Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3556050 for the Treatment of Chronic Low Back Pain
Phase: PHASE2
Conditions: Chronic Low-back Pain
Sponsor: Eli Lilly and Company

This study H0P-MC-BP03 (NCT04874636) is a sub-study of Master Protocol H0P-MC-CPMP 
(NCT05986292) 
Protocol: H0P-MC-BP03 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3556050 for the 
Treatment of Chronic Low Back Pain
NCT04874636 
Approval Date: 17-Mar-2021 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
1
Title P a ge
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al 
i n v e sti g ati o n of  L Y 3 5 5 6 0 5 0 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 nt i al 
i nfor m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y 
p u bli c r el e a s e.  I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n o t b e 
r epr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
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 5 6 0 5 0 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 3
A me n d me nt N u m ber: T his is t he ori gi nal I S A
C o m p o u n d : L Y 3 5 5 6 0 5 0
St u d y P h ase: 2
S h ort Title: Cli nical Trial t o E val uate L Y 3 5 5 6 0 5 0 f or t he Treat me nt of C hr o nic L o w Bac k Pai n
Acr o n y m : B P 0 3
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:  
Master Pr ot oc ol I N D 1 4 4 9 1 5
L Y 3 5 5 6 0 5 0 I N D 1 2 9 7 5 6
A p pr o v al D ate: Pr ot oc ol 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 7- M ar- 2 0 2 1 G M T

CONFIDENTIAL
Protocol number H0P-MC-BP03
2
Medical Monitor Name and Contact Information will be provided separately

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
3
T a ble of C o nte nts
1.
Pr ot oc ol S u m m ar y ......................................................................................................5
1. 1.
S y n o psis .......................................................................................................................5
1. 2.
Sc he ma .........................................................................................................................6
1. 3.
Sc he d ule of Act i vities ( S o A) ........................................................................................7
2.
I ntr o d ucti o n ..............................................................................................................1 1
2. 1.
St u d y  Ratio nale ..........................................................................................................1 1
2. 2.
Bac k gr o u n d ................................................................................................................1 1
2. 3.
Be nefit/ Ris k Assess me nt ............................................................................................1 1
2. 3. 1.
Ris k Assess me nt .........................................................................................................1 2
2. 3. 2.
Be n efit Assess me nt .....................................................................................................1 2
2. 3. 3.
O verall Be nefit: Ris k C o ncl usi o n ................................................................................1 2
3.
O bjecti ves a n d E n d p oi nts .........................................................................................1 3
4.
St u d y Desi g n .............................................................................................................1 4
4. 1.
O verall Desi g n ............................................................................................................1 4
4. 2.
S ci e nt ific Rati o nale f or St u d y Desi g n.........................................................................1 5
4. 3.
J ustificati o n f or D ose..................................................................................................1 5
4. 4.
E n d of St u d y  Defi niti on ..............................................................................................1 5
5.
St u d y P o p ul ati o n ......................................................................................................1 6
5. 1.
I ncl usi on Cri t eria ........................................................................................................1 6
5. 2.
E xcl usi o n Cri t eria .......................................................................................................1 6
5. 3.
Lifest yle C o nsi derat i ons .............................................................................................1 7
6.
St u d y I nter ve nti o n ....................................................................................................1 8
6. 1.
St u d y  I nter ve nti on(s) A d mi nistere d ............................................................................1 8
6. 2.
Pre para tio n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y .............................................................1 8
6. 3.
Meas ures t o Mi ni mize Bias: Ra n d o mizat i on a n d Bli n di n g ..........................................1 9
6. 4.
St u d y  I nter ve nti on C o m plia nce ...................................................................................1 9
6. 5.
C o nc o mita nt T hera p y ................................................................................................. 1 9
6. 6.
D ose M o dificat i on ......................................................................................................1 9
7.
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al ....................................................................................2 1
7. 1.
Di sc o nti n uatio n of  St u d y I nter ve nti on ........................................................................2 1
8.
St u d y Assess me nts a n d Pr oce d ures .........................................................................2 2
8. 1.
S af et y Assess me nts ....................................................................................................2 2
8. 1. 1.
Vi t al Sig ns.................................................................................................................. 2 2
8. 1. 2.
Electr ocar di o gra ms .....................................................................................................2 2
8. 1. 3.
Cli nical Safet y  La b orat or y Assess me nts .....................................................................2 2
8. 2.
A d verse E ve nts a n d Seri o us A d verse E ve nts ..............................................................2 2
8. 3.
Treat me nt of O ver d ose ...............................................................................................2 2
8. 4.
P har mac o ki net ics........................................................................................................2 2
8. 5.
P har mac o d y na mics .....................................................................................................2 3
9.
St atistic al C o nsi der ati o ns .........................................................................................2 4
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CONFIDENTIAL
Protocol number H0P-MC-BP03
4
9.1.
Statistical Hypotheses.................................................................................................24
9.2.
Sample Size Determination.........................................................................................24
9.3.
Populations for Analyses ............................................................................................24
9.4.
Statistical Analyses.....................................................................................................24
9.4.1.
General Considerations...............................................................................................24
9.4.2.
Pharmacokinetics and Pharmacodynamics..................................................................25
9.4.3.
Tertiary/Exploratory...................................................................................................25
9.4.4.
Biomarkers .................................................................................................................25
9.5.
Interim Analyses.........................................................................................................25
10.
Supporting Documentation and Operational Considerations ................................26
10.1.
Appendix 1: Clinical Laboratory Tests........................................................................26
10.2.
Appendix 2: Definitions of Reproductive Requirements and 
Contraceptive Guidance..............................................................................................27
10.3.
Appendix 3: Provisions for Changes in Study Conduct During 
Exceptional Circumstances.........................................................................................31
10.4.
Appendix 4: Abbreviations .........................................................................................34

