Clinical trial NCT04495478
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2020-07-30; Completion date: 2021-05-09
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates a new formulation of ramucirumab, a drug approved for several types of cancer.

In this study of healthy participants, a small amount of ramucirumab will be given by injection either into a vein or just under the skin. Study doctors will measure the amount of ramucirumab in the bloodstream.

Side effects and tolerability will be documented. The study will last for about 16 weeks for each participant, including screening and follow up. Screening is required within 28 days prior to entering the study.

Detailed description:

Arms: arm 1: Participants received single dose of placebo administered IV. arm 2: Participants received single 350 milligram (mg) ramucirumab administered as a 60-minute intravenous infusion at a concentration of 10 milligram per millilitre (mg/mL) as one 35 mL infusion. arm 3: Participants received single dose of placebo administered SC. arm 4: Participants received single 350 mg ramucirumab SC administered at a concentration of 175 mg/mL as one 2 mL injection. arm 5: Participants received single 350 mg ramucirumab SC administered at a concentration of 87.5 mg/mL as two 2 mL injections. arm 6: Participants received single 350 mg ramucirumab SC administered at a concentration of 175 mg/mL as two 1 mL injections. arm 7: Participants received single 700 mg ramucirumab SC administered at a concentration of 175 mg/mL as two 2 mL injections.
Interventions: intervention 1: Ramucirumab - IV intervention 2: Placebo - IV intervention 3: Ramucirumab - SC intervention 4: Placebo - SC
Intervention descriptions: intervention 1: Administered IV. intervention 2: Administered IV. intervention 3: Administered SC. intervention 4: Administered SC.

Protocol documents:
Prot_000.pdf: 
 
 
 
Protocol I4T-MC-JVDT(c) 
 
 
A Single-Dose Study in Healthy Participants to Characterize Ramucirumab 
Pharmacokinetics and Investigate Injection Site Reactions Following an 
Intravenous Infusion or Subcutaneous Administration of Ramucirumab 
 
 
NCT04495478 
 
 
Approval Date: 21-Oct-2020 


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Approval Date: 21-Oct-2020 GMT


CONFIDENTIAL
I4T-MC-JVDT(c)
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Medical Monitor Name and Contact Information will be provided separately.


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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment(b)
14-Jul-2020
Amendment(a)
26-Jun-2020
Original Protocol
15-May-2020


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I4T-MC-JVDT(c)
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Amendment(c):
Overall Rationale for the Amendment:
This amendment addresses the sponsor’s and investigator’s decision to allow doses to be reduced 
for remaining groups, as required.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
Based on the safety review of Groups 1 and 2:
clarified that SC ramucirumab dosing will 
consist of up to 3 dose levels,
removed sentinel dosing for Group 3 IV 
dosing,
reduced dose from 700 mg IV to a maximum 
dose of 350 mg IV and reduced IV infusion 
volume from 70 mL to 35 mL for Group 3,
indicated that Group 6 will be optional and 
reduced maximum dose to 350 mg,
indicated that subsequent dose levels may be 
reduced, and
indicated that IV and SC doses will not exceed 
350 mg for remaining groups.
To enhance the safety of 
the participants. The 
700 mg dose was deemed 
unacceptable based on 
cases of asymptomatic 
transaminase increases, so 
the dose capped was at 
350 mg.
1.2 Schema
Updated schema to reflect dose level changes based 
on safety data from Groups 1 and 2 and revised 
Group 6 to be optional.
To enhance the safety of 
the participants.
2.1 Study Rationale
Clarified that SC ramucirumab dosing will consist of 
up to 3 dose levels for subsequent dose-escalation 
groups.
To enhance the safety of 
the participants based on 
safety review of Groups 1 
and 2.
4.1 Overall Design
Based on the safety review of Groups 1 and 2:
removed sentinel dosing for Group 3 IV 
dosing,
reduced dose from 700 mg IV to a maximum 
350 mg IV for Group 3,
indicated that Group 6 may be dosed at a 
maximum dose of 350 mg according to the 
pharmacy manual if safety results are 
acceptable and of scientific value,
clarified that SC ramucirumab dosing will 
consist of up to 3 dose levels,
indicated that subsequent dose levels may be 
adjusted based on safety reviews, 
removed Group 6 data for further 
implementation of loading dose regimen, and 
To enhance the safety of 
the participants.


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Section # and Name
Description of Change
Brief Rationale
indicated that exclusion criteria will be revised
based on transaminase increases.
4.1 Overall Design
Indicated that participants should follow local 
guidance and CRU precautions to minimize the risk 
for COVID-19.
To minimize the risk for 
COVID-19 infection.
4.3 Justification of 
Dose
Based on the safety review of Groups 1 and 2:
reduced dose from 700 mg IV to a maximum 
dose of 350 mg IV for Group 3,
reduced maximum dose level from 1400 mg to 
350 mg for Group 6,
indicated Group 6 may not be needed based on 
emerging data, 
capped maximum dose at 350 mg for all 
subsequent groups because of the acceptable 
safety profile, and
added explanation that margin of safety table 
was based on originally planned doses.
To enhance the safety of 
the participants.
5.2 Exclusion Criteria
For Exclusion Criterion [14]:
removed 1.5-fold for ULN, and
added AST and GGT.
To enhance the safety of 
the participants based on 
safety review of Groups 1 
and 2.
5.2 Exclusion Criteria
For Exclusion Criterion [15]:
removed 1.5-fold for ULN, and
removed isolated bilirubin >1 fold ULN is 
acceptable if bilirubin is fractionated and 
direct bilirubin <35%.
To enhance the safety of 
the participants based on 
safety review of Groups 1 
and 2.
5.2 Exclusion Criteria
For Exclusion Criterion [16]:
removed with exception of Gilbert’s syndrome 
or asymptomatic gallstones, and 
specified that Gilbert’s syndrome is not 
acceptable.
To enhance the safety of 
the participants based on 
safety review of Groups 1 
and 2.
6.1 Study 
Intervention(s) 
Administered
Based on the safety review of Groups 1 and 2:
reduced dose from 700 mg IV to a maximum 
of 350 mg IV for Group 3,
removed 1400 mg SC dose, and
removed reference to approximately 30 minute 
duration for SC infusion (with pump) and 
added reference to the pharmacy manual.
To enhance the safety of 
the participants.


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Section # and Name
Description of Change
Brief Rationale
8.2.3 
Electrocardiograms
Removed reference to Section 7 for QTc withdrawal 
criteria and any additional QTc readings.
To remove a reference 
that was inadvertently 
included in the protocol.
9.4.2.2 
Pharmacokinetic 
Statistical Inference
Modified the dose range investigated from 350 mg to 
1400 mg to 350 mg to 700 mg based on safety 
review of Groups 1 and 2.
To reflect dose level 
changes based on safety 
review of Groups 1 and 2.
9.5 Interim Analyses
Indicated that PK data may be reviewed for Groups 1 
and 2 if timing permits.
To add flexibility for 
reviewing PK data if 
needed.
Throughout
Minor editorial and formatting revisions
Minor and therefore have 
not been summarized
Abbreviations: AST = aspartate aminotransferase; COVID-19 = coronavirus disease 2019; CRU = clinical research 
unit; GGT = gamma-glutamyl transferase; IV = intravenous; PK = pharmacokinetic; QTc = corrected QT interval; 
SC = subcutaneous; ULN = upper limit of normal.


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I4T-MC-JVDT(c)
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Table of Contents
1.
Protocol Summary....................................................................................................10
1.1.
Synopsis.....................................................................................................................10
1.2.
Schema.......................................................................................................................13
1.3.
Schedule of Activities (SoA) ......................................................................................14
Pharmacokinetic and Immunogenicity Sampling.........................................................22
2.
Introduction..............................................................................................................24
2.1.
Study Rationale ..........................................................................................................24
2.2.
Background ................................................................................................................25
2.3.
Benefit/Risk Assessment ............................................................................................25
3.
Objectives and Endpoints.........................................................................................27
4.
Study Design .............................................................................................................29
4.1.
Overall Design............................................................................................................29
4.2.
Scientific Rationale for Study Design .........................................................................31
4.3.
Justification for Dose..................................................................................................31
4.4.
End of Study Definition..............................................................................................33
5.
Study Population ......................................................................................................34
5.1.
Inclusion Criteria........................................................................................................34
5.2.
Exclusion Criteria.......................................................................................................35
5.3.
Lifestyle Considerations .............................................................................................37
Meals and Dietary Restrictions ...................................................................................37
Caffeine, Alcohol, and Tobacco..................................................................................37
Activity ......................................................................................................................38
5.4.
Screen Failures ...........................................................................................................38
6.
Study Intervention....................................................................................................39
6.1.
Study Intervention(s) Administered ............................................................................39
Special Treatment Considerations...............................................................................40
6.2.
Preparation/Handling/Storage/Accountability .............................................................40
6.3.
Measures to Minimize Bias: Randomization and Blinding ..........................................41
Package and Labeling .................................................................................................42
6.4.
Study Intervention Compliance...................................................................................43
6.5.
Concomitant Therapy .................................................................................................43
6.6.
Dose Modification......................................................................................................43
6.7.
Intervention after the End of the Study........................................................................43
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................44
7.1.
Discontinuation of Study Intervention ........................................................................44
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................44
Discontinuation of Inadvertently Enrolled Participants ...............................................45
7.3.
Lost to Follow-Up ......................................................................................................45
8.
Study Assessments and Procedures .........................................................................46
8.1.
Efficacy Assessments .................................................................................................46


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I4T-MC-JVDT(c)
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8.2.
Safety Assessments ....................................................................................................46
Physical Examinations................................................................................................47
Vital Signs..................................................................................................................47
Electrocardiograms.....................................................................................................47
Clinical Safety Laboratory Assessments .....................................................................48
Injection Site Reactions ..............................................................................................48
Safety Monitoring.......................................................................................................49
8.3.
Adverse Events and Serious Adverse Events ..............................................................50
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................50
Method of Detecting AEs and SAEs ...........................................................................51
Follow-Up of AEs and SAEs ......................................................................................51
Regulatory Reporting Requirements for SAEs ............................................................51
Pregnancy...................................................................................................................51
Adverse Events of Special Interest..............................................................................52
Product Complaints ....................................................................................................52
8.4.
Treatment of Overdose ...............................................................................................53
8.5.
Pharmacokinetics........................................................................................................53
Bioanalysis .................................................................................................................54
8.6.
Pharmacodynamics.....................................................................................................54
8.7.
Genetics .....................................................................................................................54
8.8.
Biomarkers.................................................................................................................54
8.9.
Immunogenicity Assessments.....................................................................................54
8.10.
Health Economics.......................................................................................................55
9.
Statistical Considerations.........................................................................................56
9.1.
Statistical Hypotheses.................................................................................................56
9.2.
Sample Size Determination.........................................................................................56
9.3.
Populations for Analyses ............................................................................................56
Study Participant Disposition......................................................................................56
Study Participant Characteristics.................................................................................56
Treatment Compliance................................................................................................56
9.4.
Statistical Analyses.....................................................................................................57
Safety Analyses ..........................................................................................................57
Pharmacokinetic Analyses ..........................................................................................57
Other Safety Analyses ................................................................................................58
Immunogenicity Assessments.....................................................................................58
Other Analyses ...........................................................................................................59
9.5.
Interim Analyses.........................................................................................................59
9.6.
Data Monitoring Committee (DMC)...........................................................................59
10.
Supporting Documentation and Operational Considerations ................................60
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................60
Regulatory and Ethical Considerations........................................................................60
Informed Consent Process ..........................................................................................60
Data Protection...........................................................................................................61
Dissemination of Clinical Study Data .........................................................................61


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Data Quality Assurance ..............................................................................................62
Source Documents......................................................................................................63
Study and Site Start and Closure.................................................................................63
Publication Policy.......................................................................................................64
Long-Term Sample Retention.....................................................................................64
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................65
Blood Sampling Summary..........................................................................................67
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting......................................................68
Definition of AE.........................................................................................................68
Definition of SAE.......................................................................................................69
Recording and Follow-Up of AEs and/or SAEs ..........................................................70
Reporting SAEs..........................................................................................................72
Sponsor Surveillance Process for Dose Escalation or Group 
Expansion...................................................................................................................72
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information.................................................................................................................74
10.5.
Appendix 5: Genetics .................................................................................................76
10.6.
Appendix 6: Pharmacokinetic Profile Simulation (Intravenous 
versus Subcutaneous) .................................................................................................77
10.7.
Appendix 7: Abbreviations .........................................................................................80
10.8.
Appendix 8: Protocol Amendment History .................................................................84
11.
References.................................................................................................................88


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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Single-Dose Study in Healthy Participants to Characterize Ramucirumab 
Pharmacokinetics and Investigate Injection Site Reactions Following an 
Intravenous Infusion or Subcutaneous Administration of Ramucirumab
Short Title: Single-Dose Study in Healthy Participants to Characterize Ramucirumab 
Pharmacokinetics and Safety after Subcutaneous Administration in Comparison to 
Intravenous Infusion
Rationale:
Ramucirumab (Cyramza®; LY3009806) drug substance (hereafter referred to as ramucirumab),
administered as an intravenous (IV) infusion, is approved for several cancer indications. There 
may be an opportunity to optimize the ramucirumab pharmacokinetic (PK) profile using a 
subcutaneous (SC) formulation. The clinical development of IV ramucirumab has been exclusively 
done in cancer patients. The large clinical data with IV ramucirumab, together with the nonclinical 
toxicology data, support investigating single IV and SC doses of ramucirumab in a healthy human 
population. 
For the new, proposed ramucirumab SC route of administration, the important biopharmaceutic 
questions (such as PK and bioavailability) will be more efficiently investigated in the healthy 
human population.
The proposed study (I4T-MC-JVDT [JVDT]) will be the first-in-human study investigating single 
administration of IV ramucirumab (1 dose level) and SC ramucirumab (up to 3 dose levels) to 
establish the PK and safety profiles in healthy participants. This will allow both safe dosing of the
new SC formulation and provide single-dose ramucirumab safety and PK profiles (both IV and 
SC) on which to build the remainder of the program.
In order to ensure safety, the doses planned in the proposed study will aim to not exceed the 
plasma concentrations (maximum drug concentration [Cmax] and area under the concentration 
versus time curve [AUC]) tested in previous studies with ramucirumab IV. Furthermore, it is 
understood that SC administration of a monoclonal antibody leads to lower plasma levels (Cmax
and AUC) than the same dose administered IV. Comprehensive details on the Study JVDT design 
is presented in the overall study design section.


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Objectives and Endpoints
Objectives
Endpoints
Primary

Evaluate ramucirumab safety 
following a single dose in healthy 
participants

Assess injection site reactions 
(ISRs) following SC 
administration of ramucirumab
using ISR questionnaire

Assess ramucirumab PK 
following a single dose of IV or 
SC administration 

Incidence of adverse events (AEs), 
treatment-emergent adverse events 
(TEAEs), and serious adverse events 
(SAEs) after IV administration and SC 
administration in healthy participants

Characterization and measurement of 
incidence and severity of ISRs (including 
injection site pain) using data collected 
from the ISR questionnaire

PK parameters: 
o
IV: area under the concentration versus 
time curve (AUC) from zero to infinity 
(AUC[0-∞]), maximum drug 
concentration (Cmax), and time of 
maximum concentration (tmax)
o
SC: AUC(0-∞), Cmax, tmax after SC 
administration 
Overall Design
Study JVDT will be the first-in-human study investigating single SC or IV administration of 
ramucirumab in healthy participants. The study will be at a single site. The study will be 
participant- and investigator-blinded, randomized, and placebo-controlled 
(7 ramucirumab:3 placebo per group/dose level). Placebo will be used as a comparator for both IV 
and SC to allow interpretation of safety and tolerability data following administration. The reason 
for randomizing 10 participants per group is to ultimately ensure that at least 8 participants
(6 ramucirumab:2 placebo) in each group complete the study (that is, complete the first 40 days of 
study procedures per the schedule of events; see Section 4.4). Replacement participants may be 
enrolled if needed to reach the planned number of completers.
There will be sentinel dosing in this protocol; the initial 2 participants will be randomized/dosed
(1 ramucirumab:1 placebo), and subsequently (the next day), the remaining participants in the 
group will be dosed. This will be subject to a satisfactory safety review by the investigator. 
This will occur on the first dose of SC (Group 1).


