Clinical trial NCT04049123
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2019-11-18; Completion date: 2020-10-23
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate a new formulation of insulin lispro, LY900014, which is a drug that lowers blood sugar. The study will look at how the body processes LY900014 and the effect of LY900014 on blood sugar levels. For each participant, the study will consist of 3 periods and will last about 51 days.

Detailed description:

Arms: arm 1: 15 units (U) Insulin Lispro (Humalog) administered once, subcutaneously (SC), in one of three study periods. arm 2: 7 U, and 15 U LY900014 administered once, SC, in two of three study periods.
Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
I8B-MC-ITRY Protocol (a) 
 
A Study to Evaluate the Pharmacokinetics and Glucodynamics of LY900014 Following Single 
Dose Administration in Health Chinese Subjects 
 
NCT04049123 
 
Approval Date 20-Feb-2019 


I 8 B-M C -I TR Y Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 1
L Y 9 0 0 0 1 4
Pr ot o c o l I 8 B-M C -I T R Y( a)
A St u d y t o E v al u at e t h e P h ar m a c o ki n eti c s a n d 
Gl u c o d y n a mi c s of L Y 9 0 0 0 1 4 F oll o wi n g Si n gl e D o s e 
A d mi ni str ati o n i n H e alt h y  C hi n e s e S u bj e ct s
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s pr ot o c ol i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
( L Y 9 0 0 0 1 4), u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s.
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci al l y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .  
L Y 9 0 0 0 1 4
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Cli ni c al P h ar m a c ol o g y Pr ot o c ol A p pr o v e d o n : 1 2 D e c e m b er 2 0 1 8
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e pr o vi d e d b el o w.
A p pr o v al D at e: 2 0- F e b- 2 0 1 9 G M T


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 2
LY900014
Table of Contents
A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 Following Single Dose 
Administration in Healthy Chinese Subjects
Section
Page
Protocol I8B-MC-ITRY(a) A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 Following Single Dose Administration 
in Healthy Chinese Subjects................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................13
3.1.
Study Rationale............................................................................................................13
3.2.
Background..................................................................................................................13
3.3.
Benefit/Risk Assessment..............................................................................................14
4.
Objectives and Endpoints..................................................................................................15
5.
Study Design.....................................................................................................................16
5.1.
Overall Design .............................................................................................................16
5.2.
Number of Participants.................................................................................................17
5.3.
End of Study Definition ...............................................................................................17
5.4.
Scientific Rationale for Study Design...........................................................................17
5.5.
Justification for Dose ...................................................................................................17
6.
Study Population...............................................................................................................19
6.1.
Inclusion Criteria..........................................................................................................19
6.2.
Exclusion Criteria ........................................................................................................21
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................22
6.3.
Lifestyle and/or Dietary Requirements .........................................................................22
6.3.1.
Meals and Dietary Restrictions.............................................................................22
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................22
6.3.3.
Activity................................................................................................................23
6.4.
Screen Failures.............................................................................................................23
7.
Treatment..........................................................................................................................24
7.1.
Treatment Administered...............................................................................................24
7.1.1.
Packaging and Labeling .......................................................................................24
7.2.
Method of Treatment Assignment ................................................................................24
7.2.1.
Selection and Timing of Doses.............................................................................25


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 3
LY900014
7.3.
Blinding .......................................................................................................................25
7.4.
Dose Modification........................................................................................................25
7.5.
Preparation/Handling/Storage/Accountability...............................................................25
7.6.
Treatment Compliance .................................................................................................26
7.7.
Concomitant Therapy...................................................................................................26
7.8.
Treatment after the End of the Study............................................................................26
8.
Discontinuation Criteria ....................................................................................................27
8.1.
Discontinuation from Study Treatment.........................................................................27
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................27
8.2.
Discontinuation from the Study....................................................................................27
8.3.
Subjects Lost to Follow-up...........................................................................................28
9.
Study Assessments and Procedures ...................................................................................29
9.1.
Efficacy Assessments...................................................................................................29
9.2.
Adverse Events ............................................................................................................29
9.2.1.
Serious Adverse Events........................................................................................30
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................30
9.2.2.
Complaint Handling.............................................................................................31
9.3.
Treatment of Overdose.................................................................................................31
9.4.
Safety...........................................................................................................................31
9.4.1.
Laboratory Tests ..................................................................................................31
9.4.2.
Vital Signs ...........................................................................................................31
9.4.3.
Electrocardiograms ..............................................................................................31
9.4.4.
Physical Examination...........................................................................................32
9.4.5.
Body Weight........................................................................................................32
9.4.6.
Hip and Waist Circumference ..............................................................................32
9.4.7.
Injection-Site Assessments...................................................................................32
9.4.8.
Safety Monitoring ................................................................................................32
9.4.8.1.
Glucose Monitoring........................................................................................33
9.4.8.2.
Hepatic Safety................................................................................................34
9.5.
Pharmacokinetics .........................................................................................................35
9.5.1.
Bioanalysis...........................................................................................................35
9.6.
Glucodynamics (Euglycemic Glucose Clamp)..............................................................35
9.7.
Immunogenicity Assessments.......................................................................................36
9.8.
Genetics .......................................................................................................................36
9.9.
Biomarkers...................................................................................................................36
9.10. Health Economics ........................................................................................................36
10.
Statistical Considerations and Data Analysis.....................................................................37
10.1. Sample Size Determination ..........................................................................................37


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 4
LY900014
10.2. Populations for Analyses..............................................................................................37
10.2.1.
Study Participant Disposition ...............................................................................37
10.2.2.
Study Participant Characteristics ..........................................................................37
10.3. Statistical Analyses ......................................................................................................37
10.3.1.
Safety Analyses....................................................................................................37
10.3.1.1.
Clinical Evaluation of Safety..........................................................................37
10.3.1.2.
Statistical Evaluation of Safety.......................................................................38
10.3.2.
Pharmacokinetic Analyses....................................................................................38
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................38
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................39
10.3.3.
Glucodynamic Analyses.......................................................................................39
10.3.3.1.
Glucodynamic Parameter Estimation..............................................................39
10.3.3.2.
Glucodynamic Statistical Inference.................................................................39
10.3.4.
Interim Analyses..................................................................................................39
11.
References ........................................................................................................................40


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 5
LY900014
List of Tables
Table
Page
Table ITRY.1.
Objectives and Endpoints .......................................................................15
Table ITRY.2.
Dosing Sequences...................................................................................17
Table ITRY.3.
Investigational Products Administered....................................................24
Table ITRY.4.
Amendment Summary for Protocol I8B-MC-ITRY Amendment(a)........51


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 6
LY900014
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................41
Appendix 2.
Clinical Laboratory Tests........................................................................45
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................46
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............49
Appendix 5.
Blood Sampling Summary......................................................................50
Appendix 6.
Protocol Amendment I8B-MC-ITRY(a) Summary A Study to 
Evaluate the Pharmacokinetics and Glucodynamics of LY900014 
Following Single Dose Administration in Healthy Chinese 
Subjects..................................................................................................51


I8B-MC-ITRY Clinical Pharmacology Protocol(a) 
Page 7 
LY900014 
1. Protocol Synopsis 
Title of Study:   
A Study to Evaluate the Pharmacokinetics and Glucodynamics of LY900014 Following Single Dose Administration 
in Healthy Chinese Subjects 
The aim of this study is to assess the insulin lispro pharmacokinetic (PK) and glucodynamic (GD) profiles, and 
safety and tolerability following administration of LY900014 during a euglycemic glucose clamp in healthy Chinese 
subjects.   
Objectives/Endpoints: 
Objectives 
Endpoints 
Primary 
To evaluate the PK of insulin lispro following 
administration of single subcutaneous (SC) doses of 7 
and 15 U of LY900014 and 15 U of Humalog in 
healthy Chinese subjects. 
 
Area under the serum concentration versus time curve 
(AUC) from time zero to 10 hours (AUC[0-10h]), 
AUC from zero to infinity (AUC[0-∞]), and maximum 
observed concentration (Cmax). 
Secondary 
To evaluate the GD of insulin lispro during a 
euglycemic clamp procedure following SC doses of 7 
and 15 U of LY900014 and 15 U of Humalog in 
healthy Chinese subjects. 
To evaluate the safety and tolerability of LY900014. 
 
Total amount of glucose infused (Gtot) and maximum 
glucose infusion rate (Rmax). 
 
Adverse events (AEs). 
 
Summary of Study Design:   
Study I8B-MC-ITRY is a Phase 1, single-center, randomized, subject-blind, 3-period, crossover study to evaluate 
the PK of insulin lispro for LY900014 in healthy Chinese subjects.   
Following satisfactory completion of screening procedures, subjects will receive a dose of LY900014 or Humalog, 
according to the randomization, on Day 1 of each of 3 dosing periods and the time-concentration and time-action 
profiles of insulin lispro will be evaluated simultaneously during a euglycemic glucose clamp of approximately 
10 hours duration.  On completion of the euglycemic clamp, subjects will be provided with a meal and will undergo 
glucose monitoring prior to discharge.  Serial blood samples will be collected during the clamp procedure at 
prespecified times to assess the PK parameters of insulin lispro.  Safety assessments and an evaluation of local 
tolerability at injection sites will be conducted at prespecified times.  Local tolerability assessments will include 
injection-site assessments for signs of edema and erythema.  A physician’s medical assessment will be required 
before subjects are discharged from the clinical research unit (CRU), which will be at the discretion of the 
investigator.   


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 8
LY900014
Dosing Arms and Planned Duration for an Individual Subject:  
Subjects will be randomized to 1 of 3 dosing sequences as follows:
Dosing Sequence
Period 1 
Period 2 
Period 3 
1
15 U Humalog 
7 U LY900014
15 U LY900014
2
7 U LY900014
15 U Humalog
15 U LY900014
3
7 U LY900014
15 U LY900014
15 U Humalog
Each subject will participate in a screening visit up to 28 days prior to dosing (Day 1 of Period 1) followed by 
3 study periods each comprising a minimum of 1 night inpatient stay (Day -1 through Day 1).  Dosing in 
consecutive periods will be separated by at least 3 days and subjects will attend a follow-up ≥14 days after receiving 
the last dose of study drug.  
Number of Subjects:  
Up to 15 subjects may be randomized to ensure at least 12 subjects (4 per sequence) complete the study.  
Statistical Analysis:  
Safety:  Safety analyses will be conducted for all enrolled subjects, whether or not they completed all protocol 
requirements.  Safety parameters that will be assessed include AEs, safety laboratory parameters, vital signs, and 
electrocardiogram (ECG) parameters.  The parameters will be listed, and summarized using standard descriptive 
statistics.  Additional analysis will be performed if warranted upon review of the data.
Pharmacokinetics:  Pharmacokinetic analyses will be conducted on data from all subjects receiving at least 1 dose of 
study drug with evaluable PK.  Pharmacokinetic analyses will be conducted using standard noncompartmental 
method of analysis.  Free serum insulin lispro concentrations will be used to calculate Cmax, AUC(0-10h), and
AUC(0-∞).  Other additional parameters, such as partial AUCs, may be calculated as deemed appropriate.  
The PK parameter estimates for insulin lispro will be summarized using standard descriptive statistics.  
Glucodynamics: Glucodynamic assessments will be determined from the glucose clamp procedure, where the 
glucose infusion rate (GIR) over time will be used as a measure of insulin effect. Glucodynamic analyses will be 
conducted on those subjects who complete at least 1 clamp procedure.  A locally weighted scatterplot smoothing 
(LOESS) function will be applied to all individual GIR versus time profiles in each dosing group and/or period. The 
fitted data for each subject will be used to calculate Rmax and Gtot. Other additional GD parameters may be 
computed as necessary.  The values of these GD parameters will be summarized by treatment and/or period through 
descriptive statistics.  Mean LOESS fits of GIR versus time profiles will be generated. The GD parameter estimates 
for insulin lispro will be summarized using standard descriptive statistics.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 9
LY900014
2. Schedule of Activities


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 10
LY900014
Study Schedule Protocol I8B-MC-ITRY
Screening
Euglycemic clamp procedure 
Periods 1, 2, and 3
Follow-
up/Early 
discontinuation
Instructions/Comments
Procedure
Up to -28 
days
Day -1
Day 1a
≥14 days after 
last dose
Informed consent
X
Admission to 
CRU
X
Overnight fast
X
X
X
Subjects will fast for approximately 8 hours prior 
to screening and follow-up/early discontinuation 
and from approximately 8 hours before each dose 
until the end of the glucose clamp procedure.
Hip and waist 
circumference
Period 1 
only
Measurements taken in triplicate.
Height
X
Body weight
X
X
Medical history 
and physical 
examination
X
Medical 
assessment
X
Predose and before discharge from 
CRU 
X
Medical assessment includes medical review and 
targeted examination as appropriate.
Vital signs 
(supine): body 
temperature, 
blood pressure 
and pulse rate
X
Predose and approximately 10 hours 
postdose (end of the clamp procedure)
X
Single vital signs measurements for safety.  
12-lead ECG
X
Predose and approximately 10 hours 
postdose (end of the clamp procedure)
X
Single ECGs will be collected for safety. 
Electrocardiograms may be collected at additional 
times when deemed clinically necessary.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 11
LY900014
Screening
Euglycemic clamp procedure 
Periods 1, 2, and 3
Follow-
up/Early 
discontinuation
Instructions/Comments
Procedure
Up to -28 
days
Day -1
Day 1a
≥14 days after 
last dose
Clinical 
laboratory tests
X
X
All scheduled clinical laboratory tests will be 
conducted after at least 8 hours fasting.  To 
monitor subject safety, additional tests may be 
performed at the discretion of the investigator as 
needed throughout the study.  All testing will be 
conducted at a local laboratory.  
Serology
X
FSH
X
Female subjects only, when needed to confirm 
postmenopausal status.  
Pregnancy test
X
X
X
Female subjects only.  A serum pregnancy test 
will be performed at screening. Urine pregnancy 
tests will be performed on Day -1 of Period 1, at 
follow-up, and on Day -1 of Periods 2 and 3 if the 
time since the previous pregnancy test is >2 
weeks.
Urine drug screen 
and alcohol breath 
test
X
Study drug 
administration
X (time = 0)
Injection-site 
local tolerability 
assessments
Immediately postdose, 60, 240, and 
600 minutes postdose
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, 420, 480, 540, and 
600 minutes postdose


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 12
LY900014
Screening
Euglycemic clamp procedure 
Periods 1, 2, and 3
Follow-
up/Early 
discontinuation
Instructions/Comments
Procedure
Up to -28 
days
Day -1
Day 1a
≥14 days after 
last dose
Euglycemic 
clamp
X
0 to 10 hours postdose
If the GIR falls to zero for at least 30 minutes 
after the clamp has been underway for at least 
8 hours, the clamp will be discontinued.  
Following completion of the euglycemic clamp, 
subjects will receive a meal and undergo glucose 
monitoring as deemed necessary by the 
investigator prior to discharge.  
Blood glucose 
sampling
(euglycemic 
clamp)
Approximately every 10 minutes for
approximately 30 minutes before the
start of dosing (for baseline
measurement).  During clamp, 
sampling occurs every 2.5 to 3 minutes 
for the first 30 minutes, every 5 
minutes for 30 to 120 minutes; every 
10 minutes for 120 to 480 minutes and 
every 20 minutes for 480 to 600 
minutes.
Sampling times are relative to study drug 
administration (time 0). Failure to obtain samples
due to clinical issues, such as problems with 
venous access, will not be considered a protocol 
violation. Repeat samples for counter checking of 
apparent spurious results may be taken where 
indicated.
Immunogenicity 
sample
Predose
X
Discharge from 
CRU
X
Subjects will be discharged after completion of all 
study procedures on Day 1, at the discretion of the 
investigator.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; FSH = follicle-stimulating hormone; GIR = glucose infusion rate; 
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. Electrocardiograms and vital sign 
measurements should be scheduled before but as close as possible to the PK sampling times. 
a
There will be a minimum of 3 days between dosing in consecutive periods.  


