Clinical trial NCT03611608
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2018-08-30; Completion date: 2019-03-15
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess study drug activity by giving LY3316531 or placebo into a vein in the arm and then measuring blood flow of the skin, after capsaicin is applied to skin's surface. The study will last about 16 weeks inclusive of the screening period.

Detailed description:

Arms: arm 1: LY3316531 administered IV arm 2: The optional additional cohort (Dose 2) was not implemented as the data desired for treatment effect on dermal blood flow (DBF) was generated at the initial Dose 1 (300mg LY3316531)

LY3316531 administered IV arm 3: Placebo administered IV
Interventions: intervention 1: LY3316531 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol I9H-MC-FFAB (c) 
 
 
A Phase 1 Randomized, Placebo-Controlled Study to Determine the Effect of LY3316531 on 
Capsaicin-Induced Dermal Blood Flow in Healthy Male Subjects 
 
NCT03611608 
 
Approval Date: 06-Feb-2019 
 




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Table of Contents
A Phase 1 Randomized, Placebo-Controlled Study to 
Determine the Effect of LY3316531 on Capsaicin-Induced 
Dermal Blood Flow in Healthy Male Subjects
Section
Page
Protocol I9H-MC-FFAB(c) A Phase 1 Randomized, Placebo-Controlled 
Study to Determine the Effect of LY3316531 on Capsaicin-Induced 
Dermal Blood Flow in Healthy Male Subjects.....................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................13
3.1.
Study Rationale............................................................................................................13
3.2.
Background..................................................................................................................13
3.3.
Benefit/Risk Assessment..............................................................................................14
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................19
5.3.
End of Study Definition ...............................................................................................19
5.4.
Scientific Rationale for Study Design...........................................................................19
5.5.
Justification for Dose ...................................................................................................20
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................23
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................26
6.3.
Lifestyle and/or Dietary Requirements .........................................................................26
6.3.1.
Meals and Dietary Restrictions.............................................................................26
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................26
6.3.2.1.
Caffeine and Alcohol......................................................................................26
6.3.2.2.
Tobacco..........................................................................................................26
6.3.3.
Activity................................................................................................................27
6.3.4.
Contraception.......................................................................................................27
6.4.
Screen Failures.............................................................................................................27
7.
Treatment..........................................................................................................................28
7.1.
Treatment Administered...............................................................................................28


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7.1.1.
Packaging and Labeling .......................................................................................28
7.2.
Method of Treatment Assignment ................................................................................29
7.2.1.
Selection and Timing of Doses.............................................................................29
7.3.
Blinding .......................................................................................................................29
7.4.
Dose Modification........................................................................................................30
7.4.1.
Special Treatment Considerations ........................................................................30
7.4.1.1.
Management of Infusion Reactions.................................................................30
7.5.
Preparation/Handling/Storage/Accountability...............................................................30
7.6.
Treatment Compliance .................................................................................................31
7.7.
Concomitant Therapy...................................................................................................31
7.8.
Treatment after the End of the Study............................................................................31
8.
Discontinuation Criteria ....................................................................................................32
8.1.
Discontinuation from Study Treatment.........................................................................32
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................32
8.2.
Discontinuation from the Study....................................................................................32
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..........................................35
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.
Safety Monitoring ................................................................................................37
9.4.4.1.
Hepatic Safety................................................................................................37
9.5.
Pharmacokinetics .........................................................................................................38
9.5.1.
Bioanalysis...........................................................................................................38
9.6.
Pharmacodynamics ......................................................................................................39
9.6.1.
Total CGRP .........................................................................................................39
9.6.2.
Measurement of Dermal Blood Flow....................................................................39
9.6.3.
Immunogenicity Assessments ..............................................................................39
9.7.
Genetics .......................................................................................................................40
9.8.
Biomarkers...................................................................................................................40
9.9.
Health Economics ........................................................................................................41


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10.
Statistical Considerations and Data Analysis.....................................................................42
10.1. Sample Size Determination ..........................................................................................42
10.2. Populations for Analyses..............................................................................................43
10.2.1.
Study Participant Disposition ...............................................................................43
10.2.2.
Study Participant Characteristics ..........................................................................43
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.......................................................................44
10.3.2.
Pharmacokinetic Analyses....................................................................................44
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................44
10.3.3.
Pharmacodynamic Analyses.................................................................................45
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................45
10.3.5.
Evaluation of Immunogenicity .............................................................................45
10.3.6.
Data Review During Cohort 1..............................................................................45
10.3.7.
Interim Analyses..................................................................................................45
11.
References ........................................................................................................................47


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List of Tables
Table
Page
Table FFAB.4.1.
Objectives and Endpoints .......................................................................17
Table FFAB.5.2.
Margin of Safety for Intravenous Administration of LY3316531 
Based on Administered Dose and Predicted Exposure ............................21


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List of Figures
Figure
Page
Figure FFAB.1.
Protocol I9H-MC-FFAB study design for Cohort 1 and optional 
Cohort 2. ................................................................................................19
Figure FFAB.2.
Statistical power to detect the primary endpoint of LY3316531 
plotted against effect-size for Cohorts 1 and 2.........................................43


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................50
Appendix 2.
Clinical Laboratory Tests........................................................................54
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................55
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............58
Appendix 5.
Blood Sampling Summary......................................................................59
Appendix 6.
Protocol Amendment I9H-MC-FFAB(c) Summary
A Phase 1 Randomized, Placebo-Controlled Study to Determine 
the Effect of LY3316531 on Capsaicin-Induced Dermal Blood 
Flow in Healthy Male Subjects...............................................................60


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1. Protocol Synopsis
Title of Study:
A Phase 1 Randomized, Placebo-Controlled Study to Determine the Effect of LY3316531 on Capsaicin-Induced 
Dermal Blood Flow in Healthy Male Subjects
Rationale: 
LY3316531 is a humanized bispecific antibody that selectively binds to interleukin-23 (IL-23) and calcitonin 
gene-related peptide (CGRP).  This dual inhibitor is an innovative attempt to target pathways that affect the 
pathology associated with auto-inflammatory conditions.
This study will assess the activity of LY3316531 on CGRP neutralization via capsaicin-induced dermal blood flow 
(DBF) as measured using laser Doppler imaging (LDI) in healthy male subjects.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To assess target neutralization of CGRP following a 
single IV dose of LY3316531 versus placebo in 
healthy male subjects via capsaicin-induced DBF as 
measured using LDI
Decrease from baseline within 30 days, relative to 
placebo, in capsaicin-induced DBF (by blocking 
CGRP) following at least 1 dose level of a single IV 
dose of LY3316531
Secondary
To assess the safety and tolerability of a single dose of 
LY3316531 in healthy male subjects
To characterize the pharmacokinetics of LY3316531 
following IV administration in healthy male subjects
Incidence of adverse events, treatment-emergent 
adverse events, and serious adverse events
Cmax and AUC
Abbreviations:  AUC = area under the concentration versus time curve; CGRP = calcitonin gene-related peptide; 
Cmax = maximum observed drug concentration; DBF = dermal blood flow; IV = intravenous; LDI = laser 
Doppler imaging.
Summary of Study Design:
Study I9H-MC-FFAB is a Phase 1 single-site, randomized, subject- and investigator-blind, placebo (Pbo)-
controlled, parallel-dose group, single-dose study of LY3316531 (LY) in healthy male subjects.  The study will 
evaluate 1 cohort (Cohort 1) of 16 subjects (12 LY:4 Pbo) with a planned single dose of 300-mg LY3316531 via 
intravenous (IV) administration.  Should an effect not be observed at this starting dose, an optional cohort (Cohort 2) 
of 12 subjects (9 LY:3 Pbo) may be evaluated with a dose not to exceed 2000-mg IV or the highest tolerable and 
safe dose evaluated in the single-ascending dose Study I9H-MC-FFAA.  All subjects will be invited to attend a 
follow-up assessment of capsaicin-induced blood flow approximately 160 days post treatment administration.  
Treatment Arms and Planned Duration for an Individual Subject:  
After a screening period up to 28 days, eligible subjects will be randomized to receive the planned single IV dose of 


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LY3316531
300-mg LY3316531 or Pbo on the morning of Day 1.  Subjects will remain in the CRU for up to 32 hours after 
study drug administration and attend scheduled visits at the CRU for up to160 days to assess DBF and 
measurements for safety, tolerability, and pharmacokinetics (PK).  The decision to implement the optional Cohort 2 
will be made after reviewing the change in DBF from baseline (relative to placebo) in subjects of Cohort 1 on Day 
10 (Figure FFAB.1).  The dose to be administered in Cohort 2 will not exceed 2000-mg IV or the highest tolerable 
dose determined to be safe in Study FFAA.
Number of Subjects:
Cohort 1 is planned to enroll 16 subjects (12 LY:4 Pbo).  Optional Cohort 2 is planned to enroll 12 subjects 
(9 LY:3 Pbo). It is not planned to replace subjects; however, subjects may be replaced if necessary to meet study 
objectives or at the discretion of the Sponsor.
Statistical Analysis:
Safety:  All investigational product (IP) and related protocol procedure adverse events will be listed and, if the 
frequency of events allows, safety data will be summarized using descriptive methodology.  The incidence of 
treatment-emergent adverse events and serious adverse events will be presented by severity and by association with 
treatment as perceived by the investigator.  Symptoms reported to occur prior to treatment with the study drug will 
be distinguished from those reported as new or increased in severity during the trial.  Safety parameters that will be 
assessed include laboratory tests, vital signs, electrocardiogram, body weight, immunogenicity, and infusion
reactions.
Pharmacokinetics: PK parameter estimates for LY3316531 will be calculated using standard noncompartmental 
methods of analysis.  The primary parameters for analysis will be maximum observed drug concentration (Cmax) and 
AUC of LY3316531.  Other noncompartmental parameters, such as half-life, apparent clearance, and apparent 
volume of distribution may be reported.  Mean and individual plasma concentration versus time profiles and 
individual and summary statistics of PK parameter estimates will be generated.  Population PK analysis methods
may be utilized if necessary.
Pharmacodynamics:  Relationships between LY3316531 exposure and capsaicin-induced DBF (absolute and 
percentage changes), between LY3316531 exposure and total CGRP plasma levels, and between total CGRP plasma 
levels and capsaicin-induced DBF (absolute and percentage changes) may be explored using graphical- and 
model-based approaches.  Absolute and percentage change in DBF from baseline over all subjects will be 
summarized by providing the mean, standard deviation, median, minimum, and maximum for plasma drug 
concentration for each cohort and overall for each sample day and time combination, and maximum over the entire 
study.  Data may be log-transformed prior to summarizing if necessary.  The inter-subject and intra-subject
variabilities in human pharmacodynamic (PD) responses may also be assessed if appropriate.
Statistical:  PK/PD analyses will be conducted on data from all subjects who receive at least 1 dose of LY3316531
and have evaluable PK. If Cohort 2 is conducted, data from like treatment arms across cohorts will be pooled for the 
purpose of analysis.  Pharmacodynamic parameters, and their change from baseline, will be summarized at each 
applicable visit using descriptive statistics.  No statistical inferences will be made and no control for multiplicity is 
planned.  Additional analyses may be performed.