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Participants may receive either a single dose of IV ramucirumab or a single dose of SC 
ramucirumab (up to 3 increasing/escalating dose levels) to establish the PK and safety profiles. It 
is planned that maximum 6 groups will be sequentially enrolled and the doses envisioned are those 
below:

Group 1: SC ramucirumab 350 mg (1 injection of 2 mL×175 mg/mL)

Group 2: SC ramucirumab 700 mg (2 injections of 2 mL×175 mg/mL)

Group 3: IV ramucirumab to a maximum of 350 mg (60-minute IV infusion; maximum 
35 mL×10 mg/mL)

Group 4: SC ramucirumab 350 mg (2 injections of 2 mL×87.5 mg/mL)

Group 5: SC ramucirumab 350 mg (2 injections of 1 mL×175 mg/mL)

Optional Group 6: SC ramucirumab (maximum planned dose level, 350 mg, given as slow 
SC infusion). 
Groups 4 and 5 are planned to investigate single SC ramucirumab dose of 350 mg with different 
volume of injection (2 injections of 1 mL×175 mg/mL) and different concentration of the drug 
product (2 injections of 2 mL×87.5 mg/mL) compared to the first group dosed at 350 mg 
(1 injection of 2 mL×175 mg/mL). Data from these groups will provide insight about the effect of 
injection volumes and ramucirumab concentration on the PK and tolerability of SC ramucirumab.
The initial dose planned for Groups 3 and 6 are to be modified based on emerging data discussed 
at the safety review between sponsor and investigator (see Section 4.3 for rationale).
More precisely, following the emerging data from Groups 1 and 2, the study doses are modified 
downwards. This is pending the full safety review of all data from Groups 1 and 2. The IV dose
(Group 3) will not exceed 350 mg, and the subsequent SC doses will be capped at 350 mg
(Groups 4 through 6). In Section 4.3 (Justification for Dose), Groups 1 and 2 safety data justifying 
that change are presented in more detail.
Disclosure Statement: This is a PK and safety study to test both the marketed ramucirumab IV 
formulation and a novel ramucirumab SC formulation in healthy participants with the objective of 
comparing PK exposure and safety following both routes of administration. 
Number of Participants:
Approximately 60 participants will be enrolled and randomly assigned to study intervention to 
obtain at least 48 evaluable participants for an estimated total of at least 8 evaluable participants 
per intervention group (Section 9.2).
Intervention Groups and Duration:
Participants will be screened within 28 days prior to Day 1 of dosing for each group. Within each 
group, participants will be randomized to receive a single dose of IV or SC ramucirumab or 
placebo (7 ramucirumab:3 placebo per group). 


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The dosing groups or treatment intervention are as stated in the study design:

Group 1: SC ramucirumab 350 mg (1 injection of 2 mL×175 mg/mL)

Group 2: SC ramucirumab 700 mg (2 injections of 2 mL×175 mg/mL)

Group 3: IV ramucirumab to a maximum of 350 mg (60-minute IV infusion; maximum 
35 mL×10 mg/mL)

Group 4: SC ramucirumab 350 mg (2 injections of 2 mL×87.5 mg/mL)

Group 5: SC ramucirumab 350 mg (2 injections of 1 mL×175 mg/mL)

Optional Group 6: SC ramucirumab (maximum planned dose level, 350 mg, given as slow 
SC infusion). 
The 3 dosing groups will be sequentially enrolled/dosed after at minimum 2-week safety 
observation from the previous group has been reviewed. However, Groups 4 and 5 receiving the 
same SC ramucirumab dose as Group 1 may be dosed simultaneously to Group 3.
Participants will be admitted to the clinical research unit (CRU) as part of an inpatient visit on 
Day -1. Participants will be discharged from the CRU on Day 8 at the end of the inpatient visit 
after all study assessments for that visit have been completed and in agreement with the 
investigator. Participants will return thereafter to the CRU for clinical assessments and blood 
samples on an outpatient basis (according to the protocol Schedule of Activities) until the final 
follow-up visit approximately 12 weeks following the IV infusion or SC injection.
Data Monitoring Committee: No
1.2.
Schema
Abbreviations: IV = intravenous; LY = ramucirumab (LY3009806); Pbo = placebo; PK = pharmacokinetic(s); SC = subcutaneous.


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1.3.
Schedule of Activities (SoA)
Procedures/
Assessments
Screening Baseline
Inpatient
Outpatient EoT
F/U
Comments
Dosing
ED
Visit 
1
2
3
4
5
6
7
8
9
10
Study Day
-28 to -2
-1
1
2
3 
±1
4 
±1
5 
±1
6 
±1
7 
±1
8 
±1
12 
±1
15 
±1
22
±1
31
±2
40
±2
50
±3
90
±3
Week
-4
1
1
1
1
1
1
1
2
2
3
4
5
6
8
12
Informed consent
X
Review/confirm I/E criteria
X
P
Complete medical history 
X
Review preexisting 
conditions/AEs
X
X
P
X
X X X
X
X
X
X
X
X
X
X
X
X
AE grading will be via CTCAE
version 5.0.
Concomitant medications
X
X
P
X
X X X
X
X
X
X
X
X
X
X
X
X
Substance use 
(alcohol, tobacco)
X
X
Breath ethanol testing will be 
performed.
Physical examination
X
X
X
X
X
Complete physical examination will be 
performed at screening; brief physical 
examination at other time points.
Symptom-directed physical 
examinations may be conducted at any 
time, as deemed necessary by the 
investigator. 
Weight
X
X
P
X
X
Height
X


CONFIDENTIAL
I4T-MC-JVDT(c)
15
Schedule of Activities (SoA)
Procedures/
Assessments
Screening Baseline
Inpatient
Outpatient EoT
F/U
Comments
Dosing
ED
Visit 
1
2
3
4
5
6
7
8
9
10
Study Day
-28 to -2
-1
1
2
3 
±1
4 
±1
5 
±1
6 
±1
7 
±1
8 
±1
12 
±1
15 
±1
22
±1
31
±2
40
±2
50
±3
90
±3
Week
-4
1
1
1
1
1
1
1
2
2
3
4
5
6
8
12
Vital signs 
(PR, BP)
X
X
X
X
X X X
X
X
X
X
X
X
X
X
X
X
See Section 8.2.2 for details. Vital sign 
measurements will be measured after at 
least 5 minutes in the supine position 
(except body temperature). Blood 
pressure and heart rate will be 
collected in triplicate.
On days with concurrent ECGs, vital 
signs, and/or PK sampling, these 
measurements should occur at 
approximately the same time. ECGs 
and vital sign measurements should 
occur prior to blood draw. 
Vital sign measurements will be 
obtained:

Day 1 at predose (prior to IV or 
SC dose, but within 90 minutes 
prior to predose blood draw)

End of infusion (IV group only)

6 hours after end of infusion (IV 
group only)

Day 2 (24 hours postdose for IV 
and SC groups)

Any time for other specified visits 
(prior to blood draws at same 
visit).


CONFIDENTIAL
I4T-MC-JVDT(c)
16
Schedule of Activities (SoA)
Procedures/
Assessments
Screening Baseline
Inpatient
Outpatient EoT
F/U
Comments
Dosing
ED
Visit 
1
2
3
4
5
6
7
8
9
10
Study Day
-28 to -2
-1
1
2
3 
±1
4 
±1
5 
±1
6 
±1
7 
±1
8 
±1
12 
±1
15 
±1
22
±1
31
±2
40
±2
50
±3
90
±3
Week
-4
1
1
1
1
1
1
1
2
2
3
4
5
6
8
12
ECGs
X
X
X
X
X
X
X
X
On days with concurrent 
measurements, see vital signs row for 
more details. Participants must be 
supine for approximately 5 to 
10 minutes before ECG collection and 
remain supine but awake during ECG 
collection. Times are referenced to the 
end of dosing. 
ECGs will be obtained:

Day 1 at predose (prior to IV or 
SC dose, but within 90 minutes 
prior to predose blood draw)

End of infusion (IV group only)

6 hours after end of infusion (IV 
group only)

Day 2 (24 hours postdose for IV 
and SC groups)

Any time for other specified visits 
(prior to blood draws at same visit)
Chest x-ray
(posterior-anterior view)
X
Investigator-designated/local.
Performed at screening unless 
performed within the past 6 months, 
and x-ray/reports are available.
QuantiFERON®-TB
Gold test or TST
X
Investigator-designated/local.
Follow-up TST will occur 2 to 3 days 
after screening.


CONFIDENTIAL
I4T-MC-JVDT(c)
17
Schedule of Activities (SoA)
Procedures/
Assessments
Screening Baseline
Inpatient
Outpatient EoT
F/U
Comments
Dosing
ED
Visit 
1
2
3
4
5
6
7
8
9
10
Study Day
-28 to -2
-1
1
2
3 
±1
4 
±1
5 
±1
6 
±1
7 
±1
8 
±1
12 
±1
15 
±1
22
±1
31
±2
40
±2
50
±3
90
±3
Week
-4
1
1
1
1
1
1
1
2
2
3
4
5
6
8
12
Admission to CRU
X
Discharge from CRU
X
Following completion of Day 8
assessments.
Ramucirumab 
administration
(IV or SC)
X
HIV/Hepatitis B (surface 
antigen and core 
antibody)/Hepatitis C
X
Serum immunoglobulins
(IgG, IgM, IgA)
X
X
X
X
X
Investigator-designated/local.
Urinary drug screen
X
X
FSH
X
For women not of childbearing 
potential, FSH will be drawn to confirm 
status as defined in Inclusion Criterion 
[7b] and to be exempt for pregnancy 
tests.
Pregnancy test
X
X
X
X
Investigator-designated/local.
Serum pregnancy test will be conducted 
at screening only. Urine pregnancy test 
will be conducted at all other time 
points. A beta-human chorionic 
gonadotropin test may be performed to 
confirm a result that is positive or in the 
postmenopausal range.


CONFIDENTIAL
I4T-MC-JVDT(c)
18
Schedule of Activities (SoA)
Procedures/
Assessments
Screening Baseline
Inpatient
Outpatient EoT
F/U
Comments
Dosing
ED
Visit 
1
2
3
4
5
6
7
8
9
10
Study Day
-28 to -2
-1
1
2
3 
±1
4 
±1
5 
±1
6 
±1
7 
±1
8 
±1
12 
±1
15 
±1
22
±1
31
±2
40
±2
50
±3
90
±3
Week
-4
1
1
1
1
1
1
1
2
2
3
4
5
6
8
12
Clinical chemistry 
X
X
X
X
X
X
X
X
X
X
X
Investigator-designated/local
Hematology
X
X
X
X
X
X
X
X
X
X
X
Investigator-designated/local
Thyroid-stimulating 
hormone (including free 
T4)
X
X
X
Investigator-designated/local.
Coagulation
X
Investigator-designated/local. Perform 
as clinically indicated.
Urinalysis
X
X
X
X
X
X
X
X
X
Investigator-designated/local
Pharmacogenetics 
P


CONFIDENTIAL
I4T-MC-JVDT(c)
19
Schedule of Activities (SoA)
Procedures/
Assessments
Screening Baseline
Inpatient
Outpatient EoT
F/U
Comments
Dosing
ED
Visit 
1
2
3
4
5
6
7
8
9
10
Study Day
-28 to -2
-1
1
2
3 
±1
4 
±1
5 
±1
6 
±1
7 
±1
8 
±1
12 
±1
15 
±1
22
±1
31
±2
40
±2
50
±3
90
±3
Week
-4
1
1
1
1
1
1
1
2
2
3
4
5
6
8
12
PK sample
X
X
X X X
X
X
X
X
X
X
X
X
X
X
See PK and immunogenicity sampling 
table (Section 1.3.1) for details.
In the event of drug hypersensitivity 
reactions (immediate or 
nonimmediate), up to 3 additional 
samples will be collected for PK at the 
following time points: 

as close to the onset of the reaction 
event as possible

at the resolution of the event

approximately 90 days following 
the event
If more than 1 laboratory blood draw is 
scheduled at the same time, blood 
draws should be obtained in the 
following order:

safety laboratory tests

PK samples

immunogenicity samples


CONFIDENTIAL
I4T-MC-JVDT(c)
20
Schedule of Activities (SoA)
Procedures/
Assessments
Screening Baseline
Inpatient
Outpatient EoT
F/U
Comments
Dosing
ED
Visit 
1
2
3
4
5
6
7
8
9
10
Study Day
-28 to -2
-1
1
2
3 
±1
4 
±1
5 
±1
6 
±1
7 
±1
8 
±1
12 
±1
15 
±1
22
±1
31
±2
40
±2
50
±3
90
±3
Week
-4
1
1
1
1
1
1
1
2
2
3
4
5
6
8
12
Immunogenicity
P
X
X
X
See PK and immunogenicity sampling 
table (Section 1.3.1) for details.
In the event of drug hypersensitivity 
reactions (immediate or 
nonimmediate), up to 3 additional 
samples will be collected for 
immunogenicity at the following time 
points: 

as close to the onset of the reaction 
event as possible

at the resolution of the event

approximately 90 days following 
the event


CONFIDENTIAL
I4T-MC-JVDT(c)
21
Schedule of Activities (SoA)
Procedures/
Assessments
Screening Baseline
Inpatient
Outpatient EoT
F/U
Comments
Dosing
ED
Visit 
1
2
3
4
5
6
7
8
9
10
Study Day
-28 to -2
-1
1
2
3 
±1
4 
±1
5 
±1
6 
±1
7 
±1
8 
±1
12 
±1
15 
±1
22
±1
31
±2
40
±2
50
±3
90
±3
Week
-4
1
1
1
1
1
1
1
2
2
3
4
5
6
8
12
Injection site reaction 
assessments 
X (Predose; 
1 min ± 1 min, 
10 min ± 2 min, 
30 min ± 5 min, and 
240 min ± 10 min 
postdose)
X
(24 hr
± 4 hr
postdose)
X X X
X
X
X
X
X
X
X
X
X X
Injection site assessments will be 
performed at the indicated time points 
on each study day. The findings from 
the assessment are recorded on the ISR 
questionnaire. Injection site pain (ISP) 
assessments are part of the solicited 
and spontaneous ISR assessments. All 
positive responses of pain require an 
additional assessment using the Pain 
Visual Analog Scale (Pain VAS). If 
there are 2 injections, the ISR 
questionnaire will be filled out 
separately for each site, after both 
injections have been administered. The 
exploratory tool for injection site 
assessment (Scarletred) will be 
performed after each time the ISR 
questionnaire is administered for each 
injection. ISR assessments will be 
performed for the SC groups only. See 
Section 8.2.5 for details. 
Abbreviations: AE = adverse event; BP = blood pressure; CRU = clinical research unit; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; ED = early discontinuation; EoT = end of treatment; F/U = follow-up; FSH = follicle-stimulating hormone; HIV = human 
immunodeficiency virus; I/E = inclusion/exclusion; Ig = immunoglobulin; ISP = injection site pain; ISR = injection site reaction; IV = intravenous; 
P = predose; PK = pharmacokinetic; PR = pulse rate; SC = subcutaneous; TB = tuberculosis; TST = tuberculin skin test; VAS = visual analog scale.


CONFIDENTIAL
I4T-MC-JVDT(c)
22
Pharmacokinetic and Immunogenicity Sampling
Sample #
Day
Collection Time Point 
Relative to 
Ramucirumab Single 
Dose
Lower Limit 
For Collection 
Time
Upper Limit For 
Collection Time
Pharmacokinetic 
Analysis 
Ramucirumab/Placebo
Immunogenicity
ADA Assessment
IV
SC
ADA
IV
SC
IV and SC
1
1
-1 hr ± 5 mins 
(predose)
-65 mins
-55 mins
X
1
1
1 hr ± 5 mins 
(end of infusion)
55 mins
65 mins
X
2
1
4 hrs ± 10 mins
3 hrs 50 mins
4 hrs 10 mins
X
3
1
1
8 hrs ± 30 mins
7.5 hrs
8.5 hrs
X
X
4
2
2
24 hrs ± 1 hr
23 hrs
25 hrs
X
X
5
3
3
48 hrs ± 6 hrs
42 hrs
54 hrs
X
X
6
4
4
72 hrs ± 6 hrs
66 hrs
78 hrs
X
X
7
5
5
96 hrs ± 6 hrs
90 hrs
112 hrs
X
X
8 
6
6
120 hrs ± 6 hrs
114 hrs
126 hrs
X
X
9
7
7
144 hrs ± 6 hrs
138 hrs
150 hrs
X
X
10
8
8
168 hrs ± 6 hrs
162 hrs
174 hrs
X
X
9
12
264 hrs ± 24 hrs
240 hrs
288 hrs
X
11
10
2
15
336 hrs ± 24 hrs
312 hrs
360 hrs
X
X
X


CONFIDENTIAL
I4T-MC-JVDT(c)
23
Sample #
Day
Collection Time Point 
Relative to 
Ramucirumab Single 
Dose
Lower Limit 
For Collection 
Time
Upper Limit For 
Collection Time
Pharmacokinetic 
Analysis 
Ramucirumab/Placebo
Immunogenicity
ADA Assessment
IV
SC
ADA
IV
SC
IV and SC
11
22
End of Therapy Visit
504 hrs ± 24 hrs
480 hrs
528 hrs
X
12
12
3
31
30-day Follow-up
-
-
X
X
X
13
13
40
40 days ± 2 days
-
-
X
X
14
14
50
50 days ± 3 days
-
-
X
X
15
15
4
90
90 days ± 3 days
~ 12 weeks
-
-
X
X
X
Abbreviations: ADA = antidrug antibody; IV = intravenous; SC = subcutaneous.
The actual date and exact 24-hour clock time of sample collection should be recorded on the requisition form. Samples are requested to be taken at the specified 
time; however, aberrations to the specified sampling times will not be considered protocol deviations as long as the samples are taken and the actual sampling 
time is recorded. It is essential that the actual times of doses and samples are recorded accurately on the appropriate forms.


