Clinical trial NCT05324124
Conditions: Healthy
Keywords: Selpercatinib Food Pharmacokinetics
Sponsor: Loxo Oncology, Inc.
Start date: 2022-04-19; Completion date: 2022-06-22
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main purpose of this study is to learn about how food affects selpercatinib in healthy participants. The selpercatinib will be administered in fed and fasted states. Participation could last about 7 weeks.

Detailed description:

Arms: arm 1: Period 1: 160 milligrams (mg) Selpercatinib administered orally on Day 1 in fasted state.

Period 2: 160 mg Selpercatinib administered orally on Day 8 in fed state. arm 2: Period 1: 160 mg Selpercatinib administered orally on Day 1 in fed state.

Period 2: 160 mg Selpercatinib administered orally on Day 8 in fasted state.
Interventions: intervention 1: Selpercatinib
Intervention descriptions: intervention 1: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol J2G-MC-JZPA
An Open-Label, Randomized, Two-Period Crossover Study to Investigate the Effect of Food on 
the Pharmacokinetics of Selpercatinib in Healthy Participants
NCT05324124
Approval Date: 22-Nov-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 Z P A
1
Title P a ge
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s. It i s t h e p r o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli n i c al 
i n v e sti g ati o n of L Y 3 5 2 7 7 2 3 ( s el p er c ati ni b), 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 c i 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 m a 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, T w o -Peri o d Cr oss o ver St u d y  t o I n vesti gate t he 
Effect of F o o d o n t he P har mac o ki net ics of Selpercati ni b i n Healt h y Part ici pa nts
Pr ot oc ol N u m ber: J 2 G-M C -J Z P A
A me n d me nt N u m ber: T his is t he i nit ial pr ot oc ol.
C o m p o u n d : L Y 3 5 2 7 7 2 3 (sel percati ni b)
Brief Title: A F o o d -Effect St u d y  of Sel percat i ni b i n Health y Part ici pa nts
St u d y P h a se: 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 nc ol o 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 mpa 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: 2 2- N o v- 2 0 2 1 G M T


CONFIDENTIAL
Protocol number J2G-MC-JZPA
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Medical Monitor Name and Contact Information will be provided separately.


CONFIDENTIAL
Protocol number J2G-MC-JZPA
3
Table of Contents
1.
Protocol Summary......................................................................................................6
1.1.
Synopsis.......................................................................................................................6
1.2.
Schema.........................................................................................................................8
1.3.
Schedule of Activities (SoA) ........................................................................................9
2.
Introduction..............................................................................................................13
2.1.
Study Rationale ..........................................................................................................13
2.2.
Background ................................................................................................................13
2.3.
Benefit/Risk Assessment ............................................................................................14
3.
Objectives and Endpoints.........................................................................................15
4.
Study Design .............................................................................................................16
4.1.
Overall Design............................................................................................................16
4.2.
Scientific Rationale for Study Design .........................................................................16
4.3.
Justification for Dose..................................................................................................17
4.4.
End of Study Definition..............................................................................................17
5.
Study Population ......................................................................................................18
5.1.
Inclusion Criteria........................................................................................................18
5.2.
Exclusion Criteria.......................................................................................................19
5.2.1.
Meals and Dietary Restrictions ...................................................................................21
5.2.2.
Substance Use: Caffeine, Alcohol, and Tobacco .........................................................21
5.2.3.
Activity ......................................................................................................................21
5.3.
Screen Failures...........................................................................................................21
6.
Study Intervention(s) and Concomitant Therapy ...................................................22
6.1.
Study Intervention Administered ................................................................................22
6.1.1.
Administration Details................................................................................................22
6.2.
Preparation, Handling, Storage, and Accountability....................................................23
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................23
6.4.
Study Intervention Compliance...................................................................................23
6.5.
Dose Modification......................................................................................................23
6.6.
Continued Access to Study Intervention after the End of the 
Study..........................................................................................................................23
6.7.
Treatment of Overdose ...............................................................................................24
6.8.
Concomitant Therapy .................................................................................................24
7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal....................................................................................25
7.1.
Discontinuation of Study Intervention ........................................................................25
7.1.1.
Liver Chemistry Stopping Criteria ..............................................................................25
7.1.2.
QTc Stopping Criteria.................................................................................................26
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................26
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................26
7.3.
Lost to Follow up .......................................................................................................27
8.
Study Assessments and Procedures .........................................................................28
8.1.
Efficacy Assessments .................................................................................................28


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Protocol number J2G-MC-JZPA
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8.2.
Safety Assessments ....................................................................................................28
8.2.1.
Medical Assessment ...................................................................................................28
8.2.2.
Vital Signs..................................................................................................................28
8.2.3.
Electrocardiograms.....................................................................................................29
8.2.4.
Clinical Safety Laboratory Tests.................................................................................29
8.2.5.
Safety Monitoring.......................................................................................................30
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints .................................................................................................................32
8.3.1.
Timing and Mechanism for Collecting Events ............................................................32
8.3.2.
Pregnancy...................................................................................................................34
8.4.
Pharmacokinetics........................................................................................................35
8.5.
Pharmacodynamics.....................................................................................................36
8.6.
Genetics .....................................................................................................................36
8.7.
Biomarkers.................................................................................................................36
8.8.
Immunogenicity Assessments.....................................................................................36
8.9.
Health Economics.......................................................................................................36
9.
Statistical Considerations.........................................................................................37
9.1.
Statistical Hypotheses.................................................................................................37
9.2.
Analyses Sets .............................................................................................................37
9.2.1.
Study Participant Disposition......................................................................................37
9.2.2.
Study Participant Characteristics.................................................................................37
9.2.3.
Treatment Compliance................................................................................................37
9.3.
Statistical Analyses.....................................................................................................37
9.3.1.
Safety Analyses ..........................................................................................................38
9.3.2.
Pharmacokinetic Analyses ..........................................................................................38
9.3.3.
Pharmacodynamic Analyses .......................................................................................38
9.3.4.
Pharmacokinetic/Pharmacodynamic Analyses ............................................................39
9.4.
Interim Analysis .........................................................................................................39
9.5.
Sample Size Determination.........................................................................................39
10.
Supporting Documentation and Operational Considerations ................................40
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................40
10.1.1.
Regulatory and Ethical Considerations........................................................................40
10.1.2.
Financial Disclosure ...................................................................................................40
10.1.3.
Informed Consent Process ..........................................................................................41
10.1.4.
Data Protection...........................................................................................................41
10.1.5.
Dissemination of Clinical Study Data .........................................................................41
10.1.6.
Data Quality Assurance ..............................................................................................42
10.1.7.
Source Documents......................................................................................................43
10.1.8.
Study and Site Start and Closure.................................................................................44
10.1.9.
Publication Policy.......................................................................................................44
10.1.10. Investigator Information .............................................................................................44
10.1.11. Long-Term Sample Retention.....................................................................................45
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................46
10.2.1.
Blood Sampling Summary..........................................................................................48