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2. Schedule of Activities
Study Schedule Protocol I9H-MC-FFAB
Screening
Baseline
Postdose
Visit No.
V1
V2
V3 
V4 
V5 
V6 
V7 
V8 
V9
V10 
ED
Study Day -28 d from 
Day -2
-1
1
2
10 ± 
1 d
24 ± 
1 d
38 ± 
2 d
52 ± 
2 d
66 ± 
4 d
80 ± 
4 d
120 ± 
7 d
160 ± 
7 d
Admission to CRU
X
Discharge from CRU
X
Informed consent
X
Review/confirm I/E 
criteria
X
X
Complete medical history 
X
Complete physical 
examination
X
Predose
X
X
X
Weight
X
X
X
Height
X
Symptom-directed 
physical examination
When needed
Concomitant medications
X
Xa
X
X
X
X
X
X
X
X
Vital signs (pulse rate, 
blood pressure, and 
temperature)b,c
X
X
Predose, EOI, 
2 h, 6 h, and 
12 h after SOI
24 h after 
SOI
X
X
X
X
X
X
X
Review preexisting 
conditions/AEs
X
Xa
X
X
X
X
X
X
X
X
ECGsc,d
X
Predose, EOI, 
and 6 h after 
SOI
24 h after 
SOI
X
X
X
X
X
QuantiFERON®-TB
Gold test or TST
X


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Screening
Baseline
Postdose
Visit No.
V1
V2
V3 
V4 
V5 
V6 
V7 
V8 
V9
V10 
ED
Study Day -28 d from 
Day -2
-1
1
2
10 ± 
1 d
24 ± 
1 d
38 ± 
2 d
52 ± 
2 d
66 ± 
4 d
80 ± 
4 d
120 ± 
7 d
160 ± 
7 d
Read TST (if applicable)
Xe
Chest X-ray (PA)
Xf
HIV/HBV/HCV
X
Serum chemistry and 
hematology
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
Ethanol test and urine 
drug screen
X
X
Pharmacogenetics 
(exploratory storage 
samples for DNA)
Predose
LY3316531 or placebo 
administration (IV)
X
Immunogenicityg,h
Predose
X
X
X
X
X
X
LY3316531 
concentration (PK)g,h
Predose, EOI, 
2 h and 6 h
after SOI
24 h after 
SOI
X
X
X
X
X
X
X
X
X
Target engagement assay 
(total CGRP)
Predose
24 h after 
SOI
X
X
X
X
X
X
X
X
X
Capsaicin challenge and
LDIi
X
24-32 h 
after SOI
X
X
X
X
X
X
X
X
X
j
Abbreviations:  AE = adverse event; CGRP = calcitonin gene-related peptide; CRU = clinical research unit; d = study day; DNA = deoxyribonucleic acid; 
ECG = electrocardiogram; ED = early discontinuation; EOI = end of infusion; h = hour(s); HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = 
human immunodeficiency virus; I/E = inclusion/exclusion; IV = intravenous; LDI = laser Doppler imaging; No. = number; PA = posterior to anterior; 
PK = pharmacokinetics; SOI = start of infusion; TB = tuberculosis; TST = tuberculin skin test; V = visit.


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a
At the discretion of the CRU, the baseline measurement for this assessment can be collected at any time after subject admission to the CRU up until just 
prior to LY3316531 or placebo administration on Day 1.
b
Additional vital sign measurements may be obtained when clinically indicated.  Vital signs should be taken following an approximate 5-minute rest in 
supine position.  Temperature measurement is required only at screening and baseline.
c
ECG, vital sign, and PK sampling should occur at approximately the same time.  ECG recording and vital sign measurements should occur prior to the 
blood draw.
d
ECG should be taken following an approximate 5-minute rest in supine position.  ECGs are requested to be taken at the specified time; however, 
aberrations to specified recording times will not be considered protocol deviations as long as the ECGs are taken and the actual recording time is 
documented.  All ECGs will be collected as local safety single ECGs.
e
The follow-up TST reading should occur 2 to 3 days after V1.
f
Not required if chest X-ray was performed within the last 1 year, found to be normal, and report is available.  A lateral chest X-ray may be performed if 
clinically or radiologically indicated.
g
Samples are requested to be taken at the specified time; however, aberrations to specified sampling times will not be considered protocol deviations as long 
as the samples are taken and the actual sampling time is recorded.  It is essential that the actual times of doses and samples are recorded accurately on the 
appropriate forms.
h
In the event of drug hypersensitivity reactions (immediate or non-immediate), up to 3 additional samples will be collected each for PK and immunogenicity
at the following times: 1) as close to the onset of the reaction event as possible, 2) at the resolution of the event, and 3) 30 days following the event.
i
All subjects will have the capsaicin challenge and LDI procedure (pre-challenge and 30 and 40 minutes post-challenge) during a second screening day, V2, 
and subsequent postdose visits resulting in up to10 total capsaicin challenges per subject.  For each subject, DBF will be measured consistently on the same 
arm at all study visits.
j
If a subject discontinues from the study early, capsaicin challenge and LDI measurements may be performed at ED if possible, if deemed appropriate by the 
investigator, and if the most recent capsaicin challenge and LDI measurements for that subject were conducted 7 or more days prior to the ED visit. 


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3. Introduction
3.1.
Study Rationale
LY3316531 is a humanized bispecific antibody that selectively binds to interleukin-23 (IL-23) 
and calcitonin gene-related peptide (CGRP).  This dual inhibitor is an innovative attempt to 
target pathways involving IL-23 and CGRP that affect the pathology associated with 
auto-inflammatory conditions. Each molecule of LY3316531 can bind a maximum of one 
molecule of IL-23 and one molecule of CGRP.
Study I9H-MC-FFAB (FFAB) is a Phase 1 study being conducted to assess target neutralization 
of CGRP following a single IV dose of LY3316531 in healthy male subjects via capsaicin-
induced dermal blood flow (DBF) as measured using laser Doppler imaging (LDI).  LDI is the 
imaging technique generally used in the capsaicin-induced DBF model and studies with CGRP 
antagonists.
In addition, the safety, tolerability, and pharmacokinetics (PK) of a single dose of LY3316531 in 
healthy subjects will be evaluated.
3.2.
Background
A typical organ-specific, T-cell-driven inflammatory disease, psoriasis had been considered a 
T helper (Th) 1-type skin disease for decades until a new Th population, Th17, was identified 
(Lew et al. 2004; Steinman 2007; Weaver et al. 2007).  However, substantial clinical and basic 
research observations now suggest that the IL-23/Th17 axis is essential in the pathogenesis of 
psoriasis (Di Cesare et al. 2009).  IL-23, a member of the IL-12 family of cytokines, is a 
heterodimeric protein comprised of 2 subunits; the p40 subunit, which it shares with IL-12, and 
the p19 subunit, believed to be specific to IL-23.  IL-23 is produced by antigen-presenting cells, 
such as dendritic cells and macrophages, and plays an important role in maintenance and 
amplification of Th17 cells (Lee et al. 2004; Piskin et al. 2004).  In addition, Th17 cells and their 
downstream effector molecules, including IL-17A, IL-17F, IL-21, IL-22, and tumor necrosis 
factor alpha (TNF-α), are found at increased levels in human psoriatic skin lesions and 
circulation (Boniface et al. 2007; Lowes et al. 2008; Caruso et al. 2009; Kagami et al. 2010).
Treatment of psoriasis with biologic therapy, particularly with those agents targeting the 
IL-23/Th17 axis, has demonstrated clinical activity in patients with psoriasis (Crow 2012).  
Agents specifically targeting the IL-23 p19 subunit have demonstrated clinical activity in 
psoriasis (including LY3074828 in Study I6T-MC-AMAA) (Krueger et al. 2015; Papp et al. 
2015; Gordon et al. 2015; Kopp et al. 2015; Sofen et al. 2014) and Crohn’s disease (Sands et al. 
2015).
The calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide member of a 
family of peptides that includes amylin, adrenomedullin, and calcitonin.  The predominant form 
of CGRP is known as -CGRP, with a second isoform, -CGRP, being produced from a separate 
gene but having high sequence homology (Steenbergh et al. 1985).  Both isoforms have similar 
biological activities, but differ in their expression patterns; -CGRP is expressed mainly in the 
peripheral and central nervous system while -CGRP is expressed mostly in the enteric nervous 


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system (Mulderry et al. 1988).  The CGRP is a potent vasodilator (Brain et al. 1985).  While 
CGRP antagonists seem to restore normal tonus in CGRP-induced dilation of isolated arterial 
rings, the evidence to date suggests that CGRP antagonists do not alter basal vascular tone 
(Chaitman et al. 2012; Verheggen et al. 2002).  The CGRP has a well-established role in 
neurogenic inflammation and nociception (Hirsch et al. 2013).  It is able to facilitate the 
production and secretion of numerous pro-inflammatory mediators that lead to hyperemia, 
edema, and pain in inflamed tissues (Cady et al. 2011).  The CGRP pathway may play a specific 
role in inflammatory skin disorders having direct effects on immune cells (ie, dermal dendritic 
cells), cytokine production, and itch and pain pathologies in various dermatoses (Lotti et al. 
2014; Kashem et al. 2015).  Interestingly, CGRP regulates sensory neurons through the 
IL-23/IL-17 axis as well (Riol-Blanco et al. 2014; Ding et al. 2016).  In addition to its 
involvement in inflammation and nociception, it is believed that CGRP can increase the 
production of IL-23 (Kashem et al. 2015).
Several nonclinical studies were performed to support the use of LY3316531 in humans.  
Weekly administration of LY3316531 to cynomolgus monkeys in a general toxicology study 
resulted in no adverse drug-related findings at doses of 20 or 60 mg/kg (subcutaneous [SC]), or 
200 mg/kg (intravenous [IV]) for 3 months.  The exposure multiple and dose multiple to the 
highest human dose, based on this monkey study, are 5× and 28×, respectively.  Additionally, a
tissue cross-reactivity study was performed with LY3316531 in human and monkey tissues, 
which produced no toxicologically important difference in tissue binding between the species.
Study I9H-MC-FFAA (FFAA) is an ongoing Phase 1, first-in-human clinical study to explore the 
safety, tolerability, and PK of single and multiple doses of LY3316531 in healthy subjects and
the safety, tolerability, PK, and pharmacodynamics (PD) of a single dose of LY3316531 in 
patients with psoriasis.  
Study FFAB will test the ability of LY3316531 to neutralize CGRP in capsaicin-induced dermal 
blood flow (DBF).  Capsaicin (the active compound in hot peppers) applied to human skin 
activates nociceptor neurons via the environmental sensor TRPV1 (“Capsaicin Receptor”) and 
releases inflammatory mediators (Caterina et al. 1997) including CGRP, a potent vasodilator.  
The inhibition of CGRP can reduce capsaicin-induced DBF as measured using LDI (Van der 
Schueren et al. 2008).  Thus, capsaicin-induced DBF has been used as a CGRP-dependent PD 
biomarker, with the PD effect measured using LDI (Sinclair et al. 2010; Vermeersch et al. 2015).  
LY3316531 is a bispecific antibody that contains the binding regions from the IL-23 monoclonal 
antibody, LY3074828 (mirikizumab), and the CGRP monoclonal antibody, LY2951742
(galcanezumab). A galcanezumab study (Study CGAA) of capsaicin-induced DBF in healthy 
subjects following a single dose showed DBF was reduced at all measurements from 3 to 42 days 
postdose for the 75-, 200-, and 600-mg doses, while doses of 1, 5, and 25 mg showed no effect 
on DBF (Vermeersch et al. 2015).   
3.3.
Benefit/Risk Assessment
On the basis of the nonclinical data, LY3316531 is not considered to be a high-uncertainty
compound.  No drug-related changes occurred in safety pharmacology, immunotoxicology, or 