CONFIDENTIAL
I4T-MC-JVDT(c)
24
2.
Introduction
Ramucirumab is a human receptor-targeted monoclonal antibody (mAb) that specifically binds 
vascular endothelial growth factor (VEGF) receptor 2. Ramucirumab has been marketed 
worldwide as an intravenous (IV) formulation since 2014 and is well-established treatment, as a 
single agent and/or in combination with chemotherapy, for the following second-line indications:

gastric or gastroesophageal junction (GEJ) adenocarcinoma

non-small cell lung cancer (NSCLC)

colorectal cancer (CRC), and

hepatocellular carcinoma (HCC)
The data generated by the proposed Study I4T-MC-JVDT (JVDT) will be used to recommend a 
subcutaneous (SC) dosing regimen for ramucirumab to be used in further clinical development 
with the expectation to improve patient outcomes by changing the pharmacokinetic (PK) profile, 
relative to IV dosing, as follows:

achieve and maintain higher trough concentrations (Ctrough) with lower peak 
concentrations (Cmax) while producing comparable overall exposure at steady 
state as the IV formulation (10 mg/kg every 2 weeks [Q2W] IV),

increase the proportion of patients achieving target Ctrough (>50 g/mL), and

with an initial loading dose, ensure Ctrough >50 g/mL is achieved quickly in 
therapy.
This protocol will study both IV and SC ramucirumab in healthy participants to establish PK and 
safety after single-dose administration.
Section 2.1 and Section 4.3 provide more details about the study rationale, and dose justification
and margin of safety, respectively. 
2.1.
Study Rationale
Ramucirumab presents a biphasic disposition PK following IV administration, with a distribution 
apparent terminal elimination half-life (t1/2) of approximately 20 hours and elimination t1/2 of 
approximately 10 days to 2 weeks. Consequently, there is an initial 2-fold decline in 
ramucirumab concentration during approximately the first 3 days postdose before reaching the 
terminal phase where the ramucirumab concentration declined more slowly. 
Hence, there may be an opportunity to optimize the ramucirumab PK profile using an SC
formulation. An SC formulation would enable ramucirumab to be absorbed over a longer period 
of time than the 60-minute IV infusion, leading to a more constant ramucirumab concentration 
over the dosing interval with a higher Ctrough, lower Cmax, and lower peak-to-trough ratio under 
SC administration compared to IV administration. 
The clinical development of IV ramucirumab has been exclusively done in cancer patients. 
However, for the new proposed SC route of administration, the important biopharmaceutic 


CONFIDENTIAL
I4T-MC-JVDT(c)
25
questions (such as PK and bioavailability) will be more efficiently investigated in the healthy 
human population (questions such as PK characteristics may be answered prior to formally 
investigating the efficacy of SC ramucirumab). The large clinical data with IV ramucirumab,
together with the nonclinical toxicology data, support investigating single IV and SC doses of 
ramucirumab in a healthy human population. Section 2.3 (Benefit/Risk Assessment) and 
Section 4.3 (Dose Justification) provide details to support the clinical investigation of a single 
dose of ramucirumab in healthy participants. 
This is a single-site study in healthy participants who will receive a single dose of SC or IV 
ramucirumab. The study will be participant- and investigator-blinded, randomized, and 
placebo-controlled (7 ramucirumab:3 placebo per group/dose level). Placebo will be used as a 
comparator for both IV and SC to allow interpretation of safety and tolerability data following 
administration. Section 1.2 provides the study schema. Section 4.1 presents the study design and 
the different group/dose levels.
The study will provide the critical SC ramucirumab PK area under the concentration versus time 
curve (AUC) data to enable the determination of the bioavailability by comparison to the AUC 
following IV administration. It will also help further clinical development in terms of choice of 
dosing regimen and administration condition (in particular by assessing the effect of changing
the volume injected, or changing the concentration of SC ramucirumab solution on the exposure 
and/or tolerability). The SC ramucirumab dosing will consist of subsequent dose-escalation 
groups (up to 3 dose levels predicted to be ultimately used for therapeutic intent [see Section 4.3
for dose rationale]) to assess both safety and PK behavior (exposure and bioavailability).
2.2.
Background
See Section 2 and Section 2.1.
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of ramucirumab may be found in the Investigator’s Brochure
(IB).
The safety profile of ramucirumab given IV in adults with advanced cancers across a number of 
indications is well established. Adverse events of special interest (AESIs) identified for 
ramucirumab monotherapy include infusion-related reactions (IRRs), hypertension, proteinuria, 
arterial thromboembolic events (ATEs), bleeding/hemorrhage and gastrointestinal (GI)
perforation. Analysis of Cycle 1 data from ramucirumab monotherapy Phase 3 studies in patients 
with advanced gastric and hepatocellular carcinoma showed the majority of TEAEs reported 
were reversible Grade 1 and 2 events, occurring at similar rates in both ramucirumab and placebo 
arms. The commonly reported TEAEs were hypertension, fatigue, abdominal pain, and anemia. 
In addition to hypertension, other AESIs reported were proteinuria, bleeding/hemorrhage events,
and IRRs. Hypertension, anemia, and anaphylaxis were the events to be reported as Grade 3 
events in the ramucirumab arm. Given that the duration of treatment in this study is a single 
dose, much shorter than the duration of treatment received by cancer patients, and the trial 
population is healthy, and therefore lacking risk factors for the majority of these events


CONFIDENTIAL
I4T-MC-JVDT(c)
26
(excluding IRRs), the risk to participants of experiencing these toxicities is reduced. These risks 
are considered manageable in a clinical research unit (CRU) setting and are mitigated in the 
protocol, as the participants will be closely monitored following the single-dose administration. 
This will enable prompt identification of AEs and treatment as needed. Premedication is also 
considered to help reduce the severity of potential immediate cutaneous reactions.
The nonclinical safety profile of IV-administered ramucirumab has been evaluated in repeat-dose 
toxicity studies of up to 39-weeks duration in cynomolgus monkeys. The local irritation potential
of a single SC administration of ramucirumab, as formulated for presentation in this clinical 
protocol, has also been evaluated in monkeys. Taken together, the results of these studies support 
the safe administration of single SC doses of ramucirumab in this protocol, with exposure-based 
safety margins of 11X to 12X with respect to the maximum planned dose (see Section 4.3 for 
details).
More precisely, in nonclinical repeat-dose studies, IV ramucirumab was well tolerated and no 
adverse effects were observed after once-weekly (QW) administration of ramucirumab doses up 
to 40 mg/kg in a 5-week study, or after 11 weekly administrations of doses up to 50 mg/kg in a
39-week study in cynomolgus monkeys. Section 4.3 presents the margin of safety of the highest 
proposed single IV and SC ramucirumab dose in Study JVDT relative to the nonclinical 
no-observed-adverse-effect level (NOAEL) in the 5-week monkey study.
In the 39-week study in monkeys, renal toxicity and effects on the epiphyseal growth plate were 
observed. Because these effects emerged only after a long duration of repeated exposures, they 
are not expected following a single dose in this trial.
In the single-dose study of ramucirumab administered SC in monkeys, doses of up to 10-mg/kg 
ramucirumab were well-tolerated with no clinical signs or gross evidence of injection site 
reactions (ISRs). Non-adverse effects consisting of minimal fibroblast hypertrophy at >1 mg/kg, 
and minimal macrophage infiltrate at 10 mg/kg, were observed microscopically at the injection 
site; these effects are expected outcomes of introduction of foreign protein into the SC space and 
indicate a low potential for irritation at the injection site. 
Because ramucirumab is a biotherapeutic, no genotoxicity studies have been conducted. No 
genotoxicity is expected based on the mechanism of action. No reproductive toxicity studies 
have been conducted. Based on the mechanism of action, fetal harm would be expected and 
therefore in this study, women of childbearing potential (WOCBP) are excluded and male 
participants with partners of childbearing potential must use contraception for the required time 
period to mitigate this risk. 
There is no anticipated therapeutic benefit for the participants in this trial. However, participants 
may benefit from the screening procedures (through detection of unknown health issues) even if 
they receive no therapeutic benefit from the trial.


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I4T-MC-JVDT(c)
27
3.
Objectives and Endpoints
Objectives
Endpoints
Primary

Evaluate ramucirumab safety 
following a single dose in healthy 
participants

Assess ISRs following SC 
administration of ramucirumab using 
ISR questionnaire 

Assess ramucirumab PK following a 
single dose of IV or SC administration 

Incidence of AEs, TEAEs, and serious 
adverse events (SAEs) after IV 
administration and SC administration 
in healthy participants

Characterization and measurement of 
incidence and severity of ISRs 
(including injection site pain) using 
data collected from the ISR 
questionnaire

PK parameters: 
o
IV: area under the concentration 
versus time curve (AUC) from zero 
to infinity (AUC[0-∞]), maximum 
drug concentration (Cmax), time of 
maximum concentration (tmax)
o
SC: AUC(0-∞), Cmax, tmax after SC 
administration


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I4T-MC-JVDT(c)
28
Exploratory

Immunogenicity

Assess ISRs following SC 
administration of ramucirumab using 
Scarletred tool

The frequency and percentage of 
participants with preexisting antidrug 
antibodies (ADA) and with 
treatment-emergent antidrug antibody 
positive (TE ADA+) to ramucirumab
will be tabulated and any difference 
after IV administration versus SC
administration

For the TE ADA+ participants, the 
distribution of maximum titers will be 
described. The frequency of 
neutralizing antibodies will also be 
tabulated in TE ADA+ participants

The relationship between the presence 
of antibodies and the PK parameters,
including safety, to ramucirumab after 
IV versus SC administration

Characterization and measurement of 
incidence and severity of ISRs using 
data collected from the exploratory 
tool


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I4T-MC-JVDT(c)
29
4.
Study Design
4.1.
Overall Design
This is a single-site study in healthy participants who will receive a single dose of SC or IV 
ramucirumab. The study will be participant- and investigator-blinded, randomized, and 
placebo-controlled (7 ramucirumab:3 placebo per group/dose level). Placebo will be used as a 
comparator for both IV and SC to allow interpretation of safety and tolerability data following 
administration.
There will be sentinel dosing in this protocol; the initial 2 participants will be randomized/dosed
(1 ramucirumab:1 placebo), and subsequently (the next day), the remaining participants in the 
group will be dosed. This will be subject to a satisfactory safety review by the investigator. This 
will occur on the first dose of SC (Group 1).
In Section 4.2, additional rationale is presented for the selection of healthy participants for this 
investigation.
Participants will be screened within 28 days prior to Day 1 of dosing for each group. Participants 
will be admitted to the CRU as part of an inpatient visit on Day -1 and will be sequentially 
enrolled. In each group, participants will be randomized to receive a single dose of IV or SC 
ramucirumab or placebo (7 ramucirumab:3 placebo per group).
There will be at least a 2-week safety observation period between the titrating SC injection 
groups (Groups 1 and 2), and between the SC and IV groups (Groups 2 and 3) while local 
laboratory data is reviewed by the sponsor and investigator. If the safety review is acceptable, 
Groups 4 and 5 may be dosed simultaneously to Group 3, as no dose escalation is occurring in 
those groups. Group 6 may be dosed with an infusion pump once the sponsor has reviewed both 
the safety and PK data (Groups 1 through 3) if the safety results are acceptable and if there is 
scientific value for investigating an additional group. The dose for Group 6 will be determined
(maximum dose 350 mg). The plan for periodic reviews is presented Section 9.5.
The dose levels are provided below and may be adjusted based on safety reviews for preceding 
groups.
The participants receiving ramucirumab in each group will be administered the following dose 
level (up to 3 dose levels predicted to be ultimately used for therapeutic intent [see Section 4.3
for dose rationale]): 

Group 1 will test a ramucirumab 350-mg SC dose
o
administered at a concentration of 175 mg/mL as 1×2-mL injection.

Group 2 will test a ramucirumab 700-mg SC dose 
o
administered at a concentration of 175 mg/mL as 2×2-mL injections.


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
Group 3 will test a ramucirumab IV dose (maximum of 350 mg)
o
administered as a 60-minute infusion (maximum 35 mL×10 mg/mL).  
o
Analysis of safety and PK data from Groups 1 to 3 will allow initiation 
of Group 6.

Group 4 will test a ramucirumab 350-mg SC dose 
o
administered at a concentration of 87.5 mg/mL as 2×2-mL injections
o
The purpose is to investigate the effect of a different drug product 
concentration on PK and safety and Group 1 will be the reference 
comparison group.

Group 5 will test a ramucirumab 350-mg SC dose
o
administered at a concentration of 175 mg/mL as 2×1-mL injections
o
The purpose is to investigate the effect of a different volume 
administered at the injection site on PK and safety and Group 1 will be 
the reference comparison group.

Optional Group 6 may test SC ramucirumab dose, maximum 350 mg, to 
further understand SC ramucirumab PK and safety in healthy 
participants
o
administered at a concentration of 175 mg/mL administered via an 
infusion pump according to the pharmacy manual.
The SC injection site will be the abdomen. See Section 6.1 for details.
Following the safety review of Groups 1 and 2, the sponsor and investigator agreed to allow 
doses to be reduced for remaining groups. This may mean that less groups may need to be
studied. The asymptomatic transaminase increases observed during the safety review have also 
lead to a change in the exclusion criteria to further enhance safety of the participants. In view of 
these findings, subsequent doses will be capped at 350 mg. Lower doses may also be studied. 
These decisions will be based on emerging data (see Section 4.3 for further details).
Injection site pain (ISP) and ISRs will be monitored in each group, and a comparison of scorings 
will be used. The severity of ISP and ISRs reported across all participants will be evaluated. The 
data from Group 1, in comparison to Groups 4 and 5, will provide insight about the effect of 
injection volumes and ramucirumab concentration on ISP and ISR.
Participants will be discharged from the CRU on Day 8 after all study assessments have been 
completed and in agreement with the investigator. Participants may be required to remain in the 
CRU longer than Day 8, at the investigator’s discretion. Participants will be required to return to 
the CRU for clinical assessments and blood samples on an outpatient basis (according to the 
protocol Schedule of Activities) until the final follow-up visit approximately 12 weeks following 
the IV infusion or SC injection. The sample size is provided in Section 9.2.
Participants should follow local guidance and CRU precautions to minimize risk for coronavirus 
disease 2019 (COVID-19) infection.


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4.2.
Scientific Rationale for Study Design
The healthy population was selected to participate in this study because it is the most optimal 
setting to gather intensive PK information over an extended period of time. This PK data are 
needed to answer the scientific objectives of the study, which are to assess the bioavailability of 
ramucirumab following SC administration. Furthermore, conducting the study in healthy 
participants mitigates the potential confounding effects of disease state and concomitant 
medications in patients on the primary objective (PK and safety) of the study. It is very difficult 
to achieve the study objective in a cancer patient population. Accurate estimation of AUC is 
critical for robust estimation of bioavailability. Consequently, ramucirumab PK sampling over at 
least 12 weeks is needed to achieve that goal because of the long terminal half-life of 
ramucirumab. 
Ramucirumab IV administration is important in this study to accurately estimate the 
bioavailability, because it is not known whether ramucirumab clearance (hence exposure) is 
similar in healthy participants and cancer patients.  
Ramucirumab has not been studied in healthy human participants. However, the large clinical 
safety database of IV ramucirumab in cancer patients and the preclinical studies with 
ramucirumab administered IV and SC support investigating single IV and SC ramucirumab 
doses in healthy participants (see margin of safety in Section 4.3).
Placebo will be used as a comparator to allow optimal interpretation of safety and tolerability 
data following ramucirumab administration.
The dose justification is provided in Section 4.3.
The rationale for sample size is provided in Section 9.2.
4.3.
Justification for Dose
The overall principle for the choice of SC ramucirumab dose levels to be tested in this 
single-ascending dose study in healthy participants is:

To support appropriate dose selection in subsequent studies in cancer patients with 
multiple repeated SC ramucirumab administration

To support subsequent safe administration, in cancer patients, of ramucirumab SC 
dosing regimen leading to
o
Higher Ctrough (target 50 µg/mL) and lower Cmax for ramucirumab compared to 
IV ramucirumab 10 mg/kg Q2W 
o
Similar steady-state AUC as achieved following IV ramucirumab 10 mg/kg Q2W.
Simulations of PK profiles following SC dosing were performed, taking into account different 
constraints (for example, maximum possible drug product concentration and maximum possible 
injectable volume and dose frequency), and the most conservative (worse-case scenario) 
assumptions for bioavailability and rate of absorption (0.6 bioavailability with coefficient of 
variation [CV] 20% and rate of absorption of 0.3/day). Those assumptions are based on literature 
report about mAb PK following SC administration which indicate that 60% bioavailability is in 
the lower end of reported bioavailability (Viola et al. 2018). The 20% CV on bioavailability lead 


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to a bioavailability of 0.6 (0.44-0.79), mean (90% population prediction interval), used in these
simulations. 
All of the outcomes from those simulations, graphs, and tables are presented in Appendix 6
(Section 10.6). 
To prepare for future investigation of the above-mentioned ramucirumab SC dosing regimen in 
cancer patients, the proposed study (Study JVDT) in healthy participants will investigate single 
doses of SC ramucirumab 350 and 700 mg (with a maximum of 2 mL per injection site and a 
maximum of 2 injection sites per dose administration). The starting 350-mg SC ramucirumab 
dose is half the highest approved therapeutic dose (10 mg/kg Q2W IV). To prepare for the need 
of a loading dose in cancer patients, a ramucirumab dose of 350 mg administered SC (as a slow 
SC infusion with a pump) may also be investigated in Study JVDT.
The top planned SC ramucirumab dose in Group 6 was initially planned as a maximum dose 
level of 1400 mg in a previous protocol version. Since then, Groups 1 and 2 (350 mg and 700 mg 
SC) have been enrolled and received study treatment, and 2-week postdose safety data from 
those groups were reviewed. Consequently, after the safety review, the maximum dose is to be 
capped at 350 mg as this dose was associated with an acceptable safety profile. This edict applies 
to all subsequent groups.
The emerging data suggests Group 6 may not be needed given the planned collection of 
information at the 350 mg SC dose (Groups 1, 4, and 5).
In addition to those SC ramucirumab dose levels, a single dose of up to 350-mg ramucirumab 
administered IV (via 60-minute infusion) is planned to enable determination of the absolute 
bioavailability following SC administration. 
The initial ramucirumab SC doses will be determined from the safety data from previous clinical 
experience with IV ramucirumab, as it is understood that the IV administration leads to higher 
plasma levels and it is expected that tolerability will be better with the SC administration.
In summary, ramucirumab dose levels that are proposed for Study JVDT are:

ramucirumab IV, originally 700 mg dose level and subsequently modified to 350 mg
IV following safety review of Groups 1 and 2

ramucirumab 350 mg SC

ramucirumab 700 mg SC
The table below presents the margin of safety (based on Cmax or AUC) relative to the toxicology 
monkey study. The table uses the originally planned maximum ramucirumab dose IV and SC, in 
the absence of any ramucirumab data in healthy participants and based on the assumption that 
ramucirumab IV PK properties are similar in healthy participants and in patients and the 
assumption for bioavailability following SC as stated above.


