intervention ........................................................................32
7.1.1.
Temporary Discontinuation ........................................................................................32
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................32
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................33


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I8B-MC-ITSW(a)
5
7.3.
Lost to Follow-up .......................................................................................................33
8.
Study Assessments and Procedures .........................................................................34
8.1.
Efficacy Assessments .................................................................................................34
8.1.1.
Continuous Glucose Monitoring .................................................................................35
8.2.
Safety Assessments ....................................................................................................36
8.2.1.
Physical Examinations................................................................................................36
8.2.2.
Vital Signs..................................................................................................................36
8.2.3.
Electrocardiograms.....................................................................................................36
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................36
8.2.5.
Hypoglycemia ............................................................................................................37
8.2.6.
Safety Monitoring.......................................................................................................37
8.3.
Adverse Events and Serious Adverse Events ..............................................................38
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................38
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................38
8.3.3.
Follow-up of AEs and SAEs.......................................................................................39
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................39
8.3.5.
Pregnancy...................................................................................................................39
8.3.6.
Product Complaints ....................................................................................................39
8.4.
Treatment of Overdose ...............................................................................................40
8.5.
Pharmacokinetics........................................................................................................40
8.6.
Pharmacodynamics.....................................................................................................40
8.7.
Genetics .....................................................................................................................40
8.8.
Biomarkers.................................................................................................................40
8.9.
Immunogenicity Assessments.....................................................................................40
8.10.
Health Economics.......................................................................................................40
8.10.1.
Insulin Treatment Satisfaction Questionnaire..............................................................40
8.10.2.
Study Mealtime Insulin Experience Question..............................................................41
8.10.3.
Diabetes-Specific Attitudes about Technology Use (DSAT) .......................................41
9.
Statistical Considerations.........................................................................................42
9.1.
Statistical Hypotheses.................................................................................................42
9.2.
Sample Size Determination.........................................................................................42
9.3.
Populations for Analyses ............................................................................................42
9.4.
Statistical Analyses.....................................................................................................42
9.4.1.
General Considerations...............................................................................................42
9.4.2.
Primary Endpoint........................................................................................................44
9.4.3.
Gated/Other Secondary Endpoints ..............................................................................44
9.4.4.
Tertiary/Exploratory Endpoints...................................................................................44
9.4.5.
Other Safety Analyses ................................................................................................45
9.4.6.
Other Analyses ...........................................................................................................45
9.5.
Interim Analyses.........................................................................................................46
9.6.
Data Monitoring Committee (DMC)...........................................................................46
10.
Supporting Documentation and Operational Considerations ................................47
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................47


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I8B-MC-ITSW(a)
6
10.1.1.
Regulatory and Ethical Considerations........................................................................47
10.1.2.
Financial Disclosure ...................................................................................................47
10.1.3.
Informed Consent Process ..........................................................................................47
10.1.4.
Data Protection...........................................................................................................48
10.1.5.
Dissemination of Clinical Study Data .........................................................................48
10.1.6.
Data Quality Assurance ..............................................................................................49
10.1.7.
Source Documents......................................................................................................50
10.1.8.
Trial and Site Start and Closure ..................................................................................50
10.1.9.
Publication Policy.......................................................................................................51
10.1.10. Investigator Information .............................................................................................51
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................52
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................54
10.3.1.
Definition of AE.........................................................................................................54
10.3.2.
Definition of SAE.......................................................................................................55
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................56
10.3.4.
Reporting of SAEs<<confirmed with GPS-DJ 25Mar20>>.........................................57
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................59
10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................62
10.6.
Appendix 6: Abbreviations .........................................................................................67
11.
References.................................................................................................................70


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I8B-MC-ITSW(a)
7
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Study of LY900014 in Participants with Type 2 Diabetes using Continuous 
Glucose Monitoring
Short Title: PRONTO-Time in Range
Rationale: The aim of this study is to evaluate time in range (70-180 mg/dL [3.9-10.0 mmol/L]) 
from continuous glucose monitoring (CGM) with LY900014 treatment in a basal-bolus multiple 
daily injection (MDI) regimen in combination with insulin glargine U-100 in participants with 
type 2 diabetes (T2D).
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate time glucose values 
from continuous glucose monitoring 
(CGM) are within target range 
(70-180 mg/dL [3.9-10.0 mmol/L]) 
during the daytime period with 
LY900014 treatment 

Percentage of time with CGM glucose 
values between 70-180 mg/dL
(3.9-10.0 mmol/L) (both inclusive) during 
daytime period with 14 days of CGM use 
at Week 12 compared with baseline
Gated Secondary

To evaluate HbA1c

HbA1c change from baseline to Week 12

To evaluate time glucose values 
from CGM are within target range 
(70-180 mg/dL [3.9-10.0 mmol/L]) 
during the 24-hour period with 
LY900014 treatment

Percentage of time with CGM glucose 
values between 70-180 mg/dL
(3.9-10.0 mmol/L) (both inclusive) during 
the 24-hour period with 14 days of CGM 
use at Week 12 compared with baseline
Other Secondary

To evaluate time in hypoglycemic 
glucose ranges, obtained from CGM
use

Percentage of time with CGM glucose 
values <54 mg/dL (<3.0 mmol/L) during 
daytime and 24-hour periods with 14 days 
of CGM use at Week 12 compared with 
baseline 

To evaluate time in hyperglycemic 
glucose ranges, obtained from CGM
use

Percentage of time with sensor glucose 
values >180 mg/dL (>10.0 mmol/L) and 
>250 mg/dL (>13.9 mmol/L), during 


CONFIDENTIAL
I8B-MC-ITSW(a)
8
daytime and 24-hour periods with 14 days 
of CGM use at Week 12 compared with 
baseline 

To evaluate postprandial 
incremental AUCs, obtained from 
CGM use

Postprandial incremental AUC0-1 hour and 
incremental AUC0-2 hour at Week 12 
compared with baseline

To evaluate proportion of 
participants achieving HbA1c 
targets

The proportion of participants with HbA1c 
<7% and ≤6.5% at Week 12

To evaluate bolus, basal, and total 
daily insulin dose

Bolus, basal, and total insulin doses and 
bolus/total insulin ratio at Week 12 
compared with baseline

To evaluate severe hypoglycemia

Incidence of severe hypoglycemia events 
from baseline to Week 12

To evaluate insulin treatment 
satisfaction regarding glycemic 
control as measured by the ITSQ

Change from baseline in ITSQ glycemic 
control domain scores at Week 12 
Abbreviations: AUC = area under the curve; HbA1c = hemoglobin A1c; ITSQ = Insulin Treatment Satisfaction 
Questionnaire.
Overall Design
Study I8B-MC-ITSW (ITSW) is a Phase 3b, prospective, open-label, outpatient, multicenter, 
single-treatment-group study conducted in participants with T2D currently treated with a basal-
bolus analog MDI regimen. Participants will use unblinded CGM (Freestyle Libre 14-day 
system) for diabetes management and glucose data collection during the study. The study is 
designed to evaluate the time sensor glucose values from CGM are within target range 
(70-180 mg/dL [3.9-10.0 mmol/L]) with 12 weeks of LY900014 treatment.
LY900014 will be injected immediately (0-2 minutes) prior to each meal in combination with 
insulin glargine U-100 as basal insulin. Basal-bolus insulin doses will be titrated to achieve 
protocol glucose targets during the study.
Disclosure Statement: This is a single group treatment study.
Number of Participants:
Approximately 167 participants will be assigned to treatment such that approximately 
150 evaluable participants complete the study.
Intervention Groups and Duration:
The study includes screening, 4-week baseline, 12-week treatment, and 2-week posttreatment 
follow-up periods. Participants will continue treatment with prestudy insulins during the 4-week 
baseline period.


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I8B-MC-ITSW(a)
9
Data Monitoring Committee: No


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I8B-MC-ITSW(a)
10
1.2.
Schema


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I8B-MC-ITSW(a)
11
1.3.
Schedule of Activities (SoA)
Screen
Baseline
Treatment Period
ED
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
801
ED
Visit Window (± days)
3
3
3
3
3
3
3
3
3
3
3
7
Time (weeks)
-5
-4
-2
0
1
2
4
6
8
10
11
12
14
Telephone visits are indicated by shaded columns. Telephone visits can become office visits if needed. Site documentation will serve as the 
source 
for telephone visits.
Informed Consent Signed
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Participant eligibility review
X
Treatment assignment
X
Note: Treatment assignment should occur after completion of all Visit-4 procedures. Participants who have been assigned treatment will be asked to 
return for the ED visit.
Clinical Assessments
Participant demographics
X
Medical history and preexisting conditions
X
Physical exam/height
X
Concomitant medications
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
Body weight
X
X
X
X
X
X
X
Vital signs, blood pressure and heart rate
X
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
Note: Participants must be supine for approximately 5-10 minutes before ECG collection and remain supine, but awake, during ECG collection.
Diabetes, hypoglycemia and nutrition counseling
X
Note: Initial training at Visit 2 will include diabetes education and nutrition counseling. Appropriate site personnel will administer training and 
education using locally approved diabetes education/training materials and programs or by using other materials that may be provided by the sponsor. 
Participants may be provided abbreviated training and education at visits following Visit 2 as appropriate.
Basal and prandial insulin dose assessments
X
X
X
X
X
X
X
X
X
X
X
X
X


CONFIDENTIAL
I8B-MC-ITSW(a)
12
Screen
Baseline
Treatment Period
ED
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
801
ED
Visit Window (± days)
3
3
3
3
3
3
3
3
3
3
3
7
Time (weeks)
-5
-4
-2
0
1
2
4
6
8
10
11
12
14
Telephone visits are indicated by shaded columns. Telephone visits can become office visits if needed. Site documentation will serve as the 
source 
for telephone visits.
Supplies and IP
Dispense CGM system, CGM reader, and mobile device with 
preloaded CGM application and complete training
X
Note: Participants may be provided additional training at visits following Visit 2 as appropriate.
Dispense study supplies 
X
X
X
X
Review/discuss CGM data and hypoglycemia events
X
X
X
X
X
X
X
X
X
X
X
Upload CGM data to study vendor portal 
X
X
X
X
X
Train on use of study paper diary for collection of insulin dose 
data
X
Dispense study diary 
X
X
X
X
Remind participant of study diary requirements 
X
X
X
X
X
X
X
X
X
X
Collect/review study diary and transfer insulin dose data to 
eCRF 
X
X
X
X
X
Dispense LY900014 and Basaglar®
X
X
X
Participant returns unused study drug supplies 
X
X
X
X
Return study mobile device and CGM reader
X
X
Drug accountability
X
X
X
X
X
Laboratory Assessments (no fasting required)
HbA1c
X
X
X
X
X
X
Chemistry panel
X
Hematology
X
Serum pregnancy test (in WOCBP)
X
Urine pregnancy test
X
Note: Urine pregnancy test must be performed within 24 hours prior to IP exposure at randomization (Visit 4) and at other times at the investigator’s 
discretion.
Follicle-stimulating hormone test
X


CONFIDENTIAL
I8B-MC-ITSW(a)
13
Screen
Baseline
Treatment Period
ED
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
801
ED
Visit Window (± days)
3
3
3
3
3
3
3
3
3
3
3
7
Time (weeks)
-5
-4
-2
0
1
2
4
6
8
10
11
12
14
Telephone visits are indicated by shaded columns. Telephone visits can become office visits if needed. Site documentation will serve as the 
source 
for telephone visits.
Note: 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 have had cessation of menses for at least 1 year without an alternative medical cause.
Health Outcomes Questionnaires (to be completed on paper by study participants and data will be transferred by sites to the eCRF)
Insulin Treatment Satisfaction Questionnaire (ITSQ)
X
X
X
X
Diabetes-Specific Attitudes about Technology Use (DSAT)
X
X
X
X
Study mealtime insulin experience question
X
X
Abbreviations: CGM = continuous glucose monitoring; ECG = electrocardiogram; eCRF = electronic case report form; ED = early discontinuation; 
HbA1c = hemoglobin A1c; IP = investigational product; IWRS = interactive web-response system; WOCBP = women of childbearing potential.


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I8B-MC-ITSW(a)
14
2.
Introduction
2.1.
Study Rationale
Hemoglobin A1c (HbA1c) is widely accepted by health care providers and regulatory authorities 
as the best marker for the development of long-term diabetes complications. As a valid measure 
of glycemic control over time, HbA1c reflects average glucose over the previous 2 to 3 months. 
The role of HbA1c in clinical management should not be undervalued, however it does not 
provide information about acute glycemic excursions of hypoglycemia or hyperglycemia or 
about the degree of glucose variability. Measures in addition to HbA1c such as time in target 
glucose range as well as other CGM parameters are becoming increasingly important in diabetes 
clinical care and in patients’ daily diabetes management and should be evaluated in conjunction 
with HbA1c.
Study ITSW will evaluate glycemic control improvement assessed by HbA1c and will provide 
new CGM data, including time in range in adults with T2D treated with LY900014 in a basal-
bolus MDI regimen with insulin glargine U-100. Study ITSW will also allow assessment of 24-
hour glucose profiles and further evaluation of postprandial glucose (PPG) excursions. 
Unblinded CGM will be used for daily diabetes management and glucose data collection. Basal-
bolus insulin doses will be titrated to achieve protocol glucose targets during the study.
2.2.
Background
There have been many advances in the treatment of T2D in the last 20 years; however, reaching 
and maintaining glycemic goals remains challenging even with intensive insulin therapy 
regimens. Large surveys of people with Type 1 diabetes (T1D) and T2D have indicated that time 
in target glucose range is an important parameter to patients to improve diabetes management 
and mindset (Runge et al. 2018). Time in range is also a quantitative measure that evaluates 
treatment efficacy (Runge et al. 2018). Thus, there is a need to consider the patients’ daily 
glycemia in addition to the 2- to 3-month average, as measured by HbA1c.
Currently available, rapid-acting insulin analogs continue to be unable to match the kinetics of 
physiological postmeal insulin secretion. LY900014 is a new formulation of insulin lispro 
developed as an ultra-rapid-acting insulin with a faster onset of action and shorter duration of 
action compared to currently available rapid-acting insulin analogs, and it will more closely 
mimic endogenous insulin action in healthy subjects. These changes in pharmacokinetic (PK)
and pharmacodynamic (PD) characteristics are achieved by coformulating insulin lispro with 2 
enabling excipients, treprostinil and citrate.
The efficacy and safety profiles of LY900014 in patients with T1D and T2D have been evaluated 
in 2 randomized, active-controlled, multicenter, multinational, Phase 3, MDI clinical trials: 
Studies I8B-MC-ITRM and I8B-MC-ITRN.
Studies ITRM (patients with T1D) and ITRN (patients with T2D) studied MDI injections of
LY900014 and Humalog®, both in combination with insulin glargine or insulin degludec. The 
primary endpoint in Studies ITRM and ITRN was HbA1c change from baseline to Week 26, 


CONFIDENTIAL
I8B-MC-ITSW(a)
15
with multiplicity-adjusted objectives for 1- and 2-hour PPG excursions with standardized meal 
tests.
In Studies ITRM and ITRN, the primary objective of noninferiority for the change from baseline 
to Week 26 for HbA1c was confirmed for LY900014 compared with Humalog (when 
administered 0-2 minutes before a meal) as the upper limit of the 95% confidence interval (CI)
for the difference in change in HbA1c was less than the prespecified noninferiority margin of 
0.4%. In Study ITRM in patients with T1D, the mean HbA1c at Week 26 was 7.21% for 
LY900014 and 7.34% for Humalog. In Study ITRN in patients with T2D, the mean HbA1c at 
Week 26 was 6.92% for LY900014 and 6.86% for Humalog.
LY900014 was superior to Humalog in lowering 1- and 2-hour PPG excursions during 
standardized meal test with dosing 0 to 2 minutes before a meal. At Week 26, mean PPG 
excursions were statistically significantly lower in the LY900014 group than in the Humalog 
group at all time points from 15 minutes to 4 hours in Study ITRM and from 30 minutes to
4 hours in Study ITRN.
In Study ITRM, blinded CGM was performed in a subgroup of patients with T1D (total n=269). 
The results from the CGM substudy reflect and support key observations from the main study. 
Results showed that improvements in PPG control observed in patients in the mealtime 
LY900014 versus Humalog group (with dosing 0-2 minutes before a meal) were also associated 
with an increased time spent in target glucose range (both 71-180 mg/dL [3.9-10.0 mmol/L] and 
71-140 mg/dL [3.9-7.8 mmol/L]) during the daytime period, which is the period when prandial 
insulins are typically used.
Since Study ITRN did not include a CGM addendum in patients with T2D, Study ITSW will 
provide new CGM data in that population including time in range, assessment of 24-hour 
glucose profiles, and further evaluation of PPG excursions.
A detailed description of the chemistry, pharmacology, efficacy, and safety of LY900014 is 
provided in the Investigator’s Brochure (IB).
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.
Participants may experience the benefit of improved glycemic control with basal-bolus insulin 
dose treatment, dose titration, and use of unblinded CGM.
Considering the measures to minimize risk to participants participating in this study, the potential 
risks identified in association with LY900014 are justified by the anticipated benefits that may be 
afforded to participants with diabetes.


