Randomized Placebo-controlled Phase 2 Clinical Trial to Evaluate LY3526318 for the Treatment of Chronic Low Back Pain
Phase: PHASE2
Conditions: Chronic Low-back Pain
Sponsor: Eli Lilly and Company

This study H0P-MC-BP02 (NCT05086289) is a sub-study of Master Protocol H0P-MC-CPMP 
(NCT05986292) 
 
Protocol: H0P-MC-BP02(a) 
 
Randomized Placebo-controlled Phase 2 Clinical Trial to Evaluate LY3526318 for the Treatment of 
Chronic Low Back Pain  
 
NCT05086289  
 
Approval Date: 10-Aug-2021 

C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P
I S A: H 0 P -M C -B 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 -B P 0 2 ( a)
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s. It i s t h e p r o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli n i c al 
i n v e sti g ati o n of L Y 3 5 2 6 3 1 8 , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d C o m p a n y or it s 
s u b si di ari e s. 
N ot e t o R e g ul at or y A ut h oriti e s: T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n 
e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r e l e a s e. 
I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot be r e pr o d u c e d or 
ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
M aster Pr ot oc ol Title: A Master Pr ot oc ol f or Ra n d o mize d, Place b o -C o ntr olle d, P hase 2 
Cli nical Trials o f M ul tiple I nter ve nt i ons f or t he Treat me nt of C hr o nic 
Pai n
M aster Pr ot oc ol N u m ber: H 0 P -M C -C P M P
I S A Title: Ra n d o mize d, Place b o -C o ntr olle d, P hase 2 Cli nical Trial t o E val uate L Y 3 5 2 6 3 1 8 f or 
t he Treat me nt of C hr o nic L o w Bac k Pai n
I S A N u m ber: H 0 P -M C -B 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 : B 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: 1 0- A u g- 2 0 2 1 G M T

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
2
Medical Monitor Name and Contact Information will be provided separately.

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
3
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
23-Jun-2021
Amendment [a] 
Overall Rationale for the Amendment:
This amendment addresses changes in the exclusion criteria in response to FDA feedback based 
on in vitro data currently available.
Section # and Name
Description of Change
Brief Rationale
2.3. Benefit/Risk 
Assessment
Added sub-section headers.
For clarity.
2.3.1. Risk 
Assessment
In first paragraph, added text for the 
effect of LY3526318 on other drugs.
Clarification of the potential of LY3526318 
exposure to affect metabolism of other drugs.
2.3.1. Risk 
Assessment
Updated first bullet to specify 
CYP3A4, plus minor editorial 
changes.
For clarity.
2.3.1. Risk 
Assessment
Added a bullet for CYP3A4 and p-
glycoprotein (P-gp) substrates.
Based on in vitro data suggesting a potential for 
PK interactions.
5.1. Study 
Population
Updated numbers for inclusion and 
exclusion criteria.
To align with master protocol and ISA 
numbering system.
Updated criterion #2051 to specify 
drugs taken orally or intravenously.
Topical drugs are allowed.
Added exclusion criterion #2054 for 
participants that are taking drugs that 
are sensitive CYP3A4 substrates with 
a narrow therapeutic index.
Based on in vitro data suggesting potential 
CYP3A4 inhibition at the proposed LY3526318
dose.
Added exclusion criterion #2055 for 
participants that are taking simvastatin 
at doses greater than 20 mg/day.
Simvastatin is a sensitive CYP3A4 substrate, 
with a projected maximal increase in exposure 
<2-fold in combination with LY3526318. 
Therefore, doses of 20 mg or less are 
considered safe.
Added exclusion criterion #2056 for
participants that are taking metformin 
at doses greater than 1000 mg/day.
Based on limited data related to inhibition of 
renal transporters.
Added exclusion criterion #2057 for
participants that are taking digoxin.
Based on in vitro data suggesting a potential for 
LY3526318 to inhibit P-gp.
6.6. Concomitant 
Therapy
Under Potential Drug-Drug 
Interactions with LY3526318, added 
reference to Section 5.2 for 
concomitant medication restrictions.
Reference to added exclusion criteria.

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
4
Section # and Name
Description of Change
Brief Rationale
10.3. Appendix 3: 
List of Excluded 
Concomitant 
Medications
Added reference to Section 5.2 and the 
Manual of Operations for additional 
information.
Additional information for excluded 
concomitant medications are listed in Section 
5.2 and the Manual of Operations.
Throughout the 
protocol
Minor editorial and format changes.
Minor, therefore not described.

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
5
Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.........................................................................................................................9
1.3.
Schedule of Activities (SoA) ......................................................................................10
2.
Introduction..............................................................................................................12
2.1.
Study Rationale ..........................................................................................................12
2.2.
Background ................................................................................................................12
2.3.
Benefit/Risk Assessment ............................................................................................15
2.3.1.
Risk Assessment.........................................................................................................15
2.3.2.
Benefit Assessment.....................................................................................................16
2.3.3.
Overall Benefit Risk Conclusion.................................................................................16
3.
Objectives and Endpoints.........................................................................................17
4.
Study Design .............................................................................................................18
4.1.
Overall Design............................................................................................................18
4.2.
Scientific Rationale for Study Design .........................................................................18
4.3.
Justification for Dose..................................................................................................18
4.4.
End of Study Definition..............................................................................................19
5.
Study Population ......................................................................................................20
5.1.
Inclusion Criteria........................................................................................................20
5.2.
Exclusion Criteria.......................................................................................................20
5.3.
Lifestyle Considerations .............................................................................................20
5.3.1.
Meals and Dietary Restrictions ...................................................................................20
5.3.2.
Substance Use ............................................................................................................20
5.3.3.
Reproductive and Contraception Requirements...........................................................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 ...............................................................................................21
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 -B 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.  
G e 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 A nal ysis...................................................................................2 6
9. 3. 3.
S af et y A nal yses ..........................................................................................................2 7
9. 3. 4.
Ot her A nal yses ...........................................................................................................2 7
9. 4.
I nteri m A nal ysis .........................................................................................................2 7
9. 5.
S a m pl e Size 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 ntrace 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
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 -B 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  c hr o nic l o w bac k 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 Y 3 5 2 6 3 1 8 is efficaci o us i n relie vi n g c hr o nic l o w 
bac k pai n ( C L B 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 yri n 1 ( T R P A 1), a calci u m per mea ble n o nselecti ve cat i 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 olera bilit y of L Y3 5 2 6 3 1 8 i n t his st u d y 
p o p ul at i on. P har mac o ki net ic ( P K) pr o perties will als o be e x pl ore d. T he t otalit y of  data fr o m t his 
pr o of -of -c o nce pt st u d y will assess t he be nefit s 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 
decisi o ns f or t he cli nical de vel o p me nt of L Y3 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 C L B P disease -state a p pe n di x ( D S A; H 0 P-M C -C P M P[ 2 ]).
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 C L B 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 artici p a nt s:
A p pr o xi matel y  15 0 parti ci pa nts will be ra n d o ml y assi g ne d t o st u d y int er ve ntio n 
 wit h t he ass u m pti on t hat 1 5 % of t he partici pa nts will dr o p o ut pri or 
t o t he e n d of t he d o u ble-bli n d treat me nt peri o d.
I nter ve nti o n Gr o u ps a n d D ur ati o n:
T his st u d y  incl u des a n 8 -wee k d o u ble -bli n d treat me nt peri o d.
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 -B P 0 2 (a)
8
I nter ve nti o n N a me
L Y 3 5 2 6 3 1 8
Place b o
D os a ge Le vel(s)
N ot a p plica ble
R o ute of A d mi nistr ati o n
a n d d ur ati o n
P O 
P O
A b bre viati o ns: P O = b y m o ut h ; Q D = o nce dail y.
D at a M o nit ori n g C o m mittee : Yes
S af et y re vie ws are c o vere d b y t he Assess me nt C o m mittee c harter f or t he C hr o nic Pai n Master 
Pr ot oc ol .
C CI

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
9
1.2.
Schema
Abbreviations: PDEP = preliminary data entry period; V = visit.
*Medication washout and PDEP begins.
**Randomization to either LY3526318 or placebo.

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
10
1.3.
Schedule of Activities (SoA)
This SoA shows visits and procedures unique to the intervention-specific appendix (ISA) H0P-MC-BP02 (BP02) for LY3526318. 
Please refer to the CPMP Master Protocol and the CLBP DSA H0P-MC-CPMP(2) SoAs for additional information.
Randomization 
to ISA
Double-Blind Treatment
Early 
Discontinuation
Notes
V3
V4
V5
V6
V7
ED
Study Week
0
2
4
6
8
Visit Window (days)
±3
Physical examination
X
X
X
X
Symptom-directed physical exam (see 
Section 8.2.1) at V5, V7, and ED (if applicable).
Vital signs
X
X
X
X
X
X
At V3, vitals should be taken predose and at 
approximately 2 and 4 hours post dosing.
At V4, V5, V6, and V7, vitals should be taken 
predose.
Pulse rate, respiratory rate, blood pressure, and 
temperature taken with participant in a sitting 
position.
ECG
X
X
X
Single ECGs at V5, V7, and ED (if applicable).
Study intervention
X
X
X
X
X
See Section 6.1.
Intervention 
compliance
X
X
X
X
X
Clinical Laboratory Tests and Sample Collection
Hematology
X
X
X
X
Chemistry
X
X
X
X
Lipid panel
X
X
X
X
Urinalysis
X
Urine pregnancy
X
X
X
X
X
X
For all WOCBP at V3: collect sample before 
dosing.
Urine drug screen
X
X
X
X
See Section 5.3.2.
HbA1c
X
X
X

