Clinical trial NCT03449433
Conditions: Diabetes Mellitus, Type 1
Sponsor: Eli Lilly and Company
Start date: 2018-03-15; Completion date: 2018-08-14
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Two forms of insulin lispro (LY900014 and Humalog®) and two forms of insulin aspart (NovoRapid® and Fiasp®) will be given to trial participants with diabetes mellitus type 1 by injection under the skin. The study will assess how fast the active ingredient (insulin lispro or insulin aspart) gets into the blood stream and how long it takes the body to remove it. A test meal will be given to trial participants to assess the course of the blood sugar lowering effect of the investigational products. The safety and tolerability of LY900014 will also be assessed. Screening is required within 14 days prior to the lead in. For each participant, the study will last up to 91 days.

Detailed description:

Arms: arm 1: T1DM participants received a single, individualized, subcutaneous (SC) dose of LY900014. arm 2: T1DM participants received a single, individualized, SC dose of insulin lispro. arm 3: T1DM participants received a single, individualized, SC dose of insulin aspart. arm 4: T1DM participants received a single, individualized, SC dose of insulin aspart. arm 5: Healthy participants who received no study drug.
Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro intervention 3: Insulin Aspart intervention 4: Insulin Aspart
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC intervention 3: Administered SC intervention 4: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol: Protocol I8B-MC-ITSL(a) A Mixed Meal Tolerance Test Study to Evaluate the 
Pharmacokinetics and Pharmacodynamics of LY900014 Compared to Humalog Following a 
Single Dose in Adults with Type 1 Diabetes 
NCT03449433 
Approved: 10-Apr-2018 


I8B-MC-ITSL(a)Clinical Pharmacology Protocol
Page 1
LY900014
Protocol I8B-MC-ITSL(a)
A Mixed Meal Tolerance Test Study to Evaluate the 
Pharmacokinetics and Pharmacodynamicsof LY900014
Compared toHumalogFollowinga Single Dosein Adults 
with Type 1 Diabetes
EUDRACT: 
: 2017-003459-47
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY900014, unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this documentis subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Approval Date: 10-Apr-2018 GMT
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 
12December2017
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.


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LY900014
Table of Contents
A Mixed Meal Tolerance Test Study to Evaluate the 
Pharmacokinetics and Pharmacodynamics of LY900014 
Compared to Humalog Following a Single Dose in Adults 
with Type 1 Diabetes
Section
Page
Protocol I8B-MC-ITSL(a) A Mixed Meal Tolerance Test Study to 
Evaluate the Pharmacokinetics and Pharmacodynamics of LY900014 
Compared to Humalog Following a Single Dose in Adults with Type 
1 Diabetes...........................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................20
3.2.
Background..................................................................................................................20
3.3.
Benefit/Risk Assessment..............................................................................................21
4.
Objectives and Endpoints..................................................................................................24
5.
Study Design.....................................................................................................................25
5.1.
Overall Design .............................................................................................................25
5.1.1.
Patients with T1DM.............................................................................................26
5.1.1.1.
Lead-in and Insulin Transition........................................................................27
5.1.1.2.
Dose-Finding Assessment...............................................................................28
5.1.1.3.
Inpatient Procedures .......................................................................................29
5.1.2.
Healthy Subjects ..................................................................................................30
5.2.
Number of Participants.................................................................................................31
5.3.
End of Study Definition ...............................................................................................31
5.4.
Scientific Rationale for Study Design...........................................................................31
5.5.
Justification for Dose ...................................................................................................32
6.
Study Population...............................................................................................................33
6.1.
Inclusion Criteria..........................................................................................................33
6.1.1.
Additional Inclusion Criteria for T1DM ...............................................................34
6.1.2.
Additional Inclusion Criteria for Healthy Subjects ...............................................35
6.2.
Exclusion Criteria ........................................................................................................35
6.2.1.
Additional Exclusion Criteria for T1DM..............................................................36
6.2.2.
Additional Exclusion Criteria for Healthy Subjects ..............................................37


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6.2.3.
Additional Exclusion Criteria for Inpatient Dosing Days......................................37
6.3.
Lifestyle and/or Dietary Requirements .........................................................................38
6.3.1.
Meals and Dietary Restrictions.............................................................................38
6.3.2.
Caffeine, Alcohol and Tobacco ............................................................................38
6.3.3.
Activity................................................................................................................39
6.4.
Screen Failures.............................................................................................................39
7.
Treatment..........................................................................................................................40
7.1.
Treatment Administered...............................................................................................40
7.1.1.
Packaging and Labelling ......................................................................................41
7.2.
Method of Treatment Assignment ................................................................................41
7.2.1.
Selection and Timing of Doses.............................................................................41
7.3.
Blinding .......................................................................................................................41
7.4.
Dose Modification........................................................................................................42
7.4.1.
Special Treatment Considerations ........................................................................42
7.5.
Preparation/Handling/Storage/Accountability...............................................................42
7.6.
Treatment Compliance .................................................................................................42
7.7.
Concomitant Therapy...................................................................................................43
7.8.
Treatment after the End of the Study............................................................................44
8.
Discontinuation Criteria ....................................................................................................45
8.1.
Discontinuation from Study Treatment.........................................................................45
8.1.1.
Discontinuation of Inadvertently Enrolled Patients or 
Subjects ...............................................................................................................45
8.2.
Discontinuation from the Study....................................................................................45
8.3.
Patients or Subjects Lost to Follow-up .........................................................................46
9.
Study Assessments and Procedures ...................................................................................47
9.1.
Efficacy Assessments...................................................................................................47
9.2.
Adverse Events ............................................................................................................47
9.2.1.
Serious Adverse Events........................................................................................48
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................49
9.2.2.
Complaint Handling.............................................................................................49
9.3.
Treatment of Overdose.................................................................................................49
9.4.
Safety...........................................................................................................................49
9.4.1.
Physical Examination...........................................................................................49
9.4.2.
Laboratory Tests ..................................................................................................49
9.4.3.
Vital Signs ...........................................................................................................50
9.4.4.
Electrocardiograms ..............................................................................................50
9.4.5.
Other Tests...........................................................................................................51
9.4.5.1.
Body Weight and Height ................................................................................51


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9.4.6.
Safety Monitoring ................................................................................................51
9.4.6.1.
Hepatic Safety................................................................................................51
9.4.6.2.
Glucose Monitoring........................................................................................51
9.4.6.3.
Severe Hypoglycaemia ...................................................................................52
9.4.7.
Self-Monitored Plasma Glucose during Outpatient Period....................................53
9.4.8.
Treatment of Hyperglycaemia and Hypoglycaemia ..............................................53
9.5.
Pharmacokinetics .........................................................................................................53
9.5.1.
Bioanalysis...........................................................................................................53
9.6.
Pharmacodynamics ......................................................................................................54
9.6.1.
Glucose Samples (Run-In Period) ........................................................................54
9.6.2.
Glucose Samples (MMTT)...................................................................................54
9.7.
Genetics .......................................................................................................................54
9.8.
Biomarkers...................................................................................................................54
9.9.
Health Economics ........................................................................................................54
10.
Statistical Considerations and Data Analysis.....................................................................55
10.1. Sample Size Determination ..........................................................................................55
10.2. Populations for Analyses..............................................................................................55
10.2.1.
Study Participant Disposition ...............................................................................55
10.2.2.
Study Participant Characteristics ..........................................................................55
10.3. Statistical Analyses ......................................................................................................56
10.3.1.
Safety Analyses....................................................................................................56
10.3.1.1.
Clinical Evaluation of Safety..........................................................................56
10.3.1.2.
Statistical Evaluation of Safety.......................................................................56
10.3.2.
Pharmacokinetic Analyses....................................................................................57
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................57
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................57
10.3.3.
Pharmacodynamic Analyses.................................................................................58
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................58
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................58
10.3.4.
Interim Analyses..................................................................................................59
11.
References ........................................................................................................................60


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List of Tables
Table
Page
Table ITSL.1.
Objectives and Endpoints .......................................................................24
Table ITSL.2.
Treatments Administered........................................................................40


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List of Figures
Figure
Page
Figure ITSL.1.
Illustration of study design for Protocol I8B-MC-ITSL...........................26


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................61
Appendix 2.
Clinical Laboratory Tests........................................................................65
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................66
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............69
Appendix 5.
Blood Sampling Summary......................................................................70
Appendix 6.
Oral Glucose Tolerance Test...................................................................71
Appendix 7.
Protocol Amendment I8B-MC-ITSL(a) Summary 
A Mixed Meal Tolerance Test Study to Evaluate the 
Pharmacokinetics and Pharmacodynamics of LY900014 Compared 
to Humalog Following a Single Dose in Adults with Type 1 
Diabetes .................................................................................................72


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1. Protocol Synopsis
Title of Study:
A Mixed Meal Tolerance Test Study to Evaluate the Pharmacokinetics and Pharmacodynamics of LY900014 
Compared to Humalog Following a Single Dose in Adults with Type 1 Diabetes
Rationale: 
This study in patients with type 1 diabetes mellitus (T1DM) aims to compare the pharmacokinetic (PK) profiles of 
insulin lispro after administration of LY900014 and Humalog and their impact on postprandial blood glucose during 
a standardised mixed meal tolerance test (MMTT).  Furthermore, this study plans to characterise the PK and 
pharmacodynamics (PD) of insulin aspart analogues NovoRapid® and FIASP® in patients with T1DM under 
identical study conditions.  A non-diabetic healthy subject cohort is included in the study to characterise “normal” 
insulin secretory and glucose response during an identical standardised meal.  Healthy subjects will not receive any 
of the study drugs.
Evaluation of these meal-time insulins in the context of a standardised test meal cannot be used to infer clinical 
efficacy with the same rigour as a glycated haemoglobin assessment following long-term treatment.  However, 
assessment of these analogue insulin formulations under identical conditions provides a unique opportunity to obtain 
comparative information on the PK and PD in a setting appropriate for evaluation of meal-time insulin.
Objective(s)/Endpoints:  
Objectives
Endpoints
Primary
1.
To evaluate the differences in PK between 
LY900014 and Humalog following a single dose 
in patients with T1DM
1.
Early 50% tmax and AUC(0-30min)
Secondary
1.
To characterise the PK profiles of LY900014, 
Humalog, NovoRapid and FIASP following a 
single dose in patients with T1DM 
2.
To evaluate the differences in PD between 
LY900014 and Humalog following a single dose 
in patients with T1DM
3.
To characterise the PD response to LY900014, 
Humalog, NovoRapid and FIASP, as assessed by 
the MMTT, in patients with T1DM
1.
Early 50% tmax
2.
∆AUC(0-1h), ∆AUC(0-5h)
3.
∆AUC(0-1h), ∆AUC(0-5h)
Abbreviations:  AUC(0-30min) = area under the concentration versus time curve from time 0 to 30 minutes; ∆AUC 
= area under the baseline subtracted glucose concentration versus time curve; ∆AUC(0-1h) = ∆AUC from time 0 
to 1 hour postmeal; ∆AUC(0-5h) = ∆AUC from time 0 to 5 hours postmeal; early 50% tmax = time to early half-
maximal drug concentration; MMTT = mixed meal tolerance test; PD = pharmacodynamics; PK = 
pharmacokinetics; T1DM = type 1 diabetes mellitus.


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Summary of Study Design:
Study I8B-MC-ITSL is a clinical pharmacology, patient- and investigator-blind, randomised, 4-treatment, 4-period
crossover study in patients with T1DM.  The study also involves healthy subjects who will undergo a single MMTT 
but will not receive any study drug.
Treatment Arms and Planned Duration for an Individual Patient with T1DM:
Patients will be screened over a 14-day period prior to start of a 7- to 14-day lead-in (insulin transition) period.  
Patients will then participate in a dose-finding assessment (1 to 7 days prior to MMTT in Period 1) and subsequently 
randomised to 1 of 4 treatment sequences according to the actual randomisation table provided to the clinical 
research unit (CRU).  In each study period, patients will undergo a MMTT.  Each patient will receive a single 
individualised subcutaneous (SC) injection of LY900014, Humalog, FIASP or NovoRapid immediately before the 
standardised test meal.  All treatment procedures will be inpatient stays of approximately 2 days per period and 
require a maximum of 6 weeks to complete 4 periods.  Each study dosing will be separated by a minimum of 21 
hours and may occur on consecutive days; however, patient inclusion is subject to required screening criteria.  The 
follow-up or early discontinuation visit should occur at least 14 days after the last dose of the study drug.
Treatment Arms and Planned Duration for an Individual Healthy Subject:
Subjects will be screened over a 28-day period prior to the MMTT.  Subjects will be admitted to the CRU the 
evening before the MMTT.  Each subject will receive a standardised test meal on Day 1.  Subjects will remain 
inpatient in the CRU for 2 days.  
Treatment (applicable to patients):
For a given patient, the single individualised dose will be the same for all the treatments.
LY900014:  Single individualised SC dose per assessment period
Humalog:  Single individualised SC dose per assessment period
FIASP: Single individualised SC dose per assessment period
NovoRapid: Single individualised SC dose per assessment period
Number of Patients and Subjects:
Up to 74 patients with T1DM may be enrolled so that approximately 64 patients complete the study.  Replacement 
patients will adopt all 4 assigned crossover treatments of the original patient’s randomisation schedule.
For the healthy subject cohort, sufficient subjects will be enrolled to have 12 healthy subjects complete the study.
Statistical Analysis:
Primary statistical analyses of PK and PD parameters will be conducted on the set of patients who complete all 
treatment periods with identical prandial insulin does for the MMTTs during the study.  Supportive analyses may be 
done on the key parameters for the patients who complete at least 2 treatment periods.  Safety analyses will be 
conducted on the set of patients receiving at least 1 dose of the study drug to which they are randomised, regardless 
of whether or not they completed all protocol requirements.