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Predicted Margin of Safety at Maximum Dose in Study JVDT
Study
Dose (mg/kg) 
and Route of 
Administration
Cmax (µg/mL)
Margin of 
Safety
AUC0-168 
(mg.h/mL)
Margin of 
Safety
SNBL 023.04 
(5-week monkey) 
40 (IV)a
NOAEL
1460
-
189
-
JVDT (SAD in 
healthy participants)
10 (IV)b
211
7X
18.6
10X
20 (SC)c
139
11X
15.3
12X
Abbreviations: AUC0-168 = area under the curve during the dosing interval; Cmax = maximum observed 
concentration; IV = intravenous; PK = pharmacokinetics; popPK = population pharmacokinetics; SAD = single 
ascending dose; SC = subcutaneous.
a
40 mg/kg was the no-adverse-effect level in this study.
b 700 mg is equivalent to 10 mg/kg in a 70-kg human. Exposure values from RELAY popPK model report the 
mean, as the toxicology data report the mean, which is consistent with the median values reported in Appendix 6.
c
1400 mg is equivalent to 20 mg/kg in a 70-kg human. The human PK model simulation of SC regimen indicates 
a mean Cmax of 139 µg/mL and mean AUC over the first week AUC0-168 of 15.3 mg.h/mL following a 
ramucirumab 1400-mg SC administration. Appendix 6 reports median value (very close to these mean values).
A NOAEL of 40 mg/kg was established in a 5-week repeat dose study in monkey. At this dose, 
Cmax and AUC values are 11-fold and 12-fold higher than the anticipated systemic exposure 
following a single SC dose of 1400 mg in Study JVDT. At this dose, Cmax and AUC values are 
7-fold and 10-fold higher than the anticipated systemic exposure following a single IV dose of 
700 mg in Study JVDT. 
Therefore, nonclinical data provides support for the safety of the IV and SC dose of 
ramucirumab to be investigated in normal, healthy human participants (Section 10.6).
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed the first 40 days 
of study procedures as per the schedule of events. If a participant does not complete the 40 days 
procedure, he/she maybe replaced. 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the Schedule of Activities (SoA) for the last participant in the 
trial globally.


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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be between the ages of 18 and 60 years of age, inclusive, at the time of 
signing the informed consent.
Type of Participant and Disease Characteristics
2. Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, vital sign measurements, including 
electrocardiogram (ECG), and laboratory tests
3. Have clinical laboratory test results within normal reference range for the population or 
investigative site, or results with acceptable deviations that are judged to be not clinically 
significant by the investigator; have a urinary protein value <2+ on dipstick urinalysis
4. Have venous access sufficient to allow for blood sampling and/or administration of study 
intervention for IV administration as per the protocol
5. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures
Weight
6. Body weight within ≥70 kg and body mass index (BMI) within the range of 18 to
32 kg/m2 (inclusive)
Sex
7.
Male and/or female
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
a) Male participants:
regardless of their fertility status, with a partner of childbearing potential, must for 
the duration of the study or for 5 months following completion of study drug 
administration, whichever is longer, agree to either:
o
remain abstinent, if this is their preferred and usual lifestyle (periodic 
abstinence [for example, calendar, ovulation, symptothermal, 
postovulation methods], declaration of abstinence just for the duration of a 
trial, and withdrawal are not acceptable methods of contraception), or


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o
use condoms, and ensure the partner uses

one highly effective (˂1% failure rate) method of contraception, 
such as combination oral contraceptives, implanted contraceptives, 
or intrauterine devices, or

one effective method of contraception, such as diaphragms with 
spermicide or cervical sponges with spermicide
with pregnant partners should use condoms during intercourse for the duration of 
the study or for 5 months following completion of study drug administration, 
whichever is longer
who are in exclusively same-sex relationships (as their preferred and usual 
lifestyle) or with female partners of nonchildbearing potential are not required to 
use contraception
should refrain from sperm donation for the duration of the study or for 5 months 
following completion of study drug administration, whichever is longer.
b)
Female participants:
will not be breastfeeding or planning to breastfeed during the study
must have a negative pregnancy test at the time of screening
must be of nonchildbearing potential defined as: 
o
infertile due to surgical sterilization (bilateral oophorectomy, tubal 
ligation, or hysterectomy) or having a congenital anomaly (mullerian 
agenesis), or
o
postmenopausal, as evidenced by spontaneous amenorrhea for at least 
12 months, or
o
a woman ≥55 years of age who is not on hormone therapy and who has 
had at least 12 months of spontaneous amenorrhea, or with a diagnosis of 
menopause prior to starting hormone replacement therapy
Informed Consent
8. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Have known allergies to ramucirumab, any components of the formulation buffer matrix 
or related compounds, or history of significant atopy 


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2. Have an abnormal blood pressure (>140/90 mmHg) and/or pulse rate as determined by 
the investigator 
3. Have a history or presence of cardiovascular, respiratory, hepatic, renal, GI, endocrine, 
hematological, psychiatric, or neurological disorders that could significantly alter the 
absorption, metabolism, or elimination of drugs; or constituting a risk when taking the 
study intervention; interfere with the evaluation of injection site assessments, or any other 
medical condition that, in the judgement of the investigator, could interfere with the 
interpretation of data
4. Regularly use known drugs of abuse and/or show positive findings on urinary 
drug/alcohol screening
5. Have evidence of human immunodeficiency virus (HIV) infection and/or positive HIV 
antibodies 
6. Show evidence of hepatitis C and/or positive hepatitis C antibody 
7. Show evidence of hepatitis B and/or positive hepatitis B surface antigen 
8. Have self-perceived dullness or loss of sensation on either side of the body or the 
abdomen
9. Have donated blood of more than 500 mL within the previous 30 days of study screening
10. Have a history or presence of a bleeding disorder
11. Have had a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to 
enrollment
12. Have undergone major surgery within 28 days, or have postoperative bleeding 
complications or wound complications from a surgical procedure performed in the last 
2 months
13. Have a history of GI perforation, peptic ulceration, diverticular disease, and/or fistulae 
within 6 months prior to enrollment
14. Have alanine transaminase, aspartate aminotransferase, and gamma-glutamyl transferase 
> upper limit of normal (ULN)
15. Have bilirubin > ULN
16. Have current or chronic history of liver disease or known hepatic or biliary abnormalities
(Gilbert’s syndrome is not acceptable)
17. Evidence of hypothyroidism or hyperthyroidism based on clinical evaluation and/or an 
abnormal thyroid-stimulating hormone that, in the opinion of the investigator, would pose 
a risk to participant safety. Participants on a stable dose of thyroid replacement therapy 
for at least the prior 3 months who are clinically euthyroid and who are anticipated to 
remain on this dose throughout the trial period may be eligible if they meet the other 
criteria.
18. Have experienced any arterial thromboembolic events, including but not limited to 
myocardial infarction, stroke, transient ischemic attack, cerebrovascular accident, or 
unstable angina, ≤6 months prior to randomization.
Prior/Concomitant Therapy
19. Are currently using aspirin or other nonsteroidal anti-inflammatory drugs


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20. Have participated, within the last 30 days, in a clinical study involving a study 
intervention. If the previous study intervention has a long half-life, 5 half-lives or 30 days 
(whichever is longer) should have passed.
21. Have previously completed or withdrawn from this study or any other study investigating 
ramucirumab
22. Have used or intend to use over-the-counter or prescription medication for pain or 
inflammation within 7 days prior to Day 1 or during the study
Prior/Concurrent Clinical Study Experience
23. Are currently enrolled in a clinical trial involving a study intervention or off-label use of 
a drug or device, or are concurrently enrolled in any other type of medical research 
judged not to be scientifically or medically compatible with this trial
24. Have been treated with biologic agents (such as mAbs, including marketed drugs) within 
3 months or 5 half-lives (whichever is longer) prior to dosing
Diagnostic Assessments
25. Have tattoos or scars over the abdomen, or other factors (for example, rash, excessive 
folds of skin) that, in the investigator's opinion, would interfere with injection site 
assessments
Other Exclusions
26. Are deemed unsuitable for inclusion in the trial in the opinion of the investigator or 
sponsor
27. Have an average weekly alcohol intake that exceeds 21 units per week (males ≤65 years 
old) and 14 units per week (females [and males >65 years old, if applicable]); 
1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled 
spirit(s)
28. Are unwilling to stop alcohol consumption during study visits/time in the research unit
29. Smoke more than 10 cigarettes per day or are unable to abide by CRU smoking 
restrictions
5.3.
Lifestyle Considerations
Meals and Dietary Restrictions
There are no dietary restrictions for this study.
Caffeine, Alcohol, and Tobacco
1. During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (for example, coffee, tea, cola drinks, and chocolate) for 
24 hours before the start of dosing until after collection of the final PK and/or 
pharmacodynamic (PD) sample.
2. During each dosing session, participants will abstain from alcohol for 24 hours before the 
start of dosing until after collection of the final PK and/or PD sample.


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3. Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the CRU. 
Activity
1. Participants will abstain from strenuous exercise for 72 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light recreational 
activities during studies (for example, watching television, reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study and were not alternates.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Alternates may also be rescreened if out of the screening window. Rescreened 
participants should be assigned a new participant number. When rescreening, some screening 
tests and procedures may be repeated at the investigator’s discretion. Individuals may be 
rescreened once only. The interval between rescreenings should be at least 2 weeks. With 
rescreening, the individual must sign a new ICF. Repeating of laboratory tests once during the 
screening period or repeating screening tests once to comply with the protocol-designated 
screening period does not constitute rescreening.


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol.
6.1.
Study Intervention(s) Administered
Intervention 
Name
Ramucirumab IV 
(marketed IV 
formulation)
Ramucirumab SC 
Placebo for SC
Placebo for IV
Type 
Drug
Drug
Matching placebo
Matching placebo 
Dose 
Formulation
Vial
Vial
Vial
Vial
Unit Dose 
Strength(s)a
Experimental
Experimental
Placebo
Placebo
Dosage Level(s)a
350 mg
350 or 700 mg
NA
NA
Route of 
Administrationa
IV infusion
(Group 3)
SC injection (Groups 1,
2, 4, 5)
SC infusion with a 
pump (Group 6)
SC injection (Groups 1,
2, 4, 5)
SC infusion with a 
pump (Group 6)
IV infusion
(Group 3)
Usea
Experimental 
Experimental 
Placebo
Placebo
IMP and NIMPa
IMP
IMP
NIMP
NIMP
Sourcinga
Provided centrally 
by the sponsor  
Provided centrally by 
the sponsor  
Provided centrally by 
the sponsor  
Provided centrally 
by the sponsor  
Packaging and 
Labelinga
Study intervention 
will be provided in a 
vial. Each vial will 
be labeled as 
required per country 
requirement.
Study intervention will 
be provided in a vial. 
Each vial will be 
labeled as required per 
country requirement.
Placebo will be 
provided in a vial. Each 
vial will be labeled as 
required per country 
requirement.
Placebo will be 
provided in a vial. 
Each vial will be
labeled as required 
per country 
requirement.
Current/Former 
Names or 
Aliasesa
Ramucirumab, 
Cyramza®, 
LY3009806
Ramucirumab, 
Cyramza®, 
LY3009806
Placebo
Placebo
Abbreviations: IMP = investigational medicinal product; IV = intravenous; NA = not applicable; 
NIMP = noninvestigational medicinal product; SC = subcutaneous.
a
Information provided in this table (dose formulation, sourcing, packaging and labeling, current/former names or 
aliases) may change throughout the study or may vary by country.
The study intervention will be administered as a slow, IV infusion over at least 60 minutes in 
Group 3; and as an SC infusion (with a pump) in Group 6 per pharmacy manual; or SC injection 
in Groups 1, 2, 4, and 5. Sites must have resuscitation equipment, emergency drugs, and 
appropriately trained staff available during the IV or SC infusion/SC injection and for at least 
1 hour after participants have completed the IV or SC infusion/SC injection.
The SC injection site will be the abdomen. The study intervention will be given in the CRU by 
qualified CRU personnel as designated by the investigator. Study injections should be given by a 


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limited number of personnel for consistency. The site of administration of each injection will be 
recorded; when there is more than 1 injection, the same site will not be used but another quadrant 
will be used.
Special Treatment Considerations
6.1.1.1.
Premedication for Infusions and Subcutaneous Injections
Premedication (with IV histamine H1 antagonists such as diphenhydramine hydrochloride) is 
planned prior to ramucirumab IV infusion as specified per label for IV administration. 
Participants receiving SC infusion/injection will also receive oral premedication such as oral 
diphenhydramine. After the IV infusion/or SC infusion/injection, a 1-hour observation period 
will be completed. This will follow the label instructions to be used with the IV marketed 
material.
Any premedications given will be documented as a concomitant therapy (see Section 6.5).
6.1.1.2.
Management of Infusion Reactions
There is a risk of infusion reactions and anaphylaxis with any biological agent; therefore, all 
participants should be monitored closely. Symptoms and signs that may occur as part of an 
infusion reaction include, but are not limited to fever, chills, nausea, headache, bronchospasm, 
hypotension, angioedema, throat irritation, rash, pruritus, myalgia, and dizziness. In the event 
that a significant infusion reaction occurs, the infusion will be discontinued.
Supportive care should be employed in accordance with the symptoms/signs. Participants should 
be treated appropriately by the investigator. 
In the event of an IRR, every effort should be made to collect a blood sample for an 
antiramucirumab antibody determination as well as for ramucirumab serum concentration as 
close to the onset of the reaction as possible, at the resolution of the event, and 30 days following 
the onset of the event. In the case of generalized urticaria or anaphylaxis, additional blood and 
urine samples should be collected as described in Appendix 2 (Clinical Laboratory Tests)
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(that is, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual.


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5. Investigators should consult the study drug information provided in the Pharmacy 
Manual or label for the specific administration information (including warnings, 
precautions, contraindications, adverse reactions).
6.3.
Measures to Minimize Bias: Randomization and Blinding
Study using 
Precoded 
Randomization 
provided to site
On Day 1, participants will be assigned a unique number (randomization 
number). The randomization number encodes the participant’s assignment 
to the study, according to the randomization schedule. Each participant will 
be dispensed study intervention, labeled with his/her unique randomization 
number, throughout the study.
Participants will be sequentially enrolled to groups. Within each group, 
participants will be randomized to receive a single dose of IV or SC 
ramucirumab or placebo (7 ramucirumab:3 placebo per group).


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Blinded study with 
unblinded site 
pharmacist who is 
dispensing drug
Participants will be randomly assigned in a 7:3 ratio
(ramucirumab:placebo) to receive study intervention. Investigators will 
remain blinded to each participant’s assigned study intervention 
throughout the course of the study. In order to maintain this blind, an 
otherwise uninvolved third party will be responsible for the 
reconstitution and dispensation of all study intervention and will 
endeavor to ensure that there are no differences in time taken to dispense 
following randomization.
In the event of a Quality Assurance audit, the auditor(s) will be allowed 
access to unblinded study intervention records at the site(s) to verify that 
randomization/dispensing has been done accurately.
Blinding will be maintained throughout the conduct of the study as 
described in the separate Blinding Plan.
Emergency codes will be available to the investigator. A code, which 
reveals the study intervention group for a specific study participant, may 
be opened during the study only if the participant’s well-being requires 
knowledge of the participant’s treatment assignment.
If a participant’s study treatment assignment is unblinded, the participant 
must be discontinued from the study, unless the investigator obtains 
specific approval from an Eli Lilly and Company (Lilly) clinical 
pharmacologist (CP) or clinical research physician (CRP) for the study 
participant to continue in the study. During the study, emergency 
unblinding should occur only by accessing the study participant’s 
emergency code.
In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participant’s treatment assignment is 
warranted for medical management of the event. The participant’s safety 
must always be the first consideration in making such a determination. 
Where feasible and when timing of the emergent situation permits, the 
investigator should attempt to contact the Lilly medical monitor before 
unblinding a participant’s treatment assignment. If the investigator 
decides that unblinding is warranted, it is the responsibility of the 
investigator to promptly document the decision and rationale and notify 
Lilly as soon as possible.
Package and Labeling
Ramucirumab will be provided as a 10-mg/mL (IV) or 175-mg/mL (SC) preservative-free, sterile 
solution for injection in vials. The Pharmacy Manual will provide instructions for the preparation 
of 87.5-mg/mL SC ramucirumab. Placebo will be provided as a preservative-free, sterile solution 
for injection in vials (SC).
Ramucirumab and placebo vials should be stored under refrigeration at 2°C to 8°C (36°F to 
46°F) with protection from light.


