Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3857210 for the Treatment of Diabetic Peripheral Neuropathic Pain
Phase: PHASE2
Conditions: Diabetic Peripheral Neuropathic Pain
Sponsor: Eli Lilly and Company

This study H0P-MC-NP05 (NCT05620576) is a sub-study of Master Protocol H0P-MC-
CPMP (NCT05986292) 
 
Protocol: H0P-MC-NP05 (a) 
 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3857210 for the 
Treatment of Diabetic Peripheral Neuropathic Pain  
 
NCT05620576 
 
Approval Date: 13-Oct-2022 

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
1 
Title Page 
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 LY3857210, 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 LY3857210 for 
the Treatment of Diabetic Peripheral Neuropathic Pain 
ISA Number: H0P-MC-NP05 
Amendment Number: a 
Compound: LY3857210 
Brief Title: Phase 2 Clinical Trial to Evaluate LY3857210 for the Treatment of Diabetic 
Peripheral Neuropathic Pain 
Study Phase: 2 
Acronym: NP05  
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Numbers: 
LY3857210 IND: 156411 
Master Protocol IND: 144915 
Approval Date: Protocol H0P-MC-NP05 Amendment (a) Electronically Signed 
and Approved by Lilly on date provided below.  
 
Document ID: VV-CLIN-075079 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
2 
Medical Monitor Name and Contact Information will be provided separately. 
 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
3 
Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
25-Aug-2022 
Amendment a  
Overall Rationale for the Amendment: 
This amendment adds additional physical examinations and exclusion criteria to address 
regulatory feedback. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3. Schedule 
of Activities 
Added Physical examinations at Visits 5 and 7.   
Added note, “Complete physical examination, 
including targeted examination specified 
below, should be performed at V3 and V801 or 
ED. Targeted physical examination for skin, 
gastrointestinal tract, mammary gland in 
males, and lymph nodes should also be 
performed at V5 and V7.” 
Per regulatory feedback. 
 
Removed text in notes for vital signs, “…and 
prior to PK sample collection.” 
Editorial correction. 
5.2. 
Exclusion 
Criteria 
Modified criterion [3085], “have completed 
participated in…”. 
Clarification. 
 
8.2.1. 
Physical 
Examinations 
Added, “Complete physical examination, 
including targeted examination specified 
below, should be performed at V3 and Visit 
801 or ED. Targeted physical examinations of 
skin, gastrointestinal tract, mammary gland in 
males, and lymph nodes will also be performed 
at Visits V5 and V7 as described in the SoA. 
Any clinically significant abnormal physical 
examination findings will be reported as AEs.” 
Per regulatory feedback. 
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
4 
Section # and 
Name 
Description of Change 
Brief Rationale 
 
Removed, “…to physical examinations 
(described in Master Protocol CPMP)…” 
Editorial. 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
5 
Table of Contents 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................10 
1.3. 
Schedule of Activities (SoA) ..........................................................................................11 
2. 
Introduction ...................................................................................................................15 
2.1. 
Study Rationale ...............................................................................................................15 
2.2. 
Background .....................................................................................................................15 
2.3. 
Benefit/Risk Assessment ................................................................................................15 
2.3.1. 
Risk Assessment .............................................................................................................15 
2.3.2. 
Benefit Assessment .........................................................................................................16 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................16 
3. 
Objectives, Endpoints, and Estimands .......................................................................17 
4. 
Study Design ..................................................................................................................18 
4.1. 
Overall Design ................................................................................................................18 
4.2. 
Scientific Rationale for Study Design ............................................................................18 
4.3. 
Justification for Dose ......................................................................................................18 
4.4. 
End of Study Definition ..................................................................................................19 
5. 
Study Population ...........................................................................................................20 
5.1. 
Inclusion Criteria ............................................................................................................20 
5.2. 
Exclusion Criteria ...........................................................................................................20 
5.3. 
Lifestyle Considerations .................................................................................................21 
5.3.1. 
Substance Use .................................................................................................................21 
5.4. 
Screen Failures ................................................................................................................21 
5.5. 
Criteria for Temporarily Delaying Enrollment, Randomization, 
or Administration of Study Intervention of a Participant ...............................................21 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................22 
6.1. 
Study Intervention(s) Administered................................................................................22 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................22 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................22 
6.3.1. 
Stratification ....................................................................................................................22 
6.4. 
Study Intervention Compliance ......................................................................................22 
6.5. 
Dose Modification ..........................................................................................................22 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................22 
6.7. 
Treatment of Overdose ...................................................................................................23 
6.8. 
Concomitant Therapy .....................................................................................................23 
6.8.1. 
Permitted Medications ....................................................................................................23 
6.8.2. 
Prohibited Medications ...................................................................................................23 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................24 
7.1. 
Discontinuation of Study Intervention ............................................................................24 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................24 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
6 
7.1.2. 
Hypersensitivity ..............................................................................................................25 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................25 
7.3. 
Lost to Follow-Up ...........................................................................................................25 
8. 
Study Assessments and Procedures.............................................................................26 
8.1. 
Efficacy Assessments .....................................................................................................26 
8.2. 
Safety Assessments .........................................................................................................26 
8.2.1. 
Physical Examinations ....................................................................................................26 
8.2.2. 
Electrocardiograms .........................................................................................................26 
8.2.3. 
Clinical Safety Laboratory Tests ....................................................................................27 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................27 
8.3.1. 
Pregnancy ........................................................................................................................27 
8.3.2. 
Hypersensitivity Reactions .............................................................................................28 
8.3.3. 
Adverse Events of Special Interest .................................................................................28 
8.4. 
Pharmacokinetics ............................................................................................................29 
8.5. 
Pharmacodynamics .........................................................................................................29 
9. 
Statistical Considerations .............................................................................................30 
9.1. 
Statistical Hypotheses .....................................................................................................30 
9.2. 
Analyses Sets ..................................................................................................................30 
9.3. 
Statistical Analyses .........................................................................................................30 
9.3.1. 
General Considerations ...................................................................................................30 
9.3.2. 
Tertiary Analysis .............................................................................................................30 
9.3.3. 
Safety Analyses ...............................................................................................................30 
9.3.4. 
Exploratory Pharmacokinetic Analyses ..........................................................................31 
9.4. 
Interim Analysis ..............................................................................................................31 
9.5. 
Sample Size Determination ............................................................................................31 
10. 
Supporting Documentation and Operational Considerations ..................................32 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................32 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................33 
10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................33 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................35 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................36 
10.4.1. Definitions.......................................................................................................................36 
10.4.2. Contraception Guidance..................................................................................................37 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................39 
Approved on 13 Oct 2022 GMT
CCI
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
7 
10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................40 
10.7. 
Appendix 7: Abbreviations and Definitions ...................................................................43 
11. 
References ......................................................................................................................45 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
8 
1. 
Protocol Summary 
1.1. 
Synopsis 
ISA Title:  
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3857210 for the 
Treatment of Diabetic Peripheral Neuropathic Pain 
Brief Title: Phase 2 Clinical Trial to Evaluate LY3857210 for the Treatment of Diabetic 
Peripheral Neuropathic Pain 
Regulatory Agency Identifier Numbers:  
LY3857210 IND: 156411 
Master Protocol IND: 144915 
Rationale: 
The purpose of this study is to test whether LY3857210 is efficacious in decreasing diabetic 
peripheral neuropathic pain (DPNP). LY3857210 is a small molecule receptor antagonist of the 
P2X7 receptor, an adenosine triphosphate ligand-gated ion channel known to be involved in 
neuroinflammation and pain.  
Data will be collected to assess the safety and tolerability of LY3857210 in this study population. 
The pharmacokinetics of LY3857210 will also be explored. The totality of data from this proof-
of-concept study will assess the benefits and risks associated with LY3857210 and inform 
decisions for the clinical development of LY3857210. 
Objectives, Endpoints, and Estimands: 
The primary and secondary objectives and endpoints are stated in the Master Protocol H0P-MC-
CPMP (CPMP) and the DPNP disease-state addendum (DSA; H0P-MC-CPMP[3]).  
Overall Design: 
This is a 10-week Phase 2, randomized, double-blind, placebo-controlled study that will compare 
LY3857210 versus placebo in participants with DPNP.  
Study Population: 
In addition to inclusion and exclusion criteria described in Master Protocol CPMP and DSA 
CPMP(3), individuals may not take part in the study if they have 
 an eGFR of less than 30 mL/min/1.73 m . 
Approved on 13 Oct 2022 GMT
CCI
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
9 
Number of Participants: 
Up to approximately 125 participants will be randomly assigned to study intervention with the 
assumption that 20% of the participants will drop out prior to the end of the double-blind 
treatment period. 
Intervention Groups and Duration: 
This double-blind study includes an 8-week treatment period with a 2-week follow-up visit off 
treatment. 
Intervention Name 
LY3857210 
Placebo 
Dosage Level(s) 
45 mg daily 
Not applicable 
Route of Administration 
and Duration 
PO 
PO 
Abbreviation: PO = by mouth. 
Ethical Considerations of Benefit/Risk: 
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with LY3857210 are justified by the 
anticipated benefits that may be afforded to participants with DPNP. 
Data Monitoring Committee: Yes 
Safety reviews are covered by the Assessment Committee charter for the Chronic Pain Master 
Protocol (CPMP). 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
10 
1.2. 
Schema 
 
 
Abbreviations: PDEP = preliminary data entry period; V = visit. 
a  Medication washout and PDEP begins. 
b  Randomization to either LY3857210 or placebo.  
 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
11 
1.3. 
Schedule of Activities (SoA) 
This SoA shows visits and procedures unique to the intervention-specific appendix (ISA) H0P-MC-NP05 for LY3857210. Please refer 
to Master Protocol CPMP and the DPNP DSA CPMP(3) SoAs for additional information.  
  
Screening 
Randomiza
tion to ISA 
Double-Blind 
Treatment 
 
F/U 
Notes 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
ED 
V801   
Study Week 
Up to -6 months 
-10 to -7 days for 
most participants 
0 
2 
4 
6 
8 
+2 
  
Visit Window (days) 
 
 
 
±3 
 
±3 
 
Confirm ISA inclusion 
and exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
Physical examination 
 
 
X 
  
X 
  
X 
X 
X 
Physical examination (see Section 
8.2.1). Complete physical examination, 
including targeted examination 
specified below, should be performed at 
V3 and V801 or ED. Targeted physical 
examination for skin, gastrointestinal 
tract, mammary gland in males, and 
lymph nodes should also be performed 
at V5 and V7.  
Neurological assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
See Section 8.2.1. 
Prespecified DPNP 
medical history 
 
 
X 
 
 
 
 
 
 
Includes diagnosis and symptom onset 
date. 
Vital signs 
 
 
X 
X 
X 
X 
X 
X 
X 
At V3, vitals should be taken predose. 
Pulse rate, respiratory rate, blood 
pressure, and temperature taken with 
participant in a sitting position. 
Concomitant medication 
 
 
 
 
 
 
 
 
X 
See footnote a. 
AE 
 
 
 
 
 
 
 
 
X 
See footnote a. 
ECG (single) 
 
 
 
  
X 
  
X 
X 
X 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
12 
  
Screening 
Randomiza
tion to ISA 
Double-Blind 
Treatment 
 
F/U 
Notes 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
ED 
V801   
Study Week 
Up to -6 months 
-10 to -7 days for 
most participants 
0 
2 
4 
6 
8 
+2 
  
Visit Window (days) 
 
 
 
±3 
 
±3 
 
Placebo response video 
training (participant) 
 
X 
 
 
 
 
 
 
 
Should view at the beginning of V2. 
Study intervention 
administration 
 
 
X 
X 
X 
X 
 
  
 
See Section 6.1. Participant should be 
instructed NOT to take study 
intervention on the day of V7. 
Dispense study 
intervention to participant 
 
 
X 
X 
X 
X 
 
 
 
 
Participant returns unused 
study intervention 
 
 
 
X 
X 
X 
X 
X 
 
Participant to bring study intervention 
to every visit. 
Intervention compliance 
 
 
  
X 
X 
X 
X 
X 
 
 
Scales, Questionnaires, and Outcome Measures 
 
C-SSRS Since Last Visit 
 
 
 
 
 
 
 
 
X 
See footnote a. 
Self-Harm Supplement 
form 
 
 
 
 
 
 
 
 
X 
See footnote a. 
Self-Harm Follow-Up 
form 
 
 
 
 
 
 
 
 
X 
See footnote a. 
Complete 1 form for each event 
identified on the Self-Harm Supplement 
form. 
NRS for pain 
 
 
 
 
 
 
 
 
X 
See footnote a. 
Review eDiary compliance. 
Reinforce pain 
assessment guidelines  
 
X 
X 
X 
X 
X 
X 
 
 
Review assessment of pain. See MoO 
for additional details. 
Rescue medication usage 
reporting 
 
 
 
 
 
 
 
 
X 
See footnote a. 
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
13 
  
Screening 
Randomiza
tion to ISA 
Double-Blind 
Treatment 
 
F/U 
Notes 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
ED 
V801   
Study Week 
Up to -6 months 
-10 to -7 days for 
most participants 
0 
2 
4 
6 
8 
+2 
  
Visit Window (days) 
 
 
 
±3 
 
±3 
 
PGI 
 
 
 
 
 
 
 
 
X 
See footnote a. 
Clinical Laboratory Tests and Sample Collection 
Hematology 
 
 
 
X 
X 
X 
X 
 
X 
  
Chemistry 
 
 
 
X 
X 
X 
X 
 
X 
  
Lipid panel 
 
 
 
X 
X 
X 
X 
 
X 
  
Urinalysis 
 
 
  
  
  
  
X 
 
X 
  
Urine pregnancy 
 
 
X 
X 
X 
X 
X 
X 
 
For all WOCBP at V3: collect sample 
within 24 hours prior to dosing. 
Urine drug screen 
 
 
X 
 
X 
 
X 
X 
 
See Section 5.3.1. 
HbA1c 
 
 
X 
 
 
 
X 
X 
 
 
LY3857210 PK sample 
 
 
X 
X 
X 
X 
X 
X 
 
At V3, a PK sample should be taken 
any time after 1 hour postdose and 
prior to leaving the site. At V4, V5, V6, 
V7 and ED, a PK sample can be taken 
at any time during the site visit.  The 
date and time of each PK sample 
collected will be recorded.  The date 
and time of LY3857210 administration 
prior to the PK sample collection will 
be recorded. 
Approved on 13 Oct 2022 GMT
CCI
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
14 
  
Screening 
Randomiza
tion to ISA 
Double-Blind 
Treatment 
 
F/U 
Notes 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
ED 
V801   
Study Week 
Up to -6 months 
-10 to -7 days for 
most participants 
0 
2 
4 
6 
8 
+2 
  
Visit Window (days) 
 
 
 
±3 
 
±3 
 
Participant Devices 
Abbreviations: AE = adverse event; 
; DPMP = diabetic peripheral neuropathic pain; ECG = electrocardiogram; ED = early 
discontinuation; F/U = follow-up; HbA1c = hemoglobin A1c; ISA = intervention-specific appendix; MoO = Manual of Operations; NRS = numeric rating 
scale; PGI = patient’s global impression of change; PK = pharmacokinetic; V = visit; WOCBP = women of childbearing potential.  
a Collect in addition to schedule described in Master Protocol CPMP. 
 
Approved on 13 Oct 2022 GMT
CCI
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
15 
2. 
Introduction 
This ISA, H0P-MC-NP05 (NP05) is an appendix to Master Protocol H0P-MC-CPMP (CPMP) 
and contains unique study elements specific for LY3857210. The master protocol contains the 
overarching study elements that govern the DPNP DSA CPMP(3) and this ISA NP05.  
2.1. 
Study Rationale 
The purpose of this study is to test whether LY3857210 is efficacious in decreasing DPNP. Data 
will be collected to assess the safety and tolerability of LY3857210 in this study population. The 
PK of LY3857210 will also be explored. The totality of data from this POC study will assess the 
benefits and risks associated with LY3857210 and inform decisions for the clinical development 
of LY3857210. 
2.2. 
Background 
P2X7 is an adenosine triphosphate (ATP) ligand-gated ion channel that when activated results in 
Ca2+ influx, and cellular activation (for example, caspase 1). For a recent review article, see 
Zhang et al. 2020. Stimulation of P2X7 plays a key role in the cross talk of the glial cells and 
neurons at an over-active synapse and in neuroinflammatory conditions (Currò et al. 2020). 
Thus, inhibition of the P2X7 receptor found on glial cells in the brain and spinal cord is 
anticipated to decrease synaptic transmission.  
LY3857210 is an orally administered small-molecule receptor antagonist of the P2X7 receptor.  
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of LY3857210 may be found in the IB.  
2.3.1. 
Risk Assessment 
Study intervention 
Toxicology studies and NOAEL exposure 
Based on the observed convulsion in the 3-month dog toxicology study (reported in 1 dog) as 
well as convulsion noted in the rat in vivo micronucleus study (reported in 1 rat), a 10-fold 
Approved on 13 Oct 2022 GMT
CCI
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
16 
exposure multiple based on the observed AUC and Cmax associated with the NOEL for 
convulsions in dog (the most sensitive species) will be maintained in this study 
 
  
In addition, neurological examination will be conducted at regular intervals during the study 
period and AEs related to CNS signs and symptoms will be collected during the study. 
Participants with a history of seizures will be excluded from the study.  
Potential drug-drug interactions 
Clinical drug-drug interaction studies have not been conducted with LY3857210. Based on 
current in vitro data, LY3857210 is a potential inducer of CYP3A4, CYP1A2, CYP2B6, and 
CYP2C8. To mitigate risk, participants taking sensitive substrates with a narrow therapeutic 
index are excluded. See Section 5.2 for exclusion criteria and refer to IB for more information. 
Information on AEs expected to be related to the study intervention may be found in the IB . 
Information on SAEs that are expected in the study population independent of drug exposure will 
be assessed by the sponsor in aggregate, periodically during the course of the study, and may be 
found in the IB. 
2.3.2. 
Benefit Assessment 
Potential benefits for the study participants include:  
 information obtained from study-related medical procedures  
o physical examinations  
o laboratory tests, and  
o ECGs.  
 detailed evaluations of diabetic nerve pain, and  
 questionnaires that may improve participants understanding their own condition.  
As part of Study CPMP, participants in this ISA will report their experience using standard tools 
that may 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 
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with LY3857210 are justified by the 
anticipated benefits that may be afforded to participants with DPNP. 
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
17 
3. 
Objectives, Endpoints, and Estimands 
The CPMP Master Protocol and DPNP DSA CPMP(3) include objectives and endpoints 
applicable for this study. This table describes objectives and endpoints specific for LY3857210. 
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
18 
4. 
Study Design 
4.1. 
Overall Design 
Master Protocol CPMP describes the overall study design and study design rationale. This 
section describes visits and overall procedures unique to ISA NP05 for LY3857210 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 randomly assigned to LY3857210 or placebo  
 the site completes the NP05 baseline procedures and sample collection (excluding PK) 
prior to study intervention 
 the site collects participants’ vitals predose  
 participants receive their oral study intervention  
 the site completes PK sample collection, and 
 the site instructs participants to continue with study restrictions and NRS diary entries 
before their visit discharge. 
At Visits 4 through 7, 
 the site reviews available safety data and sample collection 
 participants continue oral study intervention (not applicable for Visit 7) and bring all 
study intervention bottles to each visit 
 the site completes all sample collection and safety monitoring noted in the SoAs, and 
 the site instructs participants to continue with study restrictions, NRS diary entries, and 
wearing of 
 before their visit discharge. 
Double-blind post-treatment follow-up period (Visit 801) 
 Participants must complete 1 post-treatment follow-up visit for safety and efficacy 
assessment at Visit 801 according to the SoA 
 the site schedules Visit 801 approximately 2 weeks after Visit 7 or ED Visit, and 
 at Visit 801, participants return the devices 
 
4.2. 
Scientific Rationale for Study Design 
Master Protocol CPMP describes the overall study design rationale.  
4.3. 
Justification for Dose 
Approved on 13 Oct 2022 GMT
CCI
CCI
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
19 
4.4. 
End of Study Definition 
A participant is considered to have completed this ISA if they have completed all required 
phases of the study including the last scheduled procedure shown in the ISA SoA. 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the ISA SoA for the last participant.  
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
20 
5. 
Study Population 
Master Protocol CPMP and DPNP DSA CPMP(3) provide eligibility criteria that must be 
followed for this study. LY3857210-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: 
Sex and contraceptive/barrier requirements 
[3075] Males and females may participate in this trial.  
No male contraception is required except in compliance with specific local 
government study requirements. 
WOCBP and WNOCBP may participate in this trial. See Section 10.4 for definitions 
and additional requirements related to contraception. 
Contraceptive use by participants should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.   
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
[3077] Have an eGFR of <30 mL/min/1.73 m , based on the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula at Visit 1 or Visit 2. 
[3078] Have known allergies to LY3857210, related compounds or any components of the 
formulation, or history of significant atopy.  
[3079] Women who are pregnant or breastfeeding. 
Approved on 13 Oct 2022 GMT
CCI
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
21 
5.3. 
Lifestyle Considerations 
See Master Protocol CPMP for lifestyle considerations.   
ISA-specific lifestyle considerations are provided below. 
5.3.1. 
Substance Use 
Positive urine drug screen will not be considered illicit use if it is a prescribed concomitant 
medication for a known preexisting condition. 
5.4. 
Screen Failures 
Screen failures are described in Master Protocol CPMP. 
5.5. 
Criteria for Temporarily Delaying Enrollment, Randomization, or 
Administration of Study Intervention of a Participant 
Not applicable to this study. 
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
22 
6. 
Study Intervention(s) and Concomitant Therapy 
6.1. 
Study Intervention(s) Administered 
This table lists the interventions used in this clinical study. 
Intervention Name 
LY3857210 
Placebo 
Dosage Level(s) 
45 mg daily 
N/A 
Route of Administration PO 
PO 
Abbreviations: N/A = not applicable; PO = by mouth. 
Packaging and labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
6.2. 
Preparation, Handling, Storage, and Accountability 
Preparation, handling, storage, and accountability are described in Master Protocol CPMP. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization and blinding are described in Master Protocol CPMP. 
6.3.1. 
Stratification 
There are no additional stratification factors for this study. 
6.4. 
Study Intervention Compliance 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning and 
counting returned capsules and documented in the source documents and CRF. A record of the 
number of study intervention capsules dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start and 
stop dates will also be recorded in the CRF. 
6.5. 
Dose Modification 
Dose modification is not permitted. 
6.6. 
Continued Access to Study Intervention after the End of the Study 
Not applicable. 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
23 
6.7. 
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. There is no 
known antidote to LY3857210 therapy.  
6.8. 
Concomitant Therapy 
6.8.1. 
Permitted Medications 
All concomitant therapies that are part of routine care for comorbidities other than chronic pain 
are allowed and may be used during the study, except as indicated in Section 6.8.2.  
Master Protocol CPMP provides more detail on concomitant therapy.  
6.8.2. 
Prohibited Medications 
A list of medications that are prohibited from Visit 2 to Visit 801 for participants randomly 
assigned to this ISA study will be provided in the Manual of Operations. Participants may return 
to their routine care after Visit 801 is completed, as clinically appropriate. 
Potential drug-drug interactions with LY3857210 
Please refer to Section 5.2, IB, and Manual of Operations for details on concomitant medication 
restrictions.  
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
24 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
Master Protocol CPMP and CPMP(3) DSA provide the reasons and procedures for 
discontinuation of intervention and participant discontinuation that must be followed for this 
study.  
7.1.1. 
Liver Chemistry Stopping Criteria 
Interrupting study intervention based on elevated liver tests 
The study intervention should be interrupted and close hepatic monitoring initiated (see Section 
8.2.5 of Master Protocol CPMP) if 1 or more of these conditions occur:  
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 weeks 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2x ULN 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL > 2x ULN  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2x ULN 
ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA 2009 and other consensus guidelines, with minor modifications. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin level; ULN = upper limit of normal. 
Resuming study intervention after elevated liver tests 
Resumption of the study intervention can be considered only in consultation with the 
Lilly-designated medical monitor and only if the liver test results return to baseline and if a 
self-limited, non-drug etiology is identified. Otherwise, the study intervention should be 
discontinued. 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
25 
7.1.2. 
Hypersensitivity  
If the investigator determines that a systemic hypersensitivity reaction has occurred related to 
study intervention administration, the participant may be permanently discontinued from the 
study intervention, and the sponsor’s designated medical monitor should be notified. If the 
investigator is uncertain about whether a systemic hypersensitivity reaction has occurred and 
whether discontinuation of study intervention is warranted, the investigator may consult the 
sponsor. 
For laboratory samples to be obtained at the time of a systemic hypersensitivity event, see 
Section 10.2.1.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
See Master Protocol CPMP. 
7.3. 
Lost to Follow-Up 
See Master Protocol CPMP. 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
26 
8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in Master Protocol CPMP , DPNP CPMP(3) 
DSA, and ISA NP05 SoAs.  
LY3857210-specific assessments and procedures are described here. 
8.1. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoAs. 
See Master Protocol CPMP and DSA CPMP(3) for additional information on efficacy 
assessments. 
8.2. 
Safety Assessments 
Planned time points for all efficacy assessments are provided in the SoAs. 
See Master Protocol CPMP and DSA CPMP(3) for additional information on safety assessments. 
Additional Study NP05-specific assessment information is provided below. 
8.2.1. 
Physical Examinations 
Complete physical examination, including targeted examination specified below, should be 
performed at V3 and Visit 801 or ED. Targeted physical examinations of skin, gastrointestinal 
tract, mammary gland in males, and lymph nodes will also be performed at Visits V5 and V7 as 
described in the SoA. Any clinically significant abnormal physical examination findings will be 
reported as AEs. 
In addition, a directed neurological assessment will be performed by the investigator (or 
designee) at the time points specified in the SoA. If abnormalities are noted at these time points, 
additional examinations should be performed as clinically necessary. The examiner should be 
familiar with the participant’s baseline examination.  
Elements of the neurological assessment include inspection for tremor, extraocular movements, 
brachial and patellar deep tendon reflexes, finger-nose pointing, and Romberg sign.   
8.2.2. 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, RR, QRS, QT, and QTcF 
intervals. Refer to Section 7.1 of Master Protocol CPMP for QTcF withdrawal criteria and any 
additional QTcF readings that may be necessary. 
Additional details related to ECG are provided in Master Protocol CPMP. 
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
27 
8.2.3. 
Clinical Safety Laboratory Tests 
See NP05 Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency for ISA NP05.  
Additional details are provided in the Master Protocol CPMP. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Appendix 3 of Master Protocol CPMP: 
 AEs 
 SAEs, and 
 PCs. 
See Master Protocol CPMP Section 8.3 for additional details. 
8.3.1. 
Pregnancy 
Collection of pregnancy information 
Male participants with partners who become pregnant 
● The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive study 
intervention. 
● After learning of a pregnancy in the female partner of a study participant, the 
investigator 
o will obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor.  
The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to 
the sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of gestational age, fetal status (presence or absence of 
anomalies), or indication for the procedure. 
Female participants who become pregnant 
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 24 
hours of learning of a participant's pregnancy.  
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
28 
● The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, 
and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 
Any termination of pregnancy will be reported, regardless of gestational age, fetal 
status (presence or absence of anomalies), or indication for the procedure. 
● While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
● A spontaneous abortion, occurring at <20 weeks gestational age, or still birth, 
occurring at ≥20 weeks gestational age, is always considered to be an SAE and 
will be reported as such.  
● Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Master Protocol Section 8.3.1. While the investigator is not obligated to actively 
seek this information in former study participants, they may learn of an SAE 
through spontaneous reporting. 
● Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention and continue directly to the follow-up phase. 
The follow-up on the pregnancy outcome should continue independent of 
intervention or study discontinuation.   
8.3.2. 
Hypersensitivity Reactions 
Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data should be provided to the sponsor in the 
designated CRFs. 
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 hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of a suspected systemic hypersensitivity event, additional blood samples should be 
collected as described in Section 10.2.1. Laboratory results are provided to the sponsor via the 
central laboratory. 
8.3.3. 
Adverse Events of Special Interest  
Convulsion is an AE of special interest for LY3857210 and will be subject to enhanced 
surveillance activities. Additionally, convulsion will be analyzed for presentation in the Clinical 
Study Report in accordance with the SAP. 
If a seizure or convulsion is reported, then contact the medical monitor as soon as possible. 
Additional evaluation or follow-up may be requested.  
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
29 
8.4. 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of LY3857210 as 
specified in the SoA  
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor. The timing of PK samples 
may be altered during the course of the study based on newly available data to ensure appropriate 
data collection. 
Instructions for the collection and handling of PK samples will be provided by the sponsor. 
The date and time (24-hour clock time) will be recorded for  
 LY3857210 administration prior to the PK sample collection, and  
 PK sample collection. 
PK samples may also be used to evaluate safety or efficacy measures related to concerns arising 
during or after the study  
8.5. 
Pharmacodynamics 
Pharmacodynamic assessments will not be evaluated in this study. 
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
30 
9. 
Statistical Considerations 
Master Protocol CPMP and DPNP DSA CPMP(3) provide statistical considerations. 
LY3857210-specific considerations are described here. 
9.1. 
Statistical Hypotheses 
Master Protocol CPMP describes the primary hypothesis.
 
 
  
9.2. 
Analyses Sets 
The populations are defined in Master Protocol CPMP . 
The PK population includes all randomly assigned participants who received a dose of 
LY3857210 and have at least 1 evaluable PK sample collected.  
9.3. 
Statistical Analyses 
If the primary analysis approach needs to be changed, the updated approach will be provided in 
the SAP and should not lead to modification of this protocol. Any other change to the data 
analysis methods described, and the justification for making the change, will be described in the 
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 more technical and 
detailed descriptions of the statistical analyses described in this section. 
9.3.1. 
General Considerations 
The primary and secondary endpoint and analyses have been described in Master Protocol 
CPMP.  
Any borrowing of placebo or treatment effect information will be specified in the ISA SAP. 
Secondary and tertiary or exploratory endpoints and analyses are described in Master Protocol 
CPMP and DPNP DSA CPMP(3).  
Handling of missing, unused, and spurious data is addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
9.3.2. 
Tertiary Analysis 
Exploratory analyses may be described in the ISA SAP. 
9.3.3. 
Safety Analyses 
Safety analyses have been described in Master Protocol CPMP. Additional ISA-specific safety 
analyses may be described in the ISA SAP.  
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
31 
9.3.4. 
Exploratory Pharmacokinetic Analyses 
Plasma concentrations for LY3857210 will be reported graphically and descriptively. Model-
based PK and exposure-response relationships for various efficacy and safety measures may be 
conducted. 
9.4. 
Interim Analysis  
An interim analysis may be conducted for internal decision making. The potential reasons for 
interim analyses could include futility analyses, early efficacy analyses, safety analyses, PK 
analyses, or other analyses needed for key business decisions and planning. 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.  
9.5. 
Sample Size Determination 
Up to approximately 125 participants will be randomly assigned to LY3857210 and placebo. It is 
expected that approximately 80% of participants will complete the double-blind treatment period 
of the study.
 
  
 
 If there is no treatment 
difference between placebo and LY3857210, the probability of meeting the primary objective 
specified above (that is, false positive) is approximately 0.059. 
Approved on 13 Oct 2022 GMT
CCI
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
32 
10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
See Master Protocol CPMP for regulatory, ethical, and study oversight considerations. 
 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
33 
10.2. 
Appendix 2: Clinical Laboratory Tests 
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 NP05.  
Other Tests 
Assayed by Lilly-designated laboratory.  
LY3857210 concentration 
 
Results will not be provided to the investigative sites. 
10.2.1. 
Laboratory Samples to be Obtained at the Time of a Systemic Hypersensitivity 
Event 
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The sponsor will use the laboratory tests results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed below if a systemic hypersensitivity event is suspected. The timing 
should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up predose samples at the next regularly scheduled laboratory sample collection 
(ideally prior to the next dose after the event) to assess post-event return-to-baseline values. 
Timing 
Laboratory Test a 
Collect from 30 minutes to 4 hours after the start of 
the event.  
● 
Note: The optimal collection time is from 1 to 2 
hours after the start of event. 
total tryptase 
complements (C3, C3a, and C5a)  
cytokine panel (IL-6, IL‐1β, IL‐10, or any cytokine 
panel that includes these 3 cytokines)  
Abbreviation: IL = interleukin. 
a All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be 
provided to the study site. If samples are not collected or are collected outside the specified time period, this will 
not be considered a protocol deviation. 
What information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
34 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
35 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
See Master Protocol Appendix 3 for information related to AE and SAE. 
 
 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
36 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Word/Phrase 
Definition 
Women of 
childbearing 
potential (WOCBP) 
Adult females are considered WOCBP unless they are WNOCBP. 
Women not of 
childbearing 
potential 
(WNOCBP) 
Females are considered WNOCBP if they 
 have a congenital anomaly such as Müllerian agenesis  
 are infertile due to surgical sterilization, or  
 are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, bilateral 
salpingo-oophorectomy, bilateral salpingectomy, or bilateral 
oophorectomy. 
Postmenopausal 
state 
The postmenopausal state is defined as a woman: 
 at any age at least 6 weeks post-surgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or  
 aged at least 40 years and up to 55 years with an intact uterus, not 
on hormone therapya, who has had cessation of menses for at 
least 12 consecutive months without an alternative medical cause, 
AND with a follicle-stimulating hormone >40 mIU/mL; or  
 55 years or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea, or 
 aged at least 55 years with a diagnosis of menopause prior to 
starting hormone replacement therapy. 
a Women should not be taking medications during amenorrhea such as 
oral contraceptives, hormones, gonadotropin-releasing hormone, anti-
estrogens, Selective estrogen receptor modulators (SERMs), or 
chemotherapy that could induce transient amenorrhea. 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
37 
10.4.2. 
Contraception Guidance 
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship as their preferred and usual lifestyle: 
Must… 
Must not… 
agree to either remain abstinent or stay 
in a same-sex relationship without 
sexual relationships with males 
 use periodic abstinence methods 
o calendar  
o ovulation  
o symptothermal, or 
o post-ovulation  
 declare abstinence just for the duration of a trial, 
or 
 use the withdrawal method 
 
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or NOT in a 
same-sex relationship as their preferred and usual lifestyle, must do the following: 
Topic 
Condition 
Pregnancy testing 
Have a negative serum test result at screening followed by a negative 
urine result within 24 hours prior to treatment exposure. See the Master 
Protocol CPMP and the NP05 Schedule of Activities for subsequent 
pregnancy testing requirements. 
Contraception 
Agree to use 1 highly effective method of contraception, or a combination 
of 2 effective methods of contraception. 
 
These forms of contraception must be used for the duration of the study. 
 
 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
38 
Examples of different forms of contraception: 
Methods 
Examples 
Highly effective 
contraception (less than 
1% failure rate) 
 female sterilization 
 combination oral contraceptive pill 
 progestin-only contraceptive pill (mini-pill) 
 implanted contraceptives 
 injectable contraceptives 
 contraceptive patch (only women <198 pounds or 90 kg) 
 total abstinence 
 vasectomy (if only sexual partner) 
 fallopian tube implants (if confirmed by hysterosalpingogram) 
 combined contraceptive vaginal ring, or  
 intrauterine devices 
Effective contraception 
 male or female condoms with spermicide  
 diaphragms with spermicide or cervical sponges 
 barrier method with use of a spermicide 
o condom with spermicide 
o diaphragm with spermicide, or 
o female condom with spermicide 
Ineffective forms of 
contraception whether 
used alone or in any 
combination 
 spermicide alone 
 periodic abstinence 
 fertility awareness (calendar method, temperature method, 
cervical mucus, or symptothermal) 
 withdrawal 
 postcoital douche, or 
 lactational amenorrhea 
 
 
 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
39 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
See Master Protocol CPMP Appendix 6 for liver safety: suggested actions and follow-up 
assessments. 
 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
40 
10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations.  
After approval by local Ethical Review Boards, regulatory bodies and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study.  
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study intervention during an extended treatment period  
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
41 
Remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments.  
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider 
at locations other than the study site when participants cannot travel to the site due to an 
exceptional circumstance if written approval is provided by the sponsor.  
Procedures performed at such visits include, but are not limited to, collection of blood 
samples, symptom-directed physical examinations, ECGs, vital signs, intervention 
accountability and compliance, AE collection, and collection of health information. 
Other alternative locations: Laboratory draws may be done at an alternate location in 
exceptional circumstances.  
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged.  
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations. 
 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may 
include:  
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit  
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 arranging delivery of study supplies. 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
Approved on 13 Oct 2022 GMT
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
42 
 When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 
Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Adjustments to visit windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual Schedule of Activities as described in Master Protocol CPMP , 
CPMP(3) DSA, and NP05 ISA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study.  
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study.  
Documentation 
Sites will identify and document the details of how participants, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner.  
 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
43 
10.7. 
Appendix 7: Abbreviations and Definitions 
Term 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AUC 
area under the curve 
AST 
aspartate aminotransferase 
CNS 
central nervous system 
CPMP 
chronic pain master protocol 
CRF 
case report form; a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
DPNP 
diabetic peripheral neuropathic pain 
DSA 
disease-state appendix 
ECG 
electrocardiogram 
ED 
early discontinuation 
eGFR 
estimated glomerular filtration rate 
IB 
Investigator’s Brochure 
ISA 
intervention-specific appendix 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
MAD 
multiple-ascending dose 
MoO 
Manual of Operations 
NRS 
numeric rating scale 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PK 
pharmacokinetics 
POC 
proof-of-concept 
Approved on 13 Oct 2022 GMT
CCI
CCI

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
44 
QTc 
corrected QT interval 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SoA 
Schedule of Activities 
WNOCBP 
Women not of childbearing potential 
WOCBP 
Women of childbearing potential 
 
 
Approved on 13 Oct 2022 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP05 (a) 
45 
11. 
References 
Currò D, Navarra P, Samengo I, Martire M. P2X7 receptors exert a permissive effect on the 
activation of presynaptic AMPA receptors in rat trigeminal caudal nucleus glutamatergic nerve 
terminals. J Headache Pain. 2020;21(1):83. https://doi.org/10.1186/s10194-020-01153-y 
[FDA] Food and Drug Administration. Guidance for Industry. Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation, July 2009. Accessed August 2022. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-induced-
liver-injury-premarketing-clinical-evaluation 
Zhang WJ, Zhu ZM, Liu ZX. The role and pharmacological properties of the P2X7 receptor in 
neuropathic pain. Brain Res Bull. 2020;155:19-28. 
https://doi.org/10.1016/j.brainresbull.2019.11.006 
 
Approved on 13 Oct 2022 GMT

Signature Page for VV-CLIN-075079 v1.0
Signature Page for VV-CLIN-075079 v1.0
Approval
Statistician
13-Oct-2022 20:15:32 GMT+0000
Approval
Medical Director
13-Oct-2022 23:04:08 GMT+0000
Approved on 13 Oct 2022 GMT
PPD
PPD