I8B-MC-ITSL(a) Clinical Pharmacology Protocol
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LY900014
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, and 
confidence intervals (CIs) will be calculated at 95%, 2-sided. No multiplicity test adjustment will be made for 
secondary objectives.
Safety:  All investigational product- and protocol procedure-related adverse events will be listed, and if the 
frequency of events allows, safety data will be summarised using descriptive methodology.  Safety parameters will 
be listed and summarised using standard descriptive statistics.
Pharmacokinetic:
The mixed-effects model will be used for the analysis of the PK time parameters (time to early half-maximal drug 
concentration [early 50% tmax], time to late half-maximal drug concentration [late 50% tmax] and time to 
maximum observed drug concentration [tmax]) without log transformation.  Least-squares means (LSmeans), 
treatment differences in LSmeans and the corresponding 95% CIs for the treatment differences will be estimated 
from the model.  The p-value on the difference between LSmeans will be used to determine statistical significance.  
The treatment ratios and 95% CIs for the ratios will be calculated using Fieller’s theorem. 
Log-transformed area under the concentration versus time curves (AUCs), maximum observed drug concentration 
(Cmax) for insulin lispro/aspart may be evaluated to estimate geometric means, ratios of geometric means and their 
corresponding 95% CIs using the same mixed-effect model as PK time parameters.   
Pharmacodynamics:
Data will be analysed for the patients during each MMTT.  The change from baseline values (the average of -30, -15 
and 0 minutes) represented as the 0-hour time point following the start of the MMTT for each patient will be 
calculated.  The area under the baseline subtracted glucose concentration versus time curve from time 0 to 1 hour
post-meal (∆AUC[0-1h]), area under the baseline subtracted glucose concentration versus time curve from time 0 to 
2 hours post-meal (∆AUC[0-2h]) and area under the baseline subtracted glucose concentration versus time curve 
from time 0 to 5 hours post-meal (∆AUC[0-5h]) will be calculated.  In addition, the change from baseline maximum 
glucose observed during the 5 hours post-meal and change from baseline 1 hour glucose and 2 hour glucose after the 
start of the meal will be calculated.  Other partial ∆AUCs may be calculated, as deemed appropriate.
Summary statistics will be presented by treatment.  All PD parameters (including ∆AUCs, glucose changes from 
baseline and time parameters) on the original scale will be analysed using the mixed-effects model that includes 
treatment, sequence and period as fixed effects and patient within sequence as a random effect. The p-value on the 
difference between LS means will be used to determine statistical significance and the corresponding 95% CIs for 
the LSmean ratios from Fieller’s theorem will be presented.


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2. Schedule of Activities


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Study Schedule Protocol I8B-MC-ITSL for Patients with T1DM
Screening
Lead-In
Dose-Finding 
Assessment
Study Period 
(Periods 1 to 4)
Follow-up/Early 
Discontinuation
Comments
Procedure
Up to 
14 days 
prior to 
lead-in
7-14 days 
prior to 
dose-finding 
assessment
1-7 days prior 
to Period 1, 
Day 1
Day -1
Day 1
≥14 days after 
discharge
Informed consent
X
At least 1 day before 
screening procedures.  
Screening procedures should 
take place no later than 
28 days after signing the 
informed consent. 
Medical history 
and physical 
examination
X
Height
X
At screening only.
Weight
X
X
X
Period 1 only.
Vital signs 
(supine):  blood 
pressure and pulse 
rate
X
Predose and 
420 minutes 
postdose
X
12-lead ECG
(supine)
X
Predose (Period 1) 
X
Single ECGs will be 
collected for safety.  
Clinical 
laboratory tests
X
X
Predose for Period 1 
only
X
Fasting laboratory test.  All 
clinical laboratory tests will 
be analysed at a local 
laboratory (see Section 
9.4.2).  
Alcohol breath 
test
X
Alcohol breath test to be 
done at admission for all 
periods.


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Screening
Lead-In
Dose-Finding 
Assessment
Study Period 
(Periods 1 to 4)
Follow-up/Early 
Discontinuation
Comments
Procedure
Up to 
14 days 
prior to 
lead-in
7-14 days 
prior to 
dose-finding 
assessment
1-7 days prior 
to Period 1, 
Day 1
Day -1
Day 1
≥14 days after 
discharge
Lead-in/insulin 
transition 
activities
X
Once patients have 
completed screening 
procedures, they will switch 
from prescribed basal 
insulin to site-provided 
insulin glargine.  Patients 
will receive general diabetes 
training.  A patient diary 
will be provided for 
recording dosing and other 
required information 
(Section 5.1.1.1).  Lead-in 
period may be extended by 2 
days as needed.
Patient admission 
to CRU
X
Admitted to CRU on the
evening of Day -1 for all 
study periods.  If the dose-
finding assessment occurs 
from Day -2, the patient may 
continue to remain inpatient 
in the CRU until the 
completion of study MMTT 
for Period 1.


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Screening
Lead-In
Dose-Finding 
Assessment
Study Period 
(Periods 1 to 4)
Follow-up/Early 
Discontinuation
Comments
Procedure
Up to 
14 days 
prior to 
lead-in
7-14 days 
prior to 
dose-finding 
assessment
1-7 days prior 
to Period 1, 
Day 1
Day -1
Day 1
≥14 days after 
discharge
Dose-finding 
MMTT
X 
Patients will undergo dose-
finding assessment with 
Humalog and a standardised 
test meal.  Dose-finding 
MMTT will occur after the 
insulin transition.  Dose-
finding assessment should 
occur between 1 and 7 days 
prior to MMTT in Period 1.  
To take place between 0700 
hours and 1100 hours.  See 
Section 5.1.1.2 for 
rescheduling.
Randomisation
X
To take place before run-in 
of Period 1 Day 1.
Pregnancy test
X
X
X
For female patients only.  
Serum pregnancy test will 
be performed at screening 
and urine pregnancy tests 
will be performed at the 
time of admission in Periods 
1 to 4 and at follow-up (see 
Appendix 2).
Standardised 
dinner
X
Approximately at 1900
hours.  The evening dinner 
will be identical for every 
period.


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Screening
Lead-In
Dose-Finding 
Assessment
Study Period 
(Periods 1 to 4)
Follow-up/Early 
Discontinuation
Comments
Procedure
Up to 
14 days 
prior to 
lead-in
7-14 days 
prior to 
dose-finding 
assessment
1-7 days prior 
to Period 1, 
Day 1
Day -1
Day 1
≥14 days after 
discharge
Medical 
assessment
X
Predose and before 
discharge from 
CRU
X
Medical assessment includes 
medical review and targeted 
examination, and as 
appropriate review of 
concomitant medication, 
patient diary and MMTT 
exclusion criteria (see 
Section 6.2.1).
Glucose 
stabilisation/run-
in
X
From approximately 7 hours 
to 30 minutes before dosing:  
IV infusion of glucose 
(dextrose solution) and/or
insulin glulisine to achieve a 
target blood glucose level of 
135±15 mg/dL (7.5±0.8 
mmol/L).  Blood glucose 
concentrations will be 
monitored at a minimum of 
30-minute intervals (see 
Sections 9.6.1 and 5.1.1.3).  
See Section 6.2.3 for 
rescheduling.


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LY900014
Screening
Lead-In
Dose-Finding 
Assessment
Study Period 
(Periods 1 to 4)
Follow-up/Early 
Discontinuation
Comments
Procedure
Up to 
14 days 
prior to 
lead-in
7-14 days 
prior to 
dose-finding 
assessment
1-7 days prior 
to Period 1, 
Day 1
Day -1
Day 1
≥14 days after 
discharge
Blood glucose 
sampling 
(MMTT)
20, 40, 60, 80, 
100, 120, 140, 
160, 180, 200, 
220, 240, 260, 
280, 300 
minutes post-
meal
-30, -15, 0 minutes 
pre-meal, 10, 20, 
30, 40, 50, 60, 70, 
80, 90, 100, 110, 
120, 135, 150, 165, 
180, 195, 210, 225, 
240, 300 minutes 
post-meal
0-minute time point sample 
to be taken at the start of the 
meal.  
Study MMTT
X
Standardised test meal will 
be administered at 
approximately 0700 hours 
(with allowance up to 1100
hours) and should be 
consumed within 15 minutes 
(see Section 5.1.1.3).  
MMTT may occur on 
consecutive days.
Study drug 
administration
X
Immediately before the start 
of meal according to the 
randomisation schedule:  
Study drug will be 
administered at 
approximately the same time 
on Day 1 of Periods 1 to 4.  
There will be at least
21 hours between study 
doses.


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Screening
Lead-In
Dose-Finding 
Assessment
Study Period 
(Periods 1 to 4)
Follow-up/Early 
Discontinuation
Comments
Procedure
Up to 
14 days 
prior to 
lead-in
7-14 days 
prior to 
dose-finding 
assessment
1-7 days prior 
to Period 1, 
Day 1
Day -1
Day 1
≥14 days after 
discharge
Insulin 
lispro/insulin 
aspart PK 
sampling
0 (predose), 1, 2, 3, 
5, 10, 15, 20, 25, 30, 
35, 40, 45, 50, 55, 
60, 70, 90, 120, 150, 
180, 240, 300, 360 
and 420 minutes 
postdose
Sampling times are relative 
to the time of study drug 
administration in each 
period.
Discharge from 
CRU
X
Patients may be discharged 
after all study procedures are 
completed.  Patients may be 
offered a meal following 
completion of all PK and PD
assessments.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; MMTT = mixed meal tolerance test; PD = pharmacodynamics; PK = pharmacokinetics. 
Note:  The CRU 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 sampling for blood glucose and laboratory samples per protocol nominal times.  ECGs and vital sign measurements should be 
scheduled before but as close as possible to the PK sampling times.


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Study Schedule Protocol I8B-MC-ITSL for Healthy Subjects
Screening
Study Period 
Comments
Procedure
Days -28 to -2
Day -1
Day 1
Informed consent
X
At least 1 day before screening procedures.  Screening 
procedures should take place no later than 28 days after 
signing the informed consent. 
Medical history and 
physical examination
X
Height
X
At screening only.
Weight
X
X
Vital signs (supine):  
blood pressure and 
pulse rate
X
12-lead ECG (supine)
X
Single ECGs will be collected for safety.
Clinical laboratory 
tests
X
Fasting laboratory test.  Laboratory tests will be analysed at a 
local laboratory.
Oral glucose 
tolerance test
X
Plasma glucose measurements before ingestion of glucose 
beverage and at 1 and 2 hours after the start of ingestion of 
glucose beverage. 
Subject admission to 
CRU
X
Admitted to CRU on the evening of Day -1.
Pregnancy test
X
X
For female subjects only.  Serum pregnancy test will be 
performed at screening and urine pregnancy tests will be 
performed at admission to the CRU (see Appendix 2).
Standardised dinner
X
Approximately at 1900 hours.
Medical assessment
X
Before discharge from CRU
Medical assessment includes medical review and targeted 
examination, and as appropriate review of concomitant 
medication and MMTT exclusion criteria (see Section 6.2.2).
Blood glucose 
sampling (MMTT)
-30, -15, 0 minutes pre-meal, 
10, 20, 30, 40, 50, 60, 70, 80, 
90, 100, 110, 120, 135, 150, 
165, 180, 195, 210, 225, 240, 
300 minutes post-meal
0-minute time point sample to be taken at the start of the 
meal.  


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LY900014
Screening
Study Period 
Comments
Procedure
Days -28 to -2
Day -1
Day 1
MMTT
X
Standardised test meal will be administered at approximately 
0700 hours (with allowance up to 1100 hours) and should be 
consumed within 15 minutes (see Section 5.1.2).  
Endogenous insulin 
sampling
0 (pre-meal), 1, 2, 3, 5, 10, 15, 
20, 25, 30, 35, 40, 45, 50, 55, 
60, 70, 90, 120, 150, 180, 240, 
300, 360 and 420 minutes 
postmeal
Sampling times are relative to the time of meal administered.  
Discharge from CRU
X
Subjects may be discharged after all study procedures are 
completed.  Subjects may be offered a meal following 
completion of all PK and PD assessments.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; MMTT = mixed meal tolerance test; PD = pharmacodynamics; PK = pharmacokinetics. 
Note:  The CRU 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 sampling for blood glucose and laboratory samples per protocol nominal times.  ECGs and vital sign measurements should be 
scheduled before but as close as possible to the PK sampling times. 


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3. Introduction
3.1.
Study Rationale
A prandial insulin with faster-on and/or faster-off characteristics might reduce glycaemic 
excursions and the incidence of postprandial hypoglycaemia compared to currently available 
insulin analogues.  LY900014 is an ultra-rapid-acting insulin lispro formulation that has shown 
an increased early absorption compared to commercially available insulin lispro (Humalog®; Eli 
Lilly and Company).  LY900014 aims to closely mimic the physiological prandial insulin 
secretion pattern, which may more effectively control postprandial glucose excursions.  FIASP®
is a new commercially available fast-acting insulin aspart formulation that displays increased 
early absorption compared to commercially available insulin aspart (FIASP® SmPC, 2017; 
NovoRapid® SmPC, 2017).
This study in patients with type 1 diabetes mellitus (T1DM) aims to compare the
pharmacokinetic (PK) profiles of insulin lispro after administration of LY900014 and Humalog 
and their impact on postprandial blood glucose during a standardised mixed meal tolerance test 
(MMTT).  Furthermore, this study plans to characterise the PK and pharmacodynamics (PD) of 
insulin aspart analogues NovoRapid and FIASP in patients with T1DM under identical study 
conditions.  A non-diabetic healthy subject cohort is included in the study to characterise 
“normal” insulin secretory and glucose response during an identical standardised test meal.
Healthy subjects will not receive any of the study drugs during the study.
Evaluation of these meal-time insulins in the context of a standardised test meal cannot be used 
to infer clinical efficacy with the same rigour as a glycated haemoglobin (HbA1c) assessment 
following long-term treatment.  However, assessment of these analogue insulin formulations 
under identical conditions provides a unique opportunity to obtain comparative information on 
the PK and PD in a setting appropriate for evaluation of meal-time insulin.
3.2.
Background
The insulin analogue insulin lispro (Humalog) has been shown to be absorbed more quickly than 
regular human insulin (Humalog package insert, 2017).  In healthy volunteers given 
subcutaneous (SC) doses of insulin lispro ranging from 0.1 to 0.4 units (U)/kg, peak serum levels 
were seen 30 to 90 minutes after dosing (Humalog package insert, 2015).  However, the general 
consensus is that rapid-acting insulin is still not rapid enough to match carbohydrate absorption 
profiles, which limits efficacy and dosing flexibility.  An ultra-rapid-acting prandial insulin 
would shift the PK/PD of insulin analogues so that they have an even faster onset to better match 
carbohydrate absorption and also allow greater flexibility in the time of dosing relative to meals.
LY900014 represents a new formulation that contains insulin lispro, treprostinil, citrate, and 
other excipients.  This formulation involves the novel use of a microdose of treprostinil 
) as an excipient to enhance the absorption of insulin lispro by local vasodilatation 
rather than as an active pharmaceutical ingredient to elicit a systemic effect.  Treprostinil is a 
prostacyclin analogue, administered either through inhalation (
, as an intravenous (IV) 
infusion or as a continuous SC administration for the treatment of symptomatic pulmonary 
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arterial hypertension (PAH) and has been approved in the US since 2002 and in Germany since 
2006 (AMIS database [WWW]).  Sodium citrate is also included in the formulation to further 
enhance the absorption of insulin lispro, at least in part by enhancing vascular permeability.  
Each of the other excipients (such as magnesium chloride) in the LY900014 formulation is listed 
in the US Food and Drug Administration (FDA)’s Generally Recognized as Safe Food Additives 
database and in the FDA’s Inactive Ingredients in Approved Drugs database.  Furthermore, the 
excipient concentration in LY900014 is within the limits identified for approved drug products in 
the FDA Inactive Ingredients in Approved Drugs database.
To date, LY900014 has been administered to approximately 89 patients with diabetes (60 T1DM 
and 29 type 2 diabetes mellitus [T2DM]) across three Phase 1b studies and approximately 
118 healthy volunteers across five Phase 1 studies.  A further 24 patients with T1DM have 
received LY900014 in the ongoing 
 Across these studies, LY900014 has 
consistently demonstrated a faster time-action profile than Humalog; however, the total insulin 
lispro exposure was similar between LY900014 and Humalog. In patients with T1DM, 
LY900014 reduced the time to early half-maximal drug concentration (early 50% tmax), a 
measure of insulin absorption, by 36.5% (p<0.0001) compared to Humalog.  LY900014 
displayed proportional increases in insulin lispro exposure (area under the concentration versus 
time curve [AUC] and maximum observed drug concentration [Cmax]) with dose.  The faster 
early insulin lispro absorption was maintained across the dose range studied (7.5 to 30 U).  In 
patients with T1DM or T2DM treated with multiple daily injections (MDIs) of insulin therapy, 
LY900014 significantly reduced postprandial glucose excursions compared to Humalog when 
both were dosed through SC injection at the start of a standardised test meal.  Additionally, 
through the use of MDIs of LY900014 for up to 2 weeks in patients with either T1DM or T2DM, 
it was found that LY900014 was well tolerated.  There were no serious adverse events (SAEs) 
related to study treatment or discontinuations from the studies because of a drug-related adverse 
event (AE).  Small numbers of treatment-emergent adverse events were reported, and there were 
no notable increases in these events in relation to any of the LY900014 formulations compared 
to those in relation to Humalog.  There were no reported cases of severe hypoglycaemia related 
to LY900014 in these studies.  Additionally, there were no reported incidences of local or 
systemic allergic reactions.
FIASP and NovoRapid (insulin aspart injection) are different formulations of the rapid-acting 
insulin analogue, insulin aspart, which when administered either SC or IV lowers blood glucose 
in patients with T1DM and T2DM. Insulin aspart is homologous with regular human insulin 
with the exception of a single substitution of the amino acid proline by aspartic acid at position 
B28, and is produced using recombinant DNA technology utilising Saccharomyces cerevisiae.  
In addition to the excipients in NovoRapid, FIASP also has arginine and nicotinamide as 
excipients (FIASP® SmPC, 2017; NovoRapid® SmPC, 2017).
3.3.
Benefit/Risk Assessment
This study will not offer any direct benefits to the patients or healthy subjects participating in the 
study.  The data from previous studies in healthy subjects and patients with T1DM and T2DM 
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have shown that LY900014 was well tolerated and the adverse drug reactions are in keeping with 
those reported for Humalog.
Potential risks associated with LY900014, derived from the known risks of insulin lispro 
(Humalog), are hypoglycaemia, hypersensitivity reactions (localised allergy and/or systemic 
allergy), undesirable effects at the injection site (injection-site reactions and lipodystrophy), and 
peripheral oedema (Humalog package insert, 2015).
Notably, across all doses in the studies that have evaluated treprostinil (
 as a local 
vasodilator with or without insulin lispro, there was no clinically significant increase in those 
AEs associated with systemic absorption of treprostinil, as described in the 
 