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
5
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 5 6 0 5 0
f or t he Treat me nt of C hr o ni c 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 5 6 0 5 0 is efficaci o us i n relie vi n g c hr o nic lo w 
bac k pai n ( C L B P) .  Data will be c ollecte d t o assess t he safety a n d t olera bilit y of L Y 3 5 5 6 0 5 0 i n 
this st u d y p o p ulati o n . P har mac o ki net ic (P K ) pr o perti es a n d p har m ac o d y na mic ( P D) effects 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 o ciat e d wit h L Y 3 5 5 6 0 5 0 a n d i nf or m decisi o n s for t he cli nical de vel o p me nt of 
L Y 3 5 5 6 0 5 0 .
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 master pr ot oc ol H 0 P-M C -
C P M P ( C P M P) a n d t he C L B P di sease-state a d de n d u m ( D S A).
O ver all Desi g n :
T his is a n 8- wee k, P hase 2 , ra nd 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 5 6 0 5 0 vers us place b o i n partici pa nts wit h C L B P .
Discl os ure St ate me nt : T hi s is a ra n d omize d, i n vesti gat or- a n d partici pa nt -bli n d, place b o -
c o ntr olle d, P hase 2 cli nical trial.
N u m ber of P artici p a nt s:
U p t o 2 0 0 partici pa nts will be ra n d omize d i n a 
 t o L Y 3 5 5 6 0 5 0 a n d pl ace b o , res pecti vel y,
wi t h t he ass u m pti on t hat a p pr o xi matel y 3 3 % 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:
P arti cipa nts will recei ve eit her L Y 3 5 5 6 0 5 0 or place b o. Base d o n t olera bilit y,  partici pa nts ma y 
ta ke u p t o a ma xi m u m of 3 ca ps ules orall y (eac h ca ps ule is  
 t wice dail y, a p pr o xi matel y 
e ver y 1 2 h o urs, f or a t otal d ose of 6 0 0 m g.
T his is a n 8 -wee k st u d y .
D at a M o nit ori n g C o m mittee: Yes
S af et y re vie ws are c o vere d b y t he Assess me nt C o m mittee c harter f or t he C hr o nic Pai n Master 
Pr ot oc ol .
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C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P- M C - B P 0 3
6
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CONFIDENTIAL
Protocol number H0P-MC-BP03
7
1.3.
Schedule of Activities (SoA)
This SoA shows visits and procedures unique to the intervention-specific appendix (ISA) H0P-MC-BP03 (BP03) for LY3556050.  
Please refer to master protocol and the CLBP DSA SoAs for additional information.  

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
8
H 0 P -M C - BP 0 3
I S A
R a n d o miz ati o n
D o u ble -Bli n d Tre at me nt
E arl y
Disc o nti n u ati o n
N otes
Visit N u m ber
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
± 3
± 3
± 3
Tele p h o ne Vi sit
X a, b
Visit wi n d o w + 2 da ys
T here will be 2 tele p h o ne visits bet wee n Visit 3 a n d Visit 4:
a Visit occ urs 4 da ys after Visit 3
 
b Visit occ urs 8 da ys after Visit 3 
 
Pr oce d ures
E val uate all I/ E criteria
X
P h ysical e xa mi nati o n
X  
X  
X  
X  
X
X
V 3 -V 7:  D o s y m pt o m -directe d p h ysical e xa mi nati o n
E C G
X  
X  
X  
X  
X
X
V 3, V 5 , a n d V 7:  S i n gle E C G bef ore i n-cli nic d osi n g a n d at 3 h o urs after 
d osi n g
V 4 , V 6 a n d E D:  Si n gle E C G
E C G i ncl u des c ollecti o n of P R i nter val, Q R S d urati o n a n d i nter val, a n d heart 
rate.
Vital si g ns
X  
X  
X  
X  
X
X
Bl o o d Press ure a n d P ulse R ate
V 3, V 5, a n d V 7:  C ollect bl o o d press ure a n d p ulse i n s u pi ne a n d sta n di n g 
p ositi o n bef ore i n -cli nic d osi n g a n d at 3 h o urs after d osi n g
V 4, V 6 , a n d E D:  C ollect bl o o d press ure o nce
C ollect ort h ostatic bl o o d press ure after 5 mi n utes s u pi ne a n d t he n 2 - 3 mi n utes 
after sta n di n g a n d c ollect p ulse after s u pi ne a n d sta n di n g bl o o d press ure .
Te m per at ure a n d Res pir at or y R ate
C ollect o nce at eac h visit
St u d y i nter ve nti o n 
X  
X  
X  
X  
X
I nter ve nti o n is ta ke n orall y, t wice dail y, a p pr o xi matel y e ver y 1 2 h o urs.
V 3, V 5, a n d V 7:  Partici pa nts ta ke t he m or ni n g d ose i n t he cli nic.
Refer t o Secti o n 6. 6 f or d ose titrati o n sc he me.
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C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
9
H 0 P -M C - BP 0 3
I S A
R a n d o miz ati o n
D o u ble -Bli n d Tre at me nt
E arl y
Disc o nti n u ati o n
N otes
Visit N u m ber
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
± 3
± 3
± 3
Tele p h o ne Vi sit
X a, b
Visit wi n d o w + 2 da ys
T here will be 2 tele p h o ne visits bet wee n Visit 3 a n d Visit 4:
a Visit occ urs 4 da ys after Visit 3
 
