Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3556050 for the Treatment of Diabetic Peripheral Neuropathic Pain
Phase: PHASE2
Conditions: Diabetic Peripheral Neuropathic Pain
Sponsor: Eli Lilly and Company

This study H0P-MC-NP03 (NCT04707157) is a sub-study of Master Protocol H0P-MC-CPMP 
(NCT05986292) 
Protocol: H0P-MC-NP03(b) 
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3556050 for 
the Treatment of Diabetic Peripheral Neuropathic Pain
NCT04707157 
Approval Date: 01-Oct-2021 

CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY3556050 unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.  
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Master Protocol Title: A Master Protocol for Randomized, Placebo-Controlled, Phase 2 
Clinical Trials of Multiple Interventions for the Treatment of Chronic Pain
Master Protocol Number: H0P-MC-CPMP 
ISA Title: Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3556050 for 
the Treatment of Diabetic Peripheral Neuropathic Pain 
ISA Number: H0P-MC-NP03 
Amendment Number: b 
Compound: LY3556050 
Study Phase: 2 
Short Title: Clinical Trial to Evaluate LY3556050 for the Treatment of Diabetic Peripheral 
Neuropathic Pain 
Acronym: NP03 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number: 
Master Protocol IND 144915 
LY3556050 IND 129756 
Approval Date: Protocol amendment (b) Electronically Signed and Approved by Lilly on date 
provided below.  
Approved on 01 Oct 2021 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
2 
Medical Monitor Name and Contact Information will be provided separately  
 
 
 
Approved on 01 Oct 2021 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
3 
Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment (a) 
12 March 2021 
Original Protocol 
23 September 2020 
Amendment [b]  
Overall Rationale for the Amendment: 
This amendment allows participants to take certain doses of metformin based upon new PK 
modeling data and metformin prescribing information (GLUCOPHAGE package insert, 2018).  
 
Section # and Name 
Description of Change 
Brief Rationale 
1.2. Schema 
Added a follow-up visit 
Adding a telephone follow-up visit for adverse 
event (AE) check 
1.3. Schedule of Activities 
(SoA) 
Added a follow-up visit and a 
corresponding row for AEs 
Adding a telephone follow-up visit for AE 
check 
AEs for the rest of the study are covered in the 
master CPMP SoA 
4.1. Overall Design 
Added follow-up visit 
Adding a telephone follow-up visit for AE 
check 
5.2. Exclusion Criteria 
Updated criterion #3034 to 
allow particular metformin 
doses 
The inclusion of selected doses of metformin for 
concomitant use is based on new PK modeling 
data and metformin prescribing information 
5.2. Exclusion Criteria 
Added criteria #3036 - #3041  
For participants taking metformin 
5.3. Lifestyle 
Considerations 
Added additional alcohol 
restrictions for binge drinking 
For participants taking metformin 
6.5. Concomitant Therapy 
Added a sub-section for 
concomitant therapy with 
metformin 
Specific metformin doses are now allowed 
7.1. Discontinuation of 
Study Intervention 
Added sub-section Metabolic 
Safety 
Provides additional information for participants 
taking metformin 
7.2. Participant 
Discontinuation/Withdrawal 
from the Study  
Added this section 
Provides additional information for participants 
taking metformin 
10.1. Appendix 1: Clinical 
Laboratory Tests 
Added bicarbonate and anion 
gap calculation to chemistry 
Participants are now allowed to take metformin 
10.1. Appendix 1: Clinical 
Laboratory Tests 
Added eGFR calculated by 
CKD-EPI equation based upon 
cystatin c 
Participants are now allowed to take metformin 
11. References 
Added Reference section 
In order to cite the metformin GLUCOPHAGE 
package insert 
Throughout the protocol 
Minor editorial and formatting 
changes 
Minor, therefore not described 
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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 -N P 0 3 (b ) 
 
