Conditions: Diabetic Peripheral Neuropathic Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 68
Healthy volunteers: no

Brief summary:
This study is being done to test the safety and efficacy of the study drug LY3556050 for the treatment of diabetic peripheral neuropathic pain. This trial is part of the chronic pain master protocol (H0P-MC-CPMP) which is a protocol to accelerate the development of new treatments for chronic pain.

Detailed description:

Arms:
arm 1: Participants received 600 mg LY3556050 twice daily (BID) every 12 hours for up to 8 weeks. arm 2: Participants received placebo BID every 12 hours for up to 8 weeks.

Interventions: intervention 1: LY3556050 intervention 2: Placebo
Intervention descriptions: intervention 1: given orally intervention 2: given orally

Protocol document:
Prot_000.pdf: 
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 
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 ) 
 
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  
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI


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 
 
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 ) 
 
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.   
 
 
 
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI
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 ) 
 
7  
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI


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  
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 ) 
 
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  
 
 
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 ) 
 
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  
 
 
 
 
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI
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 ) 
 
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.  
 
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI
C CI


CONFIDENTIAL 
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. 
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 ) 
 
1 5  
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.   
 
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 ) 
 
1 6  
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. 
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
17 
 
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.  
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
18 
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 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
19 
[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. 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
20 
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. 
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 ) 
 
2 1  
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.  
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 ) 
 
2 2  
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.   
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 ) 
 
2 3  
 
  
 
 
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 ) 
 
2 4  
 
 
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
25 
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. 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
26 
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. 
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 ) 
 
2 7  
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.  
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI
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 ) 
 
2 8  
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.   
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI
C CI
C CI
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 ) 
 
2 9  
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. 
 
A p pr o ve d o n 0 1 Oct 2 0 2 1 G M T
C CI


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
31 
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. 
 
 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
32 
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.   
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
33 
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 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
34 
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 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
35 
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.   
 
 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
36 
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  
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
37 
 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: 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
38 
 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.  
 
 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
39 
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 
 
 
 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
40 
 
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 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
41 
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 
 
 
Approved on 01 Oct 2021 GMT


CONFIDENTIAL 
Protocol number H0P-MC-NP03(b) 
 
42 
11. 
References 
Metformin [package insert].  Princeton, NJ: Bristol-Myers Squibb Company. 2018. 
 
Approved on 01 Oct 2021 GMT


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

SAP_001.pdf: 
This study H0P-MC-NP03 (NCT04707157) is a sub-study of Master Protocol H0P-MC-CPMP 
(NCT05986292)
Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3556050 for 
the Treatment of Diabetic Peripheral Neuropathic Pain
NCT04707157 
Approval Date: 06-May-2022 
H0P-MC-NP03 StaƟsƟcal Analysis Plan Version 2 


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 1 
LY3556050 
1.
Statistical Analysis Plan:
H0P-MC-NP03: Intervention-Specific Appendix (ISA) for 
LY3556050 
Confidential Information 
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
LY3556050 for the Treatment of Diabetic Peripheral Neuropathic Pain 
This is a randomized, placebo-controlled, phase 2 clinical trial to evaluate LY3556050 for 
the treatment of diabetic peripheral neuropathic pain. 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Protocol H0P-MC-NP03 
Phase 2 
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below. 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 2 
LY3556050 
2. Table of Contents 
Section 
Page 
1. 
Statistical Analysis Plan: H0P-MC-NP03: Intervention-Specific 
Appendix (ISA) for LY3556050 .............................................................................................1 
2. 
Table of Contents ....................................................................................................................2 
3. 
Revision History ......................................................................................................................5 
4. 
Study Objectives ......................................................................................................................6 
4.1. 
Primary Objective ...............................................................................................................6 
4.2. 
Secondary Objectives .........................................................................................................6 
4.3. 
Exploratory Objectives .......................................................................................................6 
5. 
Study Design ...........................................................................................................................8 
5.1. 
Summary of Study Design..................................................................................................8 
5.2. 
Determination of Sample Size ............................................................................................8 
5.3. 
Method of Assignment to Treatment ..................................................................................8 
6. 
A Priori Statistical Methods ....................................................................................................9 
6.1. 
General Considerations ......................................................................................................9 
6.2. 
Adjustments for Covariates ................................................................................................9 
6.3. 
Handling of Dropouts or Missing Data ..............................................................................9 
6.4. 
Multiple Comparisons/Multiplicity ..................................................................................10 
6.5. 
Use of an “Efficacy Subset” of Patients ...........................................................................10 
6.6. 
Patient Disposition............................................................................................................10 
6.7. 
Patient Characteristics ......................................................................................................10 
6.8. 
Treatment Compliance .....................................................................................................10 
6.9. 
Concomitant Therapy .......................................................................................................10 
6.10. Efficacy Analyses .............................................................................................................10 
6.10.1. 
Primary Outcome and Methodology ........................................................................10 
6.10.2. 
Additional Analyses of the Primary Outcome .........................................................11 
6.10.3. 
Secondary Efficacy Analyses ...................................................................................11 
6.11. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods ....................................13 
6.12. Safety Analyses ................................................................................................................13 
6.12.1. 
Extent of Exposure ...................................................................................................13 
6.12.2. 
Deaths, Other Serious Adverse Events, and Other Adverse 
Events for Review ....................................................................................................13 
6.12.3. 
Clinical Laboratory Evaluation ................................................................................15 
6.12.4. 
Vital Signs and Other Physical Findings .................................................................17 
6.12.5. 
Electrocardiograms ..................................................................................................17 
6.13. Subgroup Analyses ...........................................................................................................17 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 3 
LY3556050 
6.14. Protocol Deviations ..........................................................................................................17 
6.15. Interim Analyses and Data Monitoring ............................................................................17 
6.16. Planned Exploratory Analyses .........................................................................................18 
6.17. Totality of Evidence for Safety ........................................................................................19 
6.18. Annual Report Analyses ...................................................................................................20 
6.19. Clinical Trial Registry Analyses ......................................................................................20 
7. 
Unblinding Plan .....................................................................................................................22 
8. 
References .............................................................................................................................23 
9. 
Appendices ............................................................................................................................24 
 
 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 4 
LY3556050 
Table of Contents 
Appendix 
Page 
Appendix 1. 
Planned Laboratory Analytes and Direction of Interest ....................................25 
 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 5 
LY3556050 
3. Revision History 
Statistical analysis plan (SAP) Version 1 was approved prior to unblinding data for Study H0P-
MC-NP03 (Study NP03).  
Statistical analysis plan Version 2 was approved prior to the interim analysis. Major revisions 
include: 
 Section 4.2, for physical functioning objectives, total interference score was replaced 
with mean interference score and mean severity score was added. Proportion of 
participants with reduction from baseline was updated to at least instead of greater than 
30/50/70%.  
 Section 5.3, the method of treatment assignment description was added to align with 
protocol amendment.  
 Section 6.1, the estimand for this Intervention-Specific Appendix (ISA) was described. 
 Section 6.3, additional detail was added to describe the multiple imputation method. 
 Section 6.10.2, placebo borrowing analysis from previous and ongoing studies in Chronic 
Pain Master Protocol (CPMP) was updated and overall mean change from baseline 
assessment was described. 
 Section 6.10.3, the details for the constrained model for the secondary endpoint were 
added. The language for categorical endpoint analysis was updated to match the 
H0P-MC-CPMP (Study CPMP) SAP Version 5. Proportion of participants with reduction 
from baseline was updated to at least instead of greater than 30/50/70%. 
 Section 6.12.2, additional treatment-emergent adverse events, and narratives for patients 
with “notable” events were updated. 
 Section 6.12.3, estimated glomerular filtration rate (eGFR) shift analyses was added. 
 Section 6.12.4, detailed criteria of orthostatic vital sign summaries were elaborated. 
 Section 6.14, ‘violations’ is replaced with ‘deviations’ for consistency across CPMP 
documents, and the list of important protocol deviations is referenced in the trial issue 
management plan. 
 Section 6.15, interim analyses description were added. 
 Section 6.16, planned exploratory analyses were updated, including adding frequentist 
mixed model for repeated measures (MMRM) as sensitivity analyses and more details of 
propensity score analyses; details of propensity score analyses were elaborated; 
exploratory placebo borrowing analyses with more types of borrowing method were 
added. 
 Section 6.17, the totality of evidence for safety was added. 
 Section 7, text on maintaining the blind for assessment committee review was deleted 
since it is covered in Study CPMP SAP Version 5. 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 6 
LY3556050 
4. Study Objectives 
4.1. Primary Objective 
The primary objective of this ISA is stated in Study CPMP (a) protocol. For Study NP03, 
endpoint is defined at Visit 7, which is 8 weeks post initial treatment administration. The time 
point for secondary endpoint measurements is the same as the primary endpoint except for the 
overall measures. 
4.2. Secondary Objectives 
Secondary objectives are listed in Study CPMP SAP Version 5. Additional secondary endpoints 
specific to Study NP03 are listed below.  
Objective 
Endpoint Measure 
Other Secondary 
 
Physical Functioning 
Efficacy of LY3016859 
versus placebo  
 
Mean change from baseline to endpoint for the Brief Pain Inventory-Short 
Form (BPI-SF) for the  
o 
mean interference score 
o 
mean severity score 
o 
individual severity score, and 
o 
individual interference score. 
 
Proportion of participants with reduction from baseline greater than or equal 
to 30%, 50%, and 70% on BPI-SF for the  
o 
mean interference score 
o 
mean severity score 
o 
individual severity scores, and 
o 
individual interference scores.  
Efficacy of LY3556050 
versus Placebo 
 
Overall mean change from baseline assessment for average pain intensity 
numerical rating scale during the treatment phase 
Note: Other key secondary objectives are listed in the H0P-MC-CPMP Statistical Analysis Plan Version 5.  
Approved on 06 May 2022 GMT
CCI


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 7 
LY3556050 
Approved on 06 May 2022 GMT
CCI


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 8 
LY3556050 
5. Study Design 
5.1. Summary of Study Design 
Study CPMP protocol provides a summary of the overall study design for the CPMP. 
Intervention-Specific Appendix-specific study design is provided in Study NP03 protocol.  
5.2. Determination of Sample Size 
Up to 200 participants will be randomized in a 
 to LY3556050 and placebo, respectively. 
Assuming an overall dropout rate of approximately 33%,
 
 
 
  
 
 
If there is no treatment 
difference between placebo and LY3556050, the probability of passing the efficacy criterion 
specified above (ie, false positive) is less than 0.1. The simulation for the power calculation and 
sample size determination was carried out using the Fixed and Adaptive Clinical Trial Simulator 
Version 6.0. 
5.3. Method of Assignment to Treatment 
 
 
Approved on 06 May 2022 GMT
CCI
CCI
CCI
CCI


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 9 
LY3556050 
6. A Priori Statistical Methods 
6.1. General Considerations 
The estimand for the primary clinical question of interest has been described in Study CPMP 
SAP Version 5. The estimand is following a hypothetical strategy where the efficacy of 
LY3556050 is assessed under the assumption that the participants would have continued their 
initially randomized treatment condition even if they discontinued. Unless otherwise stated, all 
efficacy and safety analyses will be conducted for LY3556050 versus placebo, where all 
LY3556050 doses are combined. 
Other general considerations for analyses are described in Study CPMP SAP Version 5.  
6.2. Adjustments for Covariates 
The general adjustment strategy has been described in Study CPMP SAP Version 5. 
6.3. Handling of Dropouts or Missing Data 
The missing data strategy has been described in Study CPMP SAP Version 5.  
In addition to the Bayesian MMRM model described in Study CPMP SAP Version 5, to examine 
the effect of missing data, constrained cell means MMRM with multiple imputations will be 
applied as a sensitivity analysis to assess change from baseline to postbaseline measure for visual 
analog scale (VAS) and NRS. 
For these continuous efficacy endpoints, a Markov chain Monte Carlo method will be used to 
impute intermittent (nonmonotone) missing visit data and a set of Bayesian regressions will be 
used for the imputation of monotone dropouts. The variable pooled investigative site, treatment, 
age, gender, baseline pain severity categories will be included for imputing nonmonotone 
missingness, and primary adverse events (AEs) leading to treatment discontinuation can be 
included as an additional variable for imputing monotone missingness. Subject-level indicator of 
primary AEs leading to treatment discontinuation is set 1 for patients experiencing AEs in 
Preferred Terms (PTs), including Nausea, Dizziness, Fatigue, Abdominal discomfort, Abdominal 
pain lower, Abdominal pain upper, Constipation, Lethargy, and Somnolence at any time during 
double-blinded treatment period; 0 otherwise. The number of imputed data sets will be 200 and 
the initial seed for imputing intermittent missing data is 12345 and for imputing monotone 
missing data is 678910. Within the program, the seed will be used to generate 200 seeds needed 
for imputation. 
The analysis model will utilize the constrained cell means MMRM so that a common mean is 
estimated at the baseline for each imputed dataset. The pooled investigative site, treatment and 
time interaction, and baseline pain severity categories will be included as fixed effects. Results 
across the imputed datasets will be aggregated using SAS procedure MIANALYZE in order to 
compute least squares means and standard errors for the treatment comparisons. 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 10 
LY3556050 
6.4. Multiple Comparisons/Multiplicity 
There is no plan to formally adjust for multiplicity.  
6.5. Use of an “Efficacy Subset” of Patients 
There are no plans to use a modified efficacy subset.  
6.6. Patient Disposition 
The summary of patient disposition has been described in Study CPMP SAP Version 5. Kaplan-
Meier plot of time to last dosing by treatment group will also be provided to describe patient 
disposition. 
6.7. Patient Characteristics 
The summary of participant characteristics has been described in Study CPMP SAP Version 5. 
Intervention-Specific Appendix-specific considerations are described below.  
 Michigan Neuropathy Screening Instrument  
o Part A - history subscale (less than 7 versus 7 or higher) 
o Part B - physical assessment subscale (less than 3 versus 3 or higher).  
6.8. Treatment Compliance 
Treatment percentage of compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑝𝑖𝑙𝑙𝑠 𝑡𝑎𝑘𝑒𝑛 ∗100
𝑇𝑜𝑡𝑎𝑙 𝑝𝑖𝑙𝑙𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 
with total pills taken calculated by total pills dispensed – total pills returned. A patient is 
considered to be compliant overall if the percentage is between 80% and 120% from Visit 4 to 
Visit 7. The percentage of patients who are compliant with study drug will be summarized by 
treatment group. For patients who discontinue early, time after the penultimate visit will be 
excluded for calculation of treatment compliance. For example, if patient discontinued early at 
Visit 6, treatment compliance will be derived only from data collected through Visit 5. 
6.9. Concomitant Therapy 
The summary and reporting of concomitant therapy and electronic clinical outcome assessment 
compliance has been described in Study CPMP SAP Version 5. No additional covariates will be 
considered in the model of weekly rescue medication use.  
6.10. Efficacy Analyses 
6.10.1. Primary Outcome and Methodology 
The analysis of the primary outcome has been described in Study CPMP SAP Version 5. The 
longitudinal model will include average NRS during the preliminary data entry period (last 
7 days prior to randomization at Visit 3) and within each nominal week of the double-blind 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 11 
LY3556050 
treatment period as a longitudinal outcome. As noted in Section 4.1, endpoint for the primary 
analysis is defined as 8 weeks post initial treatment administration.  
Calculation of the weekly/bi-weekly time intervals used for analysis of weekly/bi-weekly mean 
scores from the electronic clinical outcome assessment device will follow the algorithm 
described in the CPMP SAP Version 5, Section 6.12.1, except that the end of the final interval 
will be determined based on the last VAS collection date, or the last scheduled visit start date if 
VAS is missing for the last scheduled visit. 
6.10.2. Additional Analyses of the Primary Outcome 
The overall mean treatment effect in change from baseline over the double-blind treatment 
period will be reported for evaluating treatment effect for NRS, VAS, as well as other secondary 
continuous efficacy endpoints.  
 
 
 
 
 
6.10.3. Secondary Efficacy Analyses 
Secondary efficacy analyses common to all ISAs within Study CPMP have been described in 
Study CPMP SAP Version 5. Study NP03 will also consider the following secondary analyses. 
The Brief Pain Inventory-Short Form (is a numeric rating scale that assesses the severity of pain 
(severity scale), its impact on daily functioning (interference scale), and other aspects of pain 
(eg, location of pain, relief from medications) in various disease states (Cleeland and Ryan 
1994). 
The table below describes the pain scales and corresponding NRS used in a modified version of 
the Brief Pain Inventory, validated for pain in diabetic polyneuropathy. Participants will rate 
their pain severity and how, during the past 24 hours, the pain has interfered with the activities 
described in this table. 
 
 
Approved on 06 May 2022 GMT
CCI


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 12 
LY3556050 
Assessment 
Topic 
Numeric Rating Scale 0-10 
4-item pain severity 
 
Worst pain in last 24 hours 
 
Least pain in the last 
24 hours 
 
Average pain 
 
Pain right now 
0 = no pain 
10 = pain as bad as you can imagine 
7-item pain interference 
 
General Activity 
 
Mood 
 
Walking ability 
 
Normal work 
 
Relations with others 
 
Sleep 
 
Enjoyment of life 
0 = does not interfere 
10 = completely interferes 
 
A Bayesian longitudinal mixed-effect MMRM analysis will be performed to evaluate the change 
from baseline to each postbaseline visit for the mean pain interference scale and the mean pain 
severity scale. The model will utilize the constrained cell means model so that a common mean 
is estimated at the baseline. More details on this approach are provided in Study CPMP SAP 
Version 5. 
Additional Bayesian MMRM analyses will be used to analyze the change from baseline to each 
postbaseline visit for  
 individual pain interference and  
 individual pain severity scales. 
The table below describes information included in the model. 
Categorical factors 
 
the interaction of treatment and visit 
o 
(constrained to estimate a common mean 
at baseline across treatments) 
 
average baseline pain severity category 
o 
(baseline NRS <7, baseline NRS ≥7) 
 
pooled investigative site 
Continuous covariates 
 
none 
Abbreviation: NRS = numeric rating scale. 
 
Other Secondary Analysis 
The proportion of participants in each treatment group meeting prespecified binary efficacy 
outcomes will be calculated for each postbaseline time point and will be used to compare 
treatment groups. The prespecified binary efficacy outcomes include the proportion of 
participants with a reduction of at least 30%, 50%, and 70% from baseline as measured by the 
 mean pain interference score 
 mean pain severity score 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 13 
LY3556050 
 individual interference scores, and 
 individual severity scores.  
A Bayesian pseudo-likelihood-based categorical repeated measures model will be used to 
estimate the proportion of participants in each treatment group meeting the prespecified 
threshold for each postbaseline time interval up to week 8 (or visit up to visit 7). These estimates 
will be used to compare treatment groups. More details on this approach are provided in 
Study CPMP SAP Version 5. 
In addition, time to first treatment response from baseline based on the prespecified binary 
thresholds above will be assessed. Analyses will be conducted according to the time to event 
analyses specified in the CPMP SAP Version 5. 
6.11. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods 
The observed plasma concentrations for LY3556050 will be reported graphically and 
summarized descriptively. Exploratory model-based pharmacokinetic (PK) and 
PK-pharmacodynamic (PD) analyses may be conducted to characterize the PK of LY3556050 in 
participants with diabetic peripheral neuropathic pain and to assess exposure-response 
relationships for efficacy and safety outcomes. Participant factors may be investigated to assess 
their effects on model parameters. Additional analyses may be conducted, as needed. Data from 
this study may be pooled with data from other studies, if appropriate. 
6.12. Safety Analyses 
The general analysis of safety has been described in Study CPMP SAP Version 5. However, 
additional ISA-specific safety considerations are described in the sections below.  
6.12.1. Extent of Exposure 
Duration of exposure (defined as time since first dose of study treatment to the last dose of study 
treatment in days) to study drug will be summarized by treatment group using descriptive 
statistics; the summary will also include the total exposure in patient years.  
Duration of exposure (days):  
Date of last dose during the double-blind treatment period – Date of first dose for the 
treatment period + 1 
Total exposure in patient years will be calculated as follows: 
Total exposure in patient years = Sum of duration (days) of exposures for all patients in 
the treatment group/365.25 
See Section 6.16 for additional dosing analyses.  
6.12.2. Deaths, Other Serious Adverse Events, and Other Adverse 
Events for Review 
Treatment-emergent adverse events by PT will be reported. 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 14 
LY3556050 
In addition to an overall listing, additional lists by PTs or System Organ Classes of interest, 
including Cardiovascular, Thyroid, and Renal functions, will be generated. 
The full summary of AEs is described in Study CPMP SAP Version 5. Other AEs for review 
coded to Medical Dictionary for Regulatory Activities (MedDRA) terms include 
 Hypothyroidism (in Standardized MedDRA Query [SMQ]) 
 Cardiac arrhythmias (in SMQ) 
o Arrhythmia related investigations, signs, and symptoms 
o Bradyarrhythmia terms, nonspecific 
o Cardiac arrhythmia terms, nonspecific 
o Conduction defects 
o Disorders of sinus node function 
o Supraventricular tachyarrhythmias 
o Tachyarrhythmia terms, nonspecific 
o Ventricular tachyarrhythmias 
 
Hypotension (in preferred MedDRA term) 
o Orthostatic hypotension  
o Blood pressure ambulatory decreased 
o Blood pressure decreased 
o Blood pressure diastolic decreased 
o Blood pressure systolic decreased 
o Blood pressure orthostatic decreased 
o Dizziness 
o Dizziness exertional 
o Presyncope 
o Syncope 
 Abnormal renal function (in MedDRA High Level Term) 
o Renal function analyses 
o Renal failure and impairment 
 Major adverse cardiovascular event (including myocardial infarction and stroke) 
o Death (MedDRA PT) 
o Cardiac arrest ((MedDRA PT) 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 15 
LY3556050 
o Cardiac death ((MedDRA PT) 
o Sudden cardiac death ((MedDRA PT) 
o Sudden death ((MedDRA PT) 
o Ischemic heart disease (SMQ) 
o Ischemic central nervous system vascular conditions (SMQ) 
 Depression (in MedDRA High Group Level Term) 
o Depressed mood disorders and disturbances 
 Congestive Heart Failure (in SMQ) 
o Cardiac Failure 
 Substance abuse (in MedDRA High Level Term) 
o Substance related and addictive disorders  
Post treatment emergent adverse event (TEAE) collected at Visit 801 may be summarized 
separately.  
Narratives will be provided for patients with the following “notable” events, in addition to the 
“notable” events listed in Study CPMP SAP Version 5: 
 treatment-emergent elevated amylase or lipase greater than 3× upper limit of normal and 
 renal treatment-emergent AEs. 
Approved on 06 May 2022 GMT
CCI


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 16 
LY3556050 
Approved on 06 May 2022 GMT
CCI


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 17 
LY3556050 
6.12.4. Vital Signs and Other Physical Findings 
The analysis of vital sign parameters is described in Study CPMP SAP Version 5. Supine, 
standing, and orthostatic vital signs data will be summarized by treatment, together with changes 
from baseline, where the baseline is defined as Visit 3 predose assessment. Figures of mean vital 
signs and mean changes from baseline profiles will be presented by treatment. Additional 
categorical criteria for abnormal treatment-emergent blood pressure and pulse measurement for 
adults in NP03 are: 
Parameter 
Criteria 
Orthostatic hypotension 
(orthostatic systolic BP, in mmHg) 
Decrease in systolic BP when 
going from 5 minutes supine to 
2-3 minutes standing of 
≥20mm Hg 
Orthostatic hypotension 
(orthostatic diastolic BP, in mmHg) 
Decrease in diastolic BP when 
going from 5 minutes supine to 
2-3 minutes standing of 
≥10mm Hg 
Orthostatic pulse rate (postural orthostatic tachycardia, in bpm) 
Increase in pulse when going 
from 5 minutes supine to 
2-3 minutes standing of ≥30 
Abbreviations: BP = blood pressure. 
6.12.5. Electrocardiograms 
The analysis of electrocardiograms parameters is described in Study CPMP SAP Version 5.  
The percentages of participants who experienced a treatment-emergent increase from PR 
interval, QRS interval, and heart rate will be summarized according to CPMP SAP Version 5, 
Table 6.10. Additionally, the percentages of participants who experienced a PR interval value 
greater or equal to 240 msec at any time will be summarized. 
6.13. Subgroup Analyses 
General subgroup analyses are described in Study CPMP SAP Version 5. There are no additional 
subgroup analyses planned.  
6.14. Protocol Deviations 
Patients with study important protocol deviations will be summarized by type of deviation and 
listed by treatment and investigative site . 
Important protocol deviations for the study are described in Study CPMP and Study NP03 Trial 
Issue Management Plans. 
6.15. Interim Analyses and Data Monitoring 
Safety review will be conducted under the auspices of an Assessment Committee according to 
the specifications set forth in the protocol. These analyses will be at the CPMP level and will 
consider data from all ongoing ISAs. Details are provided in Study CPMP SAP Version 5.  
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 18 
LY3556050 
Interim analyses are planned for Study NP03. The potential reasons for interim analyses could 
include futility analyses, early efficacy analyses, safety analyses, or other analyses needed for 
key business decisions and planning. 
6.16. Planned Exploratory Analyses 
The following analyses may be conducted for exploratory purposes: 
 Other placebo borrowing strategies may be explored as described in Study CPMP SAP 
Version 5, Section 6.12.1. 
 A frequentist MMRM analysis will be conducted as a sensitivity analysis for the primary 
and some secondary endpoints. 
 In addition, a cumulative distribution function of percent change from baseline to 
endpoint for the following Brief Pain Inventory-Short Form score will be provided for 
each treatment group: 
o mean interference score 
o mean severity score 
o individual severity scores, and 
o individual interference scores 
However, no statistical comparisons will be made between the groups.  
 The follow analysis is to explore different doses of LY3556050: 
Approved on 06 May 2022 GMT
CCI


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 19 
LY3556050 
Approved on 06 May 2022 GMT
CCI


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 20 
LY3556050 
6.18. Annual Report Analyses 
Analyses will be produced as needed for the purposes of providing periodic safety reviews to 
regulatory agencies (eg, Development Safety Update Reports.). Data from this ISA will be 
combined with data from other clinical studies that investigated LY3556050. In all analyses, a 
combined LY arm will be created which includes participants assigned to any dose of 
LY3556050 in the included studies, including LY-combination regimens.  
The following data will be summarized by treatment group: 
 enrollment (ongoing and completed)  
 demographics (race, ethnicity, and gender)  
 exposure 
o cumulative number of subjects exposed to LY3556050 
o cumulative number of subjects exposed to LY3556050 by age  
o cumulative number of subjects exposed to LY3556050 by sex  
o cumulative number of subjects exposed to LY3556050 by race 
 Cumulative summary of serious adverse events 
The following listings will be provided:  
 list of serious adverse events during the reporting period  
 list of subjects who died  
 cumulative list of subjects who discontinued due to an AE (discontinued from treatment 
or study)  
 list of subjects who discontinued due to an AE during the reporting period.  
Additional analyses may be added or omitted at the time of report submission as needed.  
6.19. Clinical Trial Registry Analyses 
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
requirements. 
Approved on 06 May 2022 GMT
CCI


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 21 
LY3556050 
Analyses provided for the Clinical Trial Registry requirements include the following: 
Summary of AEs, provided as a dataset which will be converted to an XML file. Both Serious 
Adverse Events and ‘Other’ Adverse Events are summarized by treatment group, by MedDRA 
PT. 
 A serious adverse event is an AE that is considered ‘Serious’ whether or not it is a TEAE. 
 An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious. For 
each Serious AE and ‘Other’ AE, for each term and treatment group, the following are 
provided: 
o the number of participants at risk of an event 
o the number of participants who experienced each event term, and 
o the number of events experienced. 
 Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold). 
 Adverse event reporting is consistent with other document disclosures for example, the 
clinical study report, manuscripts, and so forth.  
A summary of a baseline characteristics XML file will be provided. 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 22 
LY3556050 
7. Unblinding Plan 
The general unblinding plan is described in Study CPMP SAP Version 5 and Study CPMP 
blinding and unblinding plan Version 1. Unblinding considerations specific to Study NP03 are 
provided below.  
PK/PD Analysis Planning 
A limited number of prespecified individuals who are not part of the blinded study team and do 
not have direct site contact, data entry, or data validation responsibilities, may receive access to 
unblinded data, prior to the interim or final database lock in order to initiate the final population 
PK/PD model development processes. This will be described in the unblinding plan. Information 
that may unblind the study during the analyses will not be reported to study sites or blinded study 
team until the study has been unblinded. 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 23 
LY3556050 
8. References 
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med 
Singapore. 1994;23(2):129-138. 
Inker LA, Schmid CH, Tighiouart H, et al.; CDK-EPI Investigators. Estimating glomerular 
filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20-29. 
https://doi.org/10.1056/nejmoa1114248 
Levey AS, Coresh J, Greene T, et al.; Chronic Kidney Disease Epidemiology Collaboration. 
Using standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Int Med. 2006;145(4):247-254. 
https://doi.org/10.7326/0003-4819-145-4-200608150-00004 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 24 
LY3556050 
9. Appendices 
 
Approved on 06 May 2022 GMT


H0P-MC-NP03 Statistical Analysis Plan Version 2 
Page 25 
LY3556050 
Appendix 1. 
Planned Laboratory Analytes and Direction of 
Interest 
The H0P-MC-CPMP Statistical Analysis Plan Version 5 describes tests that may be performed 
broadly for the Chronic Pain Master Protocol. This table describes tests unique to H0P-MC-
NP03. 
Chemistry 
Additional Thyroid Tests 
Other SST-Regulated Hormones 
Other Tests 
Cystatin-C 
Free triiodothyronine (FreeT3) 
Growth hormone 
Amylase 
TSH 
Total triiodothyronine (T3) 
Insulin-like growth factor-1 (IGF-
1) 
Lipase 
 
Free thyroxine (FreeT4) 
Prolactin 
LY3556050 
concentration 
 
Total thyroxine (T4) 
Gastrin 
Serum pregnancy test 
 
 
Glucagon 
HbA1c 
 
 
Insulin 
 
Abbreviations: HbA1c = hemoglobin A1c; TSH = thyroid-stimulating hormone. 
 
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. 
Approved on 06 May 2022 GMT


Signature Page for VV-CLIN-039488 v1.0
Signature Page for VV-CLIN-039488 v1.0
Approval
06-May-2022 18:49:31 GMT+0000
Approved on 06 May 2022 GMT
PPD