Clinical trial NCT04276207
Conditions: Diabetes Mellitus, Type 1
Sponsor: Eli Lilly and Company
Start date: 2020-02-25; Completion date: 2020-08-10
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main purpose of this study is to compare LY900014 to insulin lispro (Humalog) in participants with type 1 diabetes who are using an insulin pump and have high blood sugar after eating. For each participant, the study will last about two to nine weeks.

Detailed description:

Arms: arm 1: 100 units per milliliter (U/mL) LY900014 administered by continuous subcutaneous insulin infusion (CSII) in one of two study periods. arm 2: 100 U/mL Insulin Lispro (Humalog) administered by CSII in one of two study periods.
Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro
Intervention descriptions: intervention 1: Administered by CSII intervention 2: Administered by CSII

Protocol documents:
Prot_000.pdf: 
Protocol I8B-MC-ITST (V2)
Effects of LY900014 on Recovery from Hyperglycemia Compared to Humalog in Subjects with 
Type 1 Diabetes Mellitus (T1DM) on Continuous Subcutaneous Insulin Infusion 
NCT04276207 
Approval Date: 22-Jan-2020 


Clinical Trial Protocol 
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CLINICAL TRIAL PROTOCOL 
Trial ID: I8B-MC-ITST 
Effects of LY900014 on Recovery from Hyperglycemia Compared to Humalog in 
Subjects with Type 1 Diabetes Mellitus (T1DM) on Continuous Subcutaneous Insulin 
Infusion  
Confidential Information 
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation 
of LY900014, unless such persons are bound by a confidentiality agreement with Eli 
Lilly and Company or its subsidiaries. 
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  
In the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.  
Principal Investigator: 
               Profil Mainz GmbH & Co. KG 
Author and affiliation: 
 Profil Institut für Stoffwechselforschung GmbH 
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below. 
Approval Date: 22-Jan-2020 GMT
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A G R E E M E N T O N T H E P R O T O C O L 
P ri n ci p al I n v esti g at o r: 
S p o ns o r R e p r es e nt ati v e ( Eli Lill y a n d C o m p a n y) : 
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NAMES AND ADDRESSES  
Sponsor: 
Eli Lilly and Company 
 
Lilly Corporate Center
 
Lilly Corporate Center, Indianapolis IN 46285 
U.S.A 
 
Eli Lilly and Company 
 
Sponsor’s EU Representative:  
Eli Lilly Cork Limited Island House, 
Eastgate Road, Eastgate Business Park,  
Little Island, Co. Cork,  
IRELAND,  
 
Principal Investigator: 
 
 
 
Profil Mainz GmbH & Co. KG 
Malakoff-Passage, Rheinstraße 4C 
D-55116 Mainz 
GERMANY 
 
Clinical Trial Centre:  
 
 
Profil Mainz GmbH & Co. KG 
Malakoff-Passage, Rheinstraße 4C 
D-55116 Mainz 
Germany 
 
 
Sponsor’s Responsible Medical Monitor:  
Eli Lilly and Company 
 
Lilly Corporate Center
Lilly Corporate Center, Indianapolis IN 46285 
U.S.A 
 
Safety Laboratory analysis: 
MLM Medical Labs GmbH  
  
Dohrweg 63  
D-41066 Mönchengladbach  
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Special Laboratory (insulin PK analysis): 
Charles Rivers Laboratories  Preclinical Services, 
Montreal (PCS-MTL) 
 
22022 Transcanadienne 
Senneville, Quebec H9X 3R3 
CANADA 
 
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TABLE OF CONTENTS 
Agreement on the Protocol ......................................................................................................................... 2 
Names and Addresses .................................................................................................................................. 3 
Table of Contents ........................................................................................................................................ 5 
List of Abbreviations ................................................................................................................................... 8 
1 
Synopsis ............................................................................................................................................... 10 
2 
Schematic Trial Overview ................................................................................................................. 14 
2.1 
Chronological Structure of the Trial ....................................................................................... 14 
2.2 
Trial Flow Chart ..................................................................................................................... 15 
2.3 
Assessment Schedules ............................................................................................................ 17 
3 
Introduction ........................................................................................................................................ 23 
3.1
Background Information on Investigational Medicinal Products (IMPs)...............................23
3.1.1 
Insulin lispro .............................................................................................................. 23 
3.1.2 
Insulin LY900014 ...................................................................................................... 23 
3.2 
Rationale for the Trial ............................................................................................................. 24 
4 
Objectives and Endpoints .................................................................................................................. 25 
4.1 
Objectives ............................................................................................................................... 25 
4.1.1 
Primary objective: ..................................................................................................... 25 
4.1.2 
Secondary objectives: ................................................................................................ 25 
4.1.3 
Exploratory objectives: .............................................................................................. 25 
4.2 
Endpoints ................................................................................................................................ 25 
4.2.1 
Primary endpoints: .................................................................................................... 25 
4.2.2 
Secondary endpoints: ................................................................................................ 25 
4.2.3 
Exploratory endpoints: .............................................................................................. 26 
4.2.4 
Safety endpoints: ....................................................................................................... 26 
5 
Trial Design ........................................................................................................................................ 27 
5.1 
Type of Trial ........................................................................................................................... 27 
5.2 
Randomization ........................................................................................................................ 27 
5.3 
Blinding and Code Breaking Procedures ................................................................................ 27 
5.4 
Investigational Treatment of Subjects .................................................................................... 28 
5.5 
Duration .................................................................................................................................. 29 
5.6 
Stopping Rules ........................................................................................................................ 29 
5.7 
Rationale for the Trial Design and Treatment ........................................................................ 30 
6 
Trial Population ................................................................................................................................. 31 
6.1 
Number of Subjects to be Studied .......................................................................................... 31 
6.2 
Inclusion Criteria .................................................................................................................... 31 
6.3 
Exclusion Criteria ................................................................................................................... 31 
6.4 
Dosing Visit Exclusion Criteria .............................................................................................. 34 
6.5 
Discontinuation Criteria .......................................................................................................... 34 
6.5.1 
Hepatic Criteria for Discontinuation ......................................................................... 35 
6.6 
Subject Replacement ............................................................................................................... 36 
6.7 
Rationale for Trial Population ................................................................................................ 36 
7 
Trial Materials .................................................................................................................................... 37 
7.1 
Investigational Medicinal Products (IMPs) ............................................................................ 37 
7.2 
Packaging and Labelling of Investigational Medicinal Product ............................................. 37 
7.2.1 
Storage and Drug Accountability of Investigational Medicinal Product ................... 38 


 
 
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7.2.2 
Dispensing and Return of Investigational Medicinal Products ................................. 38 
7.3
Retention Samples ..................................................................................................................38
7.4 
Preparation and Application of IMP ....................................................................................... 38 
8 
Visits and Assessments ....................................................................................................................... 39 
8.1 
Visit Procedures ...................................................................................................................... 39 
8.2 
Visit 0 – Informed Consent Visit ............................................................................................ 39 
8.3 
Visit 1 – Screening Visit ......................................................................................................... 39 
8.4 
Visit 2 and 3 – Dosing Visits .................................................................................................. 40 
8.5 
Visit 4 – Follow-up Visit ........................................................................................................ 42 
8.6 
Assessment of Treatment Compliance.................................................................................... 42 
8.7 
Assessments for Pharmacokinetics ......................................................................................... 42 
8.8 
Assessments for Pharmacodynamics ...................................................................................... 42 
8.8.1 
Run-in and other experimental procedures on Day 1 and Day 2 ............................... 43 
8.8.2 
Meal test procedure with missed meal bolus ............................................................. 44 
8.8.3 
Basal insulin suspension procedure (Day 2) .............................................................. 45 
8.9 
Assessments for Safety ........................................................................................................... 45 
8.9.1 
Clinical Assessments ................................................................................................. 45 
8.9.2 
Laboratory Assessments ............................................................................................ 48 
8.10 
Other Assessments and Dietary Requirements ....................................................................... 49 
8.11 
Volume of Blood Sampled during Trial ................................................................................. 50 
9 
Adverse Events ................................................................................................................................... 51 
9.1 
Definitions .............................................................................................................................. 51 
9.2 
Collection, Recording and Reporting of Adverse Events ....................................................... 53 
9.3 
Follow-up of Adverse Events ................................................................................................. 54 
9.4 
Hypoglycaemia ....................................................................................................................... 55 
9.5 
Pregnancy ............................................................................................................................... 56 
9.6 
Precautions .............................................................................................................................. 57 
9.7 
Complaint Handling ................................................................................................................ 57 
10 Risk-Benefit Assessment.................................................................................................................... 58 
11 Data Management .............................................................................................................................. 59 
11.1 
Case Report Forms (CRFs) ..................................................................................................... 59 
12 Monitoring Procedures ...................................................................................................................... 60 
13 Statistical Considerations .................................................................................................................. 61 
13.3.1 Pharmacokinetic Parameter Estimation ..................................................................... 62 
13.3.2 Glucodynamic Parameter Estimation ........................................................................ 63 
13.4.1 Analysis of the Primary Endpoints time to recovery from hyperglycaemia.............. 64 
13.4.2 Analysis of the Secondary GD Endpoints ................................................................. 65 
13.4.3 Analysis of the Secondary PK Endpoints .................................................................. 65 
13.4.4 Analysis of Safety Endpoints .................................................................................... 66 
13.4.5 Subject Disposition .................................................................................................... 66 
13.4.6 Other Measurements and Criteria .............................................................................. 66 
14
Independent Ethics Committee and Competent Authority............................................................67
14.1 
Independent Ethics Committee ............................................................................................... 67 
14.2 
Informed Consent Process for Subjects .................................................................................. 67 
14.3 
Competent Authority .............................................................................................................. 68 
14.4 
Premature Termination of the Trial ........................................................................................ 68 
15 Administrative Matters ..................................................................................................................... 70 
15.1 
Deviations from the Protocol .................................................................................................. 70 


 
 
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15.2 
Essential Documents ............................................................................................................... 70 
15.3
Responsibilities.......................................................................................................................70
15.4 
Reports and Publications ........................................................................................................ 71 
15.5 
Audits and Inspections ............................................................................................................ 71 
15.6 
Retention of Clinical Trial Documentation ............................................................................. 71 
References .................................................................................................................................................. 73 
APPENDIX I - Amendments .................................................................................................................... 74 
 


 
 
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LIST OF ABBREVIATIONS  
ADA  
American Diabetes Association 
AE 
 
Adverse event 
ALT 
 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
APTT  
Activated partial thromboplastin time 
AST 
 
Aspartate aminotransferase 
AUCins  
Area under the serum insulin concentration time curve 
B 
 
Bolus administration 
BMI 
 
Body mass index 
CFBL  
Change from baseline 
CI 
 
Confidence interval 
Cmax 
 
Maximum serum insulin concentration 
CRF 
 
Case report form 
CSII 
 
Continuous Subcutaneous Insulin Infusion 
ECG   
Electrocardiogram 
FAS 
 
Full analysis set 
FDA  
Food and Drug Administration 
FOIA  
Freedom of Information Act 
FSFV  
First subject first visit 
GCP 
 
Good clinical practice 
GD 
 
Glucodynamics 
GIR 
 
Glucose infusion rate 
γGT 
 
Gamma-glutamyltransferase  
HbA1C 
N-(1-deoxy)-fructosyl-haemoglobin 
HDL  
High-density lipoprotein  
HIV 
 
Human immunodeficiency virus 
IB 
 
Investigator’s Brochure 
ICH 
 
International conference on harmonisation 
IEC 
 
Independent ethics committee 
IMP 
 
Investigational medicinal product 
INR 
 
International normalised ratio  
IRB 
 
Institutional review board 
i.v. 
 
Intravenous(ly) 
LDH  
Lactic dehydrogenase 
LDL 
 
Low-density lipoprotein 
LS 
 
Least squares  
LSLV  
Last subject last visit 
mFAS  
Modified Full analysis set
NIMP  
Non-investigational medicinal product 
PAH  
Pulmonary arterial hypertension 
PD 
 
Pharmacodynamics 


 
 
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PG 
 
Plasma glucose 
PK 
 
Pharmacokinetics 
SAE 
 
Serious adverse event 
SAP 
 
Statistical analysis plan 
s.c. 
 
Subcutaneous(ly) 
SIV 
 
Site initiation visit 
SmPC  
Summary of Product Characteristics  
SOP 
 
Standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions  
T1DM  
Type 1 Diabetes Mellitus 
tmax 
 
Time to maximum observed insulin concentration  
TIF 
 
Trial investigator file 
U 
 
Units 


 
 
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1 
SYNOPSIS  
Name of Sponsor: 
Eli Lilly and Company 
Trial ID: 
I8B-MC-ITST 
Title of the trial: 
Effects of LY900014 on Recovery from Hyperglycemia Compared to Humalog in Subjects with Type 
1 Diabetes Mellitus (T1DM) on Continuous Subcutaneous Insulin Infusion 
Trial design:  
Single center, randomized, 2-treatment, subject- and investigator-blind, 2-period cross-over trial in 
subjects with T1DM.  
Clinical phase of development: 
Phase I 
Trial centre: 
Profil Mainz GmbH & Co. KG, Malakoff-Passage, Rheinstr. 4C, D-55116 Mainz, Germany 
Principal Investigator:  
 Profil Mainz GmbH & Co. KG, Malakoff-Passage, Rheinstr. 4C, D-
55116 Mainz, Germany 
Planned trial start (First Subject First Visit): 
February 2020 
Planned trial end (Last Subject Last Visit): 
June 2020 
Trial population:  
Subjects with diabetes mellitus type 1 on continuous subcutaneous insulin infusion (CSII) 
Key Objectives: 
The aim of the study is to compare the time to recovery from hyperglycemia following LY900014 
administration in comparison to Humalog® in a similar situation as when a subject experiences 
hyperglycaemia by forgetting to deliver a bolus after consuming a  meal or when there is suspension of 
insulin delivery e.g. due to a malfunction of the insulin pump. 
Primary objective:  
 
To compare the time to recovery from hyperglycaemia following a missed meal bolus with 
LY900014 vs. Humalog®, given as a correction bolus via pump infusion  
 
To compare the time to recovery from hyperglycaemia following basal insulin suspension with 
LY900014 vs. Humalog®, given as a correction bolus via syringe injection 
Secondary objectives:  
 
To compare the pharmacodynamic and insulin lispro pharmacokinetic following a correction 
bolus of LY900014 vs. Humalog® during recovery from hyperglycaemia after a missed meal 
bolus. 
 
To compare the pharmacodynamic and insulin lispro pharmacokinetic following a correction 
bolus of LY900014 vs. Humalog® during recovery from hyperglycaemia after basal insulin 
suspension. 
 
To assess the safety and tolerability of LY900014 and Humalog. 
Key Endpoints:  
Primary Endpoint(s):  
 
Time to recovery from hyperglycemia  
Secondary Endpoints: 
PG  
 
AUC(B-tPG140) 
 
AUC(B-tPG180) 
 
Rate of change in PG 
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 
PGmax 
PK 
 
tmax 
 
Early 50% tmax 
 
AUC(0-15min) 
 
AUC(0-30min) 
Safety:  
 
Adverse events 
Key inclusion and key exclusion criteria: 
Key inclusion criteria 
 
Signed and dated informed consent obtained before any trial-related activities.  
 
Male or female subjects with type 1 diabetes.  
 
Age between 18 and 64 years, both inclusive.  
 
Body Mass Index (BMI) between 18.5 and 30.0 kg/m^2, both inclusive. 
 
HbA1c <= 8.5%.  
 
Using CSII and stable insulin regimen for at least 3 months prior to inclusion into the trial. 
Key exclusion criteria 
 
Known or suspected hypersensitivity to IMP(s) or related products. 
 
Receipt of any medicinal product in clinical development within 30 days before randomization 
in this trial. 
 
Known slowing of gastric emptying and or gastrointestinal surgery that, in the opinion of the 
investigator, might change gastrointestinal motility and food absorption. 
 
Proliferative retinopathy or maculopathy as judged by the Investigator based on a recent (<1.5 
years) ophthalmologic examination.Widespread subcutaneous lipodystrophy in the abdomen. 
 
Current use of any glucose-lowering agents other than insulin within 3 months prior to 
screening. . 
 
Chronic or recent use of corticosteroids. 
Sample size: 
Up to 28 subjects are planned to be randomised so that at least 24 complete the trial 
Investigational Medical Products: 
Test product: 
Insulin lispro (LY900014), vials 100 U/mL, for subcutaneous administration (infusion via pump and 
injection via syringe). 
Reference product:
Insulin lispro (Humalog®), vials 100 U/mL, for subcutaneous administration (infusion via pump and 
injection via syringe). 
Duration of treatment:  
Subjects will receive each IMP for approximately 48 hours during two separate study visits. The IMP 
will be administered subcutaneously both via an insulin pump (continuous subcutaneous insulin 
infusion, CSII) and via a syringe injection. 
Assessments: 
The trial includes an information visit (Visit 0), a screening visit (Visit 1), two in-house study visits 
with IMP administration (Visits 2 and 3), and a follow–up visit (Visit 4). 
The information visit will take place at least 1 day prior to the screening visit in order to obtain the 
subjects informed consent. The subjects will attend the screening visit 1–28 days prior to Visit 2 to 
determine their eligibility. After screening, all eligible subjects will, in random order, undergo two in-
house study visits. Each in-house visit will comprise a 3-day stay at the trial site. The in-house visits 


 
 
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will be separated by a wash-out period of 3–14 days (between Visit 2, Day 2 and Visit 3, Day 1). Each 
subject will be randomised to a treatment sequence consisting of two treatments, i.e. LY900014 and 
Humalog®, to be administered at the two separate in-house study visits. Randomization will take place 
on Day -1 of Visit 2.  
At each of the two in-house visits, subjects will arrive at the trial site in the afternoon of Day -1. After a 
check of continued eligibility, the subjects own insulin pump will be disconnected and subjects will 
receive a study pump filled with IMP (Medtronic 640G). A new infusion set will be inserted into the 
abdominal wall. The subject’s usual basal rate settings will be programmed in the study pump and the 
basal rate infusion will be started.  
Day -1 / Day 1: recovery from hyperglycemia after missed meal bolus 
In the evening of Day -1, subjects will receive a pre-defined evening meal. The subjects will cover the 
meal with a bolus administered by the study insulin pump. Overnight, the basal insulin infusion rate 
will be running and a target fasting plasma glucose level in the range of 126 ± 20 mg/dL will be aimed 
for. A single hourly basal rate will be started from at least – 3 hours prior to meal ingestion. At approx. 
08:00 hours on Day 1, a standard liquid meal 
 will be provided. No bolus insulin 
will be administered with the aim to induce postprandial hyperglycemia (PG > 240 mg/dL). On-site 
glucose measurements 
 will be performed regularly and frequently after 
meal ingestion. As soon as a glucose measurement above the high glucose threshold (PG > 240 mg/dL) 
has been measured and the result has been confirmed by a second measurement, a correction bolus will 
be administered with the aim to bring the subject’s glucose level down to PG ≤ 140 mg/dL. Regular 
and frequent sampling for glucose on-site analysis continues and the time to reach the euglycemic 
range threshold will be documented. PK and glucose measurements will be collected until 5 hours after 
administration of the correction bolus. In case PG < 54 mg/dL, hypoglycemia rescue will be provided. 
In case PG > 306 mg/dL for more than one hour, hyperglycaemia rescue will be provided. Thereafter, 
subjects will receive a free-choice lunch and a pre-defined evening meal covered by the subject’s usual 
bolus dose. 
Day 1 / Day 2: recovery from hyperglycemia after basal insulin suspension 
After the insulin bolus given with the evening meal, no correction boli should be given 
subcutaneuously. Overnight, the basal insulin infusion rate will be running and a target fasting plasma 
glucose level in the range of 126 ± 20 mg/dL will be aimed for. The basal insulin infusion rate will be 
fixed to a single hourly rate from at least – 3 hours prior to basal insulin suspension. Basal insulin 
suspension will be performed between 8 and  10 hours after the dinner meal on Day 1. On-site glucose 
measurements 
 will be performed regularly and frequently to follow the 
rise in plasma glucose concentration above 240 mg/dL and blood samples for PK analysis will be taken 
to analyse the decline in circulating insulin levels. As soon as a glucose measurement above the high 
glucose threshold has been measured and the result has been confirmed by a second measurement a 
correction bolus will be administered via a subcutaneous injection in the periumbilical region using an 
insulin syringe. In addition, a plasma sample for ketone concentration will be taken during this time. 
Regular and frequent sampling for PK, ketone and glucose analysis continues and the time to reach a 
PG ≤ 140 mg/dL will be documented. 
After completion of basal insulin suspension procedures at Visit 3 Day 2, subjects will be switched 
back to their usual diabetes therapy and come back to the trial centre for the final examination. 
CCI
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Statistical methods: 
A sample size of up to 28 patients with T1DM will be enrolled and at least 24 subjects should complete 
this trial to achieve study objectives. The sample size is considered sufficient to evaluate a difference in 
the primary endpoint between the treatments of 32 minutes  with a power of 80%. Discontinued 
subjects may be replaced to ensure that 24 subjects complete the trial. A replacement subject will be 
assigned to the same treatment sequence as the subject being replaced. . 
Primary statistical analyses will be conducted on the set of subjects who complete the study according 
to the sequence/treatment to which they are randomized. Subjects who did not keep identical insulin 
lispro doses for LY900014 and Humalog/or had difference in the comsumption of the meal for each 
day and period will be excluded from the statistical analysis of the PK/GD parameters. Safety analyses 
will be conducted for all enrolled subjects, whether or not they complete all protocol requirements. 
Primary GD endpoint:  
Time to recovery from hyperglycemia (time of correction bolus to time when PG = 140 mg/dL, will be 
determined based on PG measurements. Exact points of intersection with PG of 140 mg/dL will be 
determined using linear interpolation. Comparisons between the treatments will be peformed per day 
using a mixed-effect model with raw endpoint as response, treatment, period and sequence as fixed 
effects and subject within sequence as a random factor. Within the model, least squares means of 
LY900014 and Humalog®, differences in least squares means and the corresponding 95% CI for the 
treatment difference will be estimated.  The p-value on the difference between least squares means will 
be used to determine statistical significance.  The treatment ratio and 95% CI for the ratio will be 
calculated using Fieller’s theorem.  
Secondary GD Endpoints: 
Secondary GD endpoints will be analysed per day using a multiplicative linear mixed model ANOVA 
with treatment, period and sequence as fixed effects and subject within sequence as a random factor. A 
multiplicative linear mixed model (log-transformed response variable) will be used for AUC endpoints 
and PGmax. Treatment ratios and corresponding 95% CIs will be determined. An additive model 
(untransformed response variable) will be used for rate of change in PG and time parameters. 
Treatment ratios and 95% CIs will be calculated by Fieller’s method. 
Secondary PK Endpoints: 
Secondary PK endpoints will be analysed per day using a linear mixed model with treatment, period 
and sequence as fixed effects and subject within sequence as a random factor. A multiplicative linear 
mixed model (log-transformed response variable) will be used for AUC endpoints. Treatment ratios 
and corresponding 95% CIs will be determined. An additive model (untransformed response variable) 
will be used for time parameters. Treatment ratios and 95% CIs will be calculated by Fieller’s method.  
Safety endpoints: 
All adverse events will be listed and summarised by descriptive statistics. All serious adverse events 
will be reported. 
 