4  
T a ble of C o nte nts  
1.  
Pr ot oc ol S u m m ar y  ..........................................................................................................6  
1. 1.  
S y n o psis  ............................................................................................................................6  
1. 2.  
Sc he ma  ..............................................................................................................................7  
1. 3.  
Sc he d ule of A cti vities ( S o A)  ............................................................................................8  
2.  
I ntr o d ucti o n ...................................................................................................................1 3  
2. 1.  
St u d y R ati o nale  ...............................................................................................................1 3  
2. 2.  
Bac k gr o u n d  .....................................................................................................................1 3  
2. 3.  
Be nefit/ Ris k Assess me nt  ................................................................................................1 3  
2. 3. 1.  
Ris k Assess me nt  .............................................................................................................1 4  
2. 3. 2.  
Be nefit Assess me nt  .........................................................................................................1 4  
2. 3. 3.  
O verall Be nefit: Ris k C o ncl usi o n  ...................................................................................1 4  
3.  
O bjecti ves a n d E n d p oi nts  ............................................................................................1 5  
4.  
St u d y Desi g n  ..................................................................................................................1 6  
4. 1.  
O verall Desi g n  ................................................................................................................1 6  
4. 2.  
Scie ntifi c Rati o nale f or St u d y Desi g n  ............................................................................1 7  
4. 3.  
J ustificati o n f or D ose ......................................................................................................1 7  
4. 4.  
E n d of St u d y Defi niti o n  ..................................................................................................1 7  
5.  
St u d y P o p ul ati o n  ...........................................................................................................1 8  
5. 1.  
I n cl usi o n Criteria ............................................................................................................1 8  
5. 2.  
E x cl usi o n Criteria  ...........................................................................................................1 8  
5. 3.  
Lif est yle C o nsi derati o ns  .................................................................................................2 0  
6.  
St u d y I nter ve nti o n  ........................................................................................................2 1  
6. 1.  
St u d y I nter v e nti o n(s) A d mi nistere d ................................................................................2 1  
6. 2.  
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  ................................................................2 1  
6. 3.  
Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g  ............................................2 2  
6. 4.  
St u d y I nter v e nti o n C o m plia nce  ......................................................................................2 2  
6. 5.  
C o nc o mita nt T hera p y  .....................................................................................................2 2  
6. 6.  
D ose M o dificati o n  ..........................................................................................................2 2  
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 5  
7. 1.  
Disc o nti n uati o n of St u d y I nter ve nti o n  ............................................................................2 5  
7. 2.  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ................................................2 5  
8.  
St u d y Assess me nts a n d Pr o ce d ures .............................................................................2 6  
8. 1.  
Safet y Assess me nts  .........................................................................................................2 6  
8. 1. 1.  
Vit al Si g ns  .......................................................................................................................2 6  
8. 1. 2.  
Electr ocar di o gra ms  .........................................................................................................2 6  
8. 1. 3.  
Cli nical Safet y La b orat or y Assess me nts  ........................................................................2 6  
8. 2.  
A d verse E v e nts a n d Seri o us A d verse E v e nts  .................................................................2 6  
8. 3.  
Treat me nt of O v er d ose  ...................................................................................................2 6  
8. 4.  
P har mac o ki netics  ............................................................................................................2 6  
8. 5.  
P har mac o d y na mics  .........................................................................................................2 7  
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CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
5 
9. 
Statistical Considerations .............................................................................................28 
9.1. 
Statistical Hypotheses .....................................................................................................28 
9.2. 
Sample Size Determination ............................................................................................28 
9.3. 
Populations for Analyses ................................................................................................28 
9.4. 
Statistical Analyses .........................................................................................................28 
9.4.1. 
General Considerations ...................................................................................................28 
9.4.2. 
Pharmacokinetics and Pharmacodynamics .....................................................................29 
9.4.3. 
Tertiary/Exploratory .......................................................................................................29 
9.4.4. 
Biomarkers ......................................................................................................................29 
9.5. 
Interim Analyses .............................................................................................................29 
10. 
Supporting Documentation and Operational Considerations ..................................30 
10.1. 
Appendix 1: Clinical Laboratory Tests ...........................................................................30 
10.2. 
Appendix 2: Definitions of Reproductive Requirements and 
Contraceptive Guidance ..................................................................................................32 
10.3. 
Appendix 3:  Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................36 
10.4. 
Appendix 4: Abbreviations .............................................................................................39 
10.5. 
Appendix 5: Protocol Amendment History ....................................................................40 
11. 
References ......................................................................................................................42 
 
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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 -N P 0 3 (b ) 
 