CONFIDENTIAL
Protocol number J2G-MC-JZPA
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10.3.
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting .......................................................................................................49
10.3.1.
Definition of AE.........................................................................................................49
10.3.2.
Definition of SAE.......................................................................................................50
10.3.3.
Definition of Product Complaints ...............................................................................51
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints .................................................................................................................51
10.3.5.
Reporting of SAEs......................................................................................................53
10.3.6.
Regulatory Reporting Requirements ...........................................................................54
10.4.
Appendix 4: Contraceptive and Barrier Guidance .......................................................55
10.5.
Appendix 5: Genetics .................................................................................................59
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................60
10.7.
Appendix 7: Example of High-Fat Breakfast ..............................................................62
10.8.
Appendix 8: Abbreviations and Definitions ................................................................64


CONFIDENTIAL
Protocol number J2G-MC-JZPA
6
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: An Open-Label Study to Investigate the Effect of Food on the Pharmacokinetics 
of Selpercatinib in Healthy Participants
Brief Title: A Food-Effect Study of Selpercatinib in Healthy Participants
Rationale:
This clinical study is being conducted to assess the effect of food on the new tablet formulation 
of selpercatinib at the highest unit strength. Two single doses of 160 mg selpercatinib will be 
administered in this study, which is supported by the available safety data and is the clinically 
recommended dose.
A previous study (LOXO-RET-18015) evaluated the effect of food and the effect of a PPI on the 
single-dose PK of selpercatinib at the clinically recommended dose of 160 mg. Exposures to 
selpercatinib under fed conditions were similar to exposures under fasting conditions. Under 
fasting conditions, coadministration of omeprazole reduced the exposure of selpercatinib (Cmax
and AUC) by 88% and 69%, respectively. These results are consistent with the pH-dependent 
solubility of selpercatinib. 
No clinically significant differences in selpercatinib AUC or Cmax were observed following
administration of a low-fat or high-fat meal (approximately 900 calories, 58 grams carbohydrate,
56 grams fat and 43 grams protein) in healthy participants.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To assess the effect of food on the PK of 
selpercatinib after a high-fat meal in healthy 
participants
AUC0-∞, AUCtlast, and Cmax of 
selpercatinib
Secondary
To assess the safety and tolerability of 160
mg of selpercatinib
Summary of the number of 
treatment-emergent AEs and serious AEs
Overall Design:
The anticipated study duration for each individual participant is approximately 7 weeks.
Screening
All participants will be screened within 28 days prior to enrollment (Day 1).


CONFIDENTIAL
Protocol number J2G-MC-JZPA
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Treatment and Assessment Period
Eligible participants will take part in 1 treatment period. Participants will be admitted to the CRU 
on Day -1. All participants will be randomized to receive either a single dose of 160 mg 
selpercatinib in the fasted or fed state on Day 1, and will have the alternate treatment (i.e., fasted 
or fed, per the randomization schedule) on Day 8.
Participants will remain resident at the CRU until Day 11. A study participant may be required to 
stay later than Day 11 for management or monitoring of an AE or a clinically significant finding, 
at the discretion of the investigator.
There will be a washout period of 7 days between dosing on Days 1 and 8.
PK blood sampling and safety assessments, including vital signs measurements, physical 
examinations, clinical laboratory tests, electrocardiograms, and AE recording, will be performed.
Follow-up
Participants will receive a follow-up phone call 7 to 10 days after the last dose of selpercatinib.
Number of Participants:
Approximately 46 participants will be enrolled to ensure that at least 38 evaluable participants 
complete the study.
Intervention Groups and Duration:
This is a single-group study, consisting of single oral doses of selpercatinib on Days 1 and 8.
All participants will be randomized to receive either a single oral dose of selpercatinib 160 mg 
will be administered in the morning of Day 1 in the fasted or fed state, and will have the alternate 
treatment (i.e. fasted or fed, per the randomization schedule) on Day 8. Both doses of 
selpercatinib will be administered 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 indicted or for study procedures.
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.
The high-fat breakfast (fat comprises approximately 50% of total calorific content) should 
consist of approximately 800 to 1000 calories in total. No additional food or substitute is 
allowed. The test meal derives approximately 150, 250, and 500 to 600 calories from protein, 
carbohydrate, and fat, respectively.
Data Monitoring Committee: No


CONFIDENTIAL
Protocol number J2G-MC-JZPA
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1.2.
Schema
Abbreviations: CRU = clinical research unit.


CONFIDENTIAL
Protocol number J2G-MC-JZPA
9
1.3.
Schedule of Activities (SoA)
Screening
Treatment Period
Follow-
Up
phone 
call
Comments
Days
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
ED
within 
7 to 10 
days 
after 
last 
dose
Informed consent
X
Inclusion and 
exclusion criteria
X
Demography
X
Participant 
admission to CRU
X
Participant 
discharge from 
CRU
X
A study participant 
may be required to 
stay later than 
Day 11 for 
management or 
monitoring of an 
AE or a clinically 
significant finding, 
at the discretion of 
the investigator.
Outpatient visit
X


CONFIDENTIAL
Protocol number J2G-MC-JZPA
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Screening
Treatment Period
Follow-
Up
phone 
call
Comments
Days
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
ED
within 
7 to 10 
days 
after 
last 
dose
Medical history 
X
Medical 
assessment
X
P
P
X
X
Full medical 
assessment to be 
performed at 
screening, and 
symptom driven 
examination to be 
done at other/any 
time point at 
physician’s 
discretion.
Height and weight
X
X
X
Height and weight 
to be measured at 
screening; weight 
only to be 
measured at Day 
11 or ED as 
appropriate.


CONFIDENTIAL
Protocol number J2G-MC-JZPA
11
Screening
Treatment Period
Follow-
Up
phone 
call
Comments
Days
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
ED
within 
7 to 10 
days 
after 
last 
dose
Serum or urine 
pregnancy test 
(women of 
childbearing 
potential only)
X
X
X
X
Serum pregnancy 
tests will be 
performed at 
screening and urine 
pregnancy test at 
all other time 
points
Follicle-
stimulating 
hormone (women 
of non-
childbearing 
potential only)
X
Human 
immunodeficiency 
virus, hepatitis B 
and C screen
X
12-lead ECG
X
P, 
2h
X
P,
2h
X
X
X
Single ECGs are 
required.
Vital signs 
(supine), pulse
rate, and blood 
pressure 
X
P, 1, 
2h
24h
X
X
P, 
1,2h
24h
X
X
X
Time points may 
be added, if 
warranted and 
agreed upon 
between Lilly and 
the investigator.
Clinical 
laboratory tests 
X
P
24h
X
P
24h
X
X
See Appendix 10.2, 
Clinical Laboratory 
Tests, for details. 


C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2 G-M C -J Z P A
1 2
Scree ni n g
Tre at me nt Peri o d
F oll o w -
U p
p h o ne 
c all
C o m me nts
D a ys
Pr oce d ure 
-2 8 t o - 2 
da y s pri or 
t o Da y 1
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
E D
wit hi n 
7 t o 1 0 
d a ys 
after 
l ast 
d ose
Ge netic sa m ple
X
Sel percati ni b 
a d mi nistrati o n 
X
X
Partici pa nt
c o ns u mes hi g h -fat
meal wit hi n 3 0 
mi n utes pri or t o 
d ose base d o n 
ra n d o mizati o n.
A d verse e ve nt 
/ Seri o us a d verse 
e ve nt re vie w
X  
X
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 
X
C o nc o mita nt 
me dicati o n re vie w
X  
X
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 
X
A b bre viati o ns: C R U = cli nical researc h u nit; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; h = h o ur; 
C CI
C CI


CONFIDENTIAL
Protocol number J2G-MC-JZPA
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2.
Introduction
Selpercatinib has been developed by Loxo Oncology, Inc. and acquired by Eli Lilly and 
Company (Lilly), and has been approved by the FDA for the treatment of advanced or metastatic 
RET-mutant MTC, and advanced or metastatic RET fusion-positive thyroid cancer, in adults and 
children ≥12 years; and for the acute treatment of metastatic RET fusion-positive NSCLC in 
adults.
Full details of the preclinical and clinical safety and tolerability data are contained in the IB.
2.1.
Study 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.
This clinical study is being conducted to assess the effect of food on the new tablet formulation 
of selpercatinib at the highest unit strength. Two single doses of 160 mg selpercatinib will be 
administered in this study, which is supported by the available safety data and is the clinically 
recommended dose.
A previous study (LOXO-RET-18015) evaluated the effect of food and the effect of a PPI on the 
single-dose PK of the selpercatinib commercial capsule formulation at the clinically 
recommended dose of 160 mg. Exposures to selpercatinib under fed conditions were similar to 
exposures under fasting conditions. Under fasting conditions, coadministration of omeprazole 
reduced the exposure of selpercatinib (Cmax and AUC) by 88% and 69%, respectively. These 
results are consistent with the pH-dependent solubility of selpercatinib. 
No clinically significant differences in selpercatinib AUC or Cmax were observed following
administration of a low-fat or high-fat meal (approximately 900 calories, 58 grams carbohydrate,
56 grams fat and 43 grams protein) in healthy subjects.
2.2.
Background
Selpercatinib (LY3527723) is a highly potent and specific small-molecule inhibitor of the RET 
kinase, with minimal inhibition of other kinase and nonkinase targets. The approved dosing 
regimen is 120 mg orally twice daily (in patients <50 kg) and 160 mg orally twice daily (in 
patients ≥50 kg).
Selpercatinib doses have been evaluated in healthy participants or patients with advanced or 
metastatic RET-mutant, advanced or metastatic RET fusion-positive thyroid cancer, and 
metastatic RET fusion-positive NSCLC across Phase 1, 2, and 3 clinical studies. Across these 
studies, single oral doses of selpercatinib were administered over a range of 20 to 720 mg. 
In previous studies (LOXO-RET-18017 and LOXO-RET-18026), multiple oral doses of 
160 mg/day selpercatinib were administered orally twice daily for 10 days in healthy 
participants. The most frequently reported (≥15% of participants regardless or attribution to 
study drug) AEs in the ongoing studies were dry mouth, diarrhea, hypertension, AST/ALT 
increased, abdominal pain, rash, ECG QT prolonged, cough, vomiting, and dyspnea.


CONFIDENTIAL
Protocol number J2G-MC-JZPA
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In the absence of acid-reducing agents, there is little effect of food on the PK of selpercatinib. 
Following dosing with 160 mg selpercatinib (2 × 80 mg) in the commercial capsule formulation, 
a high-fat breakfast resulted in an increase of approximately 9% in selpercatinib AUC and an 
approximately 14% decrease in the Cmax compared to fasting conditions.
In healthy participants the median (range) tmax of selpercatinib is 2 (1.5 to 6.0) hours and is 
eliminated with a mean (range) t1/2 of 13.6 (9.82 to 19.6) hours 
More detailed information about the PK and absorption, distribution, metabolism, and excretion 
properties of selpercatinib may be found in the IB.
2.3.
Benefit/Risk Assessment
There is no anticipated therapeutic benefit for the 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
by the FDA. The safety profile of selpercatinib is very well tolerated in healthy participants and 
is clinically manageable, with low rates of study drug discontinuation due to AEs. As outlined in 
the IB, the most common toxicities associated with selpercatinib are monitorable and reversible,
and include dry mouth, diarrhea, hypertension, fatigue, constipation, AST/ALT elevation, 
headache, nausea, edema peripheral, abdominal pain, rash, ECG QT prolonged, cough, vomiting, 
dyspnea and increased blood creatinine. Events of special interest include hypersensitivity, liver-
function test abnormalities, thrombocytopenia, and hypertension. In a recently completed study 
in healthy participants (J2G-MC-JZJV), only 1 TEAE considered to be related to selpercatinib 
was reported (dyspepsia).
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of selpercatinib can be found in the IB.


CONFIDENTIAL
Protocol number J2G-MC-JZPA
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3.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the effect of food on the PK of 
selpercatinib after a high-fat meal in healthy 
participants
AUC0-∞, AUCtlast, and Cmax of 
selpercatinib
Secondary
To assess the safety and tolerability of 160 mg 
of selpercatinib
Summary of the number of 
treatment-emergent AEs and SAEs


CONFIDENTIAL
Protocol number J2G-MC-JZPA
16
4.
Study Design
4.1.
Overall Design
This is a Phase 1, open-label, randomized, 2-period, 2-sequence crossover study of the PK of 
selpercatinib in the fed and fasted state. The anticipated study duration for each individual 
participant is up to approximately 7 weeks.
Screening
All participants will be screened within 28 days prior to enrollment (Day 1).
Treatment and Assessment Period
Eligible participants will take part in 1 treatment period. Participants will be admitted to the CRU 
on Day -1. All participants will be randomized to receive either a single dose of 160 mg 
selpercatinib in the fasted or fed state on Day 1, and will have the alternate treatment (i.e., fasted 
or fed, per the randomization schedule) on Day 8. 
Participants will remain resident at the CRU until Day 11. A study participant may be required to 
stay later than Day 11 for management or monitoring of an AE or a clinically significant finding, 
at the discretion of the investigator.
There will be a washout period of 7 days between dosing on Days 1 and 8. The doses will be 
administered at approximately the same times on Days 1 and 8. The actual time of dose 
administrations will be recorded in the participant’s eCRF.
PK blood sampling and safety assessments, including vital signs measurements, physical 
examinations, clinical laboratory tests, ECGs, and AE recording, will be performed according to 
the SoA (Section 1.3).
Follow-up
Participants will receive a follow-up phone call 7 to 10 days after the last dose of selpercatinib.
4.2.
Scientific Rationale for Study Design
This study will be open label as the study primary endpoint PK measures are objective rather 
than subjective.
Based on the t1/2 of selpercatinib of approximately 14 hours in healthy participants, a period of 
7 days between selpercatinib doses is considered sufficient time for the study drug to washout.
A randomized, 2-period crossover design will be used so that each participant serves as his/her
own control.
Conducting the study in healthy participants mitigates the potential confounding effects of the 
disease state and concomitant medications in participants with metastatic RET fusion-positive 
NSCLC, advanced or metastatic RET-mutant MTC, or advanced or metastatic RET 
fusion-positive thyroid cancer. A population of healthy participants is frequently used in the 
assessment of the PK of both small and large molecules.


CONFIDENTIAL
Protocol number J2G-MC-JZPA
17
4.3.
Justification for Dose
The dose of 160 mg is the highest approved dose for selpercatinib.
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all required 
phases of the study including the last visit or the last scheduled procedure shown in the SoA, 
follow up phone call.
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the study.


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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 21 to 65 years of age inclusive, at the time of signing the 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.
Weight
5. Have a body mass index within the range 18.5 to 35.0 kg/m2 (inclusive)
Sex and Contraceptive/Barrier Requirements
6.
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:

may participate in this study
Female participants:

of childbearing potential may participate in this study


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Protocol number J2G-MC-JZPA
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
not of childbearing potential may participate in this study
Please refer to Section 10.4 for definitions and additional guidance related to contraception.
Informed Consent
7. 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, 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. Have an abnormality in the 12-lead ECG that, in the opinion of the investigator, increases 
the risks associated with participating in the study or may confound ECG data analysis, 
including 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
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, 
and splenectomy, are considered as acceptable
10. 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
11. Have a history or presence of neuropsychiatric disease (e.g., bipolar disorder, 
schizophrenia, depression) considered as clinically significant by the investigator
12. Participants who show evidence of HIV infection and/or positive HIV antibodies. A 
negative test within 6 months of screening would not need to be repeated
13. Participants who show evidence of positive hepatitis B surface antigen. A negative test 
within 6 months of screening would not need to be repeated
14. Participants who show evidence of positive hepatitis C antibody. A negative test within 
6 months of screening would not need to be repeated. Participants with a positive 
hepatitis C antibody test result can have a confirmatory hepatitis C RNA test.


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15. Have donated blood of more than 450 mL or have participated in a clinical study that 
required similar blood volume drawn within the past 3 calendar months of study 
screening
16. Have any medical conditions, medical history, or are taking any medications which are 
contraindicated in the selpercatinib label
17. Have had lymphoma, leukemia, or any malignancy within the past 5 years except for 
basal cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years
Prior/Concomitant Therapy
18. Have participated, within the last 30 days or 5 half-lives (whichever is longer) of 
admission, in a clinical study involving an investigational product. 
19. Have previously completed or withdrawn from this study or any other study investigating 
selpercatinib, and have previously received the investigational product
20. Use of H2 blockers, proton pump inhibitors, and other drugs that affect selpercatinib 
exposure within 7 days of screening
21. 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 [≤3 g/24 hours], hormonal contraception, or hormone 
replacement therapy)
Prior/Concurrent Clinical Study Experience
22. 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
23. Have an average weekly alcohol intake that exceeds 21 units per week (males) 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)
24. Are unwilling to stop alcohol consumption 24 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
25. Are unwilling to abstain from ingesting caffeine- or xanthine-containing products (e.g., 
coffee, tea, cola drinks, and chocolate) for 24 hours prior to each admission until after 
discharge from the CRU
26. Are unable to refrain from smoking while resident at the CRU
27. Have used or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, within 30 days (or 5 half-lives, whichever is 
longest) prior to check-in, unless deemed acceptable by the investigator. All 
inhibitors/inducers of CYP3A4 are specifically excluded.
28. Are unable to consume a standardized meal within the required time frame


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Protocol number J2G-MC-JZPA
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29. 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
30. Are Lilly employees or are an employee of any third-party involved in the study who 
require exclusion of their employees
31. 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
32. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study.
5.2.1.
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.
On fed dosing days, participants will receive a high-fat meal as outlined in Section 6.1.1.
No additional food should be allowed for at least 4 hours after drug administration.
5.2.2.
Substance Use: Caffeine, Alcohol, and Tobacco
Participants will abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee,
tea, cola drinks, and chocolate) for 24 hours prior to each admission until after discharge from 
the CRU, where applicable.
Participants will abstain from alcohol for 24 hours prior to each admission until after discharge 
from the CRU, where applicable.
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 CRU.
5.2.3.
Activity
Participants will abstain from strenuous exercise during study participation. 
5.3.
Screen Failures
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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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 Administered
Table JZPA.1.
Study Interventions Administered
Study Intervention 
Selpercatinib
Dosage Formulation
Tablet
Unit Dose Strength/Dosage Level
1 160-mg tablets
(160 mg selpercatinib)
Route of Administration
Oral
Dosing Instructions
1 tablet taken 
on Days 1 and 8
6.1.1.
Administration Details
A single oral dose of selpercatinib 160 mg will be administered in the morning of Days 1 and 8
in the fasted or fed state (i.e., following consumption of a high fat meal), according to the 
randomization sequence. 
On dosing days, participants will be fasted overnight (at least 10 hours) prior to dosing. No 
additional food should be allowed for at least 4 hours after drug administration.
On fed dosing days, participants will be dosed following consumption of a high fat meal. The 
participants will complete the high-fat meal 30 minutes prior to administration of study
intervention (i.e., participants will be dosed 30 minutes after the start of the meal), and 
participants should eat this meal in 30 minutes or less. If participants take lesser time to eat, 
dosing will still occur at 30 minutes after the reference time. 
The high-fat breakfast (fat comprises approximately 50% of total calorific content) should 
consist of approximately 800 to 1000 calories in total. No additional food or substitute is 
allowed. An example of a typical test meal is provided in Appendix 7 (Section 10.7). The test 
meal derives approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and 
fat, respectively.
Participants will be encouraged to eat the full meal. Each component of the meal will be weighed 
separately and documented in grams pre and post meal to determine the percentage of the meal 
consumed in grams by the participant. The nutritional intake will be documented in grams and 
recorded in the eCRF.
Both doses of selpercatinib will be administered 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 indicted or for study procedures.


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On all dosing occasions, participants will refrain from consuming water from 1 hour predose 
until 2 hours postdose, excluding the amount of water consumed at dosing. At all other times 
during the study, participants may consume water ad libitum.
Selpercatinib tablets should be swallowed whole. Participants should not break or chew either 
tablet.
On non-dosing days, participants will adhere to meal restrictions as outlined in Section 5.2.1.
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. The investigator or designee will return all unused study interventions to Lilly or its
designee at the end of the study. In some cases, sites may destroy the material if, during
the CRU selection, the evaluator has verified and documented that the site has
appropriate facilities and written procedures to dispose of clinical materials.
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.
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 is not permitted in this study.
6.6.
Continued Access to Study Intervention after the End of the Study
Not applicable.


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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:

Contact the medical monitor immediately.

Closely monitor the participant for any AE/SAE and laboratory abnormalities 
until study intervention can no longer be detected systemically (at least 5 days).

Document the quantity of the excess dose as well as the duration of the overdose 
in the eCRF.
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:

Reason for use

Dates of administration including start and end dates

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 over-the-counter or prescription medication, including 
dietary supplements, within 14 days before the start of study intervention until discharge from 
the study.
Acetaminophen, at doses of ≤3 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 CP/CRP, or designee.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Participants discontinuing from the study prematurely for any reason must complete follow-up 
procedures per Section 1.3 of this protocol.
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 follow-up 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
The study drug should be discontinued if one or more of these conditions occur: 
Elevation
Exception
ALT or AST >5× ULN 
ALT or AST >3× ULN and either TBL >2× ULN or INR >1.5 
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for drug interruption or discontinuation 
decisions rather than TBL>2× ULN.
ALT or AST >3× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%)
ALP >3× ULN (when the source of increased ALP is the liver) 
ALP >2.5× ULN and TBL >2× ULN 
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for drug interruption or discontinuation 
decisions rather than TBL>2× ULN.
ALP >2.5× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%)
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009  
and other consensus guidelines with minor modifications
Resumption of the study drug can be considered only in consultation with the Lilly-designated 
medical monitor and only if liver test results return to approximately baseline and if a 
self-limited non-drug etiology is identified.
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix 6 
(Section 10.6).


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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 may be withdrawn from 
the study.

QTc, QTcB, QTcF >500 msec

Change from baseline in QTc >60 msec.
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QTcB 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 follow-up 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 the participant’s 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.
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected at the time of 
study discontinuation and follow-up 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.
7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was
inadvertently enrolled, then the participant should be discontinued from study treatment unless
there are extenuating circumstances that make it medically necessary for the participant to
continue on study treatment. If the investigator and the sponsor CRP agree it is medically
appropriate to continue, the investigator must obtain documented approval from the sponsor CRP
to allow the inadvertently enrolled participant to continue in the study with or without treatment


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with investigational product. Safety follow-up is as outlined in the SoA (Section 1.3), Section 8.2
(Safety Assessments), and Section 8.3 (Adverse Events, Serious Adverse Events, and Product 
Complaints) of the protocol.
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.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1).


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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.
The specifications in this protocol for the timings of safety and sample collection are given as 
targets to be achieved within reasonable limits. Modifications may be made to the time points 
based upon emerging clinical information. The scheduled time points may be subject to minor 
alterations; however, the actual time has to be correctly recorded in the CRF. Failure or being 
late (i.e., outside stipulated time allowances) to perform procedures or obtain samples due to 
legitimate clinical issues (e.g., equipment technical problems, venous access difficulty, or subject 
defaulting or turning up late on an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU will still be required to notify the sponsor in writing via a file 
note. 
8.1.
Efficacy Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Medical Assessment
A complete medical assessment will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight 
will also be measured and recorded.
A symptom driven examination may be done at other/any time point at physician’s discretion
8.2.2.
Vital Signs

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, where possible.

Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of 
dizziness or posture induced symptoms. Where orthostatic measurements are required, 


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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.
8.2.3.
Electrocardiograms

Refer to Section 7 for QTc withdrawal criteria and any additional QTc readings that may 
be necessary.

ECGs 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. ECGs may be obtained at additional times, when deemed 
clinically necessary. All ECGs recorded should be stored at the investigational site.

ECGs 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 baselined) 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.
8.2.4.
Clinical Safety Laboratory Tests

The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results 
must be retained with source documents unless a Source Document Agreement or 
comparable document cites an electronic location that accommodates the expected 
retention duration. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or 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.


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○
All protocol-required laboratory assessments, as defined in Appendix 2
(Section 10.2), must be conducted in accordance with the SoA
(Section 1.3), standard collection requirements, and laboratory manual.

If laboratory values from non-protocol specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then report the information as an AE.
8.2.5.
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.
8.2.5.1.
Hepatic Safety
Close hepatic monitoring
Laboratory tests (Appendix 6 [Section 10.6]), including ALT, AST, ALP, TBL, D. Bil, GGT, 
and CK, 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 <1.5x ULN
ALT or AST ≥3x ULN
ALP <1.5x ULN
ALP ≥2x ULN
TBL <1.5x ULN
TBL ≥2x ULN (except for patients with 
Gilbert’s syndrome)
ALT or AST ≥1.5x ULN
ALT or AST ≥2x baseline
ALP ≥1.5x ULN
ALP ≥2x baseline
TBL ≥1.5x ULN
TBL ≥1.5x 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 medical 
assessment 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. 


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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 lab 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:
If a participant with baseline 
results of... 
develops the following elevations:
ALT or AST <1.5x ULN
ALT or AST ≥3x ULN with hepatic signs/symptomsa, or 
ALT or AST ≥5x ULN
ALP <1.5x ULN
ALP ≥3x ULN
TBL <1.5x ULN
TBL ≥2x ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5x ULN
ALT or AST ≥2x baseline with hepatic signs/symptomsa, or
ALT or AST ≥3x baseline
ALP ≥1.5x ULN
ALP ≥2x baseline
TBL ≥1.5x ULN
TBL ≥2x baseline (except for patients with Gilbert’s 
syndrome) 
a 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 PT-INR; tests for viral hepatitis A, B, C, or E; tests 
for autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT 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 
(HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, 
acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, 
urinary ethyl glucuronide, and blood 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 (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), 
cardiac echocardiogram, or a liver biopsy.  
Additional hepatic data collection (hepatic safety CRF) in study participants who have abnormal 
liver tests during the study 
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions:
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN)
In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline 
on 2 or more consecutive tests


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Protocol number J2G-MC-JZPA
32
2. Elevated TBL to ≥ 2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome)
In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN)
In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline 
on 2 or more consecutive blood tests
4. Hepatic event considered to be a SAE
5. Discontinuation of study drug due to a hepatic event 
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
The definitions of the following events can be found in Appendix 3 (Section 10.3):

Adverse events (AEs)

Serious adverse events (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 (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 ICF
participation 
in study has 
ended
as soon as possible 
upon site awareness
AE CRF
N/A


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Protocol number J2G-MC-JZPA
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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Serious Adverse Event
SAE and SAE 
updates – prior 
to start of study 
intervention and
deemed 
reasonably 
possibly related 
with study 
procedures
signing of 
the ICF
start of 
intervention
within 24 hours of 
awareness
SAE paper form
SAE paper 
form
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)
Pregnancy paper 
form
Pregnancy 
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


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Protocol number J2G-MC-JZPA
34
Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
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
PC (if 
investigator 
becomes aware)
Participation 
in study has 
ended
N/A
Promptly
Product Complaint 
form
* Serious adverse events
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 learning of a pregnancy in the female partner of a study participant, the 
investigator will
o
obtain a consent to release information from the pregnant female partner 
directly, and
o
within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor.
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.


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Protocol number J2G-MC-JZPA
35
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. 
●
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol Section 8.3.1. 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 be withdrawn from the study. 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 IRB/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 the participant’s offspring.
8.4.
Pharmacokinetics
●
Plasma 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 (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. 


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Protocol number J2G-MC-JZPA
36
●
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.
8.5.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.6.
Genetics
A blood sample for DNA isolation will be collected from participants. 
See Appendix 5 (Section 10.5) for Information regarding genetic research and Appendix 1 
(Section 10.1.6) for details about sample retention and custody. 
8.7.
Biomarkers
Biomarkers are not evaluated in this study.
8.8.
Immunogenicity Assessments
Not applicable for this study.
8.9.
Health Economics
Health economics are not evaluated in this study.


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Protocol number J2G-MC-JZPA
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9.
Statistical Considerations
The statistical analysis plan (SAP) will be finalized prior to first participant first visit, and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses
9.1.
Statistical Hypotheses
The primary objective variables will be evaluated to assess the potential food effect on the PK of 
selpercatinib. 
An absence of a food effect on bioavailability will be established if the 90% confidence interval 
for the ratio of the population geometric means is contained in the equivalence limits of 80 to
125% for AUC values and Cmax.
9.2.
Analyses Sets
The following analysis sets are defined:
Participant Analysis Set
Description
Safety analysis set
All participants who received at least 1 dose of study 
intervention. Participants will be analyzed according to the 
intervention they actually received.
Pharmacokinetic analysis 
set
All participants who received both doses of study intervention 
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. Demographic characteristics may be considered in the interpretation of PK and 
safety analyses.
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.
Additional exploratory analysis of the data will be conducted as deemed appropriate.


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Protocol number J2G-MC-JZPA
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9.3.1. Safety Analyses
9.3.1.1.
Clinical Evaluation of Safety
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.
The incidence of AEs for each treatment will be presented by severity and by association with
investigational product 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 product-related SAEs will be reported.
9.3.1.2.
Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters. The parameters will be listed and summarized using standard descriptive 
statistics. 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: AUC0-∞, AUCtlast, and Cmax. 
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 the effect of food on selpercatinib. 
To make a claim of no food effect, the data should be analyzed using an average criterion, with 
the fasted treatment arm serving as the reference. 
Log-transformed Cmax, AUC0-∞, and AUCtlast parameters for selpercatinib will be evaluated 
separately. The treatment differences will be back-transformed to present the ratios of geometric 
means and the corresponding 90% CI. A mixed-effects model with sequence, period (day), and 
treatment as fixed effects and participant as a random effect will be used.
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
Not applicable for this study.


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Protocol number J2G-MC-JZPA
39
9.3.4.
Pharmacokinetic/Pharmacodynamic Analyses
Not applicable for this study.
9.4.
Interim Analysis 
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.
9.5.
Sample Size Determination
Approximately 46 participants will be enrolled to ensure that at least 38 evaluable participants 
complete the study. 
A total of 38 evaluable participants will provide approximately 80% power to have the respective 
90% confidence intervals (CIs) for the geometric mean ratios for Cmax and AUC values between 
fed and fasted treatments are within the interval of 80% to 125%, assuming a within subject CV 
of 30% for selpercatinib and that the expected ratio of means is 1.05.


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Protocol number J2G-MC-JZPA
40
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 (CIOMS) 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.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 


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Protocol number J2G-MC-JZPA
41
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
10.1.3.
Informed Consent Process
●
The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participant and answer all questions 
regarding the study.
●
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.
10.1.4.
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 the participant’s 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 their data to be used as described in the informed consent.
●
The participant must be informed that their 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.
10.1.5.
Dissemination of Clinical Study Data
Communication of Suspended or Terminated Dosing
If a decision is taken to suspend or terminate dosing in the study 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


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Protocol number J2G-MC-JZPA
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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.
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.
10.1.6.
Data Quality Assurance
●
All participant data relating to the study will be recorded on printed or electronic 
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.
●
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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Protocol number J2G-MC-JZPA
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●
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 (CTA) 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.
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Data collected via the sponsor-provided data capture system will be stored at a 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 or access 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 the Sponsor will be encoded and stored in the global 
product complaint management system.
10.1.7.
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 or entered in the CRF and 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 Section 10.1.6.


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10.1.8.
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.
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.
10.1.9.
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.
10.1.10.
Investigator Information
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial.


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10.1.11.
Long-Term Sample Retention
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development 
of selpercatinib.
Sample Type
Custodian
Retention Period After 
Last Participant Visit*
Long-term storage samples
Sponsor or Designee
15 years
Pharmacokinetics
Sponsor or Designee
1 year 
Genetics
Sponsor or Designee
15 years
*Retention periods may differ locally.


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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.
●
In circumstances where the sponsor approves local laboratory testing in lieu of 
central laboratory testing (in the table below), the local laboratory must be 
qualified in accordance with applicable local regulations.
●
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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Protocol number J2G-MC-JZPA
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Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphate 
Leukocytes (WBC) 
Platelets
Glucose (random)
Cholesterol (total, LDL-C, and HDL-C)
Total protein
Coagulationa   
Prothrombin time (PTINR)
Albumin
Total bilirubin
Activated partial thromboplastin time (aPTT)
Alkaline phosphatase (ALP)
Aspartate aminotransferase (AST)
Differential WBC (absolute counts) of
Alanine aminotransferase (ALT)
Neutrophils
Creatinine
Lymphocytes
Urea
Monocytes
Uric acid 
  Eosinophils
Basophils
Urinalysis
Specific gravity
pH
Protein
Glucose
Ketones
Bilirubin
Hepatitis B surface antigena,b
Urobilinogen
Hepatitis C antibodya,b,c
Blood
HIVa,b
Nitrite
Pregnancy test (women of childbearing potential only)f
Leukocytes
FSH (if applicable)a,e
Microscopyd
Hepatitis C RNAc
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell. 
Note: Results of these assays will be validated by the local laboratory at the time of testing. Additional tests may be 
performed or auto-calculated by the laboratory as part of its standard panel that cannot be removed. Some of the 
above parameters are calculated from measured values. Omission of calculated values will not be considered as a 
protocol violation.
a
Performed at screening only.
b
Hepatitis B surface antigen test, hepatitis C antibody test, and HIV test may be waived if they have been done 
6 months before screening with reports available for review.
c
Participants with a positive hepatitis C antibody test result can have a confirmatory hepatitis C RNA test.
d
Microscopy to be performed at the local safety laboratory if clinically indicated, per investigator’s discretion
e
FSH is to be performed for women at screening if needed to confirm postmenopausal status.
f
Serum pregnancy tests will be performed at screening and urine pregnancy test at all other time points.


C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2 G-M C -J Z P A
4 8
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, saf et 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 ZP A S a m pli n g S u m m ar y
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
2 3. 4
1
2 3. 4
Cli nical la b orat or y tests a
8
6
4 8
P har mac o ki netics - sel percati ni bb
Bl o o d discar d f or ca n n ula pate nc y
0. 3
3 4
1 0. 8
Ge netic sa m ple
1 0
1
1 0
T otal
1 6 0 . 2
T otal f or cli nical p ur p oses 
1 7 0
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.
b
A ma xi m u m of 3 sa m ples ma y be c ollecte d at a d diti o nal ti me p oi nts if warra nte d, as o utli ne d i n Secti o n 8. 4 .
C CI
C CI
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

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:
Results in death
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.
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.
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.
Is a congenital anomaly/birth defect

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.


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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 
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 product complaints:
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 


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clinical practice. AE/SAE information is reported on the appropriate CRF 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.

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 CRF page for AE/SAE and 
the Product Complaint Form for product complaints.

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/


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
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 and/or Product Information in their
assessment.

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 their 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 sponsor or designee.

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.


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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.
●
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)/Independent Ethics Committees (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
Definitions:
Woman of Childbearing Potential
Females are considered a woman of childbearing potential if:

they have had at least one cycle of menses, or

they have Tanner 4 breast development.
Any amount of spotting should be considered menarche.
Woman not of Childbearing Potential
Females are considered women not of childbearing potential if:

they have a congenital anomaly such as Mullerian agenesis, 

they are infertile due to surgical sterilization, or 

they are post-menopausal.
Examples of surgical sterilization include: hysterectomy, bilateral oophorectomy, tubal ligation.
Note: Determination can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
The post-menopausal state is defined as:
1. A woman at any age at least 6 weeks post-surgical bilateral oophorectomy with or 
without hysterectomy, confirmed by operative note; or
2. A woman at least 40 years of age and up to 55 years of age with an intact uterus, not on 
hormone therapy*, who has had cessation of menses for at least 12 consecutive months 
without an alternative medical cause, AND with a follicle-stimulating hormone 
>40 mIU/mL; or
3. A woman 55 years of age or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea; or 
4. A woman at least 55 years of age with a diagnosis of menopause prior to starting 
hormone-replacement therapy.
* Women should not be taking medications during amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor 
modulators, or chemotherapy that could induce transient amenorrhea.
Contraception Guidance:
Males
No male contraception is required except in compliance with specific local government study 
requirements.


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Females
The table below describes contraception guidance for women of childbearing potential who are 
completely abstinent as their preferred and usual lifestyle, or in a same-sex relationship, as part 
of their preferred and usual lifestyle:
Must…
Must not…
agree to either remain abstinent, or

use periodic abstinence methods
o
calendar 
o
ovulation 
o
symptothermal, or
o
post-ovulation 

declare abstinence just for the duration of 
a trial, or
stay in a same sex relationship without sexual 
relationships with males

use the withdrawal method
The table below describes contraception guidance for women of childbearing potential who are 
NOT completely abstinent as their preferred and usual lifestyle, or in a same sex relationship, as 
part of their preferred and usual lifestyle:
Topic
Explanation
Pregnancy testing
Negative serum result at screening followed by a 
negative serum result within 24 hours prior to 
treatment exposure
Note: subsequent pregnancy testing is compound 
specific
Contraception
Must agree to use 2 forms of effective 
contraception, where at least one form must be 
highly effective (less than 1% failure rate)
Examples of different forms of contraception: 
Methods
Examples
Highly effective contraception 

combination oral contraceptive pill and 
mini-pill

implanted contraceptives

injectable contraceptives

contraceptive patch (only women 
<198 pounds or 90 kg)

vasectomy (if only sexual partner)

fallopian tube implants (if confirmed by 
hysterosalpingogram)

combined contraceptive vaginal ring, or 

intrauterine devices
Effective contraception 

male or female condoms with spermicide 

diaphragms with spermicide or cervical 
sponges

barrier method with use of a spermicide


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o
condom with spermicide
o
diaphragm with spermicide, or
o
female condom with spermicide
Note: The barrier method must include use of a 
spermicide (i.e., condom with spermicide, 
diaphragm with spermicide, female condom with 
spermicide) to be considered effective.
Use of male and female condoms as a double 
barrier method is not considered effective.
Ineffective forms of contraception

spermicide alone 

immunocontraceptives

periodic abstinence

fertility awareness (calendar method, 
temperature method, combination of 
above 2, cervical mucus, symptothermal)

withdrawal

post coital douche

lactational amenorrhea
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 obtaining this consent. 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. 


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●
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. 
●
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in protocol 
Section 8.3.1. 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.


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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 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 or 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 (CSR) 
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 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
See protocol Section 8.2.5.1 for guidance on appropriate test selection.
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing.
Local testing may be performed in addition to central testing when necessary 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)


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    Hepatitis B core IgG antibody
Anti-smooth muscle antibody (ASMA) a
    HBV DNA b
Anti-actin antibody c
Hepatis C virus (HCV) testing:
Epstein-Barr virus (EBV) testing:
    HCV antibody
    EBV antibody
    HCV RNA b
    EBV DNA b
Hepatitis D virus (HDV) testing:
Cytomegalovirus (CMV) testing:
    HDV antibody
    CMV antibody
Hepatitis E virus (HEV) testing:
    CMV DNA b
    HEV IgG antibody
Herpes simplex virus (HSV) testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody
    HEV RNA b
    HSV (Type 1 and 2) DNA b
Microbiology d
Liver kidney microsomal type 1 (LKM-1) antibody
Culture:
    Blood
    Urine
a
Not required if anti-actin antibody is tested.
b
Reflex/confirmation dependent on regulatory requirements, testing availability, or both.
c
Not required if anti-smooth muscle antibody (ASMA) is tested.
d
Assayed ONLY by investigator-designated local laboratory; no central testing available.


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10.7.
Appendix 7: Example of High-Fat Breakfast
A recipe of an example high-fat breakfast that will be provided by the site is provided below. 
Please note that specifics of this breakfast may change slightly but the overall nutrition of the 
breakfast will adhere to the guidelines specified in Section 6.1.1.


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10.8.
Appendix 8: Abbreviations and Definitions
Term
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC0-∞
area under the concentration versus time curve from time zero to infinity
AUCtlast
area under the concentration versus time curve from time zero to time t, where t is the 
last measurable concentration
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum plasma concentration 
Companion diagnostic 
An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product
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.
CP
clinical pharmacologist
CRF
case report form; a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant.
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.
CRU
clinical research unit
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
eCRF
electronic case report form


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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.
FDA
Food and Drug Administration
GCP
good clinical practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IMP
Investigational Medicinal Product
INR
international normalized ratio
informed consent
A process by which a participant voluntarily confirms their willingness to participate in 
a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
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.
MTC
medullary thyroid carcinoma
NSCLC
non-small-cell lung cancer
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
pharmacokinetics


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QTc
corrected QT interval
QTcB
corrected QT interval for heart rate by Bazett’s formula
QTcF
corrected QT interval for heart rate by Fridericia’s formula
RET
ret proto-oncogene
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SoA
Schedule of Activities
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. 
TBL
total bilirubin
tmax
time to maximum plasma concentration
t1/2
half-life associated with the terminal rate constant
ULN
upper limit of normal


L e o  D o c u m e n t  I D  =  f 6 2 b 1 3 c a - 0 b 7 b - 4 2 3 c - a 6 f 6 - 7 3 5 9 a 4 f f 8 5 b 3
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 2 - N o v - 2 0 2 1  1 3 : 3 8 : 1 6  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 2 - N o v - 2 0 2 1  1 4 : 4 4 : 1 7  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-JZPA Version 1.0
An Open-Label, Randomized, Two-Period Crossover Study to Investigate the Effect of Food on the 
Pharmacokinetics of Selpercatinib in Healthy Participants
NCT05324124
Approval Date: 24-Jan-2022


Fi nal Versi o n 1. 0, 2 0 Ja n uar y 2 0 2 2
             Pa ge 1 of 1 5
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, T w o -Peri o d Cr oss o ver St u d y t o I n vesti g ate t he Effect of 
F o o d o n t he P h ar m ac o ki netics of Sel perc ati ni b i n He alt h y P artici p a nts
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 : 2 0 Ja n uar y 2 0 2 2
I nvest i gati onal Me dici nal Pr o d uct : L Y 3 5 2 7 7 2 3 (sel percat i ni b)
Pr ot oc ol Refere nce : J 2 G-M C -J Z P A
La bc or p Dr u g De vel o p me nt St u d y : 8 4 8 1 1 7 6
Cli nical P hase I
A p pr o v al D at e: 2 4- J a n- 2 0 2 2 G M T


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1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 5
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENTS............................................................................................................. 6
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 7
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 7
9.
STATISTICAL METHODOLOGY ............................................................................... 7
9.1
General.................................................................................................................... 7
9.2
Demographics and Participant Disposition............................................................... 8
9.3
Pharmacokinetic Assessment................................................................................... 8
9.3.1
Pharmacokinetic Analysis............................................................................... 8
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 11
9.4
Safety and Tolerability Assessments...................................................................... 12
9.4.1
Adverse events ............................................................................................. 12
9.4.2
Concomitant medication............................................................................... 12
9.4.3
Clinical laboratory parameters...................................................................... 13
9.4.4
Vital signs .................................................................................................... 13
9.4.5
Electrocardiogram (ECG)............................................................................. 13
9.4.6
Hepatic Monitoring ...................................................................................... 13
9.4.7
Hypersensitivity reactions............................................................................. 13
9.4.8
Other assessments......................................................................................... 13
9.4.9
Safety and Tolerability Statistical Methodology............................................ 14
10. INTERIM ANALYSES ............................................................................................... 14
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 14
12. REFERENCES ............................................................................................................ 14
13. DATA PRESENTATION ............................................................................................ 14
13.1 Derived Parameters ............................................................................................... 14
13.2 Missing Data ......................................................................................................... 14
13.3 Insufficient Data for Presentation .......................................................................... 14
14. APPENDICES ............................................................................................................. 15
Appendix 1: Document History...................................................................................... 15


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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
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
ICH
International Conference on Harmonisation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
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
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration


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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 
22 November 2021).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) 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 assess the effect of food on the PK of 
selpercatinib after a high-fat meal in healthy 
participants
Area under the concentration versus time 
curve from time zero to infinity (AUC0-∞), 
area under the concentration versus time 
curve from time zero to time t, where t is the
last measurable concentration [AUC(0-tlast)] 
and maximum observed drug concentration 
(Cmax) of selpercatinib
Secondary
To assess the safety and tolerability of 
160 mg of selpercatinib 
Summary of the number of treatment-
emergent adverse events (TEAEs) and serious 
adverse events (SAEs)


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5. STUDY DESIGN
This is a Phase 1, open-label, randomized, 2-period, 2-sequence crossover study of the PK of
selpercatinib in the fed and fasted state. The anticipated study duration for each individual
participant is up to approximately 7 weeks.
Screening
All participants will be screened within 28 days prior to enrollment (Day 1).
Treatment and Assessment Period
Eligible participants will take part in 1 treatment period. Participants will be admitted to the 
clinical research unit (CRU) on Day -1. All participants will be randomized to receive either a 
single dose of 160 mg selpercatinib in the fasted or fed state on Day 1, and will have the alternate 
treatment (i.e., fasted or fed, per the randomization schedule) on Day 8.
Participants will remain resident at the CRU until Day 11. A study participant may be required to
stay later than Day 11 for management or monitoring of an AE or a clinically significant finding,
at the discretion of the investigator.
There will be a washout period of 7 days between dosing on Days 1 and 8. The doses will be
administered at approximately the same times on Days 1 and 8. The actual time of dose
administrations will be recorded in the participant’s electronic case report form (CRF).
PK blood sampling and safety assessments, including vital signs measurements, physical
examinations, clinical laboratory tests, electrocardiograms (ECGs), and adverse event (AE)
recording, will be performed.
Follow-up
Participants will receive a follow-up phone call 7 to 10 days after the last dose of selpercatinib.
6. TREATMENTS
The following is a list of the study treatment sequence names that will be used in the TFLs.
Study Treatment Sequence
Treatment order in TFL
160 mg selpercatinib fasted / 160 mg selpercatinib fed
1
160 mg selpercatinib fed / 160 mg selpercatinib fasted
2
The following is a list of the study treatment names that will be used in the TFLs. 
Study Treatment Name
Treatment order in TFL
160 mg selpercatinib fasted
1
160 mg selpercatinib fed
2


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7. SAMPLE SIZE JUSTIFICATION
Approximately 46 participants will be enrolled to ensure that at least 38 evaluable participants 
complete the study.
A total of 38 evaluable participants will provide approximately 80% power to have the respective
90% confidence intervals (CIs) for the geometric mean ratios for Cmax and area under the curve 
(AUC) values between fed and fasted treatments are within the interval of 80% to 125%, 
assuming a within participant coefficient of variation (CV) of 30% for selpercatinib and that the 
expected ratio of means is 1.05.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all participants who received at least one dose of study 
intervention. Participants will be analyzed according to the intervention they actually received. 
The “Pharmacokinetic” population will consist of all participants who received both doses of 
study intervention 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). 
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.


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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.
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
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. 


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
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 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), 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


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
Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
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 Pharmacokinetic 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.


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
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
1. If n<6, then the dataset is too small to conduct a reliable range test.  Data will be analyzed 
with and without the atypical value, and both sets of results will be reported.  
2. If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the CSR.  Approval of the CSR will 
connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
PK parameters will be evaluated to estimate the effect of food on selpercatinib. To make a claim 
of no food effect, the data will be analyzed using an average criterion, with the fasted treatment 
arm serving as the reference.
Log-transformed Cmax, AUC(0-∞), and AUC(0-tlast) parameters for selpercatinib will be evaluated
separately. A mixed-effects model with sequence, period (day), and treatment as fixed effects 
and participant as a random effect will be used. The treatment differences will be 
back-transformed to present the ratios of geometric means and the corresponding 90% CI.


Fi nal Versi o n 1. 0, 2 0 Ja n uar y 2 0 2 2
             Pa ge 1 2 of 1 5
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
La bc or p Dr u g De vel o p me nt St u d y : 8 4 8 1 1 7 6       
Pr ot oc ol  Refere nce: J 2 G-M C -J Z P A
A n a bse nce of a f o o d effect o n bi oa vaila bilit y will be esta blis he d if t he 9 0 % CI f or t he ratio of  
t he p o p ulatio n g e o m etric mea ns base d o n l o g -tra nsf or me d data is c o ntai ne d i n t he e q ui vale nce 
li mits of 8 0 t o 1 2 5 % f or A U C val ues a n d C ma x .
E xa m ple S A S C o de:
T he t ma 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 o bser ve d me dia ns, 9 0 % CIs, a n d p -val ues fr o m t he Wilc o x o n test will be
calc ulate d.
P K para meters will be s u m marize d usi n g descri pt i ve statistics.
9. 4
S afet y a n d T oler a bilit y Assess me nts
9. 4. 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 C R F, eac h se parate se verit y 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 ditio n 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 writte 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 i nf 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 ore 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 veri t 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 o n 2 4. 1 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, i ncl u di n g t he n u m ber of i n vesti gati onal pr o d uct -relate d S A Es. 
Di sc o nti n uatio ns d ue t o A Es will be liste d.
9. 4. 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 Se pte m ber
2 0 2 1) . C o nc o mita nt me dicat i on will be liste d.
C CI
C CI
C CI
C CI
C CI
C CI
C CI


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9.4.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, and 
listed. Urinalysis data will be listed. Additionally, clinical chemistry, hematology and urinalysis 
data outside the reference ranges will be listed and flagged on individual participant data listings.
9.4.4
Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as the Day 1 predose assessment. Figures of mean vital signs and mean 
changes from baseline profiles will be presented by treatment. 
Values for individual subjects will be listed.
9.4.5
Electrocardiogram (ECG)
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.
9.4.6
Hepatic Monitoring
If a participant experiences elevated laboratory parameters, as detailed in Section 8.2.5.1 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 potential for hepatotoxicity, will be 
listed. Results from any hepatic monitoring procedures, such as a magnetic resonance 
elastography (MRE) 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.
9.4.7
Hypersensitivity reactions
For all drug hypersensitivity reactions that occur, additional follow-up data will be collected to
assess the patient’s medical history, alternative causes, and symptoms.
These data will be listed.
9.4.8
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.


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9.4.9
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
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.
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


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