 
 
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2 
SCHEMATIC TRIAL OVERVIEW 
2.1 
Chronological Structure of the Trial 
 
 
Figure 1 
Schematic overview of the chronological structure of the trial  
 
Informed 
Consent 
Day -1: 
admission 
 
Day 1: 
Missed meal 
bolus induced 
hyperglycemia 
 
Day 2: 
Basal insulin 
suspension 
induced 
hyperglycemia 
Day -1: 
admission 
 
Day 1: 
Missed meal 
bolus induced 
hyperglycemia 
 
Day 2: 
Basal insulin 
suspension 
induced 
hyperglycemia 
Final 
examination 
Screening
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Screening Period  
Study Period  
Follow-up 
≥ 1 day 
before V1 
1-28 days 
before V2 
3-14 days wash-out period 
between dosing visits 
3-7 days 
after V3 


 
 
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2.2 
Trial Flow Chart 
The trial flow chart is the master representation of the trial schedule. In case of (apparent) 
inconsistencies in the trial protocol the information provided here is the binding one.  
Table 1 
Trial Flow Chart 
Trial Period 
Screening Period 
Treatment Period 1 and 2 
Follow-up 
Visit no. 
0 
1 
2 and 3 
4 
 
Informed 
Consent 
Screening 
Induced hyperglycemia and 
recovery 
Final 
examination 
Timing 
≥ 1 day before 
Visit 1 
1-28 days 
prior to Visit 
2 
3-14 days between Visit 2 and 
Visit 3 
3-7 days 
after Visit 3 
Day 
 
 
Day -1 
Day 1 
Day 2 
 
In-house Visit/Period 
 
 
X 
X 
X 
 
Informed consent 
X 
X1 
 
 
 
 
Fasting 
 
X 
 
X 
X 
X 
Inclusion/exclusion criteria 
 
X 
X2 
 
 
 
Demographic data 
 
X 
 
 
 
 
Smoking 
and 
alcohol 
consumption habits 
 
X 
 
 
 
 
Concomitant illness and 
medical history 
 
X 
 
 
 
 
Weight, height, BMI 
 
X 
X3 
 
 
X3 
Alcohol breath test 
 
X 
X 
 
 
 
Physical examination 
 
X 
X 
 
X 
X 
Vital signs 
 
X 
X 
 
X 
X 
12-lead ECG 
 
X 
 
 
 
X 
Haematology  
 
X 
 
 
 
X 
Biochemistry 
 
X 
 
 
 
X 
Coagulation 
 
X 
 
 
 
 
Urinalysis 
 
X 
 
 
 
X 
Infectious serology  
 
X 
 
 
 
 
HbA1c, fasting C-peptide
 
X 
 
 
 
 
Pregnancy test (females 
only)5 
 
X 
X 
 
 
X 
Drug screen 
 
X 
 
 
 
 
Dosing 
visit 
exclusion/ 
withdrawal criteria 
 
 
X 
X6 
 
 
Randomization 
 
 
X4 
 
 
 
IMP administration 
 
 
X 
X 
X 
 
Missed meal bolus induced 
hyperglycemia 
 
 
 
X 
 
 
Basal insulin suspension 
induced hyperglycemia 
 
 
 
 
X 
 
Correction 
bolus 
(via 
pump) 
 
 
 
X 
 
 
Correction 
bolus 
(via 
syringe) 
 
 
 
 
X 
 
Blood sampling for insulin 
PK (see Tables 2 and 3) 
 
 
 
X 
X 
 


 
 
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Trial Period 
Screening Period 
Treatment Period 1 and 2 
Follow-up 
Visit no. 
0 
1 
2 and 3 
4 
 
Informed 
Consent 
Screening 
Induced hyperglycemia and 
recovery 
Final 
examination 
Timing 
≥ 1 day before 
Visit 1 
1-28 days 
prior to Visit 
2 
3-14 days between Visit 2 and 
Visit 3 
3-7 days 
after Visit 3 
Day 
 
 
Day -1 
Day 1 
Day 2 
 
In-house Visit/Period 
 
 
X 
X 
X 
 
Blood sampling for plasma 
glucose PD and safety (see 
Tables 2 and 3) 
 
 
 
X 
X 
 
Blood 
sampling 
for 
ketones 
 
 
 
 
X 
 
Adverse events 
 
X 
X 
X 
X 
X 
Concomitant medication 
 
X 
X 
X 
X 
X 
Pre-defined meals 
 
 
X 
X 
 
 
1 Check that informed consent has been signed and dated 
2 Re-check of subject eligibility on Visit 2 Day -1 only.  
3 Weight only 
4 V2 only 
5 Pregnancy test in women will be performed according to Section 8.9.2 
6 Re-check of dosing visit exclusion criteria. 


 
 
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2.3 
 Assessment Schedules 
Table 2 
Assessment Schedule for Visits 2 and 3, Days -1 and 1 
Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose1 
Other 
Day -1 
17:00 
 
Subject arrives at the trial site and 
continued eligibility will be checked 
 
X 
Dosing visit exclusion 
criteria, AEs, 
concomitant 
medication, alcohol 
breath test, vital signs, 
ECG, physical 
examination, urine 
pregnancy test, weight4  
17:30 
 
Randomization (Visit 2 only) 
Discontinue subject’s own insulin pump
if not using Medtronic 640G; insert new 
infusion set; 
Start study insulin pump with IMP 
(subject’s usual basal rate) 
 
 
 
18:00 
 
Pre-defined evening meal 
Covered by individual meal bolus 
 
 
X 
 
Day 1 
04:00 
 
START overnight stabilisation 
i.v. insulin glulisine or glucose infusion 
(if needed) 
Morning plasma glucose target (126 ± 
20 mg/dL) 
 
Sampling 
approx. 
every 30 
min. or 
more 
frequently, 
if needed 
 
 
05:00 
 
Fixed basal rate (single hourly rate) of 
CSII from at least -3 h until end of meal 
test (B + 5 h) 
 
 
07:30 
-30 min 
STOP i.v. insulin or glucose infusion (if 
any) 
Maintain PG at in the range of 126 ± 20 
mg/dL 
 
 
 
Day 1 
08:00 
0 
Standard liquid meal  
X (pre-
meal) 
X (pre-
meal) 
Dosing visit exclusion 
criteria, AEs, 
concomitant 
medication 
 
15min 
Liquid meal fully consumed 
 
X 
 
 
30min 
Plasma glucose measurement: 
every 10 minutes if PG ≤ 200 mg/dL 
and every 5 minutes if PG > 200 mg/dL 
 
 
X 
 
 
 
 
 
B2 
Confirmatory glucose measurement if 
PG > 240 mg/dL, followed by pump 
correction bolus 
X3 
X3 
 
 
B + 5min 
 
 
X 
X 
 
 
B + 10min 
X 
X 
 


 
 
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Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose1 
Other 
 
B + 15min 
 
 
 
 
 
 
 
 
As soon as PG ≤ 140 mg/dL is 
measured, a confirmatory PG is 
performed  
X 
X 
 
 
B + 20min 
X 
X 
 
 
B + 25min 
X 
X 
 
 
B + 30min 
X 
X 
 
 
B + 35min 
X 
X 
 
 
B + 40min 
X 
X 
 
 
B + 45min 
X 
X 
 
 
B + 50min 
X 
X 
 
 
B + 55min 
X 
X 
 
 
B + 1h 
X 
X 
 
 
B + 65min 
 
X 
 
 
B + 70min 
X 
X 
 
 
B + 75min 
 
X 
 
 
B + 80min 
 
X 
 
 
B + 85min 
 
X 
 
 
B + 90min 
X 
X 
 
 
B + 95min 
 
X 
 
 
B + 100min 
 
X 
 
 
B + 105min 
X 
X 
 
 
B + 110min 
 
X 
 
 
B + 115min 
 
X 
 
 
B + 2h 
If PG > 140 mg/dL, PG sampling will 
continue every 5 minutes 
 
If PG ≤ 140 mg/dL, PG sampling will 
be every 15 minutes 
X 
X 
 
 
(B + 125 min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 130min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 135min 
 
X 
X 
 
 
(B + 140min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 145min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 150min 
 
X 
X 
 
 
(B + 155min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 160min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 165min 
 
X 
X 
 
 
(B + 170min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 175min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 3h 
 
X 
X 
 
 
(B + 185min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 190min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 195min 
 
X 
X 
 
 
(B + 200min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 205min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 210min 
 
X 
X 
 
 
(B + 215min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 220min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 225min 
 
X 
X 
 
 
B + 230min 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 235min 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 4h 
 
X 
X 
 
 
(B + 245min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 250min) 
If PG > 140 mg/dL 
 
(X) 
 


 
 
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Page 
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2019-003493-13 
17 Jan 2020 
Final 2.0 
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Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose1 
Other 
 
B + 255min 
 
X 
X 
 
 
(B + 260min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 265min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 270 min 
 
X 
X 
 
 
(B + 275min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 280min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 285min 
 
X 
X 
 
 
(B + 290min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 295min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 5h 
End of experiment 
Resume of subject’s usual basal rate 
X 
X 
 
13:30 
 
Free-choice lunch meal 
Covered by individual meal bolus 
 
 
 
19:00 
 
Pre-defined evening meal 
Covered by individual meal bolus 
 
 
 
 
1 Plasma glucose will be analysed at the trial site using the 
 glucose analyser. 
2 B stands for time of bolus administration. 
3 Prior to bolus administration, two PK samples for PK insulin baseline determination will be taken.  
4 Only on Visit 2. 
 
 
 
CCI


 
 
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Table 3 
Assessment Schedule Example for Visits 2 and 3, Day 2 
Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose1 
Other2 
0:00 
 
Fixed basal rate (single hourly rate) of 
CSII from at least -3 h prior to basal 
insulin suspension 
 
 
 
02:00 
 
START overnight stabilisation 
i.v. insulin glulisine or glucose infusion 
(if needed) 
Plasma glucose target 126 ± 20 mg/dL 
 
 
Sampling 
approx. 
every 30 
min. or 
more 
frequently
, if needed 
 
 
 
-30 min 
STOP i.v. insulin or glucose infusion (if 
any) 
Maintain PG at in the range of 126 ± 20 
mg/dL 
X 
X 
 
 
-15 min 
 
X 
X 
 
04:00 to 
06:00 
0 
Basal insulin suspension 8-10 hours 
after dinner meal on Day 1:  
Stop basal insulin rate 
Morning plasma glucose target (126 ± 
20 mg/dL) 
 
X 
X 
X 
 
15 min 
Glucose measurement: 
every 15 minutes If PG ≤ 200 mg/dL 
and every 5 minutes If PG > 200 mg/dL 
 
Insulin PK measurement: every 15 min 
X 
X 
Ketones, every 30 min 
 
 
B3 
Confirmatory glucose measurement if 
PG > 240 mg/dL followed by IMP  
correction bolus with a syringe 
X4 
X 
Ketones5 
 
B + 5min 
As soon as PG ≤ 140 mg/dL is 
measured, a confirmatory PG is 
performed  
X 
X 
 
 
B + 10min 
X 
X 
 
 
B + 15min 
X 
X 
 
 
B + 20min 
X 
X 
 
 
B + 25min 
X 
X 
 
 
B + 30min 
X 
X 
Ketones 
 
B + 35min 
X 
X 
 
 
B + 40min 
X 
X 
 
 
B + 45min 
X 
X 
 
 
B + 50min 
X 
X 
 
 
B + 55min 
X 
X 
 
 
B + 1h 
X 
X 
Ketones 
 
B + 65min 
 
X 
 
 
B + 70min 
X 
X 
 
 
B + 75min 
 
X 
 
 
B + 80min 
 
X 
 
 
B + 85min 
 
X 
 
 
B + 90min 
X 
X 
Ketones 
 
B + 95min 
 
X 
 
 
B + 100min 
 
X 
 


 
 
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Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose1 
Other2 
 
B + 105min 
X 
X 
 
 
B + 110min 
 
X 
 
 
B + 115min 
 
X 
 
 
B + 2h 
If PG >180 mg/dL: Give additional 
correction bolus  
 
If PG > 140 mg/dL, PG sampling will 
continue every 5 minutes 
 
If PG ≤ 140 mg/dL, PG sampling will 
be every 15 minutes 
X 
X 
Ketones 
 
(B + 125 min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 130min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 135min 
 
X 
X 
 
 
(B + 140min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 145min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 150min 
 
X 
X 
Ketones 
 
(B + 155min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 160min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 165min 
 
X 
X 
 
 
(B + 170min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 175min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 3h 
 
X 
X 
Ketones 
 
(B + 185min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 190min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 195min 
 
X 
X 
 
 
(B + 200min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 205min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 210min 
 
X 
X 
Ketones 
 
(B + 215min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 220min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 225min 
 
X 
X 
 
 
B + 230min 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 235min 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 4h 
 
X 
X 
Ketones 
 
(B + 245min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 250min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 255min 
 
X 
X 
 
 
(B + 260min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 265min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 270 min 
 
X 
X 
Ketones 
 
(B + 275min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 280min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 285min 
 
X 
X 
 
 
(B + 290min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 295min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 5h 
End of experiment 
 
Subject resumes usual pump therapy 
with own insulin pump.  
 
Subject receives lunch 
X 
X 
Ketones 


 
 
Clinical Trial Protocol 
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Date 
Status / Version-No. 
Page 
I8B-MC-ITST 
2019-003493-13 
17 Jan 2020 
Final 2.0 
22 of 74 
 
Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose1 
Other2 
16:00 
 
Subject may leave the trial site or 
remain in unit overnight at the 
discretion of the Investigator 
 
 
AEs, concomitant 
medication, vital signs,  
physical examination, 
glucose for safety 
1 Plasma glucose will be analysed at the trial site using the 
 glucose analyser.  
2 Blood sampling for PG measurment including threshold confirmation and PK assessment have priority and blood 
samples for ketone assessment should be taken thereafter.   
3 B stands for time of bolus administration. 
4 Prior to bolus administration, two PK samples for PK insulin baseline determination will be taken.  
5 A plasma sample for ketone concentration will be taken preferrably prior to the administration of the correction 
bolus but may be taken immediately thereafter in case of too many simoultaneous activities delaying the time of 
dosing.  
 
CCI


 
 
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3 
INTRODUCTION 
There is an unmet medical need for fast prandial insulin analogs with improved pharmacokinetic 
(PK) and glucodynamic (GD) characteristics.  
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). LY900014 
aims to closely mimic the physiological prandial insulin secretion pattern, which may more 
effectively control postprandial glucose excursions and allow increased flexibility of the time of 
dosing relative to a meal. 
This trial is intended to test this new formulation of insulin lispro (LY900014) in subjects with 
type 1 diabetes mellitus (T1DM) using continuous subcutaneous insulin infusion (CSII). The aim 
of the study is to compare the onset of insulin action following LY900014 administration in 
comparison to Humalog® on controlling hyperglycaemia, in a similar situation as when a subject 
experiences hyperglycaemia by forgetting to deliver a bolus after consuming a meal or when 
there  is suspension of insulin delivery e.g. due to a malfunction of the insulin pump. 
3.1 
Background Information on Investigational Medicinal Products (IMPs) 
3.1.1 
Insulin lispro 
The insulin analog insulin lispro (Humalog®) has been shown to be absorbed more quickly than 
regular human insulin (Humalog® package insert, 2015). 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/GD of insulin analogs 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. 
3.1.2 
Insulin LY900014  
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 arterial 
hypertension (PAH) and has been approved in the US since 2002 and in Germany since 2006 
(AMIS database [WWW]). Sodium citrate, an excipient that speeds insulin absorption (at least in 
part by enhancing vascular permeability), is also included in the formulation to further enhance 
the absorption of insulin lispro. Each of the other excipients (such as magnesium chloride) in the 
LY900014 formulation is listed in the US Food and Drug Administration (FDA)’s Generally 
CCI
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Recognized as Safe Food Additives database and in the FDA’s Inactive Ingredients in Approved 
Drugs database.  
LY900014 has been evaluated in 19 completed Phase 1 studies and three Phase 3 clinical studies. 
Seven clinical pharmacology studies were conducted using a developmental formulation of 
LY900014 and 12 studies were conducted using the final formulation of LY900014. These 
included studies in 304 healthy subjects, 295 subjects with T1DM, and 103 subjects with T2DM 
administered at least 1 dose of LY900014. Two clinical pharmacology studies were conducted 
using CSII therapy in 54 subjects with T1D. In addition, a total of 1165 subjects with T1DM or 
T2DM received LY900014 in the Phase 3 studies. 
Potential risks associated with LY900014, derived from the known risks of insulin lispro 
(Humalog®), are hypoglycaemia, hypersensitivity reactions (localized allergy and/or systemic 
allergy), undesirable effects at the injection site (injection-site reactions and lipodystrophy), and 
peripheral edema (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
 package 
insert (2014). The exposures of treprostinil in LY900014 in this study are expected to be 
undetectable compared to those observed in the dose ranges previously explored with SC bolus 
administration of treprostinil and are expected to be substantially lower than those observed in 
the treatment of PAH. No known potential risks are associated with the microdose amount 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
 do not suggest the potential for additive or synergistic toxicity. 
3.2 
Rationale for the Trial 
Patients with T1DM sometimes experience hyperglycaemic events, despite good glycaemic 
control,  requiring immediate correction. An insulin analogue with a faster onset of action might 
benefit these patients by providing a faster transition to normoglycaemia.  
The experimental setup of this study will simulate a situation in which a subject has to correct 
hyperglycaemia after a meal where prandial bolus was missed. Similarly, the study design will 
also simulate a situation in which subjects experience malfunction of the pump with suspension 
of insulin delivery and has to correct subsequent hyperglycaemia using an injected bolus of 
insulin.  
CCI
CCI
CCI
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4 
OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
This trial investigates the pharmacodynamic and pharmacokinetic responses of LY900014 and 
Humalog® (insulin lispro) in subjects with diabetes mellitus type 1 during the following 
situations: 
4.1.1 
Primary objective: 
 
To compare the time to recovery from hyperglycaemia following a missed meal bolus with 
LY900014 vs. Humalog®, given as a correction bolus via pump infusion 
 
To compare the time to recovery from hyperglycaemia following basal insulin suspension 
with LY900014 vs. Humalog®, given as a correction bolus via syringe injection 
4.1.2 
Secondary objectives: 
 To compare the pharmacodynamic and insulin lispro pharmacokinetic following a correction 
bolus of LY900014 vs. Humalog® during recovery from hyperglycaemia following a missed 
meal bolus. 

To compare the pharmacodynamic and insulin lispro pharmacokinetic following a correction 
bolus of  LY900014 vs. Humalog® during recovery from hyperglycaemia after basal insulin 
suspension. 
 To assess the safety and tolerability of LY900014 and Humalog. 
 
4.1.3 
Exploratory objectives:  
 To assess the blood glucose response after basal insulin suspension for LY900014 vs. 
Humalog®. 
4.2 
Endpoints 
4.2.1 
Primary endpoints:  
 
Time to recovery from hyperglycemia (time of correction bolus to time when PG = 140 
mg/dL) 
4.2.2 
Secondary endpoints:  
PD endpoints: 
 
AUC(B-tPG140), area under the PG curve but above 140 mg/dL from time of correction bolus 
(B) to time when PG is 140 mg/dL) 
 
AUC(B-tPG180), area under the PG curve but above 180 mg/dL from time of correction bolus 
(B) to time when PG is 180 mg/dL) 
 
Rate of change in PG (the change in PG at the time of bolus IMP administration to PG = 140 
mg/dL measurement divided by the duration of time for this interval) 
 
PGmax, maximum observed plasma glucose 


 
 
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PK endpoint: 
 
tmax, time to maximum observed insulin concentration. 
 
Early 50% tmax, time to half-maximum before Cmax.  
 
AUC(0-15min), are under the insulin curve from 0 to 15 minutes. 
 
AUC(0-30min), are under the insulin curve from 0 to 30 minutes. 
4.2.3 
Exploratory endpoints:  
 
Time to hyperglycaemia (PG > 240 mg/dL) after basal insulin suspension 
 
Peak ketone concentration after basal insulin suspension 
4.2.4 
Safety endpoints: 
 Adverse Events 
 
Further endpoints are defined in Section 13 and may be defined in the Statistical analysis plan 
(SAP).  
 


 
 
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5 
TRIAL DESIGN 
5.1 
Type of Trial 
Single center, randomized, two-treatment, subject- and investigator-blinded, 2-period cross-over 
trial in subjects with T1DM.  
A schematic trial overview is given in Section 2, Figure 1. 
5.2 
Randomization  
This is a randomized trial. Assignment to one of two treatment sequences (LY900014 followed by 
Humalog® or Humalog® followed by LY900014) will take place at the trial site.  
The randomization list will be provided by Profil. A subject will only be randomized if he/she 
complies with all inclusion/exclusion and dosing visit exclusion criteria. Randomization should 
occur as close as possible to the first administration of IMP. When a subject is randomized in the 
trial, he/she must always be assigned to the lowest available randomization number available 
from the randomization list. Up to 28 subjects will be randomized to ensure that at least 24 can 
be evaluated.  
Randomization numbers will be as follows: 
 Randomization numbers starting with 101, 102, 103…  
 Corresponding randomization numbers for replacements: 201, 202, 203… 
Replacement subjects must always be assigned to the same sequence as the subject they replace 
(please see Section 6.6). 
5.3 
Blinding and Code Breaking Procedures 
This is a subject- and investigator-blind randomized trial. The CRU personnel who will prepare 
the pump reservoirs for each treatment period and the syringe for correction bolus administration 
on Day 2 and administer the drug (only on Day 2, Day 1 administration can be done by blinded 
personnel) will not be blinded and will be separate and distinct from those who are involved in 
subject 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. 
Treatment assignment will be kept strictly confidential and accessible only to authorized persons 
until after the time of un-blinding. Codes with treatment assignment will, however, be readily 
available to the blinded personnel in case of an emergency. 


 
 
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Two sets of sealed codes with the subject randomization number containing information about 
the treatment at each visit will be prepared for each subject. One set will be kept at the trial site 
in the office of the physician on duty (during the entire trial period), the other set will be kept 
under the responsibility of the Sponsor and are to be used in case of code break need.  
The code for a particular subject may be broken by an investigator in case of a medical 
emergency if knowing the identity of the treatment allocation could influence the treatment of 
the subject. Whenever a code is broken, the person breaking the code must record the time, date 
and reason as well as his/her initials in the source documents and on the code envelope. The 
breaking of blinded codes in case of medical emergency for one subject should not unblind the 
trial personnel to the treatment information of other subjects. The person performing the 
unblinding should inform as few people as possible about the result of the unblinding. All 
persons unblinded for a specific subject should be documented. 
If the trial site needs to break the code, the Sponsor should, if possible, be contacted prior to 
breaking the code. In all cases, the monitor must be notified within 24 hours after the code has 
been broken. 
All codes (whether broken or not) must be kept throughout the trial period. The codes kept at the 
trial site will be checked by the monitor and the close-out visit report should confirm adequate 
documentation of any code breaks (if applicable).  
5.4 
Investigational Treatment of Subjects  
Each subject will be randomly allocated to a sequence of the 2 treament periods with 
administration of LY900014 and Humalog®, respectively. During the Treatment Periods, study 
drug will be administered with a Medtronic MiniMed 640G pump and with an insulin syringe.   
A standardized infusion set (catheter with standard cannula length and tubing) will be inserted 
into the abdominal wall on Day –1 of each treatment period, which should stay at the same 
catheter insertion-site location for the complete duration of the experiments during the treatment 
period. In case of a pump occlusion alarm prior to the experimental procedures on Day 1 and 
Day 2 (i.e. after catheter insertion on Day -1 or during the night of Day 2), the infusion set 
including the catheter can be changed until 3:00 of Day 1 and Day 2. If a catheter needs to be 
changed due to a pump malfunction or occlusion alarm during the experimental procedures, the 
subject may repeat the respective study day once only if the maximum blood loss over the entire 
study (that is, the blood loss during the past study days/period and the expected blood loss of 
upcoming study days/period) will not exceed approximately 500 mL.  
Subjects will continue their individual CSII basal rate using the insulin pump during the 
experiments/treatment periods. However, during the meal test procedure on Day 1 and the basal 
insulin suspension procedure on Day 2, the basal rate will be changed to a single hourly rate 
based on the subject’s mean basal needs from at least 3 hours before the start of meal ingestion 
(Day 1) or basal insulin suspension (Day 2). On Day 1, the basal rate will remain as a single hour 


 
 
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rate 5 hours after bolus administration. On Day 2, the basal rate will be suspended until 5 hours 
after the correction bolus administration. After termination of the respective experimental 
procedure on trial Days 1 and 2, the basal rate will be changed back to the subjects individual 
basal rate.  
A bolus dose of insulin lispro (LY900014 or Humalog®) will be individualized per subject to 
correct hyperglycaemia induced by the carbohydrate content of the liquid meal on Day 1 and to 
correct hyperglycaemia due to suspension of insulin delivery by the pump. The bolus will be 
administered by means of the pump on Day 1 using a rapid single wave bolus (administration 
speed = 15 U/min). and by means of an insulin syringe on Day 2. The individualized bolus dose 
on Day 1 will be a joint decision of the subject and the investigator based on the subjects usual 
prandial needs to cover the nutritional content of the liquid meal. The correction bolus dose on 
Day 2 will be 0.2 U/kg body weight. Bolus doses will be administered when glycaemia level is 
240 mg/dL or above and confirmed by a second 
 measurement. 
The correction bolus doses of LY900014 and Humalog on the experimental days should in 
general be identical between treatment periods. However, the bolus dose of an experimental day 
can be subjected to changes when more information is gathered during the execution of the 
study, for example in case the initially planned boli are not sufficient to control hyperglycaemia 
or when the boli induce hypoglycaemia in a great proportion of subjects. 
5.5 
Duration  
Planned date for First subject first visit (FSFV): February 2020 
Planned date for Last subject last visit (LSLV): June 2020 
FSFV is defined as the first informed consent obtained in this trial. 
LSLV is defined as the last scheduled trial visit as detailed in Section 2.1. 
The end of the clinical trial is defined as LSLV. 
Actual time-lines may vary. 
The total trial duration for a subject will be about 2 to 9 weeks. 
5.6 
Stopping Rules 
No specific stopping rules in addition to Sections 6.5 and 14.4 are applicable for this trial. 
CCI


 
 
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5.7 
Rationale for the Trial Design and Treatment 
A crossover design is chosen in order to reduce variability as each subject acts as its own control. 
The total number of subjects needed with a crossover design is decreased as compared to a 
parallel group design.  
Randomization and blinding is used in order to avoid bias introduced through an association 
between allocation order of IMP and subject characteristics. 
Bolus doses administered during the meal test and basal insulin suspension procedure will be 
individualized based on individual requirements, to ensure robust and comparable PD responses 
after hyperglycemia induction and safety of the subjects. The bolus dose for the meal test will be 
based on the individual postprandial bolus of the subjects, which is believed to be sufficient to 
control hyperglycemia induced by the meal. In the case of the basal insulin suspension 
procedure, the bolus dose is based on literature, in which a large bolus dose is needed to 
overcome possible insulin resistance (1, 2). To enable an evaluation of the  insulin lispro PK and 
PD responses, the individual doses will be kept identical within each subject during both 
treatment periods (LY900014 and Humalog), and conditions during the experimental days will 
be standardized regarding meal composition, CSII basal rate and fasting conditions. 
A minimum 3-day resting period between the 2 dosing visits (Visits 2 and 3) is introduced to 
ensure a sufficient wash-out period from previous dosing to avoid any carry-over effect. 
 