6  
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 miz e 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 Dia betic Peri p h eral Ne ur o pat hic Pai n  
R ati o n ale:  
T he p ur p ose of t his st u d y is t o test w het her L Y 3 5 5 6 0 5 0 is efficaci o us i n relie vi n g dia betic 
peri p heral ne ur o pat hic p ai n  ( D P N P).  Data will be c ollecte d t o assess t he s afet y a n d t olera bilit y 
of L Y 3 5 5 6 0 5 0  i n t his st u d y p o p ulati o n.  P har mac o ki netic pr o perties a n d p har mac o d y n a mic 
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 nefits a n d ris ks ass o ciate d wit h L Y 3 5 5 6 0 5 0  a n d i nf or m decisi o ns f or t he cli nical de vel o p me nt 
of L Y 3 5 5 6 0 5 0.  
O bjecti ves a n d E n d p oi n ts: 
T he pri mar y a n d s ec o n d ar y o bje cti ves a n d e n d p oi nts are state d i n t he mast er pr ot oc ol 
H 0 P -M C -C P M P ( C P M P) a n d D P N P  disease -st ate a d de n d u m ( D S A; C P M P[3 ]). 
O ver all Desi g n:  
T his is a n 8 -wee k, P has e 2, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t hat will 
c o m pare L Y 3 5 5 6 0 5 0 vers us place b o i n partici pa nts wit h D P N P .  
Discl os ure St ate me nt :  T his is a ra n d o mize d, i n vesti gat or- a n d partici pa nt -bli n d, 
place b o -c o ntr olle d, P has e 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 o mize d i n a  
 t o L Y 3 5 5 6 0 5 0 a n d place b o, res pecti vel y, 
wit h t he ass u m pti o n t hat a p pr o xi matel y 3 3 % of t h e 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 t reat me nt peri o d.  
I nter ve nti o n Gr o u ps a n d D ur ati o n: 
Partici pa 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  
 m g), 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  
Safet y re vie ws are c o vere d b y t h e 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 -N P 0 3 (b ) 
 
7  
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CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
8 
1.3. 
Schedule of Activities (SoA) 
This SoA shows visits and procedures unique to the intervention-specific appendix (ISA) H0P-MC-NP03 (NP03) for LY3556050. 
Please refer to master protocol and the DPNP DSA SoAs for additional information.   
 
Approved on 01 Oct 2021 GMT

C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -N P 0 3 (b ) 
 
9  
H 0 P -M C -N P 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  
F oll o w - 
u p  
N otes  
Visit N u m ber  
V 3  
V 4  
V 5  
V 6  
V 7  
E D  
V 8 0 1  
 
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 V isit 
X a, b 
 
 
 
 
 
X c 
Visit wi n d o w + 2 da ys  
 
 
 
 
 
 
 
c Visit 8 0 1 occ ur s 4 -1 0 da ys after last d ose of st u d y i nter ve nti o n.   
Pr oce d ures  
 
 
E val u ate all I/ E criteria  
X  
 
 
 
 
 
 
 
P h ysical e xa mi n ati 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 n ati o n  
E C G  
X  
X  
X  
X  
X  
X  
 
V 3, V 5 , a n d V 7: S i n gle safet y 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 n cl 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 uls e 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 n e 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 n e 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 n e 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  
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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 -N P 0 3 (b ) 
 
1 0  
H 0 P -M C -N P 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  
F oll o w - 
u p  
N otes  
Visit N u m ber  
V 3  
V 4  
V 5  
V 6  
V 7  
E D  
V 8 0 1  
 
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 V isit 
X a, b 
 
 
 
 
 
X c 
Visit wi n d o w + 2 da ys  
 
 
 
 
 
 
 
c Visit 8 0 1 occ ur s 4 -1 0 da ys after last d ose of st u d y i nter ve nti o n.   
Pr oce d ures  
 
 
A Es  
 
 
 
 
 
 
X  
 
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 ( BI D), a p pr o xi matel y 
e ver y 1 2  h o urs.  
V 3, V 5, a n d V 7:  P artici p a nts ta ke t h e 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. 
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 b ef or e d osi n g.  
C he mistr y  
X  
X  
X  
X  
X  
X  
 
V 3:  C ollect la b orat or y tests b ef or e d osi n g.  
Uri n e dr u g scree n  
 
 
 
 
 
 
 
P erf 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  
 
 
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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 -N P 0 3 (b ) 
 
1 1  
H 0 P -M C -N P 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  
F oll o w - 
u p  
N otes  
Visit N u m ber  
V 3  
V 4  
V 5  
V 6  
V 7  
E D  
V 8 0 1  
 
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 V isit 
X a, b 
 
 
 
 
 
X c 
Visit wi n d o w + 2 da ys  
 
 
 
 
 