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clinical and anatomic pathology assessments as part of the 3-month toxicology study in 
cynomolgus monkeys.  In the clinical and anatomic pathology assessments following the end of 
the treatment phase, there were no adverse drug-related effects observed in cynomolgus monkeys 
receiving LY3316531, including at IV or SC injection sites.  In a tissue cross-reactivity study 
examining the binding of LY3316531 to a panel of normal human and cynomolgus monkey 
tissues, there was low-grade cytoplasmic immunoreactive binding detected in cells of most 
tissues, including some mutually-exclusive tissues, which was considered not biologically or 
toxicologically important due to the cytoplasmic pattern of immunoreactivity.
The 2 antibody binding regions in LY3316531 are the same as the respective binding regions in 
mirikizumab and galcanezumab.  Although it is too early in the clinical development of 
LY3316531 to understand how it will compare to mirikizumab and galcanezumab, clinical 
exposure, efficacy, and safety for mirikizumab and galcanezumab are briefly summarized as 
follows.  

For mirikizumab, as of February 2018, 819 clinical trial participants (245 patients with 
psoriasis, 248 patients with ulcerative colitis, 85 patients with Crohn’s disease, and 241 
healthy subjects) have been exposed to either placebo or mirikizumab.  Mirikizumab
single doses ranged from 5 to 1200 mg and multiple doses were up to a maximum of 
1000-mg IV and 300-mg SC.  Improvement of psoriasis after a single dose of 
mirikizumab has been observed in the higher-dose cohorts.  No dose-related safety or 
tolerability issues were observed in completed and ongoing clinical pharmacology studies
and in the unblinded safety data from the 2 ongoing Phase-2 studies.  A total of 1 serious 
adverse reaction (anaphylaxis) has been reported.  

For galcanezumab, as of November 2017, 3156 clinical trial participants (419 healthy 
subjects, 2586 patients with migraine, and 151 patients with osteoarthritis) have been 
exposed to galcanezumab.  Galcanezumab single doses ranged from 1 to 600 mg and 
multiple doses were up to 300 mg.  The Phase 3 clinical studies in patients with migraine 
demonstrated clinically meaningful reductions in migraine headache days and a favorable 
safety profile that includes a low incidence of serious adverse events (SAEs) and 
discontinuations due to adverse events (AEs).  Treatment-emergent adverse events 
(TEAEs) were generally mild to moderate.  A total of 1 serious adverse reaction 
(urticaria) has been reported.
Because LY3316531 has been administered only as single doses to relatively few human
subjects and only 6 of these subjects were dosed as high as 300 mg (Study FFAA), Study FFAB 
has been 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 (EMEA/CHMP/SWP/28367/07 Rev. 1).
No clinically significant adverse events or changes in laboratory safety parameters (hematology, 
clinical chemistry urinalysis), vital signs, or ECGs occurred in the ongoing Study FFAA.  
LY3316531 was administered as single IV ascending doses (3, 15, 75 and 300 mg) in a total of 
18 healthy male and female subjects (Part A, Cohorts 1 through 4).  Safety data from the 300-mg 


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IV Cohort 4 (6 subjects) in Study FFAA were reviewed and found acceptable for dosing at 300-
mg IV in Study FFAB.
Study FFAA has additional cohorts planned for a single 300-mg SC dose and up to 2000-mg IV 
doses in healthy subjects (Part A) and multiple IV doses in healthy subjects (Part B), with each 
subject evaluated over a 3-month period.  Also planned are a single-dose 300-mg cohort and 2
optional single-dose cohorts (dosage to be determined) in patients with psoriasis (Part C) 
pending analysis of safety data across all previous cohorts.
Because LY3316531 affects the immune system, there is a potential risk it could reactivate an 
infection such as tuberculosis (TB) or hepatitis B, and could raise the risk that an infection could 
become more serious than it otherwise would.  This risk will be mitigated by screening potential 
subjects for TB (using QuantiFERON®-TB Gold test and chest X-ray), hepatitis, and human 
immunodeficiency virus (HIV); and anyone who tests positive in any of these tests will be 
excluded from the study.
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of LY3316531 can be found in the Investigator’s Brochure (IB).
There is no anticipated therapeutic benefit for healthy subjects.


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4. Objectives and Endpoints
Table FFAB.4.1 shows the objectives and endpoints of the study.
Table FFAB.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess target neutralization of CGRP following a 
single IV dose of LY3316531 versus placebo in healthy 
subjects via capsaicin-induced DBF as measured using
LDI
Decrease from baseline within 30 days, relative to 
placebo, in capsaicin-induced DBF (by blocking CGRP) 
following at least 1 dose level of a single IV dose of 
LY3316531
Secondary
To assess the safety and tolerability of a single dose of 
LY3316531 in healthy subjects
To characterize the PK of LY3316531 following a single 
dose IV administration in healthy subjects
Incidence of adverse events, treatment-emergent adverse 
events, and serious adverse events
Cmax and AUC
Tertiary/Exploratory
To evaluate the formation of ADA to LY3316531
To evaluate the relationship between LY3316531 
exposure and total CGRP plasma levels
To evaluate the relationship between LY3316531 
exposure and capsaicin-induced DBF 
To evaluate the relationship between capsaicin-induced 
DBF and total CGRP plasma levels
Presence of ADA against LY3316531
Emax and EC50 for relationship between LY3316531 
exposure and CGRP plasma level
Emax and EC50 for relationship between LY3316531 
exposure and capsaicin-induced DBF
Correlation between capsaicin-induced DBF and total 
CGRP plasma levels
Abbreviations:  ADA = antidrug antibody; AUC = area under the concentration versus time curve; CGRP = 
calcitonin gene-related peptide; Cmax = maximum observed drug concentration; DBF = dermal blood flow; 
Emax = maximum effect; EC50 = effective concentration of LY3316531 that gives half-maximum effect; IV = 
intravenous; LDI = laser Doppler imaging; PK = pharmacokinetics.


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5. Study Design
5.1.
Overall Design
Study FFAB is a Phase 1 single-site, randomized, subject- and investigator-blind, placebo
(Pbo)-controlled, parallel-dose group, single-dose study of LY3316531 in healthy subjects.
After a screening period up to 28 days, subjects will be admitted to the clinical research unit 
(CRU) on Day -1 and will fast overnight. Subjects will receive a single dose of study drug or 
Pbo on Day 1 and will undergo the study assessments specified in the Schedule of Activities 
(Section 2).  Subjects may be discharged on Day 2, up to 32 hours after dose administration.  In 
case of safety concerns, subjects will be required to stay in the CRU for a longer period at the 
discretion of the investigator.  Subjects will return to the CRU during the postdose follow-up 
period (Visits 3 through 10) for a total of 8 follow-up visits through Day 160. For each follow-up 
visit, subjects will attend the CRU to have the capsaicin challenge and LDI measurement 
performed along with any other scheduled procedures.  These visits are specified in the Schedule 
of Activities (Section 2) and Figure FFAB.1.
The study will evaluate 1 cohort of 16 subjects (12 LY:4 Pbo) with a planned single dose of 300-
mg LY3316531 via IV administration.  If no treatment effect on DBF is detected in Cohort 1, an 
optional Cohort 2 (12 subjects; 9 LY:3 Pbo) may be evaluated with a dose not to exceed 2000-
mg IV or the highest tolerable dose determined to be safe in the single-ascending dose (SAD) 
Study FFAA.  The decision to implement the optional Cohort 2 will be made if a sufficiently 
large decrease from baseline, relative to placebo, in capsaicin-induced DBF is not seen with 300 
mg (Cohort 1) within 9 days of the dose (on Day 10).  Both cohorts will follow the same 
admission, treatment, and assessment schedule.  
Subjects enrolled will be followed for up to 160 days post treatment administration.  It is not 
planned to replace subjects; however, subjects may be replaced if necessary to meet study 
objectives or at the discretion of the Sponsor.  
Study governance considerations are described in detail in Appendix 3.




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5.5.
Justification for Dose
LY3316531 is a bispecific antibody that contains the binding regions from the IL-23 monoclonal 
antibody, mirikizumab, and the CGRP monoclonal antibody, galcanezumab.  The initial 300-mg 
dose selected for this study (safety to be confirmed first in Study FFAA) is based on LDI 
measurements of DBF following galcanezumab administration in human subjects; on PK, safety,
and efficacy data available from clinical studies with mirikizumab and galcanezumab; and on PK 
and safety information for LY3316531 in cynomolgus monkeys.  

Galcanezumab (CGRP antibody), DBF, and LDI in humans: following a single dose 
of galcanezumab in human subjects, capsaicin-induced DBF was reduced at all 
measurements using LDI from 3 to 42 days post-LY2951742 doses of 75-, 200-, and 600-
mg SC, while doses of 1-, 5-, and 25-mg SC showed no effect on DBF (Vermeersch et al. 
2015). The 600-mg SC dose appeared to produce maximal effect. Because the primary 
objective of the current study is to confirm the ability of LY3316531 to neutralize CGRP, 
a comparably high dose to produce maximal effect was chosen.  The effect of 300-mg IV 
dose of LY3316531 is hypothesized to be similar to that of 600-mg SC dose of 
galcanezumab on capsaicin-induced DBF, assuming similar PK and in-vivo potency.   

Mirikizumab and galcanezumab safety in humans:  the highest single doses evaluated 
for mirikizumab (1200-mg IV) and galcanezumab (600-mg SC) were found safe in 
healthy subjects.  

