Clinical trial NCT05177094
Conditions: Diabetic Peripheral Neuropathic Pain
Sponsor: Eli Lilly and Company
Start date: 2022-01-26; Completion date: 2022-10-13
Enrollment: 155 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test the safety and efficacy of study drug LY3526318 for the treatment of diabetic peripheral neuropathic pain (DPNP). 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 milligram (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_000.pdf: 
This study H0P-MC-NP02 (NCT05177094) is a sub-study of Master Protocol H0P-MC-CPMP 
(NCT05986292) 
Protocol: H0P-MC-NP02(a) 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3526318 for the 
Treatment of Diabetic Peripheral Neuropathic Pain
NCT05177094 
Approval Date: 30-Sep-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 -N P 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 -N P 0 2
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 Dia bet ic Peri p heral Ne ur o pat hic Pai n
I S A N u m ber: H 0 P -M C -N P 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 : N P 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: 3 0- S e p- 2 0 2 1 G M T


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP02(a)
2
Medical Monitor Name and Contact Information will be provided separately.


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 -N P 0 2 (a)
3
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
Ori gi n al Pr ot o c ol
0 4 -J u n -2 0 2 1
A me n d me nt [ a] 
O ver all R ati o n ale f or t he A me n d me nt:
T his a me n d me nt a d dresses c ha n ges i n t he e xcl usi o n cri t eria i n res p o nse t o F D A fee d bac k base d 
o n i n vitr o data c urre ntl y a vaila ble .
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
2. 2 . Bac k gr o u n d
U p date d p har mac o ki netics secti o n 
wit h t he latest i nf or mati o n. 
C orrecti o n t o ali g n wit h t he latest i nf or mati o n.
2. 3 . Be nefit/ Ris k 
Assess me nt
A d de d s u b -secti o n hea ders.
F or clarit y.
2. 3. 1. Ris k 
Assess me nt
I n first para gra p h, a d de d te xt f or t he 
effect of L Y 3 5 2 6 3 1 8 o n ot her dr u gs.
Clarificati o n of t he p ote ntial of L Y 3 5 2 6 3 1 8 
e x p os ure t o affect meta b olis m of ot her dr u gs.
U p date d first b ullet t o s pecif y 
C Y P 3 A 4, pl us mi n or e dit o rial 
c ha n ges.
F or clarit y.
A d de d a b ullet f or C Y P 3 A 4 a n d p -
gl yc o pr otei n ( P -g p) s u bstrates.
Base d o n i n vitr o data s u g gesti n g a p ote ntial f or 
P K i nteracti o ns.
5. St u d y P o p ulati o n
U p date d n u m bers f or i ncl usi o n a n d 
e xcl usi o n criteria.
T o ali g n wit h master pr ot oc ol a n d I S A 
n u m beri n g s yste m.
5 . 2. E xcl usi o n 
Criteria
U p date d E xcl usi o n C riteri o n # 3 0 5 1 t o 
s pecif y dr u gs ta ke n orall y or 
i ntra ve n o usl y.
T o pical dr u gs are all o we d.
A d de d E xcl usi o n C riteri o n # 3 0 5 4 f or 
partici pa nts t hat are ta ki n g dr u gs t hat 
are se nsiti ve C Y P 3 A 4 s u bstrates wit h 
a narr o w t hera pe utic i n de x .
Base d o n i n vitr o data s u g gesti n g p ote ntial 
C Y P 3 A 4 i n hi biti o n at t he pr o p ose d 
L Y 3 5 2 6 3 1 8 d ose.
A d de d E xcl usi o n C riteri o n # 3 0 5 5 f or 
partici pa nts t hat are ta ki n g si m vastati n 
at d oses greater t ha n 2 0 m g/ da y .
Si m vastati n is a se nsiti ve C Y P 3 A 4 s u bstrate, 
wit h a pr ojecte d ma xi mal i ncrease i n e x p os ure 
< 2 -f ol d i n c o m bi nati o n wit h L Y 3 5 2 6 3 1 8. 
T heref ore, d oses of 2 0 m g or less are 
c o nsi dere d safe.
A d de d E xcl usi o n C riteri o n # 3 0 5 6 f or 
partici pa nts t hat are ta ki n g di g o xi n .
Base d o n i n vitr o data s u g gesti n g a p ote ntial f or 
L Y 3 5 2 6 3 1 8 t o i n hi bit P -g p.
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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 -N P 0 2 (a)
4
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
6. 6. C o nc o mita nt 
T hera p y
U n der P ote ntial Dr u g -Dr u g 
I nteracti ons wit h L Y 3 5 2 6 3 1 8, a d de d 
refere nce t o Secti o n 5. 2 f or 
c o nc o mita nt me dicati o n restricti o ns.
Refere nce t o a d d e xcl usi o n criteria.
1 0. 3. A p pe n di x 3: 
List of E xcl u de d 
C o nc o mita nt 
Me dicati o ns
A d de d refere nce t o Secti o n 5. 2 a n d 
t he Ma n ual of O perati o ns f or 
a d diti o nal i nf or mati o n.
F or clarit y .
T hr o u g h o ut t he 
pr ot oc ol
Mi n or e dit orial a n d f or mat c ha n ges.  
Mi n or, t heref ore n ot descri be d.
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CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP02(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 ............................................................................................14
2.3.1.
Risk Assessment.........................................................................................................15
2.3.2.
Benefit Assessment.....................................................................................................15
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...........................................................20
6.
Study Intervention(s) and Concomitant Therapy ...................................................21
6.1.
Study Intervention(s) Administered ............................................................................21
6.2.
Preparation, Handling, Storage, and Accountability....................................................21
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................21
6.4.
Study Intervention Compliance...................................................................................21
6.5.
Treatment of Overdose ...............................................................................................22
6.6.
Concomitant Therapy .................................................................................................22
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................23
8.
Study Assessments and Procedures .........................................................................24
8.1.
Efficacy Assessments .................................................................................................24
8.2.
Safety Assessments ....................................................................................................24
8.2.1.
Physical Examinations................................................................................................24
8.2.2.
Electrocardiograms.....................................................................................................24
8.2.3.
Clinical Safety Laboratory Tests.................................................................................24
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints .................................................................................................................24
8.4.
Pharmacokinetics........................................................................................................24