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The study intervention will be labeled according to the country’s regulatory requirements
6.4.
Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of the 
dose will be confirmed by a second member of the study site staff. 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded on the case report form 
(CRF). The dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person administering the 
study intervention. 
6.5.
Concomitant Therapy
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study intervention until 
completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, the 
medication will not interfere with the study.
Acetaminophen, at doses of 3 grams/day, is permitted for use any time during the study.
Premedications for IRRs are permitted for use. Other concomitant medication may be considered 
on a case-by-case basis, by the investigator in consultation with the Medical Monitor, if possible.
6.6.
Dose Modification
If moderate or severe AEs are consistently observed across participants in a group or if 
unacceptable pharmacological effects, reasonably attributable to ramucirumab administration in 
the opinion of the investigator, are observed in more than 2 of the participants in a group, then no 
further participants will be dosed until a full safety review of the study has taken place. Relevant 
reporting and discussion with the Medical Monitor/Sponsor, relevant personnel, and the 
Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) will take place 
before resumption of dosing.
If the SAE occurs in 1 participant in a group, then dose escalation will be temporarily halted and 
no further participants will be dosed until a full safety review of the data has taken place. 
Relevant reporting and discussion with the Medical Monitor, relevant personnel, and the 
IRB/IEC will take place before resumption of dosing.
Refer to Section 10.3.5 of Appendix 3 for additional information about the sponsor's surveillance 
process for dose escalation and group expansion.
6.7.
Intervention after the End of the Study
Not applicable.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Participants discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per the SoA (Section 1.3) of the protocol.
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study for additional data collection consistent with routine safety 
monitoring. See the SoA (Section 1.3) for data to be collected at the time of discontinuation of 
study intervention and follow-up and for any further evaluations that need to be completed.
If a clinically significant finding is identified after enrollment, the investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed. Any new clinically relevant finding should be reported as 
an AE.
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study: 

at any time at his/her own request 

at the request of his/her designee (for example, parents or legal guardian)

at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons

if the participant becomes pregnant during the study

if enrollment in any other clinical study involving a study intervention or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

if the participant, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent
Discontinuation is expected to be uncommon.
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See the SoA (Section 1.3) for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be completed.
The participant will be permanently discontinued both from the study intervention and from the 
study at that time.


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If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant
withdraws from the study, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the participant may continue to follow study procedures dependent 
on the cause for the incorrect enrollment. If the investigator and the sponsor CRP agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
sponsor CRP to allow the inadvertently enrolled participant to continue in the study with or 
without treatment with investigational product (IP). The documented approval must contain the 
benefit/risk assessment and a robust clinical justification that continuing in the study will not 
jeopardize the participant’s safety. All inadvertently enrolled participants will complete safety 
follow-up as outlined in Section 1.3 (SoA), Section 8.2 (Safety Assessments), and Section 8.3
(Adverse Events and Serious Adverse Events) of the protocol.
7.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get IP. Public sources may be searched for vital status information. If vital status is 
determined to be deceased, this will be documented and the participant will not be considered 
lost to follow-up.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1.


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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

The specifications in this protocol for the timings of safety and sample collection are 
given as targets to be achieved within reasonable limits. Modifications may be made 
to the time points based upon emerging clinical information. The scheduled time 
points may be subject to minor alterations; however, the actual time has to be 
correctly recorded in the CRF. Failure or being late (that is, outside stipulated time 
allowances) to perform procedures or obtain samples due to legitimate clinical issues 
(for example, equipment technical problems, venous access difficulty, or participant
defaulting or turning up late on an agreed scheduled procedure) will not be 
considered as protocol deviations, but the CRU will still be required to notify the 
sponsor in writing via a file note.

Appendix 2 lists the laboratory tests that will be performed for this study.

Section 10.2.1 of Appendix 2 provides a summary of the maximum number and 
volume of invasive samples, for all sampling, during the study.

Unless otherwise stated in subsections below, all samples collected for 
specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results. Certain samples may be retained for a longer period, if 
necessary, to comply with applicable laws, regulations, or laboratory 
certification standards.
8.1.
Efficacy Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).


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Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, GI, and neurological systems. Height and weight will also 
be measured and recorded at screening.

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Vital Signs

For each participant, vital sign measurements should be conducted according to the 
SoA (Section 1.3) and following the study-specific recommendations included in a
Manual of Operations for the study. Vital sign measurements will be recorded before 
collecting any blood samples. 

Blood pressure and pulse rate should be measured after at least 5 minutes supine, and 
taken in triplicate.

If orthostatic measurements are required, participants should be supine for at least 
5 minutes and stand for at least 3 minutes.

If the participant feels unable to stand, supine vital signs only will be recorded.

Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of 
dizziness or posture-induced symptoms. Additional vital signs may be measured 
during each study period if warranted.
Electrocardiograms

Single, 12-lead ECGs will be obtained as outlined in the SoA (see Section 1.3) using 
an ECG machine that automatically calculates the heart rate and measures pulse rate, 
QRS, QT, and corrected QT intervals (QTc). 

For each participant, ECGs should be collected according to the SoA (Section 1.3) 
and the study-specific recommendations included in the Manual of Operations for the 
study.

Any clinically significant findings from ECGs that result in a diagnosis, and that 
occur after the participant receives the first dose of the study intervention, should 
be reported to the sponsor or its designee as an AE via electronic case report 
form (eCRF)

Electrocardiograms must be recorded before collecting any blood samples. 
Participants must be supine for approximately 5 to 10 minutes before ECG collection 
and remain supine but awake during ECG collection. Electrocardiograms may be 
obtained at additional times, when deemed clinically necessary. All ECGs recorded 
should be stored at the investigational site.


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
Electrocardiograms will be interpreted by a qualified investigator (the physician or 
qualified designee) at the site as soon after the time of ECG collection as possible, 
and ideally while the participant is still present, to determine whether the participant 
meets entry criteria at the relevant visit(s) and for immediate participant management, 
should any clinically relevant findings be identified. 
Clinical Safety Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and the 
SoA (Section 1.3) for the timing and frequency.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those 
which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study, or within 28 days after the last dose of study 
intervention, should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the investigator or 
medical monitor.
o
If such values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified 
and the sponsor notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, 
must be conducted in accordance with the laboratory manual and the SoA
(Section 1.3).
o
If laboratory values from nonprotocol-specified laboratory assessments,
performed at the institution’s local laboratory, require a change in 
participant management or are considered clinically significant by the 
investigator (for example, SAE, AE, or dose modification), then the results 
must be recorded in the CRF.
Injection Site Reactions

Injection site assessments using the ISR questionnaire and an exploratory tool
(Scarletred) will be performed at times specified in the SoA (Section 1.3). 

Manifestations of a local ISR may include erythema, induration, pain, pruritus, and 
edema. Injection site findings will be captured on the eCRF. 

Injection site reactions, whether recorded as a result of the prespecified (or solicited) 
assessment or spontaneously reported reactions, will be recorded as AEs only if they 
qualify as severe AEs. 


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
If a spontaneous (or unsolicited) ISR is reported by a participant or investigator, the 
ISR CRF will be used to capture additional information about this reaction (for 
example, degree and area of erythema) at additional visits until resolution of the 
event.

Injection site pain assessments are part of the solicited and spontaneous ISR 
assessments. All positive responses of pain will require an additional assessment 
using the Pain Visual Analog Scale (Pain VAS). The VAS will be performed at times 
specified in the SoA (Section 1.3). If there are 2 injections, timing will relate to the 
second injection. Pain measurements will be quantified using the 100-mm VAS pain 
score for all participants, regardless of whether they report ISP. The VAS is a 
well-validated tool (Williamson and Hoggart 2005) to assess ISP; it is presented as a 
100-mm line anchored by verbal descriptors, usually “no pain” and “worst imaginable 
pain.” The participant will be asked to rate any pain at the injection site on a scale of 
0 to 100 mm on the line immediately (within 1 minute) following the injection. 

In addition, the exploratory tool (Scarletred) will be used to acquire exploratory ISR 
data at each of the time points where the ISR data is being collected by administration 
of the ISR questionnaire. Failure to take this assessment at any of the indicated time 
points will not result in a protocol deviation.
Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study. This 
will include monitoring and recording of all AEs, including all National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades and SAEs.
The sponsor will review SAEs within time frames mandated by company procedures. The 
sponsor CP or CRP will periodically review the following data:

trends in safety data

laboratory analytes including proteinuria, reduced red blood cells, and decreased 
neutrophil count 

AEs, including monitoring of AESIs; see Section 8.3.6
When appropriate, the sponsor CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
8.2.6.1.
Hypersensitivity Reactions
In the event of a suspected systemic allergic/hypersensitivity reaction, additional safety data 
should be collected using the Infusion-related reaction/Hypersensitivity/Anaphylaxis follow-up 
form or documented via the eCRF.  

Hypersensitivity/Infusion-Related Reactions eCRFs are used to capture additional 
characteristics of the hypersensitivity/anaphylaxis/injection-related reaction that 
cannot be captured on the AE eCRF.

Each symptom of the event (for example, mucocutaneous, cardiovascular, GI, CNS, 
other) should be assessed.


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
If any of the above symptoms are observed during the assessment, a single 
generalized AE record should be entered on the AE eCRF (do not include symptoms 
in AE Term/description).

Timing of the event occurrence is important. The investigator should indicate the 
timing category that is appropriate.
8.3.
Adverse Events and Serious Adverse Events
The definitions of AEs and SAEs are provided in Appendix 3 (Section 10.3). The investigator 
will use CTCAE version 5.0 (NCI 2018) to assign AE severity grades.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7).
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting the sponsor or its designee to any event that seems unusual, even if this 
event may be considered an unanticipated benefit to the participant.
The investigator is responsible for the appropriate medical care of participants during the study.
Time Period and Frequency for Collecting AE and SAE Information
All SAEs will be collected from the signing of the ICF until participation in the study has ended.
All AEs will be collected from the signing of the ICF until participation in study has ended.
Adverse events that begin before the start of study intervention, but after signing of the ICF, will 
be recorded on the AE CRF.
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to sponsor begins after the participant has signed the ICF and has received the 
study intervention. However, if an SAE occurs after signing the ICF, but prior to receiving
ramucirumab, it needs to be reported ONLY if it is considered reasonably possibly related to 
study procedures.
All SAEs will be recorded and reported to the sponsor or designee immediately, and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify 
the sponsor.


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Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3
(Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
Follow-Up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AESIs (as defined in Section 8.3.6) will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up (as defined in Section 7.3). Further information on follow-up procedures is provided in 
Appendix 3 (Section 10.3).
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (for example, summary or listing of SAEs) from the 
sponsor will review and then file it along with the IB and will notify the IRB/IEC, if 
appropriate according to local requirements.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants, will be collected after the start of study intervention and until at 
least 12 weeks after the last dose.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours
of learning of the pregnancy and should follow the procedures outlined in Appendix 4
(Section 10.4).

Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs.

Pregnancy (maternal or paternal exposure to IP) does not meet the definition of an 
AE. However, to fulfill regulatory requirements, any pregnancy should be reported 
following the SAE process described in Appendix 4 (Section 10.4) to collect data on 
the outcome for both mother and fetus.


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Adverse Events of Special Interest 
The sponsor CP or CRP will periodically review AESIs for this program, which include:

bleeding/hemorrhagic events

liver failure/liver injury

hypertension

proteinuria

fistula

GI perforation

IRR (including hypersensitivity reactions)

wound healing complications

posterior reversible encephalopathy syndrome (PRES)

ATEs

venous thromboembolic events (VTEs)

congestive heart failure
When appropriate, the sponsor CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist. 
Product Complaints
A product complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
trial intervention. 
Sponsor collects product complaints on IP and drug delivery systems used in clinical studies in 
order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP so that the situation can be assessed.
NOTE: AEs/SAEs that are associated with a product complaint will also follow the processes 
outlined in Section 8.3.3 and Appendix 3 (Section 10.3) of the protocol.
8.3.7.1.
Time Period for Detecting Product Complaints

Product complaints that result in an AE will be detected, documented, and reported to 
the sponsor during all periods of the study in which the drug is used.

If the investigator learns of any product complaint at any time after a participant has 
been discharged from the study, and such incident is considered reasonably related to 
a drug provided for the study, the investigator will promptly notify the sponsor.


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8.3.7.2. Prompt Reporting of Product Complaints to Sponsor

Product complaints will be reported to the sponsor using the Product 
Complaint Form within 24 hours after the investigator becomes aware of the 
complaint.

The Product Complaint Form will be sent to the sponsor by the method 
provided in the form. If the primary method is unavailable, then an alternative 
method provided in the form should be utilized.
8.3.7.3.
Follow-Up of Product Complaints

Follow-up applies to all participants, including those who discontinue study 
intervention.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the product 
complaint.

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator and submitted to the sponsor.
8.4.
Treatment of Overdose
For this study, any dose of ramucirumab greater than a single dose of study intervention within a 
24-hour time period will be considered an overdose.
The sponsor does not recommend specific treatment for an overdose. Participants should receive 
appropriate supportive care measures for AESIs or other AEs, as deemed necessary by the 
investigator.
In the event of an overdose, the investigator/treating physician should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities until 
study intervention can no longer be detected systemically (at least 28 days).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics

Whole blood samples will be collected for measurement of serum concentrations of 
ramucirumab as specified in the SoA (Section 1.3), Section 1.3.1, and Section 10.2.1.

A maximum of 3 samples may be collected at additional time points during the study 
if warranted and agreed upon between the investigator and the sponsor. The timing of 
sampling may be altered during the course of the study based on newly available data 
(for example, to obtain data closer to the time of peak plasma concentrations) to 
ensure appropriate monitoring. 

Instructions for the collection and handling of biological samples will be provided by 
the sponsor. The actual date and time (24-hour clock time) of each sample will be 
recorded.


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
Samples will be used to evaluate the PK of ramucirumab. 

Genetic analyses will not be performed on these serum samples. Participant 
confidentiality will be maintained. 

Pharmacokinetic samples will be retained for a maximum of 1 year following the last 
participant visit for the study. During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses such as metabolism work, protein 
binding, and/or bioanalytical method cross-validation.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of ramucirumab will be assayed using a validated method. Analyses of samples 
collected from placebo treated participants are not planned.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last participant visit for the study.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
A blood sample for deoxyribonucleic acid (DNA) isolation will be collected from participants. 
See Appendix 5 (Section 10.5) for information regarding genetic research and Appendix 1
(Section 10.1.9) for details about sample retention and custody. 
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessments
At the visits and times specified in the SoA (Section 1.3) and Section 1.3.1, venous blood 
samples will be collected to determine antibody production against ramucirumab. Antibodies 
may be further characterized for their ability to neutralize the activity of the ramucirumab. To 
interpret the results of immunogenicity, a venous blood sample will be collected at the same time 
points to determine the plasma concentrations of ramucirumab. All samples for immunogenicity 
should be taken predose when applicable and possible.
Additionally, blood samples for the determination of ramucirumab concentration and 
antiramucirumab antibodies are to be collected at the 30-day and 90-day follow-up visits (see 
SoA [Section 1.3]).


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In the event of an IP-related IRR, see Section 6.1.1.2.
Antiramucirumab antibodies may be determined using a validated immunoassay at a laboratory 
designated by the sponsor or designee. Samples may be stored for a maximum of 15 years after 
the last participant visit for the trial, at a facility selected by the sponsor, to enable further 
analysis of immune responses to ramucirumab. The duration allows the sponsor to respond to 
regulatory requests related to the study drug.
Treatment-emergent antidrug antibodies (TE ADAs) are defined in Section 9.4.4.
The detection and characterization of antibodies to ramucirumab will be performed using a 
validated assay method at a laboratory under the supervision of the sponsor. 
Refer to Appendix 1 (Section 10.1.9) for details on Sample Retention.
8.10.
Health Economics
This section is not applicable for this study.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
Formal statistical hypothesis testing is not planned. Therefore, adjustments for multiple testing 
do not apply. 
9.2.
Sample Size Determination
Approximately 60 participants will be enrolled and randomly assigned to study intervention
(10 per group/dose level; 7 ramucirumab:3 placebo) to obtain at least 48 evaluable participants 
overall for an estimated total of at least 8 evaluable participants per intervention group
(6 ramucirumab and at least 2 placebo). The sample size is not powered on the basis of statistical 
hypothesis testing. A participant will be considered evaluable when the participant completes up 
to 40 days of study procedures. When a participant does not complete up to 40 days of study 
procedures, the sponsor will be consulted if the participant will need to be replaced.
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Entered
All participants who sign the ICF
Enrolled/Intent-to-Treat
All participants assigned to treatment, regardless of whether they 
take any doses of study treatment, or if they took the correct 
treatment. Participants will be analyzed according to the treatment 
group to which they were assigned.
Dose Evaluable
All participants who completed treatment 
Safety
All participants randomly assigned to study intervention and who 
take at least 1 dose of study intervention. Participants will be 
analyzed according to the intervention they actually received.
Pharmacokinetic Analysis
All treated participants who received 1 dose of study intervention 
and have sufficient evaluable PK samples.
Abbreviations: ICF = informed consent form; PK = pharmacokinetic.
Study Participant Disposition
A detailed description of participant disposition will be provided at the end of the study.
Study Participant Characteristics
Demographic and baseline characteristics will be summarized by treatment group.
Treatment Compliance
No analyses of treatment compliance are planned.