b Visit occ urs 8 da ys after Visit 3 
 
.
Pr oce d ures
I nter ve nti o n c o m plia nce
X  
X  
X  
X
X
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  
X
X
V 3:  C ollect la b orat or y tests bef ore d osi n g.
C he mistr y
X  
X  
X  
X  
X
X
V 3:  C ollect la b orat or y tests bef ore d osi n g.
Uri n e dr u g scree n
Perf or me d at i n vesti gat or discreti o n .
Ser u m pre g na nc y
X  
X  
X  
X
X
F or W O C B P o nl y
Uri ne pre g na nc y
X
F or W O C B P o nl y
C ollect sa m ple wit hi n 2 4 h o urs pri or t o first d ose.
Li pi d pa nel
X  
X  
X  
X  
X
X
T h yr oi d pa nel
X  
X  
X  
X  
X
X
C y stati n C
X  
X  
X  
X  
X
X
H b A 1c
X
X
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C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
1 0
H 0 P -M C - BP 0 3
I S A
R a n d o miz ati o n
D o u ble -Bli n d Tre at me nt
E arl y
Disc o nti n u ati o n
N otes
Visit N u m ber
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
± 3
± 3
± 3
Tele p h o ne Vi sit
X a, b
Visit wi n d o w + 2 da ys
T here will be 2 tele p h o ne visits bet wee n Visit 3 a n d Visit 4:
a Visit occ urs 4 da ys after Visit 3
 
b Visit occ urs 8 da ys after Visit 3 
 
Pr oce d ures
P K sa m ple
X  
X  
X  
X  
X
X
V 3:  C ollect at 3 h o urs ± 1 5 mi n utes after d osi n g. 
V 5 a n d V 7:  C ollect sa m ples bef ore d osi n g a n d at 3 h o urs ± 1 5 mi n utes after 
d osi n g.
V 4, V 6, a n d E D:  C ollect si n gle sa m ple at a n y ti me.
Rec or d date a n d ti me of c ollecti o n.
S o mat ostati n -re g ulate d 
h or m o ne sa m ple
X  
X  
X  
X  
X
X
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 = gl ycate d he m o gl o bi n; I/ E = i ncl usi o n a n d e xcl usi o n; I S A = 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.
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CONFIDENTIAL
Protocol number H0P-MC-BP03
11
2.
Introduction
This ISA BP03 is an appendix to the master protocol and contains unique study elements specific 
for LY3556050.  The master protocol contains the overarching study elements that govern the 
CLBP DSA and this ISA BP03.  
2.1.
Study Rationale
The purpose of this study is to test whether LY3556050 is efficacious in relieving CLBP.  Data
will be collected to assess the safety and tolerability of LY3556050 in this study population. PK 
properties and PD effects will also be explored.  The totality of data from this proof-of-concept 
study will assess the benefits and risks associated with LY3556050 and inform decisions for the 
clinical development of LY3556050.
2.2.
Background
Somatostatin (SST) is an inhibitory neuropeptide exerting its activity via 5 different somatostatin 
receptor (SSTR) subtypes named SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5.  Most are 
involved in homeostatic regulation of polypeptide hormones.  Given its neuronal distribution, 
SSTR4 has been of interest for its ability to modulate sensory nerve transmission and pain 
response.  
LY3556050 is a selective, potent, and full agonist of the human somatostatin receptor subtype 4 
(SSTR4) and is under development as an oral analgesic for chronic pain.  A detailed description 
of the chemistry, pharmacology, efficacy, and safety of LY3556050 is provided in the 
Investigator’s Brochure (IB).
Two Phase 1 clinical studies in healthy participants are completed, CNTX-0290-101 (CNTX) 
and J2P-MC-LXBA (LXBA).  CNTX and LXBA study results are available in the IB.  
Pharmacokinetics
The PK data from Study LXBA Part A were consistent with those observed in Study CNTX and 
support twice-daily dosing.
Safety
The highest dose of 600 mg every 12 hours is considered safe and well tolerated in healthy 
participants.
2.3.
Benefit/Risk Assessment
The IB provides detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of LY3556050.  

CONFIDENTIAL
Protocol number H0P-MC-BP03
12
2.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention LY3556050
Cardiovascular
HR:  Variable data across clinical 
studies and across doses
PR interval:  Concentration-related 
increase in duration with large 
variability
QRS interval:  
Concentration-related increase in 
duration
Vital signs and ECGs evaluated at 
each visit.  Cardiovascular safety 
parameters to be evaluated include:  
HR, PR and QRS intervals, and 
orthostatic vital signs.
Additional participant exclusion 
criteria to protect those with a
potential risk.
Discontinuation criteria for 
clinically significant changes.
Thyroid
TSH increases observed in 
Study LXBA
Labs evaluated at each visit to 
monitor thyroid function.
Additional participant exclusion
criteria to protect those with a 
potential risk.
Discontinuation criteria for 
clinically significant changes.
Abbreviations:  ECG = electrocardiogram; HR = heart rate; TSH = thyroid-stimulating hormone.
2.3.2. Benefit Assessment
This is the first study evaluating efficacy of LY3556050 in participants with CLBP.
Potential benefits for the study participants include 

study-related medical procedures 
o
physical examinations
o
laboratory tests 
o
electrocardiograms (ECGs) 