LY3316531 safety in cynomolgus monkeys: the 300-mg and 2000-mg IV doses are 
expected to produce area under the concentration versus time curves (AUCs) that are 8.5-
and 1.3-fold lower, respectively, than the AUC observed at the no-observed-adverse-
effect level dose in toxicology studies in cynomolgus monkeys (Table FFAB.5.2).
If data from the 300-mg IV dose is not sufficient to conclude that LY3316531 was able to 
reduce CGRP activity, a dose of up to 2000-mg IV or the highest tolerable dose determined 
to be safe in Study FFAA may be evaluated.


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Table FFAB.5.2.
Margin of Safety for Intravenous Administration of LY3316531
Based on Administered Dose and Predicted Exposure
Dose
(mg)
Dose
(mg/kg)
Dose
Multiplea
AUC
(µg•hr/mL)
AUC
Exposure 
Multiplea
Cmax
(µg/mL)
Cmax
Exposure
Multiplea
Cohort-1 Single Doseb
300
6
–
43600
–
180
Non-Human Primates NOAELc
200 QW
33
371250
8.5
6358
35
Cohort-2 Maximum Doseb
2000
40.0
291000
1200
Non-Human Primates NOAELc
200 QW
5
371250
1.3
6358
5.3
Abbreviations:  AUC = area under the plasma concentration versus time curve; Cmax = maximal observed drug
plasma concentration; NOAEL = no-observed-adverse-effect level; PK = pharmacokinetics; QW = once per 
week.
a
Dose multiple is the dose in animals/dose in humans based on mg/kg.  AUC exposure multiple = mean AUCtau
observed after the last dose in monkeys/predicted mean AUC(0-∞) after a single dose in humans.  Cmax exposure 
multiple = mean Cmax observed after the last dose in monkeys/predicted mean Cmax after a single dose in 
humans.
b
Body weight of human is based on the lowest permitted body weight (50 kg) for Study FFAB.  Human PK 
parameters were predicted using allometric scaling methods based on data collected following a single dose of 
LY3316531 in monkeys (Study 8340704). 
c
NOAEL determined in a 3-month repeat-dose toxicity study in monkeys (Study #20108516).


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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, chest x-ray, clinical laboratory tests, and electrocardiogram 
(ECG). 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to 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, is 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, as determined through medical history and physical 
examination
[2]
agree to either remain abstinent (if this is their preferred and usual lifestyle) or 
use condoms with spermicide as well as 1 additional highly effective method 
of contraception or effective method of contraception during the study and for 
5 months following the last dose of study drug
[3]
are between 18 and 55 years of age, inclusive, at the time of screening
[4]
have a body mass index of 18 to 32.0 kg/m2, inclusive, and a minimum body 
weight of 50 kg
[5]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator
[6]
have venous access sufficient to allow for blood sampling and administration 
of the investigational product (IP) for IV administration as per the protocol
[7]
have suitable skin characteristics for the dermal capsaicin challenge (as 
determined by clinical-staff judgment) and have demonstrated at least a 100% 
increase in dermal flow following capsaicin challenge as part of the screening 
procedures and measured through LDI
[8]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[9]
are able and willing to give signed informed consent


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6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[10] female subjects
[11] 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
[12] are Lilly employees or employees of any third-party organization involved 
with the study
[13] are currently enrolled in a clinical study involving an IP (active drug or 
placebo) or any other type of medical research judged not to be scientifically 
or medically compatible with this study or have received any nonbiologic IP 
within 30 days or 5 half-lives (whichever is longer) of their initial screening 
visit 
[14] have previously completed or withdrawn from investigating mirikizumab 
(IL-23 antibody), galcanezumab (CGRP antibody), or LY3316531 (IL-
23/CGRP bispecific antibody) and have previously received any of these IPs
[15] have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
including QTc >450 msec (male), history of congenital long QT syndrome or
other conduction abnormality
[16] have a history of or current psychiatric disorders
[17] have evidence of clinically significant active infection, fever of 100.5°F 
(38°C) or above, at baseline (Day 1); however, if deemed appropriate by the 
investigator because of potential error or other unusual circumstance, 
re-assessment of laboratory parameters including drug screen, vital signs, and 
intercurrent illness is allowed once
[18] had any surgical procedure (except for minor surgery requiring local or no 
anesthesia and without any complications or sequelae) within 12 weeks prior 
to screening, or any planned surgical procedure scheduled to occur during the 
study
[19] have received live, attenuated live, or non-live vaccine(s) within 28 days of 
screening or intend to receive during the study 
[20] have a history of multiple or severe allergies or has had an anaphylactic 
reaction to prescription or nonprescription drugs or food


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[21] have a history of allergy to humanized monoclonal antibodies or to the drug 
excipients, or have clinically significant multiple or severe drug allergies, 
intolerance to topical corticosteroids, or a history of severe posttreatment 
hypersensitivity reactions (including, but not limited to, erythema multiforme 
major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or 
exfoliative dermatitis)
[22] have had serious, opportunistic, or chronic/recurring infection within 
6 months prior to screening.  Examples include but are not limited to 
infections requiring IV antibiotics, hospitalization, or prolonged anti-infective 
treatment
[23] had 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 
recurrence for at least 3 years prior to screening and cervical carcinoma in 
situ, with no evidence of recurrence within the 5 years prior to baseline
[24] have used cigarettes or other tobacco products within the previous 3 months or 
will not agree to refrain from use during the study 
[25] have used caffeine-containing products and/or alcohol from 24 hours prior to 
all study visits and during in-clinic stays.  At all other times, alcohol 
consumption and caffeine intake are limited to no more than 2 alcoholic 
beverages or equivalent (beer [284 mL/10 ounces], wine [125 mL/4 ounces], 
or distilled spirits [25 mL/1 ounce]) per day and caffeinated beverages will be 
limited to no more than 2 units per day amounts (1 unit=120 mg of caffeine) 
[26] have had strenuous activity within 48 hours prior to admission or will not 
agree to avoid strenuous activity within 48 hours prior to each visit through 
the final follow-up visit
[27] are regular users of known drugs of abuse and/or have positive findings on 
urinary drug tests at screening; OR an average weekly alcohol intake that 
exceeds 21 units per week OR are unwilling to stop alcohol consumption 
during study visits/time in the research unit (1 unit of alcohol = 12 oz or 360 
mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits)
[28] have donated blood of more than 500 mL within the previous 30 days of study 
screening


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[29] show evidence of active or latent TB, as documented through medical history 
and examination, chest x-rays (posterior to anterior; a lateral chest X-ray may 
be performed if clinically or radiologically indicated), and TB testing:  either a 
positive tuberculin skin test (TST; defined as a skin induration >5 mm at 48 to 
72 hours, regardless of Bacillus Calmette–Guérin or other vaccination history) 
or a positive (not indeterminate) QuantiFERON-TB Gold test.  In the event of 
an indeterminate test result, 1 repeat test is allowed.  The choice to perform a 
TST or a QuantiFERON-TB Gold test will be made by the investigator 
according to local licensing and standard of care.  The QuantiFERON-TB 
Gold test can only be used in countries where it is licensed, and the use of this 
test is dependent on previous treatment(s).  This test may not be suitable if 
previous treatment(s) produce significant immunosuppression
[30] are immunocompromised
[31] have a history or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable 
of significantly altering the absorption, metabolism, or elimination of drugs; 
of constituting a risk when taking the IP; or of interfering with the 
interpretation of data
[32] intend to use herbal, over-the-counter, or prescription medication within 
14 days prior to dosing and during the study.  Certain medications, for 
example vitamin supplements, may be permitted at the discretion of the 
investigator
[33] 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
[34] have an abnormal blood pressure, pulse rate, and/or temperature as determined 
by the investigator
[35] have evidence of chronic viral infection:
[35a]  show evidence of hepatitis C and/or positive hepatitis C antibody with 
confirmed presence of hepatitis C virus ribonucleic acid at screening.
[35b]  show evidence of hepatitis B and/or positive hepatitis B surface antigen 
at screening
[35c]  show evidence of HIV infection and/or positive for HIV antibodies at 
screening
[35d]  have had symptomatic herpes zoster within 3 months prior to screening 
that constitutes (per investigator’s judgment) a risk to the subject when 
taking the study medication or that may interfere with the interpretation 
of study data
[36] have a history of significant allergies, in particular to ethanol or sensitivity to 
the fruits of capsicum plants (for example, chili peppers)


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[37] have eczema, scleroderma, psoriasis, dermatitis, keloids, tumors, ulcers, 
burns, flaps, or grafts on their forearm or other abnormality of the skin that
may interfere with the study assessments
[38] cannot avoid excess tanning (any exposure to sunlight or a tanning bed that
would cause a sunburn reaction) throughout the study and cannot cover 
forearms for 24 hours prior to each treatment period
[39] have excessive hair growth on the volar surface of the forearm or subjects 
currently using lotions, oils, depilatory preparations, or other topical 
treatments on a regular basis that cannot be discontinued for the duration of 
the study; subject has used any topical treatments within 7 days of the start of 
the study
[40] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.2.1. Rationale for Exclusion of Certain Study Candidates
The safety, tolerability, and PK of LY3316531 are being assessed in female subjects as part of 
Study FFAA.  As Study FFAB is focused only on the ability of LY3316531 to neutralize CGRP, 
the evaluation specifically in female subjects is not needed.  Female subjects are being excluded 
from Study FFAB to avoid the demonstrated hormone-dependent variations in CGRP-mediated 
DBF previously found in healthy females (Ibrahimi et al. 2017).
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 not eat after midnight during the night before study drug administration. Water 
is permitted. Subjects may eat breakfast approximately 2 hours postdose. A normal diet may be 
consumed at all other times during the study.
6.3.2. Caffeine, Alcohol, and Tobacco 
6.3.2.1.
Caffeine and Alcohol
The use of caffeine-containing products and/or alcohol is not allowed from 24 hours prior to all 
study visits and during in-clinic stays. At all other times, alcohol consumption is limited to no 
more than 2 alcoholic beverages or equivalent (beer [284 mL/10 ounces], wine [125 
mL/4 ounces], or distilled spirits [25 mL/1 ounce]) per day and caffeinated beverages will be 
limited to no more than 2 units (1 unit = 120 mg of caffeine) per day.
6.3.2.2.
Tobacco
Subjects will be excluded if they have used cigarettes or other tobacco products within 3 months 
prior to the start of this study.


