Conditions: Diabetes Mellitus, Type 1
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 31
Healthy volunteers: no

Brief summary:
This study will compare LY900014, a drug that lowers blood sugar, with insulin lispro (Humalog). Both drugs will be given by injection under the skin of the abdomen. This study will be conducted in participants with type 1 diabetes to investigate how quickly and how much LY900014 is absorbed and the effect of LY900014 on blood sugar levels in comparison with insulin lispro. The study will last about 3 to 6 weeks for each participant, not including screening.

Detailed description:

Arms:
arm 1: Single, 15 units (U)LY900014 administered subcutaneously (SC) in one of two study periods in Japanese Patients With Type 1 Diabetes Mellitus (T1DM). arm 2: Single, 15 U insulin lispro administered SC in one of two study periods in Japanese Patients With Type 1 Diabetes Mellitus.

Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro
Intervention descriptions: intervention 1: Administered SC. intervention 2: Administered SC.

Protocol document:
Prot_000.pdf: 
Pharmacokinetics and Glucodynamics of LY900014 Compared to Insulin Lispro (Humalog) 
Following Single Dose Administration in Japanese Patients With Type 1 Diabetes Mellitus  
NCT03407118  
 
Approved: 7-Nov-2017 


I8B-MC-ITRZ Clinical Pharmacology Protocol
Page 1
LY900014
Protocol I8B-MC-ITRZ
Pharmacokinetics and Glucodynamics of LY900014 
Compared to Insulin Lispro (Humalog) Following Single 
Dose Administration in Japanese Patients with Type 1 
Diabetes Mellitus
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 to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY900014
Eli Lilly Japan K. K.
Kobe, Hyogo, Japan
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 07-Nov-2017 GMT


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LY900014
Table of Contents
Pharmacokinetics and Glucodynamics of LY900014 
Compared to Insulin Lispro (Humalog) Following Single Dose 
Administration in Japanese Patients with Type 1 Diabetes 
Mellitus
Section
Page
Protocol I8B-MC-ITRZ Pharmacokinetics and Glucodynamics of 
LY900014 Compared to Insulin Lispro (Humalog) Following Single 
Dose Administration in Japanese Patients with Type 1 Diabetes 
Mellitus...............................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................17
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................19
5.1.
Overall Design .............................................................................................................19
5.1.1.
Inpatient Dosing Visits.........................................................................................20
5.1.2.
Outpatient Procedure............................................................................................21
5.2.
Number of Participants.................................................................................................21
5.3.
End of Study Definition ...............................................................................................21
5.4.
Scientific Rationale for Study Design...........................................................................22
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................24
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................26
6.3.
Lifestyle and/or Dietary Requirements .........................................................................26
6.3.1.
Meals and Dietary Restrictions.............................................................................26
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................27
6.3.3.
Activity................................................................................................................27
6.4.
Screen Failures.............................................................................................................27
7.
Treatment..........................................................................................................................28


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LY900014
7.1.
Treatment Administered...............................................................................................28
7.1.1.
Packaging and Labeling .......................................................................................28
7.1.2.
Medical Devices...................................................................................................28
7.2.
Method of Treatment Assignment ................................................................................29
7.2.1.
Selection and Timing of Doses.............................................................................29
7.3.
Blinding .......................................................................................................................29
7.4.
Dose Modification........................................................................................................30
7.5.
Preparation/Handling/Storage/Accountability...............................................................30
7.6.
Treatment Compliance .................................................................................................30
7.7.
Concomitant Therapy...................................................................................................30
7.8.
Treatment after the End of the Study............................................................................31
8.
Discontinuation Criteria ....................................................................................................32
8.1.
Discontinuation from Study Treatment.........................................................................32
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................32
8.2.
Discontinuation from the Study....................................................................................32
8.3.
Patients Lost to Follow-up............................................................................................32
9.
Study Assessments and Procedures ...................................................................................33
9.1.
Efficacy Assessments...................................................................................................33
9.2.
Adverse Events ............................................................................................................33
9.2.1.
Serious Adverse Events........................................................................................34
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................35
9.2.2.
Complaint Handling.............................................................................................35
9.3.
Treatment of Overdose.................................................................................................35
9.4.
Safety...........................................................................................................................35
9.4.1.
Laboratory Tests ..................................................................................................35
9.4.2.
Vital Signs ...........................................................................................................35
9.4.3.
Electrocardiograms ..............................................................................................36
9.4.4.
Physical Examination and Medical Assessment....................................................37
9.4.5.
Injection-site Local Tolerability Assessments.......................................................37
9.4.6.
Pain Measurements Using the Visual Analog Scale..............................................37
9.4.7.
Safety Monitoring ................................................................................................37
9.4.7.1.
Hepatic Safety................................................................................................38
9.4.7.2.
Glucose Monitoring........................................................................................38
9.5.
Pharmacokinetics .........................................................................................................40
9.5.1.
Bioanalysis...........................................................................................................40
9.6.
Pharmacodynamics ......................................................................................................40
9.6.1.
Glucodynamics ....................................................................................................40
9.6.1.1.
Euglycemic Clamp Procedure.........................................................................40


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LY900014
9.6.2.
Immunogenicity Assessments ..............................................................................41
9.7.
Genetics .......................................................................................................................41
9.8.
Biomarkers...................................................................................................................42
9.9.
Health Economics ........................................................................................................42
10.
Statistical Considerations and Data Analysis.....................................................................43
10.1. Sample Size Determination ..........................................................................................43
10.2. Populations for Analyses..............................................................................................43
10.2.1.
Study Participant Disposition ...............................................................................43
10.2.2.
Study Participant Characteristics ..........................................................................43
10.3. Statistical Analyses ......................................................................................................43
10.3.1.
Safety Analyses....................................................................................................44
10.3.1.1.
Clinical Evaluation of Safety..........................................................................44
10.3.1.2.
Statistical Evaluation of Safety.......................................................................44
10.3.1.2.1.
Statistical Evaluation of the Intensity of Injection-site 
Pain ..........................................................................................................44
10.3.2.
Pharmacokinetic Analyses....................................................................................45
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................45
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................45
10.3.3.
Pharmacodynamic Analyses.................................................................................46
10.3.3.1.
Glucodynamic Parameter Estimation..............................................................46
10.3.3.2.
Glucodynamic Statistical Inference.................................................................46
10.3.4.
Interim Analyses..................................................................................................46
11.
References ........................................................................................................................47


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List of Tables
Table
Page
Table ITRZ.1.
Objectives and Endpoints .......................................................................18
Table ITRZ.2.
Treatments Administered........................................................................28
Table ITRZ.3.
Treatment Sequences..............................................................................29


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List of Figures
Figure
Page
Figure ITRZ.1.
Study design...........................................................................................20


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................48
Appendix 2.
Clinical Laboratory Tests........................................................................52
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................53
Appendix 4.
Hepatic Monitoring Tests for Treatment-emergent Abnormality.............56
Appendix 5.
Blood Sampling Summary......................................................................57


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1. Protocol Synopsis
Title of Study:
Pharmacokinetics and Glucodynamics of LY900014 Compared to Insulin Lispro (Humalog) Following Single Dose 
Administration in Japanese Patients with Type 1 Diabetes Mellitus
Rationale:
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 closely 
mimic the physiological prandial insulin secretion pattern, which may more effectively control postprandial glucose 
excursions better than the currently available treatments.
The previous study with LY900014 in Japanese healthy subjects used an extemporaneous preparation.  The aim of 
this study is to compare the insulin lispro pharmacokinetic (PK) and glucodynamic (GD) profiles of the proposed 
LY900014 commercial formulation administered from prefilled pens with those of insulin lispro (Humalog) during a 
euglycemic clamp in Japanese patients with type 1 diabetes mellitus (T1DM).
Objectives/Endpoints:
Objectives
Endpoints
Primary
To compare the PK of insulin lispro following 
administration of a single 15-U SC dose of LY900014 
to insulin lispro (Humalog) in Japanese patients with 
T1DM.
Early 50% tmax and AUC(0-30min)
Secondary

To compare the GD during a euglycemic clamp 
following administration of a single 15-U SC dose 
of LY900014 or insulin lispro (Humalog) in 
Japanese patients with T1DM.

To evaluate the safety and tolerability of the 
proposed commercial formulation of LY900014.

Early 50% TRmax, Gtot(0-30min), Gtot(0-1h), and 
Tonset

AEs
Abbreviations:  AE = adverse event; AUC(0-30min) = area under the concentration versus time curve from time zero 
to 30 minutes; early 50% tmax = time to early half-maximal serum concentration; early 50% TRmax = time to 
early half-maximal glucose infusion rate before time to maximum glucose infusion rate; GD = glucodynamic; 
Gtot(0-30min) = total amount of glucose infused over 30 minutes; Gtot(0-1h) = total amount of glucose infused over 
1 hour; PK = pharmacokinetics; SC = subcutaneous; T1DM = type 1 diabetes mellitus; Tonset = time to onset of 
insulin action. 
Summary of Study Design:  
Study I8B-MC-ITRZ is a single center, randomized, patient- and investigator-blind, 2-treatment, 2-period, crossover
study in Japanese patients with T1DM.