  The exposures of treprostinil in LY900014 for 
participants in ongoing and future clinical studies are expected to be much lower than those 
observed in the dose ranges previously explored with SC bolus administration of treprostinil.
Accordingly, treprostinil exposure in diabetic patients is generally below the detection limit 
and is substantially lower (at least ~200-fold lower) than those observed in adults 
for the treatment of PAH. No known potential risks are associated with the microdoses of 
treprostinil in the LY900014 formulation.
In preclinical safety pharmacology and toxicity studies, or clinical pharmacology studies 
involving LY900014 or treprostinil alone, other than known risks associated with Humalog and 
 no additional risks were identified.  Additionally, local and systemic toxicity profiles 
of Humalog and Remodulin do not suggest the potential for additive or synergistic toxicity.
Potential risks associated with NovoRapid or FIASP, are hypoglycaemia, hypokalaemia
hypersensitivity reactions (localised allergy and/or systemic allergy), undesirable effects at the 
injection site (injection-site reactions and lipodystrophy), weight gain and peripheral oedema
(FIASP® SmPC, 2017; NovoRapid® SmPC, 2017).
The study includes inpatient procedures during which participants will be continuously 
monitored.  In the event patients experience hypoglycaemia during the MMTT, then the 
hypoglycaemia event will be treated as described in Section 9.4.8.  If a patient experiences 
elevated blood glucose level following food intake for more than 1 hour, insulin glulisine will be 
administered IV (see Section 9.4.8 for treatment guidelines).  Patients will maintain their basal 
insulin regimen of site-provided insulin glargine during the entire study including the MMTT 
days.  Appropriate measures will be taken to minimise the risk of hyperglycaemia (including 
conduct of a dose-finding assessment to ensure that the individualised dose is appropriate for the 
standardised test meal). 
The healthy subjects in the study will not have any study drug intervention and therefore no
potential risks associated with any of the study drugs are applicable.
Healthy subjects will undergo inpatient procedures (a single MMTT), during which participants 
will be continuously monitored.
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of LY900014 is to be found in the Investigator’s Brochure (IB).
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LY900014
More detailed information about the known and expected benefits and risks of FIASP and 
NovoRapid may be found in the following:  FIASP Summary of Product Characteristics and 
NovoRapid Summary of Product Characteristics.


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4. Objectives and Endpoints
Table ITSL.1 shows the objectives and endpoints of the study.
Table ITSL.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
1.
To evaluate the differences in PK between 
LY900014 and Humalog following a single dose in 
patients with T1DM
1.
Early 50% tmax and AUC(0-30min)
Secondary
1.
To characterise the PK profiles of LY900014, 
Humalog, NovoRapid and FIASP following a single 
dose in patients with T1DM
2.
To evaluate the differences in PD between 
LY900014 and Humalog following a single dose in 
patients with T1DM
3.
To characterise the PD response to LY900014, 
Humalog, NovoRapid and FIASP, as assessed by 
the MMTT, in patients with T1DM
1.
Early 50% tmax
2.
∆AUC(0-1h), ∆AUC(0-5h)
3.
∆AUC(0-1h), ∆AUC(0-5h)
Tertiary/Exploratory
1.
To characterise “normal” insulin secretory and 
glucose response to the MMTT in non-diabetic 
healthy subjects
2.
To evaluate the tolerability of SC doses of 
LY900014 in patients with T1DM
1.
Insulin and glucose concentrations
2.
AEs and hypoglycaemic events
Abbreviations:  AE = adverse event; AUC(0-30min) = area under the concentration versus time curve from time 0 to 
30 minutes; ∆AUC = area under the baseline subtracted glucose concentration versus time curve; ∆AUC(0-1h) = 
∆AUC from time 0 to 1 hour post-meal; ∆AUC(0-5h) = ∆AUC from time 0 to 5 hours post-meal; early 50% tmax
= time to early half-maximal drug concentration; MMTT = mixed meal tolerance test; PD = pharmacodynamics; 
PK = pharmacokinetics; SC = subcutaneous; T1DM = type 1 diabetes mellitus.


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5. Study Design
5.1.
Overall Design
Study I8B-MC-ITSL (ITSL) is a clinical pharmacology, patient- and investigator-blind, 
randomised, 4-treatment, 4-period crossover study in patients with T1DM to compare insulin 
lispro PK and PD profiles of the postprandial blood glucose during a standardised MMTT
following LY900014 in comparison to Humalog in patients with T1DM following single SC 
injections administered just before a standardised MMTT. This study will also characterise the 
PK and PD of insulin aspart analogues NovoRapid and FIASP in patients with T1DM under 
identical study conditions.  A non-diabetic healthy subject cohort, which approximately matches
to the cohort of patients with T1DM with regard to the mean body mass index (BMI) and age, is 
included with the intention of characterising the insulin secretory response to a standardised 
MMTT within normal physiology.  These subjects will undergo a single in-house MMTT and 
will not receive any of the study drugs.  Study ITSL may be conducted at 1 or more clinical 
research units (CRUs).
Figure ITSL.1 illustrates the study design.




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LY900014
Patients will be required to visit the CRU on at least 7 occasions (no more than 11 occasions if 
dose finding and/or 1 MMTT are rescheduled) as noted in the Schedule of Activities (see 
Section 2):
•
Screening visit
•
Lead-in (insulin transition) period (see Section 5.1.1.1)
•
4 inpatient CRU study visits (including dose-finding assessment [see Section 5.1.1.3])
•
A follow-up visit at least 14 days after the last dose or early discontinuation
Eligible patients who have fulfilled the entry criteria and completed all screening procedures will 
return to the CRU 7 to 14 days prior to the dose-finding assessment visit to begin a lead-in 
(insulin transition) period.  When patients visit the CRU to begin the lead-in period, patients will 
receive and review instructions on general diabetes education including measurement of 
self-monitored plasma glucose (SMPG), and on the insulin transition (see Section 9.4.7).  During 
the insulin transition period, patients will transition from their current basal insulin therapy to the 
CRU-provided insulin glargine (see Section 5.1.1.1).  Following insulin transition, patients will 
return to the CRU for dose-finding assessment (see Section 5.1.1.2) from 1 to 7 days prior to
Day 1 of Period 1.  The dose-finding assessment will involve the use of Humalog administered 
immediately (not more1 minute) before a standardised MMTT to inform the dose of prandial 
insulin (LY900014, Humalog, FIASP, or NovoRapid) to be used during the study MMTT
assessments.  Upon completion of the dose-finding assessment, patients will be randomised to 1 
of 4 treatment sequences.  Prior to the MMTT in each study period, patients will undergo a run-
in period (see Section 5.1.1.3) to achieve a predetermined glucose target of 135±15 mg/dL 
(7.5±0.8 mmol/L).  Once the glucose target is achieved, patients will proceed with the MMTT in 
which a single individualised SC dose of LY900014, Humalog, FIASP, or NovoRapid will be 
administered immediately before the standardised test meal (see Section 5.1.1.3).
Each dose of study drug (LY900014, Humalog, FIASP, and NovoRapid) will be separated by a 
minimum of 21 hours during all the treatment periods.  The maximum duration allowed for all 
4 treatment periods is approximately 6 weeks.  Patients will continue using CRU-provided 
insulin glargine and their usual rapid- or fast-acting insulin analogues (prandial insulin) during
the entire study including the lead-in period and between MMTTs (see Section 7.7 for use of 
concomitant medications and basal insulin).  During the washout periods, patients will be 
instructed to perform regular monitoring of blood glucose (see Section 9.4.7).
Following completion of all study procedures in each period, patients may be offered a meal and 
discharged from the CRU at the discretion of the investigator.
5.1.1.1.
Lead-in and Insulin Transition
After completing all screening procedures according to the Schedule of Activities (Section 2), 
patients will return to the CRU for the lead-in visit and receive instructions on the insulin 
transition.  The lead-in CRU visit is to take place 7 to 14 days prior to the dose-finding 
assessment. At the lead-in CRU visit, patients will transition from their current regimen of basal 
insulin to the CRU-provided insulin glargine according to the following guidance:


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
7 to 14 days prior to their admission to the CRU for the dose-finding assessment, 
patients will switch from neutral protamine Hagedorn (NPH) insulin, insulin detemir, 
insulin degludec or insulin glargine to the CRU-provided once-daily evening dose of 
insulin glargine.  The starting dose will be at the investigator’s discretion using patients’
current insulin regimen as the reference.

Adjustments may be made in consultation with the investigator following feedback 
obtained from the patient during at least twice-weekly telephone follow-up as part of 
the insulin-transition period.

Once a stable dose has been established, patients will remain on it till completion of the 
study.
Patients can continue current therapy with any prandial insulin throughout the study.
Additionally, at the lead-in CRU visit, patients will be provided with general diabetes training 
including, but not limited to proper insulin-injection technique, correct self-monitoring of plasma 
glucose (PG) using a standardised glucometer, interpretation of results and symptoms, and 
treatment of hypoglycaemia.  In addition to the study insulin, the CRU will also provide the 
glucometer, test strips, control solution and lancets.  A diary will also be provided as described in 
Section 9.4.7.
5.1.1.2.
Dose-Finding Assessment
After transitioning to a stable dose of insulin glargine, patients will return to the CRU anytime 
between 1 and 7 days prior to MMTT in Period 1 for the dose-finding assessment.  The 
dose-finding assessment may begin between 0700 and 1100 hours.  Patients will have fasted for
at least 10 hours prior to the standardised test meal (see Section 5.1.1.3).  The dose-finding test 
will be performed to confirm that the patient’s insulin to carbohydrate ratio is appropriate for the 
standardised MMTT for the study.  The objective of the dose-finding assessment is to determine 
an appropriate, individualised prandial insulin dose to be administered with the standardised test 
meal during the study MMTT (see Section 5.1.1.3). The prandial insulin selected from the dose-
finding assessment will be same for all insulins (Humalog, LY900014, NovoRapid and FIASP) 
assessed within the study.
The patient’s blood glucose level will be measured to select a Humalog dose for the dose-finding 
assessment as follows:
•
if the patient’s blood glucose level is within the range of 70 to 180 mg/dL (3.9 to 
10.0 mM), the patient will be given Humalog at the dose the patient would have taken 
at home
•
the dose-finding meal test should not be carried out if the patient’s blood glucose level 
is not within the range of 70 to 180 mg/dL (3.9 to 10.0 mM) prior to start of the dose-
finding meal test.  The dose-finding meal test may be rescheduled as judged by the 
investigator (see Section 6.2.3).


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Immediately (within 1 minute) after the Humalog dose has been selected and administered, 
patients will receive a standardised test meal as described in Section 6.3.1.  Patients are expected 
to complete each standardised test meal within 15 minutes of starting it.
The patient’s blood glucose level will be measured every 20 minutes for 5 hours post-meal to 
select a Humalog dose for the study MMTT as follows:
•
if the patient’s blood glucose level is within the range of 70 to 240 mg/dL (3.9 to 
13.3 mM) for 5 hours post-meal, the selected Humalog dose will be used for the 
prandial insulin dose (LY900014, Humalog, FIASP and NovoRapid) to be administered 
along with the MMTTs in all the periods but can still be adjusted if necessary based on 
the clinical judgement of the investigator.
•
if the patient’s blood glucose level is not within the range of 70 to 240 mg/dL (3.9 to 
13.3 mM), the dose of Humalog will be adjusted based on the investigator’s judgement 
or if the investigator is unable to make a decision regarding the Humalog dose after 
completing the initial test, the dose-finding assessment may be repeated once within 
7 days of the initial assessment.
•
if, during the dose-finding assessment, the patients’ blood glucose level drops below 
pre-test baseline, the investigator may make further adjustments of the insulin dose.  
Refer to Section 9.4.8 for treatment of hyperglycaemia and hypoglycaemia.
Following completion of procedures associated with the dose-finding assessment, patients may 
be offered a meal.  Dose-finding assessment should occur between 1 and 7 days prior to MMTT 
in Period 1. If the dose-finding assessment occurs from Day -2, the patient may continue to 
remain inpatient in the CRU until the completion of study MMTT on Day 1 of Period 1.
5.1.1.3.
Inpatient Procedures
Run-In
On the day before each MMTT day (that is, Day -1 in each of the 4 periods), patients will arrive 
at the CRU in the early evening (approximately 1700 hours) except for patients who undergo the 
dose-finding assessment from Day -2 of Period 1.  Patients will be advised to bring their prandial
insulin when they arrive at the CRU, which will be administered before the start of a 
standardised dinner.
Before the start of the run-in period, cannulation of 2 veins will be performed.  A variable IV 
infusion of glucose (20% dextrose solution) and/or insulin glulisine will be initiated 
(~2400 hours) in order to obtain a blood glucose target level of 135±15 mg/dL 
(7.5±0.8 mmol/L).  Any insulin infusion should be tapered off and stopped at least 30 minutes 
prior to start of the standardised test meal.  For the last 30 minutes prior to study drug 
administration, the target blood glucose concentration should be within the range without any 
glucose infusion.  If this target blood glucose range is not attained before 1100 hours, the meal 
test will be halted and may be performed on a separate visit; each meal test can only be repeated 
once (see Section 6.2.3 for rescheduling).


