Clinical trial NCT03465878
Conditions: Type 1 Diabetes Mellitus
Sponsor: Eli Lilly and Company
Start date: 2018-03-26; Completion date: 2019-11-14
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to compare LY900014 with insulin lispro (Humalog) in participants with type 1 diabetes mellitus.

There are 2 parts to this study. Part A is investigating how the body processes LY900014 and the effect of LY900014 on blood sugar levels compared to insulin lispro (Humalog) when study treatment is given by subcutaneous injection. Part B of the study is investigating how the body processes LY900014 and the effect of LY900014 on blood sugar levels compared to insulin lispro (Humalog) when study treatment is given by continuous subcutaneous insulin infusion (CSII) pump.

Screening is required within 28 days prior to the start of the study. For each participant, the study will last about 40 days in each part.

Detailed description:

Arms: arm 1: Participants received single 0.2 U/kg of body weight subcutaneous (SC) bolus injection of 100 U/mL LY900014. arm 2: Participants received single 0.2 U/kg of body weight SC bolus injection of 100 U/mL of Humalog. arm 3: Participants received single 0.2 U/kg of body weight SC bolus infusion of 100 U/mL LY900014 delivered using the continuous subcutaneous insulin infusion (CSII) pump. arm 4: Participants received single 0.2 U/kg of body weight SC bolus infusion of 100 U/mL Humalog delivered using the CSII pump.
Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro
Intervention descriptions: intervention 1: Administered via SC injection intervention 2: Administered via SC injection

Protocol documents:
Prot_000.pdf: 
Protocol: I8B-MC-ITSA(d)
A Study to Evaluate the Pharmacokinetics and Glucodynamics of LY900014 
Compared to Humalog in Children, Adolescents, and Adults With Type 1 Diabetes 
Mellitus
NCT03465878    
Approval Date: 20-Jul-2018


I8B-MC-ITSA(d)Clinical Pharmacology Protocol
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LY900014
Protocol I8B-MC-ITSA(d)
A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 Compared to Humalog in 
Children, Adolescents,and Adults with Type 1Diabetes 
Mellitus
EudraCTNumber:2017-003220-78
Confidential Information
The information contained in this protocol 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 toFreedom 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.
Approval Date: 20-Jul-2018 GMT
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 
12October2017
Amendment (a) Electronically Signed and Approved by Lilly: 21December2017
Amendment (b) Electronically Signed and Approved by Lilly:  19March2018
Amendment (c) Electronically Signed and Approved by Lilly:  17April2018
Amendment (d) Electronically Signed and Approved by Lilly
on approval date provided below.


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LY900014
Table of Contents
A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 compared to Humalog in 
Children, Adolescents, and Adultswith Type 1 Diabetes 
Mellitus
Section
Page
Protocol I8B-MC-ITSA(d) A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 Compared to Humalog in Children, 
Adolescents, and Adults with Type 1 Diabetes Mellitus......................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities.......................................................................................................11
3.
Introduction......................................................................................................................23
3.1. Study Rationale............................................................................................................23
3.2. Background..................................................................................................................23
3.3. Benefit/Risk Assessment..............................................................................................25
4.
Objectives and Endpoints..................................................................................................27
5.
Study Design.....................................................................................................................28
5.1. Overall Design.............................................................................................................28
5.1.1. 
Part A...................................................................................................................29
5.1.1.1.
Inpatient Procedures for Part A.......................................................................31
5.1.2.
Part B...................................................................................................................34
5.1.2.1.
Inpatient Procedures for Part B.......................................................................36
5.2. Number of Participants.................................................................................................40
5.3. End of Study Definition...............................................................................................40
5.4. Scientific Rationale for Study Design...........................................................................40
5.5. Justification for Dose...................................................................................................40
6.
Study Population...............................................................................................................42
6.1. Inclusion Criteria..........................................................................................................42
6.2. Exclusion Criteria........................................................................................................44
6.2.1.
Additional Exclusion Criteria for Inpatient Dosing Days......................................46
6.2.2.
Rationale for Exclusion of Certain Study Candidates...........................................46
6.3. Lifestyle and/or Dietary Requirements.........................................................................47
6.3.1.
Meals and Dietary Restrictions.............................................................................47
6.3.2.
Caffeine, Alcohol, and Tobacco...........................................................................47
6.3.3.
Activity................................................................................................................48


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LY900014
6.4. Screen Failures.............................................................................................................48
7.
Treatment..........................................................................................................................49
7.1. Treatment Administered...............................................................................................49
7.1.1.
Packaging and Labelling......................................................................................49
7.2. Method of Treatment Assignment................................................................................50
7.2.1.
Selection and Timing of Doses.............................................................................50
7.3. Blinding.......................................................................................................................50
7.4. Dose Modification........................................................................................................51
7.4.1.
Special Treatment Considerations........................................................................51
7.5. Preparation/Handling/Storage/Accountability...............................................................51
7.6. Treatment Compliance.................................................................................................51
7.7. Concomitant Therapy...................................................................................................51
7.8. Treatment after the End of the Study............................................................................52
8.
Discontinuation Criteria....................................................................................................53
8.1. Discontinuation from Study Treatment.........................................................................53
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................53
8.2. Discontinuation from the Study....................................................................................53
8.3. Patients Lost to Follow-up............................................................................................54
9.
Study Assessments and Procedures...................................................................................55
9.1. Efficacy Assessments...................................................................................................55
9.2. Adverse Events............................................................................................................55
9.2.1.
Serious Adverse Events........................................................................................56
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................57
9.2.2.
Complaint Handling.............................................................................................57
9.3. Treatment of Overdose.................................................................................................57
9.4. Safety...........................................................................................................................57
9.4.1.
Laboratory Tests..................................................................................................57
9.4.2.
Vital Signs...........................................................................................................58
9.4.3.
Electrocardiograms..............................................................................................58
9.4.4.
Other Tests...........................................................................................................58
9.4.4.1.
Hip and Waist Circumference.........................................................................58
9.4.4.2.
Body Weight and Height................................................................................58
9.4.5.
Safety Monitoring................................................................................................59
9.4.5.1.
Hepatic Safety................................................................................................59
9.4.5.2.
Glucose Monitoring........................................................................................59
9.4.5.3.
Severe Hypoglycaemia...................................................................................60
9.4.5.4.
Injection-Site Assessments (Local Tolerability)..............................................61
9.4.6.
Treatment of Hyperglycaemia and Hypoglycaemia..............................................61


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LY900014
9.5. Pharmacokinetics.........................................................................................................61
9.5.1.
Bioanalysis...........................................................................................................61
9.6. Pharmacodynamics......................................................................................................62
9.6.1.
Glucodynamic Samples........................................................................................62
9.6.1.1.
Glucose Samples (Run-In Period)...................................................................62
9.6.1.2.
Glucose Samples (MMTT).............................................................................62
9.6.2.
Immunogenicity Assessments..............................................................................62
9.7. Genetics.......................................................................................................................63
9.8. Biomarkers...................................................................................................................63
9.9.
Health Economics........................................................................................................63
10. Statistical Considerations and Data Analysis.....................................................................64
10.1. Sample Size Determination..........................................................................................64
10.2. Populations for Analyses..............................................................................................64
10.2.1. Study Participant Disposition...............................................................................64
10.2.2. Study Participant Characteristics..........................................................................64
10.3. Statistical Analyses......................................................................................................64
10.3.1. Safety Analyses....................................................................................................65
10.3.1.1. Clinical Evaluation of Safety..........................................................................65
10.3.1.2. Statistical Evaluation of Safety.......................................................................65
10.3.2. Pharmacokinetic Analyses....................................................................................65
10.3.2.1. Pharmacokinetic Parameter Estimation...........................................................65
10.3.2.2. Pharmacokinetic Statistical Inference.............................................................66
10.3.3. Glucodynamic Analyses.......................................................................................66
10.3.3.1. Glucodynamic Parameter Estimation..............................................................66
10.3.3.2. Glucodynamic Statistical Inference.................................................................67
10.3.4. Evaluation of Immunogenicity.............................................................................67
10.3.5. Interim Analyses..................................................................................................67
11. References........................................................................................................................68


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List of Tables
Table
Page
TableITSA.1.
Objectives and Endpoints.......................................................................27
TableITSA.2.
Volume of Standardised Meal According to Body Weight......................47
TableITSA.3.
Treatments Administered........................................................................49


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List of Figures
Figure
Page
FigureITSA.1.
Illustration of study design for Part A.....................................................30
FigureITSA.2.
Inpatient procedure in Part A..................................................................33
FigureITSA.3.
Illustration of study design for Part B.....................................................35
FigureITSA.4.
Inpatient procedure in Part B..................................................................39


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions................................................................70
Appendix 2.
Clinical Laboratory Tests........................................................................74
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................75
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality............78
Appendix 5.
Blood Sampling Summary......................................................................79
Appendix 6.
Protocol Amendment I8B-MC-ITSA(d) Summary 
A Study to Evaluate the Pharmacokinetics and Glucodynamics of 
LY900014 Compared to Humalog in Children, Adolescents, and 
Adults with Type 1 Diabetes Mellitus.....................................................80


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1. Protocol Synopsis
Title of Study:
A study to evaluate the pharmacokinetics and glucodynamics of LY900014 compared to Humalog in children, 
adolescents, and adults with type 1 diabetes mellitus
Rationale: 
A prandial insulin with faster-on and/or faster-off characteristics might reduce glycaemic excursions and the 
incidence of postprandial hypoglycaemia compared to currently available fast-acting insulin analogues.  LY900014 
is an ultra-rapid-acting insulin lispro formulation with increased early absorption compared to commercially 
available insulin lispro formulation (Humalog®; Eli Lilly and Company).  LY900014 aims to mimic the 
physiological prandial insulin secretion pattern, which may more effectively control postprandial glucose 
excursions.
The aim of the study is to evaluate insulin lispro pharmacokinetics (PK), glucodynamics (GD), safety, and 
tolerability of LY900014 in comparison with Humalog following a single subcutaneous (SC) dose administration 
immediately prior to a standardised liquid meal in paediatric and adult patients with type 1 diabetes mellitus 
(T1DM).  This will be the first study to evaluate LY900014 in paediatric patients with T1DM.  
Objectives/Endpoints:
Objectives
Endpoints
Primary
1.
Part A: To evaluate the PK of insulin lispro following a 
single SC dose administered through injection of LY900014 
compared to Humalog in children, adolescents, and adults 
with T1DM
2.
Part B:  To evaluate the PK of insulin lispro following a 
single SC bolus dose administered through CSII of 
LY900014 compared to Humalog in children, adolescents, 
and adults with T1DM
1.
Early 50% tmax and AUC(0-30min)
2.
Early 50% tmax and AUC(0-30min)
Secondary
1.
Part A and Part B: To evaluate the difference in GD 
response to LY900014 and Humalog administered through
SC bolus injection or CSII, as assessed using the liquid 
MMTT in children, adolescents, and adults with T1DM
2.
Part A and Part B: To evaluate the tolerability of
LY900014 following SC injection or CSII in children, 
adolescents, and adults with T1DM
1.
∆AUC(0-2h), ∆AUC(0-5h)
2.
AEs including injection/catheter insertion 
site reactions/pain, hypoglycaemia, and 
anti-insulin lispro antibodies
Abbreviations:  AE = adverse event; AUC = area under the concentration versus time curve; AUC(0-30min) = AUC 
from time zero to 30 minutes; CSII = continuous subcutaneous insulin infusion; ∆AUC = area under the baseline 
subtracted glucose concentration versus time curve; ∆AUC(0-2h) = ∆AUC from time 0 to 2 hours postmeal; 
∆AUC(0-5h) = ∆AUC from time 0 to 5 hours postmeal; early 50% tmax = time to early half-maximal drug 
concentration; GD = glucodynamics; MMTT = mixed meal tolerance test; PK = pharmacokinetics; SC = 
subcutaneous; T1DM = type 1 diabetes mellitus.


I8B-MC-ITSA(d) Clinical Pharmacology Protocol
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LY900014
Summary of Study Design:
Study I8B-MC-ITSA is a randomised, patient- and investigator-blind, 2-part study, with each part containing a 2-
period crossover assessment in children (age 6 to <12 years), adolescents (age 12 to <18 years), and adults (age 18 
to <65 years) with T1DM to evaluate the PK, GD, and tolerability of LY900014 compared to Humalog given as a 
bolus either as a SC injection or via a continuous subcutaneous insulin infusion (CSII) pump.
Treatment Arms and Planned Duration for an Individual Patient:  
The study will be conducted in 2 parts, Part A and Part B. Each part consists of a 2-period crossover to compare 
LY900014 and Humalog administered prior to a mixed meal tolerance test (MMTT). All study and treatment 
procedures will be conducted during inpatient stays of approximately 2 days per period and require a minimum of 
3 days and a maximum of 23 days to complete both periods.  In each part, after completion of the last study period
(Period 2), a 14-day safety follow-up is planned. Total duration of each part is expected to be up to 68 days.
Patients are encouraged to participate in both Part A and Part B of the study; however, study participation is not 
contingent on patients’ participation in both parts of the study.
Patients may be screened up to 28 days prior to Day -1 of Period 1 of Part A and Part B.  Patients will be admitted to 
the study site the day before the MMTT day each period and will remain until all assessments are completed on 
Day 1. On Day 1 in Period 1 for Part A and on Day -1 in Period 1 for Part B, patients will be randomised to 1 of 2 
treatment sequences.  In Part A, each patient will receive a single SC injection of both LY900014 and Humalog
immediately prior to an MMTT assessment in a crossover design. Initiation of Part B of the study may begin 
pending the review of the PK, GD, safety, and tolerability data from Part A and ongoing or planned adult CSII Phase 
1b studies.  In Part B, patients will receive a single SC bolus dose of both LY900014 and Humalog via CSII pump
immediately prior to an MMTT assessment in a crossover design.  Patients will undergo a follow-up visit at least 
14 days after the last dose of the study drug in each part.  
Treatment:
Part A: Each patient will receive a single SC bolus injection of LY900014 and Humalog.
Part B:  Each patient will receive a single SC bolus of LY900014 and Humalog via CSII pump.
Number of Patients:
Approximately 45 patients may be enrolled into the study so that approximately 36 patients (12 patients in each age 
group [6 to <12 years, 12 to <18 years, and 18 to <65 years] based on the age at initial screening) complete both 
inpatient periods in both parts of the study.  
Patients participating in Part A may continue participation in Part B.  If patients from Part A decline participation in 
Part B or drop out from Part A, additional patients will be enrolled to ensure approximately 36 patients (12 patients 
in each age group) complete both periods in Part B of the study.
Statistical Analysis:
The analyses for Part A and Part B will be conducted separately using similar statistical methods.  Primary statistical 
analyses will be conducted on the set of patients who complete both treatment periods. Supportive analyses may be 
done on the key parameters for the patients who complete at least 1 treatment period.  Safety analyses will be 
conducted for the set of patients receiving at least 1 dose of the study drug, whether or not they completed all 
protocol requirements.


I8B-MC-ITSA(d) Clinical Pharmacology Protocol
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LY900014
Safety:  All study drug- and protocol procedure-related adverse events will be listed, and if the frequency of events 
allows, safety data (including hypoglycaemic events) will be summarised using descriptive methodology.  Safety 
parameters will be listed, and may be summarised using standard descriptive statistics.
Pharmacokinetic:  Log-transformed PK parameters for insulin lispro will be evaluated to estimate least-squares 
geometric means, ratios of geometric means between LY900014 and Humalog, and their corresponding 95% CIs of 
the ratios using the mixed-effect model that includes treatment, sequence, period, age group, and treatment by age 
group interaction as fixed effects and patient within sequence as a random effect.  
The same model without log transformation will be used for the analysis of the PK time parameters (time to early 
half-maximal drug concentration [early 50% tmax], time to late half-maximal drug concentration [late 50% tmax], 
time of maximum observed drug concentration (tmax).  Least-squares means (LSmeans), treatment differences in 
LSmeans, and the corresponding 95% CIs for the treatment differences will be estimated from the model.  The 
treatment ratios and 95% CIs for the ratios using the Fieller’s theorem will be provided. 
Glucodynamic:  Data will be analysed for the patients during each MMTT. The change from baseline values (the 
average of -30, -15, and 0 minutes) represented as the 0-hour time point following the start of the MMTT for each 
patient will be calculated. The area under the baseline subtracted glucose concentration versus time curve (∆AUC) 
from time 0 to 2 hours postmeal (∆AUC[0-2h]) and ∆AUC from time 0 to 5 hours postmeal (∆AUC[0-5h]) will be 
calculated. In addition, the change from baseline maximum glucose observed during the 5 hours postmeal and 
change from baseline 1 hour glucose and 2 hour glucose after the start of the meal will be calculated. Other partial 
∆AUCs may be calculated as deemed appropriate.
Summary statistics (including number of patients, mean, standard deviation or standard error, minimum, and 
maximum) will be presented by treatment for each age group.  The GD parameters on the original scale (not log 
transformed) will be analysed using the same model used for PK parameters.  Least-squares means, treatment 
differences in LSmeans, and the corresponding 95% CIs for the treatment differences will be estimated from the 
model.  The treatment ratios and 95% CIs for the ratios will be calculated using the Fieller’s theorem.


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2. Schedule of Activities
Study Schedule Protocol I8B-MC-ITSA (Part A)
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-
upa/Early 
Discontinuationb
Comments
101
Telephone 
Visit
1 and 2
801
Day
Within 28 
days Prior 
to Day -1 
≥Day -10c
-1d
1
≥14 days After 
Last Dose of 
Study Drug
Informed Consent/Assent
X
Should be obtained before any 
study-related procedures are 
performed.
Inclusion/Exclusion Criteria
X
Medical History
X
Pre-existing Conditions
X
Age
X
Height
X
Weight
X
X
X
Physical Examination
X
Predose
X
Physical examination at 
screening.  Thereafter, targeted 
medical assessment, as 
appropriate.
Admission to Study Site
X
IWRS and Randomisation
X
Randomisation in Period 1 only.  
Age group for randomisation will 
be based on initial screening.
Previous Diabetes Therapy
Record Prandial and Basal 
Insulin Dose
X
X*
*Period 1 only.
Vital Signs (Pulse, Sitting BP)
X
Pre- and 2 hours 
postdose
X
Eligibility Assessment
X
X
X*
*Period 1 only.
Hip and Waist Circumference
X
Applicable only to adult patients.


