Clinical trial NCT05203822
Conditions: Healthy
Keywords: Clinical pharmacology Metabolite Induction of metabolism
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Start date: 2022-01-21; Completion date: 2022-07-05
Enrollment: 18 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study was to assess the effect of multiple doses of itraconazole on single dose tepotinib pharmacokinetics in healthy participants. Study details include:

Study Duration: up to 48 days Treatment Duration: single dose of tepotinib on Days 1 and 12, 11 days of treatment with itraconazole (Days 8 to 18) Visit Frequency: residence in the Clinical Research Unit from Days -1 to 4 and Days 11 to 15, ambulatory daily visits from Days 5 to 10 and 16 to 20

Detailed description:

Arms: arm 1: Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day and Day 12 under fed condition followed by single oral dose of itraconazole 200 mg on Days 8 to 11 and Days 13 to 18. On Day 12, participants received a single dose of 200 mg itraconazole simultaneously with a single dose of 500 mg Tepotinib.
Interventions: intervention 1: Tepotinib (HydroChloride hydrate) intervention 2: Itraconazole
Intervention descriptions: intervention 1: Participants received Tepotinib (Hydrochloride hydrate) Film-coated tablet with food on Day 1 and 12 in the morning. intervention 2: Participants received Itraconazole Hard-gelatin capsule with food once daily at the same time in the morning from Day 8 to Day 18; on Day 12 itraconazole is administered concomitantly with tepotinib.

Protocol documents:
Prot_000.pdf: 
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Cli nic al St u d y  Pr ot oc ol  
Title P a ge  
Cli nic al St u d y Pr ot oc ol Title:   
P hase I, O pe n -la bel, Si n gle-s e q ue n ce, Cr oss-o v er 
St u d y of t he 
Effect of 
M ulti ple 
D oses 
of 
Itrac o n az ole   
o n   
Si n gle-d ose  
Te p oti ni b 
P har mac o ki netics i n Healt h y Partici pa nts  
St u d y N u m ber:  
M S 2 0 0 0 9 5 0 0 5 3  
Pr ot oc ol V ersi o n:  
1 5  Se pte m ber  2 0 2 1  / V 1. 0  
Merc k C o m p o u n d : 
Te p oti ni b  
St u d y P h ase:  
P hase I  
S h ort Title:  
Te p oti ni b 
D r u g-D r u g Interacti o n S t u d y W it h 
Itrac o n az ole i n H ealt h y P artici pa nts  
Pri nci p al I n vesti g at or:  
 
 
 
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:  
S p o ns or:  
Affiliates of Merc k K Ga A, Dar msta dt, Ger ma n y  
F or all c o u ntri es, e x ce pt t he U S a n d Ca na d a:  
Merc k Healt hcare K Ga A, Dar msta dt, Ger ma n y  
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y  
Fra n kf urter Str. 2 5 0  
6 4 2 9 3 Dar msta dt, Ger ma n y  
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:  
E u dra C T: 2 0 2 1 -0 0 3 5 1 3 -1 9  
Ke y w or ds : 
Cli nical p har mac ol o g y, meta b olite, i n hi biti o n of 
meta b olis m  
–  C o nfi d e nti al –  
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A, D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot –  i n f ull or p art –  b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M er c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 0 2 1  b y M er c k K G a A, 
D ar m st a dt, G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d.  
 
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T a ble of C o nte nts  
Title Pa ge   
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Ta ble of C o nte nts   ..............................................................................................................2  
Ta ble of Ta bl es   
 ..............................................................................................................5  
1  
Pr ot oc ol S u m mar y  ................................................................................6  
1. 1  
S y n o psis  ................................................................................................6  
1. 2  
Sc he ma  ..................................................................................................7  
1. 3  
Sc he d ule of Acti viti es ...........................................................................8  
2  
I ntr o d u cti o n .........................................................................................1 0  
 
 
2. 2  
Bac k gr o u n d  .........................................................................................1 0  
2. 3  
Be nefit/ Ris k Assess me nt  ....................................................................1 2  
2. 3. 1  
Ris k Assess me nt  .................................................................................1 2  
2. 3. 1. 1  
P ote ntial Ris ks ass ociate d wit h t he C O VI D -1 9 Pa n de mic 
Sit uati o n  ..............................................................................................1 4  
2. 3. 2  
Be nefit Assess me nt  .............................................................................1 5  
2. 3. 3  
O verall Be nefit: Ris k C o ncl usi o n  .......................................................1 6  
3  
O bjecti ves a n d E n d p oi nts  ...................................................................1 6  
4  
St u d y Desi g n  .......................................................................................1 7  
4. 1  
O verall Desi g n  ....................................................................................1 7  
 
 
4. 3  
J ustificati o n f or D ose ..........................................................................1 8  
4. 4  
E n d of St u d y Defi niti o n  ......................................................................1 9  
5  
St u d y P o p ulati o n  .................................................................................2 0  
5. 1  
I n cl usi o n Criteria ................................................................................2 0  
5. 2  
E x cl us i o n Criteria ...............................................................................2 2  
5. 3  
Lif est yle C o nsi derati o ns  .....................................................................2 5  
5. 3. 1  
Meals a n d Dietar y Restri cti o ns  ...........................................................2 5  
5. 3. 2  
Caffei ne, Al c o h ol, T o bacc o, a n d Ca n na bi n oi d  ...................................2 6  
5. 3. 3  
Acti vit y  ...............................................................................................2 6  
5. 4  
Scree n Fail ures  ....................................................................................2 6  
5. 5  
Criteria f or T e m p oraril y Dela yi n g t he A d mi nistrati o n of St u d y 
I nter ve nti o n .........................................................................................2 6  
6  
St u d y I nter v e nti o n(s) a n d C o nc o mita nt T hera pies  .............................2 6  
6. 1  
St u d y I nter v e nti o n(s) A d mi nistrati o n  .................................................2 7  
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6. 2  
St u d y I nter v e nti o n(s) Pre parati o n, Ha n dli n g,   
 a n d 
Acc o u nta bi lit y .....................................................................................2 7  
6. 3  
Meas ures t o Mi ni mize Bias: St u d y I nter v e nti o n Assi g n me nt 
a n d Bli n di n g  ........................................................................................2 8  
6. 3. 1  
St u d y I nter v e nti o n Assi g n me nt  ..........................................................2 8  
6. 3. 2  
Bli n di n g  ..............................................................................................2 8  
6. 3. 3  
E mer ge nc y U n bli n di n g  .......................................................................2 8  
6. 4  
St u d y I nter v e nti o n C o m plia nce  ..........................................................2 9  
6. 5  
D ose M o dificati o n  ..............................................................................2 9  
6. 6  
C o nti n ue d Access t o St u d y I nter ve nti o n after t he E n d of t he 
St u d y  ...................................................................................................2 9  
6. 7  
Treat me nt of O v er d ose  .......................................................................2 9  
6. 8  
C o nc o mita nt T hera p y  .........................................................................2 9  
6. 8. 1  
Resc ue Me dici ne  .................................................................................2 9  
6. 8. 2  
Per mit te d Me dici nes ...........................................................................3 0  
6. 8. 3  
Pr o hi bite d Me dici nes  ..........................................................................3 0  
6. 8. 4  
Ot her I nter v e nti o ns  .............................................................................3 0  
7  
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici p a nt 
Disc o nti n uati o n/ Wit h dra wal  ...............................................................3 0  
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................3 0  
7. 2  
Partici pa nt Disc o nti n uati o n/ Wit h dr a wal fr o m t he St u d y ...................3 1  
7. 3  
L ost t o F oll o w -U p ...............................................................................3 2  
8  
St u d y Assess me nts a n d Pr oce d ures  ....................................................3 2  
8. 1  
Efficac y Assess me nts a n d Pr oce d ures  ................................................3 3  
8. 2  
Safet y Assess me nts a n d Pr oce d ures  ...................................................3 3  
8. 2. 1  
P h ysical E x a mi nati o ns  ........................................................................3 3  
8. 2. 2  
Vital Si g ns  ..........................................................................................3 4  
8. 2. 3  
Electr ocar di o gra ms  .............................................................................3 4  
8. 2. 4  
Cli nical Safet y La b orat or y Assess me nts  ............................................3 4  
8. 2. 5  
S uici dal I deati o n a n d Be ha vi or Ris k M o nit ori n g  ...............................3 4  
8. 3  
A d verse E v e nts, Seri o us A d verse E ve nts, a n d Ot h er Safet y 
Re p orti n g  ............................................................................................3 4  
8. 3. 1  
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts  .................................................................................................3 5  
8. 3. 2  
F oll o w -u p of A d ver se E ve nts a n d Seri o us A d verse E ve nts ...............3 5  
8. 3. 3  
Re g ulat or y Re p orti n g Re q uire me nts f or Seri o us A d verse 
E ve nts  .................................................................................................3 6  
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8. 3. 4  
Pre g n a nc y  ...........................................................................................3 6  
8. 3. 5  
Car di o vasc ular a n d Deat h E ve nts  .......................................................3 7  
8. 3. 6  
Disease -Rel ate d E ve nts a n d/ or Disease -R elate d O utc o mes N ot 
Q ualif yi n g as A Es or S A Es  ................................................................3 7  
8. 3. 7  
A d verse E v e nts of S peci al I nt erest  .....................................................3 7  
8. 4  
P har mac o ki netics  ................................................................................3 8  
 
 
 
 
8. 7  
I m m u n o ge nicit y Assess me nts ............................................................4 0  
9  
Statistical C o nsi derati o ns  ....................................................................4 0  
9. 1  
Statistical H y p ot heses  .........................................................................4 0  
9. 2  
Sa m ple Size Deter mi nati o n  ................................................................4 0  
9. 3  
A nal ys es Sets  ......................................................................................4 2  
9. 4  
Statistical A nal yses  .............................................................................4 3  
9. 4. 1  
Ef ficac y A nal yses ...............................................................................4 3  
9. 4. 2  
Safet y A nal yses  ..................................................................................4 4  
9. 4. 3  
Ot her A nal yses  ....................................................................................4 4  
9. 4. 4  
Se q ue nce of A nal yses  .........................................................................4 5  
1 0  
Ref ere n ces  ...........................................................................................4 6  
1 1  
A p pe n dices  .........................................................................................4 8  
A p pe n di x 1  
A b bre viati o ns  ......................................................................................4 9  
A p pe n di x 2  
St u d y G o ver na nce  ...............................................................................5 2  
A p pe n di x 3  
C o ntrace pti o n a n d Barrier Re q uire me nts  ...........................................5 7  
A p pe n di x 4  
A d verse E v e nts: Defi niti o ns a n d Pr oce d ures f or R ec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g  ................................................5 9  
A p pe n di x 5  
Cli nical La b orat or y Tests  ...................................................................6 5  
 
 
A p pe n di x 7  
S p o ns or Si g nat ure Pa ge  ......................................................................6 7  
A p pe n di x 8  
Pri nci pal I n v esti gat or Si g nat ure Pa ge  .................................................6 8  
 
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T a ble of T a bles  
Ta ble 1  
Te p oti ni b a n d Meta b olite P K Sa m pli n g Sc he ma  ..................................9  
Ta ble 2  
P K Sa m pli n g Ti me Wi n d o ws  .............................................................3 9  
Ta ble 3  
O ver vie w of O bser ve d I ntra partici pa nt Varia bilit y of 
Te p oti ni b P har mac o ki netic Para meters  ..............................................4 1  
Ta ble 4  
Wi dt h of t he 9 0 % CI f or t he Rati o of P har mac o ki netic 
Para meters, f or Differe nt Ge o metric Mea n Rati os, Sa m ple 
Sizes, a n d Wit hi n -Partici pa nt C Vs  .....................................................4 2  
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Brief S u m m a r y:  
T he p ur p ose of t his st u d y is t o  assess t he effect of m ulti ple d oses of itrac o n az ole o n si n gle -d ose 
te p oti ni b p har mac o ki neti cs i n healt h y p artici pa nts. St u d y d etails i ncl u de: 
•  
St u d y D urati o n: u p t o 4 8 da ys  
•  
Treat me nt D urati o n: si n gle d ose of te p oti ni b o n D a ys 1 a n d 1 2, 1 1 da ys of treat me nt  wit h 
itrac o naz ole ( Da ys 8 t o 1 8) 
•  
Visit Fre q ue n c y: resi de n ce i n t he Cli nical Researc h U nit fr o m Da ys  -1 t o 4 a n d Da ys  1 1 
t o 1 5, a m b ulat or y d ail y visits fr o m Da ys 5 t o 1 0 a n d 1 6 t o 2 0  
N u m ber of P artici p a nts: 
A 
ma xi m u m of 1 8 partici pa nts 
will be assi g ne d t o 
st u d y 
i nter ve nti o ns s uc h t hat at least 1 4 e val ua ble p artici pa nts c o m plete t he st u d y.  
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: 2 1  da ys of i nter ve nti o n peri o d i ncl u di n g Safet y 
F oll o w  U p o n Da y  2 0; si n gle d ose of te p oti ni b o n Da ys  1 a n d 1 2, 1 1  da ys of treat me n t wit h 
itrac o naz ole ( Da ys 8 t o 1 8) . 
I n v ol ve me nt of S peci al C o m mittee(s): N o  
1. 2   
Sc he m a  
 
 
 
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2  
I ntr o d ucti o n 
Te p oti ni b ( Te p met k o ®) is a hi g hl y s electi ve, re versi ble A T P -c o m petiti ve i n hi bit or of t he 
rece pt or t yr osi ne ki nas e M E T i n cli nical de vel o p me nt f or t he treat me nt of patie nts wit h e. g. , 
a d va nce d N S C L C wit h M E T e x 1 4 s ki p pi n g alterati o ns or M E T  a m plificati o n.  
Detaile d i nf or m ati o n o n t he c he mistr y, p h ar mac ol o g y, efficac y, a n d safet y of  te p oti ni b is i n t he 
I B (c urre nt versi o n). 
T here is e xte nsi ve cli nical e x perie nce i n t he use of itrac o naz ole. It was a p pr o ve d i n t he U nite d 
States i n 1 9 9 2 ( w w w. access data.f da. g o v) a n d is 
wi del y use d as a ntif u n gal a ge nt. F ull 
i nf or mati o n a b o ut t he p ote ntial si de effects of itrac o naz ole a d mi nistrati o n is descri be d i n its 
c urre ntl y a p pr o ve d S m P C a n d U S PI ( refer t o Itrac o naz ole S m P C a n d U S PI ). 
 
 
 
  
 
 
 
 
  
 
 
 
2. 2   
B ac k gr o u n d  
Te p oti ni b  
M E T, al o n g wit h its li ga n d, t he H G F ha v e bee n i m plicate d i n carci n o ge nesis a n d metastatic 
t u m or pr o gressi o n, beca use of t heir a bilit y t o e n ha nce a n gi o ge n esis, ca n cer cell pr oliferati on, 
mi grati o n a n d i n vasi o n, as 
well as c o nferri n g resista nce t o a p o pt osis. P har mac ol o gical 
i nterfere nce wit h t he H G F/ M E T a xis is c o nsi dere d a pr o misi n g str ate g y t o i n hi bit pri mar y t u m or 
gr o wt h a n d metastasis i n patie nt s wit h e. g. , N S C L C ( refer t o c urre nt tep oti ni b I B a n d U S PI ). 
Te p oti ni b   
   
 
 at 
5 0 0  m g, e x hi bi te d s u bsta ntial a n d s ustai ne d cli nical acti vit y i n partici pa nts wit h a d va nce d 
N S C L C har b ori n g M E T e x 1 4  s ki p pi n g alterati o ns acr oss t he e n d p oi nts st u die d i n t he P hase II 
VI SI O N st u d y ( M S 2 0 0 0 9 5 _ 0 0 2 2). T he efficac y a n al yses pr o vi de d str o n g e vi de nce of a cli nic all y 
mea ni n gf ul res p o nse rate, dee p a n d d ura ble res p o nses, a n d ra pi d o ns et of res p o nses. Pr o gressi o n 
free sur vi val a n d o v erall sur vi val a nal yses pr o vi de d a d diti o nal s u p p orti ve e vi de nce of te p oti ni b’s 
cli nical acti vit y. T e p oti ni b was well t olerat e d i n healt h y p artici pa nts a n d p atie nts.  
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T hese data ha v e rece ntl y le d t o mar keti n g a ut h ori zati o ns  i n se veral ge o gra p hies i ncl u di n g t he 
c o n diti o nal a p pr o val b y t he U S F D A f or treat me nt of patie nts wit h a d va nce d N S C L C har b ori n g 
M E Te x 1 4 s ki p pi n g alterati o ns ( refer t o curre nt t e p oti ni b I B a n d U S PI ). 
Te p oti ni b is classifie d as a 
 
 
 
 
 
 
 
 
 
 
 
  
   
   
   
   
   
 
   
 
 
   
 
 
   
 
 
 
 
 
 
 
  
Itr ac o n az ole 
Itr ac o n az ole is a n a ntif u n gal dr u g w hic h is a p ot e nt i n hi bit or of dr u g-meta b olizi n g e nz y mes a n d 
tra ns p orters. E nz y mes a n d tra ns p orters re p orte d t o be affecte d b y itrac o naz ole i ncl u de C Y P 3 A 4 
a n d P -g p. Se v eral dr u gs are s u bstrates f or C Y P 3 A 4 or P -g p, a n d t hese pat h wa ys are i n hi bite d b y 
itrac o naz ole si m ulta ne o usl y. T heref ore, itrac o naz ole ma y sl o w d o w n t he meta b olis m a n d re d uce 
t he acti vit y of certai n c o a d mi nistere d dr u gs a n d has t he p ote ntial t o ca use cli nicall y i m p orta nt 
dr u g -dr u g i nteracti o ns ( refer t o Itrac o n az ole S m P C a n d U S PI ). 
Itr ac o n az ole is classifie d as a B C S Class II c o m p o u n d acc or di n g t o t he F D A B C S g ui da nce. It is 
rea dil y a bs or be d fr o m t he gastr oi ntesti nal tract. Pea k plas m a c o n ce ntrati o ns of itrac o naz ole are 
reac h e d wit hi n 2 t o 5 h o urs f oll o wi n g a n oral ca ps ule d ose. T he o bser ve d a bs ol ute oral 
bi oa vaila bilit y of itrac o n az ole is a b o ut 5 5 %. T he oral bi oa vaila bilit y of itrac o naz ole is ma xi mal 
w he n itrac o naz ole ca ps ules are ta ke n i m me diat el y after a f ull meal ( Bar o ne 1 9 9 3  a nd 1 9 9 8 ). 
M ost of t he itrac o naz ole i n plas ma is b o u n d t o pr otei n ( 9 9. 8 %), wit h al b u mi n bei n g t he mai n 
bi n di n g c o m p o ne nt. O nl y 0. 2 % of t he itrac o naz ole i n plas ma is prese nt as free dr u g. Itrac o n az ole 
is distri b ute d i n a lar ge a p pare nt v ol u me i n t he b o d y ( >  7 0 0 L), s u g gesti n g e xte nsi ve distri b uti o n 
i nt o tiss ues. Itr ac o naz ol e is e xte nsi vel y m eta b olize d b y t he li ver i nt o a lar ge n u m ber of 
meta b olites. T he mai n m eta b olite is h y dr o x y -itrac o naz ole, w hic h has i n vitr o a ntif u n gal acti vit y 
c o m para ble t o itrac o n az ole ( refer t o Itrac o naz ole S m P C a n d U S PI ) a n d is als o k n o w n t o i n hi bit 
C Y P 3 A 4 ( Is o h erra ne n 2 0 0 4 ) a n d P-g p  (Le m p ers  2 0 1 6 ). Eli mi nati o n half-life of itrac o n az ole i n 
healt h y partici pa nts is i n t he ra n ge of ~ 6  ±  5  h o urs ( Lest ner  a n d H o pe 2 0 1 3 , He y k a nts  1 9 8 9 ). 
F oll o wi n g m ulti ple -d ose a d mi nistrati o n, a 2 6 %  t o 6 0 % i ncrease i n t he eli mi nati o n half-life of 
itrac o naz ole a n d a ti me-de pe n de nt re d ucti o n ( 6 9 %  t o 8 0 %) i n oral cleara nce ( C L/ F) h as bee n 
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o bser ve d  (T e m p let o n 2 0 0 8 , Haria  1 9 9 6 , Har di n  1 9 8 8 , He y ka nts  1 9 8 9 ). Itrac o naz ole is e x crete d 
mai nl y as i na cti ve meta b olites i n uri ne a n d i n feces ( refer t o Itrac o naz ole S m P C a n d U S PI ). 
2. 3   
Be nefit/ Ris k Assess me nt  
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d A Es  of  te p oti ni b ma y b e f o u n d  i n Secti o n 4. 2 , t he I B, a n d t he U S PI . 
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d A E s of itrac o naz ole ma y be f o u n d i n its S m P C a n d U S PI. 
Base d o n t he a vaila ble  n o ncli nical a n d cli nical data t o date, t he c o n d uct of t he st u d y, as s pecifie d 
i n t his pr ot oc ol, is c o nsi dere d j ustifia ble. 
2. 3. 1   
Ris k Assess me nt  
Base d o n t he c urre ntl y a vaila ble n o ncli nical as well as cli nical safet y data f or te p oti ni b, a n d t he 
lac k of ge n ot o xicit y i n n o ncli nical st u dies, t here is n o o bjecti o n a gai nst a d mi nistrati o n of si n gle 
d oses or s h ort -ter m m ulti ple a d mi nistrati o ns t o healt h y p artici pa nts. T he partici pa nts will be 
u n der cl ose m o nit ori n g f or e. g. , p ote ntial A Es, safet y la b orat or y p ara m eters, E C G, a n d vital si g ns 
i n t he cli nical researc h u nit t o re d uce t he ris k f or a n y u nt o w ar d effects of t e p oti ni b.  
E x p os ure t o te p oti ni b at differe nt d os e le vels i ncl u di n g 5 0 0  m g te p oti ni b H Cl h y drat e were well 
t olerate d b y healt h y p artici pa nts (refer t o c urre nt te p oti ni b I B). C u m ulati vel y, 7 0 2  patie nts a n d 
2 2 5  healt h y partici pa nts a n d partici pa nts wit h he patic i m pair me nt  were e x p ose d t o te p oti ni b 
( 5 0 0 m g i n t he maj orit y of st u dies i n healt h y partici pa nts a n d 3 0  m g a n d 1 0 0  m g eac h i n 1  st u d y) 
i n i nter ve nti o nal cli nical st u dies s p o ns ore d b y M erc k or a n y affiliate ( D S U R N o. 9, re p orti n g 
peri o d 2 5  Se p te m ber 2 0 2 0 t o 2 4  Mar c h 2 0 2 1 , data l oc k p oi nt 2 4 Marc h  2 0 2 1).  
N o ma xi m u m t olerate d d ose c o ul d be defi ne d i n t he first-i n-ma n st u d y  E M R 2 0 0 0 9 5 _ 0 0 1, usi n g 
u p t o 1, 4 0 0  m g o nce d ail y a d mi nistere d i n 2 1 -da y c ycles ( refer t o c urre nt te p oti ni b I B).  
N o si n gle i de ntifie d meta b olic pat h wa y c o m pris es m ore t ha n 2 5 % of t he a d mi nis tere d d ose (refer 
t o c urre nt te p oti ni b I B). T heref ore , t h e D DI p ote ntial wit h te p oti ni b as victi m t o i n hi bit ors of 
c oa d mi nistere d C Y P 3 A 4 i n hi bit ors is c o nsi dere d l o w.  
Te p oti ni b is s u bstrate t o P -g p d e pe n d e nt tra ns p ort. Ass u mi n g a w orst case i n w hic h P -g p 
m e diate d biliar y secreti o n acc o u nts f or 3 0 % of t he t otal cleara nce of te p oti ni b, t he ma xi m u m 
A U C i ncreas e t hr o u g h c o m plete i n hi biti o n of P -g p is 4 3 % ( refer t o c urre nt te p oti ni b I B). T he 
effect of c o m bi ne d i n hi biti o n of C Y P 3 A 4 a n d P -g p is u n k n o w n.  
Gl o bal Versi o n I D: C CI






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Te p oti ni b D DI wit h Itr ac o n az ole  
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D uri n g t he e ntire st u d y, all rec o m me n dati o ns iss ue d b y t h e R o bert K oc h I nstit ute as well as l o cal 
g ui deli nes will be f oll o we d wit h res pect t o t he mi ni mizati o n of t he ris k of disease s p rea di n g, 
e. g., s oci al dista nci n g, disi nfecti o n, h y gie ne, a n d weari n g of a p pr o priat e m o ut h -n ose mas ks. 
D uri n g t he pa n d e mic sit uati o n, f urt her 
meas ures acc or di n g t o rec o m me n dati o ns a n d 
re q uire me nts fr o m l ocal H ealt h A ut h orities ma y b ec o me necessar y a n d will be f oll o we d wit hi n 
t he c o nte xt of t his st u d y as far as a p plica bl e, i n or der t o e ns ure f ull i m ple me ntati o n of t he 
pri nci ples of G C P wit h pri orit y o n partici pa nt safet y i n t his st u d y als o d uri n g t he C O VI D -1 9 
pa n de mic sit uati o n.  T hes e meas ures are des cri be d i n a pre v e nti ve acti o n pla n i m ple me nte d at t he 
I n v esti gat or site. 
I n or der t o mi ni mize t he ris k c o mi n g fr o m a c urre nt i nfecti o n a n d t he ris k of getti n g i nfecte d b y 
ot her partici p a nts d uri n g t he i n -h o use p eri o ds of t he st u d y, t he f oll o wi n g meas ures are t o be 
i m ple me nte d:  
O nl y partici pa nts wit h o ut a n y s y m pt o ms of a res pir at or y disease a n d wit h o ut c o ntact t o a n y 
k n o w n S A R S -C o V -2 p ositi ve patie nt or C O VI D -1 9 patie nt will be i ncl u de d i nt o t he st u d y. 
F urt her m ore, as a p art of t he cli nical st u d y pr oce d ures, partici pa nts will be cl osel y m o nit ore d 
(i ncl u di n g f or si g ns of C O VI D-1 9 ) d uri n g t he e ntire st u d y d urati o n. T he c o nti n uati o n of t he 
st u d y i n t he case of a S A R S-C o V -2 i nfecti o n i n a st u d y partici pa nt or i n a n i de ntifie d c o ntact t o 
a S A R S -C o V -2 p ositi ve partici pa nt or C O VI D -1 9 patie nt will be deci de d at t he I n vesti gat or’s 
discre ti o n a n d i n a gree m e nt wit h t he me dical m o nit ori n g tea m. T he S p o ns or will m o nit or t he 
e ve nts relate d t o a n y S A R S -C o V -2 i nfecti o n re p orte d f oll o wi n g te p oti ni b re g ul arl y a n d u p dat e 
t he rec o m me n d ati o ns, if necessar y. 
2. 3. 2   
Be nefit Assess me nt  
Healt h y partici p a nts ma y  n ot e x pect a be nefit fr o m partici pati n g i n a cli nical st u d y wit h te p oti ni b. 
T he i ncl usi o n of healt h y partici pa nts mi ni mizes varia bilit y c o m pare d t o a st u d y i n patie nts. T his 
st u d y si g nifi ca ntl y c o ntri b utes t o t he pr ocess of d e vel o pi n g ne w t hera pi es t o areas of u n met nee d.  
Gl o bal Versi o n I D: C CI




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Te p oti ni b D DI wit h Itr ac o n az ole  
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4  
St u d y Desi g n  
4. 1  
O ver all Desi g n  
St u d y Desi g n  
Si n gle -se q u e nce 
C o ntr ol Met h o d  
Cr oss -o ver desi g n  
Si n gle or M ultice nter  
Si n gle ce nt er  
C o ntr ol Gr o u p  
N ot a p plica ble  
St u d y P o p ulati o n T y pe  
Healt h y partici pa nts  
Le v el a n d Met h o d of Bli n di n g  
O pe n -la bel 
Bias Mi ni malizati o n Met h o d(s)  
N ot a p plica ble  
St u d y I nter v e nti o n Assi g n me nt Met h o d   
N ot a p plica ble  
I n v ol ve m e nt of S pecial C o m mittee(s):  
N o  
T otal D urati o n of St u d y Partici pati o n per 
Partici pa nt  
U p t o 7  wee ks, i ncl u di n g t he Scree ni n g 
peri o d ( Da y -2 8 t o Da y  -2) a n d 2 1  da ys of 
i nter ve nti o n peri o d (last d ose of te p oti ni b o n 
Da y  1 2, last P K sa m ple c ollecte d o n 
Da y  1 9), a n d a Safet y F oll o w  U p o n Da y  2 0 
( Secti o ns 1. 2  a n d 1. 3 ). 
Pr o visi o ns f or St u d y E xte nsi o n or E ntr y i nt o 
R oll -O ver St u dies  
N ot a p plica b le 
A da pti ve As pects of St u d y Desi g n   
N ot a p plica ble  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Gl o bal Versi o n I D: C CI
C CI


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4. 3  
J ustific ati o n f or D ose  
Te p oti ni b  
T he te p oti ni b d ose t o be use d i n t his st u d y is 5 0 0 m g te p oti ni b H Cl h y drate (e q ui vale nt t o 4 5 0  m g 
free b ase) as ta blet f or m ulati o n. T his is t he cli nical d ose w hic h was e xte nsi vel y st u die d d uri n g 
cli nical de vel o p me nt a n d w hic h was rece ntl y a p pr o ve d b y t he U S F D A ( refer t o te p oti ni b U S PI). 
2  si n gle d oses of 5 0 0 m g of te p oti ni b H Cl h y drat e, c o nsisti n g of 2  ta blets ( 2 5 0 m g) eac h will be 
a d mi nistere d i n t his st u d y.  
T he 5 0 0  m g te p oti ni b H Cl h y drat e si n gle oral d ose wit h f o o d h as bee n e val uate d i n pre vi o us 
st u dies i n healt h y partici pa nts a n d was f o u n d t o be safe a n d well t olerate d ( refer t o Te p oti ni b 
I B). T h e d ose of 5 0 0 m g t e p oti ni b H Cl h y drate is t he R P 2 D f or t he treat me nt of h u ma n mali g na nt 
t u m ors (refer t o Te p oti ni b I B). T his is als o t he rec o m me n de d d osa ge ta ke n orall y o n ce dail y wit h 
f o o d (refer t o T e p oti ni b U S PI ).  
F or m ore d etaile d i nf or m ati o n o n d ose selecti o n refer t o c urre nt te p oti ni b I B.  
Itr ac o n az ole 
T he itrac o naz ole d ose t o be use d i n t his st u d y, 2 0 0 m g o nce dail y f or 4 da ys b ef ore C Y P 3 A 4 
s u bstrate a d mi nistrati o n, is a c o m m o n d osi n g re gi me n use d t o ass ess t he effect of C Y P 3 A 4 
i n hi biti o n o n t he P K of C Y P 3 A 4 s u bstrates i n dr u g-dr u g i nteracti o n st u dies of t his t y p e 
(C he n  2 0 1 9 , Li u 2 0 1 6 , Ke 2 0 1 4 , Gi b b o ns 2 0 1 5 , O da 2 0 0 3 , Bac k ma n 1 9 9 8 , Ki vist o  1 9 9 8 ). 
Itr ac o n az ole d oes n ot i n hi bit a dre nal st er oi d o ge nesis at d oses of 2 0 0 m g o nce d ail y; re versi ble 
a dre nal i ns uffi cie nc y has, h o we ver, bee n re p orte d at a d ose of 6 0 0 m g o n ce dail y  (Li u  2 0 1 6 , 
Q uei r oz-Telles 1 9 9 7 , S har ke y 1 9 9 1 ). I n a d diti o n, t he ris k of Q Tc pr ol o n gati o n is c o nsi dere d l o w 
a n d 
ma na gea ble at t he itrac o naz ole d ose of 2 0 0 
m g o n ce d ail y ( Li u  2 0 1 6 , S u n g  2 0 1 2 , 
H o ni g  1 9 9 3 ). Car diac ris ks i ncrease d wit h d oses greater t ha n 4 0 0 m g o nce dail y ( Pa ul  2 0 1 7 , 
Gl o bal Versi o n I D: C CI
C CI


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O ka m ot o  2 0 0 7 , Teaf or d  2 0 2 0 ). A d mi nistrati o n of 4 0 0 m g ha d a li mite d a d diti o nal C Y P 3 A 
i n hi bit or y effect o ver t hat o bser ve d wit h 2 0 0 m g (Te m plet o n  2 0 1 0 ) a n d is hi g her t ha n t he dail y 
d ose of 1 0 0 or 2 0 0  m g rec o m me n de d f or m ost i n dicati o ns ( refer t o Itrac o naz ole S m P C). 
Alt h o u g h 4 d a ys is n ot s ufficie nt f or attai n me nt of stea d y state, t h e 4 -d a y lea d -i n all o ws f or s o me 
acc u m ulati o n, wit h hi g her itrac o naz ole a n d meta b ol ite e x p os ure a n d t heref ore a p ote ntiall y 
greater de gree of C Y P 3 A 4 i n hi biti o n, wit h c o nsi derati o n f or p ote ntial l o gistical a n d s afet y 
c o ncer ns ass ociate d wit h a l o n ger itrac o naz ole d osi n g peri o d ( Li u 2 0 1 6 , C h e n 2 0 1 9 ).  
Itr ac o n az ole is a v aila ble as har d-gelati n ca ps ule a n d s ol uti o n; b ot h f or m ulati o ns ha ve b ee n use d 
i n D DI st u dies (Bar o ne  1 9 9 8 , Te m plet o n  2 0 1 0 , Li u  2 0 1 6 ). Alt h o u g h t he s ol uti o n pr o vi des hi g h er 
s yste mic e x p os ure, wit h less varia bilit y, t he ca ps ul e pr o vi des a de q uat e e x p os ure of itrac o naz ole 
a n d meta b olites t o e ns ure str o n g C Y P 3 A 4 i n hi biti o n w he n d ose d wit h f o o d  (Bar o ne  1 9 9 3 , 
Li u  2 0 1 6 , refer t o Itrac o n az ole U S PI a n d S m P C ). Si m ple me dicati o n i nta ke is g uara ntee d w he n 
usi n g ca ps ules. A n ot h er a d va nta ge of itrac o naz ol e h ar d -gelati n ca ps ules is t he fact, t hat t his 
f or m ulati o n d oes n ot c o ntai n h y dr o x y pr o p yl-β -c ycl o d e xtri n, w hic h is use d as a n e x ci pie nt t o 
i ncreas e t he s ol u bilit y of itrac o naz ole i n t he s ol uti o n f or m ulati o n (refer t o Itrac o naz ole U S PI a n d 
S m P C ). C ycl o d e xtri ns act b y f or mi n g i ncl usi o n c o m ple x es w hic h mi g ht affect t he P K of 
te p oti ni b as p u blis he d f or fe ne br uti ni b (C he n  2 0 2 0 , D ur k  2 0 2 0 ). 
4. 4   
E n d of St u d y Defi niti o n  
T he e n d of t he st u d y is defi ne d as t he date of  last c o ntact (relate d t o t his st u d y) wit h t he last 
partici pa nt w h o partici p ates i n t his st u d y (last p artici pa nt’s Safet y F oll o w  U p assess me nt s h o w n 
i n Secti o n 1. 3 ). 
A partici pa nt has c o m plete d t he st u d y if he/s he h as c o m plete d all st u d y parts, i ncl u di n g Safet y 
F oll o w  U p assess me nts o n Da y 2 0 ( Secti o n 1. 3 ). 
St u d y Ter mi n ati o n Crit eri a  
T he st u d y will be disc o nti n ue d or ter mi nate d if:  
•  U nacce pta ble ris k, a n y rele va nt t o xicit y, or a ne gati ve c ha n ge i n t he ris k/ be nefit assess me nt 
is i de ntifie d. T his mi g ht i ncl u de t he occ urre n ce of AE s w h ose  c haracter, se verit y or 
fre q ue n c y is ne w i n c o m paris o n t o t he e xisti n g ris k pr ofile.  
•  A n y d ata d eri ve d fr o m ot her cli nical st u dies or t o xic ol o gical st u dies bec o m e a vaila ble w hic h 
ne gati vel y i nfl ue nce t he ris k/ be nefit assess me nt.  
Ge neral i nf or mati o n o n st u d y ter mi nati o n is s pecifie d i n A p pe n di x 2 . 
Gl o bal Versi o n I D: C CI


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5  
St u d y P o p ul ati o n  
T he criteria i n Secti o n s 5. 1  a n d 5. 2  are desi g ne d t o e nr oll o nl y partici pa nts, w h o are a p pr o priate 
f or t he st u d y; t here b y, e ns uri n g t he st u d y f ulfills its o bjecti ves.  All rele va nt me dical a n d 
n o n me dical c o n diti o ns are c o nsi der e d w he n deci di n g w het her a partici p a nt is s uita ble f or t his 
st u d y. 
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o i ncl usi o n a n d e x cl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d.  
Bef ore perf or mi n g a n y st u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical 
care, t h e I n vesti gat or will c o nfir m t hat t he partici p a nt  has pr o vi de d writte n i nf or me d c o nse nt, a s 
i n dicate d i n A p pe n di x 2 . 
5. 1  
I ncl usi o n Criteri a 
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteria a p pl y:  
C ate g or y  
Criteri o n  
A ge  
1.  Are b et wee n 1 8 a n d 5 5 (i ncl usi ve) years of a ge at t h e  ti me of 
si g ni n g t he i nf or me d c o nse nt. 
T y pe of Partici pa nt 
a n d Disease 
C haracteristics  
2.  Are o vertl y h ealt h y as det er mi ne d b y me dical e val uati o n, i ncl u di n g 
n o cli nicall y si g nifica nt a b n or malit y i de ntifie d b y me dical hist or y, 
car diac m o nit ori n g, p h ysical e x a mi nati o n or la b orat or y e val uati o n 
a n d n o acti ve cli nicall y si g nifica nt dis or der, c o n diti o n, i nfecti o n or 
disease t hat w o ul d p ose a ris k t o partici pa nt safet y or i nterfere wit h 
t he st u d y e val uati o n, pr oce d ures, or c o m pleti o n at Scree ni n g a n d 
Da y  -1.  
Wei g ht  
3.  Ha ve a b o d y wei g ht wit hi n 5 0 a n d 1 0 0  k g i n cl usi ve a n d B MI wit hi n 
t he ra n ge ≥ 1 8. 5 a n d ≤ 2 9. 9 k g/ m 2 (i ncl usi ve) at Scree ni n g. 
Gl o bal Versi o n I D: C CI


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C ate g or y  
Criteri o n  
Se x a n d 
C o ntrace pti o n/ Barrier 
Re q uire me nts  
4.  Are male or fe mal e  ( n ot a W O C B P) 
T he In v esti gat or c o nfir ms t hat eac h partici pa nt a grees t o use 
a p pr o priate c o ntrace pti o n a n d 
barriers, if a p plica ble. 
T he 
c o ntrace pti o n, barrier, a n d pre g na nc y testi n g re q uire me nts are 
bel o w.  
C o ntrace pti ve use will be c o nsiste nt wit h l ocal re g ulati o ns o n 
c o ntrace pti o n met h o ds f or t h ose partici pati n g i n cli nical st u dies.  
a. Male Partici pa nts:  
A gree t o t he f oll o wi n g d uri n g t he st u d y i nter ve nti o n peri o d 
a n d f or at least  1  wee k  after t he last d ose of st u d y i nter ve nti o n:  
•  
Refrai n fr o m d o n ati n g fres h a n d u n was h e d s per m 
P L U S , eit her: 
•  
A bstai n fr o m i nterc o urse wit h a W O C B P . 
O R   
•  
Use a male c o n d o m:  
•  W he n ha vi n g se x ual i nterc o urse wit h a W O C B P, 
w h o is n ot  c urre ntl y pre g na nt, a n d  i nstr uct her t o 
use a hi g hl y effecti ve c o ntrace pti ve met h o d wit h a 
fail ure rate of < 1 % per year, as d escri be d i n 
A p pe n di x  3 , si nce a c o n d o m ma y brea k or lea k.  
b.  N ot a W O C B P , c o nfir me d at Scree ni n g, b y f ulfilli n g at least 
1  of t he f oll o wi n g criteria:  
•   
Fe males w h o are p ost me n o pa usal (a ge -relate d 
a me n orr hea ≥ 1 2 c o ns ec uti ve m o nt hs a n d i ncreas e d 
F S H >  4 0 mI U/ m L) . 
•   
D oc u me ntati o n of irre versi ble s ur gical sterilizati o n b y 
h ysterect o m y, or bilateral o o p h orect o m y , or bilateral 
sal pi n gect o m y. 
I nf or me d C o nse nt  
5.  Ca pa ble of gi vi n g si g ne d i nf or me d c o ns e nt, as i n dicate d i n  
A p pe n di x  2 , w hic h i ncl u des c o m plia nce wit h t he re q uire me nts a n d 
restricti o ns liste d i n t he I C F a n d t his pr ot oc ol. 
La b orat or y 
Para meters  
6.  All val ues f or he m at ol o g y, c o a g ulati o n, a n d bi oc he mistr y tests of 
bl o o d a n d uri nal ysis wit hi n t he n or mal ra n ge (at Scree ni n g a n d 
Da y  -1). Mi n or (s olitar y) n o ncli nicall y rele va nt e x c ursi o n(s) ar e 
all o we d as j u d ge d b y t he I n v esti gat or, h o we v er a m y l ase a n d li pas e 
s h o ul d n ot e x cee d t he U L N; A L T, A S T  a n d t otal bilir u bi n s h o ul d 
n ot e xcee d t he U L N  ×  1. 1.  
A L T = al a ni n e a mi n otr a n sf er a s e, A S T = a s p art at e a mi n otr a n sf er a s e, B MI = b o d y m a s s i n d e x,  F S H =f olli cl e 
sti m ul ati n g h or m o n e, I C F =i nf or m e d c o n s e nt f or m, U L N = u p p er li mit of n or m al,  W O C B P = w o m a n of c hil d -b e ari n g 
p ot e nti al.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 2 / 6 8 
 
 
5. 2   
E xcl usi o n Criteri a  
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
C ate g or y  
Criteri o n  
Me dical C o n diti o ns  
1.  Hist or y or prese n ce of cli nicall y rele va nt res pirat or y, 
gastr oi ntesti nal, re nal, he patic, he mat ol o gical, l y m p hatic, 
ne ur ol o gi cal, car di o vasc ular, ps yc hiatric, m usc ul os keletal, 
ge nit o uri nar y, i m m u n ol o gical, der mat ol o gical, c o n necti ve tiss ue 
diseases or dis or ders, as deter mi ne d b y me dical e val uati o n.  
 
2.  Partici pa nts wit h gall bla d der re m o v al or ot her rel e va nt s ur ger y 
of gastr oi ntesti nal tract ( ap pe n dect o m y is n ot c o nsi dere d as 
rele va nt). 
 
3.  Hist or y of a n y mali g n a nc y e x ce pt f or a de q u atel y treate d 
s u perficial basal cell carci n o ma. 
 
4.  Hist or y of e pile ps y.  
 
5.  Ascertai n e d or pres u m pti ve aller g y/ h y perse nsiti vit y t o t he acti ve 
dr u g s u bsta n ce a n d/ or e x ci pie nts; hist or y of a n a p h yl a xis t o dr u gs 
or seri o us aller gic reacti o ns lea di n g t o h os pitalizati o n or a n y 
ot her aller g y reacti o n i n ge n eral, w hi c h t he I n v esti gat or c o nsi ders 
ma y affect t he safet y of t he partici pa nt a n d/ or o utc o me of t he 
st u d y. 
 
6.  A n y c o n diti o n, i ncl u di n g fi n di n gs i n t he la b orat or y tests, me dical 
hist or y, or ot her Scree ni n g ass ess me nts, t hat i n t he o pi ni o n of t he 
I n v esti gat or c o nstit utes a n i na p pr o priate ris k or a c o ntrai n dicati o n 
f or partici pati o n i n t he st u d y or t hat c o ul d i nterfere wit h t he 
st u d y’s o bjecti ves, c o n d u ct, or e val uati o n. 
Pri or/ C o nc o mita nt 
T hera p y  
7.  M o derate or str o n g i n hi bit ors or i n d ucers of C Y P 3 A 4 a n d P -g p 
wit hi n 4 wee ks pri or t o t he first a d mi nistrati o n of st u d y 
i nter ve nti o n. 
 
8.  Use of a n y prescri be d me dici ne or o ver -t he-c o u nter dr u g or 
dietar y s u p ple me nt, i ncl u di n g her bal re m e dies, vita mi ns, a n d 
mi nerals, a ntaci ds a n d di etar y s u p ple me nts s uc h as fis h oils 
wit hi n 2  wee ks or 5  ti mes t he half -life of t he res p ecti ve dr u g, 
w hic he ver is l o n ger, pri or t o t he first a d mi nistrati o n of st u d y 
i nter ve nti o n. 
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 3 / 6 8 
 
 
C ate g or y  
Criteri o n  
 
9.  A d mi nistrati o n of li ve vacci nes or li ve -atte n uate d vir us vacci nes 
wit hi n 3 m o nt hs pri or t o Scree ni n g. A d mi nistrati o n of ot her t y pes 
of vacci n es (e. g., S A R S -C o V -2 vacci n es, fi nal b o ost) is all o we d 
u ntil 1 wee k bef ore a d missi o n t o C R U.  
N ote: I n cas e of cli nical s y m pt o ms, t he partici pa nt s h o ul d be 
s y m pt o m-free f or at least 1 wee k pri or t o a d missi o n t o C R U. 
Pri or/ C o nc urre nt 
Cli nical St u d y 
E x perie nce  
1 0.  Partici pati o n i n t he treat me nt p hase of a cli nical st u d y wit hi n 
6 0  da ys or 5 half -li ves after last d osi n g of t he pre vi o us st u d y 
dr u g, w hate ver is l o n ger, bef ore a d mi nistrati o n of st u d y dr u g.  
Dia g n ostic 
Assess me nts  
1 1.  S u pi ne s yst olic bl o o d press ure  >  1 4 0 or <  9 0  m m H g, diast olic 
bl o o d press ure >  9 0 or <  5 0  m m H g, a n d p ulse rate >  9 0 or 
<  5 0  beats per mi n ute at Scree ni n g a n d at ad missi o n o n Da y  -1 
(an y a b n or mal bl o o d press ure res ults ma y be re peate d o nce a n d if 
t he re peat res ult is wit hi n t he n or mal ran ge, it is n ot c o nsi dere d t o 
ha ve met t he e x cl usi o n criteri o n).  ( Secti o n 8. 2. 2 ) 
 
1 2.  1 2 -Lea d E C G s h o wi n g a Q Tc F > 4 5 0  ms, P R > 2 1 5  ms, or Q R S 
>  1 2 0  ms at Scree ni n g a n d at ad missi o n o n Da y  -1.  
 
1 3.  Creati ni ne cleara n ce esti mate d gl o mer ular filtrati o n rate 
acc or di n g t o t he C hr o nic Ki d ne y Disease E pi de mi ol o g y 
C olla b orati o n Creati ni ne E q uati o n ( 2 0 0 9) <  9 0  m L/ mi n at 
Scree ni n g.  
 
1 4.  Hist or y of alc o h olis m or dr u g a b use wit hi n 2  years pri or t o 
Scree ni n g, or p ositi ve f or dr u gs of a b use, nic oti ne/ c oti ni ne or 
alc o h ol b y t h e la b orat or y assa ys c o n d uct e d d uri n g Scree ni n g a n d 
o n ad missi o n o n Da y  -1.  
 
1 5.  P ositi ve f or a) he patitis B s urface a nti ge n, he p atitis B c ore 
a nti b o d y, he p atitis  C a nti b o d y, or h u m a n i m m u n o deficie nc y 
vir us  I a n d II t ests at Scree ni n g; b) S A R S-C o V -2 at Scree ni n g  
( b y ra pi d a nti ge n test) or  at ad missi o n o n  Da y  -1 ( b y P C R test). 
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4 / 6 8 
 
 
C ate g or y  
Criteri o n  
 
1 6.  Cli nicall y rele va nt fi n di n gs (e x cl u di n g 
mi n or, n ot cli nicall y 
rele va nt e x c ursi ons fr o m n or mal ra n ges as j u d ge d b y t he 
In v esti gat or) 
at 
Scree ni n g i n 
bi oc he mistr y, 
he mat ol o g y, 
c oa g ulati o n, a n d uri nal ysis e x a mi nati o ns f or t he a ge of t he 
partici pa nt, as j u d ge d b y t he I n v esti gat or:  
•  Ala ni ne a mi n otra nsferas e, as partat e a mi n otra nsferase: s h oul d 
n ot e xcee d t he U L N  ×  1. 1  
•  Creati ni ne: a b o ve n or mal li mits  
•  A bs ol ute l y m p h oc yte c o u nt, a bs ol ute ne utr o p hil c o u nt , 
a bs ol ute platelet c o u nt : b el o w li mit of refere nce ra n ge 
•  A m ylase a n d li pase a b o v e t he u p per li mit of n or mal a n d/ or 
si g ns/s y m pt o ms of pa n creatitis.  
Ot her E x cl usi o ns  
1 7.  C o ntrai n dicati o n t o itrac o naz ole ( refer t o Itrac o naz ole U S PI a n d 
S m P C ): v e ntric ular d ysf u ncti o n s uc h as c o n gesti ve heart fail ure 
or a hist or y of co n gesti ve heart fail ure , dr u g i nteracti o ns (e. g., 
c oa d mi nistrati o n of a n u m ber of C Y P 3 A 4 s u bstrates), pre g na n c y, 
h y perse nsiti vit y t o itrac o naz ole.  
 
1 8.  D o nati o n or l oss of m ore t ha n 4 5 0  m L of bl o o d i n t he 6 0  da ys 
pri or t o Scree ni n g, d o nati o n of plas ma fr o m 2  wee ks pri or t o 
Scree ni n g, or plat elets fr o m 6  wee ks pri or t o Scree ni n g.  
 
1 9.  E x cessi ve c o ns u m pti o n of x a nt hi ne -c o ntai ni n g f o o d or be vera ges 
( > 5 c u ps of c offee or e q ui vale nt a da y) or i na bilit y t o st o p 
c o ns u mi n g caffei ne at Scree ni n g a n d at ad missi o n o n Da y  -1.  
 
2 0.  C o ns u m pti o n of a n a vera ge wee kl y alc o h ol i nta ke of 
>  1 4  u nits/ wee k f or me n or >  7  u nits/ wee k f or w o me n. 1  u nit 
( 1 2 g) of alc o h ol e q uals ½  pi nt ( 2 8 5  m L) of b eer or la ger, 1  glass 
( 1 2 5 m L) of wi ne, or 1/ 6  gill ( 2 5  m L) of s pirits.  
 
2 1.  C o ns u m pti o n of alc o h ol fr o m 4 8 h o urs pri or t o first 
a d mi nistrati o n of st u d y i nter ve nti o n.  
 
2 2.  S m o ker (ci garettes, pi pes, ci gars, or ot hers) or f or mer s m o ker 
w h o st o p pe d s m o ki n g f or less t ha n 6 m o nt hs bef ore t he ti me of 
t he Scree ni n g v isit. 
 
2 3.  I nta ke of gra pefr uit, Se ville ora n ge, p o mel o, gra pefr uit h y bri ds, 
e x otic citr us fr uit, cra n berries or j uices of t hese fr uits, or St 
J o h n’s W ort, fr o m 1 4 da ys pri or t o ad missi o n o n Da y -1.  
 
2 4.  Pr o d ucts c o ntai ni n g p o p p y see ds (ca ke, r olls) ma y n ot be 
c o ns u me d wit hi n 4 8  h o urs bef ore Scree ni n g a n d eac h a d missi o n 
u ntil disc har ge.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 5 / 6 8 
 
 
C ate g or y  
Criteri o n  
 
2 5.  I n a bilit y t o c o m m u nicate or c o o perate wit h t he I n vesti gat or (e. g., 
la n g u a ge pr o ble m, illiterac y, p o or me ntal stat us) or t o c o m pl y 
wit h t he re q uire me nts of t he e ntire st u d y, i ncl u di n g di etar y 
restricti o ns. 
 
2 6.  Ot her fact ors, w hic h i n t he o pi ni o n of t he I n vesti gat or m a y 
i nterfere wit h st u d y c o n d uct. 
 
2 7.  Le gal i nca p acit y or li mite d le gal ca pacit y.  
 
2 8.  Partici pa nt is i n c ust o d y b y or der of a n a ut h orit y or a c o urt of 
la w. 
C R U = cli ni c al r e s e ar c h u nit, C Y P = c yt o c hr o m e P 4 5 0, P C R = p ol y m er a s e c h ai n r e a cti o n, P -g p = P -gl y c o pr ot ei n, 
E C G = el e ctr o c ar di o gr a m, S A R S -C o V -2 = s e v er e a c ut e r e s pir at or y s y n dr o m e c or o n a vir u s  2, S m P C = s u m m ar y of 
pr o d u ct c h ar a ct eri sti c s, U L N = u p p er li mit of n or m al, U S PI = U nit e d St at e s pr e s cr i bi n g i nf or m ati o n. 
5. 3  
Lifest yle C o nsi der ati o ns  
5. 3. 1   
Me als a n d Diet ar y Restricti o ns  
A bstai n fr o m c o ns u m pti o n of t he f oll o wi n g fr o m 1 4 da ys bef ore t he start of st u d y i nter ve nti o n 
u ntil after t he fi nal d os e: Se ville ora n ges, gra pefr uit or gra p efr uit j uice, p o mel os, e x otic citr us 
fr uits, gra pefr uit h y bri ds, cra n berries, fr uit j uices or St J o h n’s W ort.  
Pr o d ucts c o ntai ni n g p o p p y see ds (ca k e, r olls) ma y n ot be c o ns u me d wit hi n 4 8  h o urs bef ore 
Scree ni n g a n d eac h a d missi o n u ntil disc har ge.  
O n Da y 1 a n d Da y 1 2, p artici pa nts  will recei ve a si n gle d ose of 5 0 0  m g te p oti ni b H Cl h y drate 
(ta blets) i n t he m or ni n g at t he start of a sta n dar d m o derate-fat/ m o derate-cal ori e brea kfast. 
F oll o wi n g a n o ver ni g ht fast of at least 1 0 h o urs, partici pa nts s h o ul d recei v e a sta n dar d 
m o derate -fat/ mo derat e -cal orie brea kfast w hic h s h o ul d be c o ns u me d wit hi n 3 0 t o 6 0  mi n utes. 
T he start dat e a n d ti me a n d st o p ti me of t he brea kfast will be rec or de d i n t he partici pa nt’s e C R Fs 
as well as w het her t he e ntire brea kfast was c o ns u me d. If t he e ntire meal is n ot c o ns u me d, t he 
perce nt a ge of m eal c o ns u me d (i n q uartiles) s h o ul d be rec or de d.  
O n Da ys  8 t o 1 1 a n d Da ys  1 3 t o 1 8, partici pa nt s will recei ve o nce -dail y a si n gle d ose of 2 0 0  m g 
itrac o naz ole (ca ps ul es) ta ke n i m me diatel y after t he sta n dar d m o derate-fat/ m o derate-cal ori e 
brea kfast. O n Da y  1 2, partici pa nt s will recei ve a si n gle d ose of 2 0 0  m g itrac o naz ole (ca ps ules) 
si m ulta ne o usl y wit h a si n gle d ose of 5 0 0 m g te p oti ni b H Cl h y drate (ta bl ets) i n t he m or ni n g at 
t he start of a sta n d ar d m o derate-fat/ m o derate-cal orie brea k fast. 
St u d y i nter ve nti o ns will be a d mi nistere d wit h 2 4 0 m L of water i n a sta n di n g p ositi o n d uri n g t h e 
o n -site sta y at t he C R U. O n d osi n g da ys (see Sc he d ule of Assess m e nts  i n Secti o n 1. 3 ), 
partici pa nts ma y c o ns u m e water a d li bit u m  a n d s h o ul d dri n k at least 1. 5  L/ da y.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 6 / 6 8 
 
 
Sta n dar d 
m o derate -fat, 
m o derate-cal orie brea kfasts are defi ne d as f oll o ws: 4 9 0  cal ories 
c o m p ose d of a p pr o xi matel y 7 7  g of car b o h y drates, 2 8  g of pr otei n, a n d 1 3  g of fat 
(Na derer  2 0 1 5 ). 
All ot her meals d uri n g t he i n patie nt sta y at t he C R U  will be sta n dar dize d a n d n o d oc u me ntati o n 
of ti me a n d c o m plete c o ns u m pti o n is nee de d . T he partici pa nts are o nl y p er mitte d t o eat meals 
pr o vi de d b y t he C R U . T hese meals will be pr o vi de d at us ual meal ti mes of t he C R U. 
5. 3. 2   
C affei ne, Alc o h ol, T o b acc o , a n d C a n n a bi n oi d 
•  D uri n g eac h d osi n g peri o d , partici pa nts will a bstai n fr o m i n gesti n g caffei ne- or x a nt hi ne -
c o ntai ni n g pr o d ucts (e. g., c offee, tea, c ola dri n ks, a n d c h oc olat e) f or 4 8  h o urs bef ore t he start 
of d osi n g u ntil after c ollecti o n of t he fi nal P K a n d/ or P D  sa m ple. 
•  D uri n g eac h d osi n g peri o d , partici pa nts will a bstai n fr o m al c o h ol a n d ca n na bi n oi d -
c o ntai ni n g pr o d ucts f or 4 8  h o urs bef ore t he start of d osi n g u ntil after c ollecti o n of t he fi nal 
P K a n d/ or P D  sa m ple. 
•  Use of t o bacc o pr o d ucts will n ot be all o we d fr o m 6  m o nt hs bef ore t he ti me of t he Scree ni n g 
visit u ntil after t he fi nal f oll o w -u p visit.  
5. 3. 3   
Act i vit y 
Partici pa nts will a bstai n fr o m stre n u o us e x ercise f or 7 2  h o urs bef ore eac h bl o o d c ollecti o n f or 
cli nical la b orat or y tests. Partici pa nts ma y partici pate i n li g ht recreati o nal acti vities (e. g., 
watc hi n g tele visi o n or rea di n g).  
5. 4  
Scree n F ail ures  
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) will  n ot 
be rescree n e d.  
5. 5  
Criteri a f or Te m p or aril y Del a yi n g t he A d mi nistr ati o n of 
St u d y I nter ve nti o n  
N ot a p plica ble.  
6  
St u d y I nter ve nti o n(s)  a n d C o nc o mit a nt T her a pies  
St u d y i nter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s), place b o, or 
me dical de vice(s) i nte n d e d t o be a d mi nistere d t o a st u d y p artici pa nt per  t h e st u d y pr ot oc ol. 
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 7 / 6 8 
 
 
6. 1  
St u d y I nter ve nti o n(s) A d mi nistr ati o n  
I nt er v e nti o n N a m e 
T e p oti ni b ( H Cl h y dr at e)  
Itr a c o n a z ol e 
T y p e  
Dr u g  
Dr u g  
D o s e F or m ul ati o n  
Fil m -c o at e d t a bl et  
H ar d -g el ati n c a p s ul e  
U nit D o s e Str e n gt h( s)   
2 5 0 m g  
1 0 0  m g  
D o s e A m o u nt  
5 0 0 m g ( 2 t a bl et s) wit h f o o d   
2 0 0  m g ( 2 c a p s ul e s) wit h f o o d  
Fr e q u e n c y  
D a y 1 a n d 1 2 i n t h e m or ni n g   
O n c e d ail y at t h e s a m e ti m e i n t h e 
m or ni n g ( e v er y 2 4 h o ur s ± 1 h o ur) fr o m 
D a y  8 t o D a y 1 8; o n D a y 1 2 itr a c o n a z ol e 
i s a d mi ni st er e d c o n c o mit a ntl y wit h 
t e p oti ni b ( S e cti o n 5. 3. 1 ). 
R o ut e of A d mi ni str ati o n   
Or al  
Or al  
U s e  
E x p eri m e nt al  
E x p eri m e nt al  
I n v e sti g ati o n al M e di ci n al 
Pr o d u ct (I M P) a n d N o n - 
I n v e sti g ati o n al M e di ci n al 
Pr o d u ct ( NI M P)  
I M P: t e p oti ni b 
I M P: itr a c o n a z ol e 
S o ur ci n g  
S p o n s or ( M er c k H e alt h c ar e K G a A)   
S p o n s or ( M er c k H e alt h c ar e K G a A)  
P a c k a gi n g a n d L a b eli n g   
St u d y i nt er v e nti o n will b e pr o vi d e d 
a s bli st er s i n s cr e w -c a p b ottl e s t h at 
ar e p a c k a g e d a n d l a b el e d p er all 
a p pli c a bl e r e g ul at or y r e q uir e m e nt s 
a n d G o o d M a n uf a ct uri n g Pr a cti c e 
G ui d eli n e s.   
D et ail s o n p a c k a gi n g d e si g n a n d 
a d mi ni str ati o n of t e p oti ni b will b e 
d efi n e d i n t h e I M P H a n dli n g 
M a n u al.  
St u d y i nt er v e nti o n will b e s o ur c e d a s 
c o m m er ci al p a c k s a n d l a b el e d p er all 
a p pli c a bl e r e g ul at or y r e q uir e m e nt s a n d 
G o o d M a n uf a ct uri n g Pr a cti c e G ui d eli n e s . 
D et ail s o n p a c k a gi n g d e si g n a n d 
a d mi ni str ati o n of itr a c o n a z ol e will b e 
d efi n e d i n t h e I M P H a n dli n g M a n u al.  
I M P =i n v e sti g ati o n al m e di ci n al pr o d u ct. 
6. 2  
St u d y I nter ve nti o n(s) Pre p ar ati o n, H a n dli n g,   
 a n d 
Acc o u nt a bilit y  
T he In vesti gat or, i nstit uti o n, or t he hea d of t h e me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y i nter ve nti o n acc o u nt a bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (i.e., 
recei pt, rec o n ciliati o n, a n d fi nal dis p ositi o n rec or ds). 
•  U p o n recei pt of t he st u d y i nter ve nti o n(s), t he 
In vest i gat or or desi g n ee will  c o nfir m 
a p pr o priate te m perat ure c o n diti o ns ha ve b ee n 
mai ntai ne d d uri n g tra nsit a n d a n y 
discre pa n cies are re p orte d a n d res ol v e d bef ore us e.  Als o, t he res p o nsi ble pers o n will c hec k 
f or acc urat e deli ver y. F urt her g ui d a nce a n d i nf or m ati o n f or st u d y i nter ve nti o n acc o u nta bilit y 
are pr o vi d e d i n t he  I M P ha n dli n g ma n ual. 
•  O nl y p artici pa nts e nr olle d i n t he st u d y m a y recei v e st u d y i nt er ve nti o n(s) a n d o nl y a ut h orize d 
site staff ma y s u p pl y it. All st u d y i nter ve nti o n(s) will  be st ore d i n a sec ure, e n vir o n me ntall y 
c o ntr olle d , a n d m o nit ore d ( ma n ual or a ut o mate d) area, per  t he la bele d st ora ge c o n diti o ns, 
a n d wit h access li mite d t o t he In v esti gat or a n d a ut h orize d site staff.  
•  Dis pe nsi n g will be rec or de d o n t he a p pr o priate acc o u nta bilit y f or ms s o t hat acc urat e rec or ds 
will be a vaila ble f or verificati o n at eac h m o nit ori n g visit.  
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•  St u d y i nter ve nti o n(s) acc o u nta bilit y rec or ds at t he st u d y site will i ncl u de t he f oll o wi n g:  
•  C o nfir mati o n of recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m p erat ure ra n ge.  
•  T he i n ve n t or y pr o vi de d f or t he cli nical st u d y a n d pre pare d at t he site. 
•  T he d ose(s) eac h partici p a nt use d d uri n g t he st u d y.  
•  T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y u n us e d st u d y i nter ve nti o n(s).  
•  Dates, q ua ntities, batc h n u m bers, c o ntai ner n u m bers, e x pir y d ates , a n d t he partici pa nt 
n u m bers.  
•  T he I n vesti gat or site will mai ntai n rec or ds, w hic h a de q uat el y d oc u me nts t hat partici pa nts 
were pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d all st u d y i nter ve nti o n(s) pr o vi de d 
were f ull y rec o n cile d.  
•  U n use d st u d y i nter ve nti o n(s) will  n ot be discar de d or use d f or a n y p ur p os e ot her t ha n t he 
prese nt st u d y. N o st u d y i nter ve nti o n t hat is dis pe nse d t o a partici pa nt ma y be re dis pe nse d t o 
a differe nt partici pa nt.  
•  A St u d y M o nit or will peri o dicall y c ollect t he st u d y i nter v e nti o n(s) acc o u nt a bilit y f or ms.  
•  F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y i nter ve nti o n(s) are 
pr o vi de d i n t he  I M P ha n dli n g ma n ual. 
6. 3  
Me as ures t o Mi ni mize Bi as: St u d y I nter ve nti o n Assi g n me nt 
a n d Bli n di n g  
6. 3. 1   
St u d y I nter ve nti o n As si g n me nt 
N ot a p plica ble as t his is a n o nra n d o mize d st u d y.  
After i nf or me d c o nse nt pr oce d ure, e v er y p arti ci pa nt is gi ve n a scree ni n g n u m ber. O nl y 
partici pa nts w h o c o m pl y wit h all selecti o n criteria (see Secti o ns 5. 1  a n d 5. 2 ) ca n be i n cl u de d 
i nt o t he st u d y. Pri or t o t he first a d mi nistrati o n, t he partici pants e nr olle d will be assi g ne d t o a 
u ni q ue 3 -di gits assi g n me nt n u m ber i n asce n di n g n u merical or der.  
T he I n vesti gat or will kee p a rec or d relati n g t he p artici pa nt assi g n me nt n u m bers a n d t he n a mes 
of all partici p a nts (i ncl u di n g scree ni n g n u m b er a n d t he N u visa n G m b H i de ntificati o n n u m ber) 
w h o ha ve gi v e n t heir i nf or me d c o nse nt, t o all o w eas y c hec ki n g of data i n partici pa nt files, w he n 
re q uire d. T his rec or d will als o i ncl u de t he date of partici pa nt’s e nr oll me nt a n d c o m pleti o n, as 
well as partici pa nts w h o c o ul d n ot be assi g n e d t o st u d y i nter ve nti o n f or w h ate ver reas o n.  
6. 3. 2   
Bli n di n g  
N ot a p plica ble . This is a n o pe n -la bel st u d y. 
6. 3. 3   
E mer ge nc y U n bli n di n g  
N ot a p plica ble . This is a n o pe n -la bel st u d y. 
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6. 4   
St u d y I nter ve nti o n C o m pli a nce  
W he n partici pa nts are d ose d at t h e site, t h e y will recei ve st u d y i nt er ve nti o n directl y fr o m t he 
I n v esti gat or or d esi g n ee, u n der me dical s u per visi o n. T he date a n d ti me of eac h d ose a d mi nistere d 
i n t he cli nic will be rec or de d i n t he s o urce d oc u me nts a n d rec or de d i n t he C R F. T he d os e of 
st u d y i nter ve nti o n a n d st u d y partici pa nt i de ntificati o n will be c o nfir me d at t he ti me of d osi n g b y 
a me m ber of t he st u d y sit e staff ot her t ha n t he pers o n a d mi nisteri n g t h e st u d y i nter ve nti o n. St u d y 
site pers o n nel will e x a mi ne eac h partici pa nt’s m o ut h t o e ns ure t hat t h e st u d y i nter ve nti o n was 
i n geste d. 
6. 5   
D ose M o dific ati o n  
D oses will n ot be m o difie d.  
6. 6   
C o nti n ue d Access t o St u d y I nter ve nti o n after t he E n d of t he St u d y  
T he S p o ns or will n ot pr o vi de a n y a d diti o nal care t o partici pa nts after t h e y lea v e t he st u d y 
beca use s u c h care  w o ul d n ot differ fr o m w hat is n or mall y e x pecte d f or healt h y partici pa nts.  
6. 7   
Tre at me nt of O ver d ose  
F or t his st u d y, a n y d ose of st u d y i nt er ve nti o n great er t ha n t h e ma xi m u m d ose i n t he st u d y t hat is 
c o nsi dere d safe a n d well -t olerate d wit hi n a 2 4-h o ur ti me peri o d will be c o nsi dere d a n o ver d ose.  
T he S p o ns or h as n o s pecific rec o m me n dati o n f or treati n g a n o ver d ose of te p oti ni b. T he 
I n v esti gat or will use his cli nical j u d g m e nt t o ma na ge a n y o ver d ose, c o nsi d eri n g t he s y m pt o ms 
a n d a n y site pr oce d ures or sta n dar ds.  
Rec o m me n dati o n f or treat me nt of a n o ver d ose of itrac o n az ole is descri be d i n t he res p ecti ve 
S m P C.  
E ve n if n ot ass ociate d wit h a n A E or a S A E, a n y o ver d ose is rec or de d i n t he C R F a n d re p orte d 
t o gl o bal p atie nt safet y i n a n e x pe dite d ma n ner. O ver d oses are re p orted o n a S A E a n d O ver d ose 
Re p ort F or m, f oll o wi n g t he pr oce d ure i n  A p pe n di x 4 . 
6. 8  
C o nc o mit a nt T her a p y  
Rec or d i n t he C R F all c o nc o mita nt t hera pies (e. g., me dici nes or n o n dr u g i nter ve nti o ns) use d 
fr o m t he ti me t he partici pa nt si g ns t he i nf or me d c o nse nt u ntil c o m pleti o n of t he st u d y, i ncl u di n g 
a n y c h a n ges.  F or pres cri pti o n a n d o ver -t he-c o u nter me dici n es, vacci nes, vita mi ns, a n d her bal 
s u p ple me nts, rec or d t h e na me, reas o n f or us e, dat es a d mi nistere d, a n d d osi n g i nf or m ati o n. 
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n  c o nc o mita nt or pri or t h era p y.  
6. 8. 1   
Resc ue Me dici ne  
N o s pecific a nti d ote is a vaila ble f or te p oti ni b. S y m pt o matic treat me nt will be pr o vi de d i n cas e 
of a me dical e mer ge n c y.  
I n case of t o xicit y d uri n g itrac o naz ole treat me nt refer t o t he itrac o naz ole S m P C a n d U S PI. 
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6. 8. 2   
Per mitte d Me dici nes  
T he o nl y p er mitte d me dicati o ns are t h e f oll o wi n g:  
•  Paracet a m ol/ aceta mi n o p he n  u p t o 2  g p er da y, at t he discreti o n of t he I n vesti gat or.  
A n y me di ci nes t hat a re c o nsi dere d necessar y t o pr otect t he partici pa nt’s welfare i n e mer ge n cies 
ma y b e gi ve n at t he I n v esti gat or’s discreti o n, re gar dless if it res ults i n a pr ot oc ol de viati o n.  
Me dicati o ns 
ma y be gi ve n at t he I n v esti gat or’s discreti o n if dee me d necessar y f or t he 
partici pa nt’s i m me diate well bei n g. 
Me dicati o ns 
ma y be a d mi nistere d t o a d dress a d verse 
reacti o ns or a ntici pate d e mer ge nc y sit uati o ns. 
T he I n v esti gat or will rec or d all c o nc o mita nt me dicati o ns ta ke n b y t he partici pa nts d uri n g t he 
st u d y, fr o m t he date of sig nat ur e of i nf or me d c o nse nt, i n t he partici pa nt s o urce data a n d i n t he 
a p pr o priate s ecti o n of t he e C R F.  
6. 8. 3   
Pr o hi bite d Me dici nes  
Pr o hi bite d me dici nes at st u d y e ntr y are i n dicate d i n t he e x cl usi o n criteria ( Secti o n  5. 2 ). 
T he partici pa nts are pr o hi bite d fr o m usi n g prescri pti o n or o ver -t he-c o u nter me dicati o ns (a part 
fr o m t h ose descri be d a b o ve) wit hi n 2 wee ks or 5  ter mi nal half-li ves, w hic h e ver is l o n ger, pri or 
t o t he first a d mi nistrati o n of st u d y i nter ve nti o n, d uri n g t he st u d y, a n d u ntil t he Safet y F oll o w U p 
Assess me nt (t his i ncl u des her bal re me di es, vita mi ns, mi nerals, a ntaci ds a n d dietar y s u p ple m e nts 
s uc h as fis h oils). 
6. 8. 4   
Ot her I nter ve nti o ns  
A d diti o nal restricti o ns t hat st u d y partici pa nts s h o ul d a d here t o fr o m Da y  -1 u ntil Safet y F oll o w 
U p Assess me nt are detail e d i n Secti o n 5. 2 . 
7  
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al  
7. 1  
Disc o nti n u ati o n of St u d y I nter ve nti o n  
A partici p a nt m ust be wit h dra w n fr o m a d mi nistrati o n of st u d y i nter ve nti o n  if a n y of t he 
f oll o wi n g occ ur:  
•  Partici pa nt wit h dra ws c o nse nt.  
•  A partici pa nt is e nr olle d b ut is s u bse q ue ntl y disc o vere d n ot t o ha ve met i ncl usi o n/e xcl usi o n 
criteria at Scree ni n g.  
•  A E s, if disc o nti n uati o n of st u d y i nter ve nti o n is c o nsi dere d n ecess ar y b y t he I n vesti gat or 
a n d/ or desir e d b y t he partici pa nt. T his i ncl u des i n partic ular A E s of se v ere i nte nsit y a n d 
S A Es re gar dless of its rel ati o ns hi p t o st u d y i nter ve nti o n.  
•  Pre g n a nc y  
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•  Pr ot oc ol n o nc o m plia nce j u d ge d as si g nifica nt b y t he I n v esti gat or (after disc uss i o n wit h t he 
S p o ns or).  
•  Use of a n o n per mitte d c o nc o mita nt dr u g if cli ni call y rele va nt as a gree d b y S p o ns or a n d 
I n v esti gat or, as defi ne d i n Secti o n 5. 2 , w here t he pre defi ne d c o nse q ue n ce is wit h dra wal fr o m 
st u d y i nter ve nti o n. 
•  A n y e ve nts t hat u nacce pt a bl y e n da n ger t he safet y of t he partici pa nt.  
If st u d y i nter ve nti o n is per ma ne ntl y disc o nti n ue d, t he partici pa nt will  re mai n i n t he st u d y t o be 
e val uate d f or s afet y. T h e Sc he d ule of Assess me nts  ( Secti o n 1. 3 ) i n dicat es d ata t o be c ollecte d at 
t he ti me of disc o nti n uati o n of st u d y i nter ve nti o n a n d f oll o w-u p a n d f or a n y f urt her e val uati o ns 
t hat nee d t o be c o m plete d. 
If a cli nicall y si g nifica nt fi n di ng is i d e ntifie d (i ncl u di n g c h a n ges fr o m B as eli ne i n Q T i nter val 
c orrecte d usi n g Q Tc F ) after e nr oll me nt, t he I n v esti gat or or q ualifie d d esi g n ee will deter mi ne if 
t he partici pa nt ca n c o nti n ue i n t he st u d y a n d if a n y c ha n ge i n p artici pa nt ma na ge me nt is n ee d e d. 
T his re vie w of t he E C G pri nte d at t he ti me of c ollecti o n will be d oc u me nte d. A n y ne w cli nicall y 
rele va nt fi n di n g is re p orte d as a n A E. 
7. 2  
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y  
•  A partici pa nt ma y disc o nti n ue fr o m t he st u d y at a n y ti me, at his/ her o w n re q uest or at t he 
discreti o n of t he I n v esti gat or f or safet y, be h a vi oral, c o m plia nce, or a d mi nistrati ve reas o ns.  
•  T he partici pa nt ma y b e wit h dra w n b y t he I n vesti gat or d ue t o partici pati o n i n a n ot her cli nical 
st u d y. 
•  A partici pa nt m ust be wit h dra w n if a n y of t he f oll o wi n g occ urs d uri n g t he st u d y:  
•  Pre g n a nc y.  
•  A E s, if st u d y dis c o nti n uati o n is c o nsi dere d necess ar y b y t h e I n vesti gat or a n d/ or desire d 
b y t he partici p a nt. T his i ncl u des i n partic ular A E s of se vere i nte nsit y a n d S A Es 
re gar dl ess of t heir relati o nshi p t o st u d y i nter ve nti o n.  
•  Use of n o n per mitte d c o n c o mita nt me dicati o ns, as defi ne d i n Secti o n  6. 8 . H o we ver, a n y 
me dicati o ns t hat are c o nsi dere d necessar y f or t he partici pa nt’s well bei n g (e. g., 
paraceta m ol/aceta mi n o p he n u p t o 2 g per da y) ma y be gi ve n at t he discreti o n of t he 
I n v esti gat or. 
•  Pr ot oc ol n o nc o m plia nce j u d ge d as si g nifica nt b y t he I n vesti gat o r, i ncl u di n g 
n o nc o m plia nce t o t he re q uire d st u d y c o nsi derati o ns (e. g.,  f o o d/ diet re q uire me nts), as 
defi ne d i n e. g. , Secti o ns  5. 1 , 5. 2 , 5. 3. 1 , a n d 8 . 
•  P ositi ve f or S A R S -C o V -2 o n a d missi o n o n Da y  1 1.  
•  If a partici pa nt has fail e d t o atte n d sc he d ule d st u d y assess me nts, t he I n vesti gat or m ust 
deter mi ne t he reas o ns a n d t he circ u msta nces as c o m pletel y a n d acc uratel y as p ossi ble.  
•  If a partici pa nt m ust be wit h dra w n fr o m t he st u d y, t he Me dical M o nit or a n d cli nical st u d y 
lea der f or t he S p o ns or will be i nf or me d i m me diatel y. 
•  If t here is a me dical r eas o n f or t he wit h dra wal, a p pr o priate me dical care will be pr ovi de d.  
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•  At t he ti me of st u d y disc o nti n uati o n, if p ossi ble, a disc o nti n uati o n visit will be c o n d ucte d, as 
liste d i n t he Sc he d ule of Assess me nts  ( Secti o n 1. 3 ). T he Sc he d ule of Assess me nts  s pecifies 
t he data t o c ollect at st u d y disc o nti n uati o n a n d f oll o w-u p, a n d a n y a d diti o nal e val uati o ns t hat 
nee d t o be c o m plet e d.  
•  If t he p artici pa nt re v o kes c o nse nt f or t he st u d y, a n y d ata c ollecte d u p t o t hat p oi nt ma y still 
be use d, b ut n o f ut ure data ca n be ge nerate d, a n d a n y bi ol o gi cal s a m ples c ollecte d will be 
destr o ye d.  
•  
A partici pa nt has t he ri g ht at a n y ti me t o re q uest destr ucti o n of a n y bi ol o gical sa m ples ta k e n. 
T he In vesti gat or will d oc u me nt t his i n t he site st u d y rec or ds a n d t he C R F a n d i nf or m t he 
S p o ns or. T he sa m ples will be destr o ye d.  
7. 3  
L ost t o F oll o w -U p  
A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y site.  
T he f oll o wi n g acti o ns will  be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y 
visit:  
•  T he site will  atte m pt t o c o ntact t he partici pa nt a n d resc he d ul e t he misse d visit as s o o n as 
p ossi ble, c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit sc he d ule 
a n d ascertai n if t he partici pa nt wa nts t o or s h o ul d c o nti n ue i n t he st u d y.  
•  Bef ore a partici pa nt is d ee me d “l ost t o f oll o w-u p ”, t he In v esti gat or or desi g nee wi ll ma ke 
e ver y eff ort t o re gai n c o ntact wit h t he partici p a nt: 1) w here p ossi ble, ma ke 3 tele p h o ne calls ; 
2) if necess ar y, se n d a certifie d letter ( or a n e q ui vale nt l ocal met h o d) t o t he partici pa nt’s last 
k n o w n maili n g a d dress , a n d 3) if a partici p a nt has gi ve n t h e a p pr o priate c o nse nt, c o ntact t h e 
partici pa nt’s ge n eral practiti o ner or careta ker ( w here all o we d b y l ocal re g ulati o ns) f or 
i nf or mati o n. T hese c o nt act atte m pts will  be d oc u me nte d i n t he partici pa nt’s me dical rec or d.  
•  If t he partici p a nt c o nti n ues t o be u nreac ha bl e, he/s he will be dee me d as “l ost t o f oll o w -u p” . 
8  
St u d y Assess me nts a n d Pr oce d ures  
•  St u d y assess me nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he Sc he d ule of 
Assess me nts  ( Secti o n 1. 3 ). 
•  N o  pr ot oc ol wai vers or e x e m pti o ns are all o we d.  
•  I m me diat e safet y c o n cer ns are dis c usse d wit h t he S p o ns or i m me diatel y u p o n occ urre nce or 
a ware ness t o deter mi ne if t he parti ci pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y i nter ve nti o n.  
•  A d here n ce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he Sc he d ule of 
Assess me nts , is esse ntial a n d re q uire d f or st u d y c o n d uct. 
•  All scree ni n g e v al uati o ns will  be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T he In v esti gat or will mai ntai n a scree ni n g l o g t o 
rec or d d etails of all partici pa nts scree n e d, t o c o nfir m eli gi bilit y, a n d if a p plica ble, rec or d 
reas o ns f or scree ni n g fail ure. 
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I N F O R M A T I O N 
3 3 / 6 8 
 
 
•  Pri or t o perf or mi n g a n y st u d y assess m e nts t hat are n ot part of t he p arti ci pa nt’s r o uti ne 
me dical care, t he I n v esti gat or will o btai n writte n i nf or me d c o ns e nt as s pecifie d i n  
A p pe n di x  2 . 
•  Pr oce d ures c o n d u c te d as part of t he partici pa nt’s r o uti ne me dical care (e. g., bl o o d c o u nt) a n d 
o btai ne d bef ore si g ni n g of t he I C F ma y be us e d f or scree ni n g or baseli ne p ur p oses pr o vi de d 
t he pr oce d ures met t he pr ot oc ol-s pecifie d criteria a n d were p erf or me d wit hi n t he ti me fra me 
defi ne d i n t he Sc he d ule of Assess me nts .  
•  De m o gra p hic d ata c ollecte d at Scree ni n g will i ncl u de, at mi ni m u m, a ge, s e x, race (c ollecte d 
o nl y w here all o we d b y l ocal la w/re g ul ati o ns), a n d et h nicit y.  
•  N o m ore t ha n 5 0  m L of bl o o d ma y b e dra w n i n a 2 4 -h o ur peri o d, a n d n o m ore t ha n 1 5 0  m L 
of bl o o d i n a 4 -wee k peri o d.  
•  W here all o we d b y l ocal l a w/re g ulati o ns, sa m ples c ollecte d d uri n g t his cli nical st u d y ma y b e 
tra nsferre d t o a bi o ba n k a n d use d f or f ut ure researc h o utsi de t he cli nical pr ot oc ol w he n 
a d diti o nal c o nse nt f or t his p ur p ose is gi ve n. Tra nsfer t o t he bi o ba n k will be d oc u me nte d a n d 
a n y t esti n g of c o de d bi o b a n k sa m ples will n ot  be re p orte d i n t he C S R.  
•  T he l o n g -ter m st or a ge of sa m ples after st u d y c o m pleti o n f or f ut ure researc h ma y b e 
perf or me d wit h all sa m ple t y p es c ollect e d i n t he st u d y (e. g., P K, 
 
 or 
 if t he partici pa nt c o nse nts t o o pti o nal f ut ure me dical 
researc h. 
8. 1   
Effic ac y Assess me nts a n d Pr oce d ures  
N ot a p plica ble.  
8. 2   
S afet y Assess me nts a n d Pr oce d ures  
T he safet y pr ofile of t he st u d y i nter ve nti o n will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d 
a nal ysis of b aseli ne me dical c o n diti o ns, A E s, p h ysical e x a mi nati o n fi n di n gs, vital si g ns, 
electr ocar di o gra ms, a n d l a b orat or y tests . 
C o m pre he nsi ve assess m e nt of a n y p ot e ntial t o xicit y e x perie nce d b y eac h partici pa nt will be 
c o n d ucte d starti n g w he n t he partici pa nts gi ve i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y. T he 
In v esti gat or will re p ort a n y A E s, w het her o bser ve d b y t he I n v esti gat or or re p orte d b y t he 
partici pa nt; t he re p orti n g peri o d is s pecifie d i n Secti o n  8. 3 . 
8. 2. 1   
P h ysic al E x a mi n ati o ns  
•  A c o m plete p h ysical e x a mi nati o n 
will i ncl u de,  at a 
mi ni m u m, assess me nts of t he 
car di o vas c ular, res pirat or y, g astr oi ntesti nal a n d n e ur ol o gical s yste ms.  
•  A brief p h ysical e x a mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, l u n gs, 
car di o vas c ular s yste m, a n d a b d o me n (li ver a n d s plee n).  
•  I n v esti gat ors will  pa y s pecial atte nti o n t o cli nical si g ns relat e d t o pre vi o us seri o us ill nesses.  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


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Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 4 / 6 8 
 
 
8. 2. 2   
Vit al Si g ns  
•  Bl o o d press ur e a n d p artici pa nt’s p ositi o n; p ulse ; res pirat or y rate; te m perat ure a n d l ocati o n 
of meas ure m e nt , wei g ht, a n d hei g ht (at Baseli ne o nl y) will be meas ure d a n d rec or de d.  
•  Bl o o d press ure a n d p ulse meas ure m e nts will  be prece d e d b y at l east 5 mi n utes of rest f or t he 
partici pa nt i n a q uiet setti n g wit h o ut distracti o ns (e. g., tele visi o n, cell p h o nes)  a n d meas ure d 
wit h a n a ut o mate d de vice. Ma n ual tec h ni q ues will be use d o nl y if a n a ut o mate d de vice is n ot 
a vaila ble.  
•  Vital si g ns will be meas ure d i n s u pi ne p ositi o n.  
8. 2. 3   
Electr oc ar di o gr a ms  
•  Si n gle 1 2 -lea d E C G will be o btai ne d as o utli ne d i n t he Sc he d ule of Assess me nts  
( Secti o n 1. 3 ) usi n g a n E C G mac hi ne t hat a ut o maticall y meas ures heart rat e, P R, R R, Q R S, 
Q T , a n d Q Tc B or Q Tc F. D oc u me ntati o n of t he Q Tc F is ma n dat or y.  
•  1 2 -Lea d E C Gs will be rec or de d i n a s u pi ne p os iti o n f oll o wi n g 5 mi n utes of rest. 
8. 2. 4   
Cli nic al S afet y L a b or at or y Assess me nts  
•  Bl o o d a n d uri ne sa m ples will be c ollecte d f or t he cli nical la b orat or y tests liste d i n A p pe n di x  5  
at t he ti me p oi nts liste d i n t he Sc he d ul e of Assess me nts  ( Secti o n 1. 3 ). All sa m ples will  be 
clearl y i de ntifie d.  
•  A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he st u d y, as deter mi n e d nec ess ar y b y 
t he In v esti gat or or re q uir e d b y l o cal re g ul ati o ns.  
•  T he tests will be perf or me d b y N u visa n G m b H la b orat or y . 
•  T he In v esti gat or will  re vie w eac h la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y si g nifica nt c ha n ges o cc urri n g d uri n g t he st u d y as a n A E , u nless it d oes n ot  meet 
t he A E defi niti o n, as s pecifie d i n A p pe n di x 4 . T he la b orat or y re p orts will  be file d wit h t he 
s o urce d oc u m e nts. 
8. 2. 5   
S uici d al I de ati o n a n d Be h a vi or Ris k M o nit ori n g  
N ot a p plica ble.  
8. 3   
A d verse E ve nts , Seri o us A d verse E ve nts , a n d Ot her S afet y 
Re p orti n g  
•  T he defi niti o ns of a n A E a n d a S A E are i n A p pe n di x 4 . 
•  T he I n v esti gat or a n d a n y q u alifie d d esi g n ees (e. g., S u b -In vesti gat ors)  are res p o nsi ble f or 
detecti n g, d oc u me nti n g, a n d rec or di n g e ve nts t hat meet t he defi niti o n of a n A E or S A E. T he 
I n v esti gat or re mai ns res p o nsi ble f or f oll o wi n g u p AE s t hat are seri o us, c o nsi dere d relat e d t o 
t he st u d y i nter ve nti o n or st u d y pr oce d ures , or t ha t ca use d t he partici pa nt t o disc o nti n ue t he 
st u d y i nter ve nti o n or st u d y, as s p ecifie d i n Secti o n 8. 3. 2 . 
Gl o bal Versi o n I D: C CI


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Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 5 / 6 8 
 
 
•  Re q uests f or f oll o w -u p will us uall y be m a de via t he S p o ns or or C R O -d esi g nate d st u d y tea m 
me m ber , alt h o u g h i n e x ce pti o nal circ u msta nces t he gl o bal patie nt  s afet y de part me nt m a y 
c o ntact t he I n v esti gat or directl y t o o btai n f urt her i nf or mati o n or t o disc uss t he e ve nt . 
•  T he met h o d of rec or di n g, e v al uati n g, a n d assessi n g ca usalit y of A E s a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tr a ns mitti n g S A E re p orts are i n A p pe n di x 4 . 
•  All A E s a n d S A Es will be c ollecte d fr o m t he si g ni n g of t he I C F u ntil t he Safet y F oll o w U p 
Visit  at t he ti me p oi nts s pecifie d i n t he Sc h e d ule of Assess me nts  ( Secti o n 1. 3 ). Be y o n d t his 
re p orti n g peri o d, a n y n e w u ns olicite d S A Es t hat t he I n v esti gator s p o nta ne o usl y re p orts t o t he 
S p o ns or will be c ollecte d a n d pr ocess e d.  
•  All S A Es will be rec or de d a n d re p orte d t o t he S p o ns or or d esi g n ee i m me diatel y a n d u n d er 
n o circ u msta nce will t his e x cee d 2 4 h o urs, as i n dicate d i n A p pe n di x 4 . T he I n v esti gat or will 
s u b mit a n y u p d ate d S A E data t o t he S p o ns or wit hi n 2 4 h o urs of it bei n g a v aila ble usi n g t he 
sa me pr oce d ure t hat was use d f or t he i nitial re p ort. 
•  I n v esti gat ors are n ot o bli gat e d t o acti vel y s olicit i nf or mati o n o n A E s or SA Es  after t he e n d 
of st u d y partici pati o n. H o we ver, if t he In vesti gat or lear ns of a n y S A E, i n cl u di n g a deat h, at 
a n y ti me after a partici p a nt has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he 
e ve nt t o b e reas o na bl y rel ate d t o t he st u d y i nter ve nti o n or st u d y partici pati o n, t he I n v esti gat or 
will  pr o m ptl y n otif y t he S p o ns or.  
8. 3. 1   
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts  
•  At eac h st u d y visit, t he partici pa nt will be q uerie d o n c ha n ges i n his or her c o n diti o n .  
•  Care will be ta ke n n ot t o i ntr o d uce bias w he n det ecti n g AE s a n d/ or S A Es. O pe n-e n d e d a n d 
n o nlea di n g v er bal q uesti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut A E 
occ urre nces.  
•  T he met h o d of rec or di n g, e v al uati n g, a n d assessi n g ca usalit y of A E s a n d S A Es a n d t he 
pr o ce d ures f or c o m pleti n g a n d tr a ns mitti n g S A E re p orts are i n A p pe n di x 4 . 
8. 3. 2   
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts  
•  After t he i nitial A E/ S A E re p ort, t he In v esti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
pa rtici pa nt at s u bse q ue nt visits/c o ntacts. All S A Es a n d A E SIs (as defi ne d i n Secti o n  8. 3. 7 ) 
will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt  is ot her wise e x plai ne d, or t he 
partici pa nt is l ost t o f oll o w -u p (as defi ne d i n Secti o n 7. 3 ). Reas o na ble atte m pts t o o btai n t his 
i nf or mati o n will  be ma de a n d d o c u me nte d. It is als o t he I n vesti gat or’s res p o nsi bilit y t o 
e ns ure t hat a n y n ecess ar y a d diti o nal t hera pe utic meas ures a n d f oll o w -u p pr oce d ures are 
perf or me d. F urt h er i nf or mati o n o n f oll o w -u p pr oce d ures is i n A p pe n di x 4 . 
Gl o bal Versi o n I D: C CI


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C O N F I D E N T I A L  
I N F O R M A T I O N 
3 6 / 6 8 
 
 
8. 3. 3   
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us A d verse 
E ve nts  
•  Pr o m pt n otificati o n b y t he I n vesti gat or t o t he S p o ns or of a n S A E ( partic ularl y life -
t hreate ni n g a n d deat hs) is esse ntial s o t hat l e gal o bli gati o ns a n d et hical res p o nsi bilities 
t o war ds t he safet y of p artici pa nts a n d t he safet y of a st u d y i nter ve nti o n u n der cli nical 
i n vesti gati o n are met. 
•  T he S p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge nci es a b o ut t he safet y of a st u d y int er ve nti o n u n der cli nical i n vesti gati o n. T he 
S p o ns or will c o m pl y wit h c o u ntr y -s p ecific re g ulat or y re q uire me nts relati n g t o safet y 
re p orti n g t o t he re g ulat or y a ut h orit y, I R B/I E C, a n d In v esti gat ors.  
•  I n di vi d ual Cas e Safet y R e p orts will  be pre p are d f or S U S A R s acc or di n g t o l ocal re g ulat or y 
re q uire me nts a n d S p o ns or p olic y a n d f or war de d t o In v esti gat ors, as necessar y.  
•  A n In vesti gat or w h o recei ves a n I n di vi d ual C ase S afet y Re p ort descri bi n g a S U S A R or ot her 
s pecific s afet y i nf or mati o n (e. g., E mer gi n g Safet y Iss u e Re p ort, s u m mar y or listi n g of 
S A Es/ S U S A Rs) fr o m t he S p o ns or will re vie w a n d file it i n t he I n v esti gat or’s Site File a n d 
will n otif y t h e I R B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.  
8. 3. 4   
Pre g n a nc y  
•  Details of all pre g na n cies i n fe male part ners of male partici pa nts will be c ollecte d after t he 
start of st u d y i nt er ve nti o n a n d u ntil at least 3 m o nt hs after t h e last d ose of st u d y i nter ve nti o n . 
•  If a pre g na n c y is re p ort e d, t he I n vesti gat or will rec or d t h e pre g n a nc y i nf or mati o n o n t he 
a p pr o priate f or m a n d s u b m it it t o t he S p o ns or wit hi n 2 4 h o urs of fe male part ner of m ale 
partici pa nt (aft er o btai ni n g t he necessar y si g n e d i nf or me d c o nse nt fr o m t he fe male p art ner) 
pre g na nc y.  
•  W hile pre g n a nc y itself is n ot c o nsi dere d t o b e a n A E or S A E, a n y pre g na n c y c o m plicati o n 
or  electi ve ter mi nati o n of a pre g na n c y will be re p orte d as a n A E or S A E.  A d verse  pre g na n c y 
o utc o mes (e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital a n o malies, ect o pic 
pre g na nc y) are c o nsi d ere d a n d re p orte d as S A Es.  A s p o nta ne o us a b orti o n ( occ urri n g at 
<  2 2  wee ks gestati o nal a ge) or still birt h ( occ urri n g at >  2 2  wee ks gestati o n al a ge) is al w a ys 
c o nsi dere d t o be a n S A E a n d will be re p orte d as s uc h.  
•  T he partici pa nt / pre g na nt fe male p art ner will be f oll o we d t o deter mi ne  t he o utc o me of t h e 
pre g na nc y. T h e I n v esti gat or will c ollect f oll o w -u p i nf or mati o n o n t he partici pa nt / pre g n a nt 
fe male part ner a n d t he ne o nate, a n d t he i nf or mati o n will be f or war de d t o t he S p o ns or. 
Ge nerall y, f oll o w -u p will n ot be re q uire d f or l o n ger t ha n 6 t o 8 wee ks be y o n d t he esti mate d 
deli ver y d ate f or a healt h y ne w b or n. I n case of a c o n ge nital a n o mal y or ot her ill ness of t he 
ne w b or n, f oll o w -u p will c o nti n ue u ntil t he ill ness has res ol ve d or t here is a defi nite o utc o me 
of t he e ve nt.  
•  A n y p ostst u d y pre g na n c y relate d S A E c o nsi d ere d reas o na bl y relate d t o t he st u d y 
i nter ve nti o n b y t he I n v esti gat or will be re p orte d t o t he S p o ns or as s pecifie d i n Secti o n 8. 3. 3 . 
W hile t he I n v esti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n i n f or mer st u d y 
partici pa nts  / pr e g na nt fe male part ner, he or s h e ma y l ear n of a n S A E t hr o u g h s p o nta ne o us 
re p orti n g. 
Gl o bal Versi o n I D: C CI


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M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 7 / 6 8 
 
 
•  A n y fe m ale p artici pa nt w h o b ec o mes pre g n a nt w hile partici pati n g i n t he st u d y will 
disc o nti n ue st u d y i nter ve nti o n or be wit h dra w n fr o m t he st u d y.  
8. 3. 5   
C ar di o v asc ul ar a n d De at h E ve nts  
N ot a p plica ble.  
8. 3. 6   
Dise ase -Rel ate d E ve nts a n d/ or Dise ase -Rel ate d O utc o mes 
N ot Q u alif yi n g as A E s or S A Es 
N ot a p plica ble.  
8. 3. 7   
A d verse E ve nts of S pec i al I nterest 
F or t his st u d y, A E SIs i ncl u de o nl y t he f oll o wi n g:  
•  A Es s u g gesti ve of dr u g -i n d uce d li ver i nj ur y i n cl u di n g h e patic/li ver fail ure a n d he patitis 
( n o ni nfecti o us) are c o nsi dere d A E SIs. 
A E SIs will be re p orte d t o t he S p o ns or ( or del e gate) i m me diat el y m a n ner as d escri be d i n 
A p pe n di x 4 .  
Gl o bal Versi o n I D: C CI


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C O N F I D E N T I A L  
I N F O R M A T I O N 
3 8 / 6 8 
 
 
8. 4  
P h ar m ac o ki netics  
C ollecti o n of Pl as m a f or P h ar m ac o ki netic A n al ysis  
F or details o n P K sa m pli n g ti me p oi nts, see t he Sc he d ule of Assess me nts  i n Secti o n 1. 3 , a n d 
Ta ble 1  a n d T a ble 2 .  
T he f oll o wi n g P K para meters will be calc ulat e d, w he n a p pr o priate, f or te p oti ni b a n d  
 
: 
S y m b ol  
D efi niti o n  
A U C 0 -∞ 
T h e A U C fr o m ti m e z er o ( d o si n g ti m e) e xtr a p ol at e d t o i nfi nit y, b a s e d o n t h e 
pr e di ct e d v al u e f or t h e c o n c e ntr ati o n at tl a st, a s e sti m at e d u si n g t h e li n e ar 
r e gr e s si o n fr o m λz d et er mi n ati o n. A U C 0 -∞= A U C 0 -tl a st + C l a st pr e d/ λ z 
A U C 0 -tl a st 
T h e ar e a u n d er t h e c o n c e ntr ati o n -ti m e c ur v e ( A U C) fr o m ti m e z er o ( = d o si n g 
ti m e) t o t h e ti m e of t h e l a st q u a ntifi a bl e c o n c e ntr ati o n (tl a st), c al c ul at e d u si n g 
t h e mi x e d l o g-li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g d o w n). 
A U C 0 -2 4 h  
T h e A U C fr o m ti m e z er o ( = d o si n g ti m e) t o ti m e p oi nt 2 4  h o ur s. C al c ul at e d 
u si n g t h e mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g d o w n). 
A U C 0 -tl a st / D o s e 
T h e d o s e n or m ali z e d A U C fr o m ti m e z er o t o t h e l a st s a m pli n g ti m e (tl a st) at 
w hi c h t h e c o n c e ntr ati o n i s at or a b o v e t h e l o w er li mit of q u a ntifi c ati o n. 
N or m ali z e d u si n g t h e a ct u al d o s e, u si n g t h e f or m ul a A U C 0 -tl a st/ D o s e. 
A U C 0 -2 4 h / D o s e 
T h e d o s e n or m ali z e d A U C fr o m ti m e z er o t o ti m e p oi nt 2 4  h o ur s. N or m ali z e d 
u si n g t h e a ct u al d o s e, u si n g t h e f or m ul a A U C0 -2 4 t / D o s e. 
C m a x  
M a xi m u m o b s er v e d c o n c e ntr ati o n.  
C m a x / D o s e 
T h e d o s e n or m ali z e d m a xi m u m c o n c e ntr ati o n. N or m ali z e d u si n g t h e a ct u al 
d o s e, a n d t h e f or m ul a C m a x / D o s e. 
T m a x  
T h e ti m e t o r e a c h t h e m a xi m u m o b s er v e d c o n c e ntr ati o n c oll e ct e d d uri n g a 
d o si n g i nt er v al ( u nl e s s ot h er wi s e d efi n e d, t a k e t h e 1 st o c c urr e n c e i n c a s e of 
m ulti pl e/i d e nti c al C
m a x  v al u e s)  
t1/ 2  
A p p ar e nt t er mi n al h alf -lif e. T1/ 2  = l n ( 2)/ λ z 
λ z 
T er mi n al fir st or d er ( eli mi n ati o n) r at e c o n st a nt. D et er mi n e d fr o m t h e t er mi n al 
sl o p e of t h e l o g -tr a n sf or m e d c o n c e ntr ati o n c ur v e u si n g li n e ar r e gr e s si o n o n 
t er mi n al d at a p oi nt s of t h e c ur v e. 
C L/ F ( p ar e nt dr u g o nl y)  
T h e a p p ar e nt t ot al b o d y cl e ar a n c e of st u d y i nt er v e nti o n f oll o wi n g e xtr a v a s c ul ar 
a d mi ni str ati o n.  
C L/ F = D o s e p o  / A U C0 -∞. 
P ar e nt dr u g, o nl y.  
V Z / F ( p ar e nt dr u g o nl y) 
T h e a p p ar e nt v ol u m e of di stri b uti o n d uri n g t h e t er mi n al p h a s e f oll o wi n g 
e xtr a v a s c ul ar a d mi ni str ati o n  
V z/ F = D o s e/(A U C 0 -∞× λ z) f oll o wi n g si n gl e d o s e. 
P ar e nt dr u g, o nl y.  
A U C e xtra % 
T h e A U C  fr o m ti m e tl a st e xtr a p ol at e d t o i nfi nit y gi v e n a s p er c e nt a g e of A U C 0 -∞. 
A U C e xtr a %  = ( e xtr a p ol at e d ar e a/ A U C 0 -∞)× 1 0 0.  
 
 
  
 
 
 
  
 
Gl o bal Versi o n I D: C CI
C CI
C
CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 9 / 6 8 
 
 
•  W h ole bl o o d 
sa m ples of a p pr o xi matel y 2  m L per c ollecti o n f or meas ure me nt of plas ma  
c o nce ntr ati o ns of te p oti ni b a n d its   
 
will be 
c ollecte d. C ollecti o n ti mes are s pecifi e d i n t he Sc he d ule of Assess me nts  ( Secti o n 1. 3 ) a n d 
Ta ble 1 . T he act ual date a n d ti me ( 2 4-h o ur cl oc k ti me) of eac h  sa m ple will be rec or de d t o 
calc ulate act ual ti me ela pse d si nce t he pri or d os e a d mi nistrati o n.  
•  T he q ua ntificati o n of te p oti ni b a n d its 
 i n 
plas ma will be perf or me d usi n g a vali date d assa y met h o d. C o nce ntrati o ns will b e use d t o 
e val uate t he P K of t e p oti ni b a n d its meta b olites.  
•  Re mai ni n g sa m ples c ollecte d f or a nal ys es of te p oti ni b c o nce ntrati o n ma y als o be use d t o 
e val uate safet y or efficac y as p ects rel ate d t o c o ncer ns arisi n g d uri n g or after t he st u d y.  
•  Details o n pr oces ses f or c ollecti o n a n d ha n dli n g of t hese sa m ples are i n t he La b orat or y 
Ma n ual. Rete nti o n ti me a n d p ossi ble a nal ys es of sa m ples after t he e n d of st u d y are s pecifie d 
i n t he res pecti ve I C F. 
•  P K para meters will be deri ve d usi n g n o n c o m part m e ntal met h o ds wit h t he  vali date d c o m p uter 
pr o gra m.  
T he e x act date a n d ti me of sa m ple c ollecti o n a n d st u d y i nter ve nti o n ( 2 4 -h o ur cl oc k ti me) m ust 
be rec or de d i n t he e C R F a n d will be use d i n t he calc ulati o n of P K para met ers. T he acce pte d ti me 
de viati o ns fr o m pla n ne d te p oti ni b P K ti mes t hat will n ot be c o nsi dere d a pr ot oc ol vi olati o n are 
liste d bel o w (Ta ble 2 ). 
T a ble 2   
P K S a m pli n g Ti me Wi n d o w s 
Pr o c e d ur e  
Ti m e P oi nt ( R el ati v e Ti m e)  
Wi n d o w All o w a n c e  
P h ar m a c o ki n eti c s  
Pr e d o s e  
- 6 0 mi n  
1 t o 1 2 h o ur s p o st d o s e  
- 5 / + 5 mi n  
> 1 2 t o 2 4 h o ur s p o st d o s e  
- 3 0 / + 3 0 mi n  
> 2 4 t o 7 2 h o ur s p o st d o s e  
- 6 0 / + 6 0 mi n  
> 7 2 t o 1 6 8 h o ur s p o st d o s e  
- 1 8 0 / + 1 8 0 mi n  
A n y d e viati o n fr o m t he a b o ve -me nti o ne d ti me wi n d o ws re q uires a c o m me nt i n t he e C R F a n d 
ma y b e disc usse d i n t he data re vie w meeti n g.  
C olle cti o n of Feces  f or P h ar m a c o ki netic A n al ysis  
I n b ot h i n-h o us e peri o ds of t he st u d y , all feces after a d mi nistrati o n of tep oti ni b  u ntil disc har ge 
fr o m t he C R U  (i.e., fr o m Da y 1 t o Da y 4, a n d fr o m Da y 1 2 t o Da y 1 5) will be c ollecte d f or 
e x pl orat or y te p oti ni b p har mac o ki netic  a n al ysis.   
•  T o e ns ure defecati o n, partici pa nt s will recei ve a mil d la xati ve o n t he e ve ni n gs of Da y  3 a n d 
Da y 1 4 . 
•  T he e x act date a n d ti me of sa m ple c ollecti o n a n d st u d y i nter ve nti o n ( 2 4 -h o ur cl oc k ti me) 
m ust be rec or de d i n t he e C R F .  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 0 / 6 8 
 
 
•  T he c u m ulati ve a m o u nt ( % of d ose) of t e p oti ni b e x crete d i n t he feces d uri n g t his ti me will 
be q ua ntifie d.  
•  Details o n pr ocesses f or c ollecti o n a n d ha n dli n g of t hese sa m ples are i n t he La b orat or y 
Ma n ual.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9  
St atistic al C o nsi der ati o ns  
All pla n ne d a nal ys es defi ne d i n t his pr ot oc ol will be descri be d i n t he I A P t hat will be fi nalize d 
bef ore t h e data base l oc k.  
C ha n ges i n t he c o n d u ct of t he st u d y or pla n ne d a nal ys es, if a n y, will be re p orte d i n t he 
a p pr o priate s ecti o n of t he I A P a n d i n t he cli nical st u d y re p ort.  
9. 1  
St atistic al H y p ot hes es 
T he statistical a nal ysis of st u d y d ata will be p urel y  descri pti ve; n o h y p ot hesis tests will be 
perf or me d. A d efi niti o n of pri mar y, s ec o n d ar y a n d 
 o bjecti ves a n d e n d p oi nts 
ca n be f o u n d i n Secti o n  3 . 
9. 2  
S a m ple Size Deter mi n ati o n  
A ma xi m u m of  1 8  partici pa nts will be assi g ne d t o  st u d y i nter ve nti o ns s uc h t hat at least 
1 4  e val ua ble p artici pa nts c o m plete t he st u d y . 
Alt h o u g h n o h y p ot hesis tests will be perf or me d, t h e sa m ple size of t he st u d y s h o u l d be s ufficie nt 
t o esti mate t he differe nce bet wee n d osi n g c o n diti o ns wit h a de q uate precisi o n.  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 1 / 6 8 
 
 
A vaila ble i nf or mati o n o n i ntra partici pa nt varia bilit y of te p oti ni b P K para meters f oll o wi n g 
a d mi nistrati o n of T F 2 a n d/ or T F 3 u n der differe nt d osi n g c o n diti o ns, o bser ve d i n st u dies 
M S 2 0 0 0 9 5 _ 0 0 4 4, 
M S 2 0 0 0 9 5 _ 0 0 3 8 a n d 
M S 2 0 0 0 9 5 _ 0 0 3 9 are prese nte d i n 
Ta ble 3 . T he 
i ntrapartici pa nt  C V is a p pr o xi matel y bet wee n 1 0. 4 % a n d 1 8. 0 % f or A U C 0 -∞ a n d A U C 0 -tlast, a n d 
f or Cma x  bet wee n 1 2. 7 % a n d 1 6. 4 %.  
T a ble 3   
O ver vie w of 
O bser ve d Intr a p artici p a nt  V ari a bilit y of Te p oti ni b 
P h ar m a c o ki netic P ar a meters  
 
 
 
Mi x e d Intr a p arti ci p a nt  C V  
St u d y  
C o m p ari s o n  
N  
A U C 0 -tl a st  
A U C 0 -∞ 
C m a x  
M S 2 0 0 0 9 5 _ 0 0 4 4 
P art A  
T F 3 v er s u s T F 2 
(f a st e d) 
3 8   
1 5. 7 7 %  
1 5. 8 3 %   
1 3. 9 4 %  
M S 2 0 0 0 9 5 _ 0 0 4 4 
P art B  
T F 2 (f e d v er s u s 
f a st e d) 
1 4   
1 7. 9 6 %  
1 7. 9 5 %   
1 2. 6 7 %  
M S 2 0 0 0 9 5 _ 0 0 4 4 
P art C  
T F 3 (f e d v er s u s 
f a st e d) 
1 2   
1 4. 9 3 %  
1 5. 1 0 %   
1 6. 7 9 %  
M S 2 0 0 0 9 5 _ 0 0 3 8   
5 ×  1 0 0 m g T F 3 
v er s u s 2 ×  2 5 0 m g 
T F 3 (f a st e d)  
1 8   
1 5. 2 6 %  
1 5. 2 9 %   
1 6. 3 7 %  
M S 2 0 0 0 9 5 _ 0 0 3 9   
T e p oti ni b F e d + 
O m e pr a z ol e v er s u s 
T e p oti ni b F e d  
1 2   
1 0. 4 1 %  
1 0. 9 3 %   
1 6. 2 2 %  
C V = C o effi ci e nt of V ari ati o n , N = n u m b er of p arti ci p a nt s. 
T h us, ass u mi n g a n i ntra partici pa nt C V ( %) of 1 0 %, 1 5 %, a n d 2 0 % f or A U C a n d C ma x  of 
te p oti ni b, t he precisi o n f or t he esti mate d rati o (c oa d mi nistrati o n of te p oti ni b a n d itrac o naz ole 
vers us te p oti ni b al o ne) t o be ac hie ve d wit h a gi ve n n u m ber of e v al ua ble partici pa nts is 
s u m marize d i n Ta ble 4 . Ass u mi n g a C V of 2 0 %, if 1 4 e val ua ble partici pa nts are i ncl u de d i n t he 
st u d y a n d t he o bser ve d rati o is e x actl y 1. 0, t h e n t he 9 0 %  CI f or t he rati o will be c o nt ai ne d wit h 
8 0 % pr o ba bilit y i n 0. 8 0 5 t o 1. 2 4 2. If t he o bser ve d rati o is e x actl y 2. 0, t he n t he c orres p o n di n g 
li mits are 1. 6 1 1 t o 2. 4 8 4. 
T his precisi o n is c o nsi de re d a d e q uate t o c h aracteri ze t he effect of m ulti ple d oses of itrac o n az ole 
o n t he P K of te p oti ni b. A f urt her i ncrease i n sa m ple size d oes n ot s u bsta ntiall y i m pr o ve t he 
precisi o n. O n t h e ot her h a n d, e v e n wit h a sli g htl y s maller n u m ber of c o m plete d partici pa n ts, t he 
precisi o n will be mar ke dl y decrease d.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 2 / 6 8 
 
 
T a ble 4   
Wi dt h of t he 9 0 % CI f or t he R ati o of P h ar m ac o ki netic  P a r a meters, f or 
Differe nt 
Ge o metric 
M e a n 
R ati os, 
S a m ple 
Sizes , a n d  
Wit hi n -
P artici p a nt C Vs  
 
 
9 0 % C o nfi d e n c e I nt er v al wit h 8 0 % T ol er a n c e Pr o b a bilit y  
O b s er v e d Tr e at m e nt R ati o  N (t ot al)   
C V = 1 0 %   
C V = 1 5 %  
C V = 2 0 %  
1. 0 0 0  
1 0   
0. 8 7 1 -1. 1 4 8  
0. 8 1 4 -1. 2 2 9  
0. 7 6 1 -1. 3 1 5  
 
1 2   
0. 8 8 6 -1. 1 2 9  
0. 8 3 4 -1. 1 9 8  
0. 7 8 6 -1. 2 7 2  
 
1 4   
0. 8 9 7 -1. 1 1 5  
0. 8 4 9 -1. 1 7 7  
0. 8 0 5 -1. 2 4 2  
 
1 6   
0. 9 0 5 -1. 1 0 5   
0. 8 6 1 -1. 1 6 1  
0. 8 2 0 -1. 2 2 0  
 
1 8   
0. 9 1 1 -1. 0 9 7   
0. 8 7 0 -1. 1 4 9  
0. 8 3 2 -1. 2 0 2  
2. 0 0 0  
1 0   
1. 7 4 3 -2. 2 9 5   
1. 6 2 8 -2. 4 5 7  
1. 5 2 1 -2. 6 2 9  
 
1 2   
1. 7 7 2 -2. 2 5 7  
1. 6 6 9 -2. 3 9 7  
1. 5 7 3 -2. 5 4 3  
 
1 4  
1. 7 9 3 -2. 2 3 1  
1. 6 9 9 -2. 3 5 4  
1. 6 1 1 -2. 4 8 4  
 
1 6   
1. 8 1 0 -2. 2 1 0  
1. 7 2 2 -2. 3 2 3  
1. 6 4 0 -2. 4 3 9  
 
1 8   
1. 8 2 3 -2. 1 9 5  
1. 7 4 1 -2. 2 9 8  
1. 6 6 3 -2. 4 0 5  
5. 0 0 0  
1 0   
4. 3 5 7 -5. 7 3 8  
4. 0 6 9 -6. 1 4 4  
3. 8 0 4 -6. 5 7 3  
 
1 2   
4. 4 3 0 -5. 6 4 3   
4. 1 7 2 -5. 9 9 2  
3. 9 3 2 -6. 3 5 8  
 
1 4   
4. 4 8 3 -5. 5 7 6   
4. 2 4 7 -5. 8 8 6  
4. 0 2 6 -6. 2 0 9  
 
1 6   
4. 5 2 4 -5. 5 2 6   
4. 3 0 5 -5. 8 0 7  
4. 0 9 9 -6. 0 9 8  
 
1 8   
4. 5 5 7 -5. 4 8 6   
4. 3 5 2 -5. 7 4 5  
4. 1 5 8 -6. 0 1 2  
C al c ul ati o n p erf or m e d i n R v er si o n 3. 5. 1.  
C V = c o effi ci e nt of v ari ati o n.  
9. 3  
A n al yses  Sets  
T he a nal ysis sets are s pecifie d bel o w.  T he fi nal decisi o n t o e x cl u de partici pa nts fr o m a n y 
a nal ysis s ets will be ma de d uri n g a data re vie w meeti n g pri or t o data b ase l oc k.  
A n al y si s S et  
D e s cri pti o n  
S cr e e ni n g ( S C R)   
All p arti ci p a nt s, w h o pr o vi d e d i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s 
e nr oll m e nt a n d st u d y i nt er v e nti o n st at u s i n t h e st u d y.  
S af et y ( S A F)  
All p arti ci p a nt s, w h o w er e a d mi ni st er e d a n y d o s e of a n y st u d y i nt er v e nti o n.  
A n al y s e s will c o n si d er p arti ci p a nt s a s tr e at e d.  
P h ar m a c o ki n eti c ( P K)   
T h e P K A n al y si s S et i s a s u b s et of t h e S A F, a n d t h e P K p o p ul ati o n will i n cl u d e all 
p arti ci p a nt s:  
W h o h a v e c o m pl et e d t h e st u d y wit h o ut a n y r el e v a nt pr ot o c ol d e vi ati o n s a n d f a ct or s 
li k el y t o aff e ct t h e c o m p ar a bilit y of P K r e s ult s.  
Wit h a d e q u at e st u d y i nt er v e nti o n c o m pli a n c e.  
Wit h e v al u a bl e P K d at a, i. e., n o n mi s si n g v al u e s f or pri m ar y e n d p oi nt s.  
If p arti ci p a nt s r e c ei v e d pr o hi bit e d c o n c o mit a nt t h er a p y or m e di ci n e s, a s s p e cifi e d i n 
S e cti o n  6. 8. 3 , t h e y will b e e x cl u d e d fr o m t h e P K p o p ul ati o n. 
All P K a n al y s e s will b e b a s e d o n t hi s a n al y si s s et.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 3 / 6 8 
 
 
9. 4  
St atistic al A n al yses  
Statistical a nal ysis will be perf or me d usi n g t he c o m p uter pr o gra m pac ka ge S A S ® S yste m 
(release 9. 2 or later versi o n; S A S I nstit ute, Car y N C, U S A). M ore details o n t he statistical 
a nal ysis will be prese nte d i n t he I A P pri or t o data base l oc k.  
T he statistical a nal ysis will n ot be starte d u ntil all data ha ve bee n c orrecte d a n d c h ec ke d f or 
pla usi bilit y, a n d u ntil all necessar y c o di n g a n d ass ess me nts ha ve bee n c o m plete d.  
Me dical hist or y a n d A E ter ms will be c o de d wit h t he lat est versi o n of M e d D R A (Versi o n  2 3. 0 
or later); c o n c o mita nt me dicati o n will be c o de d wit h 
W H O Dr u g Dicti o nar y, 
W H O Dr u g 
Refere n ce List a n d A nat o mical T hera pe utic C he mical Classificati o n S yst e m, latest versi o ns. 
Versi o ns of dicti o naries use d f or c o di n g will be d efi ne d i n t he Dat a  Ma na ge me nt Pla n.  
All data rec or de d d uri n g t he st u d y will be prese nte d i n i n di vi d ual data listi n gs.  
F or d e m o gra p hic (e. g., a ge, se x, race, etc.), B aseli ne a n d s afet y assess me nts, c o nti n u o us 
meas ure me nts will be s u m marize d b y mea ns of d escri pti ve statisti cs (i.e., n u m ber a n d p erce nta ge 
of o bser vati o ns, n u m ber a n d perce nta ge of missi n g o bser vati o ns, mea n, S D, me dia n, t he first 
a n d t hir d q uartile [ Q 1 a n d Q 3], Mi n, a n d M a x) a n d cate g orical dat a will be s u m marize d b y m ea ns 
of fre q u e nc y ta bles (i.e., c o u nt a n d perce nta ges), if n ot state d ot her wise.  
All data will be e val u ate d as o bser ve d, n o i m p utati o n met h o d f or missi n g val ues. T he ha n dli n g 
of c o nce ntrati o n val ues b el o w t he li mit of q ua ntificati o n will be descri be d i n t he I A P.  
9. 4. 1   
Effic ac y A n al yses  
N ot a p plica ble.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 4 / 6 8 
 
 
9. 4. 2   
S afet y A n al yses  
All safet y a nal yses will be perf or me d o n t he Safet y A nal ysis S et.  
R ef er e n c e #  
E n d p oi nt  
St ati sti c al A n al y si s  
Pri m ar y   
 
N ot a p pli c a bl e  
S e c o n d ar y   
 
 
2 –  S af et y   
N at ur e, o c c urr e n c e, s e v erit y , a n d 
s eri o u s n e s s  of T E A E s  
A E c o u nt s a n d p arti ci p a nt s wit h A E s will b e s u m m ari z e d 
f or e a c h tr e at m e nt b y S O C a n d P T.  
I n a d diti o n, A E s will b e t a b ul at e d a n d li st e d p er p arti ci p a nt 
a n d a n al y z e d b y s e v erit y a n d r el ati o n s hi p t o st u d y 
i nt er v e nti o n. 
 
A b s ol ut e v al u e s a n d c h a n g e s i n 
s af et y  l a b or at or y t e st s fr o m ti m e 
of fir st d o s e t o e n d of st u d y 
p arti ci p ati o n  
S af et y l a b or at or y p ar a m et er s will b e li st e d f or e a c h 
p arti ci p a nt i n cl u di n g c h a n g e s fr o m B a s eli n e a n d fl a g s f or 
m e a s ur e m e nt s o ut si d e t h e r ef er e n c e r a n g e s, w h er e 
a p pli c a bl e.  
L a b or at or y p ar a m et er s ( h e m at ol o g y a n d cli ni c al 
c h e mi str y) will b e s u m m ari z e d b y ti m e p oi nt i n cl u di n g b ot h 
a b s ol ut e v al u e s a n d c h a n g e s fr o m B a s eli n e.  
 
Si n gl e 1 2 -l e a d E C G s e v al u at e d 
b y I n v e sti g at or fr o m ti m e of fir st 
d o s e t o e n d of st u d y p arti ci p ati o n  
E C G d at a will b e  s u m m ari z e d b y a b s ol ut e a n d c h a n g e s 
fr o m B a s eli n e v al u e s b y tr e at m e nt u si n g d e s cri pti v e 
st ati sti c s. Cli ni c al n ot e w ort h y E C G fi n di n g s f or i n di vi d u al 
p arti ci p a nt s will b e li st e d a n d s u m m ari z e d a s a p pr o pri at e.  
 
Vit al si g n s a s s e s s e d fr o m ti m e of 
fir st d o s e t o e n d of st u d y 
p arti ci p ati o n  
Vit al si g n s b y p arti ci p a nt, i n cl u di n g c h a n g e s fr o m 
B a s eli n e, will b e li st e d a n d s u m m ari z e d b y tr e at m e nt a n d 
ti m e p oi nt u si n g d e s cri pti v e st ati sti c s. 
 
 
 
 
A E = a d v er s e e v e nt; E C G = el e ctr o c ar di o gr a m; P T = pr ef err e d t er m; S O C = s y st e m or g a n cl a s s; T E A E =tr e at m e nt -
e m er g e nt a d v er s e e v e nt.  
9. 4. 3   
Ot her A n al yses  
A n al ysis of Pri m a r y E n d p oi nts  
T he effect of c oa d mi nistrati o n of itrac o naz ole o n te p oti ni b e x p os ure will be assesse d. A ge neral 
li near m o del wit h a fi x e d effect f or T R E A T M E N T a n d a ra n d o m effect f or S U BJ E C T will be 
a p plie d t o t he l o g -tra nsf or me d P K p ara m eters Cma x , A U C0 -tlast a n d A U C 0 -∞ base d o n t he P K 
a nal ysis set . Treat me nt differe nces o n t h e l o g s cale of te p oti ni b wit h itrac o naz ole versus te p oti ni b 
al o ne ( Da y 1 2 v ers us Da y 1) will be esti mate d f or t he C ma x , A U C0 -tlast a n d A U C 0 -∞ t o get her wit h 
t heir 9 0 % CIs. P oi nt esti mates a n d CIs will be bac k tra nsf or m e d t o t h e ori gi nal scale f or 
prese ntati o n.  
T he a nal ysis will be re p eate d wit h b ot h S U B J E C T a n d T R E A T M E N T as fi xe d effects.  
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 5 / 6 8 
 
 
 
 
 
 
9. 4. 4   
Se q ue nce of A n al yses  
All fi nal, pla n ne d a n al ys es i de ntifie d i n t he cli nical st u d y pr ot oc ol will be perf or me d o nl y after 
t he last partici pa nt has c o m plete d t he last visit; i.e., Safet y F oll o w U p  wit h all st u d y data 
i n-h o use, all data q ueries res ol ve d, a n d t he data base l oc ke d.  
Gl o bal Versi o n I D: C CI
C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 6 / 6 8 
 
 
1 0  
Refere nces  
Bac k m a n J T, Ki vist ö K T, Ol k k ola K T, et al. T he area u n der t he plas ma c o nce ntrati o n -ti me c ur ve 
f or oral mi daz ola m is 4 0 0-f ol d lar ger d uri n g treat me nt wit h itrac o naz ole t ha n wit h rifa m pici n. 
E ur J Cli n P har mac ol. 1 9 9 8; 5 4: 5 3 -8.  
Bar o ne J A, K o h J G, Bier ma n R H, et al. F o o d i nteracti o n a n d stea d y -state p har mac o ki netics of 
itrac o naz ole 
ca ps ules i n 
healt h y 
m ale 
v ol u nteers. 
A nti micr o b 
A ge nts 
C he m ot her. 
1 9 9 3; 3 7: 7 7 8 -8 4.   
Bar o n e J A, 
M os k o vitz B L, G uar nieri J, et al. E n ha nce d bi oa vaila bilit y of itrac o naz ole i n 
h y dr o x y pr o p yl -beta -c ycl o de xtri n s ol uti o n vers us ca ps ules i n healt h y v ol u nteers. A nti micr o b 
A ge nts C he m ot her. 1 9 9 8; 4 2: 1 8 6 2 -5.  
C he n Y, Ca bal u T D, Calle gari E, et al. Rec o m me n dati o ns f or t he Desi g n of Cli nical Dr u g -Dr u g 
I nteracti o n 
St u dies  
Wit h 
Itrac o naz ole  
Usi n g 
a  
Mec h a nistic 
P h ysi ol o gicall y-Base d 
P har mac o ki netic M o del. C P T P har mac o metrics S yst P har mac ol. 2 0 1 9; 8: 6 8 5 -9 5.  
C he n Y, Ma F, J o nes N S, et al. P h ysi ol o gicall y -base d p har mac o ki netic m o del‐i nf or me d dr u g 
de vel o p me nt f or fe n e br uti ni b: 
u n dersta n di n g 
c o m ple x 
dr u g‐ dr u g i nteracti o ns. 
C P T 
P har mac o metrics S yst P har mac ol. 2 0 2 0 J u n; 9( 6): 3 3 2 – 4 1.  
D ur k M R, J o nes N S, Li u J, et al. U n dersta n di n g t he effect of h y dr o x y pr o p yl -β -c ycl o de xtri n o n 
fe ne br uti ni b a bs or pti o n i n a n itrac o naz ole-fe n e br uti ni b dr u g-dr u g i nteracti o n st u d y. Cli n 
P har mac ol T her. 2 0 2 0 Dec; 1 0 8( 6): 1 2 2 4 -3 2.  
Gi b b o ns J A, de Vries M, Kra u wi n kel W, et al. P har mac o ki netic d r u g interacti o n st u dies wit h 
enzal uta mi de. Cli n  P har mac o ki net. 2 0 1 5; 5 4: 1 0 5 7 -6 9.  
Har di n T C, Gra y bill J R, Fetc hic k R, et al. P har mac o ki netics of itrac o naz ole f oll o wi n g oral 
a d mi nistrati o n t o n or mal v ol u nteers. A nti micr o b A ge nts C he m ot her. 1 9 8 8; 3 2: 1 3 1 0 -3.  
Haria M, Br ys o n H M, a n d G oa K L. Itrac o naz ole. A r ea p praisal of its p har mac ol o gi cal pr o perties 
a n d t hera p e utic use i n t he ma na ge me nt of s u perfici al f u n gal i nfecti o ns. Dr u gs. 1 9 9 6; 5 1: 5 8 5 -6 2 0. 
Errat u m i n: Dr u gs 1 9 9 6; 5 2: 2 5 3.  
He y ka nts J, Va n Peer A, Va n de Vel de V, et al. T he cli nical p har mac o ki netics of itr ac o n az ole: 
a n o ver vie w. M yc oses. 1 9 8 9; 3 2 S u p pl 1: 6 7 -8 7.  
   
   
   
   
  
 
  
 
   
  
   
 
   
   
 
 
 
   
 
 
 
Is o h erra ne n N, K u nze KL, Alle n K E, et al. R ole of itrac o naz ole meta b olites i n C Y P 3 A 4 
i n hi biti o n. Dr u g Meta b Dis p os. 2 0 0 4; 3 2: 1 1 2 1 -3 1.  
Itr ac o n az ole S m P C.   
htt ps:// w w w. me dici nes. or g. u k/e m c/ pr o d uct/ 5 9 1 4 # gref. Last accesse d o n 2 0  J ul y 2 0 2 1.  
Itr ac o n az ole U S PI.   
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d o cs/la bel/ 2 0 1 0/ 0 2 2 4 8 4s 0 0 0l bl. p df . Last accesse d 
o n 2 0  J ul y 2 0 2 1.  
Gl o bal Versi o n I D: C CI
C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 7 / 6 8 
 
 
Ke A B, Za me k -Glisz cz y ns ki 
MJ, Hi g gi ns J W, et al. Itrac o naz ole a n d clarit hr o m yci n as 
ket oc o naz ole alter nati ves f or cli nical C Y P 3 A i n hi biti o n st u dies.  Cli n P har mac ol T her. 
2 0 1 4; 9 5: 4 7 3 -6.  
Ki vist ö K T, Ka nt ola T, Ne u v o ne n PJ. Differe nt effects of itrac o n az ole o n t he p har mac o ki netics 
of fl u vastati n a n d l o vastati n. Br J Cli n P har mac ol. 1 9 9 8; 4 6: 4 9 -5 3.  
Le m p ers VJ, va n de n He u vel JJ, R ussel F G, et al. I n hi bit ory p ote ntial of antif u n gal d r u gs o n 
A T P -b i n di n g cassette tra ns p orters P-g l yc o pr otei n, 
M R P 1 t o 
M R P 5, B C R P, a n d B S E P. 
A nti micr o b A ge nts C he m ot her. 2 0 1 6; 6 0: 3 3 7 2 -9.  
Lest n er J  a n d H o pe W W. Itr ac o n az ole: a n u p date o n p har mac ol o g y a n d cli ni cal use f or treat me nt 
of  i n vasi ve a n d aller gic f u n gal i nfecti o ns. E x pert O pi n Dr u g Meta b T o xic ol. 2 0 1 3; 9: 9 1 1-2 6.  
Li u  L, Bell o  A, Dresser  MJ, et al. Best p ractices f or t he u se of itrac o naz ole as a re place me nt f or 
k et oc o naz ole i n dr u g -dr u g  interacti o n st u dies. J Cli n P har mac ol.  2 0 1 6; 5 6: 1 4 3 -5 1 . 
Na derer O, J o nes L S, Z h u J, et al. T he effect of f o o d a n d f or m ulati o n o n t he p har mac o ki netics, 
safet y, a n d t olera bilit y of G S K 1 3 2 2 3 2 2 i n healt h y v ol u nteers. Cli n P har mac ol Dr u g De v. 2 0 1 5, 
4( 1): 4 9 – 5 5.  
O da M, K ote ga wa T, Ts uts u mi K, et al.  T he effect of itrac o naz ole o n t he p har mac o ki netics a n d 
p har mac o d y n a mics of br o maze pa m i n healt h y v ol u nteers. E ur J Cli n P har mac ol. 2 0 0 3; 5 9: 6 1 5 -9.  
O ka m ot o J, F u k u na mi M, a n d Ki o ka H. Fre q u e nt pre mat ure v e ntric ular c o ntracti o ns i n d uce d b y 
itrac o naz ole. Circ J. 2 0 0 7; 7 1: 1 3 2 3 -5.  
Pa ul 
V a n d 
Ra wal 
H. 
Car di ot o xicit y 
wit h itrac o naz ole. 
B MJ 
Case 
Re p. 2 0 1 7 
A pr 
1 0; 2 0 1 7: bcr 2 0 1 7 2 1 9 3 7 6.  
Q ueir oz -Telles F, P uri m K S, B o g usze ws ki C L, et al. A dre n al res p o nse t o c ortic otr o p hi n a n d 
test oster o ne d uri n g l o n g-ter m t hera p y wit h itrac o naz ole i n patie nts wit h c hr o m o blast o m yc osis. 
J A nti micr o b C he m ot her. 1 9 9 7; 4 0: 8 9 9-9 0 2.  
S har ke y P K, Ri nal di M G, D u n n J F, Har di n T C, Fet c hic k RJ, Gra y bill J R. Hi g h -d os e itrac o n az ole 
i n t he treat me nt of se v ere m yc oses. A nti micr o b A ge nts C he m ot her. 1 9 9 1 A pr; 3 5: 7 0 7-1 3.  
S u n g DJ, Ki m J G, W o n KJ, et al. Bl oc ka de of K + a n d Ca 2 + c h a n nels b y az ole a ntif u n gal a ge nts 
i n ne o natal rat ve ntric ular m y oc yt es. Bi ol P har m B ull. 2 0 1 2; 3 5: 1 4 6 9-7 5.  
Teaf or d H R, A b u Sale h O M, Villarra ga H R, et al. T he m a n y faces of itrac o naz ole car diac 
to xicit y. Ma y o Cli n Pr oc I n n o v Q ual O ut. 2 0 2 0; 4: 5 8 8 -9 4.  
Te m plet o n I, Pe n g C -C, T h u m mel K E, et al. Acc urate pre di cti o n of d ose -de pe n de nt C Y P 3 A 4 
i n hi biti o n b y itrac o naz ole a n d its meta b olites fr o m i n vitr o i n hi biti o n data. Cli n P har mac ol T her. 
2 0 1 0; 8 8: 4 9 9 -5 0 5.  
Te m plet o n I, T h u m mel K E, K harasc h E D, et al. C o ntri b uti o n of itrac o n az ole meta b olites t o 
i n hi biti o n of C Y P 3 A 4 i n vi v o. Cli n P har mac ol T her. 2 0 0 8 J a n; 8 3( 1): 7 7– 8 5.  
Te p met k o (te p oti ni b) U S PI. htt ps  :// w w w.e m dser o n o.c o m/ us-e n/ pi/te p met k o -pi. p df. Re vise d 
2/ 2 0 2 1.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 8 / 6 8 
 
 
1 1  
A p pe n dices  
 
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 9 / 6 8 
 
 
A p pe n di x 1   
A b bre vi ati o ns  
 
A E   
A d verse eve nt  
A E SI   
A d verse eve nts of special interest  
A L P   
Al kali ne p h os p hatase  
A L T   
Ala ni ne a mi n otra nsferas e  
A S T   
As partate a mi n otra nsferase  
A T P   
A de n osi ne tri p h os p hate  
B C S   
Bi o p har mace utical classificati o n syste m  
B MI   
B o d y m ass in de x  
CI  
C o nfi de nce i nter val  
CI O M S   
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces  
C O VI D -1 9   
C or o na vir us disease 2 0 1 9  
C R F   
Case re p ort for m  
C R O   
Cli nical researc h o r ga niz ati o n 
C R U   
Cli nical researc h u nit  
C S R   
Cli nical St u d y Re p ort  
C T F G   
Cli nical Trials Facilitati o n a n d C o or di nati o n Gr o u p  
C V   
C oefficie nt of v ariati o n  
C Y P   
C yt o c hr o me P 4 5 0  
D DI   
Dr u g -dr u g i nteracti o n  
D N A   
De o x yri b o n ucleic aci d  
D S U R   
De vel o p me nt safet y u p date re p ort  
E C G   
Electr ocar di o gra m  
e C R F  
Electr o nic case re p ort f or m  
E D C   
Electr o nic data ca pt ure  
E u dra C T   
E ur o pea n Cli nical Trials Data base  
F S H   
F ollicle -sti m ulati n g h or m o ne 
G C P   
G o o d Cli nical Practice  
H G F   
He pat oc yte gr o wt h fact or  
HI P A A   
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
H R T   
H or m o ne re pl ace m e nt t hera p y  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 0 / 6 8 
 
 
I A P  
I nte grate d anal ysis p la n 
I B 
I n v esti gat or’s b r oc h ure 
I C F  
I nf or me d co ns e nt for m  
I C H  
I nter nati o nal C o u ncil f or Har m o nizati o n 
I E C  
I n d e pe n de nt Et hics C o m mittee 
I R B  
I nstit uti o nal Re vie w B oar d 
I M P  
I n v esti gati o nal m e dici nal p r o d uct  
I N R  
I nter nati o nal n or malize d rati o 
I R B  
I nstit uti o nal Re vie w B oar d 
L F T   
Li ver f u ncti o n test  
Ma x   
Ma xi m u m  
Me d D R A   
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M E T   
Mese nc h y mal e pit helial tra nsiti o n fact or  
Mi n   
Mi ni m u m  
M R   
Meta b olic rati o  
N S C L C   
N o n -small cell lu n g ca n cer  
P C R   
P ol y m eras e c hai n r eacti o n  
 
 
P -g p   
P -gl yc o pr ot ei n  
P K   
P har mac o ki netic  
Q Tc B   
C orrecte d Q T i nter nal b y Bazett’s f or m ula  
Q Tc F   
C orrecte d Q T i nter val b y Fri dericia’ f or m ula  
Q T L   
Q ualit y tolera nce li mits 
S A E   
Seri o us ad verse eve nt  
S A F   
Safet y  
S A R S -C o V -2  Se vere ac ute res pirat or y s y n dr o me c or o na vir us 2  
S D   
Sta n dar d de viati o n  
S m P C   
S u m mar y of pr o d uct c haracteristics  
S o A   
Sc he d ule of ass ess me nts 
S U S A R   
S us pecte d u ne x pecte d seri o us ad verse reacti o ns  
T E A E   
Treat me nt -e mer ge nt ad v erse e v e nt  
Gl o bal Versi o n I D: C CI
C C


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 1 / 6 8 
 
 
T F 2 / T F3   
Ta blet f or m ulati o n 2 / Ta blet f or m ulati o n 3  
T S H   
T h yr oi d sti m ulati n g h or m o ne  
U L N   
U p per li mit of n or mal  
U S   
U nite d States  
U S PI   
U nite d States p rescri bi n g inf or mati o n  
W H O   
W orl d Healt h Or ga nizati o n  
W O C B P   
W o ma n of chil d -beari n g p ote ntial  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 2 / 6 8 
 
 
A p pe n di x 2   
St u d y G o ver n a nce  
Fi n a nci al Discl os ure  
•  I n v esti gat ors a n d S u b-I n vesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate 
fi na ncial i nf or mati o n, as re q ueste d, f or t h e S p o ns or t o s u b mit c o m plete a n d acc urat e fi na nci al 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y a ut h orities. T his 
i nf or mati o n is re q uire d d uri n g t he st u d y a n d f or 1 year after c o m pleti o n of t he st u d y. 
I nf or me d C o nse nt Pr ocess 
•  T he I n v esti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t h e 
partici pa nt  a n d a ns wer all q uesti o ns o n t he st u d y.  
•  Partici pa nts will  be i nf or me d t hat t heir partici pati o n is v ol u ntar y.  
•  Partici pa nts will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he 
re q uire me nts of 2 1 C FR 5 0; l ocal re g ulati o ns; I C H g ui deli nes; HI P A A re q uire me nts, w here 
a p plica ble; a n d t he I R B/I E C or st u d y ce nter.  
•  T he me dical rec or d will  i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he partici pa nt was e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was o btai ne d. 
T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt will  als o si g n t he I C F.  
•  If t he I C F is u p date d d uri n g t heir p artici pati o n i n t he st u d y, partici pa nts will  be rec o nse nt e d 
t o t he m ost c urre nt, a p pr o ve d versi o n. 
D at a Pr otecti o n  
•  T he S p o ns or will assi g n a u ni q ue i de ntifier t o p artici pa nts after o btai ni n g t h eir i nf or m e d 
c o nse nt. A n y p artici pa nt rec or ds or d atasets t hat are tra nsferre d t o t he S p o ns or will c o ntai n 
t he i de ntifier o nl y; p artici pa nt na mes or a n y i de ntifia ble inf or mati o n will n ot be tra nsferre d.  
•  T he S p o ns or will  i nf or m partici pa nts t hat t heir pers o nal st u d y-relate d d ata will be use d per 
l ocal data pr otecti o n a n d pri vac y la ws. T he le vel of discl os ure will  als o be e x plai ne d t o t he 
partici pa nt  a n d pre g na nt part ners  (if a p plica ble), w h o will be re q uire d t o gi ve c o nse nt f or 
t heir data t o be use d, as s pecifie d i n t he i nf or m e d c o nse nt. 
•  T he partici pa nt will  be i nf or me d t hat his/ her me dical rec or ds ma y be e x a mi ne d b y Cli nical 
Q ualit y Ass ura n ce a u dit ors or ot her S p o ns or -a pp oi nte d, a ut h orize d pers o n nel, b y a p pr o priate 
I R B/I E C me m bers, a n d b y re g ulat or y a ut h orit y i ns pect ors.  All s uc h pers o ns will strictl y 
mai ntai n partici pa nts’ c o nfi de ntialit y.  
St u d y A d mi nistr ati ve  
•  T he Pri nci pal I n vesti gat or liste d o n t he title p a ge re prese n ts all I n vesti gat ors f or d ecisi o ns 
a n d disc ussi o ns o n t his st u d y, per I C H G C P. T he Pri nci pal  I n v esti gat or will pr o vi de e x pert 
me dical i n p ut a n d a d vice o n t he st u d y desi g n a n d e x ec uti o n a n d is res p o nsi ble f or t he re vie w 
a n d si g n off of t he cli nical st u d y re p ort.  
•  T he st u d y will be c o n d u cte d at a si n gle ce nter, t he Cli nical P har mac ol o g y U nit of N u visa n 
G m b H, Ne u -Ul m, G er ma n y. N u visa n G m b H will be res p o nsi ble f or t he f oll o wi n g acti vities:  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 3 / 6 8 
 
 
•  Cli nical c o n d uct a n d la b orat or y ser vices  
•  Data ma na ge me nt  
•  Statistical pr o gr a m mi n g a n d a nal ysis  
•  P K a nal ysis  
•  Me dical writi n g  
•  I n d e pe n de nt m o nit ori n g 
•  Me dical m o nit ori n g  
•  Pr oject ma na ge me nt  
•  Re g ulat or y s er vices  
•  Cli nical trial s u p plies will be pr o vi de d  b y t he S p o ns or . 
•  Details of str uct ures a n d ass ociate d pr o ce d ures will be defi ne d i n a se p arat e ma n ual . 
Re g ul at or y a n d Et hic al C o nsi der ati o ns  
•  T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he pr ot oc ol a n d t he f oll o wi n g:  
•  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui d eli nes, i ncl u di n g t he 
Declarati o n of Helsi n ki a n d CI O M S I nter nati o nal Et hical G ui deli nes  
•  A p plica ble I C H G C P G ui deli nes  
•  A p plica ble la ws a n d re g ulati o ns  
•  T he pr ot oc ol, pr ot oc ol a me n d me nts (if a p plica bl e), I C F, I n vesti gat or Br oc h ure, a n d ot h e r 
rele va nt d oc u me nts (e. g., a d vertise me nts) will be s u b mitte d t o a n I R B/I E C f or re vie w a n d 
a p pr o val bef ore t he st u d y is i nitiate d.  
•  A n y pr ot oc ol a me n d m e nts (i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n writi n g a n d 
re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges, e x ce pt f or c h a n ges necess ar y 
t o eli mi nate a n i m me diat e hazar d t o st u d y p artici pa nts. W he n a p plica ble, a me n d me nts will 
be s u b mitte d t o t he a p pr o priate Healt h A ut h orities.  
•  T he pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n will be s u b mitte d or n otifie d t o t he Healt h 
A ut h orities i n acc or da nce wit h all l ocal a n d nati o nal re g ulati o ns f or eac h site.  
E mer ge nc y Me dic al S u p p ort  
•  T he S p o ns or or d esi g n ee will pr o vi de E mer ge nc y Me dical S u p p ort car ds t o partici pa nts f or 
use d uri n g t he st u d y. T h ese pr o v i de t he mea ns f or partici pa nts t o i de ntif y t he msel v es as 
partici pati n g i n a cli nical st u d y. Als o, t hese gi ve healt h care pr o vi ders access t o a n y 
i nf or mati o n a b o ut t his partici pati o n t hat ma y be n ee de d t o deter mi ne t he c o urse of me dical 
treat me nt f or t h e partici p a nt. T he i nf or mati o n o n t he E mer ge n c y Me dical S u p p ort car d m a y 
i ncl u de t he pr ocess f or e mer ge nc y u n bli n di n g (if a p plica ble). 
•  T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical st u d y I n vesti gat or cari n g f or 
t he partici pa nt. C o nse q ue ntl y, t he I n vesti gat or a grees t o pr o vi de his or her e mer ge nc y c o ntact 
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i nf or mati o n o n t he car d. If t he I n vesti gat or is a vaila ble w he n a n e ve nt occ urs, t he y will 
a ns wer a n y q u esti o ns. A n y s u bse q ue nt acti o n (e. g., u n bli n di n g) will f oll o w t he sta n dar d 
pr ocess es ta blis he d f or I n vesti gat ors. 
•  W he n t he I n v esti gat or is n ot a vaila ble, t he P hase 1  facilit y will pr o vi de t he a p pr o priate mea ns 
t o c o ntact a p h ysicia n. T his i ncl u des t he pr o visi o n of a 2 4-h o ur c o ntact n u m ber at t h e facilit y, 
w here b y t he healt h care pr o vi ders will be gi ve n access t o a n a p pr o priate p h ysicia n t o assist 
wit h t he me dical e mer ge nc y a n d t o pr o vi de s u p p ort f or t he p ote ntial u n bli n di n g of t he 
partici pa nt c o ncer ne d.  
Cli nic al St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts  
•  I ns ura nce c o vera ge will be pr ovi de d f or eac h c o u ntr y partici p ati n g i n t he st u d y. I ns ura n ce 
c o n diti o ns will  meet g o o d l ocal sta n dar ds, as a p plica ble.  
Cli nic al St u d y Re p ort  
•  After st u d y c o m pleti o n, t he S p o ns or will write a cli nical st u d y re p ort i n c o ns ultati o n wit h t he 
Pri nci pal I n v esti ga t or a n d ot her rel e va nt st u d y-a p p oi nte d e x perts of t he S p o ns or a n d N u visa n 
G m b H.  
P u blic ati o n  
•  T he res ults of t his st u d y ma y be p u blis he d or prese nte d at scie ntific meeti n gs. If t his is 
f oresee n, t he I n v esti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or bef ore 
s u b missi o n. T his all o ws Merc k t o pr otect pr o pri etar y i nf or mati o n a n d to pr o vi de c o m me nts.  
•  T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. Per sta n dar d 
e dit orial a n d et hical practice, t he S p o ns or will ge nerall y s u p p ort p u blicati o n of m ultice nter 
st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vid ual site data.  
•  A ut h ors hi p will be deter mi ne d b y a gree me nt a n d i n li ne wit h I nter nati o n al C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire m e nts.  
Disse mi n ati o n of Cli nic al St u d y D at a  
•  A s u m mar y of dat a will b e pr o vi de d t o Cli nical Tri als. g o v as well as  t o t he E ur o pea n Cli nical 
Trial Data bas e, as a p plica ble, a n d will occ ur 1 2 m o nt hs after t he last cli nic visit of t he fi nal 
st u d y partici pa nt or a n ot her a p pr o priate dat e t o meet a p plica bl e re q uire me nts. Healt h y 
partici pa nts mi g ht b e pr o vi de d wit h t he res ult s of t he me dical e xa mi nati o ns at re q uest. After 
fi nalizati o n of t he st u d y, healt h y partici pa nts mi g ht be pr o vi de d wit h t he i nf or mati o n 
p u blis he d o n Cli nical Trials. g o v a n d/ or t he E ur o pea n Cli nical Trial Data base at re q u est.  
•  After c o m pleti o n of t he st u d y, a cli nical st u d y re p ort will be writte n b y t he S p o ns or i n 
c o ns ultati o n wit h t he Pri nci pal I n v esti gat or f oll o wi n g t he g ui da nce i n I C H T o pic E 3 a n d will 
be s u b mitte d i n acc or da n ce wit h l ocal re g ulati o ns.  
Gl o bal Versi o n I D: C CI


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•  A n y a n d all scie ntific, c o m mercial, a n d tec h ni cal i nf or mati o n discl ose d b y t he S p o ns or i n 
t his pr ot oc ol or else w here s h o ul d be c o nsi dere d t he c o nfi de ntial a n d pr o pri etar y pr o pert y of 
t he S p o ns or. T he I n vesti gat or s hall h ol d s uc h i nf or mati o n i n c o nfi de nce a n d s hall n ot discl ose 
t he i nf or mati o n t o a n y t hir d part y e x ce pt t o s uc h of t he I n vesti gat or’s e m pl o yees a n d staff 
w h o ha d bee n ma de a ware t hat t he i nf or mati o n is c o nfi de ntial a n d w h o are b o u n d t o treat it 
as s uc h a n d t o w h o m discl os ure is necessar y t o e val uate t hat i nf or mati o n. T he I n v esti gat or 
s hall n ot use s uc h i nf or mati o n f or a n y p ur p ose ot h er t ha n f or det er mi ni n g m ut ual i nterest i n 
perf or mi n g t he st u d y a n d, if t he parties d eci de t o pr ocee d wit h t he st u d y, f or t he p ur p ose of 
c o n d ucti n g t h e st u d y.  
•  T he I n vesti gat or u n dersta n ds t hat t he i nf or mati o n de vel o p e d fr o m t his cli nical st u d y will be 
use d b y t h e S p o ns or i n c o n necti o n wit h t he de vel o p me nt of t he st u d y i nter ve nti o n a n d 
t heref ore ma y b e discl ose d as re q uire d t o ot her cli nical I n vesti gat ors, t o t he F D A, E M A, a n d 
t o ot her g o ver n me nt a ge n cies. T he I n v esti gat or als o u n dersta n ds t hat, t o all o w f or t he use of 
t he i nf or mati o n deri ve d fr o m t he cli nical st u d y, t h e I n vesti gat or has t he o bli gati o n t o pr o vi de 
t he S p o ns or wit h c o m plet e test res ults a n d all data de vel o pe d i n t he st u d y. N o p u blicati o n or 
discl os ure of st u d y res ults will be per mitte d e x ce pt u n der t he ter ms a n d c o n diti o ns of a 
se parat e writte n a gree me nt. 
D at a Q u alit y Ass ur a nce  
•  All partici pa nt st u d y dat a will be rec or de d o n pri nte d or el ectr o nic C R Fs or tra ns mitte d t o 
t he S p o ns or or desi g nee electr o nicall y (e. g., la b orat or y d ata). T he I n v esti gat or is res p o nsi ble 
f or verif yi n g t hat d ata e ntries are c o m plet e, acc urate, le gi ble, a n d ti mel y b y p h ysicall y or 
electr o nicall y si g ni n g t h e C R F. Det ails f or ma na gi n g C R Fs are i n t he Data Ma n a ge me nt 
Pla n . 
•  T he I n v esti gat or will  m ai ntai n acc urat e d o c u me ntati o n (s o urce dat a) t h at s u p p orts t he 
i nf or mati o n i n t he C R F. 
•  T he I n vesti gat or will  per mit st u d y -relate d m o nit ori n g, q ualit y ass ura n ce a u dits, I R B/I E C 
re vie w, a n d re g ul at or y a ge n c y i ns p ecti o ns a n d pr o vi de direct access t o t he st u d y file a n d 
s o urce dat a. 
•  Q T Ls will be pre defi ne d  i n t he O perati o nal Ma n ual t o i de ntif y s yst e matic iss ues t hat ca n 
i m pact partici pa nt safet y a n d/ or relia bilit y of st u d y res ults. T hes e pre defi ne d para m eters will 
be m o nit ore d d uri n g t he st u d y a n d i m p or ta nt de vi ati o ns fr o m t he Q T Ls a n d re me dial acti o ns 
ta ke n will be s u m marize d i n t he cli nical st u d y re p ort. 
N ote: Q T Ls will n ot b e d efi ne d i n t his P has e  I st u d y as neit her t he li mite d n u m ber of pla n ne d 
partici pa nts n or t he s h ort d urati o n of t he st u d y s u p p ort  t he c ollecti o n of mea ni n gf ul Q T Ls. 
•  M o nit ori n g details des cri bi n g strat e g y (e. g., ris k -b ase d i nitiati ves i n o perati o ns a n d q ualit y 
s uc h as Ris k Ma na ge me nt a n d Miti gati o n Strate gies a n d A nal ytical Ris k-Base d M o nit ori n g), 
met h o ds, res p o nsi bilities a n d re q uir e me nts, i ncl u di n g h a n dli n g of n o n c o m plia nce iss ues a n d 
m o nit ori n g tec h ni q ues (ce ntral, re m ote, or o n -site m o nit ori n g) are i n t he M o nit ori n g Pla n. 
•  T he S p o ns or or desi g n ee is res p o nsi ble f or d ata m a na ge me nt of t his st u d y, i ncl u di n g q u alit y 
c hec ki n g of t he da ta a n d mai ntai ni n g a vali date d data base. Dat a base l oc k will occ ur o nce 
q ualit y c o ntr ol a n d q ualit y ass ura n ce pr oce d ures ha ve bee n c o m plete d. Details will be 
o utli ne d i n Data Ma na ge me nt d oc u me nts a n d pr o ce d ures.  
Gl o bal Versi o n I D: C CI


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•  St u d y M o nit ors will perf or m o n g oi n g s o urce d a ta verificati o n t o c o nfir m t h at data i n t he C R F 
are acc urate, c o m plete, a n d verifi a ble; t hat t he s afet y a n d ri g hts of parti ci pa nts are bei n g 
pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d p er t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y 
ot her st u d y a gree me nts , I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts. 
•  T he I n vesti gat or will retai n r ec or ds a n d d o c u me nts, i ncl u di n g si g n e d I C Fs, pertai ni n g t o t he 
c o n d uct of t his st u d y f or 1 5 years after st u d y c o m pleti o n, u nless l ocal re g ulati o ns, 
i nstit uti o nal p olicies, or t he S p o ns or re q uires a l o n ger rete nti o n. N o rec or ds ma y be destr o ye d 
d uri n g t he ret e nti o n peri o d wit h o ut t he S p o ns or’s writte n a p pr o val. N o rec or ds ma y b e 
tra nsferre d t o a n ot her l ocati o n or part y wit h o ut t he S p o ns or’s writte n n otificati o n. 
S o urce D oc u m e nts  
•  S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he d ata c ollecte d. 
•  T he I n vesti gat or will  mai ntai n s o urce d o c u me nts t hat s u p p ort t he dat a rec or d e d i n t he C R Fs. 
•  Data rec or de d o n C R Fs t hat are tra nscri be d fr o m s o urce d oc u m e nts will  be c o nsiste nt wit h 
t he s o urce d oc u me nts or t he discre p a ncies will  be e x plai ne d. T he I n v esti gat or ma y nee d t o 
re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt 
me dical rec or ds will  be a vaila ble.  
•  S o urce d oc u me nts are st ore d at t he site f or t he l o n gest p ossi ble ti me per mitte d b y t he 
a p plica ble re g ulati o ns, a n d/ or as p er I C H G C P g ui deli nes, w hi c he ver is l o n ger. T he 
I n v esti gat or e ns ures t hat n o destr u cti o n of me dical rec or ds is perf or me d wit h o ut t he 
S p o ns or’s writte n a p pr o val.  
•  Defi niti o n of w hat c o nstit utes s o urce data is fo u n d i n t he S o urce Data L ocati o n F or m. 
St u d y a n d Site St art a n d Cl os ure  
T he st u d y start date is w he n t he first partici p a nt si g ns t he Inf or me d C o nse nt F or m . 
St u d y a n d Site Cl os ure  
T he I n v esti gat or ma y i nitiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use a n d 
e n o u g h n otice is gi v e n i n a d va nce of t he i nte n de d cl os ure. 
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I n v esti gat or ma y i ncl u d e:  
•  Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l ocal H ealt h A ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui d eli nes  
•  I n a de q uat e recr uit me nt of partici pa nts b y t he I n v esti gat or 
•  Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d  
•  If t he st u d y is pre m at urel y ter mi nat e d or s us pe n de d, t he S p o ns or will  pr o m ptl y i nf or m 
t he I n vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y t hir d-part y ser vice 
pr o vi ders of t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble 
re g ulat or y re q uire m e nts. T he I n v esti gat or will pr o m ptl y i nf or m t h e partici pa nts a n d 
ass ure a p pr o priate p artici pa nt t hera p y a n d/ or f oll o w -u p.  
Gl o bal Versi o n I D: C CI


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A p pe n di x 3   
C o ntr ace pti o n a n d B arrier Re q ui re me nts 
Defi niti o ns:  
W o me n of C hil d -Be ari n g P ote nti al : 
A w o ma n is of c hil d beari n g p ote ntial (fertile) f oll o wi n g 
me narc he a n d u ntil bec o mi n g 
p ost me n o pa usal u nless per ma ne ntl y sterile, as s pecifie d bel o w.  
If fertilit y is u nclear (e. g., a me n orr hea i n a d olescents or at hletes) a n d a me nstr ual c ycle ca n n ot 
be c o nfir me d bef ore t he first d ose of st u d y i nter ve nti o n, c o nsi der a d diti o nal e val uati o n.  
P ost me n o p a use:  
P ost me n o pa use is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use. 
•  A hi g h F S H le vel i n t he p ost me n o pa usal ra n ge ma y b e use d t o c o nfir m a p ost me n o pa usal 
state i n a fe male n ot usi n g h or m o nal c o ntrace pti o n or H R T. H o we ver, i n t he a bse nce of 
1 2  m o nt hs of a me n orr hea, c o nfir mati o n wit h m ore t ha n 1  F S H meas ure me nt (>  4 0  mI U/ m L)  
is re q uire d. 
•  A fe male o n H R T a n d w h ose me n o pa usal stat us are i n d o u bt will be re q uire d t o use 1  of t he 
n o nestr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if s he wis hes t o c o nti n ue her 
H R T d uri n g t he st u d y. Ot her wise, s he m ust disc o nti n ue H R T t o all o w c o nfir m ati o n of 
p ost me n o pa usal stat us bef ore st u d y e nr oll me nt.  
Per m a ne nt steriliz ati o n:  
F or t his st u d y, p er ma ne nt sterilizati o n i ncl u des:  
•  D oc u me nte d h ysterect o m y  
•  D oc u me nte d bilateral sal pi n gect o m y  
•  D oc u me nte d bilateral o o p h orect o m y  
D oc u me ntati o n ca n c o m e fr o m t he site pers o n nel’s re vie w of t he i n di vi d u al’s me dical rec or ds, 
me dical e xa mi nati o n, or me dical hist or y i nter vie w.  
F or i n di vi d uals wit h per ma ne nt i nfertilit y d u e t o a n alter nate me dical ca us e ot her t ha n t he a b o ve, 
(e. g., M ulleria n a ge n esis, a n dr o ge n i nse nsitivit y), I n vesti gat or discreti o n a p plies t o deter mi ne 
st u d y e ntr y. 
Gl o bal Versi o n I D: C CI


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C o ntr ace pti o n G ui d a nce:  
C O N T R A C E P TI V E S A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:  
Hi g hl y Eff e cti v e M et h o d s T h at H a v e L o w U s er D e p e n d e n c y  
•  
I m pl a nt a bl e pr o g e st o g e n-o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n  
•  
I U D 
•  
I U S 
•  
Bil at er al t u b al o c cl u si o n  
•  
V a s e ct o mi z e d p art n er: a hi g hl y eff e cti v e c o ntr a c e pti v e m et h o d pr o vi d e d t h at t h e p art n er i s t h e s ol e s e x u al 
p art n er of a W O C B P, a n d t h e a b s e n c e of s p er m h a s b e e n c o nfir m e d. Ot h er wi s e, u s e a n a d d iti o n al hi g hl y 
eff e cti v e m et h o d of c o ntr a c e pti o n. T h e s p er m at o g e n e si s c y cl e i s a p pr o xi m at el y 9 0 d a y s.  
Hi g hl y Eff e cti v e M et h o d s T h at Ar e U s er D e p e n d e nt  
•  
C o m bi n e d ( e str o g e n - a n d pr o g e st o g e n -c o nt ai ni n g) h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of 
o v u l ati o n 
•  
Or al  
•  
I ntr a v a gi n al 
•  
Tr a n s d er m al  
•  
I nj e ct a bl e 
•  
Pr o g e st o g e n -o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n  
•  
Or al  
•  
I nj e ct a bl e 
•  
S e x u al a b sti n e n c e: a hi g hl y eff e cti v e m et h o d o nl y  if d efi n e d a s r efr ai ni n g fr o m i nt er c o ur s e d uri n g t h e e ntir e 
p eri o d of ri s k a s s o ci at e d wit h t h e st u d y i nt er v e nti o n. T h e r eli a bilit y of s e x u al a b sti n e n c e n e e d s t o b e e v al u at e d 
i n r el ati o n t o t h e d ur ati o n of t h e st u d y a n d t h e pr ef err e d a n d u s u al lif e st yl e of t h e p arti ci p a nt. 
N ot e s:  
C o ntr a c e pti v e u s e b y m e n or w o m e n i s c o n si st e nt wit h l o c al r e g ul ati o n s o n t h e u s e of c o ntr a c e pti v e m et h o d s f or 
cli ni c al st u d y p arti ci p a nt s.  
Hi g hl y eff e cti v e m et h o d s ar e t h o s e wit h a f ail ur e r at e of <  1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. 
T y pi c al u s e f ail ur e r at e s diff er fr o m t h o s e w h e n u s e d c o n si st e ntl y a n d c orr e ctl y.  
If l o c all y r e q uir e d, i n a c c or d a n c e wit h C T F G g ui d eli n e s, a c c e pt a bl e c o ntr a c e pti v e m et h o d s ar e li mit e d t o t h o s e 
w hi c h i n hi bit o v ul ati o n a s t h e pri m ar y m o d e of a cti o n.  
P eri o di c a b sti n e n c e ( c al e n d ar, s y m pt ot h er m al, p o st o v ul ati o n m et h o d s), wit h dr a w al ( c oit u s i nt err u pt u s), 
s p er mi ci d e s o nl y, a n d l a ct ati o n a m e n orr h e a m et h o d ar e n ot  a c c e pt a bl e m et h o d s of c o ntr a c e pti o n f or t hi s st u d y. 
M al e c o n d o m a n d f e m al e c o n d o m c a n n ot b e u s e d t o g et h er ( d u e t o ri s k of f ail ur e fr o m fri cti o n).  
 
 
Gl o bal Versi o n I D: C CI












Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 4 / 6 8 
 
 
Re p orti n g of Pre g n a ncies  
•  Pre g n a nc y will  be re p ort e d w het her relate d t o t he st u d y i nter ve n ti o n usi n g t he a p plica ble 
pa per f or m.  
•  T he a p plica ble f or m will be  use d t o re p ort if a n a b n or mal o utc o me of t he pre g na n c y occ urs 
a n d t he c hil d/fet us s ustai ns a n e ve nt.  
•  Facsi mile tra ns missi o n (fa x t o mail) of t he pa per f or m or a n y f oll o w -u p i nf or mati o n is t he 
preferre d met h o d f or tra ns missi o n a n d will be d o n e wit hi n 2 4  h o urs t o t he S p o ns or or its 
desi g nee . 
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 5 / 6 8 
 
 
A p pe n di x 5   
Cli nic al L a b or at or y Tests  
T he pr ot oc ol -re q uire d cli nical la b orat or y assess me nts are i n t he f oll o wi n g ta ble: 
L a b or at or y 
A s s e s s m e nt s  
P ar a m et er s  
H e m at ol o g y   
Pl at el et c o u nt  
M e a n c or p u s c ul ar v ol u m e 
( M C V) 
W hit e Bl o o d C ell 
C o u nt wit h Diff er e nti al : 
N e utr o p hil s  
L y m p h o c yt e s  
M o n o c yt e s  
E o si n o p hil s  
B a s o p hil s  
H e m o gl o bi n  
M e a n c or p u s c ul ar h e m o gl o bi n 
( M C H) 
H e m at o crit  
Bi o c h e mi str y   
Bl o o d Ur e a 
Nitr o g e n  
P ot a s si u m   
A s p art at e a mi n otr a n sf er a s e   
Bilir u bi n  
 
Cr e ati ni n e   
S o di u m   
Al a ni n e a mi n otr a n sf er a s e   
Pr ot ei n  
 
Gl u c o s e   
C al ci u m   
Al k ali n e p h o s p h at a s e  
Al b u mi n  
 
Uri c a ci d   
C hl ori d e   
y -Gl ut a m yl tr a n sf er a s e  
C h ol e st er ol  
 
 
I n or g a ni c 
p h o s p h at e  
L a ct at e d e h y dr o g e n a s e   
Tri gl y c eri d e s  
 
 
M a g n e si u m   
Cr e ati ni n e p h o s p h o ki n a s e   
A m yl a s e  
 
 
 
 
Li p a s e  
R o uti n e Uri n al y si s  
•  
S p e cifi c gr a vit y  
•  
p H, gl u c o s e, pr ot ei n, bl o o d ( h e m o gl o bi n), k et o n e s, bilir u bi n, ur o bili n o g e n, nitrit e, 
l e u k o c yt e e st er a s e b y di p sti c k  
•  
Mi cr o s c o pi c e x a mi n ati o n (if bl o o d or pr ot ei n i s a b n or m al).  
N ot e: I n c a s e of a p o siti v e r e s ult f or h e m o gl o bi n, l e u k o c yt e e st er a s e, pr ot ei n or nitrit e, a 
uri n ar y c ell c o u nt  will b e p erf or m e d  
C o a g ul ati o n  
•  
I N R 
•  
a P T T  
Ot h er S cr e e ni n g 
T e st s  
•  
F S H  
•  
S er u m h C G  pr e g n a n c y t e st  ( a s n e e d e d f or a W O C B P) at all ti m e p oi nt s li st e d i n t h e 
S c h e d ul e of A s s e s s m e nt s  ( S e cti o n 1. 3 ) 
•  
Uri n e dr u g s cr e e n (t o i n cl u d e at mi ni m u m: a m p h et a mi n e s,  m et h a m p h et a mi n e s, 
b ar bit ur at e s, e c st a s y, c o c ai n e, o pi at e s, c a n n a bi n oi d s, b e n z o di a z e pi n e s, m et h a d o n e, 
p h e n c y cli di n e, o x y c o d o n e, a n d tri c y cli c a nti d e pr e s s a nt s, S cr e e ni n g a n d D a y  -1 / 
D a y  1 1)  
•  
S er ol o g y ( h u m a n i m m u n o d efi ci e n c y vir u s I a n d II a nti b o di e s, h e p ati ti s B s urf a c e 
a nti g e n, h e p atiti s B c or e a nti b o d y, h e p atiti s C a nti b o d y)  
•  
S A R S -C o V -2 r a pi d a nti g e n t e st at S cr e e ni n g , P C R t e st  at a d mi s si o n o n D a y  -1  
•  
T h yr oi d sti m ul ati n g h or m o n e  
•  
C oti ni n e t e st ( S cr e e ni n g a n d D a y  -1 / D a y 1 1)  
•  
Al c o h ol br e at h t e st ( S cr e e ni n g a n d D a y  -1 / D a y 1 1)  
•  
E sti m at e d Gl o m er ul ar Filtr ati o n R at e b a s e d o n C hr o ni c Ki d n e y Di s e a s e E pi d e mi ol o g y 
C oll a b or ati o n Cr e ati ni n e E q u ati o n ( 2 0 0 9)  
•  
All st u d y -r e q uir e d l a b or at or y a s s e s s m e nt s will b e p erf or m e d b y a c e ntr al l a b or at or y 
( N u vi s a n’ s cli ni c al l a b or at or y) 
a P T T = a cti v at e d p arti al t hr o m b o pl a sti n ti m e , F S H =f olli cl e sti m ul ati n g h or m o n e, h C G = h u m a n c h ori o ni c 
g o n a d otr o pi n, I N R =I nt er n ati o n al N or m ali z e d R ati o, P C R = p ol y m er a s e c h ai n r e a cti o n, S A R S -C o V -2 = s e v er e a c ut e 
r e s pir at or y s y n dr o m e c or o n a vir u s 2, W O C B P = w o m a n of c hil d -b e ari n g p ot e nti al.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 6 / 6 8 
 
 
 
 
 
 
 
 
 
 
 
  
   
   
  
   
  
   
 
   
 
  
  
   
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 7 / 6 8 
 
 
A p pe n di x 7   
S p o ns or Si g n at ure P a ge  
 
St u d y Title:  
P hase I, O pe n -la bel, Si n gle-s e q ue n ce, Cr oss-o v er St u d y 
of t he Effect of M ulti ple D oses of Itrac o naz ole o n Si n gle -
d ose Te p oti ni b P har mac o ki netics i n Healt h y Partici pa nts  
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:  
E u dra C T:  2 0 2 1 -0 0 3 5 1 3 -1 9  
Cli nic al St u d y Pr ot oc ol Versi o n:  1 5  Se pte m ber  2 0 2 1  / V 1. 0  
I a p pr o ve t h e desi g n of t he cli nical st u d y: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure  
Date of Si g nat ure  
 
N a me, ac a de mi c de gree:  
  
F u ncti o n/ Title:  
 
I nstit uti o n: 
Merc k Healt hcare K Ga A, Dar msta dt, Ger ma n y a n affiliate of  
Merc k K Ga A, Dar msta dt, Ger ma n y  
A d dress:  
Fra n kf urter Str. 2 5 0  
6 4 2 9 3 Dar msta dt, Ger ma n y  
Ge ner al Merc k P h o ne 
N u m ber:  
  
 
Ge ner al Merc k F a x 
N u m ber:  
N ot A p plica ble  
 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


Te p oti ni b  
  
  
  
  
  
  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 8 / 6 8 
 
 
A p pe n di x 8   
Pri nci p al I n vesti g at or Si g n at ure P a ge  
 
St u d y Title:  
P hase I, O pe n -la bel, Si n gle-s e q ue n ce, Cr oss-o ver St u d y 
of t he Effect of 
M ulti ple D oses of Itrac o naz ole o n 
Si n gle -d ose Te p oti ni b P har mac o ki netics i n 
Healt h y 
Partici pa nts  
Re g ul at or y 
A ge nc y I d e ntif yi n g 
N u m bers:  
E u dra C T:  2 0 2 1 -0 0 3 5 1 3 -1 9  
Cli nic al St u d y Pr ot oc ol Versi o n : 1 5  Se pte m ber  2 0 2 1  / V 1. 0  
I a p pr o ve t he desi g n of t h e cli nical st u d y, a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site 
a n d u n dersta n d a n d will c o n d uct it per t he cli nical st u d y pr ot oc ol, a n y a p pr o ve d pr ot oc ol 
a me n d me nts, I C H G C P  ( T o pic E 6) a n d all a p plica ble Healt h A ut h orit y re q uire m e nts a n d 
nati o nal la ws.  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure  
Date of Si g nat ure  
 
N a me, ac a de mi c de gree:  
F u ncti o n/ Title:  
I nstit uti o n: 
A d dress:  
Tele p h o ne n u m ber:  
F a x n u m ber:  
E -m ail a d dress:  
 
Gl o bal Versi o n I D: 
C CI
C CI

SAP_001.pdf: 
Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 /2 7  
 
 
 
I nte gr ate d A n al ysis Pl a n  
St u d y N u m ber:  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Cli nic al St u d y Pr ot oc ol 
Title:  
P hase I, O pe n -la bel, Si n gle -s e q ue n ce, Cr oss-o v er St u d y of t he 
Effect of 
M ulti ple 
D oses of Itrac o naz ole o n Si n gle -d os e 
Te p oti ni b P har mac o ki netics i n Healt h y Partici pa nts  
St u d y P h ase : 
P hase I  
Merc k C o m p o u n d : 
Te p oti ni b   
Pr ot oc ol V ersi o n:  
1 5  Se p  2 0 2 1 / Versi o n 1. 0 
I nte gr ate d A n al ysis Pl a n 
A ut h or : 
 
C o or di n ati n g A ut h or  
 
Bi o st ati sti c s, M er c k  
 
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
Bi o st ati sti c s, 
 
 
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n : 
1 8  Fe b  2 0 2 2  / Versi o n Fi nal 1. 0  
I nte gr ate d A n al ysis Pl a n 
Re vie wers:  
 
F u n cti o n  
N a m e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nfi de nti al  
T his d oc u me nt is t he pr o pert y of Merc k  Healt hcare  K Ga A, Dar mst a dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.  
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut 
e x press per missi o n of Merc k Healt hcare K Ga A, D ar msta dt, Ger ma n y or its affiliate.  
C o p yri g ht © 2 0 2 2  b y M erc k  He alt hc are  K G a A, D ar mst a dt, Ge r m a n y or its affili ate. All ri g hts reser ve d.  
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 /2 7  
 
 
A p pr o v al  P a ge   
 
I nte gr ate d A n al ysis Pl a n: M S 2 0 0 0 9 5 _ 0 0 5 3   
P hase I, O pe n -la bel, Si n gle-se q ue n ce, Cr oss-o v er St u d y o f t he Effect of M ulti ple D oses of 
Itr ac o n az ole o n Si n gle-d ose Te p oti ni b P har mac o ki netics i n Healt h y Partici pa nts  
A p pr o val of t he I A P b y all Merc k Data A nal ysis Res p o nsi ble has t o be d oc u me nte d wit hi n E D M S 
via e Si g nat ure. 
Wit h t he a p pr o val, t he Merc k res p o nsi ble f or eac h of t he a nal ysis als o ta kes 
res p o nsi bilit y t h at all re vie wers’ c o m me nts are a d dresse d a d e q uatel y. 
B y usi n g e Si g n at ure, t he si g nat ur e will a p pear at t he e n d of t he d oc u me nt.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 /2 7  
 
 
1  
T a ble of C o nte nts   
A p pr o val Pa ge  
 ..............................................................................................................2  
1  
Ta ble of C o nte nts  ..................................................................................3  
2  
List of A b br e viati o ns a n d Defi niti o n of Ter ms  ....................................5  
3  
M o dificati o n Hist or y  ............................................................................6  
4  
P ur p ose of t he I nte grate d A nal ysis Pla n  ...............................................6  
5  
O bjecti ves a n d E n d p oi nts  .....................................................................7  
6  
O ver vi e w of Pla n ne d A nal yses  .............................................................7  
7  
C ha n ges t o t he Pla n ne d A nal ys es i n t he Cli nical St u d y Pr ot o c ol  ........7  
8  
A nal ysis Sets a n d S u b gr o u ps  ................................................................8  
8. 1  
Defi niti o n of A nal ysis Sets  ...................................................................8  
8. 2  
S u b gr o u p D efi niti o n a n d Para meterizati o n  ..........................................8  
9  
Ge neral S pecificati o ns f or Data A n al ys es  ............................................8  
9. 1  
Defi niti o n of Ba s eli ne a n d C ha n ge fr o m Baseli ne ...............................9  
9. 2  
St u d y Da y / St u d y I nter v e nti o n Da y  .....................................................9  
9. 3  
Defi niti o n of D urati o n a n d ‘ Ti me Si nce’ Varia bles  .............................9  
9. 4  
I m p utati o n of Missi n g Data ................................................................1 0  
1 0  
St u d y Partici pa nts  ...............................................................................1 0  
1 0. 1  
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns  ...............................1 0  
1 0. 2  
Pr ot oc ol De viati o ns / E xcl usi o n fr o m A nal ysis Sets  ..........................1 1  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De viati o ns ............................................................1 1  
1 0. 2. 2  
Reas o ns Lea di n g t o t he E x cl usi o n fr o m a n A nal ysis Set  ...................1 1  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .............................1 2  
1 1. 1  
De m o gra p hics  .....................................................................................1 2  
1 1. 2  
Me dical Hist or y  ..................................................................................1 2  
1 1. 3  
Ot her B aseli ne C haracteristics  ............................................................1 2  
1 2  
Pre vi o us or C o nc o mita nt T hera pies/ Pr oce d ures  .................................1 2  
1 3  
St u d y I nter v e nti o n: C o m plia nce a n d E x p os ure  ..................................1 3  
1 4  
Efficac y A nal yses  ...............................................................................1 3  
1 5  
Safet y A nal yses  ..................................................................................1 4  
1 5. 1  
A d verse E v e nts  ...................................................................................1 4  
1 5. 1. 1  
All A d verse E v e nts  .............................................................................1 4  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 /2 7  
 
 
1 5. 1. 2  
A d verse E v e nts Lea di n g t o Disc o nti n uati o n of St u d y I nter ve nti o n  ...1 5  
1 5. 2  
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E v e nts  ...................................................................................1 6  
1 5. 2. 1  
Deat hs  .................................................................................................1 6  
1 5. 2. 2  
Seri o us A d verse E v e nts  ......................................................................1 6  
1 5. 2. 3  
Ot her Si g nifica nt A d verse E ve nts  ......................................................1 6  
1 5. 3  
Cli nical La b orat or y E val uati o n  ...........................................................1 6  
1 5. 4  
Vital Si g ns  ..........................................................................................1 7  
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns  ............................................1 7  
1 6  
A nal ys es of Ot her E n d p oi nts/ Esti ma n ds  ............................................1 8  
1 6. 1  
P har mac o ki netics  ................................................................................1 8  
1 6. 1. 1  
Descri pti ve Statistics of P K C o nce ntrati o n Data  ................................1 8  
1 6. 1. 2  
Descri pti ve Statistics of P K Para meter Data  ......................................1 8  
1 6. 1. 3  
Statistical A nal ysis of P K Para meter Data  .........................................1 9  
1 6. 1. 4  
Ge neral S pecificati o ns f or P K C o nce ntrati o n a n d P K Para meter 
Data  .....................................................................................................2 0  
1 6. 1. 5  
Esti mati o n of P har mac o ki netic Para meters  ........................................2 1  
1 6. 1. 5. 1  
Esti mati o n of P har mac o ki netic Para meters i n Plas ma  .......................2 1  
1 6. 1. 6  
Prese ntati o n of P K C o nce ntrati o n a n d P K Para m eter Data  ................2 4  
1 6. 1. 6. 1  
Listi n gs a n d Ta bles  .............................................................................2 4  
1 6. 1. 6. 2  
Gra p hical S u m maries a n d I n di vi d ual pl ots ( P K A nal ysis Set)  ...........2 5  
1 7  
Refere n ces  ...........................................................................................2 6  
1 8  
A p pe n dices  .........................................................................................2 7  
 
Gl o bal Versi o n I D: C CI
C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 /2 7  
 
 
2  
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms  
 
A Da M  
A nal ysis D ata M o del  
A E  
A d verse E v e nt  
A N O V A  
A nal ysis of V A RI A N C E  
B L Q  
Bel o w L o w er Li mit of Q ua ntificati o n  
C DI S C  
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m  
CI  
C o nfi de nce I nter val  
C R  
C o m plete Res p o nse  
e C R F 
electr o nic Cas e Re p ort F or m  
C S R  
Cli nical St u d y  Re p ort  
E C G  
Electr ocar di o gra m  
I A P 
I nte grate d A nal ysis Pla n 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n  
M C A R  
Missi n g C o m pletel y At Ra n d o m  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M T D  
Ma xi m u m T olerate d D ose  
P T  
Preferre d Ter m  
P K  
P har mac o ki netics  
S A E  
Seri o us A d verse E v e nt  
S D  
Sta n dar d De viati o n  
S D T M  
St u d y Data T a b ulati o n M o del  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
T L F  
Ta bles, Listi n gs, a n d Fi g ures  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 /2 7  
 
 
3  
M o dific ati o n Hist or y   
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n  
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
Fi n al  1 .0  
1 8 -F e b -2 0 2 2  
 
I niti al v er si o n. 
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n   
T he p ur p ose of t his I A P is t o d oc u me nt tec h nical a n d detaile d s pecificati o ns f or t he fi nal a nal ysis 
of data c ollecte d f or pr ot oc ol M S 2 0 0 0 9 5 _ 0 0 5 3 . Res ults of t he a nal yses des cri be d i n t his I A P will 
b e i ncl u de d i n t he C S R . A d diti o nall y, t he pla n ne d a nal yses i de ntifie d i n t his I A P ma y  be i n cl u de d 
i n re g ul at or y s u b missi o ns or f ut ure ma n uscri pts. A n y p ost-h o c, or u n pla n ne d a nal yses perf or m e d 
t o pr o vi de res ults f or i ncl usi o n i n t he CS R b ut n ot i de ntifie d i n t his pr os pecti ve I A P will be clearl y 
i de ntifie d i n t he CS R.  
T he I A P is base d u p o n Secti o n 9  ( Statistical c o nsi derati o ns ) of t he st u d y pr ot oc ol a n d pr ot oc ol 
a me n d me nts a n d is pre p are d i n c o m plia nce wit h I C H E 9. It d escri b es a n al yses pla n ne d i n t he 
pr ot oc ol a n d pr ot oc ol a m e n d me nts . 
T he w or di n g use d i n t his I A P is c h ose n t o b est matc h t he res pecti ve w or di n g i n t he st u d y pr ot oc ol 
te m plate, t he 
Cli nical St u d y 
Re p ort ( C S R) te m plate, 
C DI S C re q uire me nts a n d s pecial 
re q uire me nts f or ta ble la y o uts. T heref ore, t he f oll o wi n g a p pr oac h is use d: 
Ge nerall y, t he ter m ‘ partici pa nt’ will be use d i nstea d of ‘s u bject’ or ‘ patie nt’. H o we v er, i n t a bles 
a n d listi n gs t he ter m ‘s u bject’ will be use d t o matc h C DI S C re q uir e me nts, e x ce pt f or i n -te xt ta bles 
w here ‘ partici pa nt’ will be use d t o mat c h t he C S R a n d pr ot oc ol te m plat es. Si milarl y, t he t er m 
‘st u d y i nter ve nti o n’ will be use d i n t his d oc u me nt i nstea d of ‘treat me nt’ t o matc h pr ot oc ol a n d 
C S R te m plates, h o we ver, ta bles a n d listi n gs will use ‘treat me nt’ f or bre vit y reas o ns. E x ce pti o ns 
fr o m t his r ule are c o m m o nl y use d ter ms li ke “ o n-treat me nt”, “treat me nt-e mer ge nt”, “tr eat me nt 
p olic y”, “s u bject -years”, “ b y -s u bject ”, or na mes of e C R F p a ges li ke “ Treat me nt Ter mi nati o n” 
pa ge.  
Gl o bal Versi o n I D: 
P P D
C CI




Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 /2 7  
 
 
8  
A n al ysis Sets a n d S u b gr o u ps   
8. 1  
Defi niti o n of A n al ysis Sets   
A n al y si s S et  
D e s cri pti o n  
S cr e e ni n g ( S C R)  
All p arti ci p a nt s, w h o pr o vi d e d i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s 
e nr oll m e nt  a n d st u d y i nt er v e nti o n st at u s i n t h e st u d y.  
S af et y ( S A F)  
All p arti ci p a nt s, w h o w er e a d mi ni st er e d a n y d o s e of a n y st u d y i nt er v e nti o n.  
A n al y s e s will c o n si d er p arti ci p a nt s a s tr e at e d.  
P h ar m a c o ki n eti c ( P K ) 
T h e P K A n al y si s S et  i s a s u b s et of t h e S A F, a n d th e P K p o p ul ati o n will i n cl u d e all 
p arti ci p a nt s:  
W h o h a v e c o m pl et e d t h e st u d y wit h o ut a n y r el e v a nt pr ot o c ol d e vi ati o n s a n d f a ct or s 
li k el y t o aff e ct t h e c o m p ar a bilit y of P K r e s ult s. 
Wit h a d e q u at e st u d y i nt er v e nti o n c o m pli a n c e.  
Wit h e v al u a bl e P K d at a, i. e., n o n -mi s si n g v al u e s  f or pri m ar y e n d p oi nt s. 
If p arti ci p a nt s r e c ei v e d pr o hi bit e d c o n c o mit a nt t h er a p y or m e di ci n e s, a s s p e cifi e d i n 
S e cti o n 6. 8 . 3 of t h e C S P , t h e y will b e e x cl u d e d fr o m t h e P K p o p ul ati o n. 
All P K a n al y s e s will b e b a s e d o n t hi s a n al y si s s et.  
 
8. 2  
S u b gr o u p D efi niti o n a n d P ar a meteriz ati o n   
N ot a p plica ble.  
9  
Ge ner al S pecific ati o ns f or D at a A n al yses   
T he res ults of t his st u d y will be re p orte d usi n g s u m mar y ta bles, fi g ures, a n d data listi n gs, as 
a p pr o priate. All dat a will be s u m marize d b y st u d y i nter ve nti o n a n d/ or sc he d ule d ti me p oi nt, as 
a p plica ble.  
Listi n gs  
In t he i n di vi d ual partici p a nt data listi n g  all i n di vi d ual data w ill be liste d as meas ure d. Re peat e d 
a n d u nsc he d ule d meas ure me nts will be i ncl u de d i n t he listi n gs.  All listi n gs will be s orte d b y s u bject 
I D, st u d y i nter ve nti o n, a n d n o mi nal ti me p oi nt, as a p pr o priate.  
T a bles a n d Descri pti ve St atistics  
All data will be s u m marize d b y st u d y i nter ve nti o n a n d n o mi nal ti me p oi nt, as a p pr o priate. 
Re peate d a n d u nsc he d ul e d meas ure me nts i ncl u d e d i n t he listi n gs will n ot be use d f or statistical 
a nal ys es or s u m maries, u nless t he re peate d m eas ure m e nt was perf or me d d ue t o u nrelia ble 
va l ues/tec h nical r eas o ns, e.g ., cl otte d sa m ples.  
U nless ot her wise s pecifi e d, c o nti n u o us varia bles will be s u m marize d usi n g des cri pti ve statistics, 
i.e. t he n u m ber of partici pa nts wit h n o n-missi n g val ues ( n), t he n u m ber of partici pa nts wit h missi n g 
val ues, ( n miss), mea n, sta n dar d de viati o n, me dia n, 2 5t h perce ntile ( Q 1) a n d 7 5t h perce ntile ( Q 3), 
mi ni m u m, a n d ma xi m u m . If t h ere are n o missi n g val ues t he n u m ber of partici pa nts wit h missi n g 
val ues s h o ul d be i n dicate d b y a 0.  M ea n, Me dia n, Q 1, Q 3, Mi n, Ma x will ha ve t he sa me precisi o n 
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 /2 7  
 
 
as t he S D T M data ( deci mal places). S D will be prese nte d wit h o ne deci mal place m or e t ha n t h e 
mea n.  
Q ualitati ve varia bles will be s u m marize d b y fre q u e nc y c o u nts a n d perce nta ges. U nless ot her wise 
state d t he calc ul ati o n of pr o p orti o ns will be base d o n t he n u m ber of p artici p a nts of t he a nal ysis set 
of i nterest t h at recei ve d t he res p ecti ve st u d y i nter ve nti o n f or A E a n d P K t a bles a n d f or all ot her 
e val uati o ns t he a nal ysis set of i nterest [ N]. T heref ore, c o u nts of missi n g o bser vati o ns will be 
i ncl u de d i n t he de n o mi nat or a n d prese nt e d as a s e parate cate g or y.   
St u d y d a y 1  f or t his st u d y is defi n e d as t he start d ate of st u d y i nter ve nti o n. 
T he f oll o wi n g la bels will be use d f or t he st u d y i nter ve nti o ns i n ta bles a n d listi n gs, if n ot state d 
ot her wise:  
Te p oti ni b : 
 
Te p oti ni b: 5 0 0 m g o n Da y 1  
 
Itr ac o n az ole: 
 
Itr ac o n az ole: 2 0 0 m g o n Da y s 8 -1 1   
Itr ac o n az ole+ Te p oti ni b :  
 
Itr ac o n az ole: 
2 0 0 
m g 
o n  
Da y s 
1 2 -1 8 
pl us 
 
Te p oti ni b: 5 0 0 m g o n Da y 1 2  
All statistical a nal yses will be perf or me d usi n g S A S ® S oft ware versi o n 9. 4  or hi g her . 
9. 1  
Defi niti o n of B aseli ne  a n d C h a n ge fr o m B aseli ne   
If n ot ot her wis e s pecifie d, ‘ bas eli ne’ refers t o t he last sche d ule d 
meas ure me nt b ef ore 
a d mi nistrati o n of first st u d y i nter ve nti o n. 
H o we ver, if a partici pa nt is missi n g t he b aseli ne c ollecti o n, t he pre vi o us n o n -missi n g e v al uati o n 
c o ul d bec o me t he b aseli ne val ue (e. g. fr o m scree ni n g/a d missi o n). If n o baseli ne or pre v i o us t o 
baseli ne e val u ati o ns e xist, t he n t he baseli ne val u e will be treate d as missi n g.  
A bs ol ute c ha n ge s fr o m b aseli ne are defi n e d as   
 
a bs ol ute c ha n ge = visit val ue –  baseli ne v al ue  
9. 2  
St u d y D a y / S t u d y Inter ve nti o n D a y   
Da y 1 is t he da y of start of st u d y i nter ve nti o n, t he da y b ef ore is Da y -1 ( n o Da y 0 is defi ne d). St u d y 
da y is defi ne d relati ve t o Da y 1.  
9. 3  
Defi niti o n of D ur ati o n  a n d ‘T i me S i nce’ V ari a bles   
T he f oll o wi n g d efi niti o ns a n d  calc ul ati o ns of d urati o n , as a p plica ble, will be a p plie d:  
•  D urati o n of a d v erse e ve nt ( A E ) (i n da ys h h: m m) = e n d date a n d ti me - start date a n d ti me of 
t he A E, if missi n g ti me f or eit her t he be gi n ni n g or e n d t he n = e n d date –  start date + 1; i n case 
of m ulti ple rec or ds f or t he sa me A E, t he d urati o n will be calc ulate d o ver all t hese rec or ds  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 /2 7  
 
 
•  Da ys h h: m m fr o m d osi n g ( o nset p ost a d mi nistrati o n) = start d at e a n d ti me of t he e ve nt - dat e 
a n d ti me of last d ose a d mi nistrati o n of te p oti ni b or itrac o n az ole (calc ulate d f or eac h 
i nter ve nti o n, f or T E A Es), if missi n g ti me f or eit her t he d osi n g or e ve nt t he n da ys h h: m m fr o m 
d osi n g = e ve nt start date –  date of d ose a d m i nistrati o n + 1 
•  Relati ve ( Rel.) Da y i n st u d y of A E = start date of t he e ve nt –  date of first ad mi n + 1 (f or A Es 
o n or after t h e da y of d osi n g)  
•  Rel. Da y i n st u d y of A E = start date of t h e e ve nt –  date of first ad mi n (f or e ve nts bef ore t h e da y 
of d osi n g of t h e st u d y o nl y)  
9. 4  
I m p ut ati o n of M issi n g D at a   
I n t his P hase I P K st u d y, missi n g o bser vati o ns will be ass u me d t o be missi n g c o m pletel y a t ra n d o m 
( M C A R). N o acti o n will be ta ke n t o ha n dle missi n g dat a. A partici p a nt w h o wit h dra ws pri or t o t he 
last pla n ne d o bser vati o n i n a st u d y peri o d will be i ncl u de d i n t he a nal yses u p t o t he ti me of 
disc o nti n uati o n.  
1 0  
St u d y P artici p a nt s  
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or re p orti n g partici pa nt  dis p ositi o n a n d 
st u d y i nter ve nti o n/st u d y disc o nti n uati o ns. 
A d diti o nall y , pr oce d ures f or re p orti n g pr ot oc ol 
de viati o n s are pr o vi d e d. 
1 0. 1  
Dis p ositi o n of P artici p a nt s a n d Disc o nti n u ati o ns  
T he f oll o wi n g will be prese nte d i n a s u m mar y ta bl e:  
•  T otal n u m ber of partici pa nts scree n e d (i.e., p artici pa nts w h o  ga ve i nf or me d c o nse nt)  
•  N u m ber of scree ne d p artici pa nts w h o disc o nti n ue d fr o m t he trial pri or t o first d osi n g o verall  
a n d gr o u pe d b y t he mai n reas o n f or disc o nti n uati o n:  
•  Partici pa nt di d n ot meet all eli gi bilit y criteria  
•  Wit h dre w c o nse nt   
•  Ot her  ( C O VI D-1 9 -relate d a n d C O VI D-1 9 -n o n -relate d)  
•  N u m ber of treate d partici pa nts  
•  N u m ber a n d p erce nta ge of treate d p artici pa nts w h o c o m plete d st u d y  
•  N u m ber a n d perce nt a ge of treate d partici pa nts 
w h o disc o nti n ue d t he st u d y or 
st u d y 
i nter ve nti o n, wit h t he pri mar y reas o n of disc o nti n uati o n:  
•  A d verse e ve nt  
•  L ost t o f oll o w -u p  
•  Pr ot oc ol n o n -c o m plia nce  
•  Deat h  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 /2 7  
 
 
•  Wit h dre w c o nse nt  
•  Ot her ( C O VI D -1 9 -relate d a n d C O VI D-1 9 -n o n -relate d) 
T he n u m ber a n d perce nta ge of partici pa nts will be prese nte d b y gr o u p of st u d y i nter ve nti o n a n d 
t otal, w here a p plica ble. Perce nta ges will be prese nte d wit h res pect t o t he n u m ber of tr eate d 
partici pa nts , w here a p pli ca ble. 
A listi n g of disc o nti n ue d partici pa nts will be pr o vi de d.  
A listi n g of p artici pa nts affect e d b y t he C O VI D -1 9 relate d st u d y disr u pti o n b y u ni q u e partici pa nt 
i de ntifier will als o be pr o vi de d. 
1 0. 2  
Pr ot oc ol De vi ati o ns  / E xcl usi o n fr o m A n al ysis Sets   
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De vi ati o ns  
Listi n gs of i m p orta nt pr ot oc ol de viati o ns will be pr o vi de d i ncl u di n g t he d ate a n d relati ve da y i n 
relati o n t o first d osi n g i n t he st u d y. A disti ncti o n will be ma de b et wee n i m p or ta nt pr ot oc ol 
de viati o ns d ue t o C O VI D -1 9 vers us n ot d ue t o C O VI D -1 9. T he res pecti ve i m p orta nt pr ot oc ol 
de viati o ns will be fla g ge d acc or di n gl y.  
I m p ort a nt pr ot oc ol d e viati o ns or i m p orta nt e ve nts t hat mi g ht h a ve a n effect o n P K i ncl u de, b ut 
ma y n ot be li mite d  t o t he f oll o wi n g: 
•  A d verse e ve nts  li ke diarr hea etc. (t hese i nsta nces will be disc usse d o n a case -b y cas e basis)  
•  V o miti n g after a d mi nistrati o n f oll o wi n g oral d osi n g (t hes e i nsta nces will be disc usse d i n 
ali g n me nt wit h a p plica bl e re g ulat or y g ui d eli nes o n a case -b y case basis)  
•  Sa m ple pr ocessi n g err ors t hat ma y lea d t o i nacc urate bi oa nal ytical r es ults 
•  I n acc urate d osi n g or d osi n g err ors (e. g. d os e a d mi nistrati o n dela ye d, d ose c ha n ge or misse d 
d oses)  
•  Pre -d ose or tr o u g h s a m ple c ollecte d after t h e act u al d osi n g  
•  N o n -c o m plia nce 
wit h f o o d a n d dri n k re q uire me nts (e. g. n o n -faste d, i nc o m plete 
meal 
c o ns u m pti o n, caffei n e i nta ke)  
•  C o nc o mita nt me dicati o n, vita mi ns, dietar y or her bal s u p ple me nts  
S h o ul d o ne or m ore of t hese e ve nts b e a v aila ble at t he Data Re vie w M eeti n g, its  i m plicati o n f or 
P K e val uati o n will be disc usse d a n d a gree d a m o n gst rele va nt st u d y t ea m me m bers (e. g. S p o ns or 
Cli nical P har mac ol o g y/ Bi ostatistics/ Cli nical P har mac o ki netics 
& P har mac o d y na mics tea m 
re pres e ntati ve). A p pr o priate acti o n will be ta ke n s uc h as fla g gi n g i n di vi d ual val ues t o be e x cl u de d 
fr o m a nal ysis.  
1 0. 2. 2  
Re as o ns Le a di n g t o t he E xcl usi o n fr o m a n A n al ysis Set   
If partici pa nts are e x cl u de d fr o m t he P K A nal ysis Set, t he reas o ns f or e x cl usi o n will be liste d.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 /2 7  
 
 
Reas o ns f or e x cl u di n g i n di vi d ual P K c o nce ntrati o ns will als o be liste d se paratel y a n d fla g ge d i n 
t he mai n listi n g. 
1 1  
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics   
De m o gra p hics a n d baseli ne c haracteristics will be prese nte d f or t he S A F.   
1 1. 1  
De m o gr a p hics   
Descri pti ve statistics will be pres e nte d f or a ge, hei g ht, wei g ht, a n d b o d y mass i n de x ( B MI). 
Fre q u e nc y c o u nts a n d perce nta ges will be prese nt e d f or s e x, race, a n d et h nicit y. T he s u m mar y will 
be perf or me d o verall.  
B MI ( k g/ m2) will be deri ve d (i .e., n ot ta ke n dir ectl y fr o m t he d ata bas e) acc or di n g t o t h e f oll o wi n g 
f or m ula: 
B MI [k g/ m² ] = 
w ei g ht  [k g ] 
h ei g ht [c m ]2 × 1 0 0 0 0  
1 1. 2  
Me dic al Hist or y   
Me dical hist or y will be c o de d usi n g t he M e dical Dicti o nar y f or R e g ulat or y Acti vities ( Me d D R A), 
m ost c urre nt v ersi o n at ti me of data bas e l oc k , a n d liste d. 
T he me dical hist or y will be liste d b y p artici pa nt i ncl u di n g  preferre d ter m  ( P T) as e ve nt cate g or y 
a n d s yste m or ga n class ( S O C) b o d y ter m as B o d y S yste m cate g or y.   
1 1. 3  
Ot her B aseli ne C h ar acteristics   
Ot her baseli ne meas ur e m e nts, s uc h as vir us scree n, alc o h ol a n d dr u gs of a b use scree n, pre g na nc y 
test i n w o me n, nic oti ne a n d alc o h ol c o ns u m pti o n, will be liste d. 
Baseli ne 
c haracteristics 
wit h 
res pect 
t o 
vital 
si g ns, 
p h ysical 
e x a mi nati o ns, 
a n d 
he mat ol o g y/ bi oc h e mistr y will be part of Secti o n 1 5  ( Safet y A nal ysis ). 
1 2  
P re vi o us  or C o nc o mit a nt T her a pies / Pr oce d ures  
Me dicati o ns will be pres e nte d f or t he S A F . 
Pre vi o us me dicati o ns are defi ne d as a n y m e dicati o n disc o nti n ue d pri or t o t he a d mi nistrati o n of 
first st u d y i nter ve nti o n. C o nc o mita nt me dicati o ns are defi ne d as a n y m e dicati o n ta ke n d uri n g t he 
c o urse of t he st u d y, wit h a starti n g d ate great er t h a n or e q ual t o t h e a d mi nistrati o n of first st u d y 
i nter ve nti o n, or wit h a starti n g dat e pri or t o t he a d mi nistrati o n of first st u d y i nter ve nti o n a n d 
o n g oi n g at t he ti me of t h e first a d mi nistrati o n of st u d y i nter ve nti o n.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 /2 7  
 
 
T he W orl d Healt h Or ga niz ati o n Dr u g dicti o nar y ( W H O -D D), m ost c urre nt versi o n at ti me of 
data base l o c k , will be use d f or c o di n g of pri or a n d c o nc o mita nt me dicati o ns a n d t he y will be 
descri be d usi n g Preferre d Ter m ( P T) as a p plica ble.  
Pre vi o us a n d c o n c o mita nt me dicati o ns will be liste d. C o nc o mita nt pr oce d ure s, if a n y, will als o b e 
liste d. 
1 3  
St u d y Inter ve nti o n : C o m pli a nce a n d E x p os ure   
T he d osi n g of eac h p arti ci pa nt is m o nit ore d b y t he st u d y n urse or i n vesti gat or. A listi n g of date 
a n d ti me of eac h dr u g a d mi nistrati o n a n d eac h bl o o d sa m pli n g, i ncl u di n g ti me de viati o ns as well 
as meas ure d plas ma c o n ce ntrati o ns, will be pr o vi de d s orte d b y partici pa nt . I nf or mati o n o n meal 
i nta ke will be liste d b y p artici pa nt, if pr o vi de d. 
1 4  
Effic ac y A n al yses   
N ot a p plica ble . 
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 /2 7  
 
 
1 5  
S afet y A n al yses   
T his secti o n i ncl u des s pecificati o ns f or s u m mari zi n g safet y e n d p oi nts t h at are c o m m o n acr oss 
cli nical st u dies s uc h as a d verse e v e nts, la b orat or y tests a n d vital si g ns. 
All safet y a nal yses will be perf or me d f or t he Safet y A nal ysis Set a n d will be prese nte d b y  st u d y 
i nter ve nti o n a n d n o mi nal ti me p oi nt, as a p pr o priate.  
Safet y a nal yses will be d o ne acc or di n g t o t he as -tr eate d pri nci ple.  
1 5. 1  
A d verse E ve nts   
All A Es rec or de d d uri n g t he c o ur s e of t he st u d y will be c o d e d wit h t h e Me d D R A, latest v ersi o n at 
ti me of data base l o c k, a n d assi g ne d t o a S O C a n d a P T.  
Treat me nt -e mer ge nt A Es ( T E A Es) are t h ose e ve nts wit h o nset dates o n or after t he first 
a d mi nistrati o n of st u d y i nter ve nti o n  o n Da y 1 . A n y A E occ urri n g b ef ore t he a d mi nistrati o n of 
st u d y i nter ve nti o n o n D a y 1 a n d res ol ve d b ef ore a d mi nistrati o n of st u d y i nter ve nti o n or n ot 
w orse ni n g aft er a d mi nistrati o n of st u d y i nter ve nti o n o n Da y 1  will be i n cl u de d i n t he A E listi n gs  
b ut will n ot be i ncl u de d i n t he s u m mar y ta bl es ( u nless ot her wise state d). T h ese will be referre d t o 
as “ pre -treat me nt” A Es. A n A E occ urri n g aft er a d mi nistrati o n of a n y st u d y i nter ve nti o n will be 
c o u nte d t o war ds t he last i nter ve nti o n recei ve d bef ore t he o nset, e ve n if t he e ve nt is n ot res ol ve d at 
t he be gi n ni n g of t he f oll o wi n g i nter ve nti o n.  A n A E t hat w orse ns after a later i nter ve nti o n peri o d 
will be c o u nte d t o war ds b ot h st u d y i nter ve nti o ns. 
I n case A E-relate d dat es are partial, t he a vaila ble i nf or mati o n will be use d i n a c o nser vati ve 
a p pr oac h t o d eter mi ne w het her t he A E is treat me nt -e mer ge nt.  
All a nal yses d escri b e d i n Secti o n 1 5. 1  will be b ase d o n T E A Es if n ot ot her wis e s pecifi e d. T h e A E 
listi n gs will i ncl u de all A Es ( w het h er tr eat me nt-e mer ge nt or n ot). A Es o utsi de t he o n -tr eat me nt 
peri o d will be fla g ge d i n t he listi n gs.  
U nless ot her wise s pecifie d, T E A Es will be s u m marize d , b y n u m ber a n d perce nta ge of partici pa nts 
wit h t he T E A E i n t he cat e g or y of i nterest , as well as t he n u m ber of e ve nts, i n t otal a n d b y st u d y 
i nter ve nti o n gr o u p, pri mar y S O C a n d P T  i n al p ha betical or der f or S O C a n d decreasi n g o verall 
fre q ue n c y f or P T.  
Eac h partici pa nt will be c o u nte d o nl y o nce wit hi n ea c h S O C or P T.  
If a n e v e nt w as re p orte d m ore t ha n o nce d ue t o c h a n ge i n i nte nsit y a n d c ha n ge i n relati o ns hi p , t he 
w orst se verit y a n d t he w orst relati o ns hi p t o trial treat me nt will be ta b ulate d.  
1 5. 1. 1  
All A d verse E ve nts   
N u m ber of t reat me nt-e m er ge nt A Es a n d partici pa nts e x perie nci n g T E A Es will be s u m marize d f or 
Te p oti ni b , Itr ac o naz ole, Itrac o naz ole + T e p oti ni b a n d o verall , eac h i n ta bles wit h: 
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 /2 7  
 
 
•  T he  n u m ber a n d perce nta ge of partici pa nts wit h a n y T E A E, a n y relat e d T E A E,  a n y te p oti ni b-
relate d T E A E, a n y itrac o naz ole-relate d T E A E, a n y seri o us T E A E, a n y rel ate d seri o us T E A E, 
a n y te p oti ni b-relate d seri o us T E A E, a n y itrac o naz ole-relat e d seri o us T E A E, a n y sev ere  T E A E, 
a n y relat e d se v ere T E A E, a n y te p oti ni b-rel ate d se vere T E A E, a n y itrac o n az ole-relate d se v ere 
T E A E, a n y A Es of s pecial i nterest ( A E SI), a n y T E A E lea di n g t o deat h, a n y relate d T E A E 
lea di n g t o deat h, a n y te p oti ni b-relate d T E A E lea di n g t o deat h, a n y itrac o n az ole -relate d T E A E 
lea di n g t o d eat h, a n y T E A E lea di n g t o st u d y disc o nti n uati o n  
•  T he n u m ber a n d perce nt a ge of partici p a nts wit h at least o ne T E A E a n d t he n u m ber of e ve nts 
b y S O C a n d P T . 
•  T he n u m ber a n d perce nta ge of p artici pa nts wit h T E A Es e x cl u di n g S A Es  a n d n u m ber of e ve nts , 
wit h fre q ue n c y  of partici pa nts  ≥ 5 % i n a n y st u d y i nter ve nti o n ar m b y S O C a n d P T  
•  T he n u m ber a n d p erce nt a ge of partici p a nts wit h at least o ne T E A E a n d n u m ber of e ve nts b y 
se verit y, S O C, a n d P T  
•  T he n u m ber a n d p erce nt a ge of partici p a nts wit h at least o n e relate d T E A E , te p oti ni b-relate d 
T E A E, itrac o n az ole -relate d T E A E a n d n u m ber of e ve nts  b y S O C a n d P T  
•  T he n u m ber a n d p erce nt a ge of partici p a nts wit h at least o ne A E SI rec or de d  a n d n u m b er of 
e ve nts  b y S O C a n d P T.  
U nless ot her wis e state d, A Es will be dis pla ye d wit h S O C ter ms  s orte d al p ha beticall y a n d P Ts 
wit hi n eac h S O C ter m s orte d i n desce n di n g o v erall fre q ue n c y.  
F or deter mi ni n g i nci de n ce c o u nts, wit hi n eac h le vel of T E A E ter m, if a partici pa nt e x perie nces 
m ore t ha n o ne occ urre n ce, t he partici pa nt will o nl y be c o u nte d o nce f or t h at T E A E.  
A d verse e ve nts relate d t o a n y st u d y i nter ve nti o n  are t h ose e v e nts wit h relati o ns hi p missi n g, 
u n k n o w n or yes.  
I n case a partici pa nt ha d e ve nts wit h missi n g a n d n o n-missi n g se verit y, t he ma xi m u m n o n -missi n g 
se verit y will be dis pla ye d.  
1 5. 1. 2  
A d verse 
E ve nts 
Le a di n g t o 
Disc o nti n u ati o n 
of 
St u d y 
I nter ve nti o n  
A listi n g of T E A Es lea di n g t o disc o nti n uati o n of st u d y i nter ve nti o n, or di sc o nti n uati o n of st u d y, 
if a n y, will be pr o vi de d.   
T he fre q u e nc y ( n u m ber a n d perce nt a ge) of partici pa nts wit h T E A Es lea di n g t o per ma n e nt 
disc o nti n uati o n of eac h st u d y i nter ve nti o n b y st u d y i nter ve nti o n will als o be pr o vi de d i n a ta ble.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 6 /2 7  
 
 
1 5. 2  
De at hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts   
1 5. 2. 1  
De at hs   
A listi n g of deat hs, if a n y, will be pr o vi de d . 
1 5. 2. 2  
Seri o us A d verse E ve nts   
A listi n g of seri o us A Es ( S A Es), if a n y, will be pr o vi de d.   
S u m mar y ta ble of t he n u m ber a n d perce nta ge of partici pa nts wit h at least o ne  S A E b y S O C a n d 
P T  will als o be pr o vi de d.  
1 5. 2. 3  
Ot her Si g nific a nt A d verse E ve nts   
T he f oll o wi n g A E SI  were defi ne d : 
•  A Es s u g gesti ve of dr u g -i n d uce d li ver i nj ur y i n cl u di n g h e patic/li ver fail ure a n d he p atitis 
( n o ni nfecti o us) are c o nsi dere d A E SIs. 
M ore i nf or mati o n c a n be f o u n d i n t he C S P, secti o n 8. 3. 7.  
A E SI will be i de ntifie d i n t he A E listi n gs. S u m mar y ta bl e of t he n u m ber a n d perce nta ge of 
partici pa nts wit h at least o ne A E SI b y S O C a n d P T  will als o be pr o vi de d . 
 
1 5. 3  
Cli nic al L a b or at or y E v al u ati o n   
Listi n gs a n d s u m mar y statistics at eac h assess me nt ti me will be prese nte d usi n g t he S ystè me 
I nter nati o nal ( SI) u nits. N or mal ra n ges will b e pr o vi de d b y t he ce ntr al la b orat or y, a n d o ut of ra n ge 
fla gs will be calc ulate d base d o n t he n or mal ra n ges. La b orat or y d ata n ot tra nsferre d fr o m t he 
ce ntral la b orat or y i n SI u nits will be c o n verte d t o SI u nits bef ore pr ocessi n g. B ot h or i gi nal u nits 
a n d SI u nits will be pr o vi de d i n t he S D T M d o mai n.  
Safet y l a b orat or y p ara meters are s e parate d i nt o:  
•  He mat ol o g y (i ncl u di n g c oa g ul ati o n)  
•  Bi oc he mistr y  
•  Uri nal ysis  
•  Ot her tests  
H e mat ol o g y a n d bi oc h e mistr y will be s u m marize d b y st u d y i nter ve nti o n a n d ti me p oi nt usi n g 
descri pti ve statistics f or baseli ne (see d efi niti o n i n Secti o n 9 ), eac h e val u ati o n d uri n g t he st u d y, 
a n d c ha n ge fr o m bas eli ne t o eac h e val uati o n.  
S u m maries will i ncl u de all assess me nts fr o m scree ni n g o n. 
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 7 /2 7  
 
 
 
Listi n gs of a b n or mal test res ults (l o w a n d hi g h) will als o be pr o vi de d.   
1 5. 4  
Vit al Si g ns   
Vital si g ns da ta will be s u m marize d b y st u d y i nter ve nti o n a n d ti me p oi nt usi n g descri pti ve statistics 
f or baseli ne (see d efi niti o n i n Secti o n 9 ), eac h e val uati o n d uri n g t he st u d y, a n d c ha n ge fr o m 
baseli ne t o eac h e val u ati o n. Listi n g of vital si g ns data will be pr o vi de d.    
Vital si g n s u m maries will i ncl u de all vital si g n assess me nts fr o m scree ni n g o n. All vital si g n 
assess me nts will be liste d, a n d t h ose c ollecte d o u tsi de t he o n-treat me nt peri o d will be fla g ge d i n 
t he listi n g.  
1 5. 5  
Ot her S afet y or T oler a bilit y E v al u ati o ns    
Safet y E C G d ata will be s u m marize d b y st u d y i nter ve nti o n a n d ti me p oi nt usi n g descri pti ve 
statistics f or baseli ne (see defi niti o n i n Secti o n 9 ), eac h e v al uati o n d uri n g t he st u d y, a n d c ha n ge 
fr o m baseli ne t o e ac h e v al uati o n. Listi n g of safet y E C G data will be pr o vi de d.  
E C G s u m maries will i ncl u de all E C G assess me nts fr o m  scree ni n g o n. All E C G assess me nts will 
be liste d . 
T he a nal ysis of Q T data is c o m plicate d b y t he fact t hat t he Q T i nter val is hi g hl y c orrelate d wit h 
heart rate.  Beca use of t his c orrel ati o n, f or m ulas are r o uti nel y use d t o o btai n a c orrecte d v al ue, 
de n ote d Q Tc, w hic h is i n de pe n de nt of h eart rate. T his Q Tc i nter val is i nte n d e d t o re pres e nt t he Q T 
i nter val at a sta n dar dize d heart rate. Se veral c orrecti o n f or m ulas ha v e bee n pr o p ose d i n t he 
literat ure. T h e Q T i nter val will be c orrecte d f or h eart rate b y t h e Fri derici a’s f or m ula, Q Tc F, is 
defi ne d as   
 , 
w here R R re pres e nts t he R R i nter val of t he E C G, i n sec o n ds, a n d ca n be esti mate d as 6 0/ Heart 
Rate.   
I n v esti gat or re p orte d i nt er pret ati o n res ults will als o be ta b ulate d b y  st u d y i nter ven ti o n a n d ti me 
p oi nt  usi n g t he n u m ber a n d perce nta ge of partici p a nt s f or eac h i nter pretati o n cate g or y ( N or mal, 
A b n or mal N ot Cli nicall y Si g nifica nt [ N C S], A b n or m al Cli nicall y Si g nifica nt [ C S]).  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 8 /2 7  
 
 
1 6  
A n al yses of Ot her E n d p oi nts/ Esti m a n ds   
1 6. 1  
P h ar m ac o ki netics   
P K e val uati o n will be perf or me d b y 
.   
All statistical a nal ys es a n d descri pti ve s u m maries of P K data will be perf or me d o n t he P K  A nal ysis 
Set . 
1 6. 1. 1  
Descri pti ve St atistics o f P K C o nce ntr ati o n D at a  
P K meas ure m e nts  of te p oti ni b a n d its meta b olites 
 i n plas ma 
will be descri pti vel y s u m marize d b y da y usi n g: n u m ber of n o n -missi n g o bser vati o ns ( n), 
arit h metic mea n ( M ea n), sta n dar d de viati o n ( S D), c oefficie nt of v ariati o n ( C V %), mi ni m u m 
( Mi n), me dia n ( Me dia n) a n d ma xi m u m ( Ma x).  
Descri pti ve statistics will o nl y be calc ulat e d f or n > 2 i n w hic h a meas ure me nt  of bel o w l o wer li mit 
of q ua ntificati o n ( B L Q ) re pres e nts a vali d meas ure me nt a n d will be ta ke n as zer o f or s u m mar y 
statistics of P K c o nce ntrati o n data. 
A n y me a n or me dia n v al ue t hat is bel o w t he  l o wer li mit of q ua ntificati o n will be s h o w n as B L Q.  
Descri pti ve statistics of P K c o nce ntrati o n data will be calc ulate d usi n g val ues wit h t he sa me 
precisi o n as t he s o ur ce d ata a n d r o u n de d f or re p orti n g p ur p os es o nl y. I n e x p ort datasets, as well as 
i n t he S D T M P C d o mai n, P K c o nce ntrati o ns will be pr o vi de d wit h f ull precisi o n a n d will n ot b e 
r o u n de d. 
T he f oll o wi n g c o n v e nti o ns 
will be a p plie d 
w he n re p orti n g des cri pti ve statistics of P K 
c o nce ntr ati o n data:  
n  
0 deci mal place  
Mea n, Mi n, Me dia n, Ma x:  
3 si g nifica nt di gits  
S D:  
4 si g nifica nt di gits  
C V %:  
1 deci mal place  
1 6. 1. 2  
Des cri pti ve St atistics of P K P ar a meter D at a   
P K para meter data of te p oti ni b a n d 
 
) o n Da y 
1 a n d 1 2 will be descri pti vel y s u m marize d b y d a y usi n g: n u m ber of n o n -missi n g o bser vati o ns ( n), 
arit h metic mea n ( M ea n), sta n dar d de viati o n ( S D), c oefficie nt of v ariati o n ( C V %), mi ni m u m 
( Mi n), me dia n ( Me dia n), ma xi m u m ( Ma x), ge o metric mea n ( Ge o Mea n), t he ge o m etric c o efficie nt 
of variati o n ( Ge o C V) a n d t he 9 5 % c o nfi de n ce i nter val f or t he Ge o Mea n ( L CI 9 5 % G M, U CI 9 5 % 
G M). F or P K para meters relate d t o ti me (e. g. t ma x, tla g, tlast), o nl y n, Mi n, Me dia n, a n d Ma x ma y 
be re p ort e d.  
Gl o bal Versi o n I D: 
P P D
C CI
C CI
C CI
C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 9 /2 7  
 
 
Descri pti ve statistics will o nl y be calc ulate d f or a P K para meter w he n n > 2.  
P K par a met ers rea d directl y fr o m t he m eas ure me nts (i.e. C ma x) will be re p orte d wit h t he sa me 
precisi o n as t he s o urce data. All ot her P K para meters will be re p orte d t o 3 si g nifica nt fi g ures. I n 
e x p ort datasets, as well as i n t he S D T M P P d o mai n, P K para met ers will  be pr o vi de d wit h f ull 
precisi o n a n d will n ot be r o u n de d. D escri pti ve statistics of P K para meter d ata will be calc ulate d 
usi n g f ull precisi o n val ues a n d r o u n de d f or re p orti n g p ur p os es o nl y.  
T he f oll o wi n g c o n v e nti o ns will be a p plie d w he n re p orti n g des cri pti ve statistics of P K para meter 
data:  
n  
0 deci mal place  
Mea n, Mi n, Me dia n, M a x, Ge o Mea n, 9 5 % CI:  3 si g nifica nt di gits  
S D:  
4 si g nifica nt di gits  
C V %, Ge o C V %:  
1 deci mal place  
1 6. 1. 3  
St atistic al A n al ysis of P K P ar a meter D at a   
A n al ysis  of Pri m a r y E n d p oi nts  
T he  effect of c o -a d mi nistrati o n of itrac o naz ole o n te p oti ni b e x p os ure will be assesse d. A  ge neral 
li near m o del wit h a fi x e d effect f or T R E A T M E N T a n d a ra n d o m effect f or S U BJ E C T  will be 
a p plie d t o t he l o g-tr a nsf or me d P K para meters Cma x , A U C0 -tlast a n d A U C 0 -∞ base d  o n t he P K 
a nal ysis set . Treat me nt differe nces  o n t he l o g scale of te p oti ni b wit h itrac o naz ole v ers us te p oti ni b 
al o ne (Da y  1 2 v ers us Da y 1 ) will be esti mate d f or t he C ma x , A U C0 -tlast a n d A U C 0 -∞ t o get her wit h 
t heir 9 0 % CIs. P oi nt esti mates a n d CIs will b e bac k tra nsf or me d t o t he ori gi nal scale f or 
prese ntati o n.  
T he a nal ysis will be re p eate d wit h b ot h S U BJ E C T  a n d T R E A T M E N T  as fi x e d effects.  
 
 
  
 
 
 
 
 
 
 
  
 
 
T he a nal ysis will be re p eate d wit h b ot h S U BJ E C T  a n d T R E A T M E N T  as fi x e d effects.  
 
 
  
 
Gl o bal Versi o n I D: C CI
C CI
C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 0 /2 7  
 
 
1 6. 1. 4  
Ge ner al 
S pecific ati o ns f or 
P K 
C o nce ntr ati o n a n d 
P K 
P ar a meter D at a   
Pre d ose sa m ples t hat occ ur bef ore t he first dr u g a d mi nistrati o n will be assi g ne d a ti me of 0 h o urs, 
as if t he sa m ple ha d bee n ta ke n si m ulta ne o usl y wit h t he st u d y i nter ve nti o n a d mi nistrati o n. Sa me 
a p plies t o t he pre-d os e sa m ple after m ulti ple d oses.  
Pre d os e or tr o u g h s a m ples w hic h ha ve bee n ta ke n after t he s u bse q ue nt d osi n g will b e re p orte d as 
a pr ot oc ol de viati o n. T he res ulti n g c o n ce ntrati o ns will be i ncl u de d i n c o nce ntrati o n listi n gs b ut 
e x cl u de d fr o m descri pti v e statistics of c o nce ntr ati o ns a n d fr o m P K p ara meter esti mati o n.  
Val ues B L Q  will be ta ke n as zer o f or s u m mar y st atistics of P K c o nce ntrati o n data, P K p ara met er 
esti mati o n (e. g. A U C) a n d f or gra p hic al pres e ntati o ns.   
Missi n g c o n ce ntrati o ns (e. g. n o s a m ple, i ns uffi cie nt sa m ple v ol u me f or a nal ysis, n o  res ult or res ult 
n ot vali d) will be re p orte d a n d use d ge nerall y as “ N. R.” . A partici pa nt w h o wit h dra ws pri or t o t he 
last pla n ne d o bser vati o n will be i ncl u de d i n t he a nal yses u p t o t he ti me of disc o nti n uati o n if still 
i ncl u de d i n t he P K a nal ysis set. 
If sam ples are c ollecte d o utsi de of 1 0 % of t he P K sa m pli n g ti me wi n d o ws defi ne d i n t he C S P i n 
secti o n 8. 4, t hese will be i ncl u de d i n t he P K para meter esti mati o n ( N C A) b ut will be e x cl u de d 
fr o m t he c o nce ntrati o n s u m mar y a n d mea n/ me dia n c o nce ntr ati o n pl ots.  
P K c o nce ntr ati o ns w hic h are err o n e o us d ue t o a sa m pli n g pr ocessi n g or a nal ytical err or (as 
d oc u me nte d i n t he bi oa n al ytical re p ort) m a y be e x cl u de d fr o m t he P K a nal ysis if a gree d b y t h e 
S p o ns or. I n t his case t he rati o nale f or e x cl usi o n will be pr o vi de d i n t he C S R. A n y ot h er P K 
c o nce ntr ati o ns t hat a p pear i m pla usi ble t o t he Cli nical P har mac ol o gist/ Cli nical P K/ P D Scie ntist 
will n ot be e x cl u de d fr o m t he a nal ysis. A n y i m pl a usi ble data will be d oc u me nte d i n t he C S R.  
If i m p orta nt pr ot oc ol de viati o ns occ urre d li kel y t o affect t he P K pr ofile of p artici pa nts as s pecifie d 
i n Secti o n 1 0. 2. 1 , t he i m pacte d c o nce ntr ati o ns a n d P K para meters will be e x cl u de d fr o m s u m mar y 
statistics a n d f urt her statistical e val uati o n.  
A n y P K c o nce ntrati o ns or P K para meters e x cl u de d fr o m s u m mar y statistics will be i ncl u de d i n 
partici pa nts listi n gs a n d fla g ge d; a reas o n f or e x cl usi o n will be detaile d i n t he C S R (e. g. a f o ot n ot e 
or a ta ble of e x cl usi o ns). A n y fla gs s h o ul d be i ncl u de d i n t he st u d y s pecific C DI S C data sets.  
P K c o nce ntr ati o ns a n d P K para meters e x cl u de d fr o m s u m mar y statistics will n ot be i ncl u de d i n 
mea n/ me dia n fi g ures. Mea n pl ots will o nl y c o ntai n val ues w here n > 2.  
 
 
Gl o bal Versi o n I D: C CI
C CI




Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 2 /2 7  
 
 
S y m b ol  
D efi niti o n  
A U C 0 -∞ 
T h e A U C fr o m ti m e z er o ( d o si n g ti m e) e xtr a p ol at e d t o i nfi nit y, b a s e d o n t h e 
pr e di ct e d v al u e f or t h e c o n c e ntr ati o n at tl a st, a s e sti m at e d u si n g t h e li n e ar 
r e gr e s si o n fr o m λz d et er mi n ati o n. A U C 0 -∞= A U C 0 -tl a st + C l a st pr e d/ λ z 
A U C 0 -tl a st 
T h e ar e a u n d er t h e c o n c e ntr ati o n -ti m e c ur v e ( A U C) fr o m ti m e z er o ( = d o si n g 
ti m e) t o t h e ti m e of th e l a st q u a ntifi a bl e c o n c e ntr ati o n (t l a st), c al c ul at e d u si n g 
t h e mi x e d l o g-li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g d o w n). 
A U C 0 -2 4  
T h e A U C fr o m ti m e z er o ( = d o si n g ti m e) t o ti m e p oi nt 2 4 h o ur s. C al c ul at e d 
u si n g t h e mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g d o w n).  
A U C 0 -tl a st/ D o s e ( p ar e nt a n al yt e o nl y) A U C 0 -tl a st di vi d e d b y a ct u al d o s e.  
A U C 0 -2 4 / D o s e ( p ar e nt a n al yt e o nl y) 
A U C 0 -2 4  di vi d e d b y a ct u al d o s e.  
C m a x  
M a xi m u m o b s er v e d c o n c e ntr ati o n.  
C m a x / D o s e ( p ar e nt a n al yt e o nl y) 
C m a x  di vi d e d b y a ct u al d o s e.  
tl a g 
T h e ti m e pri or t o t h e fir st c o n c e ntr ati o n at or a b o v e L L O Q.  
T m a x  
T h e ti m e t o r e a c h t h e m a xi m u m o b s er v e d c o n c e ntr ati o n c oll e ct e d d uri n g a 
d o si n g i nt er v al ( u nl e s s ot h er wi s e d efi n e d, t a k e t h e 1 st o c c urr e n c e i n c a s e of 
m ulti pl e/i d e nti c al C
m a x  v al u e s)  
t1/ 2  
A p p ar e nt t er mi n al h alf -lif e. T 1/ 2  = l n ( 2)/ λ z 
λ z 
T er mi n al fir st or d er ( eli mi n ati o n) r at e c o n st a nt. D et er mi n e d fr o m t h e t er mi n al 
sl o p e of t h e l o g -tr a n sf or m e d c o n c e ntr ati o n c ur v e u si n g li n e ar r e gr e s si o n o n 
t er mi n al d at a p oi nt s of t h e c ur v e. 
C L/ F ( p ar e nt dr u g o nl y)  
T h e a p p ar e nt t ot al b o d y cl e ar a n c e of st u d y i nt er v e nti o n f oll o wi n g 
e xtr a v a s c ul ar a d mi ni str ati o n . 
C L/ F = D o s e p o  / A U C0 -∞. 
P ar e nt dr u g, o nl y.  
V Z / F ( p ar e nt dr ug  o nl y ) 
T h e a p p ar e nt v ol u m e of di stri b uti o n d uri n g t h e t er mi n al p h a s e f oll o wi n g 
e xtr a v a s c ul ar a d mi ni str ati o n  
V z/ F = D o s e/(A U C 0 -∞× λ z) f oll o wi n g si n gl e d o s e. 
P ar e nt dr u g, o nl y.  
A U C e xtra % 
T h e A U C fr o m ti m e t l a st e xtr a p ol at e d t o i nfi nit y gi v e n a s p er c e nt a g e of A U C 0 -∞. 
A U C e xtr a %  = ( e xtr a p ol at e d ar e a/ A U C 0 -∞)× 1 0 0.  
 
 
 
 
  
 
 
 
 
 
 
  
T he I M P d ose a d mi nistere d is gi ve n f or t he m o n o h y drate h y dr oc hl ori de salt (ie, 5 0 0 m g I M P). A 
c o n versi o n fact or f or t he free b ase I M P was calc ul ate d a n d will be a p plie d w he n ‘ d ose’ is use d i n 
deri vi n g P K p ara met er f or m ulas nee di n g a d ose v al ue ( C L/ F, V z/ F). 
C o n versi o n fact or = M olec ular wei g ht ( M W) of base I M P di vi de d b y M W of salt f or m I M P = 
4 9 2. 5 7 4 g/ m ol / 5 4 7. 0 5 g/ m ol = 0. 9 0 0  
Gl o bal Versi o n I D: 
C CI
C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 3 /2 7  
 
 
A m o u nt of d ose * c o n versi o n fact or = act ual d ose of I M P:  5 0 0 m g * 0. 9 0 0 = 4 5 0 m g  
A d diti o nal P K para meters ma y be calc ul ate d w here  a p pr o pri ate.  
U nits f or P K para meter o ut p ut will be base d o n c o nce ntr ati o n a n d d ose u nits use d i n t he st u d y, 
u nless ot her wise s pecifie d. I n case c o nce ntrati o n data u nits c ha n ge wit hi n t he st u d y, P K para meters 
will be re p ort e d usi n g c o nsiste nt u nits t hr o u g h o ut st u d y o ut p uts. I n s uc h cases, t he S p o ns or will 
s pecif y rel e va nt u nits f or re p orti n g bef ore t he fi n al P K e val uati o n.  
T he para met ers C ma x  a n d t ma x  will be o btai ne d directl y fr o m t he c o nce ntr ati o n -ti me pr ofiles. If Cma x  
occ urs at m ore t ha n o ne ti me p oi nt , tma x will be assi g ne d t o t he first occ urre n ce of C ma x . 
I n cases w here t he act ual o bser vati o n ti me is n ot e q ual t o t he sc h e d ule d o bser vati o n ti me, partial 
A U C 0 -2 4 h  u ntil 2 4 h will be calc ulate d bas e d o n t he esti mate d c o nce ntr ati o n at 2 4 h a n d n ot t he 
c o nce ntr ati o n at t he act u al o bser vati o n ti me.  
T he f oll o wi n g r ules mi g ht be a p plie d f or calc ulati o n of partial A U C, aft er a gree me nt wit h t he 
S p o ns or:  
•  I n case s uita ble re gressi o n ca n n ot be perf or me d, p artial areas ma y be calc ul ate d usi n g t he act ual 
sa m pli n g ti me pr o vi de d it is wit hi n 1 0 % of t he act ual sa m pli n g ti me.  
•  I n cases B L Q c o n ce ntrati o ns occ ur at t h e e n d of t he c ollecti o n i nter val, t h ese c o nce ntr ati o ns 
mi g ht be set t o missi n g f or calc ulati o ns of partial A U Cs. T his is a n e x e m pti o n t o t he ge neral 
B L Q ha n dli n g r ul e a n d s h o ul d be a p plie d i n cas e its a p plicati o n w o ul d res ult i n esti mati o n of 
i m pla usi ble partial A U C val ues. I m pl a usi bilit y is c o nsi dere d in cases p artial A U Cs were greater 
t ha n A U C0 -∞.   
T he f oll o wi n g P K p ara m eters will be calc ulate d f or dia g n ostic p ur p oses a n d liste d, b ut will n ot be 
s u m marize d: 
•  First ( λz l o w) a n d last ( λz u p) ti me p oi nt of t he ti me i nter val of t he l o g -li near re gressi o n t o 
d eter mi ne λz.  
•  N u m ber of dat a p oi nts ( N λ) i ncl u de d i n t he l o g -li near re gressi o n a n al ysis t o deter mi ne λz. 
•  G o o d ness of fit statistic (a dj uste d Rs q) f or calc ulati o n of λz.  
•  A U C fr o m ti me t last e xtra p olate d t o i nfi nit y gi ve n as perce nta ge of A U C 0 -. ( A U Ce xtra %) 
•  S pa n rati o of i nter val o ver w hic h t 1/ 2 was esti mates/t 1/ 2 
T he re gressi o n a nal ysis s h o ul d c o ntai n data fr o m at least 3 differe nt ti me p oi nts i n t he ter mi nal 
p hase c o nsiste nt wit h t he assess me nt of a str ai g ht li ne o n t he l o g -tra nsf or me d scale. P h oe ni x 
Wi n N o nli n “ best fit” met h o d ol o g y will b e use d as sta n dar d. If warra nte d, f urt her a dj ust me nt ma y 
be ma de b y t h e p har mac o ki neticist, after a gree me nt wit h t he S p o ns or. T he l ast q ua ntifia ble 
c o nce ntr ati o n > L L O Q s h o ul d al wa ys b e i ncl u de d i n t he re gressi o n a nal ysis, w hile t he 
c o nce ntr ati o n at t ma x  a n d a n y c o nce ntrati o ns B L Q w hic h occ ur aft er t he l ast q ua ntifia ble data p oi nt 
> L L O Q s h o ul d n ot be us e d.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4 /2 7  
 
 
If A U Ce xtra %> 2 0 % a n d/ or t he c oefficie nt of c orrelati o n ( Rs q a dj) of λz is < 0. 8 a n d/ or t he 
o bser vati o n peri o d o ver w hic h  t he re gressi o n li ne is esti mate d (s pa n rati o) is less t ha n 2-f ol d t he 
res ulti n g t1/ 2, t he rate c o nsta nts a n d all deri ve d p ara meters (e. g. t1/ 2, A U C0 -, C L etc.) will be liste d, 
fla g ge d a n d i ncl u de d i n t he para met er o ut p uts. S h o ul d m ore t ha n 1 0 % of s u bject s be fla g ge d f or 
A U C e xtra %  a n d/ or Rs q a dj (f or a partic ular a nal yt e), a se nsiti vit y a n al ysis e x cl u di n g fla g ge d 
para meters ma y be p erf or me d after disc ussi o n wit h t he S p o ns or.  
1 6. 1. 6  
Prese nt ati o n of P K C o nce ntr ati o n a n d P K P ar a meter D at a   
1 6. 1. 6. 1  
Listi n gs a n d T a bles   
T he f oll o wi n g P K ta bl es w ill be pr o d uce d ( P K A n al ysis Set): 
•  Descri pti ve statistics of c o nce ntrati o ns b y a n al yt e, matri x, da y a n d st u d y i nter ve nti o n  
•  Descri pti ve statistics of P K para met ers b y a n al yt e, matri x, da y a n d st u d y i nter ve nti o n  
T he f oll o wi n g P K Listi n gs will be pr o d u ce d ( Safet y A nal ysis Set):  
•  I n di vi d ual c o n ce ntr ati o ns b y a n al yt e, matri x, da y a n d st u d y i nter ve nti o n  
•  I n di vi d ual P K para meters b y a n al yt e, matri x, da y a n d st u d y i nter ve nti o n  
•  P K Sa m pli n g dat e, act ual ti me, n o mi nal ti me, de viati o n fr o m ti me, perce nt a ge ti me d e viati o n 
b y partici pa nt, a nal yte, m atri x a n d st u d y i nter ve nti o n (da y ) s orte d i n c hr o n ol o gical or d er 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C
C
I
C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 5 /2 7  
 
 
1 6. 1. 6. 2  
Gr a p hic al S u m m aries a n d I n di vi d u al pl ots ( P K A n al ysis Set)   
T he f oll o wi n g gra p hical s u m maries a n d i n di vi d ual pl ots will be pr o vi de d f or te p oti ni b a n d 
 
 i n plas ma: 
•  O verlai d i n di vi d ual plas ma c o nce ntrati o n v ers us ti me pl ots  o n  li near a n d s e mi-l o g s cale, usi n g 
act ual ti mes;  b y a nal yte a n d st u d y i nter ve nti o n (d a y );  
•  O verlai d i n di vi d ual plas ma c o nce ntrati o n v ers us ti me pl ots b y partici pa nt  a n d a nal yte o n li near 
a n d se mi -l o g scal e usi n g act u al ti mes . If a ny p ost -d ose c o nce ntrati o n is B L Q t he li ne 
re pres e nti n g L L O Q will be a d de d t o t he se mi-l o g pl ots. 
•  Arit h metic mea n c o nce ntrati o n ti me pl ots; li near ( ± S D f or arit h metic mea n) a n d se mi -l o g; usi n g 
sc he d ule d ( n o mi nal) ti me p oi nts b y a n al yt e, matri x a n d st u d y i nter ve nti o n ( da y ); if a n y p ost-
d ose c o nce ntrati o n is B L Q t he li ne re prese nti n g L L O Q will be a d de d t o t he se mi -l o g pl ots 
•  B o x pl ots f or pri mar y P K para meters A U C 0 -∞, A U C0 -tlast, a n d C ma x  of te p oti ni b b y st u d y 
i nter ve nti o n (da y) a n d  a n al yte. 
•  S pa g hetti pl ot of pri mar y P K para meters  A U C 0 -∞, A U C0 -tlast, a n d C ma x  of te p oti ni b  b y st u d y 
i nter ve nti o n ( da y) a n d a n al yte 
 
Gl o bal Versi o n I D: C CI
C
CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 6 /2 7  
 
 
1 7  
Refere nces   
N ot a p plica ble.  
Gl o bal Versi o n I D: C CI


Te p oti ni b  
Te p oti ni b D DI wit h Itr ac o n az ole  
M S 2 0 0 0 9 5 _ 0 0 5 3  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 7 /2 7  
 
 
1 8  
A p pe n dices   
N ot a p plica ble  
Gl o bal Versi o n I D: C CI