 
 
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6 
TRIAL POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
6.1 
Number of Subjects to be Studied 
Planned number of subjects to be randomized: Up to 28 subjects to ensure 24 evaluable subjects 
Expected number of subjects to complete the trial: 24 
6.2 
Inclusion Criteria 
1. Signed and dated informed consent obtained before any trial-related activities. Trial-related 
activities are any procedures that would not have been done during normal management of 
the subject. 
2. Male or female subject with diabetes mellitus type 1.  
3. Age between 18 and 64 years, both inclusive.  
4. Body Mass Index (BMI) between 18.5 and 30.0 kg/m^2, both inclusive. 
5. HbA1c <= 8.5%.  
6. Fasting negative C-peptide (<= 0.30 nmol/L). 
7. Total insulin dose of < 1.2 (I)U/kg/day. 
8. Diabetes duration of at least 12 months. 
9. Using CSII and a stable insulin regimen for at least 3 months prior to inclusion into the trial. 
10. Willingness to comply with study procedures including consumption of the test meal. 
11. Considered generally healthy (apart from diabetes mellitus type 1) upon completion of 
medical history and screening safety assessments, as judged by the Investigator. 
12. Have venous access sufficient to allow cannulation for blood sampling as required by the 
protocol. 
6.3 
Exclusion Criteria 
1. Known or suspected hypersensitivity to insulin lispro or any of the excipients or to any 
component of the IMP formulation. 
2. Previous participation in this trial. Participation is defined as randomized. 
3. Receipt of any medicinal product in clinical development within 30 days or at least 5 half-
lives of the related substances and their metabolites (whichever is longer) before 
randomization in this trial. 


 
 
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4. 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. 
5. History of multiple and/or severe allergies to drugs or foods or a history of severe 
anaphylactic reaction. 
6. Any history or presence of cancer except non-metastatic basal cell skin cancer or squamous 
cell skin cancer as judged by the Investigator. 
7. Any history or presence of clinically relevant comorbidity (with the exception of conditions 
associated with diabetes mellitus), as judged by the investigator 
8. Signs of acute illness as judged by the Investigator.  
9. Any serious systemic infectious disease during four weeks prior to first dosing of the trial 
drug, as judged by the Investigator. 
10. Known slowing of gastric emptying and or gastrointestinal surgery that, in the opinion of the 
investigator, might change gastrointestinal motility and food absorption. 
11. Clinically significant abnormal values for haematology, biochemistry, coagulation, or 
urinalysis as judged by the Investigator. 
12. Systolic blood pressure < 100 mmHg or >139 mmHg and/or diastolic blood pressure < 60 
mmHg or > 89 mmHg (one repeat test will be acceptable in case of suspected white-coat 
hypertension).  
13. Heart rate at rest outside the range of 50-90 beats per minute. 
14. Clinically significant abnormal standard 12-lead electrocardiogram (ECG) after 5 minutes 
resting in supine position at screening. 
15. Widespread subcutaneous lipodystrophy in the abdomen. 
16. Proliferative retinopathy or maculopathy as judged by the Investigator based on a recent 
(<1.5 years) ophthalmologic examination. 
17. Severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator.  
18. More than one episode of severe hypoglycaemia with seizure, coma or requiring assistance 
of another person during the past 6 months.  
19. Hospitalisation for diabetic ketoacidosis during the previous 6 months. 
20. Current use of any glucose-lowering agents other than insulin within 3 months prior to 
screening.  
21. Significant history of alcoholism or drug abuse as judged by the Investigator or consuming 
more than 24 grams alcohol/day (for males), 12 grams alcohol/day (for females) on average. 
22. A positive result in the alcohol and/or urine drug screen at the screening visit.  
23. Smoking more than 5 cigarettes or the equivalent per day.  


 
 
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24. Inability or unwillingness to refrain from smoking and use of nicotine substitute products one 
day before and during the inpatient period. 
25. Tested positive for Hepatitis Bs antigen.  
26. Tested positive for hepatitis C antibodies. (Presence of hepatitis C antibodies will not lead to 
exclusion if liver function tests are normal and a hepatitis C polymerase chain reaction is 
negative). 
27. Positive result to the test for HIV-1/2 antibodies or HIV-1 antigen.  
28. Any (prescription and non-prescription) medication within 14 days before first IMP 
administration, other than acceptable concomitant medication as judged by the investigator. 
29. Receiving chronic (lasting longer than 14 consecutive days), systemic, or inhaled 
glucocorticoid therapy (excluding topical, intra-articular, and intraocular preparations); or 
have received such therapy within the 4 weeks before screening . 
30. Blood donation or blood loss of more than 500 mL within the last month. 
31. Mental incapacity, unwillingness or language barriers precluding adequate understanding or 
co-operation. 
32. If female, pregnancy or breast-feeding 
33. Women of childbearing potential who are not using a highly effective contraceptive method 
34. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study. 
Explanatory note on Exclusion Criterion 33: A woman is considered of childbearing 
potential  following menarche and until becoming post-menopausal unless permanently 
sterile due to hysterectomy, or bilateral salpingectomy, or bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  
Explanatory note on Exclusion Criterion 33: Highly effective contraceptive methods are 
methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly. Such methods include: 
 combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, transdermal) 
 progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 intrauterine device (IUD) 
 intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion 
 vasectomized partner, provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of 
the surgical success (absence of sperm). 


 
 
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 sexual abstinence, defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and 
the preferred and usual lifestyle of the subject. 
6.4 
Dosing Visit Exclusion Criteria 
Subjects who fulfil one or more dosing visit exclusion criteria (see below) before start of the 
meal test procedure (on Day-1 of treatment period 1 or 2, respectively) will be excluded from the 
trial day. The trial day (and subsequently treatment period) may be rescheduled 1-14 days later. 
Each of the treatment periods can only be rescheduled once. A treatment period may not be re-
scheduled once the first meal test has begun. 
1. Consumption of alcohol within 24 hours prior to each treatment period, or a positive result of 
the breath alcohol test.Consumption of coffee, tea, chocolate, cola, energy drinks and/or 
energy drinks containing methylxanthine within 8 hours to each treatment period.  
2. Strenuous exercise within the last 48 hours prior to each treatment period.  
3. Any medical condition or AE that could interfere with glucose metabolism, as judged by the 
Investigator. 
4. Any use of prescription or non-prescription medication according to exclusion criterion no. 
20, 28 or 29. 
5. Fasting for less than 10 hours before start of meal test procedure on Day 1. 
6. Hypoglycaemia (plasma glucose <70 mg/dL) posing a safety problem (as judged by the 
Investigator) within 24 hours prior to first meal test of each treatment period. 
7. Injection of a bolus of more than 6 U of a fast-acting insulin analog between 7 and 12 hours 
before dosing. 
6.5 
Discontinuation Criteria 
A subject has the right to withdraw from the trial at any time for any reason. A subject’s trial 
participation will also be discontinued for the following reasons: 
1. At the discretion of the Investigator if judged non-compliant with trial procedures. 
2. At the discretion of the Investigator due to safety concerns. 
3. Due to a protocol violation, which, in the clinical judgement of the Investigator or after 
discussion with the Sponsor, may invalidate the trial by interfering with the PK and PD 
response of IMP. 


 
 
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4. Due to a concurrent illness, which, in the clinical judgement of the Investigator or after 
discussion with the Sponsor, may invalidate the trial by interfering with the PK and PD 
response of IMP. 
5. Adverse event (AE): Subject reports symptoms, which are considered unacceptable by the 
Investigator.  
6. If a subject experiences severe hypoglycaemia (according to Section 9.4) at any time during 
the study 
7. Pregnancy or intention to become pregnant. 
8. Enrollment in any other clinical study involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study. 
9. Participation in the study needs to be stopped for regulatory or other reasons consistent with 
applicable laws, regulations, and good clinical practice (GCP). 
In case of discontinuation following dosing with one of the IMPs the subject will, if possible, be 
called in for a complete follow-up visit. The date and reason of discontinuation will be entered 
into the CRF.  Four categories of discontinuation are distinguished:   
a) Withdrawal by subject. The reason stated by the subject for discontinuation should be stated 
b) Protocol-specific discontinuation criterion is met (from list above) 
c) Lost to follow-up: cessation of participation without notice or action by the subject 
d) Trial terminated by Sponsor 
e) Death 
f) Other 
The end of trial form will be completed for all prematurely discontinued subjects.  
6.5.1 
Hepatic Criteria for Discontinuation 
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets 1 of the following conditions after consultation with the 
Lilly designated medical monitor: 
 ALT (alanine aminotransferase ) AST (aspartate aminotransferase) >8X ULN (upper 
limit of normal) 
 ALT or AST >5X ULN  sustained for more than 2 weeks or 
 ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or INR >1.5 or 


 
 
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 ALT or AST >3X ULN the appearance of fatigue, nausea, vomiting, right upper-quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 ALP (alkaline phosphatase) >3X ULN 
 ALP>2.5X ULN and TBL >2X ULN 
 ALP>2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%). 
6.6 
Subject Replacement 
A total of 24 subjects should complete the trial according to the sample size calculation (see 
Section 13.1). To account for discontinued subjects (defined as subjects concluding participation, 
prior to completion of all protocol-required elements after enrollment/randomisation), up to 28 
subjects will be randomised. In case of more than 4 discontinued subjects, four additional 
replacement subjects may be enrolled (maximum total number of enrolled subjects will not 
exceed 32 subjects). A replacement subject will be assigned to the same treatment sequence as 
the subject being replaced.  
6.7 
Rationale for Trial Population 
The planned population for the trial will be subjects with type 1 diabetes which are an important 
target population for treatment with LY900014. Restricting the population to subjects on CSII 
will facilitate study procedures, as it will enable switching to the study treatment with a 
minimised risk for subjects safety.  
The inclusion and exclusion criteria will limit the trial population to subjects being in good 
health, which should help minimize safety risks for the subjects and which should also reduce 
variability of pharmacokinetic and pharmacodynamic response. However, the results from this 
trial are still considered to be generally applicable to all patients with type 1 diabetes using CSII 
treatment.  


 
 
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7 
TRIAL MATERIALS 
7.1 
Investigational Medicinal Products (IMPs) 
The IMPs listed in Table 4 will be used in this trial:  
Table 4: Specification of Investigational medicinal products (IMPs) used in the trial 
IMPs 
Strength 
Pharmaceutical 
dosage form 
Dose per 
administration 
Route of 
administration 
LY900014 
 
100 U/mL 
Solution for 
injection filled 
in 3.0 mL pump 
reservoir/10mL 
vial 
Basal and bolus 
infusion based 
on individual 
needs 
subcutaneous 
infusion via 
CSII/injection 
via syringe 
Humalog®  
(insulin lispro) 
100 U/mL 
Solution for 
injection filled 
in 3.0 mL pump 
reservoir/10mL 
vial 
Basal and bolus 
infusion based 
on individual 
needs 
subcutaneous 
infusion via 
CSII/injection 
via syringe 
 
Manufacturer of LY900014 is Eli Lilly and Company and will be provided by Eli Lilly. 
Manufacturer of Humalog® is Eli Lilly and Company and will be provided by Eli Lilly. 
IMPs will be administered subcutaneously in the abdomen by use of:  
 
 an insulin pump (Medtronic MiniMed 640G) and Quick Set® (Medtronic, Meerbusch, 
Germany) infusion sets. 
 an insulin syringe  
For further information please refer to the Investigators Brochure (IB) of LY900014 and to the 
Summary of Product Characteristics (SmPC) of Humalog®.  
7.2 
Packaging and Labelling of Investigational Medicinal Product 
Labelling of the IMPs will be in accordance with local regulations, trial requirements and 
Annex 13 (3). 
Enough investigational medicinal products will be packed for the scheduled number of subjects. 
A buffer volume of IMPs will be provided in case of replacement of discontinued subjects or 
damaged IMPs. 


 
 
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7.2.1 
Storage and Drug Accountability of Investigational Medicinal Product 
All IMPs will be stored and handled in accordance with the manufacturer instructions and/ or the 
product labelling at the Investigator’s site, e.g. for storage refrigerated (+2ºC to +8ºC) and 
should not be exposed to excessive heat, direct sunlight and never be frozen. 
All used, partly used and unused IMP/packaging must be kept by the Investigator and stored 
between +2ºC and +8ºC/at room temperature. Used and unused vials must be stored separately.  
The Investigator must ensure the availability of proper storage conditions and record and 
evaluate the temperature. Temperature of the refrigerator used for drug storage is monitored 
continuously, an alarm system is established. The Investigator must inform the monitor 
immediately if any IMP has been stored outside specified conditions (e.g. outside temperature 
storage). IMP that has been stored improperly must not be dispensed to any subject before it has 
been re-evaluated and approved for further use. The Investigator must take appropriate action to 
ensure correct storage.  
For the IMP, the Investigator must keep an accurate record of all IMPs received and the products 
used for each subject in a Drug Accountability Record. Storage locations, batch numbers and 
expiry dates are also documented in this form. 
The drug accountability has to be performed in a timely manner. 
7.2.2 
Dispensing and Return of Investigational Medicinal Products 
No IMPs may be dispensed to any person not enrolled in the trial. 
Upon completion of the trial, the Sponsor will be responsible for destruction or storage of IMPs 
(used, partially used or unused). These duties can be delegated to the site and must be 
documented in the trial investigator file (TIF). 
7.3 
Retention Samples  
No retention samples will be stored for this trial. 
7.4 
Preparation and Application of IMP 
IMP administration will be in accordance with the randomization list provided by Profil. 
An unblinded pharmacist at the site will fill the pump reservoirs and prepare the syringes for 
injection and attribute them to the respective subjects as per randomization schedule.  
Non-investigational medicinal product (NIMP) used in this trial will be sourced from the 
German market and used from its original packaging.  


 
 
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8 
VISITS AND ASSESSMENTS 
8.1 
Visit Procedures 
Please refer to the information given in Section 2 for a general overview of the trial visits and the 
visit assessments and procedures. The following sections describe details of the visit assessments 
and procedures. 
The Investigator must keep a subject screening and identification log.  
8.2 
Visit 0 – Informed Consent Visit  
Prior to any trial-related activities, potential subjects will be provided with oral and written 
information about the trial course, the employed investigational products and the visit 
procedures. The subjects will be fully informed of their responsibilities and their rights while 
participating in the trial as well as of the possible risks and potential benefits of participation in 
the trial. They have the opportunity to discuss all open questions and will have ample time to 
consider participation. Subjects who wish to participate in the trial will be asked to personally 
date and sign an informed consent form prior to any trial-related activities. Trial-related activities 
are any procedures that would not have been performed during normal management of the 
subject (including e.g. fasting for screening). Likewise, the Investigator must also personally 
date and sign the informed consent form prior to any trial related activities. All subjects will be 
provided with a copy of their own signed and dated informed consent form. 
8.3 
Visit 1 – Screening Visit 
A rescheduling of the screening visit (within 17 days) is allowed once in case subjects have 
failed to be fasting. 
Subjects will receive a screening number in ascending order starting with 001. 
Subjects are screening failures if they are excluded from further trial participation after the 
screening visit before randomization.  
Possible reasons for screening failure are failure to comply with all inclusion and exclusion 
criteria or withdrawal of eligible subjects after the screening visit by decision of the subject or 
the investigator. 
Screened subjects who do not meet or comply with all inclusion and exclusion criteria are 
excluded (screening failures), and their data will be recorded on a screening failure form. The 
reason for exclusion must be recorded on the screening failure form. Detailed information about 
which data will be entered into the trial database will be described in the trial specific data 
management plan. 
Re-screening of screening failures is generally not allowed according to Profil’s Standard 
operating procedures (SOPs). Re-assessment of laboratory parameters will be allowed once if 


 
 
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handling issues, damaged samples, or haemolysed samples may have confounded the 
measurement results. 
Eligible or potentially eligible subjects (lab results pending) will be provided with a Subject 
Identification Card (ID card), stating that the subject is participating in the trial and whom to 
contact (site address, Investigator name and telephone number). The subjects should be 
instructed to return the ID card to the Investigator at the last visit or to destroy the card after the 
last visit. 
The subjects are reminded of their next visit to the trial site and are instructed to comply with the 
dosing visit criteria (Section 6.4) for this visit. 
Before leaving the clinic, subjects are offered to consume a breakfast at the site. 
8.4 
Visit 2 and 3 – Dosing Visits 
Please refer to the assessment schedule in Section 2.3 for the procedures and timing of 
assessments at the dosing visits. Please refer to the later sections in this chapter for a description 
of the assessments. 
Results from the screening visit must be available at Visit 2 Day -1 and assessed to be acceptable 
by the Investigator. These results must be verified by the signing and dating of test results by the 
Investigator. The Investigator should document if out of range results are clinically significant.  
At Visit 2 Day -1, subjects that comply with all the criteria for continuation in the trial (see 
Section 6.4 and 6.5) will be randomized (see Section 5.2) and continue with the visit procedures. 
Randomization should occur as close as possible to the first administration of IMP.  
Day -1 to Day 1 – Missed meal bolus procedure 
Subjects will attend the trial site in the afternoon of Day -1 at approximately 17:00.  
Subjects’ infusion set and reservoir of the insulin pump will be changed at the trial site and filled 
with either LY900014 or Humalog® according to the randomization list. Subjects who are not 
using a Medtronic 640G insulin pump will be provided with a Medtronic 640G insulin pump and 
will be trained in its use. Users of this pump may use their own pump for the experimental 
procedures. The pump will be used for IMP administration during the respective treatment 
periods. Except where otherwise noted, subjects will continue their individual basal rate and 
bolus regimen unless safety issues arise.   
After catheter insertion a priming bolus of 1 U will be infused via CSII to ensure correct 
functioning of the pump.  
Subjects will be served a pre-defined evening meal and will cover the meal with a bolus dose of 
the IMP according to his/her individual insulin needs. 
Overnight, the basal insulin infusion rate will be maintained and a target fasting plasma glucose 
level in the range of 126 ± 20 mg/dL will be aimed for (see Section 8.8.1). In case of a pump 


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malfunction or infusion set occlusion overnight an additional infusion set change may be 
performed until 3:00 in the morning of Day 1. 
In the morning of Day 1, a single hourly basal rate will be started from at least – 3 hours prior to 
meal ingestion. From approx. 08:00 , subject will undergo a meal test procedure with missed 
meal bolus to induce hyperglycaemia which will be followed by the administration of a 
correction bolus via the pump as described in Section 8.8.1. 
 
 
 Before the start of the meal test procedure on Day 1, the dosing visit 
exclusion criteria (see Section 6.4) will be re-checked.  
Blood samples for pharmacokinetic and pharmacodynamic assessments will be taken as detailed 
in Section 2.3. After the last blood sample has been taken and all meal test related procedures 
have been completed, the patient will be served a free-choice lunch meal as detailed in 
Section 8.10.  
Day 1 to Day 2 – Basal insulin suspension procedure 
In the evening of Day 1, subjects will be served a pre-defined evening meal and will cover the 
meal with a bolus dose of the IMP according to his/her individual insulin needs. After 
administration of this bolus dose no additional correction bolus should be administered 
subcutaneously.  
Overnight, the basal insulin infusion rate will be fixed to a single hourly rate from at least – 3 
hours prior to basal insulin suspension and a target fasting plasma glucose level in the range of 
126 ± 20 mg/dL will be aimed for (see Section 8.8.1). In case of a pump malfunction or infusion 
set occlusion overnight an additional infusion set change may be performed until 3:00 in the 
morning of Day 2.  
During the night of Day 2, subjects will have their basal insulin rate suspended to induce 
hyperglycaemia followed by the administration of a correction bolus via syringe as described in 
Section 8.8.3. 
Blood samples for pharmacokinetic and pharmacodynamic assessments as well as for blood 
ketones will be taken as detailed in Section 2.3.  
After completion of the basal insulin suspension procedure, the subject will be switched back to 
his/her usual CSII therapy and will be served a free-choice meal.  
To ensure subjects safety and safe recovery from induced hyperglycaemia, the subject should 
stay at the trial site until his/her plasma glucose value have normalized, if deemed necessary by 
the Investigator.  
However, at the discretion of the Investigator or per request by the subject, the subject may stay 
at the trial site for a longer period.  
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Before leaving the trial site, the subject must be informed about the symptoms of hypoglycaemia 
and about appropriate methods to treat hypoglycaemia. The appointment for the final 
examination will be confirmed with the subject. 
8.5 
Visit 4 – Follow-up Visit 
A rescheduling of the follow-up visit (within 17 days) is allowed once in case subjects have 
failed to be fasting. If the subject has failed to be fasting at the rescheduled follow-up visit, the 
visit will be conducted in any case. 
8.6 
Assessment of Treatment Compliance 
Trained members of staff will perform all administrations of the IMP during the meal test 
procedure on Day 1 and the pump interruption procedure on Day 2 at the trial site. The 
administered doses will be recorded in the Drug Accountability Form / CRF. 
Pharmacokinetic assessments will support the surveillance of compliance with IMP 
administration. 
8.7 
Assessments for Pharmacokinetics  
Blood samples for pharmacokinetic assessment of the IMP will be taken at specified time points, 
see Section 2.3. 
A description of the sample handling and sample processing at the site will be included in the 
laboratory manual. 
IMP concentrations will be measured by the special laboratory (see Names and Addresses for 
contact details). Validation documentation for the pharmacokinetic analysis must be available 
prior to sample analysis. Furthermore, a Bioanalytical Report will be prepared. 
On Day 1 of each treatment period, the pharmacokinetic response following administration of 
the IMP as a correction bolus  given by the insulin pump to treat hyperglycemia induced by 
ingestion of a meal will be assessed as described in Section 8.4. 
On Day 2 of each treatment period, the pharmacokinetic response following administration of 
the IMP as a correction bolus given by a syringe to treat hyperglycemia after suspension of basal 
insulin delivery by the insulin pump will be assessed as described in Section 8.4. 
8.8 
Assessments for Pharmacodynamics 
On Day 1 of each treatment period, hyperglycaemia will be induced by ingestion of a liquid meal 
without respective bolus administration. After reaching hyperglycaemia, the pharmacodynamic 
response after administration of an IMP correction bolus via the insulin pump will be assessed. 