I 8 B-M C -I TR Y Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 1 3
L Y 9 0 0 0 1 4
3. I ntr o d u cti o n
3. 1.
St u d y R at i o n al e
A pra n dial i ns uli n wit h faster -o n a n d/ or faster -off c haracterist ics mi g ht re d uce gl yce mic 
e xc ursi o ns a n d t he i nci de nce of p ost pra n dial h y p o gl yce mia c o m pare d t o c urre ntl y a vaila ble 
fast-acti n g i ns uli n a nal o gs. L Y 9 0 0 0 1 4 is a n ultra-r a pid- act i n g i ns uli n lis pr o f or mulati o n t hat has 
s h o w n a n i ncrease d earl y abs or pti o n c o mpare d t o c o m merciall y  a vaila ble i ns uli n lis pr o 
f or mulat i on (H u m alo g , Eli Lill y) i n st u dies c o n d ucte d o utsi de of C hi na. L Y 9 0 0 0 1 4 ai ms t o 
clos el y mi mic t he p h ysi o l ogical pra n dial i ns uli n secretio n patter n , w hic h ma y mor e effect i vel y 
c o ntr ol p ost pra n dial gl uc ose e xc ursi o ns.
T he ai m of t his st u d y  is t o e val uate t he i ns uli n lis pr o p har mac o ki net ic ( P K) a n d gl uc o d y na mic 
( G D) pr ofiles, a n d safety a n d t olera bilit y f oll owi n g a d mi nistrati o n of  L Y 9 0 0 0 1 4 a n d H u mal o g 
d uri n g a e u gl yce mic gl uc ose cla m p i n healt h y C hi nese s u bjects.
3. 2.
B a c k gr o u n d
T he i ns uli n a nal o g, i ns uli n lis pr o ( H u mal o g), has bee n s h o w n t o be a bs or be d m ore q uic kl y t ha n 
re g ular h u ma n i ns uli n ( H u mal o g pac ka ge i nsert 2 0 1 5).   I n healt h y s u bjects gi ve n s u bc uta ne o us 
( S C) d oses of i ns uli n lis pr o ra n gi n g fr o m 0. 1 t o 0. 4 U/ k g, pea k ser u m le vels were see n 3 0 t o 
9 0 mi n utes after d osi n g ( H u malo g pac ka ge i nsert , 2 0 1 5).  T he effects of race o n H u mal o g P K 
ha ve n ot bee n assesse d.  Alt h o u g h s o me pra n dial i ns uli n a nal o gs are a bs or be d faster t ha n h u ma n 
i ns uli n, t he ge neral c o nse ns us is t hat ra pi d -acti n g i ns uli n a d mi nistere d S C eit her b y p u m ps or 
s yrin ges/ pe n i nject ors is st ill n ot ra pi d e n o u g h t o matc h car b o h y drate -a bs or pti o n pr ofiles, 
li miti n g efficac y a n d d osi n g fle xi bilit y.   Ul tr a-ra pi d-acti n g pra n dial i ns uli n w o ul d s hift t he 
P K /G D of  ins uli n a nal o gs s uc h t hat t he y ha ve a n e ve n faster o nset t o better mat c h car b o h y drate 
a bs or ptio n .  
L Y 9 0 0 0 1 4 is a n o vel f or m ulat i on of i ns uli n lis pr o t hat c o ntai ns a pr os t a c ycli n a nal o g 
(tre pr osti nil), s o di u m citrate, a n d ot her e xci pie nts. T hi s for m ulat i on i n v ol ves t he n o vel use of a 
micr o d ose of tre pr osti nil as a n e xci pie nt t o e n ha nce t he a bs or pti o n of i ns uli n lis pr o b y  lo c al  
vas o dilatati o n rat her t ha n as a n A PI t o eli cit a s yste mic effect. 
Tre pr osti nil is t he acti ve i n gre die nt i n 
 w hic h is a p pr o ve d b y t he F D A as a 
c o nti n u o us I V or S C i nf usi o n f or t he treat me nt of P A H. Tre pr osti nil has bee n a p pr o ve d i n C hi na 
si nce 2 0 1 3. S o di u m citrate, a n e xci pie nt t hat s pee ds i ns uli n a bs or pti o n ( b y e n ha nci n g vasc ular 
p er m ea bilit y), is als o i ncl u de d i n t he f or m ulati on t o f urt her e n ha nce t he a bs or pti o n of i ns uli n 
lis pr o. S o diu m  citrate a n d ot her e xcipie nts (zi nc c hl ori de a n d ma g nesi u m c hl o ride) t hat ha ve 
bee n use d i n t he L Y 9 0 0 0 1 4 P hase 1 cli nical trial f or m ulati o n are liste d i n t he F D A G R A S f o o d 
a d ditives data base ( F D A 2 0 1 8a) a n d i n t he F D A I nacti ve I n gre die nts i n A p pr o ve d Dr u gs 
data base ( F D A 2 0 1 8 b). F urt her m ore, c o nce ntrati o ns o f t hese e xci pie nts i n L Y 9 0 0 0 1 4 are wit hi n 
t he li mits i de nt ifie d f or a p pr o ve d dr u g pr o d ucts i n t he F D A I nacti ve I n gre die nts i n A p pr o ve d 
Dr u gs data base. 
L Y 9 0 0 0 1 4 has bee n e val uate d i n 1 6 c o m plete d P hase 1 st u dies f or u p t o 1 4 da y s i n d urati o n. Of 
t hese, 7 st u dies wer e c o n d ucte d usi n g a de vel o p me ntal f or m ulati o n o f L Y 9 0 0 0 1 4, a n d 9 st u dies 
C CI


I 8 B-M C -I TR Y Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 1 4
L Y 9 0 0 0 1 4
were c o n d ucte d usi n g t he fi nal f or m ulat i on of L Y 9 0 0 0 1 4. T hese i ncl u de d st u dies i n healt h y 
s u bjects ( N = 2 3 6), patie nts wit h t ype 1 dia betes ( N = 1 9 6), a n d patie nts wit h t y pe 2 dia betes 
( N= 1 0 3), a d mi nistere d at least 1 d ose of L Y 9 0 0 0 1 4. 
M ore i nf or mat i on ca n be f o u n d i n S e cti o n 5. 5 (J ustificati on f or D ose), a n d i n t he I n vesti gat or’s 
Br oc h ure (I B).
3. 3.
B e n efit/ Ri s k A s s e s s m e nt
St u d y  I 8 B-M C -I T R Y (I T R Y) will n ot offer a n y direct be nefits t o t he s u bjects parti ci pat i n g i n t he 
stu d y.   D ata fr o m st u dies wit h health y s u bjects a n d pati e nts wit h T 1 D M or T 2 D M ha ve s h o w n 
t hat L Y 9 0 0 0 1 4 is well t olerate d wit h a n a d verse dr u g reacti o n pr ofile c o nsiste nt wit h t h at of
H u m alo g .
As of  1 7 Se pte m ber 2 0 1 8, n o ne w safet y iss ues be yo n d t h ose al rea d y k n o w n f or i ns uli n lis pr o 
ha ve bee n i de nt ifie d f or L Y 9 0 0 0 1 4. Se vere h y p o gl yce mia is a n i m p orta nt i de nt ifie d ris k.  
P ote nti al i m p orta nt ris ks i ncl u de seri o us aller gic reacti o ns, me dicati on err ors, a n d l oss of
gl yce mic c o ntr ol d ue t o a nti dr u g a nt i b o dies.
N ota bl y, acr oss all d oses i n t he Lill y  cli nical st u dies t hat ha ve e val uate d tre pr osti nil as a l ocal 
vas o dilat or wit h or wit h o ut i ns uli n lis pr o, t here was n o cli nicall y si g nifica nt i ncrease i n t h ose 
A Es ass oci at e d wit h s yste mic a bs or pti o n of tre pr osti nil, as descri be d i n t he 
 pac ka ge 
i nsert ( 2 0 1 4).  M ore o ver, data fr o m Lill y P hase 1 b patie nt st u dies s h o we d t hat o nl y 1 o ut of 4 7 2 
pl as ma sa m ples ha d detecta ble tre pr osti nil le vels ta ke n fr o m a t otal of 3 0 pati e nts wit h T 1 D M 
( d oses u p t o 4 0 U per S C b ol us i nject i on) a n d 2 9 pati e nts wit h T 2 D M ( d oses u p t o 5 0 U per S C 
b o l us i njecti on) f oll o wi n g M DI a d mi nistrati o n of L Y 9 0 0 0 1 4. T he e x p os ure le vels of tre pr osti nil 
fr om t he d oses of L Y 9 0 0 0 1 4 pla n ne d i n t his st u d y are t h us e x pecte d t o be u n detecta ble a n d 
s u bsta ntiall y lo wer t ha n t h ose o bser ve d i n t he treat me nt of P A H .  
N o a d di tio n al  p ot e ntial ris ks of L Y 9 0 0 0 1 4 or tre pr osti nil al o ne were i de ntifie d i n precli nical
safety p har mac o l og y  a n d t o xicit y st u dies or cli nical p h ar m ac o l og y  st u dies. N o k n o w n p ote ntial
ris ks are ass ociate d wit h t he use of a micr o d ose of tre pr osti nil ( 
) i n t he L Y 9 0 0 0 1 4 
f or mulat i on.
A d dit i onall y , lo c al  a nd s yste mic t o xicit y pr ofiles of  H u malo g a n d 
d o n ot s u g gest t he 
p ote nti al for a d ditive or s y ner gistic t o xicit y.
F o ll owi n g a d mi nistrati o n of t he st u d y  ins uli n ( H u mal o g or L Y 9 0 0 0 1 4), s u bjects will recei ve I V 
gl uc ose i nf usi o n at a vari a ble rate t o mai ntai n e u gl yce mia u p t o 1 0 h o urs aft er i ns uli n lis pr o 
a d mi nistrati o n.  T he ai m o f t he cla m p pr oce d ure is t o mai ntai n bl o o d gluc ose ( B G) wit hi n t he 
n or m al gl yce mic ra n ge.  I n a d diti o n, t he cla m p is perf or me d w hile t he pa rtici pa nt is i n patient a n d 
u n der t he i n vest i gat or’s s u per visi on.  T hese c o nsi derati o ns s h o ul d mi ni mi ze t he ris k of 
h y p o gl yc e mia i n s u bjects partici pati n g i n St u d y I T RY.
M ore i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks, S A Es, a n d reas o na bl y 
a nt ici pate d A Es of  L Y 9 0 0 0 1 4 are t o be f o u n d i n t he I B.  
C CI
C CI
C CI


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
4. Objectives and Endpoints
Table ITRY.1 shows the objectives and endpoints of the study.
Table ITRY.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the PK of insulin lispro following 
administration of single SC doses of 7 and 15 U of 
LY900014 and 15 U of Humalog in healthy Chinese
subjects
AUC(0-10h), AUC(0-∞), and Cmax
Secondary
To evaluate the GD of insulin lispro during a euglycemic
clamp procedure following SC doses of 7 and 15 U of 
LY900014 and 15 U of Humalog in healthy Chinese
subjects
To evaluate the safety and tolerability of LY900014 
Gtot and Rmax
Adverse events
Exploratory
Explore the formation of antibodies to insulin lispro
Anti-insulin lispro antibodies
Abbreviations:  AUC(0-∞) = area under the serum concentration versus time curve from zero to infinity; 
AUC(0-10h) = area under the serum concentration versus time curve from time zero to 10 hours postdose; 
Cmax = maximum observed concentration; GD = glucodynamics; Gtot = total amount of glucose infused; 
PK = pharmacokinetics; Rmax = maximum glucose infusion rate; SC = subcutaneous.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
5. Study Design
5.1.
Overall Design
This is a Phase 1, single-center, randomized, subject-blind, 3-period, crossover study to evaluate 
the PK of insulin lispro for LY900014 in healthy Chinese subjects.
After satisfying the study entry criteria, subjects will be randomized to 1 of 3 dosing sequences 
(Section 7.2; Table ITRY.2). Subjects will be required to attend the clinical research unit (CRU)
on 5 occasions:

screening visit (up to 28 days prior to dosing [Day 1 of Period 1])

3 study periods, each comprising a 1 night inpatient stay from Day -1 to Day 1
for the clamp procedure (subjects may remain for longer in the CRU at the 
investigator’s discretion for safety reasons)

follow-up visit ≥14 days after the last dose, or early discontinuation
Subjects will be fasted (except for water and barley tea) for at least 8 hours prior to collection of
clinical safety laboratory samples and dosing, and during glucose clamp procedures according to 
the Schedule of Activities (Section 2). 
Each subject will participate in 3 inpatient visits; on Day 1 of each period, the time-concentration 
and time-action profiles of insulin lispro will be evaluated simultaneously during a euglycemic 
glucose clamp of approximately 10 hours duration.  Briefly, the aim of the euglycemic clamp is 
to maintain euglycemia after the administration of a dose of insulin by means of variable glucose 
infusion.  The variable glucose infusion maintains or “clamps” glucose at a constant euglycemic 
target; therefore, the glucose infusion rate (GIR) reflects the GD effect of the insulin.  More 
information on the clamp methodology can be found in Section 9.6.
Serial blood samples will be collected during the 10-hour glucose clamp at the times specified in 
the Study Schedule (Section 2) to assess the PK and GD parameters of LY900014.  On 
completion of the euglycemic clamp, subjects will be provided with a meal and will undergo 
glucose monitoring to ensure that there is no risk of hypoglycemia.  A physician’s medical 
assessment will be required before subjects are discharged from the CRU.  
There will be a minimum of 3 days between study doses in consecutive periods.  
There are no outpatient visits planned between study periods.  
Safety assessments and an evaluation of local tolerability at injection sites will be performed as 
specified in the Study Schedule (Section 2).  Local tolerability assessments will include 
injection-site assessments for signs of edema and erythema.
Study governance considerations are described in detail in Appendix 3.