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Study MMTT
Each patient’s individual, short-acting insulin may be administered on Day -1 before the start of 
a standardised dinner (at approximately 1900 hours).  If a correction dose of short-acting insulin 
needs to be administered after the meal, no more than 6 U of short-acting insulin should be 
administered between 7 and 12 hours before the scheduled intake of standardised test meal.  
The meal test may start in the early morning at approximately 0700 hours with allowance up to 
1100 hours, if required, to ensure the patient’s blood glucose level is stable and on target, with 
the pre-meal activities as specified in the Schedule of Activities (Section 2).  LY900014, 
Humalog, FIASP, or NovoRapid SC bolus injection will be administered immediately before the 
start of MMTT during each of the 4 treatment periods according to the randomisation schedule.  
The individualised dose for each patient will be the same for all the 4 treatment periods.  For 
each MMTT, the patient should stay in a semi-supine position for 2 hours post-meal.  The patient 
will not be allowed to consume water for 2 hours after the MMTT assessment begins; however, 
water may be consumed freely 2 hours post-meal. 
A standardised MMTT will be administered on Day 1 during each of the 4 treatment periods.  
Patients are expected to complete each standardised test meal within 15 minutes of starting it.  
Patients will be without further food intake from the start of the meal to completion of blood 
collection (approximately 420 minutes) unless required to treat hypoglycaemia (see Section 
9.4.8).
Following completion of the assessment period and sample collection (approximately 
420 minutes), patients will be offered a meal.  Patients will continue with the CRU-provided 
insulin glargine along with their usual bolus prandial insulin.  Patients will be observed 
following administration of the meal and discharged at the investigator’s discretion.
After completion of the last treatment period (Period 4), the patients will resume their pre-study 
basal insulin.
5.1.2. Healthy Subjects
The cohort of healthy subjects will be approximately matched to the cohort of patients with 
T1DM as far as possible with regard to the mean BMI and age.  The healthy subjects will be 
assessed for the PK and PD effects of their endogenous insulin.  They will not be administered 
any study drugs, but will undergo MMTT as described below.
The subjects will be required to visit the CRU on at least 3 occasions as noted in the Schedule of 
Activities (see Section 2):
•
Informed consent
•
Screening visit (including an oral glucose tolerance test [Appendix 6]) up to 28 days 
prior to MMTT
•
An inpatient CRU study visit


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Eligible healthy subjects who have satisfied the entry criteria and completed all screening 
procedures will return to the CRU on Day -1 of the inpatient visit. Subjects will be offered a 
standardised dinner (at approximately 1900 hours).
On Day 1, the MMTT may start at approximately 0700 hours, with the pre-meal activities as 
specified in the Schedule of Activities (Section 2).  A standardised MMTT will be performed on 
Day 1 and the subjects are expected to complete the standardised test meal within 15 minutes of 
starting it.  The subjects should stay in a semi-supine position for 2 hours post-meal.  The 
subjects will not be allowed to consume water for 2 hours after the MMTT assessment begins; 
however, water may be consumed freely 2 hours post-meal.
Subjects will be without further food intake from the start of the meal to completion of blood 
collection (approximately 420 minutes) unless required to treat hypoglycaemia (see 
Section 9.4.8).
Following completion of the assessment period and sample collection (approximately 
420 minutes), subjects will be offered a meal.  Subjects will be observed following 
administration of the meal and discharged at the investigator’s discretion.
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Up to 74 patients with T1DM may be enrolled so that approximately 64 patients complete the 
study.  Replacement patients will adopt all 4 assigned crossover treatments of the original 
patient’s randomisation schedule.
For the healthy subject cohort, sufficient subjects will be enrolled to have 12 healthy subjects 
complete the study.
For purposes of this study, a patient/subject completes the study when all scheduled procedures 
shown in the Schedule of Activities (see Section 2) have been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient/subject.
5.4.
Scientific Rationale for Study Design
This study has a 4-period crossover design to reduce the variability of insulin PK and PD as each 
patient will serve as his/her own control.  Also, the total number of patients needed with a 
crossover design is less than the number needed with a parallel group design.  A maximum 
duration of approximately 6 weeks is allowed for patients to complete all 4 assigned periods to 
minimise the risk of insulin resistance/changes in mean glycaemic control during the study.
This study is being conducted in patients with T1DM, as this is the target population for the 
study drugs. Additionally in patients with T1DM there is no interference of endogenous 


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insulin. A healthy subject cohort is being included to characterise the normal physiological 
insulin secretory response to a single standardised MMTT. 
Randomisation and blinding are used to avoid bias introduced through an association between 
allocation order of study drugs and patient characteristics.  The Lilly clinical pharmacologist 
(CP)/Lilly study team will be unblinded.
In each study period, patients will undergo a run-in period before the MMTT using a variable 
insulin and glucose IV infusion.  This run-in period will allow for improved comparability of the 
postprandial glucose response to a mixed meal after treatment with LY900014, Humalog, 
FIASP, and NovoRapid when administered immediately before the start of the meal.  This run-in 
aims to achieve similar preprandial glucose levels for all patients before the start of the 
standardised test meal and thereby reduces the variability of the postprandial glucose response.  
Insulin glulisine has been chosen for IV optimisation of blood glucose during the run-in because 
it does not cross-react with either the insulin lispro- or insulin aspart-specific assay used for the 
PK analysis.
Under this design, if 2 periods occur on consecutive days, the interval between the last bolus on 
the first day and the first bolus on the second day is much longer compared to the length of time 
that the treatment (LY900014, Humalog, FIASP or NovoRapid) lasts in the bloodstream; 
therefore, no carryover effect is expected.  This enables PK and PD data from the breakfast meal 
tests of each period to be analysed independently and separately.
At least 21 hours between the doses of study drug allows for a complete washout of study drug 
administered with the MMTT and glucose response and prevents carryover effects.
5.5.
Justification for Dose
The bolus dose of insulin (LY900014, Humalog, FIASP, or NovoRapid) will be individualised to 
cover the carbohydrate content in this standardised test meal.  This dose of insulin is reflective of 
clinically relevant, individualised insulin dosing, similar to the manner in which patients would 
determine the insulin dose for the carbohydrate content in a meal.  For each patient, the 
individualised prandial insulin dose for each standardised test meal must be kept identical
throughout the crossover periods.


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6. Study Population
Eligibility of patients or 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 pre-existing 
conditions will be documented.
Screening for patients may occur up to 14 days prior to the lead-in period.  Patients who are not 
enrolled within 35 days of screening may be subjected to an additional medical assessment 
and/or clinical measurements to confirm their eligibility.
Screening for healthy subjects may occur up to 28 days prior to Day 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 enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Patients or subjects are eligible for inclusion in the study only if they meet all of the following 
criteria at screening and/or enrolment:
[1]
For patients with T1DM: are male or female patients with T1DM for at least 
1 year. A diagnosis of T1DM is based on medical history with a fasting 
C-peptide level <0.30 nmol/L.
for the non-diabetic healthy subjects: are overtly healthy males or females
with normal glucose tolerance (see Section 6.1.2), as determined through 
medical history and physical examination.
a.
Male patients:
i.
No male contraception required except in compliance with specific 
local government requirements.
b. Female patients: 
i.
Women of child-bearing potential who are abstinent (if this is 
complete abstinence, as their preferred and usual lifestyle) or in a 
same sex relationship (as part of their preferred and usual lifestyle) 
must agree to either remain abstinent or stay in a same sex 
relationship without sexual relationships with males.
ii.
Otherwise, women of child-bearing potential participating in the 
study must agree to use 1 highly effective method of contraception 
until discharge from final treatment period.


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1. Women of child-bearing potential must test negative for 
pregnancy prior to initiation of treatment as indicated by a 
negative serum pregnancy test at the screening visit followed by a 
negative urine pregnancy test within 24 hours prior to exposure in 
Period 1.
2. A highly effective method of contraception includes a combined 
(oestrogen and progestogen containing) or progestogen-only 
hormonal contraception administered orally, intravaginally or 
transdermally and is associated with inhibition of ovulation.  
Alternatively, patients may use either an intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, 
or the partner should have been vasectomised. 
iii.
Women not of child-bearing potential may participate and include 
those who are
1. infertile due to surgical sterilisation (hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy), congenital anomaly 
such as Mullerian agenesis; or
2. post-menopausal – defined as a woman being amenorrhoeic for 
more than 1 year without an alternative medical cause and a serum 
follicle-stimulating hormone (FSH) level compatible with 
post-menopausal status.  An FSH level in the post-menopausal 
range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement 
therapy.
[2]
are aged 18 to 70 years, both inclusive.
[3]
have a BMI of 18.5 to 30.0 kg/m2, both 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 to allow for glucose infusion and blood 
sampling as per the protocol.
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures including the ability to
consume the standardised test meal.
[7]
are able and willing to give signed informed consent.
6.1.1. Additional Inclusion Criteria for T1DM
[8]
have an HbA1c ≤9.0% at screening.
[9]
have had no episodes of severe hypoglycaemia in the past 6 months (see 
Section 9.4.6.2).


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[10] are on stable prandial insulin and basal insulin (NPH insulin, insulin glargine 
or insulin detemir or insulin degludec) for at least 3 months before screening 
with a total insulin dose demand of ≤1.5 U/kg/day.
6.1.2. Additional Inclusion Criteria for Healthy Subjects
[11] have a fasting PG of ≤100 mg/dL, and post-challenge PG of ≤140 mg/dL  
following oral glucose tolerance test (Appendix 6) and HbA1c <5.7% at 
screening.
6.2.
Exclusion Criteria
Patients or subjects will be excluded from study enrolment if they meet any of the following 
criteria at screening and/or enrolment:
[12] are CRU personnel directly affiliated with this study and their immediate 
families.  Immediate family is defined as a spouse, biological or legal 
guardian, child or sibling.
[13] are Lilly employees or are employees of the CRU.
[14] 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.
[15] have participated, within the past 30 days or 5 half-lives (whichever is longer) 
in a clinical study involving an investigational product.
[16] have previously completed or withdrawn from this study.
[17] have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study.
[18] have a supine blood pressure at screening outside the range of 90 to 
160 mmHg for systolic or 50 to 100 mmHg for diastolic (1 repeat is allowed) 
as determined by the investigator, or results with unacceptable deviations that 
are judged by the investigator to be clinically significant for the population, or 
have a heart rate outside the range of 50 to 90 beats/minute.
[19] have known or ongoing psychiatric disorders.
[20] regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening.
[21] show evidence of an acute infection with fever or infectious disease at the 
time of study entry.
[22] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies.
[23] show evidence of hepatitis C and/or positive hepatitis C antibody (the 
presence of hepatitis C antibodies in the setting of normal liver function tests 
and a negative hepatitis C polymerase chain reaction are not an exclusion).


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[24] show evidence of hepatitis B and/or positive hepatitis B surface antigen (the 
presence of antibodies to the hepatitis B surface antigen is not an exclusion).
[25] are women who are pregnant or lactating.
[26] have a history of renal impairment (exclusion only if estimated glomerular 
filtration rate [GFR] <60 mL/minute/1.73 m2 [GFR is estimated according to 
the Chronic Kidney Disease Epidemiology Collaboration creatinine equation], 
or have a serum creatinine level ≥126 µmol/L (male) or ≥111 µmol/L 
(female).
[27] have a history of deep vein thrombosis of the leg or repeated episodes of deep 
leg vein thrombosis in first-degree relatives (parents, siblings or children) as 
judged by the investigator.
[28] are currently smoking more than 5 cigarettes (or nicotine equivalent) per day.
[29] have donated blood of more than 450 mL or more in the past 3 months or 
provided any blood donation within the last month before screening.
[30] have a significant history of alcoholism or drug abuse as judged by the 
investigator.
[31] currently consumes more than 24 g of alcohol per day for men, or more than 
12 g of alcohol per day for women (1 unit of alcohol is defined as 10 mL [8 g] 
of pure alcohol).
[32] 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.
[33] are receiving chronic (lasting longer than 14 consecutive days) systemic or 
inhaled glucocorticoid therapy (excluding topical, intra-articular and 
intraocular preparations), or have received such therapy within 4 weeks before 
screening.
[34] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.
6.2.1. Additional Exclusion Criteria for T1DM
[35] have significant lipohypertrophy in the target abdominal injection area as 
judged by the investigator.
[36] patients with T1DM having proliferative retinopathy or maculopathy and/or 
severe neuropathy; in particular, autonomic neuropathy as judged by the 
investigator based on a recent (<1.5 years) ophthalmologic examination.
[37] have a history or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, haematological, 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.