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9.4.
Statistical Analyses
Statistical analysis of this study will be the responsibility of the sponsor or its designee. The 
primary analysis of the study will occur when there are at least 8 evaluable participants 
(6 ramucirumab:2 placebo) per intervention group.
Pharmacokinetic analyses will be conducted on data from all participants who receive 1 dose of 
IP and have evaluable PK. 
Safety analyses will be conducted in the safety population.
Additional exploratory analyses of the data will be conducted as deemed appropriate. Study 
results may be pooled with the results of other studies for safety and population PK analysis 
purposes to avoid issues with post hoc analyses and incomplete disclosures of analyses.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) and the clinical study report (CSR). Additional exploratory 
analyses of the data will be conducted as deemed appropriate.
The SAP will be finalized prior to first participant, first visit, and it will include a more technical 
and detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints, including primary 
and key secondary endpoints.
Safety Analyses
9.4.1.1.
Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology.
The incidence of AEs for each treatment will be presented by severity and by association with IP
as perceived by the investigator. Adverse events reported to occur prior to study entry will be 
distinguished from those reported as new or increased in severity during the study. Each AE will 
be classified by the most suitable term from the medical regulatory dictionary.
All SAEs will be reported.
9.4.1.2.
Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital sign
measurements, and ECG parameters. The parameters will be listed, and summarized using 
standard descriptive statistics. Additional analysis will be performed if warranted upon review of 
the data.
Pharmacokinetic Analyses
9.4.2.1.
Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for ramucirumab will be calculated by standard 
noncompartmental methods of analysis.


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The primary parameters for analysis will be tmax, Cmax, and AUC of ramucirumab following IV 
and SC administration and bioavailability following SC administration. Other noncompartmental 
parameters, such as half-life, IV clearance, volume of distribution, apparent clearance, and 
volume of distribution following IV and SC ramucirumab administration may be reported.
In addition to noncompartmental analysis, non-linear mixed-effect modelling analysis of the 
Study JVDT PK data will be performed. This model will enable to estimate mean and variability 
(variance) of ramucirumab PK parameters following SC administration and to investigate 
potential covariate explaining that variability. 
9.4.2.2.
Pharmacokinetic Statistical Inference
Pharmacokinetic parameters will be evaluated to estimate ramucirumab AUC and Cmax dose 
proportionality following SC administration in the dose range investigated. Log-transformed 
ramucirumab Cmax and AUC parameters will be evaluated in a linear mixed-effects model with 
fixed effects for dose (Groups 1, 4, and 5 who received 350 mg will be combined). The treatment 
differences will be back-transformed to present the ratios of geometric means and the
corresponding 90% confidence interval (CI).
For ramucirumab SC dosing PK parameters, the tmax will be analyzed using a Wilcoxon 
rank-sum test. Estimates of the median difference based on the observed medians, 90% CIs, and 
p-values from the Wilcoxon test will be calculated.
Ramucirumab bioavailability will be estimated (see Section 9.4.2.1).
Comparison of AUC and Cmax between Group 1 and Group 4 will enable to assess the effect of 
changing the drug product concentration on the exposure. The log-transformed Cmax and AUC 
will be the response variable, and the drug product concentration (that is, Group 1 and Group 4) 
is the explanatory variable.  
Comparison of AUC and Cmax between Group 1 and Group 5 will enable to assess the effect of 
changing the volume injected at one site of injection on the exposure. The log-transformed Cmax
and AUC will be the response variable, and the volume injected (that is, Group 1 and Group 5) is 
the explanatory variable.  
Other Safety Analyses
All safety analyses will be made on the Safety Population. The most current version of the 
Medical Dictionary for Regulatory Activities (MedDRA) at the time of analysis will be used 
when reporting AEs by MedDRA terms, and CTCAE version 5.0 will be used to assign AE
severity grades.
All relevant hematology and chemistry laboratory values will be graded according to 
CTCAE version 5.0.
Immunogenicity Assessments
The frequency and percentage of participants with preexisting antidrug antibodies (ADAs) and 
with TE ADAs to ramucirumab may be tabulated. 


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Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the 
minimum required dilution if no ADAs were detected at baseline (treatment-induced ADA) or 
those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at 
baseline (treatment-boosted ADAs).
The frequency of neutralizing antibodies may also be tabulated in TE ADA-positive participants, 
when available. 
The relationship between the presence of antibodies and the PK parameters, including safety to 
ramucirumab, may be assessed.
Other Analyses
Other analyses may include analyses of assessments, which are not defined as endpoints, that 
need to be prespecified and not necessarily be reported in the CSR such as, but not limited to, 
immunogenicity, biomarkers, population PK, health care utilization endpoints and health 
technology assessment-related endpoints.
9.5.
Interim Analyses 
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended. 
However, there will be periodic reviews of data to assess safety, tolerability, and PK data. There 
will be sentinel dosing in this protocol; the initial 2 participants will be randomized/dosed
(1 ramucirumab:1 placebo), and subsequently (the next day), the remaining participants in the 
group will be dosed. The following information belongs in this section:

Safety reviews are planned prior to dose escalation after 2-week safety data are 
available.

PK data may be reviewed for Groups 1 and 2 if timing permits.

PK data will be reviewed once Group 1 through 3 PK samples have been collected 
(cutoff 2-week sample collection in Group 3).
9.6.
Data Monitoring Committee (DMC)
Not applicable.


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines
o
applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines
o
applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:
o
providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC
o
notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures
o
providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations

Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant or his/her legally authorized 
representative and answer all questions regarding the study.


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
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and is kept on file.
Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or tissue samples that are transferred to the sponsor will contain the 
identifier only; participant names or any information which would make the 
participant identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.

The sponsor has processes in place to ensure data protection, information security and 
data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach.
Dissemination of Clinical Study Data
Communication of Suspended or Terminated Dosing
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by the sponsor to all investigators (for example, by phone and/or 
email) as soon as possible. It will be a requirement that investigators respond upon receipt to 
confirm that they understand the communication and have taken the appropriate action prior to 
further dosing any participants with study intervention. Any investigator not responding will be 
followed up by the sponsor personnel prior to any further planned dosing. If a dose is planned 
imminently, the sponsor personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified.


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Reports
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation.
Data 
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (for example, 
laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. This might include laboratory tests, medical 
records, and clinical notes.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (for example, risk-based initiatives in 
operations and quality such as Risk Management and Mitigation Strategies and 
Analytical Risk-Based Monitoring), methods, responsibilities, and requirements, 
including handling of noncompliance issues and monitoring techniques are provided 
in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (for 
example, contract research organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the Clinical 
Trial Agreement unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.


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
In addition, the sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study may 
be audited by the sponsor or its representatives and/or regulatory agencies at any 
time. Investigators will be given notice before an audit occurs. 
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Data collected via the sponsor-provided data capture system(s) will be stored at third party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system(s). Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the sponsor data warehouse.
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in Section 10.1.7.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.


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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include, but are 
not limited to:

failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines

inadequate recruitment of participants by the investigator

discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance.
Long-Term Sample Retention
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development 
of ramucirumab.
Sample Type
Custodian
Retention Period After Last 
Participant Visit
Long-term storage samples
Sponsor or Designee
15 years
Biomarkers
Sponsor or Designee
15 years
PK
Sponsor or Designee
1 year 
Genetics/PD
Sponsor or Designee
15 years
Immunogenicity
Sponsor or Designee
15 years
Abbreviations: PD = pharmacodynamic; PK = pharmacokinetic.


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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed below will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s participation in the 
study.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy testing (Section 5.1)
Investigators must document their review of each laboratory safety report.
Laboratory results that could unblind the study will not be reported to investigative site or other 
blinded personnel.


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Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate 
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium (ionized/total)
Mean cell hemoglobin concentration 
Phosphorus/Phosphate 
Leukocytes (WBC)
Magnesium
Platelets
Glucose (fasting)
Differential WBC (absolute counts) of:
Blood urea nitrogen (BUN)
Neutrophils
Creatinine
Lymphocytes
Uric acid
Monocytes
Total cholesterol
Eosinophils
Total protein
Basophils
Albumin
Total bilirubin
Coagulation
Alkaline phosphatase (ALP)
Prothrombin time (PT or INR)
Aspartate aminotransferase (AST)
Partial thromboplastin time (PTT or aPTT)
Alanine aminotransferase (ALT)
Gamma-glutamyl transferase (GGT)
Urinalysis
Specific gravity
pH
Thyroid-stimulating hormone
Protein
Free thyroxine (T4)
Glucose
Hepatitis B surface antigena,b
Ketones
Hepatitis C antibodya,b
Bilirubin
HIVb
Urobilinogen
Urine drug screenc
Blood
Breath ethanol testingc
Nitrite
FSH
Microscopic examination of sedimentd
Beta human chorionic gonadotropin
Pregnancy teste
Serum Immunoglobulins
   IgG
Hypersensitivity Testsf
   IgM
Anti-LY antibodies (immunogenicity)
   IgA
LY concentration (PK)
Tryptaseg
QuantiFERON®-TB Gold Test or 
N-methylhistamine
Tuberculin Skin Test
Complements
C3a
C5a
Cytokine Panel
IL-6
IL-1β
IL-10
Basophil Activation Testh
Abbreviations: aPTT = activated partial thromboplastin time; FSH = follicle-stimulating hormone; HIV = human 
immunodeficiency virus; Ig = immunoglobulin; IL = interleukin; INR = international normalized ratio; PK = 
pharmacokinetic; PT = prothrombin; PTT = partial thromboplastin time; RBC = red blood cell; WBC = white blood cell.


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Note: Results of these assays will be validated by the local laboratory at the time of testing. Additional tests may be performed or 
auto-calculated by the laboratory as part of its standard panel that cannot be removed. Some of the above parameters are 
calculated from measured values. Omission of calculated values will not be considered as a protocol violation.
a
Performed at screening only.
b
These tests may be waived if performed within 6 months prior to screening, and if test results are available for “review” for 
Hepatitis B and C and HIV.
c
Urine drug screen and breath ethanol level will be performed at screening and repeated prior to admission to the clinical 
research unit and at other times indicated in the Schedule of Activities. 
d
Test only if dipstick result is abnormal.
e
Investigator-designated/local. Serum pregnancy test will be conducted at screening only. Urine pregnancy test will be 
conducted at all other time points. A beta human chorionic gonadotropin test may be performed to confirm a result that is 
positive or in the postmenopausal range.
f
Central laboratory. Additional tests and local laboratory tests may be performed at the discretion of the investigator.
g
If a tryptase sample is obtained more than 2 hours after the event (i.e. within 2 to 12 hours), or is not obtained because more 
than 12 hours have lapsed since the event, obtain urine for N-methylhistamine (NMH) testing. Note that for tryptase serum 
samples obtained within 2 to 12 hours of the event, urine NMH testing is performed in addition to tryptase testing. Collect the 
first void urine following the event. Obtain a follow-up urine for NMH testing at the next regularly scheduled visit or after 
4 weeks, whichever is later.
h
Antidrug antibody testing should include drug-specific IgE or the basophil activation test. The basophil activation test is an in 
vitro cell-based assay that only requires a serum sample. It is a surrogate assay for drug-specific IgE but is not specific for 
IgE.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study. 
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
35.7
1
35.7
Clinical laboratory testsa
12.5
10
125
Coagulationa
(PT or INR; PTT or aPTT)
2.7
1
2.7
Serum immunoglobulins
(IgG, IgM, IgA)
3.5
4
14
Thyroid-stimulating hormone 
(including T4)
3.5
3
10.5
Pharmacokinetics 
2.5
15
37.5
Immunogenicity
10
4
40
Hypersensitivity/Infusion-related 
reactionb
24
3
72
Pharmacogenetics
10
1
10
Total
347.4
Total for clinical purposes (rounded up to nearest 10 mL)
350
Abbreviations: Ig = immunoglobulin; INR = international normalized ratio; PT = prothrombin; PTT = partial thromboplastin 
time.
a
Additional samples may be drawn if needed for safety purposes.
b
Only in the event of drug hypersensitivity reactions (immediate or nonimmediate).


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdose should be reported regardless of sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.


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
Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (for example, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to the hospital 
for observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.

Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (for example, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is 


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appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
Recording and Follow-Up of AEs and/or SAEs
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information on the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
described in the definition of an SAE, NOT when it is rated as severe.

The investigator will use CTCAE version 5.0 (NCI 2018) to assign AE severity grades.


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship, cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor or designee.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor or designee with a copy of any 
post mortem findings, including histopathology.

New or updated information will be recorded on the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor or designee within 
24 hours of receipt of the information.


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Reporting SAEs
SAE Reporting

The investigator or site must alert Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.

Additionally, the investigator or site must alert Lilly Global Patient Safety, or its 
designee, of any SAE within 24 hours of investigator awareness of the event via a 
sponsor-approved method. If alerts are issued via telephone, they are to be immediately 
followed with official notification on study-specific SAE forms. This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE 
information.

Facsimile transmission of the SAE Form is the preferred method to transmit this 
information to the sponsor or designee.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE Form sent by overnight mail or courier 
service, or email.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE Form within the designated reporting time frames.

Contacts for SAE reporting can be found in the SAE Form.
Sponsor Surveillance Process for Dose Escalation or Group Expansion
The sponsor has systematic and robust internal processes in place that ensure safety surveillance 
of development compounds in line with Food and Drug Administration’s (FDA’s) expectations 
for safety assessment committees (SACs) (FDA 2012, 2015, 2018a, 2018b). This includes 
processes with clearly described roles and responsibilities that are owned by the sponsor’s 
Global Patient Safety organization. These processes are designed to monitor the evolving safety 
profile (that is, review of cumulative SAEs, other important safety information) by designated 
cross-functional teams in a timely manner at predefined intervals or on an ad hoc basis. In 
addition, a dedicated process may be used to perform unblinded comparisons of event rates for 
SAEs as necessary. 
This system ensures that the accumulating safety data derived from individual and multiple trials 
across a development program is reviewed on a regular basis and that important new safety 
information, such as the need for protocol modification or other relevant safety-related material,
is identified and communicated to regulators and investigators appropriately and in a timely 
fashion. An internal review of aggregate safety data occurs on at least a quarterly basis or more 
frequently, as appropriate. Any serious adverse reactions (SARs) are reported within the required 
timeline for expedited reporting.
In addition to annual periodic safety updates and to further inform investigators, a line listing 
report of suspected unexpected serious adverse reactions (SUSARs) is created and distributed to 
investigators on a biannual (twice yearly) basis. Any significant potential risk/safety concerns 
that are being monitored, as well as any results being reported in other periodic reports for the 


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compound, SAC decisions, and other significant safety data (for example, nonclinical and 
clinical findings, removal of SARs) are included in the report.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (for example, amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

documented hysterectomy

documented bilateral oophorectomy

documented tubal ligation
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(for example, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, medical history interview, or prior documented medical history at 
the site, and may be documented in the medical history.
3. Postmenopausal female is defined as women with:

at least 6 weeks postsurgical bilateral oophorectomy with-or-without hysterectomy, 
confirmed by operative note/medical records
OR

with spontaneous amenorrhea for at least 12 months, not induced by a medical condition 
such as anorexia nervosa and not taking medications during the amenorrhea (for example,
oral contraceptives, hormones, gonadotropin releasing hormone, anti-estrogens, selective 
estrogen receptor modulators [SERMs], or chemotherapy that induced the amenorrhea).
AND

if ≤ age 55, has a follicle-stimulating hormone of ≥40 mIU/mL 
Contraception Guidance:
See Section 5.1.
Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention.


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
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant’s pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at >20 weeks gestational age) is always considered to be an SAE and will 
be reported as such. 

Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section
8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting.

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study.


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10.5.
Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, mechanism of action of the drug, disease 
etiology, and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRBs/IECs allow, a blood sample will be collected for DNA 
analysis from consenting participants.

DNA samples will be used for research related to study intervention or cancer and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to study intervention and/or interventions of this drug class and cancer. 
Genetic research may consist of the analysis of 1 or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome
(as appropriate).

Additional analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand study disease or related conditions.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.

The samples will be retained while research on study intervention or study 
interventions of this class or indication continues but no longer than 15 years or other 
time period as per local requirements.


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10.6.
Appendix 6: Pharmacokinetic Profile Simulation (Intravenous versus 
Subcutaneous)
The PK profile for IV (10 mg/kg Q2W) and SC administration of ramucirumab (Left panel: 
1400-mg SC loading dose on Day 1 followed by QW SC 700 mg; Right panel: 1400-mg SC 
loading dose on Day 1 followed by twice-weekly [BIW] SC 350 mg) is shown in the figure 
below.
Abbreviations: BIW = twice weekly; IV = intravenous; LD = loading dose; Q2W = every 2 weeks; QW = once 
weekly; Ram = ramucirumab; SC = subcutaneous.


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Model-Simulated Ramucirumab AUC, Average, Trough, and Peak Concentrations 
Following Intravenous (10 mg/kg Q2W) and Subcutaneous Administration of 
Ramucirumab (1400-mg SC loading dose on Day 1 followed by either weekly [QW] SC 
700 mg or twice weekly [BIW] SC 350 mg)
10 mg/kg Q2W IV 
RELAY
SC LD 1400 mg + SC MD 
350 mg BIW
SC LD 1400 mg + SC 
MD 700 mg QW
RATIO
RATIO
SC 350 / 
IV 10
SC 700 / 
IV 10
Median
5th-95th
percentile
Median
5th-95th
percentile
Median
5th-95th
percentile
Median
Median
Week 1&2 PK parameters
AUC1 mg.h/mL
18.1
13.2-25.4
16.3
10.6-25.1
14.8
9.61-22.9
0.90
0.82
AUC2 mg.h/mL
26.2
18.2-38.2
39.2
24.8-61.5
35.8
22.6-56.2
1.50
1.37
Cav µg/mL 
Week1
108
79-151
97
63-149
88.1
57-136
0.9
0.82
Cav µg/mL 
Week2
48
30-76
136
85-217
125
77-198
2.83
2.59
Cmax µg/mL
206
153-285
141
87-227
134
83-212
0.68
0.65
Ctrough µg/mL
35
16-58
133
80-218
112
66-184
3.86
3.25
Steady state SS PK parameters
AUCss mg.h/mL
48.0
30-75
59
33-102
59
34-102
1.23
1.23
Cav µg/mL
143
90-223
176
99.4-305
176
100-305
1.23
1.23
Cmax µg/mL
285
200-412
178
100-308
186
106-318
0.62
0.65
Ctrough µg/mL
77
38-138
170
96-296
157
86-278
2.21
2.04
Ratio Ctrough
SS/WEEK1&2
2.23
1.28
1.40
Caverage to trough 
WEEK2
1.38
1.02
1.12
Peak to trough at 
SS
3.7
1.05
1.18
Abbreviations: AUCss = area under the curve at steady state over 2 weeks; AUC1 = area under the curve during the 
first week of treatment; AUC2 = area under the curve during the first 2 weeks of treatment; BIW = twice weekly; 
Cav = average concentration; Cmax = maximum concentration; Ctrough =trough min concentration at the end of the 
dosing interval; IV = intravenous; LD = loading dose; MD = maintenance dose; PK = pharmacokinetic; 
SC = subcutaneous; SS = steady state; Q2W = every 2 weeks; QW = once weekly.