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Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-
upa/Early 
Discontinuationb
Comments
101
Telephone 
Visit
1and 2
801
Day
Within 28 
days Prior 
to Day -1 
≥Day -10
c
-1
d
1
≥14 days After 
Last Dose of 
Study Drug
Clinical Laboratory Tests
X
X
See Appendix 2for details.  All 
patients of legal drinking age 
(according to local laws)will 
receive alcohol breath test on 
Day -1.
Glycated Haemoglobin(HbA1c)
Assessment
X
Urinalysis
X
X
12-Lead ECG
X
Pregnancy Test
X
X
X
Pregnancy tests will be 
performedfor all females ≥12 
yearsof age or <12yearsof age 
withonset of menses.  Serum 
pregnancy testswill be
performed at screening,and urine 
pregnancy test on Day -1 of 
Periods1and 2 (or when 
clinically indicated), and at the 
follow-up or ED visit.  Urine 
pregnancy tests at other visits 
accepted per local regulations.
Provide Evening Meal
X
Begin Overnight Fast
X
Patients will be fasted (except for 
water) for at least 10 hours 
before each test meal.
Stop CSII
X
Prior to startof run-in.
Applicable only to patients on 


I8B-MC-ITSA(d)Clinical Pharmacology Protocol
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LY900014
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-
upa/Early 
Discontinuationb
Comments
101
Telephone 
Visit
1and 2
801
Day
Within 28 
days Prior 
to Day -1 
≥Day -10
c
-1
d
1
≥14 days After 
Last Dose of 
Study Drug
CSII.
Run-in/Stabilisation of Glucose
X
(following 
evening 
meal)
Approximately at 09:00to10:00
PMinfusion of glucose (dextrose 
solution) or 
 
insulin to target a blood glucose 
concentration of 135±25mg/dL 
(7.5±1.4mmol/L).  Blood 
glucose concentrations will be 
monitored at a minimum of 30-
to 60-minute intervals.
Study Drug Administration
(Single SC injection)
X
Time of studydrug 
administration = 0 hour.
Study drug will be administered 
at approximately the same times 
on Day 1 of each study period.
Immunogenicity Sample
Predose
X
Injection-Site Evaluation
0,60,and 240minutes 
postdose
Time 0: Assessments of 
injection-site local tolerability 
will occur immediately following 
the injection.
Directions for Preparing for PK 
and MMTT Visits
X
Patients will receive preparatory 
instructions as part of their pre-
study telephone consultation(see 
Section6.3,for details).
Mixed Meal Tolerance Test 
(MMTT)
X
A standard liquid meal will be 
administered at the MMTT time 
“0” (as soon as possible after 
CCI


I8B-MC-ITSA(d) Clinical Pharmacology Protocol
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LY900014
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-
upa/Early 
Discontinuationb
Comments
101
Telephone 
Visit
1 and 2
801
Day
Within 28 
days Prior 
to Day -1 
≥Day -10c
-1d
1
≥14 days After 
Last Dose of 
Study Drug
administration of study drug) and 
should be consumed within 
15 minutes.
Blood Glucose Sampling 
(MMTT)
-30, -15, 0 (premeal), 
10, 20, 30, 40, 50, 60, 
70, 80, 90, 100, 110, 
120, 135, 150, 165, 
180, 195, 210, 225, 
240, 300 minutes 
postmeal
Time is referenced to meal start 
time, i.e., time 0.  Time 0 is 
collected immediately prior to 
start of meal consumption.
Insulin Lispro PK Sampling
0, 5, 10, 15, 20, 25, 30, 
35, 40, 45, 50, 60, 70, 
90, 120, 150, 180, 240, 
300, 360, and 420 
minutes postdose
Sampling times are relative to the 
time of study drug treatment 
administration (t = 0) in  each 
period
Transition to NPH Twice Daily 
Therapy 7-3 days Prior to Day -1
X
Applicable only to patients using 
multiple daily injection therapy.  
Patient can return to pre-study 
basal insulin following 
completion of MMTT sampling 
period per investigator’s decision 
and allowing for transition to 
NPH prior to next dosing.
Resume Prestudy CSII Rate
X
Applicable only to patients on 
CSII.
CSII with the patient’s prestudy
insulin will be restarted after 


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LY900014
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-
upa/Early 
Discontinuationb
Comments
101
Telephone 
Visit
1 and 2
801
Day
Within 28 
days Prior 
to Day -1 
≥Day -10c
-1d
1
≥14 days After 
Last Dose of 
Study Drug
completion of assessment period 
(approximately 420 minutes 
postdose).
Adverse Events/Hypoglycaemia
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
Patient Discharge from Study 
Site
X
If the next MMTT (Period 2) is 
scheduled on the next day, the 
patient may be discharged after 
the second MMTT (Period 2).
Abbreviations:  BP = blood pressure; CSII = continuous subcutaneous insulin infusion; ECG = electrocardiogram; ED = early discontinuation; IWRS = 
Interactive Web Response System; MMTT = mixed meal tolerance test; NPH = neutral protamine Hagedorn; PK = pharmacokinetics; SC = subcutaneous.
a
Safety follow-up visit should occur at least 14 days after the last dose.
b
Early discontinuation procedures will be performed at least 14 days after a patient stops the study after receiving study drug on Day 1 of Period 1 and 
before Day 1 of Period 2.
c
This is a telephone visit.
d
In case of dosing on consecutive days, the medical assessments to be conducted on Day -1 of Period 2 may be done on Day 1 of Period 1.
Note:  The study site should schedule activities as appropriate.  In cases where several study procedures are scheduled at the same time, the order of priority will 
be as follows:  pharmacokinetic samples including blood sampling for blood glucose and laboratory samples per protocol nominal times.  Electrocardiograms
and vital sign measurements should be scheduled before but as close as possible to the PK sampling times.  Injection-site assessments can be done after PK 
sampling.


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LY900014
Study Schedule Protocol I8B-MC-ITSA (Part B)
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-upa/Early 
Discontinuationb
Comments
102
Telephone 
Visit
3 and 4
802
Day
Within 28 
days Prior 
to Day -1
≥Day -10c
-1d
1
≥14 days After 
Discharge
Informed Consent/Assent
Xe
Should be obtained 
before any study-related 
procedures are 
performed.
Inclusion/Exclusion Criteria
X
Medical History
X
Pre-existing Conditions
X
For patients continuing 
from Part A, a review 
will be performed to 
record any changes from 
the previous screening.
Age
X
Applicable only to newly 
enrolled patients.  For 
patients participating 
from Part A, age at initial 
screening (Part A) will 
be used for reporting 
purposes.
Height
X
Weight
X
X
X
Physical Examination
X
Predose
X
Physical examination at 
screening.  Thereafter, 
targeted medical 
assessment, as 
appropriate.
Admission to Study Site
X


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LY900014
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-upa/Early 
Discontinuationb
Comments
102
Telephone 
Visit
3and 4
802
Day
Within 28 
days Prior 
to Day -1
≥Day -10
c
-1
d
1
≥14 days After 
Discharge
IWRS and Randomisation
X
Randomisation at Period 
1 only.  Age group for 
randomisation will be 
based on initial 
screening.
Previous Diabetes Therapy
Record Prandial and Basal Insulin 
Dose
X
X*
*Period 1 only.
Vital Signs (Pulse, Sitting BP)
X
Pre-and 2 hours 
postdose
X
Hip and Waist Circumference
X
Applicable only to adult 
patients.
Eligibility Assessment
X
X
X*
*Period 1 only.
Clinical Laboratory Tests
X
X
See Appendix 2for 
details.  All patients of 
legal drinking age 
(according to local laws) 
will receive alcohol 
breath test on Day -1.
Glycated Haemoglobin (HbA1c) 
Assessment
X
Urinalysis
X
X
12-Lead ECG
X


I8B-MC-ITSA(d) Clinical Pharmacology Protocol
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LY900014
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-upa/Early 
Discontinuationb
Comments
102
Telephone 
Visit
3 and 4
802
Day
Within 28 
days Prior 
to Day -1
≥Day -10c
-1d
1
≥14 days After 
Discharge
Pregnancy Test
X
X
X
Pregnancy tests will be 
performed for all females 
≥12 years of age or < 12 
years of age with onset 
of menses.  Serum 
pregnancy tests will be  
performed at screening, 
and urine pregnancy test 
on Day -1 of Periods 1 
and 2 (or when clinically 
indicated), and at the 
follow-up or ED visit.  
Urine pregnancy tests at 
other visits accepted per 
local regulations.
Provide Evening Meal and 
Administer Bolus Insulin Infusion
X
Provide instructions for 
replacement of pump 
reservoir/tubing/infusion 
set containing IP to occur 
following evening meal.  
Prandial insulin to be 
patient’s usual insulin.  
Begin Overnight Fast
X
Patients will be fasted 
(except for water) for at 
least 10 hours before 
each test meal.


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LY900014
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-upa/Early 
Discontinuationb
Comments
102
Telephone 
Visit
3and 4
802
Day
Within 28 
days Prior 
to Day -1
≥Day -10
c
-1
d
1
≥14 days After 
Discharge
Reduce CSII basal rate
X
Prior to start of run-in.
Applicable only to 
patients on CSII.  Basal 
rate to be reduced to 
0.1U/hour.
Run-in/Stabilisation of Glucose
X
(following 
evening 
meal)
Approximately at 09:00 
to10:00PMinfusion of 
glucose (dextrose 
solution) or 
 
 insulin to target a 
blood glucose 
concentration of 
135±25mg/dL 
(7.5±1.4mmol/L).  
Blood glucose 
concentrations will be 
monitored at a minimum 
of 30-to 60-minute 
intervals.
Study Drug Administration
(Single Bolus via CSII)
X
Time of study drug 
administration = 0 hour.
Study drug will be 
administered at 
approximately the same 
times on Day 1 of each 
study period.
Immunogenicity Sample
Predose
X
CCI


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LY900014
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-upa/Early 
Discontinuationb
Comments
102
Telephone 
Visit
3and 4
802
Day
Within 28 
days Prior 
to Day -1
≥Day -10
c
-1
d
1
≥14 days After 
Discharge
Catheter-Site Evaluation
0, 20,40, 60,and 240 
minutes postdose
Time 0:  Assessments 
will occur immediately 
following the study drug 
administration.
Directions for Preparing for PK 
and MMTT Visits
X
Patients will receive 
preparatory instructions 
as part of their pre-study 
telephone consultation 
(see Section6.3, for
details). 
Mixed Meal Tolerance Test
X
A standard liquid meal 
will be administered at 
the MMTT time “0” (as 
soon as possible after 
administration of study 
drug) and should be 
consumed within 
15minutes.
Blood Glucose Sampling (MMTT)
-30, -15, 0 (premeal), 
10, 20, 30, 40, 50, 60, 
70, 80, 90, 100, 110, 
120, 135, 150, 165, 
180, 195, 210, 225, 
240, 300 minutes
(postmeal)
Time is referenced to 
meal start time.  Time 0 
is collected immediately 
prior to start of meal 
consumption.


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LY900014
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-upa/Early 
Discontinuationb
Comments
102
Telephone 
Visit
3 and 4
802
Day
Within 28 
days Prior 
to Day -1
≥Day -10c
-1d
1
≥14 days After 
Discharge
Insulin Lispro PK Sampling
0, 5, 10, 15, 20, 25, 30, 
35, 40, 45, 50, 60, 70, 
90, 120, 150, 180, 240, 
300, 360, and 420 
minutes postdose
Sampling times are 
relative to the time of 
study drug treatment 
administration (t = 0) in 
each period.
Transition to NPH Twice Daily 
Therapy 7-3 days Prior to Day -1
X
Applicable only to 
patients using multiple 
daily injection therapy.  
Patient can return to pre-
study basal insulin 
following completion of 
MMTT sampling period 
per investigator’s
decision and allowing for 
transition to NPH prior 
to next dosing.
Resume Prestudy CSII Rate
X
Applicable only to 
patients on CSII.
CSII with the patient’s 
prestudy insulin will be 
restarted after 
completion of 
assessment period 
(approximately 
420 minutes postdose).
Adverse Events/Hypoglycaemia
X
X
X
X
X
Concomitant Medications
X
X
X
X
X


I8B-MC-ITSA(d) Clinical Pharmacology Protocol
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LY900014
Visits
Screening
Study Periods
(Periods 1 and 2)
Follow-upa/Early 
Discontinuationb
Comments
102
Telephone 
Visit
3 and 4
802
Day
Within 28 
days Prior 
to Day -1
≥Day -10c
-1d
1
≥14 days After 
Discharge
Patient Discharge from Study Site
X
If the next MMTT 
(Period 2) is scheduled 
on the next day, the 
patient may be 
discharged after the 
second MMTT 
(Period 2).
Abbreviations: BP = blood pressure; CSII = continuous subcutaneous insulin infusion; ECG = electrocardiogram; ED = early discontinuation; 
IWRS = Interactive Web Response System; MMTT = mixed meal tolerance test; NPH = neutral protamine Hagedorn; PK = pharmacokinetics; 
SC = subcutaneous.
a
Safety follow-up visit should occur at least 14 days after the completion of Period 2.
b
Early discontinuation procedures will be performed at least 14 days after a patient stops the study after receiving study drug on Day 1 of Period 1 and 
before Day 1 of Period 2.
c
This is a telephonic visit.
d
In case of dosing on consecutive days, the medical assessments to be conducted on Day -1 of Period 2 may be done on Day 1 of Period 1.
e
Not applicable for patients continuing from Part A.
Note:  The study site should schedule activities as appropriate.  In cases where several study procedures are scheduled at the same time, the order of priority will 
be as follows:  pharmacokinetic samples including blood sampling for blood glucose and laboratory samples per protocol nominal times.  Vital sign and 
measurements should be scheduled before but as close as possible to the PK sampling times.  Catheter-site assessments can be performed after PK sampling.


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LY900014
3. Introduction
3.1.
Study Rationale
A prandial insulin with faster-on and/or faster-off characteristics might reduce glycaemic 
excursions and the incidence of postprandial hypoglycaemia compared to currently available 
fast-acting insulin analogues.  LY900014 is an ultra-rapid-acting insulin lispro formulation with 
increased early absorption compared to commercially available insulin lispro formulation 
(Humalog®; Eli Lilly and Company).  LY900014 aims to mimic the physiological prandial 
insulin secretion pattern, which may more effectively control postprandial glucose excursions.
This faster profile may help to overcome commonly observed difficulties in insulin therapy in 
paediatric patients such as increasing weight, height, and caloric needs as well as unpredictable 
eating behaviour of young children and peripheral resistance of puberty.
The aim of the study is to evaluate insulin lispro pharmacokinetics (PK), glucodynamics (GD), 
safety, and tolerability of LY900014 in comparison with Humalog following a single 
subcutaneous (SC) dose administration immediately prior to a standardised liquid meal in 
paediatric and adult patients with type 1 diabetes mellitus (T1DM).  This will be the first study to 
evaluate LY900014 in paediatric patients with T1DM. 
3.2.
Background
The insulin analogue, insulin lispro (Humalog), has shown to be absorbed more quickly than 
regular human insulin (RHI) (Humalog package insert, 2015).  In healthy volunteers given SC 
doses of insulin lispro ranging from 0.1 to 0.4 units (U)/kg, peak serum levels were seen 30 to 
90 minutes after dosing (Humalog package insert, 2015).  The persistent delays in absorption and 
variability in the duration of action of currently available rapid-acting insulin analogues
contribute to commonly observed difficulties of insulin therapy in youths (due to increasing 
weight, height, peripheral resistance of puberty, changes in caloric needs, and unpredictable 
eating behaviour of younger youths; Cengiz 2012).  An ultra-rapid-acting prandial insulin would 
shift the PK/GD of insulin analogues so that they have an even faster onset to better match 
carbohydrate absorption and lead to improved postprandial glucose that also allows greater 
flexibility in the time of dosing relative to meals.
Regional evidence suggests that the incidence of T1DM in youths is increasing in the US 
(Lipman et al. 2013) and Europe (EURODIAB ACE Study Group 2000).  Estimates of T1DM
prevalence in the paediatric population in the US come from the Centers for Disease Control and 
Prevention-sponsored SEARCH for Diabetes in Youth (SEARCH) Study (SEARCH for Diabetes 
in Youth Study Group 2009), which collects diabetes diagnosis information from multiple 
centres throughout the US.  This study estimated the 2001 prevalence of T1DM among children
under 10 years of age to be 0.76 per 1000; amongst adolescents 10 to 19 years of age, the risk 
more than doubled to 2.28 cases per 1000.  More recently, the SEARCH study estimated that in 
2011 the total number of youth in the US <20 years of age with T1DM was 166,984 (Pettit et al. 
2014).  As with adults, intensive diabetes management through maintenance of tight glycaemic
control helps to delay onset and slow the progression of complications of the disease in youths 
(DCCT 1993).  Tight glycaemic control is achieved via intensive insulin therapy, which requires 


I8B-MC-ITSA(d)Clinical Pharmacology Protocol
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LY900014
dietary discipline, frequent blood glucose 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 youths. Intensive insulin treatment in 
T1DMshould be initiatedearly in disease progression and theimproved glycaemiccontrol may 
have a lasting impact on reducing the onset of diabetic complications.  
LY900014 represents a new formulation that contains insulin lispro, treprostinil, citrate,and 
other excipients.  This formulation involves the novel use ofa microdose of treprostinil 
s an excipient to enhance the absorption of insulin lispro by local vasodilatation 
rather than as an active pharmaceutical ingredient to elicit a sy 
fect.  Treprostinil is a 
prostacyclin analogue, administered either through inhalation 
, as an intravenous (IV) 
infusion,or as a continuous SC administrationfor the treatment of symptomatic pulmonary 
arterial hypertension (PAH) and has been approved in the US since 2002 and for SC 
administrationin Germany since 2005
  In adults dosed with 
LY900014, systemic treprostinil was unmeasurable and no haemodynamic effects were noted 
with a treprostinil dose equivalent that contained in 
 of LY900014.  Sodium citrate, an 
excipient that speeds up insulin absorption (at least in part by enhancing vascular permeability), 
is also included in the formulation to further enhance the absorption of insulin lispro.  Each of 
the other excipients (such as magnesium chloride) in the LY900014 formulation is listed in the 
US Food and Drug Administration (FDA)’s Generally Recognized as Safe Food Additives 
database and in the FDA’s Inactive Ingredients in Approved Drugs database.  Furthermore, 
concentration ofthe excipientsin LY900014 is within the limits identified for approved drug 
products in the FDA Inactive Ingredients in Approved Drugs database.
To date, LY900014 has been administered to approximately 89 adult patientswith diabetes 
(60T1DM and 29 type 2 diabetes mellitus[T2DM]). The total insulin lispro exposure was 
similar between LY900014 and Humalog; however,LY900014 demonstrated a faster and earlier 
insulin lispro absorption compared to Humalog.LY900014 displayed proportional increases in 
insulin lispro exposure (area under the concentration versus time curve [AUC]and maximum 
observed drug concentration(C
max
CCI
) with dose. The faster early insulin lispro absorption was 
maintained across the dose range studied (7.5to 15U). Additionally, through the use of multiple 
daily injections of LY900014 for up to 2weeks in patients with either T1DM or T2DM, it was 
found that LY900014 was well tolerated.  Data from these Phase 1b studies show there was only 
1 sample with quantifiable plasma treprostinil concentrations from approximately 472 samples 
taken from a total of 60patients with T1DM and T2DM following administration of LY900014 
using doses up to 50U per SC bolus injection. In addition, no quantifiable plasma treprostinil 
concentrations were observed with continuous subcutaneous insulin infusion(CSII)therapy 
during the basal infusion or after the bolus dose in 30patients. There were no serious adverse 
events (SAEs) related to study treatment or discontinuations from the studies because of a drug-
related adverse event (AE).Small numbers of treatment-emergent adverse eventswere reported, 
and there were no notable increases in these events in relation to any of the LY900014 
formulations compared to those in relation to Humalog.There were no reported cases of severe 
hypoglycaemia.  Additionally, there wereno reported incidences of local or systemic allergic 
reactions.
CCI
CCI
CCI


