A Study to Evaluate the Pharmacokinetics and Glucodynamics of LY900014 Compared to Humalog® in Patients With T2DM
Phase: PHASE1
Conditions: Diabetes Mellitus, Type 2
Sponsor: Eli Lilly and Company

Protocol: A Study to Evaluate the Pharmacokinetics and Glucodynamics of LY900014 Compared to 
Humalog® in Patients With T2DM   
NCT03341312 
Approved: 12-Dec-2017 

 
 
 
 
 
  
  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
  
 
  
   
  
 
     
   
 
 
   
 
 
   
   
  
  
   
 
 
 
 
  
   
 
 
  
 
 
   
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
  
  
  
  
 
  
 
   
  
 
 
  
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 

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LY900014
Table of Contents
A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 compared to Humalog in 
Patients with T2DM
Section
Page
Protocol I8B-MC-ITRW(b) A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 compared to Humalog® in Patients 
with T2DM .........................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................18
3.1.
Study Rationale............................................................................................................18
3.2.
Background..................................................................................................................18
3.3.
Benefit/Risk Assessment..............................................................................................19
4.
Objectives and Endpoints..................................................................................................21
5.
Study Design.....................................................................................................................22
5.1.
Overall Design .............................................................................................................22
5.2.
Number of Participants.................................................................................................23
5.3.
End of Study Definition ...............................................................................................24
5.4.
Scientific Rationale for Study Design...........................................................................24
5.5.
Justification for Dose ...................................................................................................24
6.
Study Population...............................................................................................................25
6.1.
Inclusion Criteria..........................................................................................................25
6.2.
Exclusion Criteria ........................................................................................................27
6.2.1.
Additional Exclusion Criteria for Inpatient Dosing Days......................................29
6.3.
Lifestyle and/or Dietary Requirements .........................................................................29
6.3.1.
Meals and Dietary Restrictions.............................................................................30
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................30
6.3.3.
Activity................................................................................................................30
6.4.
Screen Failures.............................................................................................................30
7.
Treatment..........................................................................................................................31
7.1.
Treatment Administered...............................................................................................31
7.1.1.
Packaging and Labeling of Investigational Medicinal 
Product ................................................................................................................31
7.2.
Method of Treatment Assignment ................................................................................32

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7.2.1.
Selection and Timing of Doses.............................................................................32
7.3.
Blinding .......................................................................................................................32
7.4.
Dose Modification........................................................................................................33
7.4.1.
Special Treatment Considerations ........................................................................33
7.5.
Preparation/Handling/Storage/Accountability...............................................................33
7.6.
Treatment Compliance .................................................................................................34
7.7.
Concomitant Therapy...................................................................................................34
7.8.
Treatment after the End of the Study............................................................................35
8.
Discontinuation Criteria ....................................................................................................36
8.1.
Discontinuation from Study Treatment.........................................................................36
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................36
8.2.
Discontinuation from the Study....................................................................................36
8.3.
Patients Lost to Follow-up............................................................................................37
9.
Study Assessments and Procedures ...................................................................................38
9.1.
Efficacy Assessments...................................................................................................38
9.2.
Visit Description ..........................................................................................................38
9.2.1.
Lead-In and Insulin Transition .............................................................................38
9.2.2.
Dose-Finding Assessment ....................................................................................39
9.2.3.
Study Period CRU Visits......................................................................................40
9.2.3.1.
Run-In............................................................................................................40
9.2.3.2.
Study MMTT .................................................................................................40
9.3.
Adverse Events ............................................................................................................40
9.3.1.
Serious Adverse Events........................................................................................41
9.3.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................42
9.3.2.
Complaint Handling.............................................................................................42
9.4.
Treatment of Overdose.................................................................................................42
9.5.
Safety...........................................................................................................................43
9.5.1.
Physical Examination...........................................................................................43
9.5.2.
Laboratory Tests ..................................................................................................43
9.5.3.
Vital Signs ...........................................................................................................43
9.5.4.
Electrocardiograms ..............................................................................................43
9.5.5.
Other Tests...........................................................................................................44
9.5.5.1.
Hip and Waist Circumference.........................................................................44
9.5.5.2.
Body Weight and Height ................................................................................44
9.5.6.
Safety Monitoring ................................................................................................44
9.5.6.1.
Hepatic Safety................................................................................................44
9.5.6.2.
Glucose Monitoring........................................................................................45
9.5.6.3.
Severe Hypoglycemia.....................................................................................46

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9.5.6.4.
Injection Site Assessments (Local Tolerability) ..............................................46
9.5.7.
Self-Monitored Plasma Glucose during Outpatient Period....................................46
9.5.8.
Treatment of Hyperglycemia and Hypoglycemia..................................................47
9.6.
Pharmacokinetics Samples ...........................................................................................47
9.6.1.
Bioanalysis...........................................................................................................47
9.7.
Pharmacodynamics ......................................................................................................47
9.7.1.
Glucodynamics Samples ......................................................................................48
9.7.1.1.
Glucose Samples (Run-In Period)...................................................................48
9.7.1.2.
Glucose Samples (MMTT) .............................................................................48
9.7.2.
Samples for Immunogenicity Assessments...........................................................48
9.8.
Genetics .......................................................................................................................48
9.9.
Exploratory Biomarkers ...............................................................................................49
9.9.1.
C-Peptide .............................................................................................................49
9.10. Health Economics ........................................................................................................49
10.
Statistical Considerations and Data Analysis.....................................................................50
10.1. Sample Size Determination ..........................................................................................50
10.2. Populations for Analyses..............................................................................................50
10.2.1.
Study Participant Disposition ...............................................................................50
10.2.2.
Study Participant Characteristics ..........................................................................50
10.3. Statistical Analyses ......................................................................................................50
10.3.1.
Safety Analyses....................................................................................................51
10.3.1.1.
Clinical Evaluation of Safety..........................................................................51
10.3.1.2.
Statistical Evaluation of Safety.......................................................................51
10.3.2.
Pharmacokinetic Analyses....................................................................................51
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................51
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................52
10.3.3.
Glucodynamic Analyses.......................................................................................52
10.3.3.1.
Glucodynamic Parameter Estimation..............................................................52
10.3.3.2.
Glucodynamic Statistical Inference.................................................................53
10.3.4.
Evaluation of Immunogenicity .............................................................................53
10.3.5.
C-Peptide .............................................................................................................53
10.3.6.
Interim Analyses..................................................................................................53
11.
References ........................................................................................................................54

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List of Tables
Table
Page
Table ITRW.1.
Objectives and Endpoints .......................................................................21
Table ITRW.2.
Treatments Administered........................................................................31

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List of Figures
Figure
Page
Figure ITRW.1.
Illustration of study design for Protocol I8B-MC-ITRW.........................22

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................55
Appendix 2.
Clinical Laboratory Tests........................................................................59
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................60
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............63
Appendix 5.
Blood Sampling Summary......................................................................64
Appendix 6.
Protocol Amendment I8B-MC-ITRW(b) Summary:  A Study to 
Evaluate the Pharmacokinetics and Glucodynamics of LY900014 
compared to Humalog® in Patients with T2DM .....................................65

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1. Protocol Synopsis
Title of Study:
A Study to Evaluate the Pharmacokinetics and Glucodynamics of LY900014 compared to Humalog in Patients with 
T2DM
Rationale: 
LY900014 is an ultra-rapid acting insulin lispro formulation with increased early absorption compared to 
commercially available insulin lispro formulation (Humalog, Eli Lilly).  LY900014 aims to mimic the 
physiological prandial insulin secretion pattern, which may more effectively control postprandial glucose excursions 
and allow increased flexibility of the time of dosing relative to a meal.
The aim of this study is to compare the insulin lispro pharmacokinetic (PK), glucodynamic (GD), and tolerability
profiles of insulin lispro following administration of either LY900014 or Humalog during a mixed meal tolerance 
test (MMTT) in patients with type 2 diabetes mellitus (T2DM).
Objectives/Endpoints:
Objectives
Endpoints
Primary
1.
To evaluate the PK of insulin lispro following a 
single SC injection of LY900014 and Humalog in 
patients with T2DM.
1.
Early 50% tmax and AUC(0-30min)
Secondary
1.
To evaluate the effect of injection-to-meal timings 
(immediately before the start of meal, and
20 minutes following the start of the meal) on the 
GD response to LY900014 compared to Humalog, 
as measured by the MMTT.
1.
∆AUC(0-2hr), ∆AUC(0-5hr)
2.
To evaluate the tolerability of LY900014.
2.
AEs and hypoglycemic events
Abbreviations: AE = adverse event; AUC(0-30min) = area under the concentration versus time curve (AUC) from 
time zero to 30 minutes; ∆AUC = area under the baseline subtracted glucose concentration versus time curve; 
early 50% tmax = time to early half-maximal drug concentration; GD = glucodynamics; MMTT = mixed meal 
tolerance test; PK = pharmacokinetics; SC = subcutaneous; T2DM = type 2 diabetes mellitus.
Summary of Study Design:
Study I8B-MC-ITRW is a Phase 1, randomized, patient and investigator blind, 2-treatment, 4-period crossover study 
to evaluate meal to dose-timing in patients with T2DM.
Treatment Arms and Planned Duration for an Individual patient:
Patients will be screened over a 14-day period prior to start of an approximate 2-week lead-in/insulin transition 
period.  Patients will then participate in a dose-finding assessment (Day -1 of Period 1) and subsequently 

