Clinical trial NCT03740919
Conditions: Type 1 Diabetes Mellitus
Keywords: prandial insulin multiple daily injections pediatric patients postmeal dosing
Sponsor: Eli Lilly and Company
Start date: 2019-04-07; Completion date: 2021-07-02
Enrollment: 751 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The reason for this study is to compare the study drug LY900014 to insulin lispro (Humalog) in children and adolescents with type 1 diabetes (T1D).

Detailed description:

Arms: arm 1: Participants received 100 units per milliliter (U/mL) insulin lispro (Humalog) administered subcutaneously (SC), 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. arm 2: Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. arm 3: Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro intervention 3: Insulin Glargine intervention 4: Insulin Degludec
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC intervention 3: Administered SC intervention 4: Administered SC

Protocol documents:
Prot_000.pdf: 
I8B-MC-ITSB (b) Protocol 
 
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Humalog with an Open-
Label Postprandial LY900014 Treatment Group in Children and Adolescents with Type 1 
Diabetes PRONTO-Peds 
 
NCT03740919 
 
 
Approval Date: 30-Apr-2020  


I8B-MC-ITSB (b) Clinical Protocol
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LY900014
Protocol I8B-MC-ITSB (b)
A Prospective, Randomized, Double-Blind Comparison of 
LY900014 to Humalog with an Open-Label Postprandial 
LY900014 Treatment Group in Children and Adolescents 
with Type 1 Diabetes
PRONTO-Peds
2018-002371-18 (EUDRA CTA)
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.
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 26 October 2018.
Protocol amendment (a) electronically signed and approved by Lilly on date provided 
below
Approval Date: 30-Apr-2020 GMT


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Table of Contents
Section
Page
Protocol I8B-MC-ITSB (b) A Prospective, Randomized, Double-Blind 
Comparison of LY900014 to Humalog with an Open-Label 
Postprandial LY900014 Treatment Group in Children and 
Adolescents with Type 1 Diabetes PRONTO-Peds..............................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................6
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.2.
Background..................................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................21
5.1.
Overall Design .............................................................................................................21
5.2.
Number of Participants.................................................................................................22
5.3.
End of Study Definition ...............................................................................................22
5.4.
Scientific Rationale for Study Design...........................................................................23
5.5.
Justification for Dose ...................................................................................................23
6.
Study Population...............................................................................................................24
6.1.
Inclusion Criteria..........................................................................................................24
6.2.
Exclusion Criteria ........................................................................................................26
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................28
6.3.
Lifestyle Restrictions....................................................................................................28
6.4.
Screen Failures.............................................................................................................28
7.
Treatments........................................................................................................................29
7.1.
Treatments Administered .............................................................................................29
7.1.1.
Packaging and Labeling .......................................................................................29
7.1.2.
Medical Devices...................................................................................................30
7.2.
Method of Treatment Assignment ................................................................................30
7.2.1.
Selection and Timing of Doses.............................................................................30
7.2.1.1.
Target Glucose Values for Titration of Insulin Therapy ..................................30
7.2.1.2.
Timing of Doses.............................................................................................31
7.2.1.2.1.
Basal Insulin Adjustment ..........................................................................32
7.2.1.2.2.
Prandial Insulin Adjustment......................................................................32


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7.3.
Blinding .......................................................................................................................33
7.4.
Dosage Modification....................................................................................................33
7.5.
Preparation/Handling/Storage/Accountability...............................................................33
7.6.
Treatment Compliance .................................................................................................34
7.7.
Concomitant Therapy...................................................................................................34
7.8.
Treatment after the End of the Study............................................................................34
8.
Discontinuation Criteria ....................................................................................................36
8.1.
Discontinuation from Study Treatment.........................................................................36
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................36
8.1.2.
Temporary Discontinuation from Study Treatment...............................................37
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................37
8.2.
Discontinuation from the Study....................................................................................37
8.3.
Lost to Follow-Up........................................................................................................38
9.
Study Assessments and Procedures ...................................................................................39
9.1.
Efficacy and Safety Assessments..................................................................................39
9.1.1.
Primary Efficacy Assessments .............................................................................39
9.1.2.
Secondary Efficacy Assessments..........................................................................39
9.1.3.
Safety Assessments..............................................................................................39
9.1.4.
Appropriateness of Assessments ..........................................................................40
9.1.5.
Study Procedures .................................................................................................40
9.1.5.1.
Self-Monitored Blood Glucose .......................................................................40
9.1.5.2.
Use of Personal CGM or FGM .......................................................................41
9.2.
Adverse Events ............................................................................................................41
9.2.1.
Serious Adverse Events........................................................................................42
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................43
9.2.2.
Complaint Handling.............................................................................................43
9.3.
Treatment of Overdose.................................................................................................44
9.4.
Safety...........................................................................................................................45
9.4.1.
Hypoglycemia......................................................................................................45
9.4.2.
Severe Hypoglycemia ..........................................................................................46
9.4.3.
Vital Signs, Height, and Weight ...........................................................................46
9.4.4.
Laboratory Tests ..................................................................................................46
9.4.5.
Immunogenicity Assessments ..............................................................................46
9.4.6.
Safety Monitoring ................................................................................................47
9.4.6.1.
Hepatic Safety Monitoring..............................................................................47
9.5.
Pharmacokinetics .........................................................................................................48
9.6.
Pharmacodynamics ......................................................................................................48
9.7.
Pharmacogenomics ......................................................................................................48


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9.8.
Health Economics ........................................................................................................48
10.
Statistical Considerations ..................................................................................................49
10.1. Sample Size Determination ..........................................................................................49
10.2. Populations for Analyses..............................................................................................49
10.3. Statistical Analyses ......................................................................................................50
10.3.1.
General Statistical Considerations ........................................................................50
10.3.2.
Treatment Group Comparability...........................................................................51
10.3.2.1.
Patient Disposition..........................................................................................51
10.3.2.2.
Patient Characteristics ....................................................................................52
10.3.2.3.
Concomitant Therapy .....................................................................................52
10.3.3.
Efficacy Analyses ................................................................................................52
10.3.3.1.
Primary Analyses ...........................................................................................52
10.3.3.1.1.
Sensitivity Analyses for Missing Data.......................................................53
10.3.3.1.2.
Additional Analyses for the Primary Endpoint ..........................................53
10.3.3.2.
Secondary Analyses........................................................................................53
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................54
10.3.4.
Safety Analyses....................................................................................................54
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................55
10.3.6.
Evaluation of Immunogenicity .............................................................................55
10.3.7.
Other Analyses.....................................................................................................56
10.3.7.1.
Subgroup Analyses.........................................................................................56
10.3.8.
Interim Analyses..................................................................................................56
11.
References ........................................................................................................................57
12.
Appendices .......................................................................................................................59


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List of Tables
Table
Page
Table ITSB.1.
Schedule of Activities....................................................................................11
Table ITSB.2.
Objectives and Endpoints...............................................................................19
Table ITSB.3.
Treatment Regimens......................................................................................29
Table ITSB.4.
Glucose Target Values...................................................................................31
List of Figures
Figure
Page
Figure ITSB.1.
Illustration of study design for Clinical Protocol I8B-MC-ITSB.....................22
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................60
Appendix 2.
Clinical Laboratory Tests...............................................................................64
Appendix 3.
Study Governance Considerations..................................................................65
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................69
Appendix 5.
Sampling Summary .......................................................................................70
Appendix 6.
Classification of Contraceptive Methods........................................................71
Appendix 7.
Protocol Amendment History.........................................................................72


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1.
Synopsis
Title of Study: 
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Humalog with an 
Open-Label Postprandial LY900014 Treatment Group in Children and Adolescents with Type 1 
Diabetes: PRONTO-Peds
Rationale: 
The aim of this study is to demonstrate that an ultra-rapid formulation of insulin lispro, 
LY900014, is noninferior to Humalog on glycemic control as measured by change from baseline 
to Week 26 in hemoglobin A1c (HbA1c) in pediatric patients with type 1 diabetes (T1D), when 
administered in a double-blind manner as prandial insulin (0 to 2 minutes prior to the meal) in 
combination with basal insulin.  
Objectives/Endpoints:
Objectives
Endpoints
Primary Objective
1.
To test the hypothesis that LY900014 is 
noninferior to Humalog on glycemic control 
(NIM=0.4% for HbA1c) in patients 1 to <18 
years of age with T1D when administered as 
prandial insulin (0 to 2 minutes prior to the 
meal) in combination with basal insulin as
part of a multiple daily injection regimen for 
26 weeks
1. Difference between LY900014 and Humalog in 
change from baseline to Week 26 in HbA1c
Gated Objective
2.
To test the hypothesis that LY900014 
administered as postprandial insulin up to 
20 minutes after the start of a meal 
(LY900014+20) is noninferior to Humalog, 
administered as prandial insulin (0 to 2 
minutes prior to the meal), on glycemic 
control (NIM=0.4% for HbA1c)
2. Change from baseline to Week 26 in HbA1c
3.
To test the hypothesis that LY900014 is 
superior to Humalog in improving glycemic 
control (HbA1c) when administered as 
prandial insulin (0 to 2 minutes prior to the 
meal)
3. Difference between LY900014 and Humalog in 
change from baseline to Week 26 in HbA1c
Other Secondary Objectives
4.
To compare LY900014, LY900014+20, and 
Humalog with respect to the incidence and 
rate of documented post-dose hypoglycemia
4. Rate (events/patient/year) and incidence (percentage
of patients with events) of documented post-dose
hypoglycemic events within 1 and 2 hours after the 
prandial dose from Weeks 0 through 26
5.
To compare LY900014, LY900014+20, and 
Humalog with respect to the incidence and 
rate of documented hypoglycemia
5. Rate (events/patient/year) and incidence (percentage
of patients with events) of documented 
hypoglycemic events from Weeks 0 through 26


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6.
To compare LY900014, LY900014+20, and 
Humalog on the rate of severe hypoglycemic 
events
6. Rate (events/patient/100 years) of severe 
hypoglycemic events from Weeks 0 through 26
7.
To compare LY900014, LY900014+20, and 
Humalog with respect to total, basal, and 
prandial insulin dose
7. Change from baseline in total, basal, and prandial 
insulin doses and prandial/total insulin dose ratios at 
Week 26
8.
To compare LY900014, LY900014+20, and 
Humalog with respect to the proportion of 
patients achieving HbA1c targets
8. The proportion of patients with HbA1c<7% and 
<7.5% at Week 26
9.
To compare LY900014, LY900014+20, and 
Humalog with respect to 7-point SMBG
9. Change from baseline to Week 26 in 7-point SMBG 
values
Abbreviations:  HbA1c = hemoglobin A1c; NIM = noninferiority margin; SMBG = self-monitored blood glucose; 
T1D = type 1 diabetes.
Summary of Study Design:  
Study I8B-MC-ITSB (ITSB) is a Phase 3, prospective, randomized, outpatient, multinational, 
multicenter, parallel, active-controlled study conducted in children and adolescent patients with 
T1D currently using a multiple-daily-injection (MDI) regimen.  
Treatment Arms and Duration:  
The study includes a 1-week screening with a 4-week lead-in period, followed by a 26-week 
treatment period and a 2-week safety follow-up period.  In 2 of the treatment groups, LY900014 
and Humalog will be administered immediately (0 to 2 minutes) prior to each meal in a 
double-blind manner.  A third open-label treatment group consists of LY900014 administered up 
to 20 minutes after the start of a meal (LY900014+20).  
Number of Patients:
Approximately 945 participants will be screened to achieve 708 randomized and 600 patients 
completing 26 weeks of treatment for an estimated total of 240 completers per blinded treatment 
group and 120 completers for the open-label treatment group.  
Statistical Analysis:
The primary analysis is for the treatment period through Week 26.
Efficacy analyses will be conducted on all randomized patients according to the treatment the 
patients are assigned.  The analyses for the primary and gated objectives will be performed for 
the efficacy estimand, including data collected prior to permanent discontinuation of 
investigational product (IP) and for the intention-to-treat (ITT) estimand, including all data 
collected regardless of IP use.  The primary endpoint will also be analyzed using the 
Per-Protocol (PP) and Completer populations.
Safety analyses will be conducted on the Safety population.  Analyses of adverse events (AEs)
will include 2 sets of analyses, unless otherwise specified.  The first set of analyses will include 
data collected prior to permanent discontinuation of IP.  The second set of analyses will include 


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all data collected during the course of the entire study, including the follow-up visit, regardless 
of IP use.  Analyses of hypoglycemia will use data collected prior to permanent discontinuation 
of IP, while analyses for post treatment may be performed as needed.  Analyses of safety 
laboratory measurements will be performed on all data during the planned treatment period 
regardless of IP use.
Baseline is defined as the last non-missing measurement at or before the randomization 
visit (Visit 4), unless otherwise specified.  
For the United States (US) Food and Drug Administration (FDA) submission (using the ITT 
estimand), the missing endpoints will be imputed by the copy reference approach. The reference 
for each treatment group is from the retrieved dropout patients who discontinue IP but have the 
measurement at the primary endpoint in the same treatment group. If there are only a limited 
number of patients in the reference group that leads to a failure in performing the proposed 
multiple imputation analysis such that the model cannot converge, or the number of records in 
the reference group is less than the number of records with missing data, the missing endpoints 
will be imputed by the patient-level observed baseline value plus a noise, assuming a washout of 
any potential treatment effect (or “return to baseline”). The noise follows a normal distribution,
with the variability estimated from the “washout HbA1c data”. The “washout HbA1c data” will 
be derived by subtracting the corresponding treatment mean at Week 26 from individual 
non-missing HbA1c values at Week 26. After imputation, the primary efficacy comparison will 
be based on the contrast between LY900014 and Humalog from an analysis of 
covariance (ANCOVA).  The model for the change from baseline to the Week 26 HbA1c 
endpoint will include treatment and strata (pooled country, type of basal insulin, and age group) 
as fixed effects and baseline HbA1c as a covariate. The final estimates will be the combined 
estimates from at least 1000 imputations.  
For non-FDA submissions and publications, the primary efficacy comparison will be based on 
the contrast between LY900014 and Humalog at Week 26 (Visit 15) from the mixed-effect 
model repeated-measure (MMRM) analysis of change from baseline in HbA1c, including data 
collected from all randomized patients prior to permanent discontinuation of IP through Week 26 
(efficacy estimand).  
For both primary analysis approaches, LY900014 will be declared noninferior to Humalog if the 
upper limit of the 2-sided 95% confidence interval (CI) for the least-squares (LS) mean 
difference in the change from baseline in HbA1c for LY900014 minus Humalog is below +0.4%.  
In addition, the 95% CI for the treatment difference will be compared to an alternative NIM of 
+0.3%.  Both estimands will be tested at the full significance level of 0.05.  
A restricted maximum likelihood-based 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 HbA1c will include the fixed class effects of treatment, strata (pooled 
country, type of basal insulin, and age group), visit, and treatment-by-visit interaction, as well as 
the continuous, fixed covariate of baseline value.  For analyses of variables other than HbA1c, 


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the HbA1c stratum (≤8.0%, >8.0%) will be included in the model.  An unstructured covariance 
structure will be used to model the within-patient errors.  Significance tests will be based on LS 
means and Type III tests.  
An ANCOVA will also be used to analyze continuous variables.  The model for the change from 
baseline to the Week 26 HbA1c endpoint will include treatment and strata (pooled country, type 
of basal insulin, and age group) as fixed effects and baseline as a covariate.  Unless otherwise 
stated, missing endpoints will be imputed using the last-observation-carried-forward (LOCF) 
approach, using only postbaseline data.  For analyses of variables other than HbA1c, the HbA1c 
stratum (≤8.0%, >8.0%) will be included in the model.
Hypoglycemia rates will be summarized for periods of 30 days, 1 year, and 100 years (severe 
hypoglycemia only).  The rate of severe hypoglycemia per 100 years will be compared between 
treatment groups using the empirical method (details will be described in statistical analysis 
plan [SAP]).  For each of the other categories of hypoglycemia, the number of hypoglycemia 
events during a specific period after randomization (for example, Weeks 0 to 12 of treatment 
period) will be analyzed by using a negative binomial regression model. The model will include 
treatment and age group as covariates.  An offset defined as the log transformation of treatment 
exposure in the specific period (days)/365.25 days (or 30 days) will be included in the model to 
estimate the rate of hypoglycemia per year (or per 30 days).  The proportion of patients with at 
least 1 hypoglycemic event in each category during a specific period after randomization will be 
analyzed using a logistic regression model including treatment and age group as covariates.  
Continuous safety variables, as well as the change from baseline for these variables, will be 
analyzed by MMRM or ANCOVA models.  For categorical variables, Fisher’s exact test or 
Pearson’s chi-square test will be used to compare treatment groups, unless otherwise specified.  


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2.
Schedule of Activities


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Table ITSB.1.
Schedule of Activities
Screena
Lead-In
Treatment Period
Safety 
Follow-Up
EDb
eCRF Visit Number
1
2
3c
4
5c
6c
7
8c
9c
10
11c
12
13c
14c
15
801d
ED
Weeks from Randomization
−5
−4
-2
0
2
4
6
8
10
12
15
18
21
24
26
28
Visit Window (±days)
3
3
3
7
7
7
7
7
7
7
7
7
7
7
7
Informed Consent/Assent (if 
applicable)
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient eligibility review
X
X
Randomization
X
Clinical Assessments
Demographic datae
X
Medical history, preexisting 
conditions
X
Previous diabetes therapy
X
Record Personal CGM/FGM use 
(yes/no)
X
Heightf
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
Vital signs (sitting SBP, DBP, and 
HR)g
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events and product 
complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Focused physical exam (including 
skin evaluation)
h
X
X
X
X
X
X
X
X
Basal insulin dose assessmenti
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Basal insulin dose titration
j
X
X
X
X
X
X
X
X
X


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Screena
Lead-In
Treatment Period
Safety 
Follow-Up
EDb
eCRF Visit Number
1
2
3c
4
5c
6c
7
8c
9c
10
11c
12
13c
14c
15
801d
ED
Weeks from Randomization
−5
−4
-2
0
2
4
6
8
10
12
15
18
21
24
26
28
Visit Window (±days)
3
3
3
7
7
7
7
7
7
7
7
7
7
7
7
Prandial insulin dose assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prandial insulin dose titrationi
X
X
X
X
X
X
X
Ancillary Supplies/Diaries/IP
Dispense blood glucose meter and 
ancillary supplies and complete 
trainingk,l
X
X
X
X
X
Diabetes education and nutrition 
counselingl
X
Dispense study diaries and 
complete trainingl
X
X
X
X
X
Collect study diaries
X
X
X
X
X
X
Dispense IP
X
X
X
X
X
Train on collecting 4- and 7-point 
SMBG profilesm
X
Remind patient of 7-point SMBG 
requirements
X
X
X
Review and discuss SMBG
(and/or CGM/FGM) and 
hypoglycemia data from patient 
study diary
X
X
X
X
X
Discuss SMBG (and/or 
CGM/FGM) and hypoglycemia 
data with patient
X
X
X
X
X
X
X
X
Review/discuss only severe hypo 
data after completion of study 
treatment
X


I8B-MC-ITSB (b) Clinical Protocol
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Screena
Lead-In
Treatment Period
Safety 
Follow-Up
EDb
eCRF Visit Number
1
2
3c
4
5c
6c
7
8c
9c
10
11c
12
13c
14c
15
801d
ED
Weeks from Randomization
−5
−4
-2
0
2
4
6
8
10
12
15
18
21
24
26
28
Visit Window (±days)
3
3
3
7
7
7
7
7
7
7
7
7
7
7
7
Patient returns unused study drug
or open-label Humalog supplies
X
X
X
X
X
X
Drug accountability log
X
X
X
X
X
X
Laboratory Assessments
Pregnancy test, serum/urine 
(applicable females only)n
X
X
Urinalysis (screening) 
X
HbA1c
X
X
X
X
X
X
Clinical chemistry
X
X
X
Hematology
X
X
X
Antilispro antibodies
X
X
X
X
X
X


I8B-MC-ITSB (b) Clinical Protocol
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LY900014
Abbreviations: DBP = diastolic blood pressure; eCRF = electronic case report form; ED = early discontinuation; HbA1c = hemoglobin A1c; HR = heart rate; IP
= investigational product; IWRS = interactive web-response system; SBP = systolic blood pressure; SMBG = self-monitored blood glucose; WHO = World 
Health Organization.
a
Patients who rescreen will start at Visit 1..
b Randomized patients who decide to discontinue will be asked to return for the ED visit. If a patient discontinues during an office visit that visit may be 
treated as the ED visit.  If a patient discontinues via telephone, they will be asked to return for the ED visit.
c
Telephone visits are indicated by shaded columns. Telephone visits can become office visits. Site documentation will serve as the source for telephone visits.
d V801 will be a telephone visit; this visit can become an office visit.  
e
Medical history to include investigator review of immunization status with patient and caregiver.
f
In order to obtain accurate measurements, length should be measured using an infantometer and height should be measured using a stadiometer (WHO Child 
Growth Standards).  
g Blood pressure measurements should be determined correctly, using the appropriate-sized cuff for the child’s age and with the child seated and relaxed.
h A qualified medical professional must perform a medical assessment at each site visit.  During each office visit, the skin surrounding the injection sites should 
be assessed.  
i
Basal insulin dose assessment should be made during the lead-in period and as needed during the study.  
j
Basal insulin should be adjusted during the lead-in period so as to achieve or maintain BG targets with a focus on the prebreakfast BG.  Prandial insulin 
should be titrated with an emphasis during the first 12 weeks after randomization in order to reach optimal dosing and achieve BG targets.  Adjustment of 
basal and prandial insulin doses may continue throughout the 26-week treatment period in order to achieve or maintain glycemic targets based on changes in 
lifestyle, individual circumstances or for safety reasons.  
k Glucose monitoring supplies will be dispensed at each office visit, as needed.  
l
Initial training at Visit 2 may include diabetes education and nutrition counseling. Appropriate site personnel will administer training and education using 
locally approved diabetes education/training materials or other materials provided by the sponsor. Patients may be provided abbreviated training and 
education at visits following Visit 2, as appropriate.  
m Patients who wear personal CGM/FGM approved for dosing decisions may be trained to use their sensor data for 4-point BG values and record in diary or 
download the BGs for investigator review.
n Serum pregnancy test must be performed in female patients of childbearing potential (see inclusion criterion [9]) at Visit 1 followed by a urine pregnancy test 
within 24 hours prior to IP exposure at randomization (Visit 4) and at other times at the investigator’s discretion. When required per local regulations and/or 
institutional guidelines, local pregnancy testing will occur at mandatory times during the study treatment period.


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3.
Introduction
3.1.
Study Rationale
Young children with type 1 diabetes (T1D) are susceptible to glucose variability due to increased 
insulin sensitivity and unpredictable eating and physical activity.  Often, their cognitive 
immaturity and inability to verbalize symptoms present a challenge for recognizing and treating 
hypoglycemia.  It is well known that fear of hypoglycemia, particularly among parents of 
children with diabetes, impacts T1D management and quality of life. Children with T1D 
experience different insulin requirements due to increasing weight, height, and caloric needs, 
which poses challenges with glucose control and insulin therapy.  The current rapid-acting 
insulin analogs are not as fast and as short-acting as needed to meet these challenges. A prandial 
insulin with faster onset and/or faster offset characteristics might reduce glycemic excursions and 
decrease the incidence of delayed postprandial hypoglycemia compared to currently available 
rapid-acting insulin analogs.  LY900014 is an ultra-rapid-acting insulin lispro formulation with 
increased early absorption compared to Humalog®; Eli Lilly and Company.  LY900014 aims to 
mimic the physiological prandial insulin secretion pattern, which may more effectively control 
postprandial glucose (PPG) excursions.  
The aim of this study is to demonstrate that an ultra-rapid formulation of insulin lispro, 
LY900014, is noninferior to Humalog on glycemic control as measured by change from baseline 
to Week 26 in hemoglobin A1c (HbA1c) in pediatric patients with T1D, when administered in a 
double-blind manner as prandial insulin in combination with basal insulin.  
3.2.
Background
Regional evidence suggests that the incidence of T1D in youth is increasing in the United 
States (US; Lipman et al. 2013) and Europe (EURODIAB ACE Study Group 2000).  Estimates 
of T1D prevalence in the pediatric population in the US come from the Centers for Disease 
Control and Prevention–sponsored SEARCH for Diabetes in Youth Study Group (SEARCH).
The SEARCH study estimated that in 2011, the total number of youth in the US <20 years of age 
with T1D was 166,984 (Pettitt et al. 2014).
As with adults, intensive diabetes management through maintenance of tight glycemic control 
helps to delay onset and slow the progression of complications of the disease in 
youth (DCCT 1993).  Tight glycemic control is achieved via intensive insulin therapy, which 
requires dietary discipline, frequent blood glucose (BG) monitoring, and multiple injections of 
insulin (both rapid- and long-acting insulin) to mimic the natural pattern of insulin release, the 
combination of which represents a major burden on the patient, especially youth.  Intensive 
insulin treatment in T1D should be initiated early in disease progression and the improved 
glycemic control may have a lasting impact on reducing the onset of diabetic complications.  
There have been many advances in the treatment of T1D in the last 20 years; however, reaching 
and maintaining glycemic goals remain challenging even under intensive insulin therapy 
regimens.  Only, approximately, 30% of insulin-requiring diabetes patients are able to reach the 
goal HbA1c target of <7% (Casagrande et al. 2013).  Currently available rapid-acting insulin 


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analogs continue to be unable to match the kinetics of physiological postmeal insulin secretion.  
Thus, there remains a need to continue to develop formulations with a time-action profile that 
more closely approximates that of endogenous insulin secretion.  
Ideally, currently available rapid-acting insulin analogs should be injected 10 to 15 minutes prior 
to meal consumption in order to optimally control PPG.  However, many persons inject their 
rapid-acting insulin at the time of the meal or after the meal.  This may be particularly true for 
children due to unpredictable eating patterns.  According to survey data from the T1D Exchange 
on the timing of prandial insulin injection, 16.3% of patients indicated that they inject 15 minutes 
prior to meals, 33% inject 1 to 14 minutes prior to meals, 38.6% inject at the time of the meal, 
and 12.1% inject after the start of a meal.  Because patients often inject later than recommended,
there is a greater mismatch between insulin action and postprandial BG elevations.  With 
postmeal dosing, the mismatch between the rise in BG and the onset of insulin action is even 
more pronounced.  For the development of an ultra-rapid insulin, it will be important to 
understand the relationship between the time-action profile of the insulin, insulin injection 
timing, and meal timing in order to maximize improvements in postprandial glycemic control 
and minimize hypoglycemia risk.  An insulin with higher early concentration and peak exposure 
along with a shorter duration should improve early postprandial control and limit postmeal 
hyperglycemia while reducing late postprandial hypoglycemia due to lower insulin exposure.  
A new pharmaceutical innovation that may allow more effective control of PPG levels is 
LY900014, 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.  The changes in pharmacokinetic and pharmacodynamic (PK and PD)
characteristics are achieved by coformulating insulin lispro with treprostinil and ingredients 
Generally Recognized as Safe by the Food and Drug Administration (FDA) as excipients.  
Treprostinil, as an excipient, enhances the absorption of insulin lispro by local vasodilatation 
rather than as an active pharmaceutical ingredient that elicits a systemic effect.  Treprostinil has 
been approved in the US since 2002 (Remodulin package insert, 2018) and in Europe since 2005 
(PMR [WWW]).  Sodium citrate, an excipient that speeds insulin absorption, is also included in 
the formulation to further enhance the absorption of insulin lispro.  Furthermore, the excipient 
concentration in LY900014 is within the limits identified for approved drug products in the FDA 
Inactive Ingredients in Approved Drugs database.
Please refer to the Humalog local product labeling (for example, Humalog package insert, 2017; 
Humalog Summary of Product Characteristics, 2018) for more information regarding Humalog.
The Investigator’s Brochure (IB) describes the clinical and nonclinical development of 
LY900014.  
3.3.
Benefit/Risk Assessment
The faster action profiles seen with rapid-acting insulins offer the potential to more safely and 
effectively simulate normal insulin profiles in patients with T1D with earlier and higher peaks 
and shorter duration of action. Yet, it is apparent that the absorption rates of currently available 
rapid-acting insulin analogs are still not fast enough to eliminate postmeal hyperglycemia and 