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LY900014
3.3. Benefit/Risk Assessment
CCI
This study will not offer any direct benefits to the patients participating in the study.  The data 
from previous adult studies in healthy subjects and patients with T1DM and T2DM have shown 
that LY900014 was well tolerated and the adverse drug reactions are in keeping with those 
reported for Humalog.
Potential risks associated with LY900014, derived from the known risks of insulin lispro 
(Humalog), are hypoglycaemia, hypersensitivity reactions (localised allergy and/or systemic 
allergy), undesirable effects at the injection site (injection-site reactions and lipodystrophy), and 
peripheral oedema(Humalog package insert, 2015).
Notably, across all doses in theadultstudies that have evaluated treprostinil as a local vasodilator 
with or without insulin lispro, there was no clinically significant increase in those AEsassociated 
with systemic absorption of treprostinil, as described in the
The exposures of treprostinil in LY900014 in this study are
compared to those observed in the dose ranges previously explored with SC bolus administration 
of treprostinil and are expected to be substantially lower than those observed in the treatment of 
PAH.
There arelimited data on the use of treprostinil in paediatric patients.  Paediatricassessments 
have not been required for treprostinil because of its orphan drug designation; thus, the safety 
and effectiveness of treprostinil in paediatricpatients have not been established 
 
.  Subcutaneous treprostinil has been evaluated in children with PAH in an 
observational study (n=8).  Patients initially received a fixed treprostinil dose of 1.25 ng/kg/min, 
which was gradually increased according to general and local tolerance, reaching a median of 
40ng/kg/min (range, 37 to 60 ng/kg/min) over the duration of follow-up (6-to 18-month time 
period) after initiation of treprostinil therapy.  Six children had symptomatic and haemodynamic 
response to the addition of SC treprostinil, with manageable control of local injection-site 
discomfort (Levy et al.2011).  The amount of treprostinil will vary based upon the LY900014 
dose administered
and treprostinil exposure has not been 
detected in adults a
 1b multiple daily injection (MDI)
studiesor withCSII therapy during the basal infusion (up to 1.6 U/h containing16ng/hof 
treprostinil) or after the bolus dose 
On average, the 
paediatricpopulation will use a lower preprandial insulin dose, further lowering exposure to 
treprostinil in this population. 
In preclinical safety pharmacology and toxicity studies, or clinical pharmacology studies 
involving LY900014 or treprostinil alone, other than knownrisks associated with Humalog and 
, no additional risks were identified.  Repeat SC dosing with treprostinil sodium for 
up to 26 weeks was well tolerated in rats and dogs.  Survival was not affected in rats at doses up 
to 0.1 mg/kg/day and in dogs at doses up to 0.07 mg/kg/day.  Clinical signs were limited to 
transient, dose-related flushing of the extremities secondary to the vasodilatory pharmacology of 
treprostinil in rats only.  No evidence of injection-site reactions to treprostinil occurred either 
CCI
CCI
CCI
CCI


I8B-MC-ITSA(d)Clinical Pharmacology Protocol
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LY900014
when treprostinil was injected alone in 13-or 26-week repeat-dose toxicity studies in rats and 
dogs or when treprostinil was injected in combination with insulin lispro in a 2-week local 
tolerance study in rats.  Furthermore, there was no indication of systemictarget organ toxicity in 
either rats or dogs.  No evidence of genotoxicity was demonstrated with treprostinil in a standard 
battery of genetic toxicity tests.  There was no evidence of reproductive toxicity or teratogenicity 
in rats and no evidence of teratogenicity in rabbits
 
 
hus, there are no known potential risks associated with the use of small 
amounts of treprostinil 
 in the LY900014 formulation.
Additionally, local and systemic toxicity profiles of Humalog and  
 do not suggest the 
potential for additive or synergistic toxicity.
The study includes inpatient procedures during which participants will be continuously 
monitored.  Patients will be without further oral food intake following consumption of liquid test 
meal to completion of blood glucose collection (approximately 300 minutes) unless requiredto 
treat hypoglycaemia, as defined by the plasma glucose (PG) level ≤70 mg/dL (3.9 mM) with 
symptoms or any PG ≤60 mg/dL (3.0 mM) during the inpatient period, i.e., reversed with either 
rapidly absorbable oral carbohydrates or IV glucose.  If a patient’s blood glucose concentration 
rises above 300 mg/dL (16.7 mM) for more than 1 hour, RHI will be administered IV.  
Appropriate measures will be taken to minimise the risk of hyperglycaemia(see Section 9.4.6
CCI
).  
More detailed information about the known and expected benefits and risks of Humalog may be 
found in the following:  Summary of Product Characteristics (SPC) (Humalog SPC [EPAR] 
[WWW]); known andexpected benefits and risks of treprostinil may be found in the package 
insert for treprostinil (
More information about the known and expected benefits, risks, SAEs,and reasonably 
anticipated AEs of LY900014is to be found in the Investigator’s Brochure (IB).
CCI
CCI
CCI


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LY900014
4.Objectivesand Endpoints
TableITSA.1shows the objectives and endpoints of the study.
TableITSA.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
1. Part A: To evaluate the PKof insulin lispro 
following a single SCbolusdose administered 
throughinjection of LY900014 compared to 
Humalog in children, adolescents,and adults with 
T1DM
2. Part B: To evaluate the PK of insulin lispro 
following a single SC bolus dose administered 
throughCSII of LY900014 compared to Humalog 
in children, adolescents,and adults with T1DM
1. Early 50% tmaxand AUC(0-30min)
2. Early 50% tmaxand AUC(0-30min)
Secondary
1. PartA and Part B:  To evaluate the differencein GD 
response to LY900014 and Humalogadministered 
throughSC bolus injection or CSII, as assessed 
using the liquid MMTT in children, adolescents,
and adults with T1DM
2. Part A and Part B:  To evaluate the tolerability of 
LY900014 following SC injection or CSIIin 
children, adolescents,and adults with T1DM
1. ∆AUC(0-2h), ∆AUC(0-5h)
2. AEs including injection/catheter insertion site 
reactions/pain, hypoglycaemia, and anti-insulin 
lispro antibodies
Abbreviations:  AE = adverse event; AUC = area under the concentration versus time curve; AUC(0-30min) = AUC 
from time zero to 30 minutes; ∆AUC = area under the baseline subtracted glucose concentration versus time 
curve; ∆AUC(0-2h)= area under the baseline subtracted glucose concentration versus from time 0 to 2hours 
postmeal;∆AUC(0-5h)= area under the baseline subtracted glucose concentration versus from time 0 to 5 hours 
postmeal; CSII = continuous subcutaneous insulin infusion; early 50% t
max= time to early half-maximal drug 
concentration; GD = glucodynamics; MMTT = mixed meal tolerance test; PK = pharmacokinetic(s); 
SC=subcutaneous; T1DM = type 1 diabetes mellitus.


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5.Study Design
5.1. Overall Design
This is a Phase 1, randomised, 2-part, patient-and investigator-blind, 2-period crossover study in 
children (age 6 to <12 years),adolescents (age 12 to <18 years),and adults (age 18 to <65 years) 
with T1DM currently using a CSII pumpor MDIs.  The aim is to evaluate insulin lispro PK, GD, 
and tolerability of LY900014in comparison with insulin lispro (reference) following a single 
dose SC administration immediately prior to a standardised liquid meal.
During the screening visit, patients will receive a diary to document any AEs and/or 
hypoglycaemic events.  Transition instructions pertinent tothose patients receiving MDI who 
will transition their basal insulin to twice daily neutral protamine Hagedorn (NPH)will be 
provided and reviewed during the telephone call (on or before Day –10) discussed below.
All patients who are currently usingeithera CSII pump or receiving MDI and are eligible to 
participate in the study based on the results of the screening procedures (within 28 days of 
Day -1 of Period 1)will be contacted via a telephone callon or before Day -10.  This telephone 
call willconfirm their eligibility and address any questions participants and parents/guardians
may have about the upcoming test meal visits.  Patients entering the study on CSII therapy will 
remain on their current basal rate and bolus settings during the lead-in period and will be 
instructed to bring additional pump supplies when they arrive at the study site.
Those patients receiving MDI and who will transition from their basal insulin to twice daily NPH 
insulin will review the site-provided instructionsduring this call.  The investigatorwill ensure
the patients are providedwith NPH as required.  Patients or their parents/guardians may call the 
site at any time to address questionsor concernsas they arise(including, but not limited to the 
transition phase).  In lieu of a telephone call on or before Day -10 to review insulin transition 
instructions, a site visit may be scheduled atthe investigator’s discretion.  
This study comprises of 2parts:Part A and Part B.  During Part A, patients will receive a single 
dose of LY900014 and Humalog on 1 occasion each as SC bolus injection and in Part B a single 
dose of LY900014 and Humalog on 1 occasion each as SC bolus via CSII.
Patients will be randomised on Day 1 of Period 1 inPart A and Day -1 ofPeriod 1 inPart B.For 
each age group, patients will be randomised to 1 of the 2 treatment sequences (first double-blind 
LY900014 then double-blind Humalog, and first double-blind Humalog then double-blind 
LY900014) in 1:1 ratio. In both parts, dosing in Period 1 and Period 2 can occur on consecutive 
days but not more than 22daysapart.  Forpatients available for dosing on consecutive days, the 
medical assessments scheduled for Day -1of Period 2 may be done on Day1 of Period 1.  
Patients will undergo a rescreening visit if dosing visit between Part A and Part B ismore than 
28days apart.  Patients who participate inPart A may continue to Part B; however,patients who 
complete Part A but discontinue prior toPart B may be replaced by newly enrolled patients in 
Part B.  Newly enrolled patients will be randomised to 1 of 2treatment sequences after 
completing the screening per the Schedule of Activities (Section2) and are expected to complete 


I8B-MC-ITSA(d)Clinical Pharmacology Protocol
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LY900014
only Part B activities.  Before each MMTT, a run-in period to stabilise blood glucose will occur.  
Details of run-in activities are described in Section5.1.1.1, 5.1.2.1,and in Section 2.  
A formal interim analysis is planned when all patients complete Part A(Section10.3.5).  Lilly 
intends to complete Part A to inform studydesign ofthe paediatric Phase 3 study.Initiation of 
Part B of the study may begin pending review of the PK, GD, safety, and tolerability datafrom 
Part A and ongoing or planned adult CSII Phase 1b studies.
5.1.1. Part A
In each period, patients will undergo an overnight run-in period followed by an MMTT(see 
Section5.1.1.1).  Each patient will receivesingle 0.2U/kg of body weight SC injectionsof 
LY900014 and Humalog.  The study drug will beadministered immediately before the start of a 
test meal(see Section6.3.1)per the assigned treatment sequence.  Thisdose ofinsulin before the 
MMTTs for each patient will be the samefor each test meal throughout the crossover periods; 
this dose will also be maintained for the patient in Part B.
FigureITSA.1illustrates the study design for Part A.


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LY900014
Abbreviations: MDI = multiple daily injection; MMTT = mixed meal tolerance test; NPH = neutral 
protamine Hagedorn; SC = subcutaneous; T = telephonevisit; T1DM = type 1 diabetes mellitus.
a
At study entry, patients on MDI therapy with any basal insulin other than NPH twice daily will 
transition to NPH twice daily therapy approximately 7to 3 days prior to Day -1 of Period 1.
b
Insulin transition is applicable if Period 2 occurs >3to 7daysafter Period 1.
The second MMTT assessment may occur on consecutive daysbut no more than 22days after the first 
MMTT.
FigureITSA.1.
Illustration of study design for Part A.
Patients will be required to attend the study siteon 3 or 4 occasionsfor Part Aas described 
below:
Ascreening visit (up to 28 days prior to Day -1 of Period 1).  The informed 
consent/assent will be obtained during this visitand patients will be provided 
a diary to document any AEs and/or hypoglycaemic events.  Atelephone visit 
is planned after screening and on or prior to Day -10 toinform patients of 
their eligibility, provide instructionsand address any questions participants 
and parents may have about the upcoming test meal visits.
Twoseparate inpatient overnight stays from Day –1 to Day 1 (1 in each study 
period for MMTTs).  These inpatient stays mayoccur on consecutive nights.
Afollow-up visit at least 14 days afterthe last dose or early discontinuation if 
the patient discontinues afterPart A.
Duration
Within 28 days prior to Day -1
Screening 
Period 1
Period 
2
Follow-up
 Visit 
>14 days after last 
study drug dose
Site Inpatient 
Site Inpatient 
Wash-out
≥1 to ≤22 days 
Single 0.2U/kg
SC dose
Humalog
Single 0.2U/kg
SC dose
LY900014
Run
-in
Single 0.2U/kg
SC dose
Humalog
Single 
0.2 U/kg 
SC dose 
LY900014
MMTT1
MMTT 2
~7 hrsMMTT
~7 hrsMMTT
Run
-in and
 
insulin 
transitionb
≥ Day -10T 
Cohort 1: ≥ 6 to <12 years
Cohort 2: ≥12 to <18 years
Cohort 3: ≥18 to <65 years 
T1DMpatients 
Insulin 
transition
a


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Patients will be discharged from the study siteon Day 1 (at least 7 hours after the test meal) or 
later, if deemed necessary for safety monitoring as determined by the investigator.
Patients entering the study on MDI therapy with any basal insulin other than NPH twice daily 
will transition to NPH twice daily therapy approximately 7 to 3days prior to Day -1 of Period 1.  
Transition guidelines, including dosages and timing, willbe determined by the investigator and 
will be based on the needs of individual patient. 
On Day -1, the last injection of NPH prior to the MMTT will occur in the morning and will 
resume only after the completion of the MMTT assessment (~7 hours postdose on Day1).
5.1.1.1. Inpatient Procedures forPart A
On the day before each MMTT day(i.e., Day –1 in each of the 2 periods), patients will arrive at 
the study site in the early evening (approximately 05:00PM).  The patient’s short-acting insulin 
will be administered before the start of a standardised dinner. Before the start of a run-in period, 
the cannulation of the veinwill be performed.At the start of the run-in period, patients entering 
the study on CSII therapy will suspend all insulin delivery and disconnect tubing from the 
infusion site.  
Start of the run-in period will occur following the evening meal (approximately at 09:00 or 
10:00PM).The run-in period will start with a variable IV infusion of glucose (5% dextrose 
solution) or RHIto reach a target glucose level of 135±25mg/dL (7.5±1.4mmol/L).  If this 
target glucose level is not attained before 11:00AM onDay 1, MMTT will be halted and may be 
performed on a separate visit; anMMTT can only be rescheduled (up to 7 days) once for each 
study period.  During the run-in period, blood glucose concentrations will be monitored at a 
minimum of 30-to 60-minute intervals(see Sections7.4.1and 9.6.1).
The run-in period will end oncethe target blood glucose level is attained and remains stable 
without intervention for at least 20 minutes before the scheduled start time of MMTT on Day 1. 
The MMTT will start in the early morning at approximately 08:00 AM with allowance up to 
11:00 AM, if required, to ensure the patient’s blood glucose is stable and on target, with the 
premeal activities as specified in the Schedule of Activities (Section2).  LY900014 or Humalog 
SC bolus injection will be administered immediately before the start of MMTT using an insulin 
syringe.  The liquid test meal will be administered on Day 1 for each of the 2treatment periods.  
A detailed description of the test meal is presented in Section6.3.1.  Patients are expected to 
complete each test meal within 15 minutesof starting the meal.  Patients will be without further 
oral food intake following consumption of liquid test mealto completion of blood glucose 
collection (approximately 300 minutes) unless required to treat hypoglycaemia, as defined by the 
PG level ≤70 mg/dL (3.9 mM)with symptoms or any PG ≤60mg/dL (3.0 mM)during the 
inpatient period, i.e., reversed with either rapidly absorbable oral carbohydrates or IV glucose.  If 
a patient’s blood glucose concentration rises above 300mg/dL (16.7 mM) for more than 1 hour, 
RHIwill be administered IV.  In both cases, blood samples for blood glucose (for safety) will be 
taken and PK samples will be collected as planned.  For each MMTT, the patient should stay in a 
sitting or semisupine position for 2 hours postdose and the patient will not be allowed to 
consume water for 2 hours after dosing (see FigureITSA.2).  If necessary, patients may be given 


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a low carbohydrate snack (<20 g carbohydrate), which does not require an insulin dose, after GD 
assessments (approximately 300 minutes postdose).  Following completion of the assessment 
period and sample collection (approximately 420 minutes), patients will be offered a meal.  For 
patients who were using MDI therapy, the investigator shall provide guidance on whether they 
should resume their prestudy basal insulin at the end of Period 1 or continue with NPH 
depending on the length of time between Period 1 and Period 2.  Patients may return to pre-study 
basal insulin following completion of Period 2 MMTT sampling period with investigator’s 
guidance.  For CSII patients, the insulin pump may be resumed at the usual rates and settings 
with prestudy insulin and bolus mealtime insulin will be administered.  A new infusion set may 
be required. 
Patients will be observed following administration of the meal and discharged at the 
investigator’s discretion.