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LY900014
Treatment Arms and Planned Duration for an Individual Patient:  
Patients will be randomized to 1 of 2 treatment sequences.  The study includes up to a 28-day screening period, 
2 treatment periods (2 days inpatient for each period) with 3 to 28 days washout between Periods 1 and 2, and a 
follow-up period at least 14 days after last dose.
LY900014:  Single 15-U subcutaneous (SC) dose 
Insulin lispro (Humalog):  Single 15-U SC dose
Number of Patients: 
Up to 40 patients may be enrolled in order that approximately 28 patients complete the study.  
Statistical Analysis:
The primary statistical analyses for PK will be conducted on patients who receive at least 1 dose of study drug and 
have measurable and evaluable insulin lispro concentrations. The primary statistical analysis for GD will be 
conducted on those patients who complete at least 1 clamp procedure and have evaluable GD parameters. 
Supportive analyses will be done on the key parameters for the patients who complete all treatment periods with 
evaluable data. Safety analyses will be conducted for all enrolled patients, whether or not they completed all 
protocol requirements.
Safety: All investigational product and protocol procedure adverse events will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology. Safety parameters that will be 
assessed include safety laboratory parameters, vital signs, and electrocardiogram parameters as well as injection-site 
reactions. The parameters will be listed and summarized using standard descriptive statistics.
Pharmacokinetics: 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 PK parameter estimates for insulin lispro will be 
calculated using standard noncompartmental methods of analysis.
Log-transformed maximum observed concentration (Cmax) and area under the concentration versus time curve
(AUC) for insulin lispro will be evaluated to estimate least-squares geometric means, ratios of geometric means 
between LY900014 and Humalog, and their corresponding 95% confidence intervals (CIs) using the mixed-effects 
model that includes treatment, sequence, and period 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 serum concentration (early 50% tmax), time to late half-maximal serum concentration (late 50% tmax),
time to maximum observed drug concentration (tmax), and half-life associated with the terminal rate constant in 
noncompartmental analysis (t1/2). Least-squares means, treatment differences in least-squares means, 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.
As plasma treprostinil concentrations after administration of LY900014 are expected to be very low, a descriptive 
statistical analysis may be conducted if sufficient data are available for this analysis. The primary analysis of the 
treprostinil concentrations will be focused on assessing tmax and Cmax.


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LY900014
Glucodynamics: The GD assessments will be determined from the euglycemic clamp procedure, where the glucose 
infusion rate (GIR) over time will be used as a measure of insulin effect. The GD analyses will be conducted on 
those patients who complete at least 1 clamp procedure.
A locally weighted scatterplot smoothing (LOESS) function will be applied to all individual GIR versus time 
profiles in each treatment group and/or period. The fitted data for each patient will be used to calculate the GD 
parameters. The values of these GD parameters will be summarized by treatment through descriptive statistics. 
Mean LOESS fits of GIR versus time profiles will be generated.
The GD statistical model will be the same as the model used for the analysis of the PK parameters. The following 
variables will be log-transformed prior to analysis:  maximum GIR (Rmax), total amount of glucose infused (Gtot), 
total amount of glucose infused over 30 minutes (Gtot[0-30min]), and total amount of glucose infused over 1 hour 
(Gtot[0-1h]).
The same model without log transformation will be used for the analysis of the GD time parameters:  time to onset 
of insulin action (Tonset), time to Rmax (TRmax), time to early half-maximal GIR before TRmax (early 50% TRmax), and
time to half-maximal GIR after TRmax (late 50% TRmax).  Least-squares means, treatment differences in least-squares 
means, and the corresponding 95% CIs for the treatment differences will be estimated from the model. The p-value 
for the difference between least-squares means will be used to determine statistical significance.  The treatment 
ratios and 95% CIs for the ratios will be calculated using Fieller’s theorem. 
The analyses described above will also be performed on the population of patients who complete and have evaluable 
GD data for both study periods.


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LY900014
2. Schedule of Activities


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LY900014
Study Schedule Protocol I8B-MC-ITRZ
Screening
Treatment Periods 1 and 2
Follow-up
/ED
Comments
Procedure
Within 28 
days prior 
to Day 1
Day -1
Day 1
Day 2
≥14 days 
after last 
dose
Informed Consent
X
The ICF will be signed after sufficient explanation by site staff and 
sufficient time to understand ICF contents. The study ICF must be 
signed before any study screening procedures are performed, but 
this does not have to be within 28 days of treatment start (Day 1). 
No window is defined; however, the patient will have to re-sign the 
study ICF in case it has been updated/revised.
Patient Admission to CRU
X
Patient Discharge from CRU
X
After completion of all study procedures, at the discretion of the 
investigator. Patients may be discharged before Day 2, but all 
procedures will be competed.
Overnight Fast
X
X
X
At least 8 hours prior to the screening visit, and at least 8 hours 
prior to each dose until the end of the euglycemic clamp on Day 1.  
Up to 20 g of carbohydrates will be allowed to prevent 
hypoglycemia.
Standardized Meal
X
X
Patients will receive short-acting insulin either via an injection or 
via a bolus dose from the insulin pump before the start of a 
standardized dinner on Day -1, 6 hours prior to dosing, and along 
with the meal given after the euglycemic clamp procedure.  If the 
clamp procedure is completed in <10 hours, then the meal should 
be delayed until the last PK sample has been taken, unless the 
investigator deems it necessary.
Run-in & Stabilization of 
Blood Glucose
X
To start approximately 1 to 6 hours prior to study drug dosing.
Randomization
X
The randomization should be performed on Day -1 after CRU 
admission in Period 1 only.
Study Drug Administration
X
Time = 0 minutes.
Height
X
Weight
X
Predose
X


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LY900014
Screening
Treatment Periods 1 and 2
Follow-up
/ED
Comments
Procedure
Within 28 
days prior 
to Day 1
Day -1
Day 1
Day 2
≥14 days 
after last 
dose
Hip & Waist Circumference
X
Triplicate measurement of hip and waist circumference will be 
required.
Physical Examination
X
X
X
X
Full physical examination at screening.  Symptom-driven physical 
examination at all other time points.  Assessments on Day 2
performed prior to discharge from CRU. If the patient is 
discharged before Day 2, assessments will be completed before 
discharge.
Alcohol Breath Test
X
X
X
Medical Assessment
X
X
X
X
X
Medical history at screening.  Medical review at other time points, 
where appropriate.  Assessments on Day 1 performed at end of 
clamp procedure.  Assessments on Day 2 performed prior to 
discharge from CRU. If the patient is discharged before Day 2, 
assessments will be completed before discharge.
Adverse Events Monitoring
X
X
X
X
X
Vital Signs (supine)
X
X
Predose, 0.5, 
2 hours
X
Collected after the patient is supine for at least 5 minutes.  Body 
temperature at screening only.  Predose vital signs may be 
collected up to 2 hours before the start of the euglycemic clamp.  
12-lead ECGs
X
Predose
(triplicate×3), 30, 
120 minutes
X
Patients must be supine for at least 5 minutes before ECG 
collection and remain supine but awake during ECG collection.  A 
single local safety ECG will be measured at screening and 
follow-up. ECGs on Day 1 will be taken in triplicate. Predose 
triplicate ECGs will be collected 3 times (total 9 ECGs) over a 
10-minute interval during the blood glucose stabilization period 
approximately 30 minutes before dosing and start of the 
euglycemic clamp.
Clinical Laboratory Tests
X
Up to 2 hours 
predose in 
Period 1 only
X
See Appendix 2, Clinical Laboratory Tests, for details.  Samples 
collected after a fast of at least 8 hours. Additional tests may be 
performed at the discretion of the investigator.
Pregnancy Test 
X
X
X
Female patients only. Serum pregnancy test at screening, and urine 
pregnancy test at all other time points.