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[38] have, except for the current regimen of insulin therapy and concomitant 
medication(s) (for example, antihypertensive medication, lipid-lowering 
agent, thyroid hormone replacement medication, hormonal contraception, 
hormonal replacement therapy), regular use of or intended use of any 
over-the-counter or prescription medications or nutritional supplements that 
promote weight loss within 14 days before dosing.
[39] have type 2 diabetes and use other injectable or oral medications to treat 
hyperglycaemia (such as GLP-1 receptor agonists, metformin, or SGLT2 
inhibitors)
[40] have known allergies to treprostinil (
, insulin lispro, insulin 
glulisine, insulin glargine, FIASP, insulin aspart-related compounds or any 
components of the formulation, or a history of significant atopy.
[41] any significant changes in insulin regimen and/or unstable blood glucose 
control within the past 3 months prior to screening as assessed by the 
investigator.
6.2.2. Additional Exclusion Criteria for Healthy Subjects
[42] have a history or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, haematological, 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.
[43] are healthy nondiabetic volunteers that currently use any medications that 
impact insulin secretion or elevate glucose (such as beta blockers, thiazide 
diuretics, and niacin)
6.2.3. Additional Exclusion Criteria for Inpatient Dosing Days
Patients or subjects who fulfil 1 or more inpatient dosing-day exclusion criteria will be excluded 
from study drug administration for that MMTT day.  A single inpatient treatment period can be 
rescheduled 1 to 14 days later.  Each treatment period can only be rescheduled once.
The following exclusion criteria apply to the day before each MMTT day:
[44] any medical condition or AE that could interfere with glucose metabolism, as 
judged by the investigator.
[45] during the run-in period and up to 2 hours prior to the start of the MMTT, 
episodes of non-severe hypoglycaemia (symptoms or BG ≤70 mg/dL 
[3.9 mmol/L]) can be treated with 15 to 20 g of carbohydrate. If a 
hypoglycaemia episode requires more than approximately 20 g of 
carbohydrate within 8 hours of the start of the MMTT or the patient 
experiences a severe hypoglycaemia episode up to 1 week prior to MMTT (as 
defined in Section 9.4.6.2 and 9.4.6.3), the MMTT must be rescheduled.
CCI




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6.3.3. Activity
Patients and subjects will be encouraged to maintain their regular exercise and insulin regimen 
adaptation (for patients with T1DM only) during the outpatient period; however, they should not 
undertake vigorous or prolonged exercise at least 24 hours before each dosing day at the CRU.  
While in-patient, movement will be restricted to retain the integrity of connections to infusion(s) 
and the study procedures.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of LY900014 administered through SC injection with 
Humalog, FIASP and NovoRapid.  Insulin glargine (non-investigational drug) with a dose 
strength of 100 U/mL will be provided as the basal insulin from lead-in until the follow-up visit.  
Table ITSL.2 shows the treatment regimens.
Table ITSL.2.
Treatments Administered
Treatment Name
LY900014
FIASP
Humaloga
NovoRapid
Dosage Strength
100 U/mL (vial)
100 U/mL (vial)
100 U/mL (vial)
100 U/mL (vial)
Unit Dose 
Strength(s)
Single dose, 
individualised dosing
Single dose, 
individualised dosing
Single dose, 
individualised dosing
Single dose, 
individualised dosing
Route of 
Administration
Subcutaneous
Subcutaneous
Subcutaneous
Subcutaneous
Timing of Dose
Bolus immediately 
before start of the 
MMTT
Bolus immediately 
before start of the 
MMTT
Bolus immediately 
before start of the 
MMTT
Bolus immediately 
before start of the 
MMTT
Abbreviation:  MMTT = mixed meal tolerance test.
a
Two vials per patient will be used: 1 for the dose-finding MMTT and 1 for the test assessment.  Single 
individualised dose during dose-finding MMTT and a single dose per the randomisation schedule.
The investigator or designee is responsible for

explaining the correct use of the investigational product(s) to the CRU personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensation and collection and

returning all unused medications to Lilly or its designee at the end of the study.
Note:  In some cases, the CRU may destroy the material if, during the selection of CRU, the 
evaluator has verified and documented that the CRU has appropriate facilities and written 
procedures to dispose of clinical materials. 
Each dose of study drug will be prepared by the investigator or designee and treatments will be 
administered using an insulin U-100 SC syringe.  Each insulin vial will be labelled appropriately 
and dispensed to qualified study site personnel for administration.  All study drugs will be given 
through SC injection by qualified and appropriately trained CRU personnel, at the CRU, as 
designated by the investigator.  For SC dose administration, an insulin syringe will be used for 
the dose administration with an appropriate size of needle to ensure all injections are delivered to 
a consistent target depth into the SC space; if an 8-mm (or greater) needle is used to administer 
the injection, the skinfold should be pinched.  


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Injections will be rotated among different injection sites on the anterior abdominal wall during 
the 4 study periods (that is, left lower and upper quadrants, and right lower and upper quadrants).  
Study injections should be given by a limited number of individuals for consistency.
7.1.1. Packaging and Labelling
The study insulin (LY900014, Humalog, FIASP, and NovoRapid) will be provided to the CRU 
in unblinded vials.
During the lead-in (insulin transition) period and between each MMTT, insulin glargine will be 
provided to the patients in pens.
All clinical study materials provided to the investigator will be stored in a secure place and 
allocated and dispensed by appropriately trained persons.  The allocation and dispensing of the 
investigational products will be fully documented and verified by a second person.  Detailed 
records of the amounts of the investigational product received, dispensed and remaining at the 
end of the study will be maintained.
The investigational products will be labelled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
The study drug to be injected on a given treatment day will be determined according to the 
randomisation schedule.
7.2.1. Selection and Timing of Doses
The SC dose of insulin (LY900014, Humalog, FIASP and NovoRapid) will be individualised per 
patient to cover the carbohydrate content of the standardised test meal based on the results from 
the dose-finding assessment (see Section 5.1.1.2).  The individualised insulin dose of LY900014,
Humalog, FIASP or NovoRapid for each patient must be kept identical for the standardised test 
meals throughout the crossover periods.
Patients will be provided with the appropriate insulin glargine for self-administration during the 
outpatient period(s) of the study.  Patients will be instructed to select and rotate their injection 
sites in the abdominal area and to administer the SC treatment.
The doses during the inpatient period will be administered immediately before a standardised test 
meal and will be administered at approximately the same times on each day.  The actual time of 
all dose administrations will be recorded in the patient’s electronic case report form (eCRF).
7.3.
Blinding
This is a patient- and investigator-blind study.  The CRU personnel who administer the drug will 
not be blinded and will be separate and distinct from those who are involved in patient care. The 
sponsor including the Lilly CP/Lilly study team will be unblinded. Blinding will be maintained 
throughout the conduct of the study as described in a separate blinding document.


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Emergency codes will be available to the CRU.  A code that reveals the treatment group for a 
specific patient may be opened during the study only if the patient’s well-being requires 
knowledge of the patient’s treatment assignment.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
Dose adjustments are not allowed during the study MMTT procedure.  However, dose 
adjustments may be made during the insulin transition period or between MMTTs based on the 
recommendation of the CRU investigator (see Section 7.7).
7.4.1. Special Treatment Considerations
Lilly will provide insulin glargine during the lead-in period and throughout the study.  Patients
can continue current therapy with their prandial insulin therapy throughout the study.
Commercially available insulin glulisine and 20% dextrose will be used during the run-in period 
to stabilise blood glucose prior to the start of the meal test.  Insulin glulisine may also be used to 
treat hyperglycaemia during the meal test (see Section 5.1.1.3).
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 products
received and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive the study drugs or study materials, and only 
authorised CRU personnel may supply or administer investigational products. All 
investigational products should be stored in an environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions with access 
limited to the investigator and authorised CRU personnel.
The unused study drugs must be stored at the CRU under refrigerated conditions (between 2°C 
and 8°C) in a locked and secure place.  Insulin must not be frozen.
The investigator is responsible for study treatment accountability, reconciliation and record 
maintenance (such as receipt, reconciliation and final disposition records).
7.6.
Treatment Compliance
The investigational products will be administered at the CRU, and documentation of treatment 
administration will occur at the CRU.


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Every attempt will be made to select patients who have the ability to understand and comply with 
instructions.  Noncompliant patients may be discontinued from the study.  The time and day of 
drug administration will be recorded.  Drug accountability records will be maintained by the 
CRU.
The specifications in this protocol for the timings of safety, PK and PD sampling are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon the safety and PK information obtained.  The scheduled time points may be subject 
to minor alterations; however, the actual time must be correctly recorded in the eCRF.  Failure to 
obtain samples due to clinical issues, such as problems with venous access, will not be 
considered a protocol violation, but written documentation will have to be provided to the 
sponsor for all missing samples (regardless of reasons) to facilitate data reconciliation before 
completion of the study.
Any major modifications that might affect the conduct of the study, patient safety and/or data 
integrity will be detailed in a protocol amendment.
7.7.
Concomitant Therapy
Patients will continue the basal insulin regimen established during the insulin transition period
throughout the entire study except when presenting safety issues or to prevent any medical 
problems (see Section 7.4); in this case, the investigator will as far as practically possible discuss 
a change in the regimen with the Lilly CP. Any change in the basal insulin regimen will be 
captured in the patients’ diary and eCRF.
Patients can continue current therapy with prandial insulin throughout the study.
In both patients with T1DM and healthy subjects, any chronic systemic or inhaled glucocorticoid 
therapy (excluding topical, intra-articular and intraocular preparations) should be excluded.  
Additional drugs are to be avoided during the study unless required to treat an AE or for the 
treatment of an ongoing medical problem.
In general for both patients with T1DM and healthy subjects, the addition of new concomitant 
medications should be avoided; however, paracetamol (maximum 4 g/24 hours) may be 
administered at the discretion of the investigator for treatment of headache, etc.  If the need for 
concomitant medication (other than paracetamol) arises, inclusion or continuation of the patient 
or subject may be at the discretion of the investigator after consultation with a Lilly CP or 
clinical research physician (CRP).  Any medication used during the course of the study must be 
documented.
Patients with T1DM and healthy subjects may continue their stable concomitant medication at 
the time of study entry at regular, unchanged doses during the study; for example, 
antihypertensive medications, lipid-lowering agents, thyroid hormone replacement medications, 
hormonal contraception or hormonal replacement therapies.


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Patients with T1DM and healthy subjects should not initiate new over-the-counter or prescription 
medications or nutritional supplements that affect blood glucose or the body’s sensitivity to 
insulin or that promote weight loss 14 days before dosing or throughout the study.
Patients should not apply any creams or lotions to the abdominal skin on the morning of the 
injection or during the inpatient study procedure.
7.8.
Treatment after the End of the Study
Patients will revert to their previous insulin regimen after the final study MMTT and associated 
procedures have been completed.
Not applicable to healthy subjects.


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8. Discontinuation Criteria
Patients or subjects discontinuing from the study prematurely for any reason must complete AE
and follow-up 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 patient or subject meets 1 of the following conditions after consultation 
with the Lilly-designated medical monitor:

alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >5X
upper limit of normal (ULN) for healthy subjects, 8X ULN for patients

ALT or AST >3X ULN for healthy subjects, 5X ULN for patients sustained 
for more than 2 weeks or

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or
international normalised ratio >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 >2.5 ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
8.1.1. Discontinuation of Inadvertently Enrolled Patients or Subjects
If the sponsor or investigator identifies a patient or subject who did not meet enrolment criteria 
and was inadvertently enrolled, the patient or subject must be discontinued from the study.
8.2.
Discontinuation from the Study
Patients or subjects will be discontinued under the following circumstances:

Enrolment in any other clinical study involving an investigational product or enrolment 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)

positive drug screen, positive pregnancy test administered on Day -1 of Period 1 or any 
use of prescription or non-prescription medication according to Exclusion Criterion [38].

Investigator Decision
o
if the patient or subject, for any reason, requires treatment with another 
therapeutic agent that has been demonstrated to be effective for treatment of the 


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study indication, discontinuation from the study occurs prior to introduction of the 
new agent

Subject Decision
o
the patient or subject requests to be withdrawn from the study.
Patients who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).
8.3.
Patients or Subjects Lost to Follow-up
A patient or 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 CRU.  The CRU personnel are expected to 
make diligent attempts to contact patients or subjects who fail to return for a scheduled visit or 
were otherwise unable to be followed up by the CRU.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations or 
laboratory certification standards.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients and 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 patient or subject.
The investigator is responsible for the appropriate medical care of patients and 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 patient or subject to discontinue the investigational 
product before completing the study.  The patient or subject should be followed up until the 
event resolves, stabilises 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, CRU personnel will record, via electronic data 
entry, the occurrence and nature of each patient’s or subject’s pre-existing conditions, including 
clinically significant signs and symptoms of the disease under treatment in the study.  
Additionally, the CRU personnel will record any change in the condition(s) and the occurrence 
and nature of any AEs.
The investigator will categorise the severity of an AE as well as interpret and document whether 
or not an AE has a reasonable possibility of being related to study treatment, or a study 
procedure, taking into account the disease, concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the investigational product, study device and/or study procedure and the AE.


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Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a patient’s or subject’s investigational product is discontinued as a result of an AE, the CRU 
personnel must report this to Lilly or its designee via an electronic data entry.
Hypoglycaemic events are AEs of special interest and will be collected and reported throughout 
the trial as described in Section 9.4.6.3.  All hypoglycaemic events will be recorded in the 
hypoglycaemia module of the eCRF, this allows for the collection of comprehensive safety 
information relating to these events.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalisation

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 hospitalisation but may jeopardise the patient or may require intervention to prevent 1 
of the other outcomes listed in the definition above.
The CRU personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
Additionally, the CRU 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 electronic data entry after signing informed consent, SAE 
reporting to the sponsor begins after the patient or 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 and patients once they 
have discontinued from and/or completed the study (the patient or subject summary eCRF has 
been completed).  However, if the investigator learns of any SAE, including a death, at any time 
after a patient or 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. 


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Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfil regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and foetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to investigational product or procedure.  Lilly 
has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, to monitor quality and to 
facilitate process and product improvements.
The patients and 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 so that the situation can be 
assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY900014, Humalog, FIASP or NovoRapid is 
considered any dose higher than the dose assigned through randomisation.
Excess insulin administration may cause hypoglycaemia and hypokalaemia.  Mild episodes of 
hypoglycaemia usually can be treated with oral glucose.  More severe episodes with coma, 
seizure or neurologic impairment may be treated with intramuscular/SC glucagon or 
concentrated IV glucose.  Sustained carbohydrate intake and observation may be necessary 
because hypoglycaemia may recur after apparent clinical recovery.  Hypokalaemia must be 
corrected appropriately.
Refer to the IB, Humalog, FIASP and/or NovoRapid Product Label (Humalog package insert, 
2015; NovoRapid® product monograph, 2016; FIASP® SmPC, 2017).
9.4.
Safety
9.4.1. Physical Examination
Physical examinations and routine medical assessments will be conducted, as specified in the 
Schedule of Activities and as clinically indicated (Section 2).
9.4.2. Laboratory Tests
For each patient and subject, laboratory tests detailed in Appendix 2 should be conducted 
according to the Schedule of Activities (Section 2).  Patients will be fasted for at least 8 hours 
prior to the clinical laboratory tests.


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With the exception of safety laboratory test results that may unblind the study, Lilly or its 
designee will provide the investigator with the results of laboratory tests analysed by a central 
vendor, if a central vendor is used for the study.
9.4.3. Vital Signs
For each patient and subject, vital sign 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.
If orthostatic measurements are required, patients and subjects should be supine for at least 
5 minutes and stand for at least 2 minutes.
If the patient or subject feels unable to stand, supine vital signs only will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
9.4.4. Electrocardiograms
For each patient and subject, ECGs should be collected according to the Schedule of Activities 
(Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient or subject receives the first dose of the investigational product should be reported to Lilly,
or its designee, as an AE via electronic data entry. 
For each patient and subject, a single 12-lead digital ECG will be collected according to the 
Schedule of Activities (Section 2).  Electrocardiograms must be recorded before collecting any 
blood samples.  Patients and subjects must be supine for at least 5 minutes before ECG collection 
and remain supine but awake during ECG collection.  Electrocardiograms may be obtained at 
additional times, when deemed clinically necessary.  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 CRU as soon after the time of ECG collection as possible, and ideally while the 
patient or subject is still present, to determine whether the patient or subject meets entry criteria 
at the relevant visit(s) and for immediate patient or subject management, should any clinically 
relevant findings be identified.  
If a clinically significant finding is identified (including, but not limited to, changes in 
QT/corrected QT interval from baseline) after enrolment, the investigator will determine if the 
patient or subject can continue in the study.  The investigator, or qualified designee, is 
responsible for determining if any change in patient and 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.