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On Day 2 of each treatment period, the pharmacodynamic response after suspension of insulin 
delivery by the insulin pump will be assessed as well as after administration of a correction bolus 
via syringe as described in Section 8.4. 
Plasma glucose will be analysed at the trial site using the 
 glucose analyzer 
 
 at the specified time intervals prior to and specified time 
points after IMP bolus administration according to Section 2.3. 
8.8.1 
Run-in and other experimental procedures on Day 1 and Day 2 
Invasive procedures 
Two intravenous cannulas (catheters) will be inserted: One cannula will be inserted in a vein of a 
forearm for sampling for serial PK and PD measurements. This cannula will be kept open by use 
of a mandrin/stylet. For controlled variable infusion of glucose or insulin glulisine (Apidra®) 
during the run-in period, a forearm vein of the contralateral arm will be cannulated with an 
adequate polytetrafluoroethylene (PTFE) catheter. 
Run-in procedures 
The run-in period will start during the night prior to the correction bolus administration of IMP 
on Day 1 and prior to basal insulin suspension on Day 2, at the preferred times described in 
Section 2.3 (i.e. at preferrably 4:00 hours on Day 1 and 2:00 hours on Day 2) or earlier if deemed 
necessary by the Investigator. Subjects should stay fasted after intake of the dinner meal on Day 
-1 and Day 1 until the end of the experimental procedures on the following day.
A variable i.v. infusion of insulin glulisine (15 U Apidra® [100 U/mL] in 49 mL saline and 1 mL 
of subject’s blood) or glucose (20%, diluted with saline prior to infusion) will be initiated in 
order to obtain a plasma glucose target range of 126 ± 20 mg/dL. The insulin infusion rate and 
glucose infusion rate (GIR) will be recorded. Any insulin glulisine infusion should be stopped 
from 30 minutes prior to meal ingestion/basal insulin suspension, any glucose infusion should be 
stopped from 30 minutes prior to meal ingestion/basal insulin suspension. 
The PG must be kept within a range of 126 ± 20 mg/dL the last 30 min prior to start of meal 
intakte. The PG level must not exceed each target range for more than 5 min, otherwise the run-
in period should be adequately extended in order to fulfil the target ranges. Start of meal intake 
on Day 1 should start between 8:00 to 10:00 hours (8:00 preferred). Basal insulin suspension on 
Day 2 should start approx. 8-10 hours after the dinner meal on Day 1. The PG level prior to the 
start of the meal test and basal insulin suspension procedure during treatment period 2 should be 
similar to that of treatment period 1, if feasible.  
Procedures in case of hypoglycaemia and hyperglycaemia during missed meal bolus and 
basal insulin suspension procedures 
In case subject’s plasma glucose concentration falls below 54 mg/dL (3.0 mmol/L, level 2 
hypoglycaemia), the subject must be treated with either oral administration of rapidly absorbable 
carbohydrates or i.v. glucose as judged by the investigator to stop the hypoglycaemic episode 
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and the experimental procedure will be terminated. Date and time of termination (i.e., the start 
time of any treatment given for this hypoglycaemic episode) will be documented in the CRF. 
Hypoglycaemia with plasma glucose concentrations below 70 mg/dL (level 1) should not be 
treated until the completion of the meal test unless hypoglycaemic related symptoms are 
unacceptable for the subject.   
In case subject’s plasma glucose concentration rises above 306 mg/dL for more than 1 hour after 
correction bolus administration, or if the investigator deems it necessary, the subject will be 
treated with an additional bolus of the IMP (subcutaneously) at discretion of the investigator. 
The time of administration and amount of additional bolus will be documented in the CRF. 
In both cases, blood samples for PK analysis will still be taken as planned.  
8.8.2 
Meal test procedure with missed meal bolus 
Meal test period 
A fixed composition meal will be served as liquid meal and should be consumed completely by 
the subject within 15 minutes after IMP administration. Ingestion of the meal will start after PG 
stabilisation and is defined as time point 0 (zero). No insulin bolus will be administered at this 
time point with the aim to induce postprandial hyperglycemia (PG > 240 mg/dL).
On Day 1, a liquid meal was chosen to rapidly increase plasma glucose concentration. The 
composition of the liquid meal is: 55% of carbohydrates, 15% protein and 30% fat. The liquid 
meal 
 provides 63g of carbohydrates. The 
meals will be consistent for both treatment periods and for all individual subjects. However, 
adaptations in the planned amounts can be done for an individual subject when experience is 
gathered during the experimental procedures. 
After completion of liquid meal intake, the subject should refrain from eating until the end of the 
meal test. Water consumption is not allowed during the first 2 hours after meal intake. Subjects 
will be required to consume the complete meal within the given time frame. In case the subject is 
not able to complete the meal on a meal test day, left-overs have to be weighed and respective 
non-consumed carbohydrates calculated and documented in the CRF. If a subject consumes less 
than the planned amount of the meal on the first treatment period the amount will be identical on 
the second treatment period. If this happens during the second treatment period the non-
consumed amount will be weighted and documented. 
Plasma glucose will be monitored until PG > 240 mg/dL has been measured and the result has 
been confirmed by a second measurement. At this time point (time point B0 (B zero)) the 
subjects individual bolus dose to cover the meal will be administered via the insulin pump. 
Blood samples for PK and PD assessments will be taken for the follwing 5 hours (see Section 
2.3, Table 2). 
In case subjects plasma glucose will not reach the PG >240 mg/dL, the meal test procedure will 
be aborted and repeated within 1-14 days. The subject will stay inhouse to proceed with trial 
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procedures until the end of the treatment period and an appointment for the repetition of the meal 
test procedure will be made, if feasible.  
Subjects will be asked to lie in a semi-supine position after meal intake until 2 hours after IMP 
administration and in a supine or semi-supine position thereafter until the last blood sample for 
PK and PD has been taken. During the intake of the mixed meal the subjects will be allowed to 
sit. 
After the end of the meal test procedure, the subject will continue with trial procedures as 
described in Section 8.4. 
8.8.3 
Basal insulin suspension procedure (Day 2) 
Basal insulin suspension will start at any time between 8 and 10 hours after the dinner meal on 
Day 1 (e.g. between 4:00 and 6:00). Once plasma glucose will be in the target range, the basal 
rate will be set to zero (temporary basal rate of 0%) to suspended insulin delivery. Plasma 
glucose will be monitored regularly to follow the rise in plasma glucose concentration above 240 
mg/dL and blood samples for PK analysis will be taken to analyse the decline in circulating 
insulin levelsaccording to Section 2.3 Table 3. As soon as a glucose measurement above 240 
mg/dL has been measured and the result has been confirmed by a second measurement. 
Thereafter, a correction bolus of 0.2 U/kg body weight of the IMP will be administered via a 
subcutaneous injection in the periumbilical region using an insulin syringe. In addition, a plasma 
sample for ketone concentration will be taken during this time. During the following 5 hours 
blood samples for pharmacokinetic and pharmacodynamic assessments as well as for 
determination of blood ketones will be taken according to Section 2.3, Table 3.  
The subject should stay in bed during the basal insulin suspension procedure and will not be 
allowed to consume anything except for water until the last blood sample for pharmacokinetic 
and pharmacodynamic assessment has been taken.  
After the end of the basal insulin suspension procedure, the subject will resume their usual 
insulin treatment with their own pumps and continue with trial procedures as described in 
Section 8.4. 
8.9 
Assessments for Safety 
8.9.1 
Clinical Assessments 
Adverse events 
Adverse events (AEs) will be recorded in accordance with the procedures described in Section 9. 
Any clinically significant worsening of a previous finding must be reported as an AE. 
During each contact with the trial site staff (site visits and telephone contacts) the subject must 
be asked about changes of their health status. This must be documented in the subject’s medical 
record. 


 
 
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Concomitant illness and medical history 
A concomitant illness is any illness that is present at the start of the trial (i.e. after signing the 
informed consent). 
Medical history is an account of medical events that the subject has experienced in the past. 
 Concomitant illnesses present at the start of the trial will be recorded in the CRF at screening.  
 Relevant medical conditions/illnesses in the past will be recorded in the CRF at screening. 
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset, date of resolution or continuation. 
Any change to a concomitant illness should be recorded during the trial, including end date, if 
applicable. A clinically significant worsening of a concomitant illness must be reported 
according to Section 9. 
Physical examination 
An examination of the following body systems will be performed: 
 Head, ears, eyes, nose, throat (HEENT), incl. thyroid gland 
 Heart, lung, chest 
 Abdomen 
 Skin and mucosae 
 Musculoskeletal system 
 Nervous system 
 Lymph node 
 Other findings  
At the screening visit, any abnormality will be recorded and described in the CRF including the 
Investigator’s assessment of clinical significance (‘abnormal, not clinically significant’ or 
‘abnormal, clinically significant’). Clinically significant findings at the screening visit should be 
recorded as concomitant illness. 
At subsequent visits, any clinically significant deterioration of a pre-existing condition as well as 
any new clinically significant findings will be recorded as AEs. 
Vital signs 
An examination of the following vital signs will be performed: 
 Diastolic and systolic blood pressure (mmHg) are measured after at least 5 min rest in a 
supine position. At the screening visit blood pressure is measured in both arms. The blood 
pressure from the arm with the higher systolic value is transcribed into the CRF and this arm 
is used for all subsequent measurements of the subject’s blood pressure in this trial.  
 Pulse (beats per min) measured after at least 5 min rest in a supine position. 
 Body temperature, tympanic (oC). 
 Respiratory frequency. 


 
 
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In addition to the pre-specified assessments in Sections 2.2 and 2.3, blood pressure and pulse 
may be assessed at any time during the trial at the discretion of the Investigator. Additional 
measurements will not be recorded in the CRF.  
Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be performed. 
ECG parameters (Heart rate, PQ, QRS, QT, QTcB) and any abnormality will be recorded and 
described in the CRF including the Investigator’s assessment of clinical significance (‘abnormal, 
not clinically significant’ or ‘abnormal, clinically significant’). Clinically significant findings at 
at the screening visit should be recorded as concomitant illness.  
Mean result (as reported by the ECG device) will be reported as heart rate. Aggregate data will 
be reported for all intervals. PQ will be reported as PR. 
At subsequent visits, any clinically significant deterioration of a pre-existing condition as well as 
any new clinically significant findings will be recorded as AEs. 
Plasma glucose for safety 
During the trial, plasma glucose levels will be monitored at the trial site by a laboratory method 
(
 Glucose Analyzer; 
 for safety and for 
pharmacodynamic assessments on Day 1 and Day 2. At the discretion of the Investigator 
additional plasma glucose measurements for safety may be made when there is a suspicion of a 
hypoglycaemic or hyperglycaemic episode. Plasma glucose measurements for safety should only 
be recorded in the CRF in case they are related to a hypoglycaemic episode. Hyperglycaemic 
episodes will not be recorded in the CRF unless these are assessed as severe adverse events by 
the investigator.  
 In case of symptomatic Level 1 hypoglycaemic event (see Section 9.4) or in case of any 
Level 2 hypoglycemic event (see Section 9.4) outside the meal test and basal insulin 
suspension procedure (see Section 8.8.1 for respective treatement), the subject must be 
treated to alleviate the hypoglycaemic symptoms and/or to normalise plasma glucose ≥ 70 
mg/dL. Rapid absorbable carbohydrates or i.v. glucose may be administered. 
 In case of asymptomatic Level 1 hypoglycaemic events, the plasma glucose testing will be 
repeated at least every 15 min until plasma glucose is ≥ 70 mg/dL. 

In case of an elevated plasma glucose concentration (PG > 180 mg/dL) outside the meal test 
and basal insulin suspension procedure (see Section 8.8.1 for respective treatement), the 
subject may be treated to lower the plasma glucose level within the normal range if deemed 
necessary by the investigator. 
 Treatment of hypoglycaemia during the meal test and pump suspension procedure will be as 
described in Sections 8.4 and 8.8.1. 
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8.9.2 
Laboratory Assessments 
The safety parameters that will be determined at the safety laboratory are listed in Table 5. 
The safety laboratory will perform a first check on their values for safety parameters and flag 
any values outside the reference range. The Investigator must evaluate all results outside the 
reference range (clinically significant or not clinically significant). Before the Investigator starts 
the trial (i.e. obtains informed consent from the first subject), the laboratory reference ranges 
must be available in the Investigator’s Trial File. The results provided by the safety laboratory 
will be part of the trial database. 
 
Table 5 
Routine laboratory safety tests 
Haematology 
 
Haematocrit 
Leucocytes 
Haemoglobin 
Neutrophile granulocytes (total count and relative) 
Erythrocytes 
Lymphocytes (total count and relative) 
Mean corpuscular volume (MCV) 
Monocytes (total count and relative) 
Mean corpuscular haemoglobin (MCH) 
Eosinophile granulocytes (total count and relative) 
Mean corpuscular haemoglobin concentration (MCHC) 
Basophile granulocytes (total count and relative) 
Thrombocytes (platelets) 
 
 
 
Biochemistry 
 
Sodium 
Uric acid 
Potassium 
Total protein 
Calcium 
Albumin 
Chloride 
Total bilirubin 
Phosphate 
Creatine kinase 
Creatinine 
Alkaline phosphatase 
Urea 
Gamma-glutamyltransferase (γ-GT) 
AST (aspartate aminotransferase, GOT) 
Lactic dehydrogenase (LDH) 
ALT (alanine aminotransferase, GPT) 
 
Total cholesterol 
High-density lipoprotein (HDL) cholesterol 
Low-density lipoprotein (LDL) cholesterol 
Triglycerides 
 
 
Coagulation (screening only) 
 
International normalized ratio (INR) 
Activated partial thromboplastin time (APTT) 
 
 
Urinalysis 
 
Protein 
Leucocytes 
Glucose 
pH 
Erythrocytes 
Ketones 
 
 
Infectious serology (screening only) 
 
Hepatitis B surface antigen 
HIV-1/2 combi 
Hepatitis C antibodies 
 
 
 
Other 
 
HbA1c (screening only) 
serum β-HCG (females only; screening only) 
C-peptide (screening only) 
 
 
 
 


 
 
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Pregnancy test 
For all female participants, a pregnancy test will be performed at the safety laboratory on a blood 
(serum) sample obtained at the screening visit and at Visits 2-4 from a urine sample at the trial 
site. The pregnancy test will be performed according to local regulation. 
8.10 Other Assessments and Dietary Requirements 
Demography 
 Age 
 Sex 
 Race 
Concomitant medication 
A concomitant medication is any medication, other than the IMPs and current diabetes 
treatment (including insulins for diabetes therapy wash-out), which is taken during the trial, 
including screening and follow-up periods. 
Details of any concomitant medication must be recorded at trial entry (i.e. at screening). Any 
changes in concomitant medication must be recorded at each visit as they occur. The information 
collected for each concomitant medication includes (at a minimum) trade name or generic name, 
indication, start date and stop date or continuation. A change in medication due to an AE must be 
recorded and reported according to Section 9. If the change in medication influences the 
subject’s eligibility to continue in the trial, the Sponsor and monitor must be informed. 
Diagnosis of diabetes and current diabetes treatment
 Date of diagnosis of diabetes 
 Current diabetes treatment [start date, product name(s), dose(s)] 
Body measurements 
 Height (cm), without shoes 
 Body weight (kg), only wearing underwear 
 Body mass index (kg/m2) calculated by the Investigator based on height and body weight 
(body weight/height2) 
Alcohol breath test 
An alcohol breath test will be performed using an alcohol meter (‰) by standard procedures at 
the trial site.  
Screening for drugs of abuse  
At the screening visit, a urine quick test for the presence of drugs of abuse (e.g. amphetamine, 
barbiturates, benzodiazepines, cannabis, cocaine, methadone, methamphetamine, opiates, 


 
 
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phencyclidine and tricyclic antidepressants) will be performed at the trial site from at least 5 mL 
fresh mid-stream urine using a stick.    
Fasting 
Fasting is defined as abstinence from food and beverage consumption (other than water) for at 
least 10 hours. Intake of rapidly absorbable carbohydrates (not more than 20 g carbohydrate) will 
be allowed if necessary to prevent hypoglycaemia. 
Subjects should arrive fasting prior to screening and follow-up and should be fasting prior to 
dosing at the dosing visit.  
Dietary Requirements 
No specific nutritional regimen is required during the outpatient periods of the trial.  
During the inpatient periods, specific dietary restrictions apply. During the inpatient periods, 
consumption of foods or drinks other than those served at the clinical unit is prohibited. 
The dinner meals on Day -1 and Day 1 will be identical pre-defined meals.  
The liquid meal for the meal test procedures will be identical on all meal test days and the 
relation of nutrients as described in Section 8.8.1. 
All other meals during the in-house period are free-choice meals, i.e. meals (and snacks) can be 
chosen by the subject from a list of meals given in a menu. 
Intake of the liquid meal on Day 1 will be supervised by the study staff and the consumption will 
be documented as described in Section 8.8.2. 
8.11 Volume of Blood Sampled during Trial  
A total amount of approximately 400 mL blood will be drawn from each subject during the trial. 
Additional blood samples may be drawn at the discretion of the Investigator (e.g. glucose for 
safety). 
 
Blood samples storage 
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. 
The pharmacokinetic samples will be stored for up to maximum of 1 year following last subject 
last visit. All other samples will be destroyed at the latest after finalisation of the clinical trial 
report.  
 


 
 
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9 
ADVERSE EVENTS 
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject. The investigator is responsible for the 
appropriate medical care of subjects during the study. 
Investigators must document their review of each laboratory safety report. 
If a subject’s IMP is discontinued as a result of an AE, study site personnel must report this to 
Lilly or its designee via eCRF. 
9.1 
Definitions 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a trial subject administered an IMP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavourable and unintended sign (for example, an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational medicinal product, whether or 
not considered related to the investigational medicinal product.  
Note: This includes also events that occur after the subject has signed the informed consent.    
AEs include: 
 A clinically significant worsening of a concomitant illness. 
 A clinical laboratory abnormality which is clinically significant, i.e. any abnormality that 
suggests a disease and/or organ toxicity and is of a severity that requires active 
management. Active management includes active treatment or further investigations, for 
example change of medicine dose or more frequent follow-up due to the abnormality. 
The following should not be recorded as AEs: 
 Pre-planned procedure, unless the condition for which the procedure was planned has 
worsened after the subject has signed the informed consent. 
 Pre-existing conditions which had started before the subject signed the informed consent. 
This also applies to previously unknown conditions which have been found as a result of 
assessments done as part of the study procedures (pre-existing conditions should be 
reported as medical history or concomitant illness). 
Treatment Emergent Adverse Event (TEAE) 
A TEAE is an AE that emerges during treatment, having been absent pretreatment, or worsens 
relative to the pretreatment state.  
In this trial, AEs occurring from first dosing until the follow-up visit will be considered as 
treatment emergent. 


 
 
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Serious Adverse Event (SAE) 
A SAE is any untoward medical occurrence that at any dose:  
 results in death  
 is life-threatening  
 requires inpatient hospitalisation or prolongation of existing hospitalisation, 
 results in persistent or significant disability or incapacity,  
 is a congenital anomaly or birth defect, or 
 events that may require intervention to prevent one of the above listed outcomes. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
An AE, fulfilling one of the criteria of seriousness and being assessed as related to IMP 
application, the nature or severity of which is not consistent with the applicable reference 
document (e.g. IB for an unapproved investigational product or package leaflet/SmPC for an 
approved product). 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. 
Other Significant Adverse Events 
Other significant adverse events will be defined as marked haematological and other laboratory 
abnormalities (other than those meeting the definition of serious) and any events that led to an 
intervention, including withdrawal of test drug/investigational product treatment, dose reduction, 
or significant additional concomitant therapy, other than those reported as serious adverse 
events (4). 
Intensity of an Adverse Event 
The maximum intensity (severity) of all AEs must be assessed by the Investigator and 
documented. Severity should be graded when the AE outcome is known: 
Mild:  
 A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
Moderate:  
A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
research participant. 
Severe:  
A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.
A ‘severe’ reaction does not necessarily deem the AE as ‘serious’ and a SAE may not be ‘severe’ 
in nature. 


 
 
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Causality relationship to IMP 
The causality of each AE should be assessed by the Investigator according to the following 
classification: 
Probable: 
Good reason and sufficient documentation to assume a causal relationship. 
Possible: 
A causal relationship is conceivable and cannot be dismissed. 
Unlikely: 
The event is most likely related to aetiology other than the trial product. 
Outcome of an Adverse Event 
The outcome of all AEs must be assessed by the Investigator and documented by his/her staff. 
The following definitions should be used: 
Recovered/resolved:  The subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed at the first trial-related activity 
after the subject signed the informed consent.  
Recovering/resolving: The condition is improving and the subject is expected to recover from the 
event. This term is only applicable if the subject has completed the trial. 
Recovered/resolved  
with sequelae:  
The subject has recovered from the condition, but with lasting effect due to 
a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE. 
Not recovered/ 
not resolved:  
The condition of the subject has not improved and the symptoms are 
unchanged, or the outcome is not known. 
Fatal:  
This term is only applicable if the subject died from a condition related to 
the reported AE. Outcomes of other reported AEs in a subject before 
he/she died should be assessed as "recovered/resolved", 
"recovering/resolving", "recovered/ resolved with sequelae" or "not 
recovered/not resolved". An AE with fatal outcome must be reported as an 
SAE.
Unknown:  
This term is only applicable if the subject is lost to follow-up. 
9.2 
Collection, Recording and Reporting of Adverse Events 
All events meeting the definition of an AE must be collected and reported from the time the 
subject signs the informed consent until the end of the post-treatment follow-up period. At each 
contact with the site (visit or telephone, excluding safety visits, where the subject is not seeing 
the Investigator or his staff (e.g. visits to the laboratory)) the subject must be asked about AEs. 


