Clinical trial NCT04230122
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2020-02-17; Completion date: 2020-06-04
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to learn more about how safe and how well tolerated LY3478006 is when given by injection into a vein or just under the skin to healthy participants. Blood tests will be done to check how much LY3478006 is in the bloodstream and how long the body takes to get rid of it. For each participant, the study will last up to about 16 weeks, including screening.

Detailed description:

Arms: arm 1: Participants received single dose of 10 mg LY3478006 administered IV. Due to early termination of the study Cohort 2 to 6 (30 mg, 100 mg, 300 mg, 600 mg, and 1000 mg LY3478006 IV) were not explored for safety reasons following dosing of the first 4 participants in Cohort 1. arm 2: Participants received single dose of placebo administered IV. Placebo IV Cohorts 2 through 6 were not explored as study was terminated for safety reasons following dosing of the first 4 participants in cohort 1. arm 3: 100 mg LY3478006 cohort 7 SC dose was not explored as study was terminated for safety reasons following dosing of the first 4 participants in cohort 1. arm 4: Placebo cohort 7 SC dose were not explored as study was terminated for safety reasons following dosing of the first 4 participants in cohort 1.
Interventions: intervention 1: LY3478006 - IV intervention 2: LY3478006 - SC intervention 3: Placebo - IV intervention 4: Placebo - SC
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered SC intervention 3: Administered IV intervention 4: Administered SC

Protocol documents:
Prot_000.pdf: 
J2F-MC-OHAA(a) Clinical Pharmacology Protocol
Page 1
LY3478006
Protocol J2F-MC-OHAA(a)
A Single Ascending Dose Study to Evaluate Safety, 
Tolerability, and Pharmacokinetics of LY3478006 in 
Healthy Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY3478006, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
LY3478006
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:
04 November 2019
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 26-Dec-2019 GMT


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Table of Contents
A Single Ascending Dose Study to Evaluate Safety, 
Tolerability, and Pharmacokinetics of LY3478006 in Healthy 
Subjects
Section
Page
Protocol J2F-MC-OHAA(a) A Single Ascending Dose Study to Evaluate 
Safety, Tolerability, and Pharmacokinetics of LY3478006 in Healthy 
Subjects ..............................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3.
Benefit/Risk Assessment..............................................................................................15
4.
Objectives and Endpoints..................................................................................................16
5.
Study Design.....................................................................................................................17
5.1.
Overall Design .............................................................................................................17
5.2.
Number of Participants.................................................................................................18
5.3.
End of Study Definition ...............................................................................................18
5.4.
Scientific Rationale for Study Design...........................................................................19
5.5.
Justification for Dose ...................................................................................................19
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................23
6.3.
Lifestyle and/or Dietary Requirements .........................................................................25
6.3.1.
Meals and Dietary Restrictions.............................................................................25
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................25
6.3.3.
Activity................................................................................................................25
6.3.4.
Male Contraceptive Requirements........................................................................25
6.4.
Screen Failures.............................................................................................................26
7.
Treatment..........................................................................................................................27
7.1.
Treatment Administered...............................................................................................27
7.1.1.
Packaging and Labeling .......................................................................................28
7.2.
Method of Treatment Assignment ................................................................................28
7.2.1.
Selection and Timing of Doses.............................................................................28


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7.3.
Blinding .......................................................................................................................28
7.4.
Dose Modification........................................................................................................29
7.4.1.
Dose Decision/Escalation.....................................................................................29
7.4.2.
Special Treatment Considerations ........................................................................30
7.4.2.1.
Premedication for Infusions............................................................................30
7.4.2.2.
Management of Infusion Reactions.................................................................30
7.5.
Preparation/Handling/Storage/Accountability...............................................................31
7.6.
Treatment Compliance .................................................................................................31
7.7.
Concomitant Therapy...................................................................................................31
7.8.
Treatment after the End of the Study............................................................................32
8.
Discontinuation Criteria ....................................................................................................33
8.1.
Discontinuation from Study Treatment.........................................................................33
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................33
8.1.2.
Systemic Allergic/Hypersensitivity Reactions ......................................................33
8.2.
Discontinuation from the Study....................................................................................33
8.3.
Subjects Lost to Follow-up...........................................................................................33
9.
Study Assessments and Procedures ...................................................................................34
9.1.
Efficacy Assessments...................................................................................................34
9.2.
Adverse Events ............................................................................................................34
9.2.1.
Serious Adverse Events........................................................................................35
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................36
9.2.2.
Complaint Handling.............................................................................................36
9.3.
Treatment of Overdose.................................................................................................36
9.4.
Safety...........................................................................................................................36
9.4.1.
Laboratory Tests ..................................................................................................36
9.4.2.
Vital Signs ...........................................................................................................36
9.4.3.
Electrocardiograms ..............................................................................................37
9.4.4.
Other Tests...........................................................................................................37
9.4.4.1.
Neurological Examinations.............................................................................37
9.4.4.2.
Pupillometry Assessments ..............................................................................38
9.4.5.
Safety Monitoring ................................................................................................39
9.4.5.1.
Injection/Infusion Site Reactions ....................................................................39
9.4.5.2.
Allergic/Hypersensitivity Events ....................................................................39
9.4.5.3.
Hepatic Safety................................................................................................40
9.5.
Pharmacokinetics .........................................................................................................41
9.5.1.
Bioanalysis...........................................................................................................41
9.6.
Pharmacodynamics ......................................................................................................41
9.7.
Immunogenicity Assessments.......................................................................................42


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9.8.
Genetics .......................................................................................................................42
9.9.
Biomarkers...................................................................................................................42
9.10. Health Economics ........................................................................................................43
10.
Statistical Considerations and Data Analysis.....................................................................44
10.1. Sample Size Determination ..........................................................................................44
10.2. Populations for Analyses..............................................................................................44
10.2.1.
Study Participant Disposition ...............................................................................44
10.2.2.
Study Participant Characteristics ..........................................................................44
10.3. Statistical Analyses ......................................................................................................44
10.3.1.
Safety Analyses....................................................................................................44
10.3.1.1.
Clinical Evaluation of Safety..........................................................................44
10.3.1.2.
Statistical Evaluation of Safety.......................................................................45
10.3.2.
Pharmacokinetic Analyses....................................................................................45
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................45
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................45
10.3.3.
Evaluation of Immunogenicity .............................................................................46
10.3.4.
Data Review During the Study.............................................................................46
10.3.5.
Interim Analyses..................................................................................................47
11.
References ........................................................................................................................48
12.
Appendices .......................................................................................................................50


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List of Tables
Table
Page
Table OHAA.1.
Objectives and Endpoints .......................................................................16
Table OHAA.2.
Margin of Safety for Intravenous Administration of LY3478006 
Based on Administered Dose and Predicted Human Exposure and 
Actual Animal Exposure.........................................................................21
Table OHAA.3.
Treatments Administered........................................................................27


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List of Figures
Figure
Page
Figure OHAA.1.
Illustration of study design for Protocol J2F-MC-OHAA........................18


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................51
Appendix 2.
Clinical Laboratory Tests........................................................................55
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................56
Appendix 4.
Blood Sampling Summary......................................................................59
Appendix 5.
Laboratory Testing for Hypersensitivity Events......................................60
Appendix 6.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............62
Appendix 7.
Protocol Amendment J2F-MC-OHAA(a) Summary
A Single Ascending Dose Study to Evaluate Safety, Tolerability, 
and Pharmacokinetics of LY3478006 in Healthy Subjects ......................63


J2F-MC-OHAA(a) Clinical Pharmacology Protocol
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1. Protocol Synopsis
Title of Study:
A Single Ascending Dose Study to Evaluate Safety, Tolerability, and Pharmacokinetics of LY3478006 in Healthy 
Subjects
Rationale: 
This first-in-human study will investigate the safety, tolerability, and pharmacokinetics (PK) of LY3478006 after 
single escalating intravenous (IV) doses and a single subcutaneous (SC) dose of LY3478006 in healthy subjects.  
The data generated in this study will be used to guide the design of future clinical studies.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To assess the safety and tolerability following single 
doses of LY3478006 in healthy subjects, including 
those of Japanese origin.
Frequency of serious adverse events (SAEs) and 
treatment-emergent adverse events (TEAEs)
Secondary
To assess the serum PK of LY3478006 following 
single IV or SC doses of LY3478006 in healthy 
subjects.
To estimate the absolute bioavailability of LY3478006 
following a single SC dose relative to a single IV dose 
in healthy subjects.
Maximum observed drug concentration (Cmax) and 
area under the concentration versus time curve from 
zero to infinity (AUC0-∞)
Absolute bioavailability
Summary of Study Design:
Study J2F-MC-OHAA is a Phase 1, subject- and investigator-blind, placebo-controlled, randomized, parallel, single 
ascending dose study in healthy subjects.
Treatment Cohorts and Planned Duration:  
Seven cohorts (Cohorts 1 to 7) of healthy subjects will be studied.  In each cohort, 8 subjects will be randomized 
(3:1 ratio) to receive LY3478006 or placebo (6 LY3478006 subjects and 2 placebo subjects).  Four of the 8 healthy 
subjects enrolled in Cohorts 3, 4, 5, and 6 are planned to be of Japanese origin (first generation; randomized [3:1 
ratio] to receive LY3478006 or placebo).
Cohorts 1 through 6 will be sequentially enrolled to test 6 single ascending dose levels of LY3478006 (planned dose 
levels of 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, and 1000 mg) or placebo administered intravenously (IV).  
Subjects in Cohorts 1 through 6 may be dosed in at least 2 dosing groups (approximately 4 subjects in each group) 
on separate days.  Study drug will be administered to 1 subject at a time (study drug infusion can start for a given 
subject after the end of infusion of the previous subject).  Safety data through Day 15 postdose must be evaluated 


J2F-MC-OHAA(a) Clinical Pharmacology Protocol
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from at least 6 of 8 subjects prior to the decision to dose escalate to the subsequent cohort.  Cohort 7 will be enrolled 
to test 1 dose level of LY3478006 (planned dose level of 100 mg, a higher dose level may be administered but not to 
exceed 300 mg) or placebo administered subcutaneously (SC).  All subjects in Cohort 7 may be dosed on a single 
day.
Subjects will have up to a 4-week screening period, will be admitted to the clinical research unit (CRU) on Day -1, 
and their eligibility will be confirmed prior to dosing on Day 1.  Subjects will remain resident in the CRU and may 
be discharged on Day 5 after all study procedures have been completed, at the discretion of the investigator.  
Subjects will return to the CRU as outpatients at predetermined visits up to approximately 12 weeks postdose for 
safety assessment and collection of PK, pharmacodynamic (PD) biomarker, and immunogenicity samples.  The
follow-up period may be extended by adding up to 3 outpatient visits if necessary based on the emerging PK data.  
Subjects who do not develop treatment-emergent antidrug antibodies (TE-ADA), or whose ADA at the end of the 
follow-up period do not meet TE-ADA criteria, may be discharged from the study at the end of the follow-up period 
if deemed appropriate by the investigator.  Subjects whose ADA meets the TE-ADA criteria at the end of the 
follow-up period will continue outpatient visits to monitor ADA until the signal returns to baseline or for up to 
12 months after the end of the follow-up period (or early termination), whichever is sooner.
Number of Subjects:
Up to 70 healthy subjects may be enrolled so that approximately 56 subjects complete the study.  It is planned that 
16 of these 56 subjects will be of Japanese origin (first generation).  
Statistical Analysis:
Summary statistics data tabulations and data graphs by ethnicity (Japanese and non-Japanese) will be provided as 
appropriate.  
Adverse events will be listed, and if the frequency of events allows, safety data will be summarized using 
descriptive methodology.  The incidence of symptoms for each treatment will be presented by severity and by 
association with the study drug as perceived by the investigator.  The number of IP-related SAEs will be reported.  
Safety parameters, including safety laboratory, vital signs, neurologic examination, and pupillometry, will be listed
and summarized using standard descriptive statistics.  
Pharmacokinetic parameters for LY3478006 will be calculated by standard noncompartmental methods of analysis
(NCA).  The primary parameters for analysis will be Cmax and AUC0-∞.  Pharmacokinetic parameter estimates 
from the NCA will be evaluated to delineate effects of dose proportionality.  Log-transformed Cmax and AUC 
estimates will be evaluated in a linear model with log-transformed IV dose for healthy subjects as explanatory 
variable.  The treatment differences will be back-transformed to present the ratios of geometric means and the 
corresponding 90% confidence intervals.  For the SC dose, the bioavailability relative to IV infusion at the same 
dose will be evaluated via a log-transformed model.


