Clinical trial NCT05620563
Conditions: Osteoarthritis
Sponsor: Eli Lilly and Company
Start date: 2022-11-22; Completion date: 2023-06-12
Enrollment: 147 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the efficacy and safety of LY3857210 in participants with Osteoarthritic Pain. This trial is part of the chronic pain master protocol, H0P-MC-CPMP (NCT05986292), which is a protocol to accelerate the development of new treatments for chronic pain.

Detailed description:

Arms: arm 1: Participants received 45 milligram (mg) LY3857210 orally once daily for up to 8 weeks. arm 2: Participants received placebo orally once daily for up to 8 weeks.
Interventions: intervention 1: LY3857210 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally

Protocol documents:
Prot_000.pdf: 
This study H0P-MC-OA05 (NCT05620563) is a sub-study of Master Protocol H0P-MC-CPMP 
(NCT05986292) 
Protocol H0P-MC-OA05 (a) 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3857210 for the 
Treatment of Osteoarthritis Pain
NCT05620563 
Approval Date: 14-Oct-2022 


CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY3857210, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.  
 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Master Protocol Title: A Master Protocol for Randomized, Placebo-Controlled, Phase 2 
Clinical Trials of Multiple Interventions for the Treatment of Chronic 
Pain 
Master Protocol Number: H0P-MC-CPMP 
ISA Title: Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3857210 for 
the Treatment of Osteoarthritis Pain 
ISA Number: H0P-MC-OA05 
Amendment Number: a 
Compound: LY3857210 
Brief Title: Phase 2 Clinical Trial to Evaluate LY3857210 for the Treatment of Osteoarthritis 
Pain 
Study Phase: 2 
Acronym: OA05  
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Numbers: 
LY3857210 IND: 156411 
Master Protocol IND: 144915 
Approval Date: Protocol H0P-MC-OA05 Amendment (a) Electronically Signed and Approved 
by Lilly on date provided below.  
Document ID: VV-CLIN-075080 
 
 
Approved on 14 Oct 2022 GMT


CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
2 
Medical Monitor Name and Contact Information will be provided separately. 
Approved on 14 Oct 2022 GMT


C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (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 n al Pr ot o c ol  
2 6 -A u g -2 0 2 2  
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 ds a d diti o nal p h ysi cal e xa m i nati o ns a n d e x cl usi o n criteria t o a d dress 
re g ulat or y fee d bac k. 
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. 3. Sc he d ule 
of Acti vities  
A d de d P h ysic al e x a mi nati o ns at Visits 5 a n d 7.   
A d de d n ote, “ C o m plete p h ysical e x a mi nati o n , 
i ncl u di n g tar gete d p h ysic al e x a mi nati o n  
s pecifie d bel o w, s h o ul d b e perf or me d at V 3 
a n d V 8 0 1 or E D. T ar get e d e x a mi nati o n  f or 
s ki n, gastr oi ntesti nal tract, ma m mar y gla n d i n 
males , a n d l y m p h n o d es s h o ul d als o be 
perf or me d at V 5 a n d V 7. ” 
Per re g ulat or y fee d b ac k.  
 
Re m o ve d te xt i n n ote s f or vital si g ns, “ …a n d 
pri or t o P K sa m ple c ollecti o n.”  
E dit orial c orrecti o n.  
5. 2. 
E x cl usi o n 
Criteria  
M o difie d criteri o n [1 0 8 5 ], “ ha ve c o m plete d  
partici pate d i n …”.  
Clarificati o n.  
 
8. 2. 1. 
P h ysical 
E x a mi nati o ns  
A d de d, “ C o m plete p h ysi cal e x a mi nati o n , 
i ncl u di n g tar gete d e x a mi nati o n  s pecifie d 
bel o w, s h o ul d be perf or me d at V 3 a n d Visit 
8 0 1 or E D. Tar gete d p h ysical e xa mi nati o ns of 
s ki n, gastr oi ntesti nal tract, ma m mar y gla n d i n 
males , a n d l y m p h n o d es will als o be perf or m e d 
at V isits V 5 a n d V 7 as descri be d i n t he S o A. 
A n y cli nicall y si g nifica nt a b n or mal p h ysical 
e x a mi nati o n fi n di n gs will be re p orte d as A Es. ” 
Per re g ulat or y fee d b ac k.  
A p pr o ve d o n 1 4 Oct 2 0 2 2 G M T
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CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
4 
Section # and 
Name 
Description of Change 
Brief Rationale 
 
Removed, “…to physical examinations 
(described in the Master Protocol CPMP)…” 
Editorial. 
 
Approved on 14 Oct 2022 GMT


CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
5 
Table of Contents 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................10 
1.3. 
Schedule of Activities (SoA) ..........................................................................................11 
2. 
Introduction ...................................................................................................................15 
2.1. 
Study Rationale ...............................................................................................................15 
2.2. 
Background .....................................................................................................................15 
2.3. 
Benefit/Risk Assessment ................................................................................................15 
2.3.1. 
Risk Assessment .............................................................................................................15 
2.3.2. 
Benefit Assessment .........................................................................................................16 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................16 
3. 
Objectives, Endpoints, and Estimands .......................................................................17 
4. 
Study Design ..................................................................................................................18 
4.1. 
Overall Design ................................................................................................................18 
4.2. 
Scientific Rationale for Study Design ............................................................................18 
4.3. 
Justification for Dose ......................................................................................................18 
4.4. 
End of Study Definition ..................................................................................................19 
5. 
Study Population ...........................................................................................................20 
5.1. 
Inclusion Criteria ............................................................................................................20 
5.2. 
Exclusion Criteria ...........................................................................................................20 
5.3. 
Lifestyle Considerations .................................................................................................21 
5.3.1. 
Substance Use .................................................................................................................21 
5.4. 
Screen Failures ................................................................................................................21 
5.5. 
Criteria for Temporarily Delaying Enrollment, Randomization, 
or Administration of Study Intervention of a Participant ...............................................21 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................22 
6.1. 
Study Intervention(s) Administered................................................................................22 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................22 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................22 
6.3.1. 
Stratification ....................................................................................................................22 
6.4. 
Study Intervention Compliance ......................................................................................22 
6.5. 
Dose Modification ..........................................................................................................22 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................22 
6.7. 
Treatment of Overdose ...................................................................................................23 
6.8. 
Concomitant Therapy .....................................................................................................23 
6.8.1. 
Permitted Medications ....................................................................................................23 
6.8.2. 
Prohibited Medications ...................................................................................................23 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................24 
7.1. 
Discontinuation of Study Intervention ............................................................................24 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................24 
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
6  
7. 1. 2.  
H y p erse nsiti vit y  ..............................................................................................................2 5  
7. 2.  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ................................................2 5  
7. 3.  
L ost t o F oll o w -U p  ...........................................................................................................2 5  
8.  
St u d y Assess me nts a n d Pr o ce d ures .............................................................................2 6  
8. 1.  
Efficac y Assess me nts  .....................................................................................................2 6  
 
 
8. 2.  
Safet y Assess me nts  .........................................................................................................2 6  
8. 2. 1.  
P h ysical E x a mi nati o ns  ....................................................................................................2 6  
8. 2. 2.  
Electr ocar di o gra ms  .........................................................................................................2 6  
8. 2. 3.  
Cli nical Safet y La b orat or y Tests  ....................................................................................2 7  
8. 3.  
A d verse E v e nts, Seri o us A d verse E v e nts, a n d Pr o d uct 
C o m plai nts  ......................................................................................................................2 7  
8. 3. 1.  
Pre g n a nc y  ........................................................................................................................2 7  
8. 3. 2.  
H y p erse nsiti vit y Reacti o ns  .............................................................................................2 8  
8. 3. 3.  
A d verse E v e nts of S peci al I nt erest  .................................................................................2 8  
8. 4.  
P har mac o ki netics  ............................................................................................................2 9  
8. 5.  
P har mac o d y na mics  .........................................................................................................2 9  
8. 6.  
Ge netics  ..........................................................................................................................2 9  
8. 7.  
Bi o mar kers  ......................................................................................................................2 9  
8. 8.  
I m m u n o ge nicit y Assess me nts.........................................................................................2 9  
8. 9.  
Me dical Res o urce Utiliz ati o n a n d Healt h Ec o n o mi cs  ....................................................2 9  
9.  
St atistic al C o nsi der ati o ns  .............................................................................................3 0  
9. 1.  
Statistical H y p ot heses  .....................................................................................................3 0  
9. 2.  
A nal ys es Sets  ..................................................................................................................3 0  
9. 3.  
Stati stical A nal yses .........................................................................................................3 0  
9. 3. 1.  
Ge neral C o nsi derati o ns  ...................................................................................................3 0  
9. 3. 2.  
Tertiar y A n al ysis  .............................................................................................................3 0  
9. 3. 3.  
Safet y A nal yses  ...............................................................................................................3 1  
9. 3. 4.  
E x pl orat or y P har mac o ki netic A nal yses  ..........................................................................3 1  
9. 4.  
I nteri m A nal ysis ..............................................................................................................3 1  
9. 5.  
Sa m ple Siz e Deter mi nati o n  ............................................................................................3 1  
1 0.  
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns  ..................................3 2  
1 0. 1.  
A p pe n di x 1: Re g ulat or y, Et hical, a n d St u d y O versi g ht 
C o nsi derati o ns  ................................................................................................................3 2  
1 0. 2.  
A p pe n di x 2: Cli nical La b orat or y Tests  ...........................................................................3 3  
1 0. 2. 1.  La b orat or y Sa m ples t o b e O bt ai ne d at t he Ti me of a S yste mic 
H y p erse nsiti vit y E v e nt  ....................................................................................................3 3  
1 0. 3.  
A p pe n di x 3: A d verse E v e nts a n d Seri o us A d verse E ve nts: 
Defi niti o ns  a n d Pr oce d ures f or Rec or di n g, E val uati n g, F oll o w -
u p, a n d Re p orti n g  ............................................................................................................3 4  
1 0. 4.  
A p pe n di x 4: C o ntrace pti ve a n d Barri er G ui da nce  ..........................................................3 5  
1 0. 4. 1.  Defi niti o ns .......................................................................................................................3 5  
1 0. 4. 2.  C o ntrace pti o n G ui da nce ..................................................................................................3 5  
1 0. 5.  
A p pe n di x 5: Li ver Safet y: S u g geste d Acti o ns a n d F oll o w -u p 
Assess me nts  ....................................................................................................................3 8  
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CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
7 
10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................39 
10.7. 
Appendix 7: Abbreviations and Definitions ...................................................................42 
11. 
References ......................................................................................................................44 
 
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
8  
1.  
Pr ot oc ol S u m m ar y  
1. 1.  
S y n o psis  
I S A Title:  
Ra n d o m iz e d, P lace b o-C o ntr olle d, P hase 2 C li nical T rial t o E val uate L Y 3 8 5 7 2 1 0  f or t he 
T reat me nt of O st e oart hritis P ai n. 
Brief  Title:  P hase 2 Cli nical Trial t o E val uate L Y 3 8 5 7 2 1 0 f or t he Treat me nt of Oste oart hritis 
Pai n  
Re g ul at or y A ge nc y I de ntifier N u m bers :  
L Y 3 8 5 7 2 1 0 I N D: 1 5 6 4 1 1  
Master Pr ot oc ol I N D: 1 4 4 9 1 5  
R ati o n ale:  
T he p ur p ose of t his st u d y is t o test w het her L Y 3 8 5 7 2 1 0 is efficaci o us i n  relie vi n g k n ee pai n d u e 
t o oste oart hritis ( O A). L Y 3 8 5 7 2 1 0 is a s mall m olec ule rece pt or a nta g o nist of t he P 2 X 7 rece pt or, 
a n a de n osi ne tri p h os p hat e li ga n d -gate d i o n c h a n n el k n o w n t o be i n v ol ve d i n ne ur oi nfla m mati o n 
a n d pai n.  
Data will be c ollecte d t o assess t he safet y a n d t olera bilit y of L Y 3 8 5 7 2 1 0 i n t his st u d y p o p ulati o n. 
T he p har mac o ki netics of L Y 3 8 5 7 2 1 0  will als o be e x pl ore d. T he t otalit y of data fr o m t his pr o of -
of -c o nce pt st u d y will assess t he be nefits a n d ris ks ass ociate d wit h L Y 3 8 5 7 2 1 0 a n d i nf or m 
decisi o ns f or t he cli nic al de vel o p me nt of L Y 3 8 5 7 2 1 0.  
O bjecti ves , E n d p oi nts , a n d Esti m a n ds: 
T he pri mar y a n d s ec o n d ar y o bje cti ves  a n d e n d p oi nts are state d i n t he Mast er Pr ot oc ol H 0 P -M C -
C P M P ( C P M P) a n d t he O A  disease -state a d d e n d u m ( D S A; H 0 P-M C -C P M P[ 1 ]).  
O ver all Desi g n : 
T his is a 1 0 -wee k , P has e 2, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t hat will 
c o m pare L Y 3 8 5 7 2 1 0 vers us place b o i n partici pa nts wit h O A  of t he k nee .  
St u d y P o p ul ati o n : 
I n a d diti o n t o t he i ncl usi o n a n d e x cl usi o n criteria descri be d i n t he Mast er Pr ot oc ol C P M P a n d 
D S A  C P M P( 1) , i n di vi d uals ma y n ot ta k e part i n t he st u d y if t he y h a ve  
 
 
 
 a n e G F R of less t ha n 3 0 mL / mi n/ 1. 7 3 m2, or 
 
 
A p pr o ve d o n 1 4 Oct 2 0 2 2 G M T
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CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
9 
Number of Participants: 
Up to approximately 125 participants will be randomly assigned to study intervention with the 
assumption that 20% of the participants will drop out prior to the end of the double-blind 
treatment period. 
Intervention Groups and Duration: 
This double-blind study includes an 8-week treatment period with a 2-week follow-up visit off 
treatment. 
Intervention Name 
LY3857210 
Placebo 
Dosage Level(s) 
45 mg daily 
Not applicable 
Route of Administration 
and Duration 
PO 
PO 
Abbreviation: PO = by mouth. 
Ethical Considerations of Benefit/Risk: 
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with LY3857210 are justified by the 
anticipated benefits that may be afforded to participants with OA. 
Data Monitoring Committee: Yes 
Safety reviews are covered by the Assessment Committee charter for the Chronic Pain Master 
Protocol (CPMP). 
 
Approved on 14 Oct 2022 GMT


CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
10 
1.2. 
Schema 
 
Abbreviations: PDEP = preliminary data entry period; V = visit. 
a Medication washout and PDEP begins. 
b Randomization to either LY3857210 or placebo.  
 
 
Approved on 14 Oct 2022 GMT










C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
1 5  
2.  
I ntr o d ucti o n 
T his I SA  H 0 P -M C -O A 0 5  (O A 0 5 ) is a n a p pe n di x t o t he Master Pr ot oc ol H 0 P -M C -C P M P 
( C P M P) a n d c o ntai ns u ni q ue st u d y ele me nts s pecific f or L Y 3 8 5 7 2 1 0. T he master pr ot oc ol 
c o ntai ns t he o verarc hi n g st u d y ele me nts t hat g o v er n t he O A  D S A C P M P( 1)  a n d t his I S A O A 0 5 .  
2. 1.  
St u d y R ati o n ale  
T he p ur p ose of t his st u d y is t o test w het her L Y 3 8 5 7 2 1 0 is efficaci o us i n relie vi n g k n ee pai n d u e 
t o O A . Data  will be c ollecte d  t o assess t he safet y a n d t olera bilit y of L Y 3 8 5 7 2 1 0  i n t his st u d y 
p o p ulati o n . T he P K  of L Y 3 8 5 7 2 1 0 will als o be e x pl ore d . T he t otal it y of data fr o m t his P O C 
st u d y will assess t he be n efit s a n d ris ks ass ociate d wit h  L Y 3 8 5 7 2 1 0  a n d i nf or m decisi o ns f or t he 
cli nical de vel o p me nt of L Y 3 8 5 7 2 1 0 . 
2. 2.  
B ac k gr o u n d  
P 2 X 7 is a n a de n osi ne tri p h os p hate  li ga n d-gate d i o n c ha n nel t hat w h e n acti vate d res ults i n Ca 2 +  
i nfl u x, a n d cell ular acti vati o n (f or e x a m ple, cas pas e 1). F or a rece nt re vie w article, see Z ha n g et 
al. 2 0 2 0. Sti m ulati o n of P 2 X 7 pla ys a k e y r ole i n t he cr osstal k of t he glial cells a n d ne ur o ns at a n 
o ver -acti ve s y na pse a n d i n ne ur oi nfla m mat or y c o n diti o ns ( C urrò  et al. 2 0 2 0). T h us, t he 
i n hi biti o n of t he P 2 X 7 rece pt or f o u n d o n glial cells i n t he brai n a n d s pi nal c or d is a ntici pate d t o 
decrease s y na ptic tra ns missi o n.  
L Y 3 8 5 7 2 1 0 is a n oral l y a d mi nistere d, s mall-m olec ule rece pt or a nta g o nist of t he P 2 X 7 rece pt or.  
2. 3.  
Be nefit/ Ris k Assess me nt  
M ore detaile d i nf o r mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o n a bl y 
e x pecte d A Es  of L Y 3 8 5 7 2 1 0 ma y b e f o u n d i n t he I B.  
2. 3. 1.  
Ris k Assess me nt  
St u d y inter ve nti o n  
A p pr o ve d o n 1 4 Oct 2 0 2 2 G M T
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
1 6  
T o xic ol o gy st u dies a n d N O A E L ex p os ure  
Base d o n t h e o bser ve d c o n v ulsi o n i n t he 3 -m o nt h d o g t o xic ol o g y st u d y (re p orte d i n 1 d o g) as 
well as c o n v ulsi o n n ote d i n t he rat i n vi v o micr o n ucle us st u d y (re p orte d i n 1 rat), a 1 0 -f ol d 
e x p os ure m ulti ple base d o n t he o bser ve d A U C a n d C ma x  ass ociate d wit h t he N O E L f or 
c o n v ulsi o ns i n d o g (t he m ost se nsiti ve s pecies) will be mai ntai ne d i n t his st u d y 
 
  
I n a d diti o n, ne ur ol o gical e x a mi nati o n will be c o n d ucte d at re g ul ar i nter vals d uri n g t he st u d y 
peri o d a n d  A Es r elate d t o C N S si g ns , a n d s y m pt o ms will be c ollecte d d uri n g t he st u d y.  
Partici pa nts wit h a hist or y of s eiz ures will be e x c l u de d fr o m t he st u d y.  
P ote nti al dr u g -dr u g i nter acti o ns  
Cli nical dr u g -dr u g i nteracti o n st u dies ha ve n ot bee n c o n d ucte d wit h L Y 3 8 5 7 2 1 0 . Base d o n 
c urre nt i n vitr o data, L Y 3 8 5 7 2 1 0  is a p ote ntial i n d ucer of C Y P 3 A 4, C Y P 1 A 2, C Y P 2 B 6 , a n d 
C Y P 2 C 8 . T o miti gate ris k,  partici pa nts ta ki n g  se nsiti ve s u bstrates wit h a narr o w t hera pe utic 
i n de x are e x cl u de d. See Secti o n 5. 2  f or e x cl usi o n criteria a n d refer t o I B f or m ore i nf or mati o n . 
I nf or mati o n o n A Es e x pecte d t o be rel ate d t o t he st u d y i nter ve nti o n ma y b e f o u n d i n t he I B. 
I nf or mati o n o n S A Es t hat are e x pecte d i n t he st u d y p o p ulati o n i n de pe n d e nt of dr u g e x p os ure will 
be assesse d b y t he s p o ns or i n a g gre gate, peri o dica ll y d uri n g t he c o urse of t he st u d y, a n d ma y be 
f o u n d i n t he I B. 
2. 3. 2.  Be nefit Assess me nt  
P ote ntial be nefits f or t he st u d y partici p a nts i ncl u de  
 i nf or mati o n o btai ne d fr o m st u d y-relate d me dical pr oce d ures  
o  p h ysical e x a mi nati o ns  
o  la b orat or y tests, a n d  
o  E C Gs  
 detail e d e val uati o ns of O A  
o  k nee e x a mi nati o ns , a n d 
o  k nee X -ra ys, a n d 
 O A -ass oci ate d q uesti o n n aires t hat ma y i m pr o ve p artici pa nts u n dersta n di n g t heir o w n 
c o n diti o n.  
As part of St u d y C P M P, partici pa nts i n t his I S A will re p ort t heir e x perie nce usi n g sta n dar d t o ols 
t hat ma y c o ntri b ute t o t he assess me nt of n o v el treat me nts f or O A . I n a d diti o n, data c ollecte d 
fr o m t his st u d y ma y  als o i m pr o ve o ur u n dersta n di n g of O A  pat h o ge n esis. B ot h of w hic h ma y 
lea d t o t he de vel o p me nt of ne w treat me nt wit h i m pr o ve d safet y a n d efficac y pr ofile c o m pare d t o 
sta n dar d of care.  
2. 3. 3.  O ver all Be nefit Ris k C o ncl usi o n  
Ta ki n g i nt o acc o u nt t he meas ures ta k e n t o mi ni mize ris k t o partici pa nts parti ci pati n g i n t his 
st u d y, t he p ote ntial ris ks i de ntifie d i n ass ociati o n wit h L Y 3 8 5 7 2 1 0  are j ustifie d b y t he 
a ntici pate d be nefits t hat ma y b e aff or de d t o partici pa nts wit h O A . 
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
1 7  
3.  
O bjecti ves , E n d p oi nts , a n d Esti m a n ds  
T he Master Pr ot oc ol C P M P a n d O A  D S A C P M P( 1)  i ncl u de o bjecti ves a n d e n d p oi nts a p plica ble 
f or t his st u d y  T his ta ble descri bes o bjecti ves a n d e n d p oi nts s pecific f or L Y 3 8 5 7 2 1 0  
A p pr o ve d o n 1 4 Oct 2 0 2 2 G M T
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
1 8  
4.  
St u d y Desi g n  
4. 1.  
O ver all  Desi g n  
T he Master Pr ot oc ol C P M P descri bes t he o verall st u d y desi g n a n d  st u d y d esi g n rati o nale. T his 
secti o n descri bes visits a n d o verall pr oce d ures u ni q ue t o I S A O A 0 5  f or L Y 3 8 5 7 2 1 0 i n a d diti o n 
t o t he pr oce d ures o utli ne d i n C P M P a n d C P M P( 1) .  
D o u ble -b li n d tre at me nt p eri o d ( Visits 3 t hr o u g h 7)  
Eac h visit is a n o ut patie nt visit . 
At Visit 3  
 partici pa nts are ra n d o ml y assi g ne d t o L Y 3 8 5 7 2 1 0  or place b o  
 t he site c o m pletes t he O A 0 5  baseli ne pr oce d ures a n d sa m ple c ollecti o n  (e x cl u di n g P K) 
pri or t o st u d y i nter ve nti o n  
 t he site c ollects partici pa nts’  vitals pre d ose  
 partici pa nts recei ve t heir oral st u d y i nter ve nti o n  
 t he site c o m pletes P K sa m ple c ollecti o n, a n d 
 t he site i nstr ucts partici pa nts t o c o nti n ue wit h st u d y restricti o ns a n d N R S diar y e ntries 
bef ore t h eir visit disc har ge.  
At Visits 4 t hr o u g h 7  
 t he site re vie ws a v aila ble safet y data a n d sa m ple c ollecti o n  
 partici pa nts c o nti n ue oral st u d y i nter ve nti o n ( n ot a p plica ble f or V 7) a n d bri n g all st u d y 
i nter ve nti o n b ottles t o eac h visit 
 t he site c o m pletes all sa m ple c ollecti o n a n d safet y m o nit ori n g n ot e d i n t he S o A s, a n d 
 the site i nstr ucts partici pa nts t o c o nti n ue wit h st u d y restricti o ns, N R S diar y e ntri es , a n d 
weari n g of
 b ef ore t h eir visit disc har ge. 
D o u ble -b li n d p osttre at me nt foll o w -u p p eri o d ( Visit 8 0 1)  
 Partici pa nts m ust c o m plete 1 p osttreat me nt f oll o w -u p visi t f or safet y a n d efficac y 
assess me nt at Visit 8 0 1 acc or di n g t o t he S o A  
 t he site sc he d ules Visit 8 0 1 a p pr o xi matel y 2 wee ks after Visit 7 or E D Visit, a n d 
 at Visit 8 0 1, partici pa nts ret ur n t he de vi ces (
 
4. 2.  
Scie ntific R ati o n ale f or St u d y Desi g n  
T he Master Pr ot oc ol C P M P descri bes t he o verall st u d y desi g n rati o nale.   
4. 3.  
J ustific ati o n f or D ose  
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
1 9  
4. 4.  
E n d of St u d y  Defi niti o n  
A partici pa nt is c o nsi dere d t o ha ve c o m plet e d t h is I S A if t he y h a ve c o m plete d all re q uire d 
p hases of t he st u d y i ncl u di n g t he last sc h e d ule d pr oce d ure s h o w n i n t he I S A S o A . 
T he e n d of t he st u d y is d efi ne d as t he d ate of t he l ast visit of t he last partici pa nt i n t he st u d y or 
last sc he d ule d pr oce d ure s h o w n i n t he I S A S o A  f or t he last partici pa nt.  
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
2 0  
5.  
St u d y P o p ul ati o n  
T he Master Pr ot oc ol C P M P  a n d O A  D S A C P M P( 1)  pr o vi de eli gi bilit y criteria t hat m ust be 
f oll o we d f or t his st u d y. L Y 3 8 5 7 2 1 0-s pecifi c i ncl usi o n a n d e x cl usi o n criteria are liste d h ere. 
5. 1.  
I ncl usi o n Criteri a 
Partici pa nts are eli gi ble t o be  i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y: 
Se x a n d co ntr ace pti ve/ b arrier re q uire me nts  
[ 1 0 7 5] Males a n d fe m ales ma y p artici pate i n t his trial.  
N o male c o ntrace pti o n is re q uire d e x ce pt i n c o m plia nce wit h s pecific l ocal 
g o ver n me nt st u d y re q uir e me nts. 
W O C B P  a n d W N O C B P ma y p artici pate i n t his trial. See Secti o n  1 0. 4  f or d efi niti o ns 
a n d a d diti o nal re q uir e me nts relate d t o c o ntrace pti o n.  
C o ntrace pti ve use b y p artici pa nts  s h o ul d be c o nsiste nt wit h l ocal re g ulati o ns 
re gar di n g t he m et h o ds of c o ntrace pti o n f or t h ose p artici pati n g i n cli nical st u dies.   
5. 2.  
E xcl usi o n Criteri a   
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criter ia a p pl y: 
[ 1 0 7 7] Ha ve a n e G F R of < 3 0 m L / mi n/ 1. 7 3 m2, base d o n t he C hr o nic Ki d ne y Disease 
E pi de mi ol o g y C olla b orati o n f or m ula at Visit 1 or Visit 2.  
[ 1 0 7 8] Ha ve k n o w n aller gies t o L Y 3 8 5 7 2 1 0, relate d c o m p o u n ds or a n y c o m p o ne nts of t he 
f or m ulati o n, or hist or y of si g nifica nt at o p y.  
[ 1 0 7 9] W o me n w h o are pre g na nt or breastf ee di n g.  
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
2 1  
5. 3.  
Lifest yle C o nsi der ati o ns  
See  t he Master Pr ot oc ol C P M P f or lifest yl e c o nsi derati o ns.   
I S A-s p ecific lifest yl e c o nsi derati o ns are pr o vi de d bel o w.  
5. 3. 1.  
S u bst a nce Use  
P ositi ve uri ne dr u g scree n will n ot be c o nsi dere d illicit use if it is a prescri be d c o nc o mita nt 
me dicati o n f or a k n o w n pree xisti n g c o n diti o n . 
5. 4.  
Scree n F ail ures  
Scree n fail ures are des cri be d i n t he Master Pr ot oc ol C P M P.  
5. 5.  
Criteri a f or Te m p o r aril y Del a yi n g E nr oll me nt, R a n d o miz ati o n, or 
A d mi nistr ati o n of St u d y I nter ve nti o n of a P artici p a nt  
N ot a p plica ble t o t his st u d y.  
 
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CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
22 
6. 
Study Intervention(s) and Concomitant Therapy 
6.1. 
Study Intervention(s) Administered 
This table lists the interventions used in this clinical study. 
Intervention Name 
LY3857210 
Placebo 
Dosage Level(s) 
45 mg daily 
N/A 
Route of Administration 
PO 
PO 
Abbreviations: N/A = not applicable; PO = by mouth. 
Packaging and labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
6.2. 
Preparation, Handling, Storage, and Accountability 
Preparation, handling, storage, and accountability are described in the Master Protocol CPMP. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization and blinding are described in the Master Protocol CPMP. 
6.3.1. 
Stratification 
There are no additional stratification factors for this study. 
6.4. 
Study Intervention Compliance 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning and 
counting returned capsules and documented in the source documents and CRF. A record of the 
number of study intervention capsules dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start and 
stop dates will also be recorded in the CRF. 
6.5. 
Dose Modification 
Dose modification is not permitted. 
6.6. 
Continued Access to Study Intervention after the End of the Study 
Not applicable. 
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Protocol number H0P-MC-OA05 (a) 
23 
6.7. 
Treatment of Overdose 
In case of suspected overdose, participants should be monitored for any signs or symptoms of 
adverse reactions or effects, and supportive care should be provided as necessary. There is no 
known antidote to LY3857210 therapy.  
6.8. 
Concomitant Therapy 
6.8.1. 
Permitted Medications 
All concomitant therapies that are part of routine care for comorbidities other than chronic pain 
are allowed and may be used during the study, except as indicated in Section 6.8.2.  
The Master Protocol CPMP provides more detail on concomitant therapy.  
6.8.2. 
Prohibited Medications 
A list of medications that are prohibited from Visit 2 to Visit 801 for participants randomly 
assigned to this ISA study will be provided in the Manual of Operations. Participants may return 
to their routine care after Visit 801 is completed, as clinically appropriate. 
Potential drug-drug interactions with LY3857210 
Please refer to Section 5.2, IB, and Manual of Operations for details on concomitant medication 
restrictions.  
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CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
24 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
The Master Protocol CPMP and OA DSA CPMP(1) provide the reasons and procedures for 
discontinuation of intervention and participant discontinuation that must be followed for this 
study.  
7.1.1. 
Liver Chemistry Stopping Criteria 
Interrupting study intervention based on elevated liver tests 
The study intervention should be interrupted and close hepatic monitoring initiated (see Section 
8.2.5 of the Master Protocol CPMP) if 1 or more of these conditions occur:  
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 weeks 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2x ULN. 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL > 2x ULN  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2x ULN. 
ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA 2009 and other consensus guidelines, with minor modifications. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin level; ULN = upper limit of normal. 
Resuming study intervention after elevated liver tests 
Resumption of the study intervention can be considered only in consultation with the 
Lilly-designated medical monitor and only if the liver test results return to baseline and if a 
self-limited, non-drug etiology is identified. Otherwise, the study intervention should be 
discontinued. 
 
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Protocol number H0P-MC-OA05 (a) 
25 
7.1.2. 
Hypersensitivity  
If the investigator determines that a systemic hypersensitivity reaction has occurred related to 
study intervention administration, the participant may be permanently discontinued from the 
study intervention, and the sponsor’s designated medical monitor should be notified. If the 
investigator is uncertain about whether a systemic hypersensitivity reaction has occurred and 
whether discontinuation of study intervention is warranted, the investigator may consult the 
sponsor. 
For laboratory samples to be obtained at the time of a systemic hypersensitivity event, see 
Section 10.2.1.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
See the Master Protocol CPMP. 
7.3. 
Lost to Follow-Up 
See the Master Protocol CPMP. 
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
2 6  
8.  
St u d y Assess me nts a n d Pr oce d ures  
St u d y pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he Master Pr ot oc ol  C P M P, O A  D S A  
C P M P( 1) , a n d I S A O A 0 5  S o As.  
L Y 3 8 5 7 2 1 0 -s pecifi c assess me nts a n d pr oce d ures are descri be d here.  
8. 1.  
Effic ac y Assess me nts  
Pla n ne d ti me p oi nts f or all efficac y assess me nts are pr o vi de d i n t he S o As.  See t he Master 
Pr ot oc ol C P M P a n d O A  D S A C P M P( 1)  f or a d diti o nal i nf or mati o n o n effi cac y assess me nts.  
8. 2.  
S afet y Assess me nts  
Pla n ne d ti me p oi nts f or all efficac y assess me nts are pr o vi de d i n t he S o As.  
See t he Master Pr ot oc ol C P M P a n d O A  D S A C P M P( 1)  f or a d diti o nal i nf or mati o n o n safet y 
assess me nts.  A d diti o nal St u d y O A 0 5 -s pecific assess me nt i nf or mati o n is pr o vi de d bel o w. 
8. 2. 1.  
P h ysic al E x a mi n ati o ns  
C o m plete p h ysical e x a mi nati o n , i ncl u di n g tar gete d e x a mi nati o n  s pecifie d bel o w, s h o ul d be 
perf or me d at V 3 a n d Visit 8 0 1 or E D.  Tar gete d p h ysical e x a mi nati o ns of s ki n, gastr oi ntesti nal 
tract, ma m mar y gla n d i n males, a n d l y m p h n o d es will als o be perf or m e d at V isits V 5 a n d V 7  as 
descri be d i n t he S o A. A n y cli nic all y si g nifica nt a b n or mal p h ysic al e xa mi nati o n fi n di n gs will be 
re p orte d as A Es. 
I n a d diti o n, a direct e d ne u r ol o gic al assess me nt  will be perf or me d b y t h e i n vesti gat or ( or 
desi g nee) at t he ti me p oi nts s pecifie d i n t he S o A. If a b n or malities are n ote d at t hese ti me p oi nts, 
a d diti o nal e x a mi nati o ns s h o ul d be perf or me d as cli nicall y n ecess ar y. T he e x a mi ner s h o ul d be 
fa miliar wit h t he partici p a nt’s baseli ne e x a mi nati o n.  
Ele me nts of t he ne ur ol o gical assess me nt  i ncl u de i ns pecti o n f or tre m or, e xtra oc ular m o ve m e nts, 
brac hial a n d p atellar d ee p te n d o n refle x es, fi n ger -n ose p oi nti n g, a n d R o m b er g si g n.   
8. 2. 2.  
Electr oc a r di o gr a ms  
Si n gle  1 2 -lea d E C G will be o btai ne d as o utli ne d i n t he S o A (see Secti o n 1. 3 ) usi n g a n E C G 
mac hi ne t hat a ut o maticall y calc ulates t he h eart rat e a n d meas ures P R, R R, Q R S, Q T, a n d Q Tc F 
i nter vals. Refer t o Secti o n 7. 1. of  t he Master Pr ot oc ol C P M P f or Q Tc F  wit h dra wal criteria a n d 
a n y a d diti o nal Q Tc F  rea di n gs t hat ma y be n ecess ar y. 
A d diti o nal details relate d t o E C G are pr o vi de d i n t he Master Pr ot oc ol C P M P.  
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Protocol number H0P-MC-OA05 (a) 
27 
8.2.3. 
Clinical Safety Laboratory Tests 
See OA05 Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency for ISA OA05.  
Additional details are provided in the Master Protocol CPMP. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Appendix 3 of the Master Protocol 
CPMP: 
 AEs 
 SAEs, and 
 PCs. 
See the Master Protocol CPMP Section 8.3 for additional details. 
8.3.1. 
Pregnancy 
Collection of pregnancy information 
Male participants with partners who become pregnant 
● The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive study 
intervention. 
● After learning of a pregnancy in the female partner of a study participant, the 
investigator  
o will obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor.  
The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to 
the sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of gestational age, fetal status (presence or absence of 
anomalies), or indication for the procedure. 
Female participants who become pregnant 
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 24 
hours of learning of a participant’s pregnancy.  
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Protocol number H0P-MC-OA05 (a) 
28 
● The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate 
and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 
Any termination of pregnancy will be reported, regardless of gestational age, fetal 
status (presence or absence of anomalies), or indication for the procedure. 
● While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
● A spontaneous abortion, occurring at <20 weeks gestational age, or still birth, 
occurring at ≥20 weeks gestational age, is always considered to be an SAE and 
will be reported as such.  
● Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in the 
Master Protocol Section 8.3.1. While the investigator is not obligated to actively 
seek this information in former study participants, they may learn of an SAE 
through spontaneous reporting. 
● Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention and continue directly to the follow-up phase. 
The follow-up on the pregnancy outcome should continue independent of 
intervention or study discontinuation.   
8.3.2. Hypersensitivity Reactions 
Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data should be provided to the sponsor in the 
designated CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of a suspected systemic hypersensitivity event, additional blood samples should be 
collected as described in Section 10.2.1. Laboratory results are provided to the sponsor via the 
central laboratory. 
8.3.3. Adverse Events of Special Interest  
Convulsion is an AE of special interest for LY3857210 and will be subject to enhanced 
surveillance activities. Additionally, convulsion will be analyzed for presentation in the Clinical 
Study Report in accordance with the SAP. 
If a seizure or convulsion is reported, then contact the medical monitor as soon as possible. 
Additional evaluation or follow-up may be requested.  
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C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
2 9  
8. 4.  
P h ar m ac o ki ne tics 
Bl o o d  sa m ples will be c ollecte d f or meas ure me nt of plas ma c o nce ntrati o ns of L Y 3 8 5 7 2 1 0 as 
s pecifie d i n t he S o A.  
A ma xi m u m of 3  sa m ples ma y be c ollecte d at a d diti o nal ti me p oi nts d uri n g t he st u d y if 
warra nte d a n d a gree d u p o n bet wee n t he i n v esti gat or a n d t he s p o ns or. T h e ti mi n g of P K sa m ples 
ma y b e altere d d uri n g t he c o urse of t he st u d y b ase d o n ne wl y a vaila ble d ata  t o e ns ure a p pr opriate 
data c ollecti o n .  
I nstr u cti o ns f or t he c ollecti o n a n d ha n dli n g of P K  sa m ples will be pr o vi de d b y t he s p o ns or. 
T he date a n d ti me ( 2 4 -h o ur cl oc k ti me) will be rec or de d f or  
 L Y 3 8 5 7 2 1 0 a d mi nistrati o n pri or t o t he P K sa m ple c ollecti o n, a n d  
 P K sa m ple c ol lecti o n. 
P K sa m ples ma y als o be use d t o e val uate s afet y or efficac y meas ures  relate d t o c o ncer ns arisi n g 
d uri n g or after t he st u d y .  
8. 5.  
P h ar m ac o d y n a mics  
P har mac o d y na mic assess me nts will n ot be e val uate d i n t his st u d y . 
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Protocol number H0P-MC-OA05 (a) 
32 
10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
See the Master Protocol CPMP for regulatory, ethical, and study oversight considerations. 
 
 
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Protocol number H0P-MC-OA05 (a) 
34 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
See the Master Protocol Appendix 3 for information related to AE and SAE. 
 
 
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CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
38 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
See the Master Protocol CPMP Appendix 6 for liver safety: suggested actions and follow up 
assessments. 
 
 
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Protocol number H0P-MC-OA05 (a) 
39 
10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations.  
After approval by local Ethical Review Boards, regulatory bodies and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study.  
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study intervention during an extended treatment period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
Approved on 14 Oct 2022 GMT


C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
4 0  
Re m ote visits  
Tele m e dici ne:  Tele p h o n e or tec h n ol o g y -assiste d virt ual visits, or b ot h, are acce pta ble t o 
c o m plete a p pr o priate ass ess me nts.  
M o bile he alt hc are:  Healt hcare visits ma y be perf or me d b y a m o bile healt h care pr o vi der 
at l ocati o ns ot her t ha n t h e st u d y site w he n partici p a nts ca n n ot tra v el t o t he site d ue t o a n 
e x ce pti o nal circ u msta nce if writte n a p pr o val is pr o vi de d b y t he s p o ns or .  
Pr oce d ures p erf or me d at s uc h visits i ncl u de, b ut are n ot li mite d t o, c ollecti o n of bl o o d 
sa m ples, s y m pt o m-directe d p h ysic al e xa mi nati o ns, E C Gs, vita l si g ns, i nter ve nti o n 
acc o u nta bilit y a n d c o m plia nce, A E c ollecti o n, a n d c ollecti o n of healt h i nf or mati o n.  
Ot her alter n ative l oc ati o ns:  La b orat or y dra ws ma y be d o n e at a n alter nat e l ocati o n i n 
e x ce pti o nal circ u msta nces.  
I n s o urce d o c u me nts a n d t he C R F, t he st u d y site s h o ul d ca pt ure t he visit met h o d, wit h a s pecific 
e x pla nati o n f or a n y data missi n g beca us e of misse d i n -pers o n site visits.  
Re gar dless of t he t y pe of re m ote visits i m ple me nte d, t he pr ot oc ol re q uire m e nts re gar di n g t he 
re p orti n g of A Es, S A Es, a n d P Cs  re mai n u nc ha n ge d.  
E v er y eff ort s h o ul d be m a de t o e na bl e partici pa nts t o ret ur n t o o n -site visits as s o o n as 
reas o na bl y p ossi ble, w hil e e ns uri n g t he safet y of b ot h t he partici pa nts a n d t he site staff. 
L oc al l a b or at or y testi n g o pti o n  
L ocal la b orat or y te sti n g ma y b e c o n d uct e d i n lie u of ce ntr al la b orat or y t esti n g. T he l ocal 
la b orat or y m ust be q ualifie d i n acc or da nce wit h a p plica ble l ocal r e g ulati o ns. 
 
St u d y i nter ve nti o n  a n d a ncill ar y s u p plies (i ncl u di n g p artici p a nt di aries)  
W he n a  partici pa nt is u na ble t o g o t o t he site t o recei ve st u d y s u p plies d uri n g n or mal o n -site 
visits, t he site s h o ul d w or k wit h t he s p o ns or t o deter mi ne a p pr o priate acti o ns. T hese acti o ns ma y 
i ncl u de:  
 as ki n g t he p artici pa nt t o g o t o t he site a n d recei ve st u d y s u p plies fr o m site staff 
wit h o ut c o m pleti o n of a f ull st u d y visit  
 as ki n g t he p artici pa nt’s d esi g nee t o g o t o t he site a n d recei v e st u d y s u p plies o n a 
partici pa nt’s be h alf, a n d  
 arra n gi n g d eli ver y of st u d y s u p plies . 
T hese re q uire me nts m ust be met bef ore acti o n is ta ke n:  
 Alter nate deli ver y of st u d y i nter ve nti o n s h o ul d be perf or me d i n a ma n ner t hat d oes 
n ot c o m pr o mise treat me nt bli n di n g a n d e ns ures pr o d uct i nte grit y. T h e e xisti n g 
pr ot oc ol re q uire m e nts f or pr o d uct acc o u nta bilit y re mai n u nc ha n ge d, i ncl u di n g 
verificati o n of p artici pa nt’s recei pt of st u d y s u p pli es.  
A p pr o ve d o n 1 4 Oct 2 0 2 2 G M T
C CI


CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
41 
 When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 
Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Adjustments to visit windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual Schedule of Activities as described in the Master Protocol CPMP, OA 
DSA CPMP(1), and ISA OA05. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study.  
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study.  
Documentation 
Sites will identify and document the details of how participants, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner.  
 
 
Approved on 14 Oct 2022 GMT


C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -O A 0 5  (a) 
4 2  
1 0. 7.  
A p pe n di x 7 : A b bre vi ati o ns  a n d Defi niti o ns  
T er m  
D efi niti o n  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsferase  
A U C  
area u n der t he c ur ve  
A S T  
as partate a mi n otra nsferase  
C N S  
ce ntral ner v o us s yste m  
C P M P  
c hr o nic pai n master pr ot oc ol  
C R F  
case re p ort f or m; a pri nte d, o ptical, or electr o nic d oc u me nt d esi g ne d t o rec or d all of t he 
pr ot oc ol -re q uire d i nf or mati o n t o be re p orte d t o t he s p o ns or f or eac h trial partici pa nt. 
D S A  
d isease-state a p pe n di x  
E C G  
electr ocar di o gra m 
E D  
earl y disc o nti n uati o n  
e G F R  
esti mate d gl o mer ular filtrati o n rate  
I B 
I n vesti gat or’s Br oc h ure  
I S A 
inter ve nti o n -s pecific a p pe n di x 
i nt eri m a n al y si s 
A n i nteri m a nal ysis is a n a nal ysis of cli nical st u d y data, se p arate d i nt o treat me nt gr o u ps, 
t hat is c o n d ucte d bef ore t he fi nal re p orti n g data b ase is creat e d/l oc ke d. 
M A D  
m ulti ple -asce n di n g d ose  
M o O  
Ma n ual of O perati o ns  
N O A E L  
N o  o bser ve d  a d verse  effect le vel 
N O E L  
n o o bser va ble effect le vel  
N R S  
n u meric rati n g scale  
p arti ci p a nt  
E q ui vale nt t o C DI S C ter m “s u bj ect”: a n i n di vi d ual w h o partici pates i n a cli nical trial, 
eit her as reci pie nt of a n i n vesti gati o nal me dici nal pr o d uct or as a c o ntr ol 
P C  
pr o d uct c o m plai nt  
P K  
p har mac o ki netics  
P O C  
p r o of-of -c o nce pt  
A p pr o ve d o n 1 4 Oct 2 0 2 2 G M T
C CI


CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
43 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QTc 
corrected QT interval 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SoA 
Schedule of Activities 
WNOCBP 
Women not of childbearing potential 
WOCBP 
Women of childbearing potential 
 
 
Approved on 14 Oct 2022 GMT


CONFIDENTIAL 
Protocol number H0P-MC-OA05 (a) 
44 
11. 
References 
Currò D, Navarra P, Samengo I, Martire M. P2X7 receptors exert a permissive effect on the 
activation of presynaptic AMPA receptors in rat trigeminal caudal nucleus glutamatergic nerve 
terminals. J Headache Pain. 2020;21(1):83. https://doi.org/10.1186/s10194-020-01153-y 
[FDA] Food and Drug Administration. Guidance for Industry. Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation, July 2009. Accessed August 2022. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-induced-
liver-injury-premarketing-clinical-evaluation 
Zhang WJ, Zhu ZM, Liu ZX. The role and pharmacological properties of the P2X7 receptor in 
neuropathic pain. Brain Res Bull. 2020;155:19-28. 
https://doi.org/10.1016/j.brainresbull.2019.11.006 
Approved on 14 Oct 2022 GMT


Si g nat ure Pa ge f or V V- C LI N- 0 7 5 0 8 0 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 7 5 0 8 0 v 1. 0
A p pr o val
1 3- Oct- 2 0 2 2 2 0: 1 9: 3 8 G M T + 0 0 0 0
A p pr o val
1 4- Oct- 2 0 2 2 1 3: 2 3: 4 6 G M T + 0 0 0 0
A p pr o ve d o n 1 4 Oct 2 0 2 2 G M T
P P D
P P D

SAP_001.pdf: 
This study H0P-MC-OA0S (NCT05620563) is a sub-study of Master Protocol H0P-MC-CPMP 
(NCT05986292) 
H0P-MC-OA0S: Statistical Analysis Plan Version 2 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3857210 for the 
Treatment of Osteoarthritis Pain
NCT05620563 
Approval Date: 27-Jun-2023 


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 1  
L Y 3 8 5 7 2 1 0  
1.  St ati sti c al A n al y si s Pl a n:  
H 0 P -M C -O A 0 5 : I nt er v e nti o n-S p e cifi c A p p e n di x (I S A) f or 
L Y 3 8 5 7 2 1 0   
 
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 t h e i nf or m ati o n c o nt ai n e d 
wit hi n it m a y n ot b e r e pr 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 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.    
N ot e t o R e g ul at or y A ut h orit i 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 nf or 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 ati 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 e pr 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.  
 
L Y 3 8 5 7 2 1 0 P ai n fr o m O st e o art hriti s of t h e K n e e  
T hi s i s  a  r a n d o mi z e d, pl a c e b o-c o ntr oll e d , P h a s e 2 cli ni c al tri al  t o e v al u at e L Y 3 8 5 7 2 1 0 f or 
t h e tr e at m e nt of p ai n i n p arti ci p a nt s w h o h a v e b e e n di a g n o s e d wit h o st e o art hriti s of t h e 
k n e e.  
Eli Lill y a n d C o m p a n y  
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5 
Pr ot o c ol H 0 P -M C -O A 0 5  
P h a s e 2  
 
 
 
 
 
D oc u me nt I D:  V V -C LI N -0 9 3 3 4 1  
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 2  
L Y 3 8 5 7 2 1 0  
2.  T a bl e of C o nt e nt s   
S e cti o n  
P a g e   
1.  
Statistical A nal ysis Pla n: H 0 P -M C -O A 0 5: I nter ve nti o n -S pecific 
A p pe n di x (I S A) f or L Y 3 8 5 7 2 1 0  .............................................................................................1  
2.  
Ta ble of C o nte nts  ....................................................................................................................2  
3.  
A b bre viati o ns a n d Defi niti o ns  .................................................................................................4  
4.  
Re visi o n Hist or y  ......................................................................................................................6  
5.  
St u d y O bjecti ves  ......................................................................................................................7  
5. 1.  
Pri mar y O bj ecti ve  ...............................................................................................................7  
5. 2.  
Sec o n dar y O bj ecti ves  .........................................................................................................7  
5. 3.  
E x pl orat or y O bjecti ves  .......................................................................................................8  
6.  
St u d y Desi g n  ...........................................................................................................................9  
6. 1.  
S u m mar y of St u d y Desi g n ..................................................................................................9  
6. 2.  
Deter mi nati o n of Sa m ple Size  ............................................................................................9  
6. 3.  
Met h o d of Assi g n me nt t o Treat me nt  ..................................................................................9  
7.  
A Pri ori Statistical Met h o ds  ..................................................................................................1 0  
7. 1.  
Ge neral C o nsi derati o ns  ....................................................................................................1 0  
7. 2.  
A dj ust me nts f or C o variat es  ..............................................................................................1 0  
7. 3.  
Ha n dli n g of Dr o p o uts or Missi n g Data  ............................................................................1 0  
7. 4.  
M ulti ple C o m paris o ns/ M ulti plicit y  ..................................................................................1 0  
7. 5.  
Use of a n “ Efficac y S u bs et” of Partici pa nts  .....................................................................1 0  
7. 6.  
Partici pa nt  Dis p ositi o n  .....................................................................................................1 0  
7. 7.  
Partici pa nt  C haract eristics  ................................................................................................1 1  
7. 8.  
Treat me nt C o m plia nce  .....................................................................................................1 1  
7. 9.  
C o nc o mita nt T hera p y a n d e C O A C o m plia nce  .................................................................1 1  
7. 1 0.  Efficac y A nal yses  .............................................................................................................1 1  
7. 1 0. 1.  
Pri mar y O ut c o me a n d M et h o d ol o g y  ........................................................................1 1  
7. 1 0. 2.  
A d diti o nal A nal yses of t he Pri mar y O utc o me  .........................................................1 2  
7. 1 0. 3.  
Sec o n dar y Efficac y A nal ys es  ...................................................................................1 2  
7. 1 0. 3. 1.  
Ke y Sec o n dar y A nal ysis  ....................................................................................1 3  
7. 1 0. 3. 2.  
Ot her Sec o n d ar y A nal ysis  ..................................................................................1 3  
 
 
7. 1 1.  P har mac o ki netic/ P har mac o d y n a mic Met h o ds  .................................................................1 4  
7. 1 2.  Safet y A nal yses  ................................................................................................................1 4  
7. 1 2. 1.  
E xte nt of E x p os ure  ...................................................................................................1 4  
7. 1 2. 2.  
A d verse E v e nts  ........................................................................................................1 5  
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T
C CI


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 3  
L Y 3 8 5 7 2 1 0  
7. 1 2. 3.  
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her N ota ble 
A d verse E v e nts  ........................................................................................................1 5  
7. 1 2. 4.  
Ne ur ol o gical E x a m  ..................................................................................................1 5  
7. 1 2. 5.  
Cli nical La b orat or y E val uati o n  ................................................................................1 5  
7. 1 2. 6.  
Vital Si g ns a n d Ot her P h ysical Fi n di n gs  .................................................................1 6  
7. 1 2. 7.  
Electr ocar di o gra ms  ..................................................................................................1 6  
7. 1 2. 8.  
S uici dal I deati o n or Be ha vi or  ..................................................................................1 6  
7. 1 3.  S u b gr o u p A nal ys es  ...........................................................................................................1 6  
7. 1 4 . Pr ot oc ol De viati o ns  ..........................................................................................................1 7  
7. 1 5.  I nteri m A nal yses a n d Data M o nit ori n g ............................................................................1 7  
7. 1 6.  Pla n ne d E x pl orat or y A nal yses  .........................................................................................1 7  
7. 1 7.  T otalit y of E vi de nce f or Efficac y  .....................................................................................1 7  
7. 1 8.  T otalit y of E vi de nce f or Safet y  ........................................................................................1 8  
7. 1 9.  A n n ual Re p ort A nal yses  ...................................................................................................1 9  
7. 2 0.  Cli nical Trial Re gistr y A nal yses  ......................................................................................1 9  
8.  
U n bli n di n g Pla n  .....................................................................................................................2 1  
9.  
Refere n ces  .............................................................................................................................2 2  
 
 
 
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 4  
L Y 3 8 5 7 2 1 0  
3.  A b br e vi ati o n s a n d D efi niti o n s   
T er m  
D efi niti o n  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsferase  
A PI  
a vera ge pai n i nte nsit y  
A S T  
as partate a mi n otra nsferase  
bli n di n g/ m a s ki n g  
A si n gle -bli n d st u d y is o ne i n w hic h t he i n vesti gat or a n d/ or t he i n vesti gat or’s staff are 
a ware of t he treat me nt b ut t he  partici pa nt  is n ot, or vice versa, or w he n t he s p o ns or is 
a ware of t he treat me nt b ut t he i n vesti gat or a n d/ t he i n vesti gat or’s staff a n d t he 
partici pa nt  are n ot.  
A d o u ble -bli n d st u d y is o ne i n w hic h neit her t he partici pa nt  n or a n y of t he i n vesti gat or 
or s p o ns or staff w h o are i n v ol ve d i n t he treat me nt or cli nical e val uati o n of t he s u bj ects 
are a ware of t he treat me nt recei ve d.  
B M A  
Ba yesia n m o del a vera gi n g  
c L D A  
c o nstrai ne d l o n git u di nal data a nal ysis  
c o m pl ai nt  
A c o m plai nt is a n y writte n, el ectr o nic, or oral c o m m u nicati o n t hat alle ges deficie ncies 
relate d t o t he i de ntit y, q ualit y, p urit y, d ura bilit y, relia bilit y, safet y or effecti ve ness, or 
perf or ma nce of a dr u g or dr u g deli ver y s yste m.  
c o m pli a n c e  
A d here nce t o all st u d y -relate d, g o o d cli nical practice ( G C P), a n d a p plica ble re g ulat or y 
re q uire me nts. 
C P M P  
H 0 P M C C P M P  
C T R  
Cli nical Trial Re gistr y  
E C G  
electr ocar di o gra m 
e C O A  
electr o nic Cli nical O utc o me Assess me nt 
e G F R  
esti mate d gl o mer ular filtrati o n rate  
e nr oll  
T he act of assi g ni n g a partici p a nt  t o a treat me nt. P artici pa nts  w h o are e nr olle d i n t he 
st u d y are t h ose w h o ha ve bee n assi g ne d t o a treat me nt.  
F D A  
U nite d States F o o d a n d Dr u g A d mi nistrati o n  
F M Q  
F D A Me dical Q uer y  
G C P  
g o o d cli nical practice  
G F R  
gl o mer ular filtrati o n rate  
I S A 
i nter ve nti o n-s pecific a p pe n di x 
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 5  
L Y 3 8 5 7 2 1 0  
T er m  
D efi niti o n  
L D A  
l o n git u di nal data a nal ysis 
L L T  
lo west le vel ter m  
L Y  
L Y 3 8 5 7 2 1 0  
M e d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  
M M R M  
mi xe d -effect m o del f or re peate d meas ures  
N R S  
n u meric rati n g scale  
O A 0 5  
H 0 P M C -O A 0 5  
p arti ci p a nt  
E q ui vale nt t o C DI S C ter m “s u bj ect”:  a n i n di vi d ual w h o partici pates i n a cli nical trial, 
eit her as reci pie nt of a n i n vesti gati o nal me dici nal pr o d uct or as a c o ntr ol  
P D  
p har mac o d y na mic  
P D E P  
preli mi nar y data e ntr y peri o d  
P K  
p har mac o ki netic  
 
 
P T  
p referre d ter m 
P T E A E  
p ost -treat me nt-e mer ge nt  a d verse e ve nt  
Q T c F  
Fri dericia’s c orrecte d Q T i nter val  
S A P  
statistical a nal ysis pla n 
s cr e e n  
T he act of deter mi ni n g if a n i n di vi d ual meets mi ni m u m re q uire me nts t o bec o me part of 
a p o ol of p ote ntial ca n di dates f or partici pati o n i n a cli nical st u d y.  
S M Q  
Sta n dar dise d Me d D R A Q uer y  
S O C  
s yste m or ga n class 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt:  A n u nt o war d me dical o cc urre nce t hat e mer ges 
d uri n g a defi ne d treat me nt peri o d, ha vi n g bee n a bse nt pretreat me nt, or w orse ns relati ve 
t o t he pretreat me nt state, a n d d oes n ot necessaril y ha ve t o ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.  
T o E  
totalit y of e v i de nce  
U L N  
u p per li mit of n or mal  
V A S  
vis ual a nal o g scale  
W O M A C  
Wester n O ntari o a n d Mc Mast er U ni versit y Art hritis I n de x  
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T
C CI


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 6  
L Y 3 8 5 7 2 1 0  
4.  R e vi si o n Hi st or y   
S A P Versi o n 1 was a p pr o ve d o n 2 0 J a n uar y 2 0 2 3 pri or t o u n bli n di n g  data f or St u d y  H 0 P -M C -
O A 0 5  (O A 0 5 ).  
S A P Versi o n 2 was a p pr o ve d pri or t o u n bli n di n g data f or fi nal l oc k. Maj or re visi o ns i ncl u de d: 
 Secti o n 7. 1 2. 3: c ha n ge S M Q t o F M Q , w hic h is F D A ne w sta n d ar d . 
 
 Secti o n 7. 1 8: a d de d seiz ures i n t he t otalit y of e vi de nce of safet y.  
 
 
 
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T
C CIC CI




H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 8  
L Y 3 8 5 7 2 1 0  
5. 3.  E x pl or at or y O bj e cti v e s   
E x pl orat or y o bjec ti ves a n d e n d p oi nts  s pecific t o St u d y O A 0 5  are f o u n d i n Ta ble O A 0 5. 5 .2 . 
T a bl e O A 0 5. 5 .2 .  
E x pl or at or y  O bj e cti v e s a n d E n d p oi nt s S p e cifi c t o St u d y H 0 P -M C -
O A 0 5   
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T
C CI


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 9  
L Y 3 8 5 7 2 1 0  
6.  St u d y D e si g n   
6. 1.  S u m m ar y of St u d y D e si g n   
T he C P M P pr ot oc ol  pr o vi des a s u m mar y of t he o v erall st u d y d esi g n  f or t he c hr onic pai n master 
pr ot oc ol . I S A-s pecific st u d y desi g n is pr o vi de d i n t he O A 0 5  pr ot oc ol.    
6. 2.  D et er mi n ati o n of S a m pl e Si z e   
U p  t o ap pr o xi matel y 1 2 5  partici pa nts will be ra n d o mize d i n a   
 t o L Y 3 8 5 7 2 1 0 a n d 
place b o, res pecti vel y. It is e x pecte d t hat a p pr o xi matel y 8 0 %  of partici pa nts , will c o m plete t he 
d o u ble -bli n d treat me nt p eri o d of t he st u d y.
 
 
 
  
 
 
. If t here is n o treat me nt differe nce bet wee n place b o a n d L Y 3 8 5 7 2 1 0 , t he 
pr o ba bilit y of passi n g t he pri mar y o bjecti ve s pecifie d a b o ve (t hat is, false p ositi ve rate) is 
a p pr o xi matel y 0. 0 9 8 . T h e si m ulati o n f or t he p o wer calc ulati o n a n d s a m ple size deter mi nati o n 
was carrie d o ut usi n g  t he R pac ka ge si mfast v 1. 3. 0. 9 0 0 0 .  
 
 
 If t here is n o treat me nt differe n ce b et wee n 
place b o a n d L Y 3 8 5 7 2 1 0 , t he pr o ba bilit y of passi n g t he efficac y criteri o n s p ecifie d a b o v e f or 
a vera ge pai n i nte nsit y (t h at is, false p ositi ve) is a p pr o xi matel y 0. 0 3 7 . 
6. 3.  M et h o d of A s si g n m e nt t o Tr e at m e nt   
T he met h o d of treat me nt assi g n me nt is descri be d i n t he C P M P S A P Versi o n 5 .  
 
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T
C CI
C CI
C CI
C CI


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 1 0  
L Y 3 8 5 7 2 1 0  
7.  A Pri ori St ati sti c al M et h o d s   
7. 1.  G e n er al C o n si d er ati o n s   
T he esti ma n d f or t he pri mar y cli nical q uesti o n of i nterest has bee n d escri be d i n t he C P M P S A P 
Versi o n 5 .  
T he ke y sec o n dar y cli nical q uesti o n of i nterest is: W hat is t he treat me nt differe n ce b et wee n 
L Y 3 8 5 7 2 1 0  a n d place b o assesse d usi n g mea n c ha n ge fr o m baseli ne t o Wee k 8  f or pai n as 
meas ure d b y t he W O M A C ®  pai n s u bscale i n parti ci pa nts wit h oste oart hritis of t he k nee 
re gar dl ess of i nitiati o n of resc ue m e dicati o n or ot h er all o we d co nc o mita nt me dicati o n a n d 
ass u mi n g t hat t he y w o ul d ha ve c o nti n ue d i nitiall y ra n d o mize d treat me nt c o n diti o n?  
 Tre at me nt c o n diti o n : t he ra n d o mize d treat me nt al o n g wit h p ote ntial use of resc ue 
me dicat i o n or ot her all o we d c o nco mita nt me dicati o ns re gar dless o f a d here nce.  
 P o p ul ati o n : partici pa nts wit h c hr o nic pai n c o n diti o ns.  
 E n d p oi nt : c ha n ge fr o m baseli ne t o Wee k 8  i n t he W O M A C® pai n s u bscale.  
 I nterc urre nt e ve nts: the i nterc urre nt e ve nt is treat me nt disc o nti n uati o n f or a n y reas o n.  
 P o p u l ati o n-le vel s u m m ar y: diffe re n ce i n mea n c ha n ges fr o m b aseli ne bet wee n 
treat me nt c o n diti o ns. 
T he esti ma n d is f oll o wi n g a h y p ot h etical strate g y w here efficac y of L Y 3 8 5 7 2 1 0  is assesse d 
u n der t he ass u m pti o n t hat t he partici pa nts w o ul d h a ve c o nti n ue d t heir i nitiall y ra n d o mize d 
treat me nt c o n diti o n e ve n if t he y disc o nti n ue d.  
U nless ot her wise s pecifie d, efficac y a n d s afet y a nal yses will be c o n d u cte d f or t he 8 -wee k 
d o u ble -bli n d peri o d  a n d se parat el y f or t he e ntire 1 0 -wee k st u d y peri o d .  
Ot her ge neral  c o nsi derati o ns f or a nal yses are d escri be d  i n t he C P M P S A P Versi o n 5 .  
7. 2.  A dj u st m e nt s f or C o v ari at e s   
T he ge neral a dj ust me nt strate g y has bee n descri be d i n t he C P M P S A P Versi o n 5 .  
7. 3.  H a n dli n g of Dr o p o ut s or Mi s si n g D at a   
T he missi n g data strate g y has b ee n des cri be d i n t he C P M P S A P Versi o n 5 .  
7. 4.  M ulti pl e C o m p ari s o n s/ M ulti pli cit y   
T here is n o pla n t o f or m all y a dj ust f or m ulti plicit y.  
7. 5.  U s e of a n “ Effi c a c y S u b s et ” of P arti ci p a nt s   
T here are n o pla ns t o use a m o difie d effi cac y s u bs et.  
7. 6.  P arti ci p a nt  Di s p o siti o n   
T he s u m mar y of partici pa nt  dis p ositi o n has bee n descri be d i n t he C P M P S A P Versi o n 5 .  
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 1 1  
L Y 3 8 5 7 2 1 0  
7. 7.  P arti ci p a nt  C h ar a ct eri sti c s   
T he s u m mar y of partici pa nt c haracteristics has bee n descri be d i n t he C P M P S A P Versi o n 5.  
7. 8.  Tr e at m e nt C o m pli a n c e   
Treat me nt perce nt a ge of c o m plia nce will be  calc ulate d as:  
𝑇𝑜𝑡𝑎𝑙 𝑝𝑖𝑙𝑙𝑠 𝑡𝑎𝑘𝑒𝑛∗1 0 0
𝑇𝑜𝑡𝑎𝑙 𝑝𝑖𝑙𝑙𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑
%  
wit h t otal pills ta ke n calc ulate d b y t otal pills dis pe nse d mi n us  t otal pills ret ur ne d. A patie nt is 
c o nsi dere d t o be c o m plia nt f or a gi ve n peri o d if t his perce nta ge  is bet wee n 8 0 % a n d 1 2 0 %. 
T reat me nt c o m plia nce will be assesse d at Visits 5  a n d 7  (a n d earl y disc o nti n uati o n visit, if 
a p plica ble); at Visits 4 a n d 6 , t he i n vesti gati o nal pr o d uct will n ot be ret ur ne d t o t he site. 
Treat me nt c o m plia nce will be re p orte d f or t he 8 wee ks of t he treat me nt peri o d ( Visit 3 t o 
Visit  7 ). T he perce nta ge of patie nts w h o are c o m plia nt wit h st u d y dr u g will be s u m marize d b y 
treat me nt gr o u p. F or pati e nts w h o disc o nti n ue earl y, ti me after t he p e n ulti mate visit will be 
e x cl u de d f or cal c ulati o n of treat me nt c o m plia nce. F or e x a m ple, if t he patie nt disc o nti n ue d earl y 
at Visit 6, treat me nt c o m plia nce will be deri ve d o nl y fr o m d ata c ollecte d t hr o u g h Visit 5.  
C o m paris o ns bet wee n treat me nt gr o u p f or treat me nt  c o m plia nce will be perf or me d usi n g a 
Fis her’s E xact test.  Listi n gs f or treat me nt c o m plia nce of  i n di vi d ual patie nts b y treat me nt peri o d 
will als o be pr o vi de d.    
De pe n di n g o n t he le v el of o bser ve d tr eat me nt c o m plia nce, a n d w here a p pr o priate, se nsiti vit y  
a nal ys es of pri mar y e n d p oi nts  ma y be c o n d u cte d b y e x cl u di n g p atie nts wit h p o or treat me nt  
c o m plia nce.  
7. 9.  C o n c o mit a nt T h er a p y  a n d e C O A C o m pli a n c e   
T he s u m mar y a n d re p orti n g of c o nc o mita nt t hera p y  a n d e C O A c o m plia nce  has bee n des cri be d i n 
t he C P M P S A P Versi o n 5 . N o a d diti o nal c o variat es will be c o nsi dere d i n t he m o del s of wee kl y 
resc ue m e dicati o n use.  
C o nc o mita nt t hera p y will be re p ort e d se paratel y f or t he 8 wee ks of t he d o u ble-bli n d peri o d  a n d 
f or t he e ntire 1 0 -wee k  st u d y per i o d. 
7. 1 0.  Effi c a c y A n al y s e s   
7. 1 0. 1.  Pri m ar y O ut c o m e a n d M et h o d ol o g y   
T he a nal ysis of t he pri mar y o utc o m e  has bee n des cri be d i n t he C P M P S A P Versi o n 5 , a n d it 
c o nstrai ns baseli ne mea ns t o be e q ual bet wee n ar ms .
As n ote d i n Secti o n 5. 1 , e n d p oi nt 
f or t he pri mar y a nal ysis is defi ne d as  8  wee ks p ost i nitial treat me nt  a d mi nistrati o n .  
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T
C CI


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 1 2  
L Y 3 8 5 7 2 1 0  
Calc ulati o n of t he wee kl y/ bi -wee kl y ti me i nter vals use d f or a n al ysis of wee kl y/ bi wee kl y mea n 
sc ores fr o m t he e C O A de vice will f oll o w t he al g orit h m descri be d i n t he C P M P S A P  Versi o n 5,  
Secti o n  6. 1 2. 1, e x ce pt t hat t he e n d of t he fi nal i nter val will be deter mi ne d base d o n t he last V A S 
c ollecti o n date, or t he l ast sc he d ule d visit start date if V A S res ults are missi n g f or t h e last 
sc he d ule d visit. 
7. 1 0. 2.  A d diti o n al A n al y s e s of t h e Pri m ar y O ut c o m e   
Descri pti ve statistics of pri mar y o utc o me varia bles b y de m o gra p hics, dis p ositi o n, disease 
c haracteristics, a n d tr eat me nt a d mi nistrati o n ma y be s u m marize d b y I S A, i n or der t o e x a mi ne t he 
p o p ulati o n h o m o ge neit y ass u m pti o n bet wee n I S As.  
7. 1 0. 3.  S e c o n d ar y Effi c a c y A n al y s e s   
Sec o n dar y efficac y a n al yses c o m m o n t o all I S As wit hi n C P M P ha ve bee n descri be d i n t he 
C P M P S A P Versi o n 5. U nless ot her wise s pecifie d, t he ti me  p oi nt f or sec o n dar y e n d p oi nt 
meas ure me nts is t he sa m e as t hat f or t he pri mar y e n d p oi nt. St u d y O A 0 5  will als o c o nsi der t he 
f oll o wi n g sec o n dar y a nal ys es. 
T he Wester n O ntari o a n d Mc Master U ni versities Oste oart hritis I n de x ( Bell a m y 2 0 0 5) is a 
vali date d i nstr u m e nt t hat is e xte nsi vel y use d t o e val uate t he res p o nse t o me dicati o ns f or t he 
treat me nt of oste oart hritic pai n. T he W  
O M A C ®  versi o n L K 3. 1 will be a d mi nistere d 
acc or di n g t o t he Sc h e d ule of Acti vities.  
T his 2 4 -q uesti o n W O M A C ®  a n d its s u bscales are descri be d in Ta ble O A 0 5. 7 .1 . 
T a bl e O A 0 5. 7 .1 .  
W O M A C S u b s c al e s a n d N u m b er s  of Q u e sti o n s  
Di me nsi o ns/ S u bsc ales  N u m ber of Q uesti o ns  
pai n  
5  
stiff ness 
2  
p h ysical f u ncti o n   
1 7  
A b bre viati o n: W O M A C = Wester n O ntari o a n d Mc Master U ni versit y Art hritis I n de x . 
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T
C CI


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 1 3  
L Y 3 8 5 7 2 1 0  
T he partici pa nts will rec or d t heir res p o ns es usi n g a 0 t o 4 Li kert scale f or eac h q uesti o n:  
 0 = n o pai n ( or stiff n ess or di ffic ult y), a n d  
 4 = e xtre me pai n ( or stiff ness or diffic ult y).  
T he sc ores f or eac h s u bs cale will be calc ulate d b y s u m mi n g t he sc ores of t he q uesti o ns i n t he 
res pecti ve s u bs cale f or eac h partici p a nt at eac h ti me p oi nt. 
T he ra n ge of p ossi ble sc ores f or eac h s u bs cale is p ai n = 0 t o 2 0, stiff ness = 0 t o 8, a n d p h ysical 
f u ncti o n = 0 t o 6 8. 
7. 1 0. 3. 1.  K e y S e c o n d ar y A n al y si s   
A Ba yesia n l o n git u di nal M M R M  a nal ysis  will be perf or me d t o e val uate t h e c ha n ge fr o m 
baseli ne t o eac h p ost baseli ne visit u p t o Wee k 8 a n d se parat el y u p t o Wee k 1 0 f or t he W O M A C®  
pai n s u bscale, p h ysical f u ncti o n s u bscale, a n d stiff ness s u bscale. T he m o del will utilize t he 
c L D A m o del s o t hat a c o m m o n mea n is esti mate d at baseli ne . M ore d etails o n t his a p pr oac h are 
pr o vi de d i n t he C P M P S A P Versi o n 5.  
I nf or mati o n i ncl u de d i n t he m o del is descri be d i n Ta ble O A 0 5. 7 .2 . 
T a bl e O A 0 5. 7 .2 .  
B a y e si a n L o n git u di n al M M R M  A n al y si s I nf or m ati o n 
C ate g oric al f act ors   
  t he i nteracti o n of treat me nt a n d ti me p oi nt (c o nstrai ne d t o est i mate a 
c o m m o n mea n at baseli ne acr oss treat me nts)  
  a vera ge baseli ne pai n se verit y cate g or y ( baseli ne N R S < 7, baseli ne 
N R S  ≥ 7)  
  p o ole d i n vesti gati ve site  
C o nti n u o us c o v ari ates   
  n o ne  
A b bre viati o n s: M M R M = mi xe d -effect m o del f or re peate d meas ures ; N R S = n u meric rati n g scale.  
7. 1 0. 3. 2.  Ot h er S e c o n d ar y A n al y si s   
T he pr o p orti o n of partici p a nts i n eac h treat me nt gr o u p meeti n g pres pecifie d bi nar y res p o nse 
t hres h ol ds ( 3 0 %, 5 0 %, a n d 7 0 %) will be cal c ulate d f or eac h p ost baseli ne ti me p oi nt a n d will be 
use d t o c o m pare tr eat me nt gr o u ps f or W O M A C ®  pai n a n d p h ysical f u ncti o n s u bscales.  
A Ba yesia n pse u d o -li keli h o o d– base d cate g orical re peate d m eas ures m o del will be use d t o 
esti mate t he pr o p orti o n  of part ici pa nts i n eac h treat me nt gr o u p meeti n g t he pres pecifi e d 
t hres h ol d f or eac h p ost baseli ne ti me i nter val u p t o Wee k 8  a n d se paratel y u p t o Wee k 1 0 . T hese 
esti mates  will be use d t o c o m pare tr eat me nt gr o u ps.  M ore details o n t his a p pr oac h are pr o vi d e d 
i n t he CP M P S A P Versi o n 5.  
T he m o del will i ncl u de t he cate g orical a n d c o nti n u o us c o variates descri be d f or t he ke y 
sec o n dar y a nal ysis. 
I n a d diti o n, ti me t o first treat me nt r es p o nse fr o m baseli ne base d o n t h e pres pecifie d bi nar y 
t hres h ol ds a b o ve will be assesse d. A nal ys es will be c o n d ucte d acc or di n g t o t he ti me t o e ve nt 
a nal ys es s pecifie d i n t he C P M P S A P Versi o n 5.  
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 1 4  
L Y 3 8 5 7 2 1 0  
7. 1 1.  P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c M et h o d s   
T he plas ma c o n ce ntrati o ns f or L Y 3 8 5 7 2 1 0 will be re p orte d gra p hicall y a n d s u m marize d 
descri pti vel y  acr oss t he st u d y visits .  
E x pl orat or y m o del -bas e d a nal ys es ma y be c o n d uct e d t o assess t he relati o ns hi p of L Y 3 8 5 7 2 1 0 
plas ma c o nce ntrati o ns t o efficac y a n d / or safet y o ut c o mes.  
A d diti o nal a nal ys es ma y be c o n d ucte d, as nee d e d.  
Data fr o m t his st u d y m a y be p o ole d wit h data fr o m ot her st u dies.  
7. 1 2.  S af et y A n al y s e s   
T he ge neral a nal ysis of safet y  has b ee n des cri be d i n t he St u d y C P M P S A P Versi o n 5 . H o we v er, 
a d diti o nal I S A-s p ecific s afet y c o nsi derati o ns are descri be d i n t he secti o ns bel o w.  
7. 1 2. 1.  E xt e nt of E x p o s ur e   
D urati o n of e x p os ure ( defi ne d as ti me si nce first d ose of st u d y treat me nt t o last d ose of st u d y 
treat me nt i n da ys) t o st u d y dr u g will be s u m marize d b y treat me nt gr o u p usi n g des cri pti ve 
statistics; t he s u m mar y will als o i ncl u de t he t otal e x p os ure i n patie nt years.  
D ura ti o n of e x p os ure ( da ys): 
Date of last d ose d uri n g t he d o u ble -bli n d treat me nt peri o d –  Date of first d ose f or t he  
treat me nt peri o d + 1. 
T otal e x p os ure i n patie nt years will be calc ulate d as f oll o ws:  
S u m mar y  of d urati o n ( da ys) of e x p os ures f or all p atie nts i n t he  treat me nt gr o u p / 3 6 5. 2 5.   
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T
C CI


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 1 5  
L Y 3 8 5 7 2 1 0  
7. 1 2. 2.  A d v er s e E v e nt s   
T he ge neral a nal ysis of A Es  has bee n d escri be d i n t he C P M P S A P Versi o n 5.  
T his I S A will re p ort T E A Es  se paratel y f or t he e ntire 8 -wee k d o u ble -bli n d peri o d , t he 2-wee k 
p ost -treat me nt peri o d, a n d t he e ntire 1 0 -wee k st u d y. F or T E A Es i n t he d o u ble -bli n d peri o d, t he 
baseli ne will be pri or t o first d ose date.  
A P T E A E  is defi ne d as a n eve nt t hat first occ urs or w orse ns i n se v erit y after d o u ble -bli n d 
treat me nt p hase (after Visit 7 ) a n d o n or bef ore st u d y disc o nti n uati o n. T his I S A will re p ort 
P T E A Es f or t he  p ost -treat me nt peri o d , as t he y are i m p orta nt f or assessi n g wit h dra wal or a b use 
lia bilit y p ote ntial. T h e Me d D R A L L T will be use d i n t he p ost -treat me nt-e m er ge nt c o m p utati o n. 
T he ma xi m u m se verit y f or eac h L L T d uri n g t he d o u ble -bli n d treat me nt peri o d ( Visits 3 t hr o u g h 
7 ) will be use d as a refere nce.  
T he baseli ne of P T E A E is fr o m t he first d osi n g d ate t o Visit 7 . T he p ost-treat me nt p hase will be 
i ncl u de d as p ost baseli ne f or t his a nal ysis. W hile u n us ual, it is p ossi ble t o ha ve a missi n g s e verit y 
f or e ve nts.
 
P T E A Es  will be deter mi ne d b y 
c o m pari n g wit h treat me nt  peri o d.  
P T E A Es will be s u m marize d b y P T a n d b y P T  wit hi n S O C  i n partici pa nts w h o recei ve d 
L Y 3 8 5 7 2 1 0 . 
7. 1 2. 3.  D e at h s, Ot h er S eri o u s A d v er s e E v e nt s, a n d Ot h er N ot a bl e 
A d v er s e E v e nt s   
T E A Es  b y P T  will be re p orte d.  
T he ge neral  s u m mar y of A Es  is descri be d i n t he C P M P S A P Versi o n 5 . Ot her A Es i ncl u de  
 A b use lia bilit y a n d wit h dra wal  p ote ntial  f oll o wi n g t he m ost rece nt  Lill y G ui da nce f or 
Assess me nt of A b use P ot e ntial d uri n g Cli nical De vel o p me nt . 
 Seiz ures F M Q b ot h narr o w a n d br oa d t er ms will be a nal yz e d . 
7. 1 2. 4.  N e ur ol o gi c al E x a m   
I n t his I S A, ne ur ol o gi cal e x a m  res ults will be re p orte d f or t he e ntire 1 0 -wee k st u d y peri o d.  
St u d y  O A 0 5  will c o nsi der t he f oll o wi n g a nal yses f or t he Ne ur ol o gical E x a m, w hic h e val uates 
6  ite ms a n d will be  s u m marize d b y n or mal/a b n or mal perce nt a ge b y ite m. I n a d diti o n, we will 
s u m marize s hift ta bles f or eac h ite m i n t he Ne ur ol o gical E x a m. 
7. 1 2. 5.  Cli ni c al L a b or at or y  E v al u ati o n   
T he ge neral a n al ysis of l a b orat or y p ara met ers  is d escri be d i n t he C P M P S A P Versi o n 5 .  
I n t his I S A, la b orat or y res ults will be re p orte d f or t he e ntire 1 0 -wee k st u d y peri o d.  St u d y O A 0 5  
will als o c o nsi der t he f oll o wi n g a n al yses of la b a n al ytes us e d t o assess re nal f u ncti o n. T he 
pla n ne d s u m maries f or t h ese a nal ytes are t h e sa me as t h ose t hat ha ve b ee n d escri be d i n t he St u d y 
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T
C CI


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 1 6  
L Y 3 8 5 7 2 1 0  
C P M P S A P Versi o n 5 ; h o we ver, t he re p orti n g of these a nal ytes will be se p arate fr o m t he ge n eral 
a nal ysis of la b orat or y p ara meters.  
 Re nal data a n al ys es : 
o  S er u m creati ni ne (c ha n ge fr o m baseli ne i n m g/ d L)  
o  e G F R; C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n (al g orit h m usi n g 
ser u m creati ni ne) Al g orit h m: Pr o vi de d b y ce ntral l a b orat or y  
o  F or e G F R calc ulati o n, we will s u m marize s hift ta bles of e G F R c ha n ges f or 
baseli ne vers us  p ost bas eli ne b y mi ni m u m, ma xi m u m , a n d last o bser ve d e G F R 
res ult: 
▪ Cate g or y 1: N or mal or i n creas e i n G F R ( ≥9 0 m L/ mi n/ 1. 7 3 m 2 ) 
▪ Cate g or y 2: M il d re d ucti o n i n G F R ( 6 0 t o 8 9 m L/ mi n/ 1. 7 3 m 2 ) 
▪ Cate g or y 3a: M o derate (a) re d u cti o n i n G F R ( 4 5  t o 5 9 m L/ mi n/ 1. 7 3 m 2 ) 
▪ Cate g or y 3 b: M o derat e ( b) re d ucti o n i n G F R ( 3 0  t o 4 4 m L/ mi n/ 1. 7 3 m 2 ) 
▪ Cate g or y 4: Se vere re d u cti o n i n G F R ( 1 5  t o 2 9 m L/ mi n/ 1. 7 3 m 2 ) 
▪ Cate g or y 5: Ki d ne y fail ure ( G F R < 1 5 m L/ mi n/ 1. 7 3 m 2  or dial ysis) . 
A b n or mal e G F R is s pecifie d bel o w a n d will be s u m marize d i n t he la b orat or y  s u m mar y ta bles. 
 A b n or mal lo w : < 9 0 m L/ mi n/ 1. 7 3 m2  
 A b n or mal h i g h: As s p ecifie d b y ce ntral la borat or y . 
7. 1 2. 6.  Vit al Si g n s a n d Ot h er P h y si c al Fi n di n g s   
T he a nal ysis of vital si g n para meters  is descri be d i n t he C P M P S A P Versi o n 5 . 
Vital si g ns will be re p orte d se paratel y f or t h e 8-wee k treat me nt peri o d a n d t he e ntire 1 0 -w ee k 
st u d y peri o d. 
7. 1 2. 7.  El e ctr o c ar di o gr a m s   
T he a nal ysis of E C G  para meters is descri be d i n t he C P M P S A P Versi o n 5 . E C G  will be re p orte d 
se parat el y f or t he 8-wee k treat me nt peri o d a n d t he e ntire 1 0 -wee k st u d y peri o d. 
7. 1 2. 8.  S ui ci d al I d e ati o n  or B e h a vi or   
Re p orti n g of s uici d al i deati o n/ be ha vi or t hr o u g h t h e C ol u m bia S uici de -Se verit y Rati n g Scale has 
bee n descri be d i n t he C P M P S A P Versi o n 5. S uici dal i deati o n/ be ha vi or will be re p orte d 
se parat el y f or t he 8-wee k treat me nt peri o d a n d t he e ntire 1 0-wee k st u d y peri o d. 
7. 1 3.  S u b gr o u p A n al y s e s   
Ge neral s u b gr o u p a n al ys es are d escri b e d i n t he C P M P S A P Versi o n 5 .  
St u d y O A 0 5  will als o c o nsi der t he s u b gr o u p a n al ys es f or t he pri mar y efficac y o utc o me a n d ke y 
sec o n dar y o ut c o me (see Ta ble O A 0 5. 7 .3 ). 
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H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
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L Y 3 8 5 7 2 1 0  
7. 1 8.  T ot alit y of E vi d e n c e f or S af et y   
T he t otalit y of e vi de nce a nal ysis a p pr oac h f or safet y data h as bee n briefl y d escri be d i n t he 
C P M P S A P Versi o n 5 . T he ke y safet y e ve nts t o b e c o nsi dere d f or St u d y O A 0 5  are liste d bel o w 
b y d o mai n:  
Ge ner al A E I nf or m ati o n  
 Seri o us A Es  i ncl u di n g deat h relate d t o st u d y treat me nt 
 St u d y dis c o nti n uati o n d ue t o A E  
 Treat me nt disc o nti n uati o n d ue t o A E . 
C ar di o v asc ul ar  
 Q Tc F  pr ol o n gati o n: > 6 0 msec i ncrease  or  Q Tc F  > 5 0 0 msec   
 Seri o us car diac dis or ders A E . 
Li ver f u ncti o n  
 D r u g-i n d uce d li ver i nj ur y: at least 1 of t he  f oll o wi n g 2 c o n diti o ns: 
Met a b olic f u ncti o n  
 Seri o us h y p o gl yce mia  A E  
 Seri o us h y per gl yce mia A E   
 Treat me nt -e mer ge nt h e m o gl o bi n A 1c : S hift fr o m l o w/ n or mal at baseli ne t o hi g h at least 
o nce . 
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T
C CI
C CI


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 1 9  
L Y 3 8 5 7 2 1 0  
Re n al f u ncti o n  
 Treat me nt -e mer ge nt a b n or mal e G F R: S hifts  
o  Mil d at baseli ne t o m o derate/se vere  
o  M o derate at baseli ne t o s e vere . 
Ne ur ol o gic f u ncti o n  
 Treat me nt -e mer ge nt a b n or mal shift  o n t he o verall ne ur ol o gi c assess me nt  
 Seri o us ne ur ol o gic e ve nts  
 S eiz ures F M Q b ot h narr o w a n d br oa d t er ms . 
7. 1 9.  A n n u al R e p ort A n al y s e s   
A nal ys es will be pr o d uce d as nee de d  f or t he p ur p oses of pr o vi di n g p eri o dic safet y re vi e ws t o 
re g ulat or y a ge ncies (f or e x a m ple, D e vel o p me nt Safet y U p dat e Re p orts) . Data fr o m t his I S A will 
be c o m bi ne d wit h data fr o m ot her cli nical st u dies t hat i n vesti gate d L Y 3 8 5 7 2 1 0 . I n all a nal yses, a 
c o m bi ne d L Y ar m will b e create d  w hic h i n cl u des partici pa nts assi g ne d t o a n y d ose of 
L Y 3 8 5 7 2 1 0 i n t he i ncl u d e d st u dies, i ncl u di n g L Y-c o m bi nati o n re gi me ns.  
T he f oll o wi n g d ata will b e s u m marize d b y treat me nt gr o u p.  
 enr oll me nt ( o n g oi n g a n d c o m plete d)  
 d e m o gra p hics (race, et h nicit y, a n d ge n der)  
 ex p os ure  
o  cu m ulati ve n u m ber of s u bjects e x p ose d t o L Y 3 8 5 7 2 1 0  
o  cu m ulati ve n u m ber of s u bjects e x p ose d t o L Y 3 8 5 7 2 1 0 b y a ge  
o  cu m ulati ve n u m ber of s u bjects e x p ose d t o L Y 3 8 5 7 2 1 0 b y se x  
o  cu m ulati ve n u m ber of s u bjects e x p ose d t o L Y 3 8 5 7 2 1 0 b y race  
 cu m ulati ve s u m mar y of s eri o us A Es.  
T he f oll o wi n g listi n gs will be pr o vi de d.  
 list of seri o us A Es  d uri n g t he re p orti n g pe ri o d  
 list of s u bjects w h o die d   
 cu m ulati ve list of s u bjects w h o disc o nti n ued  d ue t o a n A E  ( disc o nti n ue d fr o m treat me nt 
or st u d y)  
 list of s u bjects w h o disc o nti n ue d  d ue t o a n A E  d uri n g t he re p orti n g peri o d .  
A d diti o nal a nal ys es ma y be a d de d or o mitte d at t h e ti me of re p ort s u b missi o n as nee de d.  
7. 2 0.  Cli ni c al Tri al R e gi str y A n al y s e s   
A d diti o nal a nal ys es will be perf or me d f or t h e p ur p ose of f ulfilli n g t he C T R re q uire me nts.   
A nal ys es  pr o vi de d f or t h e C T R re q uire me nts i ncl u de t he f oll o wi n g:  
S u m mar y of A Es , pr o vi d e d as a dat aset t hat will be c o n verte d t o a n X M L file . B ot h 
“Seri o us ” A Es  a n d “Ot her ” A Es  are s u m marize d b y treat me nt gr o u p  a n d b y Me d D R A P T . 
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
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L Y 3 8 5 7 2 1 0  
 A seri o us A E  is a n A E  t h at is c o nsi dere d “Seri o us ” w het her  or n ot  it is a treat me nt 
e mer ge nt.  
 A n A E  is c o nsi dere d i n t he “Ot her ” cate g or y if it is b ot h a T E A E a n d is n ot seri o us. F or 
eac h “Seri o us ” A E a n d “Ot her ” A E, f or eac h ter m a n d treat me nt gr o u p, t h e f oll o wi n g are 
pr o vi de d:  
o  t he n u m ber of partici pa nts at ris k of a n e v e nt 
o  t he n u m ber of partici pa nts w h o e x perie nce d eac h e ve nt ter m 
o  t he n u m ber of e v e nts e x perie nce d. 
 C o nsiste nt wit h w w w. Cli nical Trials. g o v re q uire m e nts, “Ot her ” A Es t hat occ ur i n fe wer 
t ha n 5 % of partici pa nts  i n e very treat me nt gr o u p ma y n ot be i n cl u de d if a 5 % t hres h ol d is 
c h ose n ( 5 % is t he mi ni m u m t hres h ol d).  
 A E re p orti n g is c o nsiste nt wit h ot her d oc u me nt discl os ures f or e x a m ple, t he Cli nical 
St u d y R e p ort a n d  ma n us cri pts .  
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H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 2 1  
L Y 3 8 5 7 2 1 0  
8.  U n bli n di n g Pl a n   
T he  ge neral  u n bli n di n g pla n is descri be d i n t he C P M P S A P Versi o n 5  a n d i n t he C P M P Bli n di n g 
a n d U n bli n di n g Pla n  Versi o n 2 . U n bli n di n g c o nsi derati o ns s pecifi c t o St u d y O A 0 5  are pr o vi de d 
bel o w.  
P K /P D A n al ysis Pl a n ni n g  
A li mite d n u m ber of pres pecifie d i n di vi d uals w h o are n ot part of t he bli n de d st u d y tea m a n d d o 
n ot ha ve direct site c o ntact, data e ntr y, or data vali dati o n res p o nsi bilities, ma y recei ve access t o 
u n bli n de d data, pri o r t o a n i nteri m or fi nal data bas e l oc k, t o i nitiate t he P K a n d/ or P K/P D m o del 
de vel o p me nt pr ocesses. T his will be descri be d i n t he u n bli n di n g pla n. I nf or mati o n t hat  ma y 
u n bli n d t he st u d y d uri n g t he a nal yses will n ot be re p orte d t o st u d y sites or bli n de d st u d y  tea m 
u ntil t he st u d y h as bee n u n bli n de d.  
A p pr o ve d o n 2 7 J u n 2 0 2 3 G M T


H 0 P -M C -O A 0 5  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 2 2  
L Y 3 8 5 7 2 1 0  
9.  R ef er e n c e s   
Bella m y N. T h e W O M A C K nee a n d Hi p Oste oart hritis I n dices: d e vel o p me nt, vali dati o n, 
gl o balizati o n a n d i nfl ue n ce o n t he de v el o p me nt of t he A U S C A N Ha n d Ost e oart hritis I n dices. 
Cli n Ex p R he u m at ol . 2 0 0 5; 2 3( 5 s u p pl 3 9): S 1 4 8-S 1 5 3.  
Sil va L, Za n ella G. R o b ust lea ve -o ne -o ut cr oss -v ali dati o n f or hi g h -di me nsi o nal Ba yesia n 
m o d els. 2 0 2 2. htt ps:// d oi. or g/ 1 0. 4 8 5 5 0/ar Xi v. 2 2 0 9. 0 9 1 9 0  
 
 
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Si g nat ure Pa ge f or V V- C LI N- 0 9 3 3 4 1 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 9 3 3 4 1 v 1. 0
A p pr o val
2 7-J u n- 2 0 2 3 1 5: 4 9: 0 5 G M T + 0 0 0 0
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