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randomised to 1 of 4 treatment sequences according to the actual randomization table provided to the site.  In each 
study period, patients will undergo an MMTT.  Each patient will receive a single subcutaneous injection of either 
LY900014 or Humalog either immediately before the test meal or 20 minutes following the start of the test meal.  
All treatment procedures will be inpatient stays of approximately 2 days per period and require a maximum of 
6 weeks to complete 4 periods.  Each study dosing will be separated by a minimum of 21 hours and may occur on 
consecutive visits, however patient inclusion is subject to required screening criteria. The follow-up or early 
discontinuation visit should occur at least 14 days after the last dose of the study drug.
Treatment:
LY900014:  Single individualized SC dose per assessment period
Humalog: Single individualized SC dose per assessment period
Number of Patients: Up to 36 patients may be enrolled to ensure that at least 30 patients will complete the study.  
Thirty completing patients will provide greater than 95% power to demonstrate a 2-fold increase in the serum insulin 
lispro AUC(0-30min) between LY900014 and Humalog when both are given immediately before meals. 
Statistical Analysis:  Primary statistical analyses of PK and GD parameters will be conducted on the set of patients
who complete all treatment periods.  Supportive analyses may be done on the key parameters for the patients who 
complete at least the first period of treatment.  Safety analyses will be conducted on the set of patients receiving at 
least 1 dose of the study drug to which they are randomized, regardless of whether or not they complete all protocol 
requirements.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, and 
confidence intervals (CIs) will be calculated at 95%, 2-sided.
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.  Safety parameters will be listed and summarized 
using standard descriptive statistics.
Pharmacokinetic:  Log-transformed AUCs, Cmax, CL/F and Vz/F for insulin lispro will be evaluated to estimate 
geometric means, ratios of geometric means of insulin lispro within LY900014 to Humalog, and the corresponding 
95% CIs of the ratios using the mixed-effects model that includes treatment and period as fixed effects and patient 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 (LSmeans), treatment differences in LSmeans, and the 
corresponding 95% CIs for the treatment differences will be estimated from the model.  The p-value on the 
difference between LS means will be used to determine statistical significance. The treatment ratios and 95% CIs 
for the ratios will be calculated using Fieller’s theorem. 
Glucodynamic:  Data will be analyzed for the patients during each MMTT.  The change from baseline values (the 
average of -30, -15, and 0 minutes) represented as the 0-hour time point following the start of the MMTT for each 
patient will be calculated. The area under the baseline subtracted glucose concentration versus time curve from time 
0 to 2hr (∆AUC[0-2h]) and area under the baseline subtracted glucose concentration versus time curve from time 
0 to 5hr post meal (∆AUC[0-5h]) will be calculated. In addition, the change from baseline maximum glucose 

I8B-MC-ITRW(b) Clinical Pharmacology Protocol
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observed during the 5 hours postmeal and change from baseline 1-hour glucose and 2-hour glucose post the start of 
the meal will be calculated. Other partial ∆AUCs may be calculated as deemed appropriate. 
Summary statistics will be presented by treatment and by timing of dose (all 4 combinations of treatment and timing 
of dose).  The GD parameters on the original scale will be analyzed using the mixed-effects model that includes
treatment, timing of dose, treatment-by-timing of dose interaction, and period as fixed effects and patient as a 
random effect. 
The p-value on the difference between LS means will be used to determine statistical significance and the 
corresponding 95% CIs for the LS Mean ratios from Fieller’s theorem will be presented.

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2. Schedule of Activities

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Study Schedule Protocol I8B-MC-ITRW
Sign 
Informed 
Consent
Screening
Lead-in
Study Period (Periods 1 to 4)
Follow-
up/Early 
discontinuation
Comments
Procedure
Days -30
to -17
14 days prior 
to Day -2
Day -1
Day 1
≥14 days after 
discharge
Informed Consent
X
At least 1 day before screening 
procedures.  Screening 
procedures should take place no 
later than 28 days after signing 
the informed consent (see 
Section 9.5.2).
Medical history and 
physical examination
X
Hip and waist 
circumference
X
Period 1 only. 
Height
X
At screening only
Weight
X
X
Period 1 only.
Vital signs:  blood 
pressure and pulse rate
X
Predose, 30 and 
120 minutes 
postdose
X
Vital signs will be taken while 
patients are supine at screening
and semi-supine on Day 1.
12-lead ECG 
X
Predose 
(Period 1)
X
Single ECGs will be collected 
for safety. 
Clinical laboratory tests
X
Predose for 
Period 1 only
X
Fasting laboratory test for 
screening and follow-up.  
Screening laboratory tests will be 
analyzed at a local laboratory
(see Section 9.5.2).

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Study Schedule Protocol I8B-MC-ITRW
Sign 
Informed 
Consent
Screening
Lead-in
Study Period (Periods 1 to 4)
Follow-
up/Early 
discontinuation
Comments
Procedure
Days -30 
to -17 
14 days prior 
to Day -2
Day -1
Day 1
≥14 days after 
discharge
Lead-in/insulin 
transition activities
X (Period 1 
only)
Once patients have completed 
screening procedures, switch 
from prescribed short-acting and 
basal insulin to site-provided 
Humalog and insulin glargine
respectively.  Patients receive 
general diabetes training.  A
patient diary will be provided for 
recording dosing and other 
required information (Section
9.2.1). Lead-in period may be 
extended by 2 days (eg, 16 days 
prior to Day -2) as needed.
Patient admission to 
CRU
X
Admitted to CRU evening Day -
2 or early morning Day -1
(Period 1 only).  For Periods 2 –
4, patients may be admitted 
evening of Day -1.
Dose-finding
X
(Period 1 
only)
Following insulin transition
patients will undergo dose-
finding with Humalog and a test 
meal.  To take place between 
07:00 and 11:00.  Blood glucose 
concentrations will be monitored 
every 20 minutes for 5 hours 
postmeal (see Section 9.2.2).  
See Section 6.2.1 for 
rescheduling.

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Study Schedule Protocol I8B-MC-ITRW
Sign 
Informed 
Consent
Screening
Lead-in
Study Period (Periods 1 to 4)
Follow-
up/Early 
discontinuation
Comments
Procedure
Days -30 
to -17 
14 days prior 
to Day -2
Day -1
Day 1
≥14 days after 
discharge
Randomization 
X
To take place before run-in of 
Period 1 Day 1.
Pregnancy test
X
X
X
Serum pregnancy test will be 
performed at screening and urine 
pregnancy tests will be 
performed at admission for 
Period 1 and at follow-up (see 
Appendix 2).
Standard dinner
X
Approximately 19:00
Medical assessment
X
Predose and 
before discharge 
from CRU
X
Medical assessment includes 
medical review, and targeted 
examination, and as appropriate, 
review of concomitant 
medication, patient diary and 
MMTT exclusion criteria (see 
Section 6.2.1).

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Study Schedule Protocol I8B-MC-ITRW
Sign 
Informed 
Consent
Screening
Lead-in
Study Period (Periods 1 to 4)
Follow-
up/Early 
discontinuation
Comments
Procedure
Days -30 
to -17 
14 days prior 
to Day -2
Day -1
Day 1
≥14 days after 
discharge
Glucose 
stabilization/run-in
X 
From approximately 7 hours to 
30 minutes before dosing:  
infusion of glucose (dextrose 
solution) or insulin glulisine to 
achieve a target blood glucose 
concentration of 135 ±15 mg/dL
(7.5 ±0.8 mmol/L).  Blood 
glucose concentrations will be 
monitored at a minimum of 
30-minute intervals (see Section 
9.2.3.1 and 9.7.1.1). See Section 
6.2.1 for rescheduling. 
Blood glucose sampling
(MMTT)
-30, -15, 0
minutes pre-meal, 
10, 20, 30, 40, 50, 
60, 70, 80, 90, 
100, 110, 120, 
135, 150, 165, 
180, 195, 210, 
225, 240, 300
minutes post-meal
0-minute time point sample to be 
taken at the start of the meal. 
Mixed meal tolerance 
test (MMTT)
X
Standardized liquid test meal will 
be administered at approximately 
08:00 (with allowance to 11:00)
and should be consumed within 
15 minutes (see Section 9.2.3.2).  
Study periods to be separated by 
a minimum 21-hour washout.