J2F-MC-OHAA(a) Clinical Pharmacology Protocol
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2. Schedule of Activities


J2F-MC-OHAA(a) Clinical Pharmacology Protocol
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Study Schedule Protocol J2F-MC-OHAA
Study Day
Procedure
Screening
≤28 days 
prior to 
Day 1 
-1
1
2
3
5
8
10 
(±1)
15 
(±1)
22 
(±1)
29
(±1)
43 
(±2)
57 
(±2)
71 
(±4)
Day 85 
(±4)m or 
E/T
Informed Consent
X
Outpatient Visit
X
X
X
X
X
X
X
X
X
X
CRU Admission
X
CRU Discharge
X
Medical History
X
Height
X
Weight
X
X
X
Physical Examinationa
X
X
Predose
24 hr
X
X
X
X
X
X
X
X
X
X
X
Directed Neurological 
Examination
X
X
24 hr
X
X
X
X
X
X
X
Pupillometry
X
X
X
X
ECGb
X
Predose
(1, -0.5, 0 hr), 
end of 
infusionc, 3, 
6, 12 hr
24 hr
48 
hr
X
X
X
X
X
X
X
X
X
AEd and Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Administratione
0 hr
Vital Signsf
X
Predose, end 
of infusionc, 
3, 6, 12 hr
24 hr
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testg
X
X
X
Serology (Hepatitis B 
Surface Antigen, HIV, 
Hepatitis C Antibody)
X


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Study Schedule Protocol J2F-MC-OHAA
Study Day
Procedure
Screening
≤28 days 
prior to 
Day 1 
-1
1
2
3
5
8
10 
(±1)
15 
(±1)
22 
(±1)
29
(±1)
43 
(±2)
57 
(±2)
71 
(±4)
Day 85 
(±4)m or 
E/T
Clinical Laboratory Tests
X
X
Predoseg
24 hr
X
X
X
X
X
X
X
X
X
Urinalysis
X
Predose
X
X
X
X
Urine Drug Screen, 
Ethanol Breath Test
X
X
PK Sampleh
Predose, end of 
infusionc, 3, 6, 
12 hr
24 hr
48 
hr
X
X
X
X
X
X
X
X
X
X
NGF Sample
Predose, end of 
infusionc, 3, 6, 
12 hr
24 hr
48 
hr
X
X
X
X
X
X
X
X
X
X
Immunogenicityi
Predose
X
X
X
Skin Punch Biopsiesj
Predose
X
Non-Pharmacogenetic 
Storage Samplesk
Predose
X
X
Storage Pharmacogenetic 
Samplesl
Predose
Abbreviations:  ADA = antidrug antibody; AE = adverse event; CRU = clinical research unit; ECG = electrocardiogram; E/T = early termination; HIV = human 
immunodeficiency virus; hr = hour; IV = intravenous; NGF = nerve growth factor, PK = pharmacokinetics; SC = subcutaneous; TE-ADA = treatment-
emergent antidrug antibody.  
Note: Study procedures scheduled relative to IV dosing time are to occur from the time of the start of infusion; e.g., 3 hours postdose would be 3 hours after the 
start of the IV infusion.
a
Full physical examination on Day -1 and Day 85 or E/T (may include body temperature and respiratory rate).  At all other time points, the examination will 
include at a minimum, an assessment of skin, injection site, and oral cavity.  
b
Single safety ECGs.
c
End of infusion procedures are only applicable for subjects enrolled in IV cohorts (Cohorts 1 through 6), and are not required for subjects enrolled in SC 
Cohort 7.
d
Post-treatment blood samples will be collected in subjects who experience generalized urticaria or if anaphylaxis is suspected following infusion 
(Section 9.4.5.2).


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Study Schedule Protocol J2F-MC-OHAA
e
For Cohorts 1 through 6, IV infusion duration must be at least 30 minutes, and infusion duration may be increased further as deemed necessary if infusion 
reaction is observed.
f
Supine and orthostatic (standing) blood pressure and pulse rate at all time points.  Predose vital signs can be taken on Day 1 at any time prior to the scheduled 
dosing; at other times, vital signs should be taken as close to the scheduled time as possible. Body temperature and respiratory rate may be measured at the 
times of the full physical examination, or at any other time if clinically indicated.
g
Serum hCG pregnancy test performed at screening.  Urine pregnancy test performed at all other time points, and at the investigator’s discretion.  
h
PK sampling times are given as targets to be achieved within reasonable limits.
i
For subjects who develop TE-ADA, additional outpatient visits may be required to monitor ADA until they return to baseline.  Additional safety assessments 
and samples for immunogenicity and PK should be taken at these additional visits, as described in Section 9.7.
j
Two skin biopsies (6-mm punches) taken from the abdomen at each time point for each subject.  The “Predose” biopsy samples may be taken on Day -1 or 
predose on Day 1.
k
Serum and plasma storage samples will be collected. 
l
Pharmacogenomic sample may be taken on Day -1 or any time prior to dosing on Day 1.
m If 12 weeks is shorter than 5 half-lives of LY3478006 based on the emerging PK data, up to 3 additional visits will be added to ensure a follow-up period of
approximately 5 half-lives after study drug dosing.  Study activities for these additional visits will be the same as for the Day 85 visit.


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3. Introduction
3.1.
Study Rationale
LY3478006 is an antibody being developed as a treatment for chronic pain conditions.  The 
antibody binds selectively to the TrkA receptor and inhibits nerve growth factor (NGF)-
dependent receptor activation. 
LY3478006 has not been administered to humans.  This first-in-human study will investigate the 
safety, tolerability, and pharmacokinetics (PK) of LY3478006 after single escalating intravenous 
(IV) doses and a single subcutaneous (SC) dose of LY3478006 in healthy subjects.  The data 
generated in this study will be used to guide the design of future clinical studies.
3.2.
Background
Adequate treatment of acute and chronic pain is severely hindered by the continued broad 
utilization of medications with either limited efficacy and/or significant safety concerns, such as 
nonsteroidal anti-inflammatory drugs and opioids.  Novel, preferably non-opioid, therapeutic 
options for pain management are desperately needed to address this unmet medical need.
Nerve growth factor has a clear role in the development of the central and peripheral nervous 
system, but its primary role in adulthood appears to be as a sensitizing agent in a variety of 
chronic pain conditions.  Nerve growth factor has been reported to be elevated in the plasma of 
patients with chronic pain (Hefti et al. 2006), and antibodies targeting NGF have shown clinical 
efficacy in a wide range of chronic pain conditions including osteoarthritis, chronic low back 
pain, and painful diabetic neuropathy (Chang et al. 2016).  Anti-NGF antibodies, including 
tanezumab, have been shown to bind NGF and prevent engagement with both NGF receptors, 
TrkA and p75 (La Porte et al. 2014).
The 140 kDa TrkA receptor (encoded by the NTRK1 gene) is the high affinity receptor for NGF 
and is expressed in central nervous system (CNS), sensory, and sympathetic neurons as well as 
several subtypes of circulating immune cells.  The p75 receptor (encoded by the NGFR gene) is 
the low affinity receptor for NGF that also binds other members of the neurotrophin family 
(BDNF and NT3, among others).  The p75 receptor is widely expressed in the peripheral nervous 
system (PNS) and CNS, as well as many other tissues, and is often found in cells expressing 
other neurotrophin receptors (TrkA, TrkB, and TrkC).  While the p75 receptor may play a role in 
NGF-dependent sensitization, key transcriptional mechanisms thought to support long-term 
chronic pain states are more closely linked to NGF signaling through TrkA, via the formation of 
the NGF/TrkA signaling endosome (Mantyh et al. 2011; Wasner et al. 2003).
Elevated tissue and/or plasma levels of NGF play a key role in NGF-dependent sensitization, but 
NGF may also be released by tissues directly adjacent to neuronal receptors.  It remains unclear 
what role these local circuit effects may play in overall NGF sensitization, but direct receptor 
inhibition may more efficiently inhibit these interactions versus the NGF sequestration strategy 
employed by the existing clinical anti-NGF antibodies.  LY3478006 is an antibody that binds the 
TrkA receptor and blocks the interaction of NGF with TrkA.  LY3478006 has shown efficacy in 
a preclinical model of gait impairment, an assay that is sensitive to NGF-dependent mechanisms 


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LY3478006
(Adams et al. 2016).  Clinical studies with LY3478006 will examine the potential for a selective 
TrkA therapeutic to achieve long-lasting efficacy in chronic pain conditions, offering a 
significant improvement over existing standards of care.  
3.3.
Benefit/Risk Assessment
There is no anticipated therapeutic benefit for subjects in this study.
Two safety topics emerged during the development of anti-NGF antibodies:  atrophy of 
sympathetic neurons in animal studies, and an increased incidence of rapidly progressing 
osteoarthritis (RPOA) in human clinical trials.  Sympathetic neuronal atrophy was not associated 
with demonstrable deficits in sympathetic function, and recovered with drug washout in adult 
animals (Angeletti et al. 1971; Bjerre et al. 1975; Belanger et al. 2017).  Further, no major effects 
on sympathetic function have been reported in clinical trials to date in patients dosed with 
tanezumab (Brown et al. 2014; Brown et al. 2015) or in tanezumab-treated monkeys subjected to 
head-up tilt challenge (Belanger et al. 2017).  In nonclinical repeat dose studies in rats (1-month) 
and non-human primates (3 months) minimal neuronal hypertrophy rather than atrophy was 
observed with LY3478006.  No neuronal necrosis clinical sequelae were observed.  Given the 
potential for compounds acting along this pathway to affect sympathetic function, this study will 
monitor for evidence of sub-clinical effects on autonomic function using pupillometry, which has 
been shown to detect dysfunction of both sympathetic and parasympathetic systems (Ferrari et al. 
2010; Muppidi et al. 2013).  While the likely mechanisms are unknown, RPOA in humans 
remains a potential risk for anti-TrkA inhibitors.  
The nonclinical safety information for LY3478006 adequately supports the transition from 
preclinical status to a clinical, single-dose study.  LY3478006 has not been administered to 
humans previously, thus the study is designed to be conducted in accordance with principles 
outlined in the Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical 
Trials with Investigational Medicinal Products (EMA 2017).  Any identified risks are considered 
to be monitorable and manageable at the planned single ascending dose range of 10 mg to 
1000 mg for LY3478006 in healthy subjects.
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of LY3478006 are to be found in the 
Investigator’s Brochure (IB).


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LY3478006
4. Objectives and Endpoints
Table OHAA.1 shows the objectives and endpoints of the study.
Table OHAA.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the safety and tolerability following single 
doses of LY3478006 in healthy subjects, including those 
of Japanese origin.
Frequency of SAEs and TEAEs
Secondary
To assess the serum PK of LY3478006 following single 
IV or SC doses of LY3478006 in healthy subjects.
Cmax and AUC0-∞
To estimate the absolute bioavailability of LY3478006 
following a single SC dose relative to a single IV dose in 
healthy subjects.
Absolute bioavailability
Exploratory
To assess the changes in serum NGF levels following 
single IV and SC doses of LY3478006 in healthy 
subjects.
Serum NGF levels over time
To assess the changes in skin pTrkA and tTrkA levels 
following single IV and SC doses of LY3478006 in 
healthy subjects.
Pre and postdose pTrkA and tTrkA levels 
To assess the serum PK of LY3478006 following single 
IV doses of LY3478006 in healthy Japanese subjects.
Cmax and AUC0-∞
Abbreviations:  AUC0-∞= area under the concentration versus time curve (AUC) from zero to infinity; 
Cmax = maximum observed drug concentration; IV = intravenous; NGF = nerve growth factor; 
PK = pharmacokinetics; SAEs = serious adverse events; SC = subcutaneous; TEAEs = treatment-emergent 
adverse events.


