Clinical trial NCT05080660
Conditions: Osteoarthritis Osteo Arthritis Knee
Sponsor: Eli Lilly and Company
Start date: 2021-10-12; Completion date: 2022-06-06
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test safety and efficacy of study drug LY3526318 in for the treatment of knee pain due to with osteoarthritis (OA). 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 250 mg of LY3526318 orally, once daily for the first 4 weeks and were switched to placebo once daily for the next 4 weeks of the treatment period. arm 2: Participants received placebo orally, once daily, for 8-weeks treatment period.
Interventions: intervention 1: LY3526318 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol documents:
Prot_004.pdf: 
This study H0P-MC-OA02 (NCT05080660) is a sub-study of Master Protocol H0P-MC-CPMP 
(NCT05986292) 
Protocol: H0P-MC-OA02 (a) 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3526318 for the 
Treatment of Osteoarthritis Pain
NCT05080660 
Approval Date: 10-Aug-2021 


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
1
Title P a ge
I nter ve nti o n-S pecific A p pe n di x (I S A) f or L Y 3 5 2 6 3 1 8: H 0 P -M C -O A 0 2 ( a)
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s. It i s t h e p r o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli n i c al 
i n v e sti g ati o n of L Y 3 5 2 6 3 1 8 , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d C o m p a n y or it s 
s u b si di ari e s. 
N ot e t o R e g ul at or y A ut h oriti e s: T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al i 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 e l 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 be 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 .
M aster Pr ot oc ol Title: A Master Pr ot oc ol f or Ra n d o mize d, Place b o -C o ntr olle d, P hase 2 
Cli nical Trials o f M ul tiple I nter ve nt i ons f or t he Treat me nt of C hr o nic 
Pai n
M aster Pr ot oc ol N u m ber: H 0 P -M C -C P M P
I S A Title: Ra n d o mize d, Place b o -C o ntr olle d, P hase 2 Cli nical Trial t o E val uate L Y 3 5 2 6 3 1 8 f or 
t he Treat me nt of Oste oart hritis Pai n
I S A N u m ber: H 0 P -M C -O A 0 2
A me n d me nt N u m ber: a
C o m p o u n d : L Y 3 5 2 6 3 1 8
St u d y P h ase: 2
Acr o n y m : O A 0 2
S p o ns or N a me: El i Lill y  a n d C o mpa n y
Le g al Re gistere d A d dress: I n dia na p olis, I n dia na, U S A 4 6 2 8 5
Re g ul at or y A ge nc y I de ntifier N u m ber
L Y 3 5 2 6 3 1 8 I N D: 1 5 0 1 9 1
Master Pr ot oc ol I N D: 1 4 4 9 1 5
A p pr o v al D ate: Pr ot oc ol A me n d me nt (a) El ectr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n date 
pr o vi de d bel o w.
A p pr o v al D at e: 1 0- A u g- 2 0 2 1 G M T


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
2
Medical Monitor Name and Contact Information will be provided separately.


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
3
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
04-Jun-2021
Amendment [a] 
Overall Rationale for the Amendment:
This amendment addresses changes in the exclusion criteria in response to FDA feedback based 
on in vitro data currently available.
Section # and Name
Description of Change
Brief Rationale
2.3. Benefit/Risk 
Assessment
Added sub-section headers.
For clarity.
2.3.1. Risk 
Assessment
In first paragraph, added text for the 
effect of LY3526318 on other drugs.
Clarification of the potential of LY3526318 
exposure to affect metabolism of other drugs.
2.3.1. Risk 
Assessment
Updated first bullet to specify
CYP3A4, plus minor editorial 
changes.
For clarity.
2.3.1. Risk 
Assessment
Added a bullet for CYP3A4 and p-
glycoprotein (P-gp) substrates.
Based on in vitro data suggesting a potential for
PK interactions.
5.1. Study 
Population
Updated numbers for inclusion and 
exclusion criteria.
To align with master protocol and ISA 
numbering system.
Updated criterion #1051 to specify
drugs taken orally or intravenously.
Topical drugs are allowed.
Added exclusion criterion #1054 for 
participants that are taking drugs that 
are sensitive CYP3A4 substrates with 
a narrow therapeutic index.
Based on in vitro data suggesting potential 
CYP3A4 inhibition at the proposed LY3526318
dose.
Added exclusion criterion #1055 for 
participants that are taking simvastatin 
at doses greater than 20 mg/day.
Simvastatin is a sensitive CYP3A4 substrate, 
with a projected maximal increase in exposure 
<2-fold in combination with LY3526318. 
Therefore, doses of 20 mg or less are 
considered safe.
Added exclusion criterion #1056 for
participants that are taking metformin 
at doses greater than 1000 mg/day.
Based on limited data related to inhibition of 
renal transporters.
Added exclusion criterion #1057 for
participants that are taking digoxin.
Based on in vitro data suggesting a potential for 
LY3526318 to inhibit P-gp.
6.6. Concomitant 
Therapy
Under Potential Drug-Drug 
Interactions with LY3526318, added 
reference to Section 5.2 for 
concomitant medication restrictions.
Reference to added exclusion criteria.


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
4
Section # and Name
Description of Change
Brief Rationale
10.3. Appendix 3: 
List of Excluded 
Concomitant 
Medications
Added reference to Section 5.2 and the 
Manual of Operations for additional 
information.
Additional information for excluded 
concomitant medications are listed in Section 
5.2 and the Manual of Operations.
Throughout the 
protocol
Minor editorial and format changes.
Minor, therefore not described.


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
5
Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.........................................................................................................................9
1.3.
Schedule of Activities (SoA) ......................................................................................10
2.
Introduction..............................................................................................................12
2.1.
Study Rationale ..........................................................................................................12
2.2.
Background ................................................................................................................12
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 and Endpoints.........................................................................................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 .............................................................................................20
5.3.1.
Meals and Dietary Restrictions ...................................................................................20
5.3.2.
Substance Use ............................................................................................................20
5.3.3.
Reproductive and Contraception Requirements...........................................................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
6.4.
Study Intervention Compliance...................................................................................22
6.5.
Treatment of Overdose ...............................................................................................22
6.6.
Concomitant Therapy .................................................................................................23
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................24
8.
Study Assessments and Procedures .........................................................................25
8.1.
Efficacy Assessments .................................................................................................25
8.2.
Safety Assessments ....................................................................................................25
8.2.1.
Physical Examinations................................................................................................25
8.2.2.
Electrocardiograms.....................................................................................................25
8.2.3.
Clinical Safety Laboratory Tests.................................................................................25
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints .................................................................................................................25
8.4.
Pharmacokinetics........................................................................................................25


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
6
8. 5.
P har mac o d y na mics .....................................................................................................2 6
9.
St atistic al C o nsi der ati o ns .........................................................................................2 7
9. 1.
Stati stical H y p ot heses................................................................................................. 2 7
9. 2.
A nal yses Sets .............................................................................................................2 7
9. 3.
Stati stical A nal yses .....................................................................................................2 7
9. 3. 1.
Ge neral C o nsi derati o ns ...............................................................................................2 7
9. 3. 2.
E x pl or at or y  E n d p oi nt A nal ysis...................................................................................2 7
9. 3. 3.
S af et y A nal yses ..........................................................................................................2 7
9. 3. 4.
Ot her A nal yses ...........................................................................................................2 8
9. 4.
I nteri m A nal ysis .........................................................................................................2 8
9. 5.
S a m ple Si ze Deter mi nat i on .........................................................................................2 8
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 ................................2 9
1 0. 1.
A p pe n di x 1: Cli nical La b orat or y  Tests........................................................................2 9
1 0. 2.
A p pe n di x 2: C o ntrace pti ve a n d Barrier G ui da nce .......................................................3 0
1 0. 2. 1.
Defi nit i ons ..................................................................................................................3 0
1 0. 2. 2.
C o ntrace pti o n G ui da nce ..............................................................................................3 1
1 0. 3.
A p pe n di x 3: List of E xcl u de d C o nc o mit a nt Me dic atio ns ............................................3 4
1 0. 4.
A p pe n di x 4: Pr o visi o ns f or C ha n ges i n St u d y C o n d uct D uri n g 
E xce pt i onal Ci rc u msta nces .........................................................................................3 7
1 0. 5.
A p pe n di x 5: A b bre viat i ons .........................................................................................4 0
1 1.
Refere nces .................................................................................................................4 3
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C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
7
1.
Pr ot oc ol S u m m ar y
1. 1.
S y n o psis
Pr ot oc ol Title:
Ra n d o mize d, place b o - c o ntr olle d, P hase 2 cli nical trial t o e val uate L Y 3 5 2 6 3 1 8 f or t he treat me nt 
of  oste oart hritis pai n.
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 Y3 5 2 6 3 1 8 is efficaci o us i n relie vi n g k nee pai n d ue 
t o oste oart hritis ( O A). L Y 3 5 2 6 3 1 8 is a s mall m o lec ule t hat i n hi bits tra nsie nt rece pt or pr otei n 
an k yri n 1, a cal ci u m per mea ble n o nselect i ve cati on c ha n nel t h at is k n o w n t o be i n v ol ve d i n pai n 
a n d i nfla m mat i on .  
Data will be c ollecte d t o assess t he safet y a n d t olera bilit y of L Y3 5 2 6 3 1 8 i n t his st u d y p o p ulat i on. 
P har mac o ki net ic pr o perties will  als o be ex 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 Y3 5 2 6 3 1 8 a n d i nf or m decisio ns f or t he 
cli nical de vel o p me nt of L Y 3 5 2 6 3 1 8.
O bjecti ves a n d E n d p oi nt s:
T he pri mar y  a n d sec o n dar y o bjecti ves a n d e n d p oi nts are state d i n t he M aster P r ot oc ol H 0 P-M C -
C P M P ( C P M P) a n d O A disease -state a d de 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 n 8- wee k, P hase 2, ra n d o mize d, d o u ble -bli n d, pl ace b o -c o ntr olle d st u d y t hat will 
c o mpare L Y 3 5 2 6 3 1 8 vers us place b o i n partici pa nts wit h O A i n t he k nee .
Discl os ure St ate me nt:
T his is a ra n d o mize d, i n vest i gat or-a n d partici pa nt -bli n d, pl ace b o -c o ntr olle d, P hase 2 cli nical 
trial.
N u m ber of P artici p a nt s:
A p pr o xi matel y  15 0 parti ci pa nts will be ra n d o ml y assi g ne d t o st u d y int er ve ntio n 
) wit h t he ass u m pti o n t hat 1 5 % of t he partici pa nts will dr o p o ut 
pri or t o t he e n d of t he d o u ble -bli n d treat me nt peri o d.
I nter ve nti o n Gr o u ps a n d D ur ati o n :
T his st u d y  i ncl u des a n 8-wee k d o u ble -bli n d treat me nt peri o d.
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C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
8
I nter ve nti o n N a me
L Y 3 5 2 6 3 1 8
Place b o
D os a ge Le vel(s)
N ot a p plica ble
R o ute of A d mi nistr ati o n
a n d D ur ati o n
P O 
P O
A b bre viati o ns: P O = b y m o ut h ; Q D = o nce dail y.
D at a M o nit ori n g C o m mittee : Yes
S af et y re vie ws are c o vere d b y t he Assess me nt C o m mittee c harter f or t he C hr o nic Pai n Master 
Pr ot oc ol .
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CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
9
1.2.
Schema
Abbreviations: PDEP = preliminary data entry period; V = visit.
* Medication washout and PDEP begins.
** Randomization to either LY3526318 or placebo.  


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
10
1.3.
Schedule of Activities (SoA)
This SoA shows visits and procedures unique to the intervention-specific appendix (ISA) H0P-MC-OA02 for LY3526318. Please 
refer to the CPMP Master Protocol and the OA DSA H0P-MC-CPMP(1) SoAs for additional information.  
Randomization 
to ISA
Double-Blind Treatment
Early 
Discontinuation
Notes
V3
V4
V5
V6
V7
ED
Study Week
0
2
4
6
8
Visit Window (days)
±3
Physical examination
X
X
X
X
Symptom directed physical exam (see Section 
8.2.1) at V5, V7, and ED (if applicable).
Vital signs
X
X
X
X
X
X
At V3, vitals should be taken predose and at 
approximately 2 and 4 hours post dosing. 
At V4, V5, V6, and V7, vitals should be taken 
predose.
Pulse rate, respiratory rate, blood pressure, and 
temperature taken with participant in a sitting 
position.
ECG
X
X
X
Single ECGs at V5, V7, and ED (if applicable).
Study intervention
X
X
X
X
X
See Section 6.1
Intervention 
compliance
X
X
X
X
X
Clinical Laboratory Tests and Sample Collection
Hematology
X
X
X
X
Chemistry
X
X
X
X
Lipid panel
X
X
X
X
Urinalysis
X
Urine pregnancy
X
X
X
X
X
X
For all WOCBP at V3: collect sample before 
dosing.
Urine drug screen
X
X
X
X
See Section 5.3.2.
HbA1c
X
X
X


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
1 1
R a n d o miz ati o n 
t o I S A
D o u ble -Bl i n d Tre at me nt
E arl y 
Disc o nti n u ati o n
N otes
V 3
V 4
V 5
V 6
V 7
E D
St u d y Wee k
0
2
4
6
8
Visit Wi n d o w ( d a ys)
± 3
P K sa m ple
X
X  
X  
X  
X
X
At V 3 , s a mpl e s s h o ul d be ta ke n at 2 a n d 4 h o urs 
( ± 1 5 mi n utes) p ost d osi n g. 
At V 4, V 5, V 6 a n d V 7, a sa m ple f or P K s h o ul d 
be ta ke n bef ore t he d ose is a d mi nistere d; 
partici pa nts s h o ul d be as ke d t o refrai n fr o m 
ta ki n g t heir d ose o n V 4- V7 u ntil t he y ha ve t heir 
cli nic visit a n d after t he bl o o d sa m ple is ta ke n. 
T he date a n d ti me of L Y 3 5 2 6 3 1 8 a d mi nistrati o n
pri or t o t he P K sa m pli n g will be rec or de d , i.e. ,
t he d ose a d mi nistere d i n t he cli nic at V 3 a n d t he 
last at h o me d ose pri or t o eac h of V 4, V 5, V 6 ,
a n d V 7.
P artici p a nt De vice
Partici pa nt ret ur ns 
de vice
X
X
 
A b bre viati o ns: 
; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; H b A 1c = he m o gl o bi n A 1c ; I SA = i nter ve nti o n-s pecific a p pe n di x; 
P K = p har mac o ki netic; V = v isit; W O C B P
= w o me n of c hil d beari n g p ote ntial.
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C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
1 2
2.
I ntr o d ucti o n
T his i nter ve nt i on- s pecific a p pe n di x (I S A) H 0 P -M C -O A 0 2 ( O A 0 2) is a n a p pe n di x t o t he H 0 P -
M C -C P M P (C P M P )
Master P r ot oc ol 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 5 2 6 3 1 8 . 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 ver n t he 
os te oart hritis (O A ) disease-state a p pe n di x ( D S A) C P M P( 1) a n d t his I S A O A 0 2. 
2. 1.
St u d y R ati o n ale
T he p u r p ose of t his st u d y is t o test w het her L Y 3 5 2 6 3 1 8 is efficaci o us i n relie vi n g k nee pai n d ue 
t o O A. Data will be c ollecte d t o assess t he safety a n d t olera bilit y of L Y 3 5 2 6 3 1 8 i n t his st u d y 
p o p ul at i on. P har mac o ki net ic (P K ) pr o perties will als o be e x pl ore d . T he t otality of  data fr o m t his 
pr o of -of  c o nce pt ( P o C) stu d y will  assess t he be nefit s a n d ris ks ass ociate d wit h L Y 3 5 2 6 3 1 8 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 5 2 6 3 1 8.
2. 2.
B ac k gr o u n d
T he tra nsie nt rece pt or p ote ntial ( T R P ) io n c ha n nel fa mil y c o m pr ises a gr o u p of 2 8 n o nselecti ve 
catio n c ha n nels t hat are dist i nct fr om classical v o lta ge gate d io n c ha n nels. A m o n g t hese, 
tra nsie nt rece pt or p ote ntial a n k yri n 1 ( T R P A 1) is a calci u m-p er m ea ble n o nselect i ve cati on 
c ha n nel, w hic h is e x presse d i n t he a x o ns a n d i n b ot h peri p heral a n d ce ntral ter mi nals of 
n oci ce pt ors. It is als o c o nsi dere d t o be i m p orta nt as a c he m ose ns or of n ocice pti o n ( K o vist o et al. 
2 0 1 8; Maat uf et al. 2 0 1 9; Wa n g et al. 2 0 1 9 ). T R P A 1’s i n v ol ve me nt i n pai n a n d i nfla m mati on 
a n d its l ocalizat i on i n se ns or y ne ur o ns are k n o w n ( B o d ki n a n d Brai n 2 0 1 1 ; Üc kert et al. 2 0 1 7). 
D ue t o i ts r ole i n e v o ki n g pai n a n d elicit i n g a n a versi ve res p o nse, T R P A 1 ma y be a pr o misi n g 
tar get f or treati n g pai n (Be ne mei et al. 2 0 1 7; Berta et al. 2 0 1 7; De marti ni et al. 2 0 1 7; Maat uf et 
al. 2 0 1 9; Wa n g et al. 2 0 1 9).
L Y 3 5 2 6 3 1 8 is a n orall y a d mi nistere d, p ote nt, a n d select i ve n o vel a nta g o nist of T R P A 1 u n der 
de vel o p me nt b y  Lill y. 
L Y 3 5 2 6 3 1 8 has bee n e v al uate d i n 2 c o mplete d a n d 1 o n g oi n g P hase 1 cli nical st u dies. 
C o m plete d 
St u d y
J 2 D-M C -C V A A ( C V A A)
P o p ul ati o n
Healt h y  partici pa nts
St u d y Desi g n
2 -part, place b o -c o ntr olle d, ra n d o mize d, si n gle a n d m ulti ple-d ose escalati o n st u d y.
L Y 3 5 2 6 3 1 8 
D ose
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C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
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1 3
O bjecti ves 
Part A: T o e val uate safet y , t olera bilit y, a n d P K of L Y 3 5 2 6 3 1 8 i n healt h y partici pa nts 
f oll o wi n g a si n gle oral d ose.
Part B: T o e val uate sa fety, t olera bilit y, a n d P K of L Y 3 5 2 6 3 1 8 i n healt h y partici pa nts 
f oll o wi n g m ulti ple o nce-dail y  oral d oses f or 1 4 da ys.
C o m plete d 
St u d y 
J 2 D-M C -C V A B ( C V A B)
P o p ul ati o n
Healt h y  fe male partici pa nts
St u d y Desi g n
R a n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, 4- wa y cr oss o ver st u d y.
L Y 3 5 2 6 3 1 8 
D ose
Eac h partici pa nt was ra n d o ml y assi g ne d t o recei ve 4 u ni q ue d oses of st u d y dr u g i n a rati o of 
3 L Y 3 5 2 6 3 1 8: 1 place b o, i n a cr oss o ver ma n ner wit h at least 1 4 da y s of was h o ut bet wee n 
d oses. 
O bjecti ves 
T o assess tar get e n ga ge me nt of T R P A 1 wit h ci n na mal de h y de ( C A) -i n d uce d der mal bl o o d 
fl o w ( D B F) after a si ngle d ose of L Y 3 5 2 6 3 1 8 .
O n g oi n g St u d y 
J 2 D-M C -C V A C ( C V A C)
P o p ul ati o n
Healt h y  partici pa nts
St u d y Desi g n
R a n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, S A D ( Part A) a n d m ulti ple d ose ( M D ; Part B) 
st u d y.
L Y 3 5 2 6 3 1 8
D ose
O bjecti ves 
Part A: T o e val uate t he safet y, t olera bilit y, a n d P K of L Y 3 5 2 6 3 1 8 after a si n gle oral d ose 
a d mi nistrati o n .
Part B: T o e val uate t he safet y, t olera bilit y, a n d P K of L Y 3 5 2 6 3 1 8 after m ulti ple oral d ose 
a d mi nistrati o ns.
P h ar m ac o ki netics 
C CI
C CI
C CI
C CI
C CI
C CI


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
1 4
P h ar m ac o d y n a mics
 
 
 
 
 
S afet y
 
 
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
1 5
2. 3.
Be nefit/ Ris k Assess me nt
Cli nic al S afet y
I n St u d y C V A A, n o cli nicall y si g nifica nt safety or t ol era bilit y c o ncer ns were i de ntifie d at t he 
hi g hest si n gle d ose a d mi nistere d (
) or t he hi g hest mul tiple d ose a d mi nistere d ( 
 
). A d dit i onall y , preli mi nar y data usi n g a ne w f or m ulati on of 
L Y 3 5 2 6 3 1 8 i n St u d y  C V A C s h o we d n o cli nicall y sig nifica nt safet y or t ol era bilit y c o ncer ns at 
hi g her e x p os ures f o ll owi n g si n gle or m ul tiple d oses  
 
T o xic ol o g y S t u dies a n d N O A E L E x p os ure
 
 
 
2. 3. 1.
Ris k Assess me nt
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
16
More information about the known and expected risks, SAEs, and reasonably anticipated 
AEs of LY3526318 may be found in the IB. Information on AEs expected to be related to the 
investigational product may be found in Section 7 (Reference Safety Information for 
Assessment of Expectedness of Serious Adverse Reactions) of the IB. Information on SAEs 
that are expected in the study population independent of drug exposure will be assessed by 
the sponsor in aggregate, periodically during the course of the study, and may be found in 
Section 5 (Effects in Humans) of the IB.
2.3.2. Benefit Assessment
Potential benefits for the study participants include 

information obtained from study-related medical procedures 
o
physical examinations 
o
laboratory tests 
o
ECGs 

detailed evaluations of OA 
o
knee examinations 
o
knee X-rays

OA-associated questionnaires that may improve participants understanding their own 
condition. 
As part of Study CPMP, participants to this ISA may report their experience using standard tools 
that will contribute to the assessment of novel treatments for OA. In addition, data collected from 
this study may also improve our understanding of OA pathogenesis. Both of which may lead to 
the development of new treatment with improved safety and efficacy profile compared to 
standard of care.
2.3.3. Overall Benefit Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with LY3526318 are justified by the 
anticipated benefits that may be afforded to participants with OA.


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
17
3.
Objectives and Endpoints
The CPMP Master Protocol and OA DSA CPMP(1) include objectives and endpoints applicable 
for this study. This table describes objectives and endpoints specific for LY3526318.
Objectives
Endpoints
Tertiary/Exploratory
Measure the PK of LY3526318 in participants with 
OA.
Measure of plasma concentrations of LY3526318 to 
enable PK evaluations.
Abbreviations: OA = osteoarthritis; PK = pharmacokinetic.


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
1 8
4.
St u d y Desi g n
4. 1.
O ver all Desi g n
T he C P M P Master Pr ot oc ol descri bes t he o verall st u d y  desi g n a n d st u d y d esig n r ati o nale. T his 
secti on descri bes visits a n d o verall pr oce d ures u ni q ue t o I S A O A 0 2 f or L Y 35 2 6 3 1 8 i n a d diti on 
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 - Bli n d Tre at me nt Peri 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

parti ci pa nts are ra n d o mize d t o L Y 3 5 2 6 3 1 8 or pl ace b o  

t he sit e c o mpletes t he O A 0 2 baseli ne pr oce d ures a n d sa m ple c o llecti on 

parti ci pa nts recei ve t heir or al st u d y int er ve nt i on 

t he site c ollects partici pa nts vitals at 2 a n d 4 h o urs after t he c o m pleti on of t he oral 
a d mi nistrati o n 

t he sit e c o mpletes all p ost- treat me nt sa mple c ollecti o n a n d safet y  mo ni t ori n g, 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 restrict i ons a n d N u meric Rat i n g 
Scal e ( N R S) diar y e ntries bef ore t heir visit disc har ge.
At  Visits 4 t hr o u g h 7

t he site re vie ws a vaila ble safet y data a n d c o m pletes pre -d ose pr oce d ures a n d sa m ple 
c ollect i on

parti ci pa nts c o nti n ue oral st u d y int er ve nt i on

t he sit e c o mpletes all sa m ple c ollecti o n a n d safet y m o nit ori n g n ote d i n t he Sc he d ules of 
Act i vities (S o As ), 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 r estrict i ons a n d N R S diar y  e ntries 
bef ore t heir visit d isc har ge.
4. 2.
Scie ntific R ati o n ale f or St u d y Desi g n
T he m aster pr ot oc ol descri bes t he o verall st u d y desig n rati o nale.
4. 3.
J u stific ati o n f or D ose
C CI
C CI


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (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 p lete d t his I S A if he or s he has c o m plete d all re q uire d 
p hases of t he st u d y  incl u di n g t he 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 .
T he e n d o f t he st u d y is defi ne d as t he date of t he last visit of t h e 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.
C CI
C CI


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
2 0
5.
St u d y P o p ul ati o n
T he C P M P Master Pr ot oc ol a n d O A C P M P( 1 ) D S A pr o vide eli gi bilit y cri t eria t hat must be 
f oll owe d f or t hi s st u d y. L Y 35 2 6 3 1 8- s pecific i ncl usi o n a n d e xcl usi on cri t eria are liste d here.
5. 1.
I ncl usi o n Criteri a
P arti cipa 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 h e fol l owi n g criteria a p pl y:
[ 1 0 5 0]
A re me n or w o me n w h o a bide b y t he re pr o d ucti ve a n d c o ntrace pti ve 
re q uire me nts pr o vide d i n O A 0 2 Sect i on 1 0. 2 , A p pe n di x 2.
5. 2.
E xcl u si o n Criteri a
P arti cipa nts are e xcl u de d fr o m  t he st u d y if a n y of t he f o ll owi n g cri t eria a p pl y:
 
 
[ 1 0 5 2]
Ha ve a n e G F R of less t ha n 3 0 ml/ mi n/ 1. 7 3 m 2, base d o n t he C hr o nic 
Ki d ne y Disease E pi de mi o l og y  C olla b oratio n ( C K D -E PI) f or m ula at Visit 1 or 
Vi sit 2.
[ 1 0 5 3]
W o m e n w h o are pre g na nt or breastfee di n g .
 
 
5. 3.
Lifest yle C o nsi der ati o ns
5. 3. 1.  
Me als a n d Diet ar y Restricti o ns
Refrai n fr o m c o ns u m pti o n o f Se ville ora n ges, gra pefr uit , or gra pefr uit j uice fr o m 5 da y s bef ore
t he start of st u d y int er ve nt i on u nt il after t he fi nal d ose.
5. 3. 2.
S u bst a nce Use
P osi tive uri n e 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 mit a nt 
me dicat i on f or a k n o w n pre-e xisti n g c o n dit i on.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
21
5.3.3.
Reproductive and Contraception Requirements
Reproductive requirements and contraceptive guidance are provided in Section 10.2, Appendix 
2.  


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
2 2
6.
St u d y I nter ve nti o n (s) a n d C o nc o mit a nt T her a p y
St u d y  i nter ve nt i on is defi ne d as a ny i n vesti gati onal i nter ve nt i on (s), mar kete d pr o d uct(s), 
pl ace b o , or m e dical de vice(s) i nte n de d t o be a d mi nistere d t o / use d b y a st u d y partici pa nt 
acc or di n g t o t he st u d y pr ot oc ol .
6. 1.
St u d y I nter ve nti o n(s) A d mi nistere d
T he st u d y  int er ve nt i on will be a d mi nistere d orall y ,
    
I nter ve nti o n N a me
L Y 3 5 2 6 3 1 8
Place b o
D ose F or m ul ati o n
Ca ps ule 
Ca ps ule
U nit D ose Stre n gt h(s)
D os a ge Le vel(s)
R o ute of A d mi nistr ati o n
P O
P O
Use
e x peri me ntal 
place b o
I M P a n d NI M P
I M P
NI M P
A b bre viati o ns: I M P = i n vesti gati o nal me dici nal pr o d uct; N A = n ot a p plica ble; NI M P = n o ni n vesti gati o nal me dici nal 
pr o d uct; P O = b y m o ut h; Q D = o nce dail y.
6. 2.
Pre p ar ati o n , H a n dli n g , St or a ge , a n d Acc o u nt a bilit y
T he C P M P Master Pr ot oc ol pr o vi des m ore detail o n pre parati o n, ha n dli n g, st ora ge, a n d 
acc o u nta bilit y re q uire me nts.
6. 3.
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
N o a d di tio n al  stratificati on fact ors are c o nsi dere d f or t his I S A.  
6. 4.
St u d y I nter ve nti o n C o m pli a nce
W he n partici pa nts self -a d mi nister st u d y i nter ve nti o n(s) at h o me, c o m plia nce wit h st u d y  
i nter ve nt i on will be assesse d at eac h visit. C o m plia nce will be assesse d b y direct q uesti o ni n g, 
c o u nti n g ret ur ne d ca ps ules, a n d d oc u me nte d i n t he s o urce d oc u me nts a n d case re p ort f or m 
(C R F ). 
A rec or d of t he n u m ber of st u d y int er ve nt i on ca ps ul es di s pe nse d t o a n d ta ke n b y eac h partici pa nt 
m ust be mai ntai ne d a n d rec o ncile d wit h st u d y  int er ve nt i on a n d c o m plia nce rec or ds. I nter ve nti o n 
start a n d st o p dates, will als o be rec or de d i n t he C R F.
6. 5.
Tre at me nt of O ver d ose
I n case of s us pecte d o ver d ose, partici pa nts s h o ul d be m o nit ore d f or a n y  sig ns or s y m pt o m s of 
a d verse reacti o ns or effects, a n d s u p p orti ve care s h o ul d be pr o vi de d as necessar y. T here is n o 
k n o w n a nt i d ote t o L Y 3 5 2 6 3 1 8 t hera p y.
C CI
C CI
C CI
C CI
C CI
C CI


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
2 3
6. 6.
C o nc o mit a nt T her a p y
All c o nc o mit a nt  t hera pies t hat are part of r o uti ne care f or c o m or bi dities ot h er t ha n c hr o nic pai n
are all o we d a n d ma y be use d d uri n g t he st u d y , if it is per mitte d base d o n t he eli gi bilit y crit eria. 
T he C P M P Master Pr ot oc ol pr o vi des m ore detail o n c o nc o mit a nt t hera p y.  
A list of me dicati o ns t hat are pr o hi bite d fr om Visi t 2 t o Visit 7 f or partici pa nts ra n d o mize d t o 
t his I S A st u d y will be pr o vide d i n t he Ma n ual of O perati o ns . P artici pa nts ma y ret ur n t o t heir 
sta n dar d of care after Visit 7 is c om p lete d, as cli nicall y a p pr o priate.
 
C CI
C CI


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
24
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
The CPMP Master Protocol and CPMP(1) DSA provides the reasons and procedures for 
discontinuation of intervention and participant discontinuation that must be followed for this 
study.  


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
ISA: H0P-MC-OA02(a)
25
8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the CPMP Master Protocol, OA CPMP(1)
DSA, and ISA OA02 SoAs.  
LY3526318-specific assessments and procedures are described here.
8.1.
Efficacy Assessments
Planned time points for all efficacy assessments are provided in the SoAs.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoAs. 
8.2.1.
Physical Examinations
Symptom directed physical examinations of skin, eyes, mouth, lungs, and gastrointestinal tract 
will be performed at each visit as described in the SoA. Any clinically significant abnormal 
physical examination findings will be reported as AEs. 
8.2.2.
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, RR, QRS, QT, and QTcF intervals. 
8.2.3.
Clinical Safety Laboratory Tests
See OA02 Section 10.1 (Appendix 1) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency for ISA OA02. 
8.3.
Adverse Events, Serious Adverse Events, and Product Complaints
See the CPMP Master Protocol for additional details.
8.4.
Pharmacokinetics
●
Blood samples will be collected for measurement of plasma concentrations of 
LY3526318 as specified in the SoA. 
●
A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor. The 
timing of sampling may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. 
●
Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded.
●
The date and time (24-hour clock time) of LY3526318 administration prior to the 
PK sampling will be recorded i.e. the dose administered in the clinic at Visit 3 and 
the last at home dose prior to each of Visit 4, Visit 5, Visit 6, and Visit 7.


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
2 6
●
S a m ples will  be use d t o e val uate t he P K of  L Y 3 5 2 6 3 1 8. Sa m ples c o llecte d f or 
a nal yses o f L Y 3 5 2 6 3 1 8 plas ma c o nce ntrati o ns ma y als o be use d t o e valuate 
safety or efficac y  as pects relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y.
Dr u g c o nce ntrati o n i nf or mat i on t hat ma y u n bli n d t he st u d y  will n ot be re p orte d t o i n vesti gati ve 
sites or bli n de d pers o n nel u ntil t he st u d y has bee n u n bli n de d.
8. 5.
P h ar m ac o d y n a mics
P har mac o d y na mic para meters a re n ot e val uate d i n t his st u d y.
C CI
C CI


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
2 7
9.
St atistic al C o nsi der ati o ns
T he C P M P M aster P r ot oc ol a n d O A D S A C P M P( 1) pr o vi de statist ical c o nsi derati ons.
L Y 3 5 2 6 3 1 8- s pecific c o nsi derat i ons are descri be d here.
9. 1.
St atistic al H y p ot heses
T he C P M P Master Pr ot oc ol descri bes t he pri mar y  h y p ot hesis.
 
 
T he ke y  sec o n dar y null  h y p ot hesis is t hat t here is n o differe nce bet wee n L Y 3 5 2 6 3 1 8 a n d place b o 
o n t he ke y  sec o n dar y e n d p oi nt, t he mea n c ha n ge fr o m baseli ne t o e n d p oi nt f or t he W O M A C ® 
Pai n S u bscale Sc ore.
 
 
 
9. 2.
A n al yses Sets
T he p o p ulat i ons are defi ne d i n t he C P M P Master Pr ot oc ol .
T he P K p o p ulati o n i ncl u des all ra n d o mize d part ici pa nts w h o recei ve d a d ose of L Y3 5 2 6 3 1 8 a n d 
ha ve at least 1 e val ua ble P K sa m ple c o llecte d. 
9. 3.
St atistic al A n al yses
A n y c ha n ge t o t he data a nal ysis met h o ds descri be d i n t his I S A will re q uire a n a me n d me nt o nl y if 
it c ha n ges a pri nci pal feat ure of t he I S A. A n y ot her c ha n ge t o t he data a nal ysis met h o ds 
descri be d, a n d t he j ust ificati on f or ma ki n g t he c ha n ge, will be descri be d i n t he statist ical a nal ysis 
pl a n ( S A P) a n d t he cli nical st u d y re p ort. A d ditio nal  e xpl orat o r y a nal yses of t he data will be 
c o n d ucte d as dee me d a p pr o priate.
T he I S A S A P will be fi nalize d pri or t o u n bli n di n g, a n d it will i ncl u de m ore tec h nical a n d 
detaile d descri pt i on s of  t he statistical a nal yses descri be d i n t his secti on.
9. 3. 1.
Ge ner al C o nsi der ati o ns
T he pri mar y  e n d p oi nt a n d a nal yses ha ve bee n descri be d i n t he C P M P Master Pr ot oc ol. 
A n y b orr o wi n g of place b o or treat me nt effect i nf or mat i on will be s pecifie d i n t he I S A S A P. 
Sec o n dar y  a n d tertiar y/ e x plor at or y  e n d p oi nts a n d a nal yses are descri be d i n t he C PM P Master 
Pr ot oc ol  a n d O A D S A C P M P( 1). 
9. 3. 2. 
E x pl or at or y E n d p oi nt A n al ysis
E x pl or at or y  a nal yses ma y be descri be d i n t he I S A S A P.
9. 3. 3. 
S afet y A n al yse s
S af et y a nal yses ha ve bee n descri be d i n t he C P M P Master Pr ot oc ol. A d dit i on al  I S A-s pecific 
safety a nal yses ma y be describe d i n t he I S A S A P. 
C CI
C CI
C CI
C CI


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
2 8
9. 3. 4.
Ot her A n al yses
9. 3. 4. 1.
P h ar m ac o ki netic a n d P h ar m ac o d y n a mic A n al yses
T he o bser ve d plas ma c o nce ntrati o ns f or L Y 3 5 2 6 3 1 8 will be re p orte d gra p hicall y a n d 
descri pt i vel y.
P har mac o ki net ic m o deli n g a n d e x p os ure -res p o nse a nal yses of efficac y meas ures ma y be 
c o n d ucte d. If c o n d ucte d, t he a nal yses will be perf or me d usi n g p o p ulat i on a nal ysis s o ftware, 
N O N M E M ® , if data allo ws. T he versi o n of  a n y s oft ware use d f or t he a nal ysis will be 
d oc u m e nte d, a n d t he pr o gra m will meet t he Lill y re q uire me nts of s oft ware vali dat i on. It i s 
p ossi ble t hat ot her vali date d, e q ui vale nt P K s oft ware pr o gra ms ma y  be use d if a p pr o priate, 
warra nte d, a n d a p pr o ve d b y Gl o bal P K/ p har mac o d y na mic ma na ge me nt. Data ma y be p o ole d 
wi t h data fr o m ot her st u dies for a n i nte grate d P K a n d/ or P K/ p ha r mac o d y na mic a nal ysis.
A li mite d n u m ber of pre-i de ntifie d i n di vi d uals i n de pe n de nt of t he st u d y  t e a m ma y recei ve access 
t o u n bli n de d data, as s pecifie d i n t he u n bli n di n g pla n, pri or t o t he i nteri m or fi nal data base l oc k, 
i n or der t o i nitiate t he fi nal p o p ulat i on P K a n d/ or e x p os ure -res p o nse m o del de vel o p me nt 
pr ocesses. 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 sit es or t he bli n de d st u d y  tea m u ntil t he st u d y has bee n u n bli n de d.
9. 4.
I nteri m A n al ysis 
A n i nteri m a nal ysis ma y be c o n d ucte d f or i nter nal decisi o n ma k i n g. U n bli n di n g details w o ul d be 
s pecifie d i n t he u n bli n di n g pla n sect i on of t he S A P or i n a se parate u n bli n di n g d oc u me nt. T he 
S A P will descri be a n y  int eri m a nal yses i n greater detail s h o ul d t hey occ ur. 
9. 5.
S a m ple Size Deter mi n ati o n
U p t o ap pr o xi matel y 1 5 0 partici pa nts will be ra n d o mize d i n a  
 rati o t o L Y 3 5 2 6 3 1 8 a n d 
pl ace b o, res pecti vel y. It is e x pecte d t hat a p pr o xi matel y 8 5 % of parti ci pa nts will c o m p lete t he 
d o u bl e- bli n d treat me nt peri 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 5 2 6 3 1 8 , t he pr o ba bility of  
passi n g t he efficac y criteri o n s pecifie d a b o ve (i.e., false p osi tive) is a p pr o xi matel y 0. 1 . T he 
si m ulati on f or t he p o wer calc ulat i on a n d sa m ple size deter mi nat i on was carrie d o ut i n F A C T S 
Versi o n 6. 0 .
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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
1 0. 1.
A p pe n di x 1 : Cli nic al L a b or at or y Tests
T he C P M P Master Pr ot oc ol descri bes tests t hat ma y be perf or me d at a d di tio nal t i mes n ote d i n 
t he S o A f or t his I S A. T his ta ble descri bes tests u ni q ue f or I S A O A 0 2 .  
Ot her Tests
L Y 3 5 2 6 3 1 8 
c o nce ntrati o n
Ur i ne pre g na nc y
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10.2.
Appendix 2: Contraceptive and Barrier Guidance
10.2.1.
Definitions
Word/Phrase
Definition
Women of 
childbearing 
potential
Females are considered women of childbearing potential (WOCBP) if

they have had at least 1 cycle of menses, or

they have Tanner 4 breast development.
Any amount of spotting should be considered menarche. If Tanner Staging of 
breasts is performed as part of study procedures, please refer to the Reproductive, 
Pregnancy and Pediatrics Safety Committee Safety Guidance for Children in 
Clinical Trial regarding Tanner staging.
Women not of 
childbearing 
potential
Females are considered women not of childbearing potential (WNOCBP) if

they have a congenital anomaly such as Mullerian agenesis 

they are infertile due to surgical sterilization, or 

they are post-menopausal.
Examples of surgical sterilization include: hysterectomy, bilateral oophorectomy, 
or tubal ligation.
Postmenopausal 
state
The post-menopausal state should be defined as:
1.
A woman at any age at least 6 weeks post-surgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or 
2.
A woman at least 40 years of age and up to 55 years old with an intact 
uterus, not on hormone therapy*, who has had cessation of menses for at 
least 12 consecutive months without an alternative medical cause, AND 
with a follicle-stimulating hormone >40 mIU/mL; or 
3.
A woman 55 or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea, or
4.
A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy
* Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, 
selective estrogen receptor modulators (SERMs), or chemotherapy that could 
induce transient amenorrhea.
Reproductive 
Toxicology 
Studies
Embryo-fetal studies are toxicity studies in pregnant animals designed to identify 
abnormalities in the development of fetuses, which could indicate potential for 
teratogenicity in humans. The relevant dosing period is during organogenesis.


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10.2.2.
Contraception Guidance
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle
Must…
Must not…
agree to either remain abstinent, or

use periodic abstinence methods
o
calendar 
o
ovulation 
o
symptothermal, or
o
post-ovulation 

declare abstinence just for the duration of 
a trial, or
stay in a same-sex relationship without sexual 
relationships with males
use the withdrawal method
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle
Topic
Condition
Pregnancy testing
Negative urine result at screening followed by a 
negative serum result within 24 hours prior to 
treatment exposure.
Note: Subsequent pregnancy testing is compound 
specific.
Contraception
Agree to use 2 forms of effective contraception, 
where at least 1 form must be highly effective 
(less than 1% failure rate)
Examples of different forms of contraception 
Methods
Examples
Highly effective contraception 

combination oral contraceptive pill and 
mini-pill

implanted contraceptives

injectable contraceptives

contraceptive patch (only women 
<198 pounds or 90 kg)

total abstinence

vasectomy (if only sexual partner)

fallopian tube implants (if confirmed by 
hysterosalpingogram)

combined contraceptive vaginal ring, or 

intrauterine devices


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
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32
Effective contraception 

male or female condoms with spermicide 

diaphragms with spermicide or cervical 
sponges

barrier method with use of a spermicide
o
condom with spermicide
o
diaphragm with spermicide, or
o
female condom with spermicide
Note: The barrier method must include use of a 
spermicide (i.e., condom with spermicide, 
diaphragm with spermicide, female condom with 
spermicide) to be considered effective.
Ineffective forms of contraception

spermicide alone 

immunocontraceptives

periodic abstinence

fertility awareness (calendar method, 
temperature method, combination of 
above 2, cervical mucus, symptothermal)

withdrawal,

post coital douche

lactational amenorrhea
Topic
Guidance
Contraception for men receiving a genotoxic drug 
and have a female partner of childbearing 
potential

Agree to remain abstinent (if this is their 
preferred and usual lifestyle), or 

use 1 additional effective method of 
contraception
The table below describes contraception guidance for all men.
Topic
Guidance
For all men
should refrain from sperm donation for the 
duration of the study and for the predicted time 
until estimated plasma levels of partner would be 
below the level of toxicologic concern, plus 
90 days.
Contraception for men with partners of 
childbearing potential 

either remain abstinent (if this is their 
preferred and usual lifestyle), or

must use condoms during intercourse for 
the duration of the study, and 

for the predicted time until estimated 
plasma levels of partner would be below 
the level of toxicologic concern, plus 
90 days
Contraception for men in exclusively same sex 
relationships, as their preferred and usual lifestyle
Are not required to use contraception


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP 
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33
Examples of highly effective, effective, and unacceptable methods of contraception can be found 
below
Methods
Examples
Highly effective contraception 

combination oral contraceptive pill and 
mini-pill

implanted contraceptives

injectable contraceptives

contraceptive patch (only women 
<198 pounds or 90 kg)

total abstinence

vasectomy (if only sexual partner)

fallopian tube implants (if confirmed by 
hysterosalpingogram)

combined contraceptive vaginal ring, or 

intrauterine devices
Effective contraception 

male or female condoms with spermicide 

diaphragms with spermicide or cervical 
sponges

barrier method with use of a spermicide
o
condom with spermicide
o
diaphragm with spermicide, or
o
female condom with spermicide
Note: The barrier method must include use of a 
spermicide (i.e., condom with spermicide, 
diaphragm with spermicide, female condom with 
spermicide) to be considered effective.
Ineffective forms of contraception

spermicide alone 

immunocontraceptives

periodic abstinence

fertility awareness (calendar method, 
temperature method, combination of 
above 2, cervical mucus, symptothermal)

withdrawal

post coital douche, or

lactational amenorrhea


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
3 4
1 0. 3.
A p pe n di x 3: List of E xcl u de d C o nc o mit a nt Me dic ati o ns
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10.4.
Appendix 4: 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.
Remote visits


C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P 
I S A: H 0 P- M C -O A 0 2 (a)
3 8
Tele me dici ne: T el e p h o ne or tec h n o l og y -assiste d virt ual visits, or b ot h, are acce pta ble t o 
c o mplete a p pr o pri ate assess me nts. 
M o bile he alt hc are:
Heal t hcare visits m a y be perf or me d b y a mo bile heal t hcare pr o vider 
at lo c ati o ns ot her t ha n t he st u d y  site w he n partici pa nts ca n n ot tra vel t o t he site d ue t o a n 
e xce 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 perf or me d at s uc h visit s i ncl u de, b ut are n ot li mite d t o, c ollect i on of bl o o d 
sa m ples, s y m pt o m directe d p h ysical e xa mi nat i ons, E C Gs, vital si g ns, i nter ve nt i on 
acc o u nta bilit y a n d c o m plia nce, A E c ollect i on, a n d c ollect i on of healt h i nf or mati o n.
Ot her alter n ati ve l oc ati o ns: La b orat or y  dra ws ma y be d o ne at a n alter nate l ocati o n i n 
e xce pti o nal circ u msta nces.  
I n s o urce d oc u me nts a n d t he C R F, t he st u d y sit e s h o uld ca pt ure t he visit met h o d, wit h a s pecific 
e x pla nat i on f or a n y data missi n g beca use of misse d i n- pers o n site visits.
Re gar dless of t he t y p e of  r e mote visi ts i m ple me nte d, t he pr ot oc ol re q uire me nts re gar di n g t he 
re p orti n g of A Es, S A Es, a n d pr o d uct c o m plai nts re mai n u nc ha n ge d. 
E v er y eff ort s h o uld be ma de t o e na ble part ici 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 hile e ns uri n g t he safety 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 testi n g ma y be c o n d ucte d i n lie u of ce ntral la b orat or y testi n g. T he lo c al  
la b orat or y must be q ualifie d i n acc or da nce wi t h a p plica ble lo c al  re g ulati ons.
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
parti ci p a 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-sit e 
visit s, 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 act i ons ma y 
i ncl u de:  

as ki n g t he partici 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 with o ut c o m plet i on of a f ull st u d y  visit, 

as ki n g t he partici pa nt’s desi g nee t o g o t o t he site a n d recei ve st u d y  s u p plies 
o n a parti ci pa nt’s be half, a n d

arra n gi n g deli ver y of st u d y s u p plies.
T hese re q uire me nts m ust be met bef ore a ctio n i s ta ke n:

Alt er nate deli ver y of st u d y int er ve ntio n s h o ul d be perf or m e d i n a ma n ner t hat 
d oes n ot c o m pr o mise treat m e nt bli n di n g a n d e ns ures pr o d uct i nte grit y.  T he 
e xist i n g pr ot oc ol re q uire me nts f or pr o d uct acc o u nta bility re mai n u nc ha n ge d, 
i ncl u di n g verificati on of partici pa nt’s recei pt of st u d y  s u p plies.
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
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 CPMP Master Protocol, 
CPMP(3) DSA, and NP02 ISA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study.
Documentation
Sites will identify and document the details of how participants, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records.
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 


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10.5.
Appendix 5: Abbreviations
Term
Definition
AE
adverse event
AITC
allyl isothiocyanate
blinding/masking
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received.
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
maximum serum/plasma concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice, and applicable regulatory 
requirements.
CRF
case report form
CV%
percent coefficient of variation
CYP3A
cytochrome P450 enzymes 3A
DDI
drug-drug interaction
data monitoring 
committee
A data monitoring committee is a group of independent scientists who are appointed to 
monitor the safety and scientific integrity of a human research intervention, and to make 
recommendations to the sponsor regarding the stopping of a study for efficacy, or for 
harms, or for futility. The composition of the committee is dependent upon the scientific 
skills and knowledge required for monitoring the particular study.
DSA
disease-state addendum
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
enroll
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment.
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
IMP
Investigational Medicinal Product


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informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed, and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ISA
intervention-specific appendix
NIMP
noninvestigational medicinal product
NOAEL
no observed adverse effect level
NRS
Numeric Rating Scale
OA
osteoarthritis
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PK
pharmacokinetics
PO
by mouth
PoC
proof-of-concept
OA
osteoarthritis
QD
once daily
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
t1/2
elimination half-life


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TEAE
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
tmax
time to maximum plasma concentration
TRP
transient receptor potential
TRPA1
transient receptor potential ankyrin 1
WOCBP
women of childbearing potential


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11.
References
Benemei S, De Logu F, Li Puma SL, et al. The anti-migraine component of butterbur extracts, 
isopetasin, desensitizes peptidergic nociceptors by acting on TRPA1 cation channel. Br J 
Pharmacol. 2017;174(17):2897-2911. https://doi.org/10.1111/bph.13917
Berta T, Qadri Y, Tan PH, Ji RR. Targeting dorsal root ganglia and primary sensory neurons for 
the treatment of chronic pain. Expert Opin Ther Targets. 2017;2(7)1:695-703.
https://doi.org/10.1080/14728222.2017.1328057
Bodkin JV, Brain SD. Transient receptor potential ankyrin 1: emerging pharmacology and 
indications for cardiovascular biology. Acta Physiol (Oxf). 2011;203(1):87-98. 
https://doi.org/10.1111/j.1748-1716.2010.02203.x 
Demartini C, Tassorelli C, Zanaboni AM, et al. The role of the transient receptor potential 
ankyrin type-1 (TRPA1) channel in migraine pain: evaluation in an animal model. J Headache 
Pain. 2017;18(1):94. https://doi.org/10.1186/s10194-017-0804-4
Hansten PD, Horn JR. Top 100 Drug Interactions of 2018: A Guide to Patient Management. 
H&H Publications; 2018.
Kovisto A, Jalava N, Bratty Ry, Pertovaara A. TRPA1 antagonists for pain relief. 
Pharmaceuticals (Basel). 2018;11(4):117-135. https://doi.org/10.3390/ph11040117
Maatuf Y, Geron M, Priel A. The role of toxins in the pursuit for novel analgesics. Toxins
(Basel). 2019;11(2):131-164. https://doi.org/10.3390/toxins11020131
Ückert S, Albrecht K, Bannowsky A, et al. Expression and distribution of the transient receptor 
potential cationic channel A1 (TRPA1) in the human clitoris-comparison to male penile 
erectile tissue. Int J Impot Res. 2017;29(5):179-183. https://doi.org/10.1038/ijir.2017.15
University of Washington. Drug interaction solutions. Accessed June 01, 2021. 
https://www.druginteractionsolutions.org/
Wang XL, Cui LW, Liu Z, et al. Effects of TRPA1 activation and inhibition on TRPA1 and 
CGRP expression in dorsal root ganglion neurons. Neural Regen Res. 2019;14(1):140-148. 
https://doi.org/10.4103/1673-5374.243719


A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 0 - A u g - 2 0 2 1  1 9 : 1 4 : 0 9  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 0 - A u g - 2 0 2 1  2 0 : 0 1 : 1 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D
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P P D
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SAP_005.pdf: 
This study H0P-MC-OA02 (NCT05080660) is a sub-study of Master Protocol H0P-
MC-CPMP (NCT05986292)
Statistical Analysis Plan Version 2 H0P-MC-OA02 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3526318 for 
the Treatment of Osteoarthritis Pain
NCT05080660 
Approval Date: 13-Jun-2022 


H0P-MC-OA02 Statistical Analysis Plan Version 2 
Page 1 
LY3526318 
1.
Statistical Analysis Plan:
H0P-MC-OA02: Intervention-Specific Appendix (ISA) for 
LY3526318 
Confidential Information 
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
LY3526318 Pain from Osteoarthritis of the Knee 
This is a randomized, placebo-controlled, Phase 2 clinical trial to evaluate LY3526318 for 
the treatment of pain in participants who have been diagnosed with osteoarthritis of the 
knee. 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Protocol H0P-MC-OA02 
Phase 2 
Statistical Analysis Plan electronically signed and approved by Lilly on date 
provided below 
Approved on 13 Jun 2022 GMT


H0P-MC-OA02 Statistical Analysis Plan Version 2 
Page 2 
LY3526318 
2.
Table of Contents
Section 
Page 
1.
Statistical Analysis Plan: H0P-MC-OA02: Intervention-Specific
Appendix (ISA) for LY3526318 .............................................................................................1
2.
Table of Contents ....................................................................................................................2
3.
Revision History ......................................................................................................................4
4.
Study Objectives ......................................................................................................................5
4.1.
Primary Objective ...............................................................................................................5
4.2.
Secondary Objectives .........................................................................................................5
4.3.
Exploratory Objectives .......................................................................................................5
5.
Study Design ...........................................................................................................................7
5.1.
Summary of Study Design..................................................................................................7
5.2.
Determination of Sample Size ............................................................................................7
5.3.
Method of Assignment to Treatment ..................................................................................7
6.
A Priori Statistical Methods ....................................................................................................8
6.1.
General Considerations ......................................................................................................8
6.2.
Adjustments for Covariates ................................................................................................8
6.3.
Handling of Dropouts or Missing Data ..............................................................................8
6.4.
Multiple Comparisons/Multiplicity ....................................................................................9
6.5.
Use of an “Efficacy Subset” of Patients/Subjects ..............................................................9
6.6.
Patient/Subject Disposition ................................................................................................9
6.7.
Participant Characteristics ..................................................................................................9
6.8.
Treatment Compliance .......................................................................................................9
6.9.
Concomitant Therapy and eCOA Compliance ...................................................................9
6.10. Efficacy Analyses .............................................................................................................10
6.10.1. 
Primary Outcome and Methodology ........................................................................10
6.10.2. 
Additional Analyses of the Primary Outcome .........................................................10
6.10.3. 
Secondary Efficacy Analyses ...................................................................................10
6.10.3.1. 
Key Secondary Analysis ....................................................................................11
6.10.3.2. 
Other Secondary Analysis ..................................................................................11
6.11. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods ....................................11
6.12. Safety Analyses ................................................................................................................12
6.12.1.
Extent of Exposure ...................................................................................................12
6.12.2.
Adverse Events ........................................................................................................12
6.12.3.
Deaths, Other Serious Adverse Events, and Other Adverse 
Events for Review ....................................................................................................13
6.12.4.
Clinical Laboratory Evaluation ................................................................................13
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6.12.5. 
Vital Signs and Other Physical Findings .................................................................14 
6.12.6. 
Electrocardiograms ..................................................................................................14 
6.12.7. 
Suicidal Ideation or Behavior ..................................................................................14 
6.13. Subgroup Analyses ...........................................................................................................14 
6.14. Protocol Deviations ..........................................................................................................15 
6.15. Interim Analyses and Data Monitoring ............................................................................15 
6.16. Planned Exploratory Analyses .........................................................................................15 
6.17. Totality of Evidence for Safety ........................................................................................15 
6.18. Annual Report Analyses ...................................................................................................16 
6.19. Clinical Trial Registry Analyses ......................................................................................17 
7. 
Unblinding Plan .....................................................................................................................18 
7.1. 
PKPD Analysis Planning ..................................................................................................18 
8. 
References .............................................................................................................................19 
 
 
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3. Revision History 
Statistical Analysis Plan (SAP) Version 1 was approved on 16 December 2021 prior to 
unblinding data for H0P-MC-OA02 (OA02). 
SAP Version 2 was approved prior to unblinding data for Proof of Concept (PoC) lock. Major 
revisions included: 
 Section 5.2, assumptions for Average Pain Intensity as measured by the Numeric 
Rating Scale (API-NRS) power calculations were added. 
 Section 6.1, the language describing active-treatment and post–active-treatment 
periods was made clearer. 
 Section 6.8, language was added to describe handling of specific edge cases when 
calculating treatment compliance. 
 Section 6.9, language describing reporting electronic Clinical Outcomes 
Assessment (eCOA) compliance separately for the active-treatment period was 
removed, since eCOA compliance is already reported on a weekly basis. 
 Section 6.10.1, language describing the derivation of nominal weeks for deriving 
the primary outcome was updated to handle a specific edge case observed in the 
BP03 readout. 
 Section 6.12.7, a section on suicidal ideation and behavior was added to include 
language that it would be reported separately for the active-treatment period. 
 Section 6.17, clarified the definition of Hy’s Law and added a new endpoint under the 
Liver Function domain called DILI (drug-induced liver injury). 
 Section 7, added language that a CPMP-level blinding and unblinding plan now 
exists. 
 
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4. Study Objectives 
4.1. Primary Objective 
The primary objective of this intervention-specific appendix (ISA) is stated in the 
H0P-MC-CPMP (a) protocol. Additional blinded details regarding LY3526318 dosing that are 
not included in the protocol can be found in the Ethics Review Board (ERB) supplement for 
Study OA02. For Study OA02, endpoint is defined as 4 weeks post initial treatment 
administration at Visit 5. Unless otherwise specified, the time point for secondary endpoint 
measurements is the same as that for the primary endpoint. 
Objectives 
Endpoint 
Primary 
 
Efficacy of LY3526318 versus placebo for pain 
intensity 
Mean change from baseline assessment to 4 weeks for 
average pain intensity as measured by the NRS 
Abbreviation: NRS = Numeric Rating Scale. 
4.2. Secondary Objectives 
Secondary objectives applicable to all ISAs are listed in the H0P-MC-CPMP (CPMP) SAP 
Version 5. 
The key secondary objective for Study OA02 is to evaluate whether LY3526318 is superior to 
placebo in reducing pain as measured by the mean change from baseline assessment to Week 4 
for pain intensity measured by the Western Ontario and McMaster University Arthritis Index 
(WOMAC®) pain subscale. 
Additional secondary endpoints specific to Study OA02 are listed below. 
Objective 
Endpoint Measure 
Other Secondary 
 
Efficacy of LY3526318 versus 
placebo for overall improvement 
Mean change from baseline assessment to 4 weeks for overall improvements 
as measured by the Patient Global Impression of Change 
Efficacy of LY3526318 versus 
placebo  
 
Mean change from baseline to endpoint on the WOMAC® stiffness and 
physical function subscale 
 
Proportion of participants with reduction from baseline greater than or 
equal to 30%, 50%, and 70% on the WOMAC® pain subscale at each 
time point 
 
Proportion of participants with reduction from baseline greater than or 
equal to 30%, 50%, and 70% on the WOMAC® physical function 
subscale at each time point 
Abbreviation: WOMAC = Western Ontario and McMaster University Arthritis Index. 
4.3. Exploratory Objectives 
The following exploratory objectives and endpoints are specific to Study OA02. 
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Objectives 
Endpoints 
Tertiary/Exploratory 
 
Characterization of the pharmacokinetics of 
LY3526318 in participants with OA 
Assessment of plasma concentrations of LY3526318 to 
enable pharmacokinetic evaluations 
(Duration of response) Efficacy of LY3526318 versus 
placebo 
Mean change from baseline assessment up to 8 weeks 
for average pain intensity as measured by the NRS 
Abbreviations: NRS = Numeric Rating Scale; OA = osteoarthritis. 
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H 0 P -M C -O A 0 2  St ati sti c al A n al y si s Pl a n V er si o n 2  
P a g e 7  
L Y 3 5 2 6 3 1 8  
5.  St u d y D e si g n  
5. 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 2  pr ot oc ol . 
I n t his I S A, patie nts i n t h e L Y 3 5 2 6 3 1 8 treat me nt ar m recei ve L Y 3 5 2 6 3 1 8 f or t he first 4 w ee ks of 
t he d o u ble-bli n d peri o d  (acti ve-tr eat me nt peri o d) a n d s witc h t o place b o f or t he last 4 wee ks of 
t he d o u ble-bli n d peri o d  ( p ost– acti ve-treat me nt peri o d) starti n g o n t he da y of Visit 5. Place b o 
patie nts recei ve place b o f or t he e ntire 8 -wee k , d o u ble -bli n d peri o d. A d diti o nal details of t he 
st u d y desi g n ma y be f o u n d i n t he E R B s u p ple me nt f or St u d y  O A 0 2 . 
F or t he a nal yses liste d i n t his S A P, e x ce pt f or treat me nt c o m plia nce, we defi ne acti ve -treat me nt  
peri o d a n d p ost – acti ve tr eat me nt peri o d as f oll o ws. T he first 4 wee ks of t h e d o u ble -bli n d peri o d 
(acti ve-tr eat me nt peri o d) e n ds at t he da y of Visit 5. T he last 4 wee ks of t he d o u ble-bli n d peri o d 
( p ost– acti ve-tr eat me nt peri o d) be gi ns t he da y after V isit 5. 
5. 2.  D et er mi n ati o n of S a m pl e Si z e  
A p pr o xi matel y 1 5 0 p arti ci pa nts will be ra n d o mize d i n a  
 rati o t o L Y 3 5 2 6 3 1 8  a n d place b o. It 
is e x pecte d t hat a p pr o xi matel y 8 5 % or 1 2 8 partici pa nts will c o m plete t he d o u ble -bli n d treat me nt 
peri o d of t he st u d y. 
 
 
 
 
If t here is n o tr eat me nt differe n ce b et wee n pl ace b o a n d L Y 3 5 2 6 3 1 8 , 
t he pr o ba bilit y of passi n g t he effic ac y criteri o n s pecifie d a b o ve (t hat is, fals e p ositi ve) is less 
t ha n 0. 1. T he si m ulati o n f or t he p o wer cal c ulati o n a n d sa m ple siz e deter mi nati o n was carrie d o ut 
usi n g t he Fi x e d a n d A da pti ve Cli nical Trial Si m ulat or ( F A C T S) Versi o n 6. 0.  
 
 
 If t here is n o tr eat me nt differe n ce b et wee n 
place b o a n d L Y 3 5 2 6 3 1 8, 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. 1. 
5. 3.  M et h o d of A s s i 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 1 3 J u n 2 0 2 2 G M T
C CI
C CI
C CI
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6. A Priori Statistical Methods 
6.1. General Considerations 
The estimand for the primary clinical question of interest has been described in the 
CPMP SAP Version 5. 
The key secondary clinical question of interest is: What is the treatment difference between 
LY3526318 and placebo assessed using mean change from baseline to Week 4 for pain as 
measured by the WOMAC® pain subscale in participants with osteoarthritis of the knee 
regardless of initiation of rescue medication or other allowed concomitant medication and 
assuming that they would have continued initially randomized treatment condition? 
 Treatment condition: the randomized treatment along with potential use of rescue 
medication or other allowed concomitant medications regardless of adherence. 
 Population: participants with chronic pain conditions. 
 Endpoint: change from baseline to Week 4 in the WOMAC® pain subscale. 
 Intercurrent events: the intercurrent event is treatment discontinuation for any reason. 
 Population-level summary: difference in mean changes from baseline between 
treatment conditions. 
The estimand is following a hypothetical strategy where efficacy of LY3526318 is assessed 
under the assumption that the participants would have continued their initially randomized 
treatment condition even if they discontinued. 
Unless otherwise specified, efficacy analyses will be conducted for the first 4 weeks of the 
double-blind period (active-treatment phase) and separately for the entire 8-week study. A post–
active-treatment population will be used for analyses of the last 4 weeks of the double-blind 
period (post–active-treatment phase) and will include all patients who do not discontinue at or 
prior to Visit 5. For treatment-emergent adverse events (TEAEs), participants in the post–active-
treatment population will be analyzed according to the treatment they receive during the active-
treatment phase. Adverse event (AE) analyses will be reported for the first 4 weeks of the 
double-blind period (active-treatment phase) and separately for the last 4 weeks of the double-
blind period (post–active-treatment phase). Some AEs may be reported for the entire 8 weeks if 
necessary. Laboratory, electrocardiogram, and vital sign results will be reported for the active-
treatment phase and separately for the entire 8-week study. 
Other general considerations for analyses are described in the CPMP SAP Version 5. 
6.2. Adjustments for Covariates 
The general adjustment strategy has been described in the CPMP SAP Version 5. 
6.3. Handling of Dropouts or Missing Data 
The missing data strategy has been described in the CPMP SAP Version 5. 
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6.4. Multiple Comparisons/Multiplicity 
There is no plan to formally adjust for multiplicity. 
6.5. Use of an “Efficacy Subset” of Patients/Subjects 
There are no plans to use a modified efficacy subset. 
6.6. Patient/Subject Disposition 
The summary of patient disposition has been described in the CPMP SAP Version 5. Disposition 
will additionally be reported for the first 4-week, active-treatment period. 
6.7. Participant Characteristics 
The summary of participant characteristics has been described in the CPMP SAP Version 5. 
6.8. Treatment Compliance 
Treatment percentage of compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑝𝑖𝑙𝑙𝑠 𝑡𝑎𝑘𝑒𝑛 ∗100
𝑇𝑜𝑡𝑎𝑙 𝑝𝑖𝑙𝑙𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑
% 
with total pills taken calculated by total pills dispensed minus total pills returned. A patient is 
considered to be compliant for a given period if this percentage is between 80% and 120%. 
Treatment compliance will be reported for the first 4 weeks of the study period (Visit 3 to 5, not 
including the day of Visit 5) and separately for the last 4 weeks of the study period (Visit 5 to 7, 
including the day of Visit 5). Note that if a patient misses returning pills at Visit 4 or Visit 5, 
there will be an issue calculating compliance for the active treatment period and alternate 
methods for calculating compliance may be considered. For patients who discontinue early, time 
after the penultimate visit will be excluded for calculation of treatment compliance. For example, 
if a patient discontinued early at Visit 6, treatment compliance will be derived only from data 
collected through Visit 5. Comparisons between treatment group for treatment compliance will 
be performed using Fisher exact test. Listings for treatment compliance of individual patients by 
treatment period will also be provided. 
Depending on the level of observed treatment compliance, and where appropriate, sensitivity 
analyses of primary or key secondaries may be conducted by excluding patients with poor 
treatment compliance. 
6.9. Concomitant Therapy and eCOA Compliance 
The summary and reporting of concomitant therapy and eCOA compliance has been described in 
the CPMP SAP Version 5. No additional covariates will be considered in the model of weekly 
rescue medication use. 
Concomitant therapy will be reported for the first 4 weeks of the double-blind period (active-
treatment phase) and separately for the entire 8 weeks of the double-blind period. 
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6.10. Efficacy Analyses 
6.10.1. Primary Outcome and Methodology 
The analysis of the primary outcome has been described in the CPMP SAP Version 5. The 
longitudinal model will include API-NRS during the preliminary data-entry period (PDEP, last 
7 days prior to randomization at Visit 3) and within each nominal week of the double-blind 
treatment period as a longitudinal outcome. As noted in Section 4.1, the endpoint for the primary 
analysis is defined as 4 weeks post initial treatment administration. 
Calculation of the weekly or biweekly time intervals used for analysis of weekly or biweekly 
mean scores from the eCOA device will follow the algorithm described in the 
Study CPMP SAP Section 6.12.1, except that the end of the final interval will be determined 
based on the last visual analog scale (VAS) result collection date or the last scheduled visit start 
date if VAS results are missing for the last scheduled visit. 
6.10.2. Additional Analyses of the Primary Outcome 
Borrowing placebo information by pooling from Studies H0P-MC-OA01 and H0P-MC-OA03 
for the evaluation of treatment effect on the mean change from baseline of API-NRS (and 
secondary outcomes of worst pain intensity as measured by the NRS, WOMAC® pain subscale, 
and VAS) will be performed following the description in CPMP SAP Version 5, Section 6.12.1. 
Descriptive statistics of primary outcome variables by demographics, disposition, disease 
characteristics, and treatment administration may be summarized by ISA to examine the 
population homogeneity assumption between ISAs. 
6.10.3. Secondary Efficacy Analyses 
Secondary efficacy analyses common to all ISAs within CPMP have been described in the 
CPMP SAP Version 5. Unless otherwise specified, the time point for secondary endpoint 
measurements is the same as that for the primary endpoint. Study OA02 will also consider the 
following secondary analyses. 
The Western Ontario and McMaster Universities Osteoarthritis Index (Bellamy 2005) is a 
validated instrument that is extensively used to evaluate the response to medications for the 
treatment of osteoarthritic pain. The WOMAC® version LK3.1 will be administered according to 
the Schedule of Activities. 
This 24-question WOMAC® and its subscales are described as follows. 
Dimensions/Subscales 
Number of Questions 
pain 
5 
stiffness 
2 
physical function 
17 
 
The participants will record their responses using a 0 to 4 Likert scale for each question: 
 0 = no pain (or stiffness or difficulty), and 
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 4 = extreme pain (or stiffness or difficulty). 
The scores for each subscale will be calculated by summing the scores of the questions in the 
respective subscale for each participant at each time point. 
The range of possible scores for each subscale is pain = 0 to 20, stiffness = 0 to 8, and physical 
function = 0 to 68. 
6.10.3.1. Key Secondary Analysis 
A Bayesian longitudinal mixed-model repeated measures analysis (MMRM) will be performed 
to evaluate the change from baseline to each postbaseline visit for the WOMAC® pain subscale, 
physical function subscale, and stiffness subscale. The model will utilize the constrained cell 
means model so that a common mean is estimated at baseline. More details on this approach are 
provided in the CPMP SAP Version 5. 
Information included in the model is described as follows. 
Categorical factors 
 
the interaction of treatment and time point 
(constrained to estimate a common mean at 
baseline across treatments) 
 
average baseline pain severity category 
(baseline NRS < 7, baseline NRS ≥ 7) 
 
pooled investigative site 
Continuous covariates 
 
none 
Abbreviation: NRS = Numeric Rating Scale. 
 
6.10.3.2. Other Secondary Analysis 
The proportion of participants in each treatment group meeting prespecified binary response 
thresholds (30%, 50%, 70%) will be calculated for each postbaseline time point and will be used 
to compare treatment groups for WOMAC® pain and physical function subscales. 
A Bayesian pseudo-likelihood–based categorical repeated measures model will be used to 
estimate the proportion of participants in each treatment group meeting the prespecified 
threshold for each postbaseline time interval up to Week 4 (or visit up to Visit 5) and separately 
up to Week 8 (or visit up to Visit 7). These estimates will be used to compare treatment groups. 
More details on this approach are provided in the CPMP SAP Version 5. 
The model will include the categorical and continuous covariates described for the key 
secondary analysis. 
In addition, time to first treatment response from baseline based on the prespecified binary 
thresholds above will be assessed. Analyses will be conducted according to the time to event 
analyses specified in the CPMP SAP Version 5. 
6.11. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods 
The observed plasma concentrations for LY3526318 over time will be reported in tabular format 
using descriptive statistics and graphically using individual and mean concentration time plots. 
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Nominal protocol time will be used for the descriptive summary and mean plot and actual time 
for the plots of individual data. 
Additional analyses may be conducted as deemed necessary on review of the data. For example, 
graphical and/or model-based pharmacokinetic (PK) and PK-pharmacodynamic (PD) analyses to 
explore exposure-response relationships for safety and/or efficacy may be conducted. Data from 
this study may be pooled with data from other studies if appropriate. 
6.12. Safety Analyses 
The general analysis of safety has been described in the CPMP SAP Version 5. However, 
additional ISA-specific safety considerations are described in the sections below. 
6.12.1. Extent of Exposure 
Duration of exposure (defined as time since first dose of study treatment to last dose of study 
treatment in days) to study drug will be summarized by treatment group using descriptive 
statistics; the summary will also include the total exposure in patient years. Extent of exposure 
will be reported separately for the first 4 weeks (active treatment) and the last 4 weeks (post–
active treatment) of the double-blind period. All patients will receive placebo starting the day of 
Visit 5. 
Duration of exposure (days): 
 For the first 4-week, active-treatment period: 
= Date of last dose during the active treatment period – Date of first dose for the active 
treatment period + 1. 
 For the last 4-week, post–active-treatment period: 
= Date of last dose during the post–active-treatment period – Date of first dose for the 
post–active-treatment period + 1.  
Total exposure in patient years will be calculated as follows: 
Total exposure in patient years = Sum of duration (days) of exposures for all patients in the 
treatment group/365.25. 
6.12.2. Adverse Events 
The general analysis of AEs has been described in the CPMP SAP Version 5. 
This ISA will report TEAEs for the first 4 weeks as well as post–treatment-emergent AEs 
(PTEAEs) for the last 4 weeks of the double-blind period. For TEAEs in the first 4 weeks of the 
double-blind period (active-treatment phase), the baseline will be prior to the first dose date. 
A PTEAE is defined as an event that first occurs or worsens in severity after the active-treatment 
phase (after Visit 5) and on or before study discontinuation. The Medical Dictionary for 
Regulatory Activities (MedDRA) Lowest Level Term (LLT) will be used in the post–treatment-
emergent computation. The maximum severity for each LLT during the active-treatment period 
(Visits 3 to 5) will be used as a reference. 
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The baseline of PTEAE is from the first dosing date to Visit 5. The post–active-treatment phase 
(after Visit 5) will be included as postbaseline for this analysis. While unusual, it is possible to 
have a missing severity for events. For an event with a missing severity during the baseline 
period, it will be treated as “mild” in severity for determining post–active-treatment emergence. 
Events with a missing severity during the post–active-treatment period will be treated as 
“severe,” and PTEAEs will be determined by comparing with the active-treatment period. 
PTEAEs will be summarized by Preferred Term and by Preferred Term within System Organ 
Class in participants who received LY3526318. 
6.12.3. Deaths, Other Serious Adverse Events, and Other Adverse 
Events for Review 
Treatment-emergent AEs by Preferred Term will be reported. 
The full summary of AEs is described in the CPMP SAP Version 5. 
6.12.4. Clinical Laboratory Evaluation 
The general analysis of laboratory parameters is described in the CPMP SAP Version 5. 
In this ISA, laboratory results will be reported for the first 4-week, active-treatment period and 
separately for the entire 8-week study period. 
Study OA02 will also consider the following analyses of laboratory analytes used to assess renal 
function. The planned summaries for these analytes are the same as those that have been 
described in the CPMP SAP; however, the reporting of these analytes will be separate from the 
general analysis of laboratory parameters. 
 Renal data analyses: 
o Serum creatinine (change from baseline in mg/dL) 
o Estimated glomerular filtration rate (eGFR; Chronic Kidney Disease 
Epidemiology Collaboration [CKD-EPI] algorithm using serum creatinine). 
Algorithm provided by the central laboratory. 
o For eGFR calculation, we will summarize shift tables of eGFR changes for 
baseline versus postbaseline by minimum, maximum, and last observed eGFR 
result. 
i. 
Category 1: Normal or increase in GFR (≥90 mL/min/1.73 m2) 
ii. 
Category 2: Mild reduction in GFR (60 to 89 mL/min/1.73 m2) 
iii. 
Category 3a: Moderate (a) reduction in GFR 
(45 to 59 mL/min/1.73 m2) 
iv. 
Category 3b: Moderate (b) reduction in GFR 
(30 to 44 mL/min/1.73 m2) 
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v. 
Category 4: Severe reduction in GFR 
(15 to 29 mL/min/1.73 m2) 
vi. 
Category 5: Kidney failure (GFR < 15 mL/min/1.73 m2 or 
dialysis) 
Abnormal eGFR is specified below and will be summarized in the laboratory summary tables: 
 Abnormal low: <90 mL/min/1.73 m2 
 Abnormal high: as specified by the central laboratory. 
6.12.5. Vital Signs and Other Physical Findings 
The analysis of vital sign parameters is described in the CPMP SAP Version 5. 
Vital signs will be reported for the first 4-week, active-treatment period and separately for the 
entire 8-week study period. 
6.12.6. Electrocardiograms 
The analysis of electrocardiogram parameters is described in the CPMP SAP Version 5. 
Electrocardiogram findings will be reported for the first 4-week, active-treatment period and 
separately for the entire 8-week study period. 
6.12.7. Suicidal Ideation or Behavior 
Reporting of suicidal ideation or behavior through the Columbia Suicide-Severity Rating Scale 
(CSSRS) has been described in the CPMP SAP Version 5. The CSSRS results will additionally 
be reported separately for the first 4-week, active-treatment period. 
6.13. Subgroup Analyses 
General subgroup analyses are described in the CPMP SAP Version 5. 
Study OA02 will also consider the following subgroup analyses for the primary efficacy 
outcome and key secondary outcome. 
Subgroup Variable 
Categories 
Kellgren-Lawrence Grade 
Categories: Grade 2, Grade 3, Grade 4  
Note: Alternative groupings may be created based on 
the number of participants classified within each 
grade (for example, <3, ≥3) 
 
The subgroup analyses will be conducted using similar modeling approaches as the primary and 
key secondary analyses. Additional factors in the model are described in the CPMP SAP 
Version 5. The treatment difference at the endpoint will be reported within each level of the 
subgroup factor along with 95% credible intervals. Frequentist MMRM may be performed as a 
sensitivity analysis using the modeling approach described in the CPMP SAP Version 5. 
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H 0 P -M C -O A 0 2  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 5 2 6 3 1 8  
6. 1 4.  Pr ot o c ol D e vi ati o n s  
Patie nts wit h st u d y -i m p orta nt pr ot oc ol de viati o ns will be s u m marize d b y t y pe of de viati o n a n d 
liste d b y treat me nt a n d i n vesti gati ve site. 
I m p ort a nt pr ot oc ol de viati o ns f or t he st u d y are d es cri be d i n t he C P M P a n d O A 0 2 Trial Iss ue 
Ma na ge me nt Pla ns.  
6. 1 5.  I nt eri m A n al y s e s a n d D at a M o nit ori n g 
Safet y re vie w will be c o n d ucte d u n der t he a us pices of a n Assess me nt C o m mittee acc or di n g t o  
t he s pecificati o ns set f ort h i n t he pr ot oc ol. T hese a nal yses will be at t he C P M P le vel a n d will 
c o nsi der data fr o m all o n g oi n g I S As. Det ails are pr o vi de d i n t he C P M P S A P  Versi o n 5 . 
I nteri m a nal yses are pla n ne d f or St u d y  O A 0 2  t o b e c o n d ucte d w he n 6 0 % of pa tie nts ha ve 
c o m plete d t he 4 -w ee k , acti ve-treat me nt peri o d. Details of t he i nteri m a nal ysis ca n be f o u n d i n 
t he Statistical A nal ysis Ce nter ( S A C ) S A P.  T he i nteri m a nal ysis will be c o n d ucte d b y a n 
i n de pe n de nt Assess me nt C o m mittee ( A C), a n d t he  A C will disse mi nate i nteri m  res ults, if 
necessar y, i n a ma n ner t h at will n ot affect t he c o n d uct of t he o n g oi n g st u d y.  
6. 1 6.  Pl a n n e d E x pl or at or y A n al y s e s  
T he f oll o wi n g a nal yses ma y b e c o n d uct e d f or e x pl orat or y p ur p oses:  
6. 1 7.  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 f or safet y a n al ysis has bee n briefl y descri be d i n t he C P M P S A P  
Versi o n 5. T his ma y be re p orte d f or a n y of t he acti ve-treat me nt peri o d, p ost– acti ve-treat me nt 
peri o d, a n d e ntire 8 -wee k st u d y peri o d. T h e ke y safet y e ve nts t o be c o nsi dere d f or St u d y O A 0 2 
are liste d bel o w b y d o mai n. 
Ge ner al a d verse ev e nt inf or m ati o n : 
 Seri o us a d verse e ve nts r elate 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 d verse e ve nt  
 Treat me nt disc o nti n uati o n d ue t o a d verse e ve nt . 
C ar di o v asc ul ar : 
 Q Tc  pr ol o n gati o n: > 6 0 msec i ncrease  
 Seri o us car diac dis or ders a d verse e ve nt . 
Li ver f u ncti o n : 
 H y’s La w case: Ser u m t otal bilir u bi n ( T B L) ≥2 U p per li mit n or mal ( U L N) a n d at least 
o ne of t he f oll o wi n g  2 c o n diti o ns : 
o  Ala ni ne ami n otra nsf eras e ( A L T ) ≥3 U L N f or at least o ne visit 
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o Aspartate aminotransferase (AST) ≥3 ULN for at least one visit. 
 DILI (drug-induced liver injury): At least one of the following 2 conditions: 
o Hy’s Law 
o ALT ≥5 ULN for at least one visit. 
Metabolic function: 
 Serious hypoglycemia adverse event 
 Treatment emergent HbA1c: Shift from low/normal at baseline to high at least once. 
Renal function: 
 Treatment-emergent abnormal eGFR: Shifts 
 Mild at baseline to moderate/severe 
 Moderate at baseline to severe. 
6.18. Annual Report Analyses 
Analyses will be produced as needed for the purposes of providing periodic safety reviews to 
regulatory agencies (for example, Development Safety Update Reports). Data from this ISA will 
be combined with data from other clinical studies that investigated LY3526318. In all analyses, a 
combined LY arm will be created, which will include participants assigned to any dose of 
LY3526318 in the included studies, including LY-combination regimens. 
The following data will be summarized by treatment group: 
 enrollment (ongoing and completed) 
 demographics (race, ethnicity, and gender) 
 exposure: 
o cumulative number of subjects exposed to LY3526318 
o cumulative number of subjects exposed to LY3526318 by age 
o cumulative number of subjects exposed to LY3526318 by sex 
o cumulative number of subjects exposed to LY3526318 by race 
 cumulative summary of serious AEs. 
The following listings will be provided. 
 list of serious AEs during the reporting period 
 list of subjects who died 
 cumulative list of subjects who discontinued because of an AE (discontinued 
treatment or study) 
 list of subjects who discontinued due to an AE during the reporting period. 
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Additional analyses may be added or omitted at the time of report submission as needed. 
6.19. Clinical Trial Registry Analyses 
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements. 
Analyses provided for the CTR requirements include the following: 
Summary of AEs will be provided as a dataset that will be converted to an XML file. 
Both “Serious” AEs and “Other” AEs are summarized by treatment group and by 
MedDRA Preferred Term. 
 A serious AE is an AE that is considered “Serious” whether or not it is 
treatment emergent. 
 An AE is considered in the “Other” category if it is both a TEAE and is not 
serious. For each “Serious” AE and “Other” AE, for each term and treatment 
group, the following are provided: 
o the number of participants at risk of an event 
o the number of participants who experienced each event term 
o the number of events experienced. 
 Consistent with www.ClinicalTrials.gov requirements, “Other” AEs that occur 
in fewer than 5% of participants in every treatment group may not be included 
if a 5% threshold is chosen (5% is the minimum threshold). 
 
AE reporting is consistent with other document disclosures, for example, the 
CSR and manuscripts. 
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7. Unblinding Plan 
The general unblinding plan is described in the CPMP SAP Version 5 and in the Study CPMP 
Blinding and Unblinding Plan Version 1. Unblinding considerations specific to Study OA02 are 
provided below. 
7.1. PKPD Analysis Planning 
A limited number of prespecified individuals who are not part of the blinded study team and do 
not have direct site contact, data entry, or data validation responsibilities may receive access to 
unblinded data prior to an interim or final database lock in order to initiate the PK and/or PKPD 
model development processes. This will be described in the unblinding plan. Information that 
may unblind the study during the analyses will not be reported to study sites or the blinded study 
team until the study has been unblinded. 
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8. References 
Bellamy N. The WOMAC Knee and Hip Osteoarthritis Indices: development, validation, 
globalization and influence on the development of the AUSCAN Hand Osteoarthritis Indices. 
Clin Exp Rheumatol. 2005;23(5 suppl 39):S148-S153. 
 
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Si g nat ure Pa ge f or V V- C LI N- 0 6 0 0 4 5 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 6 0 0 4 5 v 1. 0
A p pr o val
1 3-J u n- 2 0 2 2 1 4: 4 1: 1 9 G M T + 0 0 0 0
A p pr o ve d o n 1 3 J u n 2 0 2 2 G M T
P P D