Clinical trial NCT04782076
Conditions: Healthy
Sponsor: Loxo Oncology, Inc.
Start date: 2021-03-05; Completion date: 2021-05-17
Enrollment: 36 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study is to determine the effect of selpercatinib on the levels of dabigatran in the blood stream and how long it takes the body to remove dabigatran. This study will also look at how safe and well-tolerated of dabigatran when administered in combination with selpercatinib in healthy participants. This study will last approximately 22 to 25 days.

Detailed description:

Arms: arm 1: Participants received a single oral dose of 150 milligrams (mg) dabigatran on Day 1 and a single oral dose of 150 mg dabigatran coadministered with a single oral dose of 2 x 80 mg (160 mg) selpercatinib on Day 8.

There was a washout period of 7 days between dosing on Days 1 and 8.
Interventions: intervention 1: Dabigatran intervention 2: Selpercatinib
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol J2G-MC-JZJV (a) 
 
 
An Open-Label Study to Investigate the Effect of Selpercatinib on the Pharmacokinetics of 
Dabigatran in Healthy Volunteers 
 
 
NCT04782076 
 
 
Approval Date: 05-Mar-2021 
 
 
 
 


C O N FI D E N TI A L
Pr ot oc ol  J 2 G-M C -J ZJ V (a)
1
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 , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d C o m p a n y or it s 
s u b si di ari e s. 
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nt i al 
i nfor m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y 
p u bli c r el e a s e. I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot b e 
r epr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
Pr ot oc ol Title:
A n O pe n -La bel St u d y  t o I n vesti gate t he Effect of S el percat i ni b o n t he 
P har mac o ki net ics of Da bi gatra n i n Healt h y V o l unt eers
Pr ot oc ol N u m ber:
J 2 G-M C -J ZJ V
A me n d me nt N u m ber: (a)
C o m p o u n d : L Y 3 5 2 7 7 2 3
St u d y P h ase: P hase 1
S h ort Title: A D DI St u d y  of Sel percat i ni b a n d Da bi gatra n i n Healt h y V o l unt eers
S p o ns or N a me: El i Lill y a n d C o m pa n y  o n be half of L o x o O nc o l og 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(s) :
I N D: 1 3 3 1 9 3
A p pr o v al D ate:
Pr ot oc ol El e ctr 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: 0 5- M ar- 2 0 2 1 G M T


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
2
Medical Monitor Name and Contact Information will be provided separately.


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
3
Table of Contents
1.
Protocol Summary......................................................................................................6
1.1.
Synopsis.......................................................................................................................6
1.2.
Schema.........................................................................................................................9
1.3.
Schedule of Activities (SoA) ......................................................................................10
2.
Introduction..............................................................................................................14
2.1.
Study Rationale ..........................................................................................................14
2.2.
Background ................................................................................................................14
2.3.
Benefit/Risk Assessment ............................................................................................15
3.
Objectives and Endpoints.........................................................................................16
4.
Study Design .............................................................................................................17
4.1.
Overall Design............................................................................................................17
4.2.
Scientific Rationale for Study Design .........................................................................17
4.3.
Justification for Dose..................................................................................................17
4.4.
End of Study Definition..............................................................................................18
5.
Study Population ......................................................................................................19
5.1.
Inclusion Criteria........................................................................................................19
5.2.
Exclusion Criteria.......................................................................................................20
5.3.
Lifestyle Considerations .............................................................................................23
5.3.1.
Meals and Dietary Restrictions ...................................................................................23
5.3.2.
Caffeine, Alcohol, and Tobacco..................................................................................23
5.3.3.
Activity ......................................................................................................................23
5.4.
Screen Failures...........................................................................................................23
6.
Study Intervention....................................................................................................24
6.1.
Study Interventions Administered...............................................................................24
6.1.1.
Administration Details................................................................................................24
6.2.
Preparation/Handling/Storage/Accountability.............................................................24
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................25
6.4.
Study Intervention Compliance...................................................................................25
6.5.
Concomitant Therapy .................................................................................................25
6.6.
Dose Modification......................................................................................................26
6.7.
Intervention after the End of the Study........................................................................26
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................27
7.1.
Discontinuation of Study Intervention ........................................................................27
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................28
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................28
7.3.
Lost to Follow-up .......................................................................................................29
8.
Study Assessments and Procedures .........................................................................30
8.1.
Efficacy Assessments .................................................................................................30
8.2.
Safety Assessments ....................................................................................................30
8.2.1.
Physical Examinations................................................................................................30
8.2.2.
Vital Signs..................................................................................................................30


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
4
8.2.3.
Electrocardiograms.....................................................................................................31
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................31
8.2.5.
Safety Monitoring.......................................................................................................32
8.3.
Adverse Events and Serious Adverse Events ..............................................................34
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................34
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................34
8.3.3.
Follow-up of AEs and SAEs.......................................................................................35
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................35
8.3.5.
Pregnancy...................................................................................................................35
8.3.6.
Product Complaints ....................................................................................................36
8.4.
Treatment of Overdose ...............................................................................................37
8.5.
Pharmacokinetics........................................................................................................37
8.5.1.
Bioanalysis .................................................................................................................37
8.6.
Pharmacodynamics.....................................................................................................37
8.7.
Genetics .....................................................................................................................37
8.8.
Biomarkers.................................................................................................................38
8.9.
Immunogenicity Assessments.....................................................................................38
8.10.
Health Economics.......................................................................................................38
9.
Statistical Considerations.........................................................................................39
9.1.
Statistical Hypotheses.................................................................................................39
9.2.
Sample Size Determination.........................................................................................39
9.3.
Populations for Analyses ............................................................................................39
9.3.1.
Study Participant Disposition......................................................................................39
9.3.2.
Study Participant Characteristics.................................................................................39
9.3.3.
Treatment Compliance................................................................................................39
9.4.
Statistical Analyses.....................................................................................................40
9.4.1.
Safety Analyses ..........................................................................................................40
9.4.2.
Pharmacokinetic Analyses ..........................................................................................40
9.4.3.
Pharmacodynamic Analyses .......................................................................................41
9.4.4.
Pharmacokinetic/Pharmacodynamic Analyses ............................................................41
9.5.
Interim Analyses.........................................................................................................41
9.6.
Data Monitoring Committee .......................................................................................41
10.
Supporting Documentation and Operational Considerations ................................42
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................42
10.1.1.
Regulatory and Ethical Considerations........................................................................42
10.1.2.
Financial Disclosure ...................................................................................................42
10.1.3.
Informed Consent Process ..........................................................................................43
10.1.4.
Data Protection...........................................................................................................43
10.1.5.
Dissemination of Clinical Study Data .........................................................................43
10.1.6.
Data Quality Assurance ..............................................................................................44
10.1.7.
Source Documents......................................................................................................46
10.1.8.
Study and Site Start and Closure.................................................................................46
10.1.9.
Publication Policy.......................................................................................................46
10.1.10. Long-Term Sample Retention.....................................................................................47


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
5
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................48
10.2.1.
Blood Sampling Summary..........................................................................................50
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................51
10.3.1.
Definition of AE.........................................................................................................51
10.3.2.
Definition of SAE.......................................................................................................52
10.3.3.
Recording and Follow-up of AE and/or SAE ..............................................................53
10.3.4.
Reporting of SAEs......................................................................................................55
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................56
10.5.
Appendix 5: Genetics .................................................................................................59
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ...............................................................................................................60
10.7.
Appendix 7: Abbreviations .........................................................................................65
10.8.
Appendix 8: Protocol Amendment History .................................................................68
11.
References.................................................................................................................69


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
6
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: An Open-Label Study to Investigate the Effect of Selpercatinib on the 
Pharmacokinetics of Dabigatran in Healthy Volunteers
Short Title: A DDI Study of Selpercatinib and Dabigatran in Healthy Volunteers
Rationale:
The P-gp is a membrane-bound, efflux transporter located in the small intestine, colon, and liver 
(among other tissues), serving to limit the absorption of drugs from the gastrointestinal tract and 
to increase biliary secretion of drugs and their metabolites. Certain substrates of P-gp have been 
shown to have clinically significant drug interactions when administered with inhibitors of P-gp 
(International Transporter Consortium et al. 2010). 
This study aims to evaluate the safety, tolerability, and PK of dabigatran in the presence of 
selpercatinib. Dabigatran is a sensitive substrate of the efflux transporter P-gp (FDA Clinical 
DDI Guidance, 2020). Selpercatinib is an inhibitor of P-gp in vitro; an effect of selpercatinib on 
P-gp in the intestine cannot be ruled out. Based on the pH-dependent solubility of selpercatinib, 
the potential gut concentrations of selpercatinib are higher under fed conditions compared to 
under fasted conditions. Therefore, this study is designed to address the potential effect of 
selpercatinib on P-gp in the intestine under fed conditions to account for the worst scenario of 
selpercatinib inhibition.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the effect of selpercatinib 
on P-gp activity in healthy 
participants

Cmax and AUC(0-∞) of dabigatran to 
assess P-gp activity
Secondary

To evaluate the safety and tolerability
of dabigatran in combination with 
selpercatinib in healthy participants

To evaluate the pharmacokinetics of 
selpercatinib

Summary of the number of 
treatment-emergent adverse events and 
serious adverse events

Cmax, AUC(0-∞), and tmax of 
selpercatinib
Overall Design:
Screening
All participants will be screened within 28 days prior to enrollment (Day 1). 