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Model-Simulated Ramucirumab AUC, Average, Trough, and Peak Concentrations 
Following Intravenous (13 mg/kg QW) and Subcutaneous Administration of Ramucirumab 
(1400-mg SC loading dose on Day 1 followed by either weekly [QW] SC 700 mg or twice 
weekly [BIW] SC 350 mg)
13 mg/kg IV QW 
MTD
SC LD 1400 mg + SC MD 
350 mg BIW
SC LD 1400 mg + SC MD 
700 mg QW
RATIO-
MOS
RATIO-
MOS
IV 13 
mg/kg
QW/SC70
0
IV 13 
mg/kg
QW/SC35
0
Median
5th-95th
percentile
Median
5th-95th
percentile
Median
5th-95th
percentile
Median
Median
Week 1&2 PK parameters
AUC1 
mg.h/mL
23.5
17.1-33.1
16.3
10.6-25.1
14.8
9.61-22.9
1.6
1.4
AUC2 
mg.h/mL
58
41.2 – 83
39.2
24.8-61.5
35.8
22.6-56.2
1.6
1.5
Cav µg/mL 
Week1
140
101-197
97
63-149
88
57-136
1.6
1.5
Cav µg/mL 
Week2
205
143-297
136
85-217
125
77-198
1.6
1.5
Cmax
µg/mL
353
259-495
141
87-227
134
83-212
2.6
2.5
Ctrough
µg/mL
135
82-207
133
80-218
112
66-184
1.2
1.0
Steady state SS PK parameters
AUC,ss
mg.h/mL
125
78-194
59
33-102
59
34-102
2.11
2.11
Cav µg/mL
371
233-578
176
99.4-305
176
100-305
2.11
2.11
Cmax
µg/mL
540
366-804
178
100-308
186
106-318
2.9
3.03
Ctrough
µg/mL
270
153-433
170
96-296
157
86-278
1.72
1.59
Abbreviations: AUCss = area under the curve at steady state over 2 weeks; AUC1 = area under the curve during the 
first week of treatment; AUC2 = area under the curve during the first 2 weeks of treatment; BIW = twice weekly; 
Cav = average concentration; Cmax = maximum concentration; Ctrough =trough min concentration at the end of the 
dosing interval; IV = intravenous; LD = loading dose; MD = maintenance dose; PK = pharmacokinetic; 
SC = subcutaneous; SS = steady state; QW = once weekly. 


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10.7.
Appendix 7: Abbreviations
Term
Definition
ADA
antidrug antibody
AE
adverse event
AESI
adverse event of special interest
ATE
arterial thromboembolic event
AUC
area under the concentration versus time curve
BIW
twice weekly
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the participant are not.
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the 
participants are aware of the treatment received.
BMI
body mass index
Cav
average drug concentration during the dosing interval for a single dose
Cmax
maximum drug concentration
Ctrough
minimal/predose concentration before the next dose
CFR 
Code of Federal Regulations 
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, GCP, and applicable regulatory requirements.
COVID-19
coronavirus disease 2019
CP
clinical pharmacologist
CRC
colorectal cancer
CRF/eCRF
case report form/electronic case report form
CRP
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.


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CRU
clinical research unit
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
data monitoring committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
EDC
electronic data capture
enroll
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GEJ
gastroesophageal junction
GI
gastrointestinal
HCC
hepatocellular carcinoma
HIPAA
Health Insurance Portability and Accountability Act
HIV 
human immunodeficiency virus 
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form.
IP
investigational product
IRB
Institutional Review Board
IRR
infusion-related reaction


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ISP
injection site pain
ISR
injection site reaction
IV
intravenous(ly)
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
NSCLC
non-small cell lung cancer
participant
equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PRES
posterior reversible encephalopathy syndrome
Q2W
every 2 weeks
QTc
corrected QT interval
QW
once weekly
SAC
safety assessment committee
SAE
serious adverse event
SAP
statistical analysis plan
SAR
serious adverse reaction
SC
subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SERM
selective estrogen receptor modulator
SoA
Schedule of Activities
SUSAR
suspected unexpected serious adverse reaction
t1/2
apparent terminal elimination half-life
tmax
time of maximum concentration


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TE ADA
treatment-emergent antidrug antibody
TE ADA+
treatment-emergent antidrug antibody positive
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
VAS
visual analog scale
VEGF
vascular endothelial growth factor
VTE
venous thromboembolic event
WOCBP
woman/women of childbearing potential


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10.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment(b): 14 July 2020
Overall Rationale for the Amendment:
This amendment addresses feedback from the United States Food and Drug Administration 
(FDA).
Section # and 
Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities
Indicated that AE grading will be via 
CTCAE version 5.0
To address FDA feedback
8.2.6 Safety 
Monitoring
Indicated that safety monitoring will 
include monitoring and recording of 
all AEs, including all CTCAE 
version 5.0 grades and SAEs
To address FDA feedback
8.3 Adverse Events 
and Serious 
Adverse Events
Indicated that the investigator will 
use CTCAE version 5.0 to assign AE 
severity grades
To address FDA feedback
9.4.3 Other Safety 
Analyses
Indicated that the most current 
version of MedDRA will be used to 
report AEs and that CTCAE version 
5.0 will be used to assign AE 
severity grades. Indicated that all 
relevant hematology and chemistry 
laboratory values will be graded 
according to CTCAE version 5.0. 
To address FDA feedback
10.3.3 Recording 
and Follow-Up of 
AEs and/or SAEs
Indicated that the investigator will 
use CTCAE version 5.0 to assign AE 
severity grades
To address FDA feedback
11 References
Added reference for CTCAE version 
5.0
To address FDA feedback
Throughout
Minor editorial and formatting 
revisions
Minor and therefore have not been 
summarized
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; FDA = United 
States Food and Drug Administration; MedDRA = Medical Dictionary for Regulatory Activities; SAE = serious 
adverse event.


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Amendment(a): 26 June 2020
Overall Rationale for the Amendment:
Due to the COVID-19–related increased risks, extending the participant’s inpatient visits at the 
clinical research unit would reduce the exposure and risks.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
Modified the enrollment ratio to 
10 participants 
(7 ramucirumab:3 placebo per 
group) to complete at least 
8 participants
To capture that 10 participants per 
group will be enrolled
1.1 Synopsis
Added language to indicate that 
replacements may be enrolled
To add flexibility because 
replacements may be needed to reach 
the planned number of completers
1.1 Synopsis
Revised dosing for the remaining 
participants in the sentinel group 
from later in the morning to the 
next day
To reflect that dosing will be on the 
next day for the remaining participants 
in the sentinel group
1.1 Synopsis
Clarified that at least 48 evaluable 
participants will be enrolled and 
randomized for at least 
8 evaluable participants per group
To add clarity on number of evaluable 
participants
1.1 Synopsis
Changed CRU discharge to Day 8 
from Day 5
To reduce the risk of infections, 
changed outpatient visits for Days 6, 7, 
and 8 to inpatient visits
1.2 Schema
Modified schema to include 
7 ramucirumab:3 placebo 
participants per group instead of 
6 ramucirumab:2 placebo 
participants per group
To reflect the change in enrollment 
ratio and clarify that Group 6 will be 
randomized
1.3 Schedule of 
Activities
Changed outpatient visits for
Days 6, 7, and 8 to inpatient visits
To minimize the procedures for 
check-ins/check-outs due to 
COVID-19
1.3 Schedule of 
Activities
Indicated that breath ethanol 
testing will be performed
To clarify that breath testing will be 
done for alcohol


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Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities
Clarified that a complete physical 
examination will be performed at 
screening and brief physical 
examinations will be performed at 
other time points
To provide clarification on physical 
examinations
1.3 Schedule of 
Activities
Changed CRU discharge to Day 8 
from Day 5
To reduce the risk of infections, 
changed outpatient visits for Days 6, 7, 
and 8 to inpatient visits
2.1 Study 
Rationale
Modified the enrollment ratio to 
10 participants 
(7 ramucirumab:3 placebo per 
group) to complete at least 
8 participants 
To capture that 10 participants per 
group will be enrolled
4.1 Overall Design
Modified the enrollment ratio to 
10 participants 
(7 ramucirumab:3 placebo per 
group) to complete at least 
8 participants 
To capture that 10 participants per 
group will be enrolled
4.1 Overall Design
Revised dosing for the remaining 
participants in the sentinel group 
from later in the morning to the 
next day
To reflect that dosing will be on the 
next day for the remaining participants 
in the sentinel group 
4.1 Overall Design
Changed CRU discharge to Day 8 
from Day 5
To reduce the risk of infections, 
changed outpatient visits for Days 6, 7, 
and 8 to inpatient visits
5.1 Inclusion 
Criteria
Under inclusion criterion [7a], 
added with spermicide
To add clarity that cervical sponges 
will be used with spermicide
5.1 Inclusion 
Criteria
Under inclusion criterion [7b], 
removed regardless of 
childbearing potential
To remove unnecessary language 
because females must be of 
nonchildbearing potential
6.1 Study 
Intervention(s) 
Administered
Under the placebo for IV column, 
removed reference to SC injection 
(Groups 1, 2, 4, 5) and SC 
infusion with a pump (Group 6)
To remove duplicate information that 
was inadvertently populated under the 
placebo for IV column. The placebo 
for SC is captured under the placebo 
for SC column. 


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Section # and Name
Description of Change
Brief Rationale
6.3 Measures to 
Minimize Bias: 
Randomization 
and Blinding
Modified the enrollment ratio to 
10 participants 
(7 ramucirumab:3 placebo per 
group) to complete at least 
8 participants 
To capture that 10 participants per 
group will be enrolled
6.3 Measures to 
Minimize Bias: 
Randomization 
and Blinding
Revised ratio for randomization 
to 7:3 from 3:1
To capture that 10 participants per 
group will be enrolled
9.2 Sample Size 
Determination
Clarified that participants will be 
randomly assigned (10 per 
group/dose level; 
7 ramucirumab:3 placebo) to 
obtain at least 8 evaluable 
participants per group 
(6 ramucirumab:2 placebo)
To capture that 10 participants per 
group will be enrolled to complete at 
least 8 evaluable participants
9.2 Sample Size 
Determination
Revised to indicate that the 
participant will be considered 
evaluable instead of a completer 
when the participant completes up 
to 40 days of study procedures
To capture the number of evaluable 
participants needed for the analysis
9.2 Sample Size 
Determination
Added language to indicate that 
the sponsor will be consulted if a 
participant needs to be replaced
To add flexibility because 
replacements may not be needed if 
there are sufficient evaluable 
participants
9.4 Statistical 
Analyses
Added timeline for primary 
analysis of the study
To add clarity for primary analysis
9.5 Interim 
Analysis
Revised dosing for the remaining 
participants in the sentinel group 
from later in the morning to the 
next day
To reflect that dosing will be on the 
next day for the remaining participants 
in the sentinel group
10.2 Appendix 2 
Clinical 
Laboratory Tests
Revised ethanol testing to breath 
ethanol testing
To clarify that breath ethanol testing is 
acceptable
Throughout
Minor editorial and formatting 
revisions
Minor and therefore have not been 
summarized
Abbreviations: COVID-19 = coronavirus disease 2019; CRU = clinical research unit; IV = intravenous.


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11.
References
[FDA] United States Food and Drug Administration. Expansion Cohorts: Use in First-In-Human 
Clinical Trials to Expedite Development of Oncology Drugs and Biologics. Draft Guidance. 
Available at: https://www.fda.gov/media/115172/download. July 2018 (2018a). Accessed 
February 20, 2020. 
[FDA] United States Food and Drug Administration. Master Protocols: Efficient Clinical Trial 
Design Strategies to Expedite Development of Oncology Drugs and Biologics. Draft 
Guidance. Available at: https://www.fda.gov/media/120721/download. August 2018 (2018b). 
Accessed February 20, 2020.
[FDA] United States Food and Drug Administration. Safety Assessment for IND Safety 
Reporting. Draft Guidance. Available at: https://www.fda.gov/media/94879/download. 
December 2015. Accessed February 20, 2020.
[FDA] United States Food and Drug Administration. Safety Reporting Requirements for INDs 
and BA/BE Studies. Guidance. Available at: https://www.fda.gov/media/79394/download. 
December 2012. Accessed February 20, 2020.
[NCI] National Cancer Institute. Common terminology criteria for adverse events (CTCAE)
v5.0. Available at:
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Published 
05 January 2018. Accessed July 07, 2020.
Viola M, Sequeira J, Seiça R, et al. Subcutaneous delivery of monoclonal antibodies: how do we 
get there? J Control Release. 2018;286:301-314.
https://doi.org/10.1016/j.jconrel.2018.08.001
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin 
Nurs. 2005;14(7):798-804. https://doi.org/10.1111/j.1365-2702.2005.01121.x


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

SAP_001.pdf: 
 
 
Statistical Analysis Plan: I4T-MC-JVDT (version 2) 
 
 
A Single-Dose Study in Healthy Participants to Characterize Ramucirumab 
Pharmacokinetics and Investigate Injection Site Reactions Following an 
Intravenous Infusion or Subcutaneous Administration of Ramucirumab 
 
 
NCT04495478 
 
 
Approval Date: 25-Nov-2020 


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STATISTICAL ANALYSIS PLAN
A Single-Dose Study in Healthy Participants to Characterize Ramucirumab 
Pharmacokinetics and Investigate Injection Site Reactions Following an Intravenous 
Infusion or Subcutaneous Administration of Ramucirumab
Statistical Analysis Plan Status: Final Version 2
Statistical Analysis Plan Date: 19-November-2020
Study Drug: LY3009806
Sponsor Reference: I4T-MC-JVDT
Covance CRU Study: 1000071-8426420
Clinical Phase I
Approval Date: 25-Nov-2020 GMT


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Statistical Analysis Plan 
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1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 6
4.1
Primary Objectives and Endpoints........................................................................... 6
4.2
Exploratory Objectives and Endpoints..................................................................... 7
5.
STUDY DESIGN........................................................................................................... 7
6.
TREATMENTS............................................................................................................. 9
7.
SAMPLE SIZE JUSTIFICATION ............................................................................... 10
8.
DEFINITION OF ANALYSIS POPULATIONS.......................................................... 10
9.
STATISTICAL METHODOLOGY ............................................................................. 10
9.1
General.................................................................................................................. 10
9.2
Demographics and Participant Disposition............................................................. 11
9.3
Pharmacokinetic Assessment................................................................................. 11
9.3.1
Pharmacokinetic Analysis............................................................................. 11
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 15
9.4
Safety and Tolerability Assessments...................................................................... 16
9.4.1
Adverse events ............................................................................................. 16
9.4.2
Concomitant medication............................................................................... 16
9.4.3
Clinical laboratory parameters...................................................................... 16
9.4.4
Vital signs .................................................................................................... 16
9.4.5
Electrocardiogram (ECG)............................................................................. 17
9.4.6
Immunogenicity Assessments....................................................................... 17
9.4.7
Hypersensitivity reactions............................................................................. 17
9.4.8
Injection-Site Reactions................................................................................ 17
9.4.9
Injection-Site Pain Assessment..................................................................... 17
9.4.10
Other assessments......................................................................................... 17
9.4.11
Safety and Tolerability Statistical Methodology............................................ 18
10. INTERIM ANALYSES ............................................................................................... 18
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 18
12. REFERENCES ............................................................................................................ 18
13. DATA PRESENTATION ............................................................................................ 18
13.1 Derived Parameters ............................................................................................... 18
13.2 Missing Data ......................................................................................................... 18
13.3 Insufficient Data for Presentation .......................................................................... 19


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2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
%AUC(tlast-∞)
Percentage of AUC(0-∞) extrapolated
ADA
Anti-drug antibody
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
BQL
Below the lower limit of quantitation
CL
Apparent total body clearance of drug calculated at intravenous 
administration
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
ECG
Electrocardiogram
F
Bioavailability based on AUC(0-∞)
ICH
International Conference on Harmonisation
ISP
Injection site pain 
ISR 
Injection site reaction 
IV
Intravenous 
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SD
Standard deviation 


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t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
TE ADA
Treatment-emergent antidrug antibody
TE ADA+
Treatment-emergent antidrug antibody positive
TEAE
Treatment-emergent adverse event
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
VAS
Visual analog scale
Vss
Volume of distribution at steady state following intravenous 
administration
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz
Volume of distribution during the terminal phase after intravenous 
administration (IV administration only)
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration (SC administration only)
WHO
World Health Organization


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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
15 May 2020), Protocol Amendment (a) (final version dated 26 June 2020), Protocol 
Amendment (b) (final version dated 14 July 2020), and Protocol Amendment (c) (final version 
dated 21 October 2020).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. When the SAP 
and TFL shells are agreed upon and finalized, they will serve as the template for this study’s 
CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.