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 -N P 0 2 (a)
6
8. 5.
P har mac o d y na mics .....................................................................................................2 5
9.
St atistic al C o nsi der ati o ns .........................................................................................2 6
9. 1.
Stati stical H y p ot heses................................................................................................. 2 6
9. 2.
A nal yses Sets .............................................................................................................2 6
9. 3.
Stati stical A nal yses .....................................................................................................2 6
9. 3. 1.
Ge neral C o nsi derati o ns ...............................................................................................2 6
9. 3. 2.
E x pl or at or y  E n d p oi nt(s) A nal ysis ...............................................................................2 6
9. 3. 3.
S af et y A nal yses ..........................................................................................................2 6
9. 3. 4.
Ot her A nal yses ...........................................................................................................2 6
9. 4.
I nteri m A nal ysis .........................................................................................................2 7
9. 5.
S a m ple Si ze Deter mi nat i on .........................................................................................2 7
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 8
1 0. 1.
A p pe n di x 1: Cli nical La b orat or y  Tests........................................................................2 8
1 0. 2.
A p pe n di x 2: C o ntrace pti ve a n d Barrier G ui da nce .......................................................2 9
1 0. 2. 1.
Defi nit i ons ..................................................................................................................2 9
1 0. 2. 2.
C o ntra ce pti o n G ui da nce ..............................................................................................3 0
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 3
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 6
1 0. 5.
A p pe n di x 5: A b bre viat i ons .........................................................................................3 9
1 1.
Refere nces .................................................................................................................4 2
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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 -N P 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  di a bet ic peri p heral ne ur o pat hic 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 decreasi n g dia bet ic 
p eri p heral  ne ur o pat hi c pai n (D P N P ). 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 a n k yrin 1, a calci u m per mea ble n o nselect i ve cati on c ha n nel t hat 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 mati on . 
Data will be c ollecte d t o assess t he safet y a n d t o lera 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 e x plore d. T he t otali t 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 velo p me nt of L Y 3 5 2 6 3 1 8.
O bjecti ves a n d E n d p oi nts :
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 t he D P N P disease -state a d de n d u m ( D S A; H 0 P-M C -C P M P[ 3 ]).
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 D P N P .
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 a r tici p a nts:
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 Gro u ps a n d D ur ati o n:
T his st u d y  incl u des a n 8 -wee k d o u ble -bli n d treat me nt peri o d.
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
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CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP02(a)
8
Safety reviews are covered by the Assessment Committee charter for the Chronic Pain Master 
Protocol.


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP02(a)
9
1.2.
Schema
Abbreviations: PDEP = preliminary data entry period; V = visit.
* Medication washout and PDEP begins.
** Randomization to either LY3526318 or placebo. 


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 -N P 0 2 (a)
1 0
1. 3.
Sc he d ule of Acti vities ( S o A)
T his S o A s h o ws visits a n d pr oce d ures u ni q ue t o t he i nter ve nt i on- s pecific a p pe n di x (I S A) H 0 P -M C -N P 0 2 f or L Y 3 5 2 6 3 1 8. Please refer 
t o t he C P M P Master Pr ot oc ol
a n d t he D P N P D S A C P M P( 3 ) S o As f or a d diti onal i nf or mati o n. 
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 h ysical e xa mi nati o n
X
X
X
X
S y m pt o m d irect e d p h ysical e xa m (see Secti o n 
8. 2. 1 ) at V 5, V 7, a n d E D (if a p plica ble).
Vital si g ns
X
X  
X  
X  
X
X
At V 3 , vitals s h o ul d be ta ke n pre d ose a n d at 
a p pr o xi matel y 2 a n d 4 h o urs p ost d osi n g. 
At V 4, V 5, V 6, a n d V 7 , vitals s h o ul d be ta ke n 
pre d ose.
P ulse rate, res pirat or y rate, bl o o d press ure, a n d 
te m perat ure ta ke n wit h partici pa nt i n a sitti n g 
p ositi o n.
E C G
X
X
X
Si n gle E C Gs at V 5, V 7, a n d E D (if a p plica ble).
St u d y i nter ve nti o n
X
X  
X  
X  
X
See Secti o n 6. 1 .
I nter ve nti o n 
c o m plia nce
X  
X  
X  
X
X
Sc ales, Q uesti o n n aires , a n d O utc o me Me as ures
Cli nic al L a b or at or y Tests a n d S a m ple C ollecti o n
He mat ol o g y
X  
X  
X  
X
C he mistr y
X  
X  
X  
X
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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 -N P 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
Li pi d pa nel
X  
X  
X  
X
Uri nal ysis
X
Uri ne pre g na nc y
X
X  
X  
X  
X
X
F or all W O C B P
at V 3: c ollect sa m ple bef ore 
d osi n g .
Uri ne dr u g scree n
X
X
X
X
See Secti o n 5. 3. 2 .
H b A 1c
X
X
X
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; 
p artici 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 -V 7 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 S A = i nter ve nti o n-s pecific 
a p pe n di x; N R S = n u merical rati n g scale ; PI = pr i nci pal i n vesti gat or; P K = p har mac o ki netic; V = visit ; 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 -N P 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 -N P 0 2 ( N P 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 Pr 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 m aster 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 
di a bet ic p eri p h er al  ne ur o pat hic pai n (D P N P ) disease-state a p pe n di x ( D S A) C P M P(3 ) a n d t his 
I S A N P 0 2. 
2. 1.
St u d y R ati o n ale
T he p ur p ose of t his st u d y  is t o test w het her L Y 3 5 2 6 3 1 8 is efficaci o us i n decreasi n g D P N P . Data
will be c o llecte d t o assess t he safety a n d t olera bility of  L Y 3 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 (P K ) pr o perti es will als o be e x pl ore d . T he t otalit y of  data fr o m t his pr o of-of  
c o nce pt ( 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) i o 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 o f 
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; Ma at 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 val 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
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 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 m ulti ple o nce-dail y  oral d oses f or 1 4 da ys.
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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 -N P 0 2 (a)
1 3
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 oml 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 
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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 -N P 0 2 (a)
1 4
P h ar m ac o d y n a mics
S afet y
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 ulat i 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 oll owi n g si n gle or m ul tiple Q D 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
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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 -N P 0 2 (a)
1 5
2. 3. 1.
Ris k Assess me nt
St u d y I nter ve nti o n
M ore i nf or mat i on a b o ut t he k n o w n a n d e x pecte d ris ks, S A Es, a n d reas o na bl y a ntici pate d 
A Es of L Y 3 5 2 6 3 1 8 ma y b e f o u n d i n t he I B. I nf or mat i on o n A Es e x pecte d t o be relate d t o t he 
i n vesti gati onal pr o d uct ma y be f o u n d i n Sect i on 7 ( Refere nce Safet y  I nfor m at i on f or 
Assess me nt of  E x pecte d ness of Seri o us A d verse Reacti o ns ) of t he I B. I nf or mati o n o n S A Es 
t hat are e x pecte d i n t he st u d y p o p ulat i on i n de pe n de nt of dr u g e x p os ure will be assesse d b y 
t he s p o ns or in a g gre gate, peri o dicall y d uri n g t he c o urse of t he st u d y , a n d ma y be fo u n d i n 
Secti o n 5 ( Effects i n H u ma ns) of t he I B.
2. 3. 2.
Be nefit Assess me nt
P ote nti al be nefits for t he st u d y  p artici pa nts i ncl u de 

