Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 224
Healthy volunteers: yes

Brief summary:
The main purpose of this study is to compare the amount of selpercatinib that gets into the blood stream and how long it takes the body to get rid of it, when given as different formulations. The information about any adverse effects experienced will be collected and the tolerability of selpercatinib will also be evaluated. The study may last up to 56 days including the 28 days of screening period.

Detailed description:

Arms:
arm 1: 160 mg Selpercatinib (tablet formulation) given orally on days 1 and 15. arm 2: 160 mg Selpercatinib (2 X 80 mg capsule formulation) given orally on days 1 and 15.

Interventions: intervention 1: Selpercatinib
Intervention descriptions: intervention 1: Administered orally

Protocol document:
Prot_000.pdf: 
Protocol 05 Protocol (c) J2G-MC-JZJZ
An Open-label, Randomized Study to Evaluate the Bioequivalence of Selpercatinib Formulations
NCT05089019
Approval Date: 14-Oct-2021


C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2 G-M C -J ZJ Z(c)
1
A p pr o v al D at e: 
Title P a ge
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s. It i s t h e p r o p ert y of  
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli n i c al 
i n v e sti g ati o n of s e l p er c ati ni b (L Y 3 5 2 7 7 2 3 ) u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d 
C o m p a n y or it s s u b si di ari e s. 
N ot e t o R e g ul at or y A ut h oriti e s: T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n 
e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r e l e a s e. 
I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct E x e m pti o n 4 a n d ma y n ot b e r e pr o d u c e d or ot h er wi s e 
di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
Pr ot oc ol Title: A n O pe n -La bel, Ra n d o mize d St u d y t o E val uate t he Bi oe q ui vale nce of 
S el percat i ni b F or m ulati o ns
Pr ot oc ol N u m ber: J 2 G-M C -J ZJ Z
A me n d me nt N u m ber: ( c)
C o m p o u n d : L Y 3 5 2 7 7 2 3
Brief Title: A Bi oe q ui vale nce St u d y  of S elpercat i ni b F or m ulat i ons
St u d y P h ase: P hase 1
S p o ns or N a me: El i Lill y  a n d C o mpa n y o n be half of L o x o O n oc ol g y, I nc., a w h oll y o w ne d 
s u bsi diar y of Eli Lill y a n d C o m pa n y
Le g al Re gistere d A d dress: I n dia na p olis, I n dia na 4 6 2 8 5, U S A
Re g ul at or y A ge nc y I de ntifier N u m ber:
I N D: 1 3 3 1 9 3
A p pr o v al D ate: Pr ot oc ol El ectr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n date pr o vi de d bel o w.
A p pr o v al D at e: 1 4- O ct- 2 0 2 1 G M T


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
2
Medical Monitor Name and Contact Information will be provided separately.


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
3
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment b
13-Aug-2021
Amendment a
04-Aug-2021
Original Protocol
19-Jul-2021
Amendment (c)
This amendment is considered to be nonsubstantial.
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
Title Page and 1.1 
Protocol Synopsis

Changed the study title and brief title
to
An Open-Label, Randomized Study to 
Evaluate the Bioequivalence of
Selpercatinib Formulations

Omit the specificity around
formulations
1.1 Synopsis, Overall 
Design and 
8.5 Gastric pH

Included utilization of local anesthetic
text

Facilitate NG insertion
1.1 Synopsis, Number 
of Participants and 
Section 9.5 Sample 
Size Determination

Updated enrollment to approximately
60 participants for Stage 1

Intent is to have at least 50
participants complete
Stage 1
1.3 Schedule of 
Activities

Modified visit days for 12-lead ECG,
vital signs and clinical laboratory tests

Align with content in
protocol
4.4 End of Study 
Definition

Incorporated Day 28

Clarify last visit
5.2 Exclusion Criteria

Included 11. Inadvertent omission of
exclusion line item

Missing Exclusion Criterion
11
10.2 Appendix 2: 
Clinical Laboratory 
Tests

Incorporated total cholesterol, LDL
and HDL

Response to FDA feedback


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
4
Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.......................................................................................................................11
1.3.
Schedule of Activities (SoA) – Stages 1 and 2 ............................................................12
2.
Introduction..............................................................................................................16
2.1.
Study Rationale ..........................................................................................................16
2.2.
Background ................................................................................................................16
2.3.
Benefit/Risk Assessment ............................................................................................17
3.
Objectives and Endpoints.........................................................................................18
4.
Study Design .............................................................................................................19
4.1.
Overall Design............................................................................................................19
4.1.1.
Screening....................................................................................................................19
4.1.2.
Treatment and Assessment Period...............................................................................19
4.2.
Scientific Rationale for Study Design .........................................................................20
4.3.
Justification for Dose..................................................................................................20
4.4.
End of Study Definition..............................................................................................21
5.
Study Population ......................................................................................................22
5.1.
Inclusion Criteria........................................................................................................22
5.2.
Exclusion Criteria.......................................................................................................23
5.3.
Lifestyle Considerations .............................................................................................25
5.3.1.
Meals and Dietary Restrictions ...................................................................................25
5.3.2.
Caffeine, Alcohol, and Tobacco..................................................................................26
5.3.3.
Activity ......................................................................................................................26
5.4.
Screen Failures...........................................................................................................26
6.
Study Intervention(s) and Concomitant Therapy ...................................................27
6.1.
Study Intervention(s) Administered ............................................................................27
6.1.1.
Administration Details................................................................................................27
6.2.
Preparation, Handling, Storage, and Accountability....................................................27
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................28
6.4.
Study Intervention Compliance...................................................................................28
6.5.
Dose Modification......................................................................................................28
6.6.
Continued Access to Study Intervention After the End of the 
Study..........................................................................................................................28
6.7.
Treatment of Overdose ...............................................................................................28
6.8.
Concomitant Therapy .................................................................................................29
7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal....................................................................................30
7.1.
Discontinuation of Study Intervention ........................................................................30
7.1.1.
Liver Chemistry Stopping Criteria ..............................................................................30
7.1.2.
QTc Stopping Criteria.................................................................................................31
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................31
7.3.
Lost to Follow-up .......................................................................................................32


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
5
8.
Study Assessments and Procedures .........................................................................33
8.1.
Efficacy Assessments .................................................................................................33
8.2.
Safety Assessments ....................................................................................................33
8.2.1.
Physical Examinations................................................................................................33
8.2.2.
Height and Weight......................................................................................................33
8.2.3.
Vital Signs..................................................................................................................33
8.2.4.
Electrocardiograms.....................................................................................................34
8.2.5.
Clinical Safety Laboratory Tests.................................................................................34
8.2.6.
Pregnancy Testing ......................................................................................................34
8.2.7.
Safety Monitoring.......................................................................................................35
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints .................................................................................................................37
8.3.1.
Timing and Mechanism for Collecting Events ............................................................37
8.3.2.
Pregnancy...................................................................................................................39
8.3.3.
Product Complaints ....................................................................................................40
8.4.
Pharmacokinetics........................................................................................................40
8.5.
Gastric pH (Stage 1 only) ...........................................................................................41
8.6.
Pharmacodynamics.....................................................................................................41
8.7.
Genetics .....................................................................................................................41
8.8.
Biomarkers.................................................................................................................41
8.9.
Immunogenicity Assessments.....................................................................................41
8.10.
Health Economics.......................................................................................................41
9.
Statistical Considerations.........................................................................................42
9.1.
Statistical Hypotheses.................................................................................................42
9.2.
Analyses Sets .............................................................................................................42
9.2.1.
Study Participant Disposition......................................................................................42
9.2.2.
Study Participant Characteristics.................................................................................42
9.2.3.
Treatment Compliance................................................................................................42
9.3.
Statistical Analyses.....................................................................................................42
9.3.1.
Safety Analyses ..........................................................................................................42
9.3.2.
Pharmacokinetic Analyses ..........................................................................................43
9.3.3.
Pharmacodynamic Analyses .......................................................................................43
9.3.4.
Pharmacokinetic/Pharmacodynamic Analyses ............................................................43
9.4.
Interim Analysis .........................................................................................................43
9.5.
Sample Size Determination.........................................................................................44
10.
Supporting Documentation and Operational Considerations ................................46
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................46
10.1.1.
Regulatory and Ethical Considerations........................................................................46
10.1.2.
Informed Consent Process ..........................................................................................46
10.1.3.
Data Protection...........................................................................................................47
10.1.4.
Dissemination of Clinical Study Data .........................................................................47
10.1.5.
Data Quality Assurance ..............................................................................................48
10.1.6.
Source Documents......................................................................................................49
10.1.7.
Study and Site Start and Closure.................................................................................49
10.1.8.
Publication Policy.......................................................................................................50


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
6
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................51
10.2.1.
Blood Sampling Summary..........................................................................................53
10.3.
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting .......................................................................................................54
10.3.1.
Definition of AE.........................................................................................................54
10.3.2.
Definition of SAE.......................................................................................................55
10.3.3.
Definition of Product Complaints ...............................................................................56
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints .................................................................................................................56
10.3.5.
Reporting of SAEs......................................................................................................58
10.3.6.
Regulatory Reporting Requirements ...........................................................................58
10.4.
Appendix 4: Contraceptive and Barrier Guidance .......................................................60
10.4.1.
Definitions..................................................................................................................60
10.4.2.
Contraception Guidance..............................................................................................60
10.5.
Appendix 5: Genetics .................................................................................................63
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................64
10.7.
Appendix 7: Abbreviations and Definitions ................................................................69
10.8.
Appendix 11: Protocol Amendment History ...............................................................71
11.
References.................................................................................................................73


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
7
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: An Open-Label, Randomized Study to Evaluate the Bioequivalence of 
Selpercatinib Formulations
Brief Title: A Bioequivalence Study of Selpercatinib Formulations
Rationale:
Lilly is developing a tablet formulation in strengths of 40 mg, 80 mg, 120 mg, and 
160 mg that will replace the current commercial capsule formulation. The tablets are intended to 
offer an improved patient experience in terms of the number and size of the dosage units. The 
intention of this study is to demonstrate the clinical bioequivalence of the new 160 mg tablet 
formulation of selpercatinib as compared to the current 2 80 mg commercial capsule 
formulation of selpercatinib.
Selpercatinib has pH-dependent solubility, with decreasing solubility at higher pH. This 
pH-dependent solubility has led to an approximate 69 to 88% reduction (CV% 59.45 to 64.12) in 
selpercatinib area under the curve (AUC) when selpercatinib was given under fasted conditions 
to participants treated with the acid-reducing agent omeprazole (proton pump inhibitor).


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
8
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the bioequivalence of a
single 160-mg dose of selpercatinib as
the tablet formulation (test) compared
to the commercial capsule formulation
(reference)

Cmax, AUC(0-∞), and AUC0-tlast of
selpercatinib
Secondary

To describe the safety and tolerability
of a single 160-mg oral dose of
selpercatinib as the tablet formulation
(test) compared to the commercial
capsule formulation (reference)

Summary of the number of
treatment-emergent adverse events
and serious adverse events
Overall Design:
Screening
All participants will be screened within 28 days prior to enrollment.
Treatment Period
Stage 1
Participants will be admitted to the Clinical Research Unit (CRU) on Day -1. On the morning of 
Day 1, participants will be randomized to receive a single oral dose of 160-mg selpercatinib as 
the capsule or tablet formulation, and will be dosed according to the randomization sequence 
following an overnight fast of at least 10 hours. On Day 1, participants will also have an nasal 
gastric (NG) tube placed in the stomach prior to dosing to assess gastric pH. The NG tube should 
be inserted into the participant’s stomach no more than 60 minutes prior to selpercatinib dosing.
The use of local anesthetic (for example, lidocaine) will be allowed to facilitate the insertion of 
NG tube. Measurements will then be taken at 30 minute intervals for up to 3.5 hours following 
administration of selpercatinib, or for as long as this remains feasible. The NG tube will be 
removed from the participant after the 3.5 hour selpercatinib pharmacokinetic (PK) timepoint 
(i.e., will remain in place for approximately 4 hours after dosing). Participants will remain 
resident at the CRU until discharge on Day 7.
Participants will attend outpatient visits for the collection of PK blood samples and assessment of 
vital signs on Days 9 and 11.
Participants will be re-admitted to the CRU on Day 14 and in the morning of Day 15 will receive 
their second single oral dose of 160-mg selpercatinib as the capsule or tablet formulation, 
according to the randomization schedule, following an overnight fast of at least 10 hours. On 
Day 15, participants will also have an NG tube placed in the stomach prior to dosing to assess 


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
9
gastric pH prior to dosing to assess gastric pH. The NG tube should be inserted into the 
participant’s stomach no more than 60 minutes prior to selpercatinib dosing. The use of local 
anesthetic (for example, lidocaine) will be allowed to facilitate the insertion of NG tube.
Measurements will then be taken at 30 minute intervals for up to 3.5 hours following 
administration of selpercatinib, or for as long as this remains feasible. The NG tube will be 
removed from the participant after the 3.5 hour selpercatinib PK timepoint (i.e., will remain in 
place for approximately 4 hours after dosing). Participants will remain resident at the CRU until 
discharge on Day 21.
Participants will attend outpatient visits for the collection of blood samples and assessment of 
vital signs on Days 23, 25, and 28.
There will be a washout of at least 14 days between doses of selpercatinib.
Stage 2
Participants will be admitted to the CRU on Day -1. On the morning of Day 1, participants will 
be randomized to receive a single oral dose of 160-mg selpercatinib as the capsule or tablet 
formulation, and will be dosed according to the randomization sequence following an overnight 
fast of at least 10 hours. Participants will remain resident at the CRU until discharge on Day 7.
Participants will attend outpatient visits for the collection of PK blood samples and assessment of 
vital signs on Days 9 and 11.
Participants will be re-admitted to the CRU on Day 14 and in the morning of Day 15 will receive 
their second single oral dose of 160-mg selpercatinib as the capsule or tablet formulation, 
according to the randomization schedule, following an overnight fast of at least 10 hours. 
Participants will remain resident at the CRU until discharge on Day 21.
Participants will attend outpatient visits for the collection of blood samples and assessment of 
vital signs on Days 23, 25, and 28.
There will be a washout of at least 14 days between doses of selpercatinib.
Brief Summary:
Study JZJZ will be a Phase 1 open-label, randomized, two-period, two-formulation, 
two-sequence, two-stage adaptive crossover study in adult, heathy, male and female participants, 
following regulatory guidance. The new 160 mg tablet will be compared to 2 × 80 mg 
commercially available capsules (160 mg is the highest approved dose).
Number of Participants:
The incidence of those participants with a different PK profile (2 of 19 participants in Study 
LOXO-RET-18015) has meant that Lilly is planning to enroll up to approximately 60
participants in Stage 1. This is to ensure that at least 50 participants will complete Stage 1 and a 
sufficient variation of gastric pH will be incorporated in Stage 1.
The sample size for Stage 2 will be determined based on data from Stage 1.


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
10
In Stage 1, dropouts will not be replaced.
In Stage 2, dropouts will not be replaced, but over-enrollment of up to 20% of the determined 
sample size will be permitted to ensure a sufficient number of participants.
Intervention Groups and Duration:
Participants will participate in 1 stage of the study only. Participants will be screened within 
28 days prior to enrollment and will receive and will receive 2 single 160-mg oral doses of 
selpercatinib separated by a washout of at least 14 days.
The study duration for participants in each stage of the study is expected to be as follows:

Stage 1 = 56 days

Stage 2 = 56 days
Data Monitoring Committee: No


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
11
1.2.
Schema
Two by Two Crossover Design (Applicable to Stage 1 and Stage 2)


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
12
1.3.
Schedule of Activities (SoA) – Stages 1 and 2
Screening
Days
ED
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
9
11
14
15
1
6
1
7
18
19
20
21
23
25
28
Informed 
consent
X
Inclusion and 
exclusion 
criteria
X
Demography
X
Participant 
Admission to 
CRU
X
X
Participant 
Discharge from 
CRU
X
X
Outpatient visit
X
X
X
X
X
X
X
Medical history 
(includes 
substance usage 
[and family 
history of 
premature 
cardiovascular 
disease])a
X
X
Past and current 
medical 
conditions
X
Height and 
weightb
X
X
X
X


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
13
Screening
Days
ED
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
9
11
14
15
1
6
1
7
18
19
20
21
23
25
28
Physical 
examinationc
X
X
X
X
Serum or urine 
pregnancy test 
(women of 
childbearing 
potential only)d
X
X
X
X
X
Follicle-
stimulating 
hormone 
(postmenopausa
l women only)
X
Human 
immunodeficien
cy virus, 
hepatitis B and 
C screen
X
Urine ethanol 
test 
X
X
X
Urine drug 
screen
X
X
X
12-lead ECGe
X
X
P, 2h
X
P, 2h
X
X
X
Vital signs 
(supine)f
X
X
P, 1, 
2h
2
4
h
X
X
X
X
P, 1, 
2h
X
X
X
X
X


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
14
Screening
Days
ED
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
9
11
14
15
1
6
1
7
18
19
20
21
23
25
28
Clinical 
laboratory tests 
(include liver 
chemistries)g
X
X
2
4
h
X
X
2
4
h
X
X
X
Genetic sample
X
Gastric pH 
(Stage 1 only)h
P, 
0.5, 
1, 
1.5, 
2, 
2.5, 
3, 
3.5 h
P, 
0.5, 
1, 
1.5, 
2, 
2.5, 
3, 
3.5 h
PK samples -
Selpercatinib 
(plasma)
P, 
0.5, 
0.75, 
1, 
1.5, 
2, 
2.5, 
3, 
3.5, 
4, 6, 
8, 12 
h
2
4
, 
3
6
h
48
h
72
h
96
h
12
0
h
14
4
h
X
X
X
P, 
0.5, 
0.75, 
1, 
1.5, 
2, 
2.5, 
3, 
3.5, 
4, 6, 
8, 12 
h
2
4
, 
3
6
h
4
8
h
72
h
96
h
12
0
h
14
4
h
X
X
X
X
Randomization
X
Selpercatinib 
administration 
X
X
Adverse event 
/Serious adverse 
event review
X
X

=========================================
X


CONFIDENTIAL
Protocol number J2G-MC-JZJZ(c)
15
Screening
Days
ED
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
9
11
14
15
1
6
1
7
18
19
20
21
23
25
28
Concomitant 
medication 
review
X
X

=========================================
X
a Full medical history to be taken at screening; interim medical history to be taken at Day -1.
b Height to be measured at Screening only.
c Full physical examination to be performed at Check-in. Symptom-driven physical examinations to be performed at all other timepoints.
d Serum pregnancy test will be performed at screening. Urine pregnancy test will be performed at every admission to the CRU and at poststudy, if applicable.
e Single ECGs are required.
f Time points may be added, if warranted and agreed upon between Lilly and the investigator.
g See Appendix 2 (Section 10.2), Clinical Laboratory Tests, for details.
h NG tube placement first pH measurement done prior to dosing (see Section 8.5). The NG tube will be removed from the participant after the 3.5-hour pH 
timepoint.


C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2 G-M C -J ZJ Z(c)
1 6
2.
I ntr o d ucti o n
S el percat i ni b (L Y 3 5 2 7 7 2 3 ) has bee n de vel o pe d b y L o x o O nc ol o g y, I nc a n d ac q uire d b y Eli Lill y 
a n d C o m pa n y ( Lill y), a n d has bee n a p pr o ve d b y t he F D A f or t he treat me nt of a d va nce d or 
metastati c R E T -m ut a nt Me d ullar y T h yr oid Ca ncer ( M T C) , a n d a d va nce d or metastatic R E T 
f usi on- p osi tive t h y r oid ca ncer, i n a d ults a n d c hil dre n ≥1 2 y ears; a n d f or t he treat me nt of 
metastati c R E T f usi o n -p osi tive N S C L C i n a d ults. F ull details o f t he precli nical a n d cli nical 
safety a n d t olera bilit y data are c o ntai ne d i n t he I n vesti gat or’s Br oc h ure (I B) .
2. 1.
St u d y R ati o n ale
Lill y is de vel o pi n g a ta blet f or mulati o n i n stre n gt hs of 4 0 m g, 8 0 m g, 1 2 0 m g, a n d 1 6 0 
m g t hat will re place t he c urre nt c o m mercial ca ps ule f or mulat i on. T he ta blets are i nte n de d t o 
offer a n i m pr o ve d patie nt e x perie nce i n ter ms of t he n u m ber a n d size of t he d osa ge u nits. T he 
int e nt i on of t his st u d y  is t o de mo nstrate t he cli nical bi oe q ui vale nce of t he ne w 1 6 0 m g ta blet 
f or mulat i on of sel percat i ni b as c om pare d t o t he c urre nt 2 8 0 m g c o m mercial ca ps ule 
f or mulat i on of sel percat i ni b.
S el percat i ni b has p H -de pe n de nt s ol u bilit y,  wit h decreasi n g s ol u bilit y at hig her p H. T hi s 
p H- de pe n de nt s ol u bilit y has le d t o an a p pr o xi mate 6 9 t o 8 8% re d ucti o n ( C V % 5 9. 4 5 t o 6 4. 1 2) i n 
sel percati ni b A U C w he n sel percat i ni b was gi ve n u n der faste d c o n diti ons t o partici pa nts treate d 
wi t h t he acid- re d uci n g a ge nt o me praz ole (pr ot o n p u m p i n hi bit or ).
2. 2.
B ac k gr o u n d
S el percat i ni b ( L Y 3 5 2 7 7 2 3) is a hi g hl y p ote nt a n d s pecific s mall-m o lec ule i n hi bit or of t he R E T
ki nase, wi t h mi ni mal i n hi biti on of ot her ki nase a n d n o n ki nase tar gets.
S el percat i ni b d oses ha ve bee n e val uate d i n health y partici pa nts or patie nts wit h a d va nce d or
metastati c R E T -m ut a nt M T C, a d va nce d or metastatic R E T f usi o n- p osi tive t h y r oid ca ncer, ot her 
R E T f usi o n- p osi tive s o li d t u m ors, a n d metastatic R E T f usi o n- p osi tive N S C L C acr oss P hase 1, 2, 
a n d 3 cli nical st u dies. Acr oss t hese st u dies, si n gle oral d oses of sel percati ni b were a d mi nistere d 
o ver a ra n ge of 2 0 t o 7 2 0 m g. M ul tiple oral  d oses of 1 6 0 mg/ da y  sel percati ni b were a d mi nistere d 
orall y  t wice dail y for 1 0 d a y s i n heal t hy v o l unt eers. T he m ost fre q ue ntl y re p orte d ( ≥1 5 % of 
parti ci pa nts re gar dless o f attri b uti o n t o st u d y dr u g) Ad verse e ve nts ( A Es ) i n t he o n g oi n g 
first-i n-h u ma n d ose fi n di n g st u d y  were dr y mo ut h, diarr hea, h y perte nsi o n, A S T/ A L T i ncrease d, 
fati g ue, c o nsti patio n, e de ma peri p heral , na usea, hea dac he, bl o o d creati ni ne i ncrease d, a b d o mi nal 
pai n, ras h, E C G Q T pr ol o n ge d, c o u g h, v o mit i n g, a n d d ys p nea.
T he m e dia n t ma x of  sel percati ni b is 2 h o urs a n d is sl o wl y eli mi nate d wit h a mea n t1/ 2 of
a p pr o xi matel y 3 2 h o urs i n health y v o l unt eers. M ore detaile d i nf or mati o n a b o ut t he P K a n d
a bs or ptio n, di stri b uti on, meta b o lis m, a n d e xcreti on pr o perties o f sel percati ni b ma y be f o u n d i n
t he I B.


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Protocol number J2G-MC-JZJZ(c)
17
2.3.
Benefit/Risk Assessment
There is no anticipated therapeutic benefit for the healthy participants in this study. However, 
participants may benefit from the screening procedures (through detection of unknown health 
issues) even if they receive no therapeutic benefit from the study. 
The dose of selpercatinib to be given in this study is 160 mg, as it is the highest approved dose. 
The safety profile of selpercatinib is very well tolerated in healthy volunteers and is clinically 
manageable, with the low rates of study drug discontinuation due to AEs. 
As outlined in the IB, the most common toxicities associated with selpercatinib in patients are 
monitorable and reversible and include dry mouth, diarrhea, hypertension, fatigue, constipation, 
AST/ALT elevation, headache, nausea, edema peripheral, abdominal pain, rash, 
electrocardiogram QT prolonged, cough, vomiting, dyspnea and increased blood creatinine. 
Events of special interest include hypersensitivity, liver-function test abnormalities, 
thrombocytopenia, and hypertension. None of these events of special interest have been observed 
to date in healthy participants.
More detailed information about the known and expected benefits and risks and reasonably
expected AEs of selpercatinib may be found in the IB.


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Protocol number J2G-MC-JZJZ(c)
18
3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the bioequivalence of a 
single 160-mg dose of selpercatinib as 
the tablet formulation (test) compared 
to the commercial capsule formulation
(reference)

Cmax, AUC(0-∞), and AUC0-tlast of 
selpercatinib
Secondary

To describe the safety and tolerability 
of a single 160-mg oral dose of 
selpercatinib as the tablet formulation 
(test) compared to the commercial 
capsule formulation (reference)

Summary of the number of
treatment-emergent AEs and serious 
adverse events
Exploratory

To determine whether the PK of 
selpercatinib are altered by initial pH

Cmax, AUC(0-∞), and tmax of 
selpercatinib


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Protocol number J2G-MC-JZJZ(c)
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4.
Study Design
4.1.
Overall Design
Study JZJZ will be a Phase 1 open-label, randomized, two-period, two-formulation, two-
sequence, two-stage adaptive crossover study in adult heathy male and female participants. The 
new 160 mg tablet will be compared to 2 × 80 mg commercially available capsules (160 mg is 
the highest approved dose). The schemata in Section 1.2 illustrate the study randomization and 
crossover schema. 
Exploratory analysis of pH measurements (done via nasal gastric [NG] tube insertion and 
aspiration of gastric secretions and testing via pH meter) will be included in Stage 1 to 
understand the pH dynamics, including the potential of pH effect on absorption. The pH will not 
be measured in Stage 2 of the study. 
Safety assessments, including AEs, concomitant medications, medical assessments, clinical 
laboratory tests, vital signs, and ECGs, and blood sampling for PK, will be performed according 
to the SoA (Section 1.3).
4.1.1.
Screening
All participants will be screened within 28 days prior to enrollment.
4.1.2.
Treatment and Assessment Period
Stage 1: 
Participants will be admitted to the CRU on Day -1. On the morning of Day 1, participants will 
be randomized to receive a single oral dose of 160-mg selpercatinib as the capsule or tablet 
formulation, and will be dosed according to the randomization sequence following an overnight 
fast of at least 10 hours. On Day 1, participants will have an NG tube placed in the stomach prior 
to dosing to assess gastric pH, as outlined in Section 8.5. Participants will remain resident at the 
CRU until discharge on Day 7.
Participants will attend outpatient visits for the collection of PK blood samples and assessment of 
vital signs on Days 9 and 11.
Participants will be re-admitted to the CRU on Day 14 and in the morning of Day 15 will receive 
their second single oral dose of 160-mg selpercatinib as the capsule or tablet formulation, 
according to the randomization schedule, following an overnight fast of at least 10 hours. On 
Day 15, participants will have an NG tube placed in the stomach prior to dosing to assess gastric 
pH. Participants will remain resident at the CRU until discharge on Day 21.
Participants will attend outpatient visits for the collection of blood samples and assessment of 
vital signs on Days 23, 25, and 28.
There will be a washout of at least 14 days between doses of selpercatinib.
Stage 2: 
Participants will be admitted to the CRU on Day -1. On the morning of Day 1, participants will 
be randomized to receive a single oral dose of 160-mg selpercatinib as the capsule or tablet 


C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2 G-M C -J ZJ Z(c)
2 0
f or mulat i on, a n d will be d ose d acc or di n g t o t he ra n d o mizat i on se q ue nce f oll owi n g a n o ver ni g ht 
fast of at least 1 0 h o urs. Parti ci pa nts will re mai n r eside nt at t he C R U u nt il disc har ge o n Da y  7.
P arti cipa nts will atte n d o ut patie nt visits f or t he c ollecti o n of P K bl o o d sa m ples a n d assess me nt of 
vit al si g ns o n Da ys 9 a n d 1 1.
P arti cipa nts will be re -a d mitte d t o t he C R U o n Da y 1 4 a n d i n t he mor ni n g of Da y 1 5 will  recei ve 
t heir sec o n d si n gle oral d ose of 1 6 0-m g sel percati ni b as t he ca ps ule or ta blet f or m ulat i on, 
acc or di n g t o t he ra n d o mizati o n sc he d ule, f o ll owi n g a n o ver ni g ht fast of at least 1 0 h o urs. 
P arti cipa nts will re mai n resi de nt at t he C R U u nt il di s c har ge o n Da y 2 1.
P arti cipa nts will atte n d o ut patie nt visits f or t he c ollecti o n of bl o o d sa m ples a n d assess me nt of 
vit al si g ns o n Da ys 2 3, 2 5, a n d 2 8.
T here will be a was h o ut of at least 1 4 da ys bet wee n d oses of sel percati ni b.
4. 2.
Scie ntific R ati o n ale f or St u d y Desi g n
A si n gle 1 6 0 -m g d ose of sel percati ni b was selecte d as it is t he hi g hest pr o p ose d d ose f or 
sel percati ni b use i n a d ults.
I n or der t o all o w eac h partici pa nt t o act as his/ her o w n c o ntr ol f or safety a n d P K c o m par is o ns, a 
2- se q ue nce, 2 -peri o d cr oss o ver d esig n has bee n selecte d. T his st u d y  will als o be o pe n-la bel as 
t he st u d y pri mar y e n d p oi nt P K meas ures are o bjecti ve rat her t ha n s u bject i ve.
T he t w o -sta ge a da pti ve desi g n will be use d beca use ass u m pti o n o f i ntras u bject varia bility f or 
C ma x is n ot well esta blis he d. Sta ge 1 P K res ults will be use d t o deter mi ne i ntras u bject varia bility 
f or Cma x a n d A U C a n d t he re q uire d sa m ple size f or Sta ge 2. P ot vi n Met h o d C ( P ot vi n 2 0 0 7) will 
be use d t o c o ntr ol t he o ne- side d t y pe I err or rate ( α = 0. 0 5) f or assessi n g bi oe q ui vale nce i n 2
sta ges. ( See details i n Secti on 9. 4 ).
C o n d ucti n g t he st u d y  in healt h y part ici pa nts miti gates t he p ote ntial c o nf o u n di n g effects of t he 
di sease state a n d c o nc o mita nt me dicati o ns i n partici pa nts wit h metastatic R E T f usi o n- p osi ti ve 
N S C L C, a d va nce d or metastatic R E T -m ut a nt M T C, or a d va nce d or metastatic R E T 
f usi on- p osi tive t h y r oid ca ncer . A p o p ulat i on of healt h y part ici pa nts is fre q ue ntl y use d i n t he 
assess me nt of t he P K of b ot h s mall a n d lar ge m o lec ules.
S el percat i ni b has p H -de pe n de nt s ol u bilit y,  wit h decreasi n g s olu bili t y at hig her p H; e x pl orat or y  
a nal ysis of p H m eas ure me nt s via N G t u be place me nt, as pirat i on of gastri c secret i ons a n d tes te d 
o n a p H m eter will be i ncl u de d i n Sta ge 1 t o u n dersta n d t he p H d y na mics, i ncl u di n g t he p ote nti al 
of  p H effect o n a bs or pti o n. T he p H will n ot be meas ure d i n Sta ge 2 of t he st u d y . Sta ge 1 i s 
s ufficie ntl y size d t o e ns ure t hat wit hi n t hese n or mal heal t hy p art ici pa nts a s ufficie nt ra n ge of p H 
will be detecte d f or t he pla n ni n g of  Sta ge 2 w hi c h is pla n ne d t o f ulfill t he bi oe q ui vale nce ( B E )
g ui da nce f or c ha n ge of deli ver y  o ptio n.
T he d ose s, partici pa nt p o p ul atio n, st u d y  d uratio n, a n d sa m ple c ollect i on ti mi n g are c o nsi dere d 
a de q uate t o ac hie ve t he st u d y o bject i ves.
4. 3.
J u stific ati o n f or D ose
 
C CI


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Protocol number J2G-MC-JZJZ(c)
21
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all required 
periods of the study including the last visit, Day 28 or the last scheduled procedure shown in the 
SoA.
The end of the study is defined as the date of the last visit of the last participant in the study.


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Protocol number J2G-MC-JZJZ(c)
22
5.
Study Population
Eligibility of participants for enrollment in the study will be based on the results of screening 
medical history, physical examination, vital signs, clinical laboratory tests, and ECG.
The inclusion and exclusion criteria used to determine eligibility should be applied at screening 
only, and not continuously throughout the study. Clinical laboratory assessments and vital signs 
may be repeated from screening through Day -1 at the discretion of the investigator in order to 
confirm eligibility.
Screening may occur up to 28 days prior to enrollment. Participants who are not enrolled within 
28 days of screening may undergo an additional medical assessment and/or clinical 
measurements to confirm their eligibility. In such instances, the following screening tests and 
procedures should be repeated: clinical laboratory assessments and vital signs.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18 to 65 years of age inclusive, at the time of signing the informed
consent form (ICF).
Type of Participant 
2. Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, and vital signs.
3. Participants who have clinical laboratory test results within the normal reference range 
for the population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.
4. Participants who have venous access sufficient to allow for blood sampling as per the 
protocol.
5. Participants who are able to tolerate NG tube placement into the stomach (Stage 1 only). 
Weight
6. Have a body mass index within the range 19.0 to 35.0 kg/m2 (inclusive).
Sex and Contraceptive/Barrier Requirements
7.
Male or female
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
a.
Male participants:

Are not required to adhere to contraceptive requirements


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Protocol number J2G-MC-JZJZ(c)
23
Female participants:

Female participants of childbearing potential (see Appendix 4 [Section 10.4]) who 
are abstinent (if this is complete abstinence, as their preferred and usual lifestyle) 
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.
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence just for the duration of a study, and 
withdrawal, are not acceptable methods of contraception.

Female participants of childbearing potential, who are not abstinent as described 
above, must agree to use a highly effective method of contraception (that is, one 
with less than 1% failure rate) such as combination oral contraceptives, vaginal 
ring, implanted/injected contraceptives, intrauterine devices, or sterile partner 
until 30 days after the last dose of study medication.
o
Female participants not of childbearing potential are not required to use 
contraception. This includes females who are:

Infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy, bilateral tubal occlusion, 
or bilateral tubal ligation), or congenital anomaly (for example, 
Müllerian agenesis)

Postmenopausal as defined in Appendix 4 (Section 10.4).
Informed Consent
8. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.2),
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Have a positive pregnancy test at screening or Day -1, where applicable
2. Are planning to become pregnant during the study or within 1 month of study completion
3. Are women who are lactating
4. Have known allergies to selpercatinib-related compounds or any components of the 
formulation of selpercatinib, or history of significant atopy
5. Have a history of allergic reactions to medications or food products
6. Have a clinically significant abnormality of blood pressure and/or pulse rate as
determined by the investigator
7. Clinically significant abnormalities on ECG as determined by the investigator or
prolongation of the QTcB or QTcF >450 msec at screening
8. Have clinically significant active cardiovascular disease or history of myocardial
infarction within 6 months prior to the planned start of selpercatinib


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Protocol number J2G-MC-JZJZ(c)
24
9. Have a history or presence of cardiovascular, respiratory, renal, gastrointestinal, 
endocrine, hematological, or neurological disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs; of constituting a risk when taking the 
investigational product; or of interfering with the interpretation of data. Appendectomy,
splenectomy, and cholecystectomy are considered as acceptable
10. Have a creatinine clearance <60 mL/min, as calculated using the CKD-EPI equation
(Levey et al, 2009).
eGFR = 141 × min(Scr/K, 1)α × max(Scr/K, 1)-1.209 × 0.993age
× 1.018 (if female)
× 1.159 (if black)
11. Inadvertent omission of exclusion line item 
12. Show a history of central nervous system conditions such as strokes, transient ischemic 
attacks, significant head trauma, seizures, central nervous system infections, migraine, 
brain surgery, or any other neurological conditions that, in the opinion of the investigator,
increase the risk of participating in the study
13. Have a history or presence of neuropsychiatric disease (e.g., bipolar disorder,
schizophrenia, depression) considered as clinically significant by the investigator
14. Regularly use known drugs of abuse or show positive findings on drug screening
15. Show evidence of human immunodeficiency virus infection and/or positive human
immunodeficiency virus antibodies
16. Presence of hepatitis B surface antigen at screening or within 3 months prior to first dose
of study intervention
17. Positive hepatitis C antibody test result at screening or within 3 months prior to first dose 
of study intervention. 
NOTE: Participants with positive hepatitis C antibody due to prior resolved disease can 
be enrolled if a confirmatory negative hepatitis C RNA test is obtained
18. Positive hepatitis C RNA test result at screening or within 3 months prior to first dose of 
study intervention. 
NOTE: Test is optional and participants with negative hepatitis C antibody test are not 
required to also undergo hepatitis C RNA testing
19. Have donated blood of more than 500 mL within the previous 2 months of study
screening
20. Have any medical conditions, medical history, or are taking any medications which are
contraindicated in the selpercatinib label
Prior/Concomitant Therapy
21. Have participated, within the last 30 days of admission, in a clinical study involving an 
investigational product. If the previous investigational product has a long half-life, 5 half-
lives or 30 days (whichever is longer) should have passed.
22. Have previously completed or withdrawn from this study or any other study investigating 
selpercatinib, and have previously received the investigational product


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Protocol number J2G-MC-JZJZ(c)
25
23. Use of H2 blockers, proton pump inhibitors, and other drugs that affect selpercatinib 
exposure within 7 days of screening
24. Are intending to use over-the-counter or prescription medication, including dietary 
supplements, within 14 days prior to dosing and until study discharge (apart from 
occasional acetaminophen (≤2 g/24 hours), hormonal contraception, or hormone 
replacement therapy)
Prior/Concurrent Clinical Study Experience
25. Are currently enrolled in any other clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or medically 
compatible with this study
Other Exclusions
26. Have an average weekly alcohol intake that exceeds 21 units per week (males 
≤65 years old) and 14 units per week (females); 1 unit = 12 oz or 360 mL of beer; 5 oz 
or 150 mL of wine; 1.5 oz or 45 mL of distilled spirit(s)
27. Are unwilling to stop alcohol consumption 48 hours prior to each admission to the 
CRU, and while resident at the CRU. At all other times, participants must agree to 
consume no more than 2 units per day
28. Are smokers of more than 10 cigarettes or e-cigarettes, or 3 cigars or 3 pipes, per day 
and are unable to refrain from smoking while resident at the CRU
29. Unwilling to stop caffeine consumption 48 hours prior to admission and while resident 
at the CRU. Excessive amount is defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine).
30. Are unable to consume a standard meal (e.g., breakfast, lunch, dinner, and snack).
31. Currently use or show evidence of substance abuse (including alcohol abuse) or 
dependence within the past 6 months based on medical history at screening visit
32. Inability to comply with the dietary regimen of the CRU
33. Are Lilly employees or are an employee of any third-party involved in the study who 
require exclusion of their employees
34. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted
35. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study 
5.3.
Lifestyle Considerations
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study.
5.3.1.
Meals and Dietary Restrictions
During the confinement period, participants will consume only food and beverages that are 
provided to them by the CRU staff. Standard meals (e.g., breakfast, lunch, dinner, and snack) 
will be provided to the participants while resident at the CRU.


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Protocol number J2G-MC-JZJZ(c)
26
In both Stages 1 and 2 of the study, selpercatinib will be dosed in the fasted state on Day 1 and 
Day 15. 
On dosing occasions, the participants will be fasted overnight (at least 10 hours) prior to dosing 
and refrain from consuming water from 1 hour predose until 2 hours postdose, excluding the 
amount of water consumed during introduction of the NG tube and at dosing. Food is allowed 
from 4 hours postdose. At all other times during the study, participants may consume water ad 
libitum. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be allowed 
from 7 days prior to check-in until discharge from the study. 
5.3.2.
Caffeine, Alcohol, and Tobacco
Participants will abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, 
tea, cola drinks, and chocolate) for 48 hours prior to Day -1 until after discharge from the study.
Participants will abstain from alcohol for 48 prior to Day -1 until after discharge from the study.
Participants who use tobacco products will be instructed that use of nicotine-containing products 
(including nicotine patches) will not be permitted while they are in the clinical unit.
5.3.3.
Activity
Participants will abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities during the 
study (e.g., watching television, reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. Repeating of laboratory tests during the screening period or repeating screening tests 
to comply with the protocol designated screening period does not constitute rescreening.


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Protocol number J2G-MC-JZJZ(c)
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6.
Study Intervention(s) and Concomitant Therapy
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.
6.1.
Study Intervention(s) Administered
Table JZJZ.6.1.
Study Interventions Administered
Study Intervention 
Selpercatinib
Selpercatinib
Dosage Formulation
Capsule
Tablet
Unit Dose Strength/Dosage Level
2 80-mg capsules
(160 mg selpercatinib)
1 160-mg tablets
(160 mg selpercatinib)
Route of Administration
Oral
Oral
Dosing Instructions
2 capsules taken 
on Day 1 or Day 15, according to the 
randomization schedule
1 tablet taken 
on Day 1 or Day 15, according to the 
randomization schedule
6.1.1.
Administration Details
A single oral dose of selpercatinib 160-mg will be administered in the morning of Days 1 and 15 
with approximately 240 mL of room temperature water while in a sitting position. Participants 
will not be allowed to lie supine for 2 hours after dosing, unless clinically indicated or for study 
procedures.
Selpercatinib capsules and tablets should be swallowed whole. Participants should not break, 
crush, or chew the capsules or tablets, and should not empty the contents of the capsules.
On dosing days, participants will adhere to meal restrictions as outlined in Section 5.3.1.
6.2.
Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized study personnel.
3. The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and 
final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the study reference manual.


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Protocol number J2G-MC-JZJZ(c)
28
Note: in some cases, sites may destroy the material if the evaluator has verified and documented 
that the site has appropriate facilities and written procedures to dispose of clinical materials.
Samples of the specific batches of selpercatinib used in the study will be retained; details will be 
provided separately.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study. There is no bias as the primary endpoint is PK and objective in 
measure.
In both Stages 1 and 2, participants will be assigned a unique number (randomization number) on 
Day 1. The randomization number encodes the participant’s assignment to be dosed with either 
the capsule or tablet on Days 1 and 15 according to the randomization schedule generated prior 
to the study by the Statistics Department at Covance.
6.4.
Study Intervention Compliance
Participants are dosed at the site and will receive study intervention directly from the investigator 
or designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and recorded in the eCRF. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. Study 
site personnel will examine each participant’s mouth to ensure that the study intervention was 
ingested.
6.5.
Dose Modification
Dose modification will not be permitted in this study.
6.6.
Continued Access to Study Intervention After the End of the Study
Selpercatinib will not be made available to participants after completion of the study.
6.7.
Treatment of Overdose
For the purposes of this study, an overdose of selpercatinib is considered as any dose higher than 
the dose assigned. There is no specific antidote for selpercatinib.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AE/Serious adverse events (SAE) and laboratory 
abnormalities until study intervention can no longer be detected systemically (at least 5
days).
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF.
Decisions regarding dose interruptions will be made by the investigator in consultation with the 
medical monitor based on the clinical evaluation of the participant.


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Protocol number J2G-MC-JZJZ(c)
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6.8.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:
a. Reason for use
b. Dates of administration including start and end dates
c.
Dosage information including dose and frequency for concomitant therapy of special 
interest
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 14 days before the start of study intervention until 
discharge from the study.
Acetaminophen, at doses of ≤ 2 grams/24 hours, is permitted for use at the discretion of the 
investigator for the treatment of headache, etc. Contraceptive medication is permitted as per the 
contraception requirements (Appendix 4 [Section 10.4]), and hormone replacement therapy is 
also allowed.
Other medication may be considered on a case-by-case basis by the investigator in consultation 
with the Lilly clinical pharmacologist (CP)/clinical research physician (CRP), or designee.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Participants discontinuing from study intervention prematurely for any reason should complete 
AE and other early discontinuation procedures as per the SoA (Section 1.3). 
Participants discontinuing from the study prematurely for any reason must complete AE and 
early discontinuation procedures as per the SoA (Section 1.3). 
Discontinuation of the study as a whole is described in Appendix 1 (Section 10.1).
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for safety. See the SoA for data to be collected at the time of 
discontinuation of study intervention and discharge from the study, and for any further 
evaluations that need to be completed.
7.1.1.
Liver Chemistry Stopping Criteria
Study intervention will be discontinued for a participant if liver chemistry stopping criteria are 
met.
Phase 1 Liver Chemistry Stopping Algorithm
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; 
ULN = upper limit of normal.
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix 6 
(Section 10.6).
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*


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7.1.2.
QTc Stopping Criteria
A participant who meets either bulleted criterion following single ECG assessment should have 
ECG repeated. If the participant still meets either bulleted criterion they will be withdrawn from 
the study.

QTc, QTcB, QTcF >500 msec

Change from baseline: QTc >60 msec
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QTc using Bazett’s formula or QTcF) after enrollment, the investigator or qualified designee 
will determine if the participant can continue in the study and if any change in participant 
management is needed. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE.
See the SoA for data to be collected at the time of intervention discontinuation and discharge 
from the study, and for any further evaluations that need to be completed.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study:
●
at any time at his/her own request 
●
at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons

if the participant becomes pregnant during the study
●
if enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study
●
if the participant, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent.
Discontinuation is expected to be uncommon.
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and discharge from the study, and for any further evaluations that need to be 
completed. The participant will be permanently discontinued from both the study intervention
and the study at that time.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant
withdraws from the study, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.


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7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.


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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (Section 1.3).
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
8.1.
Efficacy Assessments
Not applicable to this study.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations
Physical examinations should be conducted according to the SoA (Section 1.3). 
A full physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.2.
Height and Weight
Height and weight will be measured and recorded at the times indicated in the SoA (Section 1.3). 
8.2.3.
Vital Signs
For each participant, vital signs measurements should be conducted according to the SoA
(Section 1.3).
Blood pressure and pulse rate should be measured singly after at least 5 minutes supine. For each 
individual participant, the same cuff size should be used throughout the study for the 
measurements of blood pressure. The cuff should be attached to the participant’s dominant arm.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. Where orthostatic measurements are required, participants should be 
supine for at least 5 minutes and then participants will stand, and standing blood pressure will be 
measured after 2 minutes, but no longer than 3 minutes. If the participant feels unable to stand, 
supine vital signs only will be collected. Additional vital signs may be measured if warranted.


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Protocol number J2G-MC-JZJZ(c)
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8.2.4.
Electrocardiograms
For each participant, single 12-lead ECGs will be obtained as outlined in the SoA (see 
Section 1.3). Refer to Section 7 for QTc withdrawal criteria and any additional QTc
readings that may be necessary.
Electrocardiograms must be recorded before collecting any blood samples. Participants must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection. Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary. All ECGs recorded should be stored at the investigational site.
Electrocardiograms will be interpreted by the investigator at the site as soon after the time of 
ECG collection as possible, and ideally while the participant is still present, to determine whether 
the participant meets entry criteria at the relevant visit(s) and for immediate participant 
management, should any clinically relevant findings be identified. 
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the participant can 
continue in the study. The investigator, or qualified designee, is responsible for determining if 
any change in participant management is needed and must document his/her review of the ECG 
printed at the time of collection. Any new clinically relevant finding should be reported as an 
AE.
8.2.5.
Clinical Safety Laboratory Tests
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant 
by the investigator or medical monitor.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the laboratory manual and 
the SoA.
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (e.g., SAE or AE), then the results must be recorded in 
the eCRF.
8.2.6.
Pregnancy Testing 
Where applicable, pregnancy tests will be performed as outlined in the SoA (see Section 1.3).


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8.2.7.
Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures. The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes including hematology and chemistry
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
8.2.7.1.
Hepatic Safety
Close hepatic monitoring
Laboratory tests (Appendix 6 [Section 10.6]), including ALT, AST, alkaline phosphatase (ALP), 
total bilirubin, direct bilirubin, gamma-glutamyl transferase, and creatine kinase, should be 
repeated within 48 to 72 hours to confirm the abnormality and to determine if it is increasing or 
decreasing, if one or more of these conditions occur:
If a participant with baseline results 
of ... 
develops the following elevations:
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN
ALP <1.5 × ULN
ALP ≥2 × ULN
TBL <1.5 × ULN
TBL ≥2 × ULN (except for patients with Gilbert’s 
syndrome)
ALT or AST ≥1.5 × ULN
ALT or AST ≥2 × baseline
ALP ≥1.5 × ULN
ALP ≥2 × baseline
TBL ≥1.5 × ULN
TBL ≥2 × baseline (except for patients with Gilbert’s 
syndrome)
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels.
Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur:


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Protocol number J2G-MC-JZJZ(c)
36
If a participant with baseline 
results of... 
develops the following elevations:
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN with hepatic signs/symptoms*, or
ALT or AST ≥5 × ULN
ALP <1.5 × ULN
ALP ≥3 × ULN
TBL <1.5 × ULN
TBL ≥2 × ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5 × ULN
ALT or AST ≥2 × baseline with hepatic signs/symptoms*, or
ALT or AST ≥3 × baseline
ALP ≥1.5 × ULN
ALP ≥2 × baseline
TBL ≥1.5 × ULN
TBL ≥1.5 × baseline (except for patients with Gilbert’s 
syndrome) 
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time/international normalized ratio; 
tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging 
study (for example, ultrasound or computed tomography scan). 
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
serum phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety eCRF) in study participants who have 
abnormal liver tests during the study:
Additional hepatic safety data collection in hepatic safety eCRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions:
1. Elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5 × ULN)
In participants with baseline ALT ≥1.5 × ULN, the threshold is ALT 
≥3 × baseline on 2 or more consecutive tests
2. Elevated TBL to ≥2 × ULN (if baseline TBL <1.5 × ULN) (except for cases of known 
Gilbert’s syndrome)
In participants with baseline TBL ≥1.5 × ULN, the threshold should be TBL 
≥2 × baseline
3. Elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5 × ULN)
In participants with baseline ALP ≥1.5 × ULN, the threshold is ALP ≥2 × baseline 
on 2 or more consecutive blood tests
4. Hepatic event considered to be an SAE
5. Discontinuation of study drug due to a hepatic event 


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Protocol number J2G-MC-JZJZ(c)
37
NOTE: the interval between the 2 consecutive blood tests should be at least 2 days.
8.3.
Adverse Events, Serious Adverse Events, and Product Complaints
Product Complaints are covered in Section 8.3.3.
The definitions of the following events can be found in Appendix 3 (Section 10.3):

AEs

SAEs

Product complaints (PCs)
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention/study (see Section 7).
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences.
8.3.1.
Timing and Mechanism for Collecting Events
This table describes the timing, deadlines, and mechanism for collecting events.
Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Adverse Event
AE
signing of 
the informed 
consent form 
(ICF)
participation 
in study has 
ended
As soon as possible 
upon site awareness
AE eCRF
N/A
Serious Adverse Event
SAE and SAE 
updates – prior 
to start of study 
intervention and
deemed 
reasonably 
possibly related 
with study 
procedures
signing of 
the informed 
consent form 
(ICF)
start of 
intervention
Within 24 hours of 
awareness
SAE paper form
SAE paper 
form


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Protocol number J2G-MC-JZJZ(c)
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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
SAE and SAE 
updates – after 
start of study 
intervention
start of 
intervention
participation 
in study has 
ended
Within 24 hours of 
awareness
SAE paper form
SAE paper 
form
SAE – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware
after 
participant’s 
study 
participation 
has ended
N/A
promptly
SAE paper form
N/A
Pregnancy
Pregnancy in 
female 
participants and 
female partners 
of male 
participants
after the start 
of study 
intervention
at least 5 
terminal half-
lives or 30 
days after the 
last dose, 
whichever is 
longer
within 24 hours (see 
Section 8.3.2)
SAE paper form
SAE paper 
form
Product Complaints
PC associated 
with an SAE or 
might have led 
to an SAE
start of study 
intervention
end of study 
intervention
within 24 hours of 
awareness
Product Complaint 
form
N/A
PC not 
associated with 
an SAE
start of study 
intervention
end of study 
intervention
within 1 business day 
of awareness
Product Complaint 
form
N/A
Updated PC 
information
—
—
as soon as possible 
upon site awareness
Originally 
completed Product 
Complaint form 
with all changes 
signed and dated by 
the investigator
N/A


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Protocol number J2G-MC-JZJZ(c)
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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
PC (if 
investigator 
becomes aware)
participation 
in study has 
ended
N/A
promptly
Product Complaint 
form
8.3.2.
Pregnancy
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 study 
intervention.
●
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, regardless of gestational age, 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. 


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Protocol number J2G-MC-JZJZ(c)
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●
Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol Section 10.1. 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 discontinue study intervention. If the participant is discontinued from the 
study, follow the standard discontinuation process and continue directly to the 
follow-up phase. The follow-up on the pregnancy outcome should continue 
independent of intervention or study discontinuation.
Prior to continuation of study intervention following pregnancy, the following must occur:
●
The sponsor and the relevant Institutional Review Board (IRB)/Independent Ethics 
Committees (IEC) give written approval.
●
The participant gives signed informed consent.
●
The investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and her offspring.
8.3.3.
Product Complaints
A product complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
study intervention. 
The sponsor collects PCs on investigational products and drug delivery systems used in clinical 
studies in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
NOTE: AEs/SAEs that are associated with a product complaint will also follow the processes 
outlined in Section 8.3.1 and Appendix 3 (Section 10.3) of the protocol.
8.4.
Pharmacokinetics
●
Venous blood samples of approximately 2 mL will be collected for measurement 
of plasma concentrations of selpercatinib as specified in the SoA (Section 1.3). 
●
A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor. The 
timing of sampling may be altered during the course of the study based on newly 
available data to ensure appropriate monitoring. 
●
Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded.


C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2 G-M C -J ZJ Z(c)
4 1
8. 5.
G astric p H ( St a ge 1 o nl y)
I n Sta ge 1 , at t he ti me p oi nts s pecifie d i n t he S o A ( Secti o n 1. 3 ), o n d osi n g da ys pri or t o 
sel percati ni b d osi n g, parti ci pa nts will ha ve a N G t u be i nserte d i nto t he st o m ac h. T he N G t u be
s h o uld be i nserte d i nt o t he partici pa nt ’s st o mac h n o more t ha n 6 0 mi n ute s pri or t o sel percati ni b
d osi n g. T he use of l ocal a nest het ic (f or e xa m ple, li d ocai ne) will be all o we d t o facilitate t he 
i nsertio n of  N G t u be. 
 
 
 
If f or s o me reas o n t he partici pa nt d oes n ot t olerate t he N G t u be after t he i nit ial p H rea di n g, t he 
t u be ca n be re m o ve d a n d t his w o ul d n ot be c o nsi dere d a pr ot oc ol vi olati on. If gastric secret i ons 
are n ot a ble t o be as pirate d at a n y time p o i nt after t he i nitial p H meas ure me nt, t his is n ot 
c o nsi dere d a pr ot oc ol vi o lati on.
T he p H m eas ure me nt data will be a d de d t o t he e C R F.
8. 6.
P h ar m ac o d y n a mics
P har mac o d y na mic para meters a re n ot e val uate d i n t his st u d y.
8. 7.
Ge netics
A bl o o d O R sali va sa m ple f or D N A is olati on will be c o llecte d fr om parti ci pa nts. 
See A p pe n di x 5 ( Secti o n 1 0. 5 ) f or I nf or mat i on re gar di n g ge netic researc h a n d A p pe n di x 1 
( Sectio n 1 0. 1 ) f or details a b o ut sa mple rete nti o n a n d cust o d y . 
8. 8.
Bi o m ar kers
Bi o m ar kers are n ot e valuate d i n t hi s st u d y.
8. 9.
I m m u n o ge nicit y Assess me nts
N ot a p plica ble f or t his st u d y .
8. 1 0.
He alt h Ec o n o mic s
T his sect i on is n ot a p plica ble f or t his st u d y.
C CI


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Protocol number J2G-MC-JZJZ(c)
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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The primary objective will be evaluated to assess the bioequivalence of the tablet formulation 
compared to the capsule formulation.
9.2.
Analyses Sets
The following populations are defined:
Population
Description
Entered
All participants who sign the ICF.
Safety
All enrolled participants who take at least 1 dose of selpercatinib, whether or 
not they completed all protocol requirements.
Pharmacokinetic Analysis
All participants who received at least 1 dose of selpercatinib and have 
evaluable PK data.
9.2.1. Study Participant Disposition
A detailed description of participant disposition will be provided at the end of the study.
9.2.2.
Study Participant Characteristics
The participant’s age, sex, and other demographic characteristics will be recorded and 
summarized.
9.2.3.
Treatment Compliance
The date and time of dosing will be recorded and listed.
9.3.
Statistical Analyses
Statistical analysis of this study will be the responsibility of the sponsor or its designee. 
Pharmacokinetic analyses will be conducted on data from all participants who received at least 1
dose of selpercatinib and have evaluable PK data. 
Safety analyses will be conducted for all enrolled participants who received at least 1 dose of 
selpercatinib, whether or not they completed all protocol requirements. 
Additional exploratory analyses of the data will be conducted as deemed appropriate.
9.3.1.
Safety Analyses
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology. 


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The incidence of AEs for each treatment will be presented by severity and by association with IP 
as perceived by the investigator. Adverse events reported to occur prior to enrollment will be 
distinguished from those reported as new or increased in severity during the study. Each AE will 
be classified by the most suitable term from the medical regulatory dictionary. 
The number of investigational SAEs will be reported.
9.3.1.1.
Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters. Additional analysis will be performed if warranted upon review of the data.
9.3.2.
Pharmacokinetic Analyses
9.3.2.1.
Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates will be calculated by standard noncompartmental methods. 
The primary PK parameters for analysis of selpercatinib will be: Cmax, AUC(0-∞), AUC0-tlast, 
and tmax. 
Other noncompartmental parameters, such as t1/2, apparent total body clearance of drug 
calculated after extravascular administration, and apparent volume of distribution during the 
terminal phase after extravascular administration, may be reported as appropriate.
9.3.2.2.
Pharmacokinetic Statistical Inference
Pharmacokinetic parameters will be evaluated to estimate bioequivalence. For the primary 
analysis, log-transformed Cmax, AUC0-tlast, and AUC(0-∞) will be evaluated in a linear mixed-
effect model with fixed effects for formulation, period, and sequence, and a random effect for 
subject. The treatment differences will be back-transformed to present the ratios of geometric 
means and the corresponding CIs.
For secondary analysis, the tmax will be analyzed using a Wilcoxon signed rank test. Estimates of 
the median difference based on the observed medians, 90% CIs, and p-values from the Wilcoxon 
test will be calculated. Pharmacokinetic parameters will be summarized using descriptive 
statistics.
9.3.3.
Pharmacodynamic Analyses
The pH data will be listed and summarized using descriptive statistics. 
9.3.4.
Pharmacokinetic/Pharmacodynamic Analyses
Not applicable for this study.
9.4.
Interim Analysis 
At completion of Stage 1, an interim analysis will be conducted to test BE and estimate the 
power before continuing to Stage 2.
In order to meet the BE criterion at a specific α level, the 2-sided confidence interval for the 
tablet-to-capsule (tablet formulation / capsule formulation) geometric mean ratio (GMR) for 


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44
AUC and Cmax at the (1-2α) level should fall within 80%-125%. The sequential design approach 
of Potvin’s Method C will be used to preserve the overall type I error rate at the 1-sided 
significance level of 0.05. 
The BE testing and alpha spending scheme is described in Figure JZJZ.9.1. At an interim 
analysis, the power will be evaluated using the intrasubject CV from Stage 1 using α level of 
0.05 assuming the true tablet-to-capsule GMR is 1.05. If Stage 1 has at least 90% power, BE will 
be tested at Stage 1 at an α level of 0.05. The study will be stopped whether BE is met or not 
met. The evaluation of the power at Stage 1 will be based on Cmax, which has higher variability.
If the power is less than 90%, BE will be tested at an α level of 0.0294 as originally proposed by 
Pocock (Pocock 1977). If the BE criterion is met, the study will be stopped. If the BE criterion is 
not met, the sample size for Stage 2 will be calculated based on the intrasubject CV at Stage 1 
and an α level of 0.0294 assuming the true tablet-to-capsule GMR is 1.05, and Stage 2 will be 
initiated. At Stage 2, BE will be evaluated using data from both stages at an α level of 0.0294. 
Figure JZJZ.9.1.
Adaptive sequential design method C (Potvin, 2007).
The Statistical Analysis Plan will describe the planned interim analyses in greater detail.
9.5.
Sample Size Determination
The incidence of those participants with a different PK profile (2 of 19 subjects in Study LOXO-
RET-18015) has meant that Lilly is planning to enroll up to approximately 60 participants in 
Stage 1. This is to ensure that at least 50 participants will complete Stage 1 and a sufficient 
variation of gastric pH will be incorporated in Stage 1. 
If the true intraparticipant CV is 30% for Cmax and 20% for AUC, the first 50 participants in 
Stage 1 will give approximately 90% power to meet BE criteria at a 1-sided α level of 0.05,
under an assumption of a GMR of 1.05.


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Table JZJZ.9.1 shows the required sample size for Stage 2 to provide the power for Cmax of 90%
based on different intrasubject CV for Cmax from Stage 1, assuming the true tablet-to-capsule 
GMR is 1.05 under scenario when the power is less than 90% and BE is not met at Stage 1. The 
actual sample size for Stage 2 will be determined based on the observed intrasubject CV at Stage 
1.
In Stage 1, dropouts will not be replaced.
In Stage 2, dropouts will not be replaced, but over-enrollment of up to 20% of the determined 
sample size will be permitted to ensure a sufficient number of participants.
Table JZJZ.9.1.
Sample Size for Stage 2 Based on Intrasubject CV for Cmax in Stage 1
Intrasubject CV for Cmax in Stage 1
Required Sample Size for Stage 2
40%
50
50%
100
60%
156
70%
216
Abbreviations: Cmax = maximum serum concentration; CV = coefficient of variation.
Note: The total sample size will be at least 50 for Stage 1 plus the required sample size for Stage 2.


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
●
This study will be conducted in accordance with the protocol and with the 
following:
○
Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines
○
Applicable ICH Good Clinical Practice (GCP) Guidelines
○
Applicable laws and regulations
●
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (for example, advertisements) must be submitted to an 
IRB/IEC by the investigator and reviewed and approved by the IRB/IEC before 
the study is initiated.
●
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.
●
Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants.
●
The investigator will be responsible for the following:
○
Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC
○
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures
○
Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
●
Investigator sites are compensated for participation in the study as detailed in the 
Clinical Trial Agreement.
10.1.2.
Informed Consent Process
●
The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions 
regarding the study.


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●
Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data 
protection requirements, where applicable, and the IRB/IEC or study center.
●
The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.
●
Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study.
●
A copy of the ICF(s) must be provided to the participant and is kept on file.
10.1.3.
Data Protection
●
Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred.
●
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for his/her data to be used as described in the informed consent.
●
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
●
The sponsor has processes in place to ensure data protection, information security 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach.
10.1.4.
Dissemination of Clinical Study Data
Communication of Suspended or Terminated Dosing
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, by phone and/or email) 
as soon as possible. It will be a requirement that investigators respond upon receipt to confirm 
that they understand the communication and have taken the appropriate action prior to further 
dosing any participants with study intervention. Any investigator not responding will be 
followed up by Lilly personnel prior to any further planned dosing. If a dose is planned 
imminently, Lilly personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified. 


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Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
Data 
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected.
10.1.5.
Data Quality Assurance
●
All participant data relating to the study will be recorded on printed or electronic 
case report forms (CRFs) unless transmitted to the sponsor or designee 
electronically (for example, laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.
●
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.
●
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.
●
Quality tolerance limits (QTLs) will be predefined to identify systematic issues 
that can impact participant safety and/or reliability of study results. These 
pre-defined parameters will be monitored during the study and important 
excursions from the QTLs and remedial actions taken will be summarized in the 
clinical study report.
●
Monitoring details describing strategy (for example, risk-based initiatives in 
operations and quality such as risk management and mitigation strategies and 
analytical risk-based monitoring), methods, responsibilities and requirements, 
including handling of noncompliance issues and monitoring techniques are 
provided in the Monitoring Plan.
●
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.
●
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations).
●
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.


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49
●
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 
Clinical Trial Agreement unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.
●
In addition, sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study 
may be audited by sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
Data collected via the sponsor-provided data capture system will be stored at third-party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and electronic transfers will be provided to the investigator 
for review and retention. Data will subsequently be transferred from the central vendor to the 
sponsor data warehouse.
Data from complaint forms submitted to sponsor will be encoded and stored in the global 
product complaint management system.
10.1.6.
Source Documents
●
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.
●
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available.
●
Definition of what constitutes source data can be found in 10.1.5.
10.1.7.
Study and Site Start and Closure
First Act of Recruitment
The study start date is the date on which the clinical study will be open for recruitment of 
participants.


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50
Study or Site Termination
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
For study termination:
●
Discontinuation of further study intervention development
For site termination:
●
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines
●
Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator
●
Total number of participants included earlier than expected.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
10.1.8.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance.


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10.2.
Appendix 2: Clinical Laboratory Tests
The tests detailed in the table below will be performed by the local laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Investigators must document their review of the laboratory safety results.


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Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate (total CO2)
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphorus 
Leukocytes (WBC) 
Platelets
Glucose (random)
Creatine kinase
Total cholesterol, LDL-C, and HDL-C
Differential WBC (absolute counts) of
Blood urea nitrogen (BUN)
Neutrophils
Uric acid 
Lymphocytes
Gamma-glutamyl transferase (GGT)
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Alkaline phosphatase (ALP)
Urinalysisa
Aspartate aminotransferase (AST)
Specific gravity
Alanine aminotransferase (ALT)
pH
Creatinine
Protein
Glucose
Ethanol testingb
Ketones
Urine drug screenb
Bilirubin
Hepatitis B surface antigenc
Urobilinogen
Hepatitis C antibodyc, d
Blood
HIVc
Nitrite
Pregnancy test (women of childbearing potential only)
Leukocyte esterase
FSH (if applicable)c, e
Abbreviations: FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell.
a
Performed by dipstick. Microscopic examination to be performed if dipstick is abnormal for blood, protein, 
nitrites, or leukocyte esterase.
b
Urine drug screen and ethanol (urine) level performed at screening and check-in.
c
Performed at screening only.
d
Participants with a positive hepatitis C antibody test result can have a confirmatory hepatitis C RNA test.
e
Postmenopausal women only.


C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2 G-M C -J ZJ Z(c)
5 3
1 0. 2. 1.
Bl o o d S a m pli n g S u m m ar y
T his ta ble s u m marizes t he a p pr o xi mate n u m ber of ve ni p u nct ures a n d bl o o d v ol u mes f or all 
bl o o d sa m pli n g (scree ni n g, safet y lab orat ori es, a n d bi oa nal ytical assa ys) d uri n g t he st u d y. 
Pr ot oc ol J 2 G- M C -J Z J Z S a m pli n g S u m m ar y ( St a ges 1 a n d 2 )
P ur p ose
Bl o o d V ol u me per 
S a m ple ( m L)
M a xi m u m N u m ber 
of Bl o o d S a m ples
M a xi m u m T ot al 
V ol u me ( m L)
Scree ni n g tests a
4 5
1
4 5
Cli nical la b orat or y tests a
1 2
8
9 6
Bl o o d discar d f or ca n n ula pate nc y
1
1
1
Ge netic sa m ple
1 0
1
1 0
T otal
2 4 4
T otal f or cli nical p ur p oses 
2 5 2
a
A d diti o nal sa m ples ma y be dra w n if nee de d f or safet y p ur p oses.
C CI


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10.3.
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated)
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.


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
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed:
a.
Results in death
b.
Is life-threatening
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
f.
Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 


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events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
10.3.3.
Definition of Product Complaints
Product Complaint

A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also PCs:
o
Deficiencies in labeling information, and
o
Use errors for device or drug-device combination products due to ergonomic 
design elements of the product.

Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements.

Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed.

An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE.
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product Complaints
AE, SAE, and Product Complaint Recording

When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation (for example, hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/product complaint information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice. AE/SAE information is reported on the appropriate eCRF page and 
product complaint information is reported on the Product Complaint Form.
Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE.


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
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the (e)CRF page for AE/SAE 
and the Product Complaint Form for PCs.

There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:

Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.

Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the research 
participant.

Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
An AE that is assessed as severe should not be confused with a SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship/

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB in his/her assessment.


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
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to sponsor or designee.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any 
post-mortem findings including histopathology.
10.3.5.
Reporting of SAEs
SAE Reporting via Paper Form

Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the medical monitor or the SAE coordinator.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SAE report.
10.3.6.
Regulatory Reporting Requirements
SAE Regulatory Reporting
Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation 
are met.


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●
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/IEC, and investigators.
●
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements.


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10.4.
Appendix 4: Contraceptive and Barrier Guidance
10.4.1.
Definitions
Woman of Childbearing Potential
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.
Women in the following categories are not considered women of childbearing potential:
1. Premenarchal
2. Female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy

Documented bilateral tubal ligation

Documented bilateral tubal occlusion
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: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female is defined as women with:

12 months of amenorrhea for women >55, with no need for follicle-stimulating hormone

12 months of amenorrhea for women >40 years old with follicle-stimulating hormone
≥40 mIU/mL and no other medical condition such as anorexia nervosa and not taking 
medications during the amenorrhea (e.g., oral contraceptives, hormones, gonadotropin 
releasing hormone, anti-estrogens, selective estrogen receptor modulators, or 
chemotherapy that induced amenorrhea)
10.4.2.
Contraception Guidance
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Male participants:

are not required to adhere to contraceptive requirements
Female participants:

Female participants of childbearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) 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-


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sex relationship without sexual relationships with males. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence 
just for the duration of a study, and withdrawal are not acceptable methods of 
contraception.

Female participants of childbearing potential, who are not abstinent as described above, 
must agree to use a highly effective method of contraception (that is, one with less than 
1% failure rate) such as combination oral contraceptives, vaginal ring, implanted/injected 
contraceptives, intrauterine devices, or sterile partner until 30 days after the last dose of 
study medication. 
o
Female participants not of childbearing potential are not required to use 
contraception. This includes females who are:

Infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy, bilateral tubal occlusion, or 
bilateral tubal ligation) or congenital anomaly (for example, Müllerian 
agenesis)

Postmenopausal, as defined above.
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 study 
intervention.
●
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 including fetal status (presence or absence of anomalies) and
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.


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●
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 
Section 8.3.2. 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 discontinue study intervention. If the participant is discontinued from the 
study intervention, follow the standard discontinuation process and continue 
directly to the follow-up phase.


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Protocol number J2G-MC-JZJZ(c)
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10.5.
Appendix 5: Genetics
Use/Analysis of DNA
●
Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to 
study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood/saliva sample will 
be collected for DNA analysis from consenting participants.
●
DNA samples will be used for research related to selpercatinib or advanced or 
metastatic RET-mutant MTC/advanced or metastatic RET fusion-positive thyroid 
cancer/metastatic RET fusion-positive NSCLC. They may also be used to develop 
tests/assays including diagnostic tests related to selpercatinib advanced or 
metastatic RET-mutant MTC/advanced or metastatic RET fusion-positive thyroid 
cancer/metastatic RET fusion-positive NSCLC. Genetic research may consist of 
the analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome or analysis of the entire genome (as appropriate).
●
Additional analyses may be conducted if it is hypothesized that this may help 
further understand the clinical data.
●
The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to selpercatinib or study interventions of this 
class to understand study disease or related conditions.
●
The results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.
●
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
●
The samples will be retained while research on selpercatinib or study 
interventions of this class or indication continues but no longer than 15 years or 
other period as per local requirements.


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10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Hepatic Evaluation Testing – Refer to protocol Hepatic Safety Section 8.2.7.1 for guidance on appropriate 
test selection.

For testing selected, analysis is required to be completed by the Lilly-designated central laboratory 
except for Microbiology.

Local testing may be performed in addition to central testing when required for immediate participant
management.

Results will be reported if a validated test or calculation is available.
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - Red Blood Cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - White Blood Cells) 
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
  Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
  Lymphocytes
Creatine kinase (CK)
  Monocytes
Other Chemistry 
  Basophils
Acetaminophen
  Eosinophils
Acetaminophen Protein Adducts
Platelets
Alkaline Phosphatase Isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Ethyl Alcohol (EtOH)
Prothrombin Time, INR (PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (Quantitative)
Hepatitis A Virus (HAV) Testing:
Immunoglobulin IgG (Quantitative)
  HAV Total Antibody
Immunoglobulin IgM (Quantitative)
  HAV IgM Antibody
Phosphatidylethanol (PEth)
Hepatis B Virus (HBV) Testing:
Urine Chemistry
  Hepatitis B surface antigen (HBsAg)
Drug Screen
  Hepatitis B surface antibody (Anti-HBs) 
Ethyl glucuronide (EtG)
  Hepatitis B core total antibody (Anti-HBc)
Other Serology
  Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA)
  Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a
  HBV DNA d
Anti-actin antibody b
Hepatis C Virus (HCV) Testing:
Epstein-Barr Virus (EBV) Testing:


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Protocol number J2G-MC-JZJZ(c)
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  HCV antibody
  EBV antibody
  HCV RNA d
  EBV DNA d
Hepatitis D Virus (HDV) Testing:
Cytomegalovirus (CMV) Testing:
  HDV antibody
  CMV antibody
Hepatitis E Virus (HEV) Testing:
  CMV DNA d
  HEV IgG antibody
Herpes Simplex Virus (HSV) Testing:
  HEV IgM antibody
  HSV (Type 1 and 2) antibody
  HEV RNA d
  HSV (Type 1 and 2) DNA d
Microbiology c
Liver Kidney Microsomal Type 1 (LKM-1) Antibody
Culture:
  Blood
  Urine
a This is not required if anti-actin antibody is tested.
b This is not required if ASMA is tested.
c Assayed by investigator-designated local laboratory ONLY; no Central Testing available.
d Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Protocol number J2G-MC-JZJZ(c)
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Evaluation of participants with treatment-emergent abnormal hepatic biochemical tests 
during a clinical trial *
Test/Procedure: 
Rationale 
Action
Close Hepatic Monitoring
Clinical Chemistry:
  Total bilirubin
  Direct bilirubin
  Alkaline phosphatase (ALP)
  Alanine aminotransferase (ALT)
  Aspartate aminotransferase (AST) b
  Gamma-glutamyl transferase (GGT)
  Creatine kinase (CK)
All: Routine follow-up
CK: Muscle injury/rhabdomyolysis
Utilize a Hepatic 
Monitoring central lab 
collection kit and select 
Clinical Chemistry 
Hematology
  Hemoglobin
  Hematocrit
  Erythrocytes (RBCs – Red Blood 
Cells)
  Leukocytes (WBCs – White Blood 
Cells)
  Differential:
  Neutrophils, segmented
  Lymphocytes
  Monocytes
  Basophils
  Eosinophils
  Platelets
  Cell Morphology (RBCs and WBCs)
Infection
Utilize a Hepatic 
Monitoring central lab 
collection kit and select 
Hematology
Medical history: a, h
  Symptoms
  Co-existing medical conditions
  Concomitant medications
  Dietary and nutritional supplements
  Exercise (excessive)
  Muscle Injury
  Alcohol consumption
  Illicit substances
Used to evaluate/rule out:
  Systemic infection or sepsis
  Ischemic or congestive hepatic injury
  Gallstone disease
  Alcoholic liver disease
  Muscle injury/rhabdomyolysis
  Acetaminophen toxicity
  Drug Induced Liver Injury (DILI) due 
to another drug, herbal or dietary 
substances
If findings are clinically 
significant, report as an 
adverse event.
Hepatitis A Virus (HAV) Testing:
  HAV Total Antibody
  HAV IgM Antibody
Used to evaluate/rule out: Acute HAV 
infection
Utilize a Hepatic 
Monitoring central lab 
collection kit and select
Hepatitis A
Hepatis B Virus (HBV) Testing:
  Hepatitis B surface antigen (HBsAg)
  Hepatitis B surface antibody 
(Anti-HBs) 
  Hepatitis B core total antibody 
(Anti-HBc)
  Hepatitis B core IgM antibody
  Hepatitis B core IgG antibody 
  HBV DNA
Used to evaluate/rule out: Acute or 
exacerbation of chronic HBV infection. 
Utilize a Hepatic 
Monitoring central lab 
collection kit and select 
Hepatitis B
Hepatis C Virus (HCV) testing: c, d
  HCV antibody
  HCV RNA
Used to evaluate/rule out: Acute or 
exacerbation of chronic HCV infection. 
Utilize a Hepatic 
Monitoring central lab 


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Protocol number J2G-MC-JZJZ(c)
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collection kit and select 
Hepatitis C
Hepatitis E Virus (HEV) Testing: e
  HEV IgG antibody
  HEV IgM antibody
  HEV RNA
Used to evaluate/rule out: Acute HEV 
infection.
Utilize a Hepatic 
Monitoring central lab 
collection kit and select 
Hepatitis E
Anti-nuclear antibody (ANA)
Anti-smooth muscle antibody (ASMA)
Anti-actin antibody
Immunoglobulin IgA
Immunoglobulin IgG
Immunoglobulin IgM
Used to evaluate/rule out: Autoimmune 
hepatitis
Utilize a Hepatic 
Monitoring central lab 
collection kit and select 
only the specific test/s 
required. 
Hepatobiliary imaging: a, h
  Ultrasonography
  Computed tomography scan
  Magnetic resonance imaging
  Magnetic resonance 
cholangiopancreatography (MRCP) g
Endoscopic retrograde 
cholangiopancreatography (ERCP) g
Used to evaluate/rule out: 
  Biliary obstruction
  Pancreatitis
  Gallstones
  Portal-vein/ hepatic vein thrombosis 
  Hepatic metastasis
Performed locally.
If findings are clinically 
significant, report as an 
adverse event.
Comprehensive Hepatic Monitoring
Coagulation:
Prothrombin Time, INR (PT-INR)
Used to evaluate/rule out:
Suspected liver failure, for patients with
elevated Total Bilirubin
Utilize a Hepatic 
Monitoring central lab 
collection kit
Epstein-Barr Virus (EBV) Testing:
  EBV antibody
  EBV DNA
Cytomegalovirus (CMV) Testing:
  CMV antibody
  CMV DNA
Herpes Simplex Virus (HSV) 
Testing:
  HSV (Type 1 and 2) antibody
  HSV (Type 1 and 2) DNA
Used to evaluate/rule out:
EBV or 
Hepatic injury due to CMV, or
HSV infection.
Utilize a Hepatic 
Monitoring central lab 
collection kit and select 
only the specific test/s 
needed.
Liver biopsy f
Used to evaluate/rule out:
Autoimmune hepatitis (AIH)
If findings are clinically 
significant, report as an 
adverse event.
Additional Hepatic Monitoring Tests
Alkaline Phosphatase Isoenzymes
Used to evaluate/differentiate: Elevated 
Alkaline Phosphatase origination from
bone or liver
Utilize a Hepatic 
Monitoring central lab 
collection kit
Liver Kidney Microsomal Type 1 
(LMK-1) Antibody
Used to evaluate: Autoimmune hepatitis 
Utilize a Hepatic 
Monitoring central lab 
collection kit
Urine Chemistry:
  Ethyl glucuronide (EtG) i
Other Chemistry:
  Phosphatidylethanol (PEth) j
Used to evaluate: Alcoholic liver 
disease 
Utilize a Hepatic 
Monitoring central lab 
collection kit
Other Chemistry:
  Acetaminophen
  Acetaminophen Protein Adducts
Used to evaluate: Acetaminophen 
toxicity 
Utilize a Hepatic 
Monitoring central lab 
collection kit
Ethyl Alcohol (EtOH)
Used to evaluate recent alcohol 
consumption
Utilize a Hepatic 
Monitoring central lab 
collection kit


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Protocol number J2G-MC-JZJZ(c)
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Haptoglobin
Used to evaluate a diagnosis of 
hemolysis
Utilize a Hepatic 
Monitoring central lab 
collection kit
Cardiology consult a
Electrocardiogram
Echocardiogram
Vital Signs:
  Blood pressure
  Pulse
Used to evaluate: Ischemic or 
congestive hepatic injury
Performed locally.
If findings are clinically 
significant, report as an 
adverse event.
Urine Chemistry:
  Drug screen
Used to evaluate: Hepatotoxicity due to 
cocaine, opiates and other illicit 
substances 
Utilize a Hepatic 
Monitoring central lab 
collection kit
Hepatitis D Virus (HDV) Testing:
  HDV antibody
Used to evaluate/rule out: Acute HDV 
infection.
Utilize a Hepatic 
Monitoring central lab 
collection kit and only 
select required test needed.
Microbiology: 
Cultures:
  Blood
  Urine
Used to evaluate/rule out: 
Sepsis or systemic infection
Perform locally.
If findings are clinically 
significant, report as an 
adverse event.
Slit lamp eye examination (Kayser-
Fleisher rings)
Genetic evaluation
Used to evaluate/rule out: 
Wilson’s disease 
Perform locally. 
If findings are clinically 
significant, report as an 
adverse event.
Other Chemistry:
  Ceruloplasmin
  Copper
Used to evaluate/rule out: 
Wilson’s disease 
Utilize a Hepatic 
Monitoring central lab 
collection kit
*This tool is to be used by the investigative site for reference during the evaluation of a participant who met hepatic 
monitoring criteria based on laboratory results and clinical judgment for a suspected liver injury during protocol 
participation. 
a Extent and type of work-up may vary by participant’s history, severity of liver injury, underlying disease, and 
geography.
b Serum AST typically (although not always) is higher than ALT.
c If anti-HCV is positive, HCV RNA is required to confirm HCV infection.
d Acute hepatitis C may be anti-HCV negative but HCV RNA positive.
e If anti-HEV IgM is positive, consider confirmation with HEV RNA by nested polymerase chain reaction.
f A liver biopsy is needed to confirm a diagnosis of AIH.
g If cholestatic injury, MRCP or ERCP may be recommended.
h Based on medical history and clinical judgment.
i Alcohol consumption in past 3 to 5 days.
j Alcohol consumption in past 3 weeks.


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Protocol number J2G-MC-JZJZ(c)
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10.7.
Appendix 7: Abbreviations and Definitions
Term
Definition
ALT
alanine aminotransferase
AST
aspartate aminotransferase
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRP
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
DMC
data monitoring committee. A data monitoring committee, or data monitoring board 
(DMB) is a group of independent scientists who are appointed to monitor the safety and 
scientific integrity of a human research intervention, and to make recommendations to 
the sponsor regarding the stopping of a study for efficacy, or for harms, or for futility. 
The composition of the committee is dependent upon the scientific skills and 
knowledge required for monitoring the particular study.
ECG
Electrocardiogram
enroll
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IMP
Investigational Medicinal Product
informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.


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Protocol number J2G-MC-JZJZ(c)
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investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ITT
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PC
product complaint
PK/PD
pharmacokinetics/pharmacodynamics
PPS
per-protocol set: The set of data generated by the subset of participant who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
QTc
corrected QT interval
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
TEAE
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.


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Protocol number J2G-MC-JZJZ(c)
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10.8.
Appendix 11: 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: 04-August-2021
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis and 4.1.2 
Treatment and 
Assessment Period 
Study design amended to move last 
outpatient visit from Day 27 to Day 28. 
To extend the treatment period by 
1 day in order to accommodate a 
longer PK sampling profile to 
match Stage 1 and Stage 2 PK 
sampling.
1.3 Schedule of 
Activities (SoA) –
Stages 1 and 2
Study design amended to move last 
outpatient visit from Day 27 to Day 28. 
To extend the treatment period by 
1 day in order to accommodate a 
longer PK sampling profile to 
match Stage 1 and Stage 2 PK 
sampling.
Amendment b: 13-August-2021
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities (SoA) –
Stages 1 and 2

PK samples - Selpercatinib (plasma) 
amended to remove 168, 192, 216, 
and 240 hours postdose on Days 1 
and 15.

Added PK samples - Selpercatinib 
(plasma) timepoints in tabular 
format and deleted the information 
“Samples will be taken at the 
following timepoints on Days 1 and 
15: predose, and 0.5, 0.75, 1, 1.5, 2, 
2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 
72, 96, 120, 144 hours postdose” 
from footnote of Schedule of 
Activities (SoA) table for consistent 
presentation.

Added gastric pH (Stage 1 only) 
timepoints in tabular format and 
deleted the information 
“Measurements will be taken at the 
following timepoints on Days 1 and 
15: predose, and 0.5, 1, 1.5, 2, 2.5, 

PK samples - Selpercatinib 
(plasma) timepoints were 
inadvertently added in 
previous versions of protocol 
(Original and amendment a) 
which have been corrected in 
current Protocol Amendment 
(b).

Final safety assessments were 
inadvertently missed in the 
table.


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Protocol number J2G-MC-JZJZ(c)
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Section # and Name
Description of Change
Brief Rationale
3, and 3.5 hours postdose” from 
footnote of SoA table for consistent 
presentation.

Added final safety assessments on 
Day 28: physical examination, 
weight, pregnancy test, 12-lead 
ECG, vital signs, and clinical 
laboratory tests
10.2.1 Blood Sampling 
Summary

Maximum number of blood Samples 
for clinical laboratory tests were 
updated to reflect changes in SoA
for final safety assessments on 
Day 28.
Final safety assessments on 
Day 28 were added to SoA –
Stages 1 and 2.
11 References

Added reference “Levey et al, 
2009”.
This reference was inadvertently 
missed in the previous versions of 
protocol (Original and 
amendment a).


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Protocol number J2G-MC-JZJZ(c)
73
11.
References
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate 
[published correction appears in Ann Intern Med. 2011 Sep 20;155(6):408]. Ann Intern Med. 
2009;150(9):604-612. https://doi.org/ 10.7326/0003-4819-150-9-200905050-00006.
Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika 
1977; 64:191–199.
Potvin D, DiLiberti CE, Hauck WW, Parr AF, Schuirmann DF, Smith RA. Sequential design 
approaches for bioequivalence studies with crossover designs. Pharmaceut. Statist. 2007,
https://doi.org/10.1002/pst.294.


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

SAP_001.pdf: 
Statistical Analysis Plan J2G-MC-JZJZ Version 1.0
An Open-label, Randomized Study to Evaluate the Bioequivalence of Selpercatinib Formulations
NCT05089019
Approval Date: 20-Oct-2021


Fi nal Versi o n 1. 0, 1 8 Oct o ber 2 0 2 1
Pa ge 1 of 1 9
S T A TI S TI C A L A N A L Y SI S P L A N
A n O pe n -L a bel, R a n d o mize d St u d y t o E v al u ate t he Bi oe q ui v ale nce of Sel perc ati ni b 
F or m ul ati o ns
Stati stical A nal ysis Pla n Stat us : Fi nal
Stati stical A nal ysis Pla n Versi o n : 1. 0
Stati stical A nal ysis Pla n Date : 1 8 Oct o ber 2 0 2 1
I nvest i gati onal Me dici nal Pr o d uct : L Y 3 5 2 7 7 2 3
Pr ot oc ol Refere nce : J 2 G-M C -J ZJ Z
La bc or p St u d y : 8 4 7 0 1 9 1
Cli nical P hase I
A p pr o v al D at e: 2 0- O ct- 2 0 2 1 G M T


Final Version 1.0, 18 October 2021
Page 2 of 19
Statistical Analysis Plan 
CONFIDENTIAL
Labcorp Study: 8470191
Protocol Reference: J2G-MC-JZJZ
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 6
5.
STUDY DESIGN........................................................................................................... 7
5.1
Overall Design ........................................................................................................ 7
5.1.1
Screening ....................................................................................................... 7
5.1.2
Treatment and Assessment Period .................................................................. 8
6.
TREATMENTS............................................................................................................. 8
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 9
8.
DEFINITION OF ANALYSIS POPULATIONS.......................................................... 10
9.
STATISTICAL METHODOLOGY ............................................................................. 10
9.1
General.................................................................................................................. 10
9.2
Demographics and Participant Disposition............................................................. 10
9.3
Pharmacokinetic Assessment................................................................................. 11
9.3.1
Pharmacokinetic Analysis............................................................................. 11
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 14
9.4
Pharmacodynamic Assessment .............................................................................. 15
9.4.1
Pharmacodynamic Statistical Methodology .................................................. 15
9.5
Safety and Tolerability Assessments...................................................................... 15
9.5.1
Adverse events ............................................................................................. 15
9.5.2
Concomitant medication............................................................................... 15
9.5.3
Clinical laboratory parameters...................................................................... 15
9.5.4
Vital signs .................................................................................................... 16
9.5.5
Electrocardiograms....................................................................................... 16
9.5.6
Hepatic Monitoring ...................................................................................... 16
9.5.7
Other assessments......................................................................................... 16
9.5.8
Safety and Tolerability Statistical Methodology............................................ 16


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10. INTERIM ANALYSES ............................................................................................... 16
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 17
12. REFERENCES ............................................................................................................ 17
13. DATA PRESENTATION ............................................................................................ 18
13.1 Derived Parameters ............................................................................................... 18
13.2 Missing Data ......................................................................................................... 18
13.3 Insufficient Data for Presentation .......................................................................... 18
14. APPENDICES ............................................................................................................. 19
Appendix 1: Document History...................................................................................... 19


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2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from time zero to
infinity
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
BE
Bioequivalence
BQL
Below the quantifiable lower limit of the assay
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
Clast
Last quantifiable drug concentration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
ECG
Electrocardiogram
GMR
Geometric mean ratio
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
NG
Nasal gastric
PD
Pharmacodynamic
PK
Pharmacokinetic
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SD
Standard deviation 
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
TEAE
Treatment-emergent adverse event


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TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
Vss/F
Apparent volume of distribution at steady state after extravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
19 July 2021), Protocol Amendment (a) (final version dated 04 August 2021), Protocol 
Amendment (b) (final version dated 13 August 2021), and Protocol Amendment (c) (final 
version dated 14 October 2021). 
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. For open-label 
studies, this SAP must be signed off prior to first participant visit for this study. When the SAP 
and TFL shells are agreed upon and finalized, they will serve as the template for this study’s 
CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the bioequivalence (BE) of a 
single 160-mg dose of selpercatinib as the 
tablet formulation (test) compared to the 
commercial capsule formulation 
(reference)

Maximum observed drug concentration 
(Cmax), area under the concentration 
versus time curve from time zero to 
infinity (AUC[0-∞]), and area under the 
concentration versus time curve from time 
zero to time t, where t is the last time 
point with a measurable concentration 
(AUC[0-tlast]) of selpercatinib
Secondary

To describe the safety and tolerability of a 
single 160-mg oral dose of selpercatinib 

Summary of the number of 
treatment-emergent adverse events 


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as the tablet formulation (test) compared 
to the commercial capsule formulation 
(reference)
(TEAEs) and serious adverse events 
(SAEs)
Exploratory

To determine whether the PK of 
selpercatinib are altered by initial pH

Cmax, AUC(0-∞), and time of maximum 
observed drug concentration (tmax) of 
selpercatinib
5. STUDY DESIGN
5.1
Overall Design
Study J2G-MC-JZJZ will be a Phase 1 open-label, randomized, two-period, two-formulation, 
two-sequence, two-stage adaptive crossover study in adult heathy male and female participants. 
The new 160 mg tablet will be compared to 2 × 80 mg commercially available capsules (160 mg 
is the highest approved dose). Figure 1 below illustrates the study randomization and crossover 
schema.
Figure 1: J2G-MC-JZJZ Study Schema
Exploratory analysis of pH measurements (done via nasal gastric [NG] tube insertion and 
aspiration of gastric secretions and testing via pH meter) will be included in Stage 1 to 
understand the pH dynamics, including the potential of pH effect on absorption. The pH will not 
be measured in Stage 2 of the study.
Safety assessments, including adverse events (AEs), concomitant medications, medical 
assessments, clinical laboratory tests, vital signs, and electrocardiograms (ECGs), and blood 
sampling for PK, will also be performed.
5.1.1
Screening
All participants will be screened within 28 days prior to enrolment.


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5.1.2
Treatment and Assessment Period
Stage 1:
Participants will be admitted to the clinical research unit (CRU) on Day -1. On the morning of 
Day 1, participants will be randomized to receive a single oral dose of 160-mg selpercatinib as 
the capsule or tablet formulation, and will be dosed according to the randomization sequence 
following an overnight fast of at least 10 hours. On Day 1, participants will have an NG tube 
placed in the stomach prior to dosing to assess gastric pH. Participants will remain resident at the
CRU until discharge on Day 7.
Participants will attend outpatient visits for the collection of PK blood samples and assessment of 
vital signs on Days 9 and 11.
Participants will be re-admitted to the CRU on Day 14 and in the morning of Day 15 will receive
their second single oral dose of 160-mg selpercatinib as the capsule or tablet formulation, 
according to the randomization schedule, following an overnight fast of at least 10 hours. On 
Day 15, participants will have an NG tube placed in the stomach prior to dosing to assess gastric 
pH. Participants will remain resident at the CRU until discharge on Day 21.
Participants will attend outpatient visits for the collection of PK blood samples and assessment of 
vital signs on Days 23, 25, and 28.
There will be a washout of at least 14 days between doses of selpercatinib.
Stage 2:
Participants will be admitted to the CRU on Day -1. On the morning of Day 1, participants will 
be randomized to receive a single oral dose of 160-mg selpercatinib as the capsule or tablet 
formulation, and will be dosed according to the randomization sequence following an overnight 
fast of at least 10 hours. Participants will remain resident at the CRU until discharge on Day 7.
Participants will attend outpatient visits for the collection of PK blood samples and assessment of 
vital signs on Days 9 and 11.
Participants will be re-admitted to the CRU on Day 14 and in the morning of Day 15 will receive 
their second single oral dose of 160-mg selpercatinib as the capsule or tablet formulation, 
according to the randomization schedule, following an overnight fast of at least 10 hours. 
Participants will remain resident at the CRU until discharge on Day 21.
Participants will attend outpatient visits for the collection of PK blood samples and assessment of 
vital signs on Days 23, 25, and 28.
There will be a washout of at least 14 days between doses of selpercatinib.
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.


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Study Treatment Name
Abbreviation
Treatment order in TFL
160 mg selpercatinib (2 x 80 mg capsules)
Capsule
1
160 mg selpercatinib (1 x 160 mg tablet)
Tablet
2
The following is a list of the study treatment sequence abbreviations that will be used in the 
TFLs.
Sequence
Study Treatment Sequence Name
Abbreviation
Treatment order in TFL
1
160 mg selpercatinib (2 x 80 mg capsules) / 160 
mg selpercatinib (1 x 160 mg tablet)
Capsule / Tablet
1
2
160 mg selpercatinib (1 x 160 mg tablet) / 160 mg 
selpercatinib (2 x 80 mg capsules)
Tablet / Capsule
2
7. SAMPLE SIZE JUSTIFICATION
The incidence of those participants with a different PK profile (2 of 19 participants in Study 
LOXO-RET-18015) has meant that Lilly is planning to enrol up to approximately 60 participants 
in Stage 1. This is to ensure that at least 50 participants will complete Stage 1 and a sufficient 
variation of gastric pH will be incorporated in Stage 1.
If the true intraparticipant coefficient of variation (CV) is 30% for Cmax and 20% for the area 
under the concentration versus time curve (AUC), the first 50 participants in Stage 1 will give 
approximately 90% power to meet BE criteria at a 1-sided α level of 0.05, under an assumption 
of a geometric mean ratio (GMR) of 1.05.
The table below shows the required sample size for Stage 2 to provide the power for Cmax of 90% 
based on different intraparticipant CV for Cmax from Stage 1, assuming the true tablet-to-capsule 
GMR is 1.05 under scenario when the power is less than 90% and BE is not met at Stage 1. The 
actual sample size for Stage 2 will be determined based on the observed intraparticipant CV at 
Stage 1. 
In Stage 1, dropouts will not be replaced.
In Stage 2, dropouts will not be replaced, but over-enrollment of up to 20% of the determined 
sample size will be permitted to ensure a sufficient number of participants.
Sample Size for Stage 2 Based on Intraparticipant CV for Cmax in Stage 1
Intraparticipant CV for Cmax in Stage 1
Required Sample Size for Stage 2
40%
50
50%
100
60%
156
70%
216
Note: The total sample size will be at least 50 for Stage 1 plus the required sample size for Stage 2. 


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8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled participants who received at least one dose of 
selpercatinib, whether or not they completed all protocol requirements, and have at least one 
postdose safety assessment.
The “Pharmacokinetic” population will consist of all participants who received at least one dose 
of selpercatinib and have evaluable PK data. Participants may be excluded from the PK summary 
statistics and statistical analysis if a participant has an AE of vomiting that occurs at or before 2 
times median time of maximum observed drug concentration (tmax). 
The “Pharmacodynamic” population will consist of all participants who received at least one 
does of selpercatinib and have evaluable PD data. Participants may be excluded from the PD 
summary statistics and statistical analysis if a participant has an AE of vomiting that occurs at or 
before 2 times median tmax.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when participants are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and n; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 
mean and geometric coefficient of variation (CV%) will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all 
participants up to the point of withdrawal, with any participants excluded from the relevant 
population highlighted. Summary statistics and statistical analyses will generally only be 
performed for participants included in the relevant analysis population. For the calculation of 
summary statistics and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual participants’ change from baseline 
values. Each individual change from baseline will be calculated by subtracting the individual 
participant’s baseline value from the value at the timepoint. The individual participant’s change 
from baseline values will be used to calculate the mean change from baseline using a SAS 
procedure such as Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Participant Disposition
Participant disposition will be summarized and listed. The demographic variables age, sex, race, 
ethnicity, country of enrolment, site ID, body weight, height and body mass index will be 
summarized and listed. All other demographic variables will be listed only.


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9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
Noncompartmental methods applied with a validated software program (Phoenix WinNonlin 
Version 8.1 or later) to the plasma concentrations of selpercatinib will be used to determine the 
following PK parameters, when possible: 
Parameter
Units
Definition
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-∞)
ng.h/mL
area under the concentration versus time curve from time zero to 
infinity
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration
Additional PK parameters may be calculated, as appropriate. 
The software and version used for the final analyses will be specified in the CSR. Any 
exceptions or special handling of data will be clearly documented within the CSR.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.

Cmax and tmax will be reported from observed values. If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule). The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 


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consecutive plasma concentrations above the lower limit of quantification, with at least 
one of these concentrations following Cmax.

The t1/2 will be calculated, when appropriate, based on the apparent terminal log-linear 
portion of the concentration-time curve. The start of the terminal elimination phase for 
each participant will be defined by visual inspection and generally will be the first point 
at which there is no systematic deviation from the log-linear decline in plasma
concentrations. Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points. If t1/2 is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t1/2 value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal 
log-linear portion of the concentration-time curve.

The parameters based on last predicted observed drug concentration (Clast) will be 
reported (except in bioequivalence and bioavailability studies, where only the observed 
parameters will be reported).
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK Parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL). Plasma concentrations reported as BQL will be set to a value of zero
when all of the following conditions are met:
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a participant or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing.

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.


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Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero. Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the CSR.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
CSR.
Treatment of Outliers during PK Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis. The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during multiple dosing, the concentration of the pre-dose sample exceeds 
all measured concentrations for that individual in the subsequent post-dose samples.

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles


Fi nal Versi o n 1. 0, 1 8 Oct o ber 2 0 2 1
Pa ge 1 4 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
La bc or p St u d y : 8 4 7 0 1 9 1
Pr ot oc ol  Refere nce: J 2 G-M C -J ZJ Z
1.
If n < 6, t he n t he dataset is t o o s mall t o c o n d uct a relia ble ra n ge test. Data will be a nal yze d 
wi t h a n d wit ho ut t he at y pical val ue, a n d b ot h set s of res ults will be re p orte d.
2.
If n6, t he n a n o bject i ve o utlier test will be use d t o c o m pare t he at ypical  v alue t o ot her 
val ues i ncl u de d i n t hat calc ulat i on:
a.
Tra nsf or m all val ues i n t he calc ulati o n t o t he l o garith mic d o mai n .
b.
F i n d t he most e xtre m e val ue fr o m t he arit h metic mea n of t he lo g tra nsf or me d
val ues a n d e xcl u de t hat val ue fr o m t he dataset.
c.
Calc ulate t he l o wer a n d u p per b o u n ds of t he ra n ge defi ne d b y t he arit h metic 
mea n ± 3 * S D of  t he re mai ni n g lo g -tra nsf or me d val ues.
d.
If t he e xtre me val ue is wit hi n t he ra n ge of arith metic mea n ± 3 * S D, t he n it is 
n ot a n o utlier a n d will be retai ne d i n t he dataset.
e.
If t he e xtre me val ue is o utsi de t he ra n ge of arit h metic mea n ± 3 * S D, t he n it is 
a n o utlier a n d will be e xcl u de d fr o m a nal ysis .
If t he re mai ni n g dataset c o ntai ns a n ot her at ypi c al  d at u m s us pecte d t o be a n o utlier a n d n ≥ 6 
f oll owi n g t he e xcl usi o n, t he n re peat ste p 2 a b o ve. T his e val uat i on ma y be re peate d as ma n y 
ti mes as necessar y, e xcl u di ng o nl y  o ne s us pecte d o utlier i n eac h iterati o n, u nt il all data 
r e mai ni n g i n t he dataset fall wi t hi n t he ra n ge of arit h met ic mea n ± 3 * S D of t he l o g -tra nsf or me d 
val ues.
Re p orti n g of E xcl u de d Val ues
I n di vi d ual val ues e xcl u de d as o utliers will be d oc u me nte d i n t he fi nal C S R . A p pr o val of t he fi nal 
C S R will c o n n ote a p pr o val of t he e xcl usi o n.
9. 3. 2
P h ar m ac o ki netic St atistic al Met h o d ol o g y
P K para meters will be e val uate d t o esti mate B E of  t he selpercat i ni b ta blet a n d ca ps ule 
for m ulat i ons . 
F or t he pri mar y  a nal ysis, lo g -tra nsf or me d Cma x, A U C( 0-tlast), a n d A U C( 0-∞) para meters will be 
e val uate d i n a li near mi xe d effect m o del wit h fi xe d effects f or treat me nt f or mulat i on, peri o d, 
se q ue nce, a n d a ra n d om effect f or partici pa nt . T he differe nces bet w ee n t he ta blet (test) a n d 
ca ps ule (r efere nce) f or mulat i ons will be bac k -tra nsf or me d t o prese nt t he rati os of ge o metric least 
s q uares mea ns a n d t he c orres p o n di n g CIs. I ntra-partici pa nt C V will be deri ve d a n d 
bi oe q ui vale nce will be met if t he CI f or t he rati o f alls wit hi n 8 0 %-1 2 5 %. 
C CI
C CI
C CI
C CI
C CI


Fi nal Versi o n 1. 0, 1 8 Oct o ber 2 0 2 1
Pa ge 1 5 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
La bc or p St u d y : 8 4 7 0 1 9 1
Pr ot oc ol  Refere nce: J 2 G-M C -J ZJ Z
F or sec o n dar y  a nal ysis, t he tma x will be a nal yze d usi n g a Wilc o x o n si g ne d ra n k test. Esti mates of 
t he me dia n differe nce base d o n t he i n di vi d ual paire d differe nces, CIs, a n d p-val ues fr o m t he 
Wilc o x o n
si g ne d ra n k test will be calc ulate d.
9. 4
P h ar m ac o d y n a mic Assess me nt
9. 4. 1
P h ar m ac o d y n a mic St atistic al Met h o d ol o g y
T he gastri c p H data ( Sta ge 1 o nl y) will be s u m marize d b y treat me nt f or m ulat i on (ca ps ule or 
ta blet) , alo n g wi t h c ha n ges fr o m baseli ne ( Da y 1 or 1 5 pre d ose, as a p plica ble). A scatter pl ot of 
pre d ose gastric p H data vers us P K para meters b y  d a y will be pr o d uce d, wit h a re gressio n li ne 
fitte d. T hi s data will als o be liste d. 
9. 5
S afet y a n d T oler a bilit y Assess me nts
9. 5. 1
A d verse e ve nts
W here c ha n ges i n se verit y are rec or de d i n t he case re port f or m ( C R F), eac h se parate se verity of  
t he A E will be re p orte d i n t he listi n gs, o nl y t he m ost se vere will be use d i n t he s u m mar y ta bles . 
A pre -e xist in g c o n dit i on is defi ne d as a c o n ditio n t hat starts bef ore t he partici pa nt has pr o vi de d 
wri tte n i nf or me d c o nse nt a n d is o n g oi n g at c o nse nt . A n o n -treat me nt e mer ge nt A E is defi ne d as 
a n A E w hic h st arts aft er inf or me d c o nse nt b ut pri or t o d osi n g . A T E A E i s defi ne d as a n A E 
w hic h occ urs p ost d ose or w hic h is prese nt pri or t o d osi n g a n d bec o mes m o re se vere p ost d ose. 
All A Es will be liste d . T E A Es will be s u m marize d b y treat me nt, se verit y a n d relat i ons hi p t o t he 
st u d y dr u g. T he fre q ue nc y (t he n u m ber of A Es , t he n u m ber of parti ci pa nt s e x perie nci n g a n A E
a n d t he perce nta ge of parti ci pa nt s e x perie nci n g a n A E ) of T E A Es will be s u m marize d b y 
treat me nt, Me dic al Dicti onar y  for Re g ulat or y  Act i vities ( Me d D R A) versi on 2 4. 0 s yst e m or ga n 
class a n d preferre d ter m. T he s u m mar y a n d fre q ue nc y A E ta bles will be prese nte d f or all 
ca usalit ies a n d t h ose c o nsi dere d relate d t o t he st u d y dr u g b y t he i n vest i gat or. A n y S A Es will be 
liste d. 
Di sc o nti n uatio ns d ue t o A Es will be liste d.
9. 5. 2
C o nc o mit a nt me dic ati o n
C o nc o mita nt me dicat i on will be c o de d usi n g t he W H O dr u g dict i onar y  ( Versio n  Marc h 2 0 2 1). 
C o nc o mita nt me dicat i on will be liste d.
9. 5. 3
Cli nic al l a b or at or y p ar a meters
All cli nical c he mistr y a n d he mat ol o g y data w ill be s u m marize d b y para meter a n d treat me nt
se q ue nce, a n d liste d. Uri nal ysis data will be liste d . A d dit i onall y , cli nical c he mistr y, he mat olo g y  
C CI
C CI
C CI
C CI


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and urinalysis data outside the reference ranges will be listed and flagged on individual 
participant data listings.
9.5.4
Vital signs
Vital signs data will be summarized by treatment sequence together with changes from baseline, 
where baseline is defined as the Day 1 or Day 15 predose assessment, as appropriate. Figures of 
mean vital signs and mean changes from baseline profiles will be presented by treatment
sequence. 
Values for individual participants will be listed.
9.5.5
Electrocardiograms
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE.
9.5.6
Hepatic Monitoring
If a participant experiences elevated laboratory parameters, as detailed in Section 8.2.7.1 of the 
protocol, additional tests will be performed to confirm the abnormality. Additional safety data 
may be collected if required, as defined in the protocol. Where applicable, the following will be 
presented.
The participants’ liver disease history and associated person liver disease history data will be 
listed. Use of acetaminophen during the study, which has a potential for hepatotoxicity, will be 
listed. Results from any hepatic monitoring procedures, such as a magnetic resonance 
elastography scan, and biopsy assessments will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual participant data listings.
9.5.7
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.5.8
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
At completion of Stage 1, an interim analysis will be conducted to test BE and estimate the 
power before continuing to Stage 2.


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In order to meet the BE criterion at a specific α level, the 2-sided confidence interval (CI) for the 
tablet-to-capsule (tablet formulation / capsule formulation) GMR for AUC and Cmax at the (1-2α) 
level should fall within 80%-125%. The sequential design approach of Potvin’s Method C will 
be used to preserve the overall type I error rate at the 1-sided significance level of 0.05.
The BE testing and alpha spending scheme is described in Figure 2. At an interim analysis, the 
power will be evaluated using the intraparticipant CV from Stage 1 using α level of 0.05 
assuming the true tablet-to-capsule GMR is 1.05. If Stage 1 has at least 90% power, BE will be 
tested at Stage 1 at an α level of 0.05. The study will be stopped whether BE is met or not met. 
The evaluation of the power at Stage 1 will be based on Cmax, which has higher variability. If the 
power is less than 90%, BE will be tested at an α level of 0.0294 as originally proposed by 
Pocock (Pocock 1977). If the BE criterion is met, the study will be stopped. If the BE criterion is 
not met, the sample size for Stage 2 will be calculated based on the intraparticipant CV at Stage 
1 and an α level of 0.0294 assuming the true tablet-to-capsule GMR is 1.05, and Stage 2 will be 
initiated. At Stage 2, BE will be evaluated using data from both stages at an α level of 0.0294. 
Figure 2: Adaptive sequential design method C (Potvin, 2007).
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.


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3. Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika 
1977; 64:191–199.
4. Potvin D, DiLiberti CE, Hauck WW, Parr AF, Schuirmann DF, Smith RA. Sequential design 
approaches for bioequivalence studies with crossover designs. Pharmaceut. Statist. 2007,
https://doi.org/10.1002/pst.294.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of participants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, “No serious adverse events occurred for this study.”


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14.
APPENDICES
Appendix 1: Document History
Status and Version
Date of Change
Summary/Reason for Changes
Final Version 1.0
NA
NA; the first version.
NA = not applicable


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A p p r o v a l  D a t e  &  T i m e :  1 9 - O c t - 2 0 2 1  1 0 : 5 2 : 1 4  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 9 - O c t - 2 0 2 1  1 5 : 4 7 : 4 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 0 - O c t - 2 0 2 1  0 9 : 3 5 : 0 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 0 - O c t - 2 0 2 1  1 7 : 3 1 : 4 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D
P P D
P P D