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5. Study Design
5.1.
Overall Design
Study J2F-MC-OHAA is Phase 1, subject- and investigator-blind, placebo-controlled, 
randomized, parallel, single-ascending dose study in healthy subjects.
Seven cohorts (Cohorts 1 to 7) of healthy subjects will be studied.  In each cohort, 8 subjects will 
be randomized (3:1 ratio) to receive LY3478006 or placebo (6 LY3478006 subjects and 
2 placebo subjects).  Four of the 8 healthy subjects enrolled in Cohorts 3, 4, 5, and 6 are planned 
to be of Japanese origin (first generation; randomized [3:1 ratio] to receive LY3478006 or 
placebo).  If the recruitment of Japanese subjects becomes limiting for a particular cohort, then 
additional non-Japanese subjects may be entered into a cohort to allow for dose escalation.  
Japanese subjects will subsequently be enrolled so that at least 3 Japanese subjects complete 
placebo and each LY3478006 dose level.  In addition, it is preferred that the non-Japanese 
subjects also be non-Asian.
Cohorts 1 through 6 will be sequentially enrolled to test 6 single ascending dose levels of 
LY3478006 (planned dose levels of 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, and 1000 mg) or 
placebo administered intravenously (IV).  Subjects in Cohorts 1 through 6 may be dosed in at 
least 2 dosing groups (approximately 4 subjects in each group) on separate days.  Study drug will 
be administered to 1 subject at a time (study drug infusion can start for a given subject after the 
end of infusion of the previous subject).  Safety data through Day 15 postdose must be evaluated 
from at least 6 of 8 subjects prior to the decision to dose escalate to the subsequent cohort (dose 
escalation criteria are described in Section 7.4.1).  Cohort 7 will be enrolled to test 1 dose level 
of LY3478006 (planned dose level of 100 mg, a higher dose level may be administered but not to 
exceed 300 mg) or placebo administered subcutaneously (SC).  All subjects in Cohort 7 may be 
dosed on a single day. Figure OHAA.1 illustrates the study design.
Subjects will have up to a 4-week screening period, will be admitted to the clinical research unit 
(CRU) on Day -1, and their eligibility will be confirmed prior to dosing on Day 1.  Subjects will 
remain resident in the CRU and may be discharged on Day 5 after all study procedures have 
been completed, at the discretion of the investigator.  Subjects will return to the CRU as 
outpatients at predetermined visits up to approximately 12 weeks postdose for safety assessment 
and collection of PK, pharmacodynamic (PD) biomarker, and immunogenicity samples.  Safety 
will be assessed by monitoring of AEs, clinical laboratory tests, vital signs (blood pressure and 
pulse rate), electrocardiograms (ECGs), directed neurological examinations, and pupillometry.  
Subjects will be followed for 12 weeks based on a projected half-life of approximately 16 days. 
This follow-up period may be extended by adding up to 3 outpatient visits if necessary based on 
the emerging PK data, to ensure a follow-up duration of at least 5 half-lives (Section 2).  Study 
activities for these additional visits will be the same as for the Day 85 visit.  For subjects who do 
not develop treatment-emergent antidrug antibodies (TE-ADAs), or whose ADA at the end of the 
follow-up period do not meet TE-ADA criteria, they may be discharged from the study at the end 
of the follow-up period if deemed appropriate by the investigator.  For subjects whose ADA 
meets the TE-ADA criteria at the end of the follow-up period, additional outpatient visits may be 


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LY3478006
required to monitor ADA until the signal returns to baseline (Section 9.7), or for up to 12 months 
after the end of the follow-up period (or early termination), whichever is sooner.  Adverse events 
and blood samples for LY3478006 concentration should also be collected at these outpatient 
visits. 
Study governance considerations are described in detail in Appendix 3.
Abbreviations:  IV = intravenous; LY = LY3478006; N = number of subjects; 
PBO = placebo; SC = subcutaneous.
Note:  Figure is for illustration purposes only.  Escalation to next cohort will take place 
following review of safety data up to Day 15.
Figure OHAA.1.
Illustration of study design for Protocol J2F-MC-OHAA.
5.2.
Number of Participants
Up to 70 healthy subjects may be enrolled so that approximately 56 subjects complete the study.  
It is planned that 16 of these 56 subjects will be of Japanese origin (first generation).  For 
purposes of this study, a subject completes the study when all scheduled procedures shown in the 
Schedule of Activities (Section 2) have been finished.  Subjects who discontinue the study 
following dose administration but before completing may be replaced at the discretion of the 
sponsor and investigator.  
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
Cohort 1
10-mg dose level, IV
N=8 (6 LY + 2 PBO)
Cohort 2
30-mg dose level, IV
N=8 (6 LY + 2 PBO)
Cohort 3
100-mg dose level, IV
N=8 (6 LY + 2 PBO), includes
4 Japanese (3 LY + 1 PBO)
Cohort 4
300-mg dose level, IV
N=8 (6 LY + 2 PBO), includes
4 Japanese (3 LY + 1 PBO)
Cohort 5
600-mg dose level, IV
N=8 (6 LY + 2 PBO), includes
4 Japanese (3 LY + 1 PBO)
Cohort 6
1000-mg dose level, IV
N=8 (6 LY + 2 PBO), includes
4 Japanese (3 LY + 1 PBO)
Cohort 7
100-mg dose level, SC
N=8 (6 LY + 2 PBO)


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5.4.
Scientific Rationale for Study Design
A subject- and investigator-blinded, randomized, placebo-controlled design was chosen to 
minimize bias in the primary objective of the study.  A parallel-group design was chosen because 
a crossover design is impractical for compounds that have long half-lives.  Additionally, a 
crossover design could confound PK data if subjects develop neutralizing ADA.  
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications in patients, and therefore provides the most unbiased 
assessment of the safety and tolerability of LY3478006 in this first human dose (FHD) study.  It 
is possible that this study will support further development of LY3478006 in Japanese patients, 
therefore, it is planned that 4 healthy Japanese subjects will be enrolled in each of Cohorts 3, 4, 
5, and 6.
While recently published European Medicines Agency guideline (EMA 2017) recommends use 
of sentinel dosing in first-in-human studies, it also allows for flexibility in a proposed dosing 
approach based on the available scientific data and preclinical assessment of a given molecule. 
The intended and exaggerated pharmacological responses of LY3478006 have been well 
characterized in multiple preclinical pharmacology models. Results of toxicology studies 
suggest that non-monitorable or clinically unmanageable concerns after single dose would be 
unlikely to occur in humans treated with LY3478006. Based on the available data, LY3478006 
does not present an uncertainty profile necessitating a sentinel dosing approach. Furthermore, 
sentinel dosing with non-high uncertainty compounds, such as LY3478006, may lead to inability 
to interpret data due to false positive AE findings in the absence of data from all cohorts or 
placebo-treated subjects.  However, for the escalating IV cohorts, each cohort may be split so 
that 4 subjects will only be dosed on a given day to allow sufficient time for study related 
procedures to be completed in a timely manner.
Periodic safety data reviews will ensure that any subject can be discontinued early, or the dose 
escalation can be terminated, in case of any AE requiring such a decision.
Safety, tolerability, PK, immunogenicity, and PD biomarker data in healthy subjects will assist in 
identifying an appropriate dose range for subsequent clinical studies.
5.5.
Justification for Dose
Human PK parameters, including clearance (CL, Q) and volume of distribution (V1, V2) were 
predicted using the allometric scaling from monkey PK parameters, with a fixed exponent of 0.8 
and 1 for clearance and volume, respectively (Wang and Prueksaritanont 2010). 
The minimal pharmacology active dose (PAD) is determined from the rat DRG pTrkA signaling 
data, and the biologically effective dose (BED) is defined from an integrated review of the 
preclinical data package detailed in the IB that included the following measures:

A prior clinical study with a nonselective small molecule TrkA inhibitor indicated that 
very high coverage over the TrkA IC50 may be required for efficacy (Loudon et al. 
2018).  The plasma concentration of LY3478006 required to achieve 30-fold coverage 


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over the human pTrkA IC50 in skin is approximately 37.4 µg/mL (human pTrkA in vitro 
IC50 = 0.83 nM, and assumes a typical antibody 10% skin:plasma partition coefficient).

The plasma concentration at the minimal effect dose (MED) of 10 mg/kg in the rat intra-
articular CFA-induced gait deficit model is 46.2 µg/mL after 3 days postdose.

The plasma concentration required to achieve significant inhibition of DRG pTrkA 
signaling at 3 days postdose is 5.7 µg/mL.
The predicted BED of 65 mg QW, 150 mg Q2W, and 400 mg Q4W are predicted to achieve a 
Ctrough above the minimal 30-µg/mL threshold for the entire dosing interval once steady state is 
reached.  The predicted PAD of 10 mg QW, 30 mg Q2W, and 80 mg Q4W are predicted to 
achieve Ctrough above the minimal 5.7-µg/mL threshold for the entire dosing interval once steady 
state is reached.  These predictions apply to both IV and SC administration as they are based 
upon Ctrough from a 2-compartment linear PK model with a bioavailability of 83%.  Once 
clinical PK data (including SC bioavailability) become available, the predicted BED will be 
refined for both the IV and SC dosing regimens.  It is currently proposed that future multiple 
dose studies will start with a monthly (Q4W) dosing regimen
A single-dose monkey PK/PD study was performed at 0.1, 0.5, and 3 mg/kg IV to explore the 
relationship between dose, exposure, and PD using the same assay and methodology compared 
to the single ascending dose study:  every animal was its own control and 4 postdose skin punch 
biopsies were collected.  These data were useful to establish the time points for the collection of 
the postdose skin punch biopsies in healthy subjects, but were not informative enough to build a 
PK/PD model as the 3 doses explored provided similar PD effect.
To establish safety and tolerability of LY3478006 and evaluate the dose/exposure-response 
relationship (via skin punch biopsies to measure pTrkA and tTrkA), a wide dose range for 
LY3478006 (10, 30, 100, 300, 600, and 1000 mg, IV) is proposed for the single ascending dose 
study performed in healthy subjects.  In addition, a single 100-mg SC dose is planned to be 
administered to define the bioavailability of LY3478006.  However, based on emerging data a 
higher dose may be administered but will not exceed 300 mg.
The no-observed-adverse-effect level (NOAEL) for LY3478006 in the monkey 3-month 
toxicology study is 170 mg/kg IV.  In rats, adverse skin lesions consistent with self-trauma 
(persistent scratching) limited the dosing of LY3478006 to approximately 1 month, and 
erosion/ulceration of the tongue was present at all doses tested in small numbers of rats (changes 
which were also consistent with injury/trauma as opposed to direct toxicity of the test article on 
the tongue).  Therefore, no NOAEL was identified in rat although the adverse changes are of 
questionable human relevance and are clinically monitorable.  As shown in Table OHAA.2, the 
proposed starting dose of 10 mg IV and maximum dose of 1000 mg IV have a sufficiently large 
margin of safety in the monkey both in terms of dose and exposure.  The starting dose of 10 mg
is anticipated to be 8-fold lower than the PAD and the top dose of 1000 mg is anticipated to be 
2.5-fold higher than the BED.  Taking the assumption that the predicted PAD dose of 80 mg 
Q4W provides 50% of the effect (assuming ED50 value based on 50% TE in DRG): with a hill 
factor of 1, the 400-mg Q4W projected BED dose is predicted to provide around ED85 and the 


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LY3478006
top dose of 1000 mg is predicted to be around ED90. The planned maximum dose (1000 mg IV) 
in humans was selected as 1/10th the repeat dose monkey NOAEL (and highest dose tested in rat) 
based on dose (mg/kg).  Pharmacokinetic projections predict that drug exposures at the 
maximum dose of 1000 mg IV will remain below 1/7th the exposures at the NOAEL in the 
monkey GLP toxicology study (dosed for 3 months).  Potential treatment-emergent changes in 
cutaneous sensation are expected to be readily evident to subjects and, in addition, scheduled 
neurologic exams will include assessments for changes in cutaneous sensation.  Scheduled 
physical examinations will also include inspection of the oral cavity.
Table OHAA.2.
Margin of Safety for Intravenous Administration of LY3478006
Based on Administered Dose and Predicted Human Exposure and 
Actual Animal Exposure
Dose
(mg/kg)
Dose
Multiplea
AUC
(µg•hr/mL)
AUC
Exposure 
Multipleb
Cmax
(µg/mL)
Cmax
Exposure 
Multiplec
Human Starting dose 
(10 mg IV)
0.167
–
1006
–
2.9
–
Rat LOAEL skin/tongued
60 (SC)
359
63600
63.2
824
284
Rat Highest Dose Tested
170 (IV)
1018
269000
267
4470
1541
Monkey NOAELe
170 (IV)
1018
728000
724
7230
2493
Human Maximum dose 
(1000 mg IV)
16.7
–
100581
–
289.9
–
Rat LOAEL skin/tongued
60 (SC)
3.6
63600
0.63
824
2.8
Rat Highest Dose Tested
170 (IV)
10.2
269000
2.7
4470
15.4
Monkey NOAELe
170 (IV)
10.2
728000
7.2
7230
24.9
Abbreviations:  AUC = area under the serum concentration × time curve; Cmax = maximal serum concentration; 
IV = intravenous; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; 
SC = subcutaneous.
a
Dose multiple is the dose in animals/dose in humans based on mg/kg and human body weight = 60 kg.  Exposure 
multiple is the calculated AUCtau,ssin animals / predicted AUC0-∞in humans (see Table 4.10 in the IB for
predicted human PK).
b
AUC multiple = mean AUCtau observed after the last dose in animal/predicted mean AUC0-∞after a single dose 
in human. AUC in rats presented is calculated as 0-96hr. AUC in monkeys presented is calculated as 0-168hr.
c
Cmax multiple = mean Cmax observed after the last dose in animal/predicted mean Cmax after a single dose in 
human.
d
Determined in a 1-month repeat dose toxicity study. 
e
NOAEL determined in a 3-month repeat dose toxicity study.
The margin of safety table presented above is based on predicted exposure following IV 
administration (100% bioavailability) and therefore provides an appropriate margin for SC 
dosing, where bioavailability cannot be higher than 100%.