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6.3.3. Activity
Strenuous activity is not allowed within 48 hours prior to admission on Day -1 and 48 hours 
prior to each visit.
6.3.4. Contraception
All subjects and their partners should agree to use a reliable method of birth control during the 
study and for 5 months following dosing of the study drug (see Inclusion Criterion [2]).
6.4.
Screen Failures
Healthy subjects who do not meet the criteria for participation in this study (screen failure) may 
not be re-screened.  However, if, for example, a subject had an intercurrent illness around the 
time of initial screening or there are issues with the quality of the laboratory safety samples (eg, 
hemolysis), re-assessment of laboratory parameters including drug screen and vital signs will be 
allowed.
In addition, participants who were eligible for inclusion in previous cohorts, but were not 
randomized for nonmedical reasons, may be reassessed, following a discussion with the sponsor.


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7. Treatment
7.1.
Treatment Administered
LY3316531 is supplied for clinical trial use as solution formulation in glass vials.  Further 
dilution may be needed for IV administration.  See Pharmacy Instructions for more information.
Placebo will be sterile saline (0.9% NaCl).  Placebo doses should be held in the pharmacy for an 
equivalent amount of time as is required to prepare doses of LY3316531.
The IP 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 6 hours after subjects have completed receiving their infusion.
All clinical trial materials provided to the investigator will be stored in a secure place, assigned 
using the interactive web response system, and dispensed by appropriately trained persons.  The
dispensing of the IPs will be fully documented.  Detailed records of the amounts of the IP
received, dispensed, and remaining at the end of the study will be maintained.
The investigator or designee is responsible for

explaining the correct use of the IP(s) to the site personnel

verifying that instructions are followed properly

maintaining accurate records of dispensing and collecting IP, and

returning all unused IP 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.
The products for the capsaicin and the vehicle solutions required for the capsaicin-induced DBF 
assessment will be supplied by the investigative site.  Pharmacy instructions for the preparation 
of these capsaicin and vehicle solutions will be provided by the investigative site.
7.1.1. Packaging and Labeling
LY3316531 and Pbo will be supplied to the investigative site by Lilly or its designee in 
accordance with current good manufacturing practices, and will be supplied with lot numbers, 
expiry dates, and certificates of analysis, as applicable.
Clinical trial materials will be labeled according to the country’s regulatory requirements.  All 
IPs will be stored, inventoried, reconciled, and destroyed according to applicable regulations.  
Clinical trial materials are manufactured in accordance with current good manufacturing
practices.
LY3316531 is supplied for clinical trial use as solution in vial with study-specific labels.  The 
2-mL vial is manufactured to contain 150 mg of LY3316531 (75 mg/mL).  Vials will be supplied 
in cartons, with the appropriate quantity specific to the planned dispensing schedule of the IP. 


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Placebo for all cohorts is 0.9% sodium chloride (sterile saline).
When prepared for dosing according to instructions, it will not be possible to distinguish between 
LY3316531 and Pbo. 
The IP must be prepared by an unblinded pharmacist who is not involved in any other 
study-related procedures.
7.2.
Method of Treatment Assignment
Randomization tables for allocation of LY3316531 or Pbo will be prepared by the statistician or 
designee for the study and provided to the site pharmacists involved in dose preparation.  
The allocation and dispensation of the IP will be fully documented and verified by a second person.  
Detailed records of the amounts of the IP received, dispensed, and remained at the end of the study 
will be maintained by the site pharmacy.
7.2.1. Selection and Timing of Doses
The dose in Cohort 1 will be 300 mg of LY3316531 administered through IV infusion.  The 
actual time of the single dose administered to each subject will be determined by the site and 
recorded in each subject’s case report form (CRF).  
A decision to implement the optional Cohort 2 will be made if a statistically significant decrease 
in capsaicin-induced DBF (relative to placebo) is not seen with 300 mg (Cohort 1) within 9 days 
of the dose (Day 10).  If Cohort 2 is conducted, the single dose not to exceed 2000 mg or the 
highest tolerable dose determined to be safe in Study FFAA will be administered through IV 
infusion over the same time period as used in Cohort 1. 
7.3.
Blinding
Study FFAB will be subject- and investigator-blind.  Pharmacy staff who prepare and dispense 
study medication are required to be unblinded to treatment allocation and are not allowed to 
participate in any other procedure of this study.  Subject treatment assignments and drug 
accountability records will be held in a secure location accessible only by individuals involved 
with study drug preparation or dispensation.  Blinding will be maintained throughout the conduct 
of the study as described in the separate Blinding Plan.
In case of an emergency, appropriate site personnel per the site’s standard operating procedure 
have 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 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.


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7.4.
Dose Modification
7.4.1. Special Treatment Considerations
7.4.1.1.
Management of Infusion Reactions
Infusion-related reaction (IRR) is a risk with any biological agent; therefore, all subjects should 
be monitored closely for IRR.  Symptoms and signs that may occur as part of an IRR include, but 
are not limited to fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, 
throat irritation, rash, pruritus, myalgia, and dizziness.  In the event that a significant IRR occurs, 
the following guidance should be followed:

The infusion should be slowed (for example, reduce infusion rate by 50% [for example, 
an infusion rate of 12 mL/hour becomes 6 mL/hour 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

Supportive care should be employed in accordance with the symptoms/signs

Premedication for the infusions is not planned.  However, if an IRR occurs in previously-
dosed subjects, appropriate pre-medication (for example, acetaminophen 500 to 1000 mg 
and/or an antihistamine administered orally 30 to 60 minutes prior to the start of infusion)
may be administered to subsequently-dose subjects as determined by the study 
investigator(s).  The decision to premedicate for infusions will be made by the 
investigator and sponsor and recorded in the study documentation.  Any premedications 
given will be documented as a concomitant therapy (see Section 7.7).
7.5.
Preparation/Handling/Storage/Accountability
LY3316531 vials should be stored at 2°C to 8°C (36°F to 46°F) in the original carton to protect it 
from light. LY3316531 vials should not be frozen.
Sterile saline vials (0.9% sodium chloride) should be stored at room temperature (15°C to 25°C 
[59°F to 77°F]).  The investigator or designee must confirm appropriate temperature conditions 
have been maintained, as communicated by Sponsor, during transit for all IPs received and any 
discrepancies are reported and resolved before use of the study treatment.
All clinical trial materials provided to the investigator will be stored in a secure place and 
allocated and dispensed by appropriately trained personnel.  The allocation and dispensation of 
the IP will be fully documented and verified by a second person.  Detailed records of the 
amounts of the IP received, dispensed, and remaining at the end of the study will be maintained.
Only participants enrolled in the study may receive IPs or study materials, and only authorized 
site staff may supply or administer IP.  All IPs should be stored in an environmentally controlled 


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and monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.
Detailed instructions for the preparation and handling of LY3316531 will be provided by the 
sponsor.
The IP must be prepared by an unblinded pharmacist who is not involved in any other study 
related procedures.
All IPs will be stored, inventoried, reconciled, and destroyed according to applicable regulations.  
Clinical trial materials are manufactured in accordance with current good manufacturing 
practices.
Detailed records of the amounts of the IP received, dispensed, and remained at the end of the 
study will be maintained by the site pharmacy.
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).
The investigative site will be responsible for obtaining United States Pharmacopeia (USP) and 
The National Formulary-grade capsaicin, performing analysis to demonstrate compliance with 
USP, and handling and storing the capsaicin powder in accordance with the manufacturer 
instructions.  The site will be responsible for preparing, handling, and storing the capsaicin 
solution to be used in the capsaicin challenges in accordance with the manufacturer instructions.
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
In general, concomitant medication should be avoided unless required to treat an AE.  
The use of chronic, stable doses of thyroxine is allowed.  The use of multivitamins and vitamin C 
is allowed until 2 days prior to entrance into the CRU.  The use of acetaminophen (paracetamol), 
up to 2 grams per day, is allowed up to 3 days before entrance into the CRU.  Thereafter and 
during the study the investigator may permit a limited amount of acetaminophen for the 
treatment of headache or any other pain.
Other medication to treat AEs will be prescribed according to the circumstances and guided by 
the investigator’s judgment.  If the need for concomitant medication (other than acetaminophen) 
arises, inclusion or continuation of the subject will be at the discretion of the investigator and
Lilly clinical pharmacologist or CRP.  In the event medication is used, the name of the drug, the 
dose and dosage regimen will be recorded in the CRF.
7.8.
Treatment after the End of the Study
This section is not applicable to this study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
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, the subject must be discontinued from the study.
8.2.
Discontinuation from the Study
Subjects will be discontinued 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
o
the investigator decides that the subject should be discontinued from the study
o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.

Sponsor Decision
o
Lilly stops the study or stops the subject’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP

Adverse event 
o
A clinically significant systemic hypersensitivity reaction occurs following 
administration of the IP (for example, drug-related symptomatic bronchospasm, 
allergy-related edema/angioedema, or hypotension) that requires parenteral 
medication, does not respond to symptomatic medication, or results in clinical 
sequelae or an anaphylactic reaction.
The nature of any conditions, clinical signs or symptoms, or abnormal laboratory values 
present at the time of discontinuation and any applicable follow-up procedures will be 
documented.  
Refer to the Schedule of Activities (Section 2) for data to be collected at the time of 
discontinuation and follow-up.


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8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he 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 5 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the subject to discontinue the IP before completing the study.  The subject should 
be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
After the informed consent form (ICF) is signed, study site personnel will record, via electronic
case report form (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 the disease, 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP, study device and/or study procedure and the AE.


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Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
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/clinical pharmacologist, 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.
Investigators are not obligated to follow subjects for AEs or SAEs 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.
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 IP or procedure.  Lilly has procedures that 
will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidances.


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9.2.2. Complaint Handling
Lilly collects product complaints on IPs 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 has a complaint 
or problem with the IP so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3316531 is considered any dose higher than the 
dose assigned through randomization.
Refer to the IB (LY3316531).
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
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
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2) and as clinically indicated.
Blood pressure and pulse rate should be measured after at least 5 minutes supine (or 
semi-recumbent if subject is unable to lie supine).
If orthostatic measurements are required, subjects should be supine for at least 5 minutes and 
subsequently stand for at least 3 minutes.
If the subject feels unable to stand, only supine vital signs will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
Body temperature will be measured as specified in the Schedule of Activities (Section 2) and as 
clinically indicated.
Body weight will be recorded as specified in the Schedule of Activities (Section 2) and as 
clinically indicated.


