A Master Protocol for Randomized, Placebo-Controlled, Phase 2 Clinical Trials of Multiple Interventions for the Treatment of Chronic Pain
Phase: PHASE2
Conditions: Osteoarthritis, Knee, Diabetic Neuropathic Pain, Chronic Low-back Pain
Sponsor: Eli Lilly and Company

Protocol: H0P-MC-CPMP (a) 
 
 
A Master Protocol for Randomized, Placebo-Controlled, Phase 2 Clinical Trials of MulƟple 
IntervenƟons for the Treatment of Chronic Pain 
 
 
NCT05986292 
 
 
Approval Date: 11-Dec-2020 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
1
Title P a ge
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al 
i n v e sti g ati o n of i nt er v e nti o n s i n cl u d e d i n t h e m a st er pr ot o c ol, u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.  
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al 
i nfor m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y 
p u bli c r el e a s e.  I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m a ti o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot b e 
r epr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
Pr ot oc ol Title:
A M aster P r ot oc ol f or R a n d o mize d, P lace b o- Co ntr olle d, P hase 2 C li nical T rials
of  Mul tiple Int er ve nt i ons f or t he T reat me nt of C hr o ni c P ai n
Pr ot oc ol N u m ber: H 0 P -M C -C P M P
A me n d me nt N u m ber: a
C o m p o u n d : M ulti -m olec ule c o de L Y 9 0 0 0 2 8
St u d y P h ase: 2
S h ort Title: A Master Pr ot oc ol f or C hr o nic Pai n
Acr o n y m: C P M P
S p o ns or N a me: El i Lill y  a n d C o mpa n y
Le g al Re gistere d A d dress: I n dia na p olis, I n dia na U S A 4 6 2 8 5
Re g ul at or y A ge nc y I de ntifier N u m ber
I N D: 1 4 4 9 1 5
A p pr o v al D ate:
Pr ot oc ol a me n d me nt (a) El e ctr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n date pr o vi de d bel o w   
A p pr o v al D at e: 1 1- D e c- 2 0 2 0 G M T

CONFIDENTIAL
Protocol number H0P-MC-CPMP(a)
2
Medical Monitor Name and Contact Information will be provided separately.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
3
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
Ori gi nal Pr ot oc ol
3 0 Ja n uar y 2 0 2 0
A me n d me nt [ a] 
O ver all R ati o n ale f or t he A me n d me nt:
T his a me n d me nt a d dresses 

F D A fee d bac k

 

c ha n ges t o t he sc he d ule o f acti vit ies

clarificatio n of  use of me dicat i ons f or c hr o nic pai n a n d resc ue me dicati o n g ui deli nes

s p o ns or pr ot oc ol te m plate u p dates t o pr o vi de m ore trial e xec ut i on fle xi bility

statistical a nal yses u p dates, a n d

ot her clarificat i ons t hr o u g h o ut t he pr ot oc ol .
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
1 .1 S y n o psis
Sec o n dar y o bjecti ves – Ot her Efficac y - c ha n ge 
i n se veral e n d p oi nts fr o m “ greater t ha n” t o 
“ greater t ha n or e q ual t o”...
Statisticia n decisi o n 
1. 1 S y n o psis
Sec o n dar y o bjecti ves – Ot her Efficac y - c ha n ge 
i n se veral e n d p oi nts fr o m “2- p oi nt re d ucti o n ” t o 
“a t least 2-p oi nt re d ucti o n ”...
Statisticia n decisi o n 
1. 1 S y n o psis
Sec o n dar y o bjecti ves – Ot her Efficac y - c ha n ge 
i n se veral e n d p oi nts fr o m “treat me nt res p o nse 
wit h a 3 0 %, 5 0 %, a n d 7 0 % re d ucti o n” t o “first 
pai n re d ucti o n of at least 3 0 %, 5 0 %, a n d 
7 0 %”...
Statisticia n decisi o n 
1. 1 S y n o psis
Sec o n dar y o bjecti ves – Ot her Efficac y - c ha n ge 
i n se veral e n d p oi nts fr o m “ Ti me t o 2-p oi nt 
re d ucti on” t o “ Ti me t o first pai n re d ucti o n of at 
least 2 p oi nts”...
Statisticia n decisi o n 
1. 1 S y n o psis
U p date d O verall Desi g n, Visit 2 t o clarif y t he 
was h o ut peri o d s h o ul d be gi n at Visit 2 , a n d t he 
rec o m me n de d mi ni m u m was h o ut is 2 da ys.
C larificati o n
1. 1 S y n o psis
C ha n ge d Data M o nit ori n g C o m mittee ( D M C) 
t o Assess me nt C o m mittee ( A C)
C orrecti o n t o m ore acc uratel y 
descri be c o m mittee
1. 3 Sc he d ule of Acti vities
U p date d n otes f or pai n me dicati o n was h o ut t o 
s pecif y t he ‘rec o m me n de d mi ni m u m was h o ut 
d urati o n is 2 da ys’ , a n d if partici pa nts are n ot 
ta ki n g me dicati o n f or c hr o nic pai n at scree ni n g, 
C larificati o n
C CI

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
4
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
a was h o ut is n ot re q uire d.
1. 3 Sc he d ule of Acti vities
A d de d f o ot n ote ‘ d’ t o a p pr o priate Visit 2 
pr oce d ures a n d re m o ve d re d u n da nt te xt fr o m 
n otes
clarificati on
1. 3 Sc he d ule of Acti vities
Re m o ve d vital si g ns pr oce d ures o n Visits 3
t hr o u g h 7
Vital si g n pr oce d ures f or t hese 
visits will be detaile d i n t he 
I S As
1. 3 Sc he d ule of Acti vities  
A d de d res pirat or y rate t o vital si g ns n otes
Base d o n F D A fee d bac k.
1. 3 Sc he d ule of Acti vities
Re m o ve d f o ot n ote “ d” a n d a d de d g ui da nce i n 
n otes secti o n
V isit 2 pr oce d ure s h o ul d be 
re peate d if > 6 0 da ys fr o m Visit 
1
1. 3 Sc he d ule of Acti vities
U p date d n otes f or resc ue me dicati o n usa ge 
re p orti n g t o clarif y t otal q ua ntit y fr o m a n y 
s o urce
clarificati on
1. 3 Sc he d ule of Acti vities
A d de d C -S S R S a n d ass ociate d Self -har m f or m 
pr oce d ures at Visit 2
c orrecti o n
1. 3 Sc he d ule of Acti vities
A d de d B 1 2, met h yl mal o nic aci d a n d 
h o m oc ystei ne t o la bs f or Visit 1
Me dical decisi o n
1. 3 Sc he d ule of Acti vities
A d de d alc o h ol c o ns u m pti o n c ollecte d at all 
Visits
Me dical decisi o n
1. 3 Sc he d ule of Acti vities
A d de d recreati o nal dr u g use c ollecte d at Visit 1
F or scree ni n g p ur p oses
1. 3 Sc he d ule of Acti vities
A d de d Self -Pai n P ositi o ni n g Q uesti o n naire at 
Visit 2
P art of t he di gital bi o mar kers 
a nal ysis
3. 0 O bjecti ves a n d E n d p oi nts
Sec o n dar y o bjecti ves – Ot her Efficac y - c ha n ge 
i n se veral e n d p oi nts fr o m “ greater t ha n” t o 
“ greater t ha n or e q ual t o”...
Statisticia n decisi o n 
3 . 0 O bjecti ves a n d E n d p oi nts
Sec o n dar y o bjecti ves – Ot her Efficac y - c ha n ge 
i n se veral e n d p oi nts fr o m “ 2-p oi nt re d ucti o n” t o 
“at least 2-p oi nt re d ucti o n”...
Statisticia n decisi o n 
3. 0 O bjecti ves a n d E n d p oi nts
Sec o n dar y o bjecti ves – Ot her Efficac y - c ha n ge 
i n se veral e n d p oi nts fr o m “treat me nt res p o nse 
wit h a 3 0 %, 5 0 %, a n d 7 0 % re d ucti o n” t o “first 
pai n re d ucti o n of at least 3 0 %, 5 0 %, a n d 
7 0 %”...
Statisticia n decisi o n 
3. 0 O bjecti ves a n d E n d p oi nts
Sec o n dar y o bjecti ves – Ot her Efficac y - c ha n ge 
i n se veral e n d poi nts fr o m “ Ti me t o 2 -p oi nt 
re d ucti on” t o “ Ti me t o first pai n re d ucti o n of at 
least 2 p oi nt”...
Statisticia n decisi o n 
4. 1. 1 Desi g n O utli ne
U p date d Visit 2 t o clarif y t he was h o ut peri o d 
s h o ul d be gi n at Visit 2.
clarificati on
4. 1. 1 Desi g n O utli ne
A d de d rec o m me n de d mi ni m u m was h o ut 
d urati o n is 2 da ys t o Visit 2.
clarificati on
5. 1 I ncl usi o n Criteria
U p date d Criteri o n # 9 t o sa y … all me dicati o ns 
ta ke n f or c hr o nic pai n c o n diti o ns …
Clarificati o n t hat all 
me dicati o ns ta ke n f or c hr o nic 
C CI
C CI

CONFIDENTIAL
Protocol number H0P-MC-CPMP(a)
5
Section # and Name
Description of Change
Brief Rationale
pain conditions, not just for 
condition under study will be 
discontinued 
5.2 Exclusion Criteria
Updated Criterion #23 to say…ideation or 
behavior occurred within the past 2 months 
prior to randomization
Clarification of 2 month 
window prior to randomization
5.2 Exclusion Criteria
Updated criteria #27 and #28 to specify when a 
participant received at least one dose of 
investigational intervention
Clarification of situations where 
a participant may not have 
received intervention in a study
5.2 Exclusion Criteria
Medical Conditions. Added criterion #32 have 
fibromyalgia
Medical decision
5.3 Lifestyle Considerations
Added sub-header Study Restrictions.  Updated 
the first bullet to say use of medications for 
chronic pain conditions.  Removed second 
bullet about modification of pharmacologic 
therapies for conditions other than chronic pain.
Clarification of information and 
removal of repeated information 
already stated in Section 6.5
5.3 Lifestyle Considerations
Added information for caffeine, alcohol and 
activities
5.4 Screen Failures
Replaced “operations manual” with the 
“schedule of activities” in the table
Correction
5.4.1 Participation in Multiple 
ISAs
Moved one bullet up and added exceptions to 2 
other bullets for participants that did not receive 
intervention
Clarification for participants 
that were randomized but did 
not receive intervention
6.2 Preparation/Handling/
Storage/Accountability
Updates to provide additional flexibility for 
study conduct
Sponsor protocol template 
updates
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding
Removed “case report form” from last bullet of 
unblinding table.  The date and reason that the 
blind was broken must be recorded in the 
source documentation of the appropriate ISA.
Correction
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding
Updates to provide additional flexibility for 
study conduct
Sponsor protocol template 
updates
6.4 Study Intervention 
Compliance
Updates to provide additional flexibility for 
study conduct
Sponsor protocol template 
updates
6.5 Concomitant Therapy
Entire section updated  
To provide more clarity for 
permitted, prohibited, and 
rescue medication
7.1 Discontinuation of Study 
Intervention
Changed DMC to AC
Corrected throughout protocol
7.2.1 Discontinuation of 
Inadvertently Enrolled 
Participants
Removed “clinical research physician” (CRP) 
from…the investigator must obtain documented 
approval from the sponsor…
Documented approval from the 
sponsor does not need to be 
from a CRP
7.3 Lost to Follow-up
Updates to provide additional flexibility for 
study conduct
Sponsor protocol template 
updates
8.1.1 Screening and 
Preliminary Data Entry Period
Numeric Rating Scale.  Replaced “Exclusion” 
with “Inclusion” criteria for the PDEP…
And updated link to Section 5.1
Correction
8.1.3.4 Sleep Quality
Updated the MOS sleep scale description
Scale update

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
6
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
8. 2. 3 Electr ocar di o gra ms
E val uati n g E C Gs. C ha n ge d “sitti n g” t o 
“s u pi ne”
C ollecti o n s h o ul d occ ur w hile 
partici pa nt is s u pi ne.
8. 2. 4 Cli nical Safet y 
La b orat o r y Assess me nts
U p dates t o pr o vi de a d diti o nal fle xi bilit y f or 
st u d y c o n d uct
S p o ns or pr ot oc ol te m plate 
u p dates
9. 3 P o p ulati o ns f or A nal yses
U p date d p o p ulati o n descri pti o n ta ble f or 
E nr olle d, M o difie d I T T, Safet y, a n d E n ha nce d 
I T T p o p ulati o ns
Base d o n fee d bac k fr o m t he 
F D A
9. 4. 1 Ge neral C o nsi derati o ns
U p date d I S A S A P i nf or mati o n f or b orr o wi n g
Statisticia n decisi o n
9. 4. 2 Pri mar y E n d p oi nt a n d 
A nal y sis
U p date d t he p o p ulati o n f or t he pri mar y efficac y 
a nal ysis, u p date d t he o utc o me varia ble, a n d 
re m o ve d t he c o nti n u o us fi xe d c o variates i n 
m o del
Per u p dates i n Secti o n 9. 3, 
fee d bac k fr o m t he F D A, a n d 
statisticia n decisi o n, 
res pecti vel y
9. 4. 2. 1 Ke y Feat ures of t he 
Ba yesia n Pri mar y Efficac y 
A nal y sis M o del
A d de d s u b -hea der f or B orr o wi n g Strate g y a n d 
u p date d te xt f or t he decisi o ns o n b orr o wi n g of 
place b o a n d treat me nt -effect i nf or mati o n  
Clarificati o n 
9. 4. 3 Sec o n dar y E n d p oi nts 
a n d A nal ysis
U p date d o utc o me varia ble a n d re m o ve d 
c o nti n u o us fi xe d c o variates i n m o del
Per F D A fee d bac k a n d s p o ns or 
decisi o n
9. 4. 3 Sec o n dar y E n d p oi nts 
a n d A nal ysis
M o ve d t he ta ble t o S ecti o n 9. 4. 3. 1 . I n t he ta ble,
u p date d t he o utc o me varia ble, re m o ve d t he 
c o nti n u o us fi xe d c o variates i n t he m o del, a n d 
u p date d t he fi xe d cate g orical effects 
Statisticia n decisi o n
9. 4. 3. 1 C o n ti n u o us Efficac y 
A nal y ses
Ta ble fr o m 9. 4. 3. m o ve d t o t his secti o n a n d 
c o nte nt u p date d.
Statisticia n decisi o n
9. 4. 3. 2 Cate g orical Efficac y 
A nal y ses
C ha n ge i n se veral e n d p oi nts fr o m “ greater 
t ha n” t o “ greater t ha n or e q ual t o”... a n d fr o m 
“ 2-p oi nt re d ucti o n …” t o “at least 2-p oi nt 
re d ucti on …”
Statisticia n decisi o n
9. 4. 3. 2 Cate g orical Efficac y 
A nal y ses
U p date d t he o utc o mes fr o m “ greater t ha n” t o 
“ greater t ha n or e q ual t o…”.
U p date d t he o utc o mes fr o m “a 2-p oi nt 
re d ucti on f r om baseli ne” t o “at least a 2 -p oi nt 
re d ucti on f r om baseli ne” .
A d de d t he m o del c o variates
Statisticia n decisi o n
9. 4. 3. 3 Ti me t o E ve nt 
Efficac y A nal yses
U p date d last 2 b ullets t o sa y, “ti me t o first pai n 
re d ucti on of at least 2 -p oi nts” …
Parallel se nte nce str uct ure of 
o utc o mes
9. 4. 3. 3 Ti me t o E ve nt 
Efficac y A nal yses
A d de d t he “ti me t o e ve nt” a nal yses base d o n 
dail y  N R S sc ore
Statisticia n decisi o n
9. 4. 4 Tertiar y/ E x pl orat or y 
E n d p oi nts
A d de d bi o mar ker a nal ysis 
S p o ns or’s decisi o n
9. 4. 7 S u b gr o u p A nal yses
S u b gr o u p a nal yses m o del c o variates are 
u p date d
Statisticia n decisi o n
9. 6 Data M o nit ori n g 
C o m mittee
C ha n ge d D M C t o A C a n d a d de d i nf or mati o n 
f or t he A C a n d A C c harter.
C orrecti o n t o m ore acc uratel y 
descri be c o m mittee a n d its 
res p o nsi bilities
1 0. 1. 1 Re g ulat or y a n d Et hical 
C o nsi derati o ns
U p dates t o pr o vi de a d diti o nal fle xi bilit y f or 
st u d y c o n d uct.  F o urt h b ullet, …” o versi g ht of 
S p o ns or pr ot oc ol te m plate 
u p dates
C CI

