Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3016859 for the Treatment of Chronic Low Back Pain
Phase: PHASE2
Conditions: Chronic Low-back Pain
Sponsor: Eli Lilly and Company

Clinical Study Protocol H0P-MC-BP01 
 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3016859 for the Treatment of 
Chronic Low Back Pain 
NCT04529096 
Approval Date: 11-May-2020 

CONFIDENTIAL
Protocol number H0P-MC-BP01
1
Title Page
Intervention-Specific Appendix (ISA) for LY3016859: H0P-MC-BP01
Confidential Information
The information contained in this document is confidential and is intended for the use of clinical investigators.  It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY3016859, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure.  Eli Lilly and Company requests consultation regarding release/redaction prior to any 
public release.  In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be 
reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Master Protocol Title: A Master Protocol for Randomized, Placebo-Controlled, Phase 2 
Clinical Trials of Multiple Interventions for the Treatment of Chronic 
Pain
Master Protocol Number: H0P-MC-CPMP
ISA Title: Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3016859 for 
the Treatment of Chronic Low Back Pain
ISA Number: H0P-MC-BP01
Amendment Number:  This is the original protocol.
Compound: LY3016859
Study Phase: 2
Acronym: BP01
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA 46285
Regulatory Agency Identifier Number(s)
Master Protocol IND: 144915 
Approval Date: Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 11-May-2020 GMT

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Protocol number H0P-MC-BP01
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Medical Monitor Name and Contact Information will be provided separately.

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Protocol number H0P-MC-BP01
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Table of Contents
1.
Protocol Summary......................................................................................................5
1.1.
Synopsis.......................................................................................................................5
1.2.
Schema.........................................................................................................................7
1.3.
Schedule of Activities (SoA) ........................................................................................8
2.
Introduction..............................................................................................................12
2.1.
Study Rationale ..........................................................................................................12
2.2.
Background ................................................................................................................13
2.3.
Benefit/Risk Assessment ............................................................................................14
2.3.1.
Risk Assessment.........................................................................................................14
2.3.2.
Benefit Assessment.....................................................................................................16
2.3.3.
Overall Benefit: Risk Conclusion................................................................................16
3.
Objectives and Endpoints.........................................................................................17
4.
Study Design .............................................................................................................18
4.1.
Overall Design............................................................................................................18
4.2.
Scientific Rationale for Study Design .........................................................................19
4.3.
Justification for Dose..................................................................................................19
4.4.
End of Study Definition..............................................................................................19
5.
Study Population ......................................................................................................20
5.1.
Inclusion Criteria........................................................................................................20
5.2.
Exclusion Criteria.......................................................................................................20
5.3.
Lifestyle Considerations .............................................................................................21
6.
Study Intervention....................................................................................................22
6.1.
Study Intervention(s) Administered ............................................................................22
6.1.1.
Special Treatment Considerations...............................................................................22
6.2.
Preparation/Handling/Storage/Accountability.............................................................24
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................24
6.4.
Study Intervention Compliance...................................................................................24
6.5.
Concomitant Therapy .................................................................................................24
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................25
7.1.
Discontinuation of Study Intervention ........................................................................25
8.
Study Assessments and Procedures .........................................................................26
8.1.
Safety Assessments ....................................................................................................26
8.1.1.
Physical Examinations................................................................................................26
8.1.2.
Electrocardiograms.....................................................................................................26
8.1.3.
Clinical Safety Laboratory Assessments .....................................................................26
8.2.
Adverse Events and Serious Adverse Events ..............................................................26
8.2.1.
Infusion Site Reactions ...............................................................................................26
8.2.2.
Hypersensitivity Reactions and Infusion-related Reactions .........................................26
8.2.3.
Adverse Events of Special Interest..............................................................................27
8.3.
Treatment of Overdose ...............................................................................................27

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Protocol number H0P-MC-BP01
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8.4.
Pharmacokinetics........................................................................................................27
8.5.
Pharmacodynamics.....................................................................................................28
8.6.
.................................................................................................................28
8.7.
Immunogenicity Assessments.....................................................................................28
9.
Statistical Considerations.........................................................................................29
9.1.
Statistical Hypotheses.................................................................................................29
9.2.
Sample Size Determination.........................................................................................29
9.3.
Populations for Analyses ............................................................................................29
9.4.
Statistical Analyses.....................................................................................................29
9.4.1.
General considerations................................................................................................29
9.4.2.
Other Analyse(s).........................................................................................................30
9.5.
Interim Analyses.........................................................................................................30
10.
Supporting Documentation and Operational Considerations ................................31
10.1.
Appendix 1: Clinical Laboratory Tests........................................................................31
10.2.
Appendix 2: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................32
10.3.
Appendix 3: Recommended Laboratory Testing for 
Hypersensitivity Events..............................................................................................35
10.4.
Appendix 9: Abbreviations .........................................................................................36
11.
References.................................................................................................................38
CCI

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Protocol number H0P-MC-BP01
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title:
Randomized, placebo-controlled, Phase 2 clinical trial to evaluate LY3016859 for the treatment 
of chronic low back pain
Rationale:
The purpose of this study is to test whether LY3016859 is efficacious in relieving chronic low 
back pain (CLBP).  LY3016859 is a high affinity humanized immunoglobulin G (IgG)4
monoclonal antibody that binds to key residues in the C-terminal regions of transforming growth 
factor-α (TGF-α) and epiregulin, preventing their binding to the epidermal growth factor receptor
(EGFR).  
Data will be collected to assess the safety and tolerability of LY3016859 in this study population. 
Pharmacokinetic properties, pharmacodynamic effects, and immunogenicity profile will also be 
explored.  The totality of data from this proof-of-concept study will assess the benefits and risks
associated with LY3016859 and inform decisions for the clinical development of LY3016859.
Objectives and Endpoints
The primary and secondary objectives and endpoints are stated in the Master Protocol H0P-MC-
CPMP (CPMP) and CLBP disease-state addendum (DSA) H0P-MC-CPMP(2) (CPMP[2]). 
Overall Design
This is a 26-week, Phase 2, randomized, double-blind, placebo-controlled study that will 
compare LY3016859 versus placebo in participants with CLBP.
Disclosure Statement: This is a randomized, investigator- and participant-blind, placebo-
controlled, Phase 2 clinical trial.
Number of Participants:
Approximately 150 participants will be randomly assigned to study intervention
(100 LY3016859 and 50 placebo) with the assumption that 15% of the participants will drop out 
prior to the end of the double-blind treatment period.
Intervention Groups and Duration:
This 26-week study includes an 8-week double-blind treatment period and an 18-week follow-up 
period.
Participants will receive an intravenous infusion every 2 weeks for a total of 4 infusions.

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Protocol number H0P-MC-BP01
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Intervention Name
LY3016859
Placebo
Dosage Level(s)
750 mg starting dose
500 mg subsequent doses
Not applicable
Route of Administration
and duration
1-hour IV infusion
1-hour IV infusion
Abbreviation: IV = intravenous.
Participants will be monitored for at least 4 hours after completion of each infusion.
Data Monitoring Committee: Yes

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Protocol number H0P-MC-BP01
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1.2.
Schema
* Medication washout and PDEP begins.
** Randomization to either LY3016859 or placebo.  
ǂ Each participant receives a 1-hour infusion at Visits 3, 4, 5, and 6.
Abbreviations:  IV = intravenous; PDEP = preliminary data entry period; V = visit.
Washout
& PDEP
Up to -6 
months
V1
V3**
Week 2
V4
Week 4
V5
Week 6
V6
Week 8
V7
-10 days to V3
V2*
Screening
Period
Randomization 
Double-Blind
Period
Placebo IV infusionǂ
LY3016859 IV infusionǂ
Week 26
V803
Follow-up
Week 12
V801
Week 16
V802

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Protocol number H0P-MC-BP01
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1.3.
Schedule of Activities (SoA)
This SoA shows visits and procedures unique to the intervention-specific appendix (ISA) H0P-
MC-BP01 (BP01) for LY3016859.  Please refer to Master Protocol H0P-MC-CPMP (CPMP) 
and the CLBP disease-state addendum (DSA) H0P-MC-CPMP(2) SoAs for additional 
information.  

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Protocol number H0P-MC-BP01
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H0P-MC-BP01 ISA
Randomization
Double-Blind Treatment
Follow-up
Early
Discontinuation
Notes
Visit Number
V3
V4
V5
V6
V7
V801
V802
V803
ED
Study Week
0
2
4
6
8
12
16
26
Visit Window 
(days)
±3
±3
±3
±3
±5
±7
±7
Minimal interval between 2 doses cannot be 
shorter than 11 days.
Physical 
examination
X
X
X
X
X
X
X
X
X
Targeted exam for skin, eyes, mouth, lungs, and 
GI tract should be performed at each visit, in 
addition to any symptom-driven exam.  Full 
physical exam should be performed at Visit 803 
or ED.
Weight 
X
Vital signs
X
X
X
X
X
X
X
X
Includes respiratory rate, blood pressure, 
temperature, and pulse rate.  All vital signs are 
collected before study intervention infusion on 
V3-V6.
ECG
X
X
X
Single safety ECGs
Study 
intervention IV 
infusion
X
X
X
X
1-hour IV administration
The timing between randomization and the first 
IV infusion may be up to, but not longer than,
2 business days to reduce participant burden.
Adverse events
X
X
X
Concomitant 
medication
X
X
X
Rescue 
medication 
usage reporting
X
If the participant discontinues after V801, this 
assessment is not needed for ED per the CPMP 
SoA.
NRS
X
If the participant discontinues after V801, this 
assessment is not needed for ED per the CPMP 
SoA.
PGI
X
If the participant discontinues after V801, this 
assessment is not needed for ED per the CPMP 
SoA.

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Protocol number H0P-MC-BP01
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H0P-MC-BP01 ISA
Randomization
Double-Blind Treatment
Follow-up
Early
Discontinuation
Notes
Visit Number
V3
V4
V5
V6
V7
V801
V802
V803
ED
Study Week
0
2
4
6
8
12
16
26
Visit Window 
(days)
±3
±3
±3
±3
±5
±7
±7
Minimal interval between 2 doses cannot be 
shorter than 11 days.
RMDQ
X
If the participant discontinues after V801, this 
assessment is not needed for ED per the CPMP 
SoA.
C-SSRS
X
X
Use C-SSRS Since Last Visit version.  
Self-Harm 
Supplement 
Form
X
X
Self-Harm 
Follow-up Form
X
X
Required if triggered by the Self-Harm 
Supplement Form per instructions.
Hematology
X
X
X
Chemistry 
X
X
X
X
X
Urine 
Chemistries
X
X
X
X
X
X
X
X
Urinalysis
X
Urine pregnancy
X
X
X
X
X
X
X
For all premenopausal females or 
postmenopausal females <50 years of age
V3: collect sample before dosing.
Urine drug 
screen
X
X
X
Hemoglobin 
A1c
X
X
X
X

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Protocol number H0P-MC-BP01
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H0P-MC-BP01 ISA
Randomization
Double-Blind Treatment
Follow-up
Early
Discontinuation
Notes
Visit Number
V3
V4
V5
V6
V7
V801
V802
V803
ED
Study Week
0
2
4
6
8
12
16
26
Visit Window 
(days)
±3
±3
±3
±3
±5
±7
±7
Minimal interval between 2 doses cannot be 
shorter than 11 days.
PK sample
X
X
X
X
X
X
X
X
X
V3-V6:  collect samples before IV infusion 
starts and within 15 minutes after IV infusion is 
complete.
V7-V803: single sample collected at any time.
Obtain PK samples from opposite arm used for 
IV infusion.  
Record date and time of collection.
Immunogenicity 
(ADA) sample
X
X
X
X
X
X
X
V3-V6:  collect sample before IV infusion starts.
Epiregulin 
sample
X
X
X
X
X
X
X
X
V3-V6:  collect sample before IV infusion starts.
V7-V803: single sample collected at any time to 
match PK.
Abbreviations:  ADA = anti-drug antibody; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early discontinuation; GI = gastrointestinal; 
ISA = intervention-specific appendix; IV = intravenous; NRS = Numeric Rating Scale for pain; PGI = Patient Global Impression of Change; PK = pharmacokinetic; 
RMDQ = Roland-Morris Disability Questionnaire; SoA = schedule of activities; V = visit.
CCI

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Protocol number H0P-MC-BP01
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2.
Introduction
This intervention-specific appendix (ISA) H0P-MC-BP01 (BP01) is an appendix to the H0P-
MC-CPMP (CPMP) Master Protocol and contains unique study elements specific for 
LY3016859.  The master protocol contains the overarching study elements that govern the 
chronic low back pain (CLBP) disease-state appendix (DSA) H0P-MC-CPMP(2) (CPMP[2]) and 
this ISA BP01.  
LY3016859 is a high affinity humanized immunoglobulin G (IgG)4 monoclonal antibody that 
binds to key residues in the C-terminal regions of transforming growth factor-α (TGF-α) and 
epiregulin, preventing their binding to the epidermal growth factor receptor (EGFR).  
Engagement of LY3016859 results in internalization of the membrane-spanning ligands and 
neutralization of mature ligand activity in vitro.  
The EGFR and epiregulin are associated with pain processing (Martin et al. 2017).  Epiregulin is 
increased in blood after nerve injury/insult (Martin et al. 2017).  Inhibition of EGFR with 
clinically available compounds strongly reduces nocifensive behavior in mouse models of 
inflammatory and chronic pain, including spinal nerve injury and chronic constriction injury
(Martin et al. 2017).
Non-controlled reports show that EGFR inhibition by various oncologic drugs provides rapid 
relief of pain (Kersten et at. 2013; Kersten et al. 2015; Juhasz et al. 2013), and the pain relief was 
independent of disease progression (Kersten and Cameron 2012).  
2.1.
Study Rationale
The purpose of this study is to test whether LY3016859 is efficacious in relieving CLBP.  Data
will be collected to assess the safety and tolerability of LY3016859 in this study population. 
Pharmacokinetic (PK) properties, pharmacodynamic (PD) effects, and immunogenicity profile 
will also be explored.  The totality of data from this proof-of-concept study will assess the
benefits and risks associated with LY3016859 and inform decisions for the clinical development 
of LY3016859.

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Protocol number H0P-MC-BP01
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2.2.
Background
LY3016859 was initially developed for the treatment of diabetic nephropathy (DN) and 
2 clinical studies were completed. 
Study
I5V-MC-TGAA (TGAA)
Population
Healthy participants
Study Design
Placebo-controlled, randomized, single-dose escalation
LY3016859 
Dose
Intravenous (IV) infusion and subcutaneous:  0.1, 1, 10, 50, 250, and 750 mg
Objectives 
Evaluate safety, tolerability, and pharmacokinetics after single IV and subcutaneous 
dosing.
Study 
I5V-MC-TGAB (TGAB)
Population
Participants with diabetic nephropathy 
Study Design
2-part, placebo-controlled, randomized, multiple dose escalation and parallel dose study
LY3016859 
Dose
Part A: dose range of 10 to 750 mg, administered as a 60-minute IV infusion once every 
3 weeks for a total of 2 doses
Part B: 60-minute IV infusion once every 3 weeks up to 5 doses, if tolerated
Doses did not exceed the maximum tolerated dose from Part A.
Objectives 
Evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics.
Change from baseline in proteinuria at 16 weeks.
Pharmacokinetics 
LY3016859 serum concentration increased more than proportionally with dose, and the terminal 
half-life increased with dose (approaching 18 days at higher doses), consistent with 
target-mediated drug disposition.  
Pharmacodynamics
LY3016859 demonstrated dose-related target engagement for both TGF-α and epiregulin.
Safety
Intravenous doses of up to 750 mg LY3016859 were safe and reasonably well-tolerated.
A detailed description of the chemistry, pharmacology, efficacy, and safety of LY3016859 is 
provided in the Investigator’s Brochure (IB).

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Protocol number H0P-MC-BP01
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2.3.
Benefit/Risk Assessment
The IB provides detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of LY3016859.
2.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention LY3016859
Development TE ADA.
Incidence of TE ADA was 50% after 
a single dose, and up to 57% after 
multiple doses.
Collect samples up to 20 weeks after 
last dose to characterize ADA 
profile. 
IV infusion may be associated with 
infusion reactions and 
hypersensitivity reactions. 
LY3016859 is a monoclonal 
antibody that will be administered 
via IV infusion.  Hypersensitivity 
reactions and infusion reactions may 
occur during treatment with such 
agents.
Monitor infusion reactions and 
hypersensitivity reactions.
Guidance on management of 
infusion and hypersensitivity 
reactions are in Sections 8.2.1 and 
8.2.2.
Dermatological adverse reactions 
similar to EGFR antagonists.
One healthy participant who 
received a single dose of 1 mg 
LY3016859 experienced a rash that 
was considered similar to those 
associated with EGFR antagonists.
Collect dermatological AEs.
Stop dosing for severe 
dermatological AEs.
Changes in eGFR in participants 
with CLBP.
A modest and non-statistically 
significant decrease in eGFR was 
observed in participants with DN 
who received LY3016859 in Part B 
of Study TGAB, but not in healthy 
participants in Study TGAA.
Exclude participants with moderate 
or severe renal impairment in the 
study.
Short dosing duration.
Monitor eGFR and stop dosing if 
necessary.
 
Fetal harm due to in utero exposure
No effects on embryo-fetal 
development in enhanced pilot 
embryo-fetal development studies in 
rats and rabbits.  Definitive 
developmental and reproductive 
toxicity studies are not yet 
completed.
Do not enroll women who are 
pregnant or breastfeeding in studies 
for LY3016859.
Study Procedures
Participant may experience 
increased CLBP symptoms.
Medications that relieve CLBP pain 
will not be allowed until Visit 801.
Rescue medication is permitted.
Standard treatment of CLBP may be 
restarted after Visit 801 based on 
investigator discretion.
CCI

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Protocol number H0P-MC-BP01
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Abbreviations:  ADA = anti-drug antibodies; AE = adverse event; CLBP = chronic low back pain; DN = diabetic 
nephropathy; EGFR = epidermal growth factor receptor; eGFR = estimated glomerular filtration rate; 
IV = intravenous; TE = treatment emergent; TGAA = Study I5V-MC-TGAA; TGAB = Study I5V-MC-TGAB.

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Protocol number H0P-MC-BP01
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2.3.2. Benefit Assessment
Potential benefits for the study participants include 

study-related medical procedures 
o
physical examinations 
o
laboratory tests 
o
electrocardiograms (ECGs) 
As part of Study CPMP, participants to this ISA will report their experience using standard tools 
that will contribute to the assessment of novel treatments for CLBP.  In addition, data collected 
from this study may also improve our understanding of pathogenesis.  Both of which may lead to 
the development of a new treatment with improved safety and efficacy profile compared to 
standard of care.
2.3.3. Overall Benefit: Risk Conclusion
The measures taken to minimize risk to participants in this study and the potential risks identified 
in association with ISA BP01 are justified by the anticipated benefits to participants with CLBP.

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Protocol number H0P-MC-BP01
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3.
Objectives and Endpoints
The CPMP Master Protocol and CLBP DSA CPMP(2) include objectives and endpoints 
applicable for this study.  This table describes objectives and endpoints specific for LY3016859.
Objectives
Endpoints
Tertiary/Exploratory
Characterize the PK and PD of LY3016859 after 
multiple IV infusions in participants with CLBP
Assessment of serum concentrations of LY3016859 
and epiregulin to enable PK and PD evaluations
Characterize immunogenicity of LY3016859
Appearance of anti-drug antibodies and neutralizing 
antibodies to LY3016859
Explore the effect of LY3016859 on the kidney
Assessment of 
urine albumin/creatinine ratio
urine protein/creatinine ratio
eGFR
Abbreviations:  CLBP = chronic low back pain; eGFR = estimated glomerular filtration rate; IV = intravenous; PD = 
pharmacodynamics; PK = pharmacokinetics.

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4.
Study Design
4.1.
Overall Design
The CPMP Master Protocol and CLBP CPMP(2) DSA describes the overall study design and 
study design rationale.  This section describes visits and overall procedures unique to ISA BP01 
for LY3016859 in addition to the procedures outlined in the CPMP Master Protocol and 
CPMP(2) DSA.  
Double-blind Treatment Period (Visits 3 through 7)
Each visit is an outpatient visit.
At Visit 3

participants are randomized to LY3016859 or placebo  

the site completes the BP01 baseline procedures and sample collection 

participants receive their first dose of study intervention via intravenous (IV) infusion 
over 1 hour 

the site observes participants in the clinic for at least 4 hours after the completion of the 
IV infusion 

the site completes all post-treatment sample collection and safety monitoring, and

the site instructs participants to continue with study restrictions and Numeric Rating 
Scale (NRS) diary entries before their visit discharge.
At Visits 4 through 6  

the site reviews available safety data and completes pre-dose procedures and sample 
collection

participants receive an IV infusion over 1 hour 

the site observes participants in the clinic for at least 4 hours after the completion of the
IV infusion

the site completes all post-treatment sample collection and safety monitoring, and

the site instructs participants to continue with study restrictions and NRS diary entries 
before their visit discharge. 
At Visit 7

the site completes all procedures and sample collection noted in the schedule of activity 
(SoA)s

no intervention is administered at this visit, and 

the site instructs participants to continue with study restrictions and NRS diary entries 
before their visit discharge. 
Post-treatment Follow-up Period (Visits 801-803) 
Participants must complete 3 post-treatment follow-up visits for safety, PK, epiregulin PD, and 
immunogenicity assessment at Visits 801 through 803, according to the SoA.

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The site schedules Visit 801 approximately 4 weeks after Visit 7. 
At Visit 801, participants return the device for NRS diary collection. 
At Visit 803, the participants are discharged from the study. 
If the participant receives at least one dose of intervention and discontinues during the double-
blind treatment period, they should complete early discontinuation procedures per the CPMP 
Master Protocol SoA, and Visit 801 should be scheduled approximately 30 days after the last 
dose of study intervention.
4.2.
Scientific Rationale for Study Design
The CPMP Master Protocol describes the overall study design rationale.
Efficacy data will be collected up to 6 weeks after the last dose, based on the long PK half-life 
and potential sustained target engagement of LY3016859.
Safety, PK, PD, and immunogenicity samples will be collected up to 20 weeks after the last 
administration of intervention to characterize the safety and clinical immunogenicity profile. 
4.3.
Justification for Dose
The proposed dose for proof-of-concept is a 750-mg starting dose followed by 500 mg every 
2 weeks IV for a total of 4 doses.  The dose level and duration are based on the available 
toxicology, safety, PK, and PD data from the completed studies detailed in the LY3016859 IB. 
Briefly, the proposed dose regimen maintains an approximate 10-fold margin of safety (MOS) 
relative to the no-observed-adverse-effect level (NOAEL) for both rat and monkey repeated dose 
toxicology studies (located in the IB) and is expected to achieve steady state exposure similar to 
the 750 mg every 3 weeks dosing regimen tested in Study TGAB.  The safety data from the 
completed TGAA and TGAB studies and the clinical management plan support testing the 
proposed dose regimen in participants with various chronic pain conditions. 
The PK analyses show a similar PK profile for LY3016859 in healthy participants and patients 
with various degrees of renal impairment, which is expected for a monoclonal antibody.  
While the degree of target engagement required for analgesic efficacy for LY3016859 has not 
been established in the clinic, the proposed dosing regimen is expected to reach steady-state 
within a month
.  If the epiregulin blockade is beneficial for CLBP, then this level of target engagement 
is expected to enable analgesic efficacy.  
4.4.
End of Study Definition
A participant is considered to have completed this ISA if he or she has completed all required 
phases of the study including the last scheduled procedure shown in the ISA SoA.
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the ISA SoA for the last participant.
CCI

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Protocol number H0P-MC-BP01
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5.
Study Population
The CPMP Master Protocol and CLBP CPMP(2) DSA provide eligibility criteria that must be 
followed for this study.  LY3016859-specific inclusion and exclusion criteria are listed here.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
[2000]
are men or women who abide by the reproductive and contraceptive requirements 
provided in BP01 Section 10.2, Appendix 2
[2001]
are willing to discontinue all pain medications for condition under study except 
rescue medication permitted per protocol until V801 in the follow-up period
[2002]
must have venous access in both arms for IV infusion and sample collection.  
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
[2003]
Have an estimated glomerular filtration rate (eGFR) of less than 70 ml/min/1.73m2
based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
formula at Visit 1 or Visit 2
[2004]
Have any clinically serious or unstable cardiovascular, musculoskeletal disorder, 
gastrointestinal (GI), endocrinologic, hematologic, hepatic, metabolic, urologic, 
pulmonary, dermatologic, immunologic, or ophthalmologic disease within 3 months 
of Visit 3
Prior/Concomitant Therapy
[2005]
have received any antibodies against nerve growth factor (NGF), antibodies against 
EGFR, or EGFR tyrosine kinase inhibitors (TKI).
[2006]
have a history of allergic reactions to monoclonal antibodies, or clinically 
significant multiple or severe drug allergies, including but not limited to erythema 
multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, 
or exfoliative dermatitis
[2007]
have a history or presence of uncontrolled asthma, eczema, significant atopy, 
significant hereditary angio-edema, or common variable immune deficiency, and
Reproductive
[2008]
women who are pregnant or breastfeeding.

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5.3.
Lifestyle Considerations
Reproductive and Contraception Requirements
Reproductive requirements and contraceptive guidance are provided in BP01 Appendix 2, 
Section 10.2.  
Caffeine and Alcohol
Participants should maintain their usual caffeine intake.  
Participants should limit their alcohol consumption for the duration of the study.  
Men up to the age of 65 should not exceed an average weekly alcohol intake of 21 units per 
week.  
Men over the age of 65 and women should not exceed an average weekly alcohol intake of
14 units per week.
One unit of alcohol equals

12 oz or 360 mL of beer 

5 oz or 150 mL of wine, or

1.5 oz or 45 mL of distilled spirits.
Activities
Participants are required to maintain similar levels of activity during the double-blind study 
period.  Starting a new exercise program or new strenuous activity is not allowed.  
Participants who receive physical therapy for CLBP should remain on the same therapy program 
(intensity and frequency) from Visit 3 to Visit 801.  New programs may be initiated after 
Visit 801.
Exposure to Sun
Participants should use sun protection and avoid sunbathing and use of sun beds for the duration 
of the study.  Sun protection may consist of protective clothing or sun protection factor (SPF) 50 
lotion.

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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol.
6.1.
Study Intervention(s) Administered
The study intervention will be administered via a slow IV infusion over approximately 1 hour by 
blinded site personnel.  The infusion rate may be reduced as deemed necessary if an infusion 
reaction is observed (see Section 6.1.1.2).  Participants will be monitored for at least 4 hours 
after completion of each infusion.  Site must have resuscitation equipment, emergency drugs, and 
appropriately training staff available during the infusion and for at least 4 hours after the 
completion of the infusion.  Participants should not use tobacco products from 1 hour before the
start of dosing until after collection of the final PK or PD sample after dosing.  
Intervention Name
LY3016859
Placebo
Type 
Biologic
Not applicable
Dose Formulation
Lyophilized powder
0.9% Sodium chloride solution
Unit Dose Strength(s)
75 mg/vial
Not applicable
Dosage Level(s)
750 mg starting dose
500 mg subsequent doses
Not applicable
Route of Administration
1-hour IV infusion
1-hour IV infusion
Use
experimental 
placebo
IMP and NIMP
IMP
NIMP
Abbreviations:  IMP = investigational medicinal product; IV = intravenous; NIMP = non-investigational medicinal 
product.
6.1.1.
Special Treatment Considerations
6.1.1.1.
Premedication for Infusions
Premedication for infusions is not planned.  However, if an infusion reaction occurs, the study 
investigator(s) should determine the appropriate premedication for subsequent infusions for that 
participant.
The investigators and sponsor may decide to use premedication for all participants.  They will 
decide this if the frequency of infusion reactions among participants warrants it.
Any premedications given will be documented as a concomitant therapy (see Section 6.5).

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6.1.1.2.
Management of Infusion Reactions
All participants should be monitored closely, as there is a risk of infusion reaction and 
hypersensitivity (including anaphylaxis) with any biological agent.  
Symptoms and Signs
Symptoms and signs that may occur as part of an infusion reaction include, but are not limited to,
fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash, 
pruritus, myalgia, and dizziness.  
Site Needs
The clinical site should have necessary equipment and medications for the management of any 
infusion reaction, which may include but is not limited to oxygen, IV fluid, epinephrine, 
acetaminophen, and antihistamine.
Management of Infusion Reactions
Investigators should grade the severity of the infusion reaction and manage infusion reactions 
based on standard of care and their clinical judgment.  If an infusion reaction occurs, then 
supportive care should be used in accordance with the signs and symptoms.
This table outlines guidance when a mild to moderate infusion reaction occurs.
If…
Then…
a mild to moderate infusion reaction occurs
the infusion rate should be slowed or stopped depending 
on the symptoms or signs present.
For example, reducing the rate by 50% from 
2 mL/minute to 1 mL/minute.
the infusion rate is slowed

the infusion should be completed at the slower rate, 
as tolerated.

subsequent infusions may be administered at the 
discretion of the investigator in agreement with the 
Lilly medical monitor. 
the infusion rate is slowed, and subsequent infusions are 
continued
the infusion rate must be maintained at the slowest 
tolerated rate used. 
The study intervention infusion should be stopped immediately and permanently if it is an 
infusion reaction

with systemic involvement, including, but not limited to, significant treatment-emergent
(TE) hypotension, bronchospasm, or wide-spread urticaria 

that does not respond to a slower infusion rate or oral medications

that is determined as clinically significant by the investigator.  
If a participant permanently discontinues from study intervention, they should complete AE
monitoring and other procedures as stated in Section 4, Study Design, and the CPMP Master 
Protocol, CPMP(2) DSA, and BP01 SoAs.

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6.2.
Preparation/Handling/Storage/Accountability
Study intervention and placebo will be prepared and verified by unblinded site personnel.
6.3.
Measures to Minimize Bias: Randomization and Blinding
No additional stratification factors are considered for this ISA.  
6.4.
Study Intervention Compliance
Participants will receive study intervention directly from the investigator or designee, under 
medical supervision.  The date and time of each study intervention administered in the clinic will 
be recorded in the source documents and case report form (CRF).  Administration of intervention
and study participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study intervention.  
6.5.
Concomitant Therapy
All concomitant therapies that are part of routine care for other comorbidities besides CLBP, are 
allowed and can be used during the study, if it is permitted based on the inclusion and exclusion 
criteria.  
A list of medications that are prohibited from Visit 2 to Visit 801 for participants randomized to 
this ISA study will be provided.  Participants may return to their standard of care after Visit 801 
is completed, as clinically appropriate.

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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
The CPMP Master Protocol and CPMP(2) DSA provides the reasons and procedures for 
discontinuation of intervention and participant discontinuation that must be followed for this 
study.  LY3016859 specific information is included here.
7.1.
Discontinuation of Study Intervention
If the investigator, after consultation with the sponsor-designated medical monitor, determines 
that a systemic hypersensitivity reaction or a serious infusion reaction has occurred related to 
study intervention administration, the participant should be permanently discontinued from the 
study intervention. 
A participant should be discontinued from study intervention if they experience a dermatological 
adverse reaction, such as acneiform rash, that is related to study intervention, and is either mild 
to moderate and does not respond to topical treatment or is severe.  The participant may continue 
in the study at the discretion of the investigator in consultation with the medical monitor or study 
sponsor physician/scientist.

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Protocol number H0P-MC-BP01
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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the CPMP Master Protocol, CLBP 
CPMP(2) DSA, and ISA BP01 SoAs.  
LY3016859-specific assessments and procedures are described here.
8.1.
Safety Assessments
Planned time points for all safety assessments are provided in the SoAs. 
8.1.1.
Physical Examinations
Targeted physical examinations of skin, eyes, mouth, lungs, and GI tract will be performed at 
each visit as described in the SoA.  Any clinically significant abnormal physical examination 
findings will be reported as AEs. 
8.1.2.
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures pulse rate, QRS, QT, and corrected QT 
interval (QTc). 
8.1.3.
Clinical Safety Laboratory Assessments
See BP01 Appendix 1 (Section 10.1) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency for ISA BP01. 
8.2.
Adverse Events and Serious Adverse Events
8.2.1.
Infusion Site Reactions
Symptoms of a local infusion site reaction may include erythema, induration, pain, pruritus, and 
edema. If an infusion site event is reported, the AE will be recorded, and additional data will be
provided to the sponsor in the CRF.
Additional blood and urine samples should be collected as described in BP01 Section 10.3, 
Appendix 3, “Recommended Laboratory Testing for Hypersensitivity Events”.  Laboratory 
results are provided to the sponsor via the central laboratory.
8.2.2.
Hypersensitivity Reactions and Infusion-related Reactions
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions.  Drugs administered via IV infusion may lead to a systemic infusion-related reaction.  
If such a reaction occurs, additional data describing each symptom should be provided to the 
sponsor in the CRF.  
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention.  It is recommended that 
participants who experience a systemic reaction be treated per the local standard of care.  

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Protocol number H0P-MC-BP01
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In the case of generalized urticaria or anaphylaxis, or moderate to severe infusion-related 
reactions, additional blood and urine samples should be collected as described in BP01 
Section 10.3, Appendix 3, “Recommended Laboratory Testing for Hypersensitivity Events.”  
Laboratory results are provided to the sponsor via the central laboratory.
8.2.3. Adverse Events of Special Interest 
Dermatological adverse reactions
EGFR antibodies or EGFR-associated TKI are associated with various dermatological AEs, 
including acneiform rashes, xerosis, pruritis, and photosensitivity.  Secondary infection can also 
develop. 
Participants should use sun protection during the study period.  Dermatological adverse reactions 
should be managed by the investigator according to standard of care.  Discontinuation of 
treatment may be considered if these AEs do not respond to topical treatment, are widespread 
(>30% body surface area), or are severe.
If any of these AEs are reported, sites will be prompted to provide additional information. 
Renal Function
Changes in eGFR were observed in participants with DN in Study TGAB (Section 2.2).  Such 
changes were reversible and were not associated with an increase in proteinuria.  Blood and urine 
samples will be collected to characterize the effects of LY3016859 on renal function, and eGFR 
will be monitored during the study. 
8.3.
Treatment of Overdose
In case of suspected overdose, participants should be monitored for any signs or symptoms of 
adverse reactions or effects, and supportive care should be provided as necessary. 
8.4.
Pharmacokinetics
Venous blood samples will be collected for measurement of LY3016859 concentrations as 
specified in the SoA.  Samples will be used to evaluate the PK of LY3016859.  
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor.  
Instructions for the collection and handling of biological samples will be provided by Lilly. 
Site personnel will record

The date and time (24-hour clock time) of LY3016859 administration (start and end of 
infusion), and

The date and time (24-hour clock time) of each PK sample.
It is essential that the times are recorded accurately.
Pharmacokinetic samples will be retained for a maximum of 2 years following last subject visit 
for the study. CCI

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Protocol number H0P-MC-BP01
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8.5.
Pharmacodynamics
Venous blood samples will be collected for the measurement of epiregulin as specified in the 
SoA.  Any remaining blood samples may be used to test other potential PD endpoints, including, 
but not limited to TGF-α. 
Instructions for the collection and handling of biological samples will be provided by Lilly.
8.7.
Immunogenicity Assessments
Visits and times
At the visits and times specified in the SoA, predose venous blood samples will be collected to 
determine antibody production against LY3016859.  The actual date and time (24-hour clock 
time) of each sample collection will be recorded.
If the immunogenicity sample at the last scheduled assessment or discontinuation visit is TE 
anti-drug antibody (ADA) positive (as defined in Section 9.4.2.1), additional samples may be 
taken until the signal returns to baseline (i.e., no longer TE-ADA positive) or for up to 1 year 
after last dose.
To aid interpretation of these results, a predose blood sample for PK analysis will be collected at 
the same time points. 
Sample collection, handling, and use
Instructions for the collection and handling of blood samples will be provided by the sponsor.
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of LY3016859 at a laboratory approved by the sponsor.  Antibodies may be further characterized 
for their ability to neutralize the activity of LY3016859.  
Sample retention
Sample retention is described in CPMP Master Protocol, Appendix 1, Section 10.1.12.
CCI

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9.
Statistical Considerations
The CPMP Master Protocol and CLBP DSA CPMP(2) provide statistical considerations.
LY3016859-specific considerations are described here.
9.1.
Statistical Hypotheses
The CPMP Master Protocol describes the primary hypothesis.  
 
. 
9.2.
Sample Size Determination
Approximately 150 participants will be randomized in a 2:1 ratio to LY3016859 and placebo, 
respectively.  It is expected that approximately 128 participants will complete the double-blind 
treatment period of the study.  
 
 
.  If there is no treatment 
difference between placebo and LY3016859, the probability of passing the efficacy criterion 
specified above (i.e., false positive) is less than 0.05.  The simulation for the power calculation 
and sample size determination was carried out in FACTS Version 6.0.
9.3.
Populations for Analyses
The populations are defined in the CPMP Master Protocol.
The PK population includes all randomized participants who received a full dose of LY3016859 
at Visit 3 and have at least 1 evaluable PK sample collected prior to dosing at or after Visit 4. 
9.4.
Statistical Analyses
Any change to the data analysis methods described in this ISA will require an amendment only if 
it changes a principal feature of the ISA.  Any other change to the data analysis methods 
described, and the justification for making the change, will be described in the statistical analysis 
plan (SAP) and the clinical study report.  Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
The ISA SAP will be finalized prior to unblinding, and it will include a more technical and 
detailed description of the statistical analyses described in this section.
9.4.1. General considerations
The primary endpoint and analyses have been described in the CPMP Master Protocol. 
CCI
CCI
CCI

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Any borrowing of placebo or treatment effect information will be specified in the ISA SAP.  
Secondary and tertiary/exploratory endpoints and analyses are described in the CPMP Master 
Protocol and CLBP DSA CPMP(2). 
9.4.2.
Other Analyse(s)
9.4.2.1.
Immunogenicity
Treatment-emergent ADAs are defined as participants

with a 2-fold (1 dilution) increase in titer than the minimum required dilution if no ADAs 
were detected at baseline (treatment-induced ADA) or 

with a 4-fold (2 dilutions) increase in titer compared with baseline if ADAs were detected 
at baseline (treatment-boosted ADA).
The frequency and percentage of participants with preexisting ADA and who are TE-ADA+ to 
LY3016859 will be tabulated.  
If neutralizing antibodies are assessed, the distribution of titers and frequency of neutralizing 
antibodies for the TE-ADA+ participants may also be tabulated.
The relationship between the presence of antibodies and PK parameters, PD response, safety, or 
efficacy to LY3016859, may also be assessed.  Additional details may be provided in the SAP.
9.4.2.2.
Pharmacokinetic and Pharmacodynamic Analyses
Pharmacokinetic and pharmacokinetic-pharmacodynamic (PK-PD) analyses may be conducted 
to explore the exposure-response relationships for various PD measures.  The analyses will be 
performed using population analysis software, NONMEM, if data allows.  The version of any 
software used for the analysis will be documented, and the program will meet the sponsor 
requirements of software validation.  It is possible that other validated, equivalent PK software 
programs may be used if appropriate, warranted, and approved by Global PK/PD management.  
Data may be pooled with data from other studies for an integrated PK/PD analysis.  The 
observed serum concentrations for LY3016859 and epiregulin will be reported graphically and 
descriptively.
A limited number of pre-identified individuals independent of the study team may receive access 
to unblinded data, as specified in the unblinding plan, prior to the interim or final database lock, 
in order to initiate the final population PK/PD model development processes.  Information that 
may unblind the study during the analyses will not be reported to study sites or blinded study 
team until the study has been unblinded.
9.5.
Interim Analyses 
An interim analysis may be conducted for internal decision making.  Unblinding details would 
be specified in the unblinding plan section of the SAP or in a separate unblinding document. The 
SAP will describe any interim analyses in greater detail should they occur. 

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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Clinical Laboratory Tests
The CPMP Master Protocol describes tests that may be performed at additional times noted in 
the SoA for this ISA.  This table describes tests unique for ISA BP01.  
Chemistry
Urine Chemistries 
Other Tests
Cystatin-C
Albumin
Immunogenicity
Creatinine
Epiregulin
ACR
LY3016859 
concentration
.
Protein
Urine pregnancy
PCR
Abbreviations: ACR = albumin/creatinine ratio; PCR = protein/creatinine ratio.
Refer to Section 10.3, Appendix 3 for recommended laboratory testing for hypersensitivity 
events.CCI

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10.2.
Appendix 2: Contraceptive Guidance and Collection of Pregnancy 
Information
Women
Women of child-bearing potential may participate in this study.
Women of child-bearing potential must test negative for pregnancy prior to initiation of 
treatment as indicated by a negative serum pregnancy test at the screening visit followed by a 
negative urine pregnancy test within 24 hours prior to exposure.
Women of child-bearing potential who are completely abstinent or in a same sex relationship, as 
part of their preferred and usual lifestyle, must agree to either remain abstinent or stay in a same 
sex relationship without sexual relationships with males.
All other women of child-bearing potential must agree to use two forms of effective 
contraception, where at least one form is highly effective (less than 1% failure rate), for the 
entirety of the study.  
Abstinence or contraception must continue for 90 days after the last dose of intervention.
Acceptable Methods of Contraception
Highly effective methods of contraception (less than 1% failure rate) comprise, but are not 
limited to

combination oral contraceptives 

implanted contraceptives, or 

intrauterine devices. 
Effective methods of contraception comprise but are not limited to diaphragms with spermicide 
or cervical sponges.  
Not Acceptable Methods of Contraception
Use of male and female condoms as a double barrier method is not considered acceptable due to 
the high failure rate when these barrier methods are combined. 
Barrier protection methods without concomitant use of a spermicide are not an effective or 
acceptable method of contraception.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence just for the duration of a trial, and withdrawal are not acceptable 
methods of contraception.
Women not of childbearing potential may participate and include those who 

have a congenital anomaly such as Mullerian agenesis 

are infertile due to surgical sterilization, or 

are post-menopausal.  
Surgical sterilization examples include

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Protocol number H0P-MC-BP01
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
hysterectomy 

bilateral oophorectomy, or 

tubal ligation.  
At least 6 weeks must have passed after surgical bilateral oophorectomy with or without 
hysterectomy, or after tubal ligation.
Post-menopausal is defined as either

a woman at least 40 years of age with an intact uterus, not on hormone therapy, who has 
cessation of menses for at least 1 year without an alternative medical cause, AND a 
follicle-stimulating hormone >40 mIU/mL

a woman 55 or older not on hormone therapy, who has had at least 12 months of 
spontaneous amenorrhea, or

a woman at least 55 years of age with a diagnosis of menopause prior to starting hormone 
replacement therapy.
Men
Men, regardless of their fertility status, must agree to either remain abstinent (if this is their 
preferred and usual lifestyle) or use condoms as well as one additional highly effective method 
of contraception (less than 1% failure rate) or effective method of contraception with non-
pregnant women of child bearing potential partners for the duration of the study and until their 
plasma concentrations are below the level that could result in a relevant potential exposure to a 
possible fetus, predicted to be 6 months after the last dose.
Men with pregnant partners should use condoms during intercourse for the duration of the study 
and until the end of estimated relevant potential exposure to the fetus, predicted to be 6 months 
after the last dose.
Acceptable Methods of Contraception
Highly effective methods of contraception (less than 1% failure rate) comprise, but are not 
limited to

combination oral contraceptives 

implanted contraceptives, or 

intrauterine devices. 
Effective methods of contraception comprise but are not limited to diaphragms with spermicide 
or cervical sponges.  
Men and their partners may choose to use a double–barrier method of contraception that must 
include use of a spermicide.
Other Guidance
Men should refrain from sperm donation for the duration of the study and until their plasma 
concentrations are below the level that could result in a relevant potential exposure to a possible 
fetus, predicted to be 6 months after the last dose. 

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Men who are in exclusively same sex relationships, as their preferred and usual lifestyle, are not 
required to use contraception. 

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Protocol number H0P-MC-BP01
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10.3.
Appendix 3: Recommended Laboratory Testing for Hypersensitivity 
Events 
Recommended laboratory tests should be performed at the time of a systemic hypersensitivity 
event.  The management of the adverse event may warrant laboratory testing beyond that 
described below and should be performed as clinically indicated.
Laboratory testing during a Systemic Hypersensitivity Event is performed to

help characterize and classify systemic hypersensitivity reactions

meet regulatory expectations, and

improve subsequent clinical management by helping to distinguish between the various 
mechanistic bases of anaphylaxis.
If anaphylaxis is suspected or generalized urticaria is present, then
1. obtain a sample within 1 to 2 hours of the event.  
a.
samples may be obtained as late as 12 hours after the event as analytes can remain 
altered for an extended period of time 
2. record the time at which the sample was collected, and
3. obtain a followup sample at the next regularly scheduled visit or after 4 weeks, whichever 
is later.
Laboratory Tests for Hypersensitivity Events
Test
Details
Tryptase
If a tryptase sample is obtained more than 2 hours after the 
event (i.e. within 2 to 12 hours), or is not obtained because 
more than 12 hours have lapsed since the event, then obtain 
urine for NMH testing. 
For tryptase serum samples obtained within 2 to 12 hours 
of the event, urine NMH testing is performed in addition to 
tryptase testing. 
Collect the first void urine following the event.  Obtain a 
follow-up urine for NMH testing at the next regularly 
scheduled visit or after 4 weeks, whichever is later.
ADA
ADA testing should include drug-specific IgE or the BAT. 
The BAT requires a serum sample.
LY3016859 PK concentration
Complement
C3a, C5a
Cytokines
IL-6, IL-1β, IL-10 (or any cytokine panel that includes 
these 3 cytokines)
Abbreviations: ADA = anti-drug antibody; BAT = basophil activation test; IgE = immunoglobulin E; 
IL-1β = interleukin 1 beta; IL-6 = interleukin 6; IL-10 = interleukin 10; NMH = N-methylhistamine; 
PK = pharmacokinetic.
NOTE: All tests will be performed by a Lilly-designated central laboratory.

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10.4.
Appendix 9: Abbreviations
Term
Definition
ADA
anti-drug antibody
AE
adverse event
blinding/masking
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received.
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CLBP
chronic low back pain 
compliance
Adherence to all study-related, good clinical practice, and applicable regulatory 
requirements.
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
DN
diabetic nephropathy
DSA
disease-state addendum
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
GI
gastrointestinal
IB
Investigator’s Brochure
IgG
immunoglobulin G
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
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, 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.
ISA
intervention-specific appendix
IV
intravenous
MOS
margin of safety
NGF
nerve growth factor

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NOAEL
no-observed-adverse-effect level
NRS
Numeric Rating Scale for pain
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
QTc
corrected QT interval
SAE
serious adverse event
SAP
statistical analysis plan
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. 
SoA
schedule of activities
SPF
sun protection factor
TE
treatment-emergent
TE-ADA+
treatment-emergent anti-drug antibody positive
TGF-α
transforming growth factor-α
TKI
tyrosine kinase inhibitors

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11.
References
Juhasz E, Kim JH, Klingelschmitt G, Walzer S. Effects of erlotinib first-line maintenance 
therapy versus placebo on the health-related quality of life of patients with metastatic non-
small-cell lung cancer. Eur J Cancer. 2013;49(6):1205-1215.
Kersten C, Cameron MG. Cetuximab alleviates neuropathic pain despite tumour progression. 
BMJ Case Rep. 2012;2012:bcr1220115374.
Kersten C, Cameron MG, Mjaland S. Epithelial growth factor receptor (EGFR)-inhibition for 
relief of neuropathic pain-A case series. Scand J Pain. 2013;4(1):3-7.
Kersten C, Cameron MG, Laird B, Mjaland S. Epidermal growth factor receptor-inhibition 
(EGFR-I) in the treatment of neuropathic pain. Br J Anaesth. 2015;115(5):761-767.
Martin LJ, Smith SB, Khoutorsky A, Magnussen CA, Samoshkin A, Sorge RE, Cho C, 
Yosefpour N, Sivaselvachandran S, Tohyama S, Cole T, Khuong TM, Mir E, Gibson DG, 
Wieskopf JS, Sotocinal SG, Austin JS, Meloto CB, Gitt JH, Gkogkas C, Sonenberg N, 
Greenspan JD, Fillingim RB, Ohrbach R, Slade GD, Knott C, Dubner R, Nackley AG, 
Ribeiro-da-Silva A, Neely GG, Maixner W, Zaykin DV, Mogil JS, Diatchenko L. Epiregulin 
and EGFR interactions are involved in pain processing. J Clin Invest. 2017;127(9):3353-3366.

Leo Document ID = 96ebf804-6a17-4538-a85c-f74fd23c8922
Approver: 
Approval Date & Time: 08-May-2020 18:23:12 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-May-2020 13:51:53 GMT
Signature meaning: Approved
PPD
PPD