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Study Schedule Protocol I8B-MC-ITRW
Sign 
Informed 
Consent
Screening
Lead-in
Study Period (Periods 1 to 4)
Follow-
up/Early 
discontinuation
Comments
Procedure
Days -30 
to -17 
14 days prior 
to Day -2
Day -1
Day 1
≥14 days after 
discharge
Study drug 
administration
X
Either immediately before meal
or 20 minutes after start of meal 
according to randomization 
schedule:  Study drug will be 
administered at approximately 
the same time on Day 1 of 
Periods 1-4.  There will be at 
least 21 hours between study 
doses.
Injection site local 
tolerability assessments
0, 20, and 60 
minutes postdose
Assessments of injection site 
local tolerability will occur 
immediately following the 
injection.
Insulin lispro PK 
sampling
0 (predose), 5, 10, 
15, 20, 25, 30, 35, 
40, 45, 50, 55, 60, 
70, 90, 120, 
150,180, 240, 
300, 360, and 420 
minutes postdose
Sampling times are relative to 
the time of study drug
administration in each period.
Pharmacogenetics 
sample
Predose for 
Period 1 only
Refer to sample collection 
instructions provided by the 
sponsor.
Immunogenicity sample
Pre-insulin 
switch
Predose for 
Periods 1 and 3
X
Additional samples may be 
collected if the investigator 
considers there is a possibility 
that an AE is immunologically 
indicated. 

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Study Schedule Protocol I8B-MC-ITRW
Sign 
Informed 
Consent
Screening
Lead-in
Study Period (Periods 1 to 4)
Follow-
up/Early 
discontinuation
Comments
Procedure
Days -30 
to -17 
14 days prior 
to Day -2
Day -1
Day 1
≥14 days after 
discharge
C-peptide
0 (predose), 30, 
60, 120, 180, 240, 
300, 360 and 420
minutes postdose
Sampling times are relative to 
the time of study drug
administration
Discharge from CRU
X
Patients may be discharged after 
all study procedures are 
completed.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; min = minutes; MMTT = mixed meal tolerance test; PK = pharmacokinetics.
Note:  The site should schedule activities as appropriate.  In cases where several study procedures are scheduled at the same time, the order of priority will be as 
follows:  PK samples including blood sampling for blood glucose and laboratory samples per protocol nominal times.  ECGs and vital sign measurements 
should be scheduled before, but as close as possible to the PK sampling times.  Injection-site assessments can be done after PK sampling. 

 
 
 
 
  
 
  
 
 
   
 
  
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
   
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
  
 
    
 
 
  
  
  
  
 
 
  
  
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
   
 
 
  
 
 
 
 
  
 
  
 
  
 
  
    
 
 
 
  
  
  
  
 
  
 
  
 
  
 
   
 
  
  
 
 
 
 
  
 
 
 
   
   
   
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
   
  
 
  
  
 
 
 
 
 
 
  
   
 
 
 
 
   
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
  
  
    
 
 
 
  
  
  
   
  
   
 
  
 
   
 
 
 
 
  
 
  
   
   
 
 
 
 
  
 
  
   
 
 
  
 
    
 
  
   
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
  
   
  
  
  
 
 
 
 
 
 
 
 
   
 
  
 
  
 
 
 
  
   
 
  
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
    

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experiences elevated blood glucose following food intake for more than 1 hour, insulin glulisine 
will be administered intravenously (see Section 9.5.8 for treatment guidelines).  Patients will 
maintain their basal insulin regimen of site-provided insulin glargine during the entire study 
including the MMTT days unless safety issues arise; in this case, the investigator will discuss a 
change of the basal insulin regimen with the sponsor clinical pharmacologist (CP) and 
implement this change, if necessary, to prevent any medical problems.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY900014 are to be found in the Investigator’s Brochure (IB). 

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4. Objectives and Endpoints
Table ITRW.1 shows the objectives and endpoints of the study.
Table ITRW.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
1.
To evaluate the PK of insulin lispro following a 
single SC injection of LY900014 and Humalog in 
patients with T2DM.
1.
Early 50% tmax and AUC(0-30min)
Secondary
1.
To evaluate the effect of injection-to-meal timings 
(immediately before the start of meal, and
20 minutes following the start of the meal) on the 
GD response to LY900014 compared to Humalog, 
as measured by the MMTT.
1.
∆AUC(0-2hr), ∆AUC(0-5hr) 
2.
To evaluate the tolerability of LY900014.
2.
AEs and hypoglycemic events
Exploratory
1.
To assess C-peptide levels following 
administration of LY900014 and Humalog.
1.
C-peptide concentration
2.
Explore the formation of anti-drug antibodies to 
insulin lispro.
2.
Anti-insulin lispro antibodies
Abbreviations:  AE = adverse event; AUC(0-30min) = area under the concentration versus time curve (AUC) from 
time zero to 30 minutes; ∆AUC = area under the baseline subtracted glucose concentration versus time curve; 
early 50% tmax = time to early half-maximal drug concentration; GD = glucodynamics; MMTT = mixed meal 
tolerance test; PK = pharmacokinetics; SC = subcutaneous; T2DM = Type 2 diabetes mellitus.

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5. Study Design
5.1.
Overall Design
Study ITRW is a Phase 1, patient- and investigator-blind, randomized, 2-treatment, 4-period 
crossover study in patients with T2DM to evaluate the insulin lispro PK and GD characteristics 
of LY900014 compared to Humalog following a single SC injection administered at 2 different 
injection-to-mealtime intervals; either immediately before or 20 minutes following the start of 
the test meal.  Study ITRW may be conducted at 1 or more clinical research units (CRUs). 
Abbreviations: ED = early discontinuation; T2DM = type 2 diabetes mellitus
Figure ITRW.1.
Illustration of study design for Protocol I8B-MC-ITRW.
Patients will be required to attend the CRU on at least 8 occasions (no more than 10 occasions if 
dose-finding and/or one MMTT rescheduled) as noted in the Study Schedule (see Section 2):

Informed consent

Screening visit 

Lead-in and insulin transition period (see Section 9.2.1)

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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.
5.4.
Scientific Rationale for Study Design
The study is a 4-period crossover design to reduce the variability of insulin PK and GD as each 
patient will act as his/her own control.  The total number of patients needed with a crossover 
design is less than the number needed with a parallel group design.  A maximum duration of 
approximately 6 weeks is allowed for patients to complete all 4 assigned periods to minimize the 
risk of insulin resistance/changes in mean glycemic control during the study.
Randomization and blinding are used to avoid bias introduced through an association between 
allocation order of IMP and patient characteristics.  The Lilly CP/Lilly study team will be 
unblinded.
In each study period, patients will undergo a run-in period before the MMTT using a variable 
insulin and glucose intravenous (IV) infusion.  This run-in period will allow for improved 
comparability of the postprandial glucose response to a mixed meal after treatment with 
LY900014 and Humalog administered either immediately before the start of the meal, or 
20 minutes following the start of the test meal. This run-in aims to achieve similar preprandial 
glucose levels for all patients before the start of the test meal and thereby reduces the variability 
of the postprandial glucose response. Insulin glulisine has been chosen for the IV optimization 
of blood glucose during the run-in because insulin glulisine does not cross-react with the insulin 
lispro–specific assay used for the PK analysis. 
Under this design, if 2 periods occur on consecutive days, the interval between the last bolus on 
the first day and the first bolus on the second day is much longer compared to the length of time 
that the treatment (LY900014 or Humalog) lasts in the bloodstream; therefore, no carryover 
effect is assumed. This enables PK and GD data from the breakfast meal tests of each period to 
be analyzed independently and separately.
A minimum of approximately 21 hours washout between the test meals allows for a complete 
washout of study drug administered with the MMTT and glucose response and prevents carry-
over effects.
5.5.
Justification for Dose
The bolus dose of insulin lispro (LY900014 or Humalog) will be individualized per patient to 
cover the carbohydrate content in this standardized liquid test meal.  This dose of insulin is 
reflective of clinically relevant, individualized insulin dosing, similar to how patients would 
determine the insulin dose for the carbohydrate content in a meal. For each patient, the 
individualized prandial insulin lispro dose in LY900014 and Humalog for each test meal must be 
kept identical throughout the crossover periods.