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Abbreviations: BG = blood glucose; CSII = continuous subcutaneous insulin infusion; IV = intravenous; MDI = multiple daily 
injection; MMTT = mixed meal tolerance test; NPH = neutral protamine Hagedorn; PK = pharmacokinetics; RHI = regular human 
insulin; SC = subcutaneous.
FigureITSA.2.
Inpatient procedure in Part A.
Dinner
Run-in
MMTT
5PM
9-10 PM
8 AM –11 AM
1 PM –4 PM
3 PM –6 PM
CSII patients:
 Stop 
basal i
nsulin
 
IV glucose/RHI 
target BG:
 135±25 mg/dL
(7.5±1.4 mmol/L)
Stable BG
≥20 mins
before MMTT
SC bolus of study drug 
via i
njection followed by 
MMTT
BG sampling
(until
 300 minspostdose)
PKsampling
(until 420 minspostdose)
Restart prestudy
insulin
T
imeline
(Approximati
on)
7 AM
MDI pati
ents:
 
Last dose of 
NPH insulin
Admission to 
study site


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Assessment of local tolerability at all injection sites will be performed as specified in the 
Schedule of Activities (Section 2), including inspection of the injection/cathetersite for signs 
such as oedema, erythema, and rash.
5.1.2. Part B
Patients who completed Part A but discontinued before the beginning of Part B may be replaced 
by newly enrolled patients in Part B.Newly enrolled patients will be randomised to 1 of 
2treatment sequences after completing the screening per the Schedule of Activities (Section2)
and are expected to complete only Part B activities.
Patients will receive either LY900014 or Humalog with an insulin lispro dose level of 0.2U/kg 
body weight, as a SC bolus dose delivered usingthe CSII pump per the assigned treatment 
sequence.  Patients will receive the assigned treatment immediately before each of the test meals.  
At the start of dosing period (Day1), a standardised test meal will be administered(see 
Section6.3.1).
FigureITSA.3illustrates the study design for Part B.


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Abbreviations:  CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injection; 
MMTT = mixed meal tolerance test; NPH = neutral protamine Hagedorn; SC = subcutaneous; T = 
telephone visit; T1DM = type 1 diabetes mellitus.
a
Prior to Period 1, patients on MDI therapy with any basal insulin other than NPH twice daily will 
transition to NPH twice daily therapy approximately 7to 3 days prior toDay -1 of Period 1.
b
Insulin transition is applicable if Period 2 occurs >3 to 7 days after Period 1.  The second MMTT 
assessment may occur on consecutive days but no more than 22days after the first MMTT.
FigureITSA.3.
Illustration of study design for Part B.
Patients will be required to attend the study siteon 3 to4occasionsfor Part B:
A screening visit (may occur up to 28 days prior to Day -1 of Period 1).  The 
informed consent/assent will be obtained fromnewly enrolled patients during 
this visitand a diary will be provided to document any AEs and/or 
hypoglycaemic events.  The informed consent/assent is not applicable to 
patients continuing from Part A.
A telephone visit is planned after screening and on or beforeDay -10 to
inform patients of their eligibility and address any questions participants and 
parents may have about the upcoming test meal visits.
Twoseparate inpatient overnight stays from Day –1 to Day 1 (1 in each study 
period for MMTTs).  These inpatient stays may occur on consecutive nights.
Duration
Within 28 days p
r
ior to Day -1
Period 1
Period 2
Follow-up Visit 
>14 days after last 
study drug dose
Site Inpatient 
Site Inpatient 
Wash-out
≥1 to ≤22 days 
Single 0.2U/kg
SC via CSII 
dose Humalog
Single 0.2U/kg
SC via CSII 
dose LY900014
Single 0.2U/kg
SC via CSII 
doseHumalog
S
ingle 0.2U/kg
SC via CSII 
dose LY900014
MMTT 1
MMTT 2
~7 hrsMMTT
~7 hrsMMTT
Run
-in and 
insulin 
transition
b
≥ Day -10T 
Cohort 1: ≥ 6 to <12 years
Cohort 2: ≥12 to <18 years
Cohort 3: ≥18 to <65 years 
T1DMpatients 
Insulin 
transitiona
Screening 
Run
-in


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Afollow-up visit at least 14 days after the last dose or early discontinuation.
Patients will be discharged from the study siteon Day 1 (atleast 7 hours after the test meal) or 
later, if deemed necessary for safety monitoring as determined by the investigator.
Patients entering the study on MDI therapy with any basal insulin other than NPH twice daily 
will transition to NPH twice daily therapy approximately 7to 3days prior to Day -1 of Period 1.  
On Day -1, the last injection of NPH prior to the MMTT will occur in the morning and will 
resume only after the completion of the MMTT assessment (~7 hours postdose on Day 1).  
5.1.2.1. Inpatient Procedures for Part B
On the day before each MMTT day(i.e., Day –1 in each of the 2 periods if performedon 
non-consecutive days), patients will arrive at the study site in the early evening (approximately 
05:00 PM).  Patients on CSII pump will be advised to bring a spare infusion set for the CSII 
pump when they arrive at the study site.  Patients who are not using
pump will be 
switched to a
pump during the inpatient procedures. A standardised 
dinner will be provided where the bolus doseof the patient’s usual insulin willbe administered 
via CSIIfor this meal.Patients on MDI will be started on
 pump 
following the evening meal.  The pump reservoir will be filled with the study insulin, either 
LY900014 or Humalog, and a new standard infusion set and catheter will be inserted after a 
priming dose has been given to test the catheter.  In case of immediate infusion set intolerance, a 
new needle can be inserted up until 12:00 AM (midnight).  Following the evening meal, patients
will continue their current pump basal rate until the start of the run-in periodat which time a 
fixed low basal rate of0.1U/hour will be maintaineduntil2hoursbefore the scheduled start 
time of MMTT.  For patients transitioning from MDI therapy, the bolus dose used for the 
evening meal will be based on their usual insulin to carbohydrate ratio and correction factor if 
applicable.  Additionally, the basal insulin rate for the period between dinner and the start of the 
overnight infusion should be determined using the 80% of the pre-studytotal daily NPH dose 
divided by 24 hours to obtain the hourly basal insulin infusion rate.  Thenew basal rate may be 
titrated as needed based on the investigator’sdiscretion.  Before the start of a run-in period, the 
cannulation of thevein will be performed.  Start of the run-in period will occur following the 
evening meal (at approximately 09:00 or 10:00 PM).  The run-in period will start with a variable 
IV infusion of glucose (5% dextrose solution) or RHItoreach a target glucose level of 
135±25mg/dL (7.5±1.4mmol/L).  If this target glucose level is not attained before 1100hours 
onDay 1, MMTT will be halted and may be performed on a separate visit; anMMTT can only 
be rescheduled (up to 7 days) once for each study period.  During the run-in period, blood 
glucose concentrations will be monitored at a minimum of 30-to 60-minute intervals.
The run-in period will end oncethe target blood glucose level is attained and remains stable 
without interventionfor at least 20 minutes immediatelybefore the scheduled start time of 
MMTT on Day 1.The MMTT will start in the early morning at approximately 08:00 AM with 
allowance up to 11:00 AM, if required, to ensure the patient’s blood glucose is stable and at 
target, with the premeal activities as specified in the Schedule of Activities (Section2
CCI
).  
LY900014 or HumalogSC boluswill be administered immediately before the start of MMTT via 
the pump.  The liquid test meal will be administered on Day 1 for each of the 2treatment 
CCI
CCI


I8B-MC-ITSA(d)Clinical Pharmacology Protocol
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periods. A detailed description of the test meal is presented in Section6.3.1.  Patients are 
expected to complete each test meal within 15 minutesof starting the meal.  Patients will be 
without further oral food intake following consumption of liquid test meal to completion of 
blood glucose collection (approximately 300 minutes) unless required to treat hypoglycaemia, as 
defined by the PG level ≤70 mg/dL (3.9 mM) with symptoms or any PG ≤60mg/dL (3.0 mM)
during the inpatient period, i.e., reversed with either rapidly absorbable oral carbohydrates or IV 
glucose.  If a patient’s blood glucoseconcentration rises above 300mg/dL (16.7 mM) for more 
than 1 hour, RHI will be administered IV.  In both cases, blood samples for blood glucose (for 
safety) will be taken and PK samples will be collected as planned.  For each MMTT, the patient 
should stay in a sitting or semisupine position for 2 hours postdose and the patient will not be 
allowed to consume water for 2 hours after dosing.  If necessary, patients may be given a low 
carbohydrate snack (<20 g carbohydrate), which does not require an insulin dose, after GD 
assessments (approximately 300minutes postdose).  If Period 2 is performed on non-consecutive 
days, following completion of the assessment period and sample collection(approximately 
420minutes), the pump will be disconnected.For patients who used CSIIpre-study, a new 
reservoir should be filled with their usual pump insulin and a new infusion set should be inserted 
as directed by the study site.  The basal rates may be returned to the patient’s usual basal settings
(see FigureITSA.4).  
For patients who were using MDI therapy, the investigator shall provide guidance on whether 
theyshould resume their pre-study basal insulin atthe end of Period 1 or continue with NPH 
depending on the length of time between Period 1 and Period 2.
All patients will be offered a meal attheconclusion of the MMTT assessment period.
For patients who opt to complete Period 2 on consecutive days, thepump reservoir will be filled 
with the other study insulin, either LY900014 or Humalog, and a new standard infusion set and 
catheter will be inserted priorto administration of the evening meal.  In case of immediate 
infusion set intolerance, a new needlecan be inserted up until 12:00 AM (midnight). A 
standardised dinner will be provided where the bolus dose for this meal will be administered via 
CSII.  Following the evening meal, patientswill continue their current pump basal rate until the 
start of the run-in period at which time a fixed low basal rate of 0.1 U/hour will be maintained 
until2hoursbefore the scheduled start time of MMTT.  A similar approach to that used in 
Period 1 will be used to manage the evening meal bolus,the run-in period, overnight basal 
insulin infusion, administration of study insulin bolus,and conduct of the MMTT.  At the end of 
the MMTT assessment period, patients who used CSII pre-study should fill a new reservoir with 
their usual pump insulin and a new infusion set should be inserted as directed by the study site.  
The basal rates may be returned to the patient’s usual basal settings.  Patients previously treated 
with MDI therapyshould resume their pre-study MDI therapy at the end of Period 2 as directed 
by the site.All patients will be offered a meal at the conclusion of the MMTT assessment 
period.  Patients will be observed following administration of the meal and discharged at the 
investigator’s discretion.


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Assessment of local tolerability at all injection sites will be performed as specified in the 
Schedule of Activities (Section 2), including inspection of the injection/cathetersite for signs 
such as oedema, erythema, and rash.
For each inpatient visit, serial blood samples will be collected over approximately 420minutes to 
assess the PK and GD response following the start of each test meal.


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Abbreviations: BG = blood glucose; CSII = continuous subcutaneous insulin infusion; IV = intravenous; MDI = multiple daily 
injection; MMTT = mixed meal tolerance test; NPH = neutral protamine Hagedorn; PK = pharmacokinetics; RHI = regular human 
insulin; SC = subcutaneous.
FigureITSA.4.
Inpatient procedure in Part B.
Dinner
Run-in
MMTT
5 PM
9-10 PM
8 AM –11 AM
1 PM –4 PM
3 PM –6
 PM
IV glucose/RHI
target BG:
 135±25mg/dL
(7.5±1.4 mmol/L)
Stable BG
≥20 mins
before MMTT
SC bolus of study drug 
via CSIIfollowed by 
MMTT
BG sampling
(until
 300 minspostdose)
PKsampling
(until
 420 minspostdose)
Restart prestudyinsulin
T
imeline
(Approximati
on)
CSII patients: Change to 
 
pump and new standard infusion set 
and catheter (study drug)
MDI patients: start 
 pump 
with study drug
Basal insulin
 rate 
changed to single hourly 
rate of 0.1 U/hour
7
 AM
MDI patients: 
Last dose of 
NPH insulin
CCI
Admission to 
study site
CCI


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5.2. Number of Participants
Approximately 45patients may be enrolled intothe studysothat approximately 36patients 
(12patients in each age group[6 to <12 years, 12 to <18 years, and 18 to <65 years]based on the 
age at initial screening) complete both inpatient periods in both the parts of the study.
Patients participating in Part A may continue participation in Part B. If patients from Part A 
decline participation in Part Bor drop out from Part A, additional patients will be enrolled to 
ensure approximately 36 patients (12 patients in each age group) complete both periods inPart B 
of the study.
5.3. End of Study Definition
End of the studyis the date of the last visit orlast scheduled procedure shown in the Schedule of 
Activities(Section 2) for the last patient.
5.4. Scientific Rationale for Study Design
Each studypart consists ofa 2-period crossover design to reduce the variability of insulin PK 
and GD, as each patient will act as his/her own control. The total number of patients needed for 
a crossover design is less than the number needed for a parallel group design.
Randomisation and blinding are used to avoid bias introduced through an association between 
allocation order of study drugand patient characteristics.  
In each study period,patients will undergo a run-in period before the MMTT using a variable 
insulin and glucose IV infusion.  This run-in will allow for improved comparability of the 
postprandial glucose response to a mixed meal after treatment with LY900014 and Humalog 
administered immediately before the start of the meal. This run-in aims to achieve similar 
preprandial glucose levels for all patients before the start of the test meal and thereby reduces the 
variability of the postprandial glucose response. Regular human insulinhas been chosen for the 
IV optimisation of PGduring the run-in because RHIdoes not cross-react with the insulin 
lispro–specific assay used for the PK analysis. 
5.5. Justification for Dose
The bolus dose of insulin lispro (LY900014 or Humalog) will be fixed dose by body weight 
(0.2U/kg). Based on previous studies of both insulin lispro (Humalog) and LY900014, a 
0.2U/kgprandialdose is necessary toprovide measurable PK and GD profiles for both study 
insulins. This dose level has been previously examined in paediatric patients with another 
rapid-acting analogue with no apparent hypoglycaemicrisk (Fath et al.2017).  Furthermore, the 
occurrence of hypoglycaemiain patients with T1DMor T2DMparticipating in previous test 
meal studies with LY900014 was also low, since patients donot receivesignificant basal insulin 
coverage during the course of the MMTT.
Meal size differs between adults andchildren.  Due to this, thevolume of theliquid test meal for 
the MMTT will beadjusted by weight for the child and adolescentpatients within the study. 
However, the adult patients in the study will receive a set volume for the MMTT.  


I8B-MC-ITSA(d)Clinical Pharmacology Protocol
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CCI
For each patient, the individualised prandial insulin lispro dose in LY900014 and Humalog for 
each test meal must be kept identical throughout the crossover periodsfor both Part A and 
PartB.  If the investigator determines that it would be unsafe to repeat the same dose, the patient 
should be discontinued.  A minimum weight of 25 kg is required for this study in order to have 
sufficient dose
 to characterise both the serum insulin lispro absorptionand elimination 
following study drug administration.


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6. Study Population
Eligibility of patients for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG). 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to Day -1 of Period 1 for both Part A and Part B.  
Patients who are not enrolled within 28 days of screening may be subjected to an additional 
medical assessment and/or clinical measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Patients are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrolment:
[1]
male or female patients with a diagnosis of T1DM based on medical history 
for at least 1 year as previously demonstrated by either documented presence 
of autoimmune antibodies (glutamic acid decarboxylases; insulin-associated 
tyrosine phosphatase antibody; insulin autoantibody; islet cell antibody) as per 
medical records, or diagnosis by an endocrinologist (paediatric or adult).
[1a] no male contraception required except in compliance with specific local 
government requirements
[1b] female patients:
i.
Post-pubertal females are defined as children and adolescents 
≥12 years of age or <12 years of age who have onset of menses
ii.
Post-pubertal females of child-bearing potential – who are abstinent (if 
this is complete abstinence, as their preferred and usual lifestyle) or in 
a same sex relationship (as part of their preferred and usual lifestyle) 
must agree to either remain abstinent or stay in a same sex relationship 
without sexual relationships with males.
iii.
Otherwise, post-pubertal females of child-bearing potential 
participating must agree to use 1 highly effective method of 
contraception for the entirety of the study.
1. Post-pubertal females of child-bearing 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.
2. One highly effective method of contraception.  The patient may 
choose to use a combined (estrogen and progestogen containing) or 


I8B-MC-ITSA(d) Clinical Pharmacology Protocol
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progestogen-only hormonal contraception administered orally, 
intravaginally, or transdermally and is associated with inhibition of 
ovulation.  Alternatively, patients may use either an intrauterine 
device, intrauterine hormone-releasing system, bilateral tubal 
occlusion, or the partner should have been vasectomised.
iv.
post-pubertal females not of child-bearing potential may participate 
and include those who are
1. infertile due to surgical sterilisation (hysterectomy or bilateral 
oophorectomy or bilateral salpingectomy), congenital anomaly such as 
Mullerian agenesis; or
2. post-menopausal – defined as no menses for 12 months without an 
alternative medical cause. A follicle-stimulating hormone level in the 
post-menopausal range may be used to confirm a post-menopausal 
state in women not using hormonal contraception or hormonal 
replacement therapy.
[2]
are aged ≥6 and <65 years
[3]
children and adolescents have a body mass index (BMI) within the 3rd and 
95th BMI percentiles with a minimum weight of 25 kg; adults have a BMI
≤28.0 kg/m2
[4]
continuous treatment with insulin for at least 12 months and with at least 
6 months of treatment using CSII pump therapy or MDI therapy consisting of 
treatment with basal insulin (including insulin glargine U100, detemir, 
degludec U100 and NPH) and rapid-acting insulin prior to the main meals of 
the day before screening
[5]
total daily dose of insulin between 0.3 and 1.5 U/kg/day, inclusive
[6]
have a glycated haemoglobin (HbA1c) ≤10% at screening
[7]
compliant with prescribed diet and insulin therapy, as determined by the 
investigator
[8]
have clinical laboratory test results within normal reference range (with the 
exception of HbA1c) for the population or investigative site, or results with 
acceptable deviations that are judged to be not clinically significant by the 
investigator
[9]
have venous access sufficient to allow for glucose infusion and blood 
sampling procedures as per protocol
[10] are reliable and willing to make themselves/their wards available for the 
duration of the study and are willing to follow study procedures


I8B-MC-ITSA(d) Clinical Pharmacology Protocol
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[11] are able and willing to give signed informed consent approved by Lilly and 
the ethical review board (ERB) governing the site or both the child/adolescent 
and a parent or legal guardian are able to understand and fully participate in 
the activities of the clinical trial and sign their assent and consent, respectively
6.2.
Exclusion Criteria
Patients will be excluded from study enrolment if they meet any of the following criteria at 
screening and/or enrolment:
[12] receiving any oral or injectable medication intended for the treatment of 
diabetes mellitus other than insulins in the 12 months prior to screening
[13] more than 1 episode of severe hypoglycaemia (defined as requiring assistance 
due to neurologically disabling hypoglycaemia, indicated by coma or 
convulsion and/or use of IV glucose or glucagon) within 6 months prior to 
screening
[14] two or more emergency room visits or hospitalisations due to poor glucose 
control (hyperglycaemia or diabetic ketoacidosis) within 6 months of 
screening
[15] post-pubertal females not using a reliable method of birth control, or intending 
to become pregnant
[16] one of the following concomitant diseases: presence of clinically significant 
hematologic, oncologic, renal, cardiac, hepatic, or gastrointestinal disease, 
proliferative retinopathy, uncontrolled celiac disease, uncontrolled 
hyperthyroidism or hypothyroidism, or adrenal insufficiency
[17] have a history of renal impairment (exclusion only if glomerular filtration rate 
[estimated GFR] <60 mL/minute/1.73 m2 [GFR is estimated according to the 
Chronic Kidney Disease Epidemiology Collaboration creatinine equation])
(Schwartz et al. 2009).
[18] hepatic:  Have obvious clinical signs or symptoms of liver disease (e.g., acute 
or chronic hepatitis as indicated by evidence and/or positive antibody/surface 
antigen to hepatitis B/C, or cirrhosis) or elevated liver enzyme measurements 
as indicated below at screening:
a.
total bilirubin level (TBL) ≥2× the upper limit of normal (ULN) (with the 
exception of Gilberts disease) as defined by the central laboratory,
OR
b. alanine aminotransferase (ALT) ≥3× ULN as defined by the central laboratory
OR
c.
aspartate aminotransferase (AST) ≥3× ULN as defined by the central laboratory


I8B-MC-ITSA(d)Clinical Pharmacology Protocol
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[19]are studysite personnel directly affiliated with this study and their immediate 
families.  Immediate family is defined as a spouse, biological or legal 
guardian, child, or sibling
[20]are Lilly employees or are employees of the study siteand their children
[21]are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study
[22]have participated, within the past 30 days, in a clinical study involving an 
investigational product.  If the previous investigational product has a long 
half-life(t
1/2), 5 half-lives or 30days (whichever is longer) shouldhave passed
[23]havepreviously completed or withdrawn from this study 
[24]have known allergies to treprostinil 
 insulin lispro, RHI, related 
compounds, or any components of the formulation, or a history of significant 
atopy
[25]Adults 
CCI
18 years of age who have donated blood of more than 450 mL or 
more in the past 3 months before screening or 
any prospective study participant who has experienced severe blood loss 
within 3 monthsprior to screeningor have known haemoglobinopathy, 
haemolyticanaemia, or sickle cell anaemia, or any other traits of haemoglobin
abnormalities known to interfere with the HbA1c measurement
[26]receiving chronic (lasting longer than 14 consecutive days) systemic 
glucocorticoid therapy (excluding topical, intraocular, intranasal, and inhaled 
preparations) or have received such therapy within 8 weeks immediately 
before screening
[27]any significantchanges in insulin regimen and/or unstable blood glucose 
control within the past 3 months prior to screening as assessed by the 
investigator
[28]have a history of in-patient psychiatric treatment, emotional, behavioural, or 
other untreated conditions that would interfere with proper participation in 
routine diabetes control and management in the past 6 months
[29]are unwilling to comply with the dietary requirements/restrictions during the 
study:(i) comply with the fasting requirements of the study, (ii) consume 
only the meals/snacks provided during the inpatient visits
[30]have, except for current regimen of insulin therapy and concomitant 
medication(s) (e.g., antihypertensive medication, lipid-lowering agent, thyroid 
hormone replacement medication, hormonal contraception, hormonal 
replacement therapy), regular use of or intended use of any over-the-counter 
or prescription medications or nutritional supplements that treat 
hyperglycaemiaor insulin resistance or that promote weight loss within 
14days before dosing


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[31]regularly use known drugs of abuse and/or show positive findings on drug 
screening
[32]show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies
[33]are women who are lactating
[34]have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females), or are unwilling to stop alcohol consumption 
for the duration of the study
(1 unit = 12 oz or 360 mL of beer; 5 oz or 150mLof wine; 1.5 oz or 45 mL of 
distilled spirits)
[35]are unable to comply with smoking restrictions during the study
[36]in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.2.1. Additional Exclusion Criteria for Inpatient Dosing Days
[37]consumption of alcohol within 24 hoursprior to admission
[38]positive serum pregnancy test at screeningor positive urine pregnancy test at 
admission to the study site
[39]consumption of coffee, tea, chocolate, cola, and/or energy drinks containing 
methyl xanthine (caffeine, theophylline, or theobromine) within 12 hours 
before each test meal assessment.
[40]strenuous exercise within the past 24 hours before each test meal assessment
[41]any medical condition or AE that could interfere with glucose metabolism, as
judged by the investigator
[42]any use of excluded prescription or nonprescription medication from 14 days 
prior to dosing and throughout the study
[43]hypoglycaemiaduring the MMTT period and less than 24 hours before dosing 
that poses a significant risk to patient’ssafety, as judged by the investigator
[44]injection of a bolus of more than 6 U of a fast-acting insulin analogue6 hours 
before dosing prior to the test meal
6.2.2. Rationale for Exclusion of Certain Study Candidates
The blood volume to be withdrawn per patient in each part of this study is approximately 
170mL which would be a challenge in children <6 years of age.  Additionally, insulin is 
individually titrated and therefore, the understanding of PK and GD in theproposed patients 
(≥6years to ≤64years) should be sufficient to inform dosing in children <6 years of age under 
the supervision of a qualified endocrinologist.  Therefore, this study will not include paediatric
patientswith T1DMfrom birth to <6 years of age.


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6.3. Lifestyle and/or Dietary Requirements
Throughout the study, patients may undergo medical assessments and review of compliance with 
requirements before continuing in the study.
6.3.1. Mealsand Dietary Restrictions
Patients will be provided standardised liquid mealsfor the MMTTs, as outlined in the Schedule 
of Activities(Section2).  An evening meal on the day prior to the MMTT and a meal following 
completion of the MMTT will also be provided.Patients will be fasted (except for water) for at 
least 10 hours before each test meal and consume each meal within approximately 15minutes.
The standardised liquid test mealwill use
For children and adolescents in 
the study, the volume of the liquid test me
ed on the patient’s body weight
(kg)during the study(Period 1 of Part A or Period 1 of Part B if patients did not participate in 
Part A of the study)as described in TableITSA.2.  Foradults, the liquid test meal will consist of 
approximately 100 g of carbohydrates total in test meal).  
pt consistent with regardto calorie and nutrient content 
across all MMTT assessments in the study.  For both parts of the study, the patient will not be 
allowed to consume water for2 hours after dosing apart from fluid provided with the meal; 
however, water may be consumed freely afterwards.
TableITSA.2.
Volume of Standardised Meal According to Body Weight
Body Weight(kg)
Volume of Meal(mL)
25-29
230
30-34
272
35-39
315
40-44
357
45-49
400
50-54
442
>55
474
While resident in the study site, patients may not consume any food or caloric drinks other than 
that provided by the study site.  When not resident in the study site, patients may resume their 
regular diet.
Following completion of study procedures, patient will be offered a meal.  The study sitewill 
record dose and time of prandial insulinadministered with end-of-study meal.
6.3.2. Caffeine, Alcohol, and Tobacco
CCI
Patients should refrain from caffeine-containing food/beverages (e.g., cola, chocolate drinks, tea, 
coffee, energy drinks containing methylxanthine [caffeine, theophylline, or theobromine]) for at 
least 12 hours before each test meal and throughout the duration of each study sitevisit,
excluding the test meal when 
may be given.
No alcohol will be allowed at least 24 hours before each study siteadmission (Day–1) and 
throughout the duration of each study sitevisit.  Between study sitevisits, daily alcohol 
consumption should not exceed 21unitsper weekfor males and 14units per week for females.
CCI
CCI
CCI


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No cigarette smoking will be permitted during the inpatient visits.
6.3.3. Activity
Patients will be encouraged to maintain their regular exercise and insulin regimen adaptation 
related to exercise during the outpatient period; however, they should not undertake vigorous or 
prolonged exercise at least 24 hours before each dosing day at the study site.  Movement will be 
restricted to retain the integrity of connections to infusion(s) and the study procedures.
6.4. Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screenedonce.  The interval between re-screenings should be at least 28 days.  Each time 
re-screening is performed, anew informed consentor assentform (see Appendix 3for details) 
must be signed andparticipantswill be assigned a new identification number.


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7.Treatment
7.1. Treatment Administered
This study involves a comparison of LY900014and Humalog administered either SC (Part A) or 
via CSII (PartB).  TableITSA.3shows the treatment regimens.  
TableITSA.3.
TreatmentsAdministered
Treatment Name
LY900014
Humalog
Dose Strength
100 U/mL
100 U/mL
Route of Administration
SCor CSII
SCor CSII
Abbreviations:  CSII = continuous subcutaneous insulin infusion; SC = subcutaneous.
The investigator or designee is responsible for
explaining the correct use of the study drug(s) to the study sitepersonnel 
verifying that instructions are followed properly
maintaining accurate records of study drugdispensing and collection
and returning all unused medicationsto Lilly or its designee at the end of the study
Each dose of study drug will be prepared by the investigator or designee and treatments will be 
administered using an insulin U-100SC in Part A or via 
 CSII bolusin 
Part B.  The rateofbolus infusion in Part B will be standardised to 0.1U/hourduring the run-in 
period.Each insulin vial will be labelled appropriately and dispensed to qualified study site
personnel for administration.  All study drugs will be given through SC injection (Part A) or via 
a
 CSII pump (PartB) at the study siteby qualified and appropriately trained site 
personnel as designated by the investigator.  For SC administration, an appropriate size of needle 
shall be used to ensure all injections are delivered to a consistent target depth into the SC space; 
if an 8-mm (or greater) needle is used to administer the injection, the skinfold should be 
pinched.The CSII infusion set and stainless steel catheter should be inserted at a 90° angle in 
the abdominal area.
Injections will be rotated among different injection sites on the anterior abdominal wall during 
the 2 study periods (i.e., left lower quadrant and right lower quadrant).  Study injections should 
be given by a limited number of individuals for consistency. 
7.1.1. Packaging and Labelling
CCI
The study insulin (LY900014 and Humalog)will be provided to the study sitein blinded vials.  
All clinical study materialsprovided to the investigator will be stored in a secure place and 
allocated and dispensed by appropriately trained persons.  The allocation and dispensing of the 
study drugs will be fully documented and verified by a second person.  Detailed records of the 
amounts of the study drugreceived, dispensed, and remaining at the end of the study will be 
maintained. 
CCI


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Regular human insulin will be provided by Lilly and will be used from their original packaging.  
The study drug will be labelled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrolment will be randomised to 1 of the 2 treatment sequences 
on Period 1 Day 1 for Part A and Period 1 Day -1 for Part B. Assignment to treatment sequences 
will be determined by a computer-generated random sequence using an interactive web response 
system (IWRS). Patients will be randomised to 1 of the 2 treatment sequences in 1:1 ratio within 
each age group (first double-blind LY900014 then double-blind Humalog, and first double-blind 
Humalog then double-blind LY900014). The randomisation in Part A and Part B is determined 
separately. Patients participating in both Part A and Part B will be randomised at the beginning 
of each part. Patients participating in only Part B will be randomised at the beginning of Part B.
7.2.1. Selection and Timing of Doses
The SC injection dose and bolus dose via CSII of insulin (LY900014 and Humalog) will be 
0.2 U/kg body weight to cover the carbohydrate content of the standardised liquid test meal. The 
insulin dose will be determined from the body weight in Period 1 of Part A or Period 1 of Part B 
if patients did not participate in Part A of the study. This insulin dose (U) of LY900014 and 
Humalog for each patient must be used for the test meals throughout the crossover periods in 
Part A and Part B.  The same total dose will be administered to a particular patient in both parts 
of the study and if the investigator determines it would be inappropriate to administer this dose, 
the patient will be discontinued from the study.
The doses will be administered at approximately the same times on Day 1 of each period.  The 
actual time of all dose administrations will be recorded in the patient’s electronic case report 
form (eCRF).
7.3.
Blinding
The study is patient- and investigator-blind with reference to the identity of the study drug 
administered, and the study drug vials will be blinded.
A limited number of study team members (not involved in the practical execution of the clinical 
study or the collection of data at the study site), will have access to the unblinded treatment 
assignments and data as described in the blinding plan.
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-labelling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All 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 
subject’s safety must always be the first consideration in making such a determination.  If the 


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investigator decides that unblinding is warranted,it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
7.4. Dose Modification
Dose adjustments are not allowed during the study MMTT procedure.  
7.4.1. Special Treatment Considerations
Regular human insulinand 5% dextrose solution will be used during the run-in period to stabilise 
blood glucose prior to the start of the meal test.  Regular human insulinmay also be provided to 
treat hyperglycaemiaduring the meal test (see Section 9.4.6).
In an effort to minimise discomfort, the study site may use a topical anaesthetic cream prior to 
venipuncture for insertion of indwelling intravascular catheter to obtain blood samples, thus 
limiting the number of needle insertions directly into patients’ skin. Additionally, the number of 
blood samples hasbeen reduced with a total blood volume of less than 200 mL to be collectedin 
each part (PartsA and B).
7.5. Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor,during transit for all study drugsreceived and any 
discrepancies are reported and resolved before use of the study drug.
Only participants enrolled in the study may receive study drugsor study materials, and only 
authorised study sitestaff may supply or administer the study drug.All study drugsshould be 
stored in anenvironmentally controlled and monitored (manual or automated) area in accordance 
with the labelledstorage conditions with access limited to the investigator and authorised study 
sitestaff.
Thestudy drugs must be stored at the study siteunder refrigerated conditions (between 2°C and 
8°C) in a locked and secure place.  Insulin must not be frozen.
The investigator is responsible for study drugaccountability, reconciliation, and record 
maintenance (such asreceipt, reconciliation,and final disposition records).
7.6. Treatment Compliance
The study drugwill be administered at the study site, and documentation of treatment 
administration will occur at the study site.
7.7. Concomitant Therapy
Patients may continue their stable concomitant medication at the time of study entry at regular, 
unchanged doses during the study; e.g., antihypertensive medication, lipid-lowering agent, 
thyroid hormone replacement medication, hormonal contraception,or hormonal replacement 
therapy.


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In general, the addition of new concomitant medication should be avoided; however, 
paracetamol, or other over-the-counter analgesics may be administered at the discretion of the 
investigator based on age appropriate dosing guidelines for treatment of headache, etc.  If the 
need for concomitant medication (other than paracetamol) arises, inclusion or continuation of the 
patient may be at the discretion of the investigator after consultation with a Lilly CP or clinical 
research physician (CRP).  Any medication used during the course of the study must be 
documented.
Patients should not initiate new over-the-counter or prescription medication or nutritional 
supplements that affect blood glucose or the body’s sensitivity to insulin or that promote weight 
loss 14 days before dosing or throughout the study.
Patients should not apply any creams or lotions to the abdominal skin on the morning of the 
injection or during the inpatient study procedure.
7.8.
Treatment after the End of the Study
Patients will continue their previous insulin regimen after the final study MMTT and associated 
procedures have been completed.


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8.DiscontinuationCriteria
Patientsdiscontinuing from the study prematurely for any reason must complete AEand 
follow-up procedures per Section 2of this protocol.
8.1. Discontinuation from Study Treatment
Discontinuation from the study and the study drugfor abnormal liver testresults will occurafter 
consultation between the investigator and the Lilly-designated medical monitorifa patient meets 
1 of the following conditions:
ALT,AST>8XULN
ALT or AST >5X ULNsustained for more than 2 weeksor
ALT or AST >3X ULN and TBL>2X ULNorinternational normalised ratio>1.5or
ALT or AST >3X ULN and the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
alkaline phosphatase (ALP)>3X ULN
ALP>2.5X ULN and TBL >2X ULN
ALP>2.5XULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrolmentcriteria and was 
inadvertently enrolled,thepatientmust be discontinued from the study.
8.2. Discontinuationfrom the Study
Patients will be discontinued under the following circumstances:
Enrolmentin any other clinical study involving an study drugor enrolmentin 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 (GCP)
Investigator decision
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
o Participation in the study needs to be stopped for safety reasons in the case of an 
abnormal clinically significant laboratoryvalue, or in the case ofsevere hypo-or 
hyperglycaemic episode (see Section 9.4.5.2and 9.4.6)
Patientdecision


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o the patient,or the patient’s parents or guardian,requests to be withdrawn from the 
study
Patients who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities(Section 2).
8.3. Patients 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.  The study sitepersonnel 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 study site.


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9.Study Assessments and Procedures
Section 2lists the Schedule of Activities, detailingthe study procedures and their timing 
(including tolerance limits for timing).
Appendix 2lists the laboratory tests that will be performed for this study.
Appendix 5provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in 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 Assessments
Not applicablefor this study.
9.2. Adverse Events
Investigators are responsible for monitoring the safety of patientswho 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 health care option, 
AEs that are serious or otherwise medically important, considered related to the study drugor the 
study, or that caused the patient to discontinue the study drugbefore completing the study.  The 
patient should be followed up until the event resolves, stabiliseswith appropriate diagnostic 
evaluation, or is reasonably explained.  The frequency of follow-up evaluations of the AE is left 
to the discretion of the investigator.
After the informed consent form (ICF)is signed, study sitepersonnel will record,via electronic 
data entry,the occurrence and nature of each patient’s preexisting conditions, including clinically 
significant signs and symptoms of the diseaseunder treatment in the study.  Additionally, study 
sitepersonnelwill record any change in the condition(s) and the occurrence and nature of any 
AEs.  
The investigator will categorise the severity of an AE as well asinterpret and document whether 
or not anAE has a reasonablepossibility of being related to study drug, or a study procedure, 
taking into account the disease, concomitant treatment,or pathologies.  
A “reasonable possibility”means that there is a potential cause and effect relationship between 
the study drug, study device,and/or study procedure and the AE.