CONFIDENTIAL
I8B-MC-ITSW(a)
16
3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate time glucose values from 
continuous glucose monitoring (CGM) 
are within target range (70-180 mg/dL
[3.9-10.0 mmol/L]) during the daytime 
period with LY900014 treatment 

Percentage of time with CGM glucose 
values between 70-180 mg/dL
(3.9-10.0 mmol/L) (both inclusive) 
during daytime period with 14 days of 
CGM use at Week 12 compared with 
baseline
Gated Secondary

To evaluate HbA1c

HbA1c change from baseline to Week 
12

To evaluate time glucose values from 
CGM are within target range (70-180 
mg/dL [3.9-10.0 mmol/L]) during the 
24-hour period with LY900014 
treatment

Percentage of time with CGM glucose 
values between 70-180 mg/dL
(3.9-10.0 mmol/L) (both inclusive) 
during the 24-hour period with 14 days 
of CGM use at Week 12 compared with 
baseline
Other Secondary

To evaluate time in hypoglycemic 
glucose ranges, obtained from CGM use

Percentage of time with CGM glucose 
values <54 mg/dL (<3.0 mmol/L)
during daytime and 24-hour periods 
with 14 days of CGM use at Week 12 
compared with baseline

To evaluate time in hyperglycemic 
glucose ranges, obtained from CGM use

Percentage of time with sensor glucose 
values >180 mg/dL (>10.0 mmol/L) and 
>250 mg/dL (>13.9 mmol/L), during 
daytime and 24-hour periods with 14 
days of CGM use at Week 12 compared 
with baseline


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Objectives
Endpoints

To evaluate postprandial incremental 
AUCs, obtained from CGM use

Postprandial incremental AUC0-1 hour
and incremental AUC0-2 hour at Week 12 
compared with baseline

To evaluate proportion of participants 
achieving HbA1c targets

The proportion of participants with 
HbA1c <7% and ≤6.5% at Week 12

To evaluate bolus, basal, and total daily 
insulin dose

Bolus, basal, and total insulin doses and 
bolus/total insulin ratio at Week 12 
compared with baseline

To evaluate severe hypoglycemia

Incidence of severe hypoglycemia 
events from baseline to Week 12

To evaluate insulin treatment 
satisfaction regarding glycemic control
as measured by the ITSQ

Change from baseline in ITSQ 
glycemic control domain scores at 
Week 12 
Tertiary/Exploratory

To evaluate proportion of participants 
achieving CGM-based glycemic targets

The proportion of participants with 
percentage of time in target CGM
glucose range (70-180 mg/dL [3.9-10.0 
mmol/L]) >70%, time in hypoglycemia 
(<54 mg/dl [<3.0 mmol/L]) <1%, and 
time in hyperglycemia (>250 mg/dL
[>13.9 mmol/L]) <5% with 14 days of 
CGM use at Week 12

To evaluate glucose profiles, obtained 
from CGM use

Average glucose for a 24-hour period 
from each 14-day CGM session at 
Week 12 compared with baseline 

To evaluate glucose variability, 
obtained from CGM use

CV with 14 days of CGM use at Week 
12 compared with baseline

To evaluate insulin treatment 
satisfaction as measured by the ITSQ

Change from baseline in ITSQ total and 
domain scores (except glycemic control 
domain) at Week 12


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Objectives
Endpoints

To characterize participants’ 
willingness to incorporate LY900014 
into diabetes management routine 

Distribution of responses to study 
mealtime insulin experience question at 
Week 12

To evaluate attitudes towards diabetes 
technology use as measured by the 
DSAT

Change from baseline in DSAT total 
score at Week 12
Abbreviations: AUC = area under the curve; CV = coefficient of variation; DSAT = Diabetes-Specific Attitudes 
about Technology Use scale; HbA1c = hemoglobin A1c; ITSQ = Insulin Treatment Satisfaction Questionnaire.


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4.
Study Design
4.1.
Overall Design
Study ITSW is a Phase 3b, prospective, open-label, outpatient, multicenter, single-treatment-
group study conducted in participants with T2D currently treated with a basal-bolus analog MDI 
regimen. Participants will use unblinded CGM (Freestyle Libre 14-day system) for diabetes 
management and glucose data collection during the study. The study is designed to evaluate the
time sensor glucose values from CGM are within target range (70-180 mg/dL
[3.9-10.0 mmol/L]) with 12 weeks of LY900014 treatment.
LY900014 will be injected immediately (0-2 minutes) prior to each meal in combination with 
insulin glargine U-100 (Basaglar®) as basal insulin. Basal-bolus insulin doses will be titrated to 
achieve protocol glucose targets during the study.
4.2.
Scientific Rationale for Study Design
Study ITSW is a Phase 3b, single-treatment-group study conducted in participants with T2D 
currently treated with a basal-bolus analog MDI regimen. Study ITSW is designed to provide 
new CGM data (including time in range) in adults with T2D treated with LY900014 in a basal-
bolus MDI regimen. Unblinded CGM will be used for daily diabetes management and glucose 
data collection. Time in range and HbA1c will be evaluated for change from baseline to 
endpoint. Additional CGM parameters including time in hypoglycemia, time in hyperglycemia, 
24-hour glucose profiles, and PPG excursions will also be evaluated.
4.2.1.
Participant Input into Study Design
The sponsor involved participants in the design of this study by engaging participants in 
simulations and other face-to-face or virtual collaborative events. The insights gained from these 
events were used to ensure that the study design is supportive of the well-being of the study 
participants and that the study procedures can be implemented effectively at the investigative 
sites.
4.3.
Justification for Dose
LY900014 will have the same insulin lispro concentration (100 U/mL) as that of commercially 
available Humalog. The dosage of basal and prandial insulins used in this study should be 
determined based on the individual needs of each participant.
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the Schedule of Activities (SoA) for the last participant in the 
trial globally.


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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.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3) 
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 at least 18 years of age at the time of signing the informed consent.
3. Male or Female
a.
Male: no contraception required.
b. 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 
visit followed by a negative urine pregnancy text within 24 hours prior to 
exposure to investigational product (IP) at Visit 4. 
Type of Participant and Disease Characteristics
4. Participants diagnosed (clinically) with type 2 diabetes mellitus for at least 1 year prior to 
screening
5. Have been treated with basal-bolus MDI therapy for at least 90 days prior to screening 
including:
a.
Basal insulin glargine U-100, in combination with bolus insulin analog (insulin 
lispro, insulin aspart, or insulin glulisine) with meals 
b. Participant must have been treated with the same type of allowed bolus insulin 
analog for at least 30 days prior to screening.
6. Participants may be treated with up to 3 of the following OAMs for T2D in accordance 
with local regulations:


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a.
Metformin
b. Dipeptidyl peptidase-4 (DPP-4) inhibitor
c.
sodium glucose cotransporter 2 (SGLT2) inhibitor
d. oral glucagon-like peptide 1 (GLP-1) agonist
Doses of oral antihyperglycemic medications (OAMs) are required to have been stable 
for at least 90 days prior to screening. Combination medications (2 or more medications 
in 1 pill) should be counted as the number of individual components.
7. Participants may be treated with injectable GLP-1 receptor agonist for T2D in accordance 
with local regulations. The GLP-1 receptor agonist dose is required to have been stable 
for at least 90 days prior to screening.
8. Have an HbA1c value ≥7.5% and ≤10% according to the central laboratory at screening 
Weight
9. Body mass index (BMI) ≤40.0 kg/m2 at screening (Visit 1).
Other Inclusions
10. Have access to a telephone, or alternative means for close monitoring/communications
11. Have refrigeration in the home or have ready access to refrigeration for storage of insulin 
therapy
12. Have a regular wake/sleep schedule (awake/work during the day and sleep during the 
night)
13. Willing to use the CGM device (Freestyle Libre) supplied for this study for glucose 
monitoring, diabetes management, and data collection per protocol
Note: If participants were using CGM prior to screening, participants may not use their 
own personal CGM device during the study baseline and treatment periods.
14. Capable of, willing, and desirous to do the following during the study:
a.
Adhere to a basal-bolus insulin MDI regimen and use of the study provided 
prandial and basal insulins according to injection instructions and protocol 
b. Follow a general daily pattern of administering prandial insulin doses with 3 main 
meals per day (morning, midday, and evening) 
c.
Able to read and understand the language(s) available for devices and application
used in the study
d. Use study-provided mobile device and associated medical application and comply 
with study requirements as required by this protocol
e.
Comply with scheduled visits and study requirements 
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
15. Have been diagnosed at any time with type 1 diabetes mellitus or latent autoimmune 
diabetes in adults


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16. Have had any episode of severe hypoglycemia (defined as requiring assistance due to 
neurologically disabling hypoglycemia) within 6 months prior to screening
17. Have had any episode of hyperglycemic hyperosmolar state or diabetic ketoacidosis 
within 6 months prior to screening
18. Have hypoglycemia unawareness as judged by the investigator
19. Have excessive insulin resistance, defined as having received a total daily dose of insulin 
>2.0 U/kg at the time of screening
20. Have cardiovascular disease within 6 months prior to screening, defined as stroke, 
decompensated heart failure (New York Heart Association Class III or IV), myocardial 
infarction, unstable angina pectoris, or coronary arterial bypass graft
21. Renal:
a.
History of renal transplantation
b. Currently receiving renal dialysis
c.
Serum creatinine >2.0 mg/dL (177 µmol/L) at screening as measured by the 
central laboratory
22. Hepatic: Have obvious clinical signs or symptoms of liver disease (excluding 
nonalcoholic fatty liver disease), acute or chronic hepatitis, cirrhosis, or elevated liver 
enzyme measurements as indicated below at screening (Visit 1):
a.
Total bilirubin level (TBL) ≥2× the upper limit of normal (ULN) (except for
Gilbert’s syndrome) as defined by the central laboratory, or
b. Alanine aminotransferase (ALT) ≥3× ULN as defined by the central laboratory, or
c.
Aspartate aminotransferase (AST) ≥3× ULN as defined by the central laboratory
23. Malignancy: 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, or are at an increased risk for developing cancer or a recurrence of cancer in the 
opinion of the investigator
24. Have any hypersensitivity or allergy to any of the insulins or excipients used in this trial
25. Hematologic: Have had a blood transfusion or severe blood loss within 90 days prior to 
screening (Visit 1) or have known hemoglobinopathy, hemolytic anemia, sickle cell 
anemia, or any other traits known to interfere with the measurement of HbA1c
26. Have presence of clinically significant gastrointestinal disease (for example, clinically 
active gastroparesis associated with wide glucose fluctuations) in the investigator’s 
opinion
27. Have a history of or are being evaluated for bariatric surgery including Roux-en-Y gastric 
bypass surgery, gastric banding, and/or gastric sleeve
28. Have any other condition (including known drug or alcohol abuse, or psychiatric disorder 
including eating disorder) that precludes the participant from following and completing 
the protocol
Prior/Concomitant Therapy
29. Have used thiazolidinedione, sulfonylurea, pramlintide, or any other oral or injectable 
medication intended for the treatment of T2D other than as specified in Inclusion criteria 
[6, 7] within 90 days prior to screening


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30. Have been on an insulin treatment regimen that includes Fiasp®, LY900014, degludec, 
detemir, neutral protamine Hagedorn insulin, regular human insulin, any premixed 
insulin, insulin human inhalation powder (Afrezza®) or any insulin therapy other than as 
specified in Inclusion criterion [5] within 90 days prior to screening
31. Have used continuous subcutaneous (SC) insulin infusion therapy within the 90 days 
prior to screening
32. Glucocorticoid therapy: Receiving chronic (lasting longer than 14 consecutive days) 
systemic glucocorticoid therapy (including intravenous, intramuscular, SC, or oral, but 
excluding topical, intraocular, intranasal, intraarticular, and inhaled preparations) or have 
received such therapy within 8 weeks immediately prior to screening (Visit 1), with the 
exception of replacement therapy for adrenal insufficiency
33. Have used any weight loss drugs (for example, prescription drugs: lorcaserin, orlistat, 
phentermine, phentermine/topiramate, naltrexone/bupropion; or over-the-counter weight 
loss medications) within 90 days prior to screening
Prior/Concurrent Clinical Study Experience
34. Are currently enrolled in any other clinical trial involving an investigational product (IP)
or any other type of medical research judged not to be scientifically or medically 
compatible with this study
35. 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
36. Have previously completed or withdrawn from this study or any other study investigating 
LY900014 after receiving at least 1 dose of the IP
Other Exclusions
37. 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
38. Are Lilly employees or representatives (including employees, temporary contract 
workers, or designees responsible for the conduct of the study)
39. Are unable and/or unwilling to provide informed consent, to make themselves available 
for the duration of the study, or to abide by study procedures
5.3.
Lifestyle Considerations
During the study, participants must avoid:
1. Donating blood or blood products
2. Major changes in diet or exercise


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5.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. Retests are also not allowed, except for cases in which results are not available from 
the original sample.
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE).


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6.
Study Intervention
Study intervention is defined as any investigational interventions, marketed products, placebo, or 
medical devices intended to be administered to a study participant according to the study 
protocol.
6.1.
Study Interventions 
Intervention Name
LY900014
Type
Drug
Dose Formulation
Solution
Unit Dose Strength(s)
100 U/mL in 3 mL cartridge
Dosage Level(s)
Individualized dosing
Route of Administration
Subcutaneous
Packaging and Labeling
LY900014 will be provided in prefilled pens. Each pen will 
be labeled as required per country requirement. 
Sourcing
Provided centrally by the sponsor, subsidiary, or designee
6.1.1.
Medical Devices
1. The Lilly manufactured medical devices provided for use in this study are:
a.
the LY900014 prefilled pen, and 
b. the insulin glargine U-100 (Basaglar) prefilled pen.
2. Instructions for use for each of the prefilled pens will be provided.
3. The FreeStyle Libre is a marketed, non-Lilly, medical device for CGM. It will also be 
provided to study participants.
6.2.
Preparation/Handling/Storage/Accountability
1. 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.
2. 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.


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3. 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).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual.
5. 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.
6. 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 an open-label, single arm study.
6.4.
Study Intervention Compliance
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by reviewing the 
participant’s glycemic control, adherence to the visit and treatment schedule, use of the study 
CGM system, adjustment of prandial insulin doses as appropriate, and completion of study 
diaries. Compliance will be documented in the source documents and the electronic case report 
form (eCRF).
Participants who are deemed noncompliant will receive additional diabetes education and 
training, as required, and the importance of compliance with the protocol will be reinforced. 
Participants who, in the opinion of the investigator, are deemed consistently noncompliant may 
be discontinued from the study.
6.5.
Concomitant Therapy
The following concomitant therapies will not be allowed during the study:

any oral or injectable medication intended for the treatment of diabetes mellitus other 
than study insulins and those specified in Section 6.5.1. Exception: short-term use of 
nonstudy insulins is permissible as outlined in Section 7.1.1.

chronic (lasting longer than 7 consecutive days) systemic glucocorticoid therapy 
excluding topical, intraocular, intranasal, inhaled, or intraarticular preparations.

Weight loss drugs (for example, prescription drugs: lorcaserin, orlistat, phentermine, 
phentermine/topiramate, naltrexone/bupropion; or over-the-counter weight loss 
medications)
6.5.1.
Management of Oral Antihyperglycemic Medications and Injectable GLP-1 
Agonist 
During the study baseline and treatment periods, participants may continue the use of: 

up to 3 of the following OAMs for the treatment of T2D: metformin, SGLT2 
inhibitor, DPP-4 inhibitor, oral GLP-1 agonist and/or 


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
an injectable GLP-1 agonist for the treatment of T2D
Please note that participants must have entered the study on these agents with stable dosing for 
90 days prior to screening (Section 5.1, Inclusion Criteria [5,6,7]). Please also refer to 
Section 5.2, Exclusion Criteria [29,30].
Oral antihyperglycemic medications and GLP-1 dosing should remain stable during the study 
baseline and treatment periods, except with the development of contraindications or for safety 
reasons. During the study, all glycemic management is to be conducted by adjustment of basal 
and prandial insulin doses.
6.6.
Dose Modification
6.6.1.
Target Glucose Values for Titration of Insulin Therapy
The overall glycemic control goals for all participants enrolled in the study are similar to those 
recommended by the American Association of Clinical Endocrinologists (Bailey et al. 2016). 
Fasting, prandial, postprandial, and bedtime glucose target values used to reach the glucose goals 
and for determination of titration in insulin therapy are listed below.
Time of Target Glucose 
Measurement
Glucose Target (Range)
Fasting or Premorning meal
Target: 100 mg/dL or 5.6 mmol/L
Range: 80 to <110 mg/dL or 4.4 to 6.1 mmol/L
Premidday meal
Target: 100 mg/dL or 5.6 mmol/L
Range: 80 to <110 mg/dL or 4.4 to 6.1 mmol/L
Preevening meal
Target: 100 mg/dL or 5.6 mmol/L 
Range: 80 to <110 mg/dL or 4.4 to 6.1 mmol/L
Prebedtime
Range: 80 to <110 mg/dL or 4.4 to 6.1 mmol/L
1-2 hour or peak postprandial 
Target: <140 mg/dL or 7.8 mmol/L 
6.6.2.
Basal Insulin Therapy and Titration 
Participants must have been treated with basal insulin glargine U-100 prior to entering the study. 
Participants will continue their prestudy basal and prandial insulin therapy during the baseline 
period from Visit 2 to 4. The allowed basal insulin regimen during the study baseline and 
treatment periods is insulin glargine U-100 once or twice daily. The same dosing frequency 
should be maintained during the study.
The initial dose of basal insulin provided by the sponsor (insulin glargine U-100) at Visit 4 may 
be unit-for-unit. The basal insulin dose may be influenced by other clinical circumstances and 


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safety considerations known to the investigator; thus, the prescribed basal insulin dose during the 
study treatment period is determined by, and the responsibility of, the investigator.
The study basal insulin can be dosed at any time during the day and should be dosed at 
approximately the same time of day during study treatment. If there is a safety concern such as 
hypoglycemia, the dose timing of basal insulin may be changed per investigator discretion.
At all clinic and telephone visits during the 12-week treatment period, basal insulin dose should 
be reviewed and adjusted by the investigator, in discussion with the participant, based on CGM 
and hypoglycemia data. Twenty-four-hour glucose profiles from CGM should be evaluated for 
optimization of basal insulin dosing. Additional discussion between visits may be required to 
enable the participant to reach the glucose targets. Investigators may use discretion and provide 
direction for participants to adjust the basal insulin dose. Basal insulin should be titrated to reach 
the protocol target glucose values during the treatment period. Decreases to the basal insulin 
dose may be made at any time during the study based upon the judgment of the investigator (for 
example, in response to hypoglycemia). The participant should contact the site with any 
questions or concerns regarding insulin dosing.
Recommendations for basal insulin dose adjustment are described below. Hypoglycemia events 
can first be assessed over the previous week as described in the table below.
Hypoglycemic Events in the Previous Week
Basal Insulin Change
2 or more nocturnal hypoglycemia events occur or 
1 severe hypoglycemia event occurs at any time 
of the day 
Decrease the basal insulin dose to the 
previous lower dose (or by 10% if this is 
first dose).
1 nocturnal hypoglycemia event occurs 
Do not increase basal insulin dose. Consider 
decrease in basal insulin dose if clinically 
indicated.
No nocturnal events occur
Titrate the basal insulin dose as described 
below.
After the hypoglycemia assessment, the fasting glucose CGM pattern over the previous 3 days 
can be used for basal insulin adjustment as described in the table below.