 
 
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All AEs, either observed by the Investigator or reported by the subject, must be recorded by the 
Investigator and evaluated. 
The Investigator should record the diagnosis, if possible. If no diagnosis can be made the 
Investigator should record each sign and symptom as individual AEs. 
All AEs must be recorded by the Investigator. One single Adverse Event Form must be used per 
AE from start to resolution. For SAEs, the Serious Adverse Event Form must also be completed.  
AE information should include the following: 
 AE term 
 Date and time of onset and resolution 
 Date of Investigator’s first information on the (S)AE (will not be collected in the CRF) 
 Seriousness 
 Severity 
 Causal relationship with IMP 
 Interruption or withdrawal of treatment with IMP and other measures taken 
 Outcome 
The date and time of the last contact with a subject subject will be entered for any ongoing AE  
where outcome is “recovering/resolving” or “not recovered/not resolved”.  
The Investigator or his/her staff must alert the Sponsor, or its designee, of any SAE as soon as 
practically possible. The Investigator must report initial information in writing (email) on all 
SAEs to the responsible medical monitor of the Sponsor immediately (within 24 hours) and to 
the Sponsor’s responsible pharmacovigilance unit after obtaining knowledge about the event.    
Name:  
Global Patient Safety 
Company:  
Eli Lilly and Company 
   
 
The Sponsor must inform the Competent Authorities and IRBs/IECs in accordance with the local 
requirements in force and ICH guideline for GCP. The trial monitor must be informed 
accordingly. 
Although all AEs are recorded in the eCRF/designated data transmission methods after signing 
informed consent, SAE reporting to the sponsor begins after the subject has signed informed 
consent and has received IMP. However, if an SAE occurs after signing informed consent, but 
prior to receiving IMP, AND when causality is considered at least possible in relation to a study 
procedure, then it MUST be reported. 
9.3 
Follow-up of Adverse Events 
Follow-up procedures may be different based on the nature (diagnosis, severity, seriousness) of 
the AE and will follow Profil’s SOP on (S)AE Handling and Reporting.   
PPD


 
 
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Non-serious AEs classified as severe or possibly/probably related to trial product will be 
followed until the subject has “recovered” or “recovered with sequelae” and all queries have 
been resolved.  
Note: Cases of chronic conditions, cancer or AEs ongoing at time of death (i.e. a subject dies 
from another AE), can be closed with an outcome of “recovering” or “not recovered”. Cases can 
be closed with an outcome of “recovering”, when the subject has completed the post-trial follow-
up period (1 week after last dosing) and is expected to recover by the Investigator . 
All other non-serious AEs will be followed up until the outcome of the event is “recovering”, 
“recovered”, “recovered with sequelae” or until the end of the post-treatment follow-up period (1 
week after last dosing), whichever comes first, and until all queries related to these AEs have 
been resolved. 
The Investigator shall follow up on all SAEs until the outcome of the event is “recovered”, 
“recovered with sequelae” or “fatal” and until all queries have been resolved, even after trial 
completion (LSLV). Note: Cases can be closed with an outcome of “recovering” when the 
subject has completed the trial and is expected by the investigator to recover. 
Follow-up actions for all SAEs will be determined after internal review and/or sponsor review.  
The follow up information should only include new (updated and/or additional) information that 
reflects the situation at the time of the Investigator’s signature. 
Follow-up information on (S)AEs will be updated using the (S)AE Form. If a non-serious event 
becomes serious during the follow-up the AE Form and SAE Form have to be used and reporting 
timelines follow those of a SAE. 
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from or completed the study.  However, if the Investigator learns of any SAE, 
including a death, at any time after a subject has been discharged from the study, and he/she 
considers the event reasonably possibly related to IMP or study participation, then the 
Investigator must promptly notify Lilly. 
The Investigator must forward follow-up information on SAEs and if previously non-serious 
AEs become SAEs to the Sponsor/both, the authorized Sponsor’s delegate for 
pharmacovigilance (Institute of Clinical Pharmacology) and the Sponsor (contact details are 
given in Section 9.2).  
9.4 
Hypoglycaemia 
Hypoglycaemia will be recorded and documented using the dedicated Hypoglycaemia Episode 
form. 


 
 
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The classification and recording of hypoglycaemia in the trial will conform to the current ADA 
guidance (5). 
 Level 1 hypoglycaemic event (Glucose Alert Value): is defined as a symptomatic or 
asymptomatic event with a measured plasma glucose concentration <70 mg/dL (<3.9 
mmol/L) but ≥54 mg/dL (3.0 mmol/L), [equivalent to a glucose concentration of <63 mg/dL 
and ≥49 mg/dL when using whole blood calibrated results] 

Level 2 hypoglycaemic event (Clinically significant hypoglycaemia): is defined as a 
symptomatic or asymptomatic event with a measured plasma glucose concentration <54 
mg/dL (3.0 mmol/L), [equivalent to a glucose concentration of <49 mg/dL when using whole 
blood calibrated results] 
For Level 1 and Level 2 hypoglycaemic events , the Investigator should also assess whether 
or not the event was accompanied by symptoms of hypoglycaemia (symptomatic or 
asymptomatic hypoglycaemic event). 
 Level 3 hypoglycaemic event (Severe hypoglycaemia): A severe event characterized by 
altered mental and/or physical status requiring assistance. Subjects had either altered mental 
status, and could not assist in their own care, or were semiconscious or unconscious, or 
experienced coma with or without seizures, and the assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions. These events may be 
associated with sufficient hypoglycaemia to induce seizure or coma. Plasma or blood glucose 
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence 
that the event was induced by a low plasma glucose concentration.  
Severe hypoglycaemia will be regarded as SAE and should be recorded on AE and SAE forms.  
Any severe hypoglycaemic episode will be accompanied by a narrative giving qualitative 
descriptions of timing of the episodes in relation to drug exposure, time of onset, time after last 
drug administration, time after meal, severity, duration, outcome of hypoglycaemia, dose of 
treatment. 
9.5 
Pregnancy 
Female subjects must be instructed to notify the Investigator immediately if they become 
pregnant or if they suspect to be pregnant during the trial. The Sponsor has a responsibility to 
monitor the outcome of all pregnancies reported during the clinical trial. 
Pregnancy (maternal or paternal exposure to IMP) 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. 


 
 
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9.6 
Precautions 
Normal precautions taken for a human trial, including the provision of emergency equipment, 
will be taken during this trial. Qualified and well-trained physicians and medical staff will 
instruct the subjects. During a subject’s participation in the trial, the Investigator should ensure 
that adequate medical care is provided to the subjects for any AEs, including clinically 
significant laboratory values related to the trial. The Investigator should inform the subject when 
medical care is needed for intercurrent illnesses of which the Investigator becomes aware.  
For further information on safety precautions for LY900014 and Humalog®, please refer to the 
current version of the IB and the SmPC for Humalog® respectively. 
9.7 
Complaint Handling 
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements. 
Subjects should be instructed to contact the Investigator as soon as possible if he or she has a 
complaint or problem with the IMP so that the situation can be assessed.


 
 
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10 RISK-BENEFIT ASSESSMENT 
Potential Risks 
Potential Benefits 
Risk-Benefit Assessment 
This study will not offer any direct benefits to the subjects participating in the study. The data 
from previous studies in healthy subjects and subjects with T1DM and T2DM have shown that 
LY900014 was well tolerated and the adverse drug reactions are in keeping with those reported 
for Humalog. 
Potential risks associated with LY900014, derived from the known risks of insulin lispro 
(Humalog), are hypoglycaemia, hypersensitivity reactions (localised allergy and/or systemic 
allergy), undesirable effects at the injection site (injection-site reactions and lipodystrophy), and 
peripheral oedema (Humalog package insert, 2015). 
Notably, across all doses in 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 Remodulin package 
insert 
  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 subjects is generally below the detection limit 
(0.010 ng/mL) 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 (LY900014  IB). 
In preclinical safety pharmacology and toxicity studies, or clinical pharmacology studies 
involving LY900014 or treprostinil alone, other than known risks associated with Humalog and 
Remodulin, 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. 
The study includes inpatient procedures during which participants will be continuously 
monitored.  Induced hyperglycaemia as well as in the event subjects experience hypoglycaemia 
during the procedures, these will be treated as described in Section 8.8. 
 
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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11 DATA MANAGEMENT 
Data Management is the responsibility of Profil Institut für Stoffwechselforschung GmbH, Neuss 
Germany.  
The complete Data Management process will be described in detail and agreed on in the Data 
Management Plan for this trial. 
Additional information to the Trial Design will be specified in the form SDTM - Trial Design 
Domain Specifications. 
11.1 Case Report Forms (CRFs) 
For this trial an electronic CRF (eCRF) will be used. 
The Data Management Department of Profil Institut für Stoffwechselforschung GmbH will 
provide the eCRF. All further information regarding the CRF and the data flow will be described 
and agreed on in the Data Management Plan. 
 


 
 
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12 MONITORING PROCEDURES 
The monitoring procedures for this trial are described in detail in the Monitoring Manual. The 
objectives of the monitoring procedures are to ensure that (i) the safety and rights of the trial 
subjects are respected, (ii) that accurate, valid and complete data are collected, and (iii) that the 
trial is conducted in accordance with the trial protocol, the principles of GCP and local 
legislation.  
The monitor must be given direct access to the TIF and source documents (original documents, 
data and records). Direct access includes permission to examine, analyse, verify and reproduce 
any record(s) and report(s) that are important to evaluation of the clinical trial. 
Key tasks of the monitor include to verify the presence of informed consent, the adherence to the 
inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety and 
efficacy variables. The monitor will also confirm the completeness of subject records, the 
adherence to the protocol and the progress in subject enrolment.  
Because no information that could reveal the identity of subjects may ever be removed from the 
trial site, the monitor will visit the site at regular intervals to perform these monitoring tasks. 
Other contact between the Investigator and monitor will be maintained as required through 
telephone calls and e-mail. The Investigator and/or key members of staff involved in the trial 
must be available to assist the monitor during all visits.  
Site Initiation Visit 
During the Site Initiation Visit (SIV) the Sponsor and/or monitor will review information on the 
IMP, the protocol, the CRFs and other key aspects of the trial with the Investigator and the key 
members of staff involved in the trial. The topics of the SIV are documented in a SIV report 
made available to the Investigator. Sponsor’s documentation on the SIV (e.g. power point 
presentation) should be filed by the Investigator. 
Source Data Verification 
Details on source data verification are specified in the Monitoring Manual. 


 
 
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13 STATISTICAL CONSIDERATIONS 
Eli Lilly will be responsible for the derivation of the PK and GD endpoints and will provide the 
derived PK and GD endpoints to Profil Institut für Stoffwechselforschung GmbH, Neuss, 
Germany. Profil will be responsible for the statistical analysis of the endpoints. The statistical 
planning and conduct of the analyses of the data will follow the principles defined in relevant 
ICH guidelines and the Sponsor’s and Profil’s SOPs. A general description of the statistical 
methods to be used is given in this chapter, specific details will be provided in the SAP. All 
statistical analyses performed at Profil will use SAS® (SAS Institute Inc., Cary, North Carolina, 
United States of America [USA]), Version 9.4 or later. PK parameters, analysed  by Eli Lilly, 
will use standard noncompartmental methods of analysis (Phoenix® version 6.3 or above). 
13.1 Sample Size Calculation 
A sample size calculation was performed based on the primary endpoint and an assumption of an 
SD of the primary endpoint of 78 min (crossover mean square error of ~55). A sample size of 24 
subjects who complete the trial is considered to be sufficient to evaluate a difference between the 
treatments of 32 minutes with a power of 80%. Discontinued subjects may be replaced to ensure 
that 24 subjects complete the trial. To take account of discontinued subjects, 28 subjects will be 
enrolled in the trial. A replacement subject will be assigned to the same treatment sequence as 
the patient being replaced. 
13.2 Selection of Subjects for Analyses 
The following analysis sets are defined in accordance with the ICH-E9 (6) guidance: 
Full Analysis Set (FAS)  
The full analysis set (FAS) is based on the intention-to-treat principle and includes all subjects 
who were treated with IMP. Subjects will contribute to the evaluation ‘as randomized’.  
Modified FAS (mFAS)  
The modified FAS includes all subjects of the FAS who complete the study according to the 
sequence/treatment to which they are randomized. Subjects will contribute to the evaluation ‘as 
randomized’. Primary and secondary statistical analyses of PK and GD parameters will be 
conducted on the set of subjects who complete all treatment periods with the same dose and meal 
intake 
 
  
Safety Analysis Set
The safety analysis set includes all enrolled subjects, whether or not they fulfilled all protocol 
requirements. Subjects in the safety set will contribute to the evaluation ‘as treated’. The safety 
analysis will be based on the safety analysis set.  
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Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. This review will be performed 
without revealing which IMP the subjects are assigned to. The blinding of the IMPs will be 
maintained for everyone involved in allocating subjects to the analysis sets until data are released 
for statistical analysis. Obviously erroneous data points may be excluded from the analyses or re-
analysed (in case of e.g. serum concentrations). The decision to re-analyse or exclude data points 
from the statistical analysis is the joint responsibility of the Sponsor, the Principal Investigator 
and the Trial Statistician.  
The subjects or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database lock. The documentation will be 
stored together with the remaining trial documentation. The subjects and observations excluded 
from analysis sets, and the reason for this, will be described in the clinical study report. 
Subjects withdrawn from the trial will be listed including the primary reason for withdrawal.  
If deemed necessary further endpoints and/or analyses may be added to the SAP. Only analyses 
not specified in the SAP will be considered as post-hoc analyses.  
All analyses will be fully detailed in the SAP. 
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.  Additional exploratory analyses of the data will 
be conducted as deemed appropriate. Study results may be pooled with the results of other 
studies for population PK analysis purposes to avoid issues with post-hoc analyses and 
incomplete disclosures of analyses. 
13.3 Statistical Methods 
13.3.1 
Pharmacokinetic Parameter Estimation 
Subjects have measurable insulin lispro concentrations will be included in the analysis dataset 
for the PK analyses.  PK 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 utilized 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. 
Free serum insulin lispro concentrations will be used to calculate several PK parameters 
including: time to early half-maximal drug concentration (early 50% tmax), maximum observed 
drug concentration (Cmax), time to maximum observed drug concentration (tmax), AUC from time 
0 to 15 minutes [AUC(0-15min)], AUC from time 0 to 30 minutes [AUC(0-30min)], and AUC 
from time zero to 5 hours [AUC(0-5h)], Other parameters may be calculated as deemed 


 
 
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appropriate, such as partial AUCs, time to late half-maximal drug concentration (late 50% tmax) 
and AUC from time zero to infinity [AUC(0-∞)], etc.  
For Day 1 (Missed Bolus following Meal):  The PK parameters will be calculated using a change 
from baseline (CFBL), as defined as the bolus dose administration (B). For each day and period, 
the average of the two samples collected immediately prior to the correction bolus will represent 
as the 0-hour time point for each subject, and will be used to subtracting the baseline value from 
all post-dose insulin lispro measurements. The CFBL PK parameters would include: CFBL 
AUCs, and Cmax.  
For Day 2 (Basal insulin suspension): As each subject will suspend their own individual basal 
rate, insulin lispro concentration at the time of administration of the correction bolus may vary 
from being detectable to undetectable (<LLOQ). Due to this, the PK parameters will be 
calucated using the CFBL insulin lispro concentrations following the correction bolus (as 
described in the Day 1 analysis).  An analysis using the raw insulin lispro concentration may be 
explored, if differences in insulin lispro concentration between treatments (LY900014 and 
Humalog) prior to the correction bolus are observed.  
Additionally, an exploratory analysis may be conducted to assess the insulin lispro PK during the 
basal insulin suspension to hyperglycemia on Day 2. PK parameters that may be explored 
include the half-life (t1/2) and apparent clearance (CL/F). The insulin lispro concentration time 
profile may be compared between LY900014 and Humalog during this time. 
Although attempts will be made to adhere to the scheduled collection times, it is recognized that 
situations arise that may compromise sample collection at the scheduled times.  Parameters will 
be individually calculated for each subject based on actual collection times and presented  by 
summary statistics.  
Individual and mean curves for the PK profiles will be plotted by treatment over the sampling 
period. Both the linear and the log-linear concentration scale will be used.  
13.3.2 
Glucodynamic Parameter Estimation 
For each study day (Day 1: meal test procedure with missed meal bolus and Day 2: basal insulin 
suspension),  the primary endpoint time to recovery from hyperglyemia after administration of a 
correction bolus will be determined per subject and period. The determination of the time to 
recovery after administration of a correction bolus will be calculated from the time of correction 
bolus administration until the time of the exact point of  time when PG is 140 mg/dL, which will 
be determined using linear interpolation. 
Similarly, for each study day, the key secondary glucodynamic endpoints include: glucose 
AUCs, PGmax and rate of change in PG will be determined.  


 
 
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The secondary endpoint rate of change in PG will be defined as the change in PG at the time of 
bolus IMP administration (B) to PG at 140mg/dl divided by the duration of time for this interval. 
based on individual measurements per subject, period and day. 
The following secondary GD AUCs will be calculated per patient, period and day: 
 the area under the PG curve, but above 140mg/dL from time of correction bolus to the 
time that the PG is 140mg/dl (AUCB-tPG140) and  

the area under the PG curve but above 180mg/dL from time of the correction bolus to 
the time that the PG is 180mg/dl (AUCB-tPG180).  
The AUCs will be calculated using the linear trapezoidal rule and using the actual times along 
with the time when PG is 140 mg/dL or 180mg/dL, which will be determined using linear 
interpolation. Additionally, calculation of baseline corrected AUC (iAUCs) using the PG at the  
administration time of the correction bolus may be explored to address possible inter-occasion 
variability. 
The secondary GD endpoint PGmax will be determined individually per subject, period and day 
based on measured PG values.  
Evaluation of the exploratory endpoint time to hyperglycemia after basal insulin suspension will 
be performed on day 2. The time will be calculated using the time of the basal insulin suspension 
until the time of the exact point of intersection with the target margin of 240 mg/dL. 
Individual and mean curves for the PD profiles will be plotted by treatment over the sampling 
period.   
13.4 Statistical Analysis 
13.4.1 
Analysis of the Primary Endpoints time to recovery from hyperglycaemia 
Subjects who did not keep identical insulin lispro doses for LY900014 and Humalog for each 
day and period or had differences in the test meal will be excluded from the statistical analysis of 
the GD parameters. 
For the primary endpoint, comparison between the treatments will be peformed per day (Day 1: 
meal test procedure with missed meal bolus, Day 2: basal insulin suspension) using a linear 
mixed model analysis of variance (ANOVA) with raw endpoint as response, treatment, period 
and sequence as fixed effects and patient within sequence as a random factor. Within the model, 
least squares means of LY900014 and Humalog®, differences in LSmeans and the 
corresponding 95% CI for the treatment difference will be estimated. The p-value on the 
difference between least squares (LS) means will be used to determine statistical significance.  
The treatment ratio and 95% CI for the ratio will be calculated using Fieller’s theorem (Chow 
SC, Liu JP. 2009). 


 
 
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13.4.2 
Analysis of the Secondary GD Endpoints
Subjects who did not keep identical insulin lispro doses for LY90014 and Humalog® for each 
day and period or had differences in the test meal will be excluded from the statistical analysis of 
the PK parameters. 
Log-transformed PG AUCs and PGmax will be evaluated to estimate geometric means, ratios of 
geometric means of insulin lispro within LY900014 to Humalog, and their corresponding 95% 
CIs of the ratios using the mixed-effects model that includes treatment (LY900014, Humalog), 
period and sequence as fixed effects and subject as a random effect. The analysis will be 
performed separated by day (Day 1: meal test procedure with missed meal bolus , Day 2: pump 
suspension).  In case of determination of baseline corrected AUCs to address possible inter-
occasion variability, iAUCs will be analysed using the same model. Analysis of iAUCs will be 
based on untransformed endpoints, if negative values occurred.  In this case,  LSmeans, 
treatment differences in LSmeans, and 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. 
The same model without log transformation will be used for the analysis of the rate of change in 
PG and exploratory GD time parameters.  Least-squares means, treatment differences in 
LSmeans, and the corresponding 95% CIs for the treatment differences will be estimated from 
the model.  The p-value on the difference between least squares (LS) means will be used to 
determine statistical significance. The treatment ratios and 95% CIs for the ratios will be 
calculated using Fieller’s theorem (Chow SC, Liu JP. 2009).  
13.4.3 
Analysis of the Secondary PK Endpoints 
Subjects who did not keep identical insulin lispro doses for LY90014 and Humalog for each day 
and period will be excluded from the statistical analysis of the PK parameters. 
Log-transformed AUCs, and Cmax, for insulin lispro will be evaluated to estimate geometric 
means, ratios of geometric means of insulin lispro within LY900014 to Humalog, and their 
corresponding 95% CIs of the ratios using the mixed-effects model that includes treatment 
(LY900014, Humalog), period and sequence as fixed effects and subject as a random effect.  
The same model without log transformation will be used for the analysis of the PK time 
parameters (time to early half-maximal drug concentration [early 50% tmax], and time of Cmax 
[tmax], [late 50% tmax if calculated]).  Least-squares means, treatment differences in LSmeans, 
and the corresponding 95% CIs for the treatment differences will be estimated from the model. 
The p-value on the difference between least squares (LS) means will be used to determine 
statistical significance.  The treatment ratios and 95% CIs for the ratios will be calculated using 
Fieller’s theorem (Chow SC, Liu JP. 2009). 


 
 
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13.4.4 
Analysis of Safety Endpoints 
Safety endpoints will be based on all reported adverse events. Allocation of adverse events to 
IMP will be conducted from start of study insulin pump with IMP on Day 1 until study pump 
disconnection on day 2. 
All adverse events will be listed and summarised by descriptive statistics. All serious adverse 
events will be reported. 
13.4.5 
Subject Disposition 
Subject disposition will be tabulated including the numbers of screened subjects, screening 
failures, subjects exposed to trial product, withdrawals including reason, subjects completing the 
trial and subjects in the FAS.  
13.4.6 
Other Measurements and Criteria 
The analysis of all other measurements and criteria will be described in the SAP. 
13.5 Interim Analysis 
No interim analysis is planned. If an unplanned interim analysis is deemed necessary, the Lilly 
clinical pharmacologist, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol. 
The Lilly study team is unblinded; the investigator shall remain blinded until database lock is 
achieved. Data may be analyzed by the Lilly study team while the trial is ongoing but no changes 
to the study design are planned. No assessment committee will be formed. 
 


 
 
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14 INDEPENDENT ETHICS COMMITTEE AND COMPETENT AUTHORITY 
The trial will be conducted according to Profil’s and /or the Sponsor’s written instructions 
(SOPs, working instructions or process descriptions). Content and definitions of Profil’s written 
instructions are based on the following relevant binding documents and standards  
 the German Medicinal Products Act (AMG) 
 the German GCP ordinance (GCP-Verordnung) 
 the Declaration of Helsinki (7) 
 the International Conference on Harmonisation Good Clinical Practice (ICH GCP) (8) 
The trial will be conducted in accordance with the above mentioned standards. 
14.1 Independent Ethics Committee
Written favourable opinion must be obtained from the responsible independent ethics committee 
(IEC) prior to commencement of the trial. Clinical trial submission and reporting requirements 
before, during and after completion of the trial will be performed in accordance with national 
law and local regulations.   
All amendments that affect subject safety or the trial integrity (substantial amendments) must not 
be implemented before favourable opinion has been obtained, unless necessary to eliminate 
hazards to the subjects. Non-substantial amendments do not require favourable opinion by the 
IEC but the respective IEC will be notified according to local requirements.  
The Sponsor and Investigator must approve any amendment in writing before its 
implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the IEC. 
The records should be filed in the Sponsor’s Trial Master File. 
14.2 Informed Consent Process for Subjects  
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirement(s) and adhere to the ICH GCP guideline (8) and the 
requirements in the Declaration of Helsinki (7). 
Prior to any trial-related activity, the Investigator must give the subject oral and written 
information in a form that the subject can read and understand about all aspects of the trial that 
are relevant to the subject’s decision to participate. The subject will be given ample time to 
decide whether or not to participate in the trial. 
The subject must be informed that his/her personal trial-related data will be used in accordance 
with the local data protection law. The level of disclosure must also be explained to the subject. 
The subject must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IEC 
members, and by inspectors from regulatory authorities. 


 
 
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A voluntary, personally signed and dated Informed Consent Form must be obtained from the 
subject prior to any trial-related activity. The Informed Consent Form must also be signed and 
dated by the physician who conducted the informed consent procedure. All subjects will be 
provided with a copy of their own signed and dated informed consent form and with any 
additional subject information.  
The responsibility for taking informed consent must remain with that of a research physician. 
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the Investigator must inform the subject in a timely manner, and a 
revised written informed consent must be obtained. 
Should a protocol amendment become necessary, the Informed Consent Form may need to be 
revised to reflect the changes to the protocol. It is the responsibility of the Sponsor to ensure that 
an amended consent form is reviewed and has received favourable opinion from IEC, and the 
Investigator has to ensure that the amended consent form is signed by all subjects subsequently 
entered in the trial and those currently in the trial, if affected by the amendment. 
14.3 Competent Authority  
An implicit or explicit approval must be obtained from the Competent Authority prior to 
commencement of the trial. Clinical trial submission and reporting requirements before, during 
and after completion of the trial will be performed in accordance with national law and local 
regulations. 
An implicit or explicit approval will also be mandatory before implementation of substantial 
changes. Non-substantial amendments do not require approval from the Competent Authority but 
will be notified according to local requirements. 
The Sponsor and Investigator must approve the amendment in writing before its implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
Competent Authority. The records should be filed in the Sponsor’s Trial Master File. 
14.4 Premature Termination of the Trial 
The Sponsor, Investigator or a pertinent regulatory authority may decide to stop the trial or part 
of the trial at any time but agreement on procedures to be followed must be obtained. 
Conditions that may warrant termination of the clinical trial include, but are not limited to: 
 Safety or administrative reasons. 
 The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled in 
the clinical trial. 
 A decision of the Sponsor to suspend or discontinue investigation of the IMP. 