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attempts to correct this by increasing the dose often result in late postmeal hypoglycemia. An
ultra-rapid insulin with a fast-in, fast-out profile will possibly reduce postprandial hyperglycemia 
and the frequency of hypoglycemia, easing the severe hypoglycemia anxiety for parents and 
patients, which often leads to under-dosing, overcorrecting, and overeating.
Heath Care Providers typically instruct patients to dose prandial insulin at the start of each meal, 
as it is assumed that this will provide the best postprandial glucose control under most 
conditions. However, patients with T1D and caregivers may administer insulin at different times 
relative to the start of a meal, depending on their experience and anticipated activities. In some 
cases, parents of young children may give the insulin dose after a child has eaten due to 
unpredictable dietary intake or low premeal BG to avoid potential hypoglycemia. It is often a 
balancing act, in which the risk of hypoglycemia (potentially severe in very young children) 
outweighs the risk of postmeal hyperglycemia in this population. Study ITSB will include an 
open-label treatment group to study dosing when given up to 20 minutes postmeal.  
In Study ITSB, investigators and study sites will be experienced in the treatment of children, 
diabetes, and in the conduct of pediatric clinical trials.  Frequent interaction with site staff will 
occur and allow for careful monitoring of BG values and hypoglycemic events.  In order to 
minimize risk and discomfort for patients, the number of procedures (including blood draws) and
office visits has been reduced to decrease time lost from work and school. 
Across all doses in the Eli Lilly and Company (Lilly) clinical studies that have evaluated 
treprostinil as a local vasodilator with or without insulin lispro, there was no clinically significant 
increase in adverse events (AEs) associated with systemic absorption of treprostinil, as described 
in the Remodulin package insert (2018; that is, headache, diarrhea, nausea, jaw pain, 
vasodilatation, edema, and hypotension).  
There are limited data on the use of treprostinil in pediatric patients.  Pediatric assessments have 
not been required for treprostinil because of its orphan drug designation; thus, the safety and 
effectiveness of treprostinil in pediatric patients have not been established (Remodulin package 
insert, 2018; Tyvaso prescribing information, 2014; Orenitram prescribing information, 2016).  
Subcutaneous (SC) treprostinil has been evaluated in children with pulmonary artery 
hypertension (PAH) in an observational study (n=8).  Six children had symptomatic and 
hemodynamic responses to the addition of SC treprostinil, with manageable control of local 
injection-site discomfort (Levy et al. 2011). A clinical study I8B-MC-ITSA (Study ITSA) is 
ongoing. The aim of Study ITSA is to evaluate PK, PD, safety, and tolerability of LY900014 in 
comparison with Humalog following a single subcutaneous (SC) dose administration 
immediately prior to a standardized liquid meal.  Study ITSA is the first study to evaluate 
LY900014 in pediatric patients with T1D.  
Preschool children often need proportionally larger bolus insulin doses, often constituting 60% to 
80% of the total daily insulin dose (TDD; Sundberg et al. 2017).  Study ITSB will allow a 
maximum TDD of 1.5 U/kg.  Assuming a TDD of 1.2 U/kg and body weight of 80 kg, a total 
insulin bolus dose would be administered in 3 bolus insulin doses of 32U containing 320 ng of 
treprostinil.  Following administration of 50 U of LY900014 by SC bolus injection in adult Phase


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1b studies, treprostinil has been undetectable in the systemic circulation.  In addition, there were 
no detectable treprostinil drug concentrations with continuous subcutaneous insulin infusion 
(CSII) therapy during the basal infusion or after the bolus dose samples from patients with T1D.
Thus, the expected treprostinil maximum drug concentration (Cmax) following LY900014 
administration would be below the assay quantitation limit of 0.010 ng/mL and would be 
approximately 200-fold lower than the average steady-state treprostinil levels in adult PAH 
patients treated with Remodulin.  The exposures of treprostinil in LY900014 are expected to be 
substantially lower than those observed in the treatment of PAH.
Females of child-bearing potential can participate in this study if they test negative for pregnancy 
at study entry and agree to maintain sexual abstinence or use a highly effective method of 
contraception throughout the study. In a fertility and early embryonic development study in 
male and female rats, there were no adverse effects of treprostinil on sperm morphology, estrus 
cyclicity, mating, fertility, conception, implantation, and embryonic survival.  Embryo-fetal 
development studies indicated that treprostinil was not teratogenic in rats or in rabbits.  In a 
prenatal and postnatal development study in rats, there was no evidence of maternal toxicity or 
adverse effects on offspring growth, behavior, and reproductions.  
More information about the known and expected benefits, risks, serious AEs (SAEs), and 
reasonably anticipated AEs of LY900014 can be found in the IB.  More detailed information 
about the known and expected benefits and risks of Humalog may be found in the country-
specific product labeling (for example, Patient Information Leaflet, Package Insert, or Summary 
of Product Characteristics).


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4.
Objectives and Endpoints
Table ITSB.2 shows the objectives and endpoints of the study.
Table ITSB.2.
Objectives and Endpoints
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
1.
To test the hypothesis that LY900014 is 
noninferior to Humalog on glycemic control 
(NIM=0.4% for HbA1c) in patients 1 to <18 
years of age with T1D, when administered as 
prandial insulin (0 to 2 minutes prior to the meal) 
in combination with basal insulin as part of a 
multiple daily injection regimen for 26 weeks
1. Difference between LY900014 and Humalog in 
change from baseline to Week 26 in HbA1c
Gated Objectives
2.
To test the hypothesis that LY900014 
administered as postprandial insulin up to 
20 minutes after the start of a meal 
(LY900014+20) is noninferior to Humalog,
administered as prandial insulin (0 to 2 minutes 
prior to the meal), on glycemic control 
(NIM=0.4% for HbA1c)
2. Change from baseline to Week 26 in HbA1c
3.
To test the hypothesis that LY900014 is superior 
to Humalog in improving glycemic control 
(HbA1c) when administered as prandial insulin
(0 to 2 minutes prior to the meal)
3. Difference between LY900014 and Humalog in 
change from baseline to Week 26 in HbA1c
Other Secondary Objectives
4.
To compare LY900014, LY900014+20, and 
Humalog with respect to the incidence and rate 
of documented post-dose hypoglycemia
4. Rate (events/patient/year) and incidence (percentage
of patients with events) of documented post-dose
hypoglycemic events within 1 and 2 hours after the 
prandial dose from Weeks 0 through Week 26
5.
To compare LY900014, LY900014+20, and 
Humalog with respect to the incidence and rate 
of documented hypoglycemia
5. Rate (events/patient/year) and incidence (percent of 
patients with events) of documented hypoglycemic 
events from Week 0 through Week 26
6.
To compare LY900014, LY900014+20, and 
Humalog on the rate of severe hypoglycemic 
events
6. Rate (events/patient/100 years) of severe 
hypoglycemic events from Weeks 0 through 26
7.
To compare LY900014, LY900014+20, and 
Humalog with respect to total, basal, and 
prandial insulin dose
7. Change from baseline in total, basal, and prandial 
insulin doses and prandial/total insulin dose ratios at 
Week 26
8.
To compare LY900014, LY900014+20, and 
Humalog with respect to the proportion of 
patients achieving HbA1c targets
8. The proportion of patients with HbA1c <7% and 
<7.5% at Week 26
9.
To compare LY900014, LY900014+20, and 
Humalog with respect to 7-point SMBG
9. Change from baseline to Week 26 in 7-point SMBG 
values 
Tertiary/Exploratory Objectives


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10. To compare LY900014, LY900014+20, and 
Humalog with respect to changes in body weight
10. Change in weight (kg) from baseline to Week 26
11. To compare LY900014, LY900014+20, and 
Humalog with respect to glycemic variability
11. Within-day and between-day glycemic variability 
measured by the standard deviation and the 
coefficient of variation of 7-point SMBG profiles
12. To compare the incidence of treatment-emergent 
anti-insulin lispro antibodies for LY900014, 
LY900014+20, and Humalog
12. Incidence of treatment-emergent anti-insulin lispro 
antibodies
Abbreviations:  HbA1c = hemoglobin A1c; NIM = noninferiority margin; SMBG = self-monitored blood glucose; 
T1D = type 1 diabetes.


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5.
Study Design
5.1.
Overall Design
Study ITSB is a Phase 3, prospective, randomized, outpatient, multinational, multicenter, 
parallel, active-controlled study, conducted in children and adolescent patients with T1D 
currently using a multiple-daily-injection (MDI) regimen.  In 2 of the treatment groups, 
LY900014 or Humalog will be administered immediately (0 to 2 minutes) prior to each meal in a 
double-blind manner. A third open-label treatment group consists of LY900014 administered 
up to 20 minutes after the start of a meal (LY900014+20).  It is not possible to blind this 
treatment group as it uses a different injection timing. The study is designed to demonstrate 
noninferiority of LY900014 when compared with Humalog in change from baseline to Week 26 
in HbA1c, when both are administered at the start of the meal.  The study includes a 1-week 
screening with a 4-week lead-in period followed by a 26-week treatment period and a 2-week 
safety follow-up period.  
The purpose of the lead-in period is to obtain blood glucose (BG) values along with basal and 
prandial insulin doses to assess basal and mealtime insulin dosing and to determine baseline 
hypoglycemia rates.  Basal insulin should be titrated by the patient or caregiver during the lead-
in period, in anticipation of increased activity or individual patient needs, so as to achieve or 
maintain glucose targets (Table ITSB.4) with an emphasis on the pre-breakfast BG.  
Investigators will have access to a patient’s glucose values; so, they may assist patients and 
caregivers with appropriate basal adjustments. The lead-in will also allow patients and 
caregivers to become familiar with the patient study diary and the documentation required 
throughout the study.  Patients treated with insulin glargine U-100 once a day (QD) or twice a 
day (BID), insulin detemir U-100 QD or BID or insulin degludec U-100 QD will be eligible for 
inclusion in the trial.  At Visit 2, patients will continue their allowed study basal insulin regimen
at the same dosing frequency (QD or BID). Patients should remain on the same basal insulin 
throughout the study; switching brands should be avoided when possible.  
During the lead-in period, patients will be switched to open- label marketed insulin lispro 
(Humalog) using a unit for unit conversion or the dose may be determined based on the 
investigator’s clinical judgement.  Prandial insulin doses will be assessed at Visits 2 and 3.
Adjustments to dose and dosing calculations may be necessary at randomization (Visit 4) to
minimize the risk of hypoglycemia or hyperglycemia.
Diabetes education and nutrition counseling, including hypoglycemia recognition and 
management should be provided.  Accuracy of carbohydrate counting should be assessed for 
those patients who dose mealtime insulin based on carb content.  Appropriate site personnel will 
administer training and education as needed using locally approved diabetes education/training 
materials and programs or other materials that may be provided by the sponsor. Patients may be 
provided additional focused training and education at visits following Visit 2 based upon patient 
needs.
At Visit 4, patients will be randomized to either blinded LY900014 or Humalog to be given at 
mealtime (0 to 2 minutes prior to the meal) or open-label LY900014 given up to 20 minutes after 


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the start of the meal.  Prandial insulin should be titrated with an emphasis during the first 12 
weeks in order to reach optimal dosing and achieve glucose targets (Table ITSB.4).  Adjustment 
of basal and prandial insulin doses may continue throughout the treatment period in order to 
achieve or maintain glycemic targets based on changes in lifestyle, individual circumstances or 
for safety reasons.  
After completion of study treatment (Visit 15 or early discontinuation [ED]), it is recommended 
that patients return to their pre-study prandial insulin; however, the choice of insulin therapy 
should be made by the investigator in consultation with the patient or caregiver.  
Study governance considerations are described in detail in Appendix 3.  Figure ITSB.1 illustrates 
the study design.  
Figure ITSB.1.
Illustration of study design for Clinical Protocol I8B-MC-ITSB.
5.2.
Number of Participants
Approximately 945 participants will be screened to achieve 708 randomized and 600 patients 
completing 26 weeks of treatment for an estimated total of 240 completers per blinded treatment 
group and 120 completers in the open-label treatment group.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2, Table ITSB.1) for the last patient.


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5.4.
Scientific Rationale for Study Design
Study ITSB is a Phase 3 study designed to evaluate LY900014 compared to Humalog in 
combination with basal insulin in children and adolescent patients with T1D.  The trial has 3 
treatment groups, 2 of which are double-blind to allow comparison of LY900014 and Humalog
when injected at the start of the meal.  The third treatment group is open-label due to inability to 
blind postprandial injection timing of LY900014 (up to 20 minutes after the start of a meal) and 
will evaluate the efficacy and safety of postprandial dosing.  The recommended time of 
administration of currently marketed rapid-acting insulins is before meals, but patients often 
inject later than recommended. The study is designed to compare a decrease in HbA1c as the 
primary endpoint. The HbA1c is a measure of glycemic control accepted by health care 
providers and regulatory authorities as a validated measure of BG control over time and is a
marker for development and progression of diabetes complications.  A 4-week lead-in period
will provide the time needed for patients taking insulin aspart or insulin glulisine, or biosimilar
insulin lispro at screening to switch to marketed insulin lispro (Humalog) with an emphasis on 
basal insulin adjustment and optimization.  While basal insulin may continue to be adjusted to 
achieve FBG targets during the 26-week treatment period, prandial insulin should be titrated with 
an emphasis on achieving optimal dosing during the first 12 weeks so the primary endpoint 
HbA1c reflects glucose control during the 3-month time period when there are minimal changes.
Adjustment of basal and prandial insulin doses may continue throughout the treatment period in 
order to achieve or maintain glycemic targets or for safety reasons.  
5.5.
Justification for Dose
LY900014 will have the same insulin lispro concentration (100 U/mL) as that of commercially 
available Humalog.  The addition of treprostinil to the insulin lispro formulation does not modify 
the physical, chemical, or biological integrity of insulin lispro.  The dosage of basal and prandial 
insulins used in this study should be determined based on the individual needs of each patient.


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6.
Study Population
Prospective approval of protocol deviations for recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study, only if they meet all the following criteria at 
screening:
Type of Patient and Disease Characteristics
[1] Male or female patients with T1D for at least 6 months and diagnosed by an 
endocrinologist (pediatric or adult), diabetes specialist, or a physician with 
expertise in treating pediatric patients with Type 1 diabetes.
Patient Characteristics
[2] Are at least 1 to <18 years of age.
[3] Are ≥16 lbs. (7.3 kg).
[4] Have been treated with only one of the following rapid-acting insulin analogs
as part of an MDI regimen for at least the last 90 days: 
a.
insulin lispro U-100, or 
b. insulin aspart 
c.
insulin glulisine or
d. Fast acting insulin aspart (must be approved for use in children in 
accordance with the local product label)
[5] Have been treated with only 1 of the following basal insulins for at least the 
last 90 days: 
a.
insulin glargine U-100 (QD or BID), or
b. insulin detemir U-100 (QD or BID), or
c.
insulin degludec U-100 (QD)
[6] Use a total daily dose of insulin 0.3 to ≤1.9 U/kg.
a.
TDD can be the average of previous 3 to 7 days
[7] Have a HbA1c value ≤9.9% according to the central laboratory.  
[8] Male patients: 
a.
no male contraception required, except in compliance with specific local 
government regulations
[9] Female patients of childbearing potential:


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a.
Post pubertal females of childbearing potential are defined as children and 
adolescents ≥12 years of age or <12 years of age who have onset of 
menses.  
b. if sexually active, must agree to use 1 highly effective form of 
contraception for the entirety of the study (Appendix 6)
c.
not pregnant or intending to become pregnant
i.
post pubertal females of childbearing potential 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 test within 24 hours prior to exposure to 
investigational product (IP) at Visit 4
d. not breastfeeding
Other Study Requirements for Patient or Caregiver
[10] Has refrigeration in the home or has access to refrigeration for storage of 
insulin.  
[11] Are capable and willing (as determined by the investigator) to do the 
following:
a.
inject insulin with the use of an insulin pen injection device according to 
written instructions
b. perform fingerstick SMBG as required by the study schedule using the 
study glucose meter provided
EXCEPTION: patients using personal continuous glucose 
monitoring (CGM) or flash glucose monitoring (FGM) devices
that are consistent with local country regulations and approved 
for use for insulin dosing decisions may use them for 4-point 
glucose testing during the study (see Section 9.1.5.2).
c.
record all information in study diary as required by this protocol
d. follow instructions for basal insulin adjustment and individualized 
prandial insulin dosing using fixed-pattern adjustment or carbohydrate 
counting, as provided by the investigator
e.
comply with the use of study insulin and scheduled visits
Informed Consent
[12] The child/adolescent and/or a parent or legal guardian are able to understand 
and willingly participate fully in the activities of the clinical trial and sign 
their age and developmentally appropriate assent and consent, as required
per local guidelines.


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6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions
[13] Have current hypoglycemic unawareness in the investigator’s opinion or 
have had more than 1 episode of severe hypoglycemia (defined as requiring 
assistance due to neurologically disabling hypoglycemia, indicated by coma 
or convulsion and/or use of intravenous glucose or glucagon) within 
6 months prior to screening (Visit 1).
[14] Have had more than 1 emergency room visit or hospitalization due to poor 
glucose control (hyperglycemia or diabetic ketoacidosis) within 6 months 
prior to screening (Visit 1).  
[15] Have any other clinically significant disorder or uncontrolled concomitant 
disease that, in the investigator's opinion, would preclude participation in the 
trial or pose a safety risk. 
[16] Renal: 
a.
history of renal transplantation,
b. currently receiving dialysis, or 
c.
have a history of renal impairment (exclusion only if glomerular 
filtration rate [estimated GFR] <60 mL/minute/1.73 m2 as defined by 
the central laboratory.
[17] Have obvious clinical signs or symptoms of liver disease in the opinion of 
the investigator (for example, acute or chronic hepatitis or cirrhosis) or 
elevated liver enzyme measurements as indicated below at screening:
a.
total bilirubin ≥2× the upper limit of normal (ULN) (with the exception 
of Gilbert’s disease) as defined by the central laboratory, or
b. alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase 
≥3×ULN as defined by the central laboratory, or
c.
aspartate aminotransferase (AST)/serum glutamic oxaloacetic 
transaminase ≥3×ULN as defined by the central laboratory
[18] Active or untreated malignancy or in remission from clinically significant 
malignancy (other than basal cell or squamous cell skin cancer) for less than 
5 years.  
[19] Known hypersensitivity or allergy to any of the study insulins or their 
excipients.  


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[20] Blood transfusion or severe blood loss within 3 months prior to Visit 1 or 
have known hemoglobinopathy, anemia, hemolytic anemia, sickle cell 
anemia, or any other traits of hemoglobin abnormalities known to interfere 
with the HbA1c measurement.  
[21] Have history of inpatient psychiatric treatment; emotional, behavioral, or 
other untreated conditions that, in the opinion of the investigator, would 
interfere with proper participation in routine diabetes control and 
management in the last 6 months.
[22] Have significant lipohypertrophy.  
[23] Retinopathy and maculopathy:  have preproliferative and proliferative 
retinopathy, or maculopathy requiring treatment or not clinically stable in 
the last 6 months, or patients with active changes in subjective eye 
symptoms as determined by the investigator if an eye exam has not been 
performed in the last 6 months.
Note:  Patients with a history of preproliferative retinopathy, proliferative retinopathy, or 
maculopathy that remains stable at least 6 months after photocoagulation, and who are 
enrolled based on investigator or subinvestigator’s judgment should continue to attend 
appropriate periodical eye examinations with an ophthalmologist.  If an eye examination 
has been performed no more than 6 months before screening, it will not have to be 
repeated; however, the investigator will need to confirm via interview that there is no 
change in subjective symptoms.
Prior/Concomitant Therapy
[24] Receiving chronic (lasting longer than 14 consecutive days) systemic 
glucocorticoid therapy (excluding topical, intraocular, intranasal, and 
inhaled preparations) or have received such therapy within the last 90 days.
[25] Have been on a treatment regimen that includes regular human insulin, 
neutral protamine Hagedorn (NPH), Afrezza® (insulin human) inhalation 
powder, any premixed insulins or use of diluted insulins within the last 90 
days.  
[26] Receiving any oral or injectable medication intended for the treatment of 
diabetes mellitus other than insulins within the last 90 days.
[27] Have been treated by CSII regimen for ≥14 days within the last 90 days.
Prior/Concurrent Clinical Trial Experience
[28] Are currently enrolled in any other clinical study involving an IP or any 
other type of medical research judged by the investigator to not to be 
scientifically or medically compatible with this study.


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[29] Have participated, within the last 30 days, in a clinical study involving an 
IP, except for Study I8B-MC-ITSA (ITSA). Patients may be considered for 
screening in this trial immediately upon ED or completion of Study ITSA 
(Parts A and B). No additional waiting period is necessary between 
participation in ITSA and ITSB.
Other Exclusions
[30] The patient or caregiver are investigator site personnel directly affiliated 
with this study or a member of their immediate families.  Immediate family 
is defined as a spouse, parent, child, or sibling, whether biological or legally 
adopted.
[31] The patient or caregiver is an immediate family member of Lilly employees 
(including employees, temporary contract workers, or designees responsible 
for the conduct of the study). Immediate family is defined as a spouse, 
parent, child, or sibling, whether biological or legally adopted.
6.2.1. Rationale for Exclusion of Certain Study Candidates
The use of LY900014 in pediatric patients is anticipated; thus, this study will specifically 
examine the safety and efficacy in a pediatric population.  Criterion [1] and Criterion [2] define 
the population needed for the purposes of this study.  Therefore, patients not meeting these
criteria are excluded.
6.3.
Lifestyle Restrictions
Not applicable.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) or were 
required to unexpectedly discontinue from the study during screening or lead-in period (e.g., due 
to enrollment pause related to the COVID-19 public health emergency) are allowed 
1 rescreening. 
All patients that rescreen will restart at Visit 1 and complete all screening procedures. 


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7.
Treatments
7.1.
Treatments Administered
This study involves a comparison of LY900014 and Humalog administered subcutaneously 0 to 
2 minutes prior to the start of the meal for 26 weeks.  In a third open-label treatment group, 
LY900014 will be administered up to 20 minutes after the start of a meal (LY900014+20) for 26 
weeks.
Table ITSB.3 shows the treatment regimens.
Table ITSB.3.
Treatment Regimens
Regimen
Dose
Strength
Dose
Administration
Route of
Administration
Timing of 
Administration
LY900014
100 U/mL Individualized 
dosing
Subcutaneous
0 to 2 minutes before start of the meal
Humalog
100 U/mL Individualized 
dosing
Subcutaneous
0 to 2 minutes before start of the meal
LY900014+20 100 U/mL Individualized
dosing
Subcutaneous
Up to 20 minutes after the start of the meal
The investigator or his/her designee is responsible for

explaining the correct use of the IP to the patient 
o
including the importance of injection site rotation for both basal and prandial 
insulin 

explaining study diary requirements for recording insulin doses and injection 
times to the patient

verifying that all study instructions are followed properly

maintaining accurate records of IP dispensing and collection

confirming that the patient returns all unused IP to the site 
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled as IP as appropriate and according to the country’s 
regulatory requirements.  Study insulins (LY900014 and Humalog) will be supplied by Lilly or 
its representative, in accordance with current good manufacturing practices, and will be supplied 
with clinical trial lot numbers.  Instruction for Use for the prefilled pen devices will be provided.
The blinded prefilled pens will contain a concentration of 100 U/mL in 3-mL cartridges of either 
LY900014 or Humalog.  The open-label prefilled pens will contain a concentration of 100 U/mL 
in 3-mL cartridges of LY900014.


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During the lead-in period, marketed 100 U/mL insulin lispro (Humalog) will be provided using 
open-label prefilled pens.
7.1.2. Medical Devices
The medical devices provided for use in the study are disposable, prefilled insulin pens.  Patients, 
caregivers and investigators will receive blinded pens in the blinded treatment arms and 
unblinded pens in the open label treatment arm.  LY900014 prefilled pens are new 
investigational combination products. The prefilled pen allows for dosing in half-unit 
increments and can dose between 0.5 and 30 units per injection. 
This study will also provide patients with FDA approved BG meters. The BG meter used in this 
study will be a meter that has received clearance from the FDA and meets the ISO 15197:2013
standard for blood glucose meters.  
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment or 
open label treatment at Visit 4.  Assignment to treatment groups will be determined by a 
computer-generated random sequence using an interactive web-response system (IWRS).  
Patients will be randomized to double-blind LY900014, double-blind Humalog, or open-label 
LY900014+20 in a 2:2:1 ratio.  Stratification will be by country, HbA1c stratum (≤8.0%, >8.0%)
based on HbA1c measured at Visit 1, type of basal insulin at randomization (insulin glargine, 
detemir, or degludec), and age group (1 to <12, 12 to <18 years).
The IWRS will be used to assign all IP (blinded and open-label) during the study.  Site personnel 
will confirm that they have located the correct prefilled pens by entering a confirmation number 
found on the prefilled pen carton into the IWRS.
7.2.1.
Selection and Timing of Doses
7.2.1.1.
Target Glucose Values for Titration of Insulin Therapy
The overall glycemic control goals for all patients enrolled in the study are similar to those 
recommended by the International Society for Pediatric and Adolescent Diabetes (DiMeglio et 
al. 2018).  The glucose target values shown in Table ITSB.4 are suggested guidelines that are 
required in order to achieve an HbA1c goal of <7.0% (53 mmol/mol) and may be used to
determine insulin dose titration. Targets may be individualized, aiming for the lowest achievable 
HbA1c without undue exposure to severe hypoglycemia.  A higher HbA1c goal (in most cases <  
7.5% (58 mmol/mol) may be appropriate in younger children who are unable to articulate 
symptoms of hypoglycemia.  