C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P
I S A: H 0 P -M C -B 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
P K sa m ple
X
X  
X  
X  
X
X
At V 3 , s a mpl e s s h o ul d be ta ke n at 2 a n d 4 h o urs 
( ± 1 5 mi n utes) p ost d osi n g.
At V 4, V 5, V 6, a n d V 7, a sa m ple f or P K s h o ul d 
be ta ke n bef ore t he d ose is a d mi nistere d; 
partici pa nts s h o ul d be as ke d t o refrai n fr o m 
ta ki n g t heir d ose o n V 4- V7 u ntil t he y ha ve t heir 
cli nic visit a n d after t he bl o o d sa m ple is ta ke n.
T he date a n d ti me of L Y 3 5 2 6 3 1 8 a d mi nistrati o n 
pri or t o t he P K sa m pli n g will be rec or de d , i.e. ,
t he d ose a d mi nistere d i n t he cli nic at V 3 a n d t he 
last at-h o me d ose pri or t o eac h of V 4, V 5 , V 6 ,
a n d V 7.
P artici p a nt De vice
Partici pa nt ret ur ns 
de vice
X
X
If a d B M de vice is use d, t he partici pa nt will 
r et ur n t he de vice t o t he site at V 7 or E D (if 
a p plica ble).
A b bre viati o ns: 
; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; H b A 1c = he m o gl o bi n A 1c ; I SA = i nter ve nti o n-s pecific a p pe n di x; 
P K = p har mac o ki netic ; V = Visit; W O C B P
= w o me n of c hil d beari n g p ote ntial.
C CI
C CI