I 8 B-M C -I TR Y Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 1 7
L Y 9 0 0 0 1 4
T a bl e I T R Y.2.  
D o si n g S e q u e n c e s
D osi n g Se q ue nce
P eri o d 1 
P eri o d 2 
P eri o d 3 
1
1 5 U H u mal o g 
7 U L Y 9 0 0 0 1 4
1 5 U L Y 9 0 0 0 1 4
2
7 U L Y 9 0 0 0 1 4
1 5 U H u mal o g
1 5 U L Y 9 0 0 0 1 4
3
7 U L Y 9 0 0 0 1 4
1 5 U L Y 9 0 0 0 1 4
1 5 U H u mal o g
5. 2.
N u m b er of P arti ci p a nt s
U p t o 1 5 s u bjects ma y be e nr o lle d s o t hat a p pr o xi matel y 1 2 s u bjects c o mplete t he st u d y ( 4 per 
se q ue nce).  F or p ur p oses of t his st u d y , a s u bject c o m pletes t he st u d y w he n all sc he d ule d 
pr oce d ures s h o w n i n t he Sc he d ule of Act i vities ha ve bee n fi nis he d .  S u bjects w h o disc o nt i n ue 
pri or t o st u d y  c o mplet i on ma y be re place d , wi t h t he re place me nt s u bject ass u mi n g t he 
di sc o nti n ue d s u bject’s d osi n g se q ue nce a n d ta ki n g part i n all 3 st u d y p erio ds.  
5. 3.
E n d of St u d y D efi niti o n
E n d of t he st u d y is t he date of t he last visit or last sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule o f 
Act i vities (Secti o n 2 ) f or t he last s u bject.
5. 4.
S ci e ntifi c R ati o n al e f or St u d y D e si g n
A p o p ulati o n o f healt h y s u bjects is selecte d base d u p o n t he li keli h o o d of less p h ysi ol ogic 
varia bilit y i n t he a bse nce of disease states t hat ma y affect m ulti ple or ga n s yste ms a n d a bse nce of 
ot her c o nf o u n di n g fact ors s uc h as c o nc o mita nt me dicat i ons.   C hi nese s u bjects are st u die d as 
C hi nes e pat ient s wit h T 1 D M or T 2 D M are a p ote ntial tar get p o p ulati o n f or L Y 9 0 0 0 1 4 a n d t he 
P K a n d G D pr ofiles o f L Y 9 0 0 0 1 4 are y et t o be st u die d i n t his p o p ulat i on
T he st u d y  is s u bject-bli n d t o mi ni mize p ote ntial data bias w hile t he cr oss o ver desi g n all o ws eac h 
s ubject t o ser ve as his or her o w n c o ntr ol, t h us re d uci n g varia bilit y.  T he st u d y desi g n uses 
L Y 9 0 0 0 1 4 d ose l e vels selecte d t o s u p p ort p ote ntial f ut ure c o m paris o n bet wee n st u dies .  
A e u gl yce mic cla m p tec h ni q ue , t he g old sta n dar d met h o d ol o g y  for assessi n g i ns uli n acti o n, will 
be use d i n t his st u d y  t o pr o vide data o n t he G D acti vit y of  eac h st u d y ins uli n lis pr o d ose (see 
Secti o n 9. 6 f or a detaile d descri pti on of t he cla m p met h o d ol o g y ).
Base d o n t he P K pr o perties of tre pr osti nil ( half -life ass ociate d wit h t he ter mi nal rate c o nsta nt i n
n o nc o m part me nt al a nal ysis [t1/ 2] = a p pr o xi matel y  h o ur) a n d H u mal o g (t1/ 2=
 h o urs), t he 
d urati o n of  t he was h o ut perio d bet wee n cla m p visits (a mi ni m u m o f 3 da y s) a n d t he d urati o n 
bet wee n t he last d ose of st u d y  dr u g a n d t he f oll o w-u p visit (at least 1 4 da ys) are c o nsi dere d 
a p pr o priate.
5. 5.
J u stifi c ati o n f or D o s e
L Y 9 0 0 0 1 4 has bee n e val uate d i n 1 6 c o m plete d P hase 1 st u dies . All teste d d oses of tre pr osti nil , 
i ns uli n lis pr o, or L Y 9 0 0 0 1 4 were well t olerate d i n de vel o p me nt st u dies i n healt hy s u bjects, a n d
i n patie nts wit h T 1 D a n d T 2 D. N o st u d y -dr u g rel ate d S A Es were re p orte d i n t he c o m plete d 
P hase 1 st u dies. 
C
C
I
C CI


I 8 B-M C -I TR Y Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 1 8
L Y 9 0 0 0 1 4
Base d o n pre vi o us st u dies of b ot h i ns uli n lis pr o ( H u mal o g) a n d L Y 9 0 0 0 1 4, t he 7 a n d 1 5 U d ose s
pl a n ne d i n t his st u d y are wi t hi n t he cli nical d ose ra n ge a n d s h o ul d pr o vi de meas ura ble P K a n d 
G D pr ofiles f or b ot h st u d y  ins uli ns.  T he i ns uli n lis pr o c o nce ntrati o ns i n t he b o d y  res ultin g f r o m 
a d mi nistrati o n of t hese d ose s t o healt h y s u bjects are a nt ici pate d t o be meas ura ble o ver t he 
sa m pli n g peri o d.  A d dit i onall y , it is a nt ici pate d t hat t his d ose will pr o vi de a n a de q uate GIR f or 
assess me nt of G D.
At  t he hi g hest d ose le vel of 1 5 U of  L Y 9 0 0 0 1 4, s u bjects will be e x pecte d t o recei ve 
a p pr o xi matel y
 tre pr osti nil i n a si n gle S C d ose, w hic h is wit hi n t he ra n ge e val uate d as safe 
a n d t olerate d i n pre vi o us st u dies. 
M ore i nf or mat i on ca n be f o u n d i n t he L Y 9 0 0 0 1 4 I B .
C CI


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LY900014
6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG).  
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.  
Screening may occur up to 28 days prior to dosing (Day 1 of Period 1).  Subjects who are not 
enrolled within 28 days of screening may be subjected to an additional medical assessment 
and/or clinical measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.  
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are overtly healthy native Chinese (all 4 grandparents to be of Chinese origin)
males or females, as determined by medical history and physical examination.  
[1a]
male subjects:
i.
No male contraception required except in compliance with specific 
local government requirements.
[1b] female subjects:
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 use 
2 effective methods of contraception for the entirety of the study (until 
discharge from the final dosing period).  
A.
Women of child-bearing potential must test negative for 
pregnancy prior to initiation of dosing 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.
B.
Either 1 highly effective method of contraception (such as 
combination oral contraceptives, implanted contraceptives or 
intrauterine device) or a combination of 2 effective methods of 
contraception (such as male or female condoms with spermicide, 
diaphragms with spermicide or cervical sponges) will be used.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
The patient may choose to use a double barrier method of 
contraception.  Barrier protection methods without concomitant 
use of a spermicide are not a reliable or acceptable method.  Thus, 
each barrier method must include use of a spermicide.  It should 
be noted that the use of male and female condoms as a double 
barrier method is not considered acceptable due to the high failure 
rate when these methods are combined.  
iii. Women not of child-bearing potential may participate and 
include those who are:
A. infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
mullerian agenesis; or
B. post-menopausal – defined as either
i.
A woman aged at least 50 years of age with an intact 
uterus, not on hormone therapy, who has had either
a)
cessation of menses for at least 1 year; or
b)
at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone >40 mIU/mL; or
ii.
A woman 55 or older not on hormone therapy, who has 
had at least 6 months of spontaneous amenorrhea; or
iii.
A woman 55 or older with a diagnosis of menopause prior 
to starting hormone replacement therapy.
[2]
are aged 18 to 65 years old, inclusive
[3]
have a body mass index (BMI) of 18 to 28 kg/m2, inclusive
[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 for glucose infusion and to allow for blood 
sampling as per the protocol
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[7]
are able and willing to give signed informed consent
[8]
are nonsmokers, have not smoked for at least 2 months before entering the 
study, and agree not to smoke (cigars, cigarettes, or pipes) or to use smokeless 
tobacco for the duration of the study
[9]
have a fasting plasma glucose value >71 mg/dL (3.9 mmol/L) and
<108 mg/dL (6.0 mmol/L) at screening


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[10] are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[11] are Lilly employees
[12] are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study
[13] have participated, within the last 30 days, in a clinical study involving an 
investigational product. If the previous investigational product has a long 
half-life, 5 half-lives or 30 days (whichever is longer) should have passed.
[14] have previously completed or withdrawn from this study or any other study 
investigating LY900014, and have previously received the investigational 
product 
[15] have known allergies to LY900014, treprostinil, related compounds or any 
components of the formulation, or history of significant atopy
[16] have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[17] have an abnormal blood pressure and/or pulse rate deemed to be clinically 
significant by the investigator
[18] have a significant history of cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable 
of significantly altering the absorption, metabolism, or elimination of drugs; 
of constituting a risk when taking the investigational product; or of interfering 
with the interpretation of data
[19] have known or ongoing psychiatric disorders
[20] regularly use known drugs of abuse and/or show positive findings on drug 
screening
[21] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies
[22] show evidence of hepatitis C and/or positive hepatitis C antibody
[23] show evidence of hepatitis B and/or positive hepatitis B surface antigen


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
[24] intend to use over-the-counter or prescription medication within 7 and 
14 days, respectively, prior to dosing (apart from vitamin/mineral 
supplements, occasional paracetamol, thyroid replacement therapy, oral 
contraceptives, or hormone replacement therapy) or during the study.  If this 
situation arises, inclusion of an otherwise suitable subject may be at the 
discretion of the investigator, preferably after consultation with a Lilly clinical 
pharmacologist (CP) or clinical research physician (CRP).
[25] have donated blood of more than 400 mL within the previous 6 months of 
study screening or donated more than 100 mL within the last 30 days. 
[26] have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females), or are unwilling to stop alcohol consumption 
from 24 hours prior to dosing and until discharge from the CRU.
(1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of 
distilled spirits)
[27] are unwilling to comply with the dietary requirements/restrictions during the 
study: (i) comply with the fasting requirements of the study, (ii) consume 
only the meals/snacks provided during the inpatient visits
[28] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.2.1. Rationale for Exclusion of Certain Study Candidates
Criteria [10] and [11] prevent conflict of interest in study participants.  Criteria [12] through [28] 
exclude medical conditions, medication intolerance, and concomitant medication use that may 
constitute a risk for the subject and/or may confound the assessment of study endpoints.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Subjects will be fasted (except for water and barley tea) for at least 8 hours prior to collection of
clinical safety laboratory samples, prior to dosing, and during glucose clamp procedure 
according to the Schedule of Activities (Section 2). Water and caffeine-free barley tea may be 
consumed freely at all times.
While resident in the CRU, subjects may not consume any food or caloric drinks other than that 
provided by the CRU.  When not resident in the CRU, subjects may resume their regular diet.
6.3.2. Caffeine, Alcohol, and Tobacco
Subjects should refrain from consuming caffeine-containing food/beverages (e.g., cola, chocolate 
drinks, tea, coffee, and energy drinks) for at least 12 hours prior to each dose and throughout the 
duration of each CRU visit.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
No alcohol will be allowed from at least 24 hours prior to each dose 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.  
No cigarette smoking will be permitted during the study.  
6.3.3. Activity
Subjects will be encouraged to maintain their regular exercise; however, they should not 
undertake vigorous or prolonged exercise from at least 48 hours prior to each dosing day. 
Should this occur, these subjects will have their dosing visits deferred or may be excluded from 
the study, as judged by the investigator to prevent interference with study results. After dosing, 
subjects should remain recumbent or sitting in the CRU until the end of the glucose clamp.  
Movement will be restricted to retain the integrity of connections to the glucose clamp and the 
study procedures.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
7. Treatment
7.1.
Treatment Administered
This study involves administration of LY900014 at 7 and 15 U, once by SC injection. The 
reference formulation will be Humalog.  Table ITRY.3 shows the dosing regimens.
Table ITRY.3.
Investigational Products Administered
Investigational Product
Name
LY900014
Humalog
Dosage Formulation
100 U/mL
100 U/mL
Dosage Levels
7, 15 U
15 U
Route of 
Administration
Subcutaneous injection
Subcutaneous injection
The investigator or designee is responsible for:

explaining the correct use of the investigational product(s) to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.  
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled as investigational product as appropriate, and according to 
the country’s regulatory requirements. Study insulins (LY900014 and insulin lispro [Humalog]) 
will be supplied by Lilly or its representative, in accordance with current good manufacturing 
practices, and will be supplied with clinical trial lot numbers. Instruction for Use for the 
prefilled devices will be provided.
The prefilled pens will contain a concentration of 100 U/mL in 3-mL cartridges of either 
LY900014 or insulin lispro.
7.2.
Method of Treatment Assignment
The investigational product to be injected on a given dosing day will be determined according to 
the dosing sequence (Table ITRY.2) assigned using a randomization schedule.


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
7.2.1. Selection and Timing of Doses
The actual date and time of all dose preparations will be documented, and the actual time of all 
dose administrations will be recorded in the subject’s electronic case report form (eCRF).  For 
each subject, the doses will be administered at approximately the same time on Day 1 of each 
study period.
The site of administration of each injection will be recorded in the eCRF.  Injection sites selected 
should be about 5 cm from the umbilicus.  An appropriately sized insulin syringe and needle will
be used in all dosing periods to ensure all injections are delivered to a consistent depth target into 
the SC space.  Injections will be rotated among different injection sites on the anterior abdominal 
wall during the 3 study periods.  
All study doses will be given in the CRU by qualified CRU personnel as designated by the 
investigator.  Study injections should be given by a limited number of individuals for 
consistency.
7.3.
Blinding
The study is subject-blind with reference to the identity of the study drug administered
(LY900014 or Humalog).  The CRU staff will not be blinded to the dose administered due to the 
difference in volume of injection in the 2 doses being studied.  The Lilly CP/Lilly study team 
will be unblinded.
7.4.
Dose Modification
Dose adjustments are not allowed in this study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all investigational product
received and any discrepancies are reported and resolved before use of the investigational 
product.
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product. All 
investigational product should be stored in an environmentally controlled and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
The study drugs must be stored at the CRU under refrigerated conditions (between 2°C and 8°C) 
in a locked and secure place.  Study drugs must not be frozen.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for investigational product accountability, reconciliation, and record maintenance 
(such as receipt, reconciliation, and final disposition records).


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of dose 
administration will occur at the site.
7.7.
Concomitant Therapy
Subjects should not use over-the-counter or prescription medication within 7 and 14 days, 
respectively, before each dosing (apart from vitamin and mineral supplements, occasional 
paracetamol, thyroid replacement therapy, oral contraceptives, or hormone replacement therapy).  
If a subject does use these medications, inclusion of the subject may be at the discretion of the 
investigator.
Subjects should not apply any creams or lotions to the abdominal skin on the morning of the 
injection or during the inpatient study procedure.
If the need for concomitant medication arises, inclusion or continuation of the subject may be at 
the discretion of the investigator after consultation with a Lilly CP or CRP.  Any additional 
medication used during the course of the study must be documented.
7.8.
Treatment after the End of the Study
This section is not applicable for this study.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
8. Discontinuation Criteria
Subjects discontinuing from the study prematurely for any reason must complete early 
discontinuation procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

alanine aminotransferase (ALT), aspartate aminotransferase (AST) >5X upper limit of 
normal (ULN)

ALT or AST >3X ULN sustained for more than 2 weeks or

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or international 
normalized ratio (INR) >1.5 or

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP>2.5X ULN and TBL >2X ULN

ALP>2.5X ULN with the appearance of fatigue, nausea, vomiting, right upper-quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%).  
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP or CRP and the investigator 
to determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP or CRP to allow 
the inadvertently enrolled subject to continue in the study with or without continued treatment 
with investigational product.  
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
8.3.
Subjects Lost to Follow-up
A subject 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 subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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LY900014
9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing.  
Appendix 2 lists the laboratory tests that will be performed for this study.  
Appendix 5 provides a summary of the maximum number and volume of invasive samples for all 
sampling, during the study.  
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.  
9.1.
Efficacy Assessments
This section is not applicable for this study.  
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects 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 subject.  
The investigator is responsible for the appropriate medical care of subjects during the study.  
Investigators must document their review of each laboratory safety report.  
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.  After the informed consent 
form (ICF) is signed, study site personnel will record, via eCRF, the occurrence and nature of 
each subject’s preexisting conditions.  Additionally, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account concomitant 
treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the investigational product 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 subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF.  


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9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.  
Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.  
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and has received investigational 
product.  However, if an SAE occurs after signing informed consent, but prior to receiving 
investigational product, AND is considered reasonably possibly related to a study procedure then 
it MUST be reported.  
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.  
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.  
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to investigational product or procedure.  Lilly 
has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidances.  