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Table ITSB.4.
Glucose Target Values
Target Range
Before meals
70 - 130 mg/dL
(4.0-7.0 mmol/L)
Postprandial (1 hr)
90 to 180 mg/dL
(5.0 to 10.0 mmol/L)
Bedtime
80-140 mg/dL
(4.4-7.8 mmol/L)
HbA1c
<7.0% (53 mmol/mol)
Abbreviations:  HbA1c = hemoglobin A1c; w/out = without.  
Source: DiMeglio et al. 2018
7.2.1.2.
Timing of Doses
Marketed insulin lispro (Humalog) will be dispensed to all patients for use throughout the lead-in 
period. At randomization (Visit 4), patients study treatment (LY900014 or Humalog) starting 
dose may be initiated unit for unit however, investigators may consider reducing the prandial or 
correction doses based on patient’s overall glycemic status or other considerations known to 
investigator in order to reduce risk of postprandial hypoglycemia.  In the blinded treatment 
groups, LY900014 and Humalog will be administered immediately prior to each meal (0 - 2 
minutes). The LY900014+20 open label treatment group will administer the dose up to 20 
minutes after the start of a meal.
Patients will administer IP within the time instructed by the investigator as determined by 
treatment randomization (blinded LY900014 or blinded Humalog; 0-2 minutes before or open-
label LY900014; up to 20 minutes after the start of the meal).  An occasional change in the 
timing of injection may be warranted due to individual circumstances and will not be considered 
a protocol violation unless deemed by the investigator to be excessive and noncompliant to study 
procedures.
The patient’s basal insulin during the study can be dosed at any time and should be taken at 
approximately the same time each day. Patients should use the same basal insulin regimen (type 
and dosing frequency) throughout the study.  Patients will record all insulin doses in the study 
diary as instructed.
Patients will be required to collect glucose values at least 4 times (before meals and bedtime) 
each day using the BG meter provided or a personal CGM/FGM that is approved for non-
adjunctive use; i.e. results may be used to make insulin dosing decisions per their local country 
regulations (Section 9.1.5).  The investigator will review glucose values at office and telephone 
visits in order to determine any insulin dose adjustments.  Once BG targets are achieved and 
basal and prandial dose titration has been optimized, daily 4-point glucose testing frequency and 
timing may be adjusted at the investigator’s discretion in consultation with patient and 
caregiver. Effort should be made to reach the BG target recommendations provided 
(Table ITSB.4).  


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7.2.1.2.1. Basal Insulin Adjustment
Basal insulin should be adjusted during the lead-in period by the patient or caregiver in 
anticipation of increased activity, individual patient needs or to facilitate optimal prandial 
insulin dosing to achieve or maintain glucose targets with an emphasis on the pre-breakfast BG.
Adjustment of basal insulin doses may continue throughout the study treatment period in order 
to achieve or maintain glycemic targets and for safety reasons.  The prescribed basal insulin 
dose is determined by, and the responsibility of, the investigator in consultation with the patient 
or caregiver. Additional discussion between visits may be required to enable the patient to reach 
glycemic targets and will be determined by the investigator.  
7.2.1.2.2. Prandial Insulin Adjustment
Prandial insulin should be titrated during the treatment period in order to reach optimal dosing 
and achieve glucose targets.  Reasonable efforts should be made to achieve these targets during 
the first 12 weeks, however prandial insulin dose adjustments may continue throughout the 
treatment period in order to achieve or maintain glycemic targets or for safety reasons such as 
hypoglycemia or unacceptable hyperglycemia.  The prescribed prandial insulin dose is 
determined by, and the responsibility of, the investigator in consultation with the patient or 
caregiver.  Modifications in the calculation of the insulin dose may be influenced by other 
clinical circumstances and safety considerations known to the investigator.  
Additional postprandial glucose monitoring may be considered during the days following 
transition to study insulin at the discretion of the investigator. Patients may use their usual 
correction factor (CF) or insulin sensitivity factor (ISF) to determine dose needed to correct a 
high BG to their target level. This may be in addition to their meal-related dose.  Investigators 
should instruct patients and caregivers of the potential for hypoglycemia if prandial insulin is 
given too frequently to a previous IP injection (insulin stacking).  
Patients may determine their prandial IP dose by pattern adjustment or carbohydrate counting, 
but they should maintain the same dosing method throughout the study.  

Pattern adjustment: The patient is prescribed a fixed dose or dose range of insulin for each 
meal.  The fixed insulin dose may be individualized for each meal.

Carbohydrate counting: The patient performs carbohydrate counting for prandial insulin 
dosing; prandial insulin dose is based upon the estimated carbohydrate content of the 
meal (as unit of insulin per grams carbohydrate).  
Based on the patient’s individual needs and glucose values, the insulin to carbohydrate ratio and 
CF should be assessed and adjusted as often as needed in order to meet the target glucose values
described in Table ITSB.4.  Postprandial SMBG values from 7-point SMBG profiles should also 
be evaluated for optimization of prandial insulin dosing.
For patients who are using pattern adjustment, the prandial insulin dose should be assessed and
adjusted as often as needed in order to achieve glucose targets.  


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Patients should attempt to eat 3 meals (morning, mid-day, and evening) with at least 3 doses of 
meal-related IP every day.  Patients may also eat a snack and inject insulin to cover the 
carbohydrates eaten if that is their usual practice.  Patients will administer IP to correct high BG 
using their usual method for determining a correction dose.  Adjustments in insulin dosage 
should also take into account individual lifestyle changes (such as exercise, illness, or stressful 
events) that may affect the insulin dose needed.  
7.3.
Blinding
This is a double-blind study; both treatment arms, LY900014 and Humalog, will be administered 
immediately prior to each meal in a double-blind manner.  Investigators, patients, and study site 
personnel will be blinded to assigned insulin regimen throughout the study. A third open-label 
treatment group consists of LY900014 administered up to 20 minutes after the start of a meal 
(LY900014+20).  To preserve the blinding of the study, the Lilly study team will remain blinded 
throughout the study; only a minimum number of Lilly personnel will see the randomization 
table and treatment assignments before the study is complete.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system. This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment. Unblinding events are recorded and reported by the IWRS.  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient safety must always be the first consideration in making such a determination.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale in the patient notes and notify Lilly as soon as 
possible.  
7.4.
Dosage Modification
See Section 7.2.1.  
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for confirming appropriate temperature 
conditions have been maintained during transit for all study treatments received and that any 
discrepancies are reported and resolved before use of the study treatment.  
Only patients enrolled in the study may receive IP, and only authorized site staff may supply or 
administer study treatment.  All study treatments should be stored in an 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.
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.


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In-use insulins should be maintained at room temperature and refrigerated material should be 
warmed to near room temperature before injecting.  In-use insulin must not be used after 
28 days.
The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The investigator or designee will assess patient compliance at each visit, based on a review of the 
patient’s glycemic control using available glucose values and HbA1c results, adherence to the 
visit and treatment schedule, and completion of the study diary.  Patients who are deemed 
noncompliant will receive additional diabetes education and training, as required, and the 
importance of compliance with the protocol will be reinforced. Patients who, in the opinion of 
the investigator, are deemed consistently noncompliant may be discontinued from IP or from the 
study. No specific study data will be collected for analysis of treatment compliance.
7.7.
Concomitant Therapy
All concomitant therapies that are part of routine care are allowed and can be used during the 
study. Those listed in the exclusion criteria cannot be used.  The subject should be encouraged 
to report any new concomitant medications after initiating the medication.  Please check with the 
study team if you have any concerns or questions about a medication the subject is taking.  
Prohibited and restricted concomitant medications are listed below.  
The following concomitant medications are NOT allowed at any time during the study 

Insulin glargine U-300, insulin degludec U-200, 

Afrezza® (inhaled insulin) 

premixed human or analog insulin

Any noninsulin diabetes treatment therapy
The following concomitant medications ARE allowed for up to a total of 14 days during the 
study

Regular human insulin, NPH or a nonstudy rapid analog insulin

Systemic glucocorticosteroid 
o
Including; intravenous, intramuscular, SC, or oral
7.8.
Treatment after the End of the Study
LY900014 will not be made available to patients after conclusion of the study.  Rapid-acting 
insulin analogs are available in all countries for use as prandial insulin.
After discontinuation of IP at the end of the treatment period or earlier, it is recommended that 
patients return to their pre-study basal and prandial insulin; however, the choice of insulin 
therapy should be made by the investigator in consultation with the patient or caregiver.  


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Investigators should provide patients with appropriate guidance for glucose monitoring and 
insulin dose adjustment throughout the follow-up period in order to maintain glycemic control.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
In the event that a patient is discontinued from the study treatment, the investigator should 
encourage the patient to remain in the study for continued safety monitoring.  If the patient 
decides to continue in the study without IP, no early termination procedures will be completed.  
Patients will continue study visits through the safety follow-up.
Lilly recognizes the importance of complete data collection.  This study includes elements to 
minimize missing data.  Randomized patients who are discontinued from IP before study 
completion are encouraged to remain in the study for continued monitoring.  For patients who 
remain in the study after early discontinuation of IP, both efficacy (including HbA1c) and safety 
data will be collected at scheduled visits.  The difference between stopping IP and discontinuing 
the study will be explained to patients as part of the informed consent, and patients will be 
encouraged to continue in the study even if they stop study drug.  In addition, study site 
investigators will be trained on the importance of complete data collection, with additional 
re-education of sites and patients as necessary.  
8.1.1.Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of IP are:

Subject Decision
o
The patient/or the patient’s designee, for example, parents or legal 
guardian requests to discontinue IP.

The investigator may decide that the patient should stop IP.  If this decision is 
made because of an AE, SAE, or a clinically significant laboratory value, the 
study drug is discontinued for that patient and appropriate measures are to be 
taken.  Lilly or its designee is to be alerted.

The patient becomes pregnant.

An investigator, study site personnel performing assessments, or patient is 
unblinded, the patient must discontinue IP.  

The patient, for any reason, requires treatment with another therapeutic regimen 
or therapeutic agent that has been demonstrated to be effective for treatment of 
the study indication with the exception of those described in Section 7.7.  
Discontinuation from IP should occur prior to introduction of the new agent.

Frequent use of prohibited concomitant medication, see Section 7.7.

Patient has not taken IP for more than 14 consecutive days.

Patient discontinuation is recommended by the DMC.

Discontinuation due to a hepatic event or liver test abnormality.  Patients who 
are discontinued from the IP due to a hepatic event or liver test abnormality 
should have additional hepatic safety data collected via case report form (CRF).


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Discontinuation of the IP for abnormal liver tests should be considered by the 
investigator when a patient meets 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

ALT or AST >8×ULN

ALT or AST >5×ULN for more than 2 weeks

ALT or AST >3×ULN and total bilirubin level (TBL) >2×ULN or 
international normalized ratio >1.5

ALT or AST >3×ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

alkaline phosphatase (ALP) >3×ULN

ALP >2.5×ULN and TBL >2×ULN

ALP >2.5×ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
8.1.2. Temporary Discontinuation from Study Treatment
Patients who temporarily discontinue the IP may have used non-study insulins.  The patient will 
be allowed to resume IP if they have not taken IP for up to a total of 14 days on up to two 
occasions.
8.1.3.Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor clinical research physician (CRP) agree that
it is medically appropriate to continue, the investigator must obtain documented approval from 
the sponsor CRP to allow the inadvertently enrolled patient to continue in the study with or 
without treatment with IP. Safety follow-up is as outlined in Section 2 (Schedule of Activities
Table ITSB.1), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

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

participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice


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
investigator decision
o
the investigator decides that the patient should be discontinued from the 
study
o
if the patient, 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

patient decision
o
the patient or the patient’s designee, for example, parents or legal guardian
requests to be withdrawn from the study
Patients discontinuing from the study prematurely for any reason should complete ED and other 
safety follow-up per Section 2 (Schedule of Activities Table ITSB.1.), Section 9.2 (Adverse 
Events), and Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient 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 patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities in Table ITSB.1.
Appendix 2 lists the laboratory tests that will be performed for this study.  Appendix 5 provides a 
summary of the maximum number and volume of invasive samples, for all sampling, during the 
study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy and Safety Assessments
9.1.1. Primary Efficacy Assessments
The primary efficacy measure is the change from baseline to Week 26 in HbA1c.
9.1.2. Secondary Efficacy Assessments
The following secondary efficacy measures will be collected at the times shown in the Schedule 
of Activities (Section 2, Table ITSB.1).  

Prandial, basal, and total insulin doses (units and units/kg) and prandial/total 
insulin ratio

Proportion of patients with HbA1c<7.0% and <7.5%

SMBG 7-point profiles (fasting, 1-hour post morning meal, pre midday meal, 1-
hour post midday meal, pre evening meal, 1 hour post evening meal, and bedtime)
o
1-hour PPG excursions
o
within- and between-day glucose variability measured by the coefficient 
of variation and standard deviation (SD).
9.1.3. Safety Assessments

Rate and incidence of hypoglycemia:
o
documented post-dose
o
documented
o
severe

Adverse events

Laboratory value assessments

Weight.


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9.1.4. Appropriateness of Assessments
All efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to diabetes mellitus.
9.1.5. Study Procedures
During this study, the patient or caregiver will be responsible for the following:
Every day

Answering study diary questions for all hypoglycemia events

Obtaining glucose value before meals and at bedtime
At least 3 days before all visits (telephone and office) 

Recording daily basal dose, including date 

Recording prandial doses, including date and time
At least 3 days during the 2 weeks before Visits 4, 10, and 15

Collecting 3 separate 7-point SMBG profiles using the study provided 
meter and recording in study diary
9.1.5.1.
Self-Monitored Blood Glucose
A study BG meter will be provided to all patients who meet screening criteria and should be used 
to obtain all 7-point SMBG values throughout the study.  Patients will be required to collect 
glucose values at least 4 times (before meals and bedtime) each day using the BG meter provided 
or a personal CGM/FGM that is approved for non-adjunctive use, (i.e. results may be used to 
make insulin dosing decisions) per their local country regulations (Section 9.1.5.2).
Patients who do not wear a personal CGM/FGM will use the study provided BG meter; 

to perform all 4-point and 7-point glucose values,

to record glucose values in their study diary, and 

to perform the glucose assessment for hypoglycemia events.  
These glucose values are used by the investigator for dose titration as well as to assess patient 
safety during the study. Once BG targets are achieved and basal and prandial dose titration has 
been optimized, daily 4-point glucose testing frequency and timing may be adjusted at the 
investigator’s discretion (in consultation with patient and caregiver) to allow for individual 
patient needs and lifestyle changes. Missing values in SMBG profiles will not be considered 
protocol deviations unless, in the opinion of the investigator, they are excessive and reflect 
noncompliance with the protocol. Patients should be encouraged to eat 3 meals on the days that 
the 7-point SMBG is monitored. 
Patients should perform SMBG with the study provided BG meter whenever hypoglycemia is 
experienced or suspected (with or without symptoms), when there is perceived increased risk as 
related to changes in dietary intake, physical activity, or inadvertent or atypical insulin dosing.  
Patients who wear personal CGM/FGM should use the study provided BG meter to confirm 
hypoglycemia symptoms or a CGM value ≤ 70mg/dL (3.9 mmol/L).


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Collection Schedule for Glucose Values
Glucose Value
How Many
When
4-point
(SMBG or 
CGM/FGM)
Daily
Daily
7-point
(SMBG)
9 total
3× during the 2 weeks prior to Visits 4, 10, and 15.
Glucose Values
Timing
4-Point (SMBG or CGM/FGM)
7-Point (SMBG)
Fasting (pre morning meal)
X
X
1 Hour post morning meal
X
Pre midday meal
X
X
1 Hour post midday meal
X
Pre evening meal
X
X
1 Hour post evening meal
X
Bedtime
X
X
9.1.5.2.
Use of Personal CGM or FGM
Patients will be allowed to use their personal CGM or FGM.  Patients who choose to wear their 
personal CGM/FGM device should make every attempt to wear it throughout the entire study.  
Personal CGM/FGM use (yes/no) will be recorded at Visit 4. 
Patients who wear a personal CGM/FGM: 

will collect 4-point glucose values using study provided BG meter OR from the 
personal CGM device if approved for non-adjunctive use. BG values from a personal 
device are to be entered into the study diary OR investigators have the discretion to 
download glucose data from a personal CGM/FGM device as per usual practice

should perform 7-point glucose values by fingerstick using study-provided BG meter, 
and

should use the study-provided BG meter to confirm hypoglycemia symptoms or a 
CGM value ≤ 70mg/dL (3.9 mmol/L). 
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate healthcare option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the patient to discontinue the IP before completing the study.  The patient should 
be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 


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reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via electronic 
data entry the occurrence and nature of each patient’s preexisting conditions, including clinically 
significant signs and symptoms of the disease under treatment in the study.  In addition, site 
personnel will record any change in the condition(s) and any new conditions as AEs. 
Investigators should record their assessment of the potential relatedness of each AE to protocol 
procedure and/or IP, via electronic data entry.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause-and-effect relationship between the IP, 
study device and/or study procedure, and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s IP is discontinued as a result of an AE, study site personnel must report this to Lilly 
or its designee via electronic data entry, clarifying, if possible, the circumstances leading to any 
dosage modifications or discontinuations of treatment.  
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent 1 of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
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
when a condition related to the prefilled pen necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or 
permanent damage to a body structure, the serious outcome of “required 
intervention” will be assigned

severe hypoglycemia events:  episodes of severe hypoglycemia as determined by 
the investigator according to the definition provided in Sections 9.4.1 and 9.4.2
must be reported as SAEs.
All AEs occurring after signing the ICF are recorded in the CRF and assessed for serious criteria.  
The SAE reporting to the sponsor begins after the patient has signed the ICF and has received IP.  
However, if an SAE occurs after signing the ICF, but prior to receiving an IP, the SAE should 
only be reported to the sponsor as per SAE reporting requirements and timelines if it is 
considered reasonably possibly related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
Pregnancy (during maternal exposure to IP) does not meet the definition of an AE.  However, to 
fulfill regulatory requirements, any maternal pregnancy should be reported following the SAE 
process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient disposition CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to IP or procedure.  United States 21 CFR 
312.32, European Union Clinical Trial Directive 2001/20/EC, and the associated detailed 
guidances or national regulatory requirements in participating countries require the reporting of 
SUSARs. Lilly has procedures that will be followed for the identification, recording, and 
expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on IPs 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.
Patients will be instructed to contact the investigator as soon as possible if he or she has a
complaint or problem with the IP or drug delivery system so that the situation can be assessed.


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
Complaints must be reported by site staff within 24 hours of notification to the clinical 
site/study personnel or within 24 hours of study/site personnel becoming aware of a 
product issue, regardless of the availability of the complaint sample.  

Retain the IP under appropriate storage conditions, if available or when obtained, until 
instructed to return it to Lilly.  

Product complaints for non-Lilly products (including concomitant drugs) that do not have 
a Lilly Product Batch or Control number are reported directly to the manufacturer per 
product label.

Follow the instructions outlined in the Product Complaint Form for other reporting 
requirements.
9.3.
Treatment of Overdose
Excess insulin administration may result in hypoglycemia.  Refer to the IB for LY900014 and 
product label for Humalog.


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9.4.
Safety
9.4.1. Hypoglycemia
Patients are encouraged to perform SMBG whenever hypoglycemia may be suspected, either by 
symptoms experienced or perceived increased risk as related to dietary intake, physical activity,
or inadvertent or atypical insulin dosing.  All patients will be instructed to treat a BG level 
≤70 mg/dL (3.9 mmol/L) as hypoglycemia.
If a hypoglycemia event is suspected, patients should measure the BG value using the study 
provided meter and record the BG value in the diary, any associated symptoms, and the 
treatment administered in the study diary.  The patient should contact the site as necessary.  All 
hypoglycemia events (severe and non-severe) must be reported on the hypoglycemia electronic 
case report form (eCRF); see below and Section 9.4.2.  All episodes of severe hypoglycemia
must be reported as SAEs on the AE eCRF page and on the SAE eCRF page.  Reports of 
hypoglycemia will be classified by the investigator as “severe” or “not severe” based upon data 
collected in the patient diary and in consultation with the patient.  Episodes of hypoglycemia not 
meeting the criteria for severe hypoglycemia should not be reported as an AE.  
Hypoglycemia will be described using the following definitions:

Documented Glucose Alert; BG≤70 mg/dL (3.9 mmol/L):  
o
Documented symptomatic hypoglycemia:  an event with typical symptoms of 
hypoglycemia.  
o
Documented asymptomatic hypoglycemia:  an event without typical symptoms of 
hypoglycemia.  
o
Documented unspecified hypoglycemia:  with no information about symptoms of 
hypoglycemia available (this has also been called unclassifiable hypoglycemia).

Documented Clinically Significant Hypoglycemia with similar criteria as above,
except for threshold BG<54 mg/dL (3.0 mmol/L)
o
Documented symptomatic hypoglycemia
o
Documented asymptomatic hypoglycemia
o
Documented unspecified hypoglycemia

Severe Hypoglycemia:  during these episodes, patients have an 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.  Blood glucose
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of BG concentration to normal is considered sufficient 
evidence that the event was induced by a low BG concentration 
(BG≤70 mg/dL [3.9 mmol/L]).  
o
Note:  Young children will frequently require assistance with treatment of 
hypoglycemia but are not experiencing signs of altered mental status or cognitive 
impairment.  Final determination should be made by the investigator and based on a 
severe hypoglycemia event meeting the description provided above.

Other Hypoglycemia:


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o
Nocturnal hypoglycemia:  any documented hypoglycemic event (including severe 
hypoglycemia) that occurs between bedtime and waking.  
o
Probable symptomatic hypoglycemia:  an event during which symptoms are 
present, but BG measurement was not reported.  
o
Overall (or total) hypoglycemia:  this category combines all cases of hypoglycemia 
(documented hypoglycemia and probable symptomatic hypoglycemia, including 
severe hypoglycemia) excluding the events of relative hypoglycemia.  Nocturnal and 
severe hypoglycemia are special cases of documented or probable hypoglycemia.  If 
an event of hypoglycemia falls into multiple subcategories, the event is only counted 
once in this category.
9.4.2. Severe Hypoglycemia
Young children, because of their age, will frequently require assistance with treatment of 
hypoglycemia, but are not experiencing signs of changes in mental status. The final 
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 child to have required assistance (that 
is, altered mental status or cognitive impairment) and is not predicated on the report of a child 
simply having received assistance.  
9.4.3. Vital Signs, Height, and Weight
For each patient, vital signs, height, and weight measurements should be conducted according to 
the Schedule of Activities (Section 2, Table ITSB.1) and following the study-specific 
recommendations.
Any clinically significant findings from vital sign measurement that result in a diagnosis and that 
occur after the patient receives the first dose of study treatment should be reported to Lilly or its 
designee as an AE via electronic data entry.
9.4.4. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2, Table ITSB.1).  
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.  
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of IP should be reported to Lilly or its designee as an AE
via electronic data entry.
9.4.5. Immunogenicity Assessments
Blood samples for immunogenicity testing will be collected for the assessment of anti-insulin 
lispro antibodies as specified in the Schedule of Activities (Section 2, Table ITSB.1).  This 
assessment will be performed using a validated assay at a laboratory approved by the sponsor.  


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Samples will be retained for a maximum of 15 years after the last patient visit or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
LY900014.  Any samples remaining after 15 years will be destroyed. 
9.4.6. Safety Monitoring
In compliance with international regulations and Good Clinical Practice guidelines, Lilly actively 
monitors and evaluates safety information for investigational drugs on an ongoing basis during 
the clinical trial program.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring board (an advisory group for this study 
formed to protect the integrity of data; refer to Interim Analyses section [Section 10.3.8]) can 
conduct additional analyses of the safety data.
The data and safety monitoring committee (DMC) consisting of pediatric experienced members 
external to the study team will review safety results at least once during the study.  The DMC 
comprises those individuals responsible for the evaluation and interpretation of the results from 
the interim analysis.  The DMC for this study will be conducted as an independent DMC.  
Therefore, the members of the DMC are external to Lilly.  Further details pertaining to the DMC 
activities may be found in the DMC charter.  Unblinding details are specified in the unblinding 
plan section of the statistical analysis plan (SAP).  
Only the DMC is authorized to evaluate unblinded interim safety analyses.  Study sites will 
receive information about interim results ONLY if they need to know for the safety of their 
patients.
9.4.6.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT≥3×ULN, ALP≥2×ULN, or elevated TBL≥2×ULN, 
liver testing (Appendix 4) should be repeated within 3 to 5 days, including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels.  
Hepatic Safety Data Collection
Additional safety data should be collected via the CRF if 1 or more of the following conditions 
occur: 

elevation of serum ALT to ≥5×ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2×ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2×ULN on 2 or more consecutive blood tests

patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests


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
hepatic event considered to be a SAE.
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics
Not applicable.
9.8.
Health Economics
Not applicable.


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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 708 patients will be randomized in order that 600 patients complete the study 
through the primary endpoint at Week 26.
Patients will be randomized in a 2:2:1 ratio to double-blind LY900014 dosed 0 to 2 minutes 
before meals, double-blind Humalog dosed 0 to 2 minutes before meals, or open-label 
LY900014 dosed up to 20 minutes after the start of a meal. Stratification will be by country, 
HbA1c stratum (≤8.0%, >8.0%), type of basal insulin (insulin glargine, insulin detemir, or 
insulin degludec), and age group (1 to <12 years, 12 to <18 years).  
Assuming a NIM of 0.4%, no true difference between treatment groups and an SD of 1.1%, 240 
completers for each double-blind treatment group will provide greater than 95% power to show 
noninferiority between LY900014 and Humalog using the upper limit of a 2-sided 95% CI 
(LY900014−Humalog).  This sample size also has more than 80% power to show noninferiority 
between LY900014 and Humalog using a 0.3% NIM at 26 weeks.  
With the assumption a difference no larger than 0.07% between treatment groups and a SD of 
1.1%, 240 completers of double-blind Humalog dosed 0 to 2 minutes before meals and 120 
completers of open-label LY900014 dosed up to 20 minutes after the start of a meal will provide 
approximately 76% power to show noninferiority between open-label LY900014+20 and double-
blind Humalog using a NIM of 0.4%. .
Assuming a 15% dropout rate during 26 weeks of treatment, approximately 708 patients (283 
patients in each double-blind treatment group and 142 patients in the open-label treatment group) 
will need to be randomized.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Entered 
All patients who give informed consent.
Randomized
All patients who are randomly assigned to study treatment at Visit 4.  Treatment group will 
be defined on the basis of the treatment the patients are assigned.
Safety
All randomized patients who receive at least 1 dose of the randomly assigned investigational 
product (IP). Treatment group will be defined on the basis of the treatment the patients are 
assigned.
Completer
Patients included in the randomized population who have completed Week 26 of study 
treatment without permanent discontinuation of IP.  Treatment group will be defined on the 
basis of the treatment the patients are assigned.  
Per Protocol
Patients included in the randomized population who have completed Week 26 of study 
treatment without permanent discontinuation of IP and without significant protocol 
deviations through Week 26 that would significantly impact the primary objective. 
Treatment group will be defined on the basis of the treatment the patients actually receive.


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10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol.  Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
SAP or the clinical study report (CSR).  Additional exploratory analyses of data will be 
conducted, as deemed appropriate.
The primary analysis is for the treatment period through Week 26.
Efficacy analyses will be conducted on all randomized patients according to the treatment the 
patients are assigned. The analyses for the primary and gated objectives will be performed for 
the efficacy estimand, including data collected prior to permanent discontinuation of IP and for 
the ITT estimand, including all data collected regardless of IP use.  The primary endpoint will 
also be analyzed using the PP and Completer populations.
Unless otherwise specified, the efficacy analyses for other secondary objectives and exploratory 
objectives will be performed for the efficacy estimand.  When change from baseline is included 
as a response variable of analysis models, the patient will be included in the analysis only if a 
baseline and at least 1 postbaseline measurement are available.  
Safety analyses will be conducted on the Safety population.  Analyses of AEs will include 2 sets 
of analyses, unless otherwise specified.  The first set of analyses will include data collected prior 
to permanent discontinuation of IP.  The second set of analyses will include all data collected 
during the course of the entire study, including the follow-up visit, regardless of IP use.  
Analyses of hypoglycemia will use data collected prior to permanent discontinuation of IP, while 
analyses for post treatment may be performed as needed.  Analyses of safety laboratory 
measurements will be performed on all data during the planned treatment period regardless of IP 
use.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and CIs will be calculated at 95%, 2-sided.  All tests of interactions between treatment 
groups and other factors will be conducted at a 2-sided alpha level of 0.10.  Countries in similar 
geographic regions with fewer than 10 patients, based on all randomized population, will be 
pooled to achieve a pooled country of at least 10 patients. All analyses using country in the 
model will use a pooled country, unless otherwise specified.  The final pooling by country and 
geographic region will be finalized prior to data lock.
Baseline is defined as the last non-missing measurement at or before the randomization 
visit (Visit 4), unless otherwise specified.  
A restricted maximum likelihood-based, mixed-effect model repeated-measure (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 


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the analysis of the primary efficacy endpoint of change from baseline in HbA1c will include the 
fixed class effects of treatment, strata (pooled country, type of basal insulin, and age group), 
visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline 
value.  For analyses of variables other than HbA1c, the HbA1c stratum (≤8.0%, >8.0%) will be 
included in the model.  An unstructured covariance structure will be used to model the 
within-patient errors.  Significance tests will be based on least-squares (LS) means and Type III 
tests.  SAS PROC MIXED will be used to perform the analysis.  If this analysis fails to 
converge, the following covariance structures will be tested, in order:

Toeplitz with heterogeneity

Autoregressive with heterogeneity

Compound symmetry with heterogeneous variances

Toeplitz

Autoregressive

Compound symmetry without heterogeneous variances.
The first covariance structure that converges will be used.  The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom.  
An analysis of covariance (ANCOVA) will also be used to analyze continuous variables.  The 
model for the change from baseline to the Week 26 HbA1c endpoint will include treatment and 
strata (pooled country, type of basal insulin, and age group) as fixed effects and baseline as a 
covariate.  Unless otherwise stated, missing endpoints will be imputed using the
last-observation-carried-forward (LOCF) approach, using only postbaseline data.  For analyses 
of variables other than HbA1c, the HbA1c stratum (≤8.0%, >8.0%) will be included in the 
model.
For continuous measures, summary statistics will include sample size, mean, SD, median, and 
minimum and maximum for both the actual and the change from baseline measurements.  The 
LS means and standard errors derived from the analysis models will also be displayed for the 
change from baseline measurements.  Treatment comparisons will be displayed showing the 
treatment difference LS means and the 95% CIs for the treatment differences along with the 
p-values for the treatment comparisons.
For categorical measures, summary statistics will include sample size, frequency, and 
percentages.  Fisher’s exact test or Pearson’s chi-square test will be used for treatment 
comparisons.  
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
A detailed description of patient disposition will be provided.  Frequency counts and percentages 
of all patients entered, randomized, completing, and/or discontinuing from the study will be 
presented for each treatment group.  Reasons for discontinuation from study treatment and from 


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the study during the treatment period will be summarized and compared between treatment 
groups using Fisher’s exact tests.  
10.3.2.2. Patient Characteristics
Standard baseline characteristics of age, age group (Age Group 1:  1 to <12, 12 to 18 years and
Age Group 2:  1 to <6, 6 to <12, 12 to <18 years), sex, ethnicity, race, height, weight, and body 
mass index (BMI) will be summarized for all randomized patients.  Summary statistics will 
include sample size, mean, SD, median, minimum and maximum for continuous measures and 
sample size, frequency, and percent for categorical measures.  Comparisons between treatment 
groups will be performed using Fisher’s exact test or Pearson’s chi-square test for categorical 
data and an analysis of variance with treatment in the model for continuous data for all patients. 
Baseline diabetes characteristics will be summarized in a similar manner.
Preexisting conditions will be summarized by treatment group using preferred term (PT) within 
system organ class (SOC). No p-values will be reported.
10.3.2.3. Concomitant Therapy
Concomitant medications used during the treatment period will be summarized and compared 
between treatment groups using Fisher’s exact test. The type of insulin therapy at study entry 
will be compared between treatment groups using Fisher’s exact tests.  
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary objective of this study is to test the hypothesis that LY900014 is noninferior to 
Humalog on glycemic control (NIM=0.4% for HbA1c) in patients 1 to <18 years of age with 
T1D, when administered as prandial insulin (0 to 2 minutes prior to the meal), in combination 
with basal insulin for 26 weeks.  There will be 2 primary analysis methods, each tested at the full 
significance level of 0.05.  
For the US FDA submission (using the ITT estimand), the missing endpoints will be imputed by 
the copy reference approach. The reference for each treatment group is from the retrieved 
dropout patients who discontinue IP but have the measurement at the primary endpoint in the 
same treatment group. If there is only a limited number of patients in the reference group that 
leads to a failure in performing the proposed multiple imputation analysis such that the model 
cannot converge, or the number of records in the reference group is less than the number of 
records with missing data, the missing endpoints will be imputed by the patient-level observed 
baseline value plus a noise, assuming a washout of any potential treatment effect (or “return to 
baseline”). The noise follows a normal distribution with the variability estimated from the 
“washout HbA1c data”. The “washout HbA1c data” will be derived by subtracting the 
corresponding treatment mean at Week 26 from individual non-missing HbA1c values at 
Week 26. After imputation, the primary efficacy comparison will be based on the contrast 
between LY900014 and Humalog from an ANCOVA.  The model for the change from baseline 
to the Week 26 HbA1c endpoint will include treatment and strata (pooled country, type of basal 


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insulin, and age group) as fixed effects and baseline HbA1c as a covariate. The final estimates 
will be the combined estimates from at least 1000 imputations. 
For non-FDA submissions and publications, the primary efficacy comparison will be based on 
the contrast between LY900014 and Humalog at Week 26 (Visit 15) from the MMRM analysis 
of change from baseline in HbA1c, including data collected from all randomized patients prior to 
permanent discontinuation of IP through Week 26 (efficacy estimand).  The analysis model and 
selection of covariance structure are described in Section 10.3.1.
For both primary analysis approaches, LY900014 will be declared noninferior to Humalog if the 
upper limit of the 2-sided 95% CI for the LS mean difference in the change from baseline in 
HbA1c for LY900014 minus Humalog is below +0.4%.  In addition, the 95% CI for the 
treatment difference will be compared to an alternative NIM of +0.3%.  Both estimands will be 
tested at the full significance level of 0.05.  
10.3.3.1.1.Sensitivity Analyses for Missing Data
A missing-not-at-random-based analysis will be performed for both the efficacy and ITT 
estimands to assess sensitivity to departures from the missing-at-random (MAR) assumption. 
The tipping point approach that will be used is similar to progressive stress test (Ratitch et 
al. 2013).  The basic idea is to impute the missing values and add a value (delta) to the imputed 
values of the experimental group and perform an analysis for the primary endpoint on the 
delta-adjusted data set to see whether the conclusion of the primary analysis is overturned.  If 
not, a larger delta is chosen and the process is repeated until the primary result is overturned.  If 
the delta required to overturn the primary result is not a plausible departure from MAR, then the 
primary result is robust to plausible departures from MAR.  Imputation under the noninferiority 
null method, in which delta equals the NIM, will be included as a special case of the progressive 
stress test.  
For the ITT estimand, the imputation of missing data will be as described for the FDA primary 
analysis and ANCOVA on the change from baseline to Week 26 in HbA1c will be used.  
For the efficacy estimand, the copy reference approach will be used to impute missing data and 
the reference group will be the Humalog treatment group.  Imputation will be for all longitudinal 
visits.
10.3.3.1.2.Additional Analyses for the Primary Endpoint
The primary MMRM analysis model will be repeated using the PP and Completer populations to 
check the sensitivity of the analysis.  If the conclusion differs from that of all randomized 
patients, the data and analyses will be further investigated.  
A secondary analysis model for the efficacy estimand will be an ANCOVA for HbA1c change 
from baseline to Week 26 (Visit 15), using the model described in Section 10.3.1.  Missing 
endpoints will be imputed using the LOCF approach using postbaseline data only.  
10.3.3.2. Secondary Analyses
Following the successful claim of the primary objective, the assessment of noninferiority 
between LY900014+20 and Humalog and superiority between LY900014 and Humalog in 


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controlling HbA1c will use gatekeeping strategy. The noninferiority between LY900014+20 and 
Humalog will be evaluated first with the significant level of 0.05 (from the primary objective).  
Once the noninferiority is achieved, the superiority test between LY900014 and Humalog will be 
performed with the significant level of 0.05 (from the gated noninferiority objective).  Both the 
assessments will be based on the analysis approaches used for the primary objective (ITT 
estimand for FDA submission and efficacy estimand for non-FDA submissions). 
HbA1c and change from baseline in HbA1c at all timepoints will be analyzed by the same 
MMRM model used for the primary analysis for the efficacy estimand. The noninferiority in 
change from baseline in HbA1c for LY900014+20 to Humalog will be based on the same model.  
Additional continuous secondary efficacy variables, as well as the change from baseline for these 
variables, will be analyzed either by the MMRM or ANCOVA models described in 
Section 10.3.1 for the efficacy estimand.  
Treatment comparisons for the proportion of patients with HbA1c<7.0% and <7.5% will be 
analyzed using a longitudinal logistic regression with repeated measurements conducted by a 
generalized linear mixed model including independent variables of treatment, baseline HbA1c 
value, visit, baseline HbA1c by visit interaction, and treatment by visit interaction.  An 
unstructured covariance structure will be used.  As a sensitivity analysis, the proportion of 
patients with HbA1c<7.0% and <7.5% at Week 26 (Visit 15), imputed using LOCF, will be 
compared using a logistic regression model including treatment and baseline HbA1c value in the 
model.  
10.3.3.3. Tertiary/Exploratory Analyses
Continuous variables and the change from baseline for these variables will be analyzed either by 
the MMRM or ANCOVA models described in Section 10.3.3.1.  Categorical variables will be 
analyzed either by model (for example, logistic regression) or by Fisher’s exact test or Pearson’s 
chi-square test.  Analysis details for the tertiary endpoints will be described in the SAP.
10.3.4. Safety Analyses
Safety measures will include AEs, hypoglycemia, vital signs and weight, treatment exposure, 
laboratory measures, and antibodies to insulin lispro.  Analyses will be performed on data 
collected from randomization through Visit 801 for both treatment groups.  
Events that are newly reported after the first dose of IP or reported to worsen in severity from 
baseline will be considered treatment-emergent AEs (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.
The SAEs, AEs reported as reason for discontinuation from the IP or study, and TEAEs will be 
summarized in tables using the MedDRA PT, sorted by decreasing frequency within the 
LY900014 treatment group.  The TEAEs will also be summarized by PT sorted by decreasing 
frequency within SOC 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 patients from 


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the given sex.  The number and proportion of patients with at least 1 event for each type of event 
will be summarized and compared between treatment groups using Fisher’s exact test.  
Hypoglycemia rates will be summarized for periods of 30 days, 1 year, and 100 years (severe 
hypoglycemia only).  The rate of severe hypoglycemia per 100 years will be compared between 
treatment groups using the empirical method (details will be described in SAP).  For each of the 
other categories of hypoglycemia, the number of hypoglycemia events during a specific
period after randomization (for example, Weeks 0 to 12 of treatment period) will be analyzed by 
using a negative binomial regression model.  The model will include treatment and age group as 
covariates.  An offset defined as the log transformation of treatment exposure in the specific 
period (days)/365.25 days (or 30 days) will be included in the model to estimate the rate of 
hypoglycemia per year (or per 30 days).  The proportion of patients with at least 1 hypoglycemic 
event in each category during a specific period after randomization will be analyzed using a 
logistic regression model including treatment and age group as covariates.  
Continuous safety variables, as well as the change from baseline for these variables, will be 
analyzed by MMRM or ANCOVA models.  For categorical variables, Fisher’s exact test or 
Pearson’s chi-square test will be used to compare treatment groups, unless otherwise specified.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.
10.3.6. Evaluation of Immunogenicity
The treatment-emergent anti-insulin lispro antibody (denoted as
treatment-emergent antidrug antibody [TEADA] throughout this document) is based on the 
change from baseline to postbaseline in the anti-insulin lispro antibody level (percent binding). 
The TEADA can be sub-classified as either treatment-induced (not detected anti-insulin lispro 
antibody at baseline) or treatment-boosted (detected anti-insulin antibody at baseline):

treatment-induced response:  change from not detected anti-insulin lispro at baseline to 
postbaseline detected anti-insulin lispro and

treatment-boosted response:  change from detected anti-insulin lispro at baseline to 
postbaseline detected anti-insulin lispro antibody level (percent binding) at least 157% of 
the baseline value.
The summary of TEADA will be provided by treatment group. Fisher’s exact test will be used 
for the treatment comparison.
The relationship between the presence of TEADA and selected efficacy and safety measures will 
also be evaluated. Analyses details will be documented in the SAP.


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10.3.7. Other Analyses
10.3.7.1. Subgroup Analyses
The following subgroups will be analyzed using the efficacy estimand to evaluate consistency of 
treatment effects on the primary efficacy measure if there are sufficient numbers of patients in 
each treatment by subgroup (for example, 10%):

Age (Age Group 1:  1 to <12, 12 to <18 years and Age Group 2:  1 to <6, 6 to <12, 12 to 
<18 years)

HbA1c stratum (≤8.0%, >8.0%)

Type of basal insulin at randomization (insulin glargine, detemir, or degludec)

Sex (male or female)

BMI (<25, ≥25 kg/m2 and <30, ≥30 kg/m2)

Duration of diabetes (using the median as the cutoff)

Race

Ethnicity

Country

Region

Prandial insulin dosing plan (carbohydrate counting, pattern adjustment).
Analyses for HbA1c and change from baseline in HbA1c will be performed using an MMRM 
model that includes the same fixed effects given for the primary analysis model plus factors of 
subgroup, 2-way interaction of subgroup and treatment, 2-way interaction of subgroup and visit, 
and 3-way interaction of treatment, visit, and subgroup.  The interaction of subgroup and 
treatment at the primary endpoint (Week 26) will be evaluated to assess the treatment by 
subgroup interaction.  
Additional subgroup analyses may also be performed.
10.3.8. Interim Analyses
There will be no interim analysis, but safety will be monitored by a DMC.  A limited number of 
pre-identified individuals may gain access to the limited unblinded data for DMC review, as 
specified in the DMC charter.  Information that may unblind the study during the analyses will 
not be reported to study sites or the blinded study team until the study has been unblinded.
Unblinding details are specified in the unblinding plan section of the SAP and the DMC charter
or in a separate unblinding plan document.


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11.
References
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
WHO consultation. Diab Med. 1998;15(7):539-553.
Bennett P. Classification and diagnosis of diabetes mellitus and impaired glucose tolerance. In: 
Pickup JC, William G, editors. Textbook of diabetes. Vol. 1. 1st ed. Oxford: Blackwell 
Scientific Publications; 1991:p 37-44.
Casagrande SS, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting A1C, 
blood pressure, and LDL goals among people with diabetes, 1988-2010. Diab Care. 
2013;36(8):2271-2279.
Chiang JL, Kirkman MS, Laffel LM, Peters AL. Type 1 diabetes through the life span: a position 
statement of the American Diabetes Association. Diab Care. 2014;37(7):2034-2054.
[DCCT] The Diabetes Control and Complications Trial Research Group. The effect of intensive 
treatment of diabetes on the development and progression of long-term complications in 
insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986.
EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in 
Europe. Lancet. 2000;355(9207):873-876.
Humalog: EPAR: Product Information. European Medicines Agency Web site. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Summary_for_the_public/human/000088/WC500050328.pdf. Accessed August 14, 2017.
Humalog [package insert]. Indianapolis (IN): Eli Lilly and Company; 2017.
Levy M, Celermajer DS, Bourges-Petit E, Del Cerro MJ, Bajolle F, Bonnet D. Add-on therapy 
with subcutaneous treprostinil for refractory pediatric pulmonary hypertension. J Pediatr. 
2011;158(4):584-588.
Lipman TH, Levitt Katz LE, Ratcliffe SJ, Murphy KM, Aguilar A, Rezvani I, Howe CJ, Fadia S, 
Suarez E. Increasing incidence of type 1 diabetes in youth: twenty years of the Philadelphia 
Pediatric Diabetes Registry. Diab Care. 2013;36(6):1597-1603.
Orenitram (treprostinil) [prescribing information]. Research Triangle Park, NC: United 
Therapeutics Corp; 2016. 
Pettitt DJ, Talton J, Dabelea D, Divers J, Imperatore G, Lawrence JM, Liese AD, Linder B, 
Mayer-Davis EJ, Pihoker C, Saydah SH, Standiford DA, Hamman RF; SEARCH for Diabetes 
in Youth Study Group. Prevalence of diabetes in U.S. youth in 2009: the SEARCH for 
diabetes in youth study. Diab Care. 2014;37(2):402-408.
DiMeglio LA, Acerini CL, Codner E, Craig ME, Hofer SE, Pillay K, Maahs DM; International 
Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 
2018. Glycemic control targets and glucose monitoring for children, adolescents, and young 
adults with diabetes. Available at: 
https://cdn.ymaws.com/www.ispad.org/resource/resmgr/consensus_guidelines_2018_/8.glyce
mic_control_targets_a.pdf. Accessed October 24, 2018.


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[PMR] Pharmaceutical and healthcare market in CEE and CIS. Remodulin approved in 
22 European countries, also Poland. PMR Web site. Available at:
http://www.ceepharma.com/news/25318/remodulin-approved-in-22-european-countries-also-
poland. Published September 1, 2005. Accessed September 16, 2016.
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat. 2013;12(6):337-347.
Remodulin [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 
2018. Available at: https://www.remodulin.com/downloads/remodulin-
prescribinginformation.pdf. Accessed October 15, 2018.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, 
Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the 
American Diabetes Association and the Endocrine Society. Diab Care. 2013;36(5):1384-1395.
Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J 
Am Soc Nephrol. 2009;4(11):1832-1843.
Tyvaso [prescribing information]. Research Triangle Park, NC: United Therapeutics 
Corporation; 2014.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.  An adverse event 
can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BG
blood glucose
BID
twice daily (twice a day)
Blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware 
of the treatment but the patient is not, or vice versa, or when the sponsor is 
aware of the treatment but the investigator and/his staff and the patient are 
not.
A double-blind study is one in which neither the patient nor any of the 
investigator or sponsor staff who are involved in the treatment or clinical 
evaluation of the patients are aware of the treatment received.
BMI
body mass index
CGM
continuous glucose monitoring
CI
confidence interval
Cmax
maximum drug concentration
Product complaint
Product complaints are a customer’s written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, 
durability, reliability, safety, effectiveness, or performance of a Lilly product 
after it is released for distribution.
CRF
case report form
CRP/CRS
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.


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CSII
continuous subcutaneous insulin infusion
CSR
clinical study report
DMC
data and safety monitoring committee
eCRF
electronic case report form
ED
early discontinuation
Enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the 
trial are those who have been assigned to a treatment.
Enter
Patients entered into a trial are those who sign the informed consent form 
directly or through their legally acceptable representatives.
ERB
ethical review board
FDA
Food and Drug Administration
FGM
flash glucose monitoring
GFR
glomerular filtration rate
HbA1c
hemoglobin A1c
IB
Investigator’s Brochure
ICF
informed consent form
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.
ITT
Intention-to-treat:  The principle that asserts that the effect of a treatment 
policy can be best assessed by evaluating on the basis of the intention to treat 
a patient (that is, the planned treatment regimen) rather than the actual 
treatment given.  It has the consequence that patients allocated to a treatment 
group should be followed up, assessed, and analyzed as members of that 
group irrespective of their compliance to the planned course of treatment.
IWRS
interactive web response system
LLT
lowest level term
LOCF
last observation carried forward
LS
least-squares


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MAR
missing-at-random
MDI
multiple-daily-injection
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effect model repeated measure
NIM
noninferiority margin
NPH
neutral protamine Hagedorn
PAH
pulmonary artery hypertension
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PP
per-protocol
PPG
postprandial glucose
PT
preferred term
QD
once a day
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
SMBG
self-monitored blood glucose
SOC
system organ class
SUSARs
suspected unexpected serious adverse reactions
T1D
type 1 diabetes
TBL
total bilirubin level
TDD
total daily insulin dose


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TEADA
treatment-emergent antidrug antibody
TEAE
treatment-emergent adverse event:  An untoward medical occurrence that 
emerges during a defined treatment period, having been absent pretreatment, 
or worsens relative to the pretreatment state, and does not necessarily have to 
have a causal relationship with this treatment.
ULN
upper limit of normal
US
United States
WHO
World Health Organization


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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase (ALP)
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Chloride
HbA1ca
Magnesium
Cholesterol
Urinalysisa
Glucose (nonfasting)
Specific gravity
Albumin
pH
Total protein
Protein
Glucose
Pregnancy Test (females only)
Ketones
Serum pregnancy test
a
Blood
Urine pregnancy testb
Urine leukocyte esterase
Nitrite
Serologya
Anti-insulin lispro antibodies
Abbreviations:  HbA1c = hemoglobin A1c; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Assayed by local- or investigator-designated laboratory.


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Appendix 3.
Study Governance Considerations
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for the following:

Ensuring that the patient/patient’s legal representative understands the nature of 
the study, the potential risks and benefits of participating in the study, and that 
their participation is voluntary.

Ensuring that informed consent is given by each patient or legal representative.  
This includes obtaining the appropriate signatures and dates on the ICF prior to 
the performance of any protocol procedures and prior to the administration of 
investigational product.

Answering any questions the patient/ patient’s legal representative may have 
throughout the study and sharing in a timely manner any new information that 
may be relevant to the patients/patient’s legal representative’s willingness to 
continue his or her participation in the study.

Ensuring that a copy of the ICF is provided to the participant or the participant’s 
legal representative and is kept on file.

Ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the date 
the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF.  
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable as required per local laws.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.  
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council
for Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF and Assent Form must be provided 
to Lilly before the study may begin at the investigative site(s).  Lilly or its representatives must 


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approve the ICF, including any changes made by the ERBs, before it is used at the investigative 
site(s).  All ICFs must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator Brochure 
(IB) Package Insert, or Summary of Product Characteristics and updates during 
the course of the study

informed consent form and Assent Form

other relevant documents (for example, curricula vitae, advertisements)
Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Pediatric endocrinologist or diabetologist, adult endocrinologist or diabetologist, internal 
medicine, or primary care physicians with experience in the care of pediatric patients with T1D
will participate as investigators in this clinical trial.
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
An investigator will be selected by the Lilly study team to serve as the CSR coordinating 
investigator.  The sponsor’s responsible medical officer and statistician will approve the final 
CSR for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.


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Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and verify data reported to detect potential errors
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  These might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture (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.
Additionally, clinical outcome assessment data (questionnaires and self-reported diary data) will 
be collected by the subject, via a paper source document and will be transcribed by the 
investigator-site personnel into the EDC system.
Data collected via the sponsor-provided data capture system(s) will be stored at third-party sites.  
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s).  Prior to decommissioning, the investigator will 
receive 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 


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and retention.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study I8B-MC-ITSB is described in the Clinical Trial Agreement.


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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly or its designee clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-Nuclear Antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-Smooth Muscle Antibody (or Anti-Actin 
Antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Sampling Summary
This table summarizes the approximate volumes for all standard laboratory and immunogenicity 
tests during the study.  Fewer samples may actually be taken, but this will not require a protocol 
amendment.
Protocol I8B-MC-ITSB Sampling Summary
Abbreviation:  ED = early discontinuation; V = visit.
a
For rescreening patients, an additional Visit 1 blood volume draw is required.
b
Additional samples may be drawn if needed for safety purposes.
c
Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with Lilly-designated Medical Monitor.
Study Visit
V1a
V4
V7
V10
V15
ED
Total
Estimated blood volumeb, mL
10
6.5
6.5
6.5
10
10
39.5
Hepatic monitoringc
3-30 mL


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Appendix 6.
Classification of Contraceptive Methods
Post pubertal females of childbearing potential are defined as children and adolescents ≥12 years 
of age or <12 years of age who have onset of menses.  Females of childbearing potential must 
use 1 highly effective method of contraception.  
Methods of Contraception
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 lb. or 90 kg

Total abstinence

Vasectomy
Females who are not of childbearing potential include those who have undergone or who have:
a.
Female sterilization
b. Hysterectomy
c.
Menopause
d. Mullerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome [also referred to as 
congenital absence of the uterus and vagina])


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Appendix 7.
Protocol Amendment History
Protocol I8B-MC-ITSB (a) A Prospective, Randomized, Double-Blind Comparison of 
LY900014 to Humalog with an Open-Label Postprandial LY900014 Treatment Group in 
Children and Adolescents with Type 1 Diabetes; PRONTO-Peds has been amended.  The new 
protocol is indicated by amendment (b) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:


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Amendment Summary for Protocol I8B-MC-ITSB Amendment (b)
Section # and Name
Description of Change
Brief Rationale
Table ITSB.1 Schedule of Activities
Added new footnote to Screen
Clarification for restart at Visit 1 for those patients 
who need to rescreen.
6.1 Inclusion Criteria
Changed insulin daily dose range and HbA1c 
acceptable values 
Changes allow for younger and active children 
using smaller doses and adolescents who require 
more insulin during puberty. Will allow broader 
range of patients including those who are in good 
control.
6.1 Inclusion Criteria
Added language defining postpubertal females
Change clarified definition of postpubertal females 
already noted in Appendix 6.
6.4 Screen Failures
Added 1 rescreen allowed
Change made to allow1 rescreen to patients who 
who had a screen fail or unexpectedly had to 
discontinue due to COVID-19 enrollment pause.
Appendix 5 Sampling Summary
Added footnote on V1
Change made to include information on 
rescreening.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Table ITSB.1. Schedule of Activities
Screena
Lead-In
Treatment Period
Safety 
Follow-Up
EDa
b
eCRF Visit Number
1
2
3bc
4
5bc
6bc
7
8cb
9bc
10
11bc
12
13bc
14bc
15
801cd
ED
Weeks from Randomization
−5
−4
-2
0
2
4
6
8
10
12
15
18
21
24
26
28
Visit Window (±days)
3
3
3
7
7
7
7
7
7
7
7
7
7
7
7
Clinical Assessments
Demographic data ed
X
Medical history, preexisting 
conditions
X
Previous diabetes therapy
X
Record Personal CGM/FGM use 
(yes/no)
X
Heightef
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
Vital signs (sitting SBP, DBP, and 
HR)fg
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events and product 
complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Focused physical exam (including 
skin evaluation)
gh
X
X
X
X
X
X
X
X
Basal insulin dose assessmentih
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Basal insulin dose titrationij
X
X
X
X
X
X
X
X
X


I8B-MC-ITSB (b) Clinical Protocol
Page 75
LY900014
Screena
Lead-In
Treatment Period
Safety 
Follow-Up
EDa
b
eCRF Visit Number
1
2
3bc
4
5bc
6bc
7
8cb
9bc
10
11bc
12
13bc
14bc
15
801cd
ED
Weeks from Randomization
−5
−4
-2
0
2
4
6
8
10
12
15
18
21
24
26
28
Visit Window (±days)
3
3
3
7
7
7
7
7
7
7
7
7
7
7
7
Ancillary Supplies/Diaries/IP
Dispense blood glucose meter and 
ancillary supplies and complete 
trainingj,k,l
X
X
X
X
X
Diabetes education and nutrition 
counselingkl
X
Dispense study diaries and 
complete trainingkl
X
X
X
X
X
Collect study diaries
X
X
X
X
X
X
Dispense IP
X
X
X
X
X
Train on collecting 4- and 7-point 
SMBG profileslm
X
Laboratory Assessments
Pregnancy test, serum/urine 
(applicable females only)mn
X
X
a
Patients who rescreen will start at Visit 1..