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9.4.5. Other Tests
9.4.5.1.
Body Weight and Height
Body weight and height will be recorded as specified in the Schedule of Activities (Section 2)
and as clinically indicated.
9.4.6. Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes

adverse events.
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.6.1.
Hepatic Safety
If a study patient or subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN or elevated 
TBL ≥2X ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, 
AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase 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 normalise 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 

patient/subject discontinued from treatment due to a hepatic event or abnormality 
of liver tests

hepatic event considered to be an SAE.
9.4.6.2.
Glucose Monitoring
Hypoglycaemia will be described using the following definitions (IHSG 2017):

Documented Glucose Alert Level (Level 1), PG ≤70 mg/dL (3.9 mmol/L):
o
Symptomatic hypoglycaemia: an event during which typical symptoms of 
hypoglycaemia are accompanied by PG ≤70 mg/dL (3.9 mmol/L)
o
Asymptomatic hypoglycaemia: an event not accompanied by typical 
symptoms of hypoglycaemia but with PG ≤70 mg/dL (3.9 mmol/L)


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o
Unspecified hypoglycaemia:  an event during which PG ≤70 mg/dL 
(3.9 mmol/L) but no information relative to symptoms of hypoglycaemia was 
recorded.

Documented Clinically Significant Hypoglycaemia (Level 2) PG <54 mg/dL 
(3.0 mmol/L):
o
Symptomatic hypoglycaemia: an event during which typical symptoms of 
hypoglycaemia are accompanied by PG ≤54 mg/dL (3.0 mmol/L)
o
Asymptomatic hypoglycaemia: an event not accompanied by typical 
symptoms of hypoglycaemia but with PG ≤54 mg/dL (3.0 mmol/L)
o
Unspecified hypoglycaemia:  an event during which PG ≤54 mg/dL 
(3.0 mmol/L) but no information relative to symptoms of hypoglycaemia was 
recorded.

Severe hypoglycaemia (Level 3):  an event requiring assistance of another person to 
actively administer carbohydrate, glucagon or other resuscitative actions.  During 
these episodes, the patient has an altered mental status and cannot assist in their care, 
is semiconscious or unconscious, or experienced coma with or without seizures and 
may require parenteral therapy.  Plasma glucose measurements may not be available 
during such an event, but neurological recovery attributable to the restoration of 
blood glucose concentration to normal is considered sufficient evidence that the event 
was induced by a low PG concentration (PG ≤70 mg/dL [3.9 mmol/L])
o
Severe hypoglycaemia requiring medical attention:  a severe 
hypoglycaemic event when patients require therapy by health care providers 
(emergency medical technicians, emergency room personnel, etc.).
Other Hypoglycaemia:

Nocturnal hypoglycaemia: any hypoglycaemic event (documented symptomatic, 
asymptomatic, probable symptomatic or severe hypoglycaemia) that occurs between 
bedtime and waking

Relative hypoglycaemia: an event during which typical symptoms of 
hypoglycaemia, which do not require the assistance of another person, are 
accompanied by PG >70 mg/dL (3.9 mmol/L), but these levels may be quickly 
approaching the 70 mg/dL (3.9 mmol/L) threshold

Overall (or total) hypoglycaemia:  This optional category combines all cases of 
hypoglycaemia.  If an event of hypoglycaemia falls into multiple subcategories, the 
event is counted only once in this category

Probable symptomatic hypoglycaemia: An event during which symptoms of 
hypoglycaemia are not accompanied by a PG measurement but that was presumably
caused by a blood glucose concentration ≤70 mg/dL (3.9 mmol/L).
9.4.6.3.
Severe Hypoglycaemia
The determination of a hypoglycaemic event as an episode of severe hypoglycaemia as defined 
above will be made by the investigator based on the medical need of the patient to have required 
assistance and is not predicated on the report of a patient simply having received assistance.  


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All hypoglycaemic events are AEs of special interest and will be recorded in the hypoglycaemia 
module of the eCRF (see Section 9.2 for details).  All episodes of severe hypoglycaemia must be 
reported as SAEs.
9.4.7. Self-Monitored Plasma Glucose during Outpatient Period
Self-monitored plasma glucose testing will consist of a minimum of daily 4-point SMPG profiles 
(preprandial for 3 meals [that is, breakfast, lunch and dinner] and at bedtime) using the 
glucometer provided by the site.  Patients will be instructed to use a diary to document any AEs, 
hypoglycaemic events, insulin doses and the SMPG values. 
During the lead-in (insulin transition) and washout period, hyperglycaemia will be monitored 
daily by fasting fingerstick glucose tests and documented in a diary.  Each patient will be 
instructed to contact the CRU personnel if his/her fasting fingerstick glucose level is >200 mg/dL.  
The patient will be managed as considered appropriate by the investigator based on the actual 
glucose value (for example, return to the CRU for evaluation).  If the patient has a fasting 
fingerstick glucose level >200 mg/dL on 2 consecutive days, the patient will be instructed to 
return to the CRU the following day to have a fasting PG performed.  If the fasting PG
>240 mg/dL is confirmed, the patient will be withdrawn from the study. 
9.4.8. Treatment of Hyperglycaemia and Hypoglycaemia
Patients and subjects will be without food intake from the start of the MMTT to completion of 
blood collection (approximately 420 minutes) unless required to treat hypoglycaemia (see 
Section 9.4.6.2 for definition of hypoglycaemia) with either rapidly absorbable oral 
carbohydrates or IV glucose. 
Patients may consume up to 20 g of carbohydrates to treat or prevent hypoglycaemia during the 
fasting periods.  If carbohydrates are administered and consumed, this must be captured in the 
patient’s diary and eCRF.
During the MMTT, if a patient experiences hyperglycaemia (blood glucose concentration ≥306 
mg/dL [17 mM]) for more than 1 hour, insulin glulisine may be administered IV.
In cases where treatment of either hypo- or hyperglycaemia require intervention, samples for 
blood glucose will be taken and PK samples will be collected as planned.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine the serum concentrations of insulin lispro and plasma or serum 
concentrations of insulin aspart in patients with T1DM.  Instructions for the collection and 
handling of blood samples will be provided by the sponsor.  The actual date and time (24-hour 
clock time) of each sampling will be recorded.
9.5.1. Bioanalysis
Samples will be analysed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.


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Serum concentrations of insulin lispro will be measured using a validated 
 
 method specific for insulin lispro at a laboratory approved by the sponsor.
Plasma or serum concentrations of insulin aspart in patients with T1DM will be measured using 
a validated 
 method specific for insulin 
aspart at a laboratory approved by the sponsor.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last patient or subject visit for the study.  
9.6.
Pharmacodynamics
The sample(s) will be stored for up to a maximum of 1 year after last patient or subject visit for 
the study at a facility selected by the sponsor.
Blood samples (approximately 0.2 mL each) will be obtained for the measurement of glucose at 
the times specified in the Schedule of Activities (Section 2) using a validated method (for 
example, glucose analyser) that will be readily available at the CRU during the inpatient periods 
in order to provide real-time glucose measurement.  Repeat samples for counter-checking of 
apparent spurious results may be taken where indicated.  Samples will be disposed of upon 
confirmation of results.
9.6.1. Glucose Samples (Run-In Period)
Blood glucose concentrations will be monitored at a minimum of 30-minute intervals during the 
run-in period on Day 1 (from approximately 7 hours before dosing).
9.6.2. Glucose Samples (MMTT)
Blood samples will be obtained for the measurement of glucose at the times specified in the 
Schedule of Activities (Section 2).  These glucose measurements will be used for patient safety 
management as well as for PD evaluations.
9.7.
Genetics
Not applicable.
9.8.
Biomarkers
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine endogenous insulin concentrations in plasma in healthy subjects 
using a commercially available validated enzyme-linked immunosorbent assay.  Instructions for 
the collection and handling of blood samples will be provided by the sponsor.  The actual date 
and time (24-hour clock time) of each sampling will be recorded.
9.9.
Health Economics
This section is not applicable for this study.
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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
An initial 74 patients with T1DM may be enrolled so that approximately 64 patients complete 
the study.  Sixty-four completing patients will provide at least 95% power to demonstrate a 
2-fold increase in the serum insulin lispro AUC from time 0 to 30 minutes (AUC[0-30min]) 
between LY900014 and the Humalog.  Testing will be done at an alpha level of 0.05 with a 
2-sided confidence interval (CI).  The sample size will also provide greater than 95% power to 
demonstrate a 35% reduction of early 50% tmax between LY900014 and Humalog.  The 
estimated standard deviation of within-subject difference on the log scale is 0.35 for 
AUC(0-30min) and 0.3 for early 50% tmax, according to an analysis of internal Lilly data (Study 
I8B-FW-ITRG) for LY900014 and Humalog administered in a repeat-dose study.
With this sample size, there is more than 95% power to detect a 40% reduction in postprandial 
glucose incremental area under the baseline subtracted glucose concentration versus time curve
from time 0 to 1 hour (∆AUC[0-1h]) between LY900014 and Humalog. With similar 
assumptions, the study is also adequately powered for the comparison between LY900014 and 
NovoRapid. 
With 64 completing patients, there is more than 95% power to detect a 20% reduction of 
early 50% tmax between LY900014 and FIASP. In addition, there is approximately 80% power 
to demonstrate a 25% reduction in postprandial glucose incremental AUC from time 0 to 1 hour 
between LY900014 and FIASP. The power calculation is based on published results of FIASP 
studies and internal Lilly data.
Patients who are randomised but drop out before completing assigned treatment may be replaced 
to ensure that approximately 64 patients complete the study.
For the healthy cohort, 12 non-diabetic healthy subjects will be evaluated for their glucose and 
insulin secretory response to the MMTT.  No treatment will be provided for this cohort.  The 
sample size for the healthy cohort was chosen to provide sufficient data in order to evaluate the 
objectives of the study, and is not intended to achieve any a priori statistical requirements.  
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of patient disposition will be recorded and provided at the end of the 
study.
10.2.2. Study Participant Characteristics
The patient’s age, sex, weight, BMI, height, race/subrace and other demographic characteristics 
will be recorded.


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10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Primary statistical analyses of PK and PD parameters for the cohort of patients with T1DM will 
be conducted on the set of patients who complete all treatment periods with identical prandial 
insulin doses for the MMTTs during the study, as the PK parameters and PD response is 
dependent on the insulin dose which is individualised for each patient.  Supportive analyses may 
be done on the key parameters for the patients who complete at least 2 treatment periods.  
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the study results.
Safety analyses will be conducted on the set of patients receiving at least 1 dose of the study drug 
to which they are randomised, regardless of whether or not they completed all protocol 
requirements.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and CIs will be calculated at 95%, 2-sided. No multiplicity test adjustment will be made 
for secondary objectives.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All treatment- and protocol procedure-related AEs will be listed, and if the frequency of events 
allows, safety data will be summarised using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with study drug as perceived by the investigator during the inpatient period. Symptoms reported 
to occur prior to enrolment will be distinguished from those reported as new or increased in 
severity during the study. Each symptom will be classified by the most suitable term from the 
Medical Dictionary for Regulatory Activities.
The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters and vital signs.  The 
parameters will be listed, and summarised using standard descriptive statistics.  Additional 
analysis will be performed if warranted upon review of the data.


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10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Patients who complete at least 1 MMTT and have measurable insulin concentrations will be
included in the analysis dataset for the PK analyses.  Pharmacokinetic analyses will be conducted 
using standard noncompartmental methods of analysis (
) on a 
computer that meets or exceeds the minimum system requirements for these programs.  It is 
possible that other validated equivalent PK software programs may be utilised if appropriate, 
warranted and approved by global PK management.  The version of any software used for the 
analysis will be documented, and the program will meet the Lilly requirements of software 
validation.
Serum insulin lispro and plasma or serum insulin aspart concentrations will be used to calculate 
several PK parameters, including time to early half-maximal drug concentration (early 50% 
tmax), time to late half-maximal drug concentration (late 50% tmax), maximum observed drug 
concentration (Cmax), time to maximum observed drug concentration (tmax), AUC from time zero 
to time t, where t is the last time point with a measurable concentration (AUC[0-tlast]), AUC(0-
30min), AUC from time 0 to 1 hour (AUC[0-1h]), AUC from time 0 to 7 hours (AUC[0-7h]) and 
AUC from time zero to infinity (AUC[0-∞]).  Additional partial AUCs may be computed as 
necessary, such as AUC from time 0 to 2 hours (AUC[0-2h]) and AUC from time 3 to 7 hours 
(AUC[3-7h]).
In addition, a graphical comparison of the “normal” insulin secretory response using the 
endogenous insulin levels following the MMTT from healthy subjects to the insulin lispro/aspart 
profile following these insulin analogues (LY900014, Humalog, FIASP or NovoRapid) in 
patients with T1DM will be performed. Additional analysis may be performed, if needed.
Although attempts will be made to adhere to the scheduled collection times, it is recognised that 
situations arise that may compromise sample collection at the scheduled times.  Parameters will 
be individually calculated for each patient based on actual collection times and presented by 
summary statistics.
Study results may be pooled with the results of other studies for population PK analysis purposes 
to avoid issues with post hoc analyses and incomplete disclosures of analyses.
10.3.2.2. Pharmacokinetic Statistical Inference
Patients who did not keep identical prandial insulin doses for the MMTTs across all periods will 
be excluded from the statistical analysis of the PK parameters.
The PK time parameters (early 50% tmax, late 50% tmax and tmax) in the original scale will be 
analysed by the mixed-effect model that includes treatment (LY900014, Humalog, FIASP, 
NovoRapid), treatment sequence and period as fixed effects and patient within sequence as a 
random effect.  Least-squares means (LSmeans), treatment differences in LSmeans and the 
corresponding 95% CIs for the treatment differences will be estimated from the model.  The 
p-value on the difference between LSmeans will be used to determine statistical significance.  
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The treatment ratios and 95% CIs for the ratios will be calculated using Fieller’s theorem (Chow 
and Liu 2009).  
Log-transformed AUCs, Cmax for insulin lispro/aspart may be evaluated to estimate geometric 
means, ratios of geometric means and their corresponding 95% CIs using the same mixed-effect 
model as PK time parameters.
Statistical significance will be achieved when the p-value for a test is less than 0.05. The 
primary comparison will be of LY900014 to Humalog. The following comparison will also be 
performed. No multiplicity test adjustment will be made for these comparisons.