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
7
Treatment and Assessment Period
Eligible participants will take part in 1 treatment period. Participants will be admitted to the CRU 
on Day -1 and remain resident in the CRU until discharge on Day 11. All participants will 
receive a single dose of 150 mg dabigatran on Day 1 and a single dose of 150 mg dabigatran 
coadministered with a single dose of 160 mg selpercatinib on Day 8. There will be a washout 
period of 7 days between dosing on Days 1 and 8.
Pharmacokinetic 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 return to the CRU for a safety follow-up visit within 14 to 17 days after the final 
dose.
Disclosure Statement: This is a Phase 1, fixed-sequence, open-label study in healthy 
participants.
Number of Participants:
Up to 40 participants will be enrolled to ensure that at least 30 evaluable participants complete.
Intervention Groups and Duration:
This is a single-group study, consisting of single oral doses of dabigatran (Day 1) and single oral 
doses of dabigatran and selpercatinib (Day 8).
Dabigatran/Selpercatinib
Day 1
Day 8
Dabigatran (150 mg)
Dabigatran (150 mg) + 
Selpercatinib (160 mg)
A single oral dose of dabigatran etexilate 150 mg will be administered in the morning of Day 1. 
On the morning of Day 8, a single dose of dabigatran etexilate 150 mg and selpercatinib 160 mg 
will be administered orally with approximately 240 mL of room temperature water while in a 
sitting position. Participants will not be allowed to lie supine for 2 hours after dosing, unless 
clinically indicated or for study procedures.
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.
Dabigatran and selpercatinib will be administered with food using a standardized unit meal.
The macronutrient composition of the standardized meals for dabigatran and selpercatinib 
administration should be targeted to provide approximately 50% of the calories from 
carbohydrates, 15% protein, and 35% fat. The total calories for the standardized meal to be 
consumed with each dose is expected to be approximately 685 calories.


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
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Participants will consume the standardized meal 30 minutes prior to administration of study 
intervention and participants should eat this meal in 30 minutes or less. No additional food 
should be allowed for at least 4 hours after drug administration.
Data Monitoring Committee: No


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
9
1.2.
Schema
Study 
Day
-28
-1
1
8
Dabigatran 150 mg
Dabigatran 150 mg + Selpercatinib 160 mg
Screening
Wash-out Period
22 to 25
Follow Up


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
10
1.3.
Schedule of Activities (SoA)
Screening
Days
Follow-
Up/ED
Comments
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
Within 
14 to 17 
days 
after 
final 
dose
Informed consent
X
Inclusion and exclusion 
criteria
X
Demography
X
Participant Admission to 
CRU
X
Participant Discharge 
from CRU
X
Outpatient visit
X
X
Medical history (includes 
substance usage [and 
family history of 
premature cardiovascular
disease])
X
Past and current medical 
conditions
X
Physical examination
X
X
X
X
Full physical 
examination 
(including height and 
weight) to be 
performed at 
screening. 


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
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Screening
Days
Follow-
Up/ED
Comments
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
Within 
14 to 17 
days 
after 
final 
dose
Symptom-driven 
physical 
examinations to be 
performed at all other 
timepoints.
Serum or urine 
pregnancy test (women 
of childbearing potential 
only)
X
X
X
X
Serum pregnancy test 
will be performed at 
screening. Urine 
pregnancy test will 
be performed at 
every admission to 
the CRU and at 
poststudy, if 
applicable.
Human 
immunodeficiency virus, 
hepatitis B and C screen
X
Urine or breath ethanol 
test 
X
X
Urine drug screen
X
X
12-lead ECG
X
P, 
2h
X
P, 
2h
X
Single ECGs are 
required.
Vital signs (supine)
X
X
P, 
1, 
2h
24h
X
P, 
1, 
2h
24h
X
Time points may be 
added, if warranted 
and agreed upon 


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
12
Screening
Days
Follow-
Up/ED
Comments
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
Within 
14 to 17 
days 
after 
final 
dose
between Lilly and the 
investigator.
Clinical laboratory tests
(include liver 
chemistries)
X
X
24h
X
24h
X
See Appendix 10.2, 
Clinical Laboratory 
Tests, for details.
Genetic sample
X
PK samples - Dabigatran 
(plasma)
P, 
0.5, 
1, 
2, 
3, 
4, 
6, 
8, 
10, 
12h
24, 
36h
48h
72h
P, 
0.5, 
1, 
2, 
3, 
4, 
6, 
8, 
10, 
12h 
24, 
36h
48h
72h
PK samples -
Selpercatinib (plasma)
P, 
0.5, 
1, 
1.5, 
2, 
3, 
4, 
6, 
8, 
10, 
12h
24, 
36h
48h
72h


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
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Screening
Days
Follow-
Up/ED
Comments
Procedure 
-28 to -2 
days prior 
to Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
Within 
14 to 17 
days 
after 
final 
dose
Selpercatinib
administration
X
Dabigatran 
administration
X
X
Adverse event /Serious 
adverse event review
X
X
=========================================
X
Concomitant medication 
review
X
X
=========================================
X


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
14
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
The P-gp is a membrane-bound, efflux transporter located in the small intestine, colon, and liver 
(among other tissues), serving to limit the absorption of drugs from the gastrointestinal tract and 
to increase biliary secretion of drugs and their metabolites. Certain substrates of P-gp have been 
shown to have clinically significant drug interactions when administered with inhibitors of P-gp 
(International Transporter Consortium et al. 2010).
This study aims to evaluate the safety, tolerability, and PK of dabigatran in the presence of 
selpercatinib. Dabigatran is a sensitive substrate of the efflux transporter P-gp (FDA Clinical 
DDI Guidance, 2020). Selpercatinib is an inhibitor of P-gp in vitro; an effect of selpercatinib on 
P-gp in the intestine cannot be ruled out. Based on the pH-dependent solubility of selpercatinib,
the potential gut concentrations of selpercatinib are higher under fed conditions compared to 
under fasted conditions. Therefore, this study is designed to address the potential effect of 
selpercatinib on P-gp in the intestine under fed conditions to account for the worst scenario of 
selpercatinib inhibition.
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.  
Selpercatinib doses have been evaluated in healthy participants or patients with advanced or 
metastatic RET-mutant MTC, 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. 
Multiple oral doses of 160 mg/day selpercatinib were administered orally twice daily for 10 days
in healthy volunteers. The most frequently reported (≥15% of participants regardless of 
attribution to study drug) AEs in the ongoing first-in-human dose finding study were dry mouth, 
diarrhea, hypertension, AST/ALT increased, fatigue, constipation, edema peripheral, nausea, 
headache, blood creatinine increased, abdominal pain, rash, ECG QT prolonged, cough, 
vomiting, and dyspnea.
The median tmax of selpercatinib is 2 hours and is slowly eliminated with a mean t1/2 of 
approximately 32 hours in healthy volunteers. More detailed information about the PK and 
absorption, distribution, metabolism, and excretion properties of selpercatinib may be found in 
the IB.


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
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Dabigatran etexilate, a competitive, direct thrombin inhibitor, is a P-gp substrate. Following 
absorption, dabigatran etexilate is hydrolyzed to form dabigatran, the active moiety. Dabigatran 
concentrations reach tmax within 2 hours of administration, and then concentrations decline in a 
biphasic manner, with a terminal t1/2 of 12 to 17 hours. Dabigatran is primarily eliminated 
through renal excretion and does not appear to be a substrate for renal transporters based on the 
reported renal clearance of 89 mL/min (Stangier 2008). Dabigatran itself is not a substrate for the 
cytochrome P450 family of metabolizing enzyme nor a substrate for P-gp, meaning that changes 
in dabigatran exposure following administration of a P-gp inhibitor would be anticipated to only 
reflect the activity of the inhibition of dabigatran etexilate transport at the intestinal wall 
(Stangier 2008). Previous studies have investigated the effect of P-gp inhibitors on dabigatran 
PK. Dabigatran AUC increased by 58% and 53% when coadministered with amiodarone and 
quinidine, respectively (Pradaxa® Prescribing Information). Ketoconazole, a strong P-gp 
inhibitor, increased dabigatran AUC and Cmax values by 138% and 135%, respectively, after a 
single dose of 400 mg, and 153% and 149%, respectively, after multiple daily 400-mg doses 
(Pradaxa® Prescribing Information).
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.
The safety profile of selpercatinib is very well tolerated in healthy volunteers and is clinically 
manageable, with the low rates of study drug discontinuation due to AEs. As outlined in the IB, 
the most common toxicities associated with selpercatinib are monitorable and reversible and 
include dry mouth, diarrhea, hypertension, fatigue, constipation, AST/ALT elevation, headache, 
nausea, edema peripheral, abdominal pain, rash, electrocardiogram QT prolonged, cough, 
vomiting, dyspnea and increased blood creatinine. Events of special interest include 
hypersensitivity, liver-function test abnormalities, thrombocytopenia, and hypertension.
The dabigatran dose to be administered in this study (150 mg) is within the therapeutic range 
(see Section 4.3), and has previously been administered to healthy volunteers with no tolerability 
concerns in other DDI studies (e.g., I8D-MC-AZEE; NCT02568397).
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of selpercatinib may be found in the IB.


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
16
3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the effect of selpercatinib 
on P-gp activity in healthy participants

Cmax and AUC(0-∞) of dabigatran to 
assess P-gp activity
Secondary

To evaluate the safety and tolerability
of dabigatran in combination with 
selpercatinib in healthy participants

To evaluate the pharmacokinetics of 
selpercatinib

Summary of the number of 
treatment-emergent adverse events 
and serious adverse events

Cmax, AUC(0-∞), and tmax of 
selpercatinib


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
17
4.
Study Design
4.1.
Overall Design
This is a Phase 1, fixed-sequence, open-label study in healthy participants that will study 
dabigatran P-gp DDI with selpercatinib. The anticipated study duration for each individual 
participant is approximately 8 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 and remain resident in the CRU until discharge on Day 11. All participants will 
receive a single dose of 150 mg dabigatran on Day 1 and a single dose of 150 mg dabigatran 
coadministered with a single dose of 160 mg selpercatinib on Day 8. There will be a washout 
period of 7 days between dosing on Days 1 and 8.
Pharmacokinetic 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 return to the CRU for a safety follow-up visit within 14 to 17 days after the final 
dose.
4.2.
Scientific Rationale for Study Design
A single 160-mg dose of selpercatinib was selected as it is the highest approved dose for 
selpercatinib use in adults.
In order to allow each participant to act as his/her own control for safety and PK comparisons, a 
fixed sequence design has been selected. This study will also be open-label as the study primary 
endpoint PK measures are objective rather than subjective.
Based on the t1/2 of dabigatran, a period of 7 days between dabigatran doses is considered 
sufficient time for the study drug to washout.
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.
4.3.
Justification for Dose
Dabigatran etexilate is currently approved in the United States to reduce the risk of stroke and 
systemic embolism in patients with nonvalvular atrial fibrillation, for the treatment of deep 


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Protocol J2G-MC-JZJV (a)
18
venous thrombosis and pulmonary embolism, and to reduce the risk of recurrence of deep venous 
thrombosis and pulmonary embolism (Pradaxa Prescribing Information). The recommended dose 
for dabigatran etexilate is 150 mg twice daily for patients with creatinine clearance >30 mL/min 
(Praxada Prescribing Information). Single oral doses of 10 to 400 mg dabigatran etexilate have 
been administered to healthy participants and were well tolerated (Stangier et al. 2008). There is 
a  possibility of an interaction of dabigatran etexilate with selpercatinib and the dose selected 
allows for this possibility. The selected 150 mg dose for this study should provide adequate 
plasma dabigatran concentrations to address the study objectives with minimal risk for AEs 
(Härtter et al. 2013).
The dose level of 160 mg is the highest approved dose for selpercatinib.
The doses will be administered at approximately the same time on Day 1 and Day 8. The actual 
time of dose administrations will be recorded in the participant’s electronic CRF.
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.
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 globally.


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Protocol J2G-MC-JZJV (a)
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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 18 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 19.0 to 35.0 kg/m2 (inclusive).
Sex
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.
Male participants:

are not required to adhere to contraceptive requirements


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Protocol J2G-MC-JZJV (a)
20
Female participants:

Female participants of childbearing potential (see Appendix 10.4) who are abstinent 
(if this is complete abstinence, as their preferred and usual lifestyle) or in a same sex 
relationship (as part of their preferred and usual lifestyle) must agree to either remain 
abstinent or stay in a same sex relationship without sexual relationships with males. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence just for the duration of a study, and withdrawal 
are not acceptable methods of contraception.

Female participants of childbearing potential, who are not abstinent as described 
above, must agree to use a highly effective method of contraception (that is, one with 
less than 1% failure rate) such as combination or oral contraceptives, 
implanted/injected contraceptives, intrauterine devices, or sterile partner until 
30 days after the last dose of study medication. 
o
Female participants not of childbearing potential are not required to use 
contraception. This includes females who are:

Infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy, or tubal ligation) or congenital 
anomaly (for example, Müllerian agenesis)

Postmenopausal as defined in Appendix 10.4.
Informed Consent
7. Capable of giving signed informed consent as described in Appendix 10.1 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- or dabigatran-related compounds or any 
components of the formulation of selpercatinib or dabigatran, 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 known bleeding disorder including prior personal or familiar history of abnormal 
bleeding, hereditary or acquired coagulation or platelet disorder, or abnormal coagulation 
test (prothrombin time/international normalized ratio or partial thromboplastin 
time/activated partial thromboplastin time greater than ULN) result at screening


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Protocol J2G-MC-JZJV (a)
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8. Clinically significant abnormalities on ECG as determined by the investigator or 
prolongation of the QTcB or QTcF >450 msec on more than 1 ECG obtained at screening
9. Have clinically significant active cardiovascular disease or history of myocardial 
infarction within 6 months prior to the planned start of selpercatinib
10. Have a history or presence of cardiovascular, respiratory, renal, gastrointestinal, 
endocrine, hematological, or neurological disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs; of constituting a risk when taking the 
investigational product; or of interfering with the interpretation of data. Appendectomy, 
splenectomy, and cholecystectomy are considered as acceptable
11. Have a creatinine clearance <60 mL/min, as calculated using the CKD-EPI equation
(Levey et al, 2009).
eGFR = 141 × min(Scr/K, 1)α × max(Scr/K, 1)-1.209 × 0.993age
× 1.018 (if female)
× 1.159 (if black)
12. Show a history of central nervous system conditions such as strokes, transient ischemic 
attacks, significant head trauma, seizures, central nervous system infections, migraine, 
brain surgery, or any other neurological conditions that, in the opinion of the investigator, 
increase the risk of participating in the study
13. Have a history or presence of neuropsychiatric disease (e.g., manic depressive illness, 
schizophrenia, depression) considered as clinically significant by the investigator
14. Regularly use known drugs of abuse or show positive findings on drug screening
15. Show evidence of human immunodeficiency virus infection and/or positive human 
immunodeficiency virus antibodies
16. Presence of hepatitis B surface antigen at screening or within 3 months prior to first dose 
of study intervention
17. Positive hepatitis C antibody test result at screening or within 3 months prior to first dose 
of study intervention. NOTE: Participants with positive hepatitis C antibody due to prior 
resolved disease can be enrolled if a confirmatory negative hepatitis C antibody RNA test 
is obtained
18. Positive hepatitis C antibody RNA test result at screening or within 3 months prior to first 
dose of study intervention. NOTE: Test is optional and participants with negative 
hepatitis C antibody test are not required to also undergo hepatitis C RNA testing
19. Have donated blood of more than 500 mL within the previous 2 months of study 
screening
20. Have any medical conditions, medical history, or are taking any medications which are 
contraindicated in the dabigatran label


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Protocol J2G-MC-JZJV (a)
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Prior/Concomitant Therapy
21. Have participated, within the last 30 days of admission, in a clinical study involving an 
investigational product. If the previous investigational product has a long half-life, 
5 half-lives or 30 days (whichever is longer) should have passed.
22. Have previously completed or withdrawn from this study or any other study investigating 
selpercatinib, and have previously received the investigational product 
23. Use of H2 blockers, proton pump inhibitors, and other drugs that affect dabigatran and/or 
selpercatinib exposure within 7 days of screening.
24. Are intending to use over-the-counter or prescription medication, including dietary 
supplements, within 14 days prior to dosing and until study discharge (apart from 
occasional acetaminophen (≤2 g/24 hours), hormonal contraception, or hormone 
replacement therapy)
Prior/Concurrent Clinical Study Experience
25. Are currently enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study
Other Exclusions
26. Have an average weekly alcohol intake that exceeds 21 units per week (males ≤65 years 
old) and 14 units per week (females); 1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL 
of wine; 1.5 oz or 45 mL of distilled spirit(s)
27. Are unwilling to stop alcohol consumption 48 hours prior to each admission to the CRU, 
and while resident at the CRU. At all other times, participants must agree to consume no 
more than 2 units per day
28. Are smokers of more than 10 cigarettes or e-cigarettes, or 3 cigars or 3 pipes, per day and 
are unable to refrain from smoking while resident at the CRU
29. Consume excessive amounts of coffee, tea, cola, or other caffeinated beverages per day, 
or are unwilling to stop caffeine consumption 48 hours prior to admission and whilst 
resident at the CRU. Excessive amount is defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine).
30. Are unable to consume a standard meal.
31. Currently use or show evidence of substance abuse (including alcohol abuse) or 
dependence within the past 6 months based on medical history at screening visit
32. Inability to comply with the dietary regimen of the CRU
33. Are Lilly employees or are an employee of any third-party involved in the study who 
require exclusion of their employees
34. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted
35. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study


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5.3.
Lifestyle Considerations
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study.
5.3.1.
Meals and Dietary Restrictions
During the confinement period, participants will consume only food and beverages that are 
provided to them by the CRU staff. Standard meals (e.g., breakfast, lunch, dinner, and snack) 
will be provided to the participants while resident at the CRU.
Dabigatran and selpercatinib will be administered with food using a standardized unit meal.
The macronutrient composition of the standardized meals for dabigatran and selpercatinib 
administration should be targeted to provide approximately 50% of the calories from 
carbohydrates, 15% protein, and 35% fat.  The total calories for the standardized meal to be 
consumed with each dose is expected to be approximately 685 calories. Subjects will be 
encouraged to eat the entire 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 subject. The nutritional 
intake will be documented in grams and recorded in the electronic case report form (eCRF).
Participants will complete the standardized meal 30 minutes prior to administration of study 
intervention and participants should eat this meal in 30 minutes or less. No additional food 
should be allowed for at least 4 hours after drug administration.
5.3.2.
Caffeine, Alcohol, and Tobacco
Participants will abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, 
tea, cola drinks, and chocolate) for 48 hours prior to admission until after discharge from the 
CRU
Participants will abstain from alcohol for 48 prior to admission until after discharge from the 
CRU.
Participants who use tobacco products will be instructed that use of nicotine-containing products 
(including nicotine patches) will not be permitted while they are in the clinical unit. 
5.3.3.
Activity
Participants will abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities during the 
study (e.g., watching television, reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention. 


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24
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
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 Interventions Administered
Table JZJV.1.
Study Interventions Administered
Study Intervention 
Selpercatinib
Dabigatran etexilate
Dosage Formulation
Capsule
Capsule
Unit dose strength(s)/Dosage 
Level(s)
2 80-mg capsules
(160 mg selpercatinib)
150-mg capsule
Route of Administration
Oral
Oral
Dosing Instructions
2 capsules taken 
on Day 8
1 capsule taken on Day 1
and 
1 capsule taken on Day 8
6.1.1.
Administration Details
A single oral dose of dabigatran etexilate 150 mg will be administered in the morning of Day 1
with approximately 240 mL of room temperature water while in a sitting position. On the 
morning of Day 8, a single dose of dabigatran etexilate 150 mg and selpercatinib 160 mg will be 
administered orally with approximately 240 mL of room temperature water while in a sitting 
position. Participants will not be allowed to lie supine for 2 hours after dosing, unless clinically 
indicated or for study procedures.
Dabigatran etexilate and selpercatinib capsules should be swallowed whole. Participants should 
not break, crush, chew, or empty the contents of either capsule.
On dosing days, participants will adhere to meal restrictions as outlined in Section 5.3.1.
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature 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 and only 
authorized site staff may supply 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 site staff.


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3. The investigator, institution, or the head of the medical institution (where applicable) is 
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.
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 prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 14 days before the start of study intervention until 
discharge from the study.
Acetaminophen, at doses of ≤ 2 grams/24 hours, is permitted for use at the discretion of the 
investigator for the treatment of headache, etc. Contraceptive medication is permitted as per the 
contraception requirements (Appendix 10.4), and hormone replacement therapy is also allowed.
Other medication may be considered on a case-by-case basis by the investigator in consultation 
with the Lilly clinical pharmacologist (CP)/clinical research physician (CRP), or designee.


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6.6.
Dose Modification
Dose modification is not permitted in this study.
6.7.
Intervention after the End of the Study
Not applicable.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Participants discontinuing from the study prematurely for any reason must complete and 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 (definitive 
discontinuation) study intervention. If study intervention is definitively 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.
Study intervention will be discontinued for a participant if liver chemistry stopping criteria are 
met.
Phase 1 Liver Chemistry Stopping Algorithm
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; 
ULN = upper limit of normal.
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix 10.6.
A participant who meets either bulleted criterion following single ECG assessment should have 
ECG repeated. If the participant still meets either bulleted criterion they will be withdrawn from 
the study.
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*


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
QTc, QTcB, QTcF >500 msec

Change from baseline: QTc >60 msec
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QTc using Bazett’s formula or QTcF) after enrollment, the investigator or qualified designee 
will determine if the participant can continue in the study and if any change in participant
management is needed. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE.
See the SoA for data to be collected at the time of intervention discontinuation and 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 his/her own request 

at the request of his/her designee (for example, parents or legal guardian)

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
Discontinuation is expected to be uncommon.
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See the 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 both from the study intervention and from 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 
with investigational product. Safety follow-up is as outlined in Section 1.3 (Schedule of 


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Activities), Section 8.2 (Safety Assessments), and Section 8.3 (Adverse Events and Serious 
Adverse Events) 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 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 10.1.


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


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


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○
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., 
SAE or AE), then the results must be recorded in the eCRF.
8.2.5.
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 10.6), including ALT, AST, ALP, TBL, direct bilirubin, gamma-
glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to confirm 
the abnormality and to determine if it is increasing or decreasing, if one or more of these 
conditions occur:
If a participant with baseline 
results of ... 
develops the following elevations:
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN
ALP <1.5 × ULN
ALP ≥2 × ULN
TBL <1.5 × ULN
TBL ≥2 × ULN (except for patients with 
Gilbert’s syndrome)
ALT or AST ≥1.5 × ULN
ALT or AST ≥2 × baseline
ALP ≥1.5 × ULN
ALP ≥2 × baseline
TBL ≥1.5 × ULN
TBL ≥2 × baseline (except for patients with 
Gilbert’s syndrome)
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 


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


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In participants with baseline TBL ≥1.5 × ULN, the threshold should be TBL 
≥2 × baseline
3. Elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5 × ULN)
In participants with baseline ALP ≥1.5 × ULN, the threshold is ALP ≥2 × baseline 
on 2 or more consecutive blood tests
4. Hepatic event considered to be an SAE
5. Discontinuation of study drug due to a hepatic event 
NOTE: the interval between the 2 consecutive blood tests should be at least 2 days.
8.3.
Adverse Events and Serious Adverse Events
Product Complaints are covered in Section 8.3.6.
Adverse 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 the definition of an AE or SAE and remain responsible for following 
up AEs 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).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All SAEs will be collected from the signing of the ICF until participation in the study has ended.
All AEs will be collected from the start of intervention until the follow-up visit.
Medical occurrences that begin before the start of study intervention but after signing of the ICF 
will be recorded on the Adverse Event eCRF.
Although all AEs after signing the ICF are recorded by the site in the eCRF/electronic data entry, 
SAE reporting to the sponsor begins after the participant has signed the ICF and has received 
study drug. However, if an SAE occurs after signing the ICF, but prior to receiving selpercatinib, 
it needs to be reported ONLY if it is considered reasonably possibly related to study procedures.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 10.3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 10.3.


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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE
occurrences.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 10.3.
8.3.4.
Regulatory Reporting Requirements for SAEs
●
Prompt notification by the investigator to the sponsor of an 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, IRB/IEC, and 
investigators.
●
An investigator who receives an investigator safety report describing an 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.
8.3.5.
Pregnancy
●
Details of all pregnancies in female participants and, if indicated, female partners 
of male participants will be collected after the start of study intervention and until 
the follow-up visit.
●
If a pregnancy is reported, the investigator should inform the sponsor within 
24 hours of learning of the pregnancy and should follow the procedures outlined 
in Appendix 10.3.
●
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
●
Pregnancy (maternal or paternal exposure to investigational product) does not 
meet the definition of an AE. However, to fulfill regulatory requirements, any 
pregnancy should be reported following the SAE process described in 
Appendix 10.4 to collect data on the outcome for both mother and fetus.


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8.3.6.
Product Complaints
A product complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
study intervention. 
The sponsor collects product complaints on investigational products and drug delivery systems 
used in clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
NOTE: AEs/SAEs that are associated with a product complaint will also follow the processes 
outlined in Section 8.3.3 and Appendix 10.3 of the protocol.
8.3.6.1.
Time Period for Detecting Product Complaints
●
Product complaints that result in an AE will be detected, documented, and 
reported to the sponsor during all periods of the study in which the drug is used.
●
If the investigator learns of any product complaint at any time after a participant 
has been discharged from the study, and such incident is considered reasonably 
related to a drug provided for the study, the investigator will promptly notify the 
sponsor.
8.3.6.2. Prompt Reporting of Product Complaints to Sponsor
●
Product complaints will be reported to the sponsor within 24 hours after the 
investigator becomes aware of the complaint.
●
The Product Complaint Form will be sent to the sponsor by email. If email is 
unavailable, then fax should be utilized.
8.3.6.3.
Follow-up of Product Complaints
●
Follow-up applies to all participants, including those who discontinue study 
intervention.
●
The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality of 
the product complaint.
●
New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator and submitted to the 
sponsor.
8.3.6.4. Regulatory Reporting Requirements for Product Complaints
●
As required by local regulations, the investigator will report to their IRB/IEC any 
unanticipated adverse device effect or unanticipated problem that resulted in an SAE, or 
any product complaint that could have led to an SAE had precautions not been taken.


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8.4.
Treatment of Overdose
For the purposes of this study, an overdose of selpercatinib or dabigatran etexilate is considered 
as any dose higher than the dose assigned. There is no specific antidote for selpercatinib.
The antidote to dabigatran is idarucizumab and may be used in case of overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 5 days).
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF.
4. In the case of emergency uncontrolled bleeding as a direct consequence of dabigatran, 
urgent referral for treatment with idarucizumab should be considered.
Decisions regarding dose interruptions will be made by the investigator in consultation with the 
medical monitor based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
●
At the times and visits specified in the SoA, venous blood samples of 
approximately 2 mL each will be collected to determine the plasma
concentrations of selpercatinib and dabigatran. 
●
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.
●
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.
8.5.1.
Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of selpercatinib and dabigatran will be assayed using a validated liquid 
chromatography with tandem mass spectrometry method.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last participant visit for the study.  
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
A blood OR saliva sample for DNA isolation will be collected from participants. 


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See Appendix 10.5 for information regarding genetic research and Appendix 10.1 for details 
about sample retention and custody.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessments
Not applicable for this study.
8.10.
Health Economics
This section is not applicable for this study.


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9.
St atistic al C o nsi der ati o ns
9. 1.
St atistic al H y p ot heses
T he pri mar y  o bjecti ve varia bles will be e val uate d t o assess t he p ote ntial dr u g -dr u g i nteracti o n. 
All tests a n d/ or esti mat i on statistics will n ot be c o nfir mat or y  b ut will c o ntri b ute t o a b o d y of 
e vi de nce t o s u p p ort fi nal c o ncl usi o ns.
9. 2.
S a m ple Size Deter mi n ati o n
A p pr o xi matel y  
 will be e nr olle d s o t hat a p pr o xi matel y 
 c o m plete 
t he st u d y. T o e valuate t he effect of sel percati ni b o n P -g p acti vit y,  it is i m p orta nt t hat t he rati o of 
ge o m etric mea ns is est i mate d wit h reas o na ble precisi on. 
 
 
9. 3.
P o p ul ati o ns f or A n al yses
T he f oll owi n g p o p ul at i ons are defi ne d:
P o p ul ati o n
Descri pti o n
E ntere d
All partici pa nts w h o si g n t he I C F .
E nr olle d/I nte nt -t o-Treat
All partici pa nts assi g ne d t o treat me nt, re gar dless of w het her t he y  
ta ke a n y d oses of i n vesti gati o nal pr o d uct, or if t he y ta ke t he 
c orrect treat me nt.
S af et y
All partici pa nts assi g ne d t o da bi gatra n a n d w h o ta ke at least 
1 d ose. 
P har mac o ki net ic A nal ysis
All partici pa nts w h o recei ve d at least 1 d ose of da bi gatra n a n d 
ha ve e val ua ble P K.
9. 3. 1.
St u d y P artici p a nt Dis p ositi o n
A detaile d descri pti o n of  p artici pa nt dis p ositio n will be pr o vi de d at t he e n d of t he st u d y .
9. 3. 2.
St u d y P artici p a nt C h ar acteristics
T he parti ci pa nt’s a ge, se x, a n d ot her de m o gra p hic c haracterist ics will be rec or de d a n d 
s u m marize d. De m o gra p hic c haracterist ics ma y be c o nsi dere d i n t he i nter pretati o n of P K a n d 
safety a nal yses.
9. 3. 3.
Tre at me nt C o m pli a nce
T he d ate a n d ti me of d osi n g will be rec or de d a n d liste d.
C CI
C CI
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9. 4.
S t atistic al A n al yses
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bilit y of  t he sp o ns or or i ts desig nee.
P har mac o ki net ic a nal yses will be c o n d ucte d o n data fr om all partici pa nts w h o recei ved at least 1
d ose of t he i n vest i gati onal pr o d uct a n d ha ve e val ua ble P K.
S af et y a nal yses will be c o n d ucte d f or all e nr o lle d partici pa nts w h o recei ve d at least 1 d ose of 
da bi gatra n , w het her or n ot t he y c o mplete d all pr ot oc ol re q uire me nts.
A d dit i onal e x plor at or y  a nal yses of t he data will be c o n d ucte d as dee me d a p pr o pri ate.
9. 4. 1.
S afet y A n al yses
9. 4. 1. 1.
Cli nic al E v al u ati o n of S afet y
All i n vesti gati onal pr o d uct a n d pr ot oc ol pr oce d ure A Es will be liste d, a n d if t he fre q ue nc y o f 
e ve nts all o ws, safet y data will be s u m marize d usi n g descri pt i ve met h o d ol o g y .
T he i nci de nce of A Es f or eac h tr e at me nt will be prese nte d b y se verit y a n d b y ass ociat i on wi t h 
i n vesti gati onal pr o d uct as percei ve d b y  t he i n vesti gat or. A d verse e ve nts re p orte d t o occ ur pri or 
t o e nr oll me nt will be dist i n g uis he d fr om t hose re p orte d as ne w or i ncrease d i n se verit y d uri n g t he 
st u d y. Eac h A E will be classifie d b y t he m ost s uita ble ter m fr o m t he me dical re g ulat or y 
di ct i onar y .
T he n u m ber of i n vest i gati onal pr o d uct -relate d S A Es will be re p orte d.
9. 4. 1. 2.
St atistic al E v al u ati o n of S afet y
S af et y para m eters t hat will be assesse d i ncl u de sa fet y la b orat or y para meters, vit al sig ns, a n d 
E C G para meters. T he para meters will be liste d a n d s u m marize d usi n g sta n dar d descri pt i ve 
statistics. A d diti onal a nal ysis will be perf or me d if warra nte d u p o n re vie w of t he data.
9. 4. 2.
P h ar m ac o ki netic A n al yses
9. 4. 2. 1.
P K P ar a met er Esti m ati o n
P har mac o ki net ic para meter esti mates will be calc ulate d b y sta n dar d n o nc om part me nt al met h o ds. 
T he pri mar y  P K para met ers for a nal ysis of da bi gatra n will be: C m a x a n d A U C( 0 -∞) . Ot her 
n o nc o m part me nt al para meters, s uc h as tma x , t1/ 2, a p pare nt t otal b o d y  cleara nce of dr u g 
calc ulate d after e xtra vasc ular a d mi nistrati o n, a n d a p pare nt v ol u me of distri b ut i on d uri n g t he 
ter mi nal p hase after e xtra vasc ular a d mi nistrati o n, ma y be re p orte d as a p pr o priate.
N o nc o m part me nt al P K para meters will als o be calc ulate d f or selpercat i ni b.
9. 4. 2. 2.
P K St atistic al I nfere nce
P har mac o ki net ic para meters will be e val uate d t o esti mate D DI f or da bigatra n. L o g -tra nsf or me d 
C m a x a n d A U C( 0-∞)
para meters f or da bi gatra n will be e val uate d se paratel y. 
 
 
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P har mac o ki net ic para meters will be s u m marize d usi n g descri pt i ve statistics.
9. 4. 3.
P h ar m ac o d y n a mic A n al yses
N ot a p plica ble f or t his st u d y .
9. 4. 4.
P h ar m ac o ki netic/ P h ar m ac o d y n a mic A n al yses
N ot a p plica ble f or t his st u d y .
9. 5.
I nteri m A n al yses 
N o i nt eri m a nal yses are pla n ne d f or t his st u d y. If a n u n pla n ne d i nteri m a nal ysis is dee me d 
necessar y  for reas o ns ot her t ha n a safet y c o ncer n, t he pr ot oc ol m ust be a me n de d.
9. 6.
D at a M o nit ori n g C o m mittee
N o data m o nit ori n g c o m mittee is re q uire d f or t his st u d y .
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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
●
This study will be conducted in accordance with the protocol and with the 
following:
○
Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines
○
Applicable ICH GCP Guidelines
○
Applicable laws and regulations
●
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
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.
●
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 the conduct of the study at the site and adherence to 
requirements of 21 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 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.


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10.1.3.
Informed Consent Process
●
The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant or his/her legally authorized 
representative and answer all questions regarding the study.
●
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act 
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 re-consented 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 or the participant’s 
legally authorized representative 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 his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.
●
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
●
The sponsor has processes in place to ensure data protection, information security,
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach.
10.1.5.
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 


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that they understand the communication and have taken the appropriate action prior to further 
dosing any participants with study intervention. Any investigator not responding will be 
followed up by Lilly personnel prior to any further planned dosing. If a dose is planned 
imminently, Lilly personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified.
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 
eCRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the eCRF.
●
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF.
●
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 (e.g., 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 eCRF 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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●
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 
clinical trial agreement unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.
●
In addition, the 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 the sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs.

To ensure accurate, complete, and reliable data, Lilly or its representatives will do the 
following:
○
provide instructional material to the study sites, as appropriate.
○
provide training to instruct the investigators and study coordinators. This 
training will give instruction on the protocol, the completion of the eCRFs, 
and study procedures.
○
make periodic visits to the study site.
○
be available for consultation and stay in contact with the study site personnel 
by mail, telephone, or fax.
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 will be used in this study for the collection of eCRF data. The 
investigator maintains a separate source for the data entered by the investigator or designee into 
the sponsor-provided electronic data capture 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 eCRF.
Data collected via the sponsor-provided data capture systems 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 systems. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and electronic transfers will be provided to the investigator 
for review and retention. Data will subsequently be transferred from the central vendor to the 
sponsor data warehouse.
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system.


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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 the CRF or entered in the electronic CRF that are transcribed 
from source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current medical 
records must be available.
10.1.8.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
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:
●
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 of participants by the investigator
●
Discontinuation of further study intervention development
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 ensures
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.


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10.1.10.
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 Patient 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.
The sponsor has a right to retain a portion of submitted biopsy tissue. Archival blocks will be 
returned to the study site. Slides and tissue samples collected on study will not be returned.


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10.2.
Appendix 2: Clinical Laboratory Tests
●
The tests detailed below will be performed by the local laboratory.
●
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.
●
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
●
Pregnancy testing will be conducted as detailed in the SoA (Section 1.3).
Investigators must document their review of each laboratory safety report.


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Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate (total CO2)
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphorus 
Leukocytes (WBC) 
Platelets
Glucose (random)
Creatine kinase
Coagulation
   Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
International normalized ratio (INR)
Differential WBC (absolute counts) of
Blood urea nitrogen (BUN)
Neutrophils
Uric acid 
Lymphocytes
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Alkaline phosphatase (ALP)
Urinalysisa
Aspartate aminotransferase (AST)
Specific gravity
Alanine aminotransferase (ALT)
pH
Creatinine
Protein
Glucose
Ethanol testingb
Ketones
Urine drug screenb
Bilirubin
Hepatitis B surface antigenc
Urobilinogen
Hepatitis C antibodyc, d
Blood
HIVc
Nitrite
Pregnancy test (women of childbearing potential only)
FSH (if applicable)c
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell.
a
Performed by dipstick.
b
Urine drug screen and ethanol (urine or breath) level performed at screening, and may be repeated prior to 
admission to the clinical research unit.
c
Performed at screening only.
d
Participants with a positive hepatitis C antibody test result can have a confirmatory hepatitis C RNA test.


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10.2.1.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol J2G-MC-JZJV Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
45
1
45
Clinical laboratory testsa
12
5
60
Pharmacokinetics - Selpercatinib
2
15
30
Pharmacokinetics - Dabigatran
2
28
56
Blood discard for cannula patency
1
1
1
Genetic sample
10
1
10
Total
202
Total for clinical purposes 
210
a
Additional samples may be drawn if needed for safety purposes.


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., 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 conditions 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 overdose should be reported regardless of sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).


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
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
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
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
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 (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect


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Other situations:

Medical or scientific judgment should be exercised 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.
Recording and Follow-up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are requested 
by the 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 the 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 1 of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. 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.


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An event is defined as ‘serious’ when it meets at least 1 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.

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.

The investigator will use clinical judgment to determine the relationship.

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, for marketed 
products, in his/her 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 the 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 the sponsor 
or designee.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an 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 the 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.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to the sponsor or designee within 
24 hours of receipt of the information.


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10.3.4.
Reporting of SAEs
SAE Reporting via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the medical monitor or the SAE coordinator.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

The investigator or site must alert the Lilly CRP/CP, or its designee, of any SAE as 
soon as practically possible.
Additionally, the investigator or site must alert Lilly Global Patient Safety, or its 
designee, of any SAE within 24 hours of investigator awareness of the event via a 
sponsor-approved method. If alerts are issued via telephone, they are to be immediately 
followed with official notification on study-specific SAE forms. This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE 
information.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Women in the following categories are not considered women of childbearing potential
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy

Documented tubal ligation
For individuals with permanent infertility due to an alternate medical cause other than the 
above (e.g., Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
NOTE: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female is defined as women with:

12 months of amenorrhea for women >55, with no need for follicle-stimulating hormone

12 months of amenorrhea for women >40 years old with follicle-stimulating hormone
≥40 mIU/mL and no other medical condition such as anorexia nervosa and not taking 
medications during the amenorrhea (e.g., oral contraceptives, hormones, gonadotropin 
releasing hormone, anti-estrogens, selective estrogen receptor modulators, or 
chemotherapy that induced amenorrhea)
Contraception Guidance:
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Male participants:

are not required to adhere to contraceptive requirements
Female participants:

Female participants of childbearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) or in a same sex relationship (as part of 


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their preferred and usual lifestyle) must agree to either remain abstinent or stay in a same 
sex relationship without sexual relationships with males. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence 
just for the duration of a study, and withdrawal are not acceptable methods of 
contraception.

Female participants of childbearing potential, who are not abstinent as described above, 
must agree to use a highly effective method of contraception (that is, one with less than 
1% failure rate) such as combination or oral contraceptives, implanted/injected 
contraceptives, intrauterine devices, or sterile partner until 30 days after the last dose of 
study medication. 
o
Female participants not of childbearing potential are not required to use 
contraception. This includes females who are:

Infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy, or tubal ligation) or congenital 
anomaly (for example, Müllerian agenesis)

Postmenopausal, as defined above.
Collection of Pregnancy Information
Male participants with partners who become pregnant
●
The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive study 
intervention.
●
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
partner’s pregnancy. The female partner will also be followed to determine the 
outcome of the pregnancy. Information on the status of the mother and child will 
be forwarded to the sponsor. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy 
will be reported including fetal status (presence or absence of anomalies) and
indication for the procedure. 
Female participants who become pregnant
●
The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 
24 hours of learning of a participant’s pregnancy. 


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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, including fetal status (presence or 
absence of anomalies) or indication for the procedure.
●
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
●
A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at >20 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 
●
Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
●
Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention. If the participant is discontinued from the 
study intervention, follow the standard discontinuation process and continue 
directly to the follow-up phase.


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10.5.
Appendix 5: Genetics
Use/Analysis of DNA
●
Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to 
study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood/saliva sample will 
be collected for DNA analysis from consenting participants.
●
DNA samples will be used for research related to selpercatinib or advanced or 
metastatic RET-mutant MTC/advanced or metastatic RET fusion-positive thyroid 
cancer/metastatic RET fusion-positive NSCLC. They may also be used to develop 
tests/assays including diagnostic tests related to selpercatinib 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 or in a 
separate study summary.
●
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
●
The samples will be retained while research on selpercatinib or study 
interventions of this class or indication continues but no longer than 15 years or 
other period as per local requirements.


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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Hepatic Evaluation Testing – Refer to protocol Hepatic Safety Section 8.2.5.1 for guidance on 
appropriate test selection.

For testing selected, analysis is required to be completed by the Lilly-designated central 
laboratory except for Microbiology.

Local testing may be performed in addition to central testing when required for immediate 
participant management.

Results will be reported if a validated test or calculation is available.
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - Red Blood Cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - White Blood Cells) 
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
    Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
    Lymphocytes
Creatine kinase (CK)
    Monocytes
Other Chemistry  
    Basophils
Acetaminophen
    Eosinophils
Acetaminophen Protein Adducts
Platelets
Alkaline Phosphatase Isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Ethyl Alcohol (EtOH)
Prothrombin Time, INR (PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (Quantitative)
Hepatitis A Virus (HAV) Testing:
Immunoglobulin IgG (Quantitative)
    HAV Total Antibody
Immunoglobulin IgM (Quantitative)
    HAV IgM Antibody
Phosphatidylethanol (PEth)
Hepatis B Virus (HBV) Testing:
Urine Chemistry
    Hepatitis B surface antigen (HBsAg)
Drug Screen
    Hepatitis B surface antibody (Anti-HBs) 
Ethyl glucuronide (EtG)
    Hepatitis B core total antibody (Anti-HBc)
Other Serology
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA)


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


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


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


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
65
Other Chemistry:
   Acetaminophen
   Acetaminophen Protein Adducts
Used to evaluate:  Acetaminophen 
toxicity 
Utilize a Hepatic 
Monitoring central lab 
collection kit
Ethyl Alcohol (EtOH)
Used to evaluate recent alcohol 
consumption
Utilize a Hepatic 
Monitoring central lab 
collection kit
Haptoglobin
Used to evaluate a diagnosis of 
hemolysis
Utilize a Hepatic 
Monitoring central lab 
collection kit
Cardiology consult a
Electrocardiogram
Echocardiogram
Vital Signs:
    Blood pressure
    Pulse
Used to evaluate:  Ischemic or 
congestive hepatic injury
Performed locally.
If findings are clinically 
significant, report as an 
adverse event.
Urine Chemistry:
   Drug screen
Used to evaluate:  Hepatotoxicity due to 
cocaine, opiates and other illicit 
substances 
Utilize a Hepatic 
Monitoring central lab 
collection kit
Hepatitis D Virus (HDV) Testing:
    HDV antibody
Used to evaluate/rule out:  Acute HDV 
infection.
Utilize a Hepatic 
Monitoring central lab 
collection kit and only 
select required test needed.
Microbiology:  
Cultures:
    Blood
    Urine
Used to evaluate/rule out:  
Sepsis or systemic infection
Perform locally.
If findings are clinically 
significant, report as an 
adverse event.
Slit lamp eye examination (Kayser-
Fleisher rings)
Genetic evaluation
Used to evaluate/rule out:  
Wilson’s disease 
Perform locally. 
If findings are clinically 
significant, report as an 
adverse event.
Other Chemistry:
    Ceruloplasmin
    Copper
Used to evaluate/rule out:  
Wilson’s disease 
Utilize a Hepatic 
Monitoring central lab 
collection kit
*This tool is to be used by the investigative site for reference during the evaluation of a participant who met hepatic 
monitoring criteria based on laboratory results and clinical judgment for a suspected liver injury during protocol 
participation. 
a Extent and type of work-up may vary by participant’s history, severity of liver injury, underlying disease, and 
geography.
b Serum AST typically (although not always) is higher than ALT 
c If anti-HCV is positive, HCV RNA is required to confirm HCV infection  
d Acute hepatitis C may be anti-HCV negative but HCV RNA positive
e If anti-HEV IgM is positive, consider confirmation with HEV RNA by nested polymerase chain reaction
f A liver biopsy is needed to confirm a diagnosis of AIH
gIf cholestatic injury, MRCP or ERCP may be recommended 
h Based on medical history and clinical judgment 
i Alcohol consumption in past 3 to 5 days
j Alcohol consumption in past 3 weeks


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
66
10.7.
Appendix 7: Abbreviations
Term
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-∞)
area under the concentration versus time curve from the time of dosing to infinity
CFR
Code of Federal Regulations
CI
confidence interval
Cmax
maximum observed plasma concentration
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
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
CV
coefficient of variation
DDI
drug-drug interaction
ECG
electrocardiogram
enroll
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
67
FDA
Food and Drug Administration
GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form.
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.
IRB
Institutional Review Board
MTC
medullary thyroid cancer
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
P-gp
P-glycoprotein
PK
pharmacokinetics
QTc
corrected QT interval
QTcF
QT interval correct for heart rate using Fridericia’s formula
RNA
ribonucleic acid
SAE
serious adverse event
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. 
SoA
Schedule of Activities
t1/2
terminal half-life
TBL
total bilirubin


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
68
tmax
time to maximum observed plasma concentration
ULN
upper limit of normal


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
69
10.8.
Appendix 8: Protocol Amendment History
Not applicable.


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
70
10.9.
Appendix 9: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment (a): 03 March 2021
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union.
Overall Rationale for the Amendment
To include clarification regarding how the percentage of the standardized meal to be 
consumed by each participant will be calculated.
Section # and 
Name
Description of Change
Brief Rationale
5 Study Population
Clinical laboratory assessments 
and vital signs may be repeated at 
the discretion of the investigator 
in order to confirm eligibility
per request from the PI
5.1 Inclusion Criteria
Bilateral salpingectomy added to 
inclusion #6 
for consistency across the 
protocol
5.2 Exclusion Criteria
ECG exclusion now applicable at 
screening only instead of during 
‘baseline period’
for clarity
5.3.1 Meals and 
Dietary Restrictions
Text amended to outline:

that components of the 
standardized meal will be 
weighed and documented 
in grams both pre- and 
post-meal to determine the 
percentage of the meal 
consumed by the 
participant.
that participants will 
complete the meal 30 
minutes prior to dosing.
for clarity
8.2.3 
Electrocardiograms
ECGs will be interpreted by the 
investigator – not a qualified 
physician or qualified designee
for clarity


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
71
10.2 Appendix 2: 
Clinical Laboratory 
Tests
Partial thromboplastin time 
removed from list of coagulation 
parameters
vendor does not perform PTT 
assay; only aPTT
Table footnote added to state that 
urinalysis will be performed by 
dipstick
for clarity
Appendix 4: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Tubal ligation added to the 
category description of women 
not of childbearing potential
for consistency across the 
protocol
Bilateral salpingectomy added to 
the category description of 
women not required to use 
contraception 
for consistency across the 
protocol


CONFIDENTIAL
Protocol J2G-MC-JZJV (a)
72
11.
References
Boehringer Ingelheim. Pradaxa® (dabigatran etexilate) prescribing information. July 2020; 
Accessed at https://docs.boehringer-
ingelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf on 10 March 2020.
FDA Clinical DDI Draft Guidance: In Vitro Drug Interaction Studies – Cytochrome P450 
Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry, 2020. Accessed 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-drug-
interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions on 
15 July 2020.
Härtter S, Sennewald R, Nehmiz G, Reilly P.  Oral bioavailability of dabigatran etexilate 
(Pradaxa(®)) after co-medication with verapamil in healthy subjects.  Br J Clin Pharmacol. 
2013 Apr; 75(4):1053-62.
International Transporter Consortium, Giacomini KM, Huang SM, et al. Membrane transporters 
in drug development. Nat Rev Drug Discov. 2010;9(3):215-236.
Levey, Andrew S., Lesley A. Stevens, Christopher H. Schmid, Yaping (Lucy) Zhang, Alejandro 
F. Castro, Harold I. Feldman, John W. Kusek, et al. 2009. “A New Equation to Estimate 
Glomerular Filtration Rate.” Annals of Internal Medicine 150 (9): 604.
Loxo Oncology, Inc. Selpercatinib (LOXO-292) – Investigator’s Brochure (Version 7.0)
01 June 2020.
Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin
inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285-295.
Stangier J, Rathgen K, Stähle H, et al. The pharmacokinetics, pharmacodynamics and tolerability 
of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin 
Pharmacol. 2007 Sep;64(3):292-303.


L e o  D o c u m e n t  I D  =  3 4 7 8 5 e 4 9 - 6 7 a 1 - 4 6 f 8 - 8 e a a - b 1 8 b b d 6 5 9 f 3 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 :  0 4 - M a r - 2 0 2 1  1 7 : 2 6 : 4 9  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 :  0 5 - M a r - 2 0 2 1  1 4 : 3 2 : 3 9  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: 
J2G-MC-JZJV Statistical Analysis Plan 
 
An Open-Label Study to Investigate the Effect of Selpercatinib on the Pharmacokinetics of 
Dabigatran in Healthy Volunteers 
 
 
NCT04782076 
 
 
Approval Date: 23-Feb-2021 
 
 


Fi nal, 2 3 Fe br uar y 2 0 2 1
             Pa ge 1 of 1 6
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 St u d y t o I n vesti g ate t he Effect of Sel perc ati ni b o n t he P h ar m ac o ki netics of 
D a bi g atr a n i n He alt h y V ol u nteers
Stati stical A nal ysis Pla n Stat us : Fi nal
Stati stical A nal ysis Pla n Date : 2 3 Fe br uar y 2 0 2 1
St u d y  Dr u g: L Y 3 5 2 7 7 2 3
S p o ns or Refere nce : J 2 G-M C -J ZJ V
C o va nce C R U St u d y : 1 0 0 0 0 7 1- 8 4 4 5 3 2 8
Cli nical P hase I
A p pr o v al D at e: 2 3- F e b- 2 0 2 1 G M T


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV
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 ..................................................... 12
9.4
Safety and Tolerability Assessments...................................................................... 12
9.4.1
Adverse events ............................................................................................. 12
9.4.2
Concomitant medication............................................................................... 13
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
Other assessments......................................................................................... 15
9.4.8
Safety and Tolerability Statistical Methodology............................................ 15
10. INTERIM ANALYSES ............................................................................................... 15
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 15
12. REFERENCES ............................................................................................................ 15
13. DATA PRESENTATION ............................................................................................ 15
13.1 Derived Parameters ............................................................................................... 15
13.2 Missing Data ......................................................................................................... 16
13.3 Insufficient Data for Presentation .......................................................................... 16


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Statistical Analysis Plan 
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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
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
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
Cmax
Maximum observed drug concentration
CRU
Clinical Research Unit
CSR
Clinical Study Report
DDI
Drug-drug interaction
ECG
Electrocardiogram
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
P-gp
P-glycoprotein
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
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV
ULN
Upper limit of normal
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after extra-
vascular administration
WHO
World Health Organization


Final, 23 February 2021
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
21 December 2020).
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 evaluate the effect of selpercatinib on 
P-glycoprotein (P-gp) activity in healthy 
participants.

Maximum observed drug concentration 
(Cmax) and area under the concentration 
versus time curve from time zero to 
infinity (AUC[0-∞]) of dabigatran to 
assess P-gp activity.
Secondary

To evaluate the safety and tolerability of 
dabigatran in combination with 
selpercatinib in healthy participants.

Summary of the number of 
treatment-emergent adverse events 
(TEAEs) and serious adverse events
(SAEs).

To evaluate the PK of selpercatinib.

Cmax, AUC(0-∞), and time of maximum 
observed drug concentration (tmax) of 
selpercatinib.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV
5. STUDY DESIGN
This is a Phase 1, fixed-sequence, open-label study in healthy participants that will study 
dabigatran P-gp drug-drug interaction (DDI) with selpercatinib. The anticipated study duration 
for each individual participant is approximately 8 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 and remain resident in the CRU until discharge on 
Day 11. All participants will receive a single dose of 150 mg dabigatran on Day 1 and a single 
dose of 150 mg dabigatran coadministered with a single dose of 160 mg selpercatinib on Day 8. 
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 (ECGs), and adverse event (AE)
recording, will be performed.
Follow-up
Participants will return to the CRU for a safety follow-up visit within 14 to 17 days after the final 
dose.
The study schema is shown in Figure 1.
Figure 1: J2G-MC-JZJV Study Schema
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs. In AE 
outputs, treatment labels will also contain “(Day X)” information.


Fi nal, 2 3 Fe br uar y 2 0 2 1
             Pa ge 7 of 1 6
Stati stical A nal ysis Pl a n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 4 4 5 3 2 8
S p o ns or Refere nce J 2 G-M C -J ZJ V
D a y
St u d y Tre at me n t N a me
Tre at me nt or der i n T F L
1
1 5 0 m g da bi gatra n 
1
8
1 5 0 m g da bi gatra n + 1 6 0 m g sel percati ni b 
2
7. S A M P L E SI Z E J U S TI FI C A TI O N
A p pr o xi matel y  
 will be e nr olle d s o t hat a p pr o xi matel y 
 c o m plete
t he st u d y. T o e valuate t he effect of  selpercati ni b o n P -g p acti vit y,  it is i m p orta nt t hat t he rati o of
ge o m etric mea ns is est i mate d wit h reas o na ble precisi on. 
 
 
8.
D E FI NI TI O N O F A N A L Y SI S P O P U L A TI O N S
T he “ E ntere d” p o p ulati o n will c o nsist of all part ici pa nts w h o si g ne d t he i nf or me d c o nse nt f or m.
T he “ E nr olle d/I nte nt -t o-Treat” p o p ulat i on will c o nsist of all partici pa nts assi g ne d t o treat me nt, 
re gar dless of w het her t he y ta ke a n y d oses of st u d y i nter ve nti on , or if t he y ta ke t he c orrect 
treat me nt.
T he “ Safet y” p o p ulat i on will c o nsist of all p arti ci pa nts assi g ne d t o da bi gatra n , a n d w h o ta ke at 
least o ne d ose of  st u d y int er ve ntio n .
T he “ P har mac o ki net ic A nal ysis ” p o p ulatio n will  c o nsist of all partici pa nts w h o recei ve d at least 
o ne d ose of da bi gatra n a n d ha ve e val ua ble P K  data . Parti cipa nt s ma y be e xcl u de d fr o m t he P K 
s u m mar y statistics a n d statistical a nal ysis if a partici pa nt has a n A E of  v omit i n g t hat occ urs at or 
bef ore 2 ti mes me dia n t ma x , or 2 ti mes i n di vi d ual tm a x if i n di vi d ual tma x is ac hie ve d. 
All pr ot oc ol de viat i ons t hat occ ur d uri n g t he st u d y will be c o nsi dere d f or t heir se verit y/ i m pact 
a n d will be ta ke n i nt o c o nsi derat i on w he n parti ci pa nts are assi g ne d t o a nal ysis p o p ulat i ons.
9. S T A TI S TI C A L M E T H O D O L O G Y
9. 1
Ge ner al
Data list i n gs will be pr o vi de d f or all d ata t hat are data base d . S u m mar y  statistics a n d statistical 
a nal ysis will o nl y be prese nte d f or data w here detaile d i n t his S A P . F or c o nti n u o us data, 
s u m mar y statistics will i ncl u de t he arit h met ic mea n, arit h metic sta n dar d de viat i on ( S D), m e dia n, 
m i ni m u m, ma xi m u m a n d N; f or l o g -n or m al data (e. g. t he P K para meters: A U Cs a n d C ma x) t he 
ge o m etric mea n a n d ge o metric c oefficie nt of variati o n will als o be prese nte d . F or cate g orical 
data, fre q ue nc y c o u nt a n d perce nta ges will be prese nte d . Data list i n gs will be pr o vi de d f or all 
parti ci pa nts u p t o t he p oi nt of wit h dra wal, wit h a n y p arti ci pa nts e xclu d e d f r o m t he rele va nt 
C CI
C CI
C CI
C CI


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Covance Clinical Study No. 1000071-8445328
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population highlighted. Summary statistics and statistical analyses will generally only be 
performed for participants included in the relevant analysis population. For the calculation of 
summary statistics and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual participants’ change from baseline 
values. Each individual change from baseline will be calculated by subtracting the individual 
participant’s baseline value from the value at the timepoint. The individual participant’s change 
from baseline values will be used to calculate the mean change from baseline using a SAS 
procedure such as Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Participant Disposition
Participant disposition will be 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 dabigatran and selpercatinib will be used to 
determine the following PK parameters, when possible: 
Parameter
Units
Definition
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-∞)
ng.h/mL
area under the concentration versus time curve from time zero to 
infinity
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration
Additional PK parameters may be calculated, as appropriate. 
The software and version used for the final analyses will be specified in the CSR. Any 
exceptions or special handling of data will be clearly documented within the CSR.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV
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.

The Cmax and tmax will be reported from observed values. If Cmax occurs at more than 
one timepoint, tmax will be assigned to the first occurrence of Cmax. 

The 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, 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 predicted last quantifiable drug concentration 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.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV

All other BQL concentrations that do not meet the above criteria will be set to missing.

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
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.


Final, 23 February 2021
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during multiple dosing, the concentration of the pre-dose sample exceeds 
all measured concentrations for that individual in the subsequent post-dose samples.

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles
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.


Fi nal, 2 3 Fe br uar y 2 0 2 1
             Pa ge 1 2 of 1 6
Stati stical A nal ysis Pl a n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 4 4 5 3 2 8
S p o ns or Refere nce J 2 G-M C -J ZJ V
9. 3. 2
P h ar m ac o ki netic St atistic al Met h o d ol o g y
 
 
 
 
 
 
 
 
P K para meters will be 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 case re p ort f or m, eac h se parate se verity of  t he A E 
will be re p orte d i n t he list i 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 i n g c o n diti on is defi ne d as a n A E 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 ns e 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 . All T E A Es will be s u m marize d b y treat me nt, se verit y a n d relat i ons hi p t o 
t he i n vesti gati onal pr o d uct . 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 nts 
e x perie nci n g a n A E a n d t he perce nta ge of parti ci pa nts e x perie nci n g a n A E ) of T E A Es will be 
C CI
C CI
C CI
C CI


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV
summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA) version 23.1 
system organ class and preferred term. The summary and frequency AE tables will be presented 
for all causalities and those considered related to the investigational product by the investigator. 
Any SAEs will be listed, including investigational-product related SAEs. 
Discontinuations due to AEs will be listed.
9.4.2
Concomitant medication
Concomitant medication will be coded using the World Health Organization (WHO) drug 
dictionary (Version WHODDSEP20B3), and listed.
9.4.3
Clinical laboratory parameters
Liver enzyme tests data (ALP, AST, ALT) will be summarized. All clinical chemistry, 
hematology, and 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. Baseline 
is defined as Day 1 predose for the first dose, and Day 7 predose for the second dose. Figures of 
mean vital signs and mean changes from baseline profiles will be presented by treatment, for the 
first 24 hours after dosing in each treatment period. 
Values for individual participants 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
Close hepatic monitoring
If a participant who had normal or near normal baseline alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBL) (i.e., <1.5× 
upper limit of normal [ULN]), experiences elevated ALT≥3× ULN, AST≥3× ULN, ALP≥2× 
ULN, or TBL≥2× ULN, laboratory tests should be repeated within 48 to 72 hours, including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyltransferase, and creatinine kinase to 
confirm the abnormality and to determine if it is increasing or decreasing.
In participants enrolled with elevated baseline ALT, AST, ALP or TBL (≥1.5× ULN), the 
thresholds for close monitoring are ALT≥2× baseline, AST≥2× baseline, ALP≥2× baseline, or 
TBL≥2× baseline.


Final, 23 February 2021
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV
At a minimum, this evaluation should include physical examination and a thorough medical 
history, including symptoms, recent illnesses, (for example, heart failure, systemic infection, 
hypotension, or seizures), recent travel, history of concomitant medications (including over-the-
counter), herbal and dietary supplements, history of alcohol drinking and other substance abuse.
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.
Comprehensive hepatic evaluation
If a study participant, who had baseline ALT, AST, ALP, TBL<1.5× ULN, experiences elevated 
ALT≥5× ULN, AST≥5× ULN, ALP ≥3× ULN, TBL ≥2× ULN, or elevated ALT, AST ≥3× ULN 
with hepatic signs/symptoms (severe fatigue, nausea, vomiting, right upper quadrant abdominal 
pain, fever, rash, and/or eosinophilia>5%), a comprehensive evaluation should be performed to 
search for possible causes of liver injury.
In participants who had elevated baseline ALT, AST, ALP, or TBL (≥1.5× ULN), the thresholds 
for performing this evaluation are ALT≥3× baseline, AST≥3× baseline, ALP≥2× baseline, 
TBL≥1.5× baseline, or ALT, AST ≥2× baseline with hepatic signs/symptoms.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time-international normalized ratio, 
viral hepatitis A, B, C, E, tests for autoimmune hepatitis, and an abdominal imaging study (for 
example, ultrasound or computed tomography scan).
Additional hepatic data collection in participants who have abnormal liver tests during the 
study
Additional hepatic safety data collection should be performed in participants who meet 1 or more 
of the following 5 conditions:
1. Elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests (if baseline 
ALT<1.5x ULN)
In participants with baseline ALT≥1.5× ULN, the threshold is ALT≥3x baseline 
on 2 or more consecutive tests
2. Elevation of TBL to ≥2× ULN (if baseline TBL <1.5× ULN)
In participants with baseline TBL ≥1.5× ULN, the threshold should be TBL ≥2x 
baseline
3. Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5× ULN)
In participants with baseline ALP≥1.5× ULN, the threshold is ALP ≥2× baseline 
on 2 or more consecutive blood tests
4. Hepatic event considered to be an SAE


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV
5. Discontinuation of the investigational product due to a hepatic event.
Where applicable, the following will be presented. The participants’ liver disease history and 
associated person liver disease history data will be listed. Any concomitant medications that have 
potential for hepatotoxicity, including acetaminophen will be listed. Results from any hepatic 
monitoring procedures, such as a magnetic resonance elastography scan, and biopsy assessments 
will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual participant data listings.
9.4.7
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.8
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 


Final, 23 February 2021
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8445328
Sponsor Reference J2G-MC-JZJV
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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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 3 - F e b - 2 0 2 1  1 3 : 4 6 : 0 4  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 3 - F e b - 2 0 2 1  1 3 : 4 9 : 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 3 - F e b - 2 0 2 1  1 5 : 2 1 : 3 5  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 3 - F e b - 2 0 2 1  1 5 : 3 0 : 3 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
P P D
P P D
P P D
P P D