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6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.  Prospective approval of protocol deviations to 
recruitment and enrollment criteria, also known as protocol waivers or exemptions, are not 
permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are overtly healthy males or female Japanese or non-Japanese subjects, as 
determined by medical history and physical examination.  
[1a] Male subjects must agree to adhere to contraception restrictions specified in 
Section 6.3.4.
[1b] Female subjects:
Women not of childbearing potential may participate and include those who are infertile 
due to surgical sterilization (hysterectomy without bilateral oophorectomy or confirmed 
tubal occlusion [not tubal ligation]).
[2]
Are aged 18 to 55 years (20 to 55 years for Japanese subjects), inclusive, at 
screening. 
[3]
Have a body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, at screening.
[4]
Have clinical laboratory test results within normal reference range for the 
investigative site, or results with acceptable deviations that are judged to be 
not clinically significant by the investigator.
[5]
Have venous access sufficient to allow for IV drug delivery and blood 
sampling as per the protocol.
[6]
Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures and CRU procedures.
[7]
Have given signed informed consent.
Additional criteria to qualify as Japanese subjects in this study:


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[8]
To qualify as a subject of Japanese origin (first-generation Japanese), the 
subject, the subject’s biological parents, and all of the subject’s biological 
grandparents must be of exclusive Japanese descent and have been born in 
Japan. 
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening:
[9] Are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[10] Are Eli Lilly and Company (Lilly) employees or employees of third-party 
organizations involved with the study who require exclusion of their 
employees.
[11] Are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study.  
[12]
Have participated, within the last 30 days, in a clinical study involving an 
investigational product.  If the previous investigational product has a long 
half-life, 5 half-lives or 30 days, whichever is longer, should have passed.
[13]
Have previously completed or withdrawn from this study or any other study 
investigating LY3478006, and have previously received the investigational 
product. 
[14]
Have known allergies to LY3478006, related compounds or any components 
of the formulation, or history of significant atopy.
[15]
Have clinically significant abnormal ECG results constituting a risk when 
taking the investigational product, as determined by the investigator.
[16]
Have persistent abnormal blood pressure and/or pulse rate as determined by 
the investigator.
[17]
Have evidence of orthostatic hypotension defined as decrease in systolic or 
diastolic of ≥20mmHg or ≥10mmHg, respectively.
[18]
Have a history or presence of cardiovascular, respiratory, hepatic, 
ophthalmological, renal, gastrointestinal, endocrine, hematological, 
neurological, or psychiatric disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs; of constituting a risk when 
taking the investigational product; or of interfering with the interpretation of 
data.
[19]
Have a history or presence of mononeuropathy, polyneuropathy, or autonomic 
neuropathy.


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LY3478006
[20]
Subjects who are not suitable for measurement of pupil size by the study 
specified methodology.
[21]
Regularly use known drugs of abuse (including cannabis) and/or show 
positive findings on urinary drug screening.
[22]
Show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies.
[23]
Have liver function test (aspartate aminotransferase [AST], alanine
aminotransferase [ALT], alkaline phosphatase [ALP], total bilirubin [TBL])
above the upper limit of normal (ULN) at screening.
[24]
Show evidence of hepatitis C and/or positive hepatitis C antibody. 
[25]
Show evidence of hepatitis B and/or positive hepatitis B surface antigen. 
[26]
Are women who are lactating.
[27]
Have used or intend to use over-the-counter or prescription medication 
(including herbal medications) within 7 days prior to dosing or during the 
study with the exception of:  vitamins and mineral supplements (not providing 
>100% of the recommended daily allowance), hormone replacement, and/or 
occasional paracetamol/acetaminophen.  If this situation arises, inclusion of an 
otherwise suitable subject may be at the discretion of the sponsor.
[28]
Have donated blood of more than 500 mL within the last month.
[29]
Have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females), or are unwilling to stop alcohol consumption 
from 48 hours prior to dosing (1 unit = 12 oz or 360 mL of beer; 5 oz or 
150 mL of wine; 1.5 oz or 45 mL of distilled spirits).
[30]
Consume more than 10 cigarettes per day or the equivalent, and/or are unable 
or unwilling to refrain from smoking, vaping, or nicotine use (including 
replacement therapy) during CRU admissions.
[31]
Have received treatment with biologic agents (such as monoclonal antibodies, 
including marketed drugs) within 3 months or 5 half-lives (whichever is 
longer) prior to dosing.
[32]
Have significant allergies to humanized monoclonal antibodies.
[33]
Have clinically significant multiple or severe drug allergies, or intolerance to 
topical corticosteroids, or severe post treatment hypersensitivity reactions 
(including, but not limited to, erythema multiforme major, linear IgA 
dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis).
[34]
Have had lymphoma, leukemia, or any malignancy within the past 5 years 
except for basal cell or squamous epithelial carcinomas of the skin that have 
been resected with no evidence of metastatic disease for 3 years.
[35]
Have had breast cancer within the past 10 years.


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[36]
In the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Subjects should fast for at least 4 hours prior to study drug administration and are required to 
remain recumbent for approximately 2 hours (unless otherwise required for procedures) after 
study drug administration and remain sedentary in a bed or chair for the subsequent 4 hours for 
observation.  Subjects are permitted to have a meal approximately 1 hour following the 
completion of dosing.  While resident in the CRU, a standard diet (or a Japanese diet, where 
appropriate) will be provided.  When outpatient, a subject’s typical diet may be consumed at all 
other meal times during the study.
Subjects will not be permitted to consume foods containing poppy seeds from 48 hours prior to 
attending the CRU on Days -1, 8, 29, and 57.
6.3.2. Caffeine, Alcohol, and Tobacco 
Consumption of caffeine- and xanthine-containing products is allowed, provided that the 
subject’s consumption has been consistent for the past 30 days.
Subjects will not be permitted to consume alcohol from 48 hours before each visit until leaving 
the CRU.  Subjects will be advised to abstain from alcohol consumption for the remainder of the 
trial until their final visit.
Subjects will not be permitted to smoke from CRU admission until discharge from the CRU.
6.3.3. Activity
Subjects should avoid strenuous exercise and/or activity from 48 hours prior to visits until 
leaving the CRU.
6.3.4. Male Contraceptive Requirements
Male subjects, regardless of their fertility status, with non-pregnant female partners of 
childbearing potential must agree to either remain abstinent (if this is their preferred and usual 
lifestyle) or use condoms as well as one additional highly effective (less than 1% failure rate) 
method of contraception (such as combination oral contraceptives, implanted contraceptives, or 
intrauterine devices) or effective method of contraception (such as diaphragms with spermicide 
or cervical sponges) for 90 days after study drug dosing.
Men and their partners may choose to use a double–barrier method of contraception. Barrier 
protection methods without concomitant use of a spermicide are not an effective or acceptable 
method of contraception. Thus, each barrier method must include use of a spermicide. It should 


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be noted, however, that the use of male and female condoms as a double barrier method is not 
considered acceptable due to the high failure rate when these barrier methods are combined.
Male subjects with pregnant partners should use condoms during intercourse for the duration of 
the study and until the end of estimated relevant potential exposure in women of childbearing 
potential, predicted to be 90 days following last dose of study drug.
Male subjects should refrain from sperm donation for the duration of the study and until 90 days 
following last dose of study drug.
Male subjects who are in exclusively same sex relationships (as their preferred and usual
lifestyle) are not required to use contraception.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.  If subjects have minor deviations in screening assessments (e.g., laboratory safety 
tests, vital signs) these may be repeated at the investigator’s discretion to confirm eligibility.


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of LY3478006 administered over a planned single ascending 
dose range of 10 mg to 1000 mg versus placebo administered by IV infusion, and following a 
single 100 mg dose versus placebo administered by SC injection.  Table OHAA.3 shows the 
treatment regimens.
In Cohorts 1 through 6, the investigational product will be administered as a slow IV infusion 
over at least 30 minutes.  Sites must have resuscitation equipment, emergency drugs, and 
appropriately trained staff available during the infusion and for at least 4 hours after subjects 
have completed their infusion.  In Cohort 7, the investigational product will be administered SC 
in the abdominal wall, approximately 5 cm from the umbilicus and skin biopsy site.  If more than 
1 SC injection is required, then each injection will be at least 5 cm apart.  The site(s) of injection 
will be recorded.
Table OHAA.3.
Treatments Administered
Treatment Name
LY3478006
Placebo
Dosage Formulation
Solution for Injection, 200 mg/4-mL
Sterile saline (0.9% sodium chloride)
Unit dose 
strength(s)/Dosage 
Level(s)
50 mg/mL
Single dose; 10 mg, 30 mg, 100 mg, 300 mg, 
600 mg, 1000 mg
N/A
Single dose; equivalent volume to each 
dose level of LY3478006
Route of 
Administration
Cohorts 1 through 6:  IV
Cohort 7:  SC
Dosing instructions
Cohorts 1 through 6:  slow IV infusion over at least 30 minutes
Cohort 7:  SC injection via syringe into the abdomen 
Abbreviations:  IV = intravenous; N/A = not applicable; SC = subcutaneous.
The investigator or designee is responsible for:

explaining the correct use of the investigational product(s) to the site personnel 

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection (this 
responsibility can only be performed by unblinded pharmacy staff)

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.


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7.1.1. Packaging and Labeling
Clinical trial materials will be labelled as investigational product (IP) as appropriate, and 
according to the country’s regulatory requirements.  Clinical trial materials are manufactured in 
accordance with current good manufacturing practices and will be supplied by Lilly or its 
representative.
The LY3478006 Injection, 200-mg/vial is supplied as sterile, preservative-free solution in a 
single-use vial for SC and IV administration.  Each milliliter of drug product solution delivers 
50 mg of LY3478006.
Placebo for all cohorts is 0.9% sodium chloride (sterile saline).
7.2.
Method of Treatment Assignment
Treatment assignment will be determined according to a randomization schedule.
7.2.1. Selection and Timing of Doses
It is planned that all subjects will receive a fixed dose of LY3478006 or placebo, according to the 
randomization schedule.  The planned dose levels are 10-, 30-, 100-, 300-, 600-, and 1000-mg 
LY3478006, administered IV to subjects in Cohorts 1 through 6, respectively.  Subjects in 
Cohort 7 will receive a planned SC dose of 100-mg LY3478006.  However, based on emerging 
data a higher dose may be administered but will not exceed 300 mg.  The actual dose for each 
cohort will be determined as described in Section 7.4.1.
The actual time of all dose administrations will be recorded in the subject’s electronic case report 
form (eCRF).  The actual duration time of infusion will be recorded in the eCRF.  If the infusion 
is terminated, this should be recorded in the eCRF.
7.3.
Blinding
This is a subject- and investigator-blind study.  The study site pharmacist will be unblinded.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.
Randomization tables for allocation of LY3478006 and placebo will be prepared by the Lilly 
statistician or designee and provided to the study site pharmacists or pharmacy staff involved in 
dose preparation.  Blinding will be maintained throughout the conduct of the study until all data 
are cleaned to an acceptable level of quality and locked.  The details are included in a separate 
Blinding Plan.
Emergency codes will be available to the investigator.  A code, which reveals the treatment 
group for a specific study subject, may be opened during the study only if the subject’s well-
being requires knowledge of the subject’s treatment assignment.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’s safety must always be the first consideration in making such a determination.  If the 


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investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
7.4.1. Dose Decision/Escalation
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
maximum planned dose (1000 mg) is reached or a lower dose in the event that the dose 
escalation stopping criteria are met as described below.  
Safety data will be the primary criteria for the dose escalation.  In addition, LY3478006 
concentrations will be reviewed to guide dose escalation, as described in Section 5.1.  ADA 
results will be reviewed by the sponsor periodically to guide dose escalation, but is not necessary 
for making dose escalation decisions.  No dose decision can occur without prior discussion and 
agreement between the investigator (or designee) and the Lilly clinical pharmacologist (CP)/
clinical research physician (CRP)/study team.  In case of disagreement, the decision of the 
investigator will be followed, except in a situation where Lilly’s proposal is the more 
conservative action (for example, where the investigator wishes to escalate and the Lilly CP/CRP 
dose not) in which case, the Lilly proposal will be followed.
Safety data collected through at least Day 15 will be evaluated from at least 6 of 8 subjects prior 
to each dose escalation.  The safety data reviewed will include at least:  AEs, clinical laboratory 
tests, vital signs, ECGs, and neurological/pupillometry examinations.
Safety data, in particular AEs, SAEs, and adverse laboratory abnormalities, will be 
independently assessed by the investigator, and will be considered related to the investigational 
product unless there is clear evidence that the event is not related.  
After review of these data, an agreement on the appropriate dose escalation will be made by the 
investigator and sponsor for the next cohort.  The magnitude of dose escalations may be reduced 
following data review, but subsequent escalations cannot be increased by more than 
approximately 3-fold (a half-log increment).
If any of the following scenarios occur, dosing at the current level and further dose escalation 
will be discontinued:
1) 2 or more subjects experience an SAE or clinically significant event that is related 
to LY3478006 administration
2) 2 or more subjects develop acute AEs of moderate severity that are considered to 
be related to LY3478006 infusion, during or within 2 hours of completing the 
infusion, that do not resolve with a reduced infusion rate and/or supportive care
(described in Section 7.4.2.2).
3) 3 or more subjects at 1 dose level experience moderate treatment-related AEs that 
impair normal activities


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4) 2 or more subjects develop AEs within 14 days of dosing that are considered to be 
related to study treatment and graded as at least moderate, clinically significant 
and not responsive to supportive care
Dosing may continue in a new dose cohort if the risk-benefit is deemed appropriate by the 
sponsor and investigator, at a dose reduced by ≥50% of the dose resulting in termination of the 
dose escalation.  Also, it is important to note that when the above criteria are met, any ongoing 
dosing at a dose level that is below the dose that triggered the stopping rule may continue when 
considered appropriate by the sponsor.
7.4.2. Special Treatment Considerations 
7.4.2.1.
Premedication for Infusions
Premedication for the infusions is not planned.  However, if an infusion reaction occurs, 
appropriate medication may be used as determined by the study investigator.  The sponsor 
should be informed when premedication for infusion reaction is recommended by the 
investigator.
If minor infusion reactions are observed, but review of the data suggests that dose escalation may 
continue, administration of acetaminophen, 500 to 1000 mg, or other appropriately indicated 
non-sedating medications may be administered orally approximately 30 to 60 minutes prior to 
the start of infusion for subsequent subjects.
The decision to implement premedication for infusions in subsequent cohorts will be made by 
the investigator and sponsor and recorded in the study documentation, along with the dose-
escalation decision.
Any premedication given will be documented as a concomitant therapy (Section 7.7).
7.4.2.2.
Management of Infusion Reactions
There is a risk of infusion reaction with any biological agent; therefore, all subjects should be 
monitored closely as described in Section 9.4.5.1.  
In the event that a significant infusion reaction occurs, the following guidance should be 
followed:

The investigational product infusion should be slowed (for example, reduce infusion rate 
by 50% [for example, an infusion rate of 12 mL/hr becomes 6 mL/hr or slower]) or 
stopped, depending on the symptoms/signs present:
o
if slowed, the infusion should be completed at the slower rate, as tolerated
o
if determined by the investigator that the infusion should no longer continue, no 
further attempts to dose the subject should be made; the subject should complete 
AE and other follow-up procedures per Section 2

Management of the infusion site reaction should proceed according to the severity of the 
reaction as described in Section 9.4.5.1.