LY900014 versus FIASP

LY900014 versus NovoRapid

Humalog versus NovoRapid
10.3.3. Pharmacodynamic Analyses
10.3.3.1. Pharmacodynamic Parameter Estimation
Patients who receive at least 1 dose of study drug and have evaluable PD data will be included in 
the analysis set for the PD analyses. 
Data will be analysed for the patients during each MMTT.  The change from baseline values (the 
average of -30, -15 and 0 minutes represented as the 0-hour time point following the start of the 
MMTT) for each patient will be calculated.  The ∆AUC[0-1h], area under the baseline subtracted 
glucose concentration versus time curve from time 0 to 2 hours post-meal (∆AUC[0-2h] and area 
under the baseline subtracted glucose concentration versus time curve from time 0 to 5 hours
post-meal (∆AUC[0-5h]) will be calculated.  In addition, the change from baseline maximum 
glucose observed during the 5 hours post-meal and change from baseline 1 hour glucose and 
2 hour glucose after the start of the meal will be calculated.  Other partial ∆AUCs may be 
calculated, as deemed appropriate.
In addition, a graphical comparison of the “normal” glucose response following the MMTT from 
healthy subjects to the glucose response following administration of these insulin analogues 
(LY900014, Humalog, FIASP or NovoRapid) in patients with T1DM will be presented.
Parameters will be individually calculated for each patient and presented by summary statistics.
10.3.3.2. Pharmacodynamic Statistical Inference
Patients who did not complete the entire meal or had significant changes in nutrient consumption 
of the standardised test meal or dose changes during the MMTTs will be excluded from all the 
statistical analysis of the PD parameters.
Summary statistics (including number of patients, mean, standard deviation or standard error, 
minimum and maximum) will be presented by treatment.  All PD parameters (including ∆AUCs, 
glucose changes from baseline and time parameters) on the original scale (not log transformed) 
will be analysed using a statistical model that includes treatment, sequence and period as fixed 


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effects and patient within sequence as a random effect.  The p-value on the difference between 
LSmeans will be used to determine statistical significance and the corresponding 95% CIs for the 
LSmean ratios from Fieller’s theorem will be presented. 
Statistical significance will be achieved when the p-value for a test is less than 0.05. The 
primary comparison will be of LY900014 to Humalog. The following comparison will also be 
performed. 

LY900014 versus FIASP

LY900014 versus NovoRapid

Humalog versus NovoRapid
No multiplicity adjustment will be done for the above pair comparisons.
10.3.4. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP/investigator or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.


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11.
References
AMIS database. 13 June 2006. DIMDI (Deutsches Institut für medizinische Dokumentation und 
Information. Available at: https://www.dimdi.de/dynamic/de/db/recherche/index.htm. 
Accessed: November 07, 2017.
Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. 3rd ed. 
Florida: Taylor and Francis Group, LLC; 2009:88-90.
FIASP [Summary of Product Characteristics]. DK-2880 Bagsværd, Denmark: Novo Nordisk 
A/S; 2017.
Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017.
[IHSG] International Hypoglycaemia Study Group. Glucose concentrations of less than 
3.0 mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the 
American Diabetes Association and the European Association for the Study of Diabetes. 
Diabetes Care. 2017;40(1):155-157.
NovoRapid [Summary of Product Characteristics]. DK-2880 Bagsværd, Denmark: Novo 
Nordisk A/S; 2017.
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Appendix 1.
Abbreviations and Definitions


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Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-30min)
AUC from time 0 to 30 minutes
blinding
A procedure in which 1 or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the patient are not.  A double-blind study is one in 
which neither the patient nor any of the investigator or sponsor staff who are involved in the 
treatment or clinical evaluation of the patients are aware of the treatment received.
BMI
body mass index
CI
confidence interval
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
clinical pharmacologist
CRF
case report form
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CRU
clinical research unit


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∆AUC
area under the baseline subtracted glucose concentration versus time curve from time 0 to 
1 hour
early 50% tmax
time to early half-maximal drug concentration
ECG
Electrocardiogram
eCRF
electronic case report form
enrol
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly.
ERB
ethical review board
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
good clinical practice
GFR
glomerular filtration rate
HbA1c
glycated haemoglobin
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorised form, or marketed products 
used for an unauthorised indication, or marketed products used to gain further information 
about the authorised form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IV
intravenous(ly)
late 50% tmax
time to late half-maximal drug concentration
LSmeans
least-squares means


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MDI
multiple daily injection
MMTT
mixed meal tolerance test
non-
investigational 
product
A product that is not being tested or used as a reference in the clinical study, but is provided 
to patients and used in accordance with the protocol, such as concomitant or rescue/escape 
medication for preventative, diagnostic or therapeutic reasons, medication to ensure 
adequate medical care and/or products used to induce a physiological response.
OGTT
oral glucose tolerance test
NPH
neutral protamine Hagedorn
PAH
pulmonary arterial hypertension
PD
pharmacodynamics(s)
PG
plasma glucose
PK
pharmacokinetic(s)
randomise
The process of assigning patients to an experimental group on a random basis.
SAE
serious adverse event
SC
subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SMPG
self-monitored plasma glucose
SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
Tmax
time to maximum observed drug concentration
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 
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Haematologya
Clinical Chemistrya
Haematocrit
Sodium
Haemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell haemoglobin
Calcium
Mean cell haemoglobin concentration 
Phosphorus
Leucocytes (WBC)
HbA1cb
Platelets
Glucosec
Absolute counts of:
Blood urea nitrogen (BUN)
Neutrophils
Uric acid
Lymphocytes
Total cholesterol
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Alkaline phosphatase (ALP)
Urinalysis
Aspartate aminotransferase (AST)
Specific gravity
Alanine aminotransferase (ALT)
pH
Creatinine
Protein
Gamma-glutamyl transferase (GGT)
Glucose
C-peptideb
Ketones
Bilirubin
Breath ethanol testingd
Urobilinogen
Urine drug screenb,d
Blood
Hepatitis B surface antigenb
Nitrite
Hepatitis C antibodyb
Leucocytes
HIVb
Microscopye
Pregnancy testf
FSHb
International normalised ratio (INR)b
Partial thromboplastin time (PTT)b
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell.
a
Results will be validated by the local laboratory at the time of initial testing.
b
Performed at screening.
c
Fasting at screening, dose-finding assessment visit and Day 1 of Period 1 and at the follow-up visit.
d
Will be repeated prior to admission to the clinical research unit and at other times indicated in the Schedule of 
Activities.
e
If clinically indicated, per investigator’s discretion.
f
Females only:  serum pregnancy test at screening and urine pregnancy test are performed as indicated in the
Schedule of Activities.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for

ensuring that the patient/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 patient/subject.  This includes obtaining 
the appropriate signatures and dates on the ICF prior to the performance of any protocol 
procedures and prior to the administration of investigational product.

answering any questions the patient/subject may have throughout the study and sharing 
in a timely manner any new information that may be relevant to the patient’s/subject’s
willingness to continue his or her participation in the study.

providing a copy of the ICF to the participant and retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by International Council for 
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 or Patient Information Leaflet, Package Insert or Summary of Product 
Characteristics and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with


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1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
2) applicable ICH GCP Guidelines
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organisation.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the patient/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, 


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


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Haematologya
Haptoglobina
Haemoglobin
Haematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear Antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised 
ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood Sampling Summary
This table summarises the approximate number of venipunctures and blood volumes for all blood 
sampling (screening, safety laboratories and bioanalytical assays) during the study.  
Protocol I8B-MC-ITSL Sampling Summary for Patients
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening 
11
1
11
Clinical laboratory testsa
9
3
27
Dose-finding assessment
0.2
15
3
Blood glucose sampling (run-in)
0.2
13 samples x 4 
periods = 52
10.4
Blood glucose sampling (MMTT)
0.2
24 samples x 4 
periods = 96
19.2
Pharmacokinetics 
3
25 samples x 4 
periods = 100
300
Total
370.6
Total for clinical purposes [rounded up to the nearest 10 mL]
380
Abbreviation:  MMTT = mixed meal tolerance test.
a
Additional samples may be drawn if needed for safety purposes.
Protocol I8B-MC-ITSL Sampling Summary for Healthy Subjects
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screeninga
11
1
11
OGTT
2
3
6
Blood glucose sampling (MMTT)
0.2
24
4.8
Endogenous insulin
3
25
75
Total
96.8
Total for clinical purposes [rounded up to the nearest 10 mL]
100
Abbreviations:  MMTT = mixed meal tolerance test; OGTT = oral glucose tolerance test.
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Oral Glucose Tolerance Test
Oral glucose tolerance test (OGTT) will be performed as a screening test in healthy subjects (see 
Section 2).
The OGTT is a 2-hour test that checks the PG levels before and 2 hours after the subject 
consumes a 75 g glucose beverage (for example, ACCU-CHEKDextroO.G-T). 
To be tested, subjects must be on a stable diet, at a stable weight, with a stable level of exercise, 
and without acute illness or recent hospitalisation. The subject has to fast overnight for at least 
8 hours, and should take nothing by mouth except water. No medication, caffeine or tobacco 
consumption is allowed until the completion of the test. The subject is given a 75 g glucose 
beverage that should be consumed in 5 minutes or less.  Three blood samples are collected to 
measure PG levels: before ingestion of the glucose beverage and at 1 hour and 2 hours after the 
start of ingestion of the glucose beverage. 


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Appendix 7.
Protocol Amendment I8B-MC-ITSL(a)
Summary 
A Mixed Meal Tolerance Test Study to Evaluate the 
Pharmacokinetics and Pharmacodynamics of LY900014 
Compared to Humalog Following a Single Dose in 
Adults with Type 1 Diabetes
Overview
Protocol I8B-MC-ITSL, A Mixed Meal Tolerance Test Study to Evaluate the Pharmacokinetics 
and Pharmacodynamics of LY900014 Compared to Humalog Following a Single Dose in Adults 
with Type 1 Diabetes, 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 as follows:

It was clarified in the protocol that the lead-in period would be 7 to 14 days prior to dose-
finding assessment, instead of at least 14 days prior to dose-finding assessment. 


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1.
Protocol Synopsis
Treatment Arms and Planned Duration for an Individual Patient with T1DM:
Patients will be screened over a 14-day period prior to start of an approximate 7- to 14-day lead-in (insulin 
transition) period. 
2.
Schedule of Activities
Study Schedule Protocol I8B-MC-ITSL for Patients with T1DM
Screening
Lead-In
Dose-
Finding 
Assessment
Study Period 
(Periods 1 to 4)
Follow-
up/Early 
Discontinuation
Comments
Procedure
Up to 
14 days 
prior to 
lead-in
Up to7-14 
days prior 
to dose-
finding 
assessment
1-7 days 
prior to 
Period 1, 
Day 1
Day -1
Day 
1
≥14 days after 
discharge




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assessment. At the lead-in CRU visit, patients will transition from their current regimen of basal 
insulin to the CRU-provided insulin glargine according to the following guidance:

At least 7 to 14 days prior to their admission to the CRU for the dose-finding assessment, 
patients will switch from neutral protamine Hagedorn (NPH) insulin, insulin detemir, 
insulin degludec or insulin glargine to the CRU-provided once-daily evening dose of 
insulin glargine.  The starting dose will be at the investigator’s discretion using patients’ 
current insulin regimen as the reference.

SAP_001.pdf: 
Statistical Analysis Plan: I8B-MC-ITSL(a) A Mixed Meal Tolerance Test Study to Evaluate the 
Pharmacokinetics and Pharmacodynamics of LY900014 Compared to Humalog Following a 
Single Dose in Adults with Type 1 Diabetes 
NCT03449433 
Approved: 8-Mar-2018 


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             Page 1 of 16
STATISTICAL ANALYSIS PLAN
A Mixed Meal Tolerance Test Study to Evaluate the Pharmacokinetics and 
Pharmacodynamics of LY900014 Compared to Humalog Following a Single Dose in Adults
with Type 1 Diabetes
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  06-March-2018
Study Drug: LY900014
Sponsor Reference:  I8B-MC-ITSL
Covance CRU Study: 1001215-8380290
Clinical Phase I
Approval Date: 08-Mar-2018 GMT


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8380290
Sponsor Reference I8B-MC-ITSL
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
4.1
Primary Objective.................................................................................................... 5
4.2
Secondary Objectives .............................................................................................. 5
4.3
Tertiary/Exploratory Objectives............................................................................... 6
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENTS............................................................................................................. 7
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 8
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 8
9.
STATISTICAL METHODOLOGY ............................................................................... 9
9.1
General.................................................................................................................... 9
9.2
Demographics and Subject Disposition.................................................................... 9
9.3
Pharmacokinetic Analyses..................................................................................... 10
9.3.1
Pharmacokinetic Parameter Estimation......................................................... 10
9.3.2
Pharmacokinetic Statistical Inference ........................................................... 10
9.4
Pharmacodynamic Analyses .................................................................................. 11
9.4.1
Pharmacodynamic Parameter Estimation...................................................... 11
9.4.2
Pharmacodynamic Statistical Inference......................................................... 12
9.5
Safety and Tolerability Assessments...................................................................... 12
9.5.1
Adverse events ............................................................................................. 12
9.5.2
Concomitant medication............................................................................... 13
9.5.3
Clinical laboratory parameters...................................................................... 13
9.5.4
Vital signs .................................................................................................... 13
9.5.5
Hepatic Monitoring ...................................................................................... 13
9.5.6
Blood Glucose Monitoring and Hypoglycemia ............................................. 13
9.5.7
Other assessments......................................................................................... 15
9.5.8
Safety and Tolerability Statistical Methodology............................................ 15
10. INTERIM ANALYSES ............................................................................................... 15
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 15
12. REFERENCES ............................................................................................................ 15
13. DATA PRESENTATION ............................................................................................ 15
13.1 Derived Parameters ............................................................................................... 15
13.2 Missing Data ......................................................................................................... 16
13.3 Insufficient Data for Presentation .......................................................................... 16


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8380290
Sponsor Reference I8B-MC-ITSL
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0 - 30min)
AUC from time 0 to 30 minutes
AUC(0 - 1h)
AUC from time 0 to 1 hour
AUC(0 – 2 h)
AUC from time 0 to 2 hours
AUC(0 - 7h)
AUC from time 0 to 7 hours
AUC(0 - ∞)
AUC from time 0 to infinity
AUC(3 – 7 h)
AUC from time 3 hours to time 7 hours
BMI
Body mass index
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
AUC(0-1h)
Area under the baseline subtracted glucose concentration versus time 
curve from time 0 to 1 hour
AUC(0-2h)
Area under the baseline subtracted glucose concentration versus time 
curve from time 0 to 2 hours
AUC(0-5h)
Area under the baseline subtracted glucose concentration versus time 
curve from time 0 to 5 hours
Early 50% tmax
Time to early half-maximal drug concentration
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8380290
Sponsor Reference I8B-MC-ITSL
ICH
International Council on Harmonisation
Late 50% tmax
Time to late half-maximal drug concentration
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
MMTT
Mixed meal tolerance test
MRAUC
Metabolic ratio based on AUC(0-) 
MRE
Magnetic resonance elastography
NA
Not applicable
PD
Pharmacodynamic
PG
Plasma glucose
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SD
Standard deviation 
SOP
Standard Operating Procedure
T1DM
Type 1 diabetes mellitus
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8380290
Sponsor Reference I8B-MC-ITSL
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 12 
December 2017).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as the 
template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective

To evaluate the differences in PK between LY900014 and Humalog following a single 
dose in patients with type 1 diabetes mellitus (T1DM).
4.2
Secondary Objectives

To characterise the PK profiles of LY900014, Humalog, NovoRapid and FIASP 
following a single dose in patients with T1DM.

To evaluate the differences in PD between LY900014 and Humalog following a single 
dose in patients with T1DM

To characterise the PD response to LY900014, Humalog, NovoRapid and FIASP, as 
assessed by the mixed meal tolerance test (MMTT), in patients with T1DM.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8380290
Sponsor Reference I8B-MC-ITSL
4.3
Tertiary/Exploratory Objectives

To characterise “normal” insulin secretory and glucose response to the MMTT in non-
diabetic healthy subjects

To evaluate the tolerability of subcutaneous (SC) doses of LY900014 in patients with 
T1DM.
5. STUDY DESIGN
Study I8B-MC-ITSL (ITSL) is a clinical pharmacology, patient- and investigator-blind,
randomised, 4-treatment, 4-period crossover study in patients with T1DM to compare insulin
lispro PK and PD profiles of the postprandial blood glucose during a standardised MMTT
following LY900014 in comparison to Humalog in patients with T1DM following single SC
injections administered just before a standardised MMTT. This study will also characterise the
PK and PD of insulin aspart analogues NovoRapid and FIASP in patients with T1DM under
identical study conditions. A non-diabetic healthy subject cohort, which approximately matches
to the cohort of patients with T1DM with regard to the mean body mass index (BMI) and age, is
included with the intention of characterising the insulin secretory response to a standardised
MMTT within normal physiology. These subjects will undergo a single in-house MMTT and
will not receive any of the study drugs. Study ITSL may be conducted at 1 or more clinical
research units (CRUs). Figure 1 illustrates the study design.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8380290
Sponsor Reference I8B-MC-ITSL
Abbreviation: MMTT = mixed meal tolerance test.
*Lead-in period up to 14 days prior to dose-finding assessment to enable transition to insulin glargine; patients 
continue use of insulin glargine and usual prandial insulin analogues throughout the study during lead-in and 
between MMTT assessments.
Dose-finding MMTT with Humalog is performed between 1 and 7 days prior to MMTT in Period 1.
4-period crossover: the 4 MMTT assessments may occur on successive days, but all should be completed within 6 
weeks.
Intravenous glucose insulin infusion is provided from 7 hours to 30 minutes prior to MMTT to achieve a stable 
baseline glucose target in the patients with type 1 diabetes mellitus.
Single MMTT is performed in non-diabetic healthy subject cohort; no lead-in period is required.
Figure 1 Illustration of study design
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
LY900014
1
Humalog
2
FIASP
3
NovoRapid
4
The following is a list of the study populations that will be used in the TFLs.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8380290
Sponsor Reference I8B-MC-ITSL
Population Name
Population order in TFL
Patients with T1DM
1
Healthy subjects
2
7. SAMPLE SIZE JUSTIFICATION
An initial 74 patients with T1DM may be enrolled so that approximately 64 patients complete
the study. Sixty-four completing patients will provide at least 95% power to demonstrate a 2-fold 
increase in the serum insulin lispro AUC from time 0 to 30 minutes (AUC[0-30min]) between 
LY900014 and the Humalog. Testing will be done at an alpha level of 0.05 with a 2-sided 
confidence interval (CI). The sample size will also provide greater than 95% power to
demonstrate a 35% reduction of early 50% tmax between LY900014 and Humalog. The estimated 
standard deviation of within-subject difference on the log scale is 0.35 for AUC(0-30min) and 
0.3 for early 50% tmax, according to an analysis of internal Lilly data (Study I8B-FW-ITRG) for 
LY900014 and Humalog administered in a repeat-dose study.
With this sample size, there is more than 95% power to detect a 40% reduction in postprandial
glucose incremental area under the baseline subtracted glucose concentration versus time curve
from time 0 to 1 hour (ΔAUC[0-1h]) between LY900014 and Humalog. With similar
assumptions, the study is also adequately powered for the comparison between LY900014 and
NovoRapid.
With 64 completing patients, there is more than 95% power to detect a 20% reduction of early 
50% tmax between LY900014 and FIASP. In addition, there is approximately 80% power to 
demonstrate a 25% reduction in postprandial glucose incremental AUC from time 0 to 1 hour
between LY900014 and FIASP. The power calculation is based on published results of FIASP
studies and internal Lilly data.
Patients who are randomised but drop out before completing assigned treatment may be replaced
to ensure that approximately 64 patients complete the study.
For the healthy cohort, 12 non-diabetic healthy subjects will be evaluated for their glucose and
insulin secretory response to the MMTT. No treatment will be provided for this cohort. The
sample size for the healthy cohort was chosen to provide sufficient data in order to evaluate the
objectives of the study, and is not intended to achieve any a priori statistical requirements.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects who receive at least 1 dose of study 
drug. Healthy volunteers will also be included in the safety population.
Primary statistical analyses of PK and PD parameters for the cohort of patients with T1DM will 
be conducted on the set of patients who complete all treatment periods with identical prandial 




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9.3
Pharmacokinetic Analyses
9.3.1 Pharmacokinetic Parameter Estimation
Patients who complete at least 1 MMTT and have measurable insulin concentrations will be
included in the analysis dataset for the PK analyses. Pharmacokinetic analyses will be conducted
using standard noncompartmental methods of analysis (Phoenix® version 6.3 or above) on a
computer that meets or exceeds the minimum system requirements for these programs. It is
possible that other validated equivalent PK software programs may be utilised if appropriate,
warranted and approved by global PK management. The version of any software used for the
analysis will be documented, and the program will meet the Lilly requirements of software
validation.
Serum insulin lispro and plasma or serum insulin aspart concentrations will be used to calculate
several PK parameters, including time to early half-maximal drug concentration (early 50% tmax), 
time to late half-maximal drug concentration (late 50% tmax), maximum observed drug
concentration (Cmax), time to maximum observed drug concentration (tmax), AUC from time zero
to time t, where t is the last time point with a measurable concentration (AUC[0-tlast]), 
AUC(0-30min), AUC from time 0 to 1 hour (AUC[0-1h]), AUC from time 0 to 7 hours 
(AUC[0-7h]) and AUC from time zero to infinity (AUC[0-∞]). Additional partial AUCs may be 
computed as necessary, such as AUC from time 0 to 2 hours (AUC[0-2h]),AUC from time 3 to 7 
hours (AUC[3-7h]), and onset of appearance of serum lispro/aspart in the blood.
In addition, a graphical comparison of the “normal” insulin secretory response using the
endogenous insulin levels following the MMTT from healthy subjects to the insulin lispro/aspart
profile following these insulin analogues (LY900014, Humalog, FIASP or NovoRapid) in
patients with T1DM will be performed. Additional analysis may be performed, if needed.
Although attempts will be made to adhere to the scheduled collection times, it is recognised that
situations arise that may compromise sample collection at the scheduled times. Parameters will
be individually calculated for each patient based on actual collection times and presented by
summary statistics.
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.
9.3.2 Pharmacokinetic Statistical Inference
Patients who did not keep identical prandial insulin doses for the MMTTs across all periods will
be excluded from the statistical analysis of the PK parameters.
The PK time parameters (early 50% tmax, late 50% tmax and tmax) in the original scale will be
analysed by the mixed-effect model that includes treatment (LY900014, Humalog, FIASP,
NovoRapid), treatment sequence and period as fixed effects and patient within sequence as a
random effect. Least-squares means (LSmeans), treatment differences in LSmeans and the
corresponding 95% CIs for the treatment differences will be estimated from the model. The
p-value on the difference between LSmeans will be used to determine statistical significance.


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The treatment ratios and 95% CIs for the ratios will be calculated using Fieller’s theorem (Chow
and Liu 20093).
Example SAS code:
proc mixed data=pk;
class patient period treatment;
model logpk = treatment period / ddfm=kr alpha=0.05;
random patient;
lsmeans treatment;
run;
Log-transformed AUCs, Cmax for insulin lispro/aspart may be evaluated to estimate geometric
means, ratios of geometric means and their corresponding 95% CIs using the same mixed-effect
model as PK time parameters.
Statistical significance will be achieved when the p-value for a test is less than 0.05. The primary 
comparison will be of LY900014 to Humalog. The following comparison will also be performed. 
No multiplicity test adjustment will be made for these comparisons.

LY900014 versus FIASP

LY900014 versus NovoRapid

Humalog versus NovoRapid
9.4
Pharmacodynamic Analyses
9.4.1 Pharmacodynamic Parameter Estimation
Patients who receive at least 1 dose of study drug and have evaluable PD data will be included in
the analysis set for the PD analyses.
Data will be analysed for the patients during each MMTT. The change from baseline values (the
average of -30, -15 and 0 minutes represented as the 0-hour time point following the start of the
MMTT) for each patient will be calculated. The ΔAUC[0-1h], area under the baseline subtracted
glucose concentration versus time curve from time 0 to 2 hours post-meal (ΔAUC[0-2h] and area
under the baseline subtracted glucose concentration versus time curve from time 0 to 5 hours
post-meal (ΔAUC[0-5h]) will be calculated. In addition, the change from baseline maximum
glucose observed during the 5 hours post-meal and change from baseline 1 hour glucose and 2 
hour glucose after the start of the meal will be calculated. Other partial ΔAUCs may be
calculated, as deemed appropriate.
For those patients patients which received treatment (insulin or glucose) for hypoglycemic or 
hyperglycemic events, the postprandial glucose collected post intervention during the MMTT 
following will not be included in the glucodynamic assessment.  These glucose parameters will 
be analyzed in 2 different ways:


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1) the glucose values collected prior to any treatment intervention due to hypoglycemic or 
hyperglycemic event.  Glucose values collected after intervention were treated as missing 
in the datafile;
2) last observation carried forward (LOCF):  the last observed glucose values prior to 
treatment intervention due to hypoglycemic or hyperglycemic event were carried forward 
to the end of the MMTT timing.
In addition, a graphical comparison of the “normal” glucose response following the MMTT from
healthy subjects to the glucose response following administration of these insulin analogues
(LY900014, Humalog, FIASP or NovoRapid) in patients with T1DM will be presented.
Parameters will be individually calculated for each patient and presented by summary statistics.
9.4.2 Pharmacodynamic Statistical Inference
Patients who did not complete the entire meal or had significant changes in nutrient consumption
of the standardised test meal or dose changes during the MMTTs will be excluded from all the
statistical analysis of the PD parameters.
Summary statistics (including number of patients, mean, standard deviation or standard error,
minimum and maximum) will be presented by treatment. All PD parameters (including ΔAUCs,
glucose changes from baseline and time parameters) on the original scale (not log transformed)
will be analysed using a statistical model that includes treatment, sequence and period as fixed 
effects and patient within sequence as a random effect. The p-value on the difference between
LSmeans will be used to determine statistical significance and the corresponding 95% CIs for the
LSmean ratios from Fieller’s theorem will be presented.
Statistical significance will be achieved when the p-value for a test is less than 0.05. The primary 
comparison will be of LY900014 to Humalog. The following comparisons will also be
performed.

LY900014 versus FIASP

LY900014 versus NovoRapid

Humalog versus NovoRapid
No multiplicity adjustment will be done for the above pair comparisons.
9.5
Safety and Tolerability Assessments
9.5.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the subject has 
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to dosing and becomes 
more severe postdose. 


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All AEs will be listed. Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA)
version 20.1system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug. Any serious AEs
will be tabulated.
9.5.2 Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version September 
2017). Concomitant medication will be listed.
9.5.3 Clinical laboratory parameters
All clinical chemistry, hematology and urinalysis data will be listed. Additionally clinical 
chemistry, hematology and urinalysis data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.5.4 Vital signs
Vital signs data will be listed for individual subjects.
9.5.5 Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality. 
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant medication of acetaminophen/paracetamol will be listed. Results from any 
hepatic monitoring procedures, such as a magnetic resonance elastography (MRE) scan, and a 
biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.5.6 Blood Glucose Monitoring and Hypoglycemia
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
any treatments administered. Each category of hypoglycemic events (defined below) will be 
listed and summarized by treatment during study and during MMTT.


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Hypoglycemia is defined as follows:

Documented Glucose Alert Level (Level 1), Plasma Glucose (PG) ≤70 mg/dL 
(3.9 mmol/L):
o
Symptomatic hypoglycemia:  an event during which typical symptoms of 
hypoglycemia are accompanied by PG ≤70 mg/dL (3.9 mmol/L)
o
Asymptomatic hypoglycemia:  an event not accompanied by typical symptoms 
of hypoglycemia but with PG ≤70 mg/dL (3.9 mmol/L)
o
Unspecified hypoglycemia:  an event during which PG ≤70 mg/dL (3.9 mmol/L) 
but no information relative to symptoms of hypoglycemia was recorded

Documented Clinically Significant Hypoglycemia (Level 2) PG <54 mg/dL 
(3.0 mmol/L):
o
Symptomatic hypoglycemia:  an event during which typical symptoms of 
hypoglycemia are accompanied by PG <54 mg/dL (3.0 mmol/L)
o
Asymptomatic hypoglycemia:  an event not accompanied by typical symptoms 
of hypoglycemia but with PG <54 mg/dL (3.0 mmol/L)
o
Unspecified hypoglycemia:  an event during which PG <54 mg/dL (3.0 mmol/L) 
but no information relative to symptoms of hypoglycemia was recorded

Severe hypoglycemia (Level 3):  an event requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions. During these 
episodes, the patient has an altered mental status and cannot assist in their care, is 
semiconscious or unconscious, or experienced coma with or without seizures and may 
require parenteral therapy. PG measurements may not be available during such an event, 
but neurological recovery attributable to the restoration of blood glucose concentration to 
normal is considered sufficient evidence that the event was induced by a low PG 
concentration (PG ≤70 mg/dL [3.9 mmol/L])
o
Severe hypoglycemia requiring medical attention:  a severe hypoglycemic 
event when patients require therapy by HCPs (EMTs, emergency room 
personnel, etc)
Other Hypoglycemia:

Nocturnal hypoglycemia:  any hypoglycemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycaemia) that occurs between 
bedtime and waking

Relative hypoglycemia:  an event during which typical symptoms of hypoglycemia, 
which do not require the assistance of another person, are accompanied by PG 


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>70 mg/dL (3.9 mmol/L), but these levels may be quickly approaching the 70 mg/dL (3.9 
mmol/L) threshold

Overall (or total) hypoglycemia:  This optional category combines all cases of 
hypoglycemia. If an event of hypoglycemia falls into multiple subcategories, the event is 
counted only once in this category

Probable symptomatic hypoglycemia:  An event during which symptoms of 
hypoglycemia are not accompanied by a PG measurement but that was presumably 
caused by a blood glucose concentration ≤70 mg/dL (3.9 mmol/L).
9.5.7
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.5.8
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. 3rd ed. 
Florida: Taylor and Francis Group, LLC; 2009:88-90
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 


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values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”