C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P
I S A: H 0 P -M C -B 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 -B P 0 2 ( B P 0 2) i s 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 ) Ma ster 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 
c hr o nic l o w bac k pai n (C L B P ) di sease-state a p pe n di x ( D S A) C P M P(2 ) a n d t his I S A B P 0 2.
2. 1.
St u d y R ati o n ale
T he p u r p ose of t his st u d y is t o test w het her L Y 3 5 2 6 3 1 8 is efficaci o us i n relie vi n g C L B P. Data
will be c o llecte d t o assess t he safety a n d t olera bilit y of L Y 3 5 2 6 3 1 8 i n t his st u d y p o p 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) io n c ha n nel fa mil y c o m pr ises a gr o u p of 2 8 n o nselecti ve 
catio n c ha n nels t hat are dist i nct fr om classical v o lta ge gate d io n c ha n nels. A m o n g t hese, 
tra nsie nt rece pt or p ote ntial a n k yri n 1 ( T R P A 1) is a calci u m-p er m ea ble n o nselect i ve cati on 
c ha n nel, w hic h is e x presse d i n t he a x o ns a n d i n b ot h peri p heral a n d ce ntral ter mi nals of 
n oci ce pt ors. It is als o c o nsi dere d t o be i m p orta nt as a c he m ose ns or of n ocice pti o n ( K o ivist 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 mat i on 
a n d its l ocalizat i on i n se ns or y ne ur o ns are k n o w n ( B o d ki n a n d Brai n 2 0 1 1; Üc kert et al. 2 0 1 7 ). 
D ue t o i ts r ole i n e v o ki n g pai n a n d elicit i n g a n a versi ve res p o nse, T R P A 1 ma y be a pr o misi n g 
tar get f or treati n g pai n (Be ne mei et al. 2 0 1 7; Berta et al . 2 0 1 7 ; De marti ni et al. 2 0 1 7 ; Maat uf et 
al. 2 0 1 9; Wa n g et al. 2 0 1 9 ).
L Y 3 5 2 6 3 1 8 is a n orall y a d mi nistere d, p ote nt, a n d select i ve n o vel a nta g o nist of T R P A 1 u n der 
de vel o p me nt b y  Lill y.
L Y 3 5 2 6 3 1 8 has bee n e v al uate d i n 2 c o mplete d a n d 1 o n g oi n g P hase 1 cli nical st u dies.
C o m plete d 
St u d y
J 2 D-M C -C V A A ( C V A A)
P o p ul ati o n
Healt h y  partici pa nts
St u d y Desi g n
2 -part, place b o -c o ntr olle d, ra n d o mize d, si n gle a n d m ulti ple-d ose escalati o n st u d y.
L Y 3 5 2 6 3 1 8 
D ose
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 -B P 0 2 (a)
1 3
O bjecti ves 
Part A: T o e val uate safet y , t olera bilit y, a n d P K of L Y 3 5 2 6 3 1 8 i n healt h y partici pa nts 
f oll o wi n g a si n gle oral d ose.
Part B: T o e val uate 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.
C o m plete d 
St u d y 
J 2 D-M C -C V A B ( C V A B)
P o p ul ati o n
Healt h y  fe male partici pa nts
St u d y Desi g n
R a n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, 4- wa y cr oss o ver st u d y.
L Y 3 5 2 6 3 1 8 
D ose
Eac h partici pa nt was ra n d o ml y assi g ne d t o recei ve 4 u ni q ue d oses of st u d y dr u g i n a rati o of 
3 L Y 3 5 2 6 3 1 8: 1 place b o, i n a cr oss o ver ma n ner wit h at least 1 4 da y s of was h o ut bet wee n 
d oses. 
O bjecti ves 
T o assess tar get e n ga ge me nt of T R P A 1 wit h ci n na mal de h y de ( C A) -i n d uce d der mal bl o o d 
fl o w ( D B F) after a si ngle d ose of L Y 3 5 2 6 3 1 8 .
O n g oi n g St u d y 
J 2 D-M C -C V A C ( C V A C)
P o p ul ati o n
Healt h y  partici pa nts
St u d y Desi g n
R a n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, S A D ( Part A) a n d m ulti ple d ose ( M D; Part B ) 
st u d y.
L Y 3 5 2 6 3 1 8
D ose
O bjecti ves 
Part A: T o e val uate t he safet y, t olera bilit y, a n d P K of L Y 3 5 2 6 3 1 8 after a si n gle oral d ose 
a d mi nistrati o n .
Part B: T o e val uate t he safet y, t olera bilit y, a n d P K of L Y 3 5 2 6 3 1 8 after m ulti ple oral d ose 
a d mi nistrati o ns.
C CI
C CI
C CI

C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P
I S A: H 0 P -M C -B P 0 2 (a)
1 4
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 -B P 0 2 (a)
1 5
2. 3.
Be nefit/ Ris k As sess 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 dit i onall y , preli mi nar y data usi n g a ne w f or m ulati on of 
L Y 3 5 2 6 3 1 8 i n St u d y  C V A C s h o we d n o cli nicall y sig nifica nt safet y or t ol era bilit y c o ncer ns at 
hi g her e x p os ures f o ll owi n g si n gle or m ul tiple d oses  
.
T o xic ol o g y S t u dies a n d N O A E L E x p os ur e
2. 3. 1.
Ris k Assess me nt
St u d y I nter ve nti o n
C CI
C CI
C CI
C CI
C CI

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
16
More information about the known and expected risks, SAEs, and reasonably anticipated 
AEs of LY3526318 may be found in the IB. Information on AEs expected to be related to the 
investigational product may be found in Section 7 (Reference Safety Information for 
Assessment of Expectedness of Serious Adverse Reactions) of the IB. Information on SAEs 
that are expected in the study population independent of drug exposure will be assessed by 
the sponsor in aggregate, periodically during the course of the study, and may be found in 
Section 5 (Effects in Humans) of the IB.
2.3.2. Benefit Assessment
Potential benefits for the study participants include

study-related medical procedures
o
physical examinations
o
laboratory tests
o
electrocardiograms (ECGs) 
o
detailed evaluations of low back pain (including X-ray at V1).
As part of Study CPMP, participants to this ISA will report their experience using standard tools 
that will contribute to the assessment of novel treatments for CLBP. In addition, data collected 
from this study may also improve our understanding of pathogenesis. Both of which may lead to 
the development of a 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 CLBP.

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
17
3.
Objectives and Endpoints
The CPMP Master Protocol and CLBP DSA CPMP(2) include objectives and endpoints 
applicable for this study. This table describes objectives and endpoints specific for LY3526318.
Objectives
Endpoints
Tertiary/Exploratory
Measure the PK of LY3526318 in participants with
CLBP.
Measure of plasma concentrations of LY3526318 to 
enable PK evaluations.
Abbreviations: CLBP = chronic low back pain; PK = pharmacokinetic.

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

C 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 -B 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.
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 -B 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 C L B P C P M P( 2 ) D S A pr o vide eli gi bilit y cri t eria t hat must be 
f oll owe d f or t hi s st u d y. L Y 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:
[ 2 0 5 0]
A re me n or w o me n w h o a bide b y t he re pr o d ucti ve a n d c o ntrace p ti ve 
re q uire me nts pr o vide d i n B P 0 2 Sect i on 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 crit eria a p pl y:
 
 
[ 2 0 5 2]
Ha ve a n e G F R of less t ha n 3 0 ml/ mi n/ 1. 7 3 m 2 base d o n t he C hr o nic 
Ki d ne y Disease E pi de mi o l og y  C olla b oratio n (C K D -E PI) f or m ula at Visit 1 or 
Vi sit 2.
[ 2 0 5 3]
W o m e n w h o are pre g na nt or breastfee di n g .
 
 
5. 3.
Lifest yle C o nsi der ati o ns
5. 3. 1.  
Me als a n d Diet ar y Restricti o ns
Refrai n fr o m c o ns u m pti o n o f Se ville ora n ges, gra pefr uit or gra pefr uit j uice fr o m 5 da ys b ef or e
t he start of st u d y int er ve nt i on u nt il after t he fi nal d ose.
5. 3. 2. 
S u bst a nce Use
P osi tive uri n e dr u g scree n will n ot be c o nsi dere d illicit use if t he s u bsta nce is a prescri be d 
c o nc o mita nt me dicat i on f or a k n o w n pre -e xist i n g c o n diti 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.
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P
I S A: H 0 P -M C -B 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 nts a n d case re p ort f or m 
(C R F ). 
A rec or d of t he n u m ber of st u d y int er ve nt i on ca ps ul es di s pe nse d t o a n d ta ke n b y eac h partici pa nt
m ust be mai ntai ne d a n d rec o ncile d wit h st u d y  int er ve nt i on a n d c o m plia nce rec or ds. I nter ve nti o n 
start a n d st o p dates, will als o be rec or de d i n t he C R F.
6. 5.
Tre at me nt of O ver d ose
I n case of s us pecte d o ver d ose, partici pa nts s h o ul d be m onit ore d f or a n y  sig ns or s y m pt o ms of 
a d verse reacti o ns or effects, a n d s u p p orti ve care s h o ul d be pr o vi de d as necessar y. T here is n o 
k n o w n a nt i d ote t o L Y 3 5 2 6 3 1 8 t hera p y.
C CI
C CI
C CI

C 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 -B P 0 2 (a)
2 2
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 her t ha n c hr o nic pai n 
are all o we d a n d ma y be use d d uri n g t he st u d y, if it is per mitte d base d o n t he eli gi bility cri t eria. 
T he C P M P Master Pr ot oc ol pr o vi des m ore detail o n c o nc o mit a nt t hera p y.
A list of me dicati o ns t hat are pr o hi bite d fr om Visi t 2 t o Visit 7 for parti ci pa nt s ra n d omize 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. Partici pa nts ma y  ret ur n t o t heir 
sta n dar d of care after Visit 7 i s c om p lete d, as cli nicall y a p pr o priate.
C CI

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
23
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
The CPMP Master Protocol and CPMP(2) DSA provides the reasons and procedures for 
discontinuation of intervention and participant discontinuation that must be followed for this 
study.

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
24
8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the CPMP Master Protocol, CLBP 
CPMP(2) DSA, and ISA BP02 SoAs.
LY3526318-specific assessments and procedures are described here.
8.1.
Efficacy Assessments
Planned time points for all efficacy assessments are provided in the SoAs.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoAs.
8.2.1.
Physical Examinations
Symptom directed physical examinations of skin, eyes, mouth, lungs, and gastrointestinal tract 
will be performed at each visit as described in the SoA. Any clinically significant abnormal 
physical examination findings will be reported as AEs.
8.2.2.
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, RR, QRS, QT, and QTcF intervals.
8.2.3.
Clinical Safety Laboratory Tests
See BP02 Section 10.1 (Appendix 1) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency for ISA BP02.
8.3.
Adverse Events, Serious Adverse Events, and Product Complaints
See the CPMP Master Protocol for additional details.
8.4.
Pharmacokinetics
●
Blood samples will be collected for measurement of plasma concentrations of 
LY3526318 as specified in the SoA.
●
A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor. The 
timing of sampling may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.
●
Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded.
●
The date and time (24-hour clock time) of LY3526318 administration prior to the 
PK sampling will be recorded i.e. the dose administered in the clinic at Visit 3 and 
the last at home dose prior to each of Visit 4, Visit 5, Visit 6, and Visit 7.

C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P
I S A: H 0 P -M C -B P 0 2 (a)
2 5
●
S a m ples will  be use d t o e val uate t he P K of L Y 3 5 2 6 3 1 8. Sa m ples c o llecte d f or
a nal yses o f L Y 3 5 2 6 3 1 8 plas ma c o nce ntrati o ns ma y als o be use d t o e valuate 
safety or efficac y  as pects relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y.
Dr u g c o nce ntrati o n i nf or 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 -B 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 C L B P D S A C P M P( 2) 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. 
 
 
 
 
 If t here is n o treat me nt 
differe nce bet wee n place b o a n d L Y 3 5 2 6 3 1 8 , t he pr o ba bility o f passi n g t he efficac y criteri o n 
s pecifie d a b o ve (i.e., false p osi tive) i s less t ha n 0. 1. T he si m ulati on f or t he p o wer calc ulati on a n d 
sa m ple size deter mi nat i on was carrie d o ut usi n g t he Fi xe d a n d A da pt i ve Cli nical Trial Si m ulat or 
(F A C T S ) Versi o n 6. 0.
9. 2.
A n al yses Sets
T he p o p ulat i ons are def i 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 at 
Vi sit 3 a n d ha ve at least 1 e valua ble P K sa m ple c ollecte d.
9. 3.
St atistic al A n al yses
A n y c ha n ge t o t he data a nal ysis met h o ds descri be d i n t his I S A will re q uire a n a me n d me nt o nl y if 
it c ha n ges a pri nci pal feat ure of t he I S A. A n y ot her c ha n ge t o t he data a nal ysis met h o ds 
descri be d, a n d t he j ust ificati on f or ma ki n g t he c ha n ge, will be descri be d i n t he st atistical a nal ysis 
pl a n ( S A P) a n d t he c li 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 descri pt i ons 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 oint s 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 C L B P D S A C P M P( 2 ).
9. 3. 2.
E x pl or at or y E n d p oi nt A n al ysis
E x pl or at or y  a nal yses ma y be descri be d i n t he I S A S A P.
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 -B P 0 2 (a)
2 7
9. 3. 3. 
S afet y A n al yse s
S af et y a nal yses ha ve bee n descri be d i n t he C P M P Master Pr ot oc ol. A d dit i on al I S A s pecific 
safety a nal yses ma y be 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 yses
T he o bser ve d plas ma c o nce ntrati o ns f or L Y 3 5 2 6 3 1 8 will be re p orte d gra p hicall y a n d 
descri pt i vel y.
P har mac o ki net ic m o deli n g a n d e x p os ur e- res p o nse a nal yses of efficac y meas ures ma y be 
c o n d ucte d. If c o n d ucte d, t he a nal yses will be perf or me d usi n g p o p ulat i on a nal ysis s o ftware, 
N O N M E M ® , if data allo ws. T he versi o n  of a n y s oft ware use d f or t he a nal ysis will be 
d oc u m e nte d, a n d t he pr o gra m will meet t he Lill y re q uire me nts of s oft ware vali dat i on. It i s 
p ossi ble t hat ot her vali date d, e q ui vale nt P K s oft ware pr o gra ms ma y  be use d if a p pr o priate, 
warra nte d, a n d a p pr o ve d b y Gl o bal P K/ p har mac o d y na mic ma na ge me nt. Data ma y be p o ole d 
wi t h data fr o m ot her stu dies f or a n i nte grate d P K a n d/ or P K/ p har mac o d y na mic a nal ysis.
A li mite d n u m ber of pre-i de ntifie d i n di vi d uals i n de pe n de nt of t he st u d y  t e a m ma y recei ve access 
t o u n bli n de d data, as s pecifie d i n t he u n bli n di n g pla n, pri or t o t he i nteri m or fi nal data base l oc k, 
i n or der t o i nitiate t he fi nal p o p ulat i on P K a n d/ or e x p os ure -res p o nse m o del de vel o p me nt 
pr ocesses. I nf or mati o n t hat ma y u n bli n d t he st u d y  d uri n g t he a nal yses will n ot be re p orte d t o 
st u d y sites or t he bli n de d st u d y tea m u ntil t he st u d y has bee n u n bli n de d.
9. 4.
I nteri m A n al ysis
A n i nteri m a nal ysis ma y be c o n d ucte d f or i nter nal decisi o n ma k i n g. U n bli n di n g details w o ul d be 
s pecifie d i n t he u n bli n di n g pla n sect i on of t he S A P or i n a se parate u n bli n di n g d oc u me nt. T he 
S A P will descri be a n y  int eri m a nal yses i n greater detail s h o uld 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 mize d i n a  
rati o t o L Y 3 5 2 6 3 1 8 a n d 
pl ace b o, res pecti vel y. It is e x pecte d t hat a p pr o xi matel y 8 5 % parti cipa nts will c o m plete t he 
d o u bl e- bli n d treat me nt  perio d of  t he st u d y. 
 
 
 
 
 If t here is n o treat me nt 
differe nce bet wee n place b o a n d L Y 3 5 2 6 3 1 8 , t he pr o ba bility 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 less t ha n 0. 0 5. T he si m ulati on f or t he p o wer calc ulati on 
a n d sa m ple size deter mi nati on was carrie d o ut i n F A C T S Versi o n 6. 0.
C CI
C CI

C O N FI D E N TI A L Master Pr ot oc ol N u m ber H 0 P -M C -C P M P
I S A: H 0 P -M C -B 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 B 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
C CI

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
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 post-menopausal.
Examples of surgical sterilization include: hysterectomy, bilateral oophorectomy, 
or tubal ligation.
Postmenopausal 
state
The post-menopausal state should be defined as:
1.
A woman at any age at least 6 weeks post-surgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or
2.
A woman at least 40 years of age and up to 55 years old with an intact 
uterus, not on hormone therapy*, who has had cessation of menses for at 
least 12 consecutive months without an alternative medical cause, AND
with a follicle-stimulating hormone >40 mIU/mL; or
3.
A woman 55 or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea, or
4.
A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.
*Women should not be taking medications during amenorrhea, such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, 
selective estrogen receptor modulators (SERMs), or chemotherapy that could 
induce transient amenorrhea.
Reproductive 
Toxicology 
Studies
Embryo-fetal studies are toxicity studies in pregnant animals designed to identify 
abnormalities in the development of fetuses, which could indicate potential for 
teratogenicity in humans. The relevant dosing period is during organogenesis.

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(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, or
stay in a same-sex relationship without sexual 
relationships with males
use the withdrawal method
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle
Topic
Condition
Pregnancy testing
Negative urine result at screening followed by a 
negative serum result within 24 hours prior to 
treatment exposure.
Note: Subsequent pregnancy testing is compound 
specific.
Contraception
Agree to use 2 forms of effective contraception, 
where at least 1 form must be highly effective 
(less than 1% failure rate).
Examples of different forms of contraception
Methods
Examples
Highly effective contraception 

combination oral contraceptive pill and 
mini-pill

implanted contraceptives

injectable contraceptives

contraceptive patch (only women 
<198 pounds or 90 kg)

total abstinence

vasectomy (if only sexual partner)

fallopian tube implants (if confirmed by 
hysterosalpingogram)

combined contraceptive vaginal ring, or

intrauterine devices

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(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, and 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, and 
symptothermal)

withdrawal

post coital douche, and

lactational amenorrhea
Topic
Guidance
Contraception for men receiving a genotoxic drug 
and have a female partner of childbearing 
potential

Agree to remain abstinent (if this is their 
preferred and usual lifestyle), or

Use 1 additional effective method of 
contraception
The table below describes contraception guidance for all men.
Topic
Guidance
For all men
should refrain from sperm donation for the 
duration of the study and for the predicted time 
until estimated plasma levels of partner would be 
below the level of toxicologic concern, plus 
90 days.
Contraception for men with partners of 
childbearing potential 

either remain abstinent (if this is their 
preferred and usual lifestyle), or

must use condoms during intercourse for 
the duration of the study, and

for the predicted time until estimated 
plasma levels of partner would be below 
the level of toxicologic concern, plus 
90 days.
Contraception for men in exclusively same-sex 
relationships, as their preferred and usual lifestyle
Are not required to use contraception.

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(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, and 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, and 
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 -B 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
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 -B P 0 2 (a)
3 4
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 -B P 0 2 (a)
3 5
C CI

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(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.

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 -B P 0 2 (a)
3 7
T he f o ll owi n g c ha n ges i n st u d y  c o n d uct will n ot be c o nsi dere d pr ot oc ol de viati ons.
Re m ot e 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 ca n n ot tra vel t o t he site d ue t o a n 
e xce pti o nal circ u msta nce if writte n a p pr o val is pr o vi de d b y t he s p o ns or .
Pr oce d ures perf or me d a t s uc h visits i ncl u de, b ut are n ot li mite d t o, c ollect i on of bl o o d 
sa m ples, s y m pt o m directe d p h ysical e xa mi nat i ons, E C Gs, vital si g ns, i nter ve nt i on 
acc o u nta bilit y a n d c o m plia nce, A E c ollect i on, a n d c ollect i on of healt h i nf or mati o n.
Ot her alter n ati ve l oc ati o ns: La b orat or y  dra ws ma y be d o ne at a n alter nate l ocati o n i n 
e xce pti o nal circ u msta nces.
I n s o urce d oc u me nts a n d t he C R F, t he st u d y sit e s h o uld ca pt ure t he visit met h o d, wit h a s pecific 
e x pla nat i on f or a n y data missi n g beca use of misse d i n-pers o n sit e visits.
Re gar dless of t he t y p e of  r e mote visi ts i m ple me nte d, t he pr ot oc ol re q uire me nts re gar di n g t he 
re p orti n g of A Es, S A Es, a n d pr o d uct c o m plai nts re mai n u nc ha n ge d.
E v er y eff ort s h o uld be ma de t o e na ble part ici pa nts t o ret ur n t o o n-site visits as s o o n as 
reas o na bl y p ossi ble, w hile e ns uri n g t he safety of  b ot h t he partici pa nts a n d t he site staff.
L oc al l a b or at or y testi n g o pti o n
L ocal  la b orat or y testi n g ma y be c o n d ucte d i n lie u of ce ntral la b orat or y testi n g. T he lo c al  
la b orat or y must be q ualifie d i n acc or da nce wi t h a p plica ble lo c al  re g ulati ons.
St u d y i nter ve nti o n a n d a ncill ar y s u p plies (i ncl u di n g p artici p a nt di aries)
W he n a
parti ci p a nt is u na ble t o g o t o t he site t o recei ve st u d y s u p plies d uri n g n or mal o n-sit e 
visit s, t he site s h o ul d w or k wit h t he s p o ns or t o deter mi ne a p pr o priate acti o ns. T hese act i ons ma y 
i ncl u de:  

as ki n g t he partici pa nt t o g o t o t he site a n d recei ve st u d y s u p plies fr o m site 
staff with o ut c o m plet i on of a f ull st u d y  visit, 

as ki n g t he partici pa nt’s desi g nee t o g o t o t he site a n d recei ve st u d y  s u p plies 
o n a parti ci pa nt’s be half, a n d

arra n gi n g deli ver y of st u d y s u p plies.
C CI

CONFIDENTIAL Master Protocol Number H0P-MC-CPMP
ISA: H0P-MC-BP02(a)
38
These requirements must be met before action is taken:

Alternate delivery of study intervention should be performed in a manner that 
does not compromise treatment blinding and ensures product integrity. The 
existing protocol requirements for product accountability remain unchanged, 
including verification of participant’s receipt of study supplies.

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(2) DSA, and BP02 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
ISA: H0P-MC-BP02(a)
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
CLBP
chronic low back pain
Cmax
maximum serum/plasma concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice, and applicable regulatory 
requirements
CRF
case report form
CV%
percent coefficient of variation
CYP3A
cytochrome P450 enzymes 3A
DDI
drug-drug interaction
data monitoring 
committee
A data monitoring committee is a group of independent scientists who are appointed to 
monitor the safety and scientific integrity of a human research intervention and to make 
recommendations to the sponsor regarding the stopping of a study for efficacy, or for 
harms, or for futility. The composition of the committee is dependent upon the scientific 
skills and knowledge required for monitoring the particular study.
DSA
disease-state appendix
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
ISA: H0P-MC-BP02(a)
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
pharmacokinetics
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-BP02(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-BP02(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.
Koivisto A, Jalava N, Bratty R, 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  =  5 8 7 a a 5 7 b - 1 a 7 e - 4 e 0 1 - b c 2 6 - 6 8 8 c 1 b 8 f 4 c f 0
A p p r o v a l  D a t e  &  T i m e :  1 0 - A u g - 2 0 2 1  1 9 : 1 7 : 0 9  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v a l  D a t e  &  T i m e :  1 0 - A u g - 2 0 2 1  2 1 : 0 1 : 1 2  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