CONFIDENTIAL
Protocol number H0P-MC-CPMP(a)
7
Section # and Name
Description of Change
Brief Rationale
study conduct for participants under their 
responsibility…”
10.1.5 Committees Structure
Changed DMC to AC and updated 
responsibilities of the SASC
Correction to more accurately 
describe committee and its 
responsibilities
10.1.7 Data Quality 
Assurance
Updates to provide additional flexibility for 
study conduct
Sponsor protocol template 
updates
10.1.7 Data Quality 
Assurance
Added digital biomarker data information
If available, digital biomarker 
devices will be used in the study
10.1.12 Long-term Sample 
Retention
Updated terminology in table and changed 
sample retention from 15 to 7 years for 
exploratory biomarker sample.
Per updated sponsor guidelines
10.2 Appendix 2: Clinical 
Laboratory Tests
Added new text for local laboratory testing
Sponsor protocol template 
updates
10.2 Appendix 2: Clinical 
Laboratory Tests
Added B12, methylmalonic acid and 
homocysteine
Per schedule of activities update
10.2 Appendix 2: Clinical 
Laboratory Tests
Pharmacogenetic and Exploratory Biomarker 
Sample Collection table, updated terminology 
and changed plasma to whole blood
Correction per updated sponsor 
guidelines.
11 References
Added Liang, Zeger 2000 reference
Used in Section 9.4.2.
Throughout the protocol
Minor editorial and formatting changes
Minor, therefore not described

CONFIDENTIAL
Protocol number H0P-MC-CPMP(a)
8
Table of Contents
1.
Protocol Summary....................................................................................................11
1.1.
Synopsis.....................................................................................................................11
1.2.
Schema.......................................................................................................................15
1.3.
Schedule of Activities (SoA) ......................................................................................16
2.
Introduction..............................................................................................................23
2.1.
Study Rationale ..........................................................................................................23
2.2.
Background ................................................................................................................23
2.3.
Benefit/Risk Assessment ............................................................................................24
3.
Objectives and Endpoints.........................................................................................25
4.
Study Design .............................................................................................................27
4.1.
Overall Design............................................................................................................27
4.1.1.
Design Outline............................................................................................................27
4.2.
Scientific Rationale for Study Design .........................................................................28
4.3.
Justification for Dose..................................................................................................29
4.4.
End of Study Definition..............................................................................................29
5.
Study Population ......................................................................................................30
5.1.
Inclusion Criteria........................................................................................................30
5.2.
Exclusion Criteria.......................................................................................................31
5.3.
Lifestyle Considerations .............................................................................................33
5.4.
Screen Failures...........................................................................................................34
5.4.1.
Participation in Multiple ISAs.....................................................................................34
6.
Study Intervention....................................................................................................36
6.1.
Study Intervention Administered ................................................................................36
6.2.
Preparation/Handling/Storage/Accountability.............................................................36
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................36
6.3.1.
Stratification...............................................................................................................37
6.4.
Study Intervention Compliance...................................................................................37
6.5.
Concomitant Therapy .................................................................................................38
6.6.
Dose Modification......................................................................................................39
6.7.
Intervention after the End of the Study........................................................................39
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................40
7.1.
Discontinuation of Study Intervention ........................................................................40
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................41
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................41
7.3.
Lost to Follow-Up ......................................................................................................42
8.
Study Assessments and Procedures .........................................................................43
8.1.
Efficacy Assessments .................................................................................................43
8.1.1.
Screening and Preliminary Data Entry Period .............................................................43
8.1.2.
Primary Efficacy Outcome Measure–Pain Intensity using 
Numeric Rating Scale .................................................................................................44

CONFIDENTIAL
Protocol number H0P-MC-CPMP(a)
9
8.1.3.
Secondary Efficacy Outcome Measures......................................................................44
8.2.
Safety Assessments ....................................................................................................45
8.2.1.
Physical Examinations................................................................................................46
8.2.2.
Vital Signs..................................................................................................................46
8.2.3.
Electrocardiograms.....................................................................................................46
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................47
8.2.5.
Hepatic Safety Monitoring..........................................................................................47
8.2.6.
Suicidal Ideation and Behavior Risk Monitoring.........................................................50
8.3.
Adverse Events and Serious Adverse Events ..............................................................51
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................51
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................51
8.3.3.
Follow-Up of AEs and SAEs ......................................................................................52
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................52
8.3.5.
Pregnancy...................................................................................................................52
8.3.6.
Complaint Handling ...................................................................................................52
8.4.
Treatment of Overdose ...............................................................................................52
8.5.
Pharmacokinetics........................................................................................................53
8.6.
Pharmacodynamics.....................................................................................................53
8.7.
Genetics .....................................................................................................................53
8.8.
Biomarkers.................................................................................................................53
8.9.
Immunogenicity Assessments.....................................................................................54
8.10.
Health Economics.......................................................................................................54
9.
Statistical Considerations.........................................................................................55
9.1.
Statistical Hypotheses.................................................................................................55
9.2.
Sample Size Determination.........................................................................................55
9.3.
Populations for Analyses ............................................................................................56
9.4.
Statistical Analyses.....................................................................................................56
9.4.1.
General Considerations...............................................................................................56
9.4.2.
Primary Endpoint and Analysis...................................................................................58
9.4.3.
Secondary Endpoints and Analysis .............................................................................60
9.4.4.
Tertiary/Exploratory Endpoints...................................................................................63
9.4.5.
Treatment Group Comparability .................................................................................63
9.4.6.
Safety Analyses ..........................................................................................................63
9.4.7.
Subgroup Analyses.....................................................................................................65
9.4.8.
Sensitivity Analysis ....................................................................................................65
9.5.
Interim Analyses.........................................................................................................65
9.6.
Data Monitoring Committee .......................................................................................66
10.
Supporting Documentation and Operational Considerations ................................67
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................67
10.1.1.
Regulatory and Ethical Considerations........................................................................67
10.1.2.
Financial Disclosure ...................................................................................................67
10.1.3.
Informed Consent Process ..........................................................................................67
10.1.4.
Data Protection...........................................................................................................68
10.1.5.
Committees Structure .................................................................................................68

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Protocol number H0P-MC-CPMP(a)
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10.1.6.
Dissemination of Clinical Study Data .........................................................................69
10.1.7.
Data Quality Assurance ..............................................................................................69
10.1.8.
Source Documents......................................................................................................70
10.1.9.
Study and Site Start and Closure.................................................................................71
10.1.10. Publication Policy.......................................................................................................71
10.1.11. Investigator Information .............................................................................................71
10.1.12. Long-Term Sample Retention.....................................................................................72
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................73
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting......................................................76
10.3.1.
Definition of AE.........................................................................................................76
10.3.2.
Definition of SAE.......................................................................................................77
10.3.3.
Recording and Follow-Up of AEs and/or SAEs ..........................................................78
10.3.4.
Reporting of SAEs......................................................................................................79
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................81
10.5.
Appendix 5: Genetics .................................................................................................83
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-Up 
Assessments ...............................................................................................................84
10.7.
Appendix 7: Abbreviations .........................................................................................87
11.
References.................................................................................................................91

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Protocol number H0P-MC-CPMP(a)
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title:
A Master Protocol for Randomized, Placebo-Controlled, Phase 2 Clinical Trials of Multiple 
Interventions for the Treatment of Chronic Pain
Rationale:
The Phase 2 proof-of-concept master protocol is designed to efficiently assess the potential 
efficacy of novel interventions in multiple chronic pain conditions.
Objectives and Endpoints
Objective
Endpoint Measure
Primary
Pain Intensity
Efficacy of each study intervention 
versus placebo
Mean change from baseline assessment to endpoint for average pain 
intensity as measured by numeric rating scale (NRS)
Secondary
Physical Functioning
Efficacy of each study intervention 
versus placebo
Mean change from baseline assessment to endpoint for physical 
functioning measures as described in the disease-state addenda (DSA)
Overall Improvement
Efficacy of each study intervention 
versus placebo
Mean change from baseline assessment to endpoint for overall 
improvement as measured by Patient’s Global Impression of Change
Other Efficacy
Efficacy of each study intervention 
versus placebo

Mean change from baseline assessment to endpoint for worst 
pain intensity as measured by NRS

Proportion of participants with a pain reduction from baseline 
greater than or equal to 30%, 50%, and 70% as measured by the 
average and worst pain responses on the NRS

Proportion of participants with at least 2-point reduction from 
baseline as measured by the average and worst pain responses on 
the NRS

Time to first pain reduction of at least 30%, 50%, and 70% from 
baseline as measured by the average and worst pain responses on 
the NRS

Time to first pain reduction of at least 2 points from baseline as 

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Protocol number H0P-MC-CPMP(a)
12
measured by the average and worst pain responses on the NRS

Mean change from baseline assessment to endpoint on the visual 
analog scale (VAS) for pain

Proportion of participants with pain reduction from baseline 
greater than or equal to 30%, 50%, and 70% as measured by 
VAS

Mean change from baseline assessment to endpoint on the Sleep 
Scale from the Medical Outcomes Study (MOS Sleep Scale)

Proportion of participants with reduction from baseline greater 
than or equal to 30%, 50%, and 70% on the physical functioning 
measures as described in the DSA, and

Summary of frequency, timing, and amount of rescue medication 
used during the treatment phase.
Emotional Functioning
Efficacy of each study intervention 
versus placebo on patient-reported 
clinical outcomes
Mean change from baseline assessment to endpoint for emotional 
functioning as measured by the EuroQol-5D 5 level questionnaire 
(EQ-5D-5L)
Overall Design
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 2, proof-of-concept 
master protocol with appendices to compare independent pain interventions versus placebo.
The master protocol

establishes entry criteria for the master protocol

establishes an overarching structure for the disease-state addenda (DSA)

outlines the randomization schema

tests a common hypothesis across multiple indications and interventions, and

facilitates advanced statistical modeling and operational efficiencies.
The DSA will contain specific study elements to appropriately define the target population and 
unique scales for assessment.  The chronic pain disease states of interest currently include
osteoarthritis, chronic low back pain, and diabetic peripheral neuropathic pain.  Disease-state 
addenda for additional pain conditions may be added as needed.
The master protocol also governs intervention-specific appendices (ISAs).  The ISAs

contain study elements specific to the interventions under study, such as dosing regimen, 
unique eligibility criteria and assessments, or other requirements

may start independently of one another as interventions become available for clinical 
testing, and

may end independently, either when an intervention has concluded, or as interim analyses 
show that an intervention’s criteria for futility or success have been met.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
1 3
Scree ni n g Peri o d
T he i n vest i gat or deter mi nes w hat D S A t he p ote ntial partici pa nt will be scree ne d f or base d o n t he 
parti ci pa nt’s c hief c o m p lai nt.
Visit 1
I ntereste d partici pa nts will
1.
sig n t he a p pr o pri ate i nf or me d c o nse nt d oc u me nt(s) pri or t o c o m pleti o n o f a n y pr oce d ures
2.
c o mpl et e m aster pr ot oc ol scree ni n g i n a d va nce of or i n parallel wit h scree ni n g f or a n y  
I S A, a n d
3.
parti ci pate i n scree ni n g f or all acti vel y e nr o lli n g I S As wi t hi n t he disease-state a d de n d u m.
T he int eracti ve w e b-res p o nse syste m  (I W R S) will be use d t o c o nfir m a ct i vel y e nr olli n g I S As
wi t hi n t he disease state-a d de n d u m.  Partici pa nts ma y o pt t o scree n f or s u bse q ue nt I S As t hat 
bec o me act i ve pri or t o Visit 2.
T he site deter mi nes t he half -life of eac h me dicatio n t he parti ci pa nt is c urre nt l y ta ki n g f or c hr o nic 
pai n t o a p pr o priatel y sc he d ule Visit 2.
Visit 2
T he a p pr o pri ate ti me t o sc he d ule Visit 2 de pe n ds o n t he 5-half -life was h o ut peri o d re q uire d f or 
me dicat i ons ta ke n f or c hr o nic pai n a n d t he mi ni m u m 7- da y p reli mi nar y d ata ent r y perio d 
( P D E P) re q uire d pri or t o Visit 3.
T he was h o ut peri o d s h o ul d be gi n at Vi sit 2.
If partici pa nts are n ot ta ki n g me dicati on f or c hr o nic pai n d uri n g scree ni n g , a was h o ut is 
n ot re q uire d.
T he rec o m me n de d mi ni m u m was h o ut d urati o n is 2 da y s.  If a partici pa nt is ta ki n g a me dicati o n 
t hat re q uires a ta pere d disc o nt i n uati on t hat is l on ger t ha n 5 half -li ves, t he n t he me dicati on la bel 
i nstr uctio ns f or disc o nt i n uati on s h o ul d be f o ll ow e d.
T he 7 -d a y  P D E P is re q uire d f or all partici pa nts re gar dless of was h o ut d urati o n .  T he P D E P 
i ncl u des dail y pa rtici pa nt  re p orti n g of pai n se verity o n t he n u meric rati n g scale a n d i nf or mat i on 
o n resc ue m e dicat i on use.
T he s cree ni n g perio d is c o m plete u p o n i n vesti gat or c o nfir mati o n of all scree ni n g pr oce d ures f or 
t he master a n d all act i ve I S As.
Visit 3
T he a p pr o pri ate ti me t o sc he d ule Visit 3 is after c o m pleti on of t he was h o ut peri o d a n d re q uire d 
P D E P.  Visit 3 is t he c o m m o n p o i nt of ra n d omizat i o n wit hi n t he master pr ot oc ol f or eac h I S A.
F oll o w - Up Visit
V isits be y o n d t he 8 -wee k treat m e nt perio d ma y  be s pecifie d i n a n i n di vi d ual I S A.
R a n d o miz ati o n a n d Bli n di n g
C CI

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Protocol number H0P-MC-CPMP(a)
14
All participants will be centrally randomized to an ISA and to study intervention within an ISA 
using an IWRS. The IWRS will be programmed with unblinding instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participants’ intervention assignment is warranted. However, the investigator should make all 
attempts to contact the Medical Monitor in advance of unblinding.
Participants
Male and female participants are eligible for inclusion in the study if they have a history of daily 
pain based on participants’ report or medical history.
Disclosure Statement:
This is a master protocol for randomized, investigator- and participant-blind, placebo-controlled, 
Phase 2 clinical trials of multiple interventions for the treatment of chronic pain.
Number of Participants:
The number of participants will be specified in each respective ISA.
Intervention Groups and Duration:
Information about study intervention is provided in each respective ISA.
Each ISA will have an 8-week double-blind treatment period.
Due to the subjective nature of pain assessments and the desire to mitigate the placebo response
seen in clinical studies evaluating pain treatments, ISAs may have an unblinded ethical review 
board supplement that contains information about study design elements such as active treatment 
initiation, duration, and termination.
Data Monitoring Committee: Yes
These committees will be established to support the master protocol and ISA teams:

Assessment Committee

Internal Steering Committee, and

Internal Statistical Analysis Subcommittee.

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Protocol number H0P-MC-CPMP(a)
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1.2.
Schema
*Medication washout and preliminary data entry period begins.
Abbreviations:  ISA = intervention-specific appendix; PDEP = preliminary data entry 
period; V = visit.
Note:  Several aspects of the study design are blinded to investigators and clinical staff. 
Depending on the ISA design, an ethical review board supplement may be used.
Optional follow-up periods beyond the 8-week double-blind period may be specified in 
an individual ISA.
Washout
& PDEP
V1
V3
Week 2
V4
Week 4
V5
Week 6
V6
Week 8
V7
-10 days to V3
V2*
Screening
Period
Randomization 
to ISA
Double-Blind
Period
Post-
treatment 
Follow-up 
Period
Screening for the master and an ISA may 
occur at the same visit
ISA A
ISA B
ISA-specific visits run in parallel to the 
master protocol visits
Placebo
Intervention
V801+
Placebo
Intervention

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Protocol number H0P-MC-CPMP(a)
16
1.3.
Schedule of Activities (SoA)
The activities applicable to all disease states and interventions studied under the master protocol 
are described in the SoA below.

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Protocol number H0P-MC-CPMP(a)
17
Screeninga
Double-Blind Treatment Period
H0P-MC-CPMP 
Master Protocol
Screening
Visit for 
Master
Pre-
Randomization 
Screening
Visit
Randomization 
to ISA
Early 
Discontinuation
Notes
Visit Number
V1b
V2c
V3
V4
V5
V6
V7
ED
Visits after V7 may be specified in the ISA.
Study Week
Up to -6 
months
-10 to -7 days 
for most 
participants
0
2
4
6
8
Procedure/
Assessments
Informed consent for 
master protocol
X
Informed consent 
for ISA
X
ISA-specific informed consent may occur after other 
V1 procedures and prior to beginning the medication 
washout if the ISA is not available at the time of initial 
screening.
Evaluate master 
protocol I/E criteria
X
X
X
Pain medication 
washout
X
Duration of washout is at least 5 half-lives of the 
longest half-life medication taken for pain. 
Recommended minimum washout duration is 2 days.
If participants are not taking medication for chronic 
pain during screening, a washout is not required.
PDEP
X
7-day minimum NRS data and rescue use medication 
collected daily at home post washout and prior to 
randomization.
Medical history
X
Family history
X

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Protocol number H0P-MC-CPMP(a)
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Screeninga
Double-Blind Treatment Period
H0P-MC-CPMP 
Master Protocol
Screening
Visit for 
Master
Pre-
Randomization 
Screening
Visit
Randomization 
to ISA
Early 
Discontinuation
Notes
Visit Number
V1b
V2c
V3
V4
V5
V6
V7
ED
Visits after V7 may be specified in the ISA.
Study Week
Up to -6 
months
-10 to -7 days 
for most 
participants
0
2
4
6
8
Demographics
X
Including age, gender, race, and ethnicity
Physical examination
X
Xd
Weight 
X
Xd
X
X
X
X
X
X
Height
X
Vital signs
X
Xd
Pulse rate, respiratory rate, blood pressure, and 
temperature taken with participant in a sitting position.
ECG
X
Xd
X
X
Triplicate ECGs.
Post randomization ECGs are included in each ISA.
AEs
X
X
X
X
X
X
X
Any events that occur after signing the ICF are 
considered AEs as defined in Section 10.3.
Preexisting 
conditions
X
Preexisting conditions not identified at V1 and started 
prior to signing the ICF should be recorded.
Concomitant 
medications
X
X
X
X
X
X
X
X
Scales, Questionnaires, and Outcome Measures
VAS for pain
X
X
X
X
X
X
X
X
V2 procedure should be repeated if >60 days from V1
NRS for pain
X
X
X
X
X
X
X
Collected daily with a take-home device. Compliance 
reviewed at each clinic visit.

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Protocol number H0P-MC-CPMP(a)
19
Screeninga
Double-Blind Treatment Period
H0P-MC-CPMP 
Master Protocol
Screening
Visit for 
Master
Pre-
Randomization 
Screening
Visit
Randomization 
to ISA
Early 
Discontinuation
Notes
Visit Number
V1b
V2c
V3
V4
V5
V6
V7
ED
Visits after V7 may be specified in the ISA.
Study Week
Up to -6 
months
-10 to -7 days 
for most 
participants
0
2
4
6
8
Rescue medication 
usage reporting
X
X
X
X
X
X
X
Total quantity from any source, collected daily with a 
take-home device. Compliance reviewed at each clinic 
visit.  See Section 6.5. for usage guidance.
Pain catastrophizing 
scale
X
PGI
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
MOS Sleep Scale
X
X
X
X
X
X
C-SSRS
X
Xd
X
X
X
X
X
X
At V1, use the C-SSRS Baseline version.  All 
subsequent assessments will use the C-SSRS Since 
Last Visit version.  
Self-Harm 
Supplement form
X
Xd
X
X
X
X
X
X
Self-Harm Follow-
Up form
X
Xd
X
X
X
X
X
X
Complete 1 form for each event identified on the Self-
Harm Supplement form.
Clinical Laboratory Tests
Hematology
X
Xd
X
X
Post randomization collections will be defined in each 
respective ISA.

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Protocol number H0P-MC-CPMP(a)
20
Screeninga
Double-Blind Treatment Period
H0P-MC-CPMP 
Master Protocol
Screening
Visit for 
Master
Pre-
Randomization 
Screening
Visit
Randomization 
to ISA
Early 
Discontinuation
Notes
Visit Number
V1b
V2c
V3
V4
V5
V6
V7
ED
Visits after V7 may be specified in the ISA.
Study Week
Up to -6 
months
-10 to -7 days 
for most 
participants
0
2
4
6
8
Chemistry
X
Xd
X
X
Post randomization collections will be defined in each 
respective ISA.
Lipid panel
X
Xd
X
X
Post randomization collections will be defined in each 
respective ISA.
Urinalysis
X
Xd
X
X
Post randomization collections will be defined in each 
respective ISA.
B12
X
Methylmalonic acid
X
Homocysteine 
X
Serum pregnancy
X
X
For women of childbearing potential.
V2 test is optional if within 30 days of V1 procedure
FSH
X
Xd
Estradiol
X
Xd
TSH
X
Xd
Post randomization collections will be defined in each 
respective ISA.
Urine drug screen
X
Collected at screening visit for all participants and by 
investigator discretion after V1.
Alcohol consumption
X
Xd
X
X
X
X
X
X

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
2 1
Scree ni n g a
D o u ble -Bli n d Tre at me nt Peri o d
H 0 P -M C -C P M P 
M aster Pr ot oc ol
Scree ni n g
Visit f or 
M aster
Pre -
R a n d o miz ati o n 
Scree ni n g
Visit
R a n d o miz ati o n 
t o I S A
E arl y 
Disc o nti n u ati o n
N otes
Visit N u m ber
V 1 b
V 2 c
V 3
V 4
V 5
V 6
V 7
E D
Visits after V 7 ma y be s pecifie d i n t he I S A.
St u d y Wee k
U p t o -6 
m o nt hs
-1 0 t o -7 da ys 
f or m ost 
partici pa nts
0
2
4
6
8
Recreati o nal dr u g 
use
X
H b A 1c
X
X d
P ost ra n d o mizati o n c ollecti o ns will be defi ne d i n eac h 
res pecti ve I SA.
HI V
X
X d
E x pl orat or y 
b i o mar ker sa m ples 
X
P ost ra n d o mizati o n c ollecti o ns will be defi ne d i n eac h 
res pecti ve I SA.
P har mac o ge netic 
sa m ple
X
P artici p a nt Q uesti o n n aire
Self -pai n p ositi o ni n g 
q uesti o n naire
X
P artici p a nt De vice
C CI

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Protocol number H0P-MC-CPMP(a)
22
Abbreviations:  AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early discontinuation; EQ-5D-5L = EuroQol-5D 
5 level questionnaire; FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; HIV = human immunodeficiency virus; ICF = informed consent form; I/E = inclusion 
and exclusion; ISA = intervention-specific appendix; MOS = Medical Outcomes Study; NRS = numeric rating scale; PDEP = preliminary data entry period; PGI = Patient 
Global Impression of Change; TSH = thyroid stimulating hormone; V = visit; VAS = visual analog scale.
a
Screening assessments may be conducted at other time points prior to randomization if they reduce participant burden.
b
The site determines the half-life of each pain medication the participant is currently taking to schedule Visit 2.  Visit 2 can be scheduled no earlier than 7 days prior to 
randomization at Visit 3 due to the required 7-day PDEP.
c
The 5-half-life washout period for pain medications must come before the required 7-day PDEP, resulting in a minimum of 10 days for most participants.
d
Visit 2 testing is optional for individuals who have completed these assessments within 60 days of Visit 1.  If the tests are repeated, the most recent results will be used for I/E
purposes.

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Protocol number H0P-MC-CPMP(a)
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2.
Introduction
Study H0P-MC-CPMP (CPMP) is a master protocol to accelerate the development of novel 
treatments for chronic pain.  This platform trial provides a framework to enable the seamless 
evaluation of efficacy and safety of interventions as hypotheses emerge.
The master protocol platform design provides an overarching infrastructure that will harness the 
benefits of operational and statistical efficiencies.
2.1.
Study Rationale
This Phase 2 proof-of-concept master protocol is designed to efficiently assess the potential 
efficacy of novel interventions in multiple chronic pain conditions.
2.2.
Background
The master protocol

establishes entry criteria for the master protocol

establishes an overarching structure for the disease-state addenda (DSA)

outlines the randomization schema

tests a common hypothesis across multiple indications and interventions, and

facilitates advanced statistical modeling and operational efficiencies.
The disease-state addenda (DSA) will contain specific study elements to appropriately define the 
target population and unique scales for assessment.  The chronic pain disease states of interest 
currently are osteoarthritis, chronic low back pain, and diabetic peripheral neuropathic pain.  
Disease-state addenda for additional pain conditions may be added as needed.
The master protocol also governs intervention-specific appendices (ISAs).  The ISAs

contain study elements specific to the interventions under study, such as dosing regimen, 
unique eligibility criteria and assessments, or other requirements

may start independently of one another as interventions become available for clinical 
testing, and

may end independently, either when an intervention has concluded, or as interim analyses 
show that an intervention’s criteria for futility or success have been met.

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Protocol number H0P-MC-CPMP(a)
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2.3.
Benefit/Risk Assessment
The overall benefit/risk assessment of each intervention is described in each respective ISA.
Information about the known and expected benefits, risks, serious adverse events (SAEs), and 
reasonably anticipated adverse events (AEs) of the interventions used in the ISAs may be found 
in their respective Investigator’s Brochures (IBs).
Detailed information about the known and expected benefits and risks of any marketed 
interventions may be found in the

Patient Information Leaflet

Patient Package Insert, or 

Summary of Product Characteristics.

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Protocol number H0P-MC-CPMP(a)
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3.
Objectives and Endpoints
Objectives and Endpoints
Objective
Endpoint Measure
Primary
Pain Intensity
Efficacy of each study intervention 
versus placebo
Mean change from baseline assessment to endpoint for average pain 
intensity as measured by the Numeric Rating Scale (NRS)
Secondary
Physical Functioning
Efficacy of each study intervention 
versus placebo
Mean change from baseline assessment to endpoint for physical 
functioning measures as described in the disease state addenda (DSA)
Overall Improvement
Efficacy of each study intervention 
versus placebo
Mean change from baseline assessment to endpoint for overall 
improvement as measured by Patient’s Global Impression of Change
Other Efficacy
Efficacy of each study intervention 
versus placebo

Mean change from baseline assessment to endpoint for worst 
pain intensity as measured by NRS

Proportion of participants with a pain reduction from baseline 
greater than or equal to 30%, 50%, and 70% as measured by 
the average and worst pain responses on the NRS

Proportion of participants with at least 2-point reduction from 
baseline as measured by the average and worst pain responses 
on the NRS

Time to first pain reduction of at least 30%, 50%, and 70% 
from baseline as measured by the average and worst pain 
responses on the NRS

Time to first pain reduction of at least 2-point from baseline as 
measured by the average and worst pain responses on the NRS

Mean change from baseline assessment to endpoint on the 
visual analog scale (VAS) for pain

Proportion of participants with pain reduction from baseline 
greater than or equal to 30%, 50%, and 70% as measured by 
VAS

Mean change from baseline assessment to endpoint on the 
Sleep Scale from the Medical Outcomes Study (MOS Sleep 
Scale)

Proportion of participants with reduction from baseline greater 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
2 6
t ha n or e q ual t o 3 0 %, 5 0 %, a n d 7 0 % o n t he p h ysical 
f u ncti o ni n g meas ures as descri be d i n t he D S A , a n d

S u m mar y of fre q ue nc y, ti mi n g , a n d a m o u nt of resc ue 
me dicati o n use d d uri n g t he treat me nt p hase.
E m oti o n al F u ncti o ni n g
Efficac y of eac h st u d y i nter ve nti o n
vers us place b o o n patie nt -re p orte d 
cli nical o utc o mes
Mea n c ha n ge f r om baseli ne assess me nt t o e n d p oi nt f or em oti o nal 
f u ncti o ni n g as meas ure d b y t he E ur o Q ol -5 D 5 le vel q uesti o n naire 
(E Q - 5 D- 5 L)
C CI

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Protocol number H0P-MC-CPMP(a)
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4.
Study Design
4.1.
Overall Design
Study Design Overview
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 2, proof-of-concept
master protocol with appendices to compare independent pain interventions versus placebo.
The master protocol contains DSA that have specific study elements to appropriately define the 
target population and unique scales for assessment.
The master protocol also governs ISAs that may start independently of other ISAs as 
interventions become available for clinical testing.
Anticipated Platform Duration
The master protocol is designed to allow interventions to enter the master protocol for an 
estimated period of 5 to 7 years.
4.1.1.
Design Outline
Screening Period
The investigator determines what DSA the potential participant will be screened for based on the 
participant’s chief complaint.
Visit 1
Interested participants will
1. sign the appropriate informed consent document(s) prior to completion of any procedures
2. complete master protocol screening in advance of or in parallel with screening for any 
ISA, and
3. participate in screening for all actively enrolling ISAs within the DSA.
The interactive web-response system (IWRS) will be used to confirm actively enrolling ISAs
within the DSA.  Participants may opt to screen for subsequent ISAs that become active prior to 
Visit 2.
The site determines the half-life of each medication the participant is currently taking for chronic 
pain to appropriately schedule Visit 2.
Visit 2
The appropriate time to schedule Visit 2 depends on the washout period required for medications 
taken for chronic pain and the minimum 7-day preliminary data entry period (PDEP) required 
prior to Visit 3.
The washout period should begin at Visit 2.
If participants are not taking medication for chronic pain during screening, a washout is 
not required.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
2 8
T he rec o m me n de d mi ni m u m was h o ut d urati o n is 2 da y s.  If a partici pa nt is ta ki n g a me dicati o n 
t hat re q uires a ta pere d disc o nt i n uati on t hat is l on ger t ha n 5 half -li ves, t he n t he me dicati on la bel 
i nstr uctio ns f or disc o nt i n uati on s h o ul d be f o ll ow e d.   
T he 7 -d a y  P D E P is re q uir e d for all  p artici pa nts re gar dless of was h o ut d urati o n .  T he P D E P 
i ncl u des dail y partici pa nt re p orti n g of pai n se verit y o n t he N u meri c R at i n g S cale ( N R S ) a n d 
i nf or mat i on o n resc u e m e dicatio n use.
T he s cree ni n g perio d is c o m plete u p o n i n vesti gat or c o nfir mati o n of all scree ni n g pr oce d ures f or 
t he master a n d all act i ve I S As.
Visit 3
T he a p pr o pri ate ti me t o sc he d ule Visit 3 is after c o m plet i on of t he was h o ut peri o d a n d re q uire d 
P D E P.   Visit 3 is t he c o m m o n p o i nt of ra n d omizat i o n wit hi n t he master pr ot oc ol f or eac h I S A.
At  t he ti me of ra n d omizati o n, t he site will c o nfir m

parti ci pa nt eli gi bilit y f or t he master pr ot oc ol, D S A , a n d eac h act i ve I S A

a d here nce wit h t he was h o ut peri o d, a n d

a d here nce wit h t he P D E P data e ntr y per t he sc he d ule of acti vities (S o A ) (Secti o n  1. 3 ).
P ote nti al p artici pa nt s will o nl y be ra n d o mize d t o a n I S A f or whic h t he y  are eli gi ble.
P arti cipa nts will be a ware of t heir I S A ra n d omiz ati o n b ut n ot t heir treat me nt ra n d o miz atio n .
F oll o w - U p Visit
V isits be y o n d t he 8 -wee k treat m e nt perio d ma y be s pecifie d i n a n i n di vi d ual I S A.
4. 2.
Scie ntific R ati o n ale f or St u d y Desi g n
T he ma ster pr ot oc ol c o nstr uct will

o ffer fle xi bility t o c o nt i n uall y a d d differe nt i nter ve nt i on s at differe nt ti me p oi nts acr oss 
differe nt partici pa nt p o p ul at i ons

ena ble efficie nt testi n g of  mul tiple pr o misi n g tar gets acr oss m ult i ple pai n states

a ll ow di rect statistical c o m paris o ns of i nter ve nt i on s st u die d wi t hi n a pai n ty pe

e na ble b orr o wi n g of
o
pl ace b o parti ci pa nt s wi t hi n a pai n ty pe, a n d
o
treat me nt -effect i nf or mat i on acr oss pai n t y p es f or a gi ve n i nter ve nt i on

facilitate s maller I S A sa mple sizes as t he tri al pr o gresses d ue t o t he a bilit y t o borr o w pl ace b o 
a n d treat me nt -effect i nf or mati o n

p r o vide p ote nti al site be nefit base d o n mul tiple t hera pi es o ffere d, a n d

o ffer c o nti n u o us scree ni n g of  partici p a nts f or fut ure i nter ve nt i on s.
T he pr o p ose d desi g n pr o vi des ma n y  u ni q ue o peratio n al a nd stati stical c halle n ges as well as 
o p p ort u nit ies t o ma ke t he best decisi o ns i n a d va nci n g m o lec ules t hr o u g h t he dr u g de vel o p me nt 
pr ocess.  
C CI

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Protocol number H0P-MC-CPMP(a)
29
The primary efficacy analysis is a Bayesian mixed-model repeated measures (MMRM) method
that allows the borrowing of placebo information within a DSA and borrowing of treatment 
difference information between different addendum pain types.  The amount of borrowing and 
the statistical methodology used to accommodate the borrowing (for example, pooling of data, 
hierarchical modeling), including the specifics of the Bayesian prior distributions, will be 
specified within each ISA.
The master protocol also allows for adaptations specified within an ISA.  The adaptations may 
include stopping for early futility, stopping for early efficacy, sample size re-estimation, or 
removal of a dose arm.
Intervention-specific design elements are described in the respective ISA.
Efficacy Assessments
The master protocol contains a core set of assessments based on the Initiative on Methods, 
Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines (Dworkin et. al. 
2005).  The recommended domains when designing chronic pain clinical studies are

pain

physical functioning

emotional functioning

participant ratings of overall improvement

adverse events (AEs), and

participant disposition.
The NRS was selected for the primary endpoint based on its demonstrated ability to detect 
changes in pain and its common use across the disease states under study.
4.3.
Justification for Dose
The justification for dose selection of each intervention is described in the respective ISA.
4.4.
End of Study Definition
The end of the master protocol will occur when all ISAs are complete and no new ISAs 
are planned.

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Protocol number H0P-MC-CPMP(a)
30
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
If participants are in the screening phase for 60 or more days, a subset of procedures must be 
repeated.  If participants are in the screening phase for 60 or more days, the most recent values 
will be used for inclusion and exclusion purposes.  Consult the SoA and the Operations Manual 
for additional guidance.
If participants are in the screening phase of the master protocol for less than 60 days and 
procedures are not required to be repeated at Visit 2, then the Visit 1 values will be used for 
inclusion and exclusion purposes unless otherwise specified.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if the following criteria apply:
Age
Age requirements for participation will be specified in the DSA and/or ISAs.
Pain Characteristics
[1]
have a visual analog scale (VAS) pain value >40 and <95 at Visits 1 and 2
[2]
have a history of daily pain for at least 12 weeks based on participant report or 
medical history
[3]
have a value of ≤30 on the pain catastrophizing scale
Weight
[4]
have a body mass index <40 kg/m2 (inclusive)
Gender
[5]
are male or female participants
Reproductive and contraceptive requirements will be specified in the ISAs.
Informed Consent and Participant Agreements
[6]
are capable of providing informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol
[7]
are reliable, willing, and able to participate in all required protocol procedures 
for the duration of the study
[8]
are willing to maintain a consistent regimen of any ongoing 
nonpharmacologic pain-relieving therapies (for example, physical therapy)
and will not start any new nonpharmacologic pain-relieving therapies during 
study participation

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Protocol number H0P-MC-CPMP(a)
31
[9]
are willing to discontinue all medications taken for chronic pain conditions,
except rescue medication permitted per protocol (Section 6.5), for the duration 
of the study
[10] must enter the required daily assessments during the PDEP for at least 5 of the 
7 days prior to randomization
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply at screening:
Medical Conditions
[11] have second- or third-degree atrioventricular (AV) heart block or AV 
dissociation or history of ventricular tachycardia
[12] have had a procedure within the past 6 months intended to produce permanent 
sensory loss in the target area of interest (for example, ablation techniques)
[13] have surgery planned during the study for any reason, related or not to the 
disease state under evaluation
[14] have, in the judgment of the investigator, an acute, serious, or unstable 
medical condition or a history or presence of any other medical illness that 
would preclude study participation
[15] there is an inability to rule out other causative or confounding sources of pain 
in the primary condition under study
[16] have had cancer within 2 years of Visit 3, except for cutaneous basal cell or 
squamous cell carcinoma resolved by excision
[32] have fibromyalgia
Diagnostic Assessments
[17] have substance use disorder as defined by the Diagnostic and Statistical 
Manual of Mental Disorders (5th edition; DSM-5; American Psychiatric 
Association)
[18] have congenital QT prolongation or QT interval corrected for heart rate using 
Fridericia’s formula (QTcF) interval measurement >450 msec for male
participants, >470 msec for female participants, or >480 msec for participants 
with bundle branch block
[19] have any clinically important abnormality at screening, as determined by 
investigator, in physical or neurological examination, vital signs, 
electrocardiogram (ECG), or clinical laboratory test results that could be 
detrimental to the participant or could compromise the study
[20] have a positive human immunodeficiency virus (HIV) test result at screening
[21] have central laboratory hepatic results at screening of

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Protocol number H0P-MC-CPMP(a)
32

alanine aminotransferase (ALT) ≥2 × the upper limit of normal (ULN)

aspartate aminotransferase (AST) ≥2 × ULN

total bilirubin (TBL) ≥1.5 × ULN, or

alkaline phosphatase (ALP) ≥1.5x ULN.
In asymptomatic individuals with a history of Gilbert’s syndrome, use TBL
of > 2 × ULN.
[22] are, in the judgment of the investigator, actively suicidal and therefore deemed 
to be at significant risk for suicide
[23] have answered ‘yes’ to either Question 4 or Question 5 on the ‘Suicidal 
Ideation’ portion of the Columbia-Suicide Severity Rating Scale (C-SSRS)
OR
have answered ‘yes’ to any of the suicide-related behaviors on the ‘suicidal behavior’
portion of the C-SSRS, and the ideation or behavior occurred within the past 
2 months prior to randomization
Prior and Concomitant Therapy/Substance of Abuse
[24] have an intolerance to acetaminophen or paracetamol or any of its excipients
[25] have a history of alcohol, illicit drug, analgesic or narcotic use disorder within 
2 years prior to Visit 1
Prior or Concurrent Clinical Trial Experience
[26] are currently enrolled in any other clinical trial involving an investigational 
intervention or any other type of medical research judged not to be 
scientifically or medically compatible with this study by the Medical Monitor
[27] have participated within the past 30 days in a clinical study and received at 
least one dose of investigational intervention, including prior CPMP ISAs
[28] have not completed all prior ISAs within the CPMP master protocol if they
received at least one dose of investigational intervention in the assigned ISA
Other Exclusions
[29] are investigator site personnel directly affiliated with this study or their 
immediate families. Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted
[30] are employees of Eli Lilly and Company (Lilly) or partners of employees of 
Lilly or employees or partners of any third-party organizations involved in 
the study
[31] have current or pending worker’s compensation, litigation, disability, or any 
other monetary settlement regarding the pain condition, or any closed claim 

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Protocol number H0P-MC-CPMP(a)
33
5.3.
Lifestyle Considerations
Study Restrictions
The following are prohibited during the study

use of medications for chronic pain conditions, except rescue medication permitted per 
protocol (Section 6.5), for the duration of the double-blind treatment period. 

use of any drugs of abuse, including but not limited to, illicit amphetamine, cocaine, 
illicit opiates, propoxyphene, methadone, methaqualone, phencyclidine, or barbiturates, 
and

initiation of nonpharmacologic pain-relieving procedures such as acupuncture or physical 
therapy, devices such as transcutaneous electrical nerve stimulation (TENS) units, or 
garments and braces.
If participants use cannabis or cannabinoids for the treatment of pain, they must discontinue 
usage for the duration of the study.
If participants use cannabis or cannabinoids for any other use, the usage should remain consistent 
for the duration of the study.
These restrictions may not apply during follow-up periods in which interventions are not taken.  
Any modifications to restrictions will be specified in the ISA.
Caffeine and Alcohol
Participants should maintain their usual caffeine intake.
Participants should limit their alcohol consumption for the duration of the study as specified 
below.  
Men up to the age of 65 years should not exceed an average weekly alcohol intake of 21 units 
per week.  
Men over the age of 65 years and women should not exceed an average weekly alcohol intake of
14 units per week.
One unit of alcohol equals

12 oz or 360 mL of beer 

5 oz or 150 mL of wine, or

1.5 oz or 45 mL of distilled spirits.
Activities
Participants are required to maintain similar levels of activity during the double-blind study 
period.  Starting a new exercise program or new strenuous activity is not allowed.  
Participants who receive physical therapy should remain on the same therapy program (intensity 
and frequency).  

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Protocol number H0P-MC-CPMP(a)
34
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the master protocol and 
appropriate ISAs but are not subsequently randomized to any ISA.  A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this master protocol (screen failure) 
may be rescreened. This table describes when a participant is considered a screen failure or 
when a participant may be rescreened.
If…
Then…
a participant does not complete screening procedures 
within 6 months of signing the master informed 
consent form
participant is considered a screen failure
a participant screen fails for the above reason
participant may be rescreened 1 time 
a participant screen fails for the pain intensity 
criterion (VAS)
participant may not be rescreened for at least 1 year 
from the date of pain severity assessment
a participant screen fails for the master protocol for 
reasons other than pain intensity criteria (VAS)
participant may be rescreened no sooner than 3 months 
from the date of screen failure
more than 60 days have passed between screening for 
the master protocol and screening for an ISA
a subset of procedures may need to be completed per 
the Schedule of Activities
a participant screen fails for a specific ISA
participant no longer has to complete the remaining 
screening procedures specific to that ISA
a participant screen fails for a specific ISA
participant is still eligible under the master protocol for 
participation in other ISAs
Abbreviations:  ISA= intervention-specific appendix; VAS = visual analog scale.
Rescreened participants should be assigned a new participant number.  Each time master 
protocol rescreening is performed, the individual must sign a new master protocol ICF.
Repeating laboratory tests during the screening period or repeating screening tests to comply 
with the protocol-designated screening period does not constitute rescreening.
5.4.1.
Participation in Multiple ISAs
Interested participants will have the opportunity to participate in multiple ISAs within the same 
disease state or for different disease states.
Participation in multiple ISAs is allowed if the participant

meets all inclusion or exclusion criteria for the master protocol, the applicable DSA, and the 
respective ISA at the time of screening

has not participated in another ISA with the same intervention

has completed the 30-day waiting period since participating in another clinical study 
involving an intervention
o
EXCEPTION – if the participant did not receive intervention, then the participant 
does not need to complete the 30-day waiting period

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Protocol number H0P-MC-CPMP(a)
35

has completed all previous ISAs without early discontinuation
o
EXCEPTION – if the participant discontinues without receiving intervention.
The intervention that the participant received in a previous ISA will have no impact on the 
randomization of treatment to the current ISA.  The number of participants who will 
participate in multiple ISAs is unknown.  Participation in more than one ISA, referred to as 
‘repeat participation,’ will be tracked at the site level, the ISA level, and at the overall master 
protocol level.
Repeat participation may introduce the potential concern that populations between ISAs may be 
too homogenous or introduce potential biases into the participant population for future ISAs, 
such as inflation or deflation of placebo response in repeat participants, or bias of completers in 
the data set.  If these issues occur, edits will be made to future amendments of the Master 
Protocol or an ISA to address this concern.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
3 6
6.
St u d y I nter ve nti o n
St u d y  i nter ve nt i on is defi ne d as a ny i n vesti gati onal i nter ve nt i on (s), mar kete d pr o d uct(s), 
pl ace b o , or m e dical de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt acc or di n g t o t he 
st u d y pr ot oc ol .
6. 1.
St u d y I nter ve nti o n A d mi nistere d
A m ult i-m o lec ule c o de of L Y 9 0 0 0 2 8 is use d f or i nter nal pur p oses.  I nter ve nt i on s pecific 
i nf or mat i on is defi ne d i n e a c h I S A.
6. 2.
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
1.
T he i n vest i gat or or desi g nee m ust c o nfir m t hat a p pr o priate st ora ge c o n dit i ons ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y  int er ve nt i on rec ei ve d a n d t hat a n y discre pa ncies 
are re p orte d a n d res ol ve d bef ore use of t he st u d y i nter ve nti on.
2.
O nl y partici pa nts e nr o lle d i n t he st u d y ma y recei ve st u d y int er ve nt i on a n d o nl y st u d y 
pers o n nel ma y s u p pl y, pre pare or a d mi nister st u d y i nter ve nt i on.
3.
All st u d y i nter ve nt i on m u st be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d 
m o nit or e d ( m a n ual or a ut o mate d) area i n acc or da nce wit h t he la bele d st ora ge c o n diti o ns 
wi t h access li mite d t o t he i n vesti gat or a n d st u d y pers o n nel.
4.
T he i n vest i gat or or a ut h orize d st ud y  pers o n nel are res p o nsi ble f or st u d y int er ve ntio n 
acc o u nta bilit y, rec o nciliat i on, a n d rec or d mai nte na nce ( t hat is, receipt, rec o nciliat i on, a n d 
fi nal dis p ositi on rec or ds).
5.
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p osit i on of u n use d st u d y  int er ve nt i ons 
are pr o vi de d i n t he I S As a n d c orres p o n di n g O perati o ns M a n u al.
6. 3.
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
T he I S As will ha ve a n 8 -wee k d o u ble -bli n d treat me nt peri o d i n w hic h partici pa nts  
 
D ue t o t he s u bject i ve nat ure of pai n assess me nts a n d t he desire t o mit i gate t he place b o res p o nse 
see n i n cli nical st u dies e val uat i n g p ote nti al pai n treat m e nts, I S As ma y ha ve a n u n bli n de d et hical 
re vie w b oar d ( E R B) s u p ple me nt t hat c o nt ai ns i nf o r mat i on a b o ut st u d y  desi g n ele me nts s uc h as 
acti ve treat me nt i nit iati on, d urati o n , a n d ter mi nat i on. 
T his ta ble descri bes h o w partici pa nts will be ra n d o mize d.
St u d y usi n g I W R S

All partici pa nts will be ce ntrall y ra n d o mize d or  assi g ne d t o a n I S A a n d
ra n d o mize d t o st u d y i nter ve nti o n wit hi n a n I S A usi n g a n I W R S

Bef ore t he st u d y is i nitiate d, t he l o gi n i nf or mati o n a n d directi o ns f or t he I W R S 
will be pr o vi de d t o eac h site

St u d y i nter ve nti o n will be dis pe nse d at t he st u d y visits as s u m marize d i n t he I S A

R et ur ne d st u d y i nter ve nti o n s h o ul d n ot be re dis pe nse d t o t he partici pa nts
A b bre viati o ns:  I S A = i nter ve nti on- s pecific a p pe n di x; I W R S = i nteracti ve we b-res p o nse s yste m.
C CI

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
3 7
T his ta ble descri bes ge neral  pr oce d ures f or u n bli n di n g.
U n bli n di n g (I W R S)

T he I W R S will be pr o gra m me d wit h u n bli n di n g i nstr ucti o ns

I n case of a n e mer ge nc y, t he i n vesti gat or has t he s ole res p o nsi bilit y f or 
deter mi ni n g if u n bli n di n g of a partici pa nts’ i nter ve nti o n assi g n me nt 
is warra nte d

Partici pa nt safet y m ust al wa ys be t he first c o nsi derati o n i n ma ki n g s uc h a 
deter mi nati o n. H o we ver, t he i n vesti gat or s h o ul d ma ke all atte m pts t o c o ntact 
t he Me dical M o nit or i n a d va nce of u n bli n di n g

If a partici pa nt’s i nter ve nti o n assi g n me nt is u n bli n de d, t he s p o ns or m ust be 
n otifie d i m me diatel y aft er brea ki n g t he bli n d e ve n if c o ns ultati o n occ urre d i n 
a d va nce

T he date a n d reas o n t hat t he bli n d was br o ke n m ust be rec or de d i n t he s o urce 
d oc u me ntati o n of t he a p pr o priate I S A , as a p plica ble
A b bre viati o ns:  I S A = i nter ve nti on- s pecific a p pe n di x; I W R S = i nteracti ve we b-res p o nse s yste m.
If a n i n vesti gat or, st u d y pers o n nel perf or mi n g assess me nts, or partici pa nt is u n bli n de d, t he 
i n vesti gat or m ust c o ntact t he st u d y s p o ns or as s o o n as p ossi ble t o deter mi ne if t he partici pa nt 
m ust be disc o nt i n ue d fr om t he st u d y. I n cases w here t here are et hical or ot her reas o ns t o ha ve 
t he partici pa nt r e mai n i n t he st u d y, t he i n vestigat or m ust o btai n s pecific a p pr o val fr o m a s p o ns or 
M e dical M o ni t or f or t he partici pa nt t o c o nti n ue i n t he st u d y.
6. 3. 1.
Str atific ati o n
If partici pa nts are eli gi ble f or m ore t ha n o ne I S A, t he y will be ra n d o ml y assi g ne d t o a n I S A
usi n g t he I W R S.  Particip ati o n i n a n I S A is n ot deci de d b y  t he sit e, p artici pa nt, or p h ysicia n.  
 
Eac h I S A will i ncl u de a stratificat i on fact or base d o n t he a vera ge baseli ne pai n se verity sc ore as 
meas ure d b y t he N R S.
T he defi nit i on of t he stratificati o n fact or is pr o vi de d as:
se vere pai n: ≥7 o n t he baseli ne N R S a vera ge pai n sc ore , or
m o derate pai n: < 7 o n t he baseli ne N R S a vera ge pai n sc ore.
A d dit i onal stratificati on fact ors ma y be defi ne d i n t he I S A or D S A.
6. 4.
St u d y I nter ve nti o n C o m pli a nce
W he n re q uire d, s t u d y int er ve nt i on will be a d mi nistere d u n der me dical s u per vis i on b y t he 
i n vesti gat or or desi g nee.  T he date a n d ti me of eac h d ose a d mi nistere d will be rec or de d i n t he 
s o urce d oc u me nts a n d rec or de d i n t he case re p ort f or m ( C R F ).  T he d ose of st u d y int er ve nt i on 
a n d st u d y partici p a nt ide nt ificati o n will be c o nfir me d pr i or t o t he ti me of d osi n g.
W he n partici pa nts self -a d mi nister st u d y int er ve nti o n(s) at h o me, c o m plia nce wit h st u d y  
i nter ve nt i on will be assesse d at eac h visit. C o m p lia nce will be assesse d b y direct q uesti o ni n g
a n d c o u nt i n g ret ur ne d st u d y int er ve nt i on per e ac h I S A a n d d oc u me nte d i n t he s o urce d oc u me nts 
a n d C R F.
A d dit i onal i nf or mati o n o n i nter ve nti on c o m plia nce will be i n t he I S A.
C CI

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6.5.
Concomitant Therapy
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with the

reason for use

dates of administration including start and end dates, and

dose and frequency.
Permitted Medication
Permitted concomitant therapy should remain stable for dosing and frequency of use throughout 
the treatment period.  The Medical Monitor should be contacted if there are any questions 
regarding concomitant therapy.
Medically required changes to concomitant medication not taken for pain may be considered on 
a case-by-case basis with the documented approval of the Medical Monitor.
Short-term use of medications such as analgesics or corticosteroids is permitted to treat medical 
conditions other than chronic pain for no more than a total of 7 days during the treatment phase. 
For these situations contact the Medical Monitor.
Rescue Medication
Permitted Rescue Medication
Acetaminophen is the ONLY allowed rescue medication.  
Maximum Daily Acetaminophen Dose
The maximum daily dose is 3000 mg per day.
This maximum amount is inclusive of combination products in which acetaminophen is 
contained.  
General guidelines for acetaminophen use and recording the dose
Beginning at Visit 2, participants will record their use and maximum total dose of 
acetaminophen daily using a take-home device.  
Rescue medication should be used at the lowest effective dose for the shortest duration possible 
throughout study participation.   
During the minimum required 7 days of the PDEP, limit use to no more than 4 days.
This table describes acetaminophen use guidance during the double-blind treatment period.
Acetaminophen Use Guidance during Visit 3 through Visit 7
Maximum dose per day
3000 mg
Maximum consecutive days
3 days
Maximum total days
14 days
The investigative site should evaluate appropriateness of rescue medication use at each visit. 
Continued education should be provided as necessary.

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Prohibited Medication
Medications for pain other than protocol permitted rescue medication are prohibited after Visit 2.
Any investigational intervention judged to be scientifically or medically incompatible with this 
study is prohibited.
These restrictions may not apply during follow-up periods in which investigational interventions 
are not taken.  Any modifications to restrictions will be specified in the ISA.
Additional information about concomitant medication use is provided in the respective ISA.
6.6.
Dose Modification
This section is not applicable for the master protocol.
6.7.
Intervention after the End of the Study
No continued access is planned after completion of each proof-of-concept master protocol ISA,
as additional efficacy would be needed to demonstrate continued access criteria.

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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention.
If study intervention is definitively discontinued, the study participant will not remain in the 
master protocol or ISA.  See the master protocol and ISA SoA for data to be collected at the time 
of discontinuation of study intervention and follow-up and for any further evaluations that need 
to be completed.
Additional criteria for discontinuation may be included in each ISA.  If an ISA criterion is more 
restrictive, it should be applied for those participants in the respective ISA.
Participants may be discontinued from study intervention if these situations occur:

based on a specific AE profile, as recommended by the Assessment Committee (AC), the 
Medical Monitor, or the study sponsor physician/scientist, in discussions with the 
Principal Investigator

incorrect enrollment

severe noncompliance to the study protocol in the judgment of the investigator

participants answered ‘yes’ to Question 4 or 5 on the ‘Suicidal Ideation’ portion of the 
C-SSRS, or

participants answered ‘yes’ to any of the suicide-related behaviors on the Suicidal 
Behavior portion of the C-SSRS.
o
a psychiatrist or appropriately trained professional may assist in the decision to 
discontinue the participant for C-SSRS responses.
Liver Safety
Discontinuation of the intervention should be considered when a participant meets one of the 
following conditions after consultation with the sponsor-designated Medical Monitor.  

ALT or AST >8 × ULN

ALT or AST >5 × ULN for more than 2 weeks

ALT or AST >3 × ULN and either TBL >2 × ULN or international normalized ratio 
(INR) >1.5, or

ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

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The discontinuation criteria are applicable for participants with no known liver disease and 
normal or near normal baseline liver tests of

ALT< 2 × ULN

TBL <1.5 × ULN, and

ALP <1.5 × ULN.
Cardiovascular Safety
If a clinically significant finding is identified including, but not limited to, changes from baseline 
in QTcF after enrollment, the investigator or qualified designee will determine if the study 
participant can continue in the master protocol or ISA, and if any change in study participant 
management is needed.
This review of the ECG printed at the time of collection must be documented. Any new 
clinically relevant finding should be reported as an AE.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the master protocol or ISA:

at any time at his/her own request 

at the request of his/her designee (for example, parents or legal guardian)

at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons

if the participant becomes pregnant

if enrollment in any other clinical study involving an investigational intervention or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with the master protocol or ISA, or

if the participant, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation should occur prior to introduction of the new agent.
Discontinuation is expected to be uncommon.
If possible, an early discontinuation visit should be conducted at the time of discontinuing from 
the master protocol/DSA or an ISA. Data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed will be included in the
master protocol/DSA and ISA.  The participant will be permanently discontinued both from the 
study intervention and from the master protocol/DSA or ISA at that time.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  If a participant
withdraws from the study, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.
7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled in the master protocol/DSA or ISA, then the participant should be 

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discontinued from study treatment unless there are extenuating circumstances that make it 
medically necessary for the participant to continue on study treatment.
If the investigator and the sponsor clinical research physician agree that it is medically 
appropriate to continue, the investigator must obtain documented approval from the sponsor to 
allow the inadvertently enrolled participant to continue in the master protocol or ISA with or 
without treatment with investigational intervention.
Safety follow-up is outlined in 
Section 1.3 (Schedule of Activities [SoA])
Section 8.2 (Safety Assessments), and
Section 8.3 (Adverse Events and Serious Adverse Events).
7.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Study personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.
Information about the discontinuation of specific sites or of the study are handled as part of the 
regulatory, ethical, and trial oversight considerations in Appendix 1.

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8.
Study Assessments and Procedures
Master protocol procedures and their timing are summarized in the SoA (Section 1.3).  
Additional SoAs are included in the DSA and may also be included in each ISA.
Protocol waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria for the master protocol, DSA, and each active ISA. The investigator 
will maintain a screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.
Self-reported questionnaires will be administered by either an electronic device or on paper.  
Participants’ self-assessments should be completed before any clinical examinations 
are performed.
8.1.
Efficacy Assessments
The master protocol contains a core set of assessments based on the IMMPACT guidelines 
(Dworkin et. al. 2005).  This table describes the assessments and corresponding measures.
Core Assessment
Measure
Pain intensity
Visual Analog Scale (VAS)* for pain
Pain intensity
Numeric Rating Scale (NRS)* for pain
Participant ratings of overall improvement
Patient Global Impression of Change (PGI)*
Emotional functioning
EuroQol-5D 5 level questionnaire (EQ-5D-5L)*
Quality of sleep
Medical Outcomes Study (MOS) Sleep Scale*
Physical functioning
Described in each disease-state addendum
* = common endpoint measure across all pain types.
8.1.1.
Screening and Preliminary Data Entry Period
Visual Analog Scale
The VAS for pain will be used at screening and at each clinic visit.  This is a graphic, single-item 
scale where participants are asked to describe their pain intensity over the past week, in the area 
under study, on a scale of 0 to 100:
0 = no pain, and
100 = worst imaginable pain.
Participants complete the VAS by placing a line perpendicular to the VAS line at a point that 
describes their pain intensity.  Inclusion criteria are described in Section 5.1.

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Numeric Rating Scale
The NRS will be used during the PDEP and daily throughout the study to describe pain severity.  
This is a numeric, single-item scale where participants are asked to describe their average and 
worst pain over the past 24 hours, on a scale of 0 to 10:
0 = no pain, and
10 = pain as bad as you can imagine.
Participants complete the NRS daily using a take-home device.  Inclusion criteria for the PDEP 
are described in Section 5.1.  Participant compliance is reviewed at each clinic visit.
8.1.2.
Primary Efficacy Outcome Measure–Pain Intensity using Numeric Rating Scale
The NRS is used across all disease states to assess pain intensity.
The primary outcome measure is the mean change from baseline to endpoint for average pain 
intensity as assessed by the NRS item
‘Please rate your pain by selecting the one number [0-10] that describes your AVERAGE 
level of [area under study] pain during the past 24 hours.’
This measure was selected based on its demonstrated ability to detect changes in pain and its 
common use across the disease states under study.
Participants complete the NRS daily using a take-home device.  Compliance is reviewed at each 
clinic visit.
8.1.3.
Secondary Efficacy Outcome Measures
8.1.3.1.
Numeric Rating Scale
A secondary measure is the mean change from baseline to endpoint for worst pain intensity as 
measured by the NRS item
‘Please rate your pain by selecting the one number [0-10] that describes your WORST
level of [area under study] pain during the past 24 hours.’
8.1.3.2.
Participant Ratings on Overall Improvement
The Patient Global Impression of Change (PGI) is used across all disease states.  It captures the 
participant’s perspective of treatment apart from sub-aspects of the general improvement.
This is a numeric scale from 1 to 7:
1 = very much better, and
7 = very much worse.
The participant is asked to
‘Mark the box that best describes how your pain symptoms are now, compared to how 
they were before you started taking this medicine.’

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8.1.3.3.
Emotional Functioning Assessments
The EQ-5D-5L health status questionnaire is used across all disease states.
The EQ-5D-5L is one of the most popular patient-completed instruments to address quality of 
life (Buchholz et. al. 2018).  It is a descriptive system that includes 5 dimensions:

mobility

self-care

usual activities

pain/discomfort, and

anxiety/depression.
The participant is asked to ‘check the ONE box that best describes your health TODAY,’
choosing from 5 options provided under each dimension.  The scores on the 5 dimensions can be 
presented as a health profile or converted to a single summary index number.
The EQ-5D-5L also includes the EQ VAS, which records the participant’s self-rated health on a 
vertical VAS of 0 to 100:
0 = the worst health you can imagine, and
100 = the best health you can imagine.
The instrument used in its EQ-5D-5L version is a short, reliable, validated, easy-to-complete 
scale with excellent test-retest reliability to address quality of life in relation to pain due to 
several diseases.
8.1.3.4.
Sleep Quality
Sleep disturbance is an important issue in pain research. Among various available instruments, 
the Medical Outcome Study (MOS) Sleep Scale provides a unique, psychometrically validated 
score for sleep disturbance.
This scale consists of 12 questions addressing the past week. Participants report how often each 
sleep symptom or problem is present on a 5-point categorical scale ranging from ‘all of the time’
to ‘none of the time.’ The question about time to fall asleep is reported by a 5-point categorical 
scale and the quantity of sleep is reported as the average number of hours slept each night.
This scale has low administration burden, has been used in different pain studies, and has been
validated in patients with neuropathic pain.
8.2.
Safety Assessments
Planned time points for safety assessments are provided in the SoA (Section 1.3).
Standard safety assessments include

physical examination

vital sign and body weight measurements

12-lead ECGs

clinical laboratory tests

hepatic safety monitoring (Appendix 6, Section 10.6)

C-SSRS, and 

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
spontaneously reported AEs.
8.2.1.
Physical Examinations
A complete physical examination will be conducted at Visit 1, as specified in the SoA.  
Symptom-directed physical examinations may also be conducted at other visits, as determined by 
the investigator, if a participant presents with complaints.
8.2.2.
Vital Signs
Vital signs (blood pressure, pulse rate, body temperature) will be measured with the participant 
in a sitting position, as specified in the SoA and as clinically indicated.  Additional vital signs 
may be measured during the study visits if warranted, as determined by the investigator, or as 
detailed in the respective ISAs.
8.2.3.
Electrocardiograms
Evaluating ECGs
Triplicate 12-lead ECGs will be collected as specified in the SoA and as clinically indicated
using an ECG machine that automatically calculates the heart rate and measures pulse rate, RR, 
QRS, QT, and QTcF intervals. Post randomization ECGs will be included in the ISA.
The ECGs should be collected

before any blood draws, procedures, or meals

after the participant is supine for at least 5 minutes

while the participant is supine, and

as closely as possible in succession, approximately 1 minute apart.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more replicates than expected at a particular time point is allowed to ensure high 
quality records.
A qualified physician (the investigator or qualified designee) at the site will interpret the ECGs
as soon after the time of ECG collection as possible and ideally while the participant is 
still present.
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator or qualified designee will
1. assess the participant for symptoms (for example, palpitations, near syncope, syncope)
2. determine if any change in participant management is needed
3. determine if the participant can continue the study, and
4. document the review of the ECG printed at the time of evaluation from at least 1 of the 
replicate ECGs from each time point.
Transmitting and Overreading Electrocardiogram Data
Digital ECGs will be transmitted electronically to a central ECG laboratory designated by 
Lilly. A cardiologist at the central ECG laboratory will then conduct a full overread of the 
replicate ECGs (including all intervals). A report based on data from this overread will be issued 

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to the investigative site. All data from the overreads will be placed in the Lilly database for 
analytical and study report purposes.
If there are differences in ECG interpretation between the investigator or qualified designee and 
the cardiologist at the central ECG laboratory, the interpretation by the investigator or qualified 
designee will be used for study entry and immediate participant management. Interpretations 
from the cardiologist at the central ECG laboratory will be used for data analysis and report 
writing purposes.
The investigator or qualified designee must document the review of the final overread ECG 
report issued by the central ECG laboratory and any alert reports.
8.2.4.
Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA (Section 1.3)
for the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with standard collection requirements, the 
laboratory manual and the SoA.
The investigator must

review the laboratory results,

document this review, and

report any clinically relevant changes occurring during the study as an AE.
The laboratory results must be retained with the source documents unless a Source Document 
Agreement or comparable document cites an electronic location that accommodates the expected 
retention duration. Clinically significant abnormal laboratory findings are those which are not 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant’s condition.
All laboratory tests with values considered clinically significantly abnormal during participation 
in the master protocol or ISA should be repeated until the values return to normal or baseline, or 
are no longer considered clinically significant by the investigator or Medical Monitor.
If such values do not return to normal or baseline within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
If laboratory values from nonprotocol-specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or are 
considered clinically significant by the investigator (for example, SAE or AE or dose 
modification), then report the information as an AE.
8.2.5.
Hepatic Safety Monitoring
Additional monitoring may be included in each ISA.  If monitoring is more restrictive in the ISA, 
then it should be applied for those participants in the respective ISA.

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Close Hepatic Monitoring
This table describes when close hepatic monitoring should occur.
If a participant with baseline... 
has the following elevations…
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN
ALP <1.5 × ULN
ALP ≥2 × ULN
TBL <1.5 × ULN
TBL ≥2 × ULN, except for those with Gilbert’s 
syndrome
ALT or AST ≥1.5 × ULN
ALT or AST ≥2 × baseline
ALP ≥1.5 × ULN
ALP ≥2 × baseline
TBL ≥1.5 × ULN
TBL ≥2 × baseline, except for those with Gilbert’s 
syndrome
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate
aminotransferase; TBL = total bilirubin; ULN = upper limit of normal.
The laboratory tests listed in Appendix 6, including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to 
confirm the abnormality and to determine whether it is increasing or decreasing.
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for the 
possible causes of the abnormal liver tests should be initiated by the investigator in consultation 
with the sponsor’s designated Medical Monitor.
At a minimum, this evaluation should include a physical examination and a thorough medical 
history, including symptoms, recent illnesses (for example, heart failure, systemic infection, 
hypotension, seizures) recent travel, history of concomitant medications (including over-the-
counter), herbal and dietary supplements, history of alcohol use, and other substance abuse.
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests.  
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks if the 
participant’s clinical condition and laboratory results stabilize.  Monitoring of ALT, AST, ALP,
and TBL should continue until levels normalize or return to approximate baseline levels.

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Comprehensive Hepatic Evaluation
This table describes when a comprehensive evaluation should occur to search for possible causes 
of liver injury.
If a participant with baseline...
has the following elevations…
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN with hepatic signs/symptoms* OR
ALT or AST ≥5 ×ULN
ALP <1.5 × ULN
ALP ≥3 × ULN
TBL <1.5 × ULN
TBL ≥2 × ULN, except for those with Gilbert’s syndrome
ALT or AST ≥1.5 × ULN
ALT or AST ≥2 × baseline with hepatic signs/symptoms* OR
ALT or AST ≥3 × baseline
ALP ≥1.5 × ULN
ALP ≥2 × baseline
TBL ≥1.5 × ULN
TBL≥1.5 × baseline, except for those with Gilbert’s syndrome
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate
aminotransferase; TBL = total bilirubin; ULN = upper limit of normal.
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%.
At a minimum, this evaluation should include a physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time (PT-INR); viral hepatitis A, B, 
C, and E; tests for autoimmune hepatitis; and an abdominal imaging study (for example, 
ultrasound or computed tomography [CT] scan).
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the sponsor’s designated Medical Monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
serum phosphatidylethanol.
Based on the circumstances and the investigator’s assessment of the participant’s 
clinical condition, the investigator should consider referring the participant for a 
hepatology/gastroenterology consultation, magnetic resonance cholangiopancreatography 
(MRCP), endoscopic retrograde cholangiopancreatography (ERCP), cardiac echocardiogram, 
or liver biopsy.  

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8.2.5.1.
Hepatic Safety Electronic Case Report Form
This table describes when additional hepatic safety data collection in the hepatic safety eCRF 
should be done.
If a participant with baseline...
has the following elevations…
ALT <1.5 ×ULN
ALT ≥5 × ULN on 2 or more consecutive blood tests
ALP <1.5 × ULN
ALP ≥2 × ULN on 2 or more consecutive blood tests
TBL <1.5 × ULN
TBL ≥2 × ULN, except for cases of known Gilbert’s syndrome
ALT ≥1.5 × ULN
ALT ≥3 × baseline on 2 or more consecutive blood tests
ALP ≥1.5 × ULN
ALP ≥2 × baseline on 2 or more consecutive blood tests
TBL ≥1.5 × ULN
TBL ≥2 × baseline
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate
aminotransferase; TBL = total bilirubin; ULN = upper limit of normal.
Note:  The interval between the 2 consecutive blood tests should be at least 2 days.
Additional criteria include

a hepatic event considered to be an SAE, and

discontinuation of study intervention due to a hepatic event (Section 7.1).
8.2.6.
Suicidal Ideation and Behavior Risk Monitoring
Participants should be monitored appropriately and observed closely for suicidal ideation and 
behavior or any other unusual changes in behavior, especially at the beginning and end of the 
course of intervention. Consideration should be given to discontinuing the study intervention in 
participants who experience signs of suicidal ideation or behavior, following a risk assessment.
Suicidal ideation and behavior will be monitored using the C-SSRS and self-harm forms.
C-SSRS and Self-Harm Forms
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicidal ideation 
and behavior during the assessment period via a questionnaire. The scale was developed by the 
National Institute of Mental Health (NIMH) trial group as a counterpart to the Columbia 
Classification Algorithm of Suicide Assessment (CCASA) categorization of suicidal events.
For this study, the C-SSRS is adapted for the assessment of the ideation and behavior categories 
only.  The Intensity of Ideation and Lethality of Behavior sections are removed.
The C-SSRS is currently referenced by the US Food and Drug Administration (FDA)
(Guidance 2012) as an acceptable scale and is used in clinical trials for neuroscience and non-
neuroscience compounds. The C-SSRS is included in the master protocol because prospective 
collection of suicidal thoughts and behaviors is recommended for compounds reviewed by the 
FDA’s Division of Anesthesiology, Addiction Medicine, and Pain Medicine, as there is often an 
enhanced risk of depression in the populations under study. As noted in the FDA guidance, 
prospective questioning will help avoid misclassification of suicidal thoughts and behaviors and 
ensure that participants who are experiencing suicidal thoughts and behaviors are properly 
recognized and adequately treated.

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The self-harm forms focus only on suicidal and nonsuicidal self-harm behaviors.  The Self-Harm 
Supplement form is a single-question.  If a self-harm event is identified, investigators will then
complete the Self-Harm Follow-Up form, which provides a description of the behavior.
8.3.
Adverse Events and Serious Adverse Events
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, that are considered related to the study intervention or study procedures, 
or that caused the participant to discontinue participation (see Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All SAEs will be collected from the start of intervention until the follow-up visit.
All AEs will be collected from the signing of the ICF for the master protocol until participation 
in an ISA or the master protocol has ended, whichever is longest.
Medical occurrences that begin before the start of study intervention but after signing of the ICF 
will be recorded on the AE CRF.
Although all AEs that occur after signing of the ICF are recorded by the site in the CRF or by 
electronic data entry, SAE reporting to sponsor begins after the participant has signed the ICF 
and has received study intervention.
If an SAE occurs after signing of the ICF, but prior to receipt of study intervention, then it needs 
to be reported ONLY if it is considered reasonably possibly related to study procedures.
All SAEs will be recorded and reported to the sponsor or designee immediately, and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3, Section 10.3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the ISA
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify 
the sponsor.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.

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8.3.3.
Follow-Up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 3, Section 10.3.
8.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs), and investigators.
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (for example, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.5.
Pregnancy
Details of all pregnancies will be collected in female participants and, if indicated in each ISA, 
female partners of male participants. The time period for collecting pregnancy information will 
be detailed in each ISA as applicable.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 4, Section 10.4.
Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6. Complaint Handling
Lilly collects product complaints on interventions used in clinical studies to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.
Participants will be instructed to contact the investigator as soon as possible if they have a 
complaint or problem with an intervention so that the situation can be assessed.
8.4.
Treatment of Overdose
In the event of an overdose, the investigator should
1. contact the Medical Monitor immediately
2. closely monitor the participant for any AEs/SAEs and laboratory abnormalities, and
3. document information about the overdose as specified in the ISA.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
5 3
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y t he i n vest i gat or i n 
c o ns ultati o n wit h t he Me dical M o nit or base d o n t he cli nical e val uat i on of t he partici pa nt.
A d dit i onal g ui da nce f or t he treat me nt of o ver d ose will be descri be d i n t he I S A as a p plica ble.
8. 5.
P h ar m ac o ki netics
P har mac o ki net ic para meters ma y be e val uate d i n t he IS As g o ver ne d b y  t his pr ot oc ol.  
I nf or mat i on o n p har mac o ki net ic sa m ple c ollecti on a n d para meter a nal ysis will be descri be d i n 
t he I S A as a p plica ble.
S a m ple rete nti o n is descri be d i n Sect i on  1 0. 1. 1 2 .
8. 6.
P h ar m ac o d y n a mics
P har mac o d y na mic para meters ma y be e val uate d i n t he I S As g o ver ne d b y t his pr ot oc ol.  
I nf or mat i on o n p har mac o d y na mic sa m ple c ollecti on a n d para meter a nal ysis will  be descri be d i n 
t he I S A as a p plica ble.
S a m ple rete nti o n is descri be d i n Sect i on  1 0. 1. 1 2 .
C CI

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
5 4
8. 9.
I m m u n o ge nicit y Assess me nts
I mm u n o ge nicit y ma y be e val uate d i n t he I S As g o ver ne d b y  t his pr ot oc ol.  I nf or mat i on o n 
i m m u n o ge nicity sa m ple c ollecti o n a n d assess me nts will be descri be d i n t he I S A as a p plica ble.
See Secti o n  1 0. 1. 1 2 f or sa mple rete nti o n i nf or mati o n.
8. 1 0.
He alt h Ec o n o mic s
T he E Q - 5 D- 5 L is a q ualit y of  life assess me nt t hat ca n pr o vi de i nf or mat i on f or health ec o n o mics
assess me nts.
C CI

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
5 5
9.
St atistic al C o nsi der ati o ns
9. 1.
St atistic al H y p ot heses
F or eac h I S A i n t his master pr ot oc ol, a Ba yesia n critical s uccess fact or ( C S F) will be defi ne d i n 
t he I S A a n d use d t o e val uate w het her t he I S A met its pri mar y e n d p o i nt. T he C S F will be 
e val uate d f or t he pri mar y effica c y e n d p oi nt, a vera ge pai n i nte nsit y as meas ure d b y t he N R S ,
usi n g t he met h o d ol o g y  descri be d i n Secti on  9. 4. 2 a n d will be calc ulate d at t he c o ncl usi o n of t he 
d o u bl e- bli n d p orti o n of eac h I S A wit hi n t he master pr ot oc ol.
T he C S F will ha ve t he ge neral f or m of:

p r o ba bility (treat m e nt effect < effect of i nterest ) > pr o ba bilit y t hres h o l d.
T he treat me nt effect will be defi ne d as t he L Y esti mate – pl ace b o esti mat e of  t he c ha n ge fr om 
baseli ne at e n d p oi nt. T he effect of i nterest is t y picall y f o u n d t hr o u g h a literat ure searc h or 
cli nical j u d ge me nt. T he pr o ba bilit y t hres h ol d is ge nerall y set t o ha ve a desire d le vel of 
c o nfi de nce i n t he treat me nt effect or t o ha ve t h e desire d o peratin g c haracterist ics u n der a ra n ge 
of  pla usi ble, ass u me d dr u g effect sce nari os of tr ut h, i ncl u di n g a n ull effect.
A d dit i onal h y p ot heses will i ncl u de t he c o mparis o n of eac h act i ve i nter ve nt i on wi t h place b o f or 
t he pres pecifie d o bjecti ves a n d e n d p o i nts defi ne d i n Secti o n  3.
9. 2.
S a m ple Size Deter mi n ati o n
T he sa m ple size , p o wer, a n d false p ositi ve rate f or eac h I S A wi t hi n t he master pr ot oc ol will  be 
pr o vi de d a n d j ust ifie d i n t he I S A.
T he sa m ple size a n d o perati n g c haracterist ics of eac h I S A wit hi n t he master pr ot oc ol will be 
e val uate d b y si m ulat i on.  T he si m ulati o ns will i ncl u de vari o us ass u me d effect sizes a n d/or 
treat me nt differe nces a n d prior di stri b uti on s pecificati o ns. Als o pr o vi de d will be a just ificati on 
of  h o w missi n g data are acc o u nte d f or , if a n d h o w place b o or treat me nt-effect i nf or mat i on is 
b orr o we d fr o m ot her I S As, a n d ot her ke y i nf or mati on nee de d t o c o n d uct a si m ulati on st u d y .
B ot h sa m ple size a n d o perati n g c haracterist ics ma y v ar y  b y I S A.  T he false p osit i ve rate is
defi ne d as t he perce nta ge of ti mes t he C S F is met , ass u mi n g t hat t he treat me nt effect is 0 at all 
p ost baseli ne visits a n d ma y var y b y I S A.
A n I S A t hat e nters t he master pr ot oc ol later i n cale n dar ti me ma y p ote ntiall y ra n d o mize fe wer 
parti ci pa nt s, si nce t here ma y be a b ol us of place b o parti ci pa nt s or treat m e nt -effect i nf or mat i on 
t hat ca n be b orr o we d a n d use d i n t he pri mar y efficac y a nal ysis. O perati n g c haracte ristics ma y 
als o var y  for t he I S As t hat e nter later i n cale n dar ti me f or t he sa me reas o n.
Eac h I S A will ra n d o mize t o b ot h t he acti ve i nter ve nt i on (s) a n d place b o 
 
  M ulti ple i nter ve nti o n ar ms ma y be i ncl u d e d i n t he I S A
 
C CI
C CI

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9.3.
Populations for Analyses
This table describes the populations that will be used for statistical analyses within each ISA of 
the master protocol. Additional intervention-specific populations for analyses may be described 
in the ISAs.
Population
Description
Entered
All participants who sign the ICF for an ISA
Enrolled (ITT)
All participants randomly assigned to an ISA
Modified ITT (mITT)
All enrolled participants who take at least 1 dose of study intervention within an 
ISA. Participants will be analyzed according to the intervention they are 
randomly assigned.
Safety
All enrolled participants who take at least 1 dose of study intervention within an 
ISA. Participants will be analyzed according to the intervention they receive.
Enhanced ITT
This population includes all participants from the modified ITT population and 
participants from the supplementary ISAs that are used to borrow 
placebo/treatment effect information for the ISA of interest
Biomarker Evaluable
All participants within the subset of participants from the biomarker of interest 
from whom a valid assay result has been obtained within an ISA
Per-Protocol
Some ISAs may define this population, and details will be provided in the ISA 
or ISA SAP.  Generally, participants will be required to have a certain level of 
compliance with the master protocol and ISA to be included in the population
Abbreviations:  ICF = informed consent form; ISA = intervention-specific appendix; ITT = intention to treat; 
SAP = statistical analysis plan.
9.4.
Statistical Analyses
9.4.1. General Considerations
Statistical analysis of the master protocol and ISAs will be the responsibility of the sponsor or 
its designee.
Multiple statistical analysis plans (SAPs) will be defined and used throughout the duration of the
entire master protocol. A single master protocol SAP will be developed, as well as an ISA SAP,
for each ISA.
The master protocol SAP describes the statistical analyses that are common across the entire 
master protocol, and the analyses will be conducted within each ISA. The analyses in the master 
protocol SAP will include

disposition reports

AE analyses

laboratory analyses

vital signs analyses, and

efficacy analyses that do not specify borrowing of placebo or treatment-effect 
information from other ISAs.
A DSA SAP will not be developed.  The DSA-specific analyses will be provided in the ISA SAP.

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The ISA SAP will contain the statistical analyses unique for each ISA and will include

the proposed strategy of borrowing placebo and/or treatment-effect information from 
other ISAs

if borrowing of placebo or treatment effect information is implemented, the Bayesian 
model and exact prior distributions used for the primary efficacy analysis and other 
Bayesian secondary analyses, and

details of analyses that are unique to the ISA or analyses that may differ from what is 
specified in the master protocol SAP.
If there is a discrepancy between the master protocol SAP and the ISA SAP, the methodology in 
the ISA SAP will be used.
Changes to the master protocol data analysis methods will require an amendment only if they
change a principal feature of the master protocol.  Any other change to the data analysis 
methods, and the justification for making the change, will be described in the respective SAP and 
the clinical study report for each respective ISA.  Additional exploratory analyses of the data will 
be conducted as deemed appropriate.
The master protocol SAP will be finalized prior to the unblinding of the first ISA.  Any updates 
to the master protocol SAP will be finalized prior to the unblinding of the respective ISA.
The ISA SAP will be finalized prior to the first unblinding of the respective ISA.
The specific baseline definitions for each analysis will be provided in the master protocol SAP.
No adjustments for multiplicity will be performed unless specified in the ISA SAP.
If the primary efficacy analysis dataset for an ISA includes data from repeat participants, all 
available data for the repeat participants will be included and used in the model. A participant by 
ISA-specific random effect (or other appropriate adjustments) will be added to the primary 
efficacy analysis model to account for the repeat participants. Specific details will be provided 
in each ISA SAP.
9.4.1.1.
Missing Data
The NRS value of average pain and worst pain over the past 24 hours will be collected daily for
each participant.  For the statistical analyses, the average NRS value of the average and worst 
pain over the past 24 hours will be calculated for both weekly intervals and biweekly intervals.
The average of the weekly intervals for the NRS will result in 8 postbaseline observations, and 
the average of the biweekly intervals will result in 4 postbaseline observations for each 
participant if a participant completes the placebo-controlled portion of the study.
The average of the weekly intervals for the NRS will be used in the primary efficacy analysis
and other analyses described below, unless otherwise specified in the SAP.
A participant must have 50% or greater of the daily NRS values during the prespecified time 
interval to calculate the average NRS value; otherwise, the average NRS value for that visit will 
be considered missing.
Missing data for other variables and analyses will be described in the master protocol SAP.

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For all Bayesian analyses, the missing values will be accounted for naturally using the Bayesian 
imputation of missing values.
9.4.2. Primary Endpoint and Analysis
The primary efficacy measure will be the same across all disease states and ISAs.
The primary efficacy analysis for an ISA will be conducted when all participants randomized to 
the ISA have completed the placebo-controlled portion of the ISA.  The follow-up period may 
vary by ISA.  Therefore, the primary efficacy analysis may be conducted prior to conclusion of 
the ISA and the collection of all follow-up data.
The primary efficacy analysis will be performed using a Bayesian MMRM method where the 
baseline information is modeled as a dependent variable. The baseline estimated means will be
constrained to be the same between treatment groups due to randomization (Liang and Zeger, 
2000).  The primary efficacy analysis of the ISA of interest will be conducted on either the 
modified intention to treat (mITT) population or enhanced ITT population (see Section 9.3). The 
enhanced ITT population includes participant level data from ongoing ISAs and/or ISAs that 
have completed. Participants from ongoing ISAs must have had the opportunity to complete the
placebo-controlled portion of the ISA to be included in the primary efficacy analysis for the ISA 
of interest. The ISA SAP will define the exact participant population included in the primary 
efficacy analysis.
The Bayesian CSF for the primary efficacy analysis will be defined in the ISA SAP for each 
respective ISA.  The 95% credible intervals will be provided for the key parameters of interest.

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This table describes information related to the primary efficacy measure.
Primary Efficacy Measure 
Mean change from baseline to endpoint for average pain intensity 
as measured by the NRS. 
The exact endpoint for each ISA will be defined in the ISA SAP 
and may be defined, for example, as the last time point, the average 
of the last 2 time points, etc.
Data Collection
The NRS average pain will be collected daily.  
Average scores will be calculated over weekly and biweekly time 
intervals and will be available for analysis. The average of the 
weekly time-interval will be used for the primary efficacy analysis.
Primary Analysis 
Efficacy of the active treatment(s) compared with placebo
Analysis Method
Bayesian MMRM analysis
Outcome Variable
The raw baseline and postbaseline values will be included in the 
response vector when fitting the statistical model. The change from 
baseline will be assessed via the statistical model. 
Fixed Categorical Effects in Model

Time interval

Interaction of treatment by time interval without the 
baseline

Average baseline pain severity category (moderate or mild
vs severe), defined by baseline NRS <7 vs baseline 
NRS ≥7

Pooled investigative site
Additional Covariates in Model
Any stratification variable used for randomization of the ISA of 
interest will also be included in the model. Additional covariates 
may also be specified at an ISA level.
Abbreviations:  ISA = intervention-specific appendix; MMRM = mixed-model repeated measures; NRS = numeric 
rating scale; SAP = statistical analysis plan.
9.4.2.1.
Key Features of the Bayesian Primary Efficacy Analysis Model
The primary efficacy analysis will be a Bayesian longitudinal MMRM analysis conducted on the 
NRS average pain score. The model will include the categorical effects and covariates described 
in Section 9.4.2. The change from baseline to each postbaseline time interval will be assessed.
The primary efficacy analysis model includes these key features:

ability to borrow placebo information from other ISAs within the DSA using a suitable
choice of informative prior on the key parameters

ability to borrow treatment-effect information from other ISAs between DSA for the
same intervention using a suitable choice of informative prior on the key parameters

ability to update and tune the model parameters as more ISAs are added to the master
protocol and more data become available

flexibility for each ISA to define the amount of borrowing that will occur by specifying
the prior distributions of key parameters in the ISA SAP

ability to define which data from additional ISAs are included in the model

flexibility to include additional covariates for each ISA as needed, and

option to specify informative priors on some model parameters based on external data
sources, for example, utilization of Bayesian Augmented Control for placebo parameters
and data to inform other key parameters.

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The ISA SAP will contain the exact specification of the model and parameters for the respective 
ISA.  
Borrowing Strategy
Each ISA will define the specific decisions on the borrowing of placebo and treatment-effect 
information, including if borrowing will be implemented and, if so, how much information to 
borrow and the specific methodology used to borrow. These decisions may vary over the course 
of the master protocol, as some borrowing strategies may perform better than others as more data 
are available to borrow.
Specific differences between ISAs, for example, method of administration or additional inclusion 
or exclusion criteria, may impact the borrowing strategy for an ISA. Adjustments may also be 
made to the primary analysis model to incorporate the difference in placebo response in different 
time periods to facilitate efficient borrowing between the placebo participants.
The current borrowing strategies considered across the master protocol for each ISA include

pooling of placebo data between ISAs within a disease state
o
note:  pooling is not being considered for borrowing treatment-effect information
for an intervention studied in multiple disease states

use of a hierarchical model with an appropriate prior on the between-study standard 
deviation (SD) (or variance) term that influences the amount of borrowing

commensurate priors with different mixture probability weights

mixture priors

meta-analytic predictive prior or meta-analytic combined prior, and

model fit with respective ISA data only (no utilization of information from other ISAs).
9.4.3.
Secondary Endpoints and Analysis
The secondary efficacy measures will be the same across all disease states and ISAs. 
9.4.3.1.
Continuous Efficacy Analyses
This table describes information related to the continuous secondary efficacy measures and 
analyses.
Key Secondary Measures

NRS worst pain

VAS for pain

PGI

MOS Sleep Scale

EQ-5D-5L

Physical functioning–described in the DSA
Data Collection
The NRS worst pain will be collected daily.
The scores for the other secondary measures will be 
collected at each visit as described in the visit schedule.
Analyses
Efficacy of active treatment(s) compared with placebo
Analysis Method
Same as primary efficacy analysis
Outcome Variable
The raw baseline and postbaseline values will be 
included in the response vector when fitting the 

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statistical model.  The change from baseline will be 
assessed via the statistical model
Fixed Categorical Effects in Model

Time interval (or visit)

Interaction of treatment by time interval (or 
visit) without the baseline

Average baseline pain severity category 
(moderate vs severe), defined by baseline 
NRS <7 vs baseline NRS ≥7

Pooled investigative site
Additional Covariates in Model
Additional covariates may also be specified at an 
ISA level.
Abbreviations:  DSA = disease-state addenda; EQ-5D-5L = EuroQol-5D 5 level questionnaire; ISA = intervention-specific 
appendix; MOS = Medical Outcomes Study; NRS = numeric rating scale; PGI = Patient Global Impression of Change; 
VAS = visual analog scale.
In addition to the primary efficacy analysis of the NRS average pain score, the change from 
baseline to each postbaseline time interval (or visit) will be analyzed using a similar Bayesian 
MMRM method as the primary efficacy analysis for select scales. A similar participant
population and borrowing strategy of the primary efficacy analysis for the ISA will be 
implemented for each scale. The ISA SAP will contain the exact specification of the model and 
parameters for each scale. The model will be fit for the following scales:

NRS worst pain with weekly average values

VAS, and

physical functioning scales described in each DSA (note: direct treatment-effect 
borrowing will not be available for the physical functioning scales, since they are only 
collected within a DSA).
Similar borrowing and modeling may be considered for other efficacy scales. The ISA SAP will 
contain the exact specification of the model and parameters for each scale.
Additional analyses will be conducted using data only from the respective ISA, which do not 
utilize any borrowing of placebo and/or treatment information. A Bayesian MMRM analysis 
will be used to evaluate the change from baseline to each postbaseline time interval (or visit)
and the comparison of treatment groups within an ISA for

NRS average pain

NRS worst pain

VAS

physical functioning scales described in each DSA

PGI

EQ-5D-5L, and

MOS Sleep Scale multi-item scores of sleep disturbance, somnolence, sleep adequacy, 
and the sleep problems index.
The Bayesian models will include the categorical effects and covariates described in 
Section 9.4.3, unless otherwise noted in the ISA SAP.

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9.4.3.2.
Categorical Efficacy Analyses
The proportion of participants in each treatment group meeting prespecified binary efficacy 
outcomes will be estimated for each postbaseline visit. The estimates will be provided from a 
longitudinal Bayesian model that includes all postbaseline observations. The average weekly 
score for the NRS will be computed and used in the comparison between treatment groups within 
an ISA.
The prespecified binary efficacy outcomes include the proportion of participants

with a pain reduction greater than or equal to 30%, 50%, and 70% from baseline as 
measured by the NRS average pain scale

with a pain reduction greater than or equal to 30%, 50%, and 70% from baseline as 
measured by the NRS worst pain scale

with a pain reduction greater than or equal to 30%, 50%, and 70% from baseline as 
measured by the VAS

with at least 2-point reduction from baseline on the NRS average pain scale

with at least 2-point reduction from baseline on the NRS worst pain scale, and

with an improvement in physical function greater than or equal to 30%, 50%, and 70% 
from baseline as measured by the physical functioning scales defined in the DSA.
The models will include treatment, time interval (or visit), interaction between treatment by time 
interval (or visit), average baseline pain severity category (moderate vs severe) as defined by 
baseline NRS less than 7 versus baseline NRS greater than or equal to 7 and pooled investigative 
site, unless otherwise noted in the ISA SAP.  The ISA SAP will contain the exact specification of 
the model and parameters for the respective ISA.
9.4.3.3.
Time to Event Efficacy Analyses
A Kaplan-Meier analysis will be conducted for these outcomes:

time to first pain reduction of at least 30%, 50%, and 70% from baseline as measured by 
the NRS average pain scale

time to first pain reduction of at least 30%, 50%, and 70% from baseline as measured by 
the NRS worst pain scale

time to first pain reduction of at least 2-points from baseline on the NRS average pain 
scale, and

time to first pain reduction of at least 2-points from baseline on the NRS worst pain scale.
For the time to event analyses, participants who do not have the event of interest by the end of 
the treatment phase will be treated as a right censored observation. 
For these analyses, the average score over a weekly interval for the NRS will be computed and 
used in the analysis. In addition, time to event analyses will also be performed using the daily 
NRS scores. 
The ISA SAP will contain the exact specification of the model and parameters for the 
respective ISA.

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9.4.4.
Tertiary/Exploratory Endpoints
A cumulative distribution function of percent change from baseline to endpoint for the NRS 
average and worst pain scales and the VAS will be provided for each treatment group.  No 
statistical comparisons will be made between the groups.
Appropriate statistical methods will be used to understand the relationship of the biomarker 
endpoints to other clinical endpoints in terms of treatment effect.  Any intervention-specific 
tertiary/exploratory analyses will be described in the respective ISA.
9.4.5.
Treatment Group Comparability
9.4.5.1.
Participant Disposition
Participants who discontinue from the study will be identified, and the extent of their
participation in the study will be reported for each ISA. A detailed description of participant 
disposition and the reasons for discontinuation will be summarized by treatment group for each 
ISA at the end of the study. Intervention-specific analyses will be detailed in each 
respective ISA.
9.4.5.2.
Participant Characteristics
Participant characteristics and baseline clinical measures will be summarized for each treatment
period. For all participant characteristics, the summaries will include descriptive statistics for 
continuous measures (sample size, mean, SD, median, minimum, and maximum) and for
categorical measures (sample size, counts and percentages).
Additional intervention-specific analyses will be specified in each respective ISA.
9.4.5.3.
Concomitant Therapy
Concomitant medications used during the study will be listed and summarized for each ISA.
The average intake (in milligrams) per day of the approved pain rescue therapy acetaminophen 
will be summarized by weekly intervals for each treatment group. The average intake per day 
over the entire placebo-controlled phase will also be compared and summarized between 
treatment groups.
9.4.5.4.
Treatment Compliance
Treatment compliance with the study intervention will be summarized by treatment for each ISA. 
Intervention-specific analyses will be described in the respective ISAs.
9.4.6.
Safety Analyses
All safety analyses will be conducted on the Safety Population for each ISA.
9.4.6.1.
Vital Signs Analyses
The mean change from baseline in pulse rate, systolic and diastolic blood pressure, temperature, 
and weight will be summarized for each treatment group.  The incidence of treatment-emergent 
abnormal high and low vital signs and weight will be summarized by treatment group.

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9.4.6.2.
Electrocardiogram Analyses
The mean change from baseline will be summarized by treatment group for the following ECG 
parameters: heart rate, PR interval, QRS duration, QT interval, and QTcF interval. All analyses 
of corrected QT will be carried out using Fridericia’s correction factor [QTcF=QT/RR0.333]). The 
incidence of treatment-emergent abnormal high and low changes in heart rate, PR interval, QRS 
duration, and QTcF interval will be summarized.
The number and percentage of participants with a QT interval greater than 500 msec and the 
percentage with a QTcF greater than 500 msec will be summarized for each treatment group. 
The percentage of participants who experienced a treatment-emergent increase from the 
maximum baseline in QTcF interval of greater than 30 msec, 60 msec, or 75 msec at any time 
will also be summarized.
9.4.6.3.
Laboratory Assesment Analyses
The mean change from baseline laboratory assessments will be summarized for each treatment 
group.  The incidence of treatment-emergent abnormal high and low laboratory assessments will 
be summarized by treatment group. In addition, listings of abnormal findings for laboratory 
analyte measurements, including qualitative measures, will be provided.
9.4.6.4.
Adverse Events
Adverse events will be classified by system organ class and preferred term as defined by the 
Medical Dictionary for Regulatory Activities (MedDRA).  A treatment-emergent adverse event 
(TEAE) is defined as an event that first occurs or worsens in severity after baseline and on or 
before the date of the last visit within the dosing period.
All conditions existing prior to randomization at Visit 3 will be used as baseline. The 
postbaseline visits during the placebo-controlled phase will be included as the postbaseline 
period for analysis.
For events that are gender specific, the denominator and computation of the percentage will only 
include participants of the given gender.
All AEs will be summarized by

number and percentage of participants who experience TEAEs

TEAEs by maximum severity

TEAEs related to study intervention

follow-up emergent AEs

AEs leading to discontinuation of intervention

AEs leading to discontinuation from the study

SAEs, and

deaths.
All AEs, including preexisting conditions, will be listed by

participant

visit

preferred term

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
treatment group

severity (mild, moderate, or severe), and

possible relationship to the study intervention.
Adverse events of special interest will be defined in the ISA.
9.4.6.5.
Columbia Suicide-Severity Rating Scale
Suicide-related thoughts and behaviors occurring during treatment will be summarized based on 
responses to the C-SSRS consistent with the C-SSRS Scoring and Data Analysis Guide 
(CSSRS [WWW]).
9.4.7.
Subgroup Analyses
Subgroup analyses will be conducted for the primary efficacy measure of NRS average pain. 
The subgroup analyses will be provided for the following subgroups using data from the 
respective ISA only:

baseline pain severity: baseline pain severity category (moderate vs severe) defined by 
baseline NRS average pain <7 versus baseline NRS average pain ≥7

gender, and

pooled investigative site.
For the subgroups of baseline pain severity and gender, the Bayesian MMRM method described 
in Section 9.4.2 will be utilized, with the relevant terms added for subgroup, subgroup-by-
treatment, subgroup-by-time interval without the baseline, and subgroup-by-treatment-by time
interval interactions without the baseline. For the pooled investigative site subgroup analysis,
the change from baseline to endpoint will be evaluated using a Bayesian model with terms for 
pooled investigative site, baseline pain severity, and treatment-by-pooled investigative site 
interaction.
9.4.8.
Sensitivity Analysis
Sensitivity analyses of the primary efficacy analysis will be conducted to evaluate the impact of 
the borrowing of placebo and treatment-effect information, as well as the impact of missing data.
A tipping point analysis will also be conducted to evaluate the impact of missing data for the 
primary efficacy analysis.
The details of the sensitivity analyses will be provided in the ISA SAP.
9.5.
Interim Analyses 
The master protocol will not require or specify interim analyses for a specific ISA.  If an interim 
analysis is planned for an ISA, the details (for example, timing, rationale, use of participants in 
other ISAs) will be provided in the ISA or ISA SAP.  The potential reasons for interim analyses 
could include futility analyses, early efficacy analyses, safety analyses, or other analyses needed 
for key business decisions and planning.
Unblinding details will be specified in the unblinding plan section of the respective ISA SAP or 
in a separate unblinding plan document.

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9.6.
Data Monitoring Committee
The AC will provide oversight for safety by reviewing unblinded data for each ISA.  The 
structure and the responsibilities of the AC will be detailed in the AC charter.
Safety analyses for review will be detailed in each ISA SAP and in the AC charter. 
The AC may evaluate additional objectives that are specific to an individual ISA, for example, 
assessing futility or early efficacy. If this is requested, details will be specified in the AC charter.
The committees that will be established to support the master protocol and ISA teams are 
described in Appendix 1, Section 10.1.5.

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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
applicable International Council for Harmonisation (ICH) good clinical practice 
(GCP) guidelines, and
o
applicable laws and regulations.

The protocol, protocol amendments, informed consent form (ICF), Investigator 
Brochure, and other relevant documents (for example, advertisements) must be 
submitted to an ERB by the investigator and reviewed and approved by the ERB before 
the study is initiated.

Any amendments to the protocol will require ERB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.

The investigator will be responsible for the following:
o
providing written summaries of the status of the study to the ERB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the ERB
o
notifying the ERB of SAEs or other significant safety findings as required by 
ERB procedures, and 
o
providing oversight of study conduct for participants under their responsibility and 
adherence to requirements of 21 CFR, ICH guidelines, the ERB, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations.
10.1.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests for the master protocol and each ISA 
in which the investigator participates and for 1 year after completion.
10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant or his/her legally authorized representative and 
answer all questions regarding the master protocol and eligible ISAs.

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
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the ERB or study center.

The medical record must include a statement that written informed consent was
obtained before the participant was entered in the master protocol and ISA, and the date 
the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and is kept on file.
Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records,
datasets, or biological samples that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable will not 
be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the ICF.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5.
Committees Structure
These committees will be established to support the master protocol and ISA teams:

Assessment Committee (AC), and

Internal Steering Committee, including a Statistical Analysis Subcommittee (SASC).
The AC will routinely (for example, quarterly) evaluate safety for all ISAs within the master 
protocol.  The safety reports will be provided for an ISA only and, as appropriate, for the 
aggregate data of an intervention if it is studied in multiple disease states.
The Internal Steering Committee will be established to support the strategic and 
technical integration of the master protocol to achieve Lilly’s overarching clinical 
development needs.
The Internal Steering Committee will function as a resource group to provide oversight of the 
master protocol including consultation, advice, analysis, and feedback to clinical teams and other 

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Protocol number H0P-MC-CPMP(a)
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interested parties during the study. It will be composed of cross-functional representatives from 
departments such as medical, statistics, clinical operations, and project management.
The SASC will be a small cross-functional group that will function as an expert panel for 
consultation, advice, and feedback to the Internal Steering Committee and the ISA teams.  One 
of the primary roles of the SASC is to generate the master protocol level integrated datasets, 
which include data from completed and ongoing ISAs.  Thus, the SASC will be unblinded to 
data from both ongoing and completed ISAs.  The SASC will

provide the AC with unblinded safety reports,

be responsible for communication with the AC, and

generate analysis reports for ongoing or completed ISAs based on the integrated datasets..
10.1.6.
Dissemination of Clinical Study Data
A clinical study report will be provided for each ISA.
10.1.7.
Data Quality Assurance
All participant data relating to the study will be recorded on a printed or electronic case report 
form (CRF), unless transmitted to the sponsor or designee electronically (for example, laboratory 
data). The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, ERB review, and regulatory 
agency inspections and provide direct access to source data documents.
Monitoring details describing strategy (for example, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques, are provided in the Monitoring Plan.
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data.
The sponsor assumes accountability for actions delegated to other individuals (for example, 
contract research organizations).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized study personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study and each 
ISA must be retained by the investigator for 15 years after study completion, unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
7 0
I n a d diti on, t he sp o ns or or i ts re prese ntati ves will p eri o di call y c hec k a sa m ple of t he parti ci pa nt
data rec or de d a gai nst s o urce d oc u me nts at t he st u d y site.  T he st u d y  ma y be a u dite d b y t he 
sp o ns or or i ts re prese ntati ves a n d/ or re g ulat or y a ge ncies at a n y ti me.  I n vesti gat ors will be gi ve n 
n oti ce bef ore a n a u dit occ urs.
D at a C a pt ure S yste m
T he i n vest i gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c o m plete ness, le gi bility,  a n d ti meli ness 
of  t he data re p orte d t o t he s p o ns or.
A n electr o nic data ca pt ure ( E D C) s yst e m will be use d i n t his st u d y for t he c ollect i on of C R F 
data.  T he i n vesti gat or mai ntai ns a se parate s o urce f or t he data e ntere d b y  t he i n vesti gat or or 
desi g nee i nt o t he s p o ns or -pr o vi de d E D C s yste m.  T he i n vest i gat or is res p o nsi ble f or t he 
i de ntificati on of a n y data t o be c o nsi dere d s o urce a n d f or t he c o nfir mat i on t hat data re p orte d are 
acc urate a n d c o m plete b y si g ni n g t he C R F.
A d dit i onall y , electr o nic c li nical o utc o m e assess me nt (e C O A) data ( partici pa nt-f oc use d o utc o me 
i nstr u me nt) will be direct l y recor de d b y  t he parti ci pa nt i nto a pr o visi o ne d ha n d -hel d de vice .  T he 
e C O A data will ser ve as t he s o urce d oc u me ntati o n, a n d t he i n vest i gat or d oes n ot mai ntai n a 
se parate writte n or electr o nic rec or d of t hese data. A ut h orize d st u d y  pers o n nel will m o ni t or 
part ici pa nt c o m plia nce wit h e C O A e ntr y a n d re-e d ucate partici pa nts o n t he i m p orta nce of 
c o mplia nce as necessar y .  S o m e e C O A data val ues ma y be bli n de d t o t he site d uri n g t he st u d y  t o 
mi ni mize a n y p ote ntial rat i n g bias.
Data c ollecte d via t he s p o ns or- pr o vi de d data ca pt ure s yste m s will be st ore d at a ve n d or selecte d 
b y t he s p o ns or . T he i n vest i gat or will ha ve c o nti n u o us access t o t he u n bli n de d da ta d uri n g t he 
st u d y a n d u ntil dec o m missi o ni n g of t he data ca pt ure s yste ms.  Pri or t o dec o m missi o ni n g, t he 
i n vesti gat or will recei ve a n arc hi val c o p y of all e C O A data f or rete nti o n.
Data m a na ge d b y a ce ntral ve n d or, s uc h as la b orat or y test data, will be st ore d electr o nicall y i n 
t he ce ntral ve n d or’s data base s yste m, a n d re p orts will be pr o vi de d t o t he i n vesti gat or f or re vie w 
a n d rete nti o n.  Data will s u bse q ue nt l y be tra nsferre d fr o m t he ce ntral ve n d or t o t he sp o ns or 
data ware h o use.
Data fr o m c o m p lai nt f or ms su b mitte d t o t he sp o ns or will be e nc o de d a n d st ore d i n t he gl o bal 
pr o d uct c o m plai nt ma na ge me nt s y st e m.
1 0. 1. 8.
S o urce D oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vest i gat or’s site.
Data re p orte d o n t he C R F or e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce d oc u me nts 
m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he 
i n vesti gat or ma y nee d t o req uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n t he 
st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.
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10.1.9.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment 
of participants.
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to

failure of the investigator to comply with the protocol, the requirements of the ERB or 
local health authorities, the sponsor’s procedures, or GCP guidelines

inadequate recruitment of participants by the investigator, or

discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ERB, the regulatory authorities, and any contract research organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
10.1.10.
Publication Policy
In accordance with the sponsor’s publication policy, the results of the ISAs conducted as a part 
of this master protocol or other relevant learning materials may be submitted for publication by a 
peer-reviewed journal.
10.1.11.
Investigator Information
Researchers at qualified clinical trial sites and with experience in the treatment of chronic pain 
will participate as investigators in this clinical trial.

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Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
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1 0. 1. 1 2.
L o n g -Ter m S a m pl e Rete nti o n
S a m ple rete nti o n e na bles use of ne w tec h n o l ogi es, res p o nse t o re g ulat or y q uesti ons, a n d 
i n vesti gati on of varia ble res p o nse t hat ma y n ot be o bser ve d u nt il later i n t he de vel o p me nt of t he 
i nter ve nt i on or after  t he i nter ve nti on  bec o me s c o m mercially a vaila ble.
* Rete nti o n peri o ds ma y differ l ocall y.
T he s p o ns or has t he rig ht t o retai n a p orti o n of s u b mitte d bi o ps y  tiss ue. Arc hi val bl oc ks will 
be ret ur ne d t o t he st u d y sit e. Sli des a n d t iss ue sa m ples c ollecte d d uri n g t he st u d y will n ot 
be ret ur ne d.
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10.2.
Appendix 2: Clinical Laboratory Tests
The clinical laboratory tests will be performed by the central laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5
of the protocol.
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations.
If the sponsor approves local laboratory testing in lieu of central laboratory testing, the local 
laboratory must be qualified in accordance with applicable local regulations.
Pregnancy testing will be done prior to randomization as noted in the SoA, Section 1.3.  
Additional testing will be detailed in each ISA.
Investigators must document their review of laboratory safety results.

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Clinical Laboratory Tests
Chemistry
Hematology and 
Differential
Urinalysis
Urine Drug 
Screen
Other Tests
Sodium
Hemoglobin
Specific gravity
Antidepressants
Hormones 
(female)
Potassium
Hematocrit
pH
Opiates
Pregnancy test 
(serum, urine)
Chloride
Erythrocyte count (RBC)
Protein
Cocaine
FSH
Bilirubin, total
MCV
Glucose
Benzodiazepines
Estradiol
Bilirubin, direct
MCH
Ketones
Barbiturates
TSH
ALP
MCHC
Bilirubin
Amphetamines
Other
ALT
Leukocytes (WBC)
Urobilinogen
Cannabinoids
HbA1C
AST
Differential (absolute)
Blood
Methadone
HIV
Urea nitrogen (BUN)
Neutrophils 
Nitrite
Phencyclidine
Creatinine, enzymatic
Bands
Leukocyte 
esterase
Propoxyphene 
Protein
Lymphocytes 
Microscopic 
examination of 
sediment
Albumin
Monocytes
Calcium
Eosinophils
Glucose
Basophils
Cholesterol
Platelets 
Triglycerides
Cell morphology
(RBC, WBC)
eGFR calculated by CKD-
EPI equation
B12
Methylmalonic acid
Homocysteine 
Lipid Panel 
HDL-C
LDL-C
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; 
eGFR = estimated glomerular filtration rate; FSH = follicle-stimulating hormone; HbA1C = hemoglobin A1C; 
HDL = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus; LDL-C = low-density 
lipoprotein cholesterol; MCH = mean cell hemoglobin; MCHC = mean cell hemoglobin concentration; 
MCV = mean cell volume; RBC = red blood cells; TSH = thyroid-stimulating hormone; WBC = white 
blood cells.

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration, even though 
it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE, unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Report such overdoses regardless of sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

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
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (for example, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:

Results in death

Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death if it were more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
o
In general, hospitalization signifies that the participant has been admitted to the 
hospital for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
‘hospitalization’ occurred or was necessary, the AE should be considered serious.
o
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.

Results in persistent disability/incapacity
o
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
o
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect

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
Other situations:
o
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
o
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3.
Recording and Follow-Up of AEs and/or SAEs
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the sponsor or designee. In these cases, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.  

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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.

A ‘reasonable possibility’ of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the Investigator’s Brochure and/or Product Information, 
for marketed products, in the assessment.

For each AE/SAE, the investigator must document in the medical notes that they
reviewed the AE/SAE and provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor or designee.

The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor or designee within 24 
hours of receipt of the information.

If a study participant dies during participation in the trial or during a recognized follow-
up period, the investigator will provide the sponsor or designee with a copy of any 
postmortem findings, including histopathology.
10.3.4.
Reporting of SAEs
SAE Reporting via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE will be the electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 

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collection tool to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE data collection tool or to the 
Medical Monitor by telephone.

Contacts for SAE reporting can be found in the Operations Manual.
SAE Reporting to via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Medical Monitor.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Operations Manual.

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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Definitions of woman of childbearing potential (WOCBP) and woman of nonchildbearing 
Potential (WONCBP) will be provided in each ISA.
Contraception Guidance:
Contraception guidance will be provided in each ISA.
Collection of Pregnancy Information:
Male participants with partners who become pregnant
The investigator will attempt to collect pregnancy information on any male study participant’s 
female partner who becomes pregnant while the male study participant is in this trial.  This 
applies only to male study participants who receive intervention.
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
sponsor within 24 hours of learning of the partner’s pregnancy. 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 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.
The participant will be followed up 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 
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 <22 weeks gestational age) or still birth (occurring at 
>22 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 Section 8.3.4. While the 
investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting.

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Any female participant who becomes pregnant while participating in the study will be withdrawn 
from the study.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P-M C -C P M P (a)
8 3
C CI

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10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-Up 
Assessments
Samples for selected tests may be obtained in the event of a treatment-emergent hepatic 
abnormality and may be required during follow-up with participants in consultation with the 
clinical research physician of the sponsor or sponsor’s designee.
This table describes hepatic-specific monitoring tests.
Hepatic Evaluation Testing 
Central testing required, except for microbiology.
Local testing may be performed in addition to central testing when required for immediate participant management.
Comments:
Hematology
Hemoglobin
Hematocrit
Erythrocytes (RBC)
Leukocytes (WBC) 
Differential:
    Neutrophils, segmented
    Lymphocytes
    Monocytes
    Basophils
    Eosinophils
Platelets
Cell morphology (RBC and WBC)
Coagulation
Prothrombin time, INR (PT-INR)
Clinical Chemistry
Total bilirubin
Direct bilirubin
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)

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Other Chemistry
Acetaminophen
Acetaminophen protein adducts
ALP isoenzymes
Ceruloplasmin
Copper
Haptoglobin
Immunoglobulin A (IgA) (quantitative)
Immunoglobulin G (IgG) (quantitative)
Immunoglobulin M (IgM) (quantitative)
Phosphatidylethanol (PEth)
Urine Chemistry
Drug Screen
Ethyl glucuronide (EtG)
Serology
Hepatitis A virus (HAV) testing:
    HAV total antibody
    HAV IgM antibody
Hepatis B virus (HBV) testing:
    Hepatitis B surface antigen (HBsAg)
    Hepatitis B surface antibody (anti-HBs)
    Hepatitis B core total antibody (anti-HBc)
    Hepatitis B core IgM antibody
    Hepatitis B core IgG antibody
    HBV deoxyribonucleic acid (DNA)
Hepatis C virus (HCV) testing:
    HCV antibody
    HCV ribonucleic acid (RNA)
Hepatitis D virus (HDV) testing:
    HDV antibody
Hepatitis E virus (HEV) testing:
    HEV IgG antibody
    HEV IgM antibody
    HEV RNA

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Other Serology
Anti-nuclear antibody (ANA)
Anti-smooth muscle antibody (ASMA)
This is not required if anti-actin antibody is tested.
Anti-actin antibody
This is not required if ASMA is tested.
Epstein-Barr Virus (EBV) testing:
    EBV antibody
    EBV DNA
Cytomegalovirus (CMV) testing:
    CMV antibody
    CMV DNA
Herpes simplex virus (HSV) testing:
    HSV (type 1 and 2) antibody
    HSV (type 1 and 2) DNA
Liver kidney microsomal type 1 (LKM-1) antibody
Microbiology
Assayed by investigator-designated local laboratory
ONLY; no central testing available.
Culture:
    Blood
    Urine
Abbreviations:  INR = international normalized ratio; RBC = red blood cell; WBC = white blood cell.

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10.7.
Appendix 7: Abbreviations
Term
Definition
AC
Assessment Committee
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) intervention, whether or not related 
to the medicinal (investigational) intervention.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AV
atrioventricular
blinding/masking
A double-blind study is one in which neither the participant nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the participants are 
aware of the treatment received.
CCASA
Columbia Classification Algorithm of Suicide Assessment
CIOMS
Council for International Organizations of Medical Sciences
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CSF
critical success factor
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
computed tomography
DPNP
diabetic peripheral neuropathic pain
DSA
disease-state addenda
eCOA
electronic clinical outcome assessment
EDC
electronic data capture
ECG
electrocardiogram

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enroll
The act of assigning a participant to a treatment.  Participants who are enrolled in the study 
are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EQ-5D-5L
EuroQol-5D 5 level questionnaire
ERB
ethical review board
ERCP
endoscopic retrograde cholangiopancreatography
FDA
US Food and Drug Administration
GCP
good clinical practice
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMMPACT
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
informed consent
A process by which a participant voluntarily confirms his or her willingness to participate in 
a particular study, after having been informed of all aspects of the study that are relevant to 
the participant’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.
INR
international normalized ratio
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.
intervention
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including products already on the market when used or assembled 
(formulated or packaged) in a way that is different from the authorized form, or marketed 
products used for an unauthorized indication, or marketed products used to gain further 
information about the authorized form.
IRB
Institutional Review Board
ISA
intervention-specific appendix

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ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a participant (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
participants allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of treatment.
IWRS
interactive web-response system
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-model repeated measures
MOS
Medical Outcomes Study
MCRP
magnetic resonance cholangiopancreatography
NIMH
National Institute of Mental Health
NRS
numeric rating scale
participant
Equivalent to CDISC term ‘subject’: an individual who participates in a clinical trial, either 
as a recipient of an investigational medicinal product or as a control.
PDEP
preliminary data entry period
PGI
Patient’s Global Impression of Change
PT
prothrombin time
QTc
corrected QT interval
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
serious adverse event
SAP
statistical analysis plan
SASC
Statistical Analysis Subcommittee
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. 
SD
standard deviation
SoA
schedule of activities
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  An untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with 
this treatment.
TENS
transcutaneous electrical nerve stimulation

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ULN
upper limit of normal
VAS
visual analog scale

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11.
References
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: 
American Psychiatric Association, 2013.
Buchholz I, Janssen MF, Kohlmann T, Feng YS. A systematic review of studies comparing the 
measurement properties of the three-level and five-level versions of the EQ-5D. 
PharmacoEconomics. 2018;36(6):645-661.
[CSSRS] The Columbia Lighthouse Project. The Columbia Protocol for Research. Columbia-
Suicide Severity Rating Scale Scoring and Data Analysis Guide. Version 2.0. Available at: 
http://cssrs.columbia.edu/wp-content/uploads/ScoringandDataAnalysisGuide-for-Clinical-
Trials-1.pdf. Published February 2013. Accessed January 30, 2019.
Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki 
G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad 
AR, Kramer LD, Manning DC, Martin S, McCormick CG, McDermott MP, McGrath P, 
Quessy S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, Simon L, 
Stauffer JW, Stein W, Tollett J, Wernicke J, Witter J; IMMPACT. Core outcome measures for 
chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113(1-2):9-19.
Liang KY, Zeger S. Longitudinal data analysis of continuous and discrete responses for pre–post 
designs. Sankhyā: The Indian Journal of Statistics, (Series B). 2000;62(1):134–148.

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