 
 
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If a trial is prematurely terminated or suspended, the Investigator should promptly inform the 
subjects and assure appropriate therapy and follow-up. Furthermore, the Sponsor should 
promptly inform the IEC and provide a detailed written explanation. The pertinent regulatory 
authorities should be informed according to national regulations. 
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation 
should be provided to the IEC in case it will have an impact on the planned follow-up of the 
subjects who have participated in the trial. Necessary actions needed to protect the subjects 
should be described. 


 
 
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15 ADMINISTRATIVE MATTERS 
15.1 Deviations from the Protocol 
A deviation from the protocol is in general an unplanned non-compliance with the protocol that 
is not implemented or intended as a systematic change. The Investigator, or person designated by 
the Investigator, should document and explain any deviation from the protocol and inform the 
Sponsor and/or monitor. The deviation must be evaluated for its root cause and classification 
(important/non-important). Corrections (if possible) and/or corrective/preventive actions are to 
be documented and implemented. The documentation must be kept in the TIF and the Sponsor’s 
Trial Master File. Each deviation is listed in a deviation log. 
15.2 Essential Documents 
Essential Documents, as outlined in ICH GCP Chapter 8, are those documents that individually 
and collectively permit evaluation of the conduct of a trial and the quality of the data produced. 
These documents serve to demonstrate the compliance of the Investigator, Sponsor, and monitor 
with the standards of GCP and with all applicable regulatory requirements. 
Essential Documents also serve a number of other important purposes. Filing essential 
documents at the Investigator/institution and Sponsor sites in a timely manner can greatly assist 
in the successful management of a trial by the Investigator, Sponsor, and monitor. These 
documents are also the ones that are usually audited by the Sponsor’s independent audit function 
and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the 
trial conduct and the integrity of data collected. 
Trial files should be established at the beginning of the trial, both at the Investigator’s site 
(Investigator Site File) and at the Sponsor’s office (Trial Master File). A final close-out of a trial 
can only be done when the monitor has reviewed both Investigator/institution and Sponsor files 
and confirmed that all necessary documents are in the appropriate files. 
15.3 Responsibilities 
The trial related responsibilities are defined in the trial specific Responsibility Split List, which is 
an essential part of the trial contract. In this document the distribution of responsibilities between 
Sponsor, Profil and third parties (e.g. contract laboratories) is specified. 
The Investigator is accountable for the conduct of the trial according to the approved protocol, 
ICH-GCP (8) and Declaration of Helsinki (7). For responsibilities delegated, the Investigator 
should maintain a list of appropriately qualified persons to whom he has delegated specified 
significant trial-related duties. The Principal Investigator will acknowledge receipt of the IB, 
discuss and approve the protocol and review and sign the Integrated Clinical Trial Report. 


 
 
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The Investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The Investigator will prevent 
any unauthorized access to data or any other processing of data against applicable law. 
Pharmacovigilance tasks are the responsibility of Eli Lilly and are outlined in detail in the Safety 
Management Plan for this trial. 
15.4 Reports and Publications 
The Principal Investigator of the trial will review and sign the clinical trial report on behalf of 
Profil Institut für Stoffwechselforschung GmbH. A summary of the final clinical trial report will 
be submitted to the IEC and Competent Authority. 
According to the Declaration of Helsinki (7) Investigators and Sponsors ‘have ethical obligations 
with regard to the publication and dissemination of the results of research’.   
The trial design and results may be published as one or more original research manuscripts / 
abstracts and presented at a scientific meeting. The Investigator and Sponsor reserve the right to 
review any proposed presentation of the results of this trial before they are submitted for 
publication. Authorship on any publication(s) resulting from this clinical trial will be assigned 
according to the recommendations of the International Committee of Medicinal Journal Editors 
(ICMJE) (9). 
Participating subjects will not be identified by name in any published reports about the clinical 
trial.  
15.5 Audits and Inspections  
In the event of an audit, representatives of the Sponsor or designee, or national and international 
regulatory authorities may request access to all trial records for inspection and copying. Such 
access must be stated in the informed consent form signed by the subject. 
15.6 Retention of Clinical Trial Documentation 
Profil will maintain the subject’s medical file according to local regulations. 
Profil will archive the documentation pertaining to the trial in an archive after completion or 
discontinuation of the trial if not otherwise notified. Profil should not destroy any documents 
without prior permission from the Sponsor. 
The documentation includes all the raw data generated during the clinical trial, the TIF and a 
copy of the clinical report. The documents will be retained for a period of at least 15 years at 
archives by Profil, or its sub-contractor. After this period, the Sponsor will be contacted and their 
advice sought on the return or further retention of the trial records. 


 
 
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The Sponsor will maintain the documentation pertaining to the trial in accordance with national 
regulations.  


 
 
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REFERENCES 
 
1. 
Guerci B, Meyer L, Salle A, Charrie A, Dousset B, Ziegler O, et al. Comparison of 
metabolic deterioration between insulin analog and regular insulin after a 5-hour 
interruption of a continuous subcutaneous insulin infusion in type 1 diabetic patients. The 
Journal of clinical endocrinology and metabolism. 1999;84(8):2673-8.
 
2. 
Attia N, Jones TW, Holcombe J, Tamborlane WV. Comparison of human regular and 
lispro insulins after interruption of continuous subcutaneous insulin infusion and in the 
treatment of acutely decompensated IDDM. Diabetes care. 1998;21(5):817-21. 
 
3.
The rules governing medicinal products in the European Union. Volume 4. EU guidelines 
to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use. 
Annex 13. Investigational Medicinal Products. 2010. 
 
4. 
ICH E3 Guideline for Industry, Structure and Content of Clinical Study Reports. 1996. 
 
5.
6. Glycemic Targets: Standards of Medical Care in Diabetes-2019. Diabetes care. 
2019;42(Suppl 1):S61-s70. 
 
6. 
ICH Harmonised Tripartite Guideline. Statistical Principles for clinical trials E9. 
International Conference on Harmonisation E9 Expert Working Group: 1998. 
 
7. 
Declaration of Helsinki. Ethical Principles for Medical Research Involving Human 
Subjects.  64th WMA General Assembly; Fortaleza, Brazil2013. 
 
8. 
ICH Harmonised Tripartite Guideline. Good Clinical Practice. 1996. 
 
9. 
International Committee of Medical Journal Editors: Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals [press 
release]. 2013. 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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APPENDIX I - AMENDMENTS 
 
Amendment a 
Overall Rationale for the Amendment: 
This protocol was amended to comply with BfArM recommendations. 
Section # and Name 
Description of Change 
6.3. Exclusion Criteria 
Updated hypersensitivity criterion to include active 
substance or to any of the excipients to exclusion 
criterion 1 
Added 5 half-lives to exclusion criterion 3 
Updated blood pressure range to acceptable values of 
exclusion criterion 12 
6.5.1. Discontinuation of 
Inadvertently Enrolled Subjects 
Deleted section 
9.4. Hypoglyceamia 
Removed reference to adverse event 
 
 


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S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D

SAP_001.pdf: 
Statistical Analysis Plan I8B-MC-ITST (V1)
Effects of LY900014 on Recovery from Hyperglycemia Compared to Humalog in Subjects with 
Type 1 Diabetes Mellitus (T1DM) on Continuous Subcutaneous Insulin Infusion 
NCT04276207 
Approval Date: 15Jul2020 


 
 
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STATISTICAL ANALYSIS PLAN 
 
 
Trial ID: I8B-MC-ITST 
Effects of LY900014 on Recovery from Hyperglycemia Compared to Humalog in Subjects 
with Type 1 Diabetes Mellitus (T1DM) on Continuous Subcutaneous Insulin Infusion  
 
 
Trial Phase: 1 
 
 
 
 
 
 
 
 
 
Author: 
 
Profil Institut für Stoffwechselforschung GmbH 
PPD


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VERSION HISTORY 
Version number 
Date  
Reason for change 
0.1 
 
 
13 Feb 2020 
New 
0.2 
 
 
16 Mar 2020 
Incorporation of comments from Lilly 
0.3 
 
 
31 Mar 2020 
Incorporation of comments from Lilly 
0.4 
 
 
18 May 2020 
Incorporation of comments from Lilly 
0.5 
 
 
25 Jun 2020 
Incorporation of comments from Lilly 
1.0 
 
 
14 Jul 2020 
Incorporation of comments from Lilly 
 
 
PPD


 
 
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TABLE OF CONTENTS 
Page 
Signatures ........................................................................................................................................ 2 
Version History ............................................................................................................................... 3 
Table of Contents ............................................................................................................................ 4 
List of Tables ................................................................................................................................... 6 
List of Figures ................................................................................................................................. 6 
List of Appendices .......................................................................................................................... 6 
List of Abbreviations ....................................................................................................................... 7 
1 
Introduction ............................................................................................................................. 9 
1.1 
Objectives of Statistical Analysis Plan ................................................................................. 9 
1.2 
Scope .................................................................................................................................... 9 
2 
Study Objectives and Endpoints ........................................................................................... 10 
3 
Study Design and Description ............................................................................................... 12 
3.1 
Study Design ...................................................................................................................... 12 
3.2 
Investigational Medicinal Products .................................................................................... 14 
3.3 
Planned Number of Participants ......................................................................................... 15 
3.4 
Randomisation Code Creation ........................................................................................... 16 
4 
Analysis Variables................................................................................................................. 17 
4.1 
Demographic and Baseline Characteristics ........................................................................ 17 
4.2 
Assessments for Pharmacokinetics .................................................................................... 18 
4.3 
Assessments for Pharmacodynamics ................................................................................. 19 
4.4 
Exploratory Endpoints ........................................................................................................ 20 
4.5 
Safety Endpoint .................................................................................................................. 20 
4.5.1 
Adverse Events .................................................................................................. 20 
4.6 
Assessments for Safety ....................................................................................................... 23 
4.6.1 
Hypoglycaemic Events ...................................................................................... 23 
4.6.2 
Laboratory Safety Parameters ............................................................................ 24 
4.6.3 
Electrocardiograms ............................................................................................ 24 
4.6.4 
Vital Signs ......................................................................................................... 25 
4.6.5 
Physical Examination ........................................................................................ 25 
4.6.6 
Plasma Glucose for Safety ................................................................................. 26 
4.7 
Other Assessments ............................................................................................................. 26 
5 
Statistical Methodology ........................................................................................................ 27 
5.1 
Analysis Sets ...................................................................................................................... 27 


 
 
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5.2 
Protocol Deviations ............................................................................................................ 27 
5.3 
Coding ................................................................................................................................ 28 
5.4 
Missing, Unused and Spurious Data .................................................................................. 28 
5.5 
Presentation of Results ....................................................................................................... 29 
5.5.1 
Presentation of Summary Statistics and Individual Data .................................. 29 
5.5.2 
Presentation of Hypothesis Tests ....................................................................... 29 
5.5.3 
Baseline Definition ............................................................................................ 29 
5.6 
Analysis and Presentation of Demographic and Baseline Characteristics ......................... 30 
5.7 
Analysis of Primary Endpoints Time to Recovery from Hyperglycaemia ........................ 30 
5.8 
Analysis of Secondary PD Endpoints ................................................................................ 31 
5.9 
Analyses of PK Parameters ................................................................................................ 32 
5.10 Analyses of Safety Parameters ........................................................................................... 32 
5.10.1 
Analysis of Adverse Events ............................................................................... 33 
5.10.2 
Analysis of Hypoglycaemic Events ................................................................... 34 
5.10.3 
Analysis of Laboratory Safety Parameter .......................................................... 35 
5.10.4 
Analysis of Electrocardiograms ......................................................................... 36 
5.10.5 
Analysis of Vital Signs ...................................................................................... 36 
5.10.6 
Analysis of Physical Examinations ................................................................... 36 
5.11 Analysis of Other Exploratory Parameters ......................................................................... 36 
5.12 Analysis of Plasma Glucose for Safety .............................................................................. 36 
5.13 Analysis of Other Assessments .......................................................................................... 37 
5.14 Subject Disposition ............................................................................................................ 37 
5.15 Treatment Compliance ....................................................................................................... 37 
5.16 Important Protocol Deviations ........................................................................................... 38 
5.17 Screening Failures and Discontinuations ........................................................................... 38 
5.18 Interim Analysis ................................................................................................................. 38 
6 
Items for Statistical Documentation ...................................................................................... 39 
7 
Software ................................................................................................................................ 40 
8 
References ............................................................................................................................. 41 
9 
Change in Statistical Analysis from the Protocol.................................................................. 42 
Appendix 1 - Trial Flow Chart ...................................................................................................... 43 
Appendix 2 – Assessment Schedule (for Visits 2 and 3) .............................................................. 45 


 
 
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List of Tables 
Page 
Table 1 
Objectives and endpoints ...............................................................................................10 
Table 2 
Treatments administered ...............................................................................................14 
 
List of Figures 
Page 
Figure 1 
Study Design .................................................................................................................14 
 
List of Appendices 
Page 
Appendix 1 - Trial Flow Chart .................................................................................................................... 43 
Appendix 2 – Assessment Schedule (for Visits 2 and 3) ............................................................................ 45 


 
 
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LIST OF ABBREVIATIONS 
Please note that definitions and abbreviations of pharmacokinetic and efficacy parameters are not 
contained in this list. They can be found in Section 4.2 and 4.3 of this SAP. Abbreviations for 
laboratory safety parameters, which are only used once in Section 4.6.2, are also not listed here. 
 
ADA 
American diabetes association 
AE 
adverse events 
AESI 
Adverse Event of Special Interest 
ANOVA 
analysis of variance 
B 
Bolus administration 
BP 
blood pressure 
BMI 
body mass index 
CFBL 
Change from baseline 
CI 
confidence interval 
CSII 
Continuous Subcutaneous Insulin Infusion 
CSR 
Clinical study report 
CV 
coefficient of variation 
DBR 
database release 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eVAS 
electronic visual analogue scale 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSFV 
First subject first visit 
FUP 
follow-up 
GCP 
Good clinical practice 
GD 
Glucodynamics 
GIR 
 
  glucose infusion rate 
HbA1c 
glycated haemoglobin 
HR 
heart rate 
iAUC 
baseline corrected AUC 
IC 
informed consent 


 
 
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ICH 
International council for harmonisation 
IMP 
Investigational medicinal product 
INR 
International normalised ratio  
i.v. 
Intravenous(ly) 
LLOQ 
lower limit of quantification 
LS 
Least squares  
LSLV 
Last subject last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
Modified Full analysis set
NIMP 
Non-investigational medicinal product 
PAH 
Pulmonary arterial hypertension 
PD 
pharmacodynamic 
PG 
plasma glucose 
PK 
pharmacokinetics 
QTc 
corrected QT interval 
QTcB 
Qtc corrected by Bazett 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SFAS 
safety analysis set 
s.c. 
subcutaneous(ly) 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse events 
T1DM 
type 1 diabetes mellitus 
U 
Units 


 
 
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1 
INTRODUCTION 
1.1 
Objectives of Statistical Analysis Plan 
The statistical analysis plan (SAP) describes in detail the statistical analyses to be conducted on 
the data from the Phase 1 trial I8B-MC-ITST. 
The SAP elaborates on the statistical analyses outlined in the protocol, and any deviations are 
clearly stated in the present SAP including the reason for the deviation. The trial will be 
evaluated according to the specifications given in this analysis plan. However, deviations from 
the SAP may be necessary in which case the nature of and the reason for the deviations will be 
documented and explained in the clinical study report (CSR). 
1.2 
Scope 
This SAP is based on the finalized protocol Version 2.0, dated 17-Jan-2020. 


 
 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
The purpose of this study is to compare the time to recovery from hyperglycemia following 
LY900014 administration in comparison to Humalog® in a similar situation as when a subject 
experiences hyperglycaemia by forgetting to deliver a bolus when consuming a meal or when 
there is suspension of insulin delivery e.g. due to a malfunction of the insulin pump in subjects 
with Type 1 Diabetes Mellitus (T1DM).
Table 1 shows the objective and endpoints of the study. 
Table 1
Objectives and endpoints
Objectives 
Endpoints 
Primary 
 To compare the time to recovery from 
hyperglycaemia following a missed meal 
bolus with LY900014 vs. Humalog®, 
given as a correction bolus via pump 
infusion 
 To compare the time to recovery from 
hyperglycaemia following basal insulin 
suspension 
with 
LY900014 
vs. 
Humalog®, given as a correction bolus via 
syringe injection 
PD endpoints: 
 Time to recovery from hyperglycemia 
(time of correction bolus to time when 
plasma glucose [PG]) = 140 mg/dL) 
Secondary
 To compare the pharmacodynamics and 
insulin lispro pharmacokinetics following 
a correction bolus of LY900014 vs. 
Humalog® 
during 
recovery 
from 
hyperglycaemia following a missed meal 
bolus. 
 To compare the pharmacodynamics and 
insulin lispro pharmacokinetics following 
a correction bolus of  LY900014 vs. 
Humalog® 
during 
recovery 
from 
hyperglycaemia 
after 
basal 
insulin 
suspension. 
PK endpoints:
 tmax, time to maximum observed insulin 
concentration. 
 Early 50% tmax, time to half-maximum 
before Cmax.  
 AUC(0-15min), are under the insulin curve 
from 0 to 15 minutes. 
 AUC(0-30min), are under the insulin curve 
from 0 to 30 minutes. 
 
PD endpoints: 
 AUC(B-tPG140), area under the PG curve but 
above 140 mg/dL from time of correction 
bolus (B) to time when PG is 140 mg/dL) 
 AUC(B-tPG180), area under the PG curve but 
above 180 mg/dL from time of correction 
bolus (B) to time when PG is 180 mg/dL) 


 
 
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Objectives 
Endpoints 
 Rate of change in PG (the change in PG at 
the time of bolus IMP administration to 
PG = 140 mg/dL measurement divided by 
the duration of time for this interval) 
 PGmax, 
maximum 
observed 
plasma 
glucose 
Exploratory 
 To assess the blood glucose response after 
basal insulin suspension for LY900014 vs. 
Humalog®. 
 
 Time to hyperglycaemia 
(PG > 240 mg/dL) after basal insulin 
suspension 
 Peak ketone concentration after basal 
insulin suspension 
Safety 
 To assess the safety and tolerability of 
LY900014 and Humalog®. 
Safety endpoints: 
 AEs 
Safety assessments: 
 Hypoglycaemic episodes 
 Laboratory safety parameters 
 Physical examination 
 Vital signs 
 ECG 


 
 
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3 
STUDY DESIGN AND DESCRIPTION 
3.1 
Study Design 
The study is a phase 1, single-centre, randomised, 2-treatment, subject- and investigator-blind, 2-
way cross-over trial in subjects with T1DM. The trial will be carried out in one center in 
Germany. 
The study consists of a: 
 informed consent (Visit 0) 
 a screening visit (Visit 1) 
 two in-house study visits with IMP administration (Visits 2 and 3) 
 a follow–up (FUP) visit (Visit 4) 
Figure 1 shows the study design of the study. 
The information visit will take place at least 1 day prior to the screening visit in order to obtain 
the subjects informed consent. The subjects will attend the screening visit 1–28 days prior to 
Visit 2 to determine their eligibility. After screening, all eligible subjects will, in random order, 
undergo two in-house study visits. Each in-house visit will comprise a 3-day stay at the trial site. 
The in-house visits will be separated by a wash-out period of 3–14 days (between Visit 2, Day 2 
and Visit 3, Day 1). Each subject will be randomised to a treatment sequence consisting of two 
treatments, i.e. LY900014 and Humalog®, to be administered at the two separate in-house study 
visits. Randomisation will take place on Day -1 of Visit 2.  
At each of the two in-house visits, subjects will arrive at the trial site in the afternoon of Day -1. 
Subjects’ infusion set and reservoir of the insulin pump will be changed at the trial site and filled 
with either LY900014 or Humalog® according to the randomisation list. Subjects who are not 
using a Medtronic 640G insulin pump will be provided with a Medtronic 640G insulin pump and 
will be trained in its use. Users of this pump may use their own pump for the experimental 
procedures. The subject’s usual basal rate settings will be programmed in the study pump and the 
basal rate infusion will be started.  
Day -1 / Day 1: recovery from hyperglycemia after missed meal bolus 
In the evening of Day -1, subjects will receive a pre-defined evening meal. The subjects will 
cover the meal with a bolus of IMP. Overnight, the basal insulin infusion rate will be running 
and a target fasting plasma glucose level in the range of 126 ± 20 mg/dL will be aimed for. A 
single hourly basal rate will be started from at least – 3 hours prior to meal ingestion. At approx. 


 
 
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08:00 hours on Day 1, a standard liquid meal 
 
 will be provided. No bolus 
insulin will be administered with the aim to induce postprandial hyperglycemia (PG > 240 
mg/dL). On-site glucose measurements 
 will be performed 
regularly and frequently after meal ingestion. As soon as a glucose measurement above the high 
glucose threshold (PG > 240 mg/dL) has been measured and the result has been confirmed by a 
second measurement, a correction bolus will be administered with the aim to bring the subject’s 
glucose level down to PG ≤ 140 mg/dL. Regular and frequent sampling for glucose on-site 
analysis continues and the time to reach the euglycemic range threshold will be documented. PK 
and glucose measurements will be collected until 5 hours after administration of the correction 
bolus. In case PG < 54 mg/dL, hypoglycemia rescue will be provided. In case PG > 306 mg/dL 
for more than one hour, hyperglycaemia rescue will be provided. Thereafter, subjects will 
receive a free-choice lunch and a pre-defined evening meal covered by the subject’s usual bolus 
dose. 
Day 1 / Day 2: recovery from hyperglycemia after basal insulin suspension 
After the insulin bolus given with the evening meal, no correction boli should be given 
subcutaneuously. Overnight, the basal insulin infusion rate will be running and a target fasting 
plasma glucose level in the range of 126 ± 20 mg/dL will be aimed for. The basal insulin 
infusion rate will be fixed to a single hourly rate from at least – 3 hours prior to basal insulin 
suspension. Basal insulin suspension will be performed between 8 and 10 hours after the dinner 
meal on Day 1. On-site glucose measurements 
 will be performed 
regularly and frequently to follow the rise in plasma glucose concentration above 240 mg/dL and 
blood samples for PK analysis will be taken to analyse the decline in circulating insulin levels. 
As soon as a glucose measurement above the high glucose threshold has been measured and the 
result has been confirmed by a second measurement a correction bolus will be administered via a 
subcutaneous injection in the periumbilical region using an insulin syringe. In addition, a plasma 
sample for ketone concentration will be taken during this time. Regular and frequent sampling 
for PK, ketone and glucose analysis continues and the time to reach a PG ≤ 140 mg/dL will be 
documented. 
After completion of basal insulin suspension procedures at Visit 3 Day 2, subjects will be 
switched back to their usual diabetes therapy and come back to the trial centre for the final 
examination. 
Up to 28 subjects will be randomised in this trial to ensure that at least approximately 24 subjects 
complete both the periods to enable evaluation of the primary objective. The subjects will be 
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randomly allocated to one of two treatment sequences (LY900014 followed by Humalog® or 
Humalog® followed by LY900014). 
 