I8B-MC-ITSB (b) Clinical Protocol
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LY900014
6.1.
Inclusion Criteria
Patients are eligible to be included in the study, only if they meet all the following criteria at 
screening:
[5] Have been treated with only one 1 of the following basal insulins for at least 
the last 90 days: 
a.
insulin glargine U-100 (QD or BID), or
b. insulin detemir U-100 (QD or BID), or
c.
insulin degludec U-100 (QD)
[6] Use a total daily dose of insulin 0.35 to ≤1.95 U/kg.
a.
TDD can be the average of previous 3 to 7 days 
[7] Have an HbA1c value ≥6.5% and ≤9.5%, HbA1c value ≤9.9% according to 
the central laboratory.  
[8] Male patients: 
a.
no male contraception required, except in compliance with specific local 
government regulation
[9] Female patients of childbearing potential:
a.
Post pubertal females of childbearing potential are defined as children and 
adolescents ≥12 years of age or <12 years of age who have onset of 
menses  
6.4.
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 when results are not available from the 
original sample.or were required to unexpectedly discontinue from the study during screening or 
lead-in period (e.g., due to enrollment pause related to the COVID-19 public health emergency) 
are allowed 1 rescreening.  
All patients that rescreen will restart at Visit 1 and complete all screening procedures. 


I8B-MC-ITSB (b) Clinical Protocol
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Appendix 5.
Sampling Summary
Protocol I8B-MC-ITSB Sampling Summary
Abbreviation:  ED = early discontinuation; V = visit.
a
For rescreening patients, an additional Visit 1 blood volume draw is required.
ab Additional samples may be drawn if needed for safety purposes.
bc Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with Lilly-designated Medical Monitor.
Study Visit
V1aV1
V4
V7
V10
V15
ED
Total
Estimated blood volume,ab, mL
10
6.5
6.5
6.5
10
10
39.5
Hepatic monitoringbc
3-30 mL


Leo Document ID = 6ec65f49-6319-4aff-8f32-73e9b233e460
Approver: 
Approval Date & Time: 30-Apr-2020 19:17:05 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 30-Apr-2020 19:33:05 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
ITSB SAP v3 
 
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Humalog with an Open-
Label Postprandial LY900014 Treatment Group in Children and Adolescents with Type 1 
Diabetes PRONTO-Peds 
 
NCT03740919 
 
 
Approval Date: 20-Jan-2021 


I8B-MC-ITSB Statistical Analysis Plan Version 3
Page 1
LY900014
1.
Statistical Analysis Plan:  
I8B-MC-ITSB:  A Prospective, Randomized, Double-Blind 
Comparison of LY900014 to Humalog with an Open-Label 
Postprandial LY900014 Treatment Group in Children and 
Adolescents with Type 1 Diabetes
PRONTO -Peds
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly
and Company or its subsidiaries.  
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY900014
Study I8B-MC-ITSB is a Phase 3, prospective, randomized, outpatient, multinational, 
multicenter, parallel, active-controlled study conducted in children and adolescent patients 
with T1D currently using a MDI regimen.  
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8B-MC-ITSB
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly on 
07 March 2019
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly on 
13 August 2020
Statistical Analysis Plan Version 3 electronically signed and approved by Lilly on date
provided below.
Approval Date: 20-Jan-2021 GMT


I8B-MC-ITSB Statistical Analysis Plan Version 3
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LY900014
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I8B-MC-ITSB:  A Prospective, 
Randomized, Double-Blind Comparison of LY900014 to Humalog 
with an Open-Label Postprandial LY900014 Treatment Group in 
Children and Adolescents with Type 1 Diabetes PRONTO -Peds........................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
5.
A Priori Statistical Methods ................................................................................................9
5.1.
General Considerations ..................................................................................................9
5.2.
Adjustments for Covariates ..........................................................................................13
5.3.
Handling of Dropouts or Missing Data.........................................................................13
5.4.
Multicenter Studies ......................................................................................................14
5.5.
Multiple Comparisons/Multiplicity...............................................................................14
5.6.
Patient Disposition .......................................................................................................14
5.7.
Patient Characteristics ..................................................................................................15
5.8.
Treatment Compliance .................................................................................................15
5.9.
Important Protocol Deviations......................................................................................15
5.10. Concomitant and Prior Therapy....................................................................................16
5.11. Efficacy Analyses ........................................................................................................16
5.11.1.
Primary Outcome and Methodology.....................................................................16
5.11.2.
Additional Analyses of the Primary Outcome.......................................................17
5.11.3.
Sensitivity Analyses for Missing Data..................................................................18
5.11.4.
Analysis of Gated Objectives ...............................................................................19
5.11.5.
Other Secondary Efficacy Analyses .....................................................................19
5.11.6.
Health Outcomes Analyses...................................................................................20
5.11.7.
Analyses of Exploratory Objectives .....................................................................20
5.12. Safety Analyses............................................................................................................21
5.12.1.
Extent of Exposure...............................................................................................21
5.12.2.
Adverse Events ....................................................................................................21
5.12.3.
Deaths..................................................................................................................23
5.12.4.
Hypoglycemic Events and Other Adverse Events.................................................23
5.12.4.1.
Hypoglycemic Events.....................................................................................23
5.12.4.2.
Systemic Hypersensitivity Reaction................................................................26
5.12.4.3.
Injection Site Reaction....................................................................................26
5.12.4.4.
Hepatobiliary Events ......................................................................................26


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LY900014
5.12.4.4.1.
Treatment-Emergent Potential Hepatic Disorder.......................................26
5.12.4.4.2.
Liver Enzyme Lab Values.........................................................................27
5.12.4.4.3.
Treatment-Emergent Elevation of Liver Enzyme Lab 
Values ......................................................................................................27
5.12.5.
Clinical Laboratory Evaluation.............................................................................29
5.12.6.
Vital Signs and Other Physical Findings...............................................................29
5.12.7.
Immunogenicity...................................................................................................30
5.12.7.1.
Treatment Emergent Anti-Insulin Lispro Antibody.........................................31
5.12.8.
Patient Narratives.................................................................................................32
5.13. Subgroup Analyses.......................................................................................................32
5.13.1.
Subgroup Analyses for HbA1c.............................................................................32
5.13.2.
Subgroup Analyses for Hypoglycemic Events......................................................33
5.14. Interim Analyses and Data Monitoring.........................................................................34
5.15. Clinical Trial Registry Analyses...................................................................................34
6.
Unblinding Plan................................................................................................................36
6.1.
Safety Monitoring ........................................................................................................36
6.2.
Site Level Unblinding ..................................................................................................36
6.3.
Sponsor/Trial Level Unblinding ...................................................................................36
7.
References ........................................................................................................................37
8.
Appendices .......................................................................................................................39


I8B-MC-ITSB Statistical Analysis Plan Version 3
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Table of Contents
Table
Page
Table ITSB.4.1.
Objectives and Endpoints .........................................................................7
Table ITSB.5.1.
Patient Populations ...................................................................................9
Table ITSB.5.2.
Baseline and Postbaseline Definitions and Patient 
Population by Study Period and Type of Analysis ..................................11
Table ITSB.5.3.
Treatment-Emergent Adverse Event Analysis Periods ............................23
Table ITSB.5.4.
Summary of Analyses for Endpoints Related to 
Hypoglycemia ........................................................................................25
Table ITSB.5.5.
Categorical Criteria for Abnormal Treatment-Emergent 
Blood Pressure and Pulse Measurement for Children and 
Adolescents............................................................................................30
Table APP.2.1.
Objectives and Endpoints for CGM Addendum......................................42
Table APP.2.2.
Guidance Recommended CGM Targets of Glycemic 
Control...................................................................................................46


I8B-MC-ITSB Statistical Analysis Plan Version 3
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Table of Contents
Appendix
Page
Appendix 1.
Empirical Estimation of Relative Event Rate ..........................................40
Appendix 2.
Statistical Analysis Plan for Continuous Glucose 
Monitoring (CGM).................................................................................42


I8B-MC-ITSB Statistical Analysis Plan Version 3
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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved on 7 March 2019. This version was
based on Protocol I8B-MC-ITSB approved on 26 October 2018, Protocol Addendum I8B-MC-
ITSB(1) approved on 29 October 2018, and Protocol Addendum I8B-MC-ITSB(3) approved on 
28 November 2018 and (3.1) amended on 06 March 2019.  
Statistical Analysis Plan Version 2 was approved prior to the first unblinding of the study team. 
This version is based on Protocol I8B-MC-ITSB (b) approved on 30 Apr 2020, Protocol 
Addendum (3.2) approved on 24 Jan 2020, Addendum (4) approved on 06 March 2019, 
Addendum (5) approved on 14 June 2019 and Addendum (6) approved on 17 June 2019. The 
main types of changes are:

Changing 2-sided significance level for tests of interactions between treatment groups 
and subgroup variables from 0.05 to 0.1

Adding baseline and postbaseline definition table

Adding description of subject disposition reporting during the lead-in phase due to re-
screening. Protocol Amendment (b) allows one screening for subjects that failed 
screening or terminated before randomization due to COVID-19. Structure of some 
disposition table need to be modified to account for it.

Changing the analysis population of the ITT estimand for the primary endpoint analysis
to include all randomized patients, whether or not they have a postbaseline HbA1c 
assessment. The rationale is to follow the FDA guideline to include all randomized 
patients in the analysis.

Adding a sensitivity analysis for the ITT estimand using an alternative imputation rule to 
account for patients with missing data due to COVID-19 related reasons. 
Statistical Analysis Plan Version 3 was approved prior to the first unblinding of the study team. 
The main types of changes are:

Adding a Kaplan-Meier plot of time to onset of the TEAE for TEAEs occurring in ≥1% 
of patients.

Adding subgroup analyses using the ITT estimand for HbA1c.

Adding use of personal CGM/FGM as a subgroup variable for the subgroup analyses of 
HbA1c and hypoglycemic events.

Clarifying that site personnel and patients are unblinded to the open-label treatment group 
in the Unblinding Plan.  


I8B-MC-ITSB Statistical Analysis Plan Version 3
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4.
Study Objectives
Table ITSB.4.1 shows the objectives and endpoints of the study.
Table ITSB.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
1.
To test the hypothesis that LY900014 is 
noninferior to Humalog on glycemic control 
(NIM=0.4% for HbA1c) in patients 1 to 
<18 years of age with T1D, when 
administered as prandial insulin (0 to 
2 minutes prior to the meal), in combination 
with basal insulin as part of a multiple daily 
injection regimen for 26 weeks
1.
Difference between LY900014 and Humalog in 
change from baseline to Week 26 in HbA1c 
Gated Objective
2.
To test the hypothesis that LY900014
administered as postprandial insulin up to 
20 minutes after the start of a meal, 
(LY900014+20), is noninferior to Humalog, 
administered as prandial insulin (0 to 
2 minutes prior to the meal), on glycemic 
control (NIM=0.4% for HbA1c)
2.
Change from baseline HbA1c values at Week 26
3.
To test the hypothesis that LY900014 is 
superior to Humalog in improving glycemic 
control (HbA1c) when administered as 
prandial insulin (0 to 2 minutes prior to the 
meal).
3.
Difference between LY900014 and Humalog in 
change from baseline to Week 26 in HbA1c
Other Secondary Objectives
4.
To compare LY900014, LY900014 +20, and 
Humalog with respect to the incidence and 
rate of documented post-dose hypoglycemia
4.
Rate (events/patient/year) and incidence (percent 
of patients with events) of documented post-dose 
hypoglycemic events within 1 and 2 hours after 
the prandial dose from Week 0 through Week 26
5.
To compare LY900014, LY900014 +20, and 
Humalog with respect to the incidence and 
rate of documented hypoglycemia
5.
Rate (events/patient/year) and incidence (percent
of patients with events) of documented 
hypoglycemic events from Week 0 through Week 
26
6.
To compare LY900014, LY900014 +20, and 
Humalog on the rate of severe hypoglycemic 
events
6.
Rate (events/patient/100 years) of severe 
hypoglycemic events from Week 0 through Week 
26


I8B-MC-ITSB Statistical Analysis Plan Version 3
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Objectives and Endpoints
Objectives
Endpoints
7.
To compare LY900014, LY900014 +20, and 
Humalog with respect to total, basal, and 
prandial insulin dose
7.
Change from baseline in total, basal, and 
prandial insulin doses and prandial/total insulin 
dose ratios at Week 26
8.
To compare LY900014, LY900014 +20, and 
Humalog with respect to the proportion of 
patients achieving HbA1c targets
8.
The proportion of patients with HbA1c <7% and 
<7.5% at Week 26
9.
To compare LY900014, LY900014+20, and 
Humalog with respect to 7-point SMBG
9.
Change from baseline to Week 26 in 7-point 
SMBG values
Tertiary/Exploratory Objectives
10. To compare LY900014, LY900014 +20, and 
Humalog with respect to changes in body 
weight
10. Change in weight (kg) from baseline to Week 26
11. To compare LY900014, LY900014 +20, and 
Humalog with respect to glycemic variability
11. Within-day and between-day glycemic 
variability measured by the standard deviation 
and the coefficient of variation of 7-point SMBG 
profiles
12. To compare the incidence of treatment-
emergent positive anti-insulin lispro 
antibodies for LY900014, LY900014 +20, and 
insulin lispro
12. Incidence of treatment-emergent positive anti-
insulin lispro antibodies
Abbreviations: HbA1c = hemoglobin A1c; NIM = noninferiority margin; SMBG = self-monitored blood glucose; 
T1D = type 1 diabetes.


I8B-MC-ITSB Statistical Analysis Plan Version 3
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LY900014
5.
A Priori Statistical Methods
5.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (hereafter,
Lilly).  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 this SAP and/or in the clinical study report (CSR).  Additional exploratory analyses 
will be conducted, as deemed appropriate.
For purposes of analysis, the following populations are defined in Table ITSB.5.1:
Table ITSB.5.1.
Patient Populations
Population
Description
Entered 
All patients who sign informed consent.
Enrolled
All patients who receive at least 1 dose of open-label Humalog during the lead-in period
Randomized
All patients who are randomly assigned to study treatment at Visit 4.  Treatment group will be 
defined on the basis of the treatment the patients are assigned.
Safety
All randomized patients who receive at least 1 dose of the randomly assigned IP.  Treatment 
group will be defined on the basis of the treatment the patients are assigned.
Completer
Patients included in the Randomized Population who have completed Week 26 of study 
treatment without permanent discontinuation of IP.  Treatment group will be defined on the 
basis of the treatment the patients are assigned.
Per Protocol
Patients included in the Randomized Population who have completed Week 26 of study 
treatment without permanent discontinuation of IP and without significant protocol deviations 
through Week 26 that would significantly impact the primary objective.  
Treatment group will be defined on the basis of the treatment the patients actually receive.
PedsQL
A subset of the Randomized Population who have an informed consent for the PedsQL
addendum signed by parent(s)/legal guardian(s) and questionnaires completed at both baseline 
and post-baseline.
CGM
A subset of the Randomized population who have an inform consent for CGM addendum 
signed by parent(s)/legal guardian(s) and valid CGM data at baseline or post-baseline.
Abbreviation:  CGM = continuous glucose monitoring; IP = investigational product; PedsQL = Pediatric Quality of 
Life.
Unless otherwise stated, the efficacy analyses will be conducted on the Randomized Population, 
and the safety analyses will be conducted on the Safety Population.
Efficacy analyses will be conducted on all randomized patients according to the treatment the 
patients are assigned.  The analyses for the primary and gated objectives will be performed for 
the efficacy estimand including data collected prior to permanent discontinuation of 
investigational product (IP) and for the intention-to-treat (ITT) estimand including all data 
collected regardless of IP use.  The primary endpoint will also be analyzed using the Per Protocol 
(PP) and Completer populations.


I8B-MC-ITSB Statistical Analysis Plan Version 3
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LY900014
Unless otherwise specified, the efficacy analyses for other secondary objectives and exploratory 
objectives will be performed for the efficacy estimand.  When change from baseline is included 
as a response variable of analysis models, the patient will be included in the analysis only if a 
baseline and at least 1 postbaseline measurement are available, except for the analysis for ITT 
estimand on primary endpoint.  The analysis for the ITT estimand will include all randomized 
patients with a baseline.  
Safety analyses will be conducted on the Safety Population.  Analyses of adverse events (AEs)
will include 2 sets of analyses, unless otherwise specified.  The first set of analyses will include 
data collected prior to permanent discontinuation of IP.  The second set of analyses will include 
all data collected during the course of the entire study including the follow-up visit, regardless of 
IP use.  Analyses of hypoglycemia will use data collected prior to permanent discontinuation of 
IP; while analyses for post-treatment may be performed as needed.  Analyses of safety laboratory 
measurements will be performed on all data during the planned treatment period regardless of IP 
use.
The data on IP is defined based on the following rules:

For data only measured at an office visit (for example, vital signs, safety laboratory tests,
and questionnaires) will be considered as on IP if the measurement was performed at or 
prior to the cutoff date defined as 14 days after the last IP dose date

For data collected as running records with an exact date stamp such as AEs and 
hypoglycemia events from patient diary where the dates of the measures were not tied 
with the date of an office visit, postbaseline data with dates ≤ (last study drug dose date 
+1 day) will be considered as data on IP.

For insulin dose data including both basal and prandial insulin dose, the dose used 
between the first IP dose date and the last IP dose date will be considered as data on IP.

For the 7-point self-monitored blood glucose (SMBG) profiles, the profiles measured 
after the first IP dose date and prior to the last IP dose date will be considered as data on 
IP.  
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and confidence interval (CI) will be calculated at 95%, 2-sided.  All tests of interactions 
between treatment groups and other factors will be conducted at a 2-sided alpha level of 0.05.  
Countries in similar geographic regions with fewer than 10 patients, based on all Randomized 
Population, will be pooled to achieve a pooled country of at least 10 patients.  All analyses using 
country in the model will use a pooled country, unless otherwise specified.  The final pooling by 
country and geographic region will be finalized prior to data lock.
Table ITSB.5.2 shows the definition of baseline and post-baseline for each variable to be 
analyzed. The baseline variables are derived from the evaluable data during the baseline period.


I8B-MC-ITSB Statistical Analysis Plan Version 3
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Table ITSB.5.2.
Baseline and Postbaseline Definitions and Patient Population by Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline Observations
Lead-In Period
HbA1c ANCOVA
All Randomized Patients
Visit 1
Visit 4 prior to initiation of IP
Basal, bolus, and total 
insulin doses, and 
bolus/total insulin dose 
ratios continuous analysis
All Randomized Patients
Not applicable
Visit 3-4
TEAE
All Enrolled Patients
Prior to first dose of 
open-label insulin lispro 
(or Visit 2 date if the 
dose date is missing)
The entire lead-in period after first dose of open-label 
insulin lispro and prior to the first dose of IP (or Visit 4 if 
the dose date is missing)
26-Week Treatment Period (including Safety Follow-Up Visit where applicable)
HbA1c ANCOVA (ITT 
estimand)
All Randomized Patients
Last of Visits 1-4
Visit 15 with imputation for patients who discontinue 
study prior to Visit 15
HbA1c MMRM (efficacy 
estimand)
All Randomized Patients with a baseline 
and at least one post-baseline observation 
while on IP
Last of Visits 1-4
Visits 7, 10, and 15 prior to discontinuation of IP
HbA1c categorical 
analysis longitudinal 
logistic regression
All Randomized Patients with a baseline 
and at least one post-baseline observation 
while on IP 
Last of Visits 1-4
Visits 7, 10, and 15 prior to discontinuation of IP
CGM outcomes
All Randomized Patients with at least one 
from baseline and post-baseline 
observations
Visit 4
Visit 15
Basal, bolus, and total 
insulin doses, and 
bolus/total insulin dose 
ratios continuous analysis
All Randomized Patients
Last of Visits 3-4
Visits 5-15 prior to discontinuation of IP


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Baseline and Postbaseline Definitions and Patient Population by Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline Observations
7-point SMBG
All Randomized Patients with a baseline 
and at least one post-baseline 
observation
Visit 4 prior to 
initiation of IP
Visits 10 and 15 prior to discontinuation of IP
Health outcomes (PedsQL)
All Randomized Patients with a baseline 
and a post-baseline observation
Visit 4
Visits 15 prior to discontinuation of IP
Safety Laboratory Tests 
(chemistry, hematology) –
continuous analysis
All Patients in the Safety Population 
with a baseline and a post-baseline 
observation
Last of Visits 1-4
Last of Visits 5-15 (planned including early 
discontinuation visits) regardless of IP use
Safety Laboratory Tests 
(chemistry, hematology) –
categorical analysis
All Patients in the Safety Population 
with a normal baseline (with respect to 
the direction being analyzed) and a post-
baseline observation
Last of Visits 1-4
Visits 5-15 (including unplanned visits) regardless of 
IP use
Hypoglycemia events
Safety Population
All Visits 2-4
All Visits 5-15 prior to discontinuation of IP
Weight and vital signs
All Patients in the Safety Population 
with a baseline and a post-baseline 
observation
Last of Visits 1-4
Visits 7, 10, 12, 15 prior to discontinuation of IP
Anti-insulin lispro antibodies 
Safety Population
Visit 4
Visits 7, 10, 15 regardless of IP use
TEAE
Safety Population
Prior to first dose of 
randomized IP (or v4 
date if missing), after 
first dose of open label 
Humalog (or v2 date if 
missing)
From randomization to Week 26 prior to 
discontinuation of IP OR from randomization to safety 
follow-up
Abbreviations: ANCOVA = analysis of covariance; HbA1c = hemoglobin A1c; IP = investigational product; ITT = intention-to-treat; MMRM = mixed-effect 
repeated measures model; PedsQL = Pediatric Quality-of-Life; SMBG = self-monitored blood glucose; TEAE = treatment-emergent adverse event.


I8B-MC-ITSB Statistical Analysis Plan Version 3
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LY900014
For continuous measures, summary statistics will include sample size, mean, standard deviation 
(SD), median, minimum, and maximum for both the actual and the change from baseline 
measurements.  Least-squares (LS) means and standard errors derived from the analysis models 
will also be displayed.  Treatment comparisons will be displayed showing the treatment 
difference LS means and the 95% CIs for the treatment differences, along with the p-values for 
the treatment comparisons.
For categorical measures, summary statistics will include sample size, frequency, and 
percentages.  Fisher’s exact test or Pearson’s chi-square test will be used for treatment 
comparisons.
For laboratory values, both conventional (CN) and Système International (SI) units will be 
presented.  Therefore, both % and mmol/mol will be presented for hemoglobin A1c (HbA1c) and 
both mg/dL and mmol/L will be presented for glucose measurements.  
All baseline measures will be analyzed using an analysis of covariance (ANCOVA) model that 
has treatment as the model term.
5.2.
Adjustments for Covariates
Stratification factors of this study include country, HbA1c stratum (≤8.0%, >8.0% ), type of 
basal insulin at randomization (insulin glargine, detemir or degludec), and age group (1 to <12, 
12 to <18 years).  Stratification factors will be entered into the interactive web-response system
(IWRS) for randomization and also collected in the database by electronic case report form 
(eCRF) or central laboratory.  The analysis models will use the stratification factors as collected 
in the database.
For the primary analysis of HbA1c, the stratification factor of HbA1c stratum will not be 
included.  Instead, the continuous value of baseline HbA1c will be included in the analysis 
models.  
Other efficacy analyses will include the stratification factors as noted in Sections 5.11 and 5.12.
5.3.
Handling of Dropouts or Missing Data
The analysis for the primary and gated objectives will be performed for the ITT estimand 
including all data collected through Week 26 regardless of IP use and the efficacy estimand 
including data collected prior to permanent discontinuation of IP through Week 26. 
For the US Food and Drug Administration (FDA) submission, the ITT estimand will be used.  
For the analysis of HbA1c, imputation of missing data will be performed as described in 
Section 5.11.1.  
For non-FDA submissions, the efficacy estimand will be used.  The missing data will be 
addressed by using a mixed-effect model repeated measures (MMRM) analysis.  The MMRM 
model provides consistent estimator when data are missing at random.  The model implicitly 
adjusts for missing data through a variance-covariance structure.  An ANCOVA model will also 


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be used in the analysis of HbA1c.  Unless otherwise stated, missing endpoints will be imputed 
using the last-observation carried forward (LOCF) approach, using only postbaseline data.
5.4.
Multicenter Studies
Countries in similar geographic regions with fewer than 10 patients, based on the Randomized 
Population, will be pooled to achieve a pooled country of at least 10 patients.  All analyses using 
country in the model will use a pooled country, unless otherwise specified.  The final pooling by 
country and geographic region will be finalized prior to data lock.
5.5.
Multiple Comparisons/Multiplicity
The test for superiority in HbA1c change from baseline (the second gated objective) will be 
conducted only when the test for noninferiority (the first gated objective) has been achieved. 
The gated objectives won’t be conducted if the primary objective cannot be met.
No multiplicity test adjustment will be made for other objectives.
5.6.
Patient Disposition
Patient disposition will be displayed in a flowchart showing the number of patients entered,
randomized, and discontinued during the study.
Frequency counts and percentages of all randomized patients completing and discontinuing from 
the study will be presented for each treatment group.  Reasons for discontinuation from the study 
and study treatment from randomization to the end of the study will be compared between 
treatment groups using Fisher’s exact test.  
Frequency counts and percentages of all patients entered and discontinued from the study prior to 
the lead-in period will be summarized for all entered patients. A similar summary will also be 
provided for the lead-in period using Enrolled Population.  
A listing of the primary reason for treatment discontinuation and study discontinuation will be 
generated for the Randomized Population. 
Patient allocation by investigator, grouped by country, will be summarized indicating the number 
of patients who enter the study, the number of patients who receive at least 1 dose of open-label 
Humalog during the lead-in period, the number of patients who are randomized to study 
treatment, and the number of patients who discontinue the study or study treatment during the 
26-week treatment period.
A listing of the randomization treatment assignment will be generated for all randomized 
patients. 
I8B-MC-ITSB Protocol Amendment (b) allows 1 rescreening of patients who had a screen 
failure or unexpectedly had to discontinue before randomization due to COVID-19 enrollment 
pause. A listing will be presented to show the patient’s previous patient number and current 
patient number. Disposition tables during the lead-in phase will be further classified such that 
rescreening is taken into account.