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
If a subject’s infusion reaction is sufficiently severe to discontinue the infusion, then 
subsequent infusions may be administered to subjects with premedication at the 
discretion of the investigator following agreement with the Lilly CRP or CP (Section 
7.4.2.1).

If a subject’s infusion rate is reduced due to an infusion reaction, then subsequent 
infusions may be administered to subjects at the discretion of the investigator following 
agreement with the Lilly CRP or CP.  If further infusions are administered, the infusion 
rate must not exceed the slowest rate used to complete the infusion on the occasion the 
infusion reaction occurred.  Premedication may be administered at the discretion of the 
investigator (Section 7.4.2.1).
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all IP received and any 
discrepancies are reported and resolved before use of the study treatment.
Only subjects enrolled in the study may receive IP or study materials, and only authorized site 
staff may supply or administer IP.  All IP should be stored in an environmentally controlled and 
monitored (manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation and final disposition records).
7.6.
Treatment Compliance
The IP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7.
Concomitant Therapy
Subjects on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study.  These medications include vitamins and mineral 
supplements (not providing >100% of the recommended daily allowance), hormone replacement, 
and/or occasional paracetamol/acetaminophen (Exclusion Criterion 26).
In general, concomitant medication should be avoided; however, acetaminophen (1 gram, 
maximum 3 grams/24 hours) may be administered at the discretion of the investigator for 
treatment of headaches, etc.  Additional drugs are to be avoided during the study unless required 
to treat an AE or for the treatment of an ongoing medical problem.
If the need for concomitant medication (other than acetaminophen) arises, inclusion or 
continuation of the subject may be at the discretion of the investigator after consultation with a 
Lilly CP or CRP.  Any medication used during the course of the study must be documented.


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7.8.
Treatment after the End of the Study
This section is not applicable for this study.


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8. Discontinuation Criteria
Subjects who discontinue treatment or the study early will have early termination procedures 
performed as shown in the Schedule of Activities (Section 2).
8.1.
Discontinuation from Study Treatment
Dose escalation discontinuation criteria are presented in Section 7.4.1.  Subjects whose infusion 
is stopped before its completion (such as due to an infusion reaction), may continue in the study 
for safety monitoring if deemed appropriate by the sponsor and investigator.
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
investigational product.  
8.1.2. Systemic Allergic/Hypersensitivity Reactions
All biologic agents carry the risk of systemic allergic/hypersensitivity reactions.  Clinical 
manifestations of these reactions are described in Section 9.4.5.2.  Systemic 
allergic/hypersensitivity reactions may possibly lead to a subject’s permanent discontinuation.  
The investigator, after consultation with the sponsor, determines that a clinically significant 
hypersensitivity reaction has occurred.
8.2.
Discontinuation from the Study
Subjects will be discontinued from the study in the following circumstances:

Enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator decision:  the investigator decides that the subject should be discontinued
from the study

Subject decision:  the subject requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 4 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
The investigator will record all relevant AE and SAE information in the electronic case report 
form (eCRF).  After the informed consent form (ICF) is signed, study site personnel will record, 
via eCRF, the occurrence and nature of each subject’s preexisting conditions, including clinically 
significant signs and symptoms of the disease under treatment in the study.  Additionally, site 
personnel will record any change in the condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account concomitant 
treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP and/or study procedure and the AE.


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


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9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to investigational product or procedure.  Lilly 
has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3478006 is considered any dose higher than the 
dose assigned through randomization.  There is no specific antidote for LY3478006.  In the event 
of an overdose, the subject should receive supportive care and any AEs should be documented.  
Refer to the IB.
9.4.
Safety
Laboratory tests, vital signs, ECGs, neurological examinations, and pupillometry assessments 
will be conducted according to the Schedule of Activities (Section 2).
9.4.1. Laboratory Tests
The safety laboratory tests detailed in Appendix 2 will be conducted for each subject.
With the exception of safety laboratory test results that may unblind the study, Lilly or its 
designee will provide the investigator with the results of laboratory tests analyzed by a central 
vendor, if a central vendor is used for the study.
9.4.2. Vital Signs
Supine and orthostatic (standing) blood pressure and pulse rate will be measured; subjects should 
be supine for at least 5 minutes and stand for at least 2 minutes.  If the measurements do not meet 
the criteria for orthostatic (postural) hypotension, no further measurements are needed.  If the 
standing blood pressure measurements show systolic blood pressure and diastolic blood pressure 
decreases of ≥20 mmHg or ≥10 mmHg, the sequence of supine and standing measurements 
should be repeated up to 2 more times.  
If the subject feels unable to stand, supine vital signs only will be recorded.  In addition, 
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 and agreed upon between the sponsor and investigator.


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9.4.3. Electrocardiograms
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the IP should be reported to Lilly, or its designee, as an AE via 
eCRF.
Electrocardiograms must be recorded before collecting any blood samples.  Subjects must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection.  Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary.  All ECGs recorded should be stored at the investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the subject can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in subject management is needed, and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
AE.
9.4.4. Other Tests 
9.4.4.1.
Neurological Examinations
Neurological examinations will be performed to evaluate the following:

Strength of muscle groups (including those of the head and neck, upper limbs, and lower 
limbs),

Deep tendon reflexes, and

Sensation (tactile, vibration, joint position sense, and pin prick) of index fingers and great 
toes.
New or worsened abnormality on the neurologic exam should be reported as an AE.  Subjects 
will be referred to a consulting neurologist for neurologic evaluation in the following 
circumstances:

A subject experiences a significant change from baseline neurological examination 

A subject experiences an AE suggestive of peripheral neuropathy or abnormal peripheral 
sensation that is serious, or results in subject’s discontinuation from the study, or is 
ongoing at the end of the subject’s participation in the study, or is severe; including but 
not limited to
o
allodynia, 


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o
burning sensation, 
o
carpal tunnel syndrome, 
o
dysesthesia, 
o
hyperesthesia, 
o
hyperpathia, 
o
hypoesthesia, 
o
neuralgia, 
o
neuritis,
o
neuropathy peripheral,
o
pallanesthesia, 
o
paresthesia, 
o
peripheral sensory neuropathy, 
o
sciatica,
o
sensory disturbance, 
o
sensory loss, 
o
tarsal tunnel syndrome
9.4.4.2.
Pupillometry Assessments
Dynamic pupillometry assessments will be performed to evaluate sympathetic autonomic 
nervous system function using a commercially available pupillometer (NeurOptics, Inc. 2017).  
Assessments will be made, where possible, by the same trained individual, at the same time of 
day (for example, between 10 AM and 12 PM), in the same light-controlled environment, and 
same eye.  Subjects will sit in a darkened room and adapt for 5 minutes before each assessment.  
Objective measurements will include the following:

Maximum diameter (maximum pupil size before constriction)

Minimum diameter (pupil diameter at peak constriction)

Delta % change (% of change [size-min]/size) as a %

Latency of constriction (time of onset of constriction following initiation of the light 
stimulus)

Constriction velocity (average velocity of how the pupil diameter is constricting 
measured in millimeters per second)

Maximum constriction velocity (maximum velocity of how the pupil diameter is 
constricting measured in millimeters per second)


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
Dilation velocity (the average pupillary velocity when, after having reached the peak of 
constriction, the pupil tends to recover and to dilate back to the initial resting size, 
measured in millimeters per second

Time to reach 75% recovery (the time to reach 75% of the original baseline pupil 
diameter after the peak of the constriction).
9.4.5. Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes

AEs
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the personnel 
included in the Blinding Plan.
9.4.5.1.
Injection/Infusion Site Reactions
Symptoms of a local injection/infusion site reaction may include erythema, induration, pain, 
pruritus, and edema.  If an injection/infusion site event is reported, the AE will be recorded, and 
additional data will be provided to the sponsor in the eCRF.
Injection/infusion sites may be inspected and photographically documented.
9.4.5.2.
Allergic/Hypersensitivity Events
All biologic agents carry the risk of systemic allergic/hypersensitivity reactions.  Clinical 
manifestations of these reactions may include but are not limited to skin rash, pruritus (itching), 
dyspnea, urticaria (hives), angioedema (for example, swelling of the lips and/or tongue), 
hypotension, and anaphylactic reaction. If such a reaction occurs, additional data describing 
each symptom should be provided to the sponsor in the eCRF.
All subjects will be monitored closely for symptoms and signs that may occur as part of a
systemic infusion reaction (Section 7.4.2.2).
Sites will have appropriate advanced cardiac life support (ACLS) trained medical staff and 
appropriate medical equipment including a crash cart on site when study participants are 
receiving study drug.  It is recommended that participants who experience a systemic 
hypersensitivity reaction be treated per the local standard of care.


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In the presence of generalized urticaria, or if anaphylaxis is suspected, blood samples should be 
collected for hypersensitivity tests after the subject is stabilized and as directed in Appendix 5.  
The laboratory results will be provided to the sponsor via the central laboratory.
9.4.5.3.
Hepatic Safety
Close monitoring
If a study participant who had normal or near normal baseline ALT, AST, ALP, TBL (i.e., 
<1.5x ULN) experiences elevated ALT≥3x ULN, AST≥3x ULN, ALP ≥2x ULN, or TBL≥2x, 
laboratory tests (Appendix 6) should be repeated within 48 to 72 hours, including ALT, AST, 
ALP, TBL, gamma-glutamyl transferase (GGT) and creatine kinase (CK) to confirm the 
abnormality and to determine if it is increasing or decreasing.
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses, (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over the counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
2 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize.
Comprehensive hepatic evaluation  
If a study participant experiences elevated ALT≥5x ULN, AST≥5x ULN, ALP ≥3x ULN, 
TBL≥2x ULN, or elevated ALT, AST≥3x ULN with hepatic signs/symptoms (severe fatigue, 
nausea, vomiting, right upper quadrant abdominal pain, fever, rash, and/or eosinophilia >5%), a 
comprehensive evaluation should be performed to search for possible causes of liver injury. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for viral hepatitis A, B, C, E, tests for autoimmune 
hepatitis, and an abdominal imaging study (for example, ultrasound or computed tomography 
[CT] scan). 
Based on the patient’s history and initial results, further testing should be considered, in 
consultation with the Lilly designated medical monitor, including tests for HDV, CMV, EBV, 
acetaminophen levels, acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, 
blood alcohol levels, urinary ethylglucuronide, and serum phosphatidylethanol.  Based on the 
circumstances and the investigator’s assessment of the participant’s clinical condition, the 
investigator should consider referring the participant for a hepatologist/gastroenterologist 
consultation, MRCP, ERCP, cardiac echocardiogram, or a liver biopsy.  


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Additional hepatic data collection (hepatic safety CRF) in study participants who have abnormal 
liver tests during the study 
Additional hepatic safety data collection (hepatic safety CRF) should be performed in study 
participants who meet 1 or more of the following 5 conditions:
1. Elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests
2. Elevated TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)
3. Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests
4. Hepatic event considered to be a SAE
5. Discontinuation of study drug due to a hepatic event 
Note: the interval between the two consecutive blood tests should be at least 2 days.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities, venous blood samples of 
approximately 3 mL each will be collected to determine the serum concentrations of 
LY3478006. A maximum of 5 samples may be collected at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  Instructions for 
the collection and handling of blood samples will be provided by the sponsor.  The actual date 
and time (24-hour clock time) of each sampling will be recorded.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.  Any PK data shared during dose
escalation discussions will be in a blinded summary format.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Serum concentrations of LY3478006 will be assayed using a validated enzyme-linked 
immunosorbent assay method.  Analyses of samples collected from placebo-treated subjects are 
not planned.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last patient visit for the study.  During this time, 
samples remaining after the bioanalysis may be used for exploratory metabolism studies or 
exploratory analyses such as bioanalytical assay validation or cross-validation exercises.  
9.6.
Pharmacodynamics
Not applicable.