Informed 
Consent 
Day -1: 
admission 
 
Day 1: 
Missed meal 
bolus induced 
hyperglycemia 
 
Day 2: 
Basal insulin 
suspension 
induced 
hyperglycemia 
Day -1: 
admission 
 
Day 1: 
Missed meal 
bolus induced 
hyperglycemia 
 
Day 2: 
Basal insulin 
suspension 
induced 
hyperglycemia 
Final 
examination 
Screening 
        
        
        
        
        
            
      
    
          
      
-   
     
   
          
 -    
    
          
 -         
   -           
                      
 -       
         
 
Figure 1 
Study Design 
The schedule of assessments performed at each visit is given in Appendix 1. 
A description of inclusion and exclusion criteria is given in the protocol Sections 6.2-6.3. 
3.2 
Investigational Medicinal Products 
Subjects will receive LY900014 followed by Humalog® or Humalog® followed by LY900014 as 
described in Table 2. 
Table 2 
Treatments administered 
IMPs 
Strength 
Pharmaceutical 
dosage form 
Dose per 
administration 
Route of 
administration 
LY900014 
100 U/mL 
Solution for injection 
filled in 3.0 mL pump 
reservoir/10mL vial 
Basal and bolus 
infusion based 
on individual 
needs 
subcutaneous 
infusion via 
CSII/injection 
via syringe 
Humalog®  
(insulin lispro) 
100 U/mL 
Solution for injection 
filled in 3.0 mL pump 
reservoir/10mL vial 
Basal and bolus 
infusion based 
on individual 
needs 
subcutaneous 
infusion via 
CSII/injection 
via syringe 
 


 
 
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IMPs will be administered subcutaneously in the abdomen by use of:  
 
 an insulin pump (Medtronic MiniMed 640G) and Quick Set® (Medtronic, Meerbusch, 
Germany) infusion sets. 
 an insulin syringe  
3.3 
Planned Number of Participants 
Up to 28 subjects will be randomised in this trial to ensure that at least approximately 24 subjects 
complete both the periods to enable evaluation of the primary objective. 
A sample size calculation was performed based on the primary endpoint and an assumption of an 
SD of the primary endpoint of 78 min (crossover mean square error of ~55). A sample size of 24 
subjects who complete the trial is considered to be sufficient to evaluate a difference between the 
treatments of 32 minutes with a power of 80%. Discontinued subjects may be replaced to ensure 
that 24 subjects complete the trial. To take account of discontinued subjects, 28 subjects will be 
randomised in the trial. A replacement subject will be assigned to the same treatment sequence 
as the subject being replaced. 
Subject Replacement: 
To account for discontinued subjects (defined as subjects concluding participation, prior to 
completion of all protocol-required elements after enrollment/ randomisation), up to 28 subjects 
will be randomised. In case of more than 4 discontinued subjects, four additional replacement 
subjects may be enrolled (maximum total number of enrolled subjects will not exceed 32 
subjects). A replacement subject will be assigned to the same treatment sequence as the subject 
being replaced.  
Screening Failures: 
Screened subjects who do not meet or comply with all inclusion and exclusion criteria are 
excluded (screening failures), and their data will be recorded on a screening failure form. The 
reason for exclusion must be recorded on the screening failure form. Re-screening of screening 
failures is generally not allowed. 
Planned number of sites: 
One site in Germany: 
  Profil Institut für Stoffwechselforschung GmbH in Neuss 


 
 
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3.4 
Randomisation Code Creation 
The Profil Institut für Stoffwechselforschung GmbH, 41460 Neuss, will generate the 
randomisation codes using the computer program 
 
 
 
 
 
When a subject is randomised in the study, he/she must always be assigned to the lowest 
available randomisation number available from the randomisation list. Up to 28 subjects will be 
randomised to ensure that at least 24 can be evaluated.  
Randomisation numbers will be as follows: 
 Randomisation numbers starting with 101, 102, 103…  
A replacement subject will be assigned to the same treatment as the subject being replaced. For 
randomisation numbers for replacements 100 will be added to the randomisation number of the 
subject being replaced. 
 Corresponding randomisation numbers for replacements: 201, 202, 203… 
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4 
ANALYSIS VARIABLES  
4.1 
Demographic and Baseline Characteristics 
The following demographic variables and baseline characteristics will be collected at screening: 
 Age 
 Sex 
 Race 
 Body Weight, Height, Body mass index (BMI) 
 Diabetes duration, diagnosis of diabetes and current diabetes treatment 
 Concomitant illness and medical history  
 Serology 
(hepatitis 
B 
surface 
antigen, 
hepatitis 
C 
antibodies 
and 
human 
immunodeficiency virus -1/2 combi) 
 Coagulation (International normalized ratio and activated partial thromboplastin time) 
 N-(1-deoxy)-fructosyl-haemoglobin (HbA1c) 
 Fasting C-Peptide 
 Smoking & alcohol habits  
 Serum β-HCG (females only) 
 Drugs of abuse  
The BMI will be calculated based on the height and weight measured at screening according to 
the following formula: 
BMI [kg/m2] = weight [kg] / (height [m] x height [m]). 
HbA1c will be presented in % as well as in mmol/mol using the following conversion: 
HbA1c (mmol/mol) = [HbA1c (%) – 2.15]*10.929. 
Diabetes duration in years will be calculated as difference between year of informed consent was 
signed and year of diabetes diagnosis. 
A medical history is a condition that started and ended prior to when the informed consent form 
(ICF) is signed. Concomitant illnesses present at the start of the trial and relevant medical 
conditions, which deemed to be relevant by the Investigator, will be recorded in the electronic 
case report form (eCRF) at screening. The information collected for concomitant illness and 
medical history should include diagnosis, date of onset, date of resolution or continuation. 
Any change to a concomitant illness should be recorded during the trial, including end date, if 
applicable. A clinically significant worsening of a concomitant illness must be reported as AE. 


 
 
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For all female participants, a pregnancy test will be performed at the safety laboratory in a blood 
(serum) sample obtained at the screening visit. 
A urine quick test for the presence of drugs of abuse (e.g. amphetamine, barbiturates, 
benzodiazepines, cannabis, cocaine, methadone, methamphetamine, opiates, phencyclidine and 
tricyclic antidepressants) will be performed at the trial site from at least 5 mL fresh mid-stream 
urine using a stick.    
4.2 
Assessments for Pharmacokinetics 
Eli Lilly will be responsible for the derivation of the PK endpoints and will provide the derived 
PK endpoints to Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany.  
Subjects have measurable insulin lispro concentrations will be included in the analysis dataset 
for the PK analyses. PK 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 utilized 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. 
Free serum insulin lispro concentrations will be used to calculate several PK parameters 
including: time to early half-maximal drug concentration (early 50% tmax), maximum observed 
drug concentration (Cmax), time to maximum observed drug concentration (tmax), AUC from time 
0 to 15 minutes (AUC(0-15min)), AUC from time 0 to 30 minutes (AUC(0-30min)), and AUC from 
time zero to 5 hours (AUC(0-300min)). Other parameters may be calculated as deemed appropriate, 
such as partial AUCs, time to late half-maximal drug concentration (late 50% tmax) and AUC 
from time zero to infinity (AUC(0-∞)), etc. 
For Day 1 (Missed Bolus following Meal): The PK parameters will be calculated using change 
from baseline (CFBL), which is defined as the bolus dose administration (B). For each day and 
period, the average of the two samples collected immediately prior to the correction bolus will 
represent the 0-min time point for each subject and will be used to subtract the baseline value 
from all post-dose insulin lispro measurements. The CFBL PK parameters would include: CFBL 
AUCs and Cmax.  
For Day 2 (Basal insulin suspension): As each subject will suspend their own individual basal 
rate, insulin lispro concentration at the time of administration of the correction bolus may vary 
from being detectable to undetectable (<LLOQ). Due to this, the PK parameters will be 


 
 
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calculated using the CFBL insulin lispro concentrations following the correction bolus (as 
described in the Day 1 analysis). An analysis using the raw insulin lispro concentration may be 
explored, if differences in insulin lispro concentration between treatments (LY900014 and 
Humalog®) prior to the correction bolus are observed.  
Additionally, an exploratory analysis may be conducted to assess the insulin lispro PK during the 
basal insulin suspension to hyperglycemia on Day 2. PK parameters that may be explored 
include the half-life (t1/2) and apparent clearance (CL/F). The insulin lispro concentration time 
profile may be compared between LY900014 and Humalog® during this time. 
Although attempts will be made to adhere to the scheduled collection times, it is recognized that 
situations arise that may compromise sample collection at the scheduled times. Parameters will 
be individually calculated for each subject based on actual collection times and presented by 
summary statistics.  
4.3 
Assessments for Pharmacodynamics 
Eli Lilly will be responsible for the derivation of the PD endpoints and will provide the derived 
PD endpoints to Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany.  
For each study day (Day 1: meal test procedure with missed meal bolus and Day 2: basal insulin 
suspension), the primary endpoint time to recovery from hyperglycemia after administration of a 
correction bolus will be determined per subject and period. The determination of the time to 
recovery after administration of a correction bolus will be calculated from the time of correction 
bolus administration until the time of the exact point of time when PG is 140 mg/dL, which will 
be determined using linear interpolation. 
Similarly, for each study day, the key secondary PD endpoints include: glucose AUCs, PGmax 
and rate of change in PG will be determined. 
The secondary endpoint rate of change in PG will be defined as the change in PG at the time of 
bolus IMP administration (B) to PG at 140 mg/dl divided by the duration of time for this 
interval, based on individual measurements per subject, period and day. 
The following secondary GD AUCs will be calculated per patient, period and day: 
 the area under the PG curve, but above 140 mg/dL from time of correction bolus to the 
time that the PG is 140mg/dl (AUCB-tPG140) and  


 
 
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 the area under the PG curve but above 180mg/dL from time of the correction bolus to the 
time that the PG is 180mg/dl (AUCB-tPG180).  
The AUCs will be calculated using the linear trapezoidal rule and using the actual times along 
with the time when PG is 140 mg/dL or 180mg/dL, which will be determined using linear 
interpolation. Additionally, calculation of baseline corrected AUC (iAUCs) using the PG at the 
administration time of the correction bolus may be explored to address possible inter-occasion 
variability. 
The secondary GD endpoint PGmax will be determined individually per subject, period and day 
based on measured PG values.  
4.4 
Exploratory Endpoints 
Evaluation of the exploratory endpoint time to hyperglycemia after basal insulin suspension will 
be performed on Day 2. The time will be calculated using the time of the basal insulin 
suspension until the time of the exact point of intersection with the target margin of 240 mg/dL.  
The ketone concentration will be measured on Day 2. The peak of ketone concentration will be 
defined as the maximum of the measured ketone concentrations. 
4.5 
Safety Endpoint 
4.5.1 Adverse Events 
An AE is any untoward medical occurrence in a trial subject administered an IMP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavourable and unintended sign (for example, an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to the 
IMP.  
Note: This includes events that occur after the subject has signed the informed consent.  
AEs include: 
 A clinically significant worsening of a concomitant illness. 
 A clinical laboratory abnormality which is clinically significant, i.e. any abnormality that 
suggests a disease and/or organ toxicity and is of a severity that requires active 
management. Active management includes active treatment or further investigations, for 
example change of medicine dose or more frequent follow-up due to the abnormality. 


 
 
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A Treatment Emergent Adverse Event (TEAE) is an AE that emerges during treatment, having 
been absent pretreatment, or worsens relative to the pretreatment state. In this trial, AEs 
occurring from first dosing (basal rate) until the follow-up visit will be considered as treatment 
emergent. 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening  
 requires inpatient hospitalisation or prolongation of existing hospitalisation, 
 results in persistent or significant disability or incapacity,  
 is a congenital anomaly or birth defect, 

or events that may require intervention to prevent one of the above listed outcomes.
Severe hypoglycaemia will be regarded as SAE and will be recorded on AE and SAE forms. 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
An AE, fulfilling one of the criteria of seriousness and being assessed as related to IMP 
application, the nature or severity of which is not consistent with the applicable reference 
document (e.g. IB for an unapproved investigational product or package leaflet/SmPC for an 
approved product). 
 
Other Significant Adverse Events 
Other significant adverse events will be defined as marked haematological and other laboratory 
abnormalities (other than those meeting the definition of serious) and any events that led to an 
intervention, including withdrawal of test drug/investigational product treatment, dose reduction, 
or significant additional concomitant therapy, other than those reported as serious adverse 
events (2).  
The maximum intensity (severity) of all AEs must be assessed by the investigator and 
documented. Severity will be graded when the AE outcome is known: 
 Mild 
 Moderate 
 Severe  
A ‘severe’ reaction does not necessarily deem the AE as ‘serious’ and a SAE may not be ‘severe’ 
in nature. 
The causality relationship to study treatment and study procedure of each AE will be assessed by 
the Investigator according to the following classification: 


 
 
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 Probable 
 Possible 
 Unlikely 
The outcome of all AEs must be assessed by the Investigator and documented by his/her staff. 
The following definitions will be used: 
 Recovered/resolved  
 Recovering/resolving 
 Recovered/resolved with sequelae 
 Not recovered/not resolved 
 Fatal 
 Unknown 
AE information will include the following: 
 AE term 
 Date and time of onset and resolution 
 Seriousness 
 Severity 
 Causal relationship to IMP 
 Interruption or withdrawal of treatment with IMP and other measures taken 
 Outcome 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA); 
details are described in the trial specific Data Management Plan. 
Missing date and time data will only be replaced if at least the year exists and will be replaced as 
follows: 
 AE start date and time: 
o Month: 1 (January) 
o Day: 1 
o Hour: 0 
o Minute: 0 
o Second: 0 
 AE stop date and time: 
o Month: 12 (December) 
o Day: 28, 29, 30 or 31 (last day of the month in the given year) 


 
 
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o Hour: 23 
o Minute: 59 
o Second: 59 
Imputed dates and times will be within the time window from earliest possible start date/time to 
last possible end date/time. Imputed dates/times outside this time window must be adapted by 
earliest possible start date/time and last possible end date/time. 
If the year is missing, then the date will not be imputed. 
4.6 
Assessments for Safety 
4.6.1 Hypoglycaemic Events 
Hypoglycaemia will be recorded and documented using the dedicated Hypoglycaemia Episode 
form. 
The classification and recording of hypoglycaemia in the trial will conform to the current ADA 
guidance (3): 
 Level 1 hypoglycaemic event (Glucose Alert Value): is defined as a symptomatic or 
asymptomatic event with a measured plasma glucose concentration <70 mg/dL (<3.9 
mmol/L) but ≥54 mg/dL (3.0 mmol/L), [equivalent to a glucose concentration of <63 
mg/dL and ≥49 mg/dL when using whole blood calibrated results] 
 Level 2 hypoglycaemic event (Clinically significant hypoglycaemia): is defined as a 
symptomatic or asymptomatic event with a measured plasma glucose concentration <54 
mg/dL (3.0 mmol/L), [equivalent to a glucose concentration of <49 mg/dL when using 
whole blood calibrated results] 
 
For Level 1 and Level 2 hypoglycaemic events, the Investigator should also assess whether 
or not the event was accompanied by symptoms of hypoglycaemia (symptomatic or 
asymptomatic hypoglycaemic event). 
 
 Level 3 hypoglycaemic event (Severe hypoglycaemia): A severe event characterized by 
altered mental and/or physical status requiring assistance. Subjects had either altered 
mental status, and could not assist in their own care, or were semiconscious or 
unconscious, or experienced coma with or without seizures, and the assistance of another 
person to actively administer carbohydrate, glucagon, or other resuscitative actions. 
These events may be associated with sufficient hypoglycaemia to induce seizure or coma. 
Plasma or blood glucose measurements may not be available during such an event, but 


 
 
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neurological recovery attributable to the restoration of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.  
 
Severe hypoglycaemia will be regarded as SAE and should be recorded on AE and SAE forms.  
The number of episodes and the percentage of exposed subjects having at least one episode will 
be provided. 
4.6.2 Laboratory Safety Parameters 
If not otherwise stated the following assessments will be performed at screening as well as 
during FUP: 
Haematology 
 
Haematocrit 
Leucocytes 
Haemoglobin 
Neutrophile granulocytes (total count and relative) 
Erythrocytes 
Lymphocytes (total count and relative) 
Mean corpuscular volume (MCV) 
Monocytes (total count and relative) 
Mean corpuscular haemoglobin (MCH)
Eosinophile granulocytes (total count and relative)
Mean corpuscular haemoglobin concentration (MCHC) 
Basophile granulocytes (total count and relative) 
Thrombocytes (platelets)
 
 
Biochemistry 
 
Sodium 
Uric acid 
Potassium 
Total protein 
Calcium 
Albumin 
Chloride
Total bilirubin
Phosphate 
Creatine kinase 
Creatinine 
Alkaline phosphatase 
Urea 
Gamma-glutamyltransferase (γ-GT) 
AST (aspartate aminotransferase, GOT) 
Lactic dehydrogenase (LDH) 
ALT (alanine aminotransferase, GPT) 
 
Total cholesterol
High-density lipoprotein (HDL) cholesterol
Low-density lipoprotein (LDL) cholesterol 
Triglycerides 
 
 
Urinalysis 
 
Protein 
Leucocytes 
Glucose 
pH 
Erythrocytes
Ketones
4.6.3 Electrocardiograms 
A standard 12-lead ECG will be performed. An ECG will be performed at screening and FUP.  
ECG parameters (Heart rate, PR, QRS, QT, QTcB) and any abnormality will be recorded and 
described in the CRF including the Investigator’s assessment of clinical significance (‘abnormal, 
not clinically significant’ or ‘abnormal, clinically significant’). Clinically significant findings at 
the screening visit will be recorded as concomitant illness.  


 
 
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Mean result (as reported by the ECG device) will be reported as heart rate. Aggregate data will 
be reported for all intervals. PQ will be reported as PR. 
At subsequent visits, any clinically significant deterioration of a pre-existing condition as well as 
any new clinically significant findings will be recorded as AEs. 
4.6.4 Vital Signs 
An examination of the following vital signs will be performed at screening, dosing visits (Day -1 
and 2) and FUP. 
 Diastolic and systolic blood pressure (BP) is measured after at least 5 min rest in a supine 
position.  
 Pulse (beats per min) measured after at least 5 min rest in a supine position 
 Body temperature, tympanic (oC). 
 Respiratory frequency 
In addition to the pre-specified assessments in protocol Section 2, BP and pulse may be assessed 
at any time during the trial at the discretion of the Investigator. 
4.6.5 Physical Examination 
An examination of the following body systems will be performed at screening, dosing visits 
(Day -1 and 2) and FUP: 
 Head, ears, eyes, nose, throat (HEENT), incl. thyroid gland
 Heart, lung, chest 
 Abdomen 
 Skin and mucosae 
 Musculoskeletal system 
 Nervous system 
 Lymph node 
 Other findings 
 
At the screening visit, any abnormality will be recorded and described in the CRF including the 
Investigator’s assessment of clinical significance (‘abnormal, not clinically significant’ or 
‘abnormal, clinically significant’). Clinically significant findings at the screening visit should be 
recorded as concomitant illness. 
 


 
 
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At subsequent visits, any clinically significant deterioration of a pre-existing condition as well as 
any new clinically significant findings will be recorded as AEs. 
4.6.6 
Plasma Glucose for Safety 
During the trial, plasma glucose levels will be monitored at the trial site by 
 Glucose 
Analyzer for safety. At the discretion of the investigator, additional blood glucose measurements 
for safety may be made when there is a suspicion of a hypoglycemic or hyperglycemic episode.
4.7 
Other Assessments 
The following variables will be evaluated: 
 Concomitant medication 
 Body Weight 
 Pregnancy test (dipstick) 
 Alcohol breath test 
 Amount of carbohydrates at standard liquid meal 
A concomitant medication is any medication, other than the IMPs, which is taken during the 
trial, including screening and follow-up periods. Details of any concomitant medication must be 
recorded at trial entry (i.e. at screening). Any changes in concomitant medication must be 
recorded at each visit as they occur. The information collected for each concomitant medication 
includes (at a minimum) trade name or generic name, indication, start date and stop date or 
continuation. 
For all female participants, a pregnancy test will be performed at the safety laboratory in a urine 
sample at the screening visit and from a urine sample at the trial site at Day -1 of Visits 2 and 3 
and at follow-up. 
An alcohol breath test will be performed at screening and Day -1 using an alcohol meter (‰) by 
standard procedures at the trial site.  
The amount of carbohydrates at standard liquid meal will be measured at both dosing visits at 
Day 1.
 
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5 
STATISTICAL METHODOLOGY 
5.1 
Analysis Sets 
The following analysis sets are defined in accordance with the International Council for 
Harmonisation (ICH)-E9 guidance (1): 
Full Analysis Set (FAS) 
The full analysis set (FAS) is based on the intention-to-treat principle and includes all subjects 
who were randomised. Subjects will contribute to the evaluation ‘as randomised’. PK and PD 
listings (subjects, who are in the FAS, but not in the mFAS will be identified) and the subject 
disposition and demographic and baseline characteristics will be based on the FAS. 
Modified FAS (mFAS) 
The modified FAS includes all subjects of the FAS who complete the study according to the 
sequence/treatment to which they are randomised. Subjects will contribute to the evaluation ‘as 
randomised’. Primary and secondary statistical analyses of PK and GD parameters will be 
conducted on the set of subjects who complete all treatment periods with the same dose and meal 
intake as the PK parameters and GD response are dependent on the insulin dose which is 
individualized by subject.  
Safety Analysis Set (SFAS) 
The safety analysis set includes all enrolled subjects that have received IMP at least once (basal 
rate) - whether or not they fulfilled all protocol requirements. Subjects in the safety set will 
contribute to the evaluation ‘as treated’. The safety analysis will be based on the safety analysis 
set. 
5.2 
Protocol Deviations 
During database cleaning, the unblinded SDTM data will be provided to Sponsor and to two 
Profil statisticians. This will still maintain the blinding as those individuals with access to the 
dataset will not be involved in the data base release (DBR) meeting. The statistical analysis will 
be provided on unblinded data before DBR.   
Deviations from the protocol will be assessed as “important” or “non-important” in agreement 
with the sponsor. Protocol or procedure deviations are defined as “important” if they are likely to 
affect the outcome of the trial (e.g. effect on target variables). All other protocol and procedure 


 
 
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deviations are regarded as non-important. For important protocol and procedure deviations a 
description will be given in the CSR.  
The subjects or observations to be excluded and the reason for their exclusion will be 
documented. Lilly’s SOP for data exclusion will be followed. A sensitivity analysis may be 
conducted to assess the impact of data exclusion on the analysis. The reason for exclusion of 
subjects and details of the sensitivity analysis will be described in the CSR. 
Subjects withdrawn from the trial will be listed including the primary reason for withdrawal.  
In any case all decisions to correct or exclude values must have a reasonable foundation and 
must be documented in the meeting minutes. 
New NTFs, protocol and procedure deviations may be written after the meeting as a result of 
findings and decisions during the DBR meeting. 
The blinded review is completed after signing the DBR meeting minutes prior to database lock. 
5.3 
Coding 
AEs, medical history, and concurrent conditions will be coded using MedDRA as described in 
the Data Management Plan. 
Concomitant medication will be coded using the drug record number from the World Health 
Organization (WHO) dictionary. 
The used version numbers will be documented in the database. 
5.4 
Missing, Unused and Spurious Data 
All available data will be included in data listings and tabulations. Unless otherwise specified in 
Section 4, no imputation of values for missing data will be performed. Imputed values will be 
presented in data listings and will be flagged. 
Missing statistics will be presented as “NC” (not calculable). For example, if individual values 
are 0, the geometric mean cannot be calculated and will be presented as “NC”. 
Variable specific information for imputing missing data is given in Section 4. 


 
 
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5.5 
Presentation of Results 
5.5.1 Presentation of Summary Statistics and Individual Data 
In general, continuous endpoints are summarized by the arithmetic mean, geometric mean, 
median, standard deviation, coefficient of variation (CV), geometric coefficient of variation, and 
minimum and maximum. Categorical variables will be presented using descriptive summary 
statistics including number of subjects and percentages. Percentages of subjects will be based on 
non-missing values.  
All PK and PD endpoints will be summarised by treatment (LY900014 and Humalog) and 
dosing day (Day 1 and 2) using descriptive statistics and will be provided by Lilly using their 
SOP. All summary PD and PK parameters and mean plots will be presented for all subjects in 
the mFAS, which is reflective of the subjects used in the statistical analysis.  
Individual PK and PD profiles will be plotted by treatment and dosing day. Individual profiles 
will be presented for all available data (FAS). Similarly, individual listing of PK and GD 
parameters will be presented for all subjects. The presentation of individual profiles and listings 
will be provided in the appendix of the CSR. 
The safety endpoint and all tolerability assessments will be summarised using frequency tables 
or descriptive statistics and will be provided by Profil. For numeric data, individual as well as 
minimum and maximum values will be presented with the same number of decimal places as the 
raw data. Descriptive statistics, such as arithmetic mean and median values will be presented 
with an additional decimal place and standard deviation data with two additional decimal places 
as the raw data. 
5.5.2 Presentation of Hypothesis Tests 
Mixed effect models will be performed between LY900014 and Humalog® using SAS procedure 
PROC MIXED. Least square means (LS-means), LS-mean differences or ratios, corresponding 
confidence intervals (CIs) and p-values will be presented. 
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.   
5.5.3 Baseline Definition 
If not stated otherwise baseline is defined as the last assessment prior to first drug intake unless 
otherwise stated.  