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5.7.
Patient Characteristics
A summary table will be generated for patient baseline characteristics using all randomized 
patients.  The variables that will be included but not limited to include the following:  age, age 
groups (age group 1:1 to <12, 12 to <18 years, and age group 2:  1 to <6, 6 to <12, 12 to 
<18 years), sex, country, ethnicity, race, height, weight, body mass index (BMI).  For continuous 
variables, the following statistics will be provided:  mean, SD, minimum, maximum, and 
median, and treatment groups will be compared using an analysis of variance model with a term 
of treatment.  For categorical variables, summary statistics will include sample size, frequency 
and percentage, and treatment groups will be compared using Fisher’s exact test or Pearson’s 
chi-square test.  A listing of patient characteristics at baseline will be provided.
A similar summary of diabetes characteristics will also be generated.  The variables that will be 
included but not limited to include the following:  duration of diabetes, the type of prandial
insulin at screening, the type of basal insulin therapy at randomization, prandial insulin dosing 
plan (carbohydrate counting or pattern adjustment), HbA1c at screening and randomization, and
HbA1c stratum. 
The above summaries of baseline and diabetes characteristics will also be provided for patients 
who participate in the Pediatric Quality of Life addendum and complete the questionnaire both at 
baseline and post-baseline.
A listing of patients whose stratification factor value entered into the IWRS (for treatment group 
assignment) is different from the clinical database will also be provided.
For all randomized patients, the number and percentage of patients with historical conditions will 
be summarized by treatment group using Medical Dictionary for Regulatory Activities
(MedDRA) Preferred Term (PT), and the number and percentage of patients with preexisting 
conditions will also be summarized by treatment group using MedDRA PT.  Historical 
conditions are conditions that end prior to first dose of IP and pre-existing conditions are 
conditions that are still ongoing at first dose of IP.  Events will be ordered by decreasing 
frequency.  No statistical comparisons between treatment groups will be performed.
5.8.
Treatment Compliance
The time intervals between prandial insulin dose administration time and the start time of the 
corresponding meal will be summarized by treatment groups based on the following categories:  
pre-meal dosing, >0 to ≤10 minutes, >10 to ≤20 minutes, and >20 minutes after the start of the 
meal for individual visits during the treatment period.
5.9.
Important Protocol Deviations
Important protocol deviations (IPD) that potentially compromise the data integrity and patients’ 
safety will be summarized by treatment group for all randomized patients. The IPDs will be 
identified by site monitoring and statistical programming using the clinical database. Patients 
with more than one IPD from the same category, subcategory, and study specific term will only 
be counted once per patient.


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The following may significantly impact the results of the primary objective:

lack of informed consent

missing HbA1c at the primary endpoint
Patients with 1 or more such deviations (lack of informed consent or missing HbA1c at endpoint) 
will be excluded from the PP population.
The listing of important protocol deviations for all randomized patients during the entire study, 
with the indication of whether to be excluded from the PP population, will also be provided. The 
IPDs identified by site monitoring and clinical database will be integrated in the listing. If the 
IPD is identified by both methods, only the site monitoring IPD will be presented.
5.10. Concomitant and Prior Therapy
Concomitant medication will be summarized and compared between treatment groups using 
Fisher’s exact test for the Randomized Population during the treatment period. The percentages 
of patients receiving each concomitant medication will be summarized by treatment using PT
nested within Anatomical Therapeutic Chemical (ATC) Level 3 code.  Medications will be 
ordered by decreasing frequency within ATC level. 
A summary of previous diabetes therapies that were discontinued prior to informed consent will 
be generated for the Randomized Population. A summary of concomitant medication used 
during the lead-in period will also be provided for the Randomized Population.
5.11. Efficacy Analyses
5.11.1. Primary Outcome and Methodology
The primary objective of this study is to test the hypothesis that LY900014 is noninferior to 
Humalog on glycemic control (noninferiority margin [NIM]=0.4% for HbA1c) in patients 1 to 
<18 years of age with T1D, when administered as prandial insulin, in combination with basal 
insulin for 26 weeks.  There will be 2 primary analysis methods, each tested at the full 
significance level of 0.05. 
For the US FDA submission (using the ITT estimand), all randomized subjects, regardless of 
their postbaseline result availability, will be included in the analysis. Due to COVID-19, patients 
are allowed to have their laboratory data collected at a local laboratory if there is any ongoing 
extenuating situation, such as travel restriction. HbA1c data collected from the local laboratory
will be included in the analysis in the same way as those collected from the central laboratory. 
The missing endpoints will be imputed by the copy reference or the return to baseline approach. 
For the copy reference approach, the reference for each treatment group is from the retrieved 
dropout patients who discontinue IP but have the measurement at the primary endpoint in the 
same treatment group. If there are only a limited number of patients in the reference group that 
leads to a failure in performing the proposed multiple imputation analysis such that the model 
cannot converge, or the number of records in the reference group is less than the number of 
records with missing data, the missing endpoints will be imputed by the return to baseline 


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approach. For the return to baseline approach, the patient-level observed baseline value plus a 
noise will be used to impute the missing endpoints. The noise follows a normal distribution with 
the variability estimated from the “washout HbA1c data.” The “washout HbA1c data” will be 
derived by subtracting the corresponding treatment mean at Week 26 from individual non-
missing HbA1c values at Week 26. After imputation, the primary efficacy comparison will be 
based on the contrast between LY900014 and Humalog from an ANCOVA.  The model for the 
change from baseline to the Week 26 HbA1c endpoint will include treatment and strata (pooled 
country, type of basal insulin, and age group) as fixed effects and baseline HbA1c as a covariate. 
The final estimates will be the combined estimates from at least 1000 imputations.
For non-FDA submissions, the primary efficacy comparison will be based on the contrast 
between LY900014 and Humalog at Week 26 (Visit 15) from the MMRM analysis of change 
from baseline in HbA1c including data collected from all randomized patients prior to permanent 
discontinuation of IP through Week 26 (efficacy estimand). In contrast to the population of ITT 
estimand, randomized patients with a baseline and at least one postbaseline result will be 
included in the analysis. The model for the analysis of the primary efficacy endpoint of change 
from baseline in HbA1c will include the fixed class effects of treatment, strata (pooled country, 
type of basal insulin, and age group), visit, and treatment-by-visit interaction, as well as the 
continuous, fixed covariates of baseline value.  An unstructured covariance structure will be used 
to model the within-patient errors.  Significance tests will be based on LS means and Type III 
tests.  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. 
For both primary analysis approaches, LY900014 will be declared noninferior to Humalog if the 
upper limit of the 2-sided 95% CI for the LS mean difference in the change from baseline in 
HbA1c for LY900014 minus Humalog is below +0.4%.  In addition, the 95% CI for the 
treatment difference will be compared to an alternative NIM of +0.3%.  Both estimands will be 
tested at the full significance level of 0.05. 
5.11.2. Additional Analyses of the Primary Outcome
The primary MMRM analysis model will be repeated using the PP and Completer populations as 
a sensitivity analysis.  If the conclusion differs from that of all randomized patients, the data and 
analyses will be further investigated.


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A secondary analysis model for the efficacy estimand will be an ANCOVA for HbA1c change 
from baseline to the study primary endpoint, using the model with strata (pooled country, type of 
basal insulin, and age group) and treatment as fixed effects and baseline as a covariate.  Missing 
endpoints will be imputed using the LOCF approach using postbaseline data only.
5.11.3. Sensitivity Analyses for Missing Data
A missing-not-at-random-based analysis will be performed for both the efficacy and ITT 
estimands to assess sensitivity of departures from the missing-at-random (MAR) assumption.
The tipping-point approach that will be used is similar to a progressive stress test (Ratitch et al. 
2013).  The basic idea is to impute the missing values and add a value (delta) to the imputed 
values of the experimental treatment group and perform an analysis for the primary endpoint on 
the delta-adjusted data set to see whether the conclusion of the primary analysis is overturned.  If 
not, a larger delta is chosen and the process repeated until the primary result is overturned.  If the 
delta required to overturn the primary result is not a plausible departure from MAR, then the 
primary result is robust to plausible departures from MAR. The initial delta is set to 0.1 with an 
increment of 0.1. Imputation under the noninferiority null method (where delta equals the 
NIM=0.4) will be included as a special case of the progressive stress test.  
For the ITT estimand, the imputation of missing data will be as described for the FDA primary 
analysis, and ANCOVA on the change from baseline to Week 26 in HbA1c will be used. 
For the efficacy estimand, the copy reference approach will be used to impute missing data and 
the reference group will be the Humalog treatment group.  Imputation will be for all longitudinal 
visits.
Sensitivity Analyses for Missing Data due to COVID-19 pandemic:
Missing data due to the pandemic represents an extraordinary circumstance, and missing data
could be more prevalent in some geographic regions than in others. Lilly has been following a 
mitigation plan that aims to reduce the impact from the pandemic. Nevertheless, Lilly expects 
missing data at the primary endpoint visit, Visit 15 HbA1c, for COVID-19 related reasons:

COVID-19 infection (adverse event) or death caused by infection,

Discontinuation of treatment due to COVID-19 related reasons,

Discontinuation of study due to COVID-19 related reasons, and

Completed the 26 week treatment period, but missed primary endpoint due to COVID-19 
related reasons.
Given those extenuating circumstances, the imputation rule as described when introducing ITT 
estimand may not be appropriate because the team assumes these subjects were to adhere to the 
study procedure if not interrupted by the pandemic. Thus a sensitivity analysis will be performed 
by applying an alternative imputation rule. In particular, for these subjects, all available Visit 15 
HbA1c values will be utilized to impute their primary endpoints, within each treatment arm. The 
original imputation rule will be applied to other patients. The process after the imputation is the 
same as that for ITT estimand.


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5.11.4. Analysis of Gated Objectives
Gatekeeping strategy will be used to control the overall type I error for testing the following 
gated objectives: noninferiority of LY900014+20 to Humalog in change from baseline to the 
study primary endpoint in HbA1c and superiority of LY900014 compared with Humalog in 
change from baseline to the study primary endpoint in HbA1c.
Following the successful claim of the primary objective, the noninferiority between 
LY900014+20 and Humalog in HbA1c change from baseline will be assessed using the same 
approach for the primary objective (ITT estimand for FDA submission and efficacy estimand for 
non-FDA submissions) with a NIM of 0.4%. Only when the noninferiority between 
LY900014+20 and Humalog is demonstrated, the superiority of LY900014 in controlling HbA1c 
compared to Humalog will be assessed. The superiority assessment will be based on the above
statistical approaches for the primary objective (ITT estimand for FDA submission and efficacy 
estimand for non-FDA submissions).  If the upper limit of the 2-sided 95% CI is below zero, 
LY900014 will be declared superior to Humalog.
5.11.5. Other Secondary Efficacy Analyses
The analyses described in Section 5.11.5 to Section 5.11.7 will include data collected from all 
randomized patients prior to permanent discontinuation of IP.
The longitudinal observations of actual and change from baseline in HbA1c up to Week 26 will 
be analyzed using the same MMRM model as for the analysis of the primary outcome.
At each visit (including both telephone and office visits), the basal daily dose and prandial 
insulin dose at different time points (morning meal, mid-day meal, evening meal and other) taken 
3 days prior to the visit will be collected in eCRF. The average daily basal insulin dose per visit 
for each patient will be used in the analysis.  Similarly, the average prandial insulin dose for each 
meal category (ie, morning meal, mid-day meal, evening meal, snack, and other) will be 
calculated, and average daily prandial insulin dose calculated as the sum of these average 
prandial insulin meal doses will be used for analysis.  If either average daily basal or average 
daily prandial insulin dose is missing, the total daily insulin dose and the prandial/total insulin 
dose ratio will be set as missing for analysis.  The analyses of insulin dose (ie, actual and change 
from baseline in total, basal, prandial insulin dose and prandial/total insulin dose ratio), will use 
an MMRM model similar to that for the primary outcome with an additional term of HbA1c 
stratum (≤8.0%, >8.0%).
Treatment comparisons for the proportion of patients with HbA1c <7.0% and <7.5% will be
analyzed using a longitudinal logistic regression with repeated measurements conducted by a
generalized linear mixed model including independent variables of treatment, baseline HbA1c
value, visit, baseline HbA1c-by-visit interaction, and treatment-by-visit interaction. An
unstructured covariance structure will be used. As a sensitivity analysis, the proportion of
patients with HbA1c <7.0% and <7.5% at Week 26 (Visit 15), imputed using LOCF, will be
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Three 7-point SMBG profiles are expected to be collected during the 2 weeks prior to specified
visits. For each time point, the average of the corresponding SMBG values from the SMBG 
profiles will be used for analysis. The analyses of the SMBG variables will use an MMRM 
model similar to that for the primary outcome with an additional term of HbA1c stratum (≤8.0%, 
>8.0%).
5.11.6. Health Outcomes Analyses
Patients and caregivers who are enrolled at sites in the US and who speak English will be asked 
to participate in Pediatric Quality of Life (PedsQL) addendum I8B-MC-ITSB(1). The PedsQL 
Population includes all randomized patients who have an informed consent for the PedsQL
addendum signed by parent(s)/legal guardian(s) and completed PedsQL questionnaire at both 
baseline (Visit 4) and post-baseline (Visit 15 or early discontinuation [ED]). The PedsQL 
Population will be used for all analyses specified in this section.
Baseline demographics and characteristics of patients participating in the PedsQL addendum will 
be summarized by treatment. The PedsQL Generic Core and PedsQL 3.2 Diabetes Module will 
be scored according to the user manuals.
For the PedsQL Generic Core (4.0) (Varni et al. 2003) and PedsQL Diabetes (3.2) (Varni et al. 
2013) scales, transformation of scores are needed as indicated by the scoring manual.  Items are 
scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always).  Items are then reversed 
scored as follows:  0=100, 1=75, 2=50, 3=25, 4=0.  The dimension scores and the summary 
scores are calculated by summing the transformed scores of the items divided by the number of 
items answered.  Moreover, for both the PedsQL Generic Core (4.0) and PedsQL Diabetes (3.2)
scales, if more than 50% of the items in the scale are missing, then the Scale Scores should not 
be computed.  If 50% or more items are completed, mean of the completed items in a scale will 
be used to impute the missing scores. 
The PedsQL Diabetes (3.2) and PedsQL Generic Core (4.0) scales will be analyzed by
ANCOVA model using treatment, strata (pooled country, type of basal insulin, and HbA1c 
stratum) as fixed effects and baseline score as a covariate.  The analyses will cover the total 
scores, all subscale scores, and dimensions.  
5.11.7. Analyses of Exploratory Objectives
The following endpoint derived from the 7-point SMBG profiles at each scheduled visit, will be 
analyzed using the MMRM model similar to that for the primary outcome with an additional 
term of HbA1c stratum (≤8.0%, >8.0%):

1-hour post-meal excursion

between-day coefficient of variation (CV) and SD 

Within-day CV and SD
The excursion of SMBG will be calculated for each meal category (morning meal, midday meal, 
evening meal and all meals). The average value of excursions from the same visit for each 
patient will be used in the analysis. 


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Blood glucose (BG) values that are out of the detectable range (BG <20 mg/dL [1.1 mmol/L] or 
BG >600 mg/dL [33.3 mmol/L]) of the glucometer will be excluded from the analysis data. For 
baseline SMBG, records that are collected on or after the first dose date will be excluded from 
the analysis. If there are multiple records on the same day and same Timepoint, only the last 
entry will be used for variable derivation. BG readings without units will not be used in the 
analysis.
At a given visit, the CV and SD on each day with the 7-point SMBG profile will be calculated 
using all the glucose values within that day, then the average values of these CVs and SDs will 
be used as the within-day CV and SD at that visit in analysis. At a given visit, the CV and SD at 
each of the 7 pre-specified SMBG time points will be calculated using the corresponding glucose 
values of the 7-point SMBG profiles, then the average values of these CVs and SDs will be used 
as the between-day CV and SD at that visit in analysis.
5.12. Safety Analyses
Safety measures will include AEs, hypoglycemia, vital signs and weight, treatment exposure, 
laboratory measures, and antibodies to Humalog.
5.12.1. Extent of Exposure
Duration of exposure to study drug will be summarized.  The following summary statistics will 
be provided:  n, mean, SD, median, minimum, maximum, and sum (ie, total patient-years of 
exposure).  The number and proportion of patients falling into the following different exposure 
categories will also be summarized:  <1 month (>0 and <30 days), ≥1 and <3 months (≥30 and 
<90 days), ≥3 and <6 months (≥90 days and <180 days), and ≥6 months (≥180 days). 
Patients who discontinue the IP prematurely are encouraged to remain in the study without study 
drug. The days on study after discontinuing IP, and the days on study from date of first study 
drug to the last study visit date up to Visit 801 will also be summarized.
5.12.2. Adverse Events
Analyses of AEs will include 2 sets of analyses, unless otherwise specified.  The first set of 
analyses will include data collected prior to permanent discontinuation of IP.  The second set of 
analyses will include all data collected during the course of the entire study including the follow-
up visit, regardless of IP use.
Events that are newly reported after the first dose of IP or reported to worsen in severity from 
baseline will be considered treatment-emergent adverse events (TEAEs).  The MedDRA Lowest 
Level Term (LLT) will be used in the treatment-emergent assessment.  The maximum severity
for each LLT during the baseline period will be used as baseline severity.  For events occurring
on the day of first dose of IP, the eCRF-collected flag will be used to determine whether the 
event started or worsened posttreatment. 
In an overview table, the number and percentage of patients who experienced a TEAE, 
experienced serious adverse event (SAE), died due to an AE, discontinued from study due to an
AE, or discontinued IP due to an AE will be summarized by treatment.


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The number and percentage of patients with TEAEs will be summarized by treatment using 
MedDRA PT nested within System Organ Class (SOC). Events will be ordered by decreasing 
frequency within SOC.  As an additional table, the percentages of patients with TEAEs will be 
summarized by treatment using MedDRA PT (without regard to SOC). Events will be ordered 
by decreasing frequency.  Statistical comparisons will be applied at both the SOC and PT levels.  
Fisher’s exact test will be performed for treatment comparison.
The number and percentage of patients with TEAEs by maximum severity will be summarized
by treatment using MedDRA PT (regardless of SOC) and data collected prior to permanent 
discontinuation of IP. For each patient and TEAE, the maximum severity for the MedDRA PT is 
the maximum postbaseline severity observed from all associated LLTs mapping to the MedDRA 
PT. No statistical comparison between treatment groups will be conducted.
The number and percentage of patients with common TEAEs (defined as ≥5% before rounding 
for LY900014 treated patients) will be summarized by treatment group using MedDRA PT 
(without regard to SOC).  Events will be ordered by decreasing frequency.  Treatment will be 
compared by Fisher’s exact test.
The number and percentage of patients who experienced a SAE including deaths and SAEs 
temporally associated or preceding deaths will be summarized by treatment group using 
MedDRA PT regardless of SOC.  Events will be ordered by decreasing frequency.  A listing of 
all SAEs will also be provided.
The number and percentage of patients who discontinued from study due to an AE will be 
summarized by treatment group using MedDRA (without regard to SOC).  The number and 
percentage of patients who discontinued IP due to an AE will be also summarized by treatment 
group using MedDRA PT (without regard to SOC).  Events will be ordered by decreasing 
frequency.  A listing of all AEs as reason for study or IP discontinuation will also be provided.
The number and percentage of patients who experienced other notable TEAEs (potential 
systemic hypersensitivity reaction, injection site reaction, and hepatic disorder) will be 
summarized by treatment group using all TEAEs regardless of IP use.  
For events that are gender specific (as defined by MedDRA), the denominator and computation 
of the percentage will include only patients from the given gender.
For TEAEs occurring in ≥1% of patients, a Kaplan-Meier plot of time to onset of the TEAE will 
be presented. 
Table ITSB.5.3 summarizes the planned analyses and the requirement of analysis data for 
different analysis periods.  A “Yes” in the IP USE column indicates that only data collected prior 
to permanent discontinuation of IP will be included. 


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Table ITSB.5.3.
Treatment-Emergent Adverse Event Analysis Periods
Analysis Period
Analysis 
Population
Analysis
IP USE
Treatment
Treatment Period 
(0-26 Weeks)
All patients in 
safety 
population
AE overview; TEAE by SOC 
and by PT; common TEAE; 
TEAEs by maximum severity; 
SAE; IP discontinuation due to 
AE; severe hypoglycemic 
events
Yes
LY900014, LY900014 
+20, Humalog
Week 0 – Visit 801
All patients in 
safety 
population
AE overview; TEAE by SOC
and by PT; common TEAE;
SAE; other notable AEs
(excluding severe 
hypoglycemic events); study 
discontinuation due to AE
All data 
regardless 
of IP use
LY900014, LY900014 
+20, Humalog
Abbreviations: AE = adverse event; IP = investigational product; PT = Preferred Term; SAE = serious adverse 
event; SOC = System Organ Class; TEAE = treatment-emergent adverse event.
5.12.3. Deaths
The listing of all deaths by patient for all enrolled patients will be provided as part of the SAE 
listing, regardless of the investigator’s or the sponsor’s judgment about causality. Each listing 
will include study identification (ID), investigator ID, patient ID, treatment group, baseline age, 
sex, associated AE, first and last dose date for open label Humalog and randomized IP, and the 
event date.
5.12.4. Hypoglycemic Events and Other Adverse Events
The analysis plans for the following AEs are discussed in Section 5.12.4.1 through 
Section 5.12.4.4:

hypoglycemic events

systemic hypersensitivity reaction

injection site reaction

hepatobiliary events
5.12.4.1. Hypoglycemic Events
Hypoglycemia events that occur during the study will be captured in eCRF. Whenever 
hypoglycemia is suspected, the patient should record the BG value, any associated symptoms, 
and the treatment administered in patient diary. 
A set of events will be considered as 1 event in analysis if the duration between adjacent events 
is within a 30 minute time window. The event with the highest severity will be selected for 
analysis with severity determined in the order of: 1) it is a severe hypoglycemia, 2) it has 
symptoms of hypoglycemia reported, and 3) it has the lowest blood glucose value. If there are 
multiple events tied in all 3 aspects, the event with the largest number of non-missing responses 


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to the questions of nocturnal hypoglycemia and post-dose time frame will be selected. If there 
are still multiple events tied, the latest event will be selected.
The following types of hypoglycemia events will be analyzed: documented hypoglycemia (with 
BG ≤70 mg/dL [3.9 mmol/L] or BG <54 mg/dL [3.0 mmol/L]), severe hypoglycemia, nocturnal
hypoglycemia, and non-nocturnal hypoglycemia (with BG ≤70 mg/dL [3.9 mmol/L] or BG 
<54 mg/dL [3.0 mmol/L]). Only severe hypoglycemia will be collected as an AE and all 
episodes of severe hypoglycemia will be considered as SAEs.  
Table ITSB.5.4 provides detailed statistical methods for each endpoint related to hypoglycemia.  
For these analyses, hypoglycemia events prior to the discontinuation of IP will be summarized.  
Additional analyses for other types of hypoglycemic events not mentioned in the table and for 
the posttreatment period may be conducted as needed.
A listing of patients with at least 1 severe hypoglycemia reported (as SAE) after randomization 
will be provided.  A list of MedDRA PTs will be used for the narrow search of potential severe 
hypoglycemia in spontaneously reported AEs.  The events identified through the search strategy 
that are also reported as SAEs will be summarized and compared between treatments.  Fisher’s 
exact test will be used to assess the treatment difference in the proportion of patients with 
potential severe hypoglycemia.


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Table ITSB.5.4.
Summary of Analyses for Endpoints Related to Hypoglycemia
Endpoint
Analysis Period
Statistical Method
Rate of hypoglycemic events (per patient 
per year)
All Documenteda
Nocturnala
Non-Nocturnal (Documented and 
occurred between waking
and bedtime)a
0-12, 0-26weeks
Negative binomial regression with 
treatment and age group as covariates, log
(exposure/365.25 days) as the offset in the 
model.
Incidence of hypoglycemic events
All Documenteda
Nocturnala
Non-Nocturnal (Documented and 
occurred between waking
and bedtime)a
0-12, 0-26weeks
Logistic regression with treatment and age 
group as covariates.
Rate of post-dose hypoglycemic events 
(per patient per year) for all 3 main 
meals
All Documented a
≤1, ≤2, ≤4, >4, and >2 to 
≤4 hours after start of 
prandial insulin dose
within 0-12, 0-26,weeks
Negative binomial regression with 
treatment and age group as covariates, log
(exposure/365.25 days) as the offset in the 
model.
Incidence of post-dose hypoglycemic 
events for all 3 main meals
All Documented a
≤1, ≤2, ≤4, >4,and >2 to 
≤4 hours after start of 
prandial dose within 0-12, 
0-26,weeks
Logistic regression with treatment and age 
group as covariates.
Rate of severe hypoglycemic events (per 
patient per 100 years)
0-12, 0-26weeks
Exposure adjusted rate 100 years 
(calculated by total number of events 
divided by total exposure for individual 
patients) will be provided and the empirical 
method (see Appendix 1 for details) will be 
used for treatment comparison.
Incidence of severe hypoglycemic events
0-12, 0-26weeks
Proportion of patients with severe 
hypoglycemia will be reported. The
treatment comparison will be based on a
logistic regression model with treatment
and age group as covariates.
a
All documented hypoglycemia and the subcategories based on the thresholds of blood glucose ≤70 mg/dL and 
blood glucose <54 mg/dL will be analyzed. 