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9.4.3. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2) 
and as clinically indicated. 
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the dose of the IP, should be reported to Lilly, or its designee, as an AE via 
eCRF.
For each subject, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities.  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 investigative 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/corrected QT 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 review of 
the ECG printed at the time of collection.  Any new clinically relevant finding should be reported 
as an AE.
9.4.4. Safety Monitoring
The Lilly clinical pharmacologist 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 clinical 
pharmacologist or CRP will periodically review the following data:

trends in safety data

laboratory analytes

adverse events including monitoring of incidence and nature of any infections, and 
infusion reactions.
When appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist.
9.4.4.1.
Hepatic Safety
If a study subject experiences elevated alanine aminotransferase (ALT) ≥3X upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2X ULN, or elevated total bilirubin (TBL) ≥2X 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, aspartate 


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aminotransferase (AST), ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine 
phosphokinase to confirm the abnormality and to determine if it is increasing or decreasing.  If 
the abnormality persists or worsens, clinical and laboratory monitoring should be initiated by the 
investigator based on consultation with the Lilly clinical pharmacologist or CRP.  Monitoring 
should continue until levels normalize and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevation of serum TBL to ≥2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be an SAE.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 5 mL each will be collected to determine the serum concentrations of 
LY3316531.  A maximum of 3 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 the 
investigative site or blinded personnel until the study has been unblinded.
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 LY3316531 will be assayed using a validated enzyme-linked 
immunosorbent assay method.  Analyses of samples collected from subjects who received Pbo
are not planned.
Bioanalytical samples collected to measure study drug concentrations will be retained for a 
maximum of 1 year following last subject visit for the study. During this time, samples 
remaining after the bioanalyses may be used for exploratory metabolism studies or exploratory 
analyses such as bioanalytical assay validation or cross-validation exercises.


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9.6.
Pharmacodynamics
9.6.1. Total CGRP
Target engagement for the CGRP part of the molecule will be assessed by measuring total CGRP 
concentrations before and after LY3316531 or Pbo administration.  CGRP concentration is 
expected to increase with target engagement as CGRP is bound to LY3316531 and takes on the 
longer half-life of the antibody.
At visits specified in the Schedule of Activities, venous blood samples of approximately 2 mL 
each will be collected for measurement of total plasma CGRP concentration.  Samples for CGRP 
measurements will be analyzed in a validated assay at a laboratory approved by the sponsor and 
stored at a facility designated by the sponsor.
The sample(s) will be stored for up to a maximum of 15 years after the last subject visit for the 
study at a facility selected by the sponsor.
9.6.2. Measurement of Dermal Blood Flow
Capsaicin-induced DBF will be measured at visits specified in the Schedule of Activities.  All 
measurements for assessment of capsaicin-induced response should be performed while the 
subjects are resting in a supine position on a comfortable bed in a quiet, temperature-controlled 
room (ambient temperature).
During each visit (screening and study periods), after at least 30 minutes acclimatization, 3
rubber O-rings will be placed on the volar surface of the forearm. After placement of the O-
rings, a baseline DBF measurement will be performed of the areas defined by the rings within 10 
minutes before capsaicin application. DBF will be measured with LDI (PeriScan PIM 3 system, 
Perimed, Stockholm, Sweden).  After the baseline measurement, 2 topical doses of 20 µL
capsaicin (1000 µg/20 µL) will be applied in the 2 proximal O-rings of the subject’s forearm. A 
20 µL topical dose of the vehicle solution will be applied in the distal ring. LDI measurements 
will again be performed at 30 and 40 minutes after the capsaicin and vehicle application.  For 
each subject, DBF will be measured consistently on the same arm at all study visits.
A detailed description of the procedure will be provided by the investigator.
9.6.3. Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities, venous blood samples will be 
collected to determine antibody production against LY3316531.  To interpret the results of 
immunogenicity, a PK sample will be collected at the same time points. All samples for 
immunogenicity should be taken predose on Day 1 and pre-capsaicin challenge at each postdose 
follow-up visit. In the event of drug hypersensitivity reactions (immediate or nonimmediate), 
additional samples will be collected as close to the onset of the event as possible, at the 
resolution of the event, and approximately 30 days following the event.  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.


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Immunogenicity will be assessed by a validated assay designed to detect antidrug antibodies 
(ADAs) in the presence of LY3316531 at a laboratory approved by the sponsor.  Antibodies may 
be further characterized and/or evaluated for their ability to neutralize the activity of 
LY3316531. 
Treatment-emergent ADAs are defined in Section 10.3.5.  If the immunogenicity titer at the last 
scheduled assessment or discontinuation visit is increasing (compared to previous measurements) 
or remains high, additional samples may be collected (approximately every 3 months for up to 1 
year after Day 160) until the titer reaches a plateau/decreases (if increasing) or remains the 
same/decreases (if high).  A PK sample will be collected at each time point.  Additional samples 
may also be collected if there is a possibility that an AE is immunologically mediated. 
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 
LY3316531.  Any samples remaining after 15 years will be destroyed.
9.7.
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 potential reasons for variable exposure 
or response to LY3316531 and to investigate genetic variants thought to play a role in 
inflammatory diseases.  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/or ERBs/institutional review boards impose shorter time limits, 
for the study at a facility selected by Lilly or its designee.  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 LY3316531 or after LY3316531 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.
9.8.
Biomarkers 
This section is not applicable for this study.


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9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The choice of sample size was based on the statistical power to meet the primary endpoint for a 
single cohort.  
 
 
  
 
 A 1-sided significance 
level of α = 0.10 and a standard deviation of 1.322 are assumed.  
 
 
  A 2-sample 
t-test with unpooled variance estimates (using Satterthwaite’s approximation to the degrees of 
freedom) is used to compute the power 
 
 
  
 
 
 
 
 
Statistical power may be increased for the LY3316531 dose used in Cohort 1 if a like dose is 
used in the optional Cohort 2 and the data are combined across cohorts.
In addition to statistical power, 12 LY and 4 Pbo subjects were chosen to be enrolled in Cohort 1 
and 9 LY and 3 Pbo subjects were chosen to be enrolled in the optional Cohort 2 for operational 
reasons and to ensure a satisfactory number of evaluable subjects, reducing the need to replace 
subjects. 
CCI
CCI
CCI
CCI
CCI
CCI




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10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic/Pharmacodynamic analyses will be conducted on data from all subjects who 
receive a dose of LY3316531 and have evaluable PK, total CGRP, or LDI data.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
All protocol deviations that occur during the study will be considered for their severity and 
impact, and will be taken into consideration when subjects are assigned to analysis populations 
prior to database lock and unblinding.  Details of subject assignment to the analysis populations 
will be listed.
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 treatment with the 
study drug 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.
The number of IP-related SAEs will be reported and summarized by preferred term.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters.  The parameters will be listed, and summarized using standard descriptive 
statistics.  Additional analysis will be performed if warranted upon review of the data.  Baseline 
for safety parameters will be defined as the last evaluable value before the first dose for each 
subject.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for LY3316531 will be calculated using standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be maximum observed drug concentration (Cmax) and 
AUC of LY3316531.  Other noncompartmental parameters, such as half-life, clearance, and 


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volume of distribution may be reported.  Mean and individual plasma concentration versus time 
profiles and individual and summary statistics of PK parameter estimates will be generated.
Population-based methods of analyses may also be performed.
10.3.3. Pharmacodynamic Analyses 
Raw DBF, capsaicin-induced changes from baseline in DBF (both absolute and percentage
changes) relative to Pbo, and plasma CGRP concentrations will be measured. Descriptive 
statistics will summarize these quantities at each dose administered.  Additional exploratory 
analyses may be conducted as deemed appropriate.
10.3.4. Pharmacokinetic/Pharmacodynamic Analyses
Analyses of the relationship between LY3316531 exposure and total CGRP plasma 
concentrations and DBF will be conducted using graphical- and model-based approaches.
Additional exploratory analyses may be performed if warranted by the data.
10.3.5. Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADA and/or with treatment-emergent 
(TE) ADA to LY3316531 will be tabulated. 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 dilutions) increase in titer compared to baseline.  For subjects with TE 
ADA, the distribution of maximum titers will be described.  The frequency and percentage of 
subjects with neutralizing antibodies, if measured, may also be tabulated for subjects with TE 
ADA.
The relationship between the presence of antibodies and the PK parameters and PD response,
including safety related to LY3316531, may be assessed.
10.3.6. Data Review During Cohort 1
Available safety and LDI data through 9 days postdose (Day 10) of Cohort 1 will be reviewed to 
determine if the optional Cohort 2 will be implemented.  The minimum number of evaluable 
subjects needed for this decision to advance to a higher dose will be 9 LY and 3 Pbo.  The 
decision to implement the optional Cohort 2 will be made if a sufficiently large decrease from 
baseline, relative to placebo, in capsaicin-induced DBF is not seen in Cohort 1 with 300 mg 
through 9 days postdose (Day 10 data review) or within 23 days postdose (Day 24 interim 
analyses).  The dose to be administered in Cohort 2 will not exceed 2000-mg IV or the highest 
tolerable dose determined to be safe in Study FFAA. The investigator will remain blinded, and 
the Lilly sponsor team will be unblinded during these reviews.  
10.3.7. Interim Analyses
A single interim analysis that includes all safety and LDI data, and may include PK data, through 
23 days postdose (Day 24) will inform the decision to proceed to Phase 2.  The interim analysis 


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will be based on the highest dose level evaluated (either Cohort 1 or optional Cohort 2, if 
implemented).


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11.
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Dagregorio G, Yssel H, Lecron JC, Morel F. A role for T cell-derived interleukin 22 in 
psoriatic skin inflammation. Clin Exp Immunol. 2007;150(3):407-415.
Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I. Calcitonin gene-related peptide is a 
potent vasodilator. Nature. 1985;313(5997):54-56.
Cady RJ, Glenn JR, Smith KM, Durham PL. Calcitonin gene-related peptide promotes cellular 
changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol 
Pain. 2011;7:94.
Caruso R, Botti E, Sarra M, Esposito M, Stolfi C, Diluvio L, Giustizieri ML, Pacciani V, 
Mazzotta A, Campione E, Macdonald TT, Chimenti S, Pallone F, Costanzo A, Monteleone G. 
Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis. Nat Med. 
2009;15(9):1013-1015.
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin 
receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816-824.
Chaitman BR, Ho AP, Behm MO, Rowe JF, Palcza JS, Laethem T, Heirman I, Panebianco DL, 
Kobalava Z, Martsevich SY, Free AL, Bittar N, Chrysant SG, Ho TW, Chodakewitz JA, 
Murphy MG, Blanchard RL. A randomized, placebo-controlled study of the effects of 
telcagepant on exercise time in patients with stable angina. Clin Pharmacol Ther. 
2012;91(3):459-466.
Crow JM. Therapeutics: silencing psoriasis. Nature. 2012;492(7429):S58-S59.
Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of 
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Montgomery D, van Aarle F, Khalilieh S. Clinical improvement in psoriasis with specific 
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Wang EEL, Hall D, Solinger A, Padula S, Scholl P. Anti–IL-23A mAb BI 655066 for 
treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker 
results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy 
Clin Immunol. 2015;136(1):116-124. 
Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, Dhodapkar M, Krueger 
JG. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with 
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Krueger JG. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. 
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Papp K, Thaci D, Reich K, Riedl E, Langley RG, Krueger JG, Gottlieb AB, Nakagawa H, 
Bowman EP, Mehta A, Li Q, Zhou Y, Shames R. Tildrakizumab (MK-3222) an anti-
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Riol-Blanco L, Ordovas-Montanes J, Perro M, Naval E, Thiriot A, Alvarez D, Paust S, Wood 
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Appendix 1.
Abbreviations and Definitions