 
 
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PK parameters for Day 1 (Missed Bolus following Meal): For each day and period, the average 
of the two samples (pre-bolus) collected immediately prior to the correction bolus will represent 
as the 0-min time point for each subject, and will be used to subtracting the baseline value for all 
post-dose insulin lispro measurements. 
PK parameters for Day 2 (Basal insulin suspension): As each subject will suspend their own 
individual basal rate, insulin lispro concentration at the time of administration of the correction 
bolus may vary from being detectable to undetectable (<LLOQ). Due to this, the PK parameters 
will be calculated using the CFBL insulin lispro concentrations following the correction bolus 
(as described in the Day 1 analysis above).  
The calculation of baseline corrected AUC (iAUCs) may be explored to address possible inter-
occasion variability. If conducted, the average of the two samples (pre-bolus) used to confirm the 
high glucose threshold (<240mg/dl) which was collected immediately prior to the correction 
bolus will represent as the 0-min time point for each subject, and will be used to subtracting the 
baseline value for all post-dose glucose measurements. 
5.6 
Analysis and Presentation of Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be presented for all subjects in the FAS. 
Individual demographic and background characteristics will be presented together with standard 
descriptive statistics as described above and will be presented in subject data listings. 
The pre-existing conditions and medical history will be summarized using frequency tables. The 
presentation will be done by system organ class (SOC) and preferred term, ordered in alphabetic 
order. 
5.7 
Analysis of Primary Endpoints Time to Recovery from Hyperglycaemia 
The PD parameters will be determined and analyzed using software SAS Version 9.4. 
 
Subjects who did not keep identical insulin lispro doses for LY900014 and Humalog® for each 
day and period or had differences in the consumption of the test meal will be excluded from the 
statistical analysis of the PD parameters. Additionally, subjects which required a rescue insulin 
dose during the treatment assessment period would be excluded in the analysis for both 
treatments (LY900014 and Humalog) periods for that day (missed bolus following meal or basal 
insulin suspension) since an accurate comparison of the treatment difference would not be 
possible. Subjects excluded from the analysis will be identified by Lilly. 
 


 
 
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For the primary endpoint, comparison between the treatments will be performed per day (Day 1: 
meal test procedure with missed meal bolus, Day 2: basal insulin suspension) using a linear 
mixed model analysis of variance (ANOVA) with raw endpoint as response, treatment, period 
and sequence as fixed effects and subject within sequence as a random factor.  
 
Within the model, least squares means of LY900014 and Humalog®, differences in LS-means 
and the corresponding 95% CI for the treatment difference will be estimated. The p-value on the 
difference between LS-means will be used to determine statistical significance. The treatment 
ratio and 95% CI for the ratio will be calculated using Fieller’s theorem [4]. 
5.8 
Analysis of Secondary PD Endpoints 
Subjects who did not keep identical insulin lispro doses for LY900014 and Humalog® for each 
day and period or had differences in the test meal will be excluded from the statistical analysis of 
the PD parameters. 
Log-transformed PG AUCs and PGmax will be evaluated to estimate geometric LSmeans, ratios 
of geometric means of insulin lispro within LY900014 to Humalog®, and their corresponding 
95% CIs of the ratios using the mixed-effects model that includes treatment (LY900014, 
Humalog®), period and sequence as fixed effects and subject within sequence as a random effect.  
Within the model the LS mean for each treatment as well as the difference of the LSmeans 
between the treatment groups and corresponding 95% CI will be calculated and exponentially 
back-transformed in order to find the estimated ratio between the insulin formulations and 
corresponding 95% CI. 
The analysis will be performed separated by day (Day 1: meal test procedure with missed meal 
bolus, Day 2: pump suspension). In case of determination of baseline corrected AUCs (iAUC) to 
address possible inter-occasion variability, iAUCs will be analysed using the same model. 
Analysis of iAUCs will be based on untransformed endpoints, if negative values occurred. In this 
case, LS-means, treatment differences in LS-means, and corresponding 95% CIs for the 
treatment differences will be estimated from the model. The p-value on the difference between 
LS-means will be used to determine statistical significance. The treatment ratios and 95% CIs for 
the ratios will be calculated using Fieller’s theorem. 
The same model without log transformation will be used for the analysis of the rate of change in 
PG and exploratory PD time parameters. LS-means, treatment differences in LS-means, and the 
corresponding 95% CIs for the treatment differences will be estimated from the model. The p-


 
 
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value on the difference between LS-means will be used to determine statistical significance. The 
treatment ratios and 95% CIs for the ratios will be calculated using Fieller’s theorem [4]. 
5.9 
Analyses of PK Parameters 
 
Analysis of the PK parameters will be done using software SAS Version 9.4. 
Subjects who did not keep identical insulin lispro doses for LY900014 and Humalog® for each 
day and period will be excluded from the statistical analysis of the PK parameters. Additionally, 
subjects which required a rescue insulin dose during the treatment assessment period would be 
excluded in the analysis for both treatments (LY900014 and Humalog) periods for that day 
(missed bolus following meal or basal insulin suspension) since an accurate comparison of the 
treatment difference would not be possible. 
 
Log-transformed AUCs and Cmax for insulin lispro will be evaluated to estimate geometric 
means, ratios of geometric means of insulin lispro within LY900014 to Humalog®, and their 
corresponding 95% CIs of the ratios using the mixed-effects model that includes treatment 
(LY900014, Humalog®), period and sequence as fixed effects and subject within sequence as a 
random effect.  
 
The same model without log transformation will be used for the analysis of the PK time 
parameters (time to early half-maximal drug concentration [early 50% tmax], and time of Cmax 
[tmax], [late 50% tmax if calculated]).  LS-means, treatment differences in LS-means, and the 
corresponding 95% CIs for the treatment differences will be estimated from the model. The p-
value on the difference between LS-means will be used to determine statistical significance. The 
treatment ratios and 95% CIs for the ratios will be calculated using Fieller’s theorem [4]. 
5.10 Analyses of Safety Parameters 
Safety endpoints will be presented for all subjects in the safety analysis set (SFAS). 
Safety of the treatment will be evaluated by AEs, hypoglycaemic events, laboratory tests, vital 
signs, ECG and physical examination. 
Safety results will be presented using descriptive statistics by visit/treatment and in subject data 
listings. In addition, listings of abnormal data will be presented. 


 
 
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5.10.1 Analysis of Adverse Events 
All AEs will be presented by individual listings and non-hypoglycaemic TEAEs (TEAEs in this 
section are non-hypoglycaemic; severe hypoglycaemia will be taken in account) will be 
presented using summary tables by treatment. The following summary tables will be presented: 
(1) Overview of Incidence of TEAEs including: 
 Number of subjects at risk 
 Incidence and number of TEAEs 
 Incidence of deaths 
 Incidence and number of serious TEAEs 
 Incidence and number of other significant TEAEs 

Incidence and number of severe TEAEs
 Incidence and number of drug related TEAEs (possibly or probably related to IMP as 
judged by the investigator) 
 
The presentation will be done by treatment. 
(2) TEAEs by MedDRA system organ class (SOC) and preferred term within each SOC and 
preferred term as well as in total including incidence and number of TEAEs. The presentation 
will be done by treatment. SOCs and preferred terms will be presented in alphabetic order. 
(3) TEAEs by SOC and preferred term and by severity, relationship, seriousness, outcome, 
action taken with study drug due to this TEAE and other action due to this TEAE. The 
presentation will be done by treatment. SOCs and preferred terms will be presented in alphabetic 
order. Within each category the presentation will be done from the lowest to the highest 
subcategory. 
(4) Separate tables for SAEs ( in case of more than 2 SAEs). 
The incidence of TEAEs will be presented with the number and percentage of participants 
affected. Percentages will be derived as ratio of number of participants affected and number of 
participants at risk multiplied by 100. 
The following will be included in the listing of AEs: 
 Screening and randomisation number
 Gender, age, race and weight 


 
 
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 Event number 
 Treatment 
 SOC and PT term 
 Event term 
 Start date and time 
 End date and time 
 Last dose date and time 
 Seriousness 
 Severity 
 Outcome 
 Relationship to IMP 
 Relationship to study device 
 Action taken with study drug due to this AE 
 Action taken with device  
 Other action taken due to this AE 
 Time since last dosing and duration 
Two AE listings will be presented, one including all AEs that occurred during the trial and one 
including only death, serious, other serious and other significant AEs (incl AEs that lead to 
discontinuation). The AE listing including all AEs does not contain AEs related to hypoglycemic 
events. These will be presented separately (see Section 5.10.2). AESIs (hepatic events) will be 
listed separately, if they will occur. 
5.10.2 Analysis of Hypoglycaemic Events 
Hypoglycaemic events will be presented for all subjects in the SFAS by individual listings, and 
summary tables. 
The following summary tables of hypoglycaemic events will be presented: 
 Hypoglycaemic events total and within each classification as given in Section 4.6, 
separated by type of the episode, outcome, treatment and treatment administration. 
 Separate tables will be presented for severe and non-severe hypoglycaemic events, if 
there are more than two severe hypoglycaemic events (Level 3).  
 All presentations will be done by treatment/visit. 


 
 
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The incidence of hypoglycaemic events will be presented with the number and percentage of 
participants affected. Percentages will be derived as ratio of number of participants affected and 
number of participants at risk multiplied by 100. 
The following will be included in the overall listing of AEs related to hypoglycaemic events: 
 Screening and randomisation number
 Gender, age, race and weight 
 Event number 
 Treatment/Visit 
 Classification (Level 1-3,) 
 Type of hypoglycaemic episode 
 Nocturnal hypoglycaemia 
 Start date and time 
 End date and time  
 Last dose date and time  
 Time since last dosing and duration of the episode 
 Lowest glucose level during the episode, if available (incl specimen) 
 Outcome  
 Treatment (incl time of treatment)  
 Glucose level before treating the episode, if available (incl specimen) 
 Treatment administration (self, capable self, not capable self) 
 Other treatment actions 
 
A separate listing of severe hypoglycaemic episodes (level 3) will be provided including 
narratives, giving qualitative descriptions of the severe episodes. 
5.10.3 Analysis of Laboratory Safety Parameter 
Laboratory safety variables (continuous values) will be summarised by descriptive statistics and 
by visit.  
 Clinical chemistry, haematology: absolute and change from screening to follow-up 
The reference range indicator (normal, low, high) per variable will be summarised by 
frequencies.  

Urinalysis: absolute and shifts from screening to follow-up


 
 
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Summaries will be performed by visit. All laboratory values will be listed by visit and subject 
number including flagging of values outside normal range (“NCS”: not clinically significant; 
“CS”: clinically significant). A listing of abnormal values will be presented in an end of text 
(EOT) listing. In case of a re-screening of a subject, it will be discussed at the DBR meeting 
which values should be included in the summary table (i.e. values from the first screening or 
values from the re-screening). The decision and the reason will be stated in the DBR meeting 
minutes. A footnote will be added to the summary table.  
5.10.4 Analysis of Electrocardiograms 
ECG data will only be collected and listed. No analysis is planned.  
5.10.5 Analysis of Vital Signs 
Vital signs data (absolute and change from Day -1 to follow-up) will be presented by individual 
listings. In addition, summaries will be presented using descriptive statistics. Qualitative vital 
signs data will be summarised in a frequency table. Summaries will be separated by visit or 
treatment period; on treatment periods summaries will be done by treatment and day. In addition 
to the pre-specified assessments in protocol Section 2, BP and pulse may be assessed at any time 
during the trial at the discretion of the Investigator. All these values will be listed. A listing of 
abnormal values including flagging of values outside normal range (“NCS”: not clinically 
significant; “CS”: clinically significant) will also be presented. 
5.10.6 Analysis of Physical Examinations 
Abnormal physical examinations will be presented. 
5.11 Analysis of Other Exploratory Parameters 
All other exploratory parameters will be presented for all subjects in the FAS by individual 
listings, summary tables and figures. All figures will be presented on linear scale. Individual 
profiles will be presented including all available data. Mean profiles will be presented including 
all data used in the statistical analysis. 
5.12 Analysis of Plasma Glucose for Safety 
Individual listings of blood glucose for safety will be presented by treatment.


 
 
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5.13 Analysis of Other Assessments 
Concomitant medication data will be presented by individual listings. In addition, tabular 
summaries will be done. 
Pregnancy test data, alcohol test and body weight will be presented by individual listings. In 
addition, tabular summaries will be done. 
Carbohydrates at standard liquid meal (in detail: Total estimated carbohydrates for a complete 
meal are 63 g, Total estimated carbohydrates for a complete meal, Meal consumed completely? 
Non-consumed carbohydrate amount, Consumed amount of carbohydrates, Consumed amount of 
carbohydrates [%]) will be presented by individual listings.  The meals will be consistent for 
both treatment periods and for all individual subjects. However, adaptations in the planned 
amounts can be done for an individual subject when experience is gathered during the 
experimental procedures.In addition, tabular summaries will be done.  
5.14 Subject Disposition 
Disposition of subjects will be tabulated including: 
 Number of Screened Subjects 
 Number of Screening Failures 
 Number of randomised subjects 
 Number and percent of subjects exposed to LY900014 and Humalog® 
 Number and percent of subjects exposed to LY900014 and Humalog® (infusion via 
pump/ Day 1) 
 Number and percent of subjects exposed to LY900014 and Humalog® (injection via 
syringe/ Day 2) 
 Number and percent of completers 
 Number and percent of discontinued subjects 
 Number and percent of subjects in each analysis set  
The calculation of percent will be based on the number of randomised subjects. Subject 
disposition and observations excluded from analysis sets will be listed. 
5.15 Treatment Compliance 
Administered doses (basal rate and bolus) of IMPs will be listed and summarized by treatment 
and dosing day, including body weight and basal insulin suspension/ bolus administration. 


 
 
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5.16 Important Protocol Deviations 
Important protocol deviations will be listed. 
5.17 Screening Failures and Discontinuations  
A listing of subjects who discontinued from the trial by reason for termination and a separate 
listing for all screening failures will be presented. 
5.18 Interim Analysis 
No interim analysis is planned. If an unplanned interim analysis is deemed necessary, the Lilly 
clinical pharmacologist, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol. 
The Lilly study team is unblinded; the investigator shall remain blinded until database lock is 
achieved. Data may be analyzed by the Lilly study team while the trial is ongoing but no changes 
to the study design are planned. No assessment committee will be formed. 


 
 
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6 
ITEMS FOR STATISTICAL DOCUMENTATION 
The statistical documentation to be included in an appendix to the CSR will include: 
 SAP 
 Relevant output from statistical analyses
 


 
 
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7 
SOFTWARE 
Software used for randomisation, parameter calculation and statistical analysis are mentioned in 
the corresponding sections of the SAP. PK parameters, analysed by Eli Lilly, will use standard 
noncompartmental methods of analysis (Phoenix® version 6.3 or above). 
 


 
 
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8 
REFERENCES 
 
1. ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials E9. 
International, Conference on Harmonisation E9 Expert Working Group. 1998. 
2. ICH E3 Guideline for Industry. Structure and Content of Clinical Study Reports. July 
1996  
3. Glycemic Targets: Standards of Medical Care in Diabetes-2019. Diabetes care. 
2019;42(Suppl 1):S61-70. 
4. Chow, S:C:; Liu, J.P. Design and Analysis of Bioavailability and Bioequivalence Studies, 
3rd Ed.:Chapman and Hall/CRC, Taylor & Francis: New York: 2009 
 
 


 
 
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9 
CHANGE IN STATISTICAL ANALYSIS FROM THE PROTOCOL 
 
1. Protocol section 4.2.2 did not include all endpoints, which were named in protocol 
section 13.3.1. These endpoints have been added. 
 


 
 
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APPENDIX 1 - TRIAL FLOW CHART 
Trial Period 
Screening Period 
Treatment Period 1 and 2 
Follow-up 
Visit no. 
0 
1 
2 and 3 
4 
 
Informed 
Consent 
Screening 
Induced hyperglycemia and 
recovery 
Final 
examination 
Timing 
≥ 1 day before 
Visit 1 
1-28 days 
prior to Visit 
2 
3-14 days between Visit 2 and 
Visit 3 
3-7 days 
after Visit 3 
Day 
 
 
Day -1 
Day 1 
Day 2 
 
In-house Visit/Period 
 
 
X 
X 
X 
 
Informed consent 
X 
X1 
 
 
 
 
Fasting 
 
X 
 
X 
X 
X 
Inclusion/exclusion criteria 
 
X 
X2 
 
 
 
Demographic data 
 
X 
 
 
 
 
Smoking 
and 
alcohol 
consumption habits 
 
X 
 
 
 
 
Concomitant illness and 
medical history 
 
X 
 
 
 
 
Weight, height, BMI 
 
X 
X3 
 
 
X3 
Alcohol breath test 
 
X 
X 
 
 
 
Physical examination 
 
X 
X 
 
X 
X 
Vital signs 
 
X 
X 
 
X 
X 
12-lead ECG 
 
X 
 
 
 
X 
Haematology  
 
X 
 
 
 
X 
Biochemistry 
 
X 
 
 
 
X 
Coagulation 
 
X 
 
 
 
 
Urinalysis 
 
X 
 
 
 
X 
Infectious serology  
 
X 
 
 
 
 
HbA1c, fasting C-peptide
 
X 
 
 
 
 
Pregnancy test (females 
only)5 
 
X 
X 
 
 
X 
Drug screen 
 
X 
 
 
 
 
Dosing 
visit 
exclusion/ 
withdrawal criteria 
 
 
X 
X6 
 
 
Randomization 
 
 
X4 
 
 
 
IMP administration 
 
 
X 
X 
X 
 
Missed meal bolus induced 
hyperglycemia 
 
 
 
X 
 
 
Basal insulin suspension 
induced hyperglycemia 
 
 
 
 
X 
 
Correction 
bolus 
(via 
pump)
 
 
 
X 
 
 
Correction 
bolus 
(via
syringe) 
 
 
 
X 
 
Blood sampling for insulin 
PK (see Tables 2 and 3) 
 
 
 
X 
X 
 
Blood sampling for plasma 
glucose PD and safety (see 
Tables 2 and 3) 
 
 
 
X 
X 
 
Blood 
sampling 
for 
ketones 
 
 
 
 
X 
 
Adverse events 
 
X 
X 
X 
X 
X 
Concomitant medication 
 
X 
X 
X 
X 
X 
Pre-defined meals 
 
 
X 
X 
 
 


 
 
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1 Check that informed consent has been signed and dated 
2 Re-check of subject eligibility on Visit 2 Day -1 only.  
3 Weight only 
4 V2 only 
5 Pregnancy test in women will be performed according to protocol section 8.9.2 
6 Re-check of dosing visit exclusion criteria. 
 
 


 
 
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APPENDIX 2 – ASSESSMENT SCHEDULE (FOR VISITS 2 AND 3) 
Approx. 
hour 
Nominal 
timing 
Activity
Insulin 
(PK) 
Plasma 
glucose1 
Other
Day -1 
17:00 
 
Subject arrives at the trial site and 
continued eligibility will be checked 
 
X 
Dosing visit exclusion 
criteria, AEs, 
concomitant 
medication, alcohol 
breath test, vital signs, 
ECG, physical 
examination, urine 
pregnancy test, weight4  
17:30 
 
Randomization (Visit 2 only) 
Discontinue subject’s own insulin pump 
if not using Medtronic 640G; insert new 
infusion set; 
Start study insulin pump with IMP 
(subject’s usual basal rate) 
 
 
 
18:00 
 
Pre-defined evening meal 
Covered by individual meal bolus 
 
 
X 
 
Day 1 
04:00 
 
START overnight stabilisation 
i.v. insulin glulisine or glucose infusion 
(if needed) 
Morning plasma glucose target (126 ± 
20 mg/dL) 
 
 
Sampling 
approx. 
every 30 
min. or 
more 
frequently, 
if needed 
 
 
05:00 
 
Fixed basal rate (single hourly rate) of 
CSII from at least -3 h until end of meal 
test (B + 5 h) 
 
 
07:30 
-30 min 
STOP i.v. insulin or glucose infusion (if 
any) 
Maintain PG at in the range of 126 ± 20 
mg/dL 
 
 
 
Day 1 
08:00 
0 
Standard liquid meal  
X (pre-
meal) 
X (pre-
meal) 
Dosing visit exclusion 
criteria, AEs, 
concomitant 
medication 
 
15min 
Liquid meal fully consumed 
 
X 
 
 
30min 
Plasma glucose measurement: 
every 10 minutes if PG ≤ 200 mg/dL 
and every 5 minutes if PG > 200 mg/dL 
 
 
X 
 
 
 
 
 
B2 
Confirmatory glucose measurement if 
PG > 240 mg/dL, followed by pump 
correction bolus 
X3 
X3 
 
 
B + 5min 
 
 
 
 
 
X 
X 
 
 
B + 10min 
X 
X 
 
 
B + 15min 
X 
X 
 
 
B + 20min 
X 
X 
 
 
B + 25min 
X 
X 
 


 
 
Statistical Analysis Plan 
Trial ID 
EudraCT-No. 
Date 
Status / Version-No. 
Page 
I8B-MC-ITST 
2019-003493-13 
15 Jul 2020 
Final 1.0 
46 of 47 
 
Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose1 
Other 
 
B + 30min 
 
 
 
 
 
As soon as PG ≤ 140 mg/dL is 
measured, a confirmatory PG is 
performed  
X 
X 
 
 
B + 35min 
X 
X 
 
 
B + 40min 
X 
X 
 
 
B + 45min 
X 
X 
 
 
B + 50min 
X 
X 
 
 
B + 55min 
X 
X 
 
 
B + 1h 
X 
X 
 
 
B + 65min 
 
X 
 
 
B + 70min 
X 
X 
 
 
B + 75min 
 
X 
 
 
B + 80min 
 
X 
 
 
B + 85min 
 
X 
 
 
B + 90min 
X 
X 
 
 
B + 95min 
 
X 
 
 
B + 100min 
 
X 
 
 
B + 105min 
X 
X 
 
 
B + 110min 
 
X 
 
 
B + 115min 
 
X 
 
 
B + 2h 
If PG > 140 mg/dL, PG sampling will 
continue every 5 minutes 
 
If PG ≤ 140 mg/dL, PG sampling will 
be every 15 minutes 
X 
X 
 
 
(B + 125 min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 130min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 135min 
 
X 
X 
 
 
(B + 140min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 145min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 150min 
 
X 
X 
 
 
(B + 155min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 160min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 165min 
 
X 
X 
 
 
(B + 170min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 175min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 3h 
 
X 
X 
 
 
(B + 185min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 190min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 195min 
 
X 
X 
 
 
(B + 200min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 205min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 210min 
 
X 
X 
 
 
(B + 215min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 220min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 225min 
 
X 
X 
 
 
B + 230min 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 235min 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 4h 
 
X 
X 
 
 
(B + 245min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 250min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 255min 
 
X 
X 
 
 
(B + 260min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 265min) 
If PG > 140 mg/dL 
 
(X) 
 


 
 
Statistical Analysis Plan 
Trial ID 
EudraCT-No. 
Date 
Status / Version-No. 
Page 
I8B-MC-ITST 
2019-003493-13 
15 Jul 2020 
Final 1.0 
47 of 47 
 
Approx. 
hour 
Nominal 
timing 
Activity 
Insulin 
(PK) 
Plasma 
glucose1 
Other 
 
B + 270 min 
 
X 
X 
 
 
(B + 275min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 280min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 285min 
 
X 
X 
 
 
(B + 290min) 
If PG > 140 mg/dL 
 
(X) 
 
 
(B + 295min) 
If PG > 140 mg/dL 
 
(X) 
 
 
B + 5h 
End of experiment 
Resume of subject’s usual basal rate 
X 
X 
 
13:30 
 
Free-choice lunch meal 
Covered by individual meal bolus 
 
 
 
19:00 
 
Pre-defined evening meal 
Covered by individual meal bolus 
 
 
 
 
1 Plasma glucose will be analysed at the trial site using the 
 glucose analyser. 
2 B stands for time of bolus administration. 
3 Prior to bolus administration, two PK samples for PK insulin baseline determination will be taken.  
4 Only on Visit 2. 
CCI