detailed evaluations of low back pain, and 

questionnaires that may improve participants understanding of their own condition. 
As part of the master protocol, participants to this ISA will report their experiences 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 chronic pain.  Together, 
these may lead to the development of a new treatment with an improved safety and efficacy 
profile compared to standard of care.
2.3.3. Overall Benefit: Risk Conclusion
The measures taken to minimize risk to participants in this study and the potential risks identified 
in association with this ISA are justified by the anticipated benefits to participants with CLBP.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
1 3
3.
O bjecti ves a n d E n d p oi nts
T he m aster pr ot oc ol a n d C L B P D S A i ncl u de o bjecti ves a n d e n d p o i nts a p plica ble f or t his st u d y.  
T his ta ble descri bes o bject i ves a n d e n d p oi nts s pecific f or L Y 3 5 5 6 0 5 0.
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C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
1 4
4.
St u d y Desi g n
4. 1.
O ver all Desi g n
T he m aster pr ot oc ol descri bes t he o verall st u d y desig n a n d st u d y  desi g n ratio nale.  T his sect i on 
descri bes visits a n d o verall pr oce d ures u ni q ue t o t his I S A f or L Y 3 5 5 6 0 5 0 i n a d diti on t o t he 
pr o c e d ures o utli ne d i n t he ma ster pr ot oc ol a n d C L B P D S A .
D o u ble - Bli n d Tre at me nt Peri o d ( Visits 3 t hr o u g h 7)
If t he partici pa nt recei ves at least 1 d ose of i nter ve nti on a n d disc o nt i n ues d uri n g t he d o u ble-bli n d 
treat me nt perio d, t he y  s h o uld c o m plete earl y  disc o nti n uati on pr oce d ures per t he master pr ot oc ol, 
C L B P D S A, a n d t hi s I S A Sc he d ule of Act i vities ( S o A).  If t here are d u plicate pr oce d ures, f oll o w 
t he B P 0 3 S o A. 
Visit 3
At  Visit 3 p ost ra n d o mizati o n

t he sit e c o mpletes t he B P 0 3 baseli ne pr oce d ures a n d sa m ple c o llecti on, 

parti ci pa nts recei ve t heir first d ose of st u d y int er ve nt i on a n d i nstr ucti o ns f or d osi n g at 
h o me,

t he sit e c o mpletes all p osttreat me nt sa m ple c o llecti o n a n d safety m o nit ori n g, a n d

t he s ite i nstr ucts partici pa nts t o c o nti n ue wit h st u d y restrict i ons a n d N u meric Rat i n g 
Scal e ( N R S) diar y e ntries bef ore t heir visit disc har ge.
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CONFIDENTIAL
Protocol number H0P-MC-BP03
15
Visits 4 through 7
At Visits 4 through 7, the site

reviews available safety data and completes predose procedures and sample collection,

reviews diary compliance, 

reviews study intervention compliance,

completes all posttreatment sample collection and safety monitoring, and

instructs participants to continue with study restrictions and NRS diary entries before 
their visit discharge.
4.2.
Scientific Rationale for Study Design
The master protocol describes the overall study design rationale.
Section 2.3.1 describes elements included in this study to further monitor cardiovascular and 
thyroid function, and the associated rationale.  
4.3.
Justification for Dose
The dose level of 600 mg BID was determined by current clinical data, efficacy pharmacology, 
and nonclinical safety data detailed in the IB.  A titration scheme is included to maximize 
tolerability of this target dose.  
Safety data from Study LXBA, and the clinical monitoring plan for this ISA, support testing the 
proposed dose regimen in participants with chronic pain conditions.
The observed LY3556050 exposure following repeated administration of 600 mg BID exceeds 
the exposure in rats where maximal pharmacological activity was consistently demonstrated 
across rodent models of neuropathic pain.  However, it is not known what exposure is required 
for efficacy in the target patient population.  Therefore, the highest dose (600 mg BID) 
previously evaluated in Study LXBA was selected for this study as this dosing regimen was 
observed to be well tolerated in healthy subjects and supported by an adequate margin of safety,
based on both monkey and rat repeated-dose toxicity studies (IB).
4.4.
End of Study Definition
A participant is considered to have completed this ISA if he or she has completed all required 
phases of the study including the last scheduled procedure shown in the ISA SoA.
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the ISA SoA for the last participant. 

CONFIDENTIAL
Protocol number H0P-MC-BP03
16
5.
Study Population
The master protocol and CLBP DSA provide eligibility criteria that must be followed for this 
study.  LY3556050 specific inclusion and exclusion criteria are listed here.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
[2025]
are men or women who abide by the reproductive and contraceptive requirements 
provided in this ISA Section 10.2, Appendix 2.
Women of childbearing potential (WOCBP) may participate and include those who

are completely abstinent or in a same-sex relationship, as part of their 
preferred and usual lifestyle, and must agree to either remain abstinent or 
stay in a same-sex relationship without sexual relationships with males, or 

must agree to use 1 highly effective method of contraception (less than 1%
failure rate), or a combination of 2 effective methods of contraception, for 
the entirety of the study.  
Women not of childbearing potential may participate and include those who

have a congenital anomaly such as Müllerian agenesis 

are infertile due to surgical sterilization, or 

are postmenopausal.  
5.2.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
[2026]
have a history within 2 years prior to Visit 1 or current evidence of syncope, 
presyncope, uncontrolled vertigo, or postural dizziness, judged to be clinically 
significant by the investigator
[2027]
have a QRS interval ≥120 msec at Visit 1 or Visit 2
[2028]
have a non-evaluable PR interval or a PR interval >200 msec at Visit 1 or Visit 2
[2029]
have a heart rate <40 bpm at Visit 1 or Visit 2
[2030]
have an estimated glomerular filtration rate (eGFR) of less than 
60 ml/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) formula at Visit 1 or Visit 2
[2031]
have clinically significant active thyroid disease, including Hashimoto’s 
thyroiditis 

CONFIDENTIAL
Protocol number H0P-MC-BP03
17
Prior/Concomitant Therapy
[2032]
have been on thyroid replacement therapy or supplements for less than 12 weeks 
or had a change in thyroid replacement therapy or supplements in the last 
12 weeks before Visit 2
[2033]
have had a change in beta blocker therapy in the last 12 weeks before Visit 2.  
This does not include a discontinuation of therapy.
[2034]
are taking medications that are known MATE1 or OCT2 substrates with the risk 
for potentially clinically significant drug-drug interactions, such as metformin, 
dofetilide and dalfampridine 
Other Exclusions
[2035]
are pregnant or breastfeeding.
5.3.
Lifestyle Considerations
Reproductive and Contraception Requirements
Reproductive requirements and contraceptive guidance are provided in this ISA, Section 10.2,
Appendix 2.  Participants should maintain a consistent lifestyle throughout participation as much 
as possible.  
Other requirements
Refer to the master protocol Section 5.3 for additional details.  