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5.12.4.2. Systemic Hypersensitivity Reaction
The number and proportion of patients experiencing treatment-emergent potential systemic 
hypersensitivity reactions will be summarized and compared by treatment group using Fisher’s
exact test.  The following MedDRA Standardized MedDRA Query (SMQ) will be used to
identify potential systemic hypersensitivity reactions from all TEAEs:

Anaphylactic reaction (SMQ). Besides using the narrow and broad terms designated 
within the SMQ, the following search algorithm will also be implemented as another 
approach to determine if a patient had an anaphylactic reaction: if a patient (had at 
least 1 event in Category A) or (had at least 1 event that is in Category B and also had 
at least 1 event that is in Category C) or (had at least 1 event that is in Category D and 
[also had at least 1 event in Category B or at least 1 event in Category C])

Angioedema (SMQ)

Hypersensitivity (SMQ)
Specifically, need to perform the following:  (1) any narrow or algorithmic term from any 1 of
the 3 SMQs indicated above (ie, combined search across narrow and algorithmic portions of all 
3 SMQs); (2) any narrow scope term within each SMQ, separately (ie, narrow SMQ search); 
(3) any term within each SMQ, separately (ie, broad SMQ search); (4) narrow scope term search 
within each SMQ, report the PT nested within each SMQ.
A similar summary will be provided for the TEAE related to study drug judged by the 
investigator. 
Note that an individual patient may contribute multiple events.  Also, a single event may satisfy
multiple SMQs, in which case the event contributes to every applicable SMQ.
5.12.4.3. Injection Site Reaction
The injection site reactions will be searched by MedDRA PTs from all TEAEs.  The number and 
percentage of patients experiencing treatment-emergent injection site reactions will be
summarized and compared by treatment group using Fisher’s exact test.  
For injection site reactions, the presence and severity of erythema, induration, pain, pruritus, and 
edema will be collected through the eCRF and will be summarized for each treatment.  There 
will be no statistical comparison between treatments. 
5.12.4.4. Hepatobiliary Events
5.12.4.4.1.
Treatment-Emergent Potential Hepatic Disorder
The percentages of patients with treatment-emergent drug-related hepatic disorder events will be 
summarized and compared by treatment group using MedDRA PT nested within each SMQ
ordered by decreasing frequency. The following SMQs based on MedDRA will be used to
identify potential hepatic disorders:

Broad and narrow terms in the Liver-related investigations, signs, and symptoms 
SMQ (20000008)


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
Broad and narrow terms in the Cholestasis and jaundice of hepatic origin SMQ 
(20000009)

Broad and narrow terms in the Hepatitis non-infections SMQ (20000010)

Broad and narrow terms in the Hepatic failure, fibrosis and cirrhosis and other liver 
damage SMQ (20000013)

Narrow terms in the Liver-related coagulation and bleeding disturbances SMQ
(20000015)
The percentage of patients with any 1 of the terms will be summarized in addition to the 
percentages for each MedDRA PT. The percentages of patients with potentially drug-related
hepatic disorders that led to permanent study treatment discontinuation will be summarized
similarly.
5.12.4.4.2.
Liver Enzyme Lab Values
The liver enzyme measures (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
alkaline phosphatase [ALP], direct bilirubin, total bilirubin) will be summarized by treatment
group. Postbaseline value and the change from baseline (last nonmissing value before 
randomization) to postbaseline value at Week 26 visit (planned test) will be summarized for 
patients who have both a baseline and at least 1 postbaseline result, and compared between 
treatment groups by using ANCOVA model with the term of treatment and baseline value of the 
response variable. All analyses will be provided in both CN and SI units.
The last nonmissing observation at or prior to Week 26 (including early discontinuation visit) 
will also be analyzed by an ANCOVA model with the term of treatment, baseline value of 
response variable. 
5.12.4.4.3.
Treatment-Emergent Elevation of Liver Enzyme Lab Values
The percentages of patients with the following elevations in hepatic laboratory tests at any time 
during the treatment period (0-26 weeks) will be summarized between treatment groups:  

The percentages of patients with postbaseline ALT measurement greater than or equal to 
3 times (3X), 5 times (5X), and 10 times (10X) the Covance upper limit of normal (ULN)
will be summarized for all patients with a postbaseline value and for the following 
subcategories based on baseline value
o
The analysis of 3X ULN will contain 4 subcategories:  

patients whose non-missing maximum baseline value is less than or equal 
to 1X ULN

patients whose maximum baseline value is greater than 1X ULN but less 
than 3X ULN

patients whose maximum baseline value is greater than or equal 3X ULN

patients whose baseline values are missing


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o
The analysis of 5X ULN will be contain 5 subcategories:  

patients whose non-missing maximum baseline value is less than or equal 
to 1X ULN

patients whose maximum baseline value is greater than 1X ULN but less 
than 3X ULN

patients whose maximum baseline value is greater than or equal to 3X 
ULN but less than 5X ULN

patients whose maximum baseline value is greater than or equal to 5X 
ULN

patients whose baseline values are missing
o
The analysis of 10X ULN will contain 6 subcategories:  

patients whose non-missing maximum baseline value is less than or equal 
to 1X ULN

patients whose maximum baseline value is greater than 1X ULN but less 
than 3X ULN

patients whose maximum baseline value is greater than or equal to 3X 
ULN but less than 5X ULN

patients whose maximum baseline value is greater than or equal to 5X 
ULN but less than 10X ULN

patients whose maximum baseline value is greater than or equal to 10X 
ULN

patients whose baseline values are missing

The percentages of patients with postbaseline AST measurement greater than or equal to 
3X, 5X, and 10X the Covance ULN will be summarized for all patients with a 
postbaseline value and for subcategories based on baseline, as described above for ALT.

The percentages of patients with post-baseline total bilirubin measurement greater than or 
equal to 2 times (2X) the Covance ULN will be summarized for all patients with a post-
baseline value and the following 4 subcategories:  
o
patients whose non-missing maximum baseline value is less than or equal to 1X 
ULN
o
patients whose maximum baseline value is greater than 1X ULN but less than 2X 
ULN
o
patients whose maximum baseline value is greater than or equal to 2X ULN
o
patients whose baseline values are missing
Baseline will be the maximum observation in the baseline period. The maximum value will be 
the maximum value from the treatment period. Planned and unplanned tests will be included.


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Graphical profiles of ALT, AST, total bilirubin, and ALP will be provided for patients with an 
ALT or AST ≥3X ULN or total bilirubin ≥2X ULN during the treatment period. A listing for 
these patients will also be provided, including the actual measurement of ALT, AST, ALP, and
total bilirubin, the corresponding reference high limits, demographics, disposition, drug 
exposure, and AEs. The review for these patients includes an assessment of the proximity of any 
ALT or AST elevation to any total bilirubin elevation, ALP levels, other potential causes, and the 
temporal association with events such as nausea, vomiting, anorexia, abdominal pain, or fatigue.
All patient data, regardless of whether on IP, will be used for the above analyses related to 
hepatobiliary events.
5.12.5. Clinical Laboratory Evaluation
The data from safety laboratory measures will be summarized at Week 26 where the lab test is 
planned to be collected. Postbaseline and change from baseline to postbaseline for laboratory 
tests will be summarized for patients who have both baseline and at least 1 postbaseline result 
and compared between treatment groups by using ANCOVA model with the term of treatment 
and baseline value of the response variable.  Analyses will be provided in both SI and CN units.
The last nonmissing observation at or prior to Week 26 (planned tests including early 
discontinuation) will also be analyzed by an ANCOVA model with the term of treatment, 
baseline value of the response variable. 
The percentages of patients with treatment-emergent abnormal, high, or low laboratory results at 
any time during the treatment period (0 to 26 weeks) will be summarized for patients who have 
both baseline and at least 1 postbaseline result and compared between treatment groups using 
Fisher’s exact tests.  A treatment-emergent abnormal result is defined as a change from normal at 
all baseline visits to abnormal at any time during the treatment period.  A treatment-emergent 
high result is defined as a change from a value less than or equal to the high limit at all baseline 
visits to a value greater than the high limit at any time during the treatment period.  A treatment-
emergent low result is defined as a change from a value greater than or equal to the low limit at 
all baseline visits to a value less than the low limit at any time during the treatment period.  
Planned and unplanned measurements will be included.  Covance reference ranges will generally 
be used to define the low and high limits.  Only patients who have normal baseline values for the 
lab being performed will be included in the analysis for treatment-emergence.  
Liver enzymes measures will not be included in the above analyses as different analyses will be 
used as described in Section 5.12.4.4.2 and Section 5.12.4.4.3.
5.12.6. Vital Signs and Other Physical Findings
Postbaseline measurements and change from baseline to post-baseline for vital signs and 
physical characteristics (systolic blood pressure, diastolic blood pressure, pulse rate, height, 
weight, BMI) at the scheduled visits will be summarized for patients who have both baseline and 
at least 1 postbaseline result. 


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The measurements during the treatment period (0 to 26 weeks) will be analyzed by an MMRM 
model with treatment, baseline value of the response variable, visit, and visit by treatment 
interaction as fixed factors and patient as the random factor.
An ANCOVA model will also be used for the analysis of the last nonmissing observation 
(planned measurements including early discontinuation) during the treatment period. The 
ANCOVA models are the same as those used for clinical laboratory measures. 
The percentages of patients with treatment-emergent high or low vital signs at any time during 
the treatment period (0 to 26 weeks) will be summarized by treatment group for patients who 
have both baseline and at least 1 postbaseline measurement. A treatment-emergent high result is 
defined as a change from a value not meeting criteria for the high limit during the baseline period
to a value meeting the criteria for the high limit at any time that meets the specified change 
amount during the treatment period. A treatment-emergent low result is defined as a change 
from a value not meeting criteria for the low limit during the baseline period to a value meeting 
the criteria for the low limit at any time that meets the specified change amount during the 
treatment period.  Treatment comparison will be based on Fisher’s exact test.  Table ITSB.5.5
will be used to define the low and high limits and change thresholds. 
Table ITSB.5.5.
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurement for Children and Adolescents
Age (years)
Systolic BP, mm Hg
(Supine or sitting –
forearm at heart level)
Diastolic BP, mm Hg
(Supine or sitting –
forearm at heart level)
Pulse/HR, bpm
(Supine or sitting)
Infant <2
Low 
≤70 and decrease ≥15
≤35 and decrease ≥10
<70 and decrease ≥25
High
≥112 and increase ≥15
≥74 and increase ≥10
>190 and increase ≥25
Child 2-4
Low
≤75 and decrease ≥15
≤40 and decrease ≥10
<60 and decrease ≥25
High
≥116 and increase ≥15
≥76 and increase ≥10
>160 and increase ≥25
Child 5-9
Low
≤80 and decrease ≥15
≤45 and decrease ≥10
<60 and decrease ≥25
High
≥122 and increase ≥15
≥78 and increase ≥10
>150 and increase ≥25
Child 10-11
Low
≤85 and decrease ≥20
≤50 and decrease ≥10
<60 and decrease ≥25
High
≥126 and increase ≥20
≥82 and increase ≥10
>140 and increase ≥25
Adolescent 12-14
Low
≤90 and decrease ≥20
≤50 and decrease ≥10
<50 and decrease ≥15
High
≥136 and increase ≥20
≥86 and increase ≥10
>120 and increase ≥15
Adolescent 15-17
Low
≤90 and decrease ≥20
≤50 and decrease ≥10
<50 and decrease ≥15
High
≥140 and increase ≥20
≥90 and increase ≥10
>100 and increase ≥15
Abbreviations: BP = blood pressure; HR = heart rate.
5.12.7. Immunogenicity
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro for all randomized patients since Visit 1 prior to the first dose of open label 
Humalog used during the lead-in.  Therefore, the blood sample result at Visit 1 will be 
considered as the anti-insulin lispro level at baseline for this study.


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The assessment of immunogenicity will include analyses of treatment-emergent anti-insulin 
lispro antibody up to Visit 15.
5.12.7.1. Treatment Emergent Anti-Insulin Lispro Antibody
The treatment-emergent anti-insulin lispro antibody (denoted as treatment-emergent antidrug 
antibody [TEADA] throughout this SAP) is based on the change from baseline (Visit 1) to post-
baseline (post-Visit 1) in the anti-insulin lispro antibody level (percent binding).  Treatment-
emergent antidrug antibody can be subclassified as either treatment induced (not detected anti-
insulin lispro antibody at baseline) or treatment boosted (detected anti-insulin antibody at 
baseline):

treatment-induced response:  change from not detected anti-insulin lispro at baseline 
(Visit 1) to postbaseline detected anti-insulin lispro

treatment-boosted response:  change from detected anti-insulin lispro at baseline (Visit 1) 
to postbaseline detected anti-insulin lispro antibody level (percent binding) at least 157% 
of the baseline value
The TEADA status will be determined using all data regardless of IP use.  The number and 
percentage of patients with positive TEADA response any time during the treatment period will 
be summarized by treatment group.  For patients with positive TEADA response any time during 
the treatment period, the number and percentage of patients with positive insulin cross-reactivity 
anytime during the treatment period, and the number and percentage of patients not meeting the 
TEADA criteria at Visit 15 (or last visit for patients who discontinue the study prior to Visit 15) 
will also be summarized by treatment group.  Treatment groups will be compared by Fisher’s 
exact test.
Both actual and change from baseline for the anti-insulin lispro antibody level in percent binding 
regardless of IP use will be summarized by scheduled visit prespecified in the protocol for 
patients with positive TEADA response anytime during the treatment period. The repeated 
measurement from Visit 1 to Visit 15 will be analyzed by an MMRM model with treatment, 
baseline value of the response variable, visit, and visit by treatment interaction as fixed factors
and patient as the random factor.  The ANCOVA model using treatment and baseline value as 
covariates will be used for the analysis of last nonmissing observation prior to or at Visit 15 and 
the analysis of maximum percent binding during the treatment period. 
A listing of anti-insulin lispro antibodies at each visit will be provided for the safety population.  
The listing will include anti-insulin lispro antibody status (detected/not detected), anti-insulin 
lispro antibody percent binding, TEADA status (positive/negative), insulin cross-reactivity 
status, and insulin cross-reactivity percent binding.
Subgroup analysis for the following selected efficacy and safety variables will be performed by 
TEADA status during the treatment period:  

hemoglobin A1c and change from baseline in HbA1c

basal, prandial, and total insulin dose

treatment-emergent injection site reaction and hypersensitivity reactions


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
event rate of all documented hypoglycemic events (based on the threshold of BG 
≤70 mg/dL)
The analyses for HbA1c and change from baseline in HbA1c will be performed using an 
MMRM model for the primary analysis and the HbA1c data up to permanent discontinuation of 
IP.  The model will include additional fixed terms of subgroup, subgroup by treatment 
interaction, subgroup by visit interaction, and 3-way interaction of treatment, subgroup, and visit. 
The subgroup analysis for insulin dose will use the MMRM model specified in Section 5.11.5
using the efficacy estimands.  The model will include additional fixed terms of subgroup, 
subgroup by treatment interaction, subgroup by visit interaction, and 3-way interaction of 
treatment, subgroup, and visit.
The incidence of treatment-emergent injection site reactions and hypersensitivity reactions will 
be analyzed by a logistic regression model including terms of treatment, subgroup, and treatment 
by subgroup interaction. All data regardless of IP use will be used for this analysis.
The negative binomial regression model specified in Table ITSB.5.4 with additional terms of
subgroup, treatment by subgroup interaction will be used for the subgroup analysis of all 
documented hypoglycemia event rate while on IP.
The interaction effects (3-way for MMRM and 2-way for ANCOVA/negative binomial 
regression model) will be evaluated using a significance level of 0.10, unadjusted.  If the 
interaction effect is significant (p<0.10), separate analysis without the terms related with the 
subgroup will be performed for each subpopulation.
5.12.8. Patient Narratives
Patient narratives will be provided for all patients in the study who experience any of the
following “notable” events prior to data cutoff for the submission:

deaths

serious adverse events

discontinuations from study (or study drug) due to AEs

pregnancy
A list of patients who meet the criteria for narratives will be provided.
5.13. Subgroup Analyses
5.13.1. Subgroup Analyses for HbA1c
The following subgroups will be analyzed for HbA1c if there are sufficient numbers of patients 
per group (eg, at least 10% in each group) for both the ITT and efficacy estimands:

age (age group 1:  1 to <12 versus 12 to <18 years and age group 2:  1 to <6, 6 to <12,
and 12 to <18 years)

Body Mass Index (BMI, <25 kg/m2, ≥25 kg/m2 and <30 kg/m2, ≥30 kg/m2)

hemoglobin A1c stratum (≤8.0% versus >8.0%)


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
sex (male versus female)

duration of diabetes (using the median as the cut-off)

race

ethnicity

country

region

type of basal insulin (glargine, degludec and detemir)

prandial insulin dosing plan (carbohydrate counting or pattern adjustment)

personal continuous glucose monitoring (CGM) or flash glucose monitoring (FGM) use 
(yes, no)
For the ITT estimand, analyses for HbA1c and change from baseline in HbA1c will be 
performed using an ANCOVA model that includes the same fixed effects and baseline as a 
covariate given for the primary analysis model plus factors of subgroup and 2-way interaction of 
subgroup and treatment. 
For the efficacy estimand, analyses for HbA1c and change from baseline in HbA1c will be 
performed using an MMRM model that includes the same fixed effects given for the primary 
analysis model plus factors of subgroup, 2-way interaction of subgroup and treatment, 2-way 
interaction of subgroup and visit, and 3-way interaction of treatment, visit, and subgroup.  The 
interaction of subgroup and treatment at the primary endpoint will be evaluated to assess the 
treatment by subgroup interaction.  
The subgroup interaction effect will be evaluated using a significance level of 0.10, unadjusted.
Additional subgroup analyses may also be performed.
5.13.2. Subgroup Analyses for Hypoglycemic Events
For the documented hypoglycemia based on the threshold of BG ≤70 mg/dL, the following 
subgroups will be analyzed:

age (age group1:  1 to <12 years and 12 to <18 years, and age group 2:  1 to <6, 6 to <12,
and 12 to <18 years)

hemoglobin A1c stratum (≤8.0% versus >8.0%)

region

type of basal insulin (glargine, degludec, and detemir)

prandial insulin dosing plan (carbohydrate counting or pattern adjustment)

personal CGM/FGM use (yes, no)
The event rate and incidence will be analyzed using the same model specified in Table ITSB.5.4
with the addition of factors for subgroup, and 2-way interaction of subgroup and treatment.  The 
2-way interaction will be used to evaluate treatment-by-subgroup interaction.


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5.14. Interim Analyses and Data Monitoring
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.
A data and safety monitoring committee (DMC) consisting of pediatric experienced members 
external to the study team will review interim safety results at least once during the study.  The 
DMC comprises those individuals responsible for the evaluation and interpretation of the results 
from the safety analysis.  The DMC for this study will be conducted as an independent 
DMC.  Therefore, the members of the DMC are external to Lilly. Further details pertaining to 
the DMC activities may be found in the DMC charter. Only safety analyses will be conducted 
for DMC review, no efficacy analysis will be conducted.  The analyses for DMC will neither be 
reported to study team nor change the study design.
5.15. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:

Summary of AEs, provided as a dataset that will be converted to an XML file. Both 
Serious Adverse Events and “Other” Non-Serious Adverse Events are summarized by 
treatment group, by MedDRA PT.
o
An AE is considered “Serious” whether or not it is a TEAE.
o
An AE is considered in the “Other” category if it is both a TEAE and is not serious.  
For each Serious AE and “Other” AE, for each term and treatment group, the 
following are provided:

the number of participants at risk of an event

the number of participants who experienced each event term

the number of events experienced
o
For each SAE, these additional terms are provided for EudraCT:

the total number of occurrences causally related to treatment

the total number of deaths

the total number of deaths causally related to treatment
o
Consistent with www.ClinicalTrials.gov requirements, “Other” AEs that occur in 
fewer than 5% of patients/subjects in every treatment group may be excluded if a 5% 
threshold is chosen.  Allowable thresholds include 0% (all events), 1%, 2%, 3%, 4%,
and 5%.  


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Adverse event reporting is consistent with other document disclosures (for example, the CSR, 
manuscripts, and so forth).


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6.
Unblinding Plan
6.1.
Safety Monitoring
An independent DMC will have the responsibility to review the safety results in order to monitor 
safety of the patients in the study until the last patient completes the treatment period. Members 
will not have contact with anyone involved in the clinical care of patients and/or enrolled in this 
study in any way that could compromise the integrity of study. A limited number of 
preidentified individuals external to the study team will perform the data analysis for the DMC 
using the limited unblinded data.  The detailed analysis and communication plan for the analyses 
will be defined in a separate DMC charter.
6.2.
Site Level Unblinding
Investigators, patients, and study site personnel will be blinded to the double-blind treatment 
groups throughout the study. Investigators, patients, and study site personnel will be unblinded 
to the open-label treatment group.
The following applies to the double-blind treatment groups:
Emergency unblinding for AEs may be performed through the IWRS.  This option may be used 
ONLY if the patient’s well-being requires knowledge of the patient’s treatment assignment.  All 
calls/website visits resulting in an unblinding event are recorded and reported by the IWRS.
The investigator should make every effort to contact the Lilly clinical research physician or 
designee prior to unblinding a patient’s treatment assignment.  If a patient’s treatment 
assignment is unblinded, Lilly must be notified immediately.
If an investigator, site personnel performing assessments, or patient is unblinded during the 
double-blinded period, the patient must discontinue the IP and will be encouraged to continue in 
the study (Protocol Section 8.1).
6.3.
Sponsor/Trial Level Unblinding
The study team will remain blinded to treatment assignments until all patients have completed 
the study and the database has been locked.  


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7. References
Baghurst PA. Calculating the mean amplitude of glycemic excursion from continuous glucose 
monitoring data: an automated algorithm. Diabetes Technol Ther. 2011;13(3):296-302.
Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, Bosi E, Buckingham BA, 
Cefalu WT, Close KL, Cobelli C, Dassau E, DeVries JH, Donaghue KC, Dovc K, Doyle FJ 3rd, 
Garg S, Grunberger G, Heller S, Heinemann L, Hirsch IB, Hovorka R, Jia W, Kordonouri O, 
Kovatchev B, Kowalski A, Laffel L, Levine B, Mayorov A, Mathieu C, Murphy HR, Nimri R, 
Nørgaard K, Parkin CG, Renard E, Rodbard D, Saboo B, Schatz D, Stoner K, Urakami T, 
Weinzimer SA, Phillip M. Clinical targets for continuous glucose monitoring data 
interpretation: recommendations from the international consensus on time in range. Diabetes 
Care 2019;42(8)1593-1603. 
Clarke W, Kovatchev B. Statistical tools to analyze continuous glucose monitor data. Diabetes 
Technol Ther. 2009;11(suppl 1):S45-S54.
Hirsch IB. Glycemic variability: it’s not just about A1c anymore! Diabetes Technol Ther. 
2005;7(5):780-783.
Kovatchev BP, Clarke WL, Breton M, Brayman K, McCall A. Quantifying temporal glucose
variability in diabetes via continuous glucose monitoring: mathematical methods and clinical 
application. Diabetes Technol Ther. 2005;7(6):849-862.
Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or dependent 
variable in analyses of change from baseline in clinical trials? Stat Med. 2009;28(20):2509-
2530.
Lu K. On efficiency of constrained longitudinal data analysis versus longitudinal analysis of 
covariance. Biometrics. 2010;66(3):891-896.
Mazze RS, Strock E, Wesley D, Borgman S, Morgan B, Bergenstal R, Cuddihy R. 
Characterizing glucose exposure for individuals with normal glucose tolerance using 
continuous glucose monitoring and ambulatory glucose profile analysis. Diabetes Technol 
Ther. 2008;10(3):149-159.
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to
statistical analysis using pattern mixture models. Pharm Stat. 2013;12(6):337-347.
Rodbard D. Interpretation of continuous glucose monitoring data: glycemic variability and 
quality of glycemic control. Diabetes Technol Ther. 2009;11(Suppl 1):S55-S67.
Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean amplitude 
of glycemic excursions, a measure of diabetic instability. Diabetes. 1970;19(9):644-655.
Service FJ, O’Brien PC, Rizza RA. Measurements of glucose control. Diabetes Care. 
1987;10(2):225-237.
Varni JW, Burwinkle TM, Jacobs JR, Gottschalk M, Kaufman F, Jones KL. The PedsQL in type 
1 and type 2 diabetes: reliability and validity of the Pediatric Quality of Life Inventory Generic 
Core Scales and type 1 Diabetes Module. Diabetes Care. 2003;26(3):631-637.


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Varni JW, Curtis BH, Abetz LN, Lasch KE, Piault EC, Zeytoonjian AA. Content validity of the 
PedsQL™ 3.2 Diabetes Module in newly diagnosed patients with type 1 diabetes mellitus ages 
8-45. Qual Life Res. 2013;22(8):2169-2181.