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Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
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
AUC
area under the concentration versus time curve
blinding
A procedure in which 1 or more parties to the study are kept unaware of the treatment
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the 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
CGRP
calcitonin gene-related peptide
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.
CRF
case report form
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CRU
clinical research unit
DBF
dermal blood flow
ECG
electrocardiogram
eCRF
electronic case report form


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enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
good clinical practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IL
interleukin
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.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
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
LDI
laser Doppler imaging
legal 
representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical study.
Pbo
Placebo
PK/PD
pharmacokinetic(s)/pharmacodynamic(s)
QTcF
corrected QT interval by Fridericia’s formula
randomize
the process of assigning subjects/patients to an experimental group on a random basis
SAE
serious adverse event


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SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions
TB
tuberculosis
TBL
total bilirubin
TE
treatment-emergent
Th
T helper
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 
TST
tuberculin skin test
ULN
upper limit of normal
USP
United States Pharmacopeia and The National Formulary


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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)
Glucose, random
Platelets
Urea
Total protein
Absolute counts of:
Albumin
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase (ALP)
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Alanine aminotransferase (ALT)
Basophils
Creatinine
Gamma-glutamyl transferase (GGT)
Urinalysis
Specific gravity
Serology
pH
Hepatitis B surface antigena
Protein
Hepatitis C antibodya,b
Glucose
HIVa
Ketones
Bilirubin
Other
Urobilinogen
Ethanol testc
Blood
Urine drug screenc
Nitrite
The QuantiFERON-TB Gold test or TSTa
Microscopyd
Immunogenicity (anti-LY3316531 antibodies)
Abbreviations:  HIV = human immunodeficiency virus; RBC = red blood cell; TST = tuberculin skin test; WBC = 
white blood cell.
a
Performed at screening only
b
A positive hepatitis C antibody laboratory assessment will be confirmed with a test for hepatitis C virus (HCV) 
ribonucleic acid (RNA).
c
Ethanol test and urine drug screen will be performed at screening and repeated prior to admission to the clinical 
research unit (Day -1), and when clinically indicated.
d
Performed if Dipstick test abnormal or at discretion of investigator


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


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1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
2) applicable ICH GCP Guidelines
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party 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/patient personal information collected will be provided in a 
written document to the subject/patient by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibody
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 cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.
Protocol I9H-MC-FFAB Sampling Summary
Purpose
Blood Volume per Sample 
(mL)
Number of Blood 
Samples
Total Volume (mL)
Screening testsa
30
1
30
Clinical laboratory testsa
12.5
10
125
Pharmacokinetics
5
13
65
Blood discard for cannula patency
2
5
10
Pharmacodynamics (total CGRP)
2
10
20
Immunogenicity
7.5
8
60
Pharmacogenetics
6
1
6
Total
316
Total for clinical purposes (rounded up to the nearest 10 mL)
320
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Protocol Amendment I9H-MC-FFAB(c) 
Summary
A Phase 1 Randomized, Placebo-Controlled Study to 
Determine the Effect of LY3316531 on Capsaicin-
Induced Dermal Blood Flow in Healthy Male Subjects
Overview
Protocol I9H-MC-FFAB, A Phase 1 Randomized, Placebo-Controlled Study to Determine the 
Effect of LY3316531 on Capsaicin-Induced Dermal Blood Flow in Healthy Male Subjects, has 
been amended.  The new protocol is indicated by Amendment (c) and will be used to conduct the 
study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Assessments will be performed for all subjects on Day 160 (visit 10) as emerging data 
from Day 120 assessments showed that many subjects continued to show inhibition of 
capsaicin induced blood flow.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1. Protocol Synopsis
Summary of Study Design:
Study I9H-MC-FFAB is a Phase 1 single-site, randomized, subject- and investigator-blind, placebo (Pbo)-
controlled, parallel-dose group, single-dose study of LY3316531 (LY) in healthy male subjects.  The study will 
evaluate 1 cohort (Cohort 1) of 16 subjects (12 LY:4 Pbo) with a planned single dose of 300-mg LY3316531 via 
intravenous (IV) administration.  Should an effect not be observed at this starting dose, an optional cohort (Cohort 2) 
of 12 subjects (9 LY:3 Pbo) may be evaluated with a dose not to exceed 2000-mg IV or the highest tolerable and 
safe dose evaluated in the single-ascending dose Study I9H-MC-FFAA.  SAll subjects will be invited to attend a 
followed for -up assessment of capsaicin-induced blood flow approximatelyto 160 days post treatment 
administration.  Assessments at Day 160 will be performed only in subjects with significant inhibition of capsaicin
induced blood flow at Day 120.  Significant inhibition of capsaicin induced blood flow is defined as an individual 
decrease (within a subject) of 50% ± 10% or more compared to the screening response to capsaicin (i.e. response to 
capsaicin at screening (pre administration) versus response on Day 120).
2. Schedule of Activities
Screening
Baseline
Postdose
Visit No.
V1
V2
V3 
V4 
V5 
V6 
V7 
V8 
V9
V10*
ED
Study Day -28 d from 
Day -2
-1
1
2
10 ± 
1 d
24 ± 
1 d
38 ± 
2 d
52 ± 
2 d
66 ± 
4 d
80 ± 
4 d
120 ± 
7 d
160 ± 
7 d
[…]
Abbreviations:…
* This visit will only be performed in subjects with significant inhibition of capsaicin induced blood flow at Visit 9, 
as defined in Section 5.1.
[…]
5.1. Overall Design
Study FFAB is a Phase 1 single-site, randomized, subject- and investigator-blind, placebo
(Pbo)-controlled, parallel-dose group, single-dose study of LY3316531 in healthy subjects.
After a screening period up to 28 days, subjects will be admitted to the clinical research unit 
(CRU) on Day -1 and will fast overnight. Subjects will receive a single dose of study drug or 
Pbo on Day 1 and will undergo the study assessments specified in the Schedule of Activities 


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(Section 2).  Subjects may be discharged on Day 2, up to 32 hours after dose administration.  In 
case of safety concerns, subjects will be required to stay in the CRU for a longer period at the 
discretion of the investigator.  Subjects will return to the CRU during the postdose follow-up 
period (Visits 3 through 109) for a total of 87 follow-up visits through Day 160120., with an 
additional visit on Day 160 if required for subjects with significant inhibition of capsaicin
induced blood flow at Day 120.  Significant inhibition of capsaicin induced blood flow is 
defined as an individual decrease (within a subject) of 50% ± 10% or more compared to the 
screening response to capsaicin (i.e. response to capsaicin at screening (pre administration) 
versus response on Day 120).  For each follow-up visit, subjects will attend the CRU to have the 
capsaicin challenge and LDI measurement performed along with any other scheduled 
procedures.  These visits are specified in the Schedule of Activities (Section 2) and 
Figure FFAB.1.
[…]
Subjects enrolled will be followed for up to160 days post treatment administration.  Assessments 
at Day 160 will be performed only in subjects with significant inhibition of capsaicin induced 
blood flow at Day 120, as defined above.  It is not planned to replace subjects; however, subjects 
may be replaced if necessary to meet study objectives or at the discretion of the Sponsor.
5.4. Scientific Rationale for Study Design
This study will assess the pharmacodynamic effects of LY3316531 using capsaicin challenge 
and LDI over 160120 days following the single dose.  An additional LDI measurement may be 
performed on Day 160, depending on emerging data, in subjects with significant inhibition of 
capsaicin-induced blood flow as defined in Section 5.1.  In addition, the PK, safety, and 
tolerability of a single dose of LY3316531 will be evaluated.
9.6.3 Immunogenicity Assessments
[…]
Treatment-emergent ADAs are defined in Section 10.3.5.  If the immunogenicity titer at the last 
scheduled assessment or discontinuation visit is increasing (compared to previous measurements) 
or remains high, additional samples may be collected (approximately every 3 months for up to 1 
year after Day 120/Day 160) until the titer reaches a plateau/decreases (if increasing) or remains 
the same/decreases (if high).  A PK sample will be collected at each time point.  Additional 
samples may also be collected if there is a possibility that an AE is immunologically mediated.


Leo Document ID = 3a6dde68-4dbc-40fe-9f9d-4d7f1ba85215
Approver: 
Approval Date & Time: 06-Feb-2019 18:52:11 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 06-Feb-2019 20:28:44 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan Version 1 I9H-MC-FFAB  
 
 
A Phase 1 Randomized, Placebo-Controlled Study to Determine the Effect of LY3316531 on 
Capsaicin-Induced Dermal Blood Flow in Healthy Male Subjects 
 
NCT03611608 
 
Approval Date: 17-Oct-2018 
 


I9H-MC-FFAB Statistical Analysis Plan Version 1.0
Page 1
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1.
Statistical Analysis Plan:  
I9H-MC-FFAB:  A Phase 1 Randomized, Placebo-
Controlled Study to Determine the Effect of LY3316531 on 
Capsaicin-Induced Dermal Blood Flow in Healthy Male 
Subjects [from protocol I9H-MC-FFAB]
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IL-23/CGRP Bispecific Antibody (LY3316531)
A single site, Phase 1, subject- and investigator- blind, placebo-controlled, parallel-dose 
group, single-dose study to assess target neutralization of CGRP following a single IV dose 
of LY3316531 versus placebo in healthy male subjects.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I9H-MC-FFAB
Phase 1


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I9H-MC-FFAB:  A Phase 1 Randomized, 
Placebo-Controlled Study to Determine the Effect of LY3316531 on 
Capsaicin-Induced Dermal Blood Flow in Healthy Male Subects 
[from protocol I9H-MC-FFAB] ..........................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
4.1.
Primary Objective ..........................................................................................................6
4.2.
Secondary Objectives.....................................................................................................6
4.3.
Exploratory Objectives...................................................................................................6
5.
Study Design.......................................................................................................................7
5.1.
Summary of Study Design..............................................................................................7
5.2.
Determination of Sample Size ........................................................................................7
5.3.
Method of Assignment to Treatment ..............................................................................8
6.
A Priori Statistical Methods ................................................................................................9
6.1.
General Considerations ..................................................................................................9
6.2.
Subject Disposition ........................................................................................................9
6.3.
Subject Characteristics .................................................................................................10
6.4.
Treatment Compliance .................................................................................................10
6.5.
Concomitant Therapy...................................................................................................10
6.6.
Primary Outcome and Methodology.............................................................................10
6.7.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................11
6.8.
Safety Analyses............................................................................................................11
6.8.1.
Adverse Events ....................................................................................................11
6.8.2.
Clinical Laboratory Evaluation.............................................................................12
6.8.3.
Vital Signs and Other Physical Findings...............................................................12
6.8.4.
Electrocardiograms ..............................................................................................12
6.9.
Interim Analyses and Data Monitoring.........................................................................12
6.10. Planned Exploratory Analyses......................................................................................12
6.11. Clinical Trial Registry Analyses...................................................................................13
7.
References (if applicable)....................................................Error! Bookmark not defined.
8.
Appendices (if applicable)...................................................Error! Bookmark not defined.


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Table of Contents
Table
Page


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Table of Contents
Figure
Page
Figure 1 Statistical power to detect the primary endpoint plotted against sample size for a 
moderately-conservative effect size scenario....................................................8


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3.
Revision History
Version
Version Date
Description of Change
SAP Version 1
15 October 2018


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4.
Study Objectives
4.1.
Primary Objective
To assess target neutralization of calcitonin gene-related peptide (CGRP) following a single 
intravenous (IV) dose of LY3316531 versus placebo in healthy male subjects via capsaicin-
induced dermal blood flow (DBF) as measured using laser Doppler imaging (LDI).
4.2.
Secondary Objectives
To assess the safety and tolerability of a single dose of LY3316531 in healthy male subjects.
To characterize the pharmacokinetics of LY3316531 following IV administration in healthy 
male subjects.
4.3.
Exploratory Objectives
To evaluate the formation of antidrug antibody (ADA) to LY3316531.
To evaluate the relationship between LY3316531 exposure and total CGRP plasma levels.
To evaluate the relationship between LY3316531 exposure and capsaicin-induced DBF.
To evaluate the relationship between capsaicin-induced DBF and total CGRP plasma levels.






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6.
A Priori Statistical Methods
6.1.
General Considerations
Data analyses will be provided by treatment groups and for all study subjects combined wherever
appropriate. For continuous variables, summary statistics will include number of subjects, mean,
median, standard deviation, minimum, and maximum. Categorical endpoints will be summarized
using number of subjects, frequency, and percentages. The interpretation of the study results will 
be the responsibility of the investigator with the pharmacokineticist and statistician. Summary 
tables, data listings and graphs will be produced with SAS version 9.4, and R version 3.5 or 
newer will be used for inferential and exploratory analyses. Other software, such as Spotfire, 
may be used as appropriate to aid the team in decision-making, at the discretion of the statistician 
and statistical analyst.
Treatment groups will be defined as the LY3316531 dose or placebo. The placebo group will
include placebo subjects from all cohorts, if applicable.
Unless otherwise specified, baseline will refer to value collected at the baseline time point. This 
is usually the value prior to first dosing occasion within the dosing period. In case a specific 
baseline value is missing, the value at the nearest time point will be used, provided that it is 
before first dosing. If there are no measurements before dosing then the baseline will be missing.
Unless otherwise specified, missing data will not be imputed and kept missing in the data 
analyses.
Pharmacokinetic/Pharmacodynamic analyses will be conducted on data from all subjects who
receive a dose of LY3316531 and have evaluable PK, total CGRP, or LDI data.
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all
protocol requirements.
All protocol deviations that occur during the study will be considered for their severity and
impact, and will be taken into consideration when subjects are assigned to analysis populations
prior to database lock and unblinding. Details of subject assignment to the analysis populations
will be listed.
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.
6.2.
Subject Disposition
All subjects who discontinue from the study will be identified, and the extent of their
participation in the study will be reported. If known, a reason for their discontinuation will be
given. A disposition table for all enrolled subjects will be provided.


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6.3.
Subject Characteristics
The subject’s age, sex, weight, height, racial designation, or other demographic and study disease
characteristics will be recorded and summarized, and may be used in the pharmacokinetic, 
pharmacodynamics, and safety analyses as quantitative or classification variables.
6.4.
Treatment Compliance
The IP will be administered at the clinical site, and documentation of treatment administration
will occur at the site. No analysis for treatment compliance will be performed.
6.5.
Concomitant Therapy
In the event medication is used, the name of the drug, the dose and the dosage regimen will be 
recorded in the CRF. Concomitant therapies will be listed.
6.6.
Primary Outcome and Methodology
The primary study objective is to assess target neutralization of CGRP following a single IV 
dose of LY3316531 versus placebo in healthy subjects via capsaicin-induced DBF as measured 
using LDI.
The primary objective is measured as decrease from baseline within 30 days, relative to placebo, 
in capsaicin-induced DBF (by blocking CGRP) following at least 1 dose level of a single IV dose 
of LY3316531. The primary objective is framed as the alternative hypothesis ܪ௔of the 
hypothesis-testing construct,
ܪ଴: ߤ௅௒= ߤ௉௕௢versus ܪ௔: ߤ௅௒> ߤ௉௕௢
where ߤ௅௒and ߤ௉௕௢represent the true mean reduction from baseline in capsaicin-induced DBF.
Statistical significance will be assessed using one-sided, two-sample ݐ-tests with significance 
established with a ݌-value less than 0.10. The test statistic, ݐ, is the Behrens-Welch test statistic 
evaluated as a Student ݐquantile with degrees of freedom using Satterthwaite’s approximation, 
and has the form,
ݐ=
ݕത௅௒−ݕത௉௕௢
ඨݏ௅௒
ଶ
݊௅௒+ ݏ௉௕௢
ଶ
݊௉௕௢
where ݊௜is the sample size and
ݏ௜
ଶ=
∑
൫ݕ௜௝−ݕത௜൯
ଶ
௡೔
௝ୀଵ
݊௜−1
is the sample variance for treatment group ݅= ܮܻ, ܾܲ݋.


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It may not be reasonable to assume the treatment groups have similar variance, therefore 
Satterthwaite’s approximation will be used to approximate the degrees of freedom, which is 
given by
݂݀=
ቈ
ೞಽೊ
మ
೙ಽೊା
ೞು್೚
మ
೙ು್೚
቉
మ
൫ೞಽೊ
మ
೙ಽೊ
ൗ
൯మ
೙ಽೊషభ
ା
ቀೞು್೚
మ
೙ು್೚
ൗ
ቁ
మ
೙ು್೚షభ
.
The test statistic will be computed for Visits 3 and 4 (post-baseline visits within 30 days of 
dosing). No correction for multiplicity will be applied, as is customary in Phase 1 trials.
In the event additional cohorts are recruited, subjects assigned to similar treatment arms will be 
pooled to assess the primary analysis. This includes subjects who are assigned to placebo, and (if 
applicable) subjects who are assigned to the same LY dosage.
6.7.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods 
All PK and PK/PD analyses will be performed by Lilly Global PK/PD/PMx. Details will be 
included in a separate analysis plan and/or described in the clinical study report (CSR).
6.8.
Safety Analyses
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and
ECG parameters. The parameters will be listed, and summarized using standard descriptive
statistics. Additional analysis will be performed if warranted upon review of the data. Baseline
for safety parameters will be defined as the last evaluable value before the first dose for each
subject.
6.8.1. Adverse Events
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 discontinuations due to adverse events will be listed. The serious adverse events (SAEs), the 
severe treatment emergent adverse events (TEAEs), the adverse events occurring on or after 
signing study informed consent document and the pre-existing conditions will be listed.
Adverse events reported to occur prior to enrollment will be distinguished from those reported as 
new or increased in severity after enrollment which will be classified as TEAEs. The incidence 
of TEAEs for each treatment group and total LY will be presented by system organ class (SOC) 
and preferred term (PT), by severity and by association with investigational product as perceived 
by the investigator. A table will present the frequency of subjects with TEAEs by Week. The 
frequency of subjects with TEAEs will be presented by treatment group, by preferred term. Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.


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6.8.2. Clinical Laboratory Evaluation
The safety laboratory parameters will be listed and summarized using standard descriptive 
statistics per treatment group.
6.8.3. Vital Signs and Other Physical Findings
Vital signs including pulse rate, SBP, DBP and body temperature will be listed. There will be a 
table summarizing vital sign parameters (pulse rate, SBP, DBP) by treatment group and by time. 
A table presenting the mean change from baseline supine vital sign parameters (pulse rate, SBP, 
DBP) by treatment group for each of these time points: Day 1 (including predose, end of 
infusion, and 2, 6, and 12 hours after start of infusion), Day 2 (24 hours after start of infusion), 
and Days 10, 24, 38, 52, 66 and 80 will be presented. The table may be split in to multiple tables, 
by time, if necessary to easily view the data.
6.8.4. Electrocardiograms
ECG parameters will be listed and summarized by treatment group and time. Mean changes from
baseline for QT and QTcF parameters will be summarized by treatment group and by time (Day 
1: predose, end of infusion, and 6 hours after start of infusion; and Day 2: 24 hours after start of 
infusion). A table of frequency of QT and QTcF >500msec at any time point will be provided by 
treatment group. A table of frequency of mean change from baseline of QT and QTcF >60msec 
at any time will be presented by treatment group. A Graph of mean changes from baseline QT 
and QTcF versus time by treatment group and a graph of mean changes from baseline QT and 
QTcF versus LY3316531 concentration by time will be provided.
6.9.
Interim Analyses and Data Monitoring
A single interim analysis that includes all safety and LDI data, and may include PK data, through
23 days post dose (Day 24) will inform the decision to proceed to Phase 2. The interim analysis
will be based on the highest dose level evaluated (either Cohort 1 or optional Cohort 2, if
implemented).
Note that the primary objective will have complete data at the time of the interim analysis, and 
therefore the analysis will be the same as described in the above sections. Safety analyses will 
also be unchanged at interim, but all safety visits may not be complete at the time the interim 
occurs. All available data will be summarized as described in the sections above.
The decision whether or not to add an additional patient cohort may be made as early as 9 LY 
and 3 Pbo subjects with Visit 3 data, however it is planned that all subjects will have completed 
Visit 4 (same as the timing for the interim analysis). The analyses will be the same as described 
in Section 6.6.
6.10. Planned Exploratory Analyses
In the event that an additional cohort is chosen (Cohort 2), and the dose of LY to be administered 
is the same across cohorts, an analysis of the primary endpoint with pooled responses across 
cohorts for subjects randomized to the same treatment group (placebo, 300mg LY) will be 


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performed. If the protocol allows for the pooled analysis, this will be part of the primary (see 
Section 6.6 for full details).
Other exploratory analyses will be performed by PK/PD and LEM functions.
6.11. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file.   
Both Serious Adverse Events and ‘Other’ Adverse Events are summarized: by treatment 
group, by MedDRA preferred term.

An adverse event is considered ‘Serious’ whether or not it is a treatment emergent 
adverse event (TEAE).

An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 


Leo Document ID = 30ea3a78-81d3-4637-9651-11db333f819d
Approver: 
Approval Date & Time: 17-Oct-2018 15:00:10 GMT
Signature meaning: Approved
PPD