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
1 8
6.
St u d y I nter ve nti o n
6. 1.
St u d y I nter ve nti o n(s) A d mi nistere d
P arti cipa nts will ta ke ca ps ules orall y , BI D, a p pr o xi matel y e ver y  1 2 h o urs , wit h or wit ho ut f o o d .  
I nter ve nti o n N a me
L Y 3 5 5 6 0 5 0
Pl ace 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)
n ot a p plica ble
D os a ge Le vel(s)
6 0 0 m g BI D, a p pr o xi matel y 
e ver y 1 2 h o urs
p lace b o t o matc h BI D
R o ute of 
A d mi nistr ati o n
or al
o r al
Use
e x peri me ntal 
p lace b o
I M P a n d NI M P
I M P 
I M P a n d NI M P
S o urci n g
L Y 3 5 5 6 0 5 0 fr o m Lill y
Place b o will be pac ka ge d, la bele d, distri b ute d, a n d 
dis pe nse d as I M P b y Lill y .
P ac k a gi n g a n d 
L a beli n g
i n b ottles
i n b ottles
A b bre viati o ns:  BI D = t wice dail y; I M P = i n vesti gati o nal me dici nal pr o d uct; NI M P = n o n -i n vesti gati o nal me dici nal 
pr o d uct.
6. 2.
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
T he i n vest i gat or or desi g nee m ust c o nfir m a ppr o priate st ora ge c o n diti o ns ha ve bee n mai ntai ne d 
d uri n g tra nsit f or all st u d y  int er ve nt i on recei ve d a n d a n y  discre pa ncies are re p orte d a n d res ol ve d 
bef ore use of t he st u d y  int er ve ntio n.
O nl y partici pa nts e nr o lle d i n t he st u d y ma y recei ve st u d y i nter ve nt i on a n d o nl y a ut h orize d site 
staff ma y s u p pl y or a d mi nister st u d y int er ve nt i on.  All st u d y  int er ve nt i on m u st be st ore d i n a 
sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da nce 
wi t h t h e la bele d st ora ge c o n ditio ns wi t h access li mite d t o t he i n vesti gat or a n d a ut h orize d site 
staff.
T he i n vest i gat or or desi g nee is res p o nsi ble f or st u d y i nter ve nti on acc o u nta bilit y,  rec o nciliati on, 
a n d rec or d mai nte na nce , t h at is, receipt, rec o nciliati o n, a n d fi nal dis p osit i on rec or d s.
T he p har mac y ma n ual c o ntai ns f urt her g ui da nce a n d i nf or mat i on f or t he fi nal dis p ositi on of 
u n use d st u d y  int er ve nt i ons . 
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C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
1 9
6. 3.
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
T his I S A c o ntai ns n o a d dit i onal stratificati on fact ors.
6. 4.
St u d y I nter ve nti o n C o m pli a nce
A rec or d of t he n u m ber of L Y 3 5 5 6 0 5 0 or m atc hi n g place b o ca ps ules dis pe nse d t o a n d ta ke n b y  
eac h partici pa nt must b e m ai 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 p lia nce 
rec or ds.  I nter ve nti on start a n d st o p dates, i ncl u di n g dates f or i nter ve nt i on dela ys , will als o be 
rec or de d i n t he case re p ort f or m ( C R F ).
6. 5.
C o nc o mit a nt T her a p y
T he m aster pr ot oc ol pr o vides details o n c o nc o mita nt t hera p y . C o nc o mita nt t hera p y  use s h o uld 
r e mai n c o nsiste nt t hr o u g h o ut t he st u d y u nless c ha n ges are me dicall y warra nte d. Pl ease c o ns ult 
t he me dical m o nit or f or q uesti o ns.  
P ote nti al Dr u g -D r u g I nter acti o ns wit h L Y 3 5 5 6 0 5 0
Pl ease r efer t o Secti o n 5. 2 f or e xcl usi on cri t eria, t he I B, a n d Ma n ual of O perat i ons f or details o n 
c o nc o mita nt me dicat i on restrict i ons.
6. 6.
D ose M o dific ati o n
T his pr ot oc ol all o ws c ha n ges t o t he d ose f or i n di vi d ual partici pa nt s, b ut t he ma xi m u m dail y d ose 
will n ot e xcee d 6 0 0 m g BI D .
T he starti n g d ose le vel is  
  
Decisi o ns t o c ha n ge t he d ose le vel will be ma de b y t he i n vesti gat or i n disc ussi on wi t h t he 
parti ci pa nts base d o n t he A Es re p orte d f or t olera bilit y.  T he me dical m o nit or s h o ul d be c o ntacte d 
as nee de d.  
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C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
2 0
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Protocol number H0P-MC-BP03
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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Protocol CPMP provides the reasons and procedures for discontinuation of intervention and 
participant discontinuation that must be followed for this study.  LY3556050-specific 
information is included here. 
7.1.
Discontinuation of Study Intervention
Cardiovascular Safety
A participant may be permanently discontinued from study intervention for these clinically 
significant or symptomatic cardiovascular findings

QTcF >500 msec

PR interval prolongation >240 msec with symptoms 

symptomatic sustained tachycardia (>120 bpm) or bradycardia (<45 bpm) at rest

development of a new left bundle branch block, or 

Mobitz type II second- or third-degree atrioventricular block.
Thyroid Safety
If thyroid-stimulating hormone (TSH) ≥10 at 2 consecutive visits, then a participant will be 
permanently discontinued from study intervention.    
If participants have TSH ≥10 at 2 consecutive visits, then 
1. collect thyroid kit samples 
2. conduct a thyroid ultrasound approximately 2 weeks after the second laboratory time 
point, and 
3. continue testing until issue resolution.   

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Protocol number H0P-MC-BP03
22
8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoAs contained in the master protocol, 
CLBP DSA, and this ISA. 
LY3556050-specific assessments and procedures are described here. 
8.1.
Safety Assessments
The SoA contains the planned time points for all safety assessments.
8.1.1.
Vital Signs
Conduct vital signs measurements for each participant according to the SoA (Section 1.3). 
Follow the study-specific recommendations included in the Manual of Operations.  
8.1.2.
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF 
intervals. 
8.1.3.
Clinical Safety Laboratory Assessments
See BP03 Section 10.1, Appendix 1 for the list of clinical laboratory tests to be performed and 
the SoA (Section 1.3) for the timing and frequency.
8.2.
Adverse Events and Serious Adverse Events
The master protocol provides details on AE and serious adverse event (SAE) collection, 
evaluation and follow-up, and SAE reporting.
8.3.
Treatment of Overdose
There is no known antidote for LY3556050 overdose.
In case of suspected overdose, participants should be monitored for any signs or symptoms of 
adverse reactions or effects, and supportive care should be provided as necessary. 
8.4.
Pharmacokinetics
Collect venous blood samples of approximately 2 mL 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.
Lilly will provide instructions for the collection and handling of biological samples. 
Site personnel will record

the date and time (24-hour clock time) of LY3556050 administration in the morning 
during both in-clinic and at home dosing, and

the date and time (24-hour clock time) of each PK sample.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
2 3
P har mac o ki net ic sa m ples will be retai ne d f or a ma xi m u m of 2 y ears f o ll owi n g last s u bject v isit 
f or t he st u d y. 
 
8. 5.
P h ar m ac o d y n a mics
P har mac o d y na mic bi o mar kers ha ve n ot bee n i de ntifie d t o date.  Data fr o m t his st u d y  will be 
use d t o f urt her e val uate t he P D of L Y 3 5 5 6 0 5 0 .
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C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
2 4
9.
St atistic al C o nsi der ati o ns
T he m aster pr ot oc ol a n d C L B P D S A pr o vi de statistical c o nsi derat i ons. L Y 3 5 5 6 0 5 0- s pecific 
c o nsi derati o ns are descri be d here.
9. 1.
St atistic al H y p ot heses
T he m aster pr ot oc ol descri bes t he pri mar y h y p ot hesis.  
 
 
9. 2.
S a m ple Size Deter mi n ati o n
U p t o 2 0 0 partici pa nts will be ra n d o mize d i n a 
 t o L Y 3 5 5 6 0 5 0 a n d pl ace b o , res pecti vel y.
Ass u mi n g a n o verall dr o p o ut rate of a p pr o xi matel y  3 3 %
 
 
 
 If t her e is n o treat me nt 
differe nce bet wee n place b o a n d L Y 3 5 5 6 0 5 0 , 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 ulat i on f or t he p o wer calc ulati o n 
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. 3.
P o p ul ati o ns f or A n al yses
T he m aster pr ot oc ol defi nes t he p o p ulati o ns f or a nal yses.
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 5 6 0 5 0 a n d 
ha ve at least 1 e val ua ble P K sa m ple. 
9. 4.
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 h is 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 cli nical st u d y re p ort.  A d ditio n al  e x plor 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 a m ore tec h nical a n d 
detaile d d escript i on of t he statist ical a nal yses descri be d i n t his secti o n. 
9. 4. 1.
Ge ner al C o nsi der ati o ns
T he m aster pr ot oc ol descri bes t he pri mar y e n d p oi nt a n d a nal yses. 
T he m aster pr ot oc ol a n d C L B P D S A descri be t he 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.
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.  
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C O N FI D E N TI A L
Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
2 5
9. 4. 2.
P h ar m ac o ki netics a n d P h ar m ac o d y n a mics
T he o bser ve d plas ma c o nce ntrati o ns f or L Y 3 5 5 6 0 5 0 will be re p orte d gra p hicall y a n d 
descri pt i vel y.  
M o d el -base d P K a n d p har m ac o ki net ic-p har m ac o d y na mic (P K P D ) a nal yses ma y be c o n d ucte d t o 
c haracterize t he P K o f L Y 3 5 5 6 0 5 0 i n partici pa nts wit h C L B P a n d t o e x pl ore e x p os ure-res p o nse 
r elat i ons hi ps f or vari o us P D meas ures usi n g s uita ble p o p ulatio n a nal ysis s oft ware.  Partici pa nt 
fact ors ma y be i n vest i gate d t o assess t heir effects o n m o del para meters.  A d diti o nal a nal yses ma y 
be c o n d ucte d, as nee de d.  
Data fr o m t his st u d y  ma y be p o ole d wit h data fr o m ot her st u dies, if a p pr o priate.  A d diti o nal 
details o n P K a n d P K P D a nal yses will be pr o vi de d i n a se parate P K P D a nal ysis pla n.  
A li mite d n u m ber of pres pecifie d i n di vi d uals w h o are n ot part of  t he bli n de d st u d y tea m a n d d o 
n ot ha ve direct site c o ntact, data e ntr y , or data vali datio n res p o nsi bilit ies, ma y recei ve acce ss t o 
u n bli n de d data, 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 ulati o n 
P K P D m o d el  de velo p me nt pr ocesses. T hi s will be descri be d i n t he u n bli n di n g pla n. I nf or mati on 
t hat ma y u n bli n d t he st u d y d uri n g t he a nal yses will n ot be re p orte d t o st u d y sites or bli n de d st u d y 
tea m u ntil t he st u d y has bee n u n bli n de d.
9. 4. 3.
Terti ar y/ E x pl or at or y
All safety a nal yses will be ma de o n t he safet y p o p ul at i on.   Descri pt i ve statistics 
 
 will be c o n d ucte d as 
dee m e d a p pr o priate.  C o nf o u n di n g fact ors, s uc h as beta bl oc ker t hera p y, ma y be a dj uste d i n t he 
statistical m o dels f or safet y a nal yses.  S u b gr o u p a nal yses of car di o vasc ular safet y e n d p o i nts wit h 
beta bl oc ker t hera p y  ma y be c o n d ucte d acc or di n gl y. 
9. 4. 4.
Bi o m ar kers
C o nsiste nt wit h t he master pr ot oc ol o bjecti ves, e x pl orat or y  fl ui d, a n d di gital bi o mar ker a nal yses 
ma y be c o n d ucte d o n sa m ples a n d data c ollecte d d uri n g t he st u d y .  
9. 5.
I nteri m A n al yses 
I nteri m a nal yses ma y be c o n d ucte d f or i nter nal decisi o n- ma ki n g.  U n bli n di n g a n d i nteri m 
a nal ysis details ma y 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 
d oc u m e nt.  
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Pr ot oc ol  n u m ber H 0 P -M C -B P 0 3
2 6
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 m aster pr ot oc ol descri bes tests t hat ma y be perf or me d at a d diti onal ti 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 t his I S A.  
C he mistr y
A d diti o n al T h yr oi d Tests
Ot her S S T -Re g ul ate d 
H or m o nes
O t her Tests
C y stati n- C
Free Trii o d ot h yr o ni ne ( Free T 3)
Gr o wt h h o r m on e
A m ylase
T S H
T otal Trii o d ot h yr o ni ne ( T 3)
I ns uli n-li ke Gr o wt h Fact or- 1 
(I G F- 1)
Li pase
Free T h y r oxi ne ( Free T 4) 
Pr olacti n
L Y 3 5 5 6 0 5 0 c o nce ntrati o n
T otal T h y r oxi ne ( T 4)
Gastri n
Ser u m pr e g na nc y test
Gl uca g o n
H b A 1c
I ns uli n
A b bre viati o ns:  H b A 1c = gl ycate d he m o gl o bi n; S S T = s o mat ostati n; T S H = t h yr oi d -sti m ulati n g h or m o ne.
T h yr oi d S afet y F oll o w -U p
T S H
Free Trii o d ot h yr o ni ne ( Free T 3)
T otal Trii o d ot h yr o ni ne ( T 3)
Free T h y r oxi ne ( Free T 4) 
T otal T h y r oxi ne ( T 4)
T h y r ogl o b uli n
A nti- T h y r ogl o b uli n
A nti- T h y r oper o xi dase A nti b o dies
I o di ne
A b bre viati o n:  T S H = t h yr oi d -sti m ulati n g h or m o ne.
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Protocol number H0P-MC-BP03
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10.2.
Appendix 2: Definitions of Reproductive Requirements and 
Contraceptive Guidance
Women
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Woman not of Childbearing Potential (non-WOCBP)
Women in the following categories are not considered WOCBP:

premenarchal

premenopausal female that is infertile due to surgical sterilization, or

postmenopausal.
Surgical sterilization examples include

hysterectomy 

bilateral oophorectomy, or 

tubal ligation.  
Postmenopausal is defined as either

a woman at least 40 years of age with an intact uterus, not on hormone therapy, who has 
cessation of menses for at least 1 year without an alternative medical cause, AND a 
follicle-stimulating hormone >40 mIU/mL

a woman 55 or older not on hormone therapy, who has had at least 12 months of 
spontaneous amenorrhea, or

a woman at least 55 years of age with a diagnosis of menopause prior to starting hormone 
replacement therapy.
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Müllerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry. 
Note:  Determination can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
Participation in the Study
Women not of childbearing potential and of childbearing potential may participate in this study.
Women not of childbearing potential include those who 

have a congenital anomaly such as Müllerian agenesis 

are infertile due to surgical sterilization, or 

are postmenopausal.  

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Protocol number H0P-MC-BP03
28
At least 6 weeks must have passed after surgical bilateral oophorectomy with or without 
hysterectomy, or after tubal ligation.
Women of childbearing potential must test negative for pregnancy prior to initiation of treatment 
as indicated by a negative serum pregnancy test at the screening visit followed by a negative 
urine pregnancy test within 24 hours prior to exposure.
Women of childbearing potential who are completely abstinent or in a same-sex relationship, as 
part of their preferred and usual lifestyle, must agree to either remain abstinent or stay in a 
same-sex relationship without sexual relationships with males.
All other WOCBP must agree to use 1 highly effective method of contraception (less than 1% 
failure rate), or a combination of 2 effective methods of contraception, for the entirety of the 
study.  
Abstinence or contraception must continue for 3 days after the last dose of intervention.
Acceptable Methods of Contraception
Highly effective methods of contraception (less than 1% failure rate) comprise, but are not 
limited to

combination oral contraceptive pill and mini-pill

implanted or injectable contraceptives

contraceptive patch (only for women <198 pounds or 90 kg)

total abstinence

vasectomy if they are the only sexual partner

fallopian tube implants if confirmed by hysterosalpingogram

combined contraceptive vaginal ring, or 

intrauterine devices. 
Effective methods of contraception comprise but are not limited to 

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.  
Not Acceptable Methods of Contraception
Ineffective methods of contraception comprise of

spermicide alone 

immuno-contraceptives

periodic abstinence

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
fertility awareness 
o
calendar method 
o
temperature method 
o
combination of calendar and temperature method
o
cervical mucus, or
o
symptothermal

withdrawal

post coital douche, or

lactational amenorrhea.
Men
No male contraception is required during study participation except in compliance with specific 
local government study requirements.
Collection of Pregnancy Information
Male participants with partners who become pregnant
The investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive LY3556050.
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
sponsor within 24 hours of learning of the partner’s pregnancy. 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. Generally, 
the follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of gestational age, fetal status (presence 
or absence of anomalies) or indication for the procedure.
Female participants who become pregnant
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study.  The initial information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a participant's 
pregnancy. 
The participant will be followed to determine the outcome of the pregnancy.  The investigator 
will collect follow-up information on the participant and the neonate and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date.  Any termination of pregnancy will be reported, including 
fetal status (presence or absence of anomalies) or indication for the procedure.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 

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A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring at 
≥20 weeks gestational age) is always considered to be an SAE and will be reported as such. 
Any poststudy pregnancy-related SAE considered reasonably related to the study intervention by 
the investigator will be reported to the sponsor as described in the master protocol Section 8.3.4.  
While the investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will be withdrawn 
from the study and will follow the standard discontinuation process.  

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10.3.
Appendix 3: 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.
Exceptional circumstances
Exceptional circumstances are rare events 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. 
Ethical Review Boards (ERBs) and regulatory bodies will be notified as early as possible to 
communicate implementation of changes in study conduct due to exceptional circumstances.  To 
protect the safety of study participants, urgent changes may be implemented before 
communication to ERBs and regulatory bodies.  Lilly will report all changes as soon as possible 
following implementation.  If approval of ERBs, regulatory bodies, or both is required per local 
regulations, the site must retain confirmation of this approval in the study records.
Additional written guidance will be provided by the sponsor in the event written approval is 
granted for changes in study conduct.  
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

Good Clinical Practice compliance, and

minimization of risk to study integrity. 
Such changes are intended to

mitigate risks of participants missing visits,

allow participants to continue safely in the study, and

maintain the data integrity of the study. 
Informed Consent
If these circumstances occur, additional consent from the participant will be obtained, if 
applicable, for:

participation in remote visits,

additional study intervention dispensed to a participant during an extended visit window, 
or 

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
alternate delivery of study intervention and ancillary supplies, as well as provision for 
their personal or medical information required prior to implementation of these 
activities.
Changes in Study Conduct
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.  Missing data 
will be captured as protocol deviations.
Remote visits
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Telemedicine:  Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments.  
Assessments to be completed in this manner include, but are not limited to, individual 
safety follow-up.
Mobile healthcare:  Healthcare visits may be performed at locations other than the study 
site (for example, participant’s home) when participants cannot travel to the site due to an 
exceptional circumstance.  Such visits will be performed by a mobile healthcare provider. 
Procedures performed at such visits include, but are not limited to, collection of blood 
samples, physical examinations, ECGs, vital signs, intervention accountability and 
compliance, AE collection, and collection of health information.
Other local procedures:  Laboratory draws may be done at an alternate location in 
exceptional circumstances.
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged. 
Every effort should be made to enable participants to return to onsite visits as soon as reasonably 
possible, while ensuring the safety of both the participants and the site staff.
Local Laboratory Testing
Local laboratory testing may be conducted in lieu of central laboratory testing.  The local 
laboratory must be qualified in accordance with applicable local regulations.
If local testing is used, PK and exploratory biomarker sample collection may not occur.
Investigational Product and Ancillary Supplies (including participant diaries)
When a participant is unable to go to the site to receive study supplies during normal onsite 
visits, the site should work with the sponsor to determine appropriate actions.  These actions may 
include:

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
asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit,

asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and

arranging delivery of study supplies. 
Alternate delivery of investigational product 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, 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 should be provided to the participant on how to return any unused or completed 
study supplies.
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid study intervention interruption and maintain overall integrity of the study.
Adjustments to Visit Windows
Participants should complete the SoA as described in the master protocol CPMP, CLBP DSA 
and this ISA whenever possible and safe to do so.  To maximize the possibility that visits are 
conducted at the clinical site, the visit windows may be adjusted to minimize missing data and 
preserve the intended conduct of the study.  Adjustments to the visit windows will be discussed 
with, and approved by, the sponsor prior to any changes.
Documentation
Changes to study conduct will be documented.
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. 
Dispensing and shipment records of 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.
The study site should capture specific explanations for any missing data and other protocol 
deviations in source documents.  
Although protocol deviations may be unavoidable in an exceptional circumstance, 
documentation of protocol deviations and missing data will be important for data analysis and 
reporting.

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10.4.
Appendix 4: Abbreviations
Term
Definition
BID
twice daily
CLBP
chronic low back pain
DSA
disease-state addendum
eGFR
estimated glomerular filtration rate
FACTS
Fixed and Adaptive Clinical Trial Simulator software tool
ISA
intervention-specific appendix
MATE1
multidrug and toxin extrusion transporter
OCT2
organic cation transporter 2
PD
pharmacodynamic
PK
pharmacokinetic
PKPD
pharmacokinetic-pharmacodynamic
PR interval
During an ECG, the period, measured in milliseconds, that extends from the beginning of 
the P wave until the beginning of the QRS complex
QRS
During an ECG, a combination of the Q wave, R wave, and S wave, representing 
ventricular depolarization
QT
During an ECG, the QT interval is the time from the start of the Q wave to the end of the 
T wave.
QTcF
QT interval using Fridericia’s correction formula
SAE
serious adverse event
SAP
statistical analysis plan
SST
somatostatin
SSTR
somatostatin receptor
TSH
thyroid-stimulating hormone
WOCBP
woman/women of childbearing potential

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