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9.7.
Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected and stored for potential future analysis to determine antibody production against 
LY3478006.  Antibodies may be further characterized for their ability to neutralize the activity 
of LY3478006.  To interpret the results of immunogenicity, a venous blood sample will be 
collected at the same time points to determine the serum concentrations of LY3478006. All 
samples for immunogenicity should be taken predose when applicable and possible.
Treatment-emergent antidrug antibodies (TE-ADAs) are defined in Section 10.3.3.  If the 
immunogenicity sample at the last scheduled assessment or discontinuation visit is TE-ADA 
positive, additional samples may be taken until the signal returns to baseline (i.e. no longer TE-
ADA positive) or for up to 1 year after last dose.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to the 
IP.  Any samples remaining after 15 years will be destroyed.
9.8.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
LY3478006 and to investigate genetic variants thought to play a role in chronic pain.  
Assessment of variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and ERBs impose shorter time limits, for the study at a facility 
selected by Lilly.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of LY3478006 or after LY3478006 is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 
9.9.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 


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clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), proteins, lipids, and other cellular elements.
Serum, plasma, whole blood RNA, whole blood for epigenetics, and skin biopsy samples for 
protein biomarkers samples for non-pharmacogenetic biomarker research will be collected at the 
times specified in the Schedule of Activities (Section 2) where local regulations allow.  
Serum NGF levels will be evaluated over time to assess changes in NGF levels following single 
IV and SC administration of LY3478006.  Abdomen skin biopsy samples will be collected and 
used to study protein biomarkers, including tTrkA and pTrkA, related to pain and/or related to 
the mechanism of action of LY3478006. 
Techniques used may include but are not limited to immunoassays. Samples may be used for 
exploratory micro array expression profiling or transcriptome sequencing. Detailed instructions 
for sample collection and handling will be provided by the sponsor. Samples will be sent to a 
sponsor-designated laboratory for immunoassays.
Samples will be used for research on the drug target, disease process, variable response to 
LY3478006, pathways associated with chronic pain, mechanism of action of LY3478006, and/or 
research method, or for validating diagnostic tools or assay(s) related to chronic pain.
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and ERBs impose shorter time limits, at a facility selected by Lilly.  
This retention period enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
LY3478006 or after LY3478006 is commercially available.  
9.10. Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 70 healthy subjects may be enrolled such that approximately 56 subjects complete the 
study.  It is planned that 16 of these 56 subjects will be of Japanese origin (first-generation).  
Subjects who are randomized but not administered treatment may be replaced to ensure that 
enough subjects complete the study.  The ethnicity of the replacement subject (Japanese or non-
Japanese) should match the ethnicity of the discontinued subject, where possible.
The sample size is customary for Phase 1 studies evaluating safety and PK parameters, and is not 
powered on the basis of statistical hypothesis testing.
10.2. Populations for Analyses
Summary statistics data tabulations and data graphs by ethnicity (Japanese and non-Japanese) 
will be provided as appropriate.
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The subject’s age, sex, race, weight, height, and other demographic characteristics will be 
summarized and may be used in the PK and safety analyses as quantitative or classification 
variables.  
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
Pharmacokinetic analyses will be conducted on data from all subjects who receive at least 1 dose 
of the IP and have evaluable PK.  Safety analyses will be conducted for all enrolled subjects, 
whether or not they completed all protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All 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 symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to study entry will be 
distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.


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The number of IP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory, vital signs, neurologic 
examination, and pupillometry.  The parameters will be listed, and summarized using standard 
descriptive statistics.  Electrocardiogram and physical examination will be performed for safety 
monitoring purposes and will not be listed or summarized.  Additional analysis will be 
performed if warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic analysis will be conducted on subjects who received LY3478006 and have 
sufficient samples collected post dose.  
Pharmacokinetic parameters for LY3478006 will be calculated by standard noncompartmental 
methods of analysis (NCA) using WinNonlin.  The primary parameters for analysis will be 
maximum observed drug concentration (Cmax) and area under the concentration versus time 
curve (AUC) from zero to infinity (AUC0-∞).  Other noncompartmental parameters, such as half-
life (t1/2), CL, volume of distribution (apparent clearance, and apparent volume of distribution 
for SC administration) may be calculated and reported as deemed appropriate. 
In addition, LY3478006 concentration time data may be analyzed using non-linear mixed effect 
modeling as implemented in software such as NONMEM.  Serum data from all subjects will be 
pooled to determine the compartmental PK parameters (for example, CL, Vss, t1/2, F) and 
between- and within-subject variability.  Covariate relationships, such as CL or volume of 
distribution versus body size (for example, body weight and body mass index) or gender, may be 
investigated through graphical exploration and may be quantified through modeling.  The effect 
of factors such as race/ethnicity (Japanese versus non-Japanese subjects) could be tested in the 
model and may be included in the final model.  
The version of any software used for the analysis will be documented, and the program will meet 
the Lilly requirements of software validation.  It is possible that other validated, equivalent PK 
software programs may be utilized if appropriate, warranted, and approved by Global PK/PD 
management. 
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameter estimates from the NCA will be evaluated to delineate effects of 
dose proportionality.  Log-transformed Cmax and AUC estimates will be evaluated in a linear 
model with log-transformed IV dose for healthy subjects as explanatory variable.  The treatment 
differences will be back-transformed to present the ratios of geometric means and the 
corresponding 90% confidence intervals (Smith et al. 2000).  
For the SC dose, the bioavailability relative to IV infusion at the same dose will be evaluated via 
a log-transformed model.  The log-transformed Cmax and AUC will be the response variable, and 
route of administration (IV/SC) is the explanatory variable. 


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10.3.3. Evaluation of Immunogenicity
Upon full assay validation, TE-ADAs will be assessed.  The frequency and percentage of 
subjects with preexisting ADA and with TE-ADA to LY3478006 may be tabulated. 
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 ADA).
The frequency of neutralizing antibodies may also be tabulated in TE-ADA+ subjects, when 
available.
The relationship between the presence of antibodies and the PK parameters and PD response
may be assessed.
10.3.4. Data Review During the Study
Data will be reviewed during the study to evaluate the safety and PK of LY3478006, inform dose 
selection/escalation decisions, and confirm inclusion of data from an adequate number of 
Japanese and non-Japanese subjects.  
The investigator and the Lilly CP/CRP will make the determination regarding dose escalation 
based on their review of the safety and tolerability data as described in Section 7.4.1.  In 
addition, the Lilly study team will review safety, tolerability, and PK data (interim access to data 
review [IAD]) to guide dose selection/cohort initiation, and/or to inform the design of subsequent 
studies.  Based upon review of data, the Lilly team and investigator will make the determination 
regarding dose selection/cohort initiation.  The investigator will remain blinded, and the Lilly 
team will be unblinded during these reviews.  Interim access to data reviews are planned as 
follows:

Prior to initiating the planned 100-mg SC dose level cohort (Cohort 7), the IAD will 
include:
o
PK and safety data from Cohorts 1, 2, and 3 (LY3478006 10- 30, and 100-mg IV 
dose levels)

Prior to initiating the 1000-mg IV dose cohort (Cohort 6), or a 300-mg SC dose level 
cohort (Cohort 7), the IAD will include:
o
PK data from Cohorts 1, 2, 3, and 4 (LY3478006 10-, 30-, 100-, and 300-mg dose 
levels)
o
Available safety data from Cohorts 1, 2, 3, 4, and 5 (LY3478006 10-, 30-, 100-, 
300-, and 600-mg dose levels).  Safety data from Cohort 5 will not be required for 
the 300-mg SC dose level cohort (Cohort 7) decision.


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10.3.5. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.


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11.
References
Adams BL, Guo W, Gors RT, Knopp KL. Pharmacological interrogation of a rodent forced 
ambulation model: leveraging gait impairment as a measure of pain behavior pre-clinically. 
Osteoarthritis Cartilage. 2016;24(11):1928-1939.
Angeletti PU, Levi-Montalcini R, Caramia F. Analysis of the effects of the antiserum to the 
nerve growth factor in adult mice. Brain Res. 1971;27(2):343-355.
Belanger P, Butler P, Butt M, Bhatt S, Foote S, Shelton D, Evans M, Arends R, Hurst S, 
Okerberg C, Cummings T, Potter D, Steidl-Nichols J, Zorbas M. From the cover: evaluation of 
the effects of tanezumab, a monoclonal antibody against nerve growth factor, on the 
sympathetic nervous system in adult cynomolgus monkeys (Macaca fascicularis): a
stereologic, histomorphologic, and cardiofunctional assessment. Toxicol Sci. 2017;158(2):319-
333.
Bjerre B, Wiklund L, Edwards DC. A study of the de- and regenerative changes in the 
sympathetic nervous system of the adult mouse after treatment with the antiserum to nerve 
growth factor. Brain Res. 1975;92(2):257-278.
Brown MT, Herrmann DN, Goldstein M, Burr AM, Smith MD, West CR, Verburg KM, Dyek 
PJ. Nerve safety of tanezumab, a nerve growth factor inhibitor for pain treatment. J Neurol Sci. 
2014;345(1-2):139-147.
Brown M, Koltzenburg M, Nguyen H, West C, Verburg K. Tanezumab does not cause 
sympathetic nervous system dysfunction in clinical osteoarthritis studies. Neurology. 
2015;84(14 Suppl):P3.303.
Chang DS, Hsu E, Hottinger DG, Cohen SP. Anti-nerve growth factor in pain management: 
current evidence. J Pain Res. 2016;9:373-383.
[EMA] Guideline on strategies to identify and mitigate risks for first-in-human and early clinical 
trials with investigational medicinal products. Available at: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-identify-
mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf. Accessed October 30, 
2019.
Ferrari GI, Marques Jefferson LB, Gandhi RA, Heller SR, Schneider FK, Tesfaye S. Using 
dynamic pupillometry as a simple screening tool to detect autonomic neuropathy in patients 
with diabetes: a pilot study. Biomed Eng Online. 2010;9(26):1-16.
Hefti FF, Rosenthal A, Walicke PA, Wyatt S, Vergara G, Shelton DL, Davies AM.  Novel class 
of pain drugs based on antagonism of NGF. Trends Pharmacol Sci. 2006;27(2):85-91.
La Porte SL, Eigenbrot C, Ultsch M, Ho WH, Foletti D, Forgie A, Lindquist KC, Shelton DL, 
Pons J. Generation of a high-fidelity antibody against nerve growth factor using library 
scanning mutagenesis and validation with structures of the initial and optimized Fab-antigen 
complexes. MAbs. 2014;6(4):1059-1068.
Loudon P, Siebenga P, Gorman D, Gore K, Dua P, van Amerogen G, Hay JL, Jan Groeneveld G, 
Butt RP. Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-


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06273340 in a battery of human evoked pain models. Br J Clin Pharmacol. 2018;84(2):301-
309.
Mantyh PW, Koltzenburg M, Mendell LM, Tive L, Shelton DL. Antagonism of nerve growth 
factor-TrkA signaling and the relief of pain. Anesthesiology. 2011;115(1):189-204.
Muppidi S, Adams-Huet B, Tajzoy E, Scribner M, Blazek P, Spaeth EB, Frohman E, Davis S, 
Vernino S. Dynamic pupillometry as an automatic testing tool. Clin Auton Res. 2013;23:297-
303.
[NeurOptics] NeurOptics® PLR™-3000 Pupillometer System—Instructions for Use © 2017 
NeurOptics, Inc. Available at: https://neuroptics.com/wp-content/uploads/2017/08/PLR-3000-
IFU_RevC.pdf. Accessed October 30, 2019.
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forque ST. 
Confidence interval criteria for assessment of dose proportionality. Pharm Res. 
2000;17(10):1278-1283.
Wang W, Prueksaritanont T. Prediction of human clearance of therapeutic proteins: simple 
allometric scaling method revisited. Biopharm Drug Dispos. 2010;31(4):253-263.
Wasner G, Schattschneider J, Binder A, Baron R. Complex regional pain syndrome--diagnostic, 
mechanisms, CNS involvement and therapy. Spinal Cord. 2003;41(2):61-75.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
ADA
antidrug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC0-∞
area under the concentration versus time curve from time zero to infinity
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received
BED
biologically effective dose
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
clinical pharmacologist
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CRU
clinical research unit


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Ctrough
trough concentration
ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form.
ERB
ethical review board
FHD
first human dose
GCP
good clinical practice
IAD
interim access to data
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
investigational
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IV
intravenous(ly)
NCA
noncompartmental methods of analysis
NGF
nerve growth factor
NOAEL
no-observed-adverse-effect-level
PAD
pharmacology active dose
PD
pharmacodynamic
PK
pharmacokinetic


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randomize
the process of assigning subjects to an experimental group on a random basis
SAE
serious adverse event
SC
subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin
TE-ADA
treatment-emergent antidrug antibody
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate 
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphorus 
Leukocytes (WBC)
Blood urea nitrogen (BUN)
Platelets
Total protein
Albumin
Differential WBC [Absolute counts and %] of:
Total bilirubin
Neutrophils
Alkaline phosphatase (ALP)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Alanine aminotransferase (ALT)
Eosinophils
Creatinine
Basophils
Urinalysis
Ethanol testinga,b
Specific gravity
Urine drug screena,b
pH
Hepatitis B surface antigena
Protein
Hepatitis C antibodya
Glucose
HIVa
Ketones
Pregnancy test
Bilirubin
FSHa
Urobilinogen
Coagulation testsa
Blood
PT/INR
Nitrite
aPTT
Abbreviations:  aPTT = activated partial thromboplastin time; FSH = follicle-stimulating hormone; HIV = human 
immunodeficiency virus; INR = international normalized ratio; PT = prothrombin time; RBC = red blood cells; 
WBC = white blood cells.
a
Required at screening only.
b
Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit and at other 
times indicated in the Schedule of Activities.  