 
 
c Visit 8 0 1 occ ur s 4 -1 0 da ys after last d ose of st u d y i nter ve nti o n.   
Pr oce d ures  
 
 
T h yr oi d pa nel  
X  
X  
X  
X  
X  
X  
 
 
C ystati n C  
X  
X  
X  
X  
X  
X  
 
 
H b A 1c  
 
 
 
 
X  
X  
 
 
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  
 
 
 
 
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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 -N P 0 3 (b ) 
 
1 2  
H 0 P -M C -N P 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  
F oll o w - 
u p  
N otes  
Visit N u m ber  
V 3  
V 4  
V 5  
V 6  
V 7  
E D  
V 8 0 1  
 
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 V isit 
X a, b 
 
 
 
 
 
X c 
Visit wi n d o w + 2 da ys  
 
 
 
 
 
 
 
c Visit 8 0 1 occ ur s 4 -1 0 da ys after last d ose of st u d y i nter ve nti o n.   
Pr oce d ures  
 
 
P artici p a nt D e vic e  
P artici pa nt ret ur ns de vice  
 
 
 
 
X  
X  
 
 
 
A b bre viati o ns: A E = a d verse e ve nt ; 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 nterve 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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Protocol number H0P-MC-NP03(b) 
 
13 
2. 
Introduction 
This intervention-specific appendix (ISA), H0P-MC-NP03 (NP03) is an appendix to the master 
protocol H0P-MC-CPMP (CPMP) and contains unique study elements specific for LY3556050.  
The master protocol contains the overarching study elements that govern the diabetic peripheral 
neuropathic pain (DPNP) disease-state addendum (DSA) and this ISA.   
2.1. 
Study Rationale 
The purpose of this study is to test whether LY3556050 is efficacious in relieving DPNP.  Data 
will be collected to assess the safety, and tolerability of LY3556050 in this study population.  
Pharmacokinetic (PK) properties, and pharmacodynamic (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 AEs of LY3556050.   
Approved on 01 Oct 2021 GMT

CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
14 
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 DPNP. 
Potential benefits for the study participants include  
 study-related medical procedures  
o physical examinations 
o laboratory tests  
o electrocardiograms (ECGs)  
 detailed evaluations of diabetic nerve 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 DPNP.  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 DPNP. 
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3.  
O bjecti ves a n d E n d p oi nts  
T he master pr ot o c ol a n d D P N P  D S A i ncl u de o bjecti ves a n d e n d p oi nts a p plica ble f or t his st u d y.  
T his ta ble descri bes o bjecti ves a n d e n d p oi nts s pecific f or L Y 3 5 5 6 0 5 0.   
 
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4.  
St u d y Desi g n  
4. 1.  
O ver all Desi g n  
T he m aster pr ot o c ol descri bes t he o verall st u d y desi g n a n d st u d y desi g n rati o nale. T his secti o n 
descri bes visits a n d o verall pr oce d ures u ni q ue t o t his I S A f or L Y 3 5 5 6 0 5 0 i n a d diti o n t o t he 
pr oce d ures o utli ne d i n t he master pr ot oc ol a n d D P N P  D S A .   
D o u ble -Bli n d T re at me nt Peri o d ( Visits 3 t hr o u g h 7)  
If t he partici p a nt recei ves at least 1 d ose of i nter v e nti o n a n d disc o nti n ues d uri n g t he d o u ble-bli n d 
treat me nt peri o d, t he y s h o ul d c o m plete earl y disc o nti n uati o n pr oce d ures p er t he master pr ot oc ol, 
D P N P D S A, a n d t his I SA  Sc he d ule of Acti vities ( S o A).  If t here are d u plicate pr oce d ures, f oll o w 
t he N P 0 3 S o A. 
Visit 3  
At Visit 3 p ost ra n d o mizati o n  
 t he site c o m pletes t he N P 0 3 baseli ne pr oce d ures a n d sa m ple c ollecti o n ,  
 partici pa nts recei ve t heir first d ose of st u d y i nter ve nti o n a n d i nstr ucti o ns f or d osi n g at 
h o me , 
 t he site c o m pletes all p osttreat me nt sa m ple c ollecti o n a n d safet y m o nit 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 restricti o ns a n d N u meric Rati n g 
Scale ( N R S) diar y e ntries bef ore t hei r visit disc har ge. 
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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. 
Follow-up Telephone Visit 
A follow-up visit to review AEs, will occur 4 to 10 days after last dose of study intervention. 
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 twice daily (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.  
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5. 
Study Population 
The master protocol and DPNP 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: 
[3025] 
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 
[3026] 
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 
[3027] 
have a QRS interval ≥120 msec at Visit 1 or Visit 2 
[3028] 
have a non-evaluable PR interval or a PR interval >200 msec at Visit 1 or Visit 2 
[3029] 
have a heart rate <40 bpm at Visit 1 or Visit 2 
[3030] 
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 
[3031] 
have clinically significant active thyroid disease, including Hashimoto’s 
thyroiditis  
Prior/Concomitant Therapy 
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[3032] 
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 
[3033] 
have had a change in beta blocker therapy in the last 12 weeks before Visit 2.  
This does not include a discontinuation of therapy 
[3034] 
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   
Metformin Exception  
Limited dosages of metformin are allowed in this study.   
 Once daily dosing 
Dose levels up to and including 750 mg extended release and 850 mg 
immediate release may be administered once daily. 
 Twice daily dosing 
Dose levels up to and including 500 mg of an immediate release 
formulation may be administered twice daily  
Additional Considerations for Participants Taking Metformin:  
Medical Conditions 
[3036] 
have a history or presence of lactic acidosis 
[3037] 
have history or presence of severe hepatic disease including cirrhosis 
[3038] 
have uncontrolled or unstable congestive heart failure 
Prior/Concomitant Therapy 
[3039] 
are taking carbonic anhydrase inhibitors if also taking metformin 
[3040] 
have had a change in metformin therapy in the last 12 weeks before Visit 2.   
[3041] 
have not maintained a stable dose of glucose-lowering agents other than 
metformin for at least 4 weeks prior to Visit 3. 
Other Exclusions 
[3035] 
are pregnant or breastfeeding. 
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5.3. 
Lifestyle Considerations 
Reproductive and Contraception Requirements 
Reproductive requirements and contraceptive guidance are provided in Section 10.2, Appendix 
2. Participants should maintain a consistent lifestyle throughout participation as much as 
possible. Refer to master protocol Section 5.3 for additional details.   
Alcohol 
In addition to the alcohol restrictions in the CPMP Master Protocol, participants should refrain 
from binge drinking for the duration of the study as specified below.   
Binge drinking is defined as consuming 5 or more units (for males), or 4 or more units (for 
females), on the same occasion. 
One unit of alcohol equals 
 12 oz or 360 mL of beer  
 5 oz or 150 mL of wine, or  
 1.5 oz or 45 mL of distilled spirits. 
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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  
Partici pa nts will ta ke ca ps ules orall y, BI D, a p pr o xi matel y e v er y 1 2  h o urs , wit h or wit h o ut f o o d.   
I nter v e 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)  
2 0 0 m g/ca ps ule  
n ot a p plica ble  
D os a ge Le vel(s)  
 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  
oral  
o ral 
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  
in b ottles  
in 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 vesti gat or or desi g nee m ust c o nfir m a p pr o priate st ora ge c o n diti o ns ha ve bee n mai nta i ne d 
d uri n g tr a nsit f or all st u d y i nter ve nti o n recei ve d a n d a n y dis cre p a ncies are re p orte d a n d res ol ve d 
bef ore us e of t he st u d y i nter ve nti o n.  
O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e st u d y i nter ve nti o n 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 i nter ve nti o n.  All st u d y i nter ve nti o n m ust 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 mat e d) area i n acc or da n ce 
wit h t he la bele d st ora ge c o n diti o ns wit h access li mite d t o t he i n vesti gat or a n d a ut h oriz e d site 
staff. 
T he i n vesti gat or or desi g nee is res p o nsi ble f or st u d y i nter ve nti o n acc o u nt a bilit y, rec o n ciliati o n, 
a n d rec or d mai nte na n ce, t hat is, recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds.  
T he p har mac y ma n ual  c o ntai n s f urt her g ui da nce a n d i nfor mati o n f or t he fi n al dis p ositi o n of 
u n use d st u d y i nter ve nti o ns.  
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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 nt ai ns n o a d diti o nal stratificati o n 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 matc hi n g p lace b o ca ps ules dis pe nse d t o a n d ta ke n b y 
eac h p artici pa nt m ust be mai ntai ne d a n d rec o ncile d wit h st u d y i nter ve nti o n 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, i ncl u di n g dat es f or i nter ve nti o n 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 master pr ot o c ol pr o vi des 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 ul d 
re 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 m e dicall y warra nte d. Please c o ns ult 
t he me dical m o nit or f or q uesti o ns.  
P ote nti al d r u g-d r u g inter acti o ns  wit h L Y 3 5 5 6 0 5 0  
Please refer t o Secti o n  5. 2  f or e x cl usi o n criteria, t he I B a n d Ma n u al of O perati o ns  f or details o n 
c o nc o mita nt me dicati o n  restricti o ns a n d d osi n g i nf or mati o n . 
C o nc o mit a nt t her a p y wit h metf or mi n 
Metf or mi n d osi n g i nf or m ati o n  
Please refer t o Secti o n 5. 2  f or t he all o we d m etf or mi n d ose le vels i n t his st u d y. 
T o li mit t he ris k of lactic aci d osis , t he o nl y metf or mi n d osa ges  all o we d i n t his st u d y are t h ose 
pre dicte d b y P K m o deli n g  t o mai ntai n plas ma c o n ce ntrati o ns bel o w  5 µ g/ m L  (G L U C O P H A G E  
pac ka ge i nsert , 2 0 1 8).     
Re q uire m e nts f or t he st u dy site  
T he st u d y site will e ns ur e partici pa nts are a ware of lactic aci d osis s y m pt o ms.   
T he st u d y site  will a d vise  t he partici pa nts t o re mai n h y drate d d uri n g t he st u d y .  
Restricti o ns f or p artici p a nts t a ki n g  m etf or mi n  
Pa rtici pants ta ki n g metf or mi n ma y  n ot start S G L T 2 i n hi bit ors (see t he Ma n ual of O perati o ns  f or 
details)  d uri n g t h e st u d y. 
T he st u d y site will a d vise t he partici pa nt t o a v oi d ra di ol o gical st u dies wit h c o ntrast t hr o u g h o ut 
partici pati o n i n t his st u d y.   
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 os e f or i n di vi d ual partici pa nts, b ut t he ma xi m u m dail y d ose 
will n ot e x c ee d 6 0 0 m g BI D.  
   
Decisi o ns t o  c ha n ge t h e d ose le vel will be ma de b y t he i n vesti gat or i n disc ussi o n wit h t he 
partici pa nts  base d o n t he a d verse e ve nts r e p orte d f or t olera bilit y. T h e me dical m o nit or s h o ul d be 
c o ntacte d as n ee d e d.   
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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.    
Metabolic Safety 
For participants taking concomitant metformin, please consult the GLUCOPHAGE label for 
participant management.  In event of an elevated anion gap, participants should be contacted 
immediately for a clinical evaluation and workup. If the participants are on metformin, they 
should be instructed to hold SSTR4 and metformin dosing. 
If lactic acidosis is clinically suspected, LY3556050 and metformin should be discontinued and 
the patient should be medically evaluated.   
7.2. 
Participant Discontinuation/Withdrawal from the Study 
If eGFR, based upon CKD-EPI equation from cystatin c, falls below 60 ml/min/1.73 m2 in a 
participant taking metformin, the participant should be discontinued from the study.  
If a diagnosis of lactic acidosis is confirmed, the subject needs to be discontinued from study 
participation. 
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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoAs contained in the master protocol 
CPMP, DPNP 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 NP03 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 adverse event (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. 
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P har mac o ki netic  sa m ples will be retai ne d f or a ma xi m u m of 2 years f oll o wi 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 v e 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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9.  
St atistic al C o nsi der ati o ns  
T he master pr ot o c ol a n d D P N P D S A pr o vi de statistical c o nsi derati o ns.  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 master pr ot o c ol descri bes t he pri mar y h y p ot h esis.  
 