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LY900014
Screening
Treatment Periods 1 and 2
Follow-up
/ED
Comments
Procedure
Within 28 
days prior 
to Day 1
Day -1
Day 1
Day 2
≥14 days 
after last 
dose
FSH
X
Women of non-childbearing potential only.
Urine Drug Screen
X
Injection-site Local 
Tolerability Assessments
0, 60, 240 minutes 
postdose, end of 
clamp procedure
Assessments at time 0 are immediately following dosing.
VAS Assessment of 
Injection-site Pain
0, 60, 240 minutes 
postdose, end of 
clamp procedure
Assessments at time 0 are immediately following dosing.
PK Sampling for Insulin 
Lispro
Predose (0), 5, 10, 
15, 20, 25, 30, 35, 
40, 45, 50, 55, 60, 
70, 90, 120, 150, 
180, 240, 300, 
360, 420, 480, 
540, 600 minutes
postdose  
Sampling times are relative to study drug administration time 
(0 minutes).
PK Sampling for Treprostinil
15, 30, 60, 
120 minutes 
postdose
Sampling times are relative to study drug administration time 
(0 minutes).
Euglycemic Clamp
From 0 up to 
10 hours postdose
Blood Glucose Monitoring 
(Euglycemic Clamp)
X
Every minute during the run-in and for the duration of the 
euglycemic clamp until up to 10 hours postdose.
Pharmacogenetics Sampling
X
Samples collected predose in Period 1 only.
Immunogenicity Sampling
X
X
Day 1 samples will be collected predose (up to 2 hours prior to 
dosing) for Period 1 and Period 2. Additional samples may be 
collected if the investigator considers an AE is possibly 
immunologically indicated.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FSH = follicle-stimulating hormone; ICF = informed 
consent form; PK = pharmacokinetic; VAS = visual analog scale.


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LY900014
Note:  The site should schedule activities as appropriate.  If multiple procedures take place at the same time point, the following order of priorities for the 
procedures should be used: PK sampling (including blood sampling for blood glucose, immunogenicity, and clinical laboratory tests), ECGs, vital signs, and 
injection-site local tolerability.  Electrocardiograms and vital sign measurements should be scheduled prior, but as close as possible, to PK sampling time 
points. Injection-site assessments and VAS assessments of injection-site pain can be conducted after PK sampling.  If the investigator decides based on 
clinical judgment not to dose a patient on a given day (eg, because of low blood glucose), the patient’s visit may be rescheduled; any procedures performed in 
that period may be repeated.




I8B-MC-ITRZ Clinical Pharmacology Protocol
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LY900014
insulin lispro exposure and total amount of glucose infused (Gtot) were similar for LY900014 
and Humalog; however, LY900014 demonstrated a faster and earlier insulin lispro absorption 
compared to Humalog.
Additionally, data from 2 Phase 1b studies showed that LY900014 was well tolerated in patients
with type 1 diabetes mellitus (T1DM; 60 patients) and in patients with type 2 diabetes mellitus 
(T2DM; 29 patients) receiving single doses, multiple daily injections (MDI), or continuous 
subcutaneous insulin infusion (CSII).  A further study in 24 patients with T1DM is ongoing. 
There were no serious adverse events (SAEs) related to study treatment or discontinuations from 
the studies because of a drug-related adverse event (AE).  Across both studies, the numbers of 
treatment-emergent AEs were low for both LY900014 and Humalog.
More information can be found in the Investigator’s Brochure (IB) of LY900014.
3.3.
Benefit/Risk Assessment
There is no anticipated therapeutic benefit for the patients participating in this study.
Data from studies with healthy subjects and patients with T1DM or T2DM have shown that 
LY900014 is well tolerated with an adverse drug reaction profile consistent with that of 
Humalog.
Potential risks associated with LY900014 are derived from the known risks of insulin lispro 
(Humalog®; Humalog package insert).  These potential risks include hypoglycemia, 
hypersensitivity reactions (localized allergy and/or systemic allergy), undesirable effects at the 
injection site (injection-site reactions and lipodystrophy), and peripheral oedema (Humalog 
package insert, Japan, 2016; Humalog interview form, 2017).
Notably, across all doses in the Lilly clinical studies that have evaluated treprostinil as a local 
vasodilator with or without insulin lispro, there was no clinically significant increase in those 
AEs associated with systemic absorption of treprostinil, as described for 
 
  Based on previous studies of LY900014 with a 15-U dose, the exposures
of treprostinil in this study are expected to be undetectable 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.
No additional potential risks of LY900014 or treprostinil alone were identified in preclinical 
safety pharmacology and toxicity studies, or clinical pharmacology studies.  No known potential 
risks are 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.
Following administration of the study insulin (Humalog or LY900014), patients will receive an 
IV glucose infusion at a variable rate to maintain euglycemia up to 10 hours after insulin 
administration.  The aim of the euglycemic clamp procedure is to maintain blood glucose within 
the normal glycemic range.  The euglycemic clamp is performed while the participant is 
inpatient and under the investigator’s supervision.  These considerations should minimize the 
risk of hypoglycemia in patients participating in 
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY900014 are to be found in the IB.  
CCI
CCI
CCI
CCI


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LY900014
4. Objectives and Endpoints
Table ITRZ.1 shows the objectives and endpoints of the study.
Table ITRZ.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To compare the PK of insulin lispro following 
administration of a single 15-U SC dose of LY900014 to 
insulin lispro (Humalog) in Japanese patients with 
T1DM.
Early 50% tmax and AUC(0-30min)
Secondary

To compare the GD during a euglycemic clamp 
following administration of a single 15-U SC dose of 
LY900014 or insulin lispro (Humalog) in Japanese 
patients with T1DM. 

To evaluate the safety and tolerability of the 
proposed commercial formulation of LY900014.

Early 50% TRmax, Gtot(0-30min), Gtot(0-1h), and 
Tonset

AEs
Abbreviations: AE = adverse event; AUC(0-30min) = area under the concentration versus time curve from time zero to 
30 minutes; early 50% tmax = time to early half-maximal serum concentration; early 50% TRmax = time to early 
half-maximal glucose infusion rate before time to maximum glucose infusion rate; GD = glucodynamic;
Gtot(0-1h) = total amount of glucose infused over 1 hour; Gtot(0-30min) = total amount of glucose infused over 
30 minutes; PK = pharmacokinetics; SC = subcutaneous; T1DM = type 1 diabetes mellitus; Tonset = time to onset 
of insulin action.  


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LY900014
5. Study Design
5.1.
Overall Design
This is a Phase 1, single center, randomized, patient- and investigator-blind, 2-treatment, 
2-period, crossover study to evaluate the PK and GD of insulin lispro following a single 15-U SC 
administration of LY900014 compared to insulin lispro (Humalog) in Japanese patients with 
T1DM.
Patients will be randomized to 1 of 2 treatment sequences according to the actual randomization 
table provided to the site (Section 7.2; Table ITRZ.3).  Each patient will participate in a 
screening visit (may occur up to 28 days prior to dosing), 2 inpatient dosing visits, and a 
follow-up visit (at least 14 days from last dose).  Before each dose, a run-in period of 
approximately 1 to 6 hours to stabilize blood glucose will occur.  Dosing visits will be separated 
by a washout period of 3 to 28 days, during which patients will resume their normal insulin 
treatment with the exemption of the insulin switch 48 to 72 hours prior to dosing as mentioned 
below.  At each treatment period, patients will receive either LY900014 or insulin lispro
(Humalog) and undergo a euglycemic clamp procedure where the time-concentration and 
time-action profiles of the study treatment will be evaluated simultaneously for up to 10 hours 
using an automated clamp device.  Briefly, the aim of the euglycemic clamp is to maintain 
euglycemia after the administration of a dose of insulin by means of variable glucose infusion.  
The variable glucose infusion maintains or “clamps” glucose at a constant euglycemic target; 
therefore, the glucose infusion rate (GIR) reflects the GD effect of the insulin.  
Figure ITRZ.1 illustrates the study design.
Prior to each dosing visit, patients with T1DM on MDI have to discontinue their basal insulin, 
according to the following guidance:

For patients using insulin degludec or insulin glargine U300, the last injection of insulin 
degludec or insulin glargine U300 should occur no later than 72 hours prior to dosing.

For patients using insulin detemir or glargine, the last injection of insulin detemir or 
glargine should occur no later than 48 hours prior to dosing.

For patients using neutral protamine Hagedorn (NPH) insulin or other intermediate-acting 
insulin, the last injection of NPH insulin or other intermediate-acting insulin should occur 
no later than 24 hours prior to dosing.
Patients requiring any infusion via CSII of insulin lispro (Humalog) will switch to insulin 
glulisine (
) at least 8 hours prior to dosing. Basal infusion rate via CSII should occur no 
later than 3 hours prior to dosing. Any injection or bolus infusion via CSII of more than 6 U of 
short-acting insulin should not occur between 11 and 6 hours prior to dosing. Any bolus 
injection or bolus infusion via CSII should occur no later than 6 hours prior to dosing.
Study governance considerations are described in detail in Appendix 3.
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carbohydrates are needed to prevent hypoglycemia less than 24 hours prior to dosing, the dosing 
visit can be rescheduled 1 to 7 days later.  Each of the dosing visits can only be rescheduled 
once.
Prior to study treatment dosing, the patient will be connected to the clamp device for continuous 
glucose monitoring and the start of the baseline run-in period.  Variable IV infusion of either 
glucose (10% to 20% dextrose solution) or insulin glulisine 
 will be started to reach a 
target blood glucose level of 100 mg/dL (Section 9.6.1).  Once the target blood glucose level is 
attained and remains stable, with the predose activities as specified in the Schedule of Activities 
(Section 2) completed, the patient will receive a dose and undergo the clamp procedure.  Serial 
blood samples will be collected during the 10-hour glucose clamp at times specified in the Study 
Schedule (Section 2) to assess the GD and the insulin lispro PK following study drug 
administration.  More information on the clamp methodology can be found in Section 9.6.
On completion of the euglycemic clamp, patients will be provided with a meal along with their 
prandial insulin treatment.  A physician’s medical assessment will be required before patients are 
discharged from the CRU.  
Safety assessments and an evaluation of local tolerability at injection sites will be performed as 
specified in the Study Schedule (Section 2).  
There are no outpatient visits planned in the washout period.
5.1.2. Outpatient Procedure
After completing each period, patients will resume their previous insulin regimen.  The 
investigator will provide instructions for transition back to a normal insulin regimen.  
Patients will return for the second dosing period within a 3- to 28-day interval, during which they 
will have to perform at least 4-point daily self-monitoring plasma glucose (SMPG).  The basal 
insulin will have to be discontinued as described above in Section 5.1.
After completing all study treatment dosing and clamp procedures, patients will resume their 
former insulin regimen and SMPG routine.  A CRU visit for follow-up or early discontinuation 
should occur at least 14 days after the last dose of study drug.
5.2.
Number of Participants
Up to 40 patients may be enrolled in order that approximately 28 patients complete the study.  If 
patients drop out of the study before completion of both treatment periods with evaluable 
primary outcome data, replacement patients may be enrolled; the replacement patients will 
assume the same treatment sequence as the patients who dropped out and will complete that 
treatment sequence in its entirety.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
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5.4.
Scientific Rationale for Study Design
The use of a crossover design allows each patient to serve as his or her own control, thereby 
reducing variability.  The study is patient- and investigator-blind to minimize potential bias.
A euglycemic clamp technique, the gold-standard methodology for assessing insulin action, will 
be used in this study to provide data on the GD activity of each study insulin lispro formulation
(see Section 9.6.1 for a detailed description of the clamp methodology).
A population of Japanese patients with T1DM will provide PK and GD profiles for potential 
comparison to 
results for non-Japanese, young adult patients 
with T1DM.
Based on the PK properties of treprostinil (half-life associated with the terminal rate constant in 
noncompartmental analysis [t1/2] = approximately 1 hour) and Humalog (t1/2 = approximately
0.92 hours), the duration of the washout period between clamp visits (a minimum of 3 days) and 
the duration between the last dose of study drug and the follow-up visit (at least 14 days) are 
considered appropriate.
5.5.
Justification for Dose
Based on previous studies of both insulin lispro (Humalog) and LY900014, the 15-U dose is 
within the clinical dose range and should provide measurable PK and GD profiles for both study 
insulins.  The safety, PK, and pharmacology of LY900014 at similar doses and with similar 
formulation composition have been assessed in 3 clinical studies in healthy subjects 
in patients with T1DM (
 
and in patients with T2DM
  In patients with T1DM, the weight-based 
total daily insulin dose for a large majority of patients is 0.4 to 0.8 U/kg/day, of which 
approximately 50% is delivered as the basal insulin dose and the other 50% is divided among 
preprandial insulin doses (Herbst and Hirsch 2002; Heller et al. 2009).  Therefore, a reasonably 
high estimate for total daily preprandial insulin dose in patients with T1DM is 0.4 U/kg/day.  For 
the ongoing 
 in non-Japanese patients with T1DM, it was estimated that the lowest 
body weight would be around 56 kg.  Thus, the 15-U dose of LY900014 was selected in 
 
to deliver approximately a 0.26-U/kg dose, which would not exceed this high estimate for 
the total daily preprandial insulin dose.  
The same 15-U dose of LY900014 is selected in this study to allow for the potential comparison 
of PK and GD with that of Study ITRR.  The expected lowest body weight for this study will be
40 kg (0.375 U/kg) and would not exceed the high estimate for total daily preprandial insulin 
dose in T1DM.
A 15-U dose of LY900014 contains 
 of treprostinil in a single SC dose, which is within 
the range evaluated as safe and tolerated in all previous studies.  The PK of treprostinil in 
LY900014 following SC administration of 15 U of LY900014 was assessed previously in 
  In these studies, treprostinil exposure was not detectable for the 
15-U dose of LY900014 (
).  Based on these results, 
treprostinil blood concentrations in this study are expected to be 
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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 enrollment.  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 enrollment criteria, also known as 
protocol waivers or exemptions, are 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 enrollment:
[1]
are Japanese male or female patients with a diagnosis of T1DM, based on the
World Health Organization classification, for at least 1 year prior to screening
[1a] male patients:
agree to use an effective method of contraception for the duration of the 
study and for 1 month following the last dose of the investigational product
[1b] female patients:  
women of childbearing potential may participate and include those who test 
negative for pregnancy before initiation of treatment based on a serum 
pregnancy test and agree to use 1 highly effective method of contraception 
or a combination of 2 effective methods of contraception during the study 
and for 1 month following the last dose of the investigational product.
women not of childbearing potential may participate in the study without 
using adequate contraceptive methods if they are:
o
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
mullerian agenesis; 
o
or postmenopausal, defined as women aged <52 years and being 
amenorrheic for more than 1 year with a serum follicle-stimulating 
hormone (FSH) level compatible with postmenopausal status, aged 
≥52 years and being amenorrheic for less than 1 year and with a serum 
FSH level compatible with postmenopausal status, or aged ≥52 years 
being amenorrheic for more than 1 year
[2] are aged at least 18 years at the time of screening


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[3]
have a body mass index (BMI) of 18.5 to 30.0 kg/m2
[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator
[5]
have venous access sufficient to allow for glucose infusion and blood 
sampling as per the protocol
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[7]
have a glycated hemoglobin <9.0% at screening
[8]
have had no episodes of severe hypoglycemia in the last 6 months
[9]
are able and willing to give signed informed consent approved by Lilly and 
the ethical review board (ERB) governing the site
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[10] are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling
[11] are Lilly employees or employees of the investigative site
[12] 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  
[13] have participated within the last 30 days in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed
[14] have previously completed or withdrawn from this study or any other study 
investigating LY900014, and have previously received the investigational 
product 
[15] have known allergies to insulin lispro, treprostinil, insulin glulisine, related 
compounds or any components of the formulation, or history of significant 
atopy
[16] have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study  
[17] have supine systolic blood pressure at screening higher than 160 mmHg or 
have a heart rate higher than 90 beats/minute.  Patients with minor deviations 
from these ranges may be included as judged by the investigator


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[18] have a significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine (other than T1DM), hematological, or 
neurological disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; of constituting a risk when taking the 
investigational product; or of interfering with the interpretation of data
[19] have known or ongoing psychiatric disorders
[20] regularly use known drugs of abuse and/or show positive findings on drug 
screening
[21] show evidence of an acute infection with fever or infectious disease at the 
time of study entry
[22] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antigen and antibodies
[23] show evidence of hepatitis C and/or positive hepatitis C antibody (the 
presence of hepatitis C antibodies in the setting of normal liver function tests 
and a negative hepatitis C polymerase chain reaction are not an exclusion)
[24] show evidence of hepatitis B and/or positive hepatitis B surface antigen (the 
presence of antibodies to the hepatitis B surface antigen is not an exclusion)
[25] show evidence of syphilis and/or are positive for syphilis test
[26] are women who are pregnant or lactating
[27] have significant lipohypertrophy in the target abdominal injection area as 
judged by the investigator
[28] have, except for current regimen of insulin therapy and concomitant 
medication(s) (for example, 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 hyperglycemia or insulin resistance or that promote weight loss within 
14 days before dosing
[29] are unwilling to refrain from smoking while resident at the CRU
[30] are receiving chronic (lasting longer than 14 consecutive days) systemic or 
inhaled glucocorticoid therapy (excluding topical, intra-articular, and 
intraocular preparations), or have received such therapy within the 4 weeks 
before screening
[31] have donated 400 mL or more blood in the last 12 weeks (males) or in the last 
16 weeks (females), any blood donation (including apheresis) within the last 
4 weeks, or total volume of blood donation within 12 months of 1200 mL 
(males)/800 mL (females) or more at screening


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[32] have a significant history of alcoholism or drug abuse as judged by the 
investigator or consuming more than 24 g of alcohol per day for men, or more 
than 12 g of alcohol per day for women
[33] are unwilling to comply with the dietary and fasting requirements/restrictions 
during the study, or are unwilling to consume only the meals/snacks provided 
while resident at the CRU
[34] have a history of renal impairment (exclusion only if estimated glomerular 
filtration rate [GFR] <60 mL/minute/1.73 m2 [GFR is estimated according to
a formula recommended by the Japanese Society of Nephrology]), or have a 
serum creatinine level ≥126 µmol/L (>1.42 mg/dL) (male) or ≥111 µmol/L 
(>1.25 mg/dL) (female)
[35] have a history of deep vein thrombosis of the leg, or repeated episodes of deep 
leg vein thrombosis in first-degree relatives (parents, siblings, or children), as 
determined by the investigator
[36] have proliferative retinopathy or maculopathy and/or severe neuropathy; in 
particular, autonomic neuropathy, as determined by the investigator based on 
a recent (<1.5 years) ophthalmologic examination
[37] have had any significant changes in insulin regimen and/or unstable blood 
glucose control within the past 3 months prior to screening, as determined by 
the investigator
[38] require daily insulin treatment >1.5 U/kg
[39] have had lymphoma, leukemia, or any malignancy within the past 5 years, 
except for basal cell or squamous epithelial carcinomas of the skin that have 
been resected with no evidence of metastatic disease for 3 years
[40] have had breast cancer within the past 10 years
[41] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.2.1. Rationale for Exclusion of Certain Study Candidates
Criteria [10] and [11] prevent conflict of interest in study participants.  Criteria [12] through [41] 
exclude medical conditions, medication intolerance, and concomitant medication use that may 
constitute a risk for the patient and/or may confound the assessment of study endpoints.
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. Meals and Dietary Restrictions
Patients will receive a standardized dinner on Day -1, and will be fasted (except for water and 
barley tea) for at least 8 hours prior to collection of clinical laboratory samples, for at least 


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8 hours prior to dosing, and during the euglycemic clamp procedure, according to the Schedule 
of Activities (Section 2).  Up to 20 g of carbohydrates will be allowed to prevent hypoglycemia, 
prior to the start of the euglycemic clamp.  Water or barley tea can be consumed freely during 
this time.  Patients will be given a meal after the euglycemic clamp procedure is completed.  If 
the clamp procedure is completed in less than 10 hours, then the meal should be delayed until the 
last PK sample has been taken, unless the investigator deems it necessary to administer the meal 
for safety reasons.
While resident in the CRU, patients may not consume any food or caloric drinks other than that 
provided by the CRU.  When not resident in the CRU, patients will be encouraged to follow their 
normal diets.  
6.3.2. Caffeine, Alcohol, and Tobacco
Patients should refrain from consuming caffeine-containing food/beverages (eg, cola, chocolate 
drinks, tea, and coffee) for at least 12 hours prior to each dose and while resident at the CRU.  
No alcohol will be allowed from at least 24 hours before and throughout the duration of each 
CRU visit.  Between CRU visits, daily alcohol should not exceed 24 g for males and 12 g for 
females.  
Smoking (cigars, cigarettes, electronic cigarettes, or pipes) and the use of smokeless tobacco will 
not be permitted while patients are resident at the CRU.  
6.3.3. Activity
Patients will be encouraged to maintain their regular exercise; however, they should not 
undertake vigorous or prolonged exercise at least 48 hours prior to each dosing day.  Should this 
occur, these patients will have their dosing visits deferred or may be excluded from this study, as 
judged by the investigator, to prevent interference with study results.
After dosing, patients should remain in the CRU either recumbent or sitting until the end of the 
glucose clamp.  Movement will be restricted to retain the integrity of connections to the glucose 
clamp and the study procedures.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once.  The interval between rescreenings should be at least 2 weeks.  If rescreening is 
performed, the individual must sign a new informed consent form (ICF) and will be assigned a 
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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of LY900014 administered once by SC injection with
Humalog administered once by SC injection.  Table ITRZ.2 shows the treatment regimens.
Table ITRZ.2.
Treatments Administered
Treatment Name
LY900014
Humalog
Dosage Formulation
100 U/mL
100 U/mL
Dose Level
15 U
15 U
Treprostinil Concentration and Approximate 
Treprostinil Dose Administered
NA
Route of Administration
Subcutaneous injection
Subcutaneous injection
The investigator or designee is responsible for:

explaining the correct use of the investigational products to site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials. 
7.1.1. Packaging and Labeling
The investigational product will be labeled according to the country’s regulatory requirements.
Study insulins (LY900014 and insulin lispro [Humalog]) will be supplied by Lilly or its 
representative, in accordance with current good manufacturing practices, and will be supplied 
with clinical trial lot numbers. Instruction for Use for the prefilled devices will be provided. 
The prefilled pens will contain a concentration of 100 U/mL in 3-mL cartridges of either 
LY900014 or insulin lispro (Humalog).
An unblinded pharmacist at the site or other site personnel who are unblinded will prepare to 
blind the prefilled pen before the treatment administration.
7.1.2. Medical Devices
The medical devices provided for use in the study are prefilled pens. LY900014 prefilled pens
are new investigational combination products.
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7.2.
Method of Treatment Assignment
Patients will be randomized to 1 of 2 treatment sequences indicated in Table ITRZ.3.
Table ITRZ.3.
Treatment Sequences
Treatment Sequence
Treatment Period 1
Treatment Period 2
1
15 U LY900014
15 U Humalog
2
15 U Humalog
15 U LY900014
7.2.1. Selection and Timing of Doses
The actual date and time of all dose preparations will be documented, and the actual time of all 
dose administrations will be recorded in the patient’s electronic case report form (eCRF).  For 
each patient, the doses will be administered at approximately the same time on Day 1 of each 
treatment period. 
All study treatments will be given in the CRU by qualified CRU personnel as designated by the 
investigator.  Injections should be given by a limited number of individuals for consistency.
Injection sites selected should be about 5 cm from the umbilicus and should be recorded in the 
patient’s eCRF.  Injections will be rotated among different injection sites on the anterior 
abdominal wall during both treatment periods (ie, left lower quadrant and right lower quadrant).  
7.3.
Blinding
This is a patient- and investigator-blind study.  The Lilly clinical pharmacologist (CP)/Lilly 
study team is unblinded. Blinding will be maintained throughout the conduct of the study as 
described in the separate Blinding Plan.
LY900014 and Humalog will be provided to the CRU in an unblinded manner.  An unblinded 
pharmacist (or designee) will prepare blinded prefilled pens for study drug administration from 
the LY900014 and Humalog.  The patients, investigators, and CRU staff other than the 
unblinded pharmacist (or designee) will be blinded to the treatment administered.
Emergency codes will be available to the investigator.  A code, which reveals the treatment 
group for a specific study patient, may be opened during the study only if the patient’s wellbeing 
requires knowledge of the patient’s treatment assignment.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient’s safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.


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7.4.
Dose Modification
Dose modifications are not allowed in this study.
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 investigational product
received and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product. All 
investigational product should be stored in an environmentally-controlled and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
Patients on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study.  Patients receiving multiple daily insulin 
injections will discontinue their basal and prandial insulin regimens as described in Section 5.1
prior to receiving study treatment.  Similarly, the patient’s insulin regimen should resume in 
between dosing periods and should be discontinued prior to the next period following the 
guidance in Section 5.1.
Patients should not use over-the-counter or prescription medications (other than their current 
regimen of insulin therapy and concomitant medication[s] [for example, antihypertensive 
medication, lipid-lowering agent, thyroid hormone replacement medication, hormonal 
contraception, hormonal replacement therapy]) or nutritional supplements that affect blood 
glucose or the body’s sensitivity to insulin or that promote weight loss 14 days before dosing 
(apart from vitamin/mineral supplements, occasional acetaminophen [paracetamol], ibuprofen, or 
hormonal replacement therapy) or throughout the study (refer to Section 6.2).
Patients should not be receiving chronic (lasting longer than 14 consecutive days), systemic, or 
inhaled glucocorticoid therapy (excluding topical, intra-articular, and intraocular preparations), 
or have received such therapy within the 4 weeks before screening.
Patients should not apply any creams or lotions to the abdominal skin on the morning of the 
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If the need for concomitant medication arises, inclusion or continuation of the patient may be at 
the discretion of the investigator and, when possible, after consultation with a Lilly CP.  Any 
additional medication used during the course of the study must be documented.
Any changes in concomitant medications from screening will be recorded upon admission to the 
CRU.
7.8.
Treatment after the End of the Study
Insulin lispro (Humalog) and LY900014 will not be made available from the sponsor to patients 
after conclusion of the study.  Patients will resume their previous insulin regimen after the study 
procedure has been completed or after discontinuation/early termination from the study.


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8. Discontinuation Criteria
Patients discontinuing from the study prematurely for any reason must complete early 
discontinuation procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Patients who discontinue the investigational product early will have procedures performed as 
shown in the Schedule of Activities (Section 2).
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/ clinical research physician
(CRP) and the investigator to determine if the patient may continue in the study.  If both agree it 
is medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly CP/CRP to allow the inadvertently enrolled patient to continue in the study with or without 
continued treatment with investigational product.  
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study.