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject.  This includes obtaining the 
appropriate signatures and dates on the informed consent form (ICF) prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant and retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for subjects.  Individual 
investigators may have additional local requirements or processes.  Study specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by International Council for 
Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator’s Brochure (IB) and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:


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


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


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Appendix 4.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol J2F-MC-OHAA Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
20.5
1
20.5
Clinical laboratory testsa,b
12.5
12
150
Pharmacokineticsb,d
3
17
51
Nerve growth factor b,d
0.5
17
8.5
Immunogenicityb,c,d
10
4
40
Pharmacogenetics
10
1
10
Non-pharmacogenetic storage 
samples
10
3
30
Totalb,c,d
310
Total for clinical purposes (rounded up to nearest 10 mL)
310
a
Additional samples may be drawn if needed for safety purposes.
b
If 12 weeks is shorter than 5 half-lives of LY3478006 based on emerging pharmacokinetic data, up to 
3 additional follow-up visits may be added, at each of which additional samples will be taken.  An additional 
blood volume of 78 mL (37.5 mL for clinical laboratory tests, 9 mL for pharmacokinetics, 1.5 mL for nerve 
growth factor, and 30 mL for immunogenicity) would be collected if the subject attended the maximum allowed 
number of follow-up visits.
c
In the event of drug hypersensitivity reactions (immediate or non-immediate), 3 additional samples will be 
collected for immunogenicity (a total additional blood volume of 30 mL [one 10-mL sample collected as close to 
the onset of the event as possible, one 10-mL sample collected at the resolution of the event, and one 10-mL 
sample collected 30 days following the event]).
d
If the immunogenicity sample at the last scheduled assessment or discontinuation visit is TE-ADA positive, up to 
4 additional outpatient visits may be required to monitor ADA until the signal returns to baseline (e.g., no longer 
TE-ADA positive) or for up to 1 year after the last dose.  An additional blood volume of 54 mL (12 mL for 
pharmacokinetics, 2 mL for nerve growth factor, and 40 mL for immunogenicity) would be collected if the 
subject attended outpatient visits for 1 year after the last dose.


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Appendix 5.
Laboratory Testing for Hypersensitivity 
Events
Laboratory testing should be performed at the time of a systemic hypersensitivity event.  The 
management of the adverse event may warrant laboratory testing beyond what is described 
herein and should be performed as clinically indicated.
Laboratory testing during a systemic hypersensitivity event is not performed for diagnostic 
purposes.  Its intent is several fold:

To help characterize and classify systemic hypersensitivity reactions

To meet regulatory expectations

To improve subsequent clinical management by helping to distinguish between the 
various mechanistic bases of anaphylaxis
Blood samples will be obtained for laboratory testing in the presence of generalized urticaria or
if anaphylaxis is suspected as follows:

After the subject has been stabilized, obtain a sample within 1 to 2 hours of the event, 
however, samples may be obtained as late as 12 hours after the event as analytes can 
remain altered for an extended period of time. Record the time at which the sample was 
collected.

Obtain a follow-up sample at the next regularly scheduled visit or after 4 weeks, 
whichever is later.
The following laboratory tests should be obtained, and will be assayed by a Lilly-designated 
laboratory:

Tryptase
Note:  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.

Anti-LY3478006 antibodies (ADA) and LY3478006 concentration (PK)
o
ADA testing should include drug-specific immunoglobulin-E (IgE)
o
If a drug-specific IgE assay is not available, a commercially-available alternative 
test that can indicate the presence of drug-specific IgE in serum is the basophil 
activation test (BAT)


J2F-MC-OHAA(a) Clinical Pharmacology Protocol
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LY3478006

Complement C3a and C5a

Cytokines IL-6, IL-1β, and IL-10 (or any cytokine panel that includes these 3 cytokines)


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LY3478006
Appendix 6.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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LY3478006
Appendix 7.
Protocol Amendment J2F-MC-OHAA(a) 
Summary
A Single Ascending Dose Study to Evaluate Safety, 
Tolerability, and Pharmacokinetics of LY3478006 in 
Healthy Subjects
Overview
Protocol J2F-MC-OHAA, A Single Ascending Dose Study to Evaluate Safety, Tolerability, and 
Pharmacokinetics of LY3478006 in Healthy Subjects, has been amended.  The new protocol is 
indicated by Amendment (a) and will be used to conduct the study in place of any preceding 
version of the protocol.
The updates to this protocol are those agreed to in Lilly’s response to a clinical information 
request sent by the Food and Drug Administration.  The overall changes and rationale for the 
changes made to this protocol are as follows:

Footnote a in Section 2 has been amended to, “Full physical examination on Day -1 and 
Day 85 or E/T (may include body temperature and respiratory rate). At all other time 
points, the examination will include at a minimum, an assessment of skin, injection site, 
and oral cavity”, to ensure that a basic physical examination is performed at each time 
point.

Exclusion criterion [23] was added per an FDA request to Section 6.2 to exclude patients 
with abnormal liver function tests at screening.  Exclusion criterion [29] was modified in 
accordance with changes made to Section 6.3.2.

Section 6.3.2 has been amended per an FDA request to state that subjects will not be 
permitted to consume alcohol from 48 hours before each visit until leaving the CRU. 
Subjects will be advised to abstain from alcohol consumption for the remainder of the 
trial until their final visit.

Section 9.4.5.2 has been amended to state that, “Sites will have appropriate advanced 
cardiac life support (ACLS) trained medical staff and appropriate medical equipment 
including a crash cart available on site when study participants are receiving study drug. 
It is recommended that participants who experience a systemic hypersensitivity reaction 
be treated per the local standard of care”, as LY3478006 may be associated with
infusion reactions and hypersensitivity reactions.


J2F-MC-OHAA(a) Clinical Pharmacology Protocol
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LY3478006
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
2.
Schedule of Activities


J2F-MC-OHAA(a) Clinical Pharmacology Protocol
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LY3478006
Study Schedule Protocol J2F-MC-OHAA
Study Day
Procedure
Screening
≤28 days 
prior to 
Day 1 
-1
1
2
3
5
8
10 
(±1)
15 
(±1)
22 
(±1)
29
(±1)
43 
(±2)
57 
(±2)
71 
(±4)
Day 85 
(±4)m or 
E/T
Informed Consent
X
Outpatient Visit
X
X
X
X
X
X
X
X
X
X
CRU Admission
X
CRU Discharge
X
Medical History
X
Height
X
Weight
X
X
X
Physical Examinationa
X
X
Predose
24 hr
X
X
X
X
X
X
X
X
X
X
X
Directed Neurological 
Examination
X
X
24 hr
X
X
X
X
X
X
X
Pupillometry
X
X
X
X
ECGb
X
Predose
(1, -0.5, 0 hr), 
end of 
infusionc, 3, 
6, 12 hr
24 hr
48 
hr
X
X
X
X
X
X
X
X
X
AEd and Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Administratione
0 hr
Vital Signsf
X
Predose, end 
of infusionc, 
3, 6, 12 hr
24 hr
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testg
X
X
X
Serology (Hepatitis B 
Surface Antigen, HIV, 
Hepatitis C Antibody)
X


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LY3478006
Abbreviations:  ADA = antidrug antibody; AE = adverse event; CRU = clinical research unit; ECG = electrocardiogram; E/T = early termination; HIV = human 
immunodeficiency virus; hr = hour; IV = intravenous; NGF = nerve growth factor, PK = pharmacokinetics; SC = subcutaneous; TE-ADA = treatment-
emergent antidrug antibody.  
Note: Study procedures scheduled relative to IV dosing time are to occur from the time of the start of infusion; e.g., 3 hours postdose would be 3 hours after the 
start of the IV infusion.
a
Full physical examination on Day -1 and Day 85 or E/T (may include body temperature and respiratory rate).  At all other time points, the examination will 
include at a minimum, an assessment of skin, injection site, and oral cavity. Symptom-driven physical examination at all other times as deemed necessary by 
the investigator.  


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LY3478006
6.2 
Exclusion Criteria
[23]
Have liver function test (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase [ALP], total bilirubin [TBL])
above the upper limit of normal (ULN) at screening.
[29]
Have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females), or are unwilling to stop alcohol consumption 
from 48 hours prior to dosing until discharge from the CRU (1 unit = 12 oz or 
360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits).
6.3.2.
Caffeine, Alcohol, and Tobacco 
Consumption of caffeine- and xanthine-containing products is allowed, provided that the 
subject’s consumption has been consistent for the past 30 days.
Subjects will not be permitted to consume alcohol from 48 hours before each visit until leaving 
the CRU.  Subjects will be advised to abstain from alcohol consumption for the remainder of the 
trial until their final visitSubjects will not exceed their habitual alcohol consumption during the 
study.  When not resident in the CRU, male subjects should be advised to limit alcohol 
consumption to no more than 21 units per week and female subjects to no more than 14 units per 
week, and all subjects should be advised to limit alcohol consumption to no more than 3 units in 
a day.
Subjects will not be permitted to smoke from CRU admission until discharge from the CRU.
9.4.5.2.
Allergic/Hypersensitivity Events
All biologic agents carry the risk of systemic allergic/hypersensitivity reactions.  Clinical 
manifestations of these reactions may include but are not limited to skin rash, pruritus (itching), 
dyspnea, urticaria (hives), angioedema (for example, swelling of the lips and/or tongue), 
hypotension, and anaphylactic reaction. If such a reaction occurs, additional data describing 
each symptom should be provided to the sponsor in the eCRF.
All subjects will be monitored closely for symptoms and signs that may occur as part of a
systemic infusion reaction (Section 7.4.2.2).
Sites should will have appropriate advanced cardiac life support (ACLS) trained medical staff
appropriately trained medical staff and appropriate medical equipment including a crash cart on 
site available when study participants are receiving study drug.  It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per the local standard 
of care.
In the presence of generalized urticaria, or if anaphylaxis is suspected, blood samples should be 
collected for hypersensitivity tests after the subject is stabilized and as directed in Appendix 5.  
The laboratory results will be provided to the sponsor via the central laboratory.