  
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 place 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 here is n o treat me nt 
differe n ce b et wee n pl ace b o a n d L Y 3 5 5 6 0 5 0, t he pr o ba bilit y of passi n g t he efficac y criteri o n 
s pecifie d a b o v e (i.e., fals e p ositi ve) is less t ha n 0. 1.  T he si m ulati o n f or t he p o wer calc ulati o n 
a n d sa m ple siz e deter mi n ati o n was carrie d o ut usi n g t he Fi x e d a n d A da pti v e 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 master pr ot o c 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 partici 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 ha n ge t o t he d ata 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 n ci pal feat ure of t he I S A.  A n y ot h er 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 ustificati o n f or ma ki n g t he c ha n ge, will be descri b e d i n t he statistical a nal ysis 
pla n ( S A P) a n d t he cli nic al st u d y re p ort.  A d diti o nal e x pl orat or y a nal yses of t he data will be 
c o n d ucte d as d ee 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 descri pti o n of t he statistical a nal yses des cri be d i n t his secti o n.  
9. 4. 1.  Ge ner al C o nsi der ati o ns  
T he master pr ot o c ol descri bes t he pri mar y e n d p oi nt a n d a nal yses.  
T he master pr ot o c ol a n d D P N P D S A descri be t he sec o n dar y a n d tertiar y/ e x pl orat 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 mati o n will be s pecifie d i n t he I S A S A P.   
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9. 4. 2.  
P h ar m a c o ki netics a n d P h ar m a c o d y n a mi cs  
T he o bser ve d plas ma c o n ce 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 pti vel y.   
M o del -base d P K a n d P K P D a nal ys es ma y be c o n d ucte d t o c haracterize t he P K of L Y 3 5 5 6 0 5 0 i n 
partici pa nts wit h D P N P a n d t o e x pl ore e x p os ure -res p o nse relati o ns hi ps f or vari o us P D meas ures 
usi n g s uita ble p o p ulati o n a nal ysis s oft ware.  Partici pa nt fact ors ma y be i n v esti 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 b e c o n d uct e d, as nee de d.   
Data fr o m t his st u d y m a y be p o ole d wit h data fr o m ot her st u dies, 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 ys es 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 nta ct, data e ntr y, or data vali dati o n res p o nsi bilities, ma y recei ve access t o 
u n bli n de d data, pri 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 del de vel o p me nt pr ocesses.  T his will be descri b e d i n t he u n bli n di n g pla n.  I nf or mati o n 
t hat ma y u n bli n d t he st u d y d uri n g t he a nal yses will n ot be re p orte d t o st u d y sites or bli n de d st u d y 
tea m u ntil t he st u d y has bee n u n bli n de d.  
9. 4. 3.  
Terti ar y/ E x pl or at or y  
All safet y a nal yses will be ma de o n t he safet y p o p ulati o n.  Descri pti ve statistics 
 
 will be c o n d ucte d as dee me 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 b e 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 n al ys es of car di o vas c ular safet y e n d p oi nts wit h beta 
bl oc k er 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 n al ys es 
ma y b e c o n d uct e 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 b e 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 d etails ma y b e s pecifie d i n t he u n bli n di n g pla n secti o n of t he S A P or i n a se parate 
d oc u me nt.   
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol n u m ber H 0 P -M C -N P 0 3 (b ) 
 
3 0  
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 master pr ot o c ol descri bes tests t hat ma y b e perf or me d at a d diti o nal ti mes n ote d i n t he S o A 
f or t his I S A.  T his ta ble d escri bes tests u ni q ue f or I S A N P 0 3.   
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  
Ot her Tests  
C ystati n -C  
Free Trii o d ot h yr o ni ne ( Free T 3)  
Gr o wt h h or m o ne  
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  
Bicar b o nate  
Free T h yr o xi ne ( Free T 4)  
Pr olacti n  
L Y 3 5 5 6 0 5 0 c o nce ntrati o n  
A ni o n ga p  
(calc ulati o n) 
T otal T h yr o xi ne ( T 4)  
Gastri n  
Ser u m pre g na nc y test  
e G F R 
calc ulate d 
b y C K D -
E PI 
e q uati o n 
base d u p o n 
c ystati n c  
 
Gl uca g o n  
H b A 1c  
 
 
I ns uli n 
 
A b bre viati o ns:  C K D -E PI  =  C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n ; e G F R = esti mate d gl o mer ular 
filtrati o n rate; H b A 1c = gl ycat e 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. 
 
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Thyroid Safety Follow-Up 
TSH 
Free Triiodothyronine (FreeT3) 
Total Triiodothyronine (T3) 
Free Thyroxine (FreeT4)  
Total Thyroxine (T4) 
Thyroglobulin 
Anti-Thyroglobulin 
Anti-Thyroperoxidase Antibodies 
Iodine 
Abbreviation:  TSH = thyroid-stimulating hormone. 
 