I8B-MC-ITRW(b) Clinical Pharmacology Protocol
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LY900014
6. Study Population
Eligibility of patients for study enrollment 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 over a 14-day period prior to the lead-in site visit.  Patients who are not 
entered within this time period, 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 male or female patients with T2DM for at least 1 year.  A diagnosis of 
T2DM is based on medical history.
a.
Male patients:
i. No male contraception required except in compliance with 
specific local government requirements.
b. Female patients:
i. Women of child-bearing potential who are abstinent (if this is 
complete abstinence, as their preferred and usual lifestyle) or in a 
same sex relationship (as part of their preferred and usual
lifestyle) must agree to either remain abstinent or stay in a same 
sex relationship without sexual relationships with males.
ii. Otherwise, women of child-bearing potential participating must 
agree to use 1 highly effective method of contraception until
discharge from final treatment period.
1. Women of child bearing potential must test negative for 
pregnancy prior to initiation of treatment as indicated 
by a negative serum pregnancy test at the screening 
visit followed by a negative urine pregnancy test within 
24 hours prior to exposure in Period 1. 
2. A highly effective method of contraception includes a 
combined (estrogen and progestogen containing) or 
progestogen-only hormonal contraception administered 
orally, intravaginally, or transdermally and is associated 
with inhibition of ovulation.  Alternatively, patients 

I8B-MC-ITRW(b) Clinical Pharmacology Protocol
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LY900014
may use either an intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, or 
the partner should have been vasectomised.
iii. Women not of childbearing potential may participate and include 
those who are:
1. infertile due to surgical sterilization (hysterectomy,
bilateral oophorectomy or bilateral salpingectomy), 
congenital anomaly such as Mullerian agenesis; or
2. post-menopausal – defined as a woman being 
amenorrheic for more than 1 year without an alternative 
medical cause and a serum follicle-stimulating hormone 
(FSH) level compatible with postmenopausal status. A 
FSH level in the post-menopausal range may be used to 
confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement 
therapy. 
[2]
are aged 18 to 70 years inclusive at the time of screening.
[3]
have a body mass index (BMI) of 18.5 kg/m
2 to 40.0 kg/m
2, both inclusive, 
at screening.
[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 procedures as per protocol.
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[7]
are able and willing to give signed informed consent approved by Lilly and 
the ethical review board (ERB) governing the site.
[8]
have a glycated hemoglobin (HbA1c) ≤9.0% at screening.
[9]
have a fasting C-peptide ≤1.0 nmol/L.  Patients who had C-peptide levels 
>1.0 nmol/L may be retested once.  If the retest yields a C-peptide 
≤1.0 nmol/L then the patient satisfies this criterion.
[10] have had no episodes of severe hypoglycemia in the last 6 months (see 
Section 9.5.6.3).
[11] are on stable prandial insulin and basal insulin (neutral protamine Hagedorn 
[NPH] insulin, insulin glargine or insulin detemir) with or without a stable 
dose of metformin for at least 3 months before screening.

I8B-MC-ITRW(b) Clinical Pharmacology Protocol
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LY900014
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[12] 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.
[13] are Lilly employees or employees of the investigational site/CRU.
[14] are currently enrolled in a clinical study involving an investigational 
product (IP) or any other type of medical research judged not to be 
scientifically or medically compatible with this study.
[15] have participated within the last 30 days in a clinical trial involving an IP.  
If the previous IP has a long half-life, 3 months or 5 half-lives (whichever is 
longer) should have passed.
[16] have previously completed or withdrawn from this study.
[17] have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study. 
[18] have a supine blood pressure at screening outside the range of 90 to 
160 mmHg for systolic or 50 to 100 mmHg for diastolic (1 repeat is 
allowed) as determined by the investigator, or results with unacceptable 
deviations that are judged by the investigator to be clinically significant for 
the population, or have a heart rate outside the range of 50 to 90 
beats/minute.
[19] have a history or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine (apart from T2DM), hematological, or 
neurological disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; of constituting a risk when taking the 
IP; or of interfering with the interpretation of data.
[20] have known or ongoing psychiatric disorders.
[21] regularly use known drugs of abuse and/or show positive findings on 
urinary drug screening.
[22] show evidence of an acute infection with fever or infectious disease at the 
time of study entry.
[23] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies.
[24] 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 
exclusions).

 
 
 
 
  
  
 
 
  
 
 
  
  
  
 
    
 
 
  
  
 
 
   
 
 
 
  
   
  
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
  
 
 
     
 
  
  
 
  
 
 
 
  
  
   
 
 
  
 
 
  
 
 
  
   
 
   
 
 
 
 
 
 
  
 
    
     
  
  
 
 
   
 
 
  
 
  
  
 
  
   
  
 
 
    
    
  
 
    
  
  
  
  
  
  
     
 
 
  
 
  
 
 
 
 
  
 
  
 
   
  
 
  
 
 
  
 
 
  
  
  
 
  
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
   
   
  
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
    
  
 
  
 
  
 
  
 
   
 
 
 
 
 
 
 
 
  
 
 

I8B-MC-ITRW(b) Clinical Pharmacology Protocol
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LY900014
[38] have regular use of or intended use of known inducers or inhibitors of 
cytochrome P450 [CYP]2C8 or niacin.  Patients taking these medications 
before study enrollment will be eligible with an appropriate washout period 
which will be evaluated by the investigator in consultation with the Lilly 
CP.
[39] 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 4 weeks 
before screening.
[40] any significant changes in insulin regimen and/or unstable blood glucose 
control within the past 3 months prior to screening as assessed by the 
investigator. 
[41] currently receiving dulaglutide therapy or have been treated with 
dulaglutide within the past 30 days.
[42] require daily insulin treatment >1.2 U/kg/body weight.
[43] in the opinion of the investigator or sponsor, are unsuitable for inclusion in 
the study.
6.2.1. Additional Exclusion Criteria for Inpatient Dosing Days
Patients who fulfil 1 or more inpatient dosing-day exclusion criteria will be excluded from 
study drug administration for that MMTT day. A single inpatient trial period can be 
rescheduled 1 to 14 days later. Each treatment period can only be rescheduled once.
The following exclusion criteria apply to the day before each MMTT day:
[44]
positive drug screen.
[45]
positive pregnancy test administered on Day -1 of Period 1.
[46]
any medical condition or AE that could interfere with glucose metabolism, as
judged by the investigator.
[47]
any use of prescription or nonprescription medication according to Exclusion
Criteria [36], [39] and [41].
[48]
hypoglycemia during the treatment period and less than 24 hours before dosing 
that poses a significant risk to patient safety, as judged by the investigator.
[49]
injection of a bolus of more than 6 U of a fast-acting insulin (Humalog) between
7 and 12 hours before test meal.
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. 

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LY900014
6.3.1. Meals and Dietary Restrictions
Patients will be fasted (except for water) for at least 10 hours before each test meal and 8 hours 
prior to screening and follow-up assessments (see Section 9.5.8 for guidelines on hypoglycemia 
treatment).  The patient will not be allowed to consume water for 2 hours after the MMTT 
assessment begins; however, water may be consumed freely 2 hours postmeal. 
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 may resume their regular diet and 
should not make major changes to the dietary habits during the study.
Following completion of study procedures, patients will be offered a meal.  Site will record dose 
and time of prandial Humalog administered with end-of-study meal.
6.3.2. Caffeine, Alcohol, and Tobacco
Patients should refrain from caffeine-containing food/beverages (for example, cola, chocolate 
drinks, tea, coffee, energy drinks containing methylxanthine [caffeine, theophylline, or 
theobromine]) for at least 12 hours before each test meal and throughout the duration of each 
CRU visit.
No alcohol will be allowed at least 24 hours before each CRU admission (Day –1) and 
throughout the duration of each CRU visit.  Between CRU visits, daily alcohol should not exceed 
3 units for males and 2 units for females (see Section 6.2, #32 for unit definition). 
No cigarette smoking will be permitted during the study.
6.3.3. Activity
Patients will be encouraged to maintain their regular exercise and insulin regimen adaptation 
related to exercise during the outpatient period; however, they should not undertake vigorous or 
prolonged exercise at least 24 hours before each dosing day at the CRU.  Movement will be 
restricted to retain the integrity of connections to infusion(s) and the study procedures.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study may not be rescreened.

 
 
 
 
 
  
  
 
   
 
 
  
  
 
  
  
 
  
   
 
 
 
 
 
 
  
 
 
 
  
  
 
  
    
   
  
  
 
 
 
  
  
  
 
  
   
      
  
 
 
 
 
  
  
  
 
  
  
  
     
 
  
 
  
  
 
 
 
 
 
 
   
   
 
  
 
 
 
 
 
   
 
 
  
  
 
  
  
 
  
  
 
  
 
  
 
 
 
  
 
 
  
  
 
  
 
 
 
 
   
 
  
   
 
  
  
  
 
 
  
 
  
   
  
 
  
   
 
  
 
   
 
  
 
  
      
   
 
  
 
   
 
 

 
 
 
  
 
 
   
   
 
 
 
  
 
   
 
 
 
  
  
  
 
  
 
  
  
  
  
 
   
 
  
   
 
 
 
 
 
 
 
   
 
 
  
  
  
 
 
  
 
    
 
  
 
 
 
 
  
 
   
  
  
 
  
  
   
  
  
 
 
 
 
 
 
   
 
 
   
  
  
 
 
  
   
 
 
  
 
  
 
 
 
 
   
 
 
 
   
 
 
   
 
  
 
 
  
 
 
  
   
 
  
  
 
 
  
 
  
 
  
 
 
 
 
   
  
 
  
  
  
 
 
 
   
 
   
  
 
 
 
  
 
 
  
 
 
   
 
 
    
  
  
  
  
 
  
 
  
 
    
 
 
  
   
 
 
 
 
   
 
 
  
 
  
 
  
   
  
   
 
 
   
 
 
 
 
  
 
  
   
 
 
 
  
 
 
  
  
 
 
 
 
 
   
 
 
  
  
 
 
 
  
  
 
 
 
  