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If fasting glucose CGM pattern is:
Adjust the basal insulin dose by:
<80 mg/dL 
(<4.4 mmol/L)
Decreasing dose to previous lower dosea
80-109 mg/dL 
(4.4-6.1 mmol/L)
No adjustment
110-129 mg/dL 
(>6.1-7.2 mmol/L)
Increasing by 1-2 units
130-149 mg/dL 
(>7.2-8.3 mmol/L)
Increasing by 2-4 units
150-179 mg/dL
(>8.3-9.9 mmol/L)
Increasing by 4-6 units
≥180 mg/dL 
(≥10.0 mmol/L)
Increasing by 6-8 units
Abbreviations: CGM = continuous glucose monitoring.
a
If there is no previous dose because this was the first assigned dose, then the basal dose should be decreased by 
10% in consultation with the investigator.
Source: Adapted from Bartley et al. 2008 and Bolli et al. 2009.
6.6.3.
Study Prandial Insulin Therapy and Titration 
Participants will continue their prestudy basal and prandial insulin therapy during the baseline 
period from Visits 2 to 4. At Visit 4, participants will start treatment with LY900014 and will 
administer their first study prandial insulin dose with the next meal following Visit 4. The total 
daily bolus insulin dose of LY900014 may be initiated unit-for-unit.
Study prandial insulin will be administered 0 to 2 minutes prior to the start of each meal 
(premorning meal, premidday meal, and preevening meal). Participants should follow a general 
daily pattern of administering prandial insulin doses with 3 main meals per day (morning, 
midday, and evening). Participants may have additional bolus insulin doses, such as with a 
snack, if clinically indicated.
This study will use 2 possible plans for determining prandial insulin dosing including:

Carbohydrate-counting plan: If the participant performed flexible carbohydrate counting 
for prandial insulin dosing (insulin to carbohydrate ratio plan) prior to study enrollment, 
this plan may be continued during the study. The prandial insulin dose is based on the 
participant’s estimated carbohydrate content of the meal (such as unit insulin per grams 
carbohydrate).

Fixed-dose plan: The participant is prescribed a fixed dose or dose range of insulin for 
each meal. The fixed dose or dose range of insulin may be individualized for each meal.


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The participant should maintain the same prandial insulin dosing plan throughout the study. 
Correction factor (for example, 1 unit of insulin per glucose [mg/dL or mmol/L] above target 
goal) may be implemented with either prandial insulin dosing plan.
Prandial insulin should be titrated to reach the protocol target glucose values during the treatment 
period. Decreases to the prandial insulin dose may be made at any time during the study based on 
the judgment of the investigator (for example, in response to hypoglycemia).
For participants who are using the carbohydrate-counting plan: the insulin to carbohydrate ratio 
(and correction factor if applicable) should be reviewed and adjusted by the investigator, in 
discussion with the patient, based on CGM and hypoglycemia data at all clinic and telephone 
visits during the 12-week treatment period. Twenty-four-hour glucose profiles, including 
premeal glucose and PPG levels, from CGM should be evaluated for optimization of prandial 
insulin dosing. Additional discussion between visits may be required to enable the participant to 
reach the glucose targets. The insulin to carbohydrate ratio may be adjusted every 3 days, or 
more often when appropriate, based on the participant’s glycemic needs and glucose levels. 
Investigators may use discretion and provide direction for participants to adjust prandial insulin 
dosing. The participant should contact the site with any questions or concerns regarding insulin 
dosing.
For participants who are using the fixed-dose plan: A participant self-titration prandial insulin 
algorithm will be utilized as described below. At all clinic and telephone visits during the 
12-week treatment period, prandial insulin dose (and correction factor if applicable) should be 
reviewed by the investigator in discussion with the participant based on CGM and hypoglycemia 
data. Twenty-four-hour glucose profiles, including premeal glucose and PPG levels, from CGM 
should be evaluated for optimization of prandial insulin dosing. Additional discussion between 
visits may be required to enable the participant to reach the glucose targets. The participant 
should contact the site with any questions or concerns regarding insulin dosing.
In the fixed-dose participant self-titration plan, assessment of the prandial insulin dose includes 
review of the previous day of CGM glucose values for the corresponding meal or bedtime as 
described in the table below. For example, if assessing the need to adjust the morning meal
prandial insulin dose, review the CGM glucose value from the previous day premidday meal.
Prandial Insulin Dose Assessed
Corresponding CGM Glucose Value for Review
Fasting or morning premeal
previous day premidday meal glucose value 
Midday premeal
previous day preevening meal glucose value 
Evening premeal
previous day bedtime glucose value 
Abbreviation: CGM = continuous glucose monitoring.
The CGM glucose value from the premeal or bedtime from the previous day is used by the 
participant as the “adjustment value” and the change in dose (either increase or decrease) is 
based upon this value as described in the table below.


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CGM Glucose
<80 mg/dL
(<4.4 mmol/L)
CGM Glucose
80-109 mg/dL
(4.4-6.1 mmol/L)
CGM Glucose
>109 mg/dL
(>6.1 mmol/L)
Decrease by 1 unit
No change
Increase by 1 unit
Abbreviations: CGM = continuous glucose monitoring.
Source: Adapted from Bergenstal et al. 2008 and Edelman et al. 2014.
For either prandial insulin dosing plan, the investigator may determine the appropriate correction 
factor for the participant to administer when premeal glucose levels are above target based on 
clinical judgment, taking into account the participant’s clinical history with previous/current
insulin regimen and recent glucose profiles. Alternatively, the correction factor may initially be 
calculated as follows:
correction factor = 1800/total daily insulin dose = estimated decrease in glucose (mg/dL) 
level per unit of prandial insulin administered, or
correction factor = 100/total daily insulin dose = estimated decrease in glucose (mmol/L) 
level per unit of prandial insulin administered
6.6.4.
Transitioning off Study Prandial Insulin Therapy
Participants will take their last doses of study prandial insulin (LY900014) and study-provided 
basal insulin glargine prior to Visit 12 or at early discontinuation.
No special instructions for transition to nonstudy prandial insulin are necessary. The investigator,
in consultation with the participant, will decide on the new prandial and basal insulin regimen, or 
other diabetes therapy, to be initiated.
6.7.
Intervention after the End of the Study
LY900014 and basal insulin glargine will not be provided to participants after completion of the 
study treatment period. Prandial and basal insulins, as well as other diabetes therapies, are 
available for the treatment of T2D.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
Participants who need to discontinue from study treatment will also be discontinued from the 
study. Please refer to Section 7.2.
7.1.1.
Temporary Discontinuation
During the study, participants who temporarily discontinue the IP may be able to resume the IP 
based on the following scenario:
The participant has not taken IP for 14 consecutive days or less:

If the treatment regimen restarts within 14 days of when the participant initially stopped 
taking IP, the participant may continue in the study and begin treatment again with IP. 
During this time, nonstudy insulins may have been used. If the participant decides to 
continue in the study, no early termination procedures will be completed. Participants 
will continue study visits through the safety follow-up.
7.2.
Participant Discontinuation/Withdrawal from the Study
Participants will be withdrawn from the study:

at any time at his/her own request 

at the request of his/her designee (for example, parents or legal guardian)

at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons

if participant has not taken IP for more than 14 consecutive days (see Section 7.1.1)

if the participant becomes pregnant during the study

if enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

if the investigator, after consultation with the sponsor-designated medical monitor, 
determines that a systemic hypersensitivity reaction has occurred related to study drug 
administration

if the participant, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

use of prohibited concomitant medication (see Section 6.5)
Discontinuation is expected to be uncommon.


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At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. The 
participant will be permanently discontinued both from the study intervention and from the study 
at that time.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant
withdraws from the study, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.
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 unless there are extenuating 
circumstances that make it medically necessary for the participant to continue in the study.
If the investigator and the sponsor clinical research physician (CRP) agree 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. 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 repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 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
Primary Efficacy Assessments
The percentage and duration of time with sensor glucose values between 70 and 180 mg/dL
(3.9-10.0 mmol/L) during the daytime hours.
Secondary Efficacy Assessments
The secondary efficacy measures in this study collected with CGM are

change in HbA1c

percentage and duration of time with sensor glucose values between 70 and 180 mg/dL 
(3.9-10.0 mmol/L) over 24 hours

percentage and duration of time with sensor glucose values <54 mg/dL (<3.0 mmol/L)
during daytime and 24-hour periods

percentage and duration of time with sensor glucose values >180 mg/dL (>10.0 mmol/L)
and >250 mg/dL (>13.9 mmol/L), during daytime and 24-hour periods

incremental area under the glucose concentration-time curve from 0 to 1 hour, 
0 to 2 hours after a meal
Other secondary efficacy measures in this collected in this study are

proportion of participants with HbA1c ≤6.5% and <7.0% 

bolus, basal and total insulin dose (units and units/kg) and bolus/total insulin ratio

change in Insulin Treatment Satisfaction Questionnaire (ITSQ) glycemic control 
domain score


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8.1.1.
Continuous Glucose Monitoring
The unblinded FreeStyle Libre 14-day CGM system will be used by all study participants from 
Visit 2 to Visit 12. This is an FDA-approved CGM system indicated for replacing blood glucose 
testing and detecting trends and tracking patterns aiding in the detection of episodes of 
hyperglycemia and hypoglycemia, facilitating both acute and long-term therapy adjustments in 
persons (age 18 and older) with diabetes.
Participants will use the:

FreeStyle Libre sensor
o
The sensor can be worn for up to 14 days. Participants will be instructed to change 
the sensor according to the product information.

FreeStyle Libre reader: 
o
for participants to scan the sensor and for sites to upload CGM data to the CGM 
vendor 
o
The reader also has a built-in blood glucose meter.

LibreLink application (app) on a study-provided mobile device
o
for participants to scan the sensor and for sites to have remote access to CGM data for 
telephone visits and as clinically indicated

Participants will be able to review CGM data for daily diabetes management with the 
reader and/or app.
Participants will receive training on the use of the system according to product information, and 
will be expected to complete the following study requirements:

Start each new sensor session with the reader first and then with the LibreLink app.

Change the sensor every 14 days or earlier if needed. 

Scan with the reader and app at least 4 times throughout the day (morning upon waking, 
prior to meals, bedtime) and as needed. After the start of a new sensor session, the sensor 
can be scanned with the reader and app in any order.
o
Make every effort to scan with the reader and app at least every 8 hours to avoid 
gaps in glucose data.
o
More frequent scanning is encouraged.
o
Participants should not ignore symptoms that may be due to hypoglycemia or 
hyperglycemia. Note that the FreeStyle Libre does not have alarms unless if the 
sensor is scanned.

Participants should check sensor glucose readings with a blood glucose meter as 
instructed according to product information when the “Check Blood Glucose” symbol 
appears, when symptoms do not match sensor readings, or when readings are suspected 
to be inaccurate.


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
The sensor must be removed before magnetic resonance imaging (MRI), computed 
tomography (CT) scan, X-ray, or diathermy treatment. 

Note and avoid substances that may interfere with sensor glucose readings including:
o
higher dose ascorbic acid (vitamin C) >1000 mg, which may raise sensor 
readings, and/or 
o
salicylic acid (contained in some pain relievers such as aspirin) >650 mg, 
which may slightly lower sensor readings
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations

A complete physical examination with measurement and record of height and weight.
8.2.2.
Vital Signs

For each participant, vital signs measurements should be conducted according to the SoA
(Section 1.3).
8.2.3.
Electrocardiograms

Single 12-lead electrocardiograms (ECGs) will be obtained as outlined in the SoA (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate and 
measures pulse rate, QRS, QT, and corrected QT intervals. 
8.2.4.
Clinical Safety Laboratory Assessments

See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
the SoA for the timing and frequency.

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the case report 
form (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 participant's 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.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2)
and Appendix 5 (Section 10.5), must be conducted in accordance with the laboratory 
manual and the SoA.


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o
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.
Hypoglycemia
Participants will use unblinded CGM for diabetes management. Participants should check sensor 
glucose readings with a blood glucose meter as instructed (also refer to Section 8.1.1). 
Participants will be instructed to treat glucose <70 mg/dL (<3.9 mmol/L) as hypoglycemia. The 
participant should contact the site as necessary.
Hypoglycemia will be described using the following definitions :

Level 1 hypoglycemia: glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 
mmol/L) as assessed by CGM

Level 2 hypoglycemia: glucose <54 mg/dL (<3.0 mmol/L) as assessed by CGM

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. 
o
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.
o
All episodes of severe hypoglycemia must be reported as serious on the AE eCRF 
page and on the SAE eCRF page. Episodes of hypoglycemia not meeting the criteria 
for severe hypoglycemia should not be reported as an AE.
8.2.6.
Safety Monitoring
8.2.6.1.
Hypersensitivity Reactions
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, 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.


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In the case of generalized urticaria or anaphylaxis, additional blood and urine samples should be 
collected as described in Appendix 2 (Section 10.2). Laboratory results are provided to the 
sponsor via the central laboratory. 
8.2.6.2.
Hepatic Monitoring
If a participant develops symptoms that warrant liver function assessment, liver function tests as 
detailed in Appendix 5 (Section 10.5) should be performed. If these tests are abnormal, clinical 
and laboratory monitoring should be initiated by the investigator. 
Laboratory tests including ALT, AST, alkaline phosphatase (ALP), TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to 
confirm the abnormality and to determine if it is increasing or decreasing, if 1 or more of these 
conditions occur. 
8.3.
Adverse Events and Serious Adverse Events
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention, study device, or study 
procedures, or that caused the participant to discontinue 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 prior to 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 Appendix 3 (Section 10.3). 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 AEs or SAEs 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 AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3).


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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/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs 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 Appendix 3 (Section 10.3).
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 
(IRBs)/Independent Ethics Committees (IECs), 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 IP) does not meet the definition of an AE. 
However, to fulfill regulatory requirements, any pregnancy should be reported following 
the SAE process to collect data on the outcome for both mother and fetus.

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 Appendix 4 
(Section 10.4).

Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Product Complaints
A product complaint is any written, electronic, or oral communication that alleges a deficiency 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
Lilly product after it is released for distribution. When the ability to use the product safely is 
impacted, the following are also product complaints: 
a.
deficiencies in labeling information, and
b. use errors for device or combination products due to ergonomic design elements of the 
product


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The sponsor collects product complaints on IPs, medical devices, 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. Complaints are also collected on comparators and 
other clinical trial material supplied, as required.
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP or device, so that the situation can be assessed.
Product complaints will be reported by the investigator to the sponsor per instructions provided 
on the study specific Product Complaint Form.
As required by local regulations, and per instructions on the product complaint form, the 
investigator will report to the sponsor and to their IRB/IEC any unanticipated adverse device 
effect or unanticipated problem that resulted in an SAE (UADE), or any device-related product 
complaint that could have led to an SAE had precautions not been taken.
8.4.
Treatment of Overdose
Excess insulin administration may result in hypoglycemia (Section 8.2.5).
8.5.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessments
Immunogenicity will not be assessed in this study.
8.10.
Health Economics
8.10.1.
Insulin Treatment Satisfaction Questionnaire
The ITSQ (Anderson et al. 2004) is a validated instrument containing 22 items that assesses 
treatment satisfaction for persons with diabetes on insulin. Items are measured on a 7-point 
Likert-type scale, where lower scores reflect better outcomes. In addition to an overall score, the 
items that make up the 5 domains of satisfaction are categorized as:

Inconvenience of Regimen (5 items)

Lifestyle Flexibility (3 items)


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
Hypoglycemic Control (5 items)

Glycemic Control (3 items)

Delivery System (6 items)
8.10.2.
Study Mealtime Insulin Experience Question
Study participants will be asked to complete a single Study Mealtime Insulin Experience 
question specifically developed for this study. This is a participant-rated assessment of their 
likelihood of incorporating the mealtime insulin used in this study (that is, LY900014) in their 
diabetes management routine. The question is rated on a 5-point scale ranging from “1- Very 
unlikely” to “5- Very likely.”
8.10.3.
Diabetes-Specific Attitudes about Technology Use (DSAT)
The Diabetes-Specific Attitudes about Technology Use scale (DSAT) is a 5-item scale that was 
originally developed to assess T1D patients’ attitudes towards diabetes-specific technology 
(Tanenbaum et al. 2017). Each item is rated on a 5-point Likert scale to indicate agreement with 
the statement, with higher scores indicating more positive attitudes about devices and technology. 
Individual ratings are summed to obtain a total score.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The primary objective of this study is to evaluate the change of time glucose values from CGM
are within target range (70-180 mg/dL [3.9-10.0 mmol/L]) during the daytime period from 
baseline to endpoint at Week 12 with LY900014 treatment.
9.2.
Sample Size Determination
Approximately 167 participants will be assigned to treatment with LY900014 such that 150 
participants complete the study through the primary endpoint at Week 12. This sample size has 
approximately 80% power to detect an increase of 4.5% time in target range (70-180 mg/dL
[3.9-10.0 mmol/L]) during the daytime period from baseline, assuming no true difference in time 
in target range between baseline and endpoint, and a standard deviation (SD) of 19.5%. 
Assuming a 10% dropout rate for 12 weeks, approximately 167 participants will need to be 
assigned.
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 enrolled participants who receive at least 1 dose of the assigned IP after Visit 4
Abbreviations: IP = investigational product.
9.4.
Statistical Analyses
9.4.1.
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 
statistical analysis plan (SAP) or the clinical study report (CSR). Additional exploratory analyses 
of data will be conducted as deemed appropriate.
The SAP will be finalized prior to the first patient first visit and it will include a more technical 
and detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints, including primary 
and key secondary endpoints. The primary analysis is for the treatment period through Week 12.
To ensure that the CGM outcome variables are only calculated from CGM session days with


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sufficient data within the 24-hour and daytime periods, the following criterion 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 for the 24-hour period
Efficacy analyses will be conducted on the treated population, including data collected prior to 
permanent discontinuation of IP. When change from baseline is included as a response variable 
of analysis models, the participant will be included in the analysis only if a baseline and a 
postbaseline measurement are available.
Safety analyses will be conducted on the treated population. Analyses of AEs and severe 
hypoglycemia will include data collected during the treatment period (Visit 4-12). AEs during 
the follow-up period will be listed. Analyses of AEs for the baseline period may be conducted as 
needed. 
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. A gatekeeper method (Westfall and Krishen 2001) will be used to
control the overall type 1 error for the primary and gated secondary objectives.
Baseline is defined as the last nonmissing measurement at or before Visit 4 unless otherwise 
specified. Daytime is defined as 0600 hours to midnight (06:00-23:59 on the 24-hour clock) and 
nighttime is defined as midnight to 0600 hours (00:00-05:59 on the 24-hour clock).
A restricted-maximum-likelihood-based, mixed model repeated measures (MMRM) analysis will 
be used to analyze continuous longitudinal variables. All the longitudinal observations at each 
scheduled postbaseline visit will be included in the analysis. The model for the analysis of the 
primary efficacy endpoint of change from baseline in time in target range (70-180 mg/dL
[3.9-10.0 mmol/L]) during daytime period will include the fixed class effect of visit, the 
covariate of baseline, and the random effect of participant. An unstructured covariance structure 
will be used to model the within-participant errors. Significance tests will be based on 
least-squares 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. 
An analysis of covariance (ANCOVA) will also be used to analyze continuous variables 
collected only at baseline and endpoint. The model will include baseline as a covariate. Unless 


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otherwise stated, missing endpoints will be imputed using the last-observation-carried-forward 
(LOCF) approach, using only postbaseline data.
For continuous measures, summary statistics will include sample size, mean, SD, median, 
minimum, and maximum for both the actual and the change from baseline measurements. 
Least-square means and standard errors derived from the analysis models will also be displayed 
for the change from baseline measurements.
For categorical measures, summary statistics will include sample size, frequency, and 
percentages.
9.4.2.
Primary Endpoint
The primary efficacy comparison will be based on the MMRM analysis of change from baseline 
in time in target range (70-180 mg/dL [3.9-10.0 mmol/L]) during daytime period including data 
collected prior to permanent discontinuation of IP. The analysis model and selection of 
covariance structure is described in Section 9.4.1.
9.4.3.
Gated/Other Secondary Endpoints
The analysis of the secondary gated objectives will be conducted if the time in target range 
(70-180 mg/dL [3.9-10.0 mmol/L]) during the daytime period at study endpoint versus baseline 
is found statistically significant for the primary efficacy analysis at a 2-sided 0.05 significance 
level (Westfall and Krishen 2001). If this contrast is significant, the secondary objectives were 
tested in sequence until the first null hypothesis in the sequence failed to be rejected at a 2-sided 
0.05 significance level. The sequential testing for gated secondary objectives is conducted in the 
following order to assess whether value at study endpoint is superior to baseline:
1. To evaluate HbA1c
2. To evaluate time glucose values from CGM are within target range (70-180 mg/dL
[3.9-10.0 mmol/L]) during the 24-hour period.
For continuous longitudinal secondary endpoints, the MMRM model similar to that for the 
primary analysis will be used. Duration and percent time in range, time in hypoglycemia, and 
time in hyperglycemia derived from CGM data will also be analyzed using an MMRM model. 
Continuous nonlongitudinal secondary endpoints will be analyzed using the ANCOVA. 
Postprandial incremental area under the curve (AUC)0-1 hour and incremental AUC0-2 hour will be 
analyzed by ANCOVA. Analysis details will be documented in the SAP. Proportion of 
participants with HbA1c <7.0% and ≤6.5% will be analyzed using a longitudinal logistic 
regression with repeated measurements conducted by a generalized linear mixed model with the 
fixed class effect of visit, the covariate of baseline HbA1c, and the random effect of participant. 
Actual and change from baseline in basal, bolus, and total dose, as well as the bolus/total insulin 
dose ratio will be analyzed by the MMRM models described in Section 9.4.1. 
9.4.4.
Tertiary/Exploratory Endpoints
Continuous variables and the change from baseline for these variables will be analyzed by either 
MMRM or ANCOVA described in Section 9.4.1. Analysis details for the tertiary endpoints will 
be described in the SAP.


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9.4.5.
Other Safety Analyses
Safety measures will include AEs, severe hypoglycemia, vital signs and weight, and treatment 
exposure.
Events that are newly reported after the first dose of IP or are reported to worsen in severity from 
baseline will be considered treatment-emergent adverse events (TEAEs). The Medical 
Dictionary for Regulatory Activities (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.
Serious adverse events, AEs reported as reason for discontinuation from the IP or study, and 
TEAEs will be summarized in tables using the MedDRA preferred term (PT), sorted by 
decreasing frequency. TEAEs will also be summarized by PT sorted by decreasing frequency 
within system organ class for all TEAEs and by maximum severity. For events that are specific 
to only 1 sex, the denominator and computation of the percentage will include only participants 
from the given sex. The number and proportion of participants with at least 1 event for each type 
of event will be summarized.
Severe hypoglycemia rates and incidence during the treatment period (Visits 4-12) will be 
summarized.
9.4.6.
Other Analyses
9.4.6.1.
Health Economics Analyses
For the ITSQ, the change from baseline to LOCF endpoint while on treatment in each domain 
transformed score (inconvenience, lifestyle, hypoglycemic control, glycemic control, and 
delivery system) and overall transformed score will be analyzed using ANCOVA.
For the DSAT, the change from baseline to LOCF endpoint, while on treatment, in each item
will be analyzed using ANCOVA.
Summary statistics, including number of participants and proportion of a categorical outcome
(5 levels) for the study mealtime insulin experience question will be provided.
9.4.6.2.
Subgroup Analyses
The following subgroups will be analyzed using data collected prior to permanent 
discontinuation of IP to evaluate consistency of results on the primary efficacy measure if there 
are sufficient numbers of participants by subgroup (for example, 10%):

age (65 years, 65 years)

baseline HbA1c (≤8%, >8%)

participant’s prior personal CGM use (yes/no)

participant’s SGLT2 use (yes/no)

participant’s injectable GLP-1 use (yes/no)

prandial dosing plan (carbohydrate counting, fixed dose) 


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
sex (male or female)

BMI (<35, ≥35 kg/m2)

duration of diabetes (using the median as the cutoff)

race

ethnicity
Analyses for primary efficacy measure will be performed using an MMRM model that includes 
the same fixed effect and covariate given for the primary analysis model plus factors of subgroup 
and 2-way interaction of subgroup and visit. The effect of subgroup at the primary endpoint 
(Week 12) will be evaluated to assess subgroup effect.
Additional subgroup analyses may also be performed.
9.5.
Interim Analyses
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.
9.6.
Data Monitoring Committee (DMC)
No DMC 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:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
o
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines
o
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:
o
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
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
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
No financial disclosure information will be collected.
10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant or his/her legally authorized representative and 
answer all questions regarding the study.


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
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative 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 requirements, where applicable, and the 
IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was entered in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative 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/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/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.

The sponsor has processes in place to ensure data protection, information security, and 
data integrity. These processes include appropriate contingency plan(s) for appropriate 
and timely response in the event of a data security breach.
10.1.5.
Dissemination of Clinical Study Data
Reports
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
Data
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, except for PK or genetic data.  Data are available to request 6 months after the 
indication studied has been approved in the US and EU and after primary publication acceptance, 
whichever is later.  No expiration date of data requests is currently set once data are made 
available. 


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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, SAP, CSR, blank or annotated CRFs, will be provided 
in a secure data sharing environment for up to 2 years per proposal. 
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 time period outlined in the Clinical Trial 
Agreement unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor.

In addition, the sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study may be 
audited by the sponsor or its representatives, and/or regulatory agencies at any time. 
Investigators will be given notice before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 


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An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided 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 third-party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems. Prior to 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 the 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.
Trial and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
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

inadequate recruitment of participants by the investigator

discontinuation of further study intervention development


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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.
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.
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
Creatine kinase (CK)
HbA1c
Abbreviations: HbA1c = hemoglobin A1c; IP = investigational product; RBC = red blood cells; WBC = white blood 
cells.
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 prior to 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 have had cessation of menses for at least 1 year without an alternative 
medical cause.
Hypersensitivity Clinical Laboratory Tests
Lab testing should be performed at the time of a systemic hypersensitivity event related to study 
drug administration. Important information about why, when, and what to test for are provided 
below. The management of the AE may warrant lab testing beyond that described below and 
should be performed as clinically indicated.


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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 1‐2 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?
o
Tryptase**
o
Antidrug antibody and LY900014 concentration (PK)
o
Antidrug antibody 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 is conducted once the assay is available, as 
appropriate. Please consult an immunologist within Global Patient Safety (GPS) for 
further guidance.
o
Complement
o
C3, C3a, and C5a
o
Cytokines
o
Interleukin (IL)‐6, IL‐1β, IL‐10 (or any cytokine panel that includes these 3 
cytokines)
* These labs 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 2-12 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 2-12 
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.
# 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: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New 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 AEs or SAEs if they fulfill the definition of an AE or SAE.
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.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.


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
Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
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.
Results in death
b.
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to hospital for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.

Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (for example, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is 


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appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
10.3.3.
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 participant’s medical 
records to the 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 
the sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories:

Mild: 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


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
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/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor or designee.

The investigator may change his/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 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor or designee with a copy of any 
postmortem findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the 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 form (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 


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available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line 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 off-
line, then the site can report this information on a paper SAE form (see next section).

Contacts for SAE reporting can be found on the paper SAE form.
SAE Reporting via Paper Form

Facsimile transmission of the SAE paper Form is the preferred method to transmit this 
information to Lilly (GPS).

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 on the SAE paper form.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 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 1 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, 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 of amenorrhea for women >55, 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, antiestrogens, 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


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
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 
negative urine pregnancy text within 24 hours prior to exposure to investigational 
product (IP) at Visit 4.

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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I8B-MC-ITSW(a)
61
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 poststudy, pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. 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 be 
withdrawn from the study.


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I8B-MC-ITSW(a)
62
10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments
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)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
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.
Comprehensive Hepatic Evaluation
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur:


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I8B-MC-ITSW(a)
63
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,a 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,a 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) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
a
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 a physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time, international normalized ratio; 
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, 
cytomegalovirus, Epstein-Barr virus, 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, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy.
Additional Hepatic Data Collection
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 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)
a.
In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline 
on 2 or more consecutive tests


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I8B-MC-ITSW(a)
64
2. Elevated TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome)
a.
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)
a.
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 an SAE
5. Discontinuation of study drug due to a hepatic event
Note: the interval between the 2 consecutive blood tests should be at least 2 days.
Hepatic Monitoring Laboratory Tests
If the investigator has confirmed liver test abnormality, he or she should select the 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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I8B-MC-ITSW(a)
65
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 
Antinuclear antibody (ANA)
    Hepatitis B core IgG antibody 
Antismooth muscle antibody (ASMA)a
    HBV DNAb
Antiactin antibodyc
Hepatis C Virus (HCV) Testing:
Epstein-Barr Virus (EBV) Testing:
    HCV antibody
    EBV antibody
    HCV RNAb
    EBV DNAb
Hepatitis D Virus (HDV) Testing:
Cytomegalovirus (CMV) Testing:
    HDV antibody
    CMV antibody
Hepatitis E Virus (HEV) Testing:
    CMV DNAb
    HEV IgG antibody
Herpes Simplex Virus (HSV) Testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody 
    HEV RNAb
    HSV (Type 1 and 2) DNAb
Microbiologyd
Liver Kidney Microsomal Type 1 (LKM-1) Antibody
Culture:
    Blood
    Urine


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I8B-MC-ITSW(a)
66
Abbreviations: INR = international normalized ratio.
a
This is not required if Anti-Actin Antibody is tested.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.
c
This is not required if Anti-smooth muscle antibody (ASMA) is tested.
d
Assayed by Investigator-designated local laboratory ONLY; no Central Testing available.


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I8B-MC-ITSW(a)
67
10.6.
Appendix 6: Abbreviations
Term
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve 
BAT
basophil activation test
BMI
body mass index
CFR
Code of Federal Regulations
CGM
continuous glucose monitoring
CI
confidence interval
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRF/eCRF
case report form/electronic case report form
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.
CSR
clinical study report
CT
computed tomography
Device deficiencies
Equivalent to product complaint
DPP-4
dipeptidyl peptidase-4
DSAT
Diabetes-Specific Attitudes about Technology Use
ECG
electrocardiogram
EDC
electronic data capture
enroll
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment.


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I8B-MC-ITSW(a)
68
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
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.
GLP-1
glucagon-like peptide 1
GPS
Global Patient Safety
HbA1c
hemoglobin A1c
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgE
immunoglobulin E
IL
interleukin
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.
IRB
Institutional Review Board
ITSQ
Insulin Treatment Satisfaction Questionnaire
IP
investigational product: A pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical trial, including products already on the market 
when used or assembled (formulated or packaged) in a way different from the 
authorized form, or marketed products used for an unauthorized indication, or marketed 
products used to gain further information about the authorized form.
Lilly
Eli Lilly and Company
LLT
lowest-level term
LOCF
last-observation-carried-forward
MDI
multiple daily injection
MedDRA
Medical Dictionary for Regulatory Activities


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69
MMRM
mixed model repeated measures
MRI
magnetic resonance imaging
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
PK/PD
pharmacokinetic(s)/pharmacodynamic(s)
PPG
postprandial glucose
PT
preferred term
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. 
SD
standard deviation
SGLT2
sodium glucose cotransporter 2
SoA
Schedule of Activities
TBL
total bilirubin level
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.
T1D
Type 1 diabetes
T2D
Type 2 diabetes
ULN
upper limit of normal
WOCBP
woman of childbearing potential


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70
11.
References
Anderson RT, Skovlund SE, Marrero D, et al. Development and validation of the insulin 
treatment satisfaction questionnaire. Clin Ther. 2004;26(4):565-578.
https://doi.org/10.1016/s0149-2918(04)90059-8
Bailey TS, Grunberger G, Bode BW, et al; American Association of Clinical Endocrinologists 
(AACE); American College of Endocrinology (ACE). American Association of Clinical 
Endocrinologists and American College of Endocrinology 2016 outpatient glucose monitoring 
consensus statement [published correction appears in Endocr Pract. 2016;22(4);516. 
https://doi.org/10.4158/1934-2403-22.4.516]. Endocr Pract. 2016;22(2):231-261.
https://doi.org/10.4158/EP151124.CS
Bartley PC, Bogoev M, Larsen J, Philotheou A. Long-term efficacy and safety of insulin detemir 
compared to Neutral Protamine Hagedorn insulin in patients with Type 1 diabetes using a 
treat-to-target basal-bolus regimen with insulin aspart at meals: a 2-year, randomized, 
controlled trial. Diabet Med. 2008;25(4):442-449. https://doi.org/10.1111/j.1464-
5491.2007.02407.x
Bergenstal RM, Johnson M, Powers MA, et al. Adjust to target in type 2 diabetes: comparison of 
a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine.
Diabetes Care. 2008;31(7):1305-1310. https://doi.org/10.2337/dc07-2137
Bolli GB, Kerr D, Thomas R, et al. Comparison of a multiple daily insulin injection regime 
(basal once-daily glargine plus mealtime lispro) and continuous subcutaneous insulin infusion 
(lispro) in type 1 diabetes: a randomized open parallel multicenter study [published correction 
appears in Diabetes Care. 2009;32(10):1944. https://doi.org/ 10.2337/dc09-er10]. Diabetes 
Care. 2009;32(7):1170-1176. https://doi.org/10.2337/dc08-1874
Edelman SV, Liu R, Johnson J, Glass LC. AUTONOMY: the first randomized trial comparing 
two patient-driven approaches to initiate and titrate prandial insulin lispro in type 2 diabetes. 
Diabetes Care. 2014;37(8):2132-2140. https://doi.org/10.2337/dc13-2664
Runge AS, Kennedy L, Brown AS, et al. Does time-in-range matter? Perspectives from people 
with diabetes on the success of current therapies and the drivers of improved outcomes. Clin 
Diabetes. 2018;36(2):112-119. https://doi.org/10.2337/cd17-0094
Tanenbaum ML, Hanes SJ, Miller KM, et al. Diabetes device use in adults with Type 1 diabetes: 
barriers to uptake and potential intervention targets. Diabetes Care. 2017;40(2):181-187. 
https://doi.org/10.2337/dc16-1536
Westfall PH and Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple testing 
procedures. J Stat Plan Inference. 2001;99(1):25-40. https://doi.org/10.1016/S0378-
3758(01)00077-5