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8. Appendices


I 8 B-M C -I TS B St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 4 0
L Y 9 0 0 0 1 4
A p p e n di x 1.
E m piri c al E sti m ati o n of R el ati v e E v e nt R at e
Tra di tio nall y , P oiss o n distri b uti on has bee n ass u me d t o dra w i nfere nce f or t he rate of rare e ve nts.   
W he n t he e ve nt is rare a n d t he sa m ple size is lar ge, it is k n o w n t hat t he o verall n u m ber of e ve nts
is a p pr o xi matel y fr o m P oiss o n distri b uti o n. H o we ver, f or s o me n ot ver y  rare e ve nts s uc h as
se vere h y p o gl yce mic e ve nts i n T 1 D pati e nt s, t he t otal n u m ber of e ve nts ma y n ot be distri b ute d
fr om P oi ss o n a n d ma y be o ver -dis perse d .  Ass u mi n g P oiss o n distri b ut i on ma y si g nifica ntl y
u n derest i mate t he varia nce, a n d t heref ore tra ditio n al  met h o d ma y re d uce t he o vera ge pr o ba bilit y 
a n d i nflate t he T y pe- I err or. A n e m pirical met h o d i n est i mati n g t he varia nce of t he relati ve e ve nt 
rate wit h o ut ass u mi n g a n y distri b ut i on o n t he n u m ber of e ve nts will be pr o vi de d i n t his a p pe n di x. 
Let    de n ote t he c o u nt res p o nse varia ble f or patie nt j i n treat me nt gr o u p i. Let   = ∑
  be 
t he t otal n u m ber of e ve nts f or treat me nt gr o u p i, a n d   de n ote t he e x p os ure f or treat me nt gr o u p 
i.  Let i = 0 f or t he c o ntr ol gr o u p a n d i = 1 f or t he e x peri me ntal treat me nt gr o u p.  T he e ve nt rate 
f or treat me nt gr o u p i ca n be calc ulate d as:
̂  =   T he e m pirical  v aria nce of ̂  is 
  ( ̂) =     ( ) =       ,
w here   is t he varia n ce of     f or treat me nt gr o u p i.  Usi n g t he d el t a-met h o d, t he varia nce of 
l o g( ̂) ca n be esti mate d as
  (l o g( ̂)) =      T he rel at i ve rate of t he e x peri me ntal treat me nt vers us t he c o ntr ol treat me nt is esti mate d as
 = ̂ ̂ T he varia nces of  a n d l o g() are 
  ( ) =    (l o g( ))
  l o g  =   (l o g(̂  )) +   (l o g(̂  )) =        +       Ass u mi n g l o g( ) is as y m pt oticall y fr o m a nor m al distrib uti o n, t he 1 0 0 (1 − )%
c o nfi de nce 
i nter val for l o g( ) ca n be c o nstr u ct e d as
l o g −       l o g , l o g +        l o g 

I 8 B-M C -I TS B St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 4 1
L Y 9 0 0 0 1 4
T he n, t he 1 0 0 (1 − )%
c o nfi de nce i nter val f or  is
 e x p  −       l o g  ,
 e x p         l o g  ( 1)
T he p -val ue f or testi n g t he n ull h y p ot hesis of   :  = 1 is calc ulate d as
 = 2 Φ  l o g/    l o g ( 2)


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Appendix 2.
Statistical Analysis Plan for Continuous 
Glucose Monitoring (CGM)
Continuous glucose monitoring (CGM) will be performed in a subset of patients in 
Study I8B-MC-ITSB (ITSB) in order to evaluate the 24-hour glucose profile captured with CGM 
for LY900014 and Humalog, when either is used in combination with basal insulin as part of a 
multiple daily injection regimen.  In 2 of the treatment groups, LY900014 and Humalog will be 
administered immediately (0 to 2 minutes) prior to each meal in a double-blind manner.  A third 
open-label treatment group consists of LY900014 administered up to 20 minutes after the start of 
a meal (LY900014 +20).  These 3 treatment groups are denoted as LY900014, Humalog and 
LY900014+20 in the study objectives.
This appendix provides the statistical analysis plan for the CGM addendum I8B-MC-ITSB(3.1).
The target range for #3 objective has been changed from “71 to 180 mg/dL” to “70 to 180 mg/dL”
to reflect the recommendations set forth in the “Clinical Targets for Continuous Glucose 
Monitoring Data Interpretation: Recommendations From the International Consensus on Time in 
Range” (Battelino et al. 2019). Similarly, one of the cut points for #5 objective has been 
changed from “≤ 70 mg/dL” to “< 70 mg/dL.”
Appendix 2.1.
Objectives and Endpoints for CGM Addendum
Table APP.2.1 shows the objectives and endpoints for CGM addendum.
Table APP.2.1.
Objectives and Endpoints for CGM Addendum
Objectives
Endpoints
Primary Objective
1.
To compare LY900014 and Humalog, when 
administered as prandial insulin (0 to 2 minutes 
prior to the start of a meal), with respect to the 
incremental glucose AUC0-2hours after the start 
of meals 
1.
Incremental AUC0-2hours after the start of 
meals from up to 10 days of continuous 
glucose monitoring (CGM) use at Week 26
Secondary Objective
2.
To compare LY administered as postprandial 
insulin up to 20 minutes after the start of a meal 
(LY900014 +20) and Humalog with respect to 
the incremental AUC0-2hours after meals
2.
Incremental AUC0-2hours after the start of 
meals from up to 10 days of continuous 
glucose monitoring (CGM) use at Week 26
3.
To compare LY900014, LY900014 +20 and 
Humalog with respect to the duration of time 
glucose values are within target range 70 to 
180 mg/dL (3.9 and 10.0 mmol/L) during 
daytime.
3.
Duration (in minutes) and percentage of time 
with glucose values within target range 70 to 
180 mg/dL (3.9 and 10.0 mmol/L) during 
daytime, both inclusive, normalized to daytime
period from up to 10 days of CGM use at 
Week 26
4.
To compare the glucose excursions after meal 
between LY900014, LY900014 +20, and 
Humalog
4.
Average glucose excursions 0 to 1, 2, 3, 
4 hours after the start of meals, from up to 
10 days of CGM use at Week 26


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Objectives and Endpoints for CGM Addendum
Objectives
Endpoints
5.
To compare LY900014, LY900014 +20, and 
Humalog with respect to the duration of time 
spent in hypoglycemic glucose ranges
5.
Duration (in minutes) and percentage of 
time with glucose values <54, and 
<70 mg/dL (3.0 and 3.9 mmol/L)
normalized to a 24-hour period from up to 
10 days of CGM use at Week 26
6.
To compare LY900014, LY900014 +20, and 
Humalog with respect to the duration of time 
spent in hyperglycemic glucose ranges
6.
Duration (in minutes) and percentage of 
time with glucose values >180 mg/dL (10.0 
mmol/L) normalized to a 24-hour period
from up to 10 days of CGM use at Week 26
7.
To compare LY900014, LY900014 +20, and 
Humalog with respect to the glucose variability 
during daytime
7.
Blood glucose risk index during daytime 
from up to 10 days of CGM use at Week 26
Appendix 2.2.
General Considerations
The Dexcom G6® Continuous Glucose Monitoring System (Dexcom G6) will be used in CGM 
addendum I8B-MC-ITSB(3.1). Patients who choose to participate in the Study ITSB CGM 
addendum (3.1) will use the Dexcom G6 system during 2 periods of time, prior to baseline and 
prior to the 26-week primary endpoint.  The Dexcom G6 will be worn for up to 10 consecutive 
days per period.
The CGM Population includes all randomized patients who have an inform consent for the CGM 
addendum signed by parent(s)/legal guardian(s) and valid CGM data at baseline (Visit 4) or 
primary endpoint (Visit 15). Unless otherwise specified, the analyses of the CGM addendum
will use the CGM Population. The data collected after permanent discontinuation of 
investigational product or during days when patients are temporarily off study treatment will be 
excluded. There will be no multiplicity adjustment.
To ensure that the CGM outcome variables are only calculated from valid CGM days with 
sufficient data within the 24-hour, the following criterion will be used to determine a valid CGM 
day:  minimum number of measures per day – at least 70% of the total measures (288 measures 
per day) that are supposed to be obtained. All the CGM derivations are based on the data from 
the valid CGM days with sufficient data defined above unless otherwise specified.
Patients will be instructed to capture the start time of 3 main meals (morning meal, mid-day 
meal, evening) when accompanied by prandial insulin dose during each CGM session in the 
patient CGM diary page. The start time will be used to derive the CGM meal related outcomes for 
each meal and across all meals. On valid CGM days, the meal related outcomes will also use the 
70% cut-point to determine a valid CGM session for the variable derivation. For example, the 
iAUC0-2hr after the morning meal for a day requires at least 70% of the 24 measures (ie, at least 
17 measures) during the 2 hour time window after the start of the morning meal. If the analysis 
time window covers the start time of the next meal (assuming TN0 relative to the start time of the 
given meal and TN0 < T) and the number of non-missing measures within 0 to TN0 is greater 
than 70% of measures within 0 to T, the derivation of the meal related outcomes within 0 to T


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will be based on the data from time 0 to TN0. Only the first meal of each type per day will be 
included in derivations
All CGM outcome variables will be derived for each patient for each visit, based on the valid 
CGM data described above.  The data will be summarized by visit and by treatment group.
For continuous measures, summary statistics will include sample size, mean, standard deviation
(SD), median, minimum, and maximum for both the actual and the change from baseline 
measurements.  Least-squares (LS) means and standard errors derived from the analysis models 
will also be provided. Treatment comparisons will be evaluated by the treatment difference LS 
means, the 95% CIs for the treatment differences, and the p-values for the treatment 
comparisons.
For categorical measures, summary statistics will include sample size, frequency, and 
percentages. Fisher’s exact test or Pearson’s chi-square test will be used for treatment 
comparisons, unless otherwise specified.
A listing of all randomized patients with CGM addendum-specific informed consent form and 
did or did not wear the blinded Dexcom G6 at least once during the study will be produced.  The 
listing will contain the dates that patients started and stopped wearing the Dexcom G6 for each 
visit during the study. 
Additional analyses not specified in this SAP may be conducted, if deemed necessary.
Appendix 2.3.
Baseline Characteristics
The following analyses planned for the main study (Section 5.7) will be repeated for the CGM 
Population:

summaries of baseline and diabetes characteristics

a listing of patients whose stratification factor value entered into the interactive web-
response system (IWRS) is different from the clinical database

a listing of patient characteristics at baseline
Appendix 2.4.
Primary CGM Outcome and Methodology
The primary outcome of the CGM addendum is the iAUC0-2hr after meals obtained from up to 
10 days of CGM use at Week 26.  The derivation of the iAUC0-2hr for each visit is outlined in 
Appendix 2.8.
An ANCOVA model with treatment, type of basal insulin, hemoglobin A1c (HbA1c) stratum 
[≤8.0% or >8.0%], and age group as fixed effects and baseline as a covariate will be used for 
treatment group comparison.  At Week 26, the treatment difference and LS mean of the 
difference estimated from the model will be provided. 
If the percentage of the patients with missing baseline values is higher than 20% of the CGM 
Population, a constrained longitudinal data analysis model (Liu et al. 2009; Lu 2010) will be 
used instead. An unstructured covariance structure will be used to model the within-patient 


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errors. If this analysis fails to converge, the following covariance structures will be tested in 
order:

compound symmetry with heterogeneous variances

compound symmetry without heterogeneous variances.

First order autoregressive
The first covariance structure that converges will be used.  The Kenward–Roger approximation 
will be used to estimate denominator degrees of freedom.
Appendix 2.5.
Secondary CGM Variables and Analysis
The following variables will be derived from the original data collected through the CGM device
and will be compared LY900014, LY900014+20 and Humalog at Week 26 using the similar 
model as the primary analysis in Appendix 2.4:

incremental AUC 0-2 hours after the start of meals (across all three main meals)

duration (in minutes) and percentage of time with glucose values between 70 and 
180 mg/dL (3.9 and 10.0 mmol/L) (both inclusive) during daytime (defined as 0600 to 
midnight), normalized to a 24-hour period

average glucose excursions 0 to 1 hour after the start of meals (across all 3 main meals)

average glucose excursions 0 to 2 hours after the start of meals (across all 3 main meals)

average glucose excursions 0 to 3 hours after the start of meals (across all 3 main meals)

average glucose excursions 0 to 4 hours after the start of meals (across all 3 main meals)

duration (in minutes) and percentage of time with glucose values <54 (3.0 mmol/L)
normalized to a 24-hour period

duration (in minutes) and percentage of time with glucose values <70 mg/dL 
(3.9 mmol/L) normalized to a 24-hour period

duration (in minutes) and percentage of time with glucose values >180mg/dL,
(10.0 mmol/L) normalized to a 24-hour period

blood glucose risk index during daytime (0600 to midnight)
Appendix 2.6.
Additional Analyses
The following key efficacy and safety outcomes collected in the main study (not through CGM 
addendum) will be analyzed using the CGM Population:

HbA1c at Week 26

incidence and rate of  documented hypoglycemic events from Week 0 to Week 26

incidence and rate of nocturnal hypoglycemic events from Week 0 to Week 26

incidence and rate of non-nocturnal hypoglycemic events from Week 0 to Week 26s

incidence and rate of severe hypoglycemic events from Week 0 to Week 26


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
change from baseline in total, basal and prandial insulin dose, and the ratio of prandial 
and total insulin dose at Week 26
The analysis methods for the above outcomes will be the same as those specified in Section 5.
Proportion of patients who have achieved the guidance (Battelino et al. 2019) recommended 
CGM targets of glycemic control (see Table APP.2.2) at Week 26 will also be summarized by 
treatment and analyzed using logistic regression model with treatment, age group and baseline as 
covariates.
Table APP.2.2.
Guidance Recommended CGM Targets of Glycemic Control
Percentage of time with sensor glucose (24-hour)
Guidance Recommendation
target range
        70-180 mg/dL (3.9-10.0 mmol/L, both inclusive
>70%
hypoglycemia range
       <70 mg/dL (3.9 mmol/L)
<4%
       <54 mg/dL (3.0 mmol/L)
<1%
hyperglycemia range
     >180 mg/dL (10.0 mmol/L)
<25%
    >250 mg/dL (13.9 mmol/L)
<5%
Appendix 2.7.
Ambulatory Glucose Profile
The following standardized glucose summary reports from ambulatory glucose profile (AGP)
will be generated, at treatment-group level and individual patient level by visit, based upon the 
observed CGM measures:

24-hour period

0 to 4 hours relative to meal starting time for morning meal, midday meal, evening meal 
and across all meals.
Appendix 2.8.
Derivation for CGM Variables
By-meal CGM outcome variables will be derived for each meal and across all meals based on the 
valid CGM sessions (Appendix 2.2). 
If any concentration below lower limit of quantification (LOQ) or above upper LOQ are 
identified, they will be treated as LOQ for calculation of the CGM parameters.  No missing 
CGM values will be imputed.


I 8 B-M C -I TS B St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 4 7
L Y 9 0 0 0 1 4
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 patie nt, 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 
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: 0 4 : 5 9, 0 0: 0 5: 0 0 t o 0 0: 0 9: 5 9, etc.) will be use d 
f or a n y deri vati o ns re q uiri n g ti me-mat c he d meas ure me nts acr oss da ys wit hi n a visit (e g, mea n of  
dail y  differe nce [ M O D D]). 
All C G M gl uc ose deri vat i ons will be c o n d ucte d i n u nits of m g/ d L a n d m m o l/ L will  als o be
pr o vi de d b y t he c o n versi o n fact or of 0. 0 5 5 5 fr o m m g/ d L. 
A p p e n di x 2. 8. 1.
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)
F or a vali d C G M meal sessi o n ( wi t h at least 7 0 % of meas ures d uri n g t he 0 t o T h o ur[s] after t he 
start of a s pecific meal) o n a vali d C G M da y , A U C    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 withi n t he ti me fra me:
A U C    =
(  −  ) + (    −  )
2
∆   w here   is gl uc ose val ue at a partic ular ti me,   is t he gl uc ose level bef ore t he start of t he gi ve n 
meal ( usi n g t he a vera ge val ues withi n t he ti me wi n d o w [ -1 9, 0] mi n ut e s relat i ve t o t he start of 
t he meal), ∆  is t he ti me i nter val bet wee n c o nsecu tive gl uc ose meas ures ,  is t he t otal n u m ber of 
tra pez oids wi t hi n t he ti me fra me 0-T a n d   is t he gl uc ose le vel at t he e n d of t he ti me fra me 0-T
( usi n g t he a vera ge val ues wit hi n t he ti me wi n d o w [ 0, 1 4] mi n utes relati ve t o t he last ti me p oi nt 
of  t he ti me fra me).  T he deri vati on re q uire t hat   a n d   val ues are b ot h a vaila b le a n d t he ne xt 
meal starts after t he e n d of t he ti me fra me 0 -T.
A U C    will be calc ulate d f or vali d meal sessi ons a n d t he a vera ge o f a visit will be use d i n t he 
a nal ysis.
A p p e n di x 2. 8. 2 . A v er a g e Gl u c o s e E x c ur si o n s
A vera ge gl uc ose e xc ursi o ns 0 t o T h o ur(s) f or eac h vali d C G M meal sessi o n, will be calc ulate d 
b y a vera gi n g t he e xc ursi o ns wi t hi n t he ti me fra me 0- T a n d pri or t o t he start ti me of ne xt meal . 
T he pre -meal gl uc ose will use t he a vera ge val ue wit hi n t he ti me wi n d o w [ -1 9, 0] mi n ut e s relat i ve 
t o t he start of t he meal. T he e xc ursi o n at ti me T is calc ulate d b y de d ucti n g t he gl uc ose at ti me T
b y pre -meal gl uc ose . 
T he a vera ge val ue fr om all vali d C G M meal sessi o ns at t he sa me visit will be use d i n t he 
a nal ysis.
A p p e n di x 2. 8. 3.
Ar e a u n d er T h e C ur v e
Area u n der t he c ur ve ( A U C) will be calc ulate d usi n g t he sta n dar d tra pez oi dal r ule b y s u m mi n g 
t he tra pez oid areas bet wee n t w o c o nsec ut i ve gl uc ose meas ures i n t he pres pecifie d ti me peri o d 
(e g, 2 4-h o ur, or 1 h o ur after t he m or ni n g meal ).


I 8 B-M C -I TS B St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 4 8
L Y 9 0 0 0 1 4
Si milar t o A U C    , c o rres p o n di n g A U C      will be deri ve d . W he n t he a nal ysis ti me wi n d o w 
c o vers t he start ti me of t he ne xt meal a n d t he n u m ber of n o n- missi n g m eas ures sat isfies t he 
re q uire d mi ni m u m n u m ber , sta n dar dize d A U C    will be deri ve d.
A p p e n di x 2. 8. 4.
B et w e e n -D a y Gl u c o s e V ari a bilit y
T he n otati o n bel o w is f or b ot h bet wee n-d a y  a n d wit hi n da y gl uc ose varia bility deri vat i on:
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 [ defi ne d as 
mi d ni g ht t o 0 6 0 0] )
n re prese nts t he n u m ber of time p oi nts wi t hi n t he ti me peri o d
k re prese nts a vali d C G M d a y  wit hi n a visit
m re prese nts n u m ber of vali d C G M da ys at a visit 
i
k,
B G
re prese nts t he gl uc ose val ue at ti me p oi nt i o n da y k u nless ot her wise s pecifie d
F or vari a bles assessi n g bet wee n - da y v aria bilit y, first deter mi ne t he varia bility f or eac h ti me 
p oi nts acr oss vali d C G M da ys wit hi n a visit t he n a vera ge acr oss all ti me p o i 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) [Clar ke a n d K o vatc he v 2 0 0 9 ]:
Mea n of dail y differe nces ( M O D D):  t his para meter is calc ulate d as t he mea n of a bs o l ute 
differe nces bet wee n gl uc ose val ues at c orres p o n di n g ti me p o i nts of c o nsec uti ve da ys.














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


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n
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LY900014
Appendix 2.8.5. Within-day glucose variability
For variables assessing within-day variability, first determine the variability within each valid 
CGM day, then average across all valid CGM days within a visit. 
Within-day glucose SD (Hirsch 2005; Rodbard 2009):
Within-day glucose CV (Clarke and Kovatchev 2009):
Inter-quartile range (IQR) [Mazze et al. 2008]:






m
k
m
k
k
m
IQR
m
IQR
1
1
k)
day 
on 
BG values
all
of
percentile
25th 
  -
(75th 
1
1
The low blood glucose index (LBGI) has been developed to quantitate both frequency and 
severity of hypoglycemia.  The LBGI has been validated as a predictor of severe hypoglycemia.  
The HBGI quantifies both frequency and severity of hyperglycemia and has been related to 
HbA1c and risk for hyperglycemia (Kovatchev et al. 2005).  Additionally, both the LBGI and 
high blood glucose index (HBGI) have a high sensitivity to changes in glycemic profiles and 
control (Kovatchev et al. 2005). Low blood glucose index is a non-negative number that 
increases as the number of low readings increases.  High blood glucose index is a non-negative 
number that increases as the number of high readings increases.
The LBGI, HBGI, and blood glucose risk index (BGRI) will be derived for each valid CGM day 
of a visit in the following steps:
Step 1:  For each blood glucose (BG [mg/dL]) at the ith time point, compute the following:
f(BGi) = 1.509×[(ln(BGi))1.084-5.381]
This transforms the BG data using a nonlinear transformation that maps the BG range of 20 to 
600 mg/dL to a symmetric interval of

10
,
10

The center of the BG scale is 112.5 mg/dL and is mapped to 0
























m
k
i
k
i
k
m
k
k
n
m
m
SD
1
2
n
1
i
,
n
1
i
,
1
1
)
n
BG
(BG
1
SD
1









m
k
i
k
k
m
k
k
SD
m
CV
m
CV
1
n
1
i
,
1
100
)
n
BG
(
1
1


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Step 2:  Compute BG risk for each reading




2
i
i
BG
f
10
BG
rl


if f(BG) < 0; otherwise rl(BGi) = 0




2
i
i
BG
f
10
BG
rh


if f(BG) > 0; otherwise rh(BGi) = 0
Assign the risk of each BG value by applying the above quadratic risk function
Value range from 0 (achieved when BG = 112.5, the center) to 100
Left side of the parabola is risk of hypoglycemia, and the right side is risk of hyperglycemia
Step 3:  Compute LBGI and HBGI



n
1
i
i)
rl(BG
n
1
LBGI



n
1
i
i)
rh(BG
n
1
HBGI
Step 4: Compute BGRI
BGRI = LBGI + HBGI
The visit averages of LBGI, HBGI and BGRI will be calculated.
Mean amplitude of glycemic excursions (MAGE) (Service et al. 1970, 1987, Baghurst 2011):  
Mean amplitude of glycemic excursions is the mean of the excursions between consecutive 
peaks and nadirs in BG that meet qualifying criteria,
where, 
BGk,l = the low point in consecutive BG time points for the kth day (nadir)
BGk,l-h = the high point in consecutive BG time points for the kth day (peak)
p = the number of qualifying excursions:  |BGk,l – BGk,l-h| ≥ 1 SDk and that follow the direction 
of the first qualifying difference within the BG time points for the kth day.
MAGE- and MAGE+ will also be calculated for both negative and positive excursions, in 
addition to MAGE+/- for all positive and negative excursions combined (Baghurst 2011).  The 
peaks and nadirs will be algorithmically (Baghurst 2011; Approach 1), using a variant that 
removes the proposed and unnecessary first step of using a smoothing function.
Appendix 2.8.6. Glucose in Target Ranges, Hypoglycemia - or 
Hyperglycemia
The percentage of time within a glucose range (target, hypo- or hyperglycemia ranges) will be 
calculated as the number of observations within the specified range divided by the number of 
p
BG
BG
MAGE
p
1
l
h
l,
l,





k
k
k


I8B-MC-ITSB Statistical Analysis Plan Version 3
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observations in the time interval (eg, 24-hour period) on all valid CGM days at the same visit.  
The duration (in minutes) within the glucose range will then be calculated as the percentage of 
time within the glucose range times the length of the period (24 hour, 18 hour, and 6 hour, for the 
periods of 24-hour, daytime or nighttime, respectively). 
For example, if a patient had a total of 13 observations with glucose values ≤70 mg/dL 
(3.9 mmol/L) out of a total of 270 non-missing observations recorded during the 24-hour period 
across a valid CGM day (with missing observations <30% of 288 measures per day) , the 
percentage of time spent in hypoglycemia during the 24-hour period for this patient on this day 
will be calculated as 13/270 = 4.8%.  For a visit, the average percentage across all valid CGM 
days during the visit will be calculated and used for the calculation of the duration (in minutes) 
with hypoglycemia (glucose value ≤70 mg/dL [3.9 mmol/L]) during the 24-hour period for this 
patient by multiplying the average percentage with 1440.
Appendix 2.8.7. Hypoglycemic/Hyperglycemic Episodes
Hypoglycemic/hyperglycemic episodes are defined as at least 10 consecutive minutes 
below/above the specified threshold, and determined by 3 or more consecutive CGM values 
meeting the criterion. For each visit, count the total number of events occurred on the valid 
CGM days.
Appendix 2.8.8. Maximum Postprandial Glucose
Maximum postprandial glucose was the highest glucose within 4 hours after morning 
meal/midday meal/evening meal on a valid CGM day.
Maximum glucose excursion was the highest glucose excursion within 4 hours after morning 
meal/midday meal/evening meal on a valid CGM day.
Time to the maximum glucose was the time to the first maximum glucose value within 4 hours 
after morning meal/midday meal/evening meal on a valid CGM day.
Appendix 2.9.
List of Derived CGM Variables
The following variables will be derived based on valid CGM data and derivation method defined 
in Appendix 2.2 and Appendix 2.8 respectively.

Incremental AUC0-1hour, AUC0-2hours, AUC0-3hours, AUC0-4hours after the start of 
morning meal, midday meal, evening meal and all three meals during each CGM section 
up to 10 days 

Average glucose excursion 0 to 1, 2, 3, 4 hours after the start of morning meal, midday 
meal, and evening meal and all three meals during each CGM section up to 10 days

Maximum glucose excursion within 4 hours after the start of morning meal, midday 
meal, evening meal and all three meals

Maximum glucose within 4 hours after the start of morning meal, midday meal, evening 
meal and all three meals

Time to the maximum glucose within 4 hours after the start of morning meal, midday 
meal, evening meal and all three meals


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
Area under the curve for a 24-hour, daytime and nighttime period

Area under the curve during the 1, 2, 3, 4 hours after the start of morning meal, midday 
meal, evening meal and all three meals corresponding to above iAUC

Between-day glucose variability during a 24-hour, daytime and nighttime period
o
standard deviation
o
coefficient of variation
o
mean of daily differences 

Within-day glucose variability during a 24-hour, daytime, nighttime period and 0-4 hour 
during morning meal, midday meal, evening meal and all three meals
o
standard deviation
o
coefficient of variation 
o
Inter-quartile range 
o
low blood glucose index
o
high blood glucose index
o
blood glucose risk index
o
mean amplitude of glycemic excursions (MAGE-, MAGE+ and MAGE+/-
combined)

Duration (in minutes) and percentage of time with glucose values within target range 70
to 180 mg/dL (3.9 and 10.0 mmol/L), both inclusive for a 24-hour, daytime and nighttime 
period

Duration (in minutes) and percentage of time with glucose values within target range 70
to 180 mg/dL (3.9 and 10.0 mmol/L), both inclusive for 0-1, 0-2, 0-3, 0-4 hours during 
morning meal, midday meal, evening meal and all meals

Duration (in minutes) and percentage of time with glucose values within target range 70 
to 140 mg/dL (3.9 and 7.8 mmol/L), both inclusive for a 24-hour, daytime and nighttime 
period

Duration (in minutes) and percentage of time with glucose values within target range 70 
to 140 mg/dL (3.9 and 7.8 mmol/L), both inclusive for 0-1, 0-2, 0-3, 0-4 hours during 
morning meal, midday meal, evening meal and all meals

Duration (in minutes) and percentage of time with glucose values within target range 54
to 69 mg/dL (3.0 and 3.8 mmol/L), both inclusive for a 24-hour, daytime and nighttime 
period

Duration (in minutes) and percentage of time with glucose values within target range 181
to 250 mg/dL (10.1 and 13.9 mmol/L), both inclusive for a 24-hour, daytime and 
nighttime period

Duration (in minutes) and percentage of time with glucose values <54 and (less than)
70 mg/dL (3.0 and 3.9 mmol/L) for a 24-hour, daytime and nighttime period

Number of hypoglycemic episodes, defined as at least 10 consecutive minutes < 54 and 
<(less than) 70 mg/dL (3.0 and 3.9 mmol/L) during up to 10 valid CGM days

Duration (in minutes) and percentage of time with glucose values >180 and >250 mg/dL 
(10.0 and 13.9 mmol/L) for a 24-hour, daytime and nighttime period

Number of hyperglycemic episodes, defined as at least 10 consecutive minutes >180 and
>250 mg/dL (10.0 and 13.9 mmol/L) during up to 10 valid CGM days


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
Ambulatory Glucose Profile for 0 to 4 hours after the start of morning meal, midday 
meal, evening meal and all meals

Ambulatory Glucose Profile for the 24-hour window

Ambulatory Glucose Profile at individual patient level

Duration (in minutes) of each individual hypoglycemic episode defined as at least 
10 consecutive minutes  < 54 and ≤(less than)70 mg/dL (3.0 and 3.9 mmol/L) 

Duration (in minutes) of each individual hyperglycemic episode defined as at least 
10 consecutive minutes >180 and >250 mg/dL (10.0 and 13.9 mmol/L) 

Number of valid CGM days for each visit


Leo Document ID = ae510c0a-e789-4013-8b32-b69df934b333
Approver: 
Approval Date & Time: 20-Jan-2021 22:13:24 GMT
Signature meaning: Approved
PPD