   
   
 
 
  
 
   
 
 
 
  
 
  
 
   
 
 
 
   
 
 
 
   
  
   
 
  
  
 
  
 
  
  
 
   
   
 
 
   
 
 
 
  
    
 
  
  
   
   
  
 
  
  
  
 
  
  

 
 
 
 
   
  
 
  
  
   
 
 
   
 
  
 
 
  
 
 
 
  
 
  
 
 
  
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
   
   
 
  
 
 
 
  
 
 
 
  
  
 
 
   
  
 
  
 
  
 
 
  
 
  
  
  
 
  
  
   
 
 
 
 
  
 
  
   
 
  
  
  
 
 
  
 
  
   
  
 
  
   
 
  
 
   
 
  
 
  
      
 
  
  
  
  
  
  
 
 
 
 
  
 
 
 
  
 
 
 
   
   
 
  
 
 
 
 
 
 
 
  
  
 
   
   
  
  
 
   
 
 
 
   
  
 
 
 
  
 
 
 
 
 
  
    
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
   
  
  
  
 
 
 
 
 
 
 
    
  
  
 
 
 
 
  
 
 
 
  
  
  
   
   
  
 
 
   
   
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 

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LY900014
7.6.
Treatment Compliance
The IP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
Every attempt will be made to select patients who have the ability to understand and comply with 
instructions.  Noncompliant patients may be discontinued from the study.  The time and day of 
drug administration will be recorded.  Drug accountability records will be maintained by the 
study site.
The specifications in this protocol for the timings of safety, PK, and GD sampling are given as 
targets, to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon the safety and PK information obtained.  The scheduled time points may be subject 
to minor alterations; however, the actual time must be correctly recorded in the CRF.  Failure to 
obtain samples due to clinical issues, such as problems with venous access, will not be 
considered a protocol violation, but written documentation will have to be provided to the 
sponsor for all missing samples (regardless of reasons) to facilitate data reconciliation before 
study completion.
Any major modifications that might affect the conduct of the study, patient safety, and/or data 
integrity will be detailed in a protocol amendment.
7.7.
Concomitant Therapy
Patients will continue the basal insulin regimen established during the insulin transition period 
throughout the entire study except when presenting safety issues (see Section 7.4); in this case, 
the investigator will discuss a change of the regimen of basal insulin to prevent any medical 
problems.  Any change in the basal insulin regimen will be captured in the patient diary and 
CRF.  
Patients who are on metformin prior to the study (stable doses for at least 3 months before 
screening) will continue metformin at unchanged doses throughout the study.
Drugs that are known inducers, or inhibitors of cytochrome P450 (CYP) 2C8 are specifically 
excluded.  Additional drugs are to be avoided during the study unless required to treat an AE or 
for the treatment of an ongoing medical problem.
In general, the addition of new concomitant medication should be avoided; however, 
paracetamol (maximum 4g/24hours) may be administered at the discretion of the investigator for 
treatment of headaches etc.  If the need for concomitant medication (other than paracetamol) 
arises, inclusion or continuation of the patient may be at the discretion of the investigator after 
consultation with a Lilly CP or CRP.  Any medication used during the course of the study must 
be documented.
Patients may continue their stable concomitant medication at the time of study entry at regular, 
unchanged doses during the study; for example, antihypertensive medication, lipid-lowering 
agents, thyroid hormone replacement medication, hormonal contraception, or hormonal 
replacement therapy.  

I8B-MC-ITRW(b) Clinical Pharmacology Protocol
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LY900014
Patients should not initiate new over-the-counter or prescription medication or nutritional 
supplements that affect blood glucose or the body’s sensitivity to insulin or that promote weight 
loss 14 days before dosing or throughout the study.
Patients should not apply any creams or lotions to the abdominal skin on the morning of the 
injection or during the inpatient study procedure.
7.8.
Treatment after the End of the Study
Patients will continue their previous insulin regimen after the final study MMTT and associated 
procedures have been completed.

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LY900014
8. Discontinuation Criteria
Patients discontinuing from the study prematurely for any reason must complete AE and follow-
up procedures per Schedule of Activities (Section 2) of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the IP for abnormal liver tests should be considered by the investigator when 
a patient meets 1 of the following conditions after consultation with the Lilly designated medical 
monitor:

ALT (alanine aminotransferase ) AST (aspartate aminotransferase) >8X for patients ULN 
(upper limit of normal)

ALT or AST >5X ULN for patients sustained for more than 2 weeks or

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or INR >1.5 or

ALT or AST >3X ULN the appearance of fatigue, nausea, vomiting, right upper-quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)

ALP (alkaline phosphatase) >3X ULN

ALP>2.5X ULN and TBL >2X ULN

ALP>2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the Sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, the patient must be discontinued from the study.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent
o
Participation in the study needs to be stopped for safety reasons in the case of a 
severe hypo- or hyperglycemic episode (see Sections 9.5.6.3 and 9.5.6.2)

Patient Decision

I8B-MC-ITRW(b) Clinical Pharmacology Protocol
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LY900014
o
the patient requests to be withdrawn from the study.
Patients who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).
8.3.
Patients Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  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 
(including tolerance limits for 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.
Investigators must document their review of each laboratory safety report.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Visit Description
9.2.1. Lead-In and Insulin Transition
After completing all screening procedures according to the Schedule of Activities (Section 2), 
patients will return to the CRU for the lead-in visit and receive instructions on the insulin 
transition.  The lead-in site visit is to take place at least 2 weeks prior to Period 1, Day -2.  At the 
lead-in site visit, patients will switch from their prescribed short-acting insulin to Humalog 
provided by the site.  Patients will also transition from their current regimen of basal insulin to 
site-provided insulin glargine according to the following guidance (patients can continue taking 
metformin throughout the study):

At least 2 weeks prior to CRU admission for Period 1, Day -2, patients will switch from 
either NPH insulin, insulin detemir or insulin glargine to using site-provided insulin 
glargine. The starting dose will be at the investigator’s discretion using patient’s current 
insulin regimen as reference.

Adjustments may be made in consultation with site investigator following feedback 
obtained from the patient during at least twice-weekly telephone follow-up as part of the 
insulin-transition period.

Once a stable dose has been established, patients will remain on it through to study 
completion.
Additionally, at the lead-in site visit, patients will be provided with general diabetes training 
including, but not limited to proper insulin-injection technique, dose calculation for short-acting 
insulins, correct self-monitoring of plasma glucose with a standardized glucometer, and 
interpretation of results, symptoms, and treatment of hypoglycemia.  In addition to the study 

 
 
 
   
  
  
 
  
 
 
 
   
    
  
  
 
 
 
   
 
 
 
 
 
   
  
 
    
 
 
 
 
 
 
 
  
  
 
 
   
 
 
 
 
 
  
 
 
 
   
  
 
 
 
 
 
 
   
   
 
   
  
 
 
 
 
  
  
   
 
  
 
  
  
 
 
 
 
 
 
 
 
 
  
  
  
 
   
   
  
 
 
  
  
    
 
  
 
 
 
  
 
   
  
 
 
 
  
 
 
  
   
    
 
 
   
  
     
 
  
 
  
   
 
 
 
 
  
  
  
   
 
 
 
  
 
  
 
  
 
  
  
 
 
  
 
  
  
   
 
 
    
 
   
 
  
  
 
  
 
 
  
  
 
 
 
 
  
 
  
   
 
  
  
 
   
 
  
 
 
  
  
    
 
  
 
  
 
  
 
 
 
  
   
 
 
 
  
   
 
  
    
 
  
 
   
 
   
  
 
 
   
  
    
 
  
  
  
 
 
 
   
 
  
 
  
  
  
 
  
 
 
 
  
 
  
 
  
 
 
 
   
 
 
  
 
  
 
 
 
 
 
 
   
 
 
 
 
   
 
 

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LY900014
Following completion of procedures associated with the dose finding assessment, patients may 
be offered a meal.  Patients will remain inpatient at the CRU until the Study MMTT for Period 1 
Day 1 the following day.
9.2.3. Study Period CRU Visits
9.2.3.1.
Run-In
Before the start of the run-in period, the cannulation of 2 veins will be performed.  A variable IV
infusion of glucose (20% dextrose solution) or insulin glulisine will be initiated in order to obtain 
a blood glucose target level of 135 ± 15 mg/dL (7.5 ± 0.8 mmol/L).  Any insulin infusion should 
be tapered off and stopped 30 minutes prior to start of the test meal.  For the last 30 minutes prior 
to trial product administration, the target blood glucose concentration should be targeted without 
any glucose infusion.  If this target glucose range is not attained before 11:00 AM, the meal test 
will be halted and may be performed on a separate visit; each meal test can only be repeated once
(see Section 6.2.1. for rescheduling).
9.2.3.2.
Study MMTT
Each patient’s individual, short-acting insulin (Humalog) may be administered before the start of 
a standard dinner (at approximately 19:00).  If a correction dose of short-acting insulin needs to 
be administered after the meal, no more than 6 U of short-acting insulin (Humalog) should be 
administered between 7 and 12 hours before the scheduled intake of the liquid test meal. 
The meal test may start in the early morning at approximately 08:00 with allowance up to 11:00, 
if required, to ensure the patient’s blood glucose is stable and at target, with the premeal 
activities as specified in the Schedule of Activities (Section 2).  LY900014 and Humalog will be 
administered at 2 different times: either immediately before the start of the meal, or 20 minutes
following the start of the test meal at each of the 4 periods according to the randomisation 
sequence.  For each MMTT, the patient should stay in a semi-supine position for 2 hours 
postdose. The patient will not be allowed to consume water for 2 hours after the MMTT 
assessment begins; however, water may be consumed freely 2 hours postmeal. 
A standardized liquid test meal will be administered on Day 1 for each of the 4 treatment 
periods.  Patients are expected to complete each test meal within 15 minutes of starting the meal.  
Patients will be without further food intake from the start of the meal to completion of blood 
collection (approximately 420 minutes) unless required to treat hypoglycemia (see Section 
9.5.8).
9.3.
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.

I8B-MC-ITRW(b) Clinical Pharmacology Protocol
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LY900014
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the patient to discontinue the IP before completing the study.  The investigator 
remains responsible for following AEs through an appropriate health care option.  All AEs will 
be followed until restoration or until a stable condition has been achieved.  The follow-up should 
not be interrupted, even if there is a reasonable explanation for the event.
After the informed consent form (ICF) is signed, study site personnel will record, via CRF, 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 categorise the severity of an AE as well as interpret and document whether 
or not an AE has a reasonable possibility of being related to study treatment, 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 IP, 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.
If a patient’s IP is discontinued as a result of an AE, study site personnel must report this to Lilly 
or its designee via CRF.
Hypoglycemic events are adverse events of special interest and will be collected and reported 
throughout the trial as described in Section 9.5.6.2.  All hypoglycemic events will be recorded in 
the hypoglycemia module of the CRF, this allows for the collection of comprehensive safety 
information relating to these events.
9.3.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 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 pre-filled pens necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or permanent 

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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 CRF after signing informed consent, SAE reporting to the 
sponsor begins after the patient has signed informed consent and has received IP.  However, if an 
SAE occurs after signing informed consent, but prior to receiving IP, 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 CRF 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 IP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements any pregnancy should be reported following the SAE 
process to collect data on the outcome for both mother and fetus.
9.3.1.1.
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 IP 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.
9.3.2. Complaint Handling
Lilly collects product complaints on IPs 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 IP or drug delivery system so that the situation can be assessed.
9.4.
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 usually can be treated with oral glucose.  More severe episodes with coma, 

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seizure, or neurologic impairment may be treated with intramuscular/SC glucagon or 
concentrated intravenous 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 and/or Humalog Product Label.
9.5.
Safety
9.5.1. Physical Examination
Physical examinations and routine medical assessments will be conducted, as specified in the 
Study Schedule and as clinically indicated (Section 2)
9.5.2. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). Patients will be fasted for at least 8 hours prior to clinical 
laboratory tests taken at screening.
9.5.3. Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Blood pressure and pulse rate should be measured after at least 10 minutes supine at screening 
and semi-supine on Day 1.
If orthostatic measurements are required, patients should be semi-recumbent for at least 
5 minutes and stand for at least 2 minutes.
If the patient feels unable to stand, semi-recumbent vital signs only will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
9.5.4. Electrocardiograms
For each patient, 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 IP, should be reported to Lilly, or its designee, as an AE via 
eCRF. 
For each patient, a single12-lead digital ECG will be collected according to the Schedule of 
Activities.  Electrocardiograms must be recorded before collecting any blood samples.  Patients 
must be supine for approximately 10 minutes before ECG collection and remain supine but 
awake during ECG collection.  Electrocardiograms may be obtained at additional times, when 
deemed clinically necessary.  All ECGs recorded should be stored at the investigational site.

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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.
9.5.5. Other Tests 
9.5.5.1.
Hip and Waist Circumference
Hip and waist circumference will be recorded as specified in the Schedule of Activities (Section
2).  The average of triplicate measurements of waist (narrowest circumference between lowest 
aspect of the ribs and anterior superior iliac crests) and the hip (widest circumference between 
the anterior superior iliac crests and the greater trochanters) circumference will be measured.
9.5.5.2.
Body Weight and Height
Body weight and height will be recorded as specified in the Schedule of Activities (Section 2)
and as clinically indicated.
9.5.6. Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes

adverse events.
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.5.6.1.
Hepatic Safety
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥2X ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and creatinine 
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. 

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Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2X ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2X 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 a SAE.
9.5.6.2.
Glucose Monitoring
Hypoglycemia will be described using the following definitions:

Documented Glucose Alert Level (Level 1), Plasma Glucose (PG) ≤70mg/dL 
(3.9 mmol/L):
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by PG ≤70 mg/dL (3.9 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical 
symptoms of hypoglycemia but with PG ≤70 mg/dL (3.9 mmol/L)
o
Unspecified hypoglycemia:  an event during which PG ≤70 mg/dL 
(3.9 mmol/L) but no information relative to symptoms of hypoglycemia was 
recorded.

Documented Clinically Significant Hypoglycemia (Level 2) PG <54 mg/dL 
(3.0 mmol/L):
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by PG ≤54 mg/dL (3.0 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical 
symptoms of hypoglycemia but with PG ≤54 mg/dL (3.0 mmol/L)
o
Unspecified hypoglycemia:  an event during which PG ≤54 mg/dL 
(3.0 mmol/L) but no information relative to symptoms of hypoglycemia was 
recorded.

Severe hypoglycemia (Level 3):  an event requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions.  During 
these episodes, the patient has an altered mental status and cannot assist in their care, 
is semiconscious or unconscious, or experienced coma with or without seizures and 
may require parenteral therapy.  Plasma glucose measurements may not be available 
during such an event, but neurological recovery attributable to the restoration of 
blood glucose concentration to normal is considered sufficient evidence that the event 
was induced by a low PG concentration (PG ≤70 mg/dL [3.9 mmol/L])
o
Severe hypoglycemia requiring medical attention:  a severe hypoglycemic 
event when patients require therapy by HCPs (EMTs, emergency room 
personnel, etc.).

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Other Hypoglycemia:

Nocturnal hypoglycemia: any hypoglycemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycemia) that occurs between 
bedtime and waking

Relative hypoglycemia: an event during which typical symptoms of hypoglycemia, 
that do not require the assistance of another person, are accompanied by PG
>70 mg/dL (3.9 mmol/L), but these levels may be quickly approaching the 70 mg/dL 
(3.9 mmol/L) threshold

Overall (or total) hypoglycemia:  This optional category combines all cases of 
hypoglycemia.  If an event of hypoglycemia falls into multiple subcategories, the 
event is only counted once in this category

Probable symptomatic hypoglycemia: An event during which symptoms of 
hypoglycemia are not accompanied by a PG measurement but that was presumably 
caused by a blood glucose concentration ≤70 mg/dL (3.9 mmol/L).
9.5.6.3.
Severe Hypoglycemia
The determination of a hypoglycemic event as an episode of severe hypoglycemia as defined 
above will be made by the investigator based on the medical need of the patient to have required 
assistance and is not predicated on the report of a patient simply having received assistance.
All hypoglycemic events are adverse events of special interest and will be recorded in the 
hypoglycemia module of the CRF (see Section 9.3. for details).  All episodes of severe 
hypoglycemia must be reported as SAEs.
9.5.6.4.
Injection Site Assessments (Local Tolerability)
Injection-site assessments for local tolerability will be conducted as specified in the Schedule of 
Activities (Section 2) and more frequently if deemed necessary by the investigator.
Digital pictures will be taken, if possible, of the injection site at the time of identification of local 
intolerability and thereafter as often as judged necessary by the investigator.  The pictures should 
include patient number, visit number, time after dosing, and a ruler for scaling.
Local tolerability at the injection site will be evaluated by means of the following objective and 
subjective assessments within the following categories:  pain (including burning), itching, 
erythema, edema, and induration/infiltration.  The assessments will be recorded by study 
personnel
9.5.7. Self-Monitored Plasma Glucose during Outpatient Period
Self-monitored plasma glucose testing will consist of a minimum of daily 4-point SMPG profiles 
(preprandial for 3 meals [that is, breakfast, lunch, and dinner] and at bedtime) using the 
glucometer provided by the site.  Patients will be instructed to use a diary to document any AEs, 
hypoglycemic events, insulin doses, and the SMPG values. 
During the lead-in/insulin transition and wash-out period, hyperglycemia will be monitored daily 
by fasting fingerstick glucose tests and documented in a diary. Each patient will be instructed to 

 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
  
  
 
   
 
   
 
 
  
   
 
  
   
  
 
 
 
 
 
  
 
  
  
  
   
 
  
 
  
  
 
 
   
 
 
 
  
  
  
 
  
 
  
 
 
 
  
 
 
 
 