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9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.  Subjects should be instructed to contact the investigator as 
soon as possible if he or she has a complaint or problem with the investigational product or drug 
delivery system so that the situation can be assessed.  
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY900014 or Humalog is considered any dose 
higher than the dose assigned through randomization.
Excess insulin administration may cause hypoglycemia and hypokalemia.  Mild episodes of
hypoglycemia can usually be treated with oral glucose.  More severe episodes with coma, 
seizure, or neurologic impairment may be treated with intramuscular/SC glucagon or 
concentrated IV glucose.  Sustained carbohydrate intake and observation may be necessary 
because hypoglycemia may recur after apparent clinical recovery.  Hypokalemia must be 
corrected appropriately.  
Refer to the LY900014 IB.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). Blood and urine samples will be collected to determine 
whether subjects meet inclusion/exclusion criteria and to monitor subject health (additional tests 
may be performed at the discretion of the investigator).  Clinical laboratory tests will be analyzed 
by a laboratory selected by Lilly.  
9.4.2.
Vital Signs
For each subject, vital signs (body temperature and supine blood pressure and pulse rate) 
measurements should be conducted according to the Schedule of Activities (Section 2).  
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  If orthostatic measurements are required, subjects should be supine 
for at least 5 minutes and stand for at least 2 minutes.  If the subject feels unable to stand, only 
supine vital signs will be recorded.  
Additional vital signs may be measured during each study period if warranted.  
9.4.3. Electrocardiograms
For each subject, a single12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms must be recorded before collecting any blood 


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
samples.  Subjects must be supine for approximately 5 to 10 minutes before ECG collection and 
remain supine but awake during ECG collection.  Electrocardiograms may be obtained at 
additional times, when deemed clinically necessary.  All ECGs recorded should be stored at the 
investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QT 
corrected for heart rate [QTc] interval from baseline) after enrollment, the investigator will 
determine if the subject can continue in the study.  The investigator, or qualified designee, is 
responsible for determining if any change in subject 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.
9.4.4. Physical Examination
Physical examinations and medical assessments will be conducted as specified in the Schedule of 
Activities and as clinically indicated (Section 2).  
9.4.5. Body Weight
Body weight will be recorded as specified in the Schedule of Activities (Section 2) and as 
clinically indicated.
9.4.6. Hip and Waist Circumference 
Hip and waist circumference will be recorded as specified in the Schedule of Activities 
(Section 2).  Waist (narrowest circumference between lowest aspect of the ribs and anterior 
superior iliac crests) and hip (widest circumference between the anterior superior iliac crests and 
the greater trochanters) circumference will be measured in triplicate and the mean calculated.
9.4.7. Injection-Site Assessments 
Injection-site local tolerability assessments will be conducted as specified in the Schedule of 
Activities and as clinically indicated (Section 2).
9.4.8. 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


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014

laboratory analytes 

AEs
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.  
9.4.8.1.
Glucose Monitoring
Hypoglycaemia will be described using the following definitions:
Documented Glucose Alert Level (Level 1), plasma glucose (PG) ≤70 mg/dL (3.9 mmol/L)

Documented symptomatic hypoglycemia:  with typical symptoms of hypoglycemia.

Documented asymptomatic hypoglycemia:  without typical symptoms of hypoglycemia.

Documented unspecified hypoglycemia:  with no information about symptoms of 
hypoglycemia available.  (This has also been called unclassifiable hypoglycemia.)
Documented Clinically Significant Hypoglycemia (Level 2) with similar criterion as above 
except for threshold PG <54 mg/dL (3.0 mmol/L)

Level 2 Documented symptomatic hypoglycemia

Level 2 Documented asymptomatic hypoglycemia

Level 2 Documented unspecified hypoglycemia
Severe hypoglycemia (Level 3)

Severe hypoglycemia: Subjects had altered mental status, and could not assist in their own 
care, or were semiconscious or unconscious, or experienced coma with or without seizures,
and the assistance of another person was to actively administer carbohydrate, glucagon, or 
other resuscitative actions. Plasma glucose measurements may not be available during such 
an event, but neurological recovery attributable to the restoration of PG concentration to
normal is considered sufficient evidence that the event was induced by a low PG
concentration (PG ≤70 mg/dL [3.9 mmol/L]).  
Other hypoglycemia:

Nocturnal hypoglycemia: Any documented hypoglycemic event (including severe 
hypoglycemia) that occurs at night and presumably during sleep.  This is captured as 
hypoglycemia that occurs between bedtime and waking.  This definition is more useful 
than the commonly used ~midnight to ~6 AM definition which does not take subjects’ 
individual sleep times into consideration, and is consistent with the American Diabetes 
Association (ADA) recommendations of reporting events that occur during sleep (ADA 
2005).  It is also important to collect the actual time when a hypoglycemic event occurred 
to allow further characterization of hypoglycemia timing (e.g., to allow analysis of 
frequency of events occurring across a 24-hr clock).  Nocturnal hypoglycemia may occur at 
severity Levels 1, 2, or 3.

Relative hypoglycemia (also referred to as Pseudohypoglycemia [Seaquist et al. 2013]): 
An event during which typical symptoms of hypoglycemia occur, that does not require the
assistance of another person and is accompanied by PG >70 mg/dL (3.9 mmol/L). The PG


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
value of subjects with chronically poor glycemic control can decrease so rapidly that
subjects may report symptoms of hypoglycemia before their PG concentration falls below 
70 mg/dL (3.9 mmol/L). Events with PG ≤70 mg/dL should not be categorized as 
relative hypoglycemia.  Evaluation and statistical analysis of this category is optional.
However, if a subject reports a relative hypoglycemia event where assistance from another
person was received or the subject experienced significant symptoms, the study team should 
clarify the circumstances to ensure the event is not a severe hypoglycemia event, and report
it appropriately.  

Probable symptomatic hypoglycemia:  Symptoms of hypoglycemia were present, but PG 
measurement was not reported.

Overall (or total) hypoglycemia: This optional category combines most cases of
hypoglycemia (documented hypoglycemia and probable symptomatic hypoglycemia, 
including severe hypoglycemia).  It does not include relative hypoglycemia.  Nocturnal and
severe hypoglycemia are special cases of documented or probable hypoglycemia. If an event 
of hypoglycemia falls into multiple subcategories, that event should only be counted once in
the category of overall (or total) hypoglycemia.
Only severe hypoglycaemic episodes will be reported separately as AEs.  All episodes of severe
hypoglycaemia will be reported as SAEs.
The goal of the euglycemic clamp is to maintain glucose concentrations at normal glycemic
levels close to a predefined target.  Therefore, glucose concentrations below 70 mg/dL will not 
routinely be recorded as hypoglycemic events during the glucose clamp procedure.  However, at 
the discretion of the investigator, decrease in glucose concentrations may be recorded as a 
hypoglycemic event based on clinical concern or related to technical issues resulting in 
hypoglycemia.  Glucose monitoring will continue after completion of the euglycemic clamp 
prior to discharge from the CRU at the discretion of the investigator.  
9.4.8.2.
Hepatic Safety
If a study subject 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.  
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 


I 8 B-M C -I TR Y Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 3 5
L Y 9 0 0 0 1 4

s u bject disc o nti n ue d fr o m treat me nt d ue t o a he patic e ve nt or a b n or malit y of li ver 
tests

h e pat ic e ve nt c o nsi dere d t o be a S A E.
9. 5.
P h ar m a c o ki n eti c s
At  t he visits a n d ti mes s pecifie d i n t he Sc he d ule of Act i vities (Secti o n 2 ), ve n o us bl o o d sa mples 
of  a p pr o xi matel y 2. 5 m L eac h will be c ollecte d t o deter mi ne t he free ser u m c o nce ntratio ns of 
i ns uli n lis pr o.  I nstr ucti o ns f or t he c ollecti on a n d ha n dli n g of bl o o d sa m p les will be pr o vi de d b y 
t he s p o ns or .  T he act ual date a n d ti me ( 2 4- h o ur cl oc k ti me) of eac h s a mpli n g will be rec or de d .  
9. 5. 1.
Bi o a n al y si s
S a m ples will  be a nal yze d at a la b orat or y a p pr o ve d b y t he s p o ns or a n d st ore d at a facility 
desi g nate d b y  t he s p o ns or.  
C o nc e ntratio ns of  free ser u m i ns uli n lis pr o will be assa ye d usi n g a 
 
  
Bi oa nal y tic al sa m ples c ollecte d t o meas ure i n vest i gati o nal pr o d uct c o nce ntrati o ns will be 
retai ne d f or a ma xi m u m of 1 y e ar fol l owi n g l ast s u bject visit f or t he st u d y .
9. 6.
Gl u c o d y n a mi c s ( E u gl y c e mi c Gl u c o s e Cl a m p)
S u bjects will part ici pate i n a e u gl yce mic cla mp f or a p pr o xi matel y 1 0 h o urs f oll owi n g 
a d mi nistrati o n of a d ose of i ns uli n as descri be d i n Secti o n 5. 1 .  
T he ai m of t he e u gl yce mic gl uc ose cla m p is t o mai ntai n e u gl yce mia t hr o u g h gl uc ose i nf usi o n 
after t he a d mi nistrati o n of a d ose of i ns uli n.  D uri n g t he gl uc ose c la m p, t he GI R will be a dj uste d 
t o mai ntai n a pre deter mi ne d tar get B G c o nce ntrati o n f or t he i n di vi d ual s u bject. T he i nte nt is t o 
mai ntai n B G c o nce ntratio ns a p pr o xi matel y at t he pre d ose tar get val ue, w hic h is defi ne d as 
5 m g/ d L bel o w t he mea n pre d ose fasti n g B G ( me a n of  pre d ose val ues rec or de d at a p pr o xi matel y 
-3 0, -2 0, a n d -1 0 mi n utes) .
T h us, B G c o nce ntrati o ns are ke pt c o nsta nt w hile t he GI R varies.  T he var yi n g GI R will reflect 
t he G D acti vit y of i ns uli n.
T he s u bjects will part ici pate i n a t otal of 3 e u gl yce mic cla mps in 3 se parate st u d y p erio ds.  
Gl uc ose cla m p st u di es will be perf or me d after a n o ver ni g ht fast of a p pr o xi matel y  8 h o urs.  T he 
GI Rs re q ui re d t o mai ntai n e ugl yc e mia a n d B G c o nce ntratio ns will  be d oc u me nte d t hr o u g h o ut t he 
pr oce d ure.  O n t he m or ni n g of t he s t u d y, a s mall cat heter will be place d i nt o a f orear m vei n, 
i deall y at t he el b o w, f or i nf usi on of gl uc ose.  T he gl uc ose is i nf use d as a 2 0 % de xtr ose s ol ut i on.   
A n ot her cat heter will be place d at t he wrist or bac k of t he ha n d, or i n t he case of diffic ult ve n o us 
access, i n t he f orear m as cl ose t o t he wrist as p ossi ble, f or bl o o d sa m pli n g.  Bl o o d sa m ples will 
be o btai ne d at t he be dsi de f or i m me diate deter mi nati o n of w h o le B G c o nce ntrati o ns usi n g a n 
a ut o mat e d gluc ose o xi dase tec h ni q ue or ot her a p pr o priate a nal y tical met h o d.  
T he ti me of st u d y  ins uli n d osi n g will be defi ne d as ti me zer o.  F oll o wi n g d osi n g, i n c o nj u nct i on 
wi t h fre q ue nt blo o d sa m pli n g f or m eas ure me nt of B G , gluc ose will be i nf use d i ntra ve n o usl y at a 
C CI


I 8 B-M C -I TR Y Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 3 6
L Y 9 0 0 0 1 4
varia ble r ate i n or der t o mai ntai n e u gl yc e mia f or a p pr o xi matel y 1 0 h o urs.  If t he GI R falls t o zer o 
f or at least 3 0 mi n utes after t he cla m p has bee n u n der wa y f or at least 8 h o urs , t he cla m p will be 
di sc o nti n ue d.
At  t he e n d of t he cla m p (a p pr o xi matel y 1 0 h o urs after st u d y  dr u g a d mi nistratio n) a n d f o ll owi n g 
c ollect i on of t he 1 0- h o ur st u d y  s a mples , t he s u bject will be fe d a n d will u n der g o gl uc ose 
m o nit ori n g as dee me d a p pr o priate b y t he i n vesti gat or.  A p h ysicia n’s me dical assess me nt will be 
re q uire d bef ore s u bjects are disc har ge d fr om t he C R U.
9. 7.
I m m u n o g e ni cit y A s s e s s m e nt s 
S a mples f or p ote nti al fut ure i m m u n o ge nicit y testi n g will be c ollecte d as i n dicate d i n t he 
Sc he d ule of  Act i vities (Secti o n 2 ).  
H u m alo g res p o nse is well-c haracterize d hist oricall y wit h cli nical a n d o n-mar ket data i n dicat i n g 
t hat i m m u n o ge nic p ote ntial is l o w a n d c o m para ble t o ot her mar kete d i ns uli ns s uc h as re g ular 
h u ma n i ns uli n ( Fi ne ber g et al . 1 9 9 6).  A nt i b o dies ma y f or m b ut d o n ot a p pear t o be cli nicall y 
c o nse q ue nt ial ( Fi ne ber g et al. 2 0 0 3).  T heref ore, bl o o d sa m ples will be st ore d a n d use d t o 
deter mi ne a nti b o d y  pr o d u ctio n a gai nst i ns uli n lis pr o, as warra nte d, base d o n cli nical 
o bser vat i ons a n d e mer gi n g data.  Res ults fr om t hese tests are n ot re q uire d f or fi nal data re vie w. 
I mm u n o ge nicit y will  be assesse d b y a vali date d 
 t o detect 
a nt i-i ns uli n lis pr o a nti b o dies i n t he prese nce of lis pr o.  I nstea d of q ua ntitati n g t he le vel of a nt i-
i ns uli n lis pr o a nti b o dies b y titer, t he  
re p orts a se mi q ua nt itati ve perce nt -bi n di n g f or eac h 
p osi tive sa m ple.  A d dit i onall y , p ositive sa m ples will be c haracterize d f or cr oss -reacti ve bi n di n g 
t o nati ve i ns uli n. P ote ntial a nal ysis o f im m u n o ge nicit y ma y be i n dicate d i n t he st atistical 
a nal ysis pla n.
S a m ples will  be retai ne d f or a ma xi m u m of 1 5 years after t he last s u bject visit, or f or a s h orter 
p eri o d if l ocal  re g ulati ons a n d Et hical Re vie w B oar ds ( E R Bs) all o w, at a facilit y selecte d b y t he 
s p o ns or.  T he d urati o n all o ws t he s p o ns or t o res p o n d t o f ut ure re g ulat or y re q uests relate d t o 
L Y 9 0 0 0 1 4 .  A n y sa m ples re mai ni n g after 1 5 years will be destr o ye d.
9. 8.
G e n eti c s
T his sect i on is n ot a p plica ble f or t his st u d y.
9. 9.
Bi o m ar k er s
T his sect i on is n ot a p plica ble f or t his st u d y.
9. 1 0. H e alt h E c o n o mi c s
T h is secti on is n ot a p plica ble f or t his st u d y.
C CI
C CI


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 15 subjects will be randomized in order that 12 subjects complete all periods of the study
(4 per sequence).
Sample size is not based on a statistical power calculation. Sample size is considered suitable to 
characterize the PK profiles of insulin lispro, and to evaluate the safety and tolerability of single 
doses of LY900014 administered SC.
If the randomized subjects discontinue from the study prior to its completion, subjects can be 
replaced. The replacement subject will adopt the original subject’s randomization schedule.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The subject’s age, sex, body weight, BMI, waist and hip circumference, height, race/subrace, and 
other demographic characteristics will be summarized.  
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic/GD analyses will be conducted on data from all subjects who receive at least 
one dose of the investigational product and have evaluable PK.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur prior 
to enrollment will be distinguished from those reported as new or increased in severity during the 