Leo Document ID = b53b5ae1-d2b5-413f-80c1-697ec66b3b34
Approver: Brian Austin Millen (AM\RM36209)
Approval Date & Time: 25-Dec-2019 17:39:18 GMT
Signature meaning: Approved
Approver: Yan Jin (AM\C056372)
Approval Date & Time: 26-Dec-2019 15:10:07 GMT
Signature meaning: Approved

SAP_001.pdf: 
J2F-MC-OHAA Statistical Analysis Plan 
 
 
 
A Single Ascending Dose Study to Evaluate Safety, Tolerability, and Pharmacokinetics of 
LY3478006 in Healthy Subjects 
 
NCT04230122 
 
Approval Date: 21-Jan-2020 
 
 
 


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             Page 1 of 14
STATISTICAL ANALYSIS PLAN
A Single Ascending Dose Study to Evaluate Safety, Tolerability, and Pharmacokinetics of 
LY3478006 in Healthy Subjects
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Date: 07-January-2020
Study Drug: LY3478006
Sponsor Reference: J2F-MC-OHAA
Covance CRU Study: 1000071-8415333
Clinical Phase I
Approval Date: 21-Jan-2020 GMT


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8415333
Sponsor Reference J2F-MC-OHAA
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES.................................................................................................. 6
4.1
Primary Objective.................................................................................................... 6
4.2
Secondary Objectives .............................................................................................. 6
4.3
Exploratory Objectives ............................................................................................ 6
5.
STUDY DESIGN........................................................................................................... 7
6.
TREATMENTS............................................................................................................. 8
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 9
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 9
9.
STATISTICAL METHODOLOGY ............................................................................... 9
9.1
General.................................................................................................................... 9
9.2
Demographics and Subject Disposition.................................................................. 10
9.3
Pharmacokinetic Assessment................................................................................. 10
9.3.1
Pharmacokinetic Analysis............................................................................. 10
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 10
9.4
Safety and Tolerability Assessments...................................................................... 10
9.4.1
Adverse events ............................................................................................. 10
9.4.2
Concomitant medication............................................................................... 11
9.4.3
Clinical laboratory parameters...................................................................... 11
9.4.4
Vital signs .................................................................................................... 11
9.4.5
Electrocardiogram (ECG)............................................................................. 11
9.4.6
Hepatic Monitoring ...................................................................................... 11
9.4.7
Immunogenicity Assessments....................................................................... 12
9.4.8
Allergic/Hypersensitivity reactions............................................................... 12
9.4.9
Injection/Infusion Site Reactions .................................................................. 12
9.4.10
Neurological Examinations........................................................................... 12
9.4.11
Pupillometry Assessments ............................................................................ 12
9.4.12
Biomarkers................................................................................................... 13
9.4.13
Serum NGF levels ........................................................................................ 13
9.4.14
Other assessments......................................................................................... 13
9.4.15
Safety and Tolerability Statistical Methodology............................................ 13


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10. DATA REVIEW DURING THE STUDY.................................................................... 13
11. INTERIM ANALYSES ............................................................................................... 14
12. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 14
13. REFERENCES ............................................................................................................ 14
14. DATA PRESENTATION ............................................................................................ 14
14.1 Derived Parameters ............................................................................................... 14
14.2 Missing Data ......................................................................................................... 14
14.3 Insufficient Data for Presentation .......................................................................... 14


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8415333
Sponsor Reference J2F-MC-OHAA
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ADA
Antidrug antibody
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC0-∞
Area under the concentration versus time curve from time zero to 
infinity
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL
Total body clearance of drug
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
ECG
Electrocardiogram
F
Bioavailability of drug
ICH
International Conference on Harmonisation
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
NCA
Noncompartmental methods of analysis
NGF
Nerve growth factor
PK
Pharmacokinetic
pTrkA
Phosphorylated tropomyosin receptor kinase
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
TBL
Total bilirubin
TE ADA
Treatment-emergent antidrug antibody


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8415333
Sponsor Reference J2F-MC-OHAA
TFLs
Tables, Figures, and Listings
tTrkA
Total Tropomyosin receptor kinase
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vss
Volume of distribution at steady state following IV administration
Vz
Volume of distribution during the terminal phase
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8415333
Sponsor Reference J2F-MC-OHAA
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
04 November 2019).
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.
4. STUDY OBJECTIVES
4.1
Primary Objective
To assess the safety and tolerability following single doses of LY3478006 in healthy subjects, 
including those of Japanese origin.
4.2
Secondary Objectives

To assess the serum PK of LY3478006 following single intravenous (IV) or 
subcutaneous (SC) doses of LY3478006 in healthy subjects.

To estimate the absolute bioavailability of LY3478006 following a single SC dose 
relative to a single IV dose in healthy subjects.
4.3
Exploratory Objectives

To assess the changes in serum nerve growth factor (NGF) levels following single IV and 
SC doses of LY3478006 in healthy subjects.

To assess the changes in skin phosphorylated TrkA (pTrkA) and total TrkA (tTrkA)
levels following single IV and SC doses of LY3478006 in healthy subjects.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8415333
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
To assess the serum PK of LY3478006 following single IV doses of LY3478006 in 
healthy Japanese subjects.
5. STUDY DESIGN
Study J2F-MC-OHAA is a Phase 1, subject- and investigator-blind, placebo-controlled, 
randomized, parallel, single-ascending dose study in healthy subjects.
Seven cohorts (Cohorts 1 to 7) of healthy subjects will be studied. In each cohort, 8 subjects will 
be randomized (3:1 ratio) to receive LY3478006 or placebo (6 LY3478006 subjects and 
2 placebo subjects). Four of the 8 healthy subjects enrolled in Cohorts 3, 4, 5, and 6 are planned 
to be of Japanese origin (first generation; randomized [3:1 ratio] to receive LY3478006 or 
placebo). If the recruitment of Japanese subjects becomes limiting for a particular cohort, then
additional non-Japanese subjects may be entered into a cohort to allow for dose escalation. 
Japanese subjects will subsequently be enrolled so that at least 3 Japanese subject’s complete 
placebo and each LY3478006 dose level. In addition, it is preferred that the non-Japanese 
subjects also be non-Asian.
Cohorts 1 through 6 will be sequentially enrolled to test 6 single ascending dose levels of 
LY3478006 
) or 
placebo administered IV. Subjects in Cohorts 1 through 6 may be dosed in at least 2 dosing 
groups (approximately 4 subjects in each group) on separate days. Study drug will be 
administered to 1 subject at a time (study drug infusion can start for a given subject after the end 
of infusion of the previous subject). Safety data through Day 15 postdose must be evaluated from 
at least 6 of 8 subjects prior to the decision to dose escalate to the subsequent cohort. Cohort 7 
will be enrolled to test 1 dose level of LY3478006
 
 or placebo administered SC. All subjects in 
Cohort 7 may be dosed on a single day. 
CCI
CCI


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Covance Clinical Study No. 1000071-8415333
Sponsor Reference J2F-MC-OHAA
Figure 1 study design.
6. TREATMENTS
The following is a list of the study treatment names that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
Placebo IV
1
Placebo SC
2
LY3478006 IV
3
LY3478006 IV
4
LY3478006 IV
5
LY3478006 SC*
6
LY3478006 IV
7
LY3478006 IV
8
LY3478006 IV
9
*
 will be replaced with actual dose received by the subjects and doses will be presented in 
ascending order.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Statistical Analysis Plan 
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7. SAMPLE SIZE JUSTIFICATION
Up to 70 healthy subjects may be enrolled such that approximately 56 subjects complete the 
study. It is planned that 16 of these 56 subjects will be of Japanese origin (first-generation). 
Subjects who are randomized but not administered treatment may be replaced to ensure that 
enough subjects complete the study. The ethnicity of the replacement subject (Japanese or non-
Japanese) should match the ethnicity of the discontinued subject, where possible. 
The sample size is customary for Phase 1 studies evaluating safety and PK parameters, and is not 
powered on the basis of statistical hypothesis testing.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received study drug and have 
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 subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Summary statistics and figures by ethnicity (Japanese and non-Japanese) will be provided as 
appropriate.
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, 
min, max and N; for log-normal data (e.g. the PK parameters: area under the concentration 
versus time curve [AUC] and maximum observed drug concentration [Cmax]) the geometric mean 
and geometric coefficient of variation (CV%) will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all subjects 
up to the point of withdrawal, with any subjects excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
subjects 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 subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’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 Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height and body mass index will be summarized by ethnicity 
(overall, Japanese and Non-Japanese) and listed. All other demographic variables will be listed 
only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
PK parameters for LY3478006 will be calculated by standard noncompartmental methods of
analysis (NCA) using Phoenix/WinNONLIN. The primary parameters for analysis will be Cmax
and area under the concentration versus time curve from zero to infinity (AUC0-∞). Other 
noncompartmental parameters, such as halflife (t1/2), total body clearance of drug (CL), volume 
of distribution during the terminal phase (Vz) (apparent clearance, and apparent volume of 
distribution for SC administration) may be calculated and reported as deemed appropriate.
Eli Lilly is responsible for the PK statistical analysis and reporting of data.
In addition, LY3478006 concentration time data may be analyzed using non-linear mixed effect
modeling as implemented in software such as NONMEM. Serum data from all subjects will be
pooled to determine the compartmental PK parameters (for example, CL, volume of distribution 
at steady state following IV administration [Vss], t1/2, bioavailability of drug [F]) and between-
subject variability. Covariate relationships, such as CL or volume of distribution versus body 
size (for example, body weight and body mass index) or gender, may be investigated through 
graphical exploration and may be quantified through modeling. The effect of factors such as 
race/ethnicity (Japanese versus non-Japanese subjects) could be tested in the model and may be 
included in the final model.
9.3.2
Pharmacokinetic Statistical Methodology
PK parameter estimates from the NCA will be evaluated to delineate effects of dose
proportionality. Log-transformed Cmax and AUC estimates will be evaluated in a linear model 
with log-transformed IV dose as a fixed effect. The treatment differences will be back-
transformed to present the ratios of geometric means and the corresponding 90% confidence 
intervals (CI). For the SC dose, the bioavailability relative to IV infusion at the same dose will be 
evaluated via a log-transformed model. The log-transformed Cmax and AUC will be the response 
variable, and route of administration (IV/SC) is the explanatory variable.
Eli Lilly is responsible for the PK statistical analysis and reporting of data.  
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 adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the subject has 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8415333
Sponsor Reference J2F-MC-OHAA
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to dosing and becomes 
more severe postdose.
All AEs will be listed. Treatment-emergent AEs will be summarized by ethnicity (overall, 
Japanese and non-Japanese), treatment, severity and relationship to the study drug. The 
frequency (the number of AEs, the number of subjects experiencing an AE and the percentage of 
subjects experiencing an AE) of treatment-emergent AEs will be summarized by ethnicity 
(overall, Japanese and Non-Japanese), treatment, Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.1 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. Any serious AEs 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 September 2019). Concomitant medication will be listed.
9.4.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, 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 subject data listings.
9.4.4
Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where
baseline is defined as the Day 1 predose assessment. Figures of mean vital signs and mean 
changes from baseline profiles will be presented by treatment.
Values for individual subjects 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
Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality. Additional safety data may be collected if 
required, as defined in the protocol. Where applicable, the following will be presented.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8415333
Sponsor Reference J2F-MC-OHAA
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant medications that have potential for hepatotoxicity, including acetaminophen 
will be listed. Results from any hepatic monitoring procedures, such as a magnetic resonance 
elastography (MRE) scan, and biopsy assessments will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.4.7
Immunogenicity Assessments
The frequency and percentage of subjects with pre-existing antidrug antibody (ADA) and with 
treatment-emergent ADAs (TE ADA) to LY3478006 will be tabulated and listed. 
For subjects 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. For subjects 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 subjects with cross-reactive and 
neutralizing antibodies, if measured, may also be tabulated for subjects with TE ADA. 
The relationship between the presence of antibodies and the PK parameters may be assessed.
Eli Lilly is responsible for the immunogenicity reporting of data.
9.4.8
Allergic/Hypersensitivity reactions
For all allergic and 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.
9.4.9
Injection/Infusion Site Reactions
Injection-site reaction data will be listed and summarized by ethnicity (overall, Japanese and 
non-Japanese) and treatment in frequency tables. The reaction data may include erythema, 
induration, pain, pruritus, and edema.
9.4.10
Neurological Examinations
New or worsened abnormality on the neurologic exam should be reported as an AE and listed. 
Neurological examination data will be listed for all subjects by treatment and timepoint.
9.4.11
Pupillometry Assessments
Pupillometry data will be listed for all subjects by treatment and timepoint.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8415333
Sponsor Reference J2F-MC-OHAA
9.4.12
Biomarkers
Abdomen skin biopsy samples will be collected to study protein biomarkers, including tTrkA 
and pTrkA. The protein biomarkers data will be summarized by ethnicity (overall, Japanese and 
Non-Japanese) and treatment and listed.
Eli Lilly is responsible for the biomarkers statistical analysis and reporting of data.
9.4.13
Serum NGF levels
Serum NGF levels will be evaluated over time to assess changes in NGF levels and will be listed 
by subject.
Summary tables, with changes from baseline where baseline is defined as the Day 1 predose 
assessment, mean (+ SD) figures, overlaying individual figures will be provided for the serum 
NGF levels by ethnicity (overall, Japanese and Non-Japanese).
Eli Lilly is responsible for the serum NGF levels statistical analysis and reporting of data.
9.4.14
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.15
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
Data Review During the Study
Data will be reviewed during the study to evaluate the safety and PK of LY3478006, inform dose
selection/escalation decisions, and confirm inclusion of data from an adequate number of
Japanese and non-Japanese subjects.
Interim data reviews are planned as follows:

Prior to initiating the planned 
SC dose level cohort (Cohort 7), it will include
o
PK and safety data from Cohorts 1, 2, and 3 (
 

Prior to initiating the 
 dose cohort (Cohort 6), or a SC dose level cohort 
(Cohort 7), it will include:
o
PK data from Cohorts 1, 2, 3, and 4 (
 
o
Available safety data from Cohorts 1, 2, 3, 4, and 5 (
 
 Safety data from Cohort 5 will not be required for 
the 
 SC dose level cohort (Cohort 7) decision.
CCI
CCI
CCI
CCI
CCI
CCI


Final, 07 January 2020
             Page 14 of 14
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8415333
Sponsor Reference J2F-MC-OHAA
11.
INTERIM ANALYSES
No interim statistical analyses are planned.
12.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
13.
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.
14.
DATA PRESENTATION
14.1
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.
14.2
Missing Data
Missing data will not be displayed in listings.
14.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = e38fe50c-6990-423a-8d37-569ab9ce8b6c
Approver: 
Approval Date & Time: 10-Jan-2020 14:10:24 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 10-Jan-2020 14:24:24 GMT
Signature meaning: Approved
Approver: 
  
Approval Date & Time: 21-Jan-2020 19:12:26 GMT
Signature meaning: Approved
PPD
PPD
PPD