 
   
  
  
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
  
   
 
 
 
      
  
  
 
  
 
 
  
  
   
  
  
  
  
   
 
  
  
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
   
 
  
  
  
  
 
  
  
 
 
 
 
 
 
  
  
 
 
  
 
 
   
  
  
 
 
  
   
   
 
  
 
 
 
  
 
 
  
 
  
   
 
   
  
   
 
   
 
  
 
 
  
 
  
 
 
 
  
 
   
 
  
  
 
 
  
  
 
  
 
 
 
  
 
 
  
   
  
 
 
 
 
   
 
 
  
  
  
 
  
   
   
 
   

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9.7.1. Glucodynamics Samples
Blood samples (approximately 0.2 mL each) will be obtained for the measurement of glucose at 
the times specified in the Schedule of Activities (Section 2) using a validated method (for 
example, glucose analyzer) that will be readily available at the investigative site during the 
inpatient periods in order to provide real-time glucose measurement.  Repeat samples for 
counter-checking of apparent spurious results may be taken where indicated.  Samples will be 
disposed of upon confirmation of results.
9.7.1.1.
Glucose Samples (Run-In Period)
Blood glucose concentrations will be monitored at a minimum of 30 minute intervals during the 
run-in period on Day 1 (from approximately 7 hours before dosing).
9.7.1.2.
Glucose Samples (MMTT)
Blood samples will be obtained for the measurement of glucose at the times specified in the 
Schedule of Activities.  These glucose measurements will be used for patient safety management
as well as for GD evaluations.
9.7.2. Samples for 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. 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.  
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 the IP.  Any samples 
remaining after 15 years will be destroyed.
9.8.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, where local regulations allow. 
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 IP and 
to investigate genetic variants thought to play a role in diabetes mellitus and related 
complications.  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. 

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Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ERBs/institutional review boards (IRBs) impose shorter time 
limits, for the study at a facility selected by Lilly or its designee.  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. 
9.9.
Exploratory Biomarkers
9.9.1. C-Peptide
Blood samples (2.5 mL) will be collected to determine serum concentrations of C-peptide as 
described in the Schedule of Activities (Section 2) using a validated method at a central 
laboratory.  These samples and any remaining serum after C-peptide analyses will be discarded.  
Instructions for the collection and handling of these samples will be provided by the sponsor. 
9.10. Health Economics
This section is not applicable for this study.

 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
  
  
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
   
  
 
 
   
 
  
  
 
 
 
 
 
 
 
 
  
   
  
 
 
   
 
 
    
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
   
 
  
 
 
  
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
  
  
   
 
 
  
 
  
  
 
 
 
 
 
  
  
  
 
 
 
 
  
 
 
  
 
 
  
  
 
 
 
 
  
 
 
  
  
      
   
 
 
  
 
 
  
   
  
 
   
 
  
   
  
  
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
   
 
   
  
  
 
 
    
  
     
 
 
 
   
   
  
   
 
 
  
  
  
 
 
  
   
 
   
 
  
 
  
 
 
   
 
 
 
   
 
 
  
   
  
 
   
   
 
   
 
 
   
   
  
  
 
  
  
 

 
 
 
 
 
  
     
 
  
  
   
 
 
 
 
  
  
   
 
  
 
 
 
  
  
 
 
  
   
 
 
 
   
  
  
  
 
 
   
 
 
 
  
 
  
 
   
 
  
  
 
  
 
 
  
 
 
 
 
  
 
  
  
 
 
  
 
 
 
 
  
    
  
 
 
 
 
 
 
   
 
 
 
 
  
  
 
 
  
  
   
 
 
 
   
 
 
  
 
  
 
  
 
 
  
  
 
  
  
  
 
  
  
 
 
  
   
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
  
  
 
 
  
  
 
  
 
 
  
  
 
 
 
 
  
 
 
  
  
 
 
   
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
   
 
    
   
 
  
 
 
 
 
  
 
   
 
 
  
  
 
 
  
 
    
  
 
 
  
 
 
  
  
 
  
  
  
  
 
   
 
   
 
  
   
 
 
  
 
  
 
 
 
 
 
  
  
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
     
 
 
  
 
 
   
 
 
 
   
 
 
 
 
  
 
 
  

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7 hours [AUC(3-7h)], and AUC from time zero to infinity [AUC(0-∞)]. In addition, the apparent 
total body clearance of drug calculated after extra-vascular administration (CL/F), and volume of 
distribution after extra-vascular administration (Vz/F) also will be determined. Other parameters 
may be calculated as deemed appropriate.  Additional partial AUCs may be computed as 
necessary, such as AUC from time zero to 2 hours.
The insulin lispro PK parameters for assessing faster insulin lispro absorption are the early 
50% tmax and AUC(0-30min).
Although attempts will be made to adhere to the scheduled collection times, it is recognized that 
situations arise that may compromise sample collection at the scheduled times.  Parameters will 
be individually calculated for each patient based on actual collection times and presented by 
summary statistics.
10.3.2.2. Pharmacokinetic Statistical Inference
Patients who did not keep identical insulin lispro doses for the MMTTs across all periods will be 
excluded from the statistical analysis of the PK parameters.
Log-transformed AUCs, Cmax, CL/F and Vz/F for insulin lispro will be evaluated to estimate 
geometric means, ratios of geometric means of insulin lispro within LY900014 to Humalog, and 
their corresponding 95% CIs of the ratios using the mixed-effects model that includes treatment 
(LY900014, Humalog) and period as fixed effects and patient 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 t 1/2). Least-squares means, treatment 
differences in LSmeans, and the corresponding 95% CIs for the treatment differences will be 
estimated from the model.  The p-value on the difference between least squares (LS) means will 
be used to determine statistical significance. The treatment ratios and 95% CIs for the ratios will 
be calculated using Fieller’s theorem (Chow and Liu 2009). 
Statistical significance will be achieved when the p-value for a test is less than 0.05.
10.3.3. Glucodynamic Analyses
10.3.3.1. Glucodynamic Parameter Estimation
Patients who receive at least 1 dose of study drug and have evaluable GD data will be included in 
the analysis set for the GD analyses. 
Data will be analyzed for the patients during each MMTT. The change from baseline values (the 
average of -30, -15, and 0 minutes represented as the 0-hour time point immediately prior to the 
start of the MMTT) for each patient will be calculated. The area under the baseline subtracted 
glucose concentration versus time curve from time 0 to 2hr (∆AUC[0-2h] and area under the 
baseline subtracted glucose concentration versus time curve from time 0 to 5hr post meal 
(∆AUC[0-5h]) will be calculated. In addition, the change from baseline maximum glucose 
observed during the 5 hours postmeal and change from baseline 1-hour glucose and 2-hour 
glucose post the start of the meal will be calculated. Other partial ∆AUCs may be calculated, as 
deemed appropriate.

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Parameters will be individually calculated for each patient and presented by summary statistics.
10.3.3.2. Glucodynamic Statistical Inference 
Patients who did not complete the entire meal or had significant changes in nutrient consumption 
of the standardized liquid test meal or dose changes during the MMTTs will be excluded from all 
the statistical analysis of the GD parameters. Summary statistics (including number of patients, 
mean, SD or standard error, minimum, and maximum) will be presented by treatment and by 
timing of dose (all 4 combinations of treatment and timing of dose).  The GD parameters on the 
original scale (not log-transformed) will be analyzed using a statistical model that includes
treatment, timing of dose (0 [immediately before the test meal], 20 minutes following the start of 
test meal), treatment-by-timing of dose interaction, and period as fixed effects and patient as a 
random effect. The p-value on the difference between LSmeans will be used to determine 
statistical significance and the corresponding 95% CIs for the LSmean ratios from Fieller’s 
theorem will be presented.
Statistical significance will be achieved when the p-value for a test is less than 0.05.
10.3.4. Evaluation of Immunogenicity
The frequency of antibody formation to insulin lispro will be determined.  The relationship 
between the presence (or absence) of antibodies and AEs will be assessed.  Likewise, the
relationship between the presence of antibodies and the PK parameters and GD response to 
insulin lispro may be assessed. 
10.3.5. C-Peptide
Mean and individual C-peptide concentration verses time plots will be presented for all 
4 combinations of treatment and timing of dose.  In addition, individual plots overlaying the 
C-peptide concentration verses time with the insulin lispro serum concentration verses time will 
be presented.  Other plots may be explored, such as the C-peptide concentrations relative to 
blood glucose concentrations during the test meal.
10.3.6. 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.

 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
  
    
  
  
  
 
   
 
  
 
 
 
 
 
 
   
  
 

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Appendix 1. Abbreviations and Definitions

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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.
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 subjects are aware of the treatment received
BMI
body mass index
CIOMS
Council for International Organizations of Medical Sciences
CI
confidence interval
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all 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
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.
CRU
clinical research unit
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

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GCP
good clinical practice
GD
glucodynamic
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
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.  
Investigational 
product (IP)
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.
IMP
investigational medicinal product
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
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
MMTT
mixed meal tolerance test
Non-
investigational 
product
A product that is not being tested or used as a reference in the clinical study, but is provided 
to subjects 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.
OAD
oral antidiabetics
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PAH
pulmonary arterial hypertension
randomize
the process of assigning subjects/patients to an experimental group on a random basis
PD
pharmacodynamic
PK
pharmacokinetic
SAE
serious adverse event

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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-monitored plasma glucose
SUSARs
suspected unexpected serious adverse reactions
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 
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus

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Appendix 2. Clinical Laboratory Tests
Safety Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate 
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphorus 
Leukocytes (WBC) 
Glucose fasting
Platelets
HbA1Cb
C-peptideb
Absolute counts of:
Blood urea nitrogen (BUN)
Neutrophils
Uric acid 
Lymphocytes
Total cholesterol 
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Alkaline phosphatase (ALP)
Urinalysis
Aspartate aminotransferase (AST)
Specific gravity
Alanine aminotransferase (ALT)
pH
Creatinine
Protein
Gamma-glutamyl transferase (GGT)
Glucose
Ketones
Breath ethanol testingc
Bilirubin
Urine drug screenb,c
Urobilinogen
Hepatitis B surface antigenb
Blood
Hepatitis C antibodyb
Nitrite
HIVb
Leucocytes
Pregnancy test e
Microscopyd
FSH b
International normalised ratio (INR)b
Partial thromboplastin time (PTT)b
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Results will be validated by the local laboratory at the time of initial testing
b
Performed at screening only
c
may be repeated prior to admission to the clinical research unit and at other times indicated in the Schedule of 
Activities
d
If clinically indicated, per investigator’s discretion
e
Females only: serum pregnancy test at screening, urine pregnancy test as indicated by Schedule of Activities

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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 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(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s). All ICFs must be compliant with the ICH guidelines
on good clinical practices (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator’s Brochure or Patient Information Leaflet, Package Insert or 
Summary of Product Characteristics 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 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 subject/patient personal information collected will be provided in a 
written document to the subject/patient by the Sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 4. Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic 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 bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability

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Appendix 5. Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study. 
Protocol I8B-MC-ITRW Sampling Summary
Purpose
Blood Volume per 
Sample(s) (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening
11
1
11
Clinical laboratory testsa
9
2
18
Dose finding assessment
0.2
15
3
Blood glucose sampling (run-in)
0.2
14 samples x 4 
periods = 56
11.2
Blood glucose sampling (MMTT)
0.2
24 samples x 4 
periods = 96
19.2
Pharmacokinetics – insulin lispro
2.5
22 samples x 4 
periods = 88
220
C-peptide
2.5
9 samples x 4 
periods = 36
90
Immunogenicity
5
4
20
Pharmacogenetics
10
1
10
Total
402.4
Total for clinical purposes 
410
a
Additional samples may be drawn if needed for safety purposes.

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Appendix 6. Protocol Amendment I8B-MC-ITRW(b)
Summary: A Study to Evaluate the 
Pharmacokinetics and Glucodynamics of 
LY900014 compared to Humalog® in Patients 
with T2DM
Overview
Protocol I8B-MC-ITRW: A Study to Evaluate the Pharmacokinetics and Glucodynamics of 
LY900014 compared to Humalog® in Patients with T2DM has been amended.  The new 
protocol is indicated by Amendment (b) and will be used to conduct the study in place of any 
preceding version of the protocol.
Changes to the protocol made to clarify text, and correct mis-statements are listed below:

Correction that Remodulin® was initially given approval in Germany in 2006

Clarification of Schedule of Activities in line with Appendix 2 that serum pregnancy test 
will be performed for all females

Clarification of fasting status in Schedule of Activities and Section 6.3.1 in line with 
fasting blood glucose required at follow-up as presented in Appendix 2

Clarify that vital signs will be taken supine at screening and semi-supine on Day 1

Establish consistency of dose-finding assessment from 07:00 to 11:00 throughout the 
protocol

Clarify patients are to remain inpatient at the CRU following completion of the 
dose-finding assessment conducted on Day -1 until completion of Day 1 procedures

Clarify that patients will contact the site if fasting fingerstick glucose level is >200 mg/dL 
rather than >240 mg/dL in line with the change to patient diary requested and approved 
by the Ethics Committee

Clarify that patients may consume up to 20 g of carbohydrates to treat or prevent 
hypoglycemia (regardless of hypoglycemia level) during fasting periods.

Clarified that injection site assessments will be conducted immediately following 
injection rather than pre-dose

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

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Study Schedule Protocol I8B-MC-ITRW
Sign 
Informed 
Consent
Screening
Lead-in
Study Period (Periods 1 to 4)
Follow-
up/Early 
discontinuation
Comments
Procedure
Days -30 
to -17
14 days prior 
to Day -2
Day   -1
Day 1
≥ 14 days after 
discharge
….
Vital signs (semi
recumbent):  blood 
pressure and pulse 
rate
X
Predose, 30 and 120 
minutes postdose
X
Vital signs will be taken while 
patients are supine at screening 
and semi-supine on Day 1. 
12-lead ECG 
X
Predose (Period 1) 
X
Single ECGs will be collected 
for safety.  
Clinical laboratory 
tests
X
Predose for Period 1 only
X
Fasting laboratory test for 
screening and follow-up.  
Screening laboratory tests will 
be analyzed at a local 
laboratory (see Section 9.5.2).  
…….
Pregnancy test
X
X
X
For female patients of 
childbearing potential only.  
Serum pregnancy test will be 
performed at screening and 
urine pregnancy tests will be 
performed at admission for 
Period 1 and at follow-up (see 
Appendix 2).
…..
Injection site local 
tolerability 
assessments
0 (predose), 20, and 60 
minutes postdose
Assessments of injection site 
local tolerability will occur 
immediately following the 
injection.

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3.2
Background
…….
LY900014 represents a new formulation that contains insulin lispro, treprostinil, citrate and other 
excipients.  This formulation involves the novel use of a microdose of treprostinil (Remodulin®) 
as an excipient to enhance the absorption of insulin lispro by local vasodilatation rather than as 
an active pharmaceutical ingredient to elicit a systemic effect. Treprostinil is a prostacyclin 
analogue, administered either through inhalation (Tyvaso®), as an intravenous (IV) infusion or as 
a continuous SC administration for the treatment of symptomatic pulmonary arterial 
hypertension (PAH) and has been approved in the US since 2002 and in Germany since 
20062007 (AMIS database [WWW])Remodulin package insert, 2014).  
6.3.1 Meals and Dietary Restrictions
Patients will be fasted (except for water) for at least 10 hours before each test meal and 8 hours 
prior to screening and follow-up assessments (see Section 9.5.8 for guidelines on hypoglycemia 
treatment).  The patient will not be allowed to consume water for 2 hours after the MMTT 
assessment begins; however, water may be consumed freely 2 hours postmeal.
9.2.2 Dose-Finding Assessment
After transitioning to a stable dose of insulin glargine, patients may return to the CRU on Period 
1, Day -1 in the early morning for the dose-finding assessment, which may begin between 07:00 
and 0911:00.  
…
Following completion of procedures associated with the dose finding assessment, patients may 
be offered a meal.  Patients will have the option to remain inpatient at the CRU until the Study 
MMTT for Period 1 Day 1 the following day.
9.5.3 Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Blood pressure and pulse rate should be measured after at least 10 minutes supine at screening
and semi-recumbentsupine on Day 1.
9.5.7
Self-Monitored Plasma Glucose during Outpatient 
Period
Self-monitored plasma glucose testing will consist of a minimum of daily 4-point SMPG profiles 
(preprandial for 3 meals [that is, breakfast, lunch, and dinner] and at bedtime) using the 
glucometer provided by the site.  Patients will be instructed to use a diary to document any AEs, 
hypoglycemic events, insulin doses, and the SMPG values. 

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During the lead-in/insulin transition and wash-out period, hyperglycemia will be monitored daily 
by fasting fingerstick glucose tests and documented in a diary.  Each patient will be instructed to 
contact the investigational site staff if his/her fasting fingerstick glucose level is >240200 mg/dL. 
9.5.8
Treatment of Hyperglycemia and Hypoglycemia
Patients will be without food intake from the start of the MMTT to completion of blood 
collection (approximately 420 minutes) unless required to treat hypoglycemia (see Section 
9.5.6.2 for definition of hypoglycemia) with either rapidly absorbable oral carbohydrates or IV 
glucose. 
Patients may consume up to 20 g of carbohydrates to treat or prevent hypoglycemia 
(Level 2 ≤54 mg/dL [see Section 9.5.6.2] during the fasting periods (See Sections 2, 6.3.1 and 
9.2.2).  If carbohydrates are administered and consumed, this must be captured in the patient’s 
diary and eCRF.
11
References
AMIS database. 13 June 2006. DIMDI (Deutsches Institut für medizinische Dokumentation und 
Information. Available at: https://www.dimdi.de/dynamic/de/db/recherche/index.htm. 
Accessed: November 07, 2017.