Leo Document ID = 3705d4cb-e98e-4654-b936-57b20fe946ca
Approver:
Approval Date & Time: 12-Jul-2020 14:33:46 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 13-Jul-2020 15:43:53 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
 
 
Statistical A nal ysis Pla n: I 8 B -M C -I T S W ( Versi o n 1) 
 
 
A St u d y of L Y 9 0 0 0 1 4 i n Partici pa nts wit h T y pe 2 Dia betes usi n g 
C o nti n u o us Gl uc ose M o nit ori n g  
 
 
N C T 0 4 6 0 5 9 9 1  
 
 
A p pr o val Date: 2 7 -Oct -2 0 2 0  


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
P a g e 1
L Y 9 0 0 0 1 4
1.
St ati sti c al A n al y si s Pl a n:  
I 8 B-M C -I T S W: A St u d y  of L Y 9 0 0 0 1 4 i n P arti ci p a nt s wit h 
T y p e 2 Di a b et e s u si n g C o nti n u o u s Gl u c o s e M o nit ori n g
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d t h e i nf or m ati o n c o nt ai n e d 
wit hi n it m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e a p pr o v al of Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s.  
N ot e t o R e g ul at or y A ut h oriti e s:
T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.
Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e. 
I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
L Y 9 0 0 0 1 4
St u d y I 8 B -M C -I T S W (I T S W) i s a P h a s e 3 b, pr o s p e cti v e, o p e n-l a b el, o ut p ati e nt, m ulti c e nt er,
si n gl e -tr e at m e nt-gr o u p st u d y c o n d u ct e d i n p arti ci p a nt s wit h T 2 D c urr e ntl y tr e at e d wit h a 
b a s al b ol u s a n al o g M DI r e gi m e n.
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol I 8 B-M C -I T SW
P h a s e 3 b
St ati sti c al A n al y si s Pl a n el e ctr o ni c all y si g n e d a n d a p pr o v e d b y Lill y o n d at e pr o vi d e d 
b el o w.
A p pr o v al D at e: 2 7- O ct- 2 0 2 0 G M T


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T a bl e of C o nt e nt s
S e cti o n
P a g e
1.
Stati stical A nal ysis Pla n:   I 8 B -M C -I T S W:  A St u d y of L Y 9 0 0 0 1 4 i n 
P arti cip a nts wi t h T yp e 2 Di a betes usi n g C o nt i n u o us Gl uc ose 
M o ni t ori n g..........................................................................................................................1
2.
Ta ble of C o nte nts ................................................................................................................2
3.
Re visi o n Hist or y .................................................................................................................7
4.
St u d y  O bjecti ves.................................................................................................................8
5.
St u d y  Desi g n.....................................................................................................................1 1
5. 1.
O verall Desi g n .............................................................................................................1 1
5. 2.
S a m ple Si ze Deter mi nat i on ..........................................................................................1 1
6.
A Pri ori  St atistical Met h o ds ..............................................................................................1 3
6. 1.
P o p ul at i ons f or A nal yses..............................................................................................1 3
6. 2.
Ge neral C o nsi derati o ns ................................................................................................1 3
6. 3.
P atie nt Dis p ositio n .......................................................................................................1 5
6. 4.
P ati e nt C haracteristics..................................................................................................1 6
6. 5.
Treat me nt C o m plia nce ................................................................................................. 1 6
6. 6.
I mp orta nt Pr ot oc ol De viat i on .......................................................................................1 6
6. 7.
C o nc o mita nt T hera p y ...................................................................................................1 6
6. 8.
Efficac y A nal yses ........................................................................................................1 7
6. 8. 1.
Pri mar y E n d p o i nt................................................................................................. 1 7
6. 8. 2.
Gate d/ Ot her Sec o n dar y  E n d p oi nts........................................................................1 7
6. 8. 3.
A nal yses of E x pl orat or y  Efficac y a n d Health O utc o m es 
O bject i ves............................................................................................................1 7
6. 9.
S af et y A nal yses ............................................................................................................1 8
6. 9. 1.
E xte n t of E x p os ure...............................................................................................1 8
6. 9. 2.
A d verse E ve nts ....................................................................................................1 9
6. 9. 3.
H y p o gl yce mic E ve nts ..........................................................................................1 9
6. 9. 4.
I njecti on Si te Reactio n .........................................................................................1 9
6. 9. 5.
Vi t al Sig ns a n d Ot her P h ysical Fi n di n gs ...............................................................1 9
6. 9. 6.
P ati e nt Narrati ves ................................................................................................. 2 0
6. 1 0.
C o nti n u o us Gl uc ose M o nit ori n g A nal ysis ....................................................................2 0
6. 1 0. 1.
Ge neral C o nsi derati o ns ........................................................................................2 0
6. 1 0. 2.
C G M Varia ble a n d A nal ysis .................................................................................2 0
6. 1 0. 2. 1.
Tar get Gl uc ose Ra n ge .....................................................................................2 0
6. 1 0. 2. 2.
H y p o gl yce mia ................................................................................................2 1
6. 1 0. 2. 3.
H y per gl yce mia ...............................................................................................2 1


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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6. 1 0. 2. 5.
Mea n gl uc ose
................................................................................................. 2 1
6. 1 0. 2. 6.
i A U C a n d mea n p ost pra n dial se ns or gl uc ose e xc ursi o ns................................. 2 1
6. 1 0. 2. 7.
Hi g hest se ns or gl uc ose ...................................................................................2 1
6. 1 0. 2. 8.
Tar get C G M gl uc ose ......................................................................................2 2
6. 1 0 . 2. 9.
Ot her C G M varia bles ......................................................................................2 2
6. 1 1.
S u b gr o u p A nal yses .......................................................................................................2 2
6. 1 2.
I nteri m A nal yses ..........................................................................................................2 3
6. 1 3.
Data M o nit ori n g C o m mittee ( D M C) ............................................................................2 3
7.
Refere nces ........................................................................................................................2 4
8.
A p pe n dices .......................................................................................................................2 5


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T a bl e
P a g e
Ta ble I T S W . 4. 1. O bject i ves a n d E n d p oi nts ................................................................................8
Ta ble I T S W . 6. 1. Baseli ne a n d P ost -Baseli ne Defi nit i ons a n d Pat ient  P o p ulat i on b y 
T y pe of A nal ysis ............................................................................................1 4


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
P a g e 5
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T a bl e of C o nt e nt s
Fi g ur e
P a g e
Fi g ure I T S W. 5. 1. Ill ustratio n of  st u d y desi g n.............................................................................1 2


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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T a bl e of C o nt e nt s
A p p e n di x
P a g e
A p pe n di x 1.
Deri vat i on of C G M Varia bles ........................................................................2 6


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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3.
R e vi si o n Hi st or y
T his stati stical a nal ysis pla n ( S A P) is t he first versi o n a n d is base d o n t he pr ot oc ol of I 8 B-M C -
I T S W a p pr o ve d o n 2 1 A pril 2 0 2 0 a n d t he f oll o wi n g a me n d me nts (a) a p pr o ve d o n 1 3 J ul y 2 0 2 0 . 
T his S A P was a p pr o ve d pri or t o t he first patie nt visit .  


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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4.
St u d y  O bj e cti v e s
T a bl e I T S W . 4. 1.
O bj e cti v e s a n d E n d p oi nt s
O bjecti ves
E n d p oi nts
Pri mar y

T o e val uate ti me gl uc ose val ues fr o m 
c o nti n u o us gl uc ose m o nit ori n g ( C G M) are 
wit hi n tar get ra n ge ( 7 0 -1 8 0 m g/ d L [ 3. 9 -1 0. 0 
m m ol/ L]) d uri n g t he da yti me peri o d wit h 
L Y 9 0 0 0 1 4 treat me nt 

Perce nta ge of ti me wit h C G M gl uc ose 
val ues bet wee n 7 0 -1 8 0 m g/ d L 
( 3. 9-1 0. 0 m m ol/ L) ( b ot h i ncl usi ve) 
d uri n g da yti me peri o d w it h 1 4 da ys of 
C G M use at Wee k 1 2 c o m pare d wit h 
baseli ne
Gate d Sec o n dar y

T o e val uate H b A 1c

H b A 1c c ha n ge fr o m baseli ne t o Wee k 
1 2

T o e val uate ti me gl uc ose val ues fr o m C G M are 
wit hi n tar get ra n ge ( 7 0 -1 8 0 m g/ d L 
[ 3. 9-1 0. 0 m m ol/ L]) d uri n g t he 2 4 -h o ur peri o d 
wit h L Y 9 0 0 0 1 4 treat me nt

Perce nta ge of ti me wit h C G M gl uc ose 
val ues bet wee n 7 0 -1 8 0 m g/ d L 
( 3. 9-1 0. 0 m m ol/ L) ( b ot h i ncl usi ve) 
d uri n g t he 2 4 -h o ur peri o d wit h 1 4 da ys 
of C G M use at Wee k 1 2 c o m pare d 
wit h baseli ne
Ot her Sec o n dar y

T o e val uate ti me i n h y p o gl yce mic gl uc ose 
ra n ges, o btai ne d fr o m C G M use

Perce nta ge of ti me wit h C G M gl uc ose 
val ues < 5 4 m g/ d L ( < 3. 0 m m ol/ L) 
d uri n g da yti me a n d 2 4 -h o ur peri o ds 
wit h 1 4 da ys of C G M use at Wee k 1 2 
c o m pare d wit h baseli ne

T o e val uate ti me i n h y per gl yce mic gl uc ose 
ra n ges, o btai ne d fr o m C G M use

Perce nta ge of ti me wit h se ns or gl uc ose 
val ues > 1 8 0 m g/ d L ( > 1 0. 0 m m ol/ L) 
a n d > 2 5 0 m g/ d L ( > 1 3. 9 m m ol/ L), 
d uri n g da yti me a n d 2 4 -h o ur peri o ds 
wit h 1 4 da ys of C G M use at Wee k 1 2 
c o m pare d wit h baseli ne


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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
T o e val uate p ost pra n dial i ncr e me ntal A U Cs, 
o btai ne d fr o m C G M use

P ost pra n dial i ncre me ntal A U C 0 -1 h o ur
a n d i ncre me ntal A U C 0 -2 h o ur at Wee k 
1 2 c o m pare d wit h baseli ne

T o e val uate pr o p orti o n of partici pa nts ac hie vi n g 
H b A 1c tar gets

T he pr o p orti o n of partici pa nts wit h 
H b A 1c < 7 % a n d ≤6. 5 % a t Wee k 1 2

T o e val uate b ol us, basal , a n d t otal dail y i ns uli n 
d ose

B ol us, basal, a n d t otal i ns uli n d oses 
a n d b ol us/t otal i ns uli n rati o at Wee k 
1 2 c o m pare d wit h baseli ne

T o e val uate se vere h y p o gl yce mia 

I nci de nce of se vere h y p o gl yce mia 
e ve nts fr o m baseli ne t o Wee k 1 2

T o e val uate i ns uli n treat me nt satisfacti o n 
re gar di n g gl yce mic c o ntr ol as meas ure d b y t he 
I T S Q

C ha n ge fr o m baseli ne i n I T S Q 
gl yce mic c o ntr ol d o mai n sc ores at 
Wee k 1 2 
T e rtiar y/ E x pl orat or y

T o e val uate pr o p orti o n of partici pa nts ac hie vi n g 
C G M -base d gl yce mic tar gets

T he pr o p orti o n of partici pa nts wit h 
perce nta ge of ti me i n tar get C G M 
gl uc ose ra n ge ( 7 0 -1 8 0 m g/ d L [ 3. 9 -
1 0. 0 m m ol/ L]) > 7 0 %, ti me i n 
h y p o gl yce mia ( < 5 4 m g/ dl [ < 3. 0 
m m ol/ L]) < 1 %, a n d ti me i n 
h y per gl yce mia ( > 2 5 0 m g/ d L [ > 1 3. 9 
m m ol/ L]) < 5 % wit h 1 4 da ys of C G M 
use at Wee k 1 2

T o e val uate gl uc ose pr ofiles, o btai ne d fr o m 
C G M use

A vera ge gl uc ose f or a 2 4 -h o ur peri o d 
fr o m eac h 1 4-da y C G M sessi o n at 
Wee k 1 2 c o m pare d wit h baseli ne 

T o e val uate gl uc ose varia bilit y, o btai ne d fr o m 
C G M use

C V wit h 1 4 da ys of C G M use at Wee k 
1 2 c o m pare d wit h baseli ne

T o e val uate i ns uli n treat me nt satisfacti o n as 
meas ure d b y t he I T S Q

C ha n ge fr o m baseli ne i n I T S Q t otal 
a n d d o mai n sc ores (e xce pt gl yce mic 
c o ntr ol d o mai n) at Wee k 1 2


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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L Y 9 0 0 0 1 4

T o c haracterize partici pa nts’ willi n g ness t o 
i nc or p orate L Y 9 0 0 0 1 4 i nt o dia betes 
ma na ge me nt r o uti ne 

Distri b uti o n of res p o nses t o st u d y 
mea lti me i ns uli n e x perie nce q uesti o n 
at Wee k 1 2

T o e val uate attit u des t o war ds dia betes 
tec h n ol o g y use as meas ure d b y t he D S A T

C ha n ge fr o m baseli ne i n D S A T t otal 
sc ore at Wee k 1 2


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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5.
St u d y  D e si g n
5. 1.
O v er all D e si g n
St u d y  I T S W is a P hase 3 b, pr os pecti ve, o pe n-label, o ut patie nt, m ultice nter, si n gle -treat me nt -
gr o u p st u d y  c o n d ucte d i n pa rtici pa nt s wit h t ype 2 di a betes ( T 2 D ) c urre ntl y t reate d wit h a basal-
b o l us a nal o g m ult i ple d ose i nject i on ( M DI ) re gi me n. Partici pa nts will use u n bli n de d c o nti n u o us 
gl uc ose m o ni t ori n g (C G M ) ( Freest yle Li bre 1 4-d a y  s yst e m) for di a betes ma na ge me nt a n d 
gl uc ose data c ollect i on d uri n g t he st u d y . T he st u d y is desi g ne d t o e val uate t he ti me se ns or 
gl uc ose val ues fr o m  C G M are wit hi n tar get ra n ge ( 7 0-1 8 0 m g/ d L [ 3. 9 -1 0. 0 m m o l/L]) wi t h 1 2 
wee ks of L Y 9 0 0 0 1 4 treat me nt.
L Y 9 0 0 0 1 4 will be i njecte d i m me diatel y  ( 0-2 mi n utes) pri or t o eac h meal i n c o m bi nat i on wi t h 
i ns uli n glar gi ne U-1 0 0 ( Basa glar ®) as basal i ns uli n. Basal -b o l us i ns uli n d oses will be titrate d t o 
ac hie ve pr ot oc ol gl uc ose tar gets d uri n g t he st u d y.
5. 2.
S a m pl e Si z e D et er mi n ati o n
A p pr o xi matel y  1 6 7 partici pa nts will be assi g ne d t o treat me nt wit h L Y 9 0 0 0 1 4 s uc h t hat 1 5 0 
parti ci pa nts c o mplete t he st u d y  t hr o u g h t he pri mar y e nd p oi nt at Wee k 1 2. 
T he pri mar y  o bjecti ve of t his st u d y is t o e valuate t he c ha n ge of t i me gl uc ose val ues fr om C G M
are wit hi n tar get ra n ge ( 7 0-1 8 0 m g/ d L [ 3. 9 -1 0. 0 m m o l/ L]) d uri n g t he da ytime peri o d fr o m 
baseli ne t o e n d p oi nt at Wee k 1 2 wit h L Y 9 0 0 0 1 4 treat me nt.
T his sa m ple size has a p pr o xi matel y  8 0 % p o wer t o detect a n i ncrease of 4. 5 % ti me i n tar get ra n ge 
( 7 0-1 8 0 m g/ d L [ 3. 9-1 0. 0 m m o l/ L]) d uri n g t he da yti me perio d f r o m baseli ne, ass u mi n g n o tr ue 
differe nce i n ti me i n tar get ra n ge bet wee n baseli ne a n d e n d p o i nt, a n d a sta n dar d de viati o n ( S D) 
of  1 9. 5 %. Ass u mi n g a 1 0 % dr o p o ut rate f or 1 2 wee ks, a p pr o xi matel y 1 6 7 partici pa nts will nee d 
t o be assi g ne d.


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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Fi g ur e I T S W. 5. 1.
Ill u str ati o n of st u d y d e si g n.


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6.
A Pri ori St ati sti c al M et h o d s
6. 1.
P o p ul ati o n s f or A n al y s e s
T he f oll owi n g p o p ul at i ons are defi ne d:
P o p ul ati o n
Descri pti o n
E ntere d
All p arti ci pa nts w h o gi ve i nf or me d c o nse nt
E nr olle d
All partici pa nts w h o c o nti n ue t he st u d y  aft er Visit 2.
Treate d
All e nr olle d partici pa nts w h o recei ve at least 1 d ose of t he assi g ne d I P after Visit 4
A b bre viati o ns: I P = i n vesti gati o nal pr o d uct.
6. 2.
G e n er al C o n si d er ati o n s
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bilit y of  Lill y or its desig nee. A n y c ha n ge t o 
t he data a nal ysis met h o ds descri be d i n t he pr ot oc ol will re q uire a n a me n d me nt O N L Y if it 
c ha n ges a pri nci pal feat ure of t he pr ot oc ol. A n y ot her c ha n ge t o t he data a nal ysis met h o ds 
descri be d i n t he pr ot oc ol, a n d t he j ust ificati on f or ma ki n g t he c ha n ge, will be descri be d i n t he 
statistical a nal ysis pla n ( S A P) or t he cli nical st u d y re p ort ( C S R). A d diti o nal e x pl orat or y a nal yses 
of  data will be co n d ucte d as dee me d a p pr o priate.
Efficac y a nal yses will be c o n d ucte d o n t he treate d p o p ulat i on, i ncl u di n g data c ollecte d pri or t o 
p er m a ne nt disc o nt i n uati on of I P. W he n c ha n ge fr o m baseli ne is i ncl u de d as a res p o nse v ari a ble 
of a n alysis m o dels , t he parti ci pa nt will be i ncl u de d i n t he a nal ysis o nl y  if a baseli ne a n d a 
p ost baseli ne meas ure me nt are a vaila ble.
S af et y a nal yses will be c o n d ucte d o n t he treate d p o p ulat i on. A nal yses of a d verse e ve nts ( A Es )
a n d se ver e h y p o gl yce mia will i ncl u de data c ollecte d d uri n g t h e treat me nt perio d a n d baseli ne 
p eri o d . Ad ver se e ve nts d uri n g t he f oll ow- u p peri o d will be liste d. 
U nless ot her wise n ote d, all tests will be c o n d ucte d at a 2 -si de d al p ha le vel of 0. 0 5, a n d 
c o nfi de nce i nter vals ( Cis) will be calc ulate d at 9 5 %, 2 -side d. A g ate kee per met h o d ( West fall a n d 
Kr is he n 2 0 0 1) will be use d t o c o ntr ol t he o verall t ype 1 err or f or t he pri mar y  a n d gate d 
sec o n dar y o bjecti ves.
Baseli ne is defi ne d as t he last n o n missi n g meas ure me nt at or bef ore Visit 4 u nless ot her wise 
s pecifie d. 
A restricte d-ma xi m u m -li keli h o o d-base d, mi xe d m o del re peate d meas ures ( M M R M) a nal ysis will 
be use d t o a nal yze c o nti n u o us l o n git u di nal varia bles. All t he l o n git u di nal o bser vat i ons at eac h 
sc he d ule d p ost baseli ne visit will be i ncl u de d i n t he a nal ysis. T he m o d el f or t he a nal ysis of t he 
pri mar y  efficac y e n d p oi nt of c ha n ge fr o m baseli ne i n ti me i n tar get ra n ge ( 7 0-1 8 0 m g/ d L
[ 3. 9-1 0. 0 m m o l/L] ) d uri n g da yt i me peri o d will i ncl u de t he fi xe d class effect of visit , t he 
c o variat e of baseli ne, a n d t he ra n d o m effect of part ici pa nt. A n u nstr uct ure d c o varia nce str uct ure 
will be use d t o m o del t he wit hi n -part ici pa nt err ors. Si g nifica nce tests will be base d o n 
least-s q uares mea ns a n d T ype III tests. S A S ® P R O C MI X E D will be use d t o perf or m t he 


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
P a g e 1 4
L Y 9 0 0 0 1 4
a nal ysis. If t his a nal ysis fails t o co n ver ge, t he f oll o wi n g c o varia nce str uct ures will be teste d i n 
or der:

T oe plitz wit h heter o ge neit y

aut ore gressi ve wit h heter o ge neit y

co m p o u n d s y m metr y  wit h heter o ge ne o us varia nces

T oe plitz

aut ore gressi ve

co m p o u n d s y m metr y  wit ho ut heter o ge ne o us varia nces
T he first c o varia nce str uct ure t hat c o n ver ges will be use d. T he Ke n war d -R o ger a p pr o xi mat i on 
will be use d t o esti mate de n o mi nat or de grees of free d o m. 
A n a nal ysis o f c o varia nce ( A N C O V A) will als o be use d t o a nal yze c o nti n u o us varia bles 
c ollecte d o nl y at baseline a n d e n d p oi nt. T he m o del will i ncl u de baseli ne as a c o variate. U nless 
ot her wi se state d, missi n g e n d p oi nts will be i m p ute d usi n g t he last-o bser vat i on- carrie d-f or war d 
( L O C F) a p pr oac h, usi n g o nl y p ost baseli ne data.
F or c o nti n u o us meas ures, s u m mar y statist ics will i ncl u de sa m ple size, mea n, sta n dar d de viati on 
(S D ), me dia n, mi ni m u m, a n d ma xi m u m f or b ot h t he act ual a n d t he c ha n ge fr om baseli ne 
meas ure me nts. Least -s q uare mea ns a n d sta n dar d err ors deri ve d fr o m t he a nal ysis m o dels will 
als o be dis pla ye d f or t he c ha n ge fr o m baseli ne meas ure me nts.
F or cate g orical meas ures, s u m mar y  st atistics will i ncl u de sa m ple size, fre q ue nc y, a n d 
perce nta ges.
T a bl e I T S W. 6. 1.
B a s eli n e a n d P o st -B a s eli n e D efi niti o n s a n d P ati e nt P o p ul ati o n b y 
T y p e of A n al y si s
A n al ysis
P atie nt P o p ul ati o n
B aseli ne O bser v ati o ns
P ost -B aseli ne 
O bser v ati o ns
H b A 1c M M R M
All treate d patie nts wit h a 
baseli ne a n d at least o n e 
p ost -baseli ne o bser vati o n 
Last of Visits 1 - 4
Visits 7, 9, a n d 1 2 pr i or t o 
disc o nti n uati o n o f I P
H b A 1c cate g orical 
a nal ysis l o n git u di nal 
l o gistic re gressi o n
All treate d patie nts wit h a 
baseli ne a n d at least o n e 
p ost -baseli ne o bser vati o n
Last of Visits 1 - 4
Visits 7, 9, a n d 1 2 pr i or t o 
disc o nti n uati o n of I P
C G M o utc o mes
All treate d patie nts wit h a 
baseli ne a n d at least o n e 
p ost -baseli ne o bser vati o n
Visit 4
Visits 7 , 9 , a n d 1 2 pr i or t o 
disc o nti n uati o n of I P
Basal, b ol us, a n d t otal
i ns uli n d oses, a n d
b ol us/t otal i ns uli n d ose
All treate d patie nts wit h a 
baseli ne a n d at least o n e 
Visit 4
Visits 6, 7, 9, a n d 1 2 pr i or 
t o disc o nti n uati o n of I P


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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L Y 9 0 0 0 1 4
rati os c o nti n u o us a nal ysis
p ost -baseli ne o bser vati o n
Healt h o utc o mes:
I T S Q, D S A T
All treate d patie nts wit h a 
baseli ne a n d a p ost -
baseli ne o bser vati o n
Last of Visits 2- 4
Visit 1 2 pr i or t o 
disc o nti n uati o n of I P
Healt h o utc o me:
St u d y mealti me i ns uli n 
e x perie nce q uesti o n
All treate d patie nts wit h a
p ost -baseli ne o bser vati o n
N A
Visit 1 2 pr i or t o 
disc o nti n uati o n of I P
Wei g ht a n d vital si g ns
All treate d patie nts wit h a 
b aseli ne a n d at least o n e 
p ost -baseli ne o bser vati o n
Last of Visits 1 - 4
Visits 7, 9, a n d 1 2 pr i or t o 
disc o nti n uati o n of I P
Se vere H y p o gl yce mia 
e ve nts
All treate d patie nts
T he e ntire baseli ne peri o d
T he e ntire treat me nt 
peri o d
T E A Es
All treate d patie nts
Fr o m Visit 2 t o t he first 
d ose of assi g ne d I P
Fr o m first d ose of assi g ne d 
I P t o last d ose of assi g ne d 
I P
F oll o w u p peri o d
P ost pra n dial i ncre me ntal 
A U Cs
All treate d patie nts wit h a 
baseli ne a n d a p ost -
baseli ne o bser vati o n
Visit 4
Visit 1 2 pr i or t o 
disc o nti n uati o n of I P
6. 3.
P ati e nt Di s p o siti o n
P ati e nt dis p ositio n will be dis pla ye d i n a fl o wc hart s h o wi n g t he n u m ber of patie nts e ntere d,
e nr o lle d, treate d, a n d disc o nti n ue d acr oss all st u d y p erio ds.
Fre q ue nc y c o u nts a n d perce nta ges of all treate d patie nts c o m plet in g a n d disc o nt i n ui n g fr om t he 
st u d y will be prese nte d. Reas o ns f or disc o nt i n uati o n fr om t he st u d y a n d st u d y treat me nt will be 
s u m marize d.
Fre q ue nc y c o u nts a n d perce nta ges of all pat ient s e ntere d, e nr olle d, a n d disc o nt i n ue d fr om t he
st u d y d uri n g t he baseli ne perio d will  be s u m marize d. Reas o ns f or disc o nt i n uati on d uri n g
scree ni n g will be s u m marize d f or all e ntere d patie nts. Reas o ns f or disc o nt i n uati on d uri n g t he 
baseli ne peri o d will be s u m marize d f or all e nr olle d patie nts.
A listi n g of t he pri mar y reas o n f or treat me nt disc o nti n uati on (if a p plica ble) a n d st u d y 
di sc o nti n uati on will  be ge nerate d f or t he treate d p o p ulat i on.
P ati e nt all ocati o n b y in vest i gat or will be s u m marize d i n dicati n g t he n u m ber of patie nts w h o 
e nter t he st u d y,  t he n u m ber of patie nts w h o partici pate i n t he baseli ne peri o d, t he n u m ber of 


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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pati e nts treate d, a n d t he n u m ber of pat ient s w h o disc o nti n ue t he st u d y d uri n g t he 1 2-Wee k 
treat me nt perio d.
6. 4.
P ati e nt C h ar a ct eri sti c s
A s u m mar y  ta ble will be ge nerate d f or patie nt a n d dia betes c haracterist ics at st u d y e ntr y usi n g all
treate d patie nts. T he f o ll owi n g varia bles will be i ncl u de d b ut n ot li mite d t o: a ge, a ge gr o u ps 
( < 6 5, ≥6 5 y ears), se x, et h nicit y,  race, hei g ht, weig ht, b o d y  mass i n de x ( B MI), B MI gr o u p ( < 2 5, 
≥2 5 t o < 3 0, ≥3 0 t o < 3 5, ≥3 5 k g/ m 2), d urati o n of dia betes, partici pa nt’s pri or C G M use, Use of 
S G L T 2, Use of i njecta ble G L P -1, pra n dial d osi n g pl a n (car b o h y drate c o u nti n g/fi xe d d ose), 
H b A 1c at st u d y  e ntr y a n d baseli ne.
F or c o nti n u o us varia bles, t he f o ll owi n g st atistics will be pr o vid e d: m ea n, S D, mi ni m u m,
ma xi m u m, a n d me dia n. F or cate g orical varia bles, s u m mar y statist ics will i ncl u de sa m ple size,
fre q ue nc y a nd perce nta ge. A list i n g of patient  c haracteristics at st u d y e ntr y will be pr o vide d.
F or all treate d patie nt s, t he n u m ber a n d perce nta ge of pat ient s wit h pree xisti n g c o n diti ons will 
als o be s u m marize d usi n g Me dical Dict i onar y  for Re g ulat or y  Act i vities ( Me d D R A) preferre d 
t er m ( P T) neste d wit hi n s yste m or ga n class ( S O C). P ree xisti n g c o n diti ons are c o n dit i ons t ha t are 
still o n g oi n g at i nf or m c o nse nt. E ve nts will be or dere d b y decreasi n g fre q ue nc y.
6. 5.
Tr e at m e nt C o m pli a n c e
N o a nal ysis f or treat me nt c o m plia nce is pla n ne d f or t his st u d y .
6. 6.
I m p ort a nt Pr ot o c ol D e vi ati o n
I mp orta nt pr ot oc ol de viat i ons (I P D) t hat p ote n tiall y co m pr o mise data i nte grit y or pati e nts’ safet y
will be s u m marize d f or all treate d patie nts. T he listi n g of i m p orta nt pr ot oc ol de viat i ons f or all 
treate d patie nts d uri n g t he e nt ire st u d y will be pr o vi de d i n t he C S R. T he I P Ds i de ntifie d b y sit e 
m o nit ori n g a n d cli nical data base will be i nte grate d i n t he list i n g. If t he I P D is i de ntifie d b y b ot h 
met h o ds, o nl y t he site m o nit ori n g I P D will be prese nte d.
6. 7.
C o n c o mit a nt T h er a p y
C o nc o mita nt me dicat i on will be s u m marize d f or t he treate d po p ul at i on d uri n g t he treat me nt 
per i ods ( 0 t o 1 2 wee ks). T he perce nta ges of patie nts recei vi n g eac h c o nc o mit a nt me dicat i on will 
be s u m marize d usi n g P T neste d wit hi n A nat o mical T hera pe utic C he mical ( A T C) Le vel 3 c o de.
Me dicat i ons will be or dere d b y  decreasi n g fre q ue nc y wit hi n A T C le vel. C o nc o m ita nt me d icatio n 
use d d uri n g t he baseli ne p eri o d will  als o be s u m marize d f or t he enr o lle d p o p ul at i on.
T he dail y basal d ose, dail y b o l us d ose, t otal i ns uli n d ose, a n d t he rati o of b ol us d ose t o t otal
i ns uli n d ose d uri n g t he baseli ne p eri o d will  be s u m marize d. T he d oses a n d b o l us/t otal ins uli n 
d ose rati os f or eac h visit will be calc ulate d as t he mea n of t he d oses f or t he last 3 da ys prior t o 
t he visit date t hat are e ntere d i n t he electr o nic case re p ort f or m ( e C R F). D oses will be 
s u m marize d i n U a n d U/ k g.


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6. 8.
Effi c a c y A n al y s e s
6. 8. 1.
Pri m ar y E n d p oi nt
T he pri mar y  efficac y c o mparis o n will  be base d o n t he M M R M a nal ysis of c ha n ge fr o m baseli ne 
i n ti me i n tar get ra n ge ( 7 0-1 8 0 m g/ d L [ 3. 9-1 0. 0 m m o l/ L]) d uri n g da y time peri o d i ncl u di n g data 
c ollecte d pri or t o per ma ne nt disc o nt i n uati on of I P. T he a nal ysis m o del a n d select i on of 
c o varia nce str uct ure is descri be d i n Sect i on 6. 2 .
6. 8. 2.
G at e d/ Ot h er S e c o n d ar y E n d p o i nt s
T he a nal ysis of t he sec o n dar y  gate d o bjecti ves will be c o n d ucte d if t he t i me i n tar get ra n ge 
( 7 0-1 8 0 m g/ d L [ 3. 9 -1 0. 0 m m o l/ L]) d uri n g t he da yti me perio d at st u d y  e n d p oi nt vers us baseli ne 
is f ou n d statist icall y si g nifica nt f or t he pri mar y efficac y a nal ysis at a 2-si de d 0. 0 5 si g nifica nce 
le vel ( Westfall a n d Kris he n 2 0 0 1). If t his c o ntrast is si g nifica nt, t he sec o n dar y o bjecti ves were 
teste d i n se q ue nce u ntil t he first n ull h y p ot hesis i n t he se q ue nce faile d t o be rejecte d at a 2-side d 
0. 0 5 si g nifica nce le vel. T he se q ue ntial testi n g f or gate d sec o n dar y o bjecti ves is c o n d ucte d i n t he 
f oll owi n g or der t o assess w het her val ue at st u d y e n d p oi nt is s u peri or t o baseli ne: 
1.
T o e val uate H b A 1c
2.
T o e val uate ti me gl uc ose val ues fr o m C G M are wit hi n tar get ra n ge ( 7 0 - 1 8 0 m g/ d L 
[ 3. 9-1 0. 0 m m o l/L]) d uri n g t he 2 4- h o ur peri o d.
F or c o nti n u o us l o n git u di nal sec o n dar y  e n d p oi nts, t he M M R M m o del si milar t o t hat f or t he 
pri mar y  a nal ysis will be use d. D urati o n a n d perce nt ti me i n ra n ge, ti me i n h y p o gl yce mia, a n d 
ti me i n h y per gl yce mia deri ve d fr o m C G M data will als o be a nal yze d usi n g a n M M R M m o d el . 
Details f or t he C G M a nal yses ca n be f o u n d i n Secti o n  6. 1 0 .
C o nti n u o us n o nl o n git u di nal sec o n dar y e n d p oi nts will be a nal yze d usi n g t he A N C O V A . 
P os t pra n dial incre me ntal  area u n der t he c ur ve (A U C) 0- 1 h o ur a n d i ncre me ntal A U C 0- 2 h o ur will be 
a nal yze d b y A N C O V A descri be d i n Secti o n 6. 2 .
Pr o p orti o n of  parti ci pa nt s wit h H b A 1c < 7. 0 % a n d ≤6. 5 % will be a nal yze d usi n g a l o n git u di nal 
l ogist ic re gressi on wi t h re peate d meas ure me nts c o n d ucte d b y a ge neralize d li near mi xe d m o del
wi t h the fi xe d class effect of visit, t he c o variat e of baseli ne H b A 1c, a n d t he ra n d o m effect of 
parti ci pa nt . 
Act ual  a n d c ha n ge fr o m baseli ne i n basal, b ol us, a n d t otal d ose, as well as t he b olus/t otal  ins uli n 
d ose rati o will be a nal yze d b y t he M M R M m o dels descr i be d i n Secti o n 6. 2 .
6. 8. 3.
A n al y s e s of E x pl or at or y Effi c a c y a n d H e alt h O ut c o m e s 
O bj e cti v e s
P r o p ortio n of  patie nts w h o ha ve ac hie ve d t he bel o w rec o m me n de d i n di vi d ual a n d c o mp osi t e 
C G M tar gets ( Batteli n o 2 0 1 9) of  gl yce mic c o ntr ol at Visit 1 2 ( 1 0 - 1 2 wee ks) will be 
s u m marize d:
perce nta ge of ti me i n tar get C G M gl uc ose ra n ge ( 7 0- 1 8 0 m g/ d L [ 3. 9 -1 0. 0 m m o l/L]) > 7 0 %


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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perce nta ge of ti me i n h y p o gl yce mia ( < 5 4 m g/ d L [ < 3. 0 m m ol/ L]) < 1 %
perce nta ge of ti me i n h y per gl yce mia ( > 2 5 0 m g/ d L [ > 1 3. 9 m m ol/ L]) < 5 %
I n a d diti on, pr o p orti o n of pat ient s w h o ha ve ac hie ve d t he bel o w rec o m me n de d i n di vi d ual C G M 
tar gets of gl yce mic c o ntr ol at Visit 1 2 ( 1 0 - 1 2 wee ks) will be s u m marize d :
perce nt a ge of ti me i n h y p o gl yce mia ( < 7 0 m g/ d L [ < 3. 0 m m ol/ L]) <4 %
perce nta ge of ti me i n h y per gl yce mia ( > 1 8 0 m g/ d L [ > 1 3. 9 m m o l/ L]) < 2 5 %
A vera ge gl uc ose f or a 2 4 -h o ur peri o d fr o m eac h 1 4-d a y  C G M sessi on at Visit 1 2 ( 1 0 - 1 2 wee ks)
a n d baseli ne (- 2- 0 wee ks) will be a nal yze d b y AN C O V A descri be d i n Sect i on 6. 2 .
Wit hi n -d a y  a n d bet wee n-da y gl yce mic varia bilit y meas ure d b y t he S D a n d t he c oefficie nt of
variat i on ( C V ) of C G M data will als o be a nal yze d b y t he A N C O V A m o d el  s pecifie d i n Secti on 
6. 2 . Details f or t he gl yce mic varia bility deri vati o n ca n be f o u n d i n A p pe n di x 1 .
I n a d diti on, C G M o utc o mes t hat are n ot i ncl u de d i n t he pri mar y  or sec o n dar y efficac y e n d p oi nts 
will be a nal yze d as e x pl orat or y efficac y en d p o i nts. Details f or t he C G M a nal yses ca n be f o u n d i n
Secti o n 6. 1 0 .
F or t he I T S Q, t he c ha n ge fr o m baseli ne t o L O C F e n d p o i nt w hile o n treat me nt i n each d o m ai n 
tra nsf or me d sc ore (i nc o n ve nie nce, lifestyle, h y p o gl yce mic c o ntr ol, gl yce mic c o ntr ol, a n d 
deli ver y  s yst e m) a n d o verall tra nsf or me d sc ore will be a nal yze d usi n g A N C O V A .
F or t he D S A T, t he c ha n ge fr o m baseli ne t o L O C F e n d p o i nt, w hile o n treat me nt , i n eac h ite m a n d 
a t otal sc ore will be a nal yze d usi n g A N C O V A .
S u m mar y  statistics, i ncl u di n g n u m ber of partici pa nts a n d pr o p orti o n of  a cate g orical o utc o me
( 5 levels) f or t he st u d y mealti me i ns uli n e x perie nce q uestio n will be pr o vi de d.
6. 9.
S af et y A n al y s e s
S af et y meas ures will i ncl u de A Es, se vere h y p o gl yce mia, vital si g ns a n d wei g ht, a n d treat me nt
e x p os ure.
C o nti n u o us safet y  varia bles, as well as t he c ha n ge fr o m baseli ne f or t hese varia bles, will be
a nal yze d eit her b y M M R M or A N C O V A m o dels. Cate g orical varia bles wi ll be s u m marize d 
u nless ot her wise s pecifie d.
6. 9. 1.
E xt e nt of E x p o s ur e
D urati o n of  e x p os ure t o st u d y dr u g will be s u m marize d base d u p o n e C R F data. T he f oll o wi n g
s u m mar y statistics will be pr o vi de d: n, mea n, S D, me dia n, mi ni m u m, ma xi m u m, a n d s u m (t hat
is, t otal patie nt -years of e x p os ure). T he n u m ber a n d pr o p orti o n of patie nts falli n g i nt o t he
f oll owi n g differe nt e x p os ure cate g ories will als o be s u m marize d: < 4 wee ks ( > 0 a n d < 2 8 da ys),
≥4 a n d < 8 wee ks ( ≥2 8 a n d < 5 6 da ys), ≥8 a n d < 1 2 wee ks ( ≥5 6 a n d < 8 4 da ys ) a n d ≥1 2 we e ks 
( ≥8 4 d a y s).


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P ati e nts w h o c o mplete t he st u d y  treat me nt perio d are re q uire d t o c o m plete a safet y f oll ow- u p
visit wit h o ut st u d y  dr u g. T he da ys o n st u d y after disc o nti n ui n g I P, a n d t he da ys o n st u d y  fr o m 
date of first st u d y  dr u g t o t he last st u d y visit date u p t o Visit 8 0 1 will als o be s u m marize d.
6. 9. 2.
A d v er s e E v e nt s
E ve nts t hat are ne wl y  re p orte d after t he first d ose of I P or are re p orte d t o w orse n i n se verity fr o m 
baseli ne will be c o nsi dere d treat me nt -e mer ge nt a d verse e ve nts ( T E A Es ). T he Me dical 
Di ct i onar y  for Re g ulat or y  Act i vities ( Me d D R A) l o west-lev el  t er m ( L L T) will be use d i n t he 
treat me nt -e mer ge nt assess me nt. T he ma xi m u m se verit y f or eac h L L T d uri n g t he baseli ne peri o d 
will be use d as baseli ne se verit y.
S erio us a d verse e ve nt s ( S A Es), A Es re p orte d as reas o n f or disc o nti n uati on fr om t he I P or st u d y, 
a n d T E A Es will be s u m marize d i n ta bles usi n g t he Me d D R A P T, s orte d b y  decreasi n g 
fre q ue nc y. Treat m e nt -e mer ge nt a d verse e ve nts will als o be s u m marize d b y  P T s orte d b y 
decreasi n g fre q ue nc y wi t hi n S O C f or all T E A Es a n d b y ma xi m u m se verity.  F or e ve nts t hat are 
s pecific t o o nl y 1 se x, t he de n o mi nat or a n d c o m p utati o n of t he perce nta ge will i ncl u de o nl y 
parti ci pa nt s fr om t he gi ve n se x. T he n u m ber a n d pr o p orti o n of parti ci pa nt s wit h at least 1 e ve nt
f or eac h ty pe of e ve nt will be s u m marize d.
6. 9. 3.
H y p o gl y c e mi c E v e nt s
O nl y se vere h y p o gl yce mia will be c ollecte d as A Es a n d all e pis o des of se vere h y p o gl yce mia will 
be c o nsi dere d as S A Es. Se vere h y p o gl yce mia rates a n d i nci de nce d uri n g t he treat me nt perio d
( Visits 4- 1 2) will be s u m marize d.
A listi n g of patie nts wit h at least 1 se vere h y p o gl yce mia re p orte d (as S A E) after Visit 4
(incl u di n g Visit 8 0 1) will be pr o vi de d.
A list of Me d D R A P Ts will be use d f or t he narr o w searc h of p ote ntial se vere h y p o gl yce mia i n
s p o ntane o usl y re p orte d A Es. T he e ve nts i de ntifie d t hr o u g h t he searc h strate g y t hat are als o
re p orte d as S A Es will be s u m marize d. 
6. 9. 4.
I nj e cti o n Sit e R e a cti o n
Inject i on site reacti o ns will be searc he d b y Me d D R A P Ts fr o m t he s p o nta ne o us A E re p orti n g of  
p ote nti al i njectio n si t e r e a ctio ns . T he n u m ber a n d perce nta ge of patie nts e x perie nci n g treat me nt -
e mer ge nt i njectio n si t e r e a ctio n A Es will  be s u m marize d.
6. 9. 5.
Vit al Si g n s a n d Ot h er P h y si c al Fi n di n g s
P os t-baseli ne meas ure me nts a n d c ha n ge fr o m baseli ne t o p ost -baseli ne f or vit al si g ns a n d
p h ysical c haracteristics (s yst olic bl o o d press ure [ S B P], diast olic bl o o d press ure [ D B P], p ulse
rate, wei g ht, B MI) at t he sc he d ule d visits will be s u m marize d f or patie nts w h o ha ve b ot h
baseli ne a n d at least 1 p ost -baseli ne res ult.
T he m eas ur e me nts d uri n g t he treat me nt peri o d ( 0 t o 1 2 wee ks) will be a nal yze d b y a n M M R M
m o d el  wit h baseli ne val ue o f t he res p o nse varia ble, visit as fi xe d fact ors a n d patie nt as t he 
ra n d om fact or.


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6. 9. 6.
P ati e nt N arr ati v e s
P ati e nt narrati ves will be pr o vi de d f or all p ati e nts i n t he st u d y w h o e x perie nce a n y of t he
f oll owi n g “n ota bl e” e ve nts:

deat hs

S A Es

di sc o nti n uati ons fr o m  st u d y ( or st u d y dr u g) d ue t o A Es

pre g na nc y
A list of patie nts w h o meet t he criteria f or narrati ves will be pr o vi de d.
6. 1 0. C o nti n u o u s Gl u c o s e M o nit ori n g A n al y si s
6. 1 0. 1. G e n er al C o n si d er ati o n s
T he a nal yses descri be d i n t his sect i on will i ncl u de data c ollecte d d uri n g t he e nt ire baseli ne 
p eri o d a n d treat m e nt perio d . Perce nta ge a n d d urati o n i n tar get ra n ge, h yp o gl yce mia, 
h y per gl yce mia will be a nal yze d f or baseli ne ( Wee k -2- 0) , Visit 7 ( Wee k 2- 4 ), Visit 9 ( Wee k 6 -
8), a n d Visit 1 2 ( Wee k 10- 1 2 ). Ot her C G M varia bles will be a nal yze d f or baseli ne ( Wee k -2- 0) 
a n d Visit 1 2 ( Wee k 1 0 -1 2).
T o e ns ure t hat t he C G M o utc o me varia bles are o nl y calc ulate d fr o m C G M sessi o n da ys wit h
s ufficie nt data wit hi n t he 2 4-h o ur, da y time ( 0 6 0 0 h o urs t o mi d ni g ht), or ni g htti me ( mi d ni g ht t o
0 6 0 0 h o urs) peri o ds, t he f o ll owi n g cri t erio n will be use d t o deter mi ne a vali d C G M sessi o n da y
t o be c o u nte d i nt o t he calc ulati on f or a visit: mi ni m u m nu m ber of  meas ures per da y – at least
7 0 % of t he t otal meas ures t hat are s u p p ose d t o be o btai ne d (i.e., 7 0 % of t he 9 6 meas ures) f or t he 
2 4- h o ur peri o d.
6. 1 0. 2. C G M V ari a bl e a n d A n al y si s
T he m eal t i me will be c ollecte d i n t he data base b y e C R F. All c o nti n u o us varia bles will be 
a nal yze d usi n g t he M M R M or A N C O V A defi ne d i n Secti o n 6. 2 . L S me a n of  t he differe nce 
bet wee n baseli ne ( Wee k -2- 0) a n d Visit 1 2 ( Wee k 1 0-1 2) will be prese nte d.
S u m mar y  statistics will i ncl u de t he n u m ber of o bser vati ons, m ea n, me dia n, ma xi m u m, 
mi ni m u m, a n d S D f or all c o nt i n u o us meas ures.  F or cate g orical meas ures, t he n u m ber of 
o bser vat i ons, pr o p orti o n, a n d fre q ue ncies will be i ncl u de d i n s u m mar y sta tistics.  All a nal yses 
will be perf or me d f or data c ollecte d b y  visit.  
Defi nit i on o f t he deri ve d varia bles is i n A p pe n di x 1 . 
6. 1 0. 2. 1. T ar g et Gl u c o s e R a n g e
Perce nta ge a n d D urati o n (i n mi n utes) of ti me per da y  gl uc ose val ues are wit hi n tar get 
ra n ge ( defi ne d as bet wee n 70 m g/ d L a n d 1 8 0 m g/ d L [ 3. 9 a n d 1 0. 0 m m o l/ L]) i ncl usi ve 
d uri n g t he da ytime peri o d, ni g htti me peri o d a n d 2 4 -h o ur peri o d.  
Perce nta ge a n d D urati o n (i n mi n utes) of ti me per da y  gl uc ose val ues are wit hi n tar get 
ra n ge ( defi ne d as bet wee n 70 m g/ d L a n d 1 4 0 m g/ d L [ 3. 9 a n d 7. 7 m m o l/ L]) i ncl usi ve 
d uri n g t he da ytime peri o d, ni g htti me peri o d a n d 2 4 -h o ur peri o d.  


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6. 1 0. 2. 2. H y p o gl y c e mi a 
Perce nta g e a n d D urati o n (i n mi n utes) of ti me per da y w here gluc ose val ues are wit hi n a 
h y p o gl yce mic ra n ge ( defi ne d as < 5 4 m g/ d L [ 3. 0 m m o l/ L]) d uri n g t he d a y time peri o d,
ni g htti me p eri o d a n d 2 4-h o ur peri o d .
Perce nta ge a n d D urati o n (i n mi n utes) of ti me per da y  w here gl uc ose val ues are wit hi n a 
h y p o gl yce mic ra n ge ( defi ne d as < 7 0 m g/ d L [ 3. 9 m m o l/ L]) d uri n g d a y time p eri o d , 
ni g htti me p eri o d a n d 2 4 h o ur peri o d .  
Perce nta ge a n d D urati o n (i n mi n utes) of ti me per da y  w here gluc ose val ues are wit hi n a 
h y p o gl yce mic ra n ge ( defi n e d as > = 5 4 m g/ d L [ 3. 0 m m o l/ L] a n d < 7 0 m g/ d L [ 3. 9 m m o l/ L]) 
d uri n g t he d a y time peri o d, ni g htti me p eri o d a n d 2 4 -h o ur peri o d .
6. 1 0. 2. 3. H y p er gl y c e mi a
Perce nta ge a n d D urati o n (i n mi n utes) of ti me per da y  gl uc ose val ues are wit hi n a 
h y per gl yce mic ra n ge ( defi ne d as > 1 8 0 m g/ d L [ 1 0. 0 m m o l/ L] d uri n g d a y ti me, ni g htti me 
a n d 2 4- h o ur peri o d .
Perce nta ge a n d D urati o n (i n mi n utes) of ti me per da y  gl uc ose val ues are wit hi n a 
h y per gl yce mic ra n ge ( defi ne d as > 1 8 0 m g/ d L [ 1 0. 0 m m o l/ L] a n d < = 2 5 0 m g/ d L [1 3. 8
m m o l/ L]) d uri n g d a y ti me, ni g htti me a n d 2 4- h o ur peri o d .
Perce nta ge a n d D urati o n (i n mi n utes) of ti me per da y  gl uc ose val ues are wit hi n a 
h y per gl yce mic ra n ge ( defi ne d as > 2 5 0 m g/ d L [ 1 3. 8 m m o l/ L]) d uri n g d a y time, ni g htti me 
a n d 2 4- h o ur peri o d.
Perce nta ge a n d D urati o n (i n mi n utes) of ti me per da y  gl uc ose val ues are wit hi n a 
h y per gl yce mic ra n ge ( defi ne d as > 3 0 0 m g/ d L [ 1 6. 5 m m o l/ L]) d uri n g d a y time, ni g htti me 
a n d 2 4- h o ur peri o d.
6. 1 0. 2. 4. Gl y c e mi c V ari a bilit y
Wit hi n -d a y  a n d bet wee n-da y gl uc ose c oeffic ie nt of variati on d uri n g 2 4 -h o ur peri o d.
Wit hi n -d a y  a n d bet wee n-da y gl uc ose sta n dar d de viati on d uri n g a 2 4 -h o ur peri o d.
O verall gl uc ose varia bilit y
6. 1 0. 2. 5. M e a n gl u c o s e 
Mea n gl uc ose val ue ( m g/ dl) d uri n g a 2 4-h o ur peri o d 
6. 1 0. 2. 6. i A U C a n d m e a n p o st pr a n di al s e n s or gl u c o s e e x c ur si o n s
i A U C a n d mea n p ost pra n dial se ns or gl uc ose e xc ursi o ns:

0 t o 1 h o ur, 0 t o 2 h o urs, 0 t o 3 h o urs, 0 t o 4 h o urs r elat i ve t o meal starti n g ti me at t he 
treat me nt le v el, e xcl u di n g data c o llecte d after t he ne xt meal e ve nt

0 t o 1 h o ur, 0 t o 2 h o urs, 0 t o 3 h o urs, 0 t o 4 h o urs relat i ve t o meal starti n g ti me b y meal 
( brea kfast, l u nc h, a n d di n ner) at t he treat me nt le vel, e xcl u di n g data c ollecte d after t he 
ne xt meal e ve nt
6. 1 0. 2. 7. Hi g h e st s e n s or gl u c o s e
Hi g hest se ns or gl uc ose after meals:


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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
0- 4 h o urs relati ve t o meal starti n g ti me at t he treat me nt le vel, e xcl u di n g data
c ollecte d after t he ne xt meal e ve nt

0 -4 h o urs relati ve t o meal starti n g ti me b y meal ( brea kfast, l u nc h a n d di n ner) at t he 
treat me nt le v el, e xcl u di n g data c ollecte d after t he ne xt meal e ve nt
6. 1 0. 2. 8. T ar g et C G M gl u c o s e 
T he pr o p orti o n of  p artici pa nts wit h perce nta ge of ti me i n tar get C G M gl uc ose ra n ge ( 7 0-
1 8 0 m g/ d L [ 3. 9 a n d 1 0. 0 m m ol/L] )> 7 0 %
T he pr o p orti o n of  p artici pa nts wit h perce nta ge of ti me i n h y p o gl yce mia ( < 5 4 m g/ dl [ 3. 0 
m m o l/ L])< 1 %

T he pr o p orti o n of partici pa nts wi t h perce nta ge of ti me i n h y per gl yce mia ( > 2 5 0 m g/ d L 
[1 3. 8 m m o l/L] )< 5 % 
T he pr o p orti o n of  p artici pa nts wit h perce nta ge of ti me i n h y p o gl yce mia ( <7 0 m g/ dl [ 3.9
m m o l/ L])< 4 %

T he pr o p orti o n of partici pa nts wit h perce nta ge of ti me i n h y per gl yce mia ( > 1 8 0 m g/ d L 
[ 10 . 0 m m o l/L] ) < 25 % 
6. 1 0. 2. 9. Ot h er C G M v ari a bl e s
T he f oll owi n g sta n dar dize d gl uc ose s u m mar y  fi g ures fr o m t he a m b ulat or y gluc ose pr ofile ( A G P) 
will be ge nerate d, base d u p o n t he o bser ve d C G M data at baseli ne ( wee k - 2- 0) a n d Visit 12 ( Wee k 
1 0- 1 2 ):

2 4- h o ur peri o d at i n di vi d ual patient  le v el

2 4- h o ur peri o d at t he treat me nt le vel
Base d u p o n t he o bser ve d C G M data a n d patie nts d ose ti me fr o m st u d y diar y at baseli ne( wee k -2-
0) a n d Vi sit 1 2 ( Wee k 1 0-1 2):

0- 4 h o urs relati ve t o meal starti n g ti me at t he treat me nt le vel, e xcl u di n g data
c ollecte d after t he ne xt meal e ve nt

0- 4 h o urs relati ve t o meal starti n g ti me b y meal ( brea kfast, l u nc h a n d di n ner) at t he 
treat me nt le v el, e xcl u di n g data c ollecte d after t he ne xt meal e ve nt
I n a d diti on, p os t pra n dial h y p o gl yce mia d uri n g t he f oll owi n g t i me i nter val after eac h meal a n d 
o verall will als o be deri ve d:  

0 t o 1 h o ur, 0 t o 2 h o urs, 2 t o 4 h o urs, 0 t o 4 h o urs r elat i ve t o meal starti n g ti me at t he 
treat me nt le v el, e xcl u di n g data c o llecte d after t he ne xt meal e ve nt

0 t o 1 h o ur, 0 t o 2 h o urs, 2 t o 4 h o urs, 0 t o 4 h o urs relat i ve t o meal starti n g ti me b y meal 
( brea kfast, l u nc h, a n d di n ner) at t he treat me nt le vel, e xcl u di n g data c ollecte d after t he 
ne xt meal e ve nt
6. 1 1. S u b gr o u p A n al y s e s
T he f o ll owi n g s u b gr o u ps will be a nal yze d usi n g data c ollec te d prior t o per m a ne nt 
di sc o nti n uati on of I P t o e val uate c o nsiste nc y o f res ults o n t he pri mar y efficac y meas ure if t here 
are s ufficie nt n u m bers of parti ci pa nt s b y s u b gr o u p (f or e xa m ple, 1 0 %):

age ( 6 5 years, 6 5 y ears)


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
baseli ne H b A 1c ( ≤8%, > 8 %)

parti ci pa nt ’s pri or pers o nal C G M use ( yes/ no)

parti ci pa nt’s S G L T 2 use ( yes/ n o)

parti ci pa nt ’s i njecta ble G L P-1 use ( yes/ n o)

pra n dial d osi n g pla n (car b o h y drate c o u nti n g, fi xe d d ose) 

se x ( m ale or fe male)

B MI ( < 3 0 , ≥3 0; < 3 5, ≥3 5 k g/ m 2)

d urati o n of d iabetes ( usi n g t he me dia n as t he c ut off )

race

et hnicit y
A nal yses f or pri mar y efficac y meas ure will  be perf or me d usi n g a n M M R M m o del t hat i ncl u des 
t he sa me fi xe d effect a n d c o variate gi ve n f or t he pri mar y a nal ysis m o del pl us fact ors of s u b gr o u p 
a n d 2-w a y  int eract i on of  s u b gr o u p a n d visit. T he effect of  s u b gr o u p at t he pri mar y e n d p oi nt 
( Wee k 12 ) will be e val uate d t o assess s u b gr o u p effect.
A d dit i onal s u b gr o u p a nal yses ma y als o be perf or me d.
6. 1 2. I nt eri m A n al y s e s
N o i nt eri m a nal yses are pla n ne d f or t his st u d y. If a n u n pla n ne d i nteri m a nal ysis is dee me d 
necessar y  for reas o ns ot her t ha n a safet y c o ncer n, t he pr ot oc ol m ust be a me n de d.
6. 1 3.
D at a M o nit ori n g C o m mitt e e ( D M C)
N o D M C is pla n ne d f or t his st u d y.


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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7.
R ef er e n c e s 
Batteli n o T, Da n ne T, Ber ge nstal R M, A miel S A, Bec k R, Bies ter T, et al. Cli nical tar gets f or
c o nti n u o us gl uc ose m o nit ori n g data i nter pretati o n: Rec o m me n dat i ons fr om t he I nter nati o nal
C o nse ns us o n Ti me i n Ra n ge. Di a betes C are . 2 0 1 9; pii: dci 1 9 0 0 2 8.
Cl ar ke W, K o vatc he v B. Statist ical t o ols t o a nal yze c o nti n u o us gl ucos e m o ni t or data. Di a betes
Tec h n ol T her . 2 0 0 9; 1 1( S u p pl 1): S - 4 5 – S- 5 4. d oi: 1 0. 1 0 8 9/ dia. 2 0 0 8. 0 1 3 8 .
Hi rsc h I B. Gl yce mic varia bility: It’s n ot j ust a b o ut A 1c a n y m ore ! Di a betes Tec h n ol T her.
2 0 0 5; 7( 5): 7 8 0 -7 8 3.
R o d bar d D. I nter pretati o n of c o nti n u o us gl uc ose m o nit ori n g data: gl yce mic varia bilit y a n d
q ualit y of  gl yce mic c o ntr ol. Di a betes Tec h n ol T her . 2 0 0 9; 1 1(s u p pl 1): S 5 5-S 6 7.
Westfall P H a n d Kris he n A. O pti mall y  wei g hte d, fi xe d se q ue nce a n d gate kee per m ulti ple testi n g
pr oce d ures. J St at Pl a n I nfere nce. 2 0 0 1; 9 9( 1): 2 5- 4 0. htt ps:// d oi. or g/ 1 0. 1 0 1 6/ S 0 3 7 8-
3 7 5 8( 0 1) 0 0 0 7 7 - 5.


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8.
A p p e n di c e s


I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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A p p e n di x 1.
D eri v ati o n of C G M V ari a bl e s
Ge ner al Deri v ati o n S pecific ati o ns
All C G M varia bles will be deri ve d f or eac h patie nt, f or eac h vali d C G M da y  a nd als o o verall f or
baseli ne ( Wee k - 2-0), Visit 7 ( Wee k 2 -4), Visi t 9 ( Wee k 6-8), a n d Visit 1 2 ( Wee k 1 0 - 1 2).
N o missi n g C G M val ues will be i m p ute d.
Si nce t he C G M val ues ma y n ot be meas ure d at t he e xact sa me ti me f or eac h da y f or a s pecific
i n di vi d ual patient , d ue t o de vice c ha n ges or ga ps i n usa ge, n o n-o verla p pi n g i nter vals (‘ b uc kets’)
of  1 5 mi n utes o ver 0 0: 0 0: 0 0 t o 2 3: 5 9: 5 9 ( 0 0: 0 0: 0 0 t o 0 0:1 4 : 5 9, 0 0:1 5: 0 0 t o 0 0: 2 9: 5 9, etc.) will 
be use d f or a n y  deri vati ons re q uiri n g ti me -matc he d meas ure me nts acr oss da y s wit hi n a visit.
All C G M gl uc ose deri vat i ons will b e c o n d ucte d i n u nits of m g/ d L a n d will be c o n verte d t o 
m m o l/ L b y mul tipl yi n g b y  0. 0 5 5 5.
O nl y rea di n gs fr o m vali d C G M da ys ( defi ne d i n Secti o n 6. 1 0. 1 ) c ollecte d d uri n g t he e nt ire 
baseli ne peri o d a n d treat me nt peri o d will be i ncl u de d i n deri vat i ons, e xcl u di n g data (if a n y) t hat 
are c ollecte d w hile pat ient s te mp oraril y are off st u d y  treat me nt.
Gl u c o s e i n T ar g et R a n g e s, H y p o gl y c e mi a - or H y p er gl y c e mi a
T he perce nta ge of ti me wit hi n a gl uc ose ra n ge (tar get, h y p o- or h y per gl yce mia ra n ges) will be
calc ulate d as t he n u m ber of o bser vati o ns wit hi n t he s pecifie d ra n ge di vi de d b y  t he n u m ber of
o bser vat i ons i n t he ti me i nter val (e. g., 2 4 -h o ur peri o d). T he d urati o n (i n mi n utes) wit hi n t he
gl uc ose ra n ge will t he n be calc ulate d as t he perce nta ge of ti me wit hi n t he gl uc ose ra n ge t i mes t he
le n gt h of t he peri o d ( 2 4 h o urs, 1 8 h o urs, f or t he peri o ds of 2 4-h o ur or da y time res pect i vel y).
F or e xa m ple, if a pat ient  ha d a t otal of 5 o bser vat i ons wit h gl uc ose val ues < 7 0 m g/ d L ( 3. 9 
m m o l/ L) o ut of a t otal of 9 0 o bser vat i ons rec or de d i n a 2 4 -h o ur peri o d, t he perce nta ge of ti me 
s pe nt i n h y p o gl yce mia d uri n g t he 2 4-h o ur peri o d f or t his pat ient  will be calc ulate d as 5/ 9 0 = 
5. 6 %. T he d urati o n (i n mi n utes) wit h h y p o gl yce mia ( gl uc ose val ue < 7 0 m g/ d L [ 3. 9 m m o l/L]) 
d uri n g t hi s 2 4-h o ur peri o d f or t his pati e nt will be c alc ulate d as t he perce nta ge of ti me wit hi n t he
gl uc ose ra n ge t i mes t he le n gt h of t he peri o d 1 4 4 0 mi n utes ( 2 4 h o urs), (i.e., 5/ 9 0 * 1 4 4 0 = 8 0
mi n utes).
I n cr e m e nt al Ar e a u n d er t h e Gl u c o s e C ur v e (i A U C)
i A U C 0-T will  be calc ulate d as t he a vera ge val ue of i A U C o n all vali d C G M da ys d uri n g t hat
visit wit h s ufficie nt data t o calc ulate t he i A U C 0 -T ( Secti o n 6. 1 0. 1 ). F or eac h da y, i A U C 0-T will  
be calc ulate d as t he s u m of areas of all i n di vi d ual tra pez oi ds wit hi n t he t i me fra me acc or di n g t o 
t he f or mula:
A U C    =
   =
(  −  ) + (    −  )
2
∆   

I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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w here A i is area of t he res pecti ve tra pez oi d, G i is gl uc ose c o nce ntrati o n at a partic ular ti me, G0 is
t he starti n g gl uc ose c o nce ntrati o n bef ore t he start of t he meal, is t he ti me i nter val bet wee n
c o nsec ut i ve C G M val ues, w hic h s h o ul d be al ways 1 5 mi n utes u nless missi n g data occ ur, a n d k is
t he t otal n u m ber of i nter vals wit hi n t he t i me fra me 0-T, a n d T c o ul d be 1 hr, 2 hr, 3 hr or 4 hr. If
t he i nter me diate ti me p oi nts are missi n g, t he ne xt a vaila ble t i me p oi nt will be use d i n calc ulati n g
t he t ra pez oid area. Als o si nce it is p ossi ble t hat G i < G 0 or G i-1 < G 0, Ai c o ul d als o be ne gat i ve.
G 0 , t he startin g gl uc ose c o nce ntrati o n, will be calc ulate d as t he a vera ge of t he C G M val ues i n t he
ti me wi n d o w [- 2 9, 0] mi ns relati ve t o t he start of t he meal (at most 2 C G M val ues); G k , t he last
gl uc ose c o nce ntrati o n, is defi ne d as t he C G M val ues i n t he wi n d o w [ 0, + 1 4 ] mi n utes relat i ve t o 
t he last ti me p o i nt of t he ti me fra me. F or e xa m ple, t o calc ulate i A U C 0 -2 hr aft er t he start of 
brea kfast, G k will be t he C G M val ues i n t he wi n d o w [ 0, +1 4 ] mi n utes relati ve t o t he 2 h o urs after 
t he start of brea kfast. T he deri vati o n o f eac h i A U C 0- T will re q uire t hat G 0 a n d G k val ues are b ot h 
a vaila ble a n d will e xcl u de data c ollecte d after t he ne xt meal e ve nt . 
M e a n S e n s or Gl u c o s e
E x c ur si o n s
Mea n se ns or gl uc ose e xc ursi o ns 0 t o T h o ur(s) i n a vali d p ost m e al time i nter val will be 
calc ulate d b y a vera gi n g all e xc ursi o n val ues wit hi n t he ti me i nter val 0- T, e xcl u di n g data 
c ollecte d after t he ne xt meal e ve nt, w here e xc ursi o ns are defi ne d as G i - G 0 as defi ne d i n i A U C.
Gl u c o s e V ari a bilit y
Gl yce mic varia bilit y will  be e val uate d usi n g t he n otati o n bel o w:

i re prese nts a ti me p oi nt wit hi n a ti me peri o d (a 2 4-h o ur peri o d, da y ti me or nig htti me)

n re prese nts t he n u m ber of ti me p oi nts wit hi n t he time peri o d

k re prese nts a da y wit hi n a visit

m re prese nts n u m ber of da ys C G M is perf or me d at a visit

B G
k ,i re prese nts t he gl uc ose val ue at ti me p oi nt i o n da y  k 
Wit hi n -D a y V ari a bilit y
F or vari a bles assessi n g wit hi n -da y vari a bilit y, first deter mi ne t he v ari a bilit y wit hi n eac h da y,
t he n a vera ge acr oss da ys wit hi n a visit.
Wit hi n -d a y  gl uc ose sta n dar d de viati on ( S D) ( Hirsc h 2 0 0 5; R o d bar d 2 0 0 9):


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Wit hi n -d a y  gl uc ose c oefficie nt of variati o n ( C V) ( Clar ke 2 0 0 9):
B et w e e n -D a y V ari a bilit y
F or vari a bles assessi n g bet wee n-d a y  v aria bilit y, first deter mi ne t he varia bility f or eac h ti me
p oi nts acr oss da ys wit hi n a visit t he n a vera ge acr oss all t i me p oi nts.
Bet wee n -d a y  gl uc ose sta n dar d de viati on ( S D) ( R o d bar d 2 0 0 9):
Bet wee n -d a y  gl uc ose c oefficie nt of variati o n ( C V):
I n a d ditio n t o t he C G M o utc o mes a b o ve, S D a n d C V i n t he dail y  mea n val ues will als o be
deri ve d.
O v er all V ari a bilit y
T he C V, S D will be calc ulate d usi n g t he sta n dar d f or m ulas acr oss c ollecte d acr oss all vali d da ys 
f or ti me i nter val i n treat me nt peri o d ( Wee k 0-1 2).
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I 8 B-M C -I TS W St ati sti c al A n al y si s Pl a n V er si o n 1
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Hi g h e st P o st pr a n di al Gl u c o s e
Hi g hest p ost pra n di al gl uc ose le vel e xc ursi o ns wit hi n 4 h o urs after meals, will be calc ulate d as
t he ma xi m u m gl uc ose val ue d uri n g 0 t o 4 h o urs after start of meal, tr u ncati n g t he data at t he ne xt
meal e ve nt.


L e o  D o c u m e n t  I D  =  6 d 0 3 6 f c c - 9 2 b e - 4 8 5 e - 9 7 a c - 2 6 8 6 a a 6 c 5 9 0 8
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 7 - O c t - 2 0 2 0  1 5 : 5 9 : 4 7  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D