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice.

the investigator decides that the patient should be discontinued from the study.

the patient requests to be withdrawn from the study.

participation in the study needs to be stopped for safety reasons in the case of a severe 
hypoglycemic episode.
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.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing.
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in 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
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
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 ICF is signed, study site personnel will record, via eCRF, the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  Additionally, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the investigational product, study device, and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above

when a condition related to the investigational device necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or permanent 
damage to a body structure, the serious outcome of “required intervention” will be 
assigned
Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
Additionally, study site personnel must alert Lilly Global 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-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the
sponsor begins after the patient has signed informed consent and has received investigational 
product.  However, if an SAE occurs after signing informed consent, but prior to receiving 
investigational product, 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 patients once they have 
discontinued from and/or completed the study (the patient summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.


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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 reports as related to investigational product or 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 investigational products 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 investigational product or 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 through randomization.
Excess insulin administration may cause hypoglycemia and hypokalemia.  Mild episodes of 
hypoglycemia can usually 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 hypoglycemia may recur after apparent clinical recovery.  Hypokalemia must be 
corrected appropriately.
Refer to the IB for LY900014 and/or Product Label for Humalog.
9.4.
Safety
9.4.1. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
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 analyzed by a central 
vendor, if a central vendor is used for the study.
9.4.2. Vital Signs
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).  At each time point, vital signs should be collected prior to any blood 
samples. Blood pressure and pulse rate should be measured after at least 5 minutes supine.
Additional vital signs may be measured during each study period if warranted.


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9.4.3. Electrocardiograms
For each patient, 12-lead digital ECGs should be collected according to the Schedule of 
Activities (Section 2).  Any clinically significant findings from ECGs that result in a diagnosis 
and that occur after the patient receives the first dose of the investigational product should be 
reported to Lilly or its designee as an AE via eCRF.
For each patient, a single 12-lead digital ECG will be collected locally at screening and follow-
up or early termination visit according to the Schedule of Activities (Section 2).  
Electrocardiograms on Day 1 will be taken in triplicate consecutively at approximately 1-minute 
interval at predose (baseline), 30, and 120 minutes postdose.  The predose triplicate ECGs will
be collected 3 times over a 10-minute interval (total 9 ECGs) during the blood glucose 
stabilization period approximately 30 minutes before administration of LY900014 or Humalog
and start of the euglycemic clamp.  
Electrocardiograms must be recorded before collecting any blood samples.  Patients must be 
supine for at least 5 minutes before ECG collection and remain supine but awake during ECG 
collection.  Electrocardiograms may be obtained at additional times, when deemed clinically 
necessary.  Collection of more ECGs (more replicates) than expected at a particular time point is 
allowed to ensure high-quality records. 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 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/QTc 
interval from baseline) after enrollment, 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 document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
AE.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) and then store the ECGs in a database.  At a future time, the 
stored ECG data may be overread at the central ECG laboratory for further evaluation of 
machine-read measurements or to meet regulatory requirements.  
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted before completion of the final 
study report (in which case, the overread data would be used).


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9.4.4. Physical Examination and Medical Assessment
Physical examinations and routine medical assessments will be conducted as specified in the 
Schedule of Activities and as clinically indicated (Section 2).  
9.4.5. Injection-site Local Tolerability Assessments
Injection-site assessments will be performed according to the Schedule of Activities (Section 2) 
and as clinically indicated.  Additional assessments will be performed until resolution, as judged 
necessary by the investigator.
Local tolerability at the injection site will be evaluated by means of assessments within the 
following categories:  pain (including burning), itching, erythema, edema, and 
induration/infiltration.
Digital pictures may be taken of the injection site at the time of identification of local 
intolerability and thereafter, as judged necessary by the investigator. The pictures should include 
patient number, visit number, time after injection, and a ruler for scaling.
An injection-site reaction should be recorded as either an AE or an SAE according to respective 
definitions/criteria. 
9.4.6.
Pain Measurements Using the Visual Analog Scale
Pain measurements will be assessed using the 100-mm validated visual analog scale (VAS) for 
pain. The VAS is a well-validated tool (Williamson and Hoggart 2005) to assess injection-site 
pain. 
The VAS (van Duinen et al. 2008) is presented as a 10-cm (100-mm) line, anchored by verbal 
descriptors, usually “no pain” and “worst imaginable pain.” The patient will be asked to mark the 
100-mm line to indicate pain intensity associated with each injection on a scale of 0 (no pain) to 
100 mm (worst imaginable pain) according to the Schedule of Activities (Section 2) and as 
clinically indicated. 
As injection-site pain is an expected AE, injection-site pain (especially transient episodes of 
pain) will generally not be considered a clinically significant event unless the duration or 
intensity of the pain interferes with normal activities of daily living or constitutes a risk to the 
wellbeing of the patient. Analgesia can be prescribed in response to pain and must be 
documented in the concomitant medication section of the eCRF. 
9.4.7. Safety Monitoring
The Lilly CP or CRP/clinical research scientist will monitor safety data throughout the course of 
the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes


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
AEs
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.7.1.
Hepatic Safety
If a study patient experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, aspartate 
aminotransferase, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase 
to confirm the abnormality and to determine if it is increasing or decreasing.  If the abnormality 
persists or worsens, clinical and laboratory monitoring should be initiated by the investigator 
based on consultation with the Lilly CP or CRP.  Monitoring should continue until levels 
normalize and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur:

elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests 

patient discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be an SAE.
9.4.7.2.
Glucose Monitoring
Hypoglycemia will be described using the following definitions:
Documented Glucose Alert Level (Level 1)
Plasma glucose ≤70 mg/dL (3.9 mmol/L)

Documented symptomatic hypoglycemia:  with typical symptoms of hypoglycemia.

Documented asymptomatic hypoglycemia:  without typical symptoms of hypoglycemia.

Documented unspecified hypoglycemia:  with no information about symptoms of 
hypoglycemia available.  (This has also been called unclassifiable hypoglycemia.)
Documented Clinically Significant Hypoglycemia (Level 2)
Similar criterion as for Level 1, except for threshold PG <54 mg/dL (3.0 mmol/L)

Level 2 documented symptomatic hypoglycemia

Level 2 documented asymptomatic hypoglycemia

Level 2 documented unspecified hypoglycemia


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Severe Hypoglycemia (Level 3)
Patient had altered mental status and could not assist in their own care, was semiconscious or 
unconscious, or experienced coma with or without seizures, and the assistance of another person 
was to actively administer carbohydrate, glucagon, or other resuscitative actions.  Plasma 
glucose measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of PG 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]).  
Other Hypoglycemia

Nocturnal hypoglycemia:  Any documented hypoglycemic event (including severe 
hypoglycemia) that occurs at night and presumably during sleep.  This is captured as 
hypoglycemia that occurs between bedtime and waking.  This definition is more useful 
than the commonly used approximately 00:00 to 06:00 definition which does not take 
patients’ individual sleep times into consideration, and is consistent with the American 
Diabetes Association recommendations of reporting events that occur during sleep
(ADA 2005).  It is also important to collect the actual time when a hypoglycemic event 
occurred to allow further characterization of hypoglycemia timing (eg, to allow analysis 
of frequency of events occurring across a 24-hour clock).  Nocturnal hypoglycemia may 
occur at severity Levels 1, 2, or 3.

Relative hypoglycemia (also referred to as pseudohypoglycemia [Seaquist et al. 2013]):  
An event during which typical symptoms of hypoglycemia occur, that does not require 
the assistance of another person and is accompanied by PG >70 mg/dL (3.9 mmol/L).  
The PG value of patients with chronically poor glycemic control can decrease so rapidly 
that patients may report symptoms of hypoglycemia before their PG concentration falls 
below 70 mg/dL (3.9 mmol/L).  Events with PG ≤70 mg/dL should not be categorized as 
relative hypoglycemia.  Evaluation and statistical analysis of this category is optional.  
However, if a patient reports a relative hypoglycemia event where assistance from 
another person was received or the patient experienced significant symptoms, the study 
team should clarify the circumstances to ensure the event is not a severe hypoglycemia 
event, and report it appropriately.  

Probable symptomatic hypoglycemia:  Symptoms of hypoglycemia were present, but PG 
measurement was not reported.

Overall (or total) hypoglycemia:  This optional category combines most cases of 
hypoglycemia (documented hypoglycemia and probable symptomatic hypoglycemia, 
including severe hypoglycemia).  It does not include relative hypoglycemia.  Nocturnal 
and severe hypoglycemia are special cases of documented or probable hypoglycemia.  If 
an event of hypoglycemia falls into multiple subcategories, that event should only be 
counted once in the category of overall (or total) hypoglycemia.
Only severe hypoglycemic episodes will be reported separately as AEs.  All episodes of severe 
hypoglycemia will be reported as SAEs.


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The goal of the euglycemic clamp is to maintain blood glucose concentrations at euglycemic
levels close to a predefined target.  Therefore, glucose concentrations below 70 mg/dL will not 
routinely be recorded as hypoglycemic events during the glucose clamp procedure.  However, at 
the discretion of the investigator, a decrease in glucose concentration may be recorded as a 
hypoglycemic event based on clinical concern or related to technical issues resulting in 
hypoglycemia.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 2.5 mL each will be collected to determine the serum concentrations of insulin 
lispro and samples of approximately 2.0 mL each will be collected to determine plasma 
concentrations of treprostinil.  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
Serum concentrations of insulin lispro will be measured using a validated 
 
 specific for insulin lispro at a laboratory approved by the sponsor.  Plasma 
concentrations of treprostinil will be measured using a 
 
 at a laboratory approved by the sponsor.  
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last patient visit for the study.  During this time, 
plasma and serum remaining may be used for other exploratory analyses on insulin lispro or 
treprostinil.
9.6.
Pharmacodynamics
9.6.1. Glucodynamics
The aim of the euglycemic clamp is to maintain euglycemic through infusion of a 10% to 20% 
glucose solution after the administration of a dose of insulin.  During the euglycemic clamp, the 
GIR will be adjusted to maintain a predetermined target blood glucose concentration for the 
individual patients.  Thus, blood glucose concentrations are kept constant while the GIR varies, 
and the varying GIR will reflect the GD activity of insulin.
9.6.1.1.
Euglycemic Clamp Procedure
Patients will participate in 2 euglycemic clamps across 2 treatment periods.  After at least 
8 hours overnight fast, the euglycemic clamp procedure will be performed for approximately 
10 hours following administration of a dose of insulin lispro according to the Schedule of 
Assessments (Section 2) and as described in Section 5.1.  
Approximately 1 to 6 hours before the planned administration of study drug, patients will be 
connected to the clamp device
for continuous blood glucose 
monitoring and receive a variable IV infusion of either insulin glulisine or glucose to obtain a 
CCI
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steady blood glucose clamp target of 100 mg/dL (±20%) (5.5 [±1.1] mmol/L).  The target blood 
glucose level of 100 mg/dL (5.5 mmol/L) ±20% (upper and lower limits included) must be kept 
at -60 to -30 minutes before trial product administration, followed by the target blood glucose 
level of 100 mg/dL (5.5 mmol/L) ±10% (upper and lower limits included) within the last 
30 minutes prior to trial product administration without any glucose infusion.  The IV insulin 
glulisine infusion (if any) is lowered as much as possible to keep the blood glucose 
concentrations at the target without having to infuse glucose.  The insulin glulisine infusion is 
tapered off and should be stopped 10 minutes 
 
minutes before trial product administration as 
measured by 
, and the onset of study insulin action occurs when blood glucose drops to 
5 mg/dL (0.3 mmol/L) from baseline.  If there are no stable blood glucose measurements with 
 in the last minutes before intended dosing, dosing should be postponed and the run-in 
period will be prolonged.  If the target blood glucose level cannot be established before 14:00, 
the visit will be terminated and the patient may be rescheduled for a new dosing visit 1 to 7 days 
later.  After the onset of action has been reached, a variable IV glucose infusion will be initiated 
in order to keep blood glucose constant at the target level.  The GIR necessary to keep the blood 
glucose concentration at the target level will be recorded using a validated data capture system at 
the CRU.  
The clamp procedure will continue for up to 10 hours after dose or until after blood glucose 
concentrations increased to >200 mg/dL (11.1 mmol/L) without any glucose being administered 
for at least 30 minutes, whichever is earlier.
At the end of the clamp procedure, the patient will receive a medical assessment and be given a 
meal along with their prandial insulin treatment.  Their basal insulin regimen may be restarted 
accordingly, albeit subjected to the stopping guidance as described in Section 5.1, prior to the 
next dosing visit, if applicable.
9.6.2. Immunogenicity Assessments
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro as described in the Schedule of Activities (Section 2).  Additional samples 
may be collected if there is a possibility that an AE is immunologically mediated.  
Immunogenicity will be assessed by a validated assay designed to detect antidrug antibodies in 
the presence of insulin lispro.
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
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
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Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
LY900014 and to investigate genetic variants thought to play a role in diabetes mellitus.  
Assessment of variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of LY900014 or after LY900014 is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 
9.8.
Biomarkers
This section is 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
Up to 40 patients will be randomized in order that approximately 28 patients complete the study.
Twenty-eight completing patients will provide approximately 92% power to demonstrate a 40% 
increase in the insulin lispro area under the concentration versus time curve (AUC) from time 
zero to 30 minutes (AUC[0-30min]) between LY900014 and Humalog. Testing will be done at an 
alpha level of 0.05 with a 2-sided confidence interval (CI). The variability was estimated by 
analyzing a Lilly internal study that showed a log-scale standard deviation of within-patient
difference in AUC(0-30min) of 0.5. Analysis of internal data showed a log-scale standard deviation 
of within-patient difference in time to early half-maximal serum concentration (early 50% tmax) 
of 0.5, which provides approximately 95% power to show a 30% reduction in early 50% tmax, 
testing with an alpha level of 0.05 and a 2-sided CI.
In addition, the study is adequately powered to evaluate the GD parameters. There is 
approximately 71% power to detect a 20% decrease in both time to onset of insulin action (Tonset) 
and time to early half-maximal GIR before time to maximum glucose infusion rate (TRmax)
(early 50% TRmax), and approximately 81% power to detect at least a 40% increase in total 
amount of glucose infused over 30 minutes (Gtot[0-30min]) and total amount of glucose infused 
over 1 hour (Gtot[0-1h]). In estimations, the log-scale standard deviation of within-patient
difference was used with 0.45 for Tonset and early 50% TRmax, and 0.6 for Gtot(0-30min) and 
Gtot(0-1h).
Patients who discontinue from the study prior to completion of both treatment periods with 
evaluable primary outcome data can be replaced to ensure that enough patients may complete the 
study.  The replacement patient will adopt the original patient’s randomized treatment sequence.
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, weight, BMI, waist and hip circumference, height, race/subrace, and other 
demographic characteristics will be summarized. 
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
The primary statistical analyses for PK will be conducted on those patients who receive at least 
1 dose of study drug and have measurable and evaluable insulin lispro concentrations. The 
primary statistical analysis for GD will be conducted on those patients who complete at least 
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Supportive analyses will be done on the key parameters for the patients who complete all 
treatment periods with evaluable data. Safety analyses will be conducted for all enrolled 
patients, whether or not they complete all protocol requirements.
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.
Summary statistics (including number of patients, mean, standard deviation or standard error, 
minimum, and maximum) will be presented for continuous variables. A linear mixed-effect 
model will be used for continuous variables unless otherwise stated in the below subsections. 
The primary comparison between LY900014 and insulin lispro (Humalog) will be performed 
using the model that includes treatment, sequence, and period as fixed effects, and patient within 
sequence as a random effect. 
Additional exploratory analyses of the data will be conducted as deemed appropriate.  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.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association
with investigational product as perceived by the investigator.  Symptoms reported to occur prior 
to enrollment will be distinguished from those reported as new or increased in severity during the 
study.  Each symptom will be classified by the most suitable term from the medical regulatory 
dictionary.
The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters.  The parameters will be listed and summarized using standard descriptive 
statistics.  Additional analysis will be performed if warranted upon review of the data.
10.3.1.2.1.Statistical Evaluation of the Intensity of Injection-site Pain
The primary study assessment will be the intensity of pain at each injection site immediately 
after the injection (time 0) as reported by the patient and measured according to the 0- to 
100-mm VAS. A Wilcoxon signed rank test will be used to analyze the time 0 (immediately 
after dosing) data.  A descriptive summary will be provided for the following categories of 
scores: 0, 1-10, 11-20, 21-30, 31-40, etc. up to the maximum category by treatment for each 
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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.
The PK analyses will be conducted using standard noncompartmental methods of analysis using
 on a computer that meets 
or exceeds the minimum system requirements for these programs. The version of any software 
used for the analysis will be documented and the program will meet the Lilly requirements of 
software validation. It is possible that other validated equivalent PK software programs may be 
utilized if appropriate, warranted, and approved by global PK management.
Free serum insulin lispro concentrations will be used to calculate several PK parameters,
including: early 50% tmax, time to late half-maximal serum concentration (late 50% tmax),
maximum observed concentration (Cmax), time to maximum observed drug concentration (tmax), 
t1/2, AUC from time zero to the last recorded time, AUC(0-30min), AUC from time zero to 1 hour, 
AUC from time zero to 10 hours, and AUC from time zero to infinity. Other parameters may be 
calculated as deemed appropriate. Additional partial AUCs may be computed as necessary. The 
primary insulin lispro PK parameters for faster insulin lispro absorption analysis are early 50% 
tmax and AUC(0-30min).
Given the predicted low systemic concentrations of treprostinil, the PK analysis of treprostinil
from the LY900014 dosing will be conducted using the available data. The primary analysis of
the treprostinil concentrations will be focused on assessing tmax and Cmax.
Although attempts will be made to adhere to the scheduled collection times (Section 2), it is
recognized that situations arise that may compromise the scheduled times. Parameters will be
individually calculated for each patient based on actual collection times and presented using
summary statistics.
10.3.2.2. Pharmacokinetic Statistical Inference
Log-transformed Cmax and AUC estimates 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 using the mixed-effects model that includes treatment, sequence, 
and period 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 (early 50% tmax, late 50% tmax, tmax, and t1/2). Least-squares means, treatment 
differences in least-squares means, 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.
Statistical significance will be achieved when the p-value for a test is less than 0.05.
The analyses described above will also be performed on the population of patients who
completed and had evaluable PK data for both study periods.
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As plasma treprostinil concentrations after administration of LY900014 are expected to be very 
low, a descriptive statistical analysis may be conducted if sufficient data are available for this 
analysis.
10.3.3. Pharmacodynamic Analyses
10.3.3.1. Glucodynamic Parameter Estimation
Glucodynamic assessments will be determined from the euglycemic clamp procedure, where the 
GIR over time will be used as a measure of insulin effect.  Glucodynamic analyses will be 
conducted on those patients who complete at least 1 clamp procedure.
A locally weighted scatterplot smoothing (LOESS) function will be applied to all individual GIR 
versus time profiles in each treatment group and/or period using 
  
The fitted data for each patient will be used to calculate the following GD parameters:  maximum 
GIR (Rmax), TRmax, early 50% TRmax, time to half-maximal GIR after TRmax (late 50% 
TRmax), Tonset, Gtot over the duration of the clamp procedure, Gtot(0-1h), and Gtot(0-30min).
The values of these GD parameters will be summarized by treatment group through descriptive 
statistics. Mean LOESS fits of GIR versus time profiles will be generated. The primary GD 
parameters for analysis are early 50% TRmax, Gtot(0-30min), Gtot(0-1h), and Tonset.
Additional partial glucose AUCs, such as Gtot over 2 hours (Gtot[0-2h]) and Gtot from 3 hours to 
10 hours (Gtot[3-10h]), may be computed as necessary.
10.3.3.2. Glucodynamic Statistical Inference
The GD statistical model will be the same as the model used for the analysis of the PK 
parameters. The following variables will be log-transformed prior to analysis:  Rmax, Gtot, 
Gtot(0-30min), and Gtot(0-1h). Additional partial glucose AUCs, such as Gtot(0-2h) and 
Gtot(3-10h), may be analyzed as necessary. For GD parameters that have at least 1 patient with a 
value equal to zero, a value equal to the smallest non-zero observed GD value for that parameter 
divided by 2 will be added to all values, and the analysis of the log-transformed data will be 
performed. In addition, as a sensitivity analysis, a nonparametric analysis will be performed for 
that parameter.
The same model without log transformation will be used for the analysis of the GD time 
parameters (Tonset, TRmax, early 50% TRmax, and late 50% TRmax). Least-squares means, 
treatment differences in least-squares means, and the corresponding 95% CIs for the treatment 
differences will be estimated from the model. The p-value for the difference between 
least-squares means will be used to determine statistical significance. The treatment ratios and 
95% CIs for the ratios will be calculated using Fieller’s theorem.
The analyses described above will also be performed on the population of patients who complete 
and have evaluable GD data for both study periods.
10.3.4. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.
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 unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AUC
area under the concentration versus time curve
AUC(0-30min)
area under the concentration versus time curve from time zero to 30 minutes
blinding
A procedure in which one 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 patients are aware of the treatment received.
BMI
body mass index
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed 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 will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
clinical pharmacologist


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CRF
case report form
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CSII
continuous subcutaneous insulin infusion
early 50% tmax
time to early half-maximal serum concentration
early 50% TRmax
time to early half-maximal glucose infusion rate before time to maximum glucose infusion 
rate
ECG
electrocardiogram
eCRF
electronic case report form
enroll
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
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
good clinical practice
GD
glucodynamic(s)
GFR
glomerular filtration rate
GIR
glucose infusion rate
Gtot
total amount of glucose infused
Gtot(0-30min)
total amount of glucose infused over 30 minutes
Gtot(0-1h)
total amount of glucose infused over 1 hour
Gtot(0-2h)
total amount of glucose infused over 2 hours
Gtot(3-10h)
total amount of glucose infused from 3 hours to 10 hours
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization


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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.
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 authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized 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 study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IV
intravenous
late 50% tmax
time to late half-maximal serum concentration
late 50% TRmax
time to half-maximal glucose infusion rate after time to maximum glucose infusion rate
LOESS
locally weighted scatterplot smoothing
MDI
multiple daily injections
non-
investigational 
product
A product that is not being tested or used as a reference in the clinical study, but is provided 
to patients and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
NPH
neutral protamine Hagedorn
randomize
The process of assigning patients to an experimental group on a random basis.
PAH
pulmonary arterial hypertension
PG
plasma glucose
PK
pharmacokinetic(s)
Rmax
maximum glucose infusion rate
SAE
serious adverse event
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SMPG
self-monitoring plasma glucose


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SUSARs
suspected unexpected serious adverse reactions 
t1/2
half-life associated with the terminal rate constant in noncompartmental analysis
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
tmax
time to maximum observed drug concentration
Tonset
time to onset of insulin action
TRmax
time to maximum glucose infusion rate
ULN
upper limit of normal
VAS
visual analog scale


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology a
Clinical Chemistry a
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Chloride
Mean cell volume 
Calcium
Mean cell hemoglobin 
Phosphorus
Mean cell hemoglobin concentration 
C-peptide (fasting)
Leukocytes (WBC) 
Glucose (fasting) c
Absolute counts of:
Blood urea nitrogen (BUN)
Neutrophils
Uric acid
Lymphocytes
Total cholesterol
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase (ALP)
Aspartate aminotransferase (AST)
Urinalysis a
Alanine aminotransferase (ALT)
Specific gravity
Creatinine
pH
Gamma-glutamyl transferase (GGT)
Protein
Glucose
Other a,d
Ketones
HbA1c
Bilirubin
Hepatitis B surface antigen
Urobilinogen
Hepatitis C core antibody
Blood
HIV antigen and antibody
Nitrite
Syphilis 
Ethanol testinge
Pregnancy test a,b
Urine drug screen
hCG
FSHf
Abbreviations:  FSH = follicle-stimulating hormone; HbA1c = glycated hemoglobin; hCG = human chorionic 
gonadotropin; HIV = human immunodeficiency virus; RBC = red blood cells; WBC = white blood cells.
a
Performed at local laboratories.
b
Female patients only.  Serum pregnancy test at screening, and urine pregnancy test at other time points.  
c
Plasma glucose measured after a fast of at least 8 hours.
d
Performed at screening only.  
e
Ethanol testing may be repeated prior to admission to the clinical research unit and at other times indicated in the 
Schedule of Activities.
f
Only applicable at screening for menopausal women, if necessary.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient 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.  This includes obtaining the 
appropriate signatures and dates on the informed consent form (ICF) prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant and retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by International Council for 
Harmonization (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site.  Lilly or its representatives must approve the ICF 
before it is used at the investigative site.  All ICFs must be compliant with the ICH guideline on 
good clinical practice (GCP).
The study site’s ERB should be provided with the following:

the current Investigator’s Brochure and updates during the course of the study

ICF

relevant curricula vitae


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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 (CIOMS) 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 organization.
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 case report forms (CRFs), and 
study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate CRF 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 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, 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 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 clinical research 
physician. 
Hepatic Monitoring Tests 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin 
 
Hematocrit 
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 (direct) bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear antibodya 
AST 
Alkaline phosphatase isoenzymesa 
GGT 
CK  
Anti-smooth muscle antibody (or anti-actin 
antibody)a 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; GGT = 
gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red blood cells; 
WBC = white blood cells. 
a Assayed by Lilly-designated laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
 




Leo Document ID = 5cbd8cdf-b57e-4ae3-8ce1-f65d7ed581e1
Approver: Hiroshi Nishiyama (AP\C115877)
Approval Date & Time: 03-Nov-2017 20:27:20 GMT
Signature meaning: Approved
Approver: Charles T Benson (AM\RM98125)
Approval Date & Time: 07-Nov-2017 19:06:30 GMT
Signature meaning: Approved

SAP_001.pdf: