Clinical trial NCT04476108
Conditions: Diabetic Peripheral Neuropathic Pain
Sponsor: Eli Lilly and Company
Start date: 2020-07-15; Completion date: 2021-11-11
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being done to test the safety and efficacy of the study drug LY3016859 for the treatment of diabetic peripheral neuropathic pain. This trial is part of the chronic pain master protocol H0P-MC-CPMP (NCT05986292) which is a protocol to accelerate the development of new treatments for chronic pain.

Detailed description:

Arms: arm 1: Participants received LY3016859 every 2 weeks with 750 mg as starting dose followed by 500 mg intravenous (IV) infusion for a total of 4 doses. arm 2: Participants received LY3016859 every 2 weeks with 750 mg as starting dose followed by 500 mg IV infusion for a total of 4 doses.
Interventions: intervention 1: LY3016859 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol Version (a) H0P-MC-NP01 
 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3016859 for the Treatment of 
Diabetic Peripheral Neuropathic Pain. 
NCT04476108 
Approval Date: 27-Mar-2020 


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP01(a)
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Title Page
Intervention-Specific Appendix (ISA) for LY3016859: H0P-MC-NP01(a)
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 Diabetic Peripheral Neuropathic Pain.
ISA Number: H0P-MC-NP01
Amendment Number: (a)
Compound: LY3016859
Study Phase: 2
Acronym: NP01
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: 27-Mar-2020 GMT


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP01(a)
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Medical Monitor Name and Contact Information will be provided separately.


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP01(a)
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
30 January 2020
Amendment (a)
Overall Rationale for the Amendment:
This amendment addresses Food and Drug Administration (FDA) feedback.
Section # and 
Name
Description of Change
Brief Rationale
Section 1.3. 
Schedule of 
Activities
Addition of visit window for post-
randomization visits
Allows flexibility for participants
Section 1.3. 
Schedule of 
Activities
Included details for vital signs and 
targeted physical examination 
Per regulatory feedback
Section 1.3. 
Schedule of 
Activities
Included additional urine pregnancy 
sample collection and updated 
description of those who would be tested
Per new toxicology data
Section 1.3. 
Schedule of 
Activities
Included additional sample collection 
time for hemoglobin A1c
Sample collection time missed in the original 
version
Section 2.3.1. 
Risk Assessment
Removed language for women of 
childbearing potential and added 
language for fetal exposure
Women of childbearing potential are now allowed 
in the study; pregnant or breastfeeding women are 
not allowed
Section 4 Study 
Design
Amended post-treatment follow-up 
period instructions
Updated to maximize data collection in the follow-
up period
Section 5.1. 
Inclusion Criteria
Removed criterion related to women not 
of childbearing potential
To account for the addition of women of 
childbearing potential to the study per toxicology 
data
Section 5.2. 
Exclusion Criteria
Addition of language related to 
ophthalmologic disease
Per regulatory feedback
Section 5.2. 
Exclusion Criteria
Removed criterion related to abnormal 
thyroid stimulating hormone levels
Covered by the master Protocol H0P-MC-CPMP
Section 5.2. 
Exclusion Criteria
Addition of criterion related to women 
who are pregnant or breastfeeding
Per regulatory feedback
Section 5.3. 
Lifestyle 
Considerations
Removed language about local 
regulations for contraception use by men 
This language is intended for global studies.  This 
study will be conducted in the United States only.
Section 6.1.1. 
Special Treatment 
Considerations
Addition of special treatment 
considerations
Per regulatory feedback
Section 8.1.1. 
Physical 
New section to include details on 
targeted physical examination 
Per regulatory feedback


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Section # and 
Name
Description of Change
Brief Rationale
Examinations
Section 10.2, 
Appendix 2
Addition of definitions and contraceptive 
guidance related to women of 
childbearing potential
To account for the addition of women of 
childbearing potential to the study per toxicology 
data
Throughout the 
protocol
Minor editorial and formatting changes
Minor, therefore not described


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Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.........................................................................................................................9
1.3.
Schedule of Activities (SoA) ........................................................................................9
2.
Introduction..............................................................................................................13
2.1.
Study Rationale ..........................................................................................................13
2.2.
Background ................................................................................................................13
2.3.
Benefit/Risk Assessment ............................................................................................14
2.3.1.
Risk Assessment.........................................................................................................15
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.
Scientific Rationale for Study Design .........................................................................19
4.2.
Justification for Dose..................................................................................................19
4.3.
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...............................................................................23
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..............................................................................28
8.3.
Treatment of Overdose ...............................................................................................28
8.4.
Pharmacokinetics........................................................................................................28


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8.5.
Pharmacodynamics.....................................................................................................29
8.6.
.................................................................................................................29
8.7.
Immunogenicity Assessments.....................................................................................29
9.
Statistical Considerations.........................................................................................30
9.1.
Statistical Hypotheses.................................................................................................30
9.2.
Sample Size Determination.........................................................................................30
9.3.
Populations for Analyses ............................................................................................30
9.4.
Statistical Analyses.....................................................................................................30
9.4.1.
General considerations................................................................................................30
9.4.2.
Other Analyses ...........................................................................................................31
9.5.
Interim Analyses.........................................................................................................31
10.
Supporting Documentation and Operational Considerations ................................32
10.1.
Appendix 1: Clinical Laboratory Tests........................................................................32
10.2.
Appendix 2: Definitions of Reproductive Requirements and 
Contraceptive Guidance..............................................................................................33
10.3.
Appendix 3: Recommended Laboratory Testing for 
Hypersensitivity Events and Infusion-related Reactions..............................................35
11.
References.................................................................................................................36
CCI


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
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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 diabetic peripheral neuropathic pain.  
Rationale:
The purpose of this study is to test whether LY3016859 is efficacious in relieving diabetic 
peripheral neuropathic pain (DPNP).  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 (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.
Objectives and Endpoints
The primary and secondary objectives and endpoints are stated in the master protocol H0P-MC-
CPMP (CPMP) and DPNP disease-state addendum ([DSA] H0P-MC-CPMP[3]).
Overall Design:
This is a 26-week, Phase 2, randomized, double-blind, placebo-controlled study that will 
compare LY3016859 versus placebo in participants with DPNP.
Disclosure Statement: This is a randomized, investigator- and participant-blind, placebo-
controlled, Phase 2 clinical trial.
Number of Participants:
Approximately 125 participants will be randomly assigned to study intervention (84 LY3016859 
and 41 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 (IV) infusion every 2 weeks for a total of 4 infusions.


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
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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
Participants will be monitored for at least 4 hours after completion of the infusion.
Data Monitoring Committee: Yes


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1.2. 
Schema 
 
 
* Medication washout and preliminary data entry period 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. 
 
1.3. 
Schedule of Activities (SoA) 
This SoA shows visits and procedures unique to the intervention-specific appendix (ISA) H0P-MC-NP01 (NP01) for LY3016859.  
Please refer to master protocol H0P-MC-CPMP (CPMP) and the diabetic peripheral neuropathic pain (DPNP) disease-state addendum 
(DSA) H0P-MC-CPMP(3) SoAs for additional information.   
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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H0P-MC-NP01  
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 V3-6. 
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. 


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
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H0P-MC-NP01  
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. 
BPI 
 
 
 
 
 
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 randomization 
Urine drug 
screen 
X 
 
X 
 
X 
 
 
 
 
 
Hemoglobin 
A1c 
X 
 
 
 
X 
 
 
X 
X 
 


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
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H0P-MC-NP01  
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 
V3-6:  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 
V3-6:  collect sample before IV infusion starts 
Epiregulin 
sample 
X 
X 
X 
 
X 
X 
X 
X 
X 
V3-6:  collect samples before IV infusion starts. 
V7-V803: single sample collected at any time to 
match PK. 
 
 
Abbreviations:  ADA = anti-drug antibody; BPI = Brief pain inventory-modified short form; C-SSRS = Columbia Suicidal Severity Rating Scale; ECG = 
electrocardiogram; GI = gastrointestinal; IV = intravenous; NRS = Numeric Rating Scale for pain; PGI = Patient Global Impression of Change; PK = 
pharmacokinetic; V = visit.    
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2.
Introduction
This ISA NP01 is an appendix to the master protocol CPMP and contains unique study elements 
specific for LY3016859.  The master protocol contains the overarching study elements that 
govern the DPNP DSA CPMP(3) and this ISA NP01.  
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 al. 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 DPNP.  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.
2.2.
Background
LY3016859 was initially developed for the treatment of diabetic nephropathy 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.


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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, and 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).
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.


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2.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk 
Mitigation Strategy
Study Intervention LY3016859
Development of treatment-emergent 
anti-drug antibodies (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 diabetic nephropathy (DN)
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 
renal impairment in the study.
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 pain symptoms.
Medications other than those 
permitted per protocol will not be 
allowed until Visit 801.
Rescue medication is permitted.
Standard treatment of pain may be 
restarted after Visit 801 based on 
investigator discretion.
Abbreviations:  ADA = anti-drug antibodies; AE = adverse events; 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.
CCI


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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)

detailed evaluations of diabetic nerve pain 

questionnaires that may improve participants understanding their own condition. 
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 DPNP.  In addition, data collected 
from this study may also improve our understanding of DPNP pathogenesis.  Both of which may 
lead to the development of 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 NP01 are justified by the anticipated benefits to participants with DPNP.


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3.
Objectives and Endpoints
The master protocol CPMP and DPNP DSA CPMP(3) include objectives and endpoints 
applicable for this study.  This table describes objectives and endpoints specific for LY3016859.
Objectives
Endpoints
Tertiary/Exploratory
Characterize the pharmacokinetics and 
pharmacodynamics of LY3016859 after multiple 
intravenous infusions in participants with diabetic 
peripheral neuropathic pain
Assessment of serum concentrations of LY3016859 
and epiregulin to enable pharmacokinetic and 
pharmacodynamic 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:  eGFR = estimated glomerular filtration rate.


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4.
Study Design
Protocol CPMP describes the overall study design and study design rationale.  This section 
describes visits and overall procedures unique to ISA NP01 for LY3016859 in addition to the 
procedures outlined in CPMP and CPMP(3).  
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 NP01 baseline procedures and sample collection 

participants receive their first dose of study intervention via 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 SoAs

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 and immunogenicity 
assessment at Visits 801-803, according to the SoA.
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. 


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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 
protocol SoA and Visit 801 should be scheduled approximately 30 days after the last dose of 
study intervention.
4.1.
Scientific Rationale for Study Design
The 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. 
4.2.
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 
Investigator’s Brochure. 
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 (Table 4.5 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 DPNP, then this level of target engagement 
is expected to enable analgesic efficacy.   
4.3.
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 Schedule of 
Activities.
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 Schedule of Activities for the last participant.
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5.
Study Population
The master protocol CPMP and DPNP DSA CPMP(3) 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:
[3000]
are men or women who abide by the reproductive and contraceptive requirements 
provided in NP01 Section 10.2, Appendix 2
[3001]
are willing to discontinue all pain medications for condition under study except 
rescue medication permitted per protocol until V801 in the follow-up period
[3002]
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
[3003]
Have an eGFR of less than 70 ml/min/1.73m2 based on CKD-EPI formula at Visit 1 
or Visit 2
[3004]
Have any clinically serious or unstable cardiovascular, musculoskeletal disorder, 
gastrointestinal, endocrinologic, hematologic, hepatic, metabolic, urologic, 
pulmonary, dermatologic, immunologic, or ophthalmologic disease within 3 months 
of Visit 3
[3005]
have megaloblastic anemia or combined degeneration of the spinal cord
Prior/Concomitant Therapy
[3006]
have received any antibodies against nerve growth factor (NGF), or antibodies 
against EGFR, or EGFR tyrosine kinase inhibitors.
[3007]
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.
[3008]
have a history or presence of uncontrolled asthma, eczema, significant atopy, 
significant hereditary angio-edema or common variable immune deficiency, and
Reproductive
[3009]
are 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 NP01 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.
Diet and Activities
Participants are required to maintain a similar diet and levels of activity during the double-blind 
study period.  Starting a new diet or exercise program or new strenuous activity is not allowed.  
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 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.  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 reconstituted with sterile water
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 and NIMP
IMP and NIMP
Sourcing
LY3016859 from Lilly
If needed, saline for reconstitution of IMP will be site 
sourced
Placebo will be procured, packaged, 
labeled, distributed and dispensed as 
IMP by Lilly
Packaging and 
Labeling
The lyophilized powder and sterile diluent for 
infusion will be provided in separate glass vials. Each 
vial will be labeled as required per country 
requirement
Placebo will be provided in a glass 
vial. Each vial will be labeled as 
required per country requirement
Abbreviations:  IMP = investigational medicinal product; NIMP = non-investigational medicinal product.


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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).
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. 


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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 
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 and NP01 
SoAs.
6.2.
Preparation/Handling/Storage/Accountability
Study intervention and placebo require refrigeration.
Study intervention and placebo will be prepared and verified by unblinded site personnel.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Stratification Variables
Estimated GFR will be used for stratification to ensure a balanced number of participants for 
analysis of renal effects.  Measurements will be collected at Visit 2 and the subsets are

greater than or equal to 90, and

less than 90. 
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 DPNP, 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
Protocol CPMP 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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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the protocol CPMP, DPNP DSA CPMP(3), 
and ISA NP01 SoAs. 
LY3016859 specific assessments and procedures are described here. 
8.1.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.1.1.
Physical Examinations
Targeted physical examinations of skin, eyes, month, 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 QTc.
8.1.3.
Clinical Safety Laboratory Assessments
See NP01 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 NP01.
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 NP01 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.  
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 NP01 


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Section 10.3, Appendix 3, “Recommended Laboratory Testing for Hypersensitivity Events”.  
Laboratory results are provided to the sponsor via the central laboratory.


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8.2.3. Adverse Events of Special Interest 
Dermatological adverse reactions
EGFR antibodies or EGFR-associated tyrosine kinase inhibitors are associated with various 
dermatological AEs, including acneiform rashes, xerosis, pruritis, and photosensitivity. 
Secondary infection can also develop. 
Participants should use sun protection for the duration of the study.  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 or 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 diabetic nephropathy in study TGAB 
(Section 2.2).  Such changes were reversible and were not associated with 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 of approximately 4 mL 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.
 
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8.5.
Pharmacodynamics
Venous blood samples of approximately 4 mL each will be collected for the measurement 
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 
treatment-emergent (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 protocol CPMP, Appendix 1, Section 10.1.12.
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9.
Statistical Considerations
The master protocol and DPNP DSA provide statistical considerations.  LY3016859 specific 
considerations are described here. 
9.1.
Statistical Hypotheses
The master protocol CPMP describes the primary hypothesis.  
 
.
9.2.
Sample Size Determination
Approximately 125 participants will be randomized in a 
 ratio to LY3016859 and placebo, 
respectively. It is expected that approximately 107 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 approximately 0.06. 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 protocol CPMP.
The pharmacokinetic 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 protocol CPMP. 
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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 protocol CPMP and 
DSA CPMP(3). 
9.4.2.
Other Analyses 
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 
positive (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 (PKPD) analyses may be conducted to 
explore the exposure-response relationships for various pharmacodynamics 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 
Lilly requirements of software validation. It is possible that other validated, equivalent PK 
software programs may be used if appropriate, warranted, and approved by Global PKPD
management.  Data may be pooled with data from other studies for an integrated PKPD 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 PKPD 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 to plan 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 master protocol CPMP describes tests that may be performed at additional times noted in the 
SoA for this ISA.  This table describes tests unique for ISA NP01.  
Chemistry
Urine Chemistries
Other Tests
Cystatin-C
Albumin
Immunogenicity
Creatinine
Epiregulin
Albumin/creatinine 
ratio (ACR)
LY3016859 
concentration
Protein
Urine pregnancy
Protein/creatinine 
ratio (PCR)
Refer to Section 10.3, Appendix 3 for recommended laboratory testing for hypersensitivity 
events.
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10.2.
Appendix 2: Definitions of Reproductive Requirements and 
Contraceptive Guidance
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

hysterectomy 


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


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10.3.
Appendix 3: Recommended Laboratory Testing for Hypersensitivity 
Events and Infusion-related Reactions
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 follow up 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 N-methylhistamine (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.
Anti-drug antibody (ADA)
ADA testing should include drug specific IgE or the 
basophil activation test (BAT).  The BAT requires a serum 
sample
LY3016859 pharmacokinetic concentration
Complement
C3a, C5a
Cytokines
IL-6, IL-1β, IL-10 (or any cytokine panel that includes 
these 3 cytokines)
All tests will be performed by a Lilly-designated central laboratory.


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP01(a)
36
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. 
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 = 673e7b7f-a892-4ab1-b712-31e1550cddf0
Approver: 
Approval Date & Time: 27-Mar-2020 14:39:21 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 27-Mar-2020 20:24:11 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan Version 3 H0P-MC-NP01 
 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3016859 for the Treatment of 
Diabetic Peripheral Neuropathic Pain. 
NCT04476108 
Approval Date: 16-Dec-2021 


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1.
Statistical Analysis Plan:  
H0P-MC-NP01: Intervention-Specific Appendix (ISA) for 
LY3016859
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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.
Epiregulin/TGFα (LY3016859) Pain for the Treatment of Diabetic Peripheral 
Neuropathic Pain
This is a randomized, placebo-controlled, phase 2 clinical trial to evaluate LY3016859 for 
the treatment of pain in participants who have been diagnosed with diabetic peripheral 
neuropathic pain.   
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol H0P-MC-NP01
Phase 2
Statistical Analysis Plan electronically signed and approved by Lilly on date provided below.
Approval Date: 16-Dec-2021 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   H0P-MC-NP01: Intervention-Specific 
Appendix (ISA) for LY3016859..........................................................................................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.......................................................................................................................8
5.1.
Summary of Study Design..............................................................................................8
5.2.
Determination of Sample Size ........................................................................................8
5.3.
Method of Assignment to Treatment ..............................................................................8
6.
A Priori Statistical Methods ................................................................................................9
6.1.
General Considerations ..................................................................................................9
6.2.
Adjustments for Covariates ............................................................................................9
6.3.
Handling of Dropouts or Missing Data...........................................................................9
6.4.
Multiple Comparisons/Multiplicity.................................................................................9
6.5.
Use of an “Efficacy Subset” of Participants....................................................................9
6.6.
Participant Disposition ...................................................................................................9
6.7.
Participant Characteristics..............................................................................................9
6.8.
Treatment Compliance .................................................................................................10
6.9.
Concomitant Therapy...................................................................................................10
6.10. Efficacy Analyses ........................................................................................................10
6.10.1.
Primary Outcome and Methodology.....................................................................10
6.10.2.
Additional Analyses of the Primary Outcome.......................................................10
6.10.3.
Secondary Efficacy Analyses ...............................................................................10
6.11. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................12
6.12. Safety Analyses............................................................................................................12
6.12.1.
Extent of Exposure...............................................................................................12
6.12.2.
Adverse Events ....................................................................................................13
6.12.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................13
6.12.4.
Clinical Laboratory Evaluation.............................................................................14
6.12.5.
Immunogenicity...................................................................................................15
6.12.6.
Vital Signs and Other Physical Findings...............................................................15


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6.12.7.
Electrocardiograms ..............................................................................................15
6.13. Subgroup Analyses.......................................................................................................15
6.14. Protocol Deviations......................................................................................................15
6.15. and H0P-MC-NP01 Trial Issue Management Plans.Interim 
Analyses and Data Monitoring .....................................................................................16
6.16. Planned Exploratory Analyses......................................................................................16
6.17. Totality of Evidence for Efficacy..................................................................................16
6.18. Totality of Evidence for Safety.....................................................................................16
6.19. Annual Report Analyses...............................................................................................17
6.20. Clinical Trial Registry Analyses...................................................................................18
7.
Unblinding Plan................................................................................................................19
8.
Reports to be Generated at Final Database Lock................................................................20
9.
References ........................................................................................................................22
10.
Appendices .......................................................................................................................23


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Table of Contents
Appendix
Page
Appendix 1.
Planned Laboratory Analytes and Direction of Interest ..................................24


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3.
Revision History
SAP Version 1 was approved prior to unblinding data for H0P-MC-NP01. 
SAP Version 2 was approved prior to unblinding H0P-MC-NP01 data for the PoC lock. The 
following updates were made. 

Section 4.2, for physical functioning objectives, total interference score was replaced 
with mean interference score and mean severity score was added. Proportion of 
participants with reduction from baseline was updated to at least (≥) instead of greater 
than (>) 30/50/70%. 

Section 6.10.3, the details for the constrained model for the secondary endpoint were 
added. The language for categorical endpoint analysis was updated to match the CPMP 
SAP. Proportion of participants with reduction from baseline was updated to at least (≥) 
instead of greater than (>) 30/50/70%.

Section 6.17, a new section was added to describe the update in the totality of evidence 
analysis for efficacy data. 

Section 6.18, a new section was added to describe the totality of evidence analysis for 
safety data.
SAP Version 3 was approved prior to the final lock. The following updates were made: 

Section 6.2, eGFR is mentioned as a stratification factor, with rationale for why it will not 
be included as a covariate in models for efficacy outcomes.

Section 6.11, bioanalytical and pharmacokinetic/pharmacodynamic analysis was updated.

Section 6.12.2, definition for post-treatment-emergent adverse events was updated.

Section 6.12.4, the analysis for renal function assessment was updated.

Section 6.12.5, immunogenicity analysis was added.

Section 6.14, ‘violations’ is replaced with ‘deviations’ for consistency across CPMP
documents, and the list of IPDs is referenced in the trial issue management plan. The
prohibited medications and drugs of abuse list was moved to the CPMP SAP because it
applies across all ISAs, and acetylsalicylic acid was added to the list of prohibited
medications.

Section 7, text on maintaining the blind for assessment committee review was deleted
from NP01 SAP V3 since it is covered in H0P-MC-CPMP SAP Version 5.

Section 8, additional analyses for the double-blinded treatment and safety follow-up
period combined was added for the final lock.


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of this ISA is stated in the H0P-MC-CPMP protocol. For H0P-MC-NP01, 
endpoint is defined as 8 weeks post initial treatment administration. 
4.2.
Secondary Objectives
Secondary objectives applicable to all ISAs are listed in the H0P-MC-CPMP SAP Version 5. 
Additional secondary endpoints specific to H0P-MC-NP01 are listed below. 
Objective
Endpoint Measure
Other Secondary
Physical Functioning
Efficacy of LY3016859 versus 
placebo 

Mean change from baseline to endpoint for the Brief Pain Inventory-Short Form 
(BPI-SF) for the 
o
Mean interference score
o
Mean severity score
o
Individual severity scores
o
Individual interference scores

Proportion of participants with reduction from baseline ≥30%, 50%, and 70% 
on BPI-SF for the 
o
Mean interference score
o
Mean severity Score
o
Individual severity scores
o
Individual interference scores
4.3.
Exploratory Objectives
The following exploratory objectives and endpoints are specific to H0P-MC-NP01.
Objectives
Endpoints
Tertiary/Exploratory
Characterize the pharmacokinetics and pharmacodynamics of 
LY3016859 after multiple intravenous infusions in 
participants with diabetic peripheral neuropathic pain
Assessment of serum concentrations of LY3016859 and 
epiregulin to enable pharmacokinetic and pharmacodynamic 
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


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Abbreviations:  eGFR = estimated glomerular filtration rate.


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5.
Study Design 
5.1.
Summary of Study Design
The H0P-MC-CPMP SAP Version 5 provides a summary of the overall study design for the 
chronic pain master protocol. This section describes ISA-specific study design components.
Post-treatment Follow-up Period (Visits 801-803) 
Participants must complete 3 post-treatment follow-up visits for safety, PK and immunogenicity 
assessment at Visits 801-803, according to the Schedule of Activities (SoA).
The site schedules Visit 801 approximately 4 weeks after Visit 7, Visit 802 approximately 8 
weeks after Visit 7, and Visit 803 approximately 18 weeks after Visit 7. 
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 
Protocol SoA and Visit 801 should be scheduled approximately 30 days after the last dose of 
study intervention.
5.2.
Determination of Sample Size
Approximately 125 participants will be randomized in a 
 ratio to LY3016859 and placebo, 
respectively. It is expected that approximately 107 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 approximately 0.06. The simulation for the power 
calculation and sample size determination was carried out in FACTS Version 6.0.
5.3.
Method of Assignment to Treatment
The method of treatment assignment is described in the H0P-MC-CPMP SAP Version 5. 
CCI
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6.
A Priori Statistical Methods
6.1.
General Considerations
The estimand for the primary clinical question of interest has been described in the H0P-MC-
CPMP SAP Version 5.   
Other general considerations for analyses are described in the H0P-MC-CPMP SAP Version 5.
6.2.
Adjustments for Covariates
The general adjustment strategy has been described in the H0P-MC-CPMP SAP Version 5. 
Randomization into H0P-MC-NP01 is stratified by estimated GFR, to ensure a balanced number 
of participants for analysis of renal effects.
The subsets are below, using the most recent of the Visit 1 or Visit 2 measurements:

greater than or equal to 90, and

less than 90.
This stratification factor will not be included in models for efficacy outcomes because this 
stratification was performed for safety reasons only.
6.3.
Handling of Dropouts or Missing Data
The missing data strategy has been described in the H0P-MC-CPMP SAP Version 5. 
6.4.
Multiple Comparisons/Multiplicity
There is no plan to formally adjust for multiplicity. 
6.5.
Use of an “Efficacy Subset” of Participants
There are no plans to use a modified efficacy subset. 
6.6.
Participant Disposition
The summary of participant disposition has been described in the H0P-MC-CPMP SAP Version 
5.
6.7.
Participant Characteristics
The summary of participant characteristics has been described in the H0P-MC-CPMP SAP
Version 5. 
ISA-specific considerations are described below. 

Michigan Neuropathy Screening Instrument
o
Part A - history subscale (<7 vs ≥ 7)
o
Part B - physical assessment subscale (<3 vs ≥ 3). 


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6.8.
Treatment Compliance
To assess the impact of compliance to the protocol specified dosing schedule, the number of days 
between each infusion will be summarized and reported by treatment arm. The summaries will 
include descriptive statistics (sample size at visit, mean, SD, median, minimum, maximum). No 
inferential statistics will be reported. 
6.9.
Concomitant Therapy
The summary and reporting of concomitant therapy has been described in the H0P-MC-CPMP 
SAP Version 5. No additional covariates will be considered in the models of weekly rescue 
medication use. 
6.10. Efficacy Analyses
6.10.1. Primary Outcome and Methodology
The analysis of the primary outcome has been described in the H0P-MC-CPMP SAP Version 5. 
The longitudinal model will include average NRS during the preliminary data entry period 
(PDEP) period and within each nominal week of the double treatment period as a longitudinal 
outcome. As noted in Section 4.1, endpoint for the primary analysis is defined as 8 weeks post 
initial treatment administration. 
6.10.2. Additional Analyses of the Primary Outcome
There are no additional analyses planned for the primary outcome. 
6.10.3. Secondary Efficacy Analyses
Secondary efficacy analyses common to all ISAs within H0P-MC-CPMP have been described in
the H0P-MC-CPMP SAP Version 5. H0P-MC-BP01 will also consider the following secondary
analyses.
The BPI-SF is a numeric rating scale that assesses the severity of pain (severity scale), its impact 
on daily functioning (interference scale), and other aspects of pain (for example, location of pain, 
relief from medications) in various disease states (Cleeland and Ryan 1994). 
This table describes the pain scales and corresponding numeric rating scale used in a modified 
version of the BPI, validated for pain in diabetic polyneuropathy.  Participants will rate their pain 
severity and how, during the past 24 hours, the pain has interfered with the activities described in 
this table.  
Assessment
Topic
Numeric Rating Scale 0-10
4-item Pain severity

Worst pain in last 24 hours

Least pain in the last 24 
hours

Average pain

Pain right now
0 = no pain
10 = pain as bad as you can 
imagine
7-item Pain interference

General Activity

Mood
0 = does not interfere
10 = completely interferes


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
Walking ability

Normal work

Relations with others

Sleep

Enjoyment of life
A Bayesian longitudinal mixed-effect model for repeated measures (MMRM) analysis will be 
performed to evaluate the change from baseline to each postbaseline visit for the mean pain 
interference scale and the mean pain severity scale. The model will utilize the constrained cell 
means model so that a common mean is estimated at the baseline. More details on this approach 
are provided in the H0P-MC-CPMP SAP Version 5.
Additional Bayesian MMRM analyses will be used to analyze the change from baseline to each 
postbaseline visit for 

individual pain interference and 

individual pain severity scales.
This table describes information included in the model.  
Categorical effects

the interaction of treatment and visit
(constrained to estimate a common mean at 
baseline across treatments)

average baseline pain severity category 
(baseline NRS < 7, baseline NRS ≥ 7)

pooled investigative site
Continuous covariates

None  
Abbreviation:  BPI-SF = Brief Pain Inventory–Modified Short form.
Other Secondary Analysis
The proportion of participants in each treatment group meeting prespecified binary efficacy 
outcomes will be calculated for each post baseline time point and will be used to compare 
treatment groups.  The prespecified binary efficacy outcomes include the proportion of 
participants:

with a reduction of at least 30%, 50%, and 70% from baseline as measured by the 
mean pain interference score, and

with a reduction of at least 30%, 50%, and 70% from baseline as measured by the 
mean pain severity score, and

with a reduction of at least 30%, 50%, and 70% from baseline as measured by the 
individual interference scores.

with a reduction of at least 30%, 50%, and 70% from baseline as measured by the 
individual severity scores.


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A Bayesian pseudo-likelihood-based categorical repeated measures model will be used to 
estimate the proportion of participants in each treatment group meeting the prespecified 
threshold for each postbaseline time interval up to week 8 (or visit up to visit 7). These estimates 
will be used to compare treatment groups. More details on this approach are provided in the 
H0P-MC-CPMP SAP Version 5.
In addition, time to first treatment response from baseline based on the prespecified binary 
thresholds above will be assessed. Analyses will be conducted according to the time to event 
analyses specified in the CPMP SAP Version 5.
6.12. Safety Analyses
The general analysis of safety has been described in the H0P-MC-CPMP SAP Version 5.
However, additional ISA-specific safety considerations are described in the sections below. 
6.12.1. Extent of Exposure
The cumulative dosage taken during the double-blind treatment period will be summarized. In 
addition, the distribution of the number of doses received during the double-blind treatment 
period will be summarized by reporting the number and percent of participants in the safety
population who received 1, 2, 3, or 4 infusions during the double-blind treatment period.
Duration of exposure to study drug (defined as the time since first injection of the study 
treatment in days) will be summarized by treatment group using descriptive statistics; the 
summary will also include the total exposure in patient years.
Duration of exposure (days):
= Date of last study visit (scheduled or unscheduled) during the double blind treatment period –
Date of first injection of the study treatment + 1
Total exposure in patient years will be calculated as follows:
Total exposure in patient years = Sum of duration (days) of exposures for all patients in the
treatment group/365.25
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6.12.2. Adverse Events
The general analysis of adverse events has been described in the H0P-MC-CPMP SAP Version 
5. 
This ISA will also consider post-treatment-emergent adverse events due to the long follow-up 
period. 
A post-treatment-emergent adverse events (PTEAE) is defined as an event that first occurs or 
worsens in severity after treatment discontinuation and on or before study discontinuation. The
Medical Dictionary for Regulatory Activities (MedDRA) Lowest Level Term (LLT) will be used
in the post-treatment-emergent computation. The maximum severity for each LLT during the
treatment period will be used as a reference. 
The baseline of PTEAE is from the first dosing date to the treatment disposition in the double-
blind treatment phase. The post-treatment follow-up period will be included as postbaseline for
this analysis. While unusual, it is possible to have a missing severity for events. Events with a 
missing severity during the post-treatment period will be treated as “severe” and post-treatment 
emergent events will be determined by comparing with treatment period. All events occurring
after the day of treatment discontinuation will be treated as post-treatment period.
PTEAEs will be summarized by preferred term and by preferred term within system organ class 
in participants who received LY3016859.
6.12.3. Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events
The general summary of adverse of events is described in the H0P-MC-CPMP SAP Version 5.
Treatment emergent adverse events of special interest will be reported separately by preferred 
term. These events include

infusion site reactions (preferred MedDRA term) 

hypersensitivity and infusion-related reactions
o
Anaphylatic reaction (SMQ)
o
Anaphylatic/anaphylactoid shock conditions (SMQ)
o
Angioedema (SMQ)
o
Hypersensitivity (SMQ)
o
Infusion-related reaction (preferred MedDRA term) 

dermatological adverse events
o
Severe cutaneous adverse reactions (SMQ)
o
Drug reaction with eosinophilia and systemic symptoms syndrome (SMQ)

abnormal renal function
o
Renal function analyses (MedDRA HLT)
o
Renal failure and impairment (MedDRA HLT)


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6.12.5. Immunogenicity
To evaluate the changes in immunogenicity data (Anti-LY3016859 Antibody (hereafter “Anti-
Drug Antibody (ADA),” Neutralizing ADA (hereafter “Neutralizing Antibody (NAb)”) after
treatment, the following statistical analyses are planned for comparison between treatment
groups. A participant is evaluable for treatment-emergent ADA (TE ADA) if the participant has
a non-missing baseline ADA result, and at least one non-missing postbaseline ADA result.

Number and percentage of patients with TE ADA+ will be summarized in the double-
blind treatment and safety follow-up period combined. The baseline is last non-missing 
result prior to the first dose and postbaseline is any measurement after Visit 3. TE ADA+
will be defined as any of the following:
o
treatment induced response: a postbaseline titer ≥ 2-fold the minimum required
dilution, titer 1:10, if the baseline status is not detected (i.e., titer less than the
minimum required dilution)
o
treatment boosted response: a postbaseline titer ≥ 4-fold of the baseline titer if the
baseline status is detected. For an example, 1:20 at baseline and 1:80 post baseline 
is treatment boosted. If baseline ADA result is detected and no titer is reported, a 
titer of 1:10 is assumed for the determination of TE ADA status.

A shift table of ADA results from maximum ADA titer at baseline to maximum ADA
titer at any postbaseline visit will be provided for LY-treated patients.
A listing of results at each visit will be provided, including ADA status (detected/not detected),
the titer for detected samples, and NAb status, for participant with ADA detected at any time.
6.12.6. Vital Signs and Other Physical Findings
The analysis of vital sign parameters is described in the H0P-MC-CPMP SAP Version 5.
6.12.7. Electrocardiograms
The analysis of electrocardiograms parameters is described in the H0P-MC-CPMP SAP Version 
5.
6.13. Subgroup Analyses
General subgroup analyses are described in the H0P-MC-CPMP SAP Version 5. There are no 
additional subgroup analyses planned. 
6.14. Protocol Deviations
Participants with study important protocol deviations will be summarized by type of deviation
and listed by treatment and investigative site.
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Important protocol deviations for the study are described in the H0P-MC-CPMP SAP Version 5
6.15. and H0P-MC-NP01 Trial Issue Management Plans.Interim 
Analyses and Data Monitoring 
Interim analyses may be conducted under the auspices of an Assessment Committee according to 
the specifications set forth in the protocol. These analyses will be at the CPMP level and will 
consider data from all ongoing ISAs. Details are provided in the H0P-MC-CPMP SAP Version 
5. 
There are no additional interim analyses planned for H0P-MC-NP01. 
6.16. Planned Exploratory Analyses
A cumulative distribution function of percent change from baseline to endpoint for the following
BPI-SF scores will be provided for each treatment group.

Mean interference score

Mean severity score

Individual severity scores

Individual interference scores
However, no statistical comparisons will be made between the groups. 
6.17. Totality of Evidence for Efficacy
The totality of evidence analysis approach for efficacy data has been described in the H0P-MC-
CPMP SAP Version 5. However, for this ISA, physical function will be assessed by Brief Pain 
Inventory - Mean Pain Interference Score instead of the Brief Pain Inventory - Total Pain 
Interference Score.
6.18. Totality of Evidence for Safety 
The totality of evidence analysis approach for safety data has been briefly described in the H0P-
MC-CPMP SAP Version 5. The key safety events to be considered for H0P-MC-NP01 are listed 
below by domain:
General Adverse Event Information

Serious adverse events related to study treatment  

Study discontinuation due to adverse event

Treatment discontinuation due to adverse event 
Cardiovascular

QTc prolongation: > 60 msec increase

Serious cardiac disorders adverse event
Liver function


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
Hy’s Law case: Serum total bilirubin ≥ 2 and ALT ≥ 3 at anytime during the double-blind 
treatment period
Metabolic function

Serious hypoglycemia adverse event 

Treatment emergent HbA1c:
o
Shift from low/normal at baseline to high at anytime during the double-blind 
treatment period or shift from high at baseline to high if the change was ≥0.005 
fraction of 1 (0.5%).
Renal function

Treatment emergent abnormal eGFR: Shifts
o
Stage 1 or 2 at baseline to Stage 3a or above at anytime during the double-blind 
treatment period
o
Stage 3a at baseline to Stage 3b or above at anytime during the double-blind 
treatment period
o
Stage 3b at baseline to Stage 4 or above at anytime during the double-blind 
treatment period
o
Stage 4 at baseline to Stage 5 at anytime during the double-blind treatment period
Dermatological

Serious or severe dermal reactions 
Hypersensitivity

Moderate to severe infusion site reactions 

Serious or severe hypersensitivity reactions
6.19. Annual Report Analyses
Analyses will be produced as needed for the purposes of providing periodic safety reviews to 
regulatory agencies (e.g. Development Safety Update Reports.) Data from this ISA will be 
combined with data from other clinical studies that investigated LY3016859. In all analyses, a 
combined LY arm will be created which includes participants assigned to any dose of 
LY3016859 in the included studies, including LY-combination regimens.
The following data will be summarized by treatment group. 

Enrollment (ongoing and completed) 

Demographics (Race, ethnicity, and gender) 

Exposure
o
Cumulative number of subjects exposed to LY3016859
o
Cumulative number of subjects exposed to LY3016859 by age 
o
Cumulative number of subjects exposed to LY3016859 by sex 


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o
Cumulative number of subjects exposed to LY3016859 by race

Cumulative summary of serious adverse events
The following listings will be provided. 

List of serious adverse events during the reporting period 

List of subjects who died

Cumulative list of subjects who discontinued due to an adverse event (discontinued from 
treatment or study) 

List of subjects who discontinued due to an adverse event during the reporting period 
Additional analyses may be added or omitted at the time of report submission as needed. 
6.20. 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.

A serious adverse event is an adverse event that 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 participants 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. 
A summary of a baseline characteristics XML file will be provided.


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7.
Unblinding Plan
The general unblinding plan is described in the H0P-MC-CPMP SAP Version 5. Unblinding 
considerations specific to H0P-MC-NP01 are provided below. 
Immunogenicity Analysis Planning
To support the assessment committee’s evaluation of immunogenicity, a limited number of 
preidentified individuals may also gain access to the unblinded data. The project statistician will 
work with the clinical immunogenicity scientist and clinical lab data scientist to determine an 
appropriate amount of ISA-level data to support this objective. The timing of the transfer of 
treatment assignment and immunogenicity data will be based on this collaboration. Information 
that may unblind the study during the analyses will not be reported to study sites or the blinded 
study team until the study has been unblinded.


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8.
Reports to be Generated at Final Database Lock
The following analysis will be performed for final database lock.

Patient disposition - the analysis of patient disposition conducted in POC lock will be
conducted in the double-blind treatment and safety follow-up period combined (DB plus 
FU).

eCOA compliance - the overall eCOA compliance analysis conducted in POC lock will
be summarized for the PDEP period plus at each nominal week up to Visit 801.

Concomitant therapy – the analysis conducted in POC lock will be repeated for DB plus 
FU period (may also include PDEP) except the listing of rescue medication use above 
protocol specified limits.

Efficacy endpoint – The weekly average pain intensity via NRS will be calculated with
extension to week 12 (Visit 801). The following analysis will be conducted across all
time points in DB plus FU based on the same model conducted in DB treatment period 
only. Nominal weeks 9-12 in the follow-up period will be derived in a similar way as 
described in section 6.12.1 of the H0P-MC-CPMP SAP Version 5, except that the days 
between V7 and V801 are split across 4 weeks.
o
Change from baseline in average pain intensity measured by weekly average of
NRS
o
Change from baseline in worst pain intensity measured by weekly average of
NRS
o
Change from baseline in DSA-specific physical functioning measures
o
Proportion of participants with a pain reduction from baseline greater than or
equal to 30%, 50%, and 70% as measured by the average pain responses on the
NRS
o
Proportion of participants with reduction from baseline greater than or equal to 
30%, 50%, and 70% on DSA-specific physical function subscale
o
Overall improvement as Measured by Patients’ Global Impression of Change
(PGI)
A frequentist MMRM analysis will be conducted as a sensitivity analysis for the
primary and some secondary endpoints.
A Bayesian MMRM subgroup analysis of baseline pain severity (<7, >=7) will be also 
evaluated for the primary endpoint. A frequentist MMRM analysis will be performed as 
a sensitivity analysis for subgroup analysis.

Safety analyses for TEAEs – the following analysis will be repeated including double 
blind and safety follow-up period unless otherwise specified.
o
Overview of adverse event, a listing of AE (also include PDEP)
o
SAE and a listing of SAE
o
TEAE and post-treatment-emergent adverse event (PTEAE) by PT, by PT within 
SOC, and PT by maximum severity. A listing of TEAE and PTEAE will be 
provided.


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o
Post-treatment emergent AE by PT, by PT within SOC for safety follow-up 
period only
o
Adverse event of special interest (ISA specific)

Laboratory measures – the analysis conducted in POC lock will be repeated in DB plus 
FU period. The additional analysis will be included
o
Summary of laboratory measures with box plot for observed value and change 
from baseline by visit, and shifts to high/low.
o
The shift table of eGFR at baseline vs. postbaseline by minimum, maximum and
last observed eGFR result will be summarized. 
o
Summary of hepatic function laboratory maximum observed result at baseline and 
any postbaseline will be presented.

Vital signs – some analysis conducted in POC lock will be repeated for combined DB 
plus FU period.

ECG - some analysis conducted in POC lock will be repeated for combined DB plus FU 
period. Additionally, a summary of ECG measures and boxplot will be provided as well 
as a listing of out of range of ECGs.

Protocol deviations – summary of important protocol deviation will be conducted for 
combined DB plus FU period.


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9.
References
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med 
Singapore. 1994 Mar;23(2):129-138.
Inker L.A., Schmid C. H., Tighiouart H., Eckfeldt J.H., Feldman H.I., Greene T., Kusek J.W., 
Manzi J., Van Lente F., Zhang Y., Coresh J., and Levey A.S. Estimating Glomerular Filtration 
Rate from Serum Creatinine and Cystatin C. N Engl J Med. 2012; 367: 20-29.
Levey A.S., Coresh J., Greene T., Stevens L.A., Zhang Y., Hendriksen S., Kusek J.W., and Van 
Lente F. Using Standardized Serum Creatinine Values in the Modification of Diet in Renal 
Disease Study Equation for Estimating Glomerular Filtration Rate. Ann Intern Med. 2006; 145: 
247-254.  


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10. Appendices


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Appendix 1.
Planned Laboratory Analytes and Direction of 
Interest
The H0P-MC-CPMP SAP Version 5 describes tests that may be performed broadly for the 
Chronic Pain Master Protocol. This table describes additional tests in H0P-MC-CPMP.  
Chemistry
Other Tests
Cystatin-C
Immunogenicity
Serum Epiregulin
LY3016859 concentration
Urine pregnancy
CCI


Leo Document ID = 612f8e9a-797c-41ff-ad77-08e18221087c
Approver: 
Approval Date & Time: 16-Dec-2021 20:12:07 GMT
Signature meaning: Approved
PPD