I 8 B-M C -I TR Y Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 3 8
L Y 9 0 0 0 1 4
st u d y.  Eac h s y m pt o m will be classifie d b y t he m ost s uita ble ter m fr o m t he me d ical re g ulat or y 
di ct i onar y .
T he n u m ber of i n vest i gati onal pr o d uct -relate d S A Es will be re p orte d.  
1 0. 3. 1. 2. St ati sti c al E v al u ati o n of S af et y
S af et y para m eters t hat will be assesse d i ncl u de safet y la borat or y para meters, vi t al sig ns, E C G 
para m eters, a n d i njecti on- site assess me nts.  T he para meters will be liste d, a n d s u m marize d usi n g 
sta n dar d descri pti ve statistics.  A d ditio nal a nal ysis will be perf or me d if w arra nte d u p o n re vie w 
of  t he data.
1 0. 3. 2. P h ar m a c o ki n eti c A n al y s e s
1 0. 3. 2. 1. P h ar m a c o ki n eti c P ar a m et er E sti m ati o n
I ns uli n lis pr o P K para meter esti mates f or L Y 9 0 0 0 1 4 a n d H u mal o g will be c o n d ucte d usi n g 
sta n dar d n o nc om part me nt al met h o ds of a nal ysis usi n g 
 
o n a c o m p uter t hat m eets or e xcee ds t he mi ni m u m s yste m 
re q uire me nts f or t hese pr o gra ms.  T he versi on of a n y  s oft ware use d f or t he a nal ysis will be 
d oc u m e nte d a n d t he pr o gra m will meet t he Lill y r e q uire me nts of s oft ware vali dati o n.  It is 
p ossi ble t hat ot her vali date d e q ui vale nt P K s oft ware pr o gra ms ma y be utilize d if a p pr o priate, 
warra nte d, a n d a p pr o ve d b y gl o bal P K ma na ge me nt.
Free ser u m i ns uli n lis pr o c o nce ntrati o ns will be use d t o calc ulate se veral P K para me ters, 
i ncl u di n g ma xi m u m o bser ve d c o nce ntrati o n ( Cm a x ), ti me t o ma xi m u m o bser ve d dr u g 
c o nce ntrati o n (tm a x ), ti me t o earl y half-ma xi mal plas ma c o nce ntrati o n (earl y 5 0 % t m a x ), ti me t o 
late half-ma xi mal dr u g c o nce ntrati o n (late 5 0 % t ma x ), area u n der t he c o nce ntr atio n vers us ti me 
c ur ve ( A U C ) fr o m ti me zer o t o 1 5 mi n utes (A U C [ 0- 1 5mi n ])), A U C fr om ti me zer o t o 3 0 
mi n utes (A U C [ 0-3 0 mi n ])), A U C fr o m ti me zer o t o 1 h o ur(A U C [ 0- 1 h]), A U C fr om ti me zer o t o 
1 0 h o urs (A U C [ 0- 1 0 h]), A U C fr om ti me 2 t o 1 0 h o urs ( A U C[ 2 -1 0 h]), A U C fr om ti me 3 t o 
1 0 h o urs (A U C [ 3- 1 0 h]), A U C fr o m ti me 0 t o t he last rec or de d ti me (A U C [ 0-tlast]), A U C fr o m 
ti me zer o t o i nfi nity (A U C [ 0- ∞]) will be deter mi ne d.  Ot her para meters ma y  be calc ulate d as 
dee m e d a p pr o priate.  A d ditio nal  p artial A U Cs ma y be c o mp ute d as necessar y , s uc h as A U C
fr om ti me zer o t o 2 h o urs.
C CI


I 8 B-M C -I TR Y Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 3 9
L Y 9 0 0 0 1 4
1 0. 3. 2. 2. P h ar m a c o ki n eti c St ati sti c al I nf er e n c e
P har mac o ki net ic para meters will be s u m marize d usi n g sta n dar d descri pt i ve statistics.  
1 0. 3. 3. Gl u c o d y n a mi c A n al y s e s 
1 0. 3. 3. 1. Gl u c o d y n a mi c P ar a m et er E sti m ati o n
Gl uc o d y na mic assess me nts will be deter mi ne d fr o m t he gl uc ose cla m p pr oce d ure, w here t he 
GI R o ver ti me will be use d as a meas ure of i ns uli n effect.  Gl uc o d y na mic a nal yses will be 
c o n d ucte d o n t h ose s u bjects w h o c o m plete at least 1 cla m p pr oce d ure.  T he a nal yses will be 
perf or m e d acc or di n g t o t he Lill y Gl o bal P har mac o ki net ics, P har mac o d y na mics, a n d Trial 
Si m ulati o n Di visi o nal Sta n dar ds.
A l ocall y wei g hte d scatter plot s m o ot hi n g ( L O E S S) f u nct i on will be a p plie d t o all i n di vi d ual GI R 
vers us ti me pr ofiles i n eac h treat me nt gr o u p a n d/ or peri o d usi n g 
  
T he fitte d data f or eac h s u bject will be use d t o calc ulate t he f o ll owi n g G D para m eters:  
ma xi m u m GI R ( R m a x ), ti me t o Rma x (tR m a x ), ti me t o half-ma xi mal GI R bef ore t R ma x (earl y 5 0 % 
tR ma x ), ti me t o half-ma xi mal GI R after t R m a x (late 5 0 % t R m a x ), ti me t o o nset of i ns uli n acti on 
( To nset ), t he t otal a m o u nt of gl uc ose inf use d o ver t he d urati o n of t he cla m p pr oce d ure ( Gt ot), t he 
t otal a mo u nt of  gluc ose i nf use d o ver 1 h o ur ( G t ot[ 0-1 h]), a n d t he t otal a mo u nt of  gluc ose i nf use d 
o ver 3 0 mi n utes ( G t ot[ 0-3 0 mi n]) . A d dit i onal partial gl uc ose A U Cs, s uc h as G t ot i nf use d o ver 
2 h o u rs ( Gt ot[ 0-2 h]), ma y be c o m p ute d as necessar y.  T he val ues o f t hese G D para meters will be 
s u m marize d b y tr e at me nt a n d/ or perio d t hr o u g h descri pt i ve statistics.  Mea n L O E S S fits of GI R 
vers us ti me pr ofiles will be ge nerate d.
1 0. 3. 3. 2. Gl u c o d y n a mi c St ati sti c al I nf er e n c e
Gl uc o d y na mic para meters will be s u m marize d usi n g sta n dar d descri pti ve statist ics.  
1 0. 3. 4. I nt eri m A n al y s e s
T his is a s u bject-bli n d st u d y; t he i n vesti gat or a n d Lill y st u d y t e a m are u n bli n de d.  Data ma y be 
a nal yze d w hile t he trial is o n g o i n g b ut n o c ha n ges t o t he st u d y desi g n are pla n ne d. A n
assess me nt c o m mittee will n ot be f or me d.   If a n u n pla n ne d i nteri m a nal ysis is dee me d necessar y, 
t he Lill y C P , C R P /i n vesti gat or, or desi g nee will c o ns ult with t he a p pr o p riat e me dical direct or or
desi g nee t o deter mi ne if it is necessar y  t o a me n d t he pr ot oc ol.
C CI


I 8 B-M C -I TR Y Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 4 0
L Y 9 0 0 0 1 4
1 1.
R ef er e n c e s
[ A D A] A merica n Dia betes Ass ociati on; W or k gr o u p o n H y p o gl yce mia. Defi ni n g a n d re p orti n g 
h y p o gl yce mia i n dia betes: a re p ort fr o m t he A merica n Dia betes Ass oc iati o n W or k gr o u p o n 
H y p o gl yce mia. Di a betes C are . 2 0 0 5; 2 8( 5): 1 2 4 5- 1 2 4 9.
[ F D A] U nite d States F o o d a n d Dr u g A d mi nistrati o n. S C O G S ( Select C o m mittee o n G R A S 
S u bsta nces). A vaila ble at: 
ht t ps:// w w w.access data.f da. g o v/scri pts/f dcc/i n de x.cf m?set = S C O G S. 2 0 1 8 a. Accesse d J u ne 
2 0, 2 0 1 8 .
[F D A] U nite d States F o o d a n d Dr u g A d mi nistrati o n. I nact i ve i n gre die nts i n a p pr o ve d dr u g 
pr o d ucts. A vaila ble at: htt p:// w w w.access data.f da. g o v/scri pts/c der/ii g/i n de x.cf m. 2 0 1 8 b. 
Accesse d J u ne 2 0, 2 0 1 8.
Fi ne ber g N S, Fi ne ber g S E, A n der s o n J H, Bir kett M A, Gi bs o n R G, H uffer d S. I m m u n ol o gic
effects of i ns uli n lis pr o [ L ys ( B 2 8), Pr o ( B 2 9) h u ma n i ns uli n] i n I D D M a n d NI D D M pat ient s
pre vi o usl y treate d wit h i ns uli n. Di a betes . 1 9 9 6; 4 5( 1 2): 1 7 5 0- 1 7 5 4.
Fi ne ber g S E, H ua n g J, Br u nelle R, G ulli ya K S, A n ders o n J H Jr. Effect of l o n g- t er m e x p os ure t o
i ns uli n lis pr o o n t he i n d ucti on of a nti b o d y  res p o nse i n patie nts wit h t ype 1 or t y pe 2 di a betes.
Di a betes C are . 2 0 0 3; 2 6( 1): 8 9-9 6.
H u m alo g [ pac ka ge i nsert]. I n di a na p o lis, I N: Eli Lill y a n d C om pa n y; 2 0 1 5.
[ pac ka ge i nsert]. Researc h Tria n gle Par k, N C: U nite d T hera pe utics C or p; 2 0 1 4.
Sea q uist E R, A n ders o n J, C hil ds B, Cr yer P, Da g o g o -Jac k S, Fis h L, Heller S R, R o dri g uez H,
R ose nz wei g J, Vi gers k y R. H y p o gl yce m ia a n d di a betes: a re p ort of a w or k gr o u p of t he
A merica n Dia betes Ass ociati o n a n d t he E n d ocri ne S ociet y. Di a betes C are. 2 0 1 3; 3 6( 5): 1 3 8 4 -
1 3 9 5.
C CI


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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Appendix 1.
Abbreviations and Definitions


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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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.
ADA
American Diabetes Association
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the serum concentration versus time curve
BG
blood glucose
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 subject is not, or vice versa, or when the sponsor is aware of the treatment but the 
investigator and/his staff and the subject are not.
BMI
body mass index
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
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
ECG
electrocardiogram
eCRF
electronic case report form


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are those 
who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or through 
their legally acceptable representatives.
ERB
Ethical Review Board
FDA
Food and Drug Administration
GCP
good clinical practice
GD
glucodynamic
GIR
glucose infusion rate
Gtot
total amount of glucose infused
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed 
consent
A process by which a subject 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 
subject’s decision to participate.  Informed consent is documented by means of a written, signed 
and dated informed consent form.  
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a 
clinical study, including products already on the market when used or assembled (formulated or 
packaged) in a way different from the authorized form, or marketed products used for an 
unauthorized indication, or marketed products used to gain further information about the 
authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is conducted 
by a team of individuals at a study site, the investigator is the responsible leader of the team and 
may be called the principal investigator.
IV
intravenous
legal 
representative
An individual or judicial or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study.
LOESS
locally weighted scatterplot smoothing
MDI
multiple daily injections
PAH
pulmonary arterial hypertension
PG
plasma glucose


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
PK
pharmacokinetic
randomize
the process of assigning subjects to an experimental group on a random basis
Rmax
maximum glucose infusion rate
SAE
serious adverse event
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of a pool of 
potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions
t1/2
half-life associated with the terminal rate constant in noncompartmental analysis
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this treatment 
tmax
time of maximum observed concentration
tRmax
time to maximum glucose infusion rate
ULN
upper limit of normal


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Haematologya:
Clinical Chemistrya:
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume (MCV)
Chloride
Mean cell hemoglobin (MCH)
Calcium
Mean cell hemoglobin concentration (MCHC)
Phosphorus 
Leukocytes (WBC)
Glucose (fasting)
Absolute counts of: 
Blood urea
Neutrophils
Uric acid
Lymphocytes
Total cholesterol
Monocytes
Total protein 
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Urinalysisa:
Creatinine
Specific gravity
Gamma-glutamyl transferase (GGT)
pH
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Blood
Pregnancy testb
FSHc,d
Serologyd
Hepatitis B surface antigen
Hepatitis C antibody
HIV
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Performed at a local laboratory.
b
Female subjects only.  A serum pregnancy test will be performed at screening.  Urine pregnancy tests will be 
performed on Day -1 of Period 1, at follow-up, and on Day -1 of Periods 2 and 3 if the time since the previous 
pregnancy test is >2 weeks, and processed on site.
c
Female subjects only, when needed to confirm postmenopausal status.
d
Performed at screening only.


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject 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 subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for subjects.  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 ERB was 
properly constituted and convened as required by International Council for Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB  and updates during the course of the study

ICF 

relevant curricula vitae


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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LY900014
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 eCRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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In addition, Lilly or its representatives will periodically check a sample of the subject 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 personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Site
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 subjects 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.


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
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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-ITRY Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
30
1
30
Clinical laboratory testsa
7.5
1
7.5
Pharmacokinetics 
2.5
75
187.5
Blood discard for cannula patency
0.5
75
37.5
Glucose monitoring (euglycemic 
clamp)
0.3
10 hours/clamp x 3 
clamps (approx.
100 samples/clamp)
b
90
Immunogenicity
5
4
20
Total
372.5
Total for clinical purposes 
380
a
Additional samples may be drawn if needed for safety purposes.
b
Includes sampling for post-clamp glucose monitoring; additional samples may be drawn if needed for safety 
purposes.


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Appendix 6.
Protocol Amendment I8B-MC-ITRY(a) 
Summary A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 Following Single Dose 
Administration in Healthy Chinese Subjects
Overview
Protocol I8B-MC-ITRY [A Study to Evaluate the Pharmacokinetics and Glucodynamics of 
LY900014 Following Single Dose Administration in Healthy Chinese Subjects] has been 
amended.  The new protocol is indicated by Amendment (a) and will be used to conduct the 
study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:
Table ITRY.4.
Amendment Summary for Protocol I8B-MC-ITRY Amendment(a)
Section # and Name
Description of Change
Brief Rationale
2. Schedule of Activities
Blood glucose sampling time during 
the first 30 minutes of the glucose 
clamp has been changed from every 
5 minutes to every 2.5 to 3 minutes.
Frequency of blood glucose 
sampling increased to ensure subject
safety and clamp quality.
9.4.1. Laboratory Tests
The requirement for the clinical 
laboratory to be central has been 
removed.
The change allows flexibility in 
laboratory selection.
Appendix 5. Blood Sampling 
Summary
The blood volume required for 
glucose monitoring has been 
amended from 72 to 90 mL.
Change reflects additional blood 
volume required to accommodate 
more frequent sampling.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 52
LY900014
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
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-ITRY Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
30
1
30
Clinical laboratory testsa
7.5
1
7.5
Pharmacokinetics 
2.5
75
187.5
Blood discard for cannula patency
0.5
75
37.5
Glucose monitoring (euglycemic 
clamp)
0.3
10 hours/clamp x 3 
clamps (approx. 
80 100 samples/cla
mp)b
7290
Immunogenicity
5
4
20
Total
354372.5
Total for clinical purposes 
360380
a
Additional samples may be drawn if needed for safety purposes.
b
Includes sampling for post-clamp glucose monitoring; additional samples may be drawn 
if needed for safety purposes.
9.4.1.Laboratory Tests
Clinical laboratory tests will be analyzed by a central laboratory selected by Lilly.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 53
LY900014
Study Schedule Protocol I8B-MC-ITRY
Screening
Euglycemic clamp procedure 
Periods 1, 2, and 3
Follow-
up/Early 
discontinuation
Instructions/Comments
Procedure
Up to -28 
days
Day -1
Day 1a
≥14 days after 
last dose
Informed consent
X
Admission to 
CRU
X
Overnight fast
X
X
X
Subjects will fast for approximately 8 hours prior 
to screening and follow-up/early discontinuation 
and from approximately 8 hours before each dose 
until the end of the glucose clamp procedure.
Hip and waist 
circumference
Period 1 
only
Measurements taken in triplicate.
Height
X
Body weight
X
X
Medical history 
and physical 
examination
X
Medical 
assessment
X
Predose and before discharge from 
CRU 
X
Medical assessment includes medical review and 
targeted examination as appropriate.
Vital signs 
(supine): body 
temperature, 
blood pressure 
and pulse rate
X
Predose and approximately 10 hours 
postdose (end of the clamp procedure)
X
Single vital signs measurements for safety.  
12-lead ECG
X
Predose and approximately 10 hours 
postdose (end of the clamp procedure)
X
Single ECGs will be collected for safety.  
Electrocardiograms may be collected at additional 
times when deemed clinically necessary.  


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 54
LY900014
Screening
Euglycemic clamp procedure 
Periods 1, 2, and 3
Follow-
up/Early 
discontinuation
Instructions/Comments
Procedure
Up to -28 
days
Day -1
Day 1a
≥14 days after 
last dose
Clinical 
laboratory tests
X
X
All scheduled clinical laboratory tests will be 
conducted after at least 8 hours fasting.  To 
monitor subject safety, additional tests may be 
performed at the discretion of the investigator as 
needed throughout the study.  All testing will be 
conducted at a local laboratory.  
Serology
X
FSH
X
Female subjects only, when needed to confirm 
postmenopausal status.  
Pregnancy test
X
X
X
Female subjects only.  A serum pregnancy test 
will be performed at screening.  Urine pregnancy 
tests will be performed on Day -1 of Period 1, at 
follow-up, and on Day -1 of Periods 2 and 3 if the 
time since the previous pregnancy test is >2 
weeks.
Urine drug screen 
and alcohol breath 
test
X
Study drug 
administration
X (time = 0)
Injection-site 
local tolerability 
assessments
Immediately postdose, 60, 240, and 
600 minutes postdose
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, 420, 480, 540, and 
600 minutes postdose


I8B-MC-ITRY Clinical Pharmacology Protocol(a)
Page 55
LY900014
Screening
Euglycemic clamp procedure 
Periods 1, 2, and 3
Follow-
up/Early 
discontinuation
Instructions/Comments
Procedure
Up to -28 
days
Day -1
Day 1a
≥14 days after 
last dose
Euglycemic 
clamp
X
0 to 10 hours postdose
If the GIR falls to zero for at least 30 minutes 
after the clamp has been underway for at least 
8 hours, the clamp will be discontinued.  
Following completion of the euglycemic clamp, 
subjects will receive a meal and undergo glucose 
monitoring as deemed necessary by the 
investigator prior to discharge.  
Blood glucose 
sampling
(euglycemic 
clamp)
Approximately every 10 minutes for
approximately 30 minutes before the
start of dosing (for baseline
measurement).  During clamp, 
sampling occurs every 5 2.5 to 3
minutes for the first 30 minutes, every 
5 minutes for 30 to 120 minutes; every 
10 minutes for 120 to 480 minutes and 
every 20 minutes for 480 to 600 
minutes.
Sampling times are relative to study drug 
administration (time 0). Failure to obtain samples 
due to clinical issues, such as problems with 
venous access, will not be considered a protocol 
violation. Repeat samples for counter checking of 
apparent spurious results may be taken where 
indicated.
Immunogenicity 
sample
Predose
X
Discharge from 
CRU
X
Subjects will be discharged after completion of all 
study procedures on Day 1, at the discretion of the 
investigator.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; FSH = follicle-stimulating hormone; GIR = glucose infusion rate; 
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. Electrocardiograms and vital sign 
measurements should be scheduled before but as close as possible to the PK sampling times. 
a
There will be a minimum of 3 days between dosing in consecutive periods.


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

SAP_001.pdf: 
I8B-MC-ITRY Statistical Analysis Plan 
 
A Study to Evaluate the Pharmacokinetics and Glucodynamics of LY900014 Following Single 
Dose Administration in Health Chinese Subjects 
 
NCT04049123 
 
Approval Date: 01-Nov-2017 


Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 1 of 1 5
S T A TI S TI C A L A N A L Y SI S P L A N
A St u d y t o E v al u ate t he P h ar m ac o ki netics a n d Gl uc o d y n a mics of L Y 9 0 0 0 1 4 F oll o wi n g 
Si n gle D ose A d mi nistr ati o n i n He alt h y C hi nese S u bjects
Stati stical A nal ysis Pla n Stat us:  Fi nal
Stati stical A nal ysis Pla n Date:  3 1- Oct o ber - 2 0 1 7
St u d y  Dr u g: L Y 9 0 0 0 1 4
S p o ns or Refere nce:  I 8 B-M C -I T R Y
Cli nical P hase I
A p pr o v al D at e: 0 1- N o v- 2 0 1 7 G M T
C CI


Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 2 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
1. T A B L E O F C O N T E N T S
1.
T A B L E O F C O N T E N T S ............................................................................................... 2
2.
A B B R E VI A TI O N S ........................................................................................................ 4
3.
I N T R O D U C TI O N ......................................................................................................... 6
4.
S T U D Y O BJ E C TI V E S .................................................................................................. 6
4. 1
Pri mar y O bject i ve.................................................................................................... 6
4. 2
Sec o n dar y  O bjecti ves .............................................................................................. 6
4. 3
E x pl or at or y  O bjecti ve.............................................................................................. 6
5.
S T U D Y D E SI G N ........................................................................................................... 7
6.
T R E A T M E N T S ............................................................................................................. 8
7.
S A M P L E SI Z E J U S TI FI C A TI O N ................................................................................. 8
8.
D E FI NI TI O N O F A N A L Y S I S P O P U L A TI O N S............................................................ 8
9.
S T A TI S TI C A L M E T H O D O L O G Y ............................................................................... 9
9. 1
Ge neral .................................................................................................................... 9
9. 2
D e m o gra p hics a n d S u bject Dis p osit i on .................................................................... 9
9. 3
P har mac o ki net ic A nal yses ....................................................................................... 9
9. 3. 1
P har mac o ki net ic Para meter Esti mati on ........................................................... 9
9. 3. 2
P har mac o ki net ic Statistical I nfere nce ........................................................... 1 0
9. 4
Gl uc o d y na mic A nal yses ........................................................................................ 1 0
9. 4. 1
Gl uc o d y na mic Para meter Esti mat i on ............................................................ 1 0
9. 4. 2
Gl uc o d y na mic Stati stical I nfere nce............................................................... 1 0
9. 5
S af et y a n d T olera bilit y Assess me nts ...................................................................... 1 0
9. 5. 1
A d verse e ve nts ............................................................................................. 1 0
9. 5. 2
C o nc o mita nt me dicat i on ............................................................................... 1 1
9. 5. 3
Cli nical la b orat or y  para meters...................................................................... 1 1
9. 5. 4
Vi t al si g ns .................................................................................................... 1 1
9. 5. 5
He pati c M o nit orin g ...................................................................................... 1 1
9. 5. 6
Bl o o d Gl uc ose M o ni t ori n g a n d H y p o gl yce mia ............................................. 1 2
9. 5. 7
I njecti on Si te Assess me nt ( L ocal T olera bility) .............................................. 1 3
9. 5. 8
I mm u n o ge nicit y ........................................................................................... 1 3
9. 5. 9
Ot her assess me nts ......................................................................................... 1 4
9. 5. 1 0
S af et y a n d T olera bilit y Statisti c al Met h o d olo g y............................................ 1 4
C CI


Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 3 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
1 0. I N T E RI M A N A L Y S E S ............................................................................................... 1 4
1 1. C H A N G E S F R O M T H E P R O T O C O L S P E CI FI E D S T A T I S TI C A L A N A L Y S E S ...... 1 4
1 2. R E F E R E N C E S ............................................................................................................ 1 4
1 3. D A T A P R E S E N T A TI O N ............................................................................................ 1 4
1 3. 1 Deri ve d Para meters ............................................................................................... 1 4
1 3. 2 Missi n g Data ......................................................................................................... 1 4
1 3. 3 I ns ufficie nt Data f or Prese ntati o n .......................................................................... 1 5
C CI


Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 4 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
2. A B B R E VI A TI O N S
A b bre viat i ons pertai n t o t he Stati stical A nal ysis Pla n ( S A P ) o nl y ( n ot t he ta bles, fi g ures a n d 
listi n gs [T F Ls ]).
A D A
A merica n dia betes ass ociat i on
A E
A d verse e ve nt
A L P
A l kali ne p h os p hatase
A L T
A la ni ne a mi n otra nsferase
A U C( 0 -3 0 mi n)
A rea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 3 0 
mi n utes
A U C( 0 -1 h)
A rea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m t i me zer o t o 1 
h o ur
A U C( 0 -1 0 h)
A rea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 1 0 
h o urs
A U C( 3 -1 0 h)
A rea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me 3 h o urs t o 
1 0 h o urs
A U C( 0 -tlast)  
Area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m t i me zer o t o 
ti me t, w here t is t he last ti me p o i nt wit h a meas ura ble c o nce ntratio n
B Q L
B elo w t he q ua nt ifia ble l o wer li mit of t he assa y
C ma x
M a xi m u m o bser ve d dr u g c o nce ntrati o n
C L/ F
A p pare nt t otal  bo d y  cleara nce of dr u g calc ulate d aft er e xtra-vasc ular
a d mi nistrati o n
C R F
Case Re p ort F or m
C S R
Cli nical St u d y  Re p ort
C R U
Cli nical Researc h U nit
C V
C oefficie nt of variat i on
Earl y 5 0 % t ma x
T i me t o earl y half-ma xi mal plas ma c o nce ntrati o n
Earl y 5 0 % t R ma x
T i me t o half-ma xi mal GI R bef ore tR ma x
E C
Earl y Cli nical 
E C G
E lectr ocar di o gra m
e. g.
F or e xa m ple ( Lat i n: exe m pli gr ati a)
G D
Gl uc o d y na mic 
GI R
Gl uc ose i nf usi o n rate
G t ot
T otal  a mo u nt of gl uc ose i nf use d
C CI


Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 5 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
G t ot( 0-1 h)
T otal  a mo u nt of gl uc ose i nf use d o ver 1 h o ur
G t ot( 0-3 0 mi n)
T otal  a mo u nt of gl uc ose i nf use d o ver 3 0 mi n utes
G t ot( 0-2 h)
T otal  a mo u nt of gl uc ose i nf use d o ver 2 h o urs
I C H
I nter nati o nal C o u ncil o n Har m o nis atio n
Late 5 0 % t ma x
T i me t o late half-ma xi mal dr u g c o nce ntrati o n
Late 5 0 % t R ma x
T i me t o half-ma xi mal GI R after t R ma x
L S
Least s q uare
L O E S S 
L ocall y  wei g hte d scatter plot s m o ot hi n g 
Me d D R A
Me dical Dict i onar y f or Re g ulat or y  Acti vities
M R E
Ma g net ic res o na nce elast o gra p h y
N A
N ot a p plica ble
P K
P har mac o ki net ic
R ma x
M a xi m u m gl uc ose i nf usi o n rate
S A P
Stati stical A nal ysis Pl a n
S C
S u bc uta ne o us 
S D
S ta n dar d de viati on 
T B L
T ot al  bilir u bi n
T F Ls
Ta bles, Fi g ures, a n d List i n gs
t1/ 2
H alf-life ass ociat e d wit h t he ter mi nal rate c o nsta nt ( λz) i n n o n-
c o mpart me nt al a nal ysis
tma x
Ti me o f ma xi m u m o bser ve d dr u g c o nce ntrati o n
T o nset
Ti me t o o nset of i ns uli n acti o n
tR ma x
T i me t o ma xi m u m gl uc ose i nf usi on rate
U L N
U p per li mit of n or mal
V z/ F
A p pare nt v ol u m e of  distri b uti on d uri n g t he ter mi nal p hase after 
e xtra-vasc ular a d mi nistrati o n
W H O
W o rld Heal t h Or ga nizati on
C CI


Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 6 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
3. I N T R O D U C TI O N
T h is S A P has bee n de vel o pe d after re vie w of t he Cli nical St u d y  Pr ot oc ol (fi nal dr af t create d i n 
Se pte m ber 2 0 1 7 ).
T his S A P descri bes t he pla n ne d a nal ys is of t he safet y, t olera bilit y, p har m ac o ki netic (P K ) a n d 
gl uc o d y na mic ( GD) data fr o m t his st u d y. A detaile d de script i on of t he pla n ne d T F Ls t o be 
prese nte d i n t he cli nical st u d y  re p ort ( C S R) is pr o vi de d i n t he acc om pa n yi n g T F L s hell 
d oc u m e nt.
T he i nte nt of t his d oc u me nt is t o pr o vi de g ui da nce f or t he statist ical a n d P K a nal yses of data. I n 
ge neral, t he a nal yses a re base d o n i nf or mati on fr o m t he pr ot oc ol, u nless t he y ha ve bee n mo difie d 
b y a gree me nt bet wee n El i Lill y a n d C o m pa n y a n d 
. A 
li mite d a m o u nt of i nf or mati on c o ncer ni n g t his st u d y (e. g., o bj ecti ves, st u d y desi g n) is gi ven t o 
hel p t he rea der’s i nter pretati o n. T hi s S A P must be si g ne d off pri or t o first s u bject a d mi nistrati o n
f or t his st u d y. W he n t he S A P a n d T F L s hells are a gree d u p o n a n d fi nalize d, t he y will ser ve as 
t he te mplate f or t hi s st u d y’s C S R.
T his S A P s u perse des t he statistical c o nsi derati ons i de ntifie d i n t he pr ot oc ol; w here 
c o nsi derati o ns are s u bsta nt iall y differe nt, t he y will be s o ide nt ifie d. If a d diti onal a nal yses are 
re q uire d t o s u p ple me nt t he pla n ne d a nal yses descri be d i n t his S A P, t he y ma y be perf or me d a nd 
will be i de nt ifie d i n t he C S R. A n y s u bsta ntial de viati o ns fr o m t his S A P will be a gree d u p o n 
bet wee n Eli Lill y a n d C o m pa n y  a n d 
a n d ide ntifie d i n t he C S R. A n y 
mi n or de viat i ons fr om t he T F Ls ma y n ot be d oc u me nte d i n t he C S R.
T his S A P is writte n wit h c o nsi derati o n of t he rec o m me n dati ons o utli ne d i n t he I nte r nati o nal 
C o u ncil o n Har m o nis atio n (I C H) E 9 G ui deli ne e nti tle d G uida nce f or I n d ustr y : Statistical 
Pri nci ples f or Cli nical Trials 1 a n d t he I C H E 3 G ui deli ne e nt itle d G ui da nce f or I n d ustr y: Str uct ure 
a n d C o nte nt of Cli nical St u d y R e p orts2.
4. S T U D Y O B J E C TI V E S
4. 1
Pri m ar y O bjecti ve

T o e val uate t he P K of i ns uli n lis pr o f o ll owi n g a d mi nistrati o n of si n gle s u bc uta ne o us (S C )
d oses of 7 a n d 1 5 U of L Y 9 0 0 0 1 4 a n d 1 5 U of H u mal o g i n healt h y C hi nese s u bjects
4. 2
Sec o n d ar y O bjecti ves

T o e val uate t he G D s of  ins uli n lis pr o d uri n g a e u gl yce mic cla m p pr oce d ure f oll o wi n g S C 
d oses of 7 a n d 1 5 U of L Y 9 0 0 0 1 4 a n d 1 5 U of H u mal o g i n healt h y C hi nese s u bjects

T o e val uate t he safet y a n d t olera bilit y of t he n o vel L Y 9 0 0 0 1 4 f or m ulati on
4. 3
E x p l or at or y O bjecti ve

E x pl ore t he f or mati o n of  a nti b o dies t o i ns uli n lis pr o.
C CI
C CI
C CI


Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 7 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
5. S T U D Y D E SI G N
T his is a P hase 1, si n gle ce nter, ra n d o mize d, s u bject- bli n d, 3 -p eri o d, cr oss o ver st u d y  t o e valu at e 
t he P K of i ns uli n lis pr o f or a n o vel L Y 9 0 0 0 1 4 f or m ulat i on i n healt h y C hi nese s u bjects.  Ta ble 1
ill ustrates t he st u d y desi g n.
After satisf yi n g t he st u d y  e ntry crit eria, s u bjects will be ra n d o mize d t o 1 of 3 treat me nt 
se q ue nces (Ta ble 1 ).  S u bjects will be re q uire d t o atte n d t he cli nical researc h u nit ( C R U) o n 5 
occasi o ns:

scree ni n g visit ( u p t o 2 8 da ys prior t o d osi n g [ Da y  1 of P erio d 1])

3 st u d y  p erio ds, eac h c o m pr isi n g a 1 ni g ht i n patie nt sta y fr om Da y   1 t o Da y 1 f or t he 
cla m p pr oce d ure (s u bjects ma y re mai n f or l o n ger i n t he C R U at t he i n vest i gat or’s 
di scretio n f or s af et y reas o ns)f oll ow- u p visi t ≥1 4 da ys after t he last d ose, or earl y 
di sc o nti n uati on
S u bjects will be faste d (e xce pt f or water a n d barle y tea) f or at least 8 h o urs pri or t o c ollect i on of 
cli nical safet y la b orat or y sa m ples a n d d osi n g, a n d d uri n g gl uc ose cla m p pr oce d ures acc or di n g t o 
t he Sc he d ule of Act i vities ( Sectio n 2 of  t he pr ot oc ol).  
Eac h s u b ject will partici pate i n 3 i n patient  visits; o n Da y 1 of eac h peri o d, t he ti me-c o nce ntratio n 
a n d ti me act i on pr ofiles o f i ns uli n lis pr o will be e val uate d si m ulta ne o usl y d uri n g a e u gl yce mic 
gl uc ose cl a m p of a p pr o xi matel y 1 0 h o urs d uratio n.  Bri efl y, t he ai m of  t he e u gl yce mic cla m p is 
t o mai ntai n e u gl yce mia after t he a d mi nistrati o n of a d ose of i ns uli n b y  mea ns of varia ble gl uc ose 
i nf usi on.  T he varia ble gl uc ose i nf usi o n mai ntai ns or “cla m ps” gl uc ose at a c o nsta nt e u gl yce mic 
tar get; t heref ore, t he gl uc ose i nfusi o n  rate ( GI R) reflects t he G D effect of t he i ns uli n.  M ore 
i nf or mat i on o n t he cl a m p met h o d olo g y  ca n be f o u n d i n Secti on 9. 6 of  t he pr ot oc ol.
O n c o m p leti on of t he e u gl yce mic cla m p, s u bjects will be pr o vi de d wit h a meal a n d will u n der g o 
gl uc ose m o ni t ori n g t o e ns ure t hat t here is n o ris k of h y p o gl yce mia.  Serial blo o d s a m ples will  be 
c ollecte d d uri n g t he 1 0 -h o ur gl uc ose cla m p at t he ti mes s pecifie d i n t he St u d y  Sc he d ule ( Sectio n 
2 of  t he pr ot oc ol) t o assess t he P K para meters a n d G D para m eters of L Y 9 0 0 0 1 4 .  T here will be a 
mi ni m u m o f 3 da y s bet wee n st u d y d oses i n c o nsec uti ve peri o ds.  
A p h ysicia n’s me dical assess me nt will be re q uire d bef ore s u bjects are disc har ge d fr o m t he C R U.  
T here are n o o ut patie nt visits pla n ne d bet wee n st u d y  p erio ds.  
S af et y assess me nts a n d a n e val uati on of l ocal t olera bilit y at i nject i on sites will be perf or me d as 
s pecifie d i n t he St u d y Sc he d ule ( Secti o n 2 of  t he pr ot oc ol).  Lo c al  t olera bilit y assess me nts will 
i ncl u de i njecti on- site assess me nts f or si g ns of e de ma a n d er yt he ma.
St u d y  g o ver na nce c o nsi derati o ns are descri be d i n detail i n A p pe n di x 3 of  t he pr ot oc ol.
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Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 8 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
T a ble 1 St u d y Desi g n
Treat me nt Se q ue nce a
P eri o d 1 
P eri o d 2 
P eri o d 3 
1
1 5 U H u mal o g 
7 U L Y 9 0 0 0 1 4
1 5 U L Y 9 0 0 0 1 4
2
7 U L Y 9 0 0 0 1 4
1 5 U H u mal o g
1 5 U L Y 9 0 0 0 1 4
3
7 U L Y 9 0 0 0 1 4
1 5 U L Y 9 0 0 0 1 4
1 5 U H u mal o g
N ote:  T his is a n e xa m ple ta ble; s u bjects will be assi g ne d a treat me nt se q ue nce acc or di n g t o t he act ual treat me nt 
sc he d ule pr o vi de d t o t he site.  
a I n eac h treat me nt peri o d, 1 5 U H u mal o g or i n dicate d d oses of t he L Y 9 0 0 0 1 4 f or m u lati o n will be a d mi nistere d.
6. T R E A T M E N T S
T he f o ll owi n g i s a list of t he st u d y tr e at me nt a b bre viat i ons t hat will be use d i n t he T F Ls.
St u d y Tre at me nt N a me
Tre at me nt or der i n T F L
7 U L Y 9 0 0 0 1 4
1
1 5 U L Y 9 0 0 0 1 4
2
1 5 U H u mal o g
3
7. S A M P L E SI Z E J U S TI FI C A TI O N
U p t o 1 5 s u bjects will be ra n d omize d i n or der t hat 1 2 s u bjects c o m plete all peri o ds o f t he st u d y 
( 4 per se q ue nce).
S a m ple size is n ot base d o n a statist ical p o wer calc ulati on.  Sa m ple size is c o nsi dere d s uita ble t o 
c haracterize t he P K pr ofiles of i ns uli n lis p r o, a n d t o e val uate t he safet y a n d t olera bilit y of  si n gle 
d oses of L Y 9 0 0 0 1 4 a d mi nistere d S C.
If t he ra n d omize d s u bjects disc o nt i n ue fr om t he st u d y prior t o i ts c o mplet i on, s u bjects ca n be 
r e place d.  T he re place me nt s u bject will a d o pt t he ori gi nal s u bject’s ra n d omizat i on sc he d ule.
8.
D E FI NI TI O N O F A N A L Y SI S P O P U L A TI O N S
T he “ Safet y” p o p ulat i on will c o nsist of all e nr olle d s u bjects, w het her or n ot t he y c o mplete d all  
pr ot oc ol  r e q uire me nts.
T he “ P har mac o ki net ic” p o p ulat i on will c o nsist of a ll s u bjects w h o recei ve d at least o ne d ose of 
t he i n vest i gati onal pr o d uct a n d ha ve e val ua ble P K data.  
T he “ Gl uc o d y na mi c” p o p ulat i on will  c o nsist of all s u bjects w h o recei ve d at least o ne d ose of 
i n vesti gati onal pr o d uct a n d ha ve e val ua ble G D data.
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Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 9 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
All pr ot oc ol de viat i ons t hat oc c ur d uri n g t he st u d y will be c o nsi dere d f or t heir se verit y/ i m pact 
a n d will be ta ke n i nt o c o nsi derat i on w he n s u bjects are assi g ne d t o a nal ysis p o p ul at i ons .
9. S T A TI S TI C A L M E T H O D O L O G Y
9. 1
Ge ner al
Data list i n gs will be pr o vi de d f or all data t hat is data base d. S u m ma r y st atistics a n d statistical 
a nal ysis will o nl y be prese nte d f or data w here detaile d i n t his S A P. F or c o nti n u o us data, 
s u m mar y statistics will i ncl u de t he arit h met ic mea n, arit h metic sta n dar d de viat i on ( S D), m e dia n, 
mi n, ma x a n d N; f or l o g -n or mal data (e . g. t he P K para meters: A U Cs a n d Cma x) t he ge o metric 
mea n a n d ge o met ric c oefficie nt of variat i on ( C V %) will als o be prese nte d . F or cate g orical data, 
fre q ue nc y c o u nt a n d perce nta ges will be prese nte d. Data list i n gs will be pr o vi de d f or all s u bjects 
u p t o t he p oi nt of wit h dra wal, wit h a n y s u bjects e xcl u de d fr o m t he rele va nt p o p ulati o n 
hi g hli g hte d. S u m mar y statist ics a n d statistical a nal yses will ge nerall y o nl y be perf or me d f or 
s u bjects i ncl u de d i n t he rele va nt a nal ysis p o p ulat i on. F or t he calc ulat i on of s u m mar y stati stics 
a n d statist ical a nal ysis, u nr o u n de d data will be use d. 
Mea n c ha n ge fr o m baseli ne is t he mea n of all i n di vi d ual s u bjects’ c ha n ge fr o m baseli ne val ues. 
Eac h i n di vi d ual c ha n ge fr o m baseli ne will be calc ulate d b y  s u btracti n g t he i n di vi d ual su bject’s 
baseli ne val ue fr o m t he val ue at t he ti me p o i nt. T he i n di vi d ual s u bject’s c ha n ge fr o m baseli ne 
val ues will be use d t o calc ulate t he mea n c ha n ge fr o m baseli ne usi n g a S A S pr oce d ure s uc h as 
Pr oc U ni variate.
Data a nal ysis will be perf or me d usi n g 
or greater.
9. 2
De m o gr a p hics a n d S u bject Dis p ositi o n
S u bj ect dis p ositio n will be liste d . T he de m o gra p hic varia b les a ge, se x, race, et h nicity, c o u ntr y of 
e nr o l me nt, site I D, b o d y wei g ht, hei g ht a n d b o d y mass i n de x will be s u m mar ize d a n d liste d.
9. 3
P h a r m ac o ki netic A n al yses
9. 3. 1
P h ar m ac o ki netic P ar a meter Esti m ati o n
I ns uli n lis pr o P K para meter esti mates f or L Y 9 0 0 0 1 4 a n d H u mal o g will be c o n d ucte d usi n g 
sta n dar d n o nc om part me nt al met h o ds of a nal ysis usi n g 
 
 o n a c o m p uter t hat meets or e xcee ds t he mi ni m u m s yste m 
re q uire me nts f or t hese pr o gra ms.  T he versi on of a n y  s oft ware use d f or t he a nal ysis will be 
d oc u m e nte d a n d t he pr o gra m will meet t he Lill y r e q uire me nts of s oft ware vali dati o n.  It is 
p oss i ble t hat ot her vali date d e q ui vale nt P K s oft ware pr o gra ms ma y be utilize d if a p pr o priate, 
warra nte d, a n d a p pr o ve d b y gl o bal P K ma na ge me nt.
Free ser u m i ns uli n lis pr o c o nce ntrati o ns will be use d t o calc ulate se veral P K para meters, 
i ncl u di n g ma xi m u m o bser ve d c o nce ntratio n ( C ma x ), ti me t o ma xi m u m o bser ve d dr u g 
c o nce ntrati o n (t ma x ), ti me t o earl y half ma xi mal plas ma c o nce ntrati o n (earl y 5 0 % t ma x ), ti me t o 
late half-ma xi mal dr u g c o nce ntrati o n (late 5 0 % t ma x ), area u n der t he c o nce ntrati o n vers us ti me 
c ur ve ( A U C) fr o m ti me zer o t o 3 0 mi n utes [ A U C( 0-3 0 mi n)], A U C fr o m ti me zer o t o 1 
C CI
C
C
I
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Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 1 0 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
h o ur[ A U C( 0 -1 h)], A U C fr o m ti me zer o t o 1 0 h o urs [ A U C( 0-1 0 h)], A U C fr o m ti me 3 t o 1 0 
h o urs [ A U C( 3 -1 0 h)], A U C fr o m ti me 0 t o t he last rec or de d ti me [ A U C( 0-tlast], A U C fr o m ti me 
zer o t o i nfi n ity [ A U C( 0 - ∞)], half-life ass ociate d wit h t he ter mi nal rate c o nsta nt i n 
n o nc o m part me nt al a nal ysis (t1/ 2), a p pare nt t otal b o d y cleara nce of dr u g calc ulate d after e xtra-
vasc ular a d mi nistrati o n ( C L/ F), a n d a p pare nt v ol u me of distri b ut i on d uri n g t he ter mi nal p hase 
after e xtra vasc ular a d mi nistrati o n ( Vz/ F) will be deter mi ne d.  Ot her para meters ma y be 
calc ulate d as dee me d a p pr o priate.  A d dit i onal partial A U Cs ma y be c o m p ute d as necessar y , s uc h 
as A U C fr o m t i me zer o t o 2 h o urs.
9. 3. 2
P h ar m ac o ki netic St atistic al I nfere nce
P har mac o ki net ic para meters will be s u m marize d usi n g sta n dar d descri pti ve statistics b y Lill y .  
9. 4
Gl uc o d y n a mic A n al yses
9. 4. 1
Gl uc o d y n a mic P ar a meter Esti m ati o n
Gl uc o d y na mic assess me nts will be deter mi ne d fr o m t he gl uc ose cla m p pr oce d ure, w here t he 
GI R o v er ti me will be use d as a meas ure of i ns uli n effect.  Gl uc o d y na mic a nal yses will be 
c o n d ucte d o n t h ose s u bjects w h o c o m plete at least 1 cla m p pr oce d ure.  T he a nal yses will be 
perf or m e d acc or di n g t o t he Lill y Gl o bal P har mac o ki net ics, P har mac o d y na mics, a n d Trial 
Si m ulati o n Di visi o nal Sta n dar ds.
A l ocall y wei g hte d scatter plot s m o ot hi n g ( L O E S S) f u nct i on will be a p plie d t o all i n di vi d ual GI R 
vers us ti me pr ofiles i n eac h treat me nt gr o u p a n d/ or peri o d usi n g 
  
T he fitte d data f or eac h s u bject will be use d t o calc ulate t he f o ll owi n g G D para m eters:  
ma xi m u m GI R ( R m a x ), ti me t o Rma x (tR m a x ), ti me t o half-ma xi mal GI R bef ore t R ma x (earl y 5 0 % 
tR ma x ), ti me t o half-ma xi mal GI R after t R m a x (late 5 0 % t R m a x ), To n set, t he t otal a m o u nt of 
gl uc ose i n f use d o ver t he d urati o n of t he cla m p pr oce d ure ( Gt ot), t he t otal a m o u nt of gl uc ose 
i nf use d o ver 1 h o ur ( Gt ot[ 0-1 h]), a n d t he t otal a mo u nt of  gluc ose i nf use d o ver 3 0 mi n utes 
( Gt ot[ 0-3 0 mi n]) . A d dit i on al  p artial gl uc ose A U Cs, s uc h as Gt ot i nf use d o ver 2 h o urs 
( Gt ot[ 0-2 h]), ma y be c o m p ute d as necessar y.  T he val ues of t hese G D para meters will be 
s u m marize d b y tr e at me nt a n d/ or perio d t hr o u g h descri pt i ve statistics.  Mea n L O E S S fits of GI R 
vers us ti me pr ofiles will be ge nerate d.
9. 4. 2
Gl uc o d y n a mic St atistic al I nfere nce
Gl uc o d y na mic para meters will be s u m marize d usi n g sta n dar d descri pti ve statist ics b y Lill y .  
9. 5
S afet y a n d T oler a bilit y Assess me nts
9. 5. 1
A d verse e ve nts
W here c ha n ges i n se verit y are rec or de d i n t he Case Re p ort F or m ( C R F ), eac h se parate se verit y 
of  t he a d verse e ve nt ( A E) will be re p orte d i n t he listi n gs , o nl y t h e most se vere will be use d i n t he 
s u m mar y ta bles. A pre -e xist i n g c o n diti on is defi ne d as a n A E t hat starts bef ore t he s u bject has 
pr o vi de d wri tte n i nf or me d c o nse nt a n d is o n g o i n g at c o nse nt. A n o n -treat me nt e mer ge nt A E is 
C CI
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Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 1 1 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
defi ne d as a n A E w hic h st arts aft er i nf or me d c o nse nt b ut pri or t o d osi n g. A treat me nt -e mer ge nt 
A E i s defi ne d as a n A E w hic h occ urs p ost d ose or w hic h is prese nt pri or t o d osi n g a n d bec o mes 
m o re se vere p ost d ose.
All A Es will  be liste d.  Treat me nt -e mer ge nt A Es will be s u m mariz e d b y tr e at me nt, se verit y a n d 
r elat i ons hi p t o t he st u d y  dr u g. T he fre q ue nc y (t he n u m ber of A E s, t he n u m ber of s u bjects 
e x perie nci n g a n A E a n d t he perce nta ge of s u bjects e x perie nci n g a n A E ) of treat me nt -e mer ge nt 
A Es will be s u m mariz e d b y treat me nt, Me di cal Dictio nar y  for Re g ulat or y  Act i vities (Me d D R A )
versi o n 2 0. 0 s yste m or ga n class a n d preferre d ter m. T he s u m mar y a n d fre q ue nc y A E ta bles will 
be prese nte d f or all ca usalit ies a n d t h ose c o nsi dere d relate d t o t he st u d y dr u g. A n y seri o us A Es
will be ta b ulate d .
9. 5. 2
C o nc o mit a nt me dic ati o n
C o nc o mita nt me dicat i on will be c o de d usi n g t he W H O dr u g dict i onar y  ( Versio n  Marc h 2 0 1 7).
C o nc o mita nt me dicat i on will be liste d.
9. 5. 3
Cli nic al l a b or at or y p ar a meters
A ll cli nical c he mistr y, h e m at olo g y a n d uri nal ysis d at a w ill be liste d. A d dit i onall y cli nical 
che mistr y , he m at olo g y a n d uri nal ysis data o utsi de t he r efere nce ra n ges will be liste d.
V al u es f or a n y  cli n ical c he mistr y, he mat olo g y  a n d uri nal ysis val ues o utsi de t he refere nce ra n ges 
will be fla g ge d o n t he i n di vi d ual s u bject data list i n gs.
9. 5. 4
Vit al si g ns
V alu es f or i n di vi d ual s u bjects will be liste d.
9. 5. 5
He p atic M o nit ori n g
If a patie nt e x perie nces ele vate d ala ni ne a mi n otra nsferase ( A L T) ≥3 × u p per li mit of n or mal 
( U L N), al kali ne p h os p hatase ( A L P) ≥2 × U L N, or ele vate d t otal bilir u bi n ( T B L) ≥2 × U L N, li ver 
tests will be perf or me d t o c o nfir m t he a b n or mality .
T he patie nts’ li ver disease hist or y  a n d ass ociate d pers o n li ver disease hist or y data will be liste d. 
A n y c o nc o mit a nt me dicatio n of  aceta mi n o p he n/ paraceta m ol will be liste d. Res ults fr o m a n y 
he pat ic m o nit ori n g pr oce d ures, s uc h as a ma g net ic res o na nce elast o gra p h y ( M R E) sca n, a n d a 
bi o ps y assess me nt will be liste d, if p erf or m e d.
He pati c ris k fact or assess me nt data will be liste d. Li ver relate d si g ns a n d s y m pt o ms data will be 
s u m marize d b y tr e at me nt a n d liste d. Alc o h ol a n d recreati o nal dr u g use data will als o be liste d.
All he pat ic c he mistr y, he mat ol o g y, c oa g ulati on, a n d ser olo g y  data will be liste d. Val ues o utsi de 
t he refere nce ra n ges will be fla g ge d o n t he i n di vi d ual pat ient  data listi n gs.
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Fi nal , 3 1 O C T 2 0 1 7
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Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
9. 5. 6
Bl o o d Gl uc ose M o nit ori n g a n d H y p o gl yce mi a
H y p o gl yce mic e ve nts will be a p pr o priatel y rec or de d i n t he C R F. I n t he case of a h y p o gl yce m ic 
e ve nt, t he act ual bl o o d gl uc ose val ue, if meas ure d, will be rec or de d i n t he C R F, t o get her wit h 
a n y treat me nts a d mi nistere d. Eac h cate g or y of h y p o gl yce mic e ve nts ( defi ne d bel o w) will be 
liste d a n d s u m marize d b y treat me nt.
H y p o gl yce mia is defi ne d as f oll o ws:
D oc u me nte d Gl uc ose Alert Le vel ( Le vel 1), pl as m a gl uc ose ( P G) ≤7 0 m g/ d L ( 3. 9 m m o l/ L)

D oc u me nte d s y m pt o m atic h y p o gl yce mi a:  wit h t y pical s y m pt o ms of 
h y p o gl yce mia.

D oc u me nte d as y m pt o m atic h y p o gl yce mi a:  wit h o ut t ypical s y mpt o m s of
h y p o gl yce mia.

D oc u me nte d u ns pecifie d h y p o gl yce mi a :  wit h n o i nf or mati o n a b o ut s y m pt o ms of 
h y p o gl yce mia a vaila ble.  ( T his has als o bee n calle d u nclassifia ble h y p o gl yce mia.)
D oc u me nte d Cli nic all y Si g nific a nt H y p o gl yce mi a ( Le vel 2) wit h si milar criteri o n as a b o ve 
e xce pt f o r t hres h ol d P G < 5 4 m g/ d L ( 3. 0 m m ol/ L)

Le vel 2 D oc u me nte d s y m pt o m atic h y p o gl yce mi a 

Le vel 2 D oc u me nte d as y m pt o m atic h y p o gl yce mi a

Le vel 2 D oc u me nte d u ns pecifie d h y p o gl yce mi a
Se vere h y p o gl yce mi a ( Le vel 3)

Se vere h y p o gl yce mi a:  S u bjects ha d alt ere d me nt al stat us, a n d c o ul d n ot assist i n t heir 
o w n care, or were se mic o nsci o us or u nc o nsci o us, or e x perie nce d c o ma wi t h or wit h o ut
seiz ures, a n d t he assista nce of a n ot her pers o n was t o acti vel y a d mi nister car b o h y drate, 
gl uca g o n, or ot her res uscitati ve actio ns. Pl as ma gl uc ose meas ure me nts ma y n ot be 
a vaila ble d uri n g s uc h a n e ve nt, b ut ne ur ol o gical rec o ver y attri b uta ble t o t he rest orati o n 
of P G c o nce ntrati o n t o n or m al is c o nsi dere d s ufficie nt e vi de nce t hat t he e ve nt was 
i n d uce d b y a lo w P G c o nce ntrati o n ( P G ≤7 0 m g / d L [ 3. 9 m mol / L]).  
Ot her h y p o gl yce mi a:

N oct ur n al h y p o gl yce mi a:
A n y d o c u m e nt e d h y p o gl yce mic e ve nt (i ncl u di n g se vere 
h y p o gl yce mia) t hat occ urs at ni g ht a n d pres u ma bl y  d uri n g slee p.  T his is ca pt ure d as 
h y p o gl yce mia t hat occ urs bet wee n be dt i me a n d wa ki n g.  T hi s defi niti on is m o re 
usef ul t ha n t he c o m m o nl y  use d ~ mi d ni g ht t o ~ 6 A M d efi nitio n  w hi c h d o es n ot t a k e 
s u bjects’ i n di vi d ual slee p ti mes i nto c o nsi d er ati o n, a n d is c o nsiste nt wit h t he 
A merica n Dia betes Ass ociati o n ( A D A) rec o m me n dati o ns of  re p ortin g e ve nts t hat 
occ ur d uri n g slee p ( A D A 2 0 0 5).  It is als o i m p orta nt t o c ollect t he act ual ti me w he n 
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Fi nal , 3 1 O C T 2 0 1 7
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Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
a h y p o gl yce mic e ve nt occ urre d t o all o w f urt her c haracterizati o n of h y p o gl yce mia 
ti mi n g (e. g., t o all o w a nal ysis of fre q ue nc y of e ve nts occ urri n g acr oss a 2 4- hr cl o c k).  
N oct ur nal h y p o gl yce mia ma y occ ur at se verit y Le vels 1, 2, or 3.

Rel ati ve h y p o gl yce mi a ( als o referre d t o as Pse u d o h y p o gl yce mi a [ Se a q uist et al. 
2 0 1 3]): A n e ve nt d uri n g w hic h t ypi c al s y mpt o m s of h y p o gl yce mia occ ur, t hat  d oes 
n ot re q uire t he assista nce of a n ot her pers o n a n d is acc o m pa nie d b y P G > 7 0 m g/ d L
( 3. 9 m m o l/ L). T he P G val ue of s u bjects wi t h c hr o nicall y p o or gl yce mic c o ntr ol ca n 
decrease s o ra pi dl y t hat s u bjects ma y re p ort s y m pt o ms of h y p o gl yce mia bef ore t heir
P G c o nce ntrati o n falls bel o w 7 0 m g/ d L ( 3. 9 m m o l/L).
E v e nts wit h P G ≤7 0 m g/ d L 
s h o ul d n ot b e c at e g ori z e d as r el at i v e h y p o gl y c e mi a.  E val uati o n a n d statistical 
a nal ysis of t his cate g or y is o pti o nal. H o we ver, if a s u bject re p orts a relati ve 
h y p o gl yce mia e ve nt w here assista nce fr o m a n ot her pers o n was recei ve d or t he s u bject
e x perie nce d si g nifica nt s y m pt o ms, t he st u d y tea m s h o ul d clarif y t he cir c u msta nces t o 
e ns ure t he e ve nt is n ot a se vere h y p o gl yce mia e ve nt, a n d re p ort it a p pr o priatel y.  

Pr o b a ble s y m pt o m atic h y p o gl yce mi a:  S y m pt o ms of h y p o gl yce mia were prese nt, 
b ut P G meas ure me nt was n ot re p orte d.

O ver all ( or t ot al) h y p o gl yce mi a:
T his o pti o nal cate g or y c o m bi nes m ost cases of
h y p o gl yce mia ( d oc u me nte d h y p o gl yce mia a n d pr o ba ble s y mpt o m atic h y p o gl yce mia, 
i ncl u di n g se vere h y p o gl yce mia).  It d oes n ot i ncl u de relati ve h y p o gl yce mia.  N o ct ur nal
a n d se vere h y p o gl yce mia are s pecial cases of d oc u me nte d or pr o ba ble h y p o gl yce mia.
If a n e ve nt of h y p o gl yce mia falls i nto m ulti p le s u bcate g ories, t hat e ve nt s h o ul d o nl y be
c o u nte d o nce i n t he cate g or y of o verall ( or t otal) h y p o gl yce mia.
O nl y se vere h y p o gl ycae mic e pis o des will be re p orte d se paratel y as A Es.  All e pis o des of se vere
h y p o gl ycae mia will  be re p orte d as S A Es.
T he g oal of t he e u gl yce mic cla m p is t o mai ntai n gl uc ose c o nce ntrati o n s at n or mal gl yce mic 
le vels cl ose t o a pre defi ne d tar get.  T heref ore, gl uc ose c o nce ntrati o ns bel o w 7 0 m g/ d L will n ot 
r o utinel y be rec or de d as h y p o gl yce mic e ve nts d uri n g t he gl uc ose cla m p pr oce d ure.  H o we ver, at 
t he discret i on of t he i n vest i gat or, decrease i n gl uc ose c o nce ntrati o ns ma y be rec or de d as a 
h y p o gl yce mic e ve nt base d o n cli nical c o ncer n or relate d t o tec h nical iss ues res ult i n g i n 
h y p o gl yce mia.  Gl uc ose m o nit ori n g will c o nt i n ue after c o mplet i on of t he e u gl yce mic cla m p 
pri or t o di sc har ge fr o m t he C R U at t he discreti on of t he i n vest i gat or.  
9. 5. 7
I njecti o n Site Assess me nt ( L oc al T oler a bilit y)
I njecti on- site assess me nt data will be liste d a n d s u m marize d i n fre q ue nc y ta bles b y treat me nt, 
a n d ti me p oi nt.
9. 5. 8
I m m u n o ge nicit y
T he fre q ue nc y of a nt i b o d y for mati o n t o i ns uli n lis pr o will be deter mi ne d. 
C CI


Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 1 4 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
9. 5. 9
Ot her assess me nts
Hi p a n d waist ci rc u mfere nce will be liste d al o n gsi de b o d y  w eig ht.
All ot her safet y assess me nts n ot detaile d i n t his secti o n will be liste d b ut n ot s u m marize d or 
statisticall y a nal yze d. 
9. 5. 1 0 S afet y a n d T oler a bilit y St atistic al Met h o d ol o g y
N o i nfere nt ial statistical a nal yses are pla n ne d.
1 0.
I N T E RI M A N A L Y S E S
T his is a s u bject-bli n d st u d y; t he i n vesti gat or a n d Lill y st u d y t e a m is u n bli n de d.  Data ma y be 
a nal yze d w hile t he tr ial is o n g oi n g b ut n o c ha n ges t o t he st u d y desi g n are pla n ne d. A n
assess me nt c o m mittee will n ot be f or me d.   If a n u n pla n ne d i nteri m a nal ysis is dee me d necessar y, 
t he Lill y C P , C R P /i n vesti gat or, or desi g nee will c o ns ult with t he a p pr o priate me dical direct o r or
desi g nee t o deter mi ne if it is necessar y  t o a me n d t he pr ot oc ol.
1 1.
C H A N G E S F R O M T H E P R O T O C O L S P E CI FI E D S T A TI S TI C A L A N A L Y S E S
T here were n o c ha n ges fr o m t he pr ot oc ol s pecifie d statistical a nal yses.
1 2.
R E F E R E N C E S
1.
I nter nati o nal C o nfere nce o n Har m o nizat i on of Te c h nical Re q uire me nts f or Re gistrati o n of 
P har mace ut icals f or H u ma n Use, I C H Har mo niz e d Triparti t e G uideli ne, Stati stical Pri nci ples 
f or Cli nical Trials ( E 9), 5 Fe br uar y 1 9 9 8.
2.
I nter nati o nal C o nfere nce o n Har m o nizati on of Tec h nical Re q uire me nts f or Re gistrat i on of 
P har mace ut icals f or H u ma n Use, I C H H ar mo niz e d Triparti t e G uideli ne, Str uct ure a n d 
C o nte nt of Cli nical St u d y  Re p orts ( E 3), 3 0 N o ve m ber 1 9 9 5.
1 3.
D A T A P R E S E N T A TI O N
1 3. 1
Deri ve d P ar a meters
I n di vi d ual deri ve d para meters (e. g. P K para meters) a n d a p pr o priate s u m mar y st atistics will be 
re p orte d t o t hree si g nifica nt fi g ures. O bser ve d c o nce ntrati o n data, e. g. C ma x , s h o uld be re p orte d 
as recei ve d. O bser ve d ti me data, e. g. tma x , s h o ul d be re p orte d as recei ve d. N a n d perce nta ge 
val ues s h o uld be re p orte d as w h ole n u m bers. Me dia n val ues s h o ul d be treate d as a n o bser ve d 
para m eter a n d re p orte d t o t he sa me n u m ber of deci mal places as mi ni m u m a n d ma xi m u m val ues.
1 3. 2
Missi n g D at a
Missi n g data will n ot be dis pla ye d i n list i n gs.
C CI


Fi nal , 3 1 O C T 2 0 1 7
             Pa ge 1 5 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
S p o ns or Refere nce I 8 B-M C -I T R Y
1 3. 3
I ns ufficie nt D at a f or Prese nt ati o n
S o m e of t he T F Ls ma y n ot ha ve s ufficie nt n u m bers of s u bjects or data f or prese ntati o n. If t his 
occ urs, t he bla n k T F L s hell will be prese nte d wit h a messa ge pri nte d i n t he ce ntre of t he ta ble, 
s uc h as, “ N o seri o us a d verse e ve nts occ urre d f or t his st u d y. ”
C CI


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