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Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a patient’s studydrugis discontinued as a result of an AE, study sitepersonnel must report this 
to Lilly or its designee via electronic data entry.
Hypoglycaemic eventsare AEs of special interest and will becollected and reported throughout 
the study as described in Section 9.4.5.2.  All hypoglycaemic events will be recorded in the 
hypoglycaemia module in the eCRF allowing for the collection of comprehensive safety 
information relating to theseevents.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1of the following:
death
initial or prolonged inpatient hospitalisation
a life-threatening experience (i.e., 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 hospitalisationbut may jeopardisethe patient or may require intervention to prevent 1
of the other outcomes listed in the definition above
when a condition related to the CSII pumpnecessitates 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.
The study sitepersonnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
Additionally, study sitepersonnel must alert LillyGlobal Patient Safety,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-hournotification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the electronic data entryafter signing informed consent,SAE 
reporting to the sponsor begins after the patient has signed informed consent and has received the 
study drug.  However, if an SAE occurs after signing informed consent, but prior to receiving the 
study drug, AND is considered Reasonably Possibly Related to a study procedure then it MUST 
be reported.
Investigators are not obligated to actively seek AEs or SAEs in patientsonce they have 
discontinued from and/or completed the study (the patientsummary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patienthas 


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been discharged from the study, and he/she considers the event reasonably possibly related to the 
study drugor study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to the study drug) does not meet the definition of an 
AE.  However, to fulfilregulatory requirements any pregnancy should be reported following the 
SAE process to collect data on the outcome for both mother and foetus.
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 reportsas related to study drugor procedure.  Lilly has 
procedures that will be followed for the 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 study drugs and drug delivery systems used in clinical trials 
in order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Patients should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drugor drug delivery system so that the situation can be 
assessed.
9.3. Treatment of Overdose
For the purposes of this study, an overdose of LY900014 or Humalog is considered any dose 
higher than the dose assigned on Day 1 of Part A.
Excess insulin administration may cause hypoglycaemiaand hypokalaemia.  Mild episodes of 
hypoglycaemiausually can be treated with oral glucose.  More severe episodes with coma, 
seizure, or neurologic impairment may be treated with intramuscular/SC glucagon or 
concentrated IV glucose.  Sustained carbohydrate intake and observation may be necessary 
because hypoglycaemiamay recur after apparent clinical recovery.  Hypokalaemiamust be 
corrected appropriately.
Refer to the IBand/or Humalog Product Label.
9.4. Safety
9.4.1. Laboratory Tests
For eachpatient, laboratory tests detailed in Appendix 2should be conducted according to the 
Schedule of Activities (Section2). 
With the exception of safety laboratory test results that may unblind the study, Lilly or its 
designee will provide the investigator with the results of laboratory tests analysedby a central 
vendor, if a central vendor is used for the study.


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9.4.2. Vital Signs
For eachpatient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2) and as clinically indicated.  
Blood pressure and pulse rate should be measured after at least 5minutes semi-supine/supine.
9.4.3. Electrocardiograms
For each patient, ECGs should be collected according to the Schedule of Activities(Section2).  
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the study drugshould be reported to Lilly, or its designee, as an 
AE via eCRF. 
For each patient, a single12-lead digital ECG will be collected according to the Schedule of 
Activities(Section2).  Electrocardiograms must be recorded before collecting any blood 
samples.  Patients must be supine for approximately 10 minutes before ECG collection and 
remain supine but awake during ECG collection.  Electrocardiograms may be obtained at 
additional times,when deemed clinically necessary.  All ECGs recorded should be stored at the 
investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the study site as soon after the time of ECG collection as possible, and ideally while 
the patient is still present,to determine whether the patient meets entry criteria at the relevant 
visit(s) and for immediate patient management, should any clinically relevant findings be 
identified.
If a clinically significant finding is identified (including, but not limited to, changes in 
QT/corrected QT interval from baseline) after enrolment, the investigator will determine if the 
patient can continue in the study.  The investigator, or qualified designee, is responsible for 
determining if any change in patient management is needed, and must documenthis/her review 
of the ECG printed at the time ofcollection.  Any new clinically relevant finding should be 
reported as anAE.
9.4.4. Other Tests
9.4.4.1. Hip and Waist Circumference
Hip and waist circumference will be recorded in adults only as specified in the Schedule of 
Activities (Section2).  The average of triplicate measurements of waist (narrowest 
circumference between the lowest aspect of the ribs and anterior superior iliac crests) and the hip 
(widest circumference between the anterior superior iliac crests and the greater trochanters) 
circumference will be measured.
9.4.4.2. Body Weight and Height
Body weight and height will be recorded as specified in the Schedule of Activities (Section 2)
and as clinically indicated.


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9.4.5. Safety Monitoring
The Lilly CPor CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CPor 
CRPwill periodically review the following data:
trends in safety data
laboratory analytes 
adverse events.
When appropriate, the Lilly CPor CRPwill consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.5.1. Hepatic Safety
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin≥2X ULN, liver tests (Appendix 4) should be repeated within 3 to5 days including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase,and creatinine kinaseto 
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 
based on consultation with the Lilly CPor CRP.  Monitoring should continue until levels 
normalise and/or are returningto approximate baseline levels. 
Additional safety data should be collected if 1or more of the following conditions occur: 
elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests
elevation ofserum TBL to ≥2X ULN (except for cases of known Gilbert’s 
syndrome)
elevation of serum ALP to ≥2X ULN on 2or more consecutive blood tests 
patient/subject discontinued from treatment due to a hepatic event or abnormality 
of liver tests
hepatic event considered to be anSAE.
9.4.5.2. Glucose Monitoring
Hypoglycaemiawill be described using the following definitions(IHSG 2017): 
Documented Glucose Alert Level (Level 1), PG ≤70mg/dL (3.9mmol/L):
Documented symptomatic hypoglycaemia:an event during which typical 
symptoms of hypoglycaemiaare accompanied by PG ≤70mg/dL (3.9mmol/L)
Documented asymptomatic hypoglycaemia:an event not accompanied by 
typical symptoms of hypoglycaemiabut with PG ≤70 mg/dL (3.9mmol/L)
Documented unspecified hypoglycaemia:  an event during which PG 
≤70mg/dL (3.9mmol/L) but no information relative to symptoms of 
hypoglycaemiawas recorded
Documented Clinically Significant Hypoglycaemia(Level 2) PG <54 mg/dL 
(3.0mmol/L):


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
Documented symptomatic hypoglycaemia:  an event during which typical 
symptoms of hypoglycaemia are accompanied by PG <54 mg/dL (3.0 mmol/L)

Documented asymptomatic hypoglycaemia:  an event not accompanied by 
typical symptoms of hypoglycaemia but with PG <54 mg/dL (3.0 mmol/L)

Documented unspecified hypoglycaemia:  an event during which PG 
<54 mg/dL (3.0 mmol/L) but no information relative to symptoms of 
hypoglycaemia was recorded

Severe hypoglycaemia (Level 3):  an event requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions.  During 
these episodes, the patient has an altered mental status and cannot assist in his/her
own care, is semiconscious or unconscious, or experienced coma with or without 
seizures.  Plasma glucose measurements may not be available during such an event, 
but neurological recovery attributable to the restoration of blood glucose 
concentration to normal is considered sufficient evidence that the event was induced 
by a low PG concentration (PG ≤70 mg/dL [3.9 mmol/L])

Severe hypoglycaemia in children: because children have limited ability to 
detect and/or self-treat hypoglycaemia, severe hypoglycaemia in children is
an event in which children have altered mental status, and cannot assist in their 
care, are semiconscious or unconscious, or in coma with or without
convulsions, and may require parenteral therapy (glucagon or IV glucose)

Severe hypoglycaemia requiring medical attention:  a severe 
hypoglycaemic event when patients require therapy by health care providers 
(emergency medical teams, emergency room personnel, etc.)
Other Hypoglycaemia:

Nocturnal hypoglycaemia: any hypoglycaemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycaemia) that occurs at night 
and presumably during sleep

Relative hypoglycaemia:  an event during which typical symptoms of 
hypoglycaemia, which do not require the assistance of another person, are 
accompanied by PG >70 mg/dL (3.9 mmol/L), but these levels may be quickly 
approaching the 70 mg/dL (3.9 mmol/L) threshold

Overall (or total) hypoglycaemia:  this optional category combines all cases of 
hypoglycaemia.  If an event of hypoglycaemia falls into multiple subcategories, the 
event is counted only once in this category

Probable symptomatic hypoglycaemia:  an event during which symptoms of 
hypoglycaemia are not accompanied by a PG measurement but that was presumably 
caused by a blood glucose concentration ≤70 mg/dL (3.9 mmol/L).
9.4.5.3.
Severe Hypoglycaemia
The determination of a hypoglycaemic event as an episode of severe hypoglycaemia as defined 
above will be made by the investigator based on the medical need of the patient to have required 
assistance and is not predicated on the report of a patient simply having received assistance.


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All hypoglycaemic events will be recorded in the eCRF.  All episodes of severe hypoglycaemia 
must be reported as SAEs. 
9.4.5.4. Injection-Site Assessments (Local Tolerability)
Injection-site (Part A) and catheter-site (Part B) assessments for local tolerability will be 
conducted as specified in the Schedule of Activities (Section 2)and more frequently if deemed 
necessary by the investigator.
Digital pictures will be taken, if possible, of the injection/cathetersite at the time of 
identification of local intolerability and thereafter as often as judged necessary by the 
investigator.  The pictures should include patient number, visit number, time after dosing, and a 
ruler for scaling.
Local tolerability at the injection/cathetersite will be evaluated by means of the following 
objective and subjective assessments within the following categories:  pain (including burning), 
itching, erythema, oedema, and induration/infiltration.  The assessments will be recorded by the 
study site personnel.
9.4.6. Treatment of Hyperglycaemiaand Hypoglycaemia
Patients will be without further oral food intake following consumption of liquid test meal to
completion of blood glucose collection (approximately 300 minutes) unless required to treat 
hypoglycaemia, as defined by the PG level ≤70 mg/dL (3.9 mM) with symptoms or any PG 
≤60mg/dL (3.0 mM)during the inpatient period, i.e., reversed with either rapidly absorbable 
oral carbohydrates or IV glucose.  If a patient’s blood glucose concentration rises above 
300mg/dL (16.7 mM) for more than 1 hour, RHI will be administered IV.  In both cases, blood 
samples for blood glucose (for safety) will be taken and PK samples will be collected as planned.  
Patients may consume up to 20 g of carbohydrates to treat or prevent hy
poglycaemia (<70mg/dL 
[see Section 9.4.5.2]) during the fasting periods.  
If a patient is experiencing hyperglycaemia(blood glucose concentration ≥300mg/dL 
[16.7mM]) during the MMTT for more than 1 hour, RHIwill be administered IV.
In cases where treatment of either hypo-or hyperglycaemiarequire intervention, blood samples 
for blood glucose will be taken and PK samples will be collected as planned.
9.5. Pharmacokinetics
At the visits and times specified in the Scheduleof Activities(Section2), venous samples willbe 
collected to determine the serum concentrations of insulin lispro.  Instructions for the collection 
and handling of blood samples will be provided by the sponsor.  The actual date and time 
(24-hour clock time) of each sampling will be recorded.
9.5.1. Bioanalysis
Samples will be analysedat a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.


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Concentrations of insulin lisprowill be assayed using a validated enzyme-linked immunosorbent 
assaymethodspecific for insulin lispro at a laboratory approved by the sponsor.  Serum 
remaining may be used for other analyses on insulin lispro.
Bioanalytical samples collected to measure study drugconcentrations will be retained for a 
maximum of 1 year following last patient visit for the study.  
9.6. Pharmacodynamics
The sample(s) will be stored until testing is completed and upon confirmation of results.  
9.6.1. Glucodynamic Samples
Blood samples will be obtained for the measurement of glucose at the times specifiedin the 
Schedule of Activities (Section 2) using a point-of-care glucose meterthat will be readily 
available at the study site during the inpatient periods in order to provide real-time glucose 
measurement.  Repeat samples for counter-checking of apparent spurious results may be taken 
where indicated.  
9.6.1.1. Glucose Samples (Run-In Period)
Blood glucose concentrations will be monitored at a minimum of 30-to 60-minute intervals 
during the run-in period on Day 1 through the use of fingerstick or an indwelling catheter to 
minimise discomfort to patients (see Section 7.4.1).
9.6.1.2. Glucose Samples (MMTT)
Blood samples will be obtained for themeasurement of glucose at the times specifiedin the 
Schedule of Activities (Section2)through the use of an indwelling catheter to minimise 
discomfort to patients.  These glucose measurements will be used for patient safety management 
as well as for GD evaluations.
9.6.2. Immunogenicity Assessments 
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro as specified in the Schedule of Activities (Section2). 
Immunogenicity will be assessed using a validated radio ligand-binding assay (RBA)to detect 
anti-insulin lispro antibodies in the presence of lispro.  Instead of quantitating the level of 
anti-insulin lispro antibodies by titre, the RBA reports a semiquantitative percent-binding for 
each positive sample.  Additionally, positive sampleswill be characterised for cross-reactive 
binding to native insulin.
Clinical and reliable on-market data indicate that the immunogenic potential of insulin lispro is 
comparable to other marketed insulins such as RHI(Fineberg et al. 1996) and, when present, 
anti-insulin antibodies do not appear to be clinically consequential (Fineberg et al. 2003).  
Therefore, rather than relying on an in vitro neutralisation assay, well-established in vivo 
measures of insulin lispro efficacy (i.e., insulin dose, HbA1c) may be utilised to directly monitor 
for any potential neutralising effect of anti-lispro antibodies.


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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 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.
9.7.
Genetics
Not applicable for this study.
9.8.
Biomarkers
Not applicable for this study.  
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The number of patients needed to complete either Part A or Part B of this study was pre-set to 12 
in each age group (6 to <12 years, 12 to <18 years, and 18 to <65 years). Twelve completing 
patients in each age group will provide approximately 90% power to demonstrate 60% increase 
in the insulin lispro area under the plasma concentration-time curve from time zero to 30 minutes
(AUC[0-30min]) between LY900014 and Humalog within each age group. The sample size will 
also provide greater than 85% power to demonstrate 30% reduction in time to early half-maximal 
drug concentration (early 50% tmax). The estimated standard deviation of within-subject 
difference on the log scale is 0.45 for AUC(0-30min) and 0.35 for early 50% tmax, according to 
an analysis of internal Lilly data and external published paediatric studies. Testing will be done 
at an alpha level of 0.05 with a 2-sided confidence interval (CI).
Approximately 45 patients (approximately 15 patients in each age group) may be enrolled in the 
study to ensure approximately 36 patients complete both inpatient periods in both parts of the 
study. If patients complete Part A but decline participation in Part B or drop out from Part A, 
additional patients may be enrolled to ensure at least 36 patients complete Part B of the study. 
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of patient disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The patient’s age, sex, height, weight, BMI, race/subrace, or other demographic characteristics 
will be recorded.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
The analyses for Part A and Part B will be conducted separately using similar statistical methods. 
Primary statistical analyses will be conducted on the set of patients who complete both treatment 
periods.  Supportive analyses may be done on the key parameters for the patients who complete 
at least one treatment period. Safety analyses will be conducted for the set of patients receiving 
at least 1 dose of the study drug, whether or not they completed all protocol requirements.
Summary statistics (including number of patients, mean, standard deviation or standard error, 
minimum, and maximum) will be presented for continuous variables.  Data from all 3 age groups 
will be pooled and analysed using a linear mixed-effect model for continuous variables unless 
otherwise stated in the succeeding subsections. The model will include treatment, sequence, 
period, age group, and the interaction of treatment and age group as fixed effects and patient 
within sequence as a random effect. The primary comparison between LY900014 and insulin 


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lispro for each age group will be based on the treatment difference or ratio of the given age group 
from the model.  
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, andCIs will be calculated at 95%, 2-sided.
Any change in 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 study results.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  
10.3.1.Safety Analyses
10.3.1.1.Clinical Evaluation of Safety
All study drug-and protocol procedure-relatedAEs will be listed, and if the frequency of events 
allows, safety data (including hypoglycaemic events) will be summarised using descriptive 
methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with study drugas perceived by the investigator.  Symptoms reported to occur prior to enrolment
will be distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the Medical Dictionary for Regulatory 
Activities.
The number of study drug-related SAEs will be reported.
10.3.1.2.Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters and vital signs.  The 
parameters will be listed, and may be summarised using standard descriptive statistics. 
Additional analysis will be performed if warranted upon review of the data.
10.3.2.Pharmacokinetic Analyses
10.3.2.1.Pharmacokinetic Parameter Estimation
Patients who receive at least 1 dose of study drug and have measurable insulin lispro 
concentrations will be included in the PK analysis dataset.
Pharmacokineticanalyses will be conducted using standard noncompartmental methods of 
analysis (
 and
software (
on a computer 
that meets or exceeds the minimum system requirements for these programs.  The version of any 
software used for the analysis will be documented and the program will meet the Lilly 
requirements of software validation.  It is possible that other validated equivalent PK software 
programs may be utilised if appropriate, warranted,and approved by global PK management.
Free serum insulin lispro concentrations will be used to calculate several PK parameters, 
including early 50% t
max, time to late half-maximal drugconcentration(late 50% t
max
CCI
), 
CCI
CCI


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maximum observed drug concentration(C
max), time of maximum observed drug concentration 
(t
max),half-life (t
1/2),and area under the plasma concentrationtime curve(AUC)from time zero 
to the last recorded time[AUC(0-tlast)], AUC from time zero to 30 minutes[AUC(0-30min)],
AUCfrom time zero to 1hour[AUC(0-1h)], AUCfrom time zero to 7hours[AUC(0-7h)], and 
AUCfrom time zero to infinity[AUC(0-∞)].  Other parameters may be calculated as deemed 
appropriate.  Additional partial AUCs may be computed as necessary.
Although attempts will be made toadhere to the scheduled collection times (Section2), it is 
recognised that situations arise that may compromise the scheduled times.  Parameters will be 
individually calculated for each patientbased on actual collection times and presented by
summary statisticsand presented byeach agegroupand treatment.
Study results may be pooled with the results of other studies for population PK analysis purposes 
to avoid issues with post hoc analyses and incomplete disclosures of analyses.  
10.3.2.2.Pharmacokinetic Statistical Inference
Log-transformed C
maxand AUC estimates for insulin lispro will be evaluated to estimate 
least-squares geometric means, ratios of geometric means between LY900014 and Humalog 
(reference), and their corresponding 95% CIs using the mixed-effectmodel that includes 
treatment, sequence,period, age group,and treatment by age group interactionas fixed effects 
and patientwithin sequence as a random effect.  
The same model without log transformation will be used for the analysis of the PK time 
parameters (early 50% t
max, late 50% t
max,andt
max).  Least-squares means(LSmeans), treatment 
differences in LSmeans, and the corresponding 95% CIs for the treatment differences will be 
estimated from the model.  The treatment ratios and 95% CIs for the ratios will be calculated 
using the Fieller’s theorem (Chow and Liu 2009). 
10.3.3.GlucodynamicAnalyses 
10.3.3.1.GlucodynamicParameter Estimation
Patients who receive at least 1 dose of study drug and have completed at least 1 MMTT 
procedurewill be included in the analysis set for the GD analyses. 
Data will be analysedfor the patients during each MMTT. The change from baseline values (the 
average of -30, -15, and 0 minutes represented as the 0-hour time point following the start of the 
MMTT) for each patient will be calculated.  The area under the baseline subtracted glucose 
concentration versus time curve (∆AUC)from time 0 to 2hourspostmeal and ∆AUCfromtime 
0 to 5hourspostmeal will be calculated. In addition, the change from baseline maximum 
glucose observed during the 5 hours postmeal and change from baseline1hour glucose and 
2hour glucose afterthe start of the meal will be calculated. Other partial ∆AUCs may be 
calculated, as deemed appropriate.
Parameters will be individually calculated for each patient and presented by summary statistics
for each age groupand treatment.


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10.3.3.2. Glucodynamic Statistical Inference
Summary statistics (including number of patients, mean, standard deviation or standard error, 
minimum, and maximum) will be presented by treatment for each age group.  The GD 
parameters on the original scale (not log transformed) will be analysed using the same model 
used for PK parameters.  Least-squares means, treatment differences in LSmeans, and the 
corresponding 95% CIs for the treatment differences will be estimated from the model.  The 
treatment ratios and 95% CIs for the ratios will be calculated using the Fieller’s theorem.
10.3.4. Evaluation of Immunogenicity
The frequency of antibody formation to insulin lispro will be determined.  The relationship 
between the presence (or absence) of antibodies and AEs will be assessed.  Likewise, the 
relationship between the presence of antibodies and the PK parameters and GD response to 
insulin lispro may be assessed.  
10.3.5. Interim Analyses
An interim analysis will be conducted after all patients complete Part A of this study to analyse 
the safety, PK, and GD data in order to support regulatory submission and future study design.  
Data may be analysed while the trial is ongoing, but no changes to the study design are planned.  
Information that may unblind the study during the analyses will not be reported to study sites 
until the study has been unblinded.  An assessment committee will not be formed.


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11.
References
Cengiz E. Undeniable need for ultrafast-acting insulin: the pediatric perspective. J Diabetes Sci 
Technol. 2012;6(4):797-801.
Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. 3rd ed. 
Florida: Taylor and Francis Group, LLC; 2009:p 88-90.
[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.
Fath M, Danne T, Biester T, Erichsen L, Kordonouri O, Haahr H. Faster-acting insulin aspart 
provides faster onset and greater early exposure vs insulin aspart in children and adolescents 
with type 1 diabetes mellitus. Pediatr Diabetes. 2017 Feb 6; doi: 10.1111/pedi.12506 [Epub 
ahead of print].
Fineberg NS, Fineberg SE, Anderson JH, Birkett MA, Gibson RG, Hufferd S. Immunologic 
effects of insulin lispro [Lys (B28), Pro (B29) human insulin] in IDDM and NIDDM patients 
previously treated with insulin. Diabetes. 1996;45(12):1750-1754.
Fineberg SE, Gulliya KS, Huang J, Anderson JH, Brunelle R. Effect of long-term exposure to 
insulin lispro on the induction of antibody response in patients with type 1 or type 2 diabetes. 
Diabetes Care. 2003;26(1):89-96.
Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017.
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.
[IHSG] International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 
mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the 
American Diabetes Association and the European Association for the Study of Diabetes. 
Diabetes Care. 2017 Jan;40(1):155-157.
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. Diabetes 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, Sayday 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. Diabetes Care. 2014;37(2):402-408.


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Schwartz GJ, Work DF. Measurement and estimation of GFR in children andadolescents. Clin J 
Am Soc Nephrol.
CCI
2009;4(11):1832–1843. 
CCI


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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 AE can therefore be any unfavourable 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
assent
Agreement from a child or other individual who is not legally capable of providing consent, 
but who can understand the circumstances and potential risks involved in participating in a 
study (required by some institutional review boards [IRBs]/ethical review boards [ERBs]). 
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
blinding
A procedure in which 1 or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
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 subjects are aware of the treatment received.
BMI
body mass index
CI
confidence interval
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation either will occur immediately after initial testing or will require that samples 
be held to be re-tested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
clinical pharmacologist


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Term
Definition
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CSII
continuous subcutaneous insulin infusion
∆AUC
area under the baseline subtracted glucose concentration versus time curve
early 50% tmax
time to early half-maximal drug concentration
ECG
Electrocardiogram
eCRF
electronic case report form
enrol
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
FDA
US Food and Drug Administration
GCP
good clinical practice
GD
glucodynamic(s)
GFR
glomerular filtration rate
HbA1c
glycated haemoglobin
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.


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Term
Definition
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorised form, or marketed products 
used for an unauthorised indication, or marketed products used to gain further information 
about the authorised form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a studysite, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IV
intravenous(ly)
IWRS
interactive web response system
late 50% t
max
time to late half-maximal plasma concentration
legal 
representative
An individual or judicial or other body authorised under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
LSmeans
least-squares means
MDI
multiple daily injection
MMTT
mixed meal tolerance test
NPH
neutral protamine Hagedorn
PAH
pulmonary arterial hypertension
PG
plasma glucose
PK
pharmacokinetic(s)
randomise
The process of assigning subjects/patients to an experimental group on a random basis.
RBA
radio ligand-binding assay
RHI
regular human insulin
SAE
serious adverse event
SC
subcutaneous(ly)
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.  
SPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
t
1/2
half-life


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Term
Definition
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
tmax
time of maximum observed drug concentration
U
Units
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Laboratory Tests
Haematologya
Clinical Chemistrya
Haematocrit
Sodium
Haemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate 
Mean cell volume 
Chloride 
Mean cell haemoglobin
Calcium
Mean cell haemoglobinconcentration 
Phosphorus 
Leucocytes (WBC) 
Glucose 
Platelets
Blood urea nitrogen (BUN)
Differential WBC absolute counts of
Uric acid 
Neutrophils
Total cholesterol 
Lymphocytes
Total protein
Monocytes
Albumin
Eosinophils
Total bilirubin
Basophils
Alkaline phosphatase (ALP)
HbA1cb
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Urinalysisa
Creatininec
Specific gravity
Gamma-glutamyl transferase (GGT)
pH
Protein
Ethanol testingd
Glucose
Urine drug screen
b,d
Ketones
Hepatitis B surface antigenb
Bilirubin
Hepatitis C antibodyb
Urobilinogen
HIVb
Blood
Nitrite
Pregnancy teste
Leucocytes
FSHb
Microscopyf
Abbreviations:  eGFR = estimated glomerular filtration rate; FSH = follicle-stimulating hormone; HbA1c = glycated
haemoglobin; HIV = human immunodeficiency virus; RBC = red blood cell; WBC = white blood cell.
a Results will be validated by the local laboratory at the time of initial testing.
b Performedat screeningonly.
c eGFR will be calculated using relevant formulae (Schwartz et al.2009).
d May be repeated prior to admission to the study site and at other times indicated in the Schedule of Activities.
e Females only, as indicated by the Schedule of Activities(see Sections 2and6.1for more information).
f If clinically indicated, per investigator’s discretion.


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Appendix 3.
Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for

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 study drug.

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.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
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, participants below the age of 18 
years will be required to provide their assent to this clinical trial.  Age-appropriate information 
about this clinical trial will be provided to participants.
Recruitment
Study-specific recruitment material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by the International Council for Harmonisation 
(ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol, ICF and Assent Form must be provided to Lilly 
before the study may begin at the investigative site(s).  Lilly or its representatives must approve 
the ICF before it is used at the investigative site(s).  All ICFs must be compliant with the ICH 
guideline on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB or Patient Information Leaflet, Package Insert or SPC and updates during 
the course of the study

ICF and Assent Form


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
relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organisation.
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.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
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 training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the eCRFs, 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 evaluate eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.


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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 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.  This 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 the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The study site must define and 
retain all source records and must maintain a record of any data where source data are directly 
entered into the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.
The purpose and use of patient personal information collected will be provided in a written 
document to the patient by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, 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.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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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 Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Haematologya
Haptoglobina
Haemoglobin
Haematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
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
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear Antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised
ratio; RBC = red blood cell; WBC = white blood cell.
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.
Blood Sampling Summary
This table summarises the approximate number of venipunctures and blood volumes for all blood 
sampling (screening, safety laboratories, and bioanalytical assays) during the study.  Fewer 
venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment.  
Protocol I8B-MC-ITSA Sampling Summary for Part A
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
20
1
20
Clinical laboratory testsa
9
1
9
Pharmacokinetics – insulin lispro
1
21 samples x 2 
periods = 42
42
Blood discard for cannula patency
1
21 samples x 2 
periods = 42
42
Blood glucose sampling (run-in)
0.6
17 samples x 2 
periods = 34
20.4
Blood glucose sampling (MMTT)
0.6
24 samples x 2 
periods = 48
28.8
Immunogenicity
5
3
15
Total
177.2
Total for clinical purposes [rounded up to nearest 10 mL]
180
Abbreviation:  MMTT = mixed meal tolerance test.
a
Additional samples may be drawn if needed for safety purposes.
Protocol I8B-MC-ITSA Sampling Summary for Part B
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
20
1
20
Clinical laboratory testsa
9
1
9
Pharmacokinetics – insulin lispro
1
21 samples x 2 
periods
42
Blood discard for cannula patency
1
21 samples x 2 
periods
42
Blood glucose sampling (run-in)
0.6
17 samples x 2 
periods = 34
20.4
Blood glucose sampling (MMTT)
0.6
24 samples x 2 
periods = 48
28.8
Immunogenicity
5
3
15
Total
177.2
Total for clinical purposes [rounded up to nearest 10 mL] 
180
Abbreviation:  MMTT = mixed meal tolerance test.
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Protocol Amendment I8B-MC-ITSA(d) 
Summary 
A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 Compared to Humalog in 
Children, Adolescents, and Adults with Type 1 Diabetes 
Mellitus
Overview
Protocol I8B-MC-ITSA(c),A Study to Evaluate the Pharmacokinetics and Glucodynamics of 
LY900014 Compared to Humalog in Children, Adolescents, and Adults with Type 1 Diabetes 
Mellitus,has been amended.  The new protocol is indicated by Amendment (d) 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 as follows:

CCI
Since 
is being providedas an optionfor the MMTT,
clarification was added to allow for only this chocolate drink during the MMTT.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.


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6.3.2.Caffeine, Alcohol, and Tobacco
Patients should refrain from caffeine-containing food/beverages (e.g., cola, chocolate drinks, tea, 
coffee, energy drinks containing methylxanthine [caffeine, theophylline, or theobromine]) for at 
least 12 hours before each test meal and throughout the duration of each study site visit,
excluding the test meal when 
 may be given.
CCI


PPD
Leo Document ID = 69f096d5-ac0d-489d-a214-63de4e49d2fb
Approver:
Approval Date & Time: 20-Jul-2018 16:04:49 GMT
Signature meaning: Approved
Approver:
Approval D
9 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
Statistical Analysis Plan (version 2): I8B-MC-ITSA
A Study to Evaluate the Pharmacokinetics and Glucodynamics of LY900014 
Compared to Humalog in Children, Adolescents, and Adults With Type 1 Diabetes 
Mellitus
NCT03465878   
Approval Date: 06-Aug-2018


I8B-MC-ITSA Statistical Analysis PlanVersion 2
Page 1
LY900014
1. Statistical Analysis Plan:  
I8B-MC-ITSA:A Study to Evaluate the Pharmacokinetics 
and Glucodynamics of LY900014 Compared to Humalog 
in Children, Adolescents, and Adults with Type 1 
Diabetes Mellitus
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-ITSAis a randomised, patient-and investigator-blind, 2-part study, with each 
part containing a 2-period crossover assessment in children (age 6 to <12 years), 
adolescents (age 12 to <18 years), and adults (age 18 to <65 years) withtype 1 diabetes 
mellitusto evaluate the Pharmacokinetics and Glucodynamicsof LY900014 compared to 
Humalog given as a bolus either as a subcutaneousinjection or via a continuous 
subcutaneous insulin infusionpump. 
Approval Date: 06-Aug-2018 GMT
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8B-MC-ITSA
Phase 1
Statistical Analysis PlanVersion 1 electronically signed and approved by Lilly:  
06 February 2018
Statistical Analysis Plan Version 2 electronically signed and approved by Lillyon date 
provided below.


I8B-MC-ITSA Statistical Analysis PlanVersion 2
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2. Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I8B-MC-ITSA:  A Study to Evaluate the 
Pharmacokinetics and Glucodynamics of LY900014 Compared to 
Humalog in Children, Adolescents, and Adults with Type 1 Diabetes 
Mellitus...............................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History.................................................................................................................5
4.
Study Objectives.................................................................................................................6
4.1. Primary Objective..........................................................................................................6
4.2. Secondary Objectives.....................................................................................................6
5.
Study Design.......................................................................................................................7
5.1. Summary of Study Design..............................................................................................7
5.2. Determination of Sample Size........................................................................................7
6.
A Priori Statistical Methods..............................................................................................10
6.1. General Considerations................................................................................................10
6.2. Demographics and Patient Disposition.........................................................................11
6.3. Pharmacokinetic Analysis............................................................................................12
6.3.1.
Pharmacokinetic Parameter Estimation................................................................12
6.3.2.
Pharmacokinetic Statistical Inference...................................................................12
6.4. Glucodynamic Analyses...............................................................................................13
6.4.1.
Glucodynamic Parameter Estimation....................................................................13
6.4.2.
Glucodynamic Statistical Inference......................................................................14
6.5. Safety and Tolerability Assessments............................................................................14
6.5.1.
Adverse Events....................................................................................................14
6.5.2.
Concomitant Medication......................................................................................14
6.5.3.
Clinical Laboratory Parameters............................................................................15
6.5.4.
Vital Signs...........................................................................................................15
6.5.5.
Blood Glucose Monitoring and Hypoglycemia.....................................................15
6.5.6.
Injection-Site Assessment....................................................................................16
6.5.7.
Immunogenicity...................................................................................................16
6.5.8.
Other Assessments...............................................................................................17
6.6. Interim Analyses..........................................................................................................17
7.
Reference..........................................................................................................................18


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Table of Contents
Table
Page
Table ITSA.6.1
Treatment and Age Group Used in TFLs...................................................11


I8B-MC-ITSA Statistical Analysis PlanVersion 2
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Table of Contents
Figure
Page
Figure ITSA.5.1.
Illustration of study design..........................................................................9


I8B-MC-ITSA Statistical Analysis PlanVersion 2
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3. Revision History
Statistical analysis Plan (SAP) Version 1 was approved prior to the first patient visit.  This 
version is based on Protocol I8B-MC-ITSA approved on 12 October 2017and amended on 21 
December 2017.  This SAP describes the planned analysis of the safety, tolerability, 
pharmacokinetic (PK),and glucodynamic (GD) data from this study.
This SAP is the second version approved prior to the completion of Part A of the I8B-MC-ITSA 
Study. The main changes are listed below:
Clarifying that post-intervention blood glucose samples should not be included in any 
analysis to determine the PK/pharmacodynamic (PD)profile
Adding that the observed values equal to 0 for PK parameters will be treated as missing.


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4. Study Objectives
4.1. Primary Objective
The primary objectives of this study are as follows:
Part A:  To evaluate the PK of insulin lispro following a single subcutaneous (SC)bolus 
dose administered by injection of LY900014 compared to Humalog in children, 
adolescents,and adults with type 1 diabetes mellitus(T1DM)
Part B:  To evaluate the PK of insulin lispro following a single SC bolus dose 
administered by continuous subcutaneous insulin infusion (CSII)of LY900014 compared 
to Humalog in children, adolescents,and adults with T1DM
4.2. Secondary Objectives
The secondary objectives of this study are as follows:
Part A:  To evaluate the difference in GD response to LY900014 and Humalog 
administered by SC bolus injection as assessed using the liquid mixed meal tolerance test 
(MMTT), in children, adolescents, and adults with T1DM
Part B:  To evaluate the difference in GD response to LY900014 and Humalog 
administered by SC bolus via CSII as assessed using the liquid MMTT, in children, 
adolescents, and adults with T1DM
Part A:  To evaluate the tolerability of LY900014 following SC injection in children, 
adolescents, and adults with T1DM
Part B:  To evaluate the tolerability of LY900014 following SC bolus via CSII in 
children, adolescents, and adults with T1DM


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5. Study Design
5.1. Summary of Study Design
This is a Phase 1, randomised, 2-part, patient-and investigator-blind, 2-period crossover study in 
children (age 6 to <12 years), adolescents (age 12 to <18 years), and adults (age 18 to <65 years) 
with T1DM currently using a CSII pump or multiple daily injection (MDI).  The aim is to 
evaluate insulin lispro PK, GD, safety, and tolerability of LY900014 in comparison with 
Humalog(reference) following a single dose SC administration immediately prior to a 
standardised liquid meal.
This study is composedof 2 parts:  Part A and Part B.  During Part A, patients will receive a 
single dose of LY900014 and Humalog on 1 occasion each as SC bolus injection and in Part B a 
single dose of LY900014 and Humalog on 1 occasion each as SC bolus via CSII.
Patients will be randomised on Day 1 of Period 1 in Part A and Day -1 of Period 1 in Part B.  For 
each age group, patients will be randomised to 1 of the 2 treatment sequences (first double-blind 
LY900014 then double-blind Humalog, and first double-blind Humalog then double-blind 
LY900014) in 1:1 ratio.  In both parts, dosing in Period 1 and Period 2 can occur on consecutive 
days but not more than 22days apart.  For patients available for dosing on consecutive days, the 
medical assessments scheduled for Day -1 of Period 2 may be done on Day1 of Period 1.  
Patients will undergo a rescreening visit if dosing visits between Part A and Part B are more than 
28 days apart.  Patients who participate in Part A may continue to Part B; however, patients who 
complete Part A but discontinue prior to Part B may be replaced by newly enrolled patients in 
Part B.  Newly enrolled patients will be randomised to 1 of 2treatment sequences after 
completing the screening and are expected to complete only Part B activities.  Before each 
MMTT, a run-in period to stabilise blood glucose will occur.
Figure ITSA.5.1illustratesthe design of Part A and Part B.
5.2. Determination of Sample Size
The number of patients needed to complete either Part A or Part B of this study was pre-setto 12 
in each age group (6 to <12 years, 12 to <18 years, and 18 to <65 years).  Twelve completing 
patients in each age group will provide approximately 90% power to demonstrate 60% increase 
in the insulin lispro area under the plasma concentration-time curve from time zero to 30 minutes 
(AUC[0-30min]) between LY900014 and Humalogwithin each age group.  The sample size will 
also provide greater than 85% power to demonstrate 30% reduction intime to early half-maximal 
drug concentration (early 50% tmax).  The estimated standard deviation of within-subject 
difference on the log scale is 0.45 for AUC(0-30min)and 0.35 for early 50% tmax, according to an 
analysis of internal Lilly data and external published paediatric studies.  Testing will be done at 
an alpha level of 0.05 with a 2-sided confidence interval (CI).
Approximately 45patients (approximately 15 patients in each age group) may be enrolled in the 
study to ensure approximately 36 patients completeboth inpatient periods(i.e.,12 completers in 
each age group) forboth parts of the study.  If patients complete Part A but decline participation 


I8B-MC-ITSA Statistical Analysis PlanVersion 2
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LY900014
in Part B or drop out from Part A, additional patients may be enrolled to ensure at least 
36patients complete Part B of the study.


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Abbreviations:  MDI = multiple daily injection; MMTT = mixed meal tolerance test; 
NPH = neutral protamine Hagedorn; SC = subcutaneous; T = telephone visit; T1DM = 
type 1 diabetes mellitus.
a
Prior to Period 1, patients on MDI therapy with any basal insulin other than 
NPH twice dailywill transition to NPH therapy twice daily approximately 7 to 3 days 
prior to Period 1.
b
Insulin transition is applicable if Period 2 occurs >3 to 7 days after Period 1.  
The second MMTT assessment may occur on consecutive days but no more than 
22days after the first MMTT.
Figure ITSA.5.1.
Illustration of study design.


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6. A Priori Statistical Methods
6.1. General Considerations
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified.  Data listings, summaries, 
and analyses will be performed by Covance Early Clinical (EC) Biometrics.  If additional 
analyses are required to supplement the planned analyses described in this SAP, they may be 
performed and will be identified in the clinical study report (CSR).  Any substantial deviations 
from this SAP will be agreed upon between Eli Lilly and Company and Covance EC Biometrics 
and identified in the CSR.  Any minor deviations from the Tables, Figures, and Listings (TFLs)
may not be documented in the CSR.
Theanalyses for Part A and Part B of the study will be conducted separately using similar
statistical methods.  Treatment comparisonsbetween LY900014 and Humalog will be conducted 
at an alpha level of 0.05 with a 2-sided CI within each age group for each part of study.
The age groupsused in the PK and GD analyses will be determined by the ageof the patientat 
initial screening.  For patients who participated in both parts of the study, the age at screening of 
Part A will be used in the analyses for both parts.  For patients newly enrolled for Part B only, 
the age at screening of Part B will be used.
The analysis populations are defined for each study part separately.  Primary statistical analyses 
for PK parameters will be conducted on the set of patients who complete both treatment periods
with an identical bolus insulin dose for the MMTTsand have measurable insulin lispro 
concentrationswithin each part of the study.  Supportive analyses may be done on the key 
parameters for the patients who complete at least1 treatment period and have measurable insulin 
lispro concentrations within each part of the study. 
Primary statistical analyses for GDparameters will be conducted on the set of patients who 
complete both treatment periods with an identical bolus insulin dose for the MMTTswithin each 
part of the study.  Supportive analyses may be done on the key parameters for the patients who 
complete at least 1 treatment period forthe MMTT within each part of the study.
The post-intervention glucose samples will be collected in the database; however, the post-
intervention glucose data will be excluded from PK andGD analyses.
Safety analyses will be conducted for the set of patients receiving at least 1 dose of the study 
drug, whether or not they completed all protocol requirements. 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when patients are assigned to analysis populations.
Summary statistics (including number of patients, mean, standard deviation or standard error, 
minimum, and maximum) will be presented for continuous variables.  Data from all 3 age groups 
will be pooled and analysed by a linear mixed-effect model for continuous variables unless 
otherwise stated in the succeeding subsections.  The model will include treatment, sequence, 
period, age group, and the interaction of treatment and age group as fixed effects and patient 


I8B-MC-ITSA Statistical Analysis PlanVersion 2
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LY900014
within sequence as a random effect.  The primary comparison between LY900014 and Humalog
for each age group will be based on the treatment difference or ratio of the given age group from 
the model.
For categorical data, frequency count and percentages will be presented in the summary table.
Data listings will be provided for all patients up to the point of withdrawal, with any patients 
excluded from the relevant population highlighted, using all data that are databased.  Summary 
statistics and statistical analyses will generally only be performed for patients included in the 
relevant analysis population.  For the calculation of summary statistics and statistical analysis, 
unrounded data will be used.
For weight and other clinical lab tests (based on data availability), mean change from baseline is 
the mean of all individual patients’ change from baseline values.  Each individual change from 
baseline will be calculated by subtracting the individual patient’s baseline value from the value at 
the timepoint.  The individual patient’s change from baseline values will be used to calculate the 
mean change from baseline using
Additional exploratory analyses of the data will be conducted as deemed appropriate.
Data analysis will be performed using 
or greater.
Table ITSA.6.1is a list of the study treatment and age group names that will be used in the 
statistical TFLs.
Table ITSA.6.1 
Treatment and Age Group Used in TFLs
Study Treatment Name
Treatment order in TFL
LY900014
1
Humalog
2
Age Group Name
Age Group Order in TFL
Children
1
Adolescents
2
Adults
3
Abbreviation:  TFL = Table, Figure, and Listing.
6.2. Demographics and Patient Disposition
CCI
Patient disposition will be listed.  The demographic variables age, sex, race, ethnicity, hip and 
waist circumference, body weight, height,and body mass index will be summarised by age 
group and listed.  In addition, screening HbA1c, previous insulin therapy (basal and prandial),
insulin administration method (CSII or MDI) at screening,and duration of T1DM will be 
summarised and listed. 
Alcohol consumption will be reported in the SDTMs in units of alcohol and will be converted to 
grams for the TFLs, where 1 unit is equal to 8 grams of pure alcohol. 
CCI


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6.3. Pharmacokinetic Analysis
6.3.1. Pharmacokinetic Parameter Estimation
Patients who receive at least 1 dose of study drug and have measurable insulin lispro 
concentrations will be included in the PK analysis dataset.The post-intervention glucose data 
will not be included in the PK analyses.
Pharmacokinetic analyses will be conducted using standard noncompartmental methods of 
analysis
 and  
software  
on a computer 
that meets or exceeds the minimum system requirements for these programs.  The version of any 
software used for the analysis will be documented and the program will meet the Lilly 
requirements of software validation.  It is possible that other validated equivalent PK software 
programs may be utilised if appropriate, warranted, and approved by global PK management.
Free serum insulin lispro concentrations will be used to calculate several PK parameters, 
including early 50% t
max, time to late half-maximal drug concentration(late 50% t
max), maximum 
observed drug concentration(C
max), time of maximum observed drug concentration (tmax), half-
life (t
1/2), and area under the plasma concentration time curve(AUC) from timezero to the last 
recorded time[AUC
(0-tlast)], AUC from time zero to 30 minutes [AUC
(0-30min)], AUCfrom time 
zero to 1 hour [AUC
(0-1h)], AUCfrom time zero to 7 hours [AUC
(0-7h)], and AUCfrom time zero 
to infinity [AUC(0-∞)].  Other parameters may be calculated as deemed appropriate.  Additional 
partial AUCs may be computed as necessary.
Although attempts willbe made to adhere to the scheduled collection times, it is recognised that 
situations arise that may compromise the scheduled times.  Parameters will be individually 
calculated for each patient based on actual collection times and presented by summary statistics 
and presented by each age groupand treatment.
Study results may be pooled with the results of other studies for population PK analysis purposes 
to avoid issues with post hoc analyses and incomplete disclosures of analyses.  
6.3.2. Pharmacokinetic Statistical Inference
The population for PK statistical analyses is defined in Section 6.1.  The PK parameters will be 
summarised by treatment and agegroup for each part of the study.
Log-transformed C
max
CCI
and AUC estimates for insulin lispro will be evaluated to estimate least-
squares geometric means, ratios of geometric means between LY900014 and Humalog 
(reference), and their corresponding 95% CIs using the statistical model that includes treatment, 
sequence, period, age group, and treatment by age group interaction as fixed effects and patient 
within sequence as a random effect.Anyobserved values equal to 0 will betreated as missing 
for the analysis.
CCI
CCI
CCI


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The same model without log transformation will be used for the analysis of the PK time 
parameters (early 50% t
max, late 50% t
max, and t
max).  Least-squares means (LSmeans), treatment 
differences in LSmeans, and the corresponding 95% CIs for the treatment differences will be 
estimated from the model.  The treatment ratios and 95% CIs for the ratios will be calculated 
using Fieller’s theorem(Chow et al. 2009).
ThePK analyses may be repeated for the population of patients who complete at least 
1treatment period and have measurable insulin lispro concentrations.
An exploratory analysis on the interaction between treatment and age group will be evaluated for 
all PK parameters using the same linear mixed-effect modelfor treatment comparison described 
previously.  This test will be used to compare whether the LY900014 versus Humalog treatment 
effect is similar among all 3 age groups.  The interaction effects will be evaluated using a 
significance level of 0.10.
6.4. Glucodynamic Analyses
6.4.1. Glucodynamic Parameter Estimation
Patients who receive at least 1 dose of study drug and have completed at least 1 MMTT 
procedure will be included in the analysis set for the GD analyses. The post-intervention glucose 
data will not be included in the GD analyses.
Data will be analysed for the patients during each MMTT.  The change from baseline values (the 
average of -30, -15, and 0 minutes represented as the 0-hour time point following the start of the 
MMTT) for each patient will be calculated.  Mean change from baseline is the mean of all 
individual patients’ change from baseline values.  Each individual change from baseline will be 
calculated by subtracting the individual patient’s baseline value from the value at the timepoint.  
The area under the baseline subtracted glucose concentration versus time curve (∆AUC) from 
time 0 to 2 hours postmeal (∆AUC[0-2h])and ∆AUC from time 0 to 5 hours postmeal
(∆AUC[0-5h]
CCI
) will be calculated.  In addition, the change from baseline maximum glucose 
observed during the 5 hours postmeal and change from baseline 1hour glucose and 2hour 
glucose after the start of the meal will be calculated.  Other partial ∆AUCs may be calculated, as 
deemed appropriate.
Parameters will be individually calculated for each patient and presented by summary statistics
for each age groupand treatment.


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6.4.2. Glucodynamic Statistical Inference
The population for GD statistical analyses is defined in Section 6.1.  The GD parameters will be 
summarized by treatment and age group for each part of the study.
The GD parameters on the original scale (not log transformed) will be analysed using the same
model used for PK parameters.  Least-squares means, treatment differences in LSmeans, and the 
corresponding 95% CIs for the treatment differences will be estimated from the model.  The 
treatment ratios and 95% CIs for the ratios will be calculated using Fieller’s theorem.
The above analyses may be repeated for the patients who complete at least 1 treatment period for 
the MMTT.
An exploratory analysis on the interaction between treatment and age group will be evaluated for 
all GD parameters using the same statistical model used for treatment comparison.  This test will 
be used to compare whether the LY900014 versus Humalog treatment effect is similar among all 
3 age groups.  The interaction effects will be evaluated using a significance level of 0.10.
6.5. Safety and Tolerability Assessments
6.5.1. Adverse Events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables.  A pre-existing condition is defined as an AE that starts before the patient has 
provided written informed consent and is ongoing at consent.  A nontreatment-emergent AE is 
defined as an AE thatstarts after informed consent but prior to dosing(prandial MMTT dosing 
for Part A and infusion set with study treatment inserted for Part B).  A treatment-emergent AE 
is defined as an AE that occurs postdose or that is present prior to the first dose and becomes 
more severe postdose. 
Treatment-emergent AEs will be summarized by treatment, age group, severity,and relationship 
to the study drug.  The frequency (the number of AEs, the number of patients experiencing an 
AE,and the percentage of patients experiencing an AE) of treatment-emergent AEs will be 
summarized by treatment, age group, Medical Dictionary for Regulatory Activities version 20.0
system organ class and preferred term.  The summary and frequency AEtables will be presented 
for all causalitiesand those considered related to the study drug. 
All AEs will be listed.  Any serious AEswill be tabulated.
6.5.2. Concomitant Medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2017).  
Concomitant medication will be listed.


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6.5.3. Clinical Laboratory Parameters
All clinical chemistry, haematology,and urinalysis data will be listed.  Values for any clinical 
chemistry, haematology,and urinalysis values outside the reference ranges will be flagged on the 
individual patient data listings.
Additionally, clinical chemistry, haematology,and urinalysis data outside the reference ranges 
will be summarized by treatment sequence and age group.
6.5.4. Vital Signs
Vital signs data will be summarized by treatment and age group, together with changes from 
baseline, where baseline is defined as predose of Day 1.  Furthermore, values for individual 
patients will be listed.
6.5.5. Blood Glucose Monitoring and Hypoglycemia
Hypoglycaemicevents will be appropriately recorded in the CRF.  In the case of a 
hypoglycaemicevent, the actual blood glucose value, if measured, will be recorded in the CRF, 
together with any treatments administered.  Each category of hypoglycaemicevents (defined 
below) will be listed and summarized by treatment and age group forinpatient during the MMTT
and inpatient run-in period (Part B only).  “During the MMTT” refers to 0to300 minutes post the 
start time of the mealor to the timeof thefirst insulin dose after the MMTT, whichever occurs 
first.  For the inpatient period prior to MMTT, the inpatient period after MMTT (from 300 
minutes post the start time of the meal or the time of the first insulin dose after MMTT, 
whichever occurs first, to the end of inpatient visit), andthe outpatient period(between Period 1 
and Period 2 or between Period 2 and the follow-up visit), similar summary will be provided by 
age group independently of randomized treatment assignment.  All hypoglycemia occurred 
during the study will be listed.
Hypoglycemia is defined as follows:
Documented Glucose Alert Level (Level 1), PG ≤70 mg/dL (3.9mmol/L):
o Documented symptomatic hypoglycaemia:  an event during which typical 
symptoms of hypoglycaemia are accompanied by PG ≤70mg/dL (3.9mmol/L)
o Documented asymptomatic hypoglycaemia:  an event not accompanied by typical 
symptoms of hypoglycaemia but with PG ≤70 mg/dL (3.9mmol/L)
o Documented unspecified hypoglycaemia:  an event during which PG ≤70mg/dL 
(3.9mmol/L) but no information relative to symptoms of hypoglycaemia was 
recorded
Documented Clinically Significant Hypoglycaemia (Level 2) PG <54 mg/dL 
(3.0mmol/L):
o Documented symptomatic hypoglycaemia:  an event during which typical 
symptoms of hypoglycaemia are accompanied by PG <54mg/dL (3.0mmol/L)
o Documented asymptomatic hypoglycaemia:  an event not accompanied by typical 
symptoms of hypoglycaemia but with PG <54 mg/dL (3.0mmol/L)


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o Documented unspecified hypoglycaemia:  an event during which PG <54mg/dL 
(3.0mmol/L) but no information relative to symptoms of hypoglycaemia was 
recorded
Severe hypoglycaemia (Level 3):  an event requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions.  During these 
episodes, the patient has an altered mental status and cannot assist in his/her own care, is 
semiconscious or unconscious, or experienced coma with or without seizures.  Plasma 
glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of blood glucose concentration to normal is 
considered sufficient evidence that the event was induced by a low PG concentration (PG 
≤70 mg/dL [3.9mmol/L])
o Severe hypoglycaemia in children:  because children have limited abilityto detect 
and/or self-treathypoglycaemia,severehypoglycaemia in children isan event in 
which childrenhave alteredmentalstatus,and cannot assist in their care, are 
semiconscious orunconscious, or in comawithorwithoutconvulsions,andmay
requireparenteraltherapy(glucagonorIVglucose)
o Severe hypoglycaemia requiring medical attention:  a severe hypoglycaemic event 
when patients require therapy by health care providers (emergency medical teams, 
emergency room personnel, etc.)
Nocturnal hypoglycaemia:  any hypoglycaemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycaemia) that occurs at night and 
presumably during sleep
Relative hypoglycaemia:  an event during which typical symptoms of hypoglycaemia, 
which do not require the assistance of another person, are accompanied by PG 
>70mg/dL (3.9 mmol/L), but these levels may be quickly approaching the 70 mg/dL 
(3.9mmol/L) threshold
Overall (or total) hypoglycaemia:  this optional category combines all cases of 
hypoglycaemia.  If an event of hypoglycaemia falls into multiple subcategories, the event 
is counted only once in this category
Probable symptomatic hypoglycaemia:  an event during which symptoms of 
hypoglycaemia are not accompanied by a PG measurement but that was presumably 
caused by a blood glucose concentration ≤70 mg/dL (3.9mmol/L).
6.5.6. Injection-Site Assessment
Injection-site assessment data will belisted and summarized in frequency tables by treatment, 
age group,and timepoint.
6.5.7. Immunogenicity
Immunogenicity data will be listedand summarized for PartsA and Bcombined.  The number of 
patients who have not detected anti-insulin lispro antibody at predose (for period 1 of Part A if 
patients participate both parts of the study or period 1 of Part B if patients participate Part B 
only) and detected anti-insulin lispro antibody at postdose (measured in all following visits after 
pre-dose) will be summarized by age group independently of randomized treatment assignment.  


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The number of patients who have detected anti-insulin lispro antibody at predose and 57% 
increase from the predose to postdosewill also be summarized in a similar way.
6.5.8. Other Assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analysed.
6.6. Interim Analyses
An interim analysis will be conducted after all patients complete Part A of this study to analyse 
the safety, PK, and GD data in order to support regulatory
 submission and future study design.  
Data may be analysed while the trial is ongoing, but no changes to the study
 design are planned.  
Information that may unblind the study during the analyses will not be reported to study sites 
until the study has been unblinded.  An assessment committee will not be formed.


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7. Reference
Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. 3rd ed. 
Florida: Taylor and Francis Group, LLC; 2009:88-90.


PPD
Leo Document ID = 393226bb-f22c-4020-aed3-5f32541fbd6e
Approver:
Approval Date & Time: 06-Aug-2018 18:52:33 GMT
Signature meaning: Approved