 
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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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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 women of childbearing potential 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 to be considered effective. 
Not Acceptable Methods of Contraception 
Ineffective methods of contraception comprise of 
 Spermicide alone 
 Immune-contraceptives 
 Periodic abstinence 
 Fertility awareness 
o Calendar method 
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o Temperature method 
o Combination of calendar and temperature method 
o Cervical mucus, or 
o Symptothermal 
 Withdrawal 
 Post coital douche, or 
 Lactational amenorrhea.  
Men 
Men are not required to use contraception during study participation. 
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.  
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 CPMP 
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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, DSA CPMP(3) 
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 
AE 
adverse event 
BID 
twice daily 
DPNP 
diabetic peripheral neuropathic pain 
DSA 
disease-state addendum 
eGFR 
estimated glomerular filtration rate 
ERB 
Ethical Review Board 
FACTS 
Fixed and Adaptive Clinical Trial Simulator software tool 
ISA 
intervention-specific appendix 
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 endo 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 
 
 
 
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10.5. 
Appendix 5: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [a] 12 March 2021 
Overall Rationale for the Amendment: 
This amendment introduces a dose titration scheme for participants. The starting dose level is 
200 mg and decisions to change the dose level will be made by the investigator, in discussion 
with the participants, based on adverse events reported for tolerability. The changes for dose 
titration affect sections throughout the ISA. Additional updates were made according to 
emerging data and changes to the master protocol. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Updates made to 
 
Number of Participants 
 
Intervention Groups and 
Duration, and 
 
Data Monitoring Committee 
Sample size and study intervention text updated for 
new dose titration scheme 
“Data monitoring committee” changed to 
“Assessment committee” for consistency with 
master CPMP protocol 
1.2 Schema 
Updated schema to show dose 
titration  
New dose titration scheme for participants 
1.3 Schedule of 
Activities (SoA) 
Added telephone visits and 
updated study intervention notes 
to include a link to the new dose 
modification section 
To implement new dose titration scheme 
1.3 Schedule of 
Activities (SoA) 
Updates were made to ECG and 
Vital signs 
Corrections for clarity 
1.3 Schedule of 
Activities (SoA) 
Replaced Urinalysis with Urine 
drug screen. 
Urinalysis was only for Visit 3, so removed. Urine 
drug screen added and performed according to 
investigator discretion 
1.3 Schedule of 
Activities (SoA) 
Added window for PK sample 
collection 
Adding flexibility 
1.3 Schedule of 
Activities (SoA) 
Added participant digital 
biomarker device for Visit 7 and 
ED 
To indicate when the participant needs to return the 
device. 
2.2 Background 
Updated information for the 2 
Phase 1 clinical studies 
Both studies are completed 
4.1 Overall Design 
Updated and added text to 
describe the new dose titration 
scheme 
New dose titration scheme for participants 
4.3 Justification for 
Dose 
Added text for the titration 
scheme 
Removed “preliminary” from the 
beginning of second paragraph 
New dose titration scheme for participants 
 
Study LXBA is now completed 
5.2 Exclusion Criteria 
Updated Criteria #3028  
Clarifications based on clinical experience and 
emerging pharmacokinetic/metabolism data 
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Section # and Name 
Description of Change 
Brief Rationale 
5.3 Lifestyle 
Considerations 
Removed text that is already in 
the master CPMP 
Master protocol updates for CPMP amendment (a) 
6.1 Study 
Intervention(s) 
Administered 
Updated text and table 
New dose titration scheme for participants. 
Emerging data allow participants to take capsules 
with or without food 
6.5 Concomitant 
Therapy 
Removed text that is duplicated 
in CPMP 
Added sub-header for drug-drug 
interactions 
Consistency across ISAs 
6.6 Dose Modification 
New section 
New dose titration scheme for participants  
8.2 Adverse Events 
and Serious Adverse 
Events 
Added text to refer to the master 
Master protocol contains AE and SAE information 
9.2 Sample Size 
Determination 
Updated sample size 
New dose titration scheme for participants 
9.3 Populations for 
Analyses 
Removed “in the SAP” 
The master protocol defines the populations for 
analyses 
10.2 Appendix 2  
Updated the acceptable and 
ineffective methods of 
contraception text 
Updates to internal Lilly guidance 
Throughout the 
protocol 
Minor editorial and formatting 
changes 
Minor, therefore not described 
 
 
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11. 
References 
Metformin [package insert].  Princeton, NJ: Bristol-Myers Squibb Company. 2018. 
 
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Si g nat ure Pa ge f or V V- C LI N- 0 0 4 2 2 9 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 0 4 2 2 9 v 1. 0
A p pr o val
A p pr o val
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
P P D
P P D