inf or m at i on o btai ne d fr o m st u d y-relate d me dical pr oce d ures 
o
p h ysical e xa mi nat i ons 
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CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP02(a)
16
o
laboratory tests 
o
ECGs 

detailed evaluations of diabetic nerve pain 

questionnaires that may improve participants understanding their own condition. 
As part of Study CPMP, participants to this ISA will report their experience using standard tools 
that may contribute to the assessment of novel treatments for DPNP. In addition, data collected 
from this study may also improve our understanding of DPNP pathogenesis. Both of which may 
lead to the development of new treatment with improved safety and efficacy profile compared to 
standard of care. 
2.3.3. Overall Benefit Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with LY3526318 are justified by the 
anticipated benefits that may be afforded to participants with DPNP.


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 -N P 0 2 (a)
1 7
3.
O bje cti ves a n d E n d p oi nts
T he C P M P Master Pr ot oc ol a n d D P N P D S A C P M P( 3 ) incl u de o bj ect i ves a n d e n d p oi nts 
a p plica ble f or t his st u d y. T his ta ble descri bes o bjecti ves a n d e n d p o i nts s pecific f or L Y 3 5 2 6 3 1 8.
O bjecti ves
E n d p oi nts
Terti ar y/ E x pl or at or y
Meas ure
t he P K of L Y 3 5 2 6 3 1 8 i n partici pa nts wit h 
D P N P .
Meas ure
of plas ma c o nce ntrati o ns of L Y 3 5 2 6 3 1 8 t o 
e na ble P K e val uati o ns.
A b bre viati o ns: D P N P = dia betic peri p heral ne ur o pat hic pai n ; N R S = N u meric Rati n g Scale ; P K = p har mac o ki netic .
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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 -N P 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 N P 0 2 f or L Y 3 5 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( 3) . 
D o u ble -B li 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 N P 0 2 baseli ne pr oce d ures ,
 
 

parti ci pa nts recei ve t heir or al st u d y int er ve nt i on 

t he sit e c ollects partici pa nts vit als at 2 a n d 4 h o urs after t he c o m plet i 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 r estrict 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 ( n ot a p plica ble f or V 7) 

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 disc har ge ( n ot a p plica ble f or V 7).
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
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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 -N P 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.
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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 -N P 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 D P N P C P M P( 3 ) D S A pr o vi de eli gi bility cri t eria t hat must be 
f oll owe d f or t hi s st u d y. L Y 3 5 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 o f t he fol l owi n g criteria a p pl y:
[ 3 0 5 0]
Are 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 N P 0 2 Secti o n 1 0. 2 , A p pe n di x 2.
5. 2.
E xcl usi 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:
 
 
[3 0 5 2]
H a 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.
[3 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 d a 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 ne dr u g scree n will n ot be c o nsi dere d illicit u se 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.
5. 3. 3.
Re pr o d ucti ve a n d C o ntr ace pti o n Re q uire me nts
Re pr o d ucti ve re q uire me nts a n d c o ntrace pti ve g ui da nce are pr o vi de d i n Sect i on 1 0. 2 ,
A p pe n di x 2 . 
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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 -N P 0 2 (a)
2 1
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  int er ve nt i on is defi ne d as a n y i n vesti gati onal i nter ve nt i on(s), m ar kete d pr o d uct(s), 
pl ace b o, or me 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 int er ve nti o n(s) at h o me, c o m plia nce wit h st u d y  
i nter ve nt i on will be assesse d at eac h visit. C o m 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 nt s 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.
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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 -N P 0 2 (a)
2 2
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 onit 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 .
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 dit ies 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 eli gi bilit y criteria. 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.
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CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP02(a)
23
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
The CPMP Master Protocol and CPMP(3) DSA provides the reasons and procedures for 
discontinuation of intervention and participant discontinuation that must be followed for this 
study. 


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 -N P 0 2 (a)
2 4
8.
St u d y Assess me nt s a n d Pr oce d ures
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he C P M P Master Pr ot oc ol , D P N P
C P M P( 3) D S A, a n d I S A N P 0 2 S o As. 
L Y 3 5 2 6 3 1 8- s pecific assess me nts a n d pr oce d ures are descri be d here.
8. 1.
Effic ac y Assess me nts
Pl a n ne d ti me p o i nts f or all efficac y assess me nts are pr o vi de d i n t he S o As.
8. 2.
S afet y Assess me nts
Pl a n ne d ti me p o i nts f or all safety assess me nts are pr o vi de d i n t he S o As. 
8. 2. 1.
P h ysic al E x a mi n ati o ns
S y m pt o m -di recte d p h ysical e xa mi nat i ons of s ki n, e y es, mo ut h, l u n gs, a n d gastr oi ntesti nal tract 
will be perf or me d at eac h visit as descri be d i n t he S o A. A n y cli nicall y si g nifica nt a b n or mal 
p h ysical e xa mi nat i on fi n di n gs will be re p orte d as A Es. 
8. 2. 2.
El ectr oc ar di o gr a ms
Si n gle 1 2 -lea d E C G will be o btai ne d as o utli ne d i n t he S o A usi n g a n E C G mac hi ne t hat 
a ut o mat icall y calc ulates t he heart rate a n d meas ures P R , R R, Q R S, Q T, a n d Q Tc F i nter vals.
8. 2. 3.
Cli nic al S afet y L a b or at or y Tests
See N P 0 2 Secti o n 1 0. 1 ( A p pe n di x 1) f or t he list of cli nical la b orat or y tests t o be perf or me d a n d 
t o t he S o A f or t he ti mi n g a n d fre q ue nc y f or I S A N P 0 2. 
8. 3.
A d verse E ve nts , Seri o us A d verse E ve nts , a n d Pr o d uct C o m pl ai nts
See t he C P M P Master Pr ot oc ol f or a d dit i onal details .
8. 4.
P h ar m ac o ki netics

Bl o o d sa m ples will be c ollecte d f or meas ure me nt of pl as ma c o nce ntrati o ns of 
L Y 3 5 2 6 3 1 8 as s pecifie d i n t he S o A. 
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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 -N P 0 2 (a)
2 5

A ma xi m u m of  3 sam ples ma y be c ollecte d at a d diti o nal t i me p oi nts d uri n g t he st u d y if 
warra nte d a n d a gree d u p o n bet wee n t he i n vest i gat or a n d t he s p o ns or. T he ti mi n g of  
sa m pli n g ma y be al tere d d uri n g t he c o urse of t he st u d y base d o n ne wl y a vaila ble data 
(e. g., t o o btai n data cl oser t o t he ti me of pea k plas ma c o nce ntrati o ns) t o e ns ure 
a p pr o priate m o nit ori n g. 

I nstr uctio ns f or t he c ollect i on a n d ha n dli n g of bi o l o gical sa m ples will be pr o vi de d b y t he 
s p o ns or. T he act ual date a n d ti me ( 2 4- h o ur cl oc k ti me) of eac h sa m ple will be rec or de d.

T he date a n d ti me ( 2 4 -h o ur cl oc k 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 Visit 3 a n d t he last 
at -h o me d ose pri or t o eac h of V isit 4, V isit 5, V isit 6, a n d V isit 7.

S a m ple s 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 
of  L Y 3 5 2 6 3 1 8 pl as ma c o nce ntratio n s ma y als o be use d t o e valuate safet y 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 mati 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 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 -N P 0 2 (a)
2 6
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 D P N P D S A C P M P( 3) pr o vi de statistical c o nsi derati o ns.
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.
 
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 Y 3 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 h a 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 statistical 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 or at or 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 descr i pti 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 P M P Master 
Pr ot oc ol  a n d D P N P D S A C P M P( 3 ). 
9. 3. 2.
E x pl or at or y E n d p oi nt(s) A n al ysis
E x pl orat o r 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 di tio n al  I S A-s pecific 
safety a nal yses ma y be descri be d i n t he I S A S A P. 
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 y ses
T he o bser ve d pl as 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.
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 -N P 0 2 (a)
2 7
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 ul at i on a nal ysis s o ftware, 
N O N M E M ® , if data allo w s. T he versio 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 war e 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 h ar 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 ma tio n t hat m a 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 oul 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 he y occ ur. 
9. 5.
S a m ple Size Deter mi n ati o n
U p t o a p pr o xi matel y 1 5 0 partici pa nts will be ra n d o mi ze d i n a 
 ratio 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  partici 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 pl ace b o a n d L Y 3 5 2 6 3 1 8 , t he pr o ba bility o f passi n g t he efficac y criteri o n 
s pecifie d a b o ve (i.e., false p ositi ve) is a p pr o xi matel y 0. 0 5. 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 nati o n was carrie d o ut i n F A C T S Versi o n 6. 0.
C CI
C CI
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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 -N P 0 2 (a)
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
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 diti o 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 N P 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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CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
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29
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 postmenopausal.
Examples of surgical sterilization include: hysterectomy, bilateral oophorectomy, 
or tubal ligation.
Postmenopausal 
state
The postmenopausal state should be defined as:
1.
A woman at any age at least 6 weeks postsurgical 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
Embryofetal 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.


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP02(a)
30
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
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
ISA: H0P-MC-NP02(a)
31
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
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 tables 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
ISA: H0P-MC-NP02(a)
32
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 -N P 0 2 (a)
3 3
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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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 -N P 0 2 (a)
3 4
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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 -N P 0 2 (a)
3 5
C CI


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP02(a)
36
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.


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 -N P 0 2 (a)
3 7
Re m ote visits
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 can 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, vita l si g ns, i nter ve nti 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 nabl 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 wit h a p plica ble l ocal re g ulat i 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 
wi t ho 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 acti o n is ta ke n:

Alt er nate deli ver y of st u d y int er ve ntio n s h o uld 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 xisti n g 
pr ot oc ol  r e 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 o n o f parti ci pa nt’s recei pt of st u d y s u p plies.
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CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
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38

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. 


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
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39
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.
DPNP
diabetic peripheral neuropathic pain
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


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
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40
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
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
Pharmacokinetic
PO
by mouth
PoC
proof-of-concept
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
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


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP02(a)
41
TRP
transient receptor potential
TRPA1
transient receptor potential ankyrin 1
WOCBP
women of childbearing potential


CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-NP02(a)
42
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


L e o  D o c u m e n t  I D  =  f 4 6 7 5 c 1 3 - b d 7 d - 4 b b 9 - 8 1 c e - d 1 6 e 3 7 5 0 4 1 9 6
A p p r o v a l  D a t e  &  T i m e :  3 0 - S e p - 2 0 2 1  1 3 : 2 4 : 4 5  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 a l  D a t e  &  T i m e :  3 0 - S e p - 2 0 2 1  1 7 : 2 3 : 3 6  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

SAP_001.pdf: 
This study H0P-MC-NP02 (NCT05177094) is a sub-study of Master Protocol H0P-MC-CPMP 
(NCT05986292) 
H0P-MC-NP02 StaƟsƟcal Analysis Plan Version 2 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3526318 for the
Treatment of Diabetic Peripheral Neuropathic Pain
NCT05177094 
Approval Date: 12-Jul-2022 


H0P-MC-NP02 Statistical Analysis Plan Version 2 
Page 1 
LY3526318 
1. Statistical Analysis Plan: 
H0P-MC-NP02: 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 for the Treatment of Diabetic Peripheral Neuropathic Pain 
This is a randomized, placebo-controlled, Phase 2 clinical trial to evaluate LY3526318 for 
the treatment of diabetic peripheral neuropathic pain.    
 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Protocol H0P-MC-NP02 
Phase 2 
Approved on 12 Jul 2022 GMT


H0P-MC-NP02 Statistical Analysis Plan Version 2 
Page 2 
LY3526318 
2. Table of Contents 
Section 
Page 
1. 
Statistical Analysis Plan: H0P-MC-NP02: 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 .......................................................................................................6 
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 ....................................................................................8 
6.5. 
Use of an “Efficacy Subset” of Participants .......................................................................8 
6.6. 
Participant Disposition .......................................................................................................8 
6.7. 
Participant Characteristics ..................................................................................................8 
6.8. 
Treatment Compliance .......................................................................................................9 
6.9. 
Concomitant Therapy and eCOA Compliance ...................................................................9 
6.10. Efficacy Analyses ...............................................................................................................9 
6.10.1. 
Primary Outcome and Methodology ..........................................................................9 
6.10.2. 
Additional Analyses of the Primary Outcome .........................................................10 
6.10.3. 
Secondary Efficacy Analyses ...................................................................................10 
6.11. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods ....................................12 
6.12. Safety Analyses ................................................................................................................12 
6.12.1. 
Extent of Exposure ...................................................................................................12 
6.12.2. 
Adverse Events ........................................................................................................12 
6.12.3. 
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ........................................................................................................13 
6.12.4. 
Clinical Laboratory Evaluation ................................................................................13 
6.12.5. 
Vital Signs and Other Physical Findings .................................................................14 
6.12.6. 
Electrocardiograms ..................................................................................................14 
Approved on 12 Jul 2022 GMT


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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 
8. 
References .............................................................................................................................19 
 
Approved on 12 Jul 2022 GMT


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3. Revision History 
Statistical analysis plan (SAP) Version 1 was approved prior to unblinding data for Study 
H0P-MC-NP02 (NP02).  
SAP Version 2 was approved prior to unblinding data for Interim lock. Major revisions included: 
 Section 6.9: language indicating that electronic Clinical Outcome Assessments (eCOA) 
compliance is described in the H0P-MC-CPMP SAP version 5 was added. 
 Section 6.15: added language to allow the planned interim analysis to additionally modify 
the final sample size and added flexible language that allows for multiple interim 
analyses to be conducted. 
 Section 6.17: clarified the definition of Hy’s Law and added a new endpoint under the 
Liver Function domain called drug-induced liver injury (DILI). 
 
Approved on 12 Jul 2022 GMT


H0P-MC-NP02 Statistical Analysis Plan Version 2 
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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 NP02. For Study NP02, 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 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 Study H0P-MC-CPMP (CPMP) SAP 
Version 5.  
Additional secondary endpoints specific to Study NP02 are listed below.  
Objective 
Endpoint Measure 
Other Secondary 
 
Physical Functioning 
Efficacy of LY3526318 
versus placebo  
 
Mean change from baseline to endpoint for the Brief Pain Inventory-Short 
Form (BPI-SF) for the  
o 
Mean interference score 
o 
Mean severity score 
o 
Individual severity scores 
o 
Individual interference scores 
 
Proportion of participants with reduction from baseline greater than or 
equal to 30%, 50%, and 70% on BPI-SF for the  
o 
Mean interference score 
o 
Mean severity Score 
o 
Individual severity scores 
o 
Individual interference scores 
 
Approved on 12 Jul 2022 GMT


H 0 P -M C -N P 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 6  
L Y 3 5 2 6 3 1 8  
4. 3.  E x pl or at or y O bj e cti v e s  
T he f oll o wi n g e x pl orat or y o bje cti ves a n d e n d p oi nts  are s pecific t o St u d y N P 0 2 . 
O bjecti ves  
E n d p oi nts  
Terti ar y/ E x pl or at or y  
 
Meas ure t he p har mac o ki netics  of L Y 3 5 2 6 3 1 8 i n 
partici pa nts wit h  D P N P  
Meas ure  of plas ma  c o nce ntrati o ns of L Y 3 5 2 6 3 1 8  t o 
e na ble p har mac o ki ne tic e val uati o ns  
( D urati o n of Res p o nse) Effica c y of L Y 3 5 2 6 3 1 8 vers us 
Place b o  
Mea n c ha n ge fr o m baseli ne assess me nt u p t o 8 wee ks 
f or a vera ge pai n i nte nsit y as meas ure d b y N R S 
A b bre viati o ns: D P N P = dia betic peri p heral ne ur o pat hic pai n ; N R S = n u meric rati n g scale.  
A p pr o ve d o n 1 2 J ul 2 0 2 2 G M T
C CI


H 0 P -M C -N P 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 N P 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-tr eat 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 b e f o u n d i n t he E R B s u p ple me nt f or St u d y N P 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 treat me nt peri o d as f oll o ws. T he first 4 wee ks of t he 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 treat me nt peri o d) be gi ns t he da y after Visit 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, 
res pecti vel y. 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 p eri o d of t he st u d y.
 
  
 
 If t here is n o treat 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 efficac y criteri o n 
s pecifie d a b o v e (ie, false p ositi ve) is a p pr o xi matel y 0. 0 6. T h e si m ulati o n f or t he p o wer 
calc ulati o n a n d sa m ple si ze 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 .   
5. 3.  M et h o d of A s si g n m e nt t o Tr e at m e nt  
T he met h o d of treat me nt assi g n me nt is descri be d i n t he C P M P S A P Versi o n 5 .  
 
A p pr o ve d o n 1 2 J ul 2 0 2 2 G M T
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.  
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.  
6.4. Multiple Comparisons/Multiplicity 
There is no plan to formally adjust for multiplicity.  
6.5. Use of an “Efficacy Subset” of Participants 
There are no plans to use a modified efficacy subset.  
6.6. Participant Disposition 
The summary of participant disposition has been described in the 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. 
ISA-specific considerations are described below.  
 Michigan Neuropathy Screening Instrument  
o Part A - history subscale (<7 vs ≥ 7) 
o Part B - physical assessment subscale (<3 vs ≥ 3) 
Approved on 12 Jul 2022 GMT


H 0 P -M C -N P 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 9  
L Y 3 5 2 6 3 1 8  
 
 
6. 8.  Tr e at m e nt C o m pli a n c e  
Treat me nt perce nt a ge of c o m plia nce will be calc ulate d as:  
𝑇𝑜𝑡𝑎𝑙 𝑝𝑖𝑙𝑙𝑠 𝑡𝑎𝑘𝑒𝑛∗1 0 0
𝑇𝑜𝑡𝑎𝑙 𝑝𝑖𝑙𝑙𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑
%  
wit h t otal pills ta ke n calc ulate d b y t otal pills dis pe nse d mi n us  t otal pills ret ur ne d. A patie nt is 
c o nsi dere d t o be c o m plia nt f or a gi ve n peri o d if t his perce nta ge is bet wee n 8 0 % a n d 1 2 0 %.  
Treat me nt c o m plia nce will be re p orte d f or t he first 4 wee ks of t he  st u d y p eri o d ( Visit 3 t o 5, n ot 
i ncl u di n g t he da y of Visit 5), a n d se paratel y f or t he last 4 wee ks of t he st u d y peri o d ( Visit 5 t o 7,  
i ncl u di n g t he da y of Visit 5). N ote t hat if a p atie nt misses ret ur ni n g pills  at Visit 4 or V isit 5, 
t here will be a n iss u e cal c ulati n g c o m plia nce f or t he acti ve  treat me nt peri o d, a n d alter nat e 
met h o ds f or calc ul ati n g c o m plia nce ma y be c o nsi dere d . F or patie nts w h o disc o nti n ue earl y, ti me 
after t he p e n ulti mate visit will be e x cl u de d f or cal c ulati o n of treat me nt c o m plia nce. F or  e x a m ple, 
if patie nt disc o nti n ue d earl y at Visit 6, treat me nt c o m plia nce will be deri ve d o nl y fr o m d ata 
c ollecte d t hr o u g h Visit 5.  C o m paris o ns bet wee n tr eat me nt gr o u p f or treat m e nt  c o m plia nce will 
be perf or me d usi n g a Fis her’s E xact test.  Listi n gs f or trea t me nt c o m plia nce of i n di vi d ual patie nts 
b y treat me nt peri o d will als o be pr o vi de d.    
De pe n di n g o n t he le v el of o bser ve d tr eat me nt c o m plia nce, a n d w here a p pr o priate, se nsiti vit y  
a nal ys es of pri mar y e n d p oi nts  ma y be c o n d u cte d b y e x cl u di n g p atie nts wit h p o or treat me nt  
c o m plia nce.  
6. 9.  C o n c o mit a nt T h er a p y  a n d e C O A C o m pli a n c e  
T he s u m mar y a n d re p orti n g of c o nc o mita nt t hera p y  a n d e C O A c o m plia nce  has bee n des cri be d i n 
t he C P M P S A P Versi o n 5 . N o a d diti o nal c o variat es will  be c o nsi dere d i n t he m o del s of wee kl y 
resc ue m e dicati o n use.  
C o nc o mita nt t hera p y will be re p ort e d f or t he first 4 wee ks of t he d o u bl e -bli n d peri o d 
(acti ve-tr eat me nt p has e), a n d se paratel y f or t h e e ntire 8 wee ks of t he d o u ble-bli n d peri o d.  
6. 1 0.  Effi c a c y A n al y s e s  
6. 1 0. 1.  Pri m ar y O ut c o m e a n d M et h o d ol o g y  
T he a nal ysis of t he pri mar y o utc o m e has bee n des cri be d i n t he C P M P S A P Versi o n 5 . T he 
l o n git u di nal m o del will i ncl u de A PI -N R S  d uri n g t he preli mi nar y dat a e ntr y peri o d ( [P D E P ], last 
7  da ys pri or t o ra n d o mizati o n at Visit 3)  a n d wit hi n eac h n o mi nal wee k of t he d o u ble treat me nt 
peri o d as a l o n git u di nal o utc o me. As n ote d i n Secti o n 4. 1 , e n d p oi nt f or t he pri mar y a nal ysis is 
defi ne d as  4  w ee ks p ost i nitial treat me nt a d mi nistrati o n .  
Calc ulati o n of t he wee kl y/ bi -wee kl y ti me i nter vals use d f or a n al ysis of wee kl y/ bi -wee kl y mea n 
sc ores fr o m t he e C O A de vice will f oll o w t he al g orit h m descri be d i n t he C P M P S A P 
A p pr o ve d o n 1 2 J ul 2 0 2 2 G M T
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Section 6.12.1, except that the end of the final interval will be determined based on the last visual 
analog scale (VAS) 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-NP01 and H0P-MC-NP03 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, Brief Pain Inventory-Short Form 
[BPI-SF] 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, in order 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 NP02 will also consider the 
following secondary analyses. 
The BPI-SF is a numeric rating scale that assesses the severity of pain (severity scale), its impact 
on daily functioning (interference scale), and other aspects of pain (for example, location of pain, 
relief from medications) in various disease states (Cleeland and Ryan 1994).   
This table describes the pain scales and corresponding numeric rating scale used in a modified 
version of the BPI, validated for pain in diabetic polyneuropathy. Participants will rate their pain 
severity and how, during the past 24 hours, the pain has interfered with the activities described in 
this table.   
Assessment 
Topic 
Numeric Rating Scale 0-10 
4-item Pain severity 
 
Worst pain in last 24 hours 
 
Least pain in the last 24 hours 
 
Average pain 
 
Pain right now 
0 = no pain 
10 = pain as bad as you can 
imagine 
7-item Pain interference 
 
General Activity 
 
Mood 
 
Walking ability 
 
Normal work 
 
Relations with others 
 
Sleep 
 
Enjoyment of life 
0 = does not interfere 
10 = completely interferes 
 
A Bayesian longitudinal mixed-effect model for repeated measures (MMRM) analysis will be 
performed to evaluate the change from baseline to each postbaseline visit for the mean pain 
interference scale and the mean pain severity scale. The model will utilize the constrained cell 
Approved on 12 Jul 2022 GMT


H0P-MC-NP02 Statistical Analysis Plan Version 2 
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LY3526318 
means model so that a common mean is estimated at the baseline. More details on this approach 
are provided in the Study CPMP SAP Version 5. 
Additional Bayesian MMRM analyses will be used to analyze the change from baseline to each 
postbaseline visit for:  
 individual pain interference, and  
 individual pain severity scales. 
This table describes information included in the model.   
Categorical effects 
 
the interaction of treatment and visit 
(constrained to estimate a common mean at 
baseline across treatments) 
 
average baseline pain severity category 
(baseline NRS < 7, baseline NRS ≥ 7) 
 
pooled investigative site 
Continuous covariates 
 
none   
Abbreviation: NRS = numeric rating scale. 
 
Other Secondary Analysis 
The proportion of participants in each treatment group meeting prespecified binary efficacy 
outcomes will be calculated for each postbaseline time point and will be used to compare 
treatment groups. The prespecified binary efficacy outcomes include the proportion of 
participants: 
 with a reduction of at least 30%, 50%, and 70% from baseline as measured by the 
mean pain interference score 
 with a reduction of at least 30%, 50%, and 70% from baseline as measured by the 
mean pain severity score 
 with a reduction of at least 30%, 50%, and 70% from baseline as measured by the 
individual interference scores, and 
 with a reduction of at least 30%, 50%, and 70% from baseline as measured by the 
individual severity scores. 
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. 
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. 
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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. 
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 upon 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 Study 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): 
1. 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 
2. 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 adverse events has been described in the CPMP SAP Version 5. 
This ISA will report TEAEs for the first 4 weeks as well as post-active-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 first dose date. 
A PTEAE is defined as an event that first occurs or worsens in severity after active-treatment 
phase (after Visit 5) and on or before study discontinuation. The Medical Dictionary for 
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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 through 5) will be used as a reference. 
The baseline of PTEAE is from the first dosing date to Visit 5. The post-active-treatment phase 
will be included as postbaseline for this analysis. While unusual, it is possible to have a missing 
severity for events. For events 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 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 Notable 
Adverse Events 
Treatment-emergent adverse events by Preferred Term will be reported. 
The general 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 NP02 will also consider the following analyses of lab analytes used to assess renal 
function. The planned summaries for these analytes are the same as those that have been 
described in the Study CPMP SAP Version 5; 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 central laboratory 
o For eGFR calculation, we will summarize shift tables of eGFR changes for 
baseline vs. postbaseline by minimum, maximum and last observed eGFR result: 
▪ Category 1: Normal or increase in GFR (≥90 mL/min/1.73m2) 
▪ Category 2: Mild reduction in GFR (60 to 89 mL/min/1.73m2) 
▪ Category 3a: Moderate (a) reduction in GFR (45 to 59 mL/min/1.73m2) 
▪ Category 3b: Moderate (b) reduction in GFR (30 to 44 mL/min/1.73m2) 
▪ Category 4: Severe reduction in GFR (15 to 29 mL/min/1.73m2) 
▪ Category 5: Kidney failure (GFR < 15 mL/min/1.73m2 or dialysis). 
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H 0 P -M C -N P 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 4  
L Y 3 5 2 6 3 1 8  
A b n or mal e G F R is s pecifie d bel o w a n d will be s u m marize d i n t he la b orat or y  s u m mar y ta bles. 
o  A b n or mal lo w : < 9 0 m L/ mi n/ 1. 7 3 m 2 
o  A b n or mal h i g h: As s p ecifie d b y ce ntr al la borat or y . 
6. 1 2. 5.  Vit al Si g n s a n d Ot h er P h y si c al Fi n di n g s  
T he a nal ysis of vital si g n para meters  is descri b e d i n t he C P M P S A P Versi o n 5 . 
Vital si g ns will be re p orte d f or t he first 4 -wee k , acti ve-treat me nt peri o d, a n d se parat el y f or t he 
e ntire 8-w ee k st u d y peri o d.  
6. 1 2. 6.  El e ctr o c ar di o gr a m s  
T he a nal ysis of el ectr ocar di o gra m  para meters is d escri be d i n t he C P M P S A P Versi o n 5 . 
Electr ocar di o gra m  will b e re p ort e d f or t he first 4 -wee k , acti ve treat me nt peri o d a n d se paratel y 
f or t he e ntire 8-wee k st u d y peri o d.  
6. 1 2. 7.  S ui ci d al I d e ati o n  or B e h a vi or  
Re p orti n g of s uici d al i deati o n/ be ha vi or t hr o u g h t h e C ol u m bia S uici de -Se verit y Rati n g Scale 
( C-S S R S) has bee n descri be d i n t he C P M P S A P Versi o n 5. C -S S R S will a d diti o nall y b e re p orte d 
se parat el y f or t he first 4-wee k acti ve treat me nt peri o d.  
6. 1 3.  S u b gr o u p A n al y s e s  
Ge neral s u b gr o u p a n al ys es are d escri b e d i n t he C P M P S A P Versi o n 5 .  
T he s u b gr o u p a n al ys es will be c o n d ucte d usi n g si milar m o deli n g a p pr oac h es as t he pri mar y 
a nal ys es. A d diti o nal fact ors i n t he m o del are d escri be d i n t he C P M P S A P Versi o n 5. T he 
treat me nt differe nce at t h e e n d p oi nt will be re p ort e d wit hi n eac h le vel of t h e s u b gr o u p fact or 
al o n g wit h 9 5 % cre di ble i nter vals. Fre q ue ntist M M R M ma y be p erf or m e d as a se nsiti vit y 
a nal ysis usi n g t he m o deli n g a p pr oac h d escri b e 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 2 J ul 2 0 2 2 G M T
C CI
C CI


H 0 P -M C -N P 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  
P artici pa 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 tr eat 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 St u d y N P 0 2 Trial 
Iss u e 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 N P 0 2 t o be c o n d ucte d w h e n 6 0 % of patie nts ha ve t he 
o p p ort u nit y t o c o m plete t he 4 -wee 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 T R P A 1 Statistical A nal ysis Ce nter ( S A C) S A P.  T he i nteri m a nal ysis ma y c ha n ge 
t he fi nal sa m ple siz e fr o m w hat is plan ne d i n t his St u d y N P 0 2 S A P.  
A d diti o nal i nteri m a nal ys es ma y b e c o n d u cte d f or reas o ns of f utilit y a nal ys es, earl y efficac y 
a nal ys es, safet y a nal yses, or ot her a n al ys es nee d e d f or ke y b usi ness decisi o ns a n d pla n ni n g.  
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: 
I n a d diti o n, a c u m ulati ve distri b uti o n f u ncti o n of pe rce nt c ha n ge fr o m bas eli ne t o e n d p oi nt f or 
t he f oll o wi n g B PI -S F s c ore will  be pr o vi de d f or eac h treat me nt gr o u p.  
 Mea n i nterfere n ce sc ore  
 Mea n se verit y s c ore  
 I n di vi d ual se v erit y sc ores 
 I n di vi d ual i nterfere nce sc ores. 
H o we ver, n o statistical c o m paris o ns will  be ma de bet wee n t he gr o u ps .  
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 a nal ysis a p pr oac h f or safet y data h as bee n briefl y d escri be d i n t he 
C P M P S A P Versi o n 5 . T his ma y be re p orte d f or a n y of t he acti ve  tr eat 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 he ke y safet y e ve nts t o be c o nsi dere d f or 
St u d y N P 0 2  are liste d bel o w b y d o mai n:  
Ge ner al A d verse E ve nt I nf 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 . 
A p pr o ve d o n 1 2 J ul 2 0 2 2 G M T
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Cardiovascular 
 QTc prolongation: >60 msec increase 
 Serious cardiac disorders adverse event. 
Liver function 
 Hy’s Law case: Serum total bilirubin (TBL) ≥2  Upper limit normal (ULN) and at least 
one of the following 2 conditions: 
o Alanine aminotransferase (ALT) ≥3 ULN for at least one visit 
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 includes 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  
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 cumulative list of subjects who discontinued due to an AE (discontinued from treatment 
or study)  
 list of subjects who discontinued due to an AE during the reporting period.  
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, 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 a 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 Clinical 
Study Report (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 CPMP Blinding 
and Unblinding Plan Version 1. Unblinding considerations specific to Study NP02 are provided 
below.  
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 blinded study 
team until the study has been unblinded. 
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8. References 
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med 
Singapore. 1994 Mar;23(2):129-138. PMID: 8080219 
 
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Si g nat ure Pa ge f or V V- C LI N- 0 6 7 6 1 8 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 6 7 6 1 8 v 1. 0
A p pr o val
1 2-J ul- 2 0 2 2 1 9: 4 0: 3 9 G M T + 0 0 0 0
A p pr o ve d o n 1 2 J ul 2 0 2 2 G M T
P P D