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4. STUDY OBJECTIVES AND ENDPOINTS
4.1
Primary Objectives and Endpoints
Primary Objectives
Primary Endpoints

Evaluate ramucirumab safety following a 
single dose in healthy participants

Incidence of adverse events (AEs),
treatment-emergent adverse events
(TEAEs), and serious adverse events 
(SAEs) after intravenous (IV)
administration and subcutaneous (SC)
administration in healthy participants

Assess injection site reactions (ISRs)
following SC administration of 
ramucirumab using ISR questionnaire

Characterization and measurement of 
incidence and severity of ISRs (including 
injection site pain [ISP]) using data 
collected from the ISR questionnaire

Assess ramucirumab PK following a 
single dose of IV or SC administration

PK parameters:
o
IV: area under the concentration 
versus time curve (AUC) from zero 
to infinity (AUC[0-∞]), maximum 
observed drug concentration 
(Cmax), time of maximum observed 
drug concentration (tmax)
o
SC: AUC(0-∞), Cmax, tmax after SC 
administration


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4.2
Exploratory Objectives and Endpoints
Exploratory Objectives
Exploratory Endpoints
Immunogenicity
The frequency and percentage of 
participants with preexisting antidrug 
antibodies (ADA) and with 
treatment-emergent antidrug antibody 
positive (TE ADA+) to ramucirumab will 
be tabulated and any difference after IV 
administration versus SC administration
For the TE ADA+ participants, the 
distribution of maximum titers will be 
described. The frequency of neutralizing 
antibodies will also be tabulated in 
TE ADA+ participants
The relationship between the presence of 
antibodies and the PK parameters, 
including safety, to ramucirumab after IV 
versus SC administration 
Assess ISRs following SC administration 
of ramucirumab using Scarletred tool
Characterization and measurement of 
incidence and severity of ISRs using data 
collected from the exploratory tool
5. STUDY DESIGN
This is a single-site study in healthy participants who will receive a single dose of SC or IV 
ramucirumab. The study will be participant- and investigator-blinded, randomized, and 
placebo-controlled (7 ramucirumab:3 placebo per group/dose level). Placebo will be used as a 
comparator for both IV and SC to allow interpretation of safety and tolerability data following 
administration.
There will be sentinel dosing in this protocol, the initial 2 participants will be randomized/dosed 
(1 ramucirumab:1 placebo), and subsequently (the next day), the remaining participants in the 
group will be dosed. This will be subject to a satisfactory safety review by the investigator. This 
will occur on both the first dose of SC (Group 1). 
Participants will be screened within 28 days prior to Day 1 of dosing for each group. Participants 
will be admitted to the clinical research unit (CRU) as part of an inpatient visit on Day -1 and 
will be sequentially enrolled. In each group, participants will be randomized to receive a single 
dose of IV or SC ramucirumab or placebo (7 ramucirumab:3 placebo per group). 


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The participants receiving ramucirumab in each group will be administered the following dose 
level (3 dose levels predicted to be ultimately used for therapeutic intent): 

Group 1 will test a ramucirumab 350-mg SC dose
o
administered at a concentration of 175 mg/mL as 1×2-mL injection.

Group 2 will test a ramucirumab 700-mg SC dose 
o
administered at a concentration of 175 mg/mL as 2×2-mL injections.

Group 3 will test a ramucirumab IV dose (maximum of 350 mg)
o
administered as a 60-minute infusion (35 mL×10 mg/mL)
o
Analysis of safety and PK data from Groups 1 to 3 will allow initiation of 
Group 6.

Group 4 will test a ramucirumab 350-mg SC dose
o
administered at a concentration of 87.5 mg/mL as 2×2-mL injections
o
The purpose is to investigate the effect of a different drug product concentration 
on PK and safety and Group 1 will be the reference comparison group.

Group 5 will test a ramucirumab 350-mg SC dose
o
administered at a concentration of 175 mg/mL as 2×1-mL injections
o
The purpose is to investigate the effect of a different volume administered at the 
injection site on PK and safety and Group 1 will be the reference comparison 
group.

Optional Group 6 may test SC ramucirumab dose, maximum 350 mg 
o
administered at a concentration of 175 mg/mL administered via an infusion pump
according to the pharmacy manual
The SC injection site will be the abdomen. 
There will be at least a 2-week safety observation period between the titrating SC injection 
groups (Groups 1 and 2), and between the SC and IV 700-mg groups (Group 2 and 3) while local 
laboratory data is reviewed by the sponsor and investigator. If the safety review is acceptable, 
Groups 4 and 5 may be dosed simultaneously to Group 3, as no dose escalation is occurring in 
those groups. Group 6 will be dosed with an infusion pump once the sponsor has reviewed both 
the safety and PK data (Groups 1 through 3) and thus confirm the dose for Group 6 (maximum 
dose 1400 mg). 
Following the safety review of Groups 1 and 2, the sponsor and investigator agreed to allow 
doses to be reduced for remaining groups. This may mean less groups may need to be studied. 
The asymptomatic transaminase increases observed during the safety review have also lead to a 
change in the exclusion criteria to further enhance the safety of the participants. In view of these 
findings, subsequent doses will be capped at 350 mg. Lower doses may also be studied. These 
decisions will be based on emerging data.
Injection site pain and ISRs will be monitored in each group, and a comparison of scorings will 
be used. The severity of ISP and ISRs reported across all participants will be evaluated. The data 
from Group 1, in comparison to Groups 4 and 5, will provide insight about the effect of injection 
volumes and ramucirumab concentration on ISP and ISR. 


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Participants will be discharged from the CRU on Day 8 after all study assessments have been 
completed and in agreement with the investigator. Participants may be required to remain in the 
CRU longer than Day 8, at the investigator’s discretion. Participants will be required to return to 
the CRU for clinical assessments and blood samples on an outpatient basis until the final 
follow-up visit approximately 12 weeks following the IV infusion or SC injection.
The study schema is shown below.
6. TREATMENTS
The following is a list of the study treatment names that will be used in the TFLs.
Study Treatment Name
Abbreviations
Treatment order in TFL
Placebo IV
A
1
Placebo SC
B
2
350 mg ramucirumab IV
C
3
350 mg ramucirumab SC (1x2 mL)
D
4
350 mg ramucirumab SC (2x2 mL)
E
5
350 mg ramucirumab SC (2x1 mL)
F
6
700 mg ramucirumab SC (2x2 mL)
G
7
XX mg ramucirumab slow SC infusion 
H
8


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7. SAMPLE SIZE JUSTIFICATION
Approximately 60 participants will be enrolled and randomly assigned to study intervention (10 
per group/dose level; 7 ramucirumab:3 placebo) to obtain at least 48 evaluable participants
overall for an estimated total of at least 8 evaluable participants per intervention group (6 
ramucirumab and at least 2 placebo). The sample size is not powered on the basis of statistical 
hypothesis testing. A participant will be considered evaluable when the participant completes up 
to 40 days of study procedures. When a participant does not complete up to 40 days of study 
procedures, the sponsor will be consulted if the participant will need to be replaced.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Enrolled/Intent-to-Treat” population will consist of all participants assigned to treatment, 
regardless of whether they took any doses of study treatment, or if they took the correct
treatment. Participants will be analyzed according to the treatment group to which they were 
assigned.
The “Safety” population will consist of all participants who received at least one dose of 
ramucirumab or placebo.
The “Pharmacokinetic” population will consist of all participants who received at least one dose 
of ramucirumab and have sufficient evaluable PK data. 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when participants are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
minimum, maximum and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the 
geometric mean and geometric coefficient of variation will also be presented. For categorical 
data, frequency count and percentages will be presented. Data listings will be provided for all 
participants up to the point of withdrawal, with any participants excluded from the relevant 
population highlighted. Summary statistics and statistical analyses will generally only be 
performed for participants included in the relevant analysis population. For the calculation of 
summary statistics and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual participants’ change from baseline 
values. Each individual change from baseline will be calculated by subtracting the individual 
participant’s baseline value from the value at the timepoint. The individual participant’s change 
from baseline values will be used to calculate the mean change from baseline using a SAS 
procedure such as Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.


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9.2
Demographics and Participant Disposition
Participant disposition will be listed. The demographic variables age, sex, race, ethnicity, body 
weight, height and body mass index will be summarized by treatment group and listed. All other 
demographic variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
PK parameter estimates will be determined using non-compartmental procedures in validated 
software program (Phoenix WinNonlin Version 8.1 or later).
Plasma concentrations of ramucirumab (LY3009806) will be used to determine the following PK 
parameters, when possible:  
Parameter
Units
Definition
AUC(0-tlast)
h*μg/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-∞)
h*μg/mL
area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-∞)
%
percentage of AUC(0-∞) extrapolated
Cmax
μg/mL
maximum observed drug concentration
tmax
H
time of maximum observed drug concentration
t1/2
H
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
CL
L/h
total body clearance of drug calculated after intravenous 
administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration (SC administration only)
Vz
L
volume of distribution during the terminal phase after intravenous
administration (IV administration only)
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration
Vss
L
volume of distribution at steady state following intravenous 
administration
F
%
bioavailability based on AUC(0-∞)
F ൌAUC ሾSCሿ
AUC ሾIVሿൈ100
Additional PK parameters may be calculated, as appropriate.


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The software and version used for the final analyses will be specified in the CSR. Any 
exceptions or special handling of data will be clearly documented within the CSR.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. 

Cmax and tmax will be reported from observed values. If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule). The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive concentrations above the lower limit of quantification, with at least one of 
these concentrations following Cmax. 

AUC(0-) values where the percentage of the total area extrapolated is more than 20% 
will be flagged. Any AUC(0-) value excluded from summary statistics will be noted in 
the footnote of the summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each participant will be defined by visual inspection and generally will be the 
first point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations. Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points. If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log-
linear portion of the concentration-time curve.

The parameters based on observed last quantifiable drug concentration will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL). Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 


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o
The compound is non-endogenous.
o
The samples are from the initial dose period for a participant or from a 
subsequent dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) 
sampling times. 

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero. Otherwise, only quantifiable concentrations will be 
used to calculate average concentrations.

Concentrations at a sampling time outside sampling time window specified in
Section 1.3.1 in the protocol, or ± 10%, will be excluded from the average 
concentration profiles.

Concentrations excluded from the mean calculation will be documented in the 
CSR.

A concentration average will be plotted for a given sampling time only if 2/3 of 
the individual data at the time point have quantifiable measurements that are 
within the sampling time window specified in the protocol or ± 10%. An average 
concentration estimated with less than 2/3 but more than 3 data points may be 
displayed on the mean concentration plot if determined to be appropriate and will 
be documented within the CSR.


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Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis. The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum. 
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test. Data will be analyzed 
with and without the atypical value, and both sets of results will be reported.
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the CSR. Approval of the CSR will 
connote approval of the exclusion.


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9.3.2
Pharmacokinetic Statistical Methodology
Ramucirumab bioavailability will be estimated. PK parameters will be evaluated to estimate 
ramucirumab AUC(0-∞) and Cmax dose proportionality following SC administration in the dose 
range investigated. Log-transformed ramucirumab Cmax and AUC(0-∞) parameters will be 
evaluated in a linear mixed effects model with fixed effects for dose (Groups 1, 4, and 5 who 
received 350 mg will be combined if appropriate). The treatment differences will be 
back-transformed to present the ratios of geometric means and the corresponding 90% 
confidence interval. 
For ramucirumab SC dosing PK parameters, the tmax will be analyzed using a Wilcoxon 
rank-sum test. Estimates of the median difference based on the observed medians, 90% CIs, and 
p-values from the Wilcoxon test will be calculated to assess similarity or not in tmax between dose 
level groups 1, 4, 5 combined compared to group 2 and group 6. 
The above-mentioned analysis investigating the relationship (e.g. linearity/proportionality) 
between ramucirumab PK parameters and dose may be adjusted/repeated in the event of 
significant difference in PK between the 350 mg SC groups (Group 1, 4, 5). Such difference 
would indicate significant impact of either injection volume or drug product concentration on the 
PK. In this scenario, the analysis, investigating the relationship (e.g. linearity/proportionality) 
between ramucirumab PK parameters and dose, may be repeated by excluding the data from one 
or two of the 350 mg SC group. 
Comparison of AUC(0-∞), Cmax and tmax between Group 1 and Group 4 will enable to assess the 
effect of changing the drug product concentration on the exposure. The log-transformed 
AUC(0-∞), Cmax and tmax will be the response variable, and the drug product concentration (that is, 
Group 1 and Group 4) is the explanatory variable. 
Comparison of AUC(0-∞), Cmax and tmax between Group 1 and Group 5 will enable to assess the 
effect of changing the volume injected at one site of injection on the exposure. The 
log-transformed AUC(0-∞), Cmax and tmax will be the response variable, and the volume injected 
(that is, Group 1 and Group 5) is the explanatory variable.
Example SAS Code:
proc mixed data=data alpha=0.1;
by parameter;
class dose;
model logpk = dose / ddfm=kr residual cl;
lsmeans dose / pdiff=control('1') alpha=0.1;
ods output lsmeans=lsm;
ods output diffs=diff;
run; 


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9.4
Safety and Tolerability Assessments
9.4.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the participant has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing. A TEAE is defined as an AE 
which occurs postdose or which is present prior to dosing and becomes more severe postdose. 
For Group 6 with SC infusion, the onset time of the AE will be relative to the start of infusion.
All AEs will be listed. TEAEs will be summarized by treatment, group, dose level, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of participants 
experiencing an AE and the percentage of participants experiencing an AE) of TEAEs will be 
summarized by treatment, group, dose level, Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.0 system organ class and preferred term. The summary and frequency AE
tables will be presented for all causalities and those considered related to the study drug by the 
investigator. CTCAE version 5.0 will be used to assign AE severity grades. Any SAEs will be 
listed. 
Discontinuations due to AEs will be listed.
9.4.2
Concomitant medication
Concomitant medication will be coded using the World Health Organization (WHO) drug 
dictionary (Version March 2020 B3). Concomitant medication will be listed.
9.4.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter, treatment, group, 
and dose level, together with changes from baseline, and listed. Urinalysis data will be listed. 
Additionally, clinical chemistry, hematology and urinalysis data outside the reference ranges will 
be listed and flagged on individual participant data listings.
Coagulation and thyroid-stimulating hormone data will be listed.
Samples for serum immunoglobulins, and their derived total, will be summarized and listed by 
parameter and treatment.
9.4.4
Vital signs
Where supine blood pressure and pulse rate are measured in triplicate, the mean value will be 
calculated and used in all subsequent calculations. 
Vital signs data will be summarized by treatment, group, and dose level, together with changes 
from baseline, where baseline is defined as the mean of the triplicate Day 1 predose assessment. 


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Figures of mean vital signs and mean changes from baseline profiles will be presented by 
treatment. 
Values for individual participants will be listed.
9.4.5
Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE.
9.4.6
Immunogenicity Assessments
The frequency and percentage of participants with preexisting ADAs and with treatment-
emergent ADAs (TE ADA) to ramucirumab will be tabulated and listed by treatment. 
For participants who are ADA negative at baseline, TE ADAs are defined as those with a titer 2-
fold (1 dilution) greater than the minimum required dilution of the assay (1:10). For participants 
who are ADA positive at baseline, TE ADAs are defined as those with a 4-fold (2 dilution) 
increase in titer compared to baseline. The frequency and percentage of participants with 
neutralizing antibodies will also be tabulated for participants with TE ADA+.
The relationship between the presence of antibodies and the PK parameters, including safety to 
ramucirumab, may be assessed. All immunogenicity analysis will be performed and reported by 
Eli Lilly.
9.4.7
Hypersensitivity reactions
For all drug hypersensitivity reactions that occur, additional follow-up data will be collected to 
assess the patient’s medical history, alternative causes, and symptoms.
These data will be listed.
9.4.8
Injection-Site Reactions
Injection-site reaction data (including erythema, induration, pain, pruritus, edema, and bleeding) 
will be listed and summarized by treatment in frequency tables. The exploratory ISR data 
collected from the Scarletred tool at the same timepoints will be reported separately.
9.4.9
Injection-Site Pain Assessment
Intensity of pain data will be quantified using a 100-mm validated VAS where 0 mm represents 
“no pain” and 100 mm represents “worst possible pain”. The data will be summarized and listed 
by treatment and timepoint.
9.4.10
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.


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9.4.11
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim analyses are planned for this study. If an unplanned interim analysis is deemed
necessary for reasons other than a safety concern, the protocol must be amended.
However, there will be periodic reviews of data to assess safety, tolerability, and PK data. There
will be sentinel dosing in this protocol, the initial 2 participants will be randomized/dosed (1 
ramucirumab:1 placebo), and subsequently (the next day), the remaining participants in the 
group will be dosed. The following information belongs in this section:

Safety reviews are planned prior to dose escalation after 2-week safety data are available.

The Lilly PK team will review the PK data for Groups 1 and 2 if timing permits.

The Lilly PK team will review the PK data once Group 1 through 3 PK samples have 
been collected (cutoff 2-week sample collection in Group 3).
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.


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13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of participants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, “No serious adverse events occurred for this study.”


Leo Document ID = 8693ba9d-9c40-43f9-ba20-0708383e5959
Approver: 
Approval Date & Time: 23-Nov-2020 15:52:32 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 23-Nov-2020 16:19:02 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 23-Nov-2020 16:19:32 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 25-Nov-2020 09:02:42 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD