A Randomized, Open-Label, Single-Dose, Two-Way Crossover Study to Evaluate the Effect of Food on the Pharmacokinetics, Safety, and Tolerability of Budesonide Oral Suspension in Healthy Adult Participants
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Takeda



T A K E D A P H A R M A C E U TI C A L S
P R O T O C O L
A R a n d o mize d, O pe n- L a bel, Si n gle -D ose, T w o -W a y Cr oss o ver St u d y t o E v al u ate t he 
Effect of F o o d o n t he P h ar m ac o ki netics, S afet y, a n d T oler a bilit y of B u des o ni de Or al 
S us pe nsi o n i n He alt h y A d ult P artici p a nts
St u d y I de ntifier:
T A K- 7 2 1- 1 0 0 3
C o m p o u n d:
T A K- 7 2 1, B u des o ni de Oral S us pe nsi o n ( B O S)
D ate:
2 2 N o v 2 0 2 2
Pr ot oc ol Versi o n
N u m ber:
Fi nal
C O N FI D E N TI A L P R O P E R T Y O F T A K E D A
T his d oc u me nt is a c o nfi de ntial c o m m u nicati o n of Ta ke da. Acce pta nce of t his d oc u me nt c o nstit utes t he a gree me nt 
b y t he reci pie nt t hat n o i nf or mati o n c o ntai ne d herei n will be p u blis he d or discl ose d wit h o ut w ritte n a ut h orizati o n 
fr o m Ta ke da e xce pt t o t he e xte nt necessar y t o o btai n i nf or me d c o nse nt fr o m t h ose pers o ns t o wh o m t he dr u g ma y be 
a d mi nistere d. F urt her m ore, t he i nf or mati o n is o nl y mea nt f or re vie w a n d c o mplia nce b y t he reci pie nt, his or her 
staff, a n d a p plica ble i nstit uti o nal re vie w c o m mittee a n d re g ulat or y a ge ncies t o e na ble c o n d uct of t he st u d y.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
T A B L E O F C O N T E N T S
1. 0 
S T U D Y S U M M A R Y ...........................................................................................................7
2. 0
S T U D Y S C H E M A TI C...................................................................................................... 1 1
3. 0
S C H E D U L E O F S T U D Y P R O C E D U R E S ....................................................................... 1 2
4. 0
I NT R O D U C TI O N ............................................................................................................. 1 4
4. 1
Bac k gr o u n d .................................................................................................................. 1 4
4. 1. 1
Cli nical P har mac ol o g y ........................................................................................... 1 4
4. 1. 2
Cli nical Safet y ........................................................................................................ 1 5
4. 2
Ra ti o nale f or t he Pr o p ose d St u d y ................................................................................ 1 5
4. 3
Be nefit/ Ris k Pr ofile ..................................................................................................... 1 6
5. 0
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S ..................................................................... 1 6
5. 1
H y p ot hesis .................................................................... . ............................................. 1 6
5. 2
St u d y  O bjecti ves .......................................................................................................... 1 6
5. 2. 1
St u d y  Pri mar y O bjecti ve............................ ........................................................... 1 6
5. 2. 2
St u d y  Sec o n dar y O bjecti ves................ ................................................................. 1 6
5. 3
E n d p oi nts ................................................ .................................................................... 1 7
5. 3. 1
Pri mar y  E n d p oi nt...................... ............................................................................ 1 7
5. 3. 2
Sec o n dar y  E n d p oi nts ............................................................................................. 1 7
6. 0
S T U D Y D E SI G N A N D D E S C RI P TI O N .......................................................................... 1 8
6. 1
St u d y  Desi g n..................... .......................................................................................... 1 8
6. 2
D ose Escalati o n ......... .................................................................................................. 1 8
6. 3
St o p pi n g R ules............................................................................................................. 1 8
6. 4
Rati o n ale f or St u d y Desi g n, D ose, a n d E n d p oi nts....................................................... 1 9
6. 4. 1
Rati o nale of St u d y  Desi g n..................................................................................... 1 9
6. 4. 2
Rati o nale f or D ose ................................................................................................. 1 9
6. 4. 3
Rati o nale f or E n d p oi nts ......................................................................................... 2 0
6. 4. 4
F ut ure Bi o me dical Researc h .................................................................................. 2 0
6. 4. 5
Critical Pr oce d ures Base d o n St u d y  O bjecti ves: Ti mi n g of Pr oce d ures................ 2 0
6. 5
St u d y  Desi g n/ D osi n g/ Pr oce d ures M o dificati o ns Per mitte d Wit hi n Pr ot oc ol 
Para meters ....................................................................................................................2 0
6. 6
St u d y  Be gi n ni n g a n d E n d/ C o m pleti o n........................................................................2 0
6. 6. 1
Defi niti o n of Be gi n ni n g of t he St u d y ..................................................................... 2 0
6. 6. 2
Defi niti o n of E n d of t he St u d y ...............................................................................2 0
6. 6. 3
Defi niti o n of St u d y  Disc o nti n uati o n......................................................................2 0
6. 6. 4
Criteria f or Pre mat ure Ter mi nati o n or S us pe nsi o n of t he St u d y ...........................2 1
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
6. 6. 5
Criteria f or Pre mat ure Ter mi nati o n or S us pe nsi o n of a Site .................................. 2 1
7. 0
S E L E C TI O N A N D DI S C O N TI N U A T I O N/ WI T H D R A W A L O F P A R TI CI P A N T S ...... 2 1
7. 1
I ncl usi o n Criteria ......................................................................................................... 2 1
7. 2
E x cl usi o n Criteria ........................................................................................................ 2 2
7. 3
E xcl u de d Me dicati o ns, S u p ple me nts, Dietar y  Pr o d ucts.............................................. 2 3
7. 4
Diet, Fl ui d, Acti vit y ..................................................................................................... 2 4
7. 4. 1
Diet a n d Fl ui d ........................................................................................................ 2 4
7. 4. 2
Acti vit y .................................................................................................................. 2 5
7. 5
Criteria f or Disc o nti n uati o n or Wit h dra wal of a Partici pa nt ....................................... 2 5
7. 6
Pr oce d ures f or Disc o nti n uati o n or Wit h dr a wal of a Partici pa nt .................................. 2 6
7. 7
Partici pa nt Re place me nt ..............................................................................................2 6
8. 0
C L I NI CA L S T U D Y M A T E R I AL M A N A G E M E N T ........ .............................................. 2 7
8. 1
Cli nical St u d y  Dr u g................................................. ................................................... 2 7
8. 1. 1
Cli nical St u d y  Dr u g L a beli n g ..................... .. .......................................................2 7
8. 1. 2
Cli nical St u d y  Dr u g I n ve nt or y a n d St ora ge........................................................... 2 7
8. 1. 3
Cli nical St u d y  Dr u g Bli n di n g.......... .. .................................................................. 2 7
8. 1. 4
Ra n d o mizati o n C o de Creati o n a n d St ora ge........................................................... 2 7
8. 1. 5
Cli nical St u d y  Bli n d Mai nte na nce/ U n bli n di n g Pr oce d ure .................................... 2 8
8. 1. 6
Acc o u nta bilit y  a n d Destr ucti o n of S p o ns or-S u p plie d Dr u gs................................. 2 8
9. 0 
S T U D Y P R O C E D U R E S................................................................................................... 2 8
9. 1
A d mi nistrati ve Pr oce d ures ........................................................................................... 2 8
9. 1. 1
I nf or me d C o nse nt Pr oce d ure ................................................................................. 2 8
9. 1. 2
I ncl usi o n a n d E xcl usi o n ......................................................................................... 2 8
9. 1. 3
Me dical Hist or y / De m o gra p h y ............................................................................... 2 8
9. 1. 4
C o nc o mita nt Me dicati o ns...................................................................................... 2 9
9. 2
Cli nical Pr oce d ures a n d Assess me nts ..........................................................................2 9
9. 2. 1
F ull P h y sical E xa mi nati o n ..................................................................................... 2 9
9. 2. 2
Hei g ht a n d Wei g ht .................................................................................................2 9
9. 2. 3
B MI ........................................................................................................................2 9
9. 2. 4
Vital Si g ns ..............................................................................................................2 9
9. 2. 5
1 2 -Lea d E C G .........................................................................................................3 0
9. 2. 6
St u d y  Dr u g A d mi nistrati o n.................................................................................... 3 0
9. 2. 7
A E M o nit ori n g .......................................................................................................3 0
9. 2. 8
La b orat or y  Pr oce d ures a n d Assess me nts...............................................................3 0
9. 3
P K Sa m ples ..................................................................................................................3 2
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
9. 3. 1
P K Meas ure me nts ..................................................................................................3 2
9. 3. 2
Bi o mar ker Meas ure me nts...................................................................................... 3 3
9. 3. 3
P G x Meas ure me nts................................................................................................ 3 3
9. 3. 4
C o nfi ne me nt ........................................................................................................... 3 4
1 0. 0
A D V E R S E E V E N T S ......................................................................................................... 3 4
1 0. 1
Defi niti o ns a n d Ele me nts of A Es................................................................................. 3 4
1 0. 1. 1 S A Es ...................................................................................................................... 3 6
1 0. 1. 2 A d verse E ve nts of S pecial I nterest ........................................................................ 3 7
1 0. 2
A E Pr oce d ures ............................................................................................................. 3 7
1 0. 2. 1 Assi g ni n g Se verit y/ I nte nsit y of A Es...................................................................... 3 7
1 0. 2. 2 Assi g ni n g Ca usalit y  of A Es................................................................................... 3 8
1 0. 2. 3 Start D ate ................................................................ .............................................. 3 8
1 0. 2. 4 E n d Date ............................................................. ................................................... 3 9
1 0. 2. 5 Patter n of A E ( Fre q ue nc y) .......................... .. ....................................................... 3 9
1 0. 2. 6 Acti o n Ta ke n Wit h St u d y Treat me nt ..................................................................... 3 9
1 0. 2. 7 O utc o me ........................................... .. .................................................................. 3 9
1 0. 2. 8 C ollecti o n a n d Re p orti n g of A Es, S A Es, S pecial I nterest A Es, a n d A b n or mal 
L F Ts ...................................... ................................................................................ 4 0
1 0. 2. 9 Safet y  Re p orti n g t o I n vesti gat ors, I R Bs or I E Cs, a n d Re g ulat or y A ut h orities ..... 4 2
1 1. 0
S T A TI S T I C A L M E T H O D S..............................................................................................4 2
1 1. 1
Statistical a n d A nal y tical Pla ns.................................................................................... 4 2
1 1. 1. 1 A nal y sis Sets . ..... .................................................................................................. 4 2
1 1. 1. 2 A nal y sis of De m o gra p h y a n d Ot her Baseli ne C haracteristics............................... 4 3
1 1. 1. 3 P K A nal y sis ........................................................................................................... 4 3
1 1. 1. 4 P D A nal y sis ........................................................................................................... 4 3
1 1. 1. 5 Saf et y A nalys is ......................................................................................................4 3
1 1. 2
I nteri m A nalys is a n d Criteria f or Early Ter mi nati o n ................................................... 4 4
1 1. 3
Deter mi nati o n of Sa m ple Size .....................................................................................4 4
1 2. 0
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E .................................................4 4
1 2. 1
St u d y -Site M o nit ori n g Visits .......................................................................................4 4
1 2. 2
Pr ot oc ol De viati o ns ......................................................................................................4 5
1 2. 3
Q ualit y  Ass ura nce A u dits a n d Re g ulat or y A ge nc y Ins pecti o ns .................................. 4 5
1 3. 0
E T HI C A L  A S P E C T S O F TH E S T U D Y ...........................................................................4 5
1 3. 1
I RB a n d/ or I E C A p pr o val ............................................................................................4 6
1 3. 2 
Partici pa nt I nf or mati o n, I nf or me d C o nse nt, a n d Partici pa nt A ut h orizati o n................ 4 6
1 3. 3
Partici pa nt C o nfi de ntialit y ...........................................................................................4 7
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1 3. 4 
P u blicati o n, Discl os ure, a n d Cli nical S t u d y Re gistrati o n P olic y.................................4 8
1 3. 4. 1 P u blicati o n a n d Discl os ure .................................................................................... 4 8
1 3. 4. 2 Cli nical St u d y  Re gistrati o n.................................................................................... 4 8
1 3. 4. 3 Cli nical St u d y  Res ults Discl os ure.......................................................................... 4 9
1 3. 5
I ns ura nce a n d C o m pe nsati o n f or I nj ur y....................................................................... 4 9
1 4. 0
A D MI NI S T R A TI V E A N D R E F E R E N C E I N F O R M A TI O N ........................................... 4 9
1 4. 1
A d mi nistrati ve I nf or mati o n ......................................................................................... 4 9
1 4. 1. 1 St u d y  C o ntact I nf or mati o n..................................................................................... 4 9
1 4. 1. 2 I n vesti gat or A gree me nt.......................................................................................... 5 0
1 4. 1. 3 St u d y -Relate d Res p o nsi bilities .............................................................................. 5 1
1 4. 1. 4 List of A b bre viati o ns ............................................................................................. 5 1
1 5. 0
D A T A H A N D LI N G A N D R E C O R D K E E PI N G .............. .............................................. 5 3
1 5. 1
C R Fs ( Electr o nic a n d Pa per) ................................... ................................................... 5 3
1 5. 2
Rec or d Rete nti o n .............................................. .. ....................................................... 5 3
1 6. 0
R E F E R E N C E S .................................................................................................................. 5 4
1 7. 0
A P P E N DI C E S ............................................. .. .................................................................. 5 5
LI S T O F I N -T E X T T A B L E S
Ta ble 3.a
Dail y  Sc he d ule of St u d y Pr oce d ures...................................................................... 1 2
Ta ble 6.a
St u d y  Treat me nts... .. ............................................................................................ 1 8
Ta ble 7.a
E xcl u de d Me dicati o ns, S u p ple me nts, a n d Dietar y  Pr o d ucts................................. 2 4
Ta ble 8.a
Ra n d o mizati o n Se q ue nce ....................................................................................... 2 7
Ta ble 9.a
Pri mar y  S peci me n C ollecti o ns............................................................................... 3 2
Ta ble 1 0.a
Ta ke da Me dicall y Si g nifica nt A E List .................................................................. 3 7
LI S T O F I N -T E X T FI G U R E S
Fi g ure 2.a
O verall St u d y  Desi g n............................................................................................. 1 1
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 6 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
LI S T O F A P P E N DI C E S
A p pe n di x A
Res p o nsi bilities of t he I n vesti gat or................................ ........................................5 5
A p pe n di x B
Ele me nts of t he Partici pa nt I nf or me d C o nse nt ...................................................... 5 7
A p pe n di x C
I n vesti gat or C o nse nt t o t he Use of Pers o nal I nf or mati o n ...................................... 6 0
A p pe n di x D
Pre g na nc y  a n d C o ntrace pti o n................................................................................ 6 1
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 7 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1. 0 
S T U D Y S U M M A R Y
N a m e of S p o ns or:
Ta ke da De vel o p me nt Ce nter A mericas, I nc. ( T D CA)
9 5 Ha y de n A ve n ue
Le xi n gt o n, M A 0 2 4 2 1
Tele p h o ne: + 1 ( 6 1 7) 6 7 9 -7 0 0 0
C o m p o u n d:
T A K- 7 2 1, b u des o ni de oral s us pe nsi o n ( B O S)
St u d y I de ntifier : T A K- 7 2 1 -1 0 0 3
P h ase: 1
Pr ot oc ol Title : A Ra n d o mize d, O pe n -La bel, Si n gle -D ose, T w o- W a y  Cr oss o ver St u d y t o E val uat e t he Effect of 
F o o d o n t he P har mac o ki netics, Safet y, a n d T olera bilit y of B u des o ni de Oral S us pe nsi o n i n Healt h y A d ult 
Partici pa nts
St u d y Desi g n:
T his is a n o pe n -la bel, si n gle-d ose, ra n d o mize d, 2 -peri o d, 2 -se q ue nce, 2-wa y cr oss o ver st u d y i n healt h y a d ult 
pa rtici pa nts.
St u d y sc he matic a n d d ose re gi me ns are s h o w n i n Fi g ure 2.a a n d Ta ble 6.a . T he sc he d ule of assess me nts is s h o w n 
i n t he Sc he d ule of St u d y Pr oce d ures ( Secti o n 3. 0 ).
O n Da y 1 of Peri o d 1, partici pa nts will be ra n d o ml y assi g ne d t o 1 of 2 treat me nt se q ue nces.
O n Da y 1 of eac h peri o d, a si n gle oral d ose of B O S will be a d mi nistere d u n der fasti n g ( Treat me nt A) or fe d 
(hi g h -fat/ hi g h-cal orie meal; Tr e at m e nt B) c o n diti o ns. P har mac o ki netic ( P K) sa m ple s will be c ollecte d pre d ose 
a n d u p t o 2 4 h o urs p ost d ose i n eac h peri o d .
T here w ill be a was h o ut of at least 2 da ys bet w ee n d oses .
Safet y a n d t olera bilit y will be assesse d t hr o u g h o ut t he st u d y b y treat me nt -e mer ge nt a d verse e ve nts ( T E A Es), 
vital si g ns, a n d cli nical la b orat or y e val uati o ns.
All partici pa nts w h o recei ve d a n y B O S (i ncl u din g partici pa nts w h o ter mi nate t he st u d y earl y) will ret ur n t o t he 
cli nical researc h u nit ( C R U) a p pr o xi matel y 3 d a y s after t he last d ose of B O S f or f oll o w-u p pr oce d ures, a n d t o 
deter mi ne if a n y a d verse e ve nt ( A E) has occ urre d si nce t he last st u d y visit.
St u d y Pri m ar y O bjecti ve:
T o assess t he relati ve bi oa vaila bilit y of a si n gle d ose of B O S a d mi nistere d u n der fasti n g a n d fe d 
( hi g h-fat/ hi g h-cal orie meal) c o n diti o ns.
St u d y Sec o n d ar y O bjecti ves:
T o assess t he safet y a n d t olera bilit y of a si n gle d ose of B O S a d mi nistere d u n der fasti n g a n d fe d 
( hi g h-fat/ hi g h-cal orie meal) c o n diti o ns.
T o e val uate ot her P K para meters of a si n gle d ose of B O S a d mi nistere d u n der fasti n g a n d fe d 
( hi g h-fat/ hi g h-cal orie meal) c o n diti o ns.
St u d y P artici p a nt P o p ul ati o n: Healt h y male a n d fe male partici pa nts a ge d 1 9 t o 5 5 years i ncl usi ve, wit h a b o d y 
mass i n de x ( B MI) of 1 8. 0 -3 2. 0 k g/ m 2, i ncl usi ve, at t he scree ni n g visit.
Pl a n ne d N u m ber of P artici p a nt s:
T w e nt y ( 2 0) partici pa nts will be e nr olle d.
Pl a n ne d N u m ber of Sites:
1
D ose Le vels:
2 m g ( 1 0 m L of 0. 2 m g/ m L ) B O S
R o ute of A d m i nistr ati o n:
Oral
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 8 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
D ur ati o n of Tre at m e nt:
Si n gle d ose
Pl a n ne d St u d y D ur ati o n :
U p t o a p pr o xi matel y 3 4 da ys i ncl u di n g t he scree ni n g 
peri o d a n d t he f oll o w- u p.
Criteri a f or I ncl usi o n:
Partici pa nts m ust f ulfill all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or partici pati o n i n t he st u d y:
1.
Healt h y, a d ult, male or fe male *, 1 9 -5 5 years of a ge, i ncl usi ve, at t he scree ni n g visit.
* Fe m ales of c hil d beari n g p ote ntial are defi ne d as all fe males p h ysi ol o gicall y ca pa ble of bec o mi n g 
pre g na nt.
Fe m ales of n o n -c hil d beari n g p ote ntial are defi ne d as f oll o ws:

Fe m ales w h o ha ve u n der g o ne o ne of t he f oll o wi n g sterilizati o n pr oce d ures at least 6 m o n t hs pri or t o 
t he first d osi n g:
–
H y ster osc o pic sterilizati o n.
–
Bilateral t u bal li gati o n or bilateral sal pi n gect o m y.
–
H y sterect o m y.
–
Bilateral o o p h orect o m y .
or

Fe m ales w h o are p ost me n o pa usal wit h a me n orr hea f or at least 1 2 m o nt hs pri or t o t he first d osi n g a n d 
f ollicle-sti m ulati n g h or m o ne ( F S H) ser u m le vels c o nsiste nt wit h p ost me n o pa usal stat us at t he scree ni n g 
visit.
2. 
Fe m ale of c hil d beari n g p ote ntial a n d male partici pa nts m ust f oll o w pr ot oc ol s pecifie d c o ntrace pti o n 
g ui da nce as descri be d i n  A p pe n di x D.
3.
C o nti n u o us n o n -s m o ker w h o has n ot use d nic oti ne- a n d t o bacc o -c o ntai ni n g pr o d ucts f or at least 3 m o nt hs 
pri or t o t he first d osi n g base d o n partici pa nt self -re p orti n g.
4.
B MI ≥1 8. 0 a n d ≤3 2. 0 k g/ m 2 at t he scree ni n g visit.
5.
Me dicall y healt h y wit h n o
cli nicall y si g nifica nt me dical hist or y, p h ysical e xa mi nati o n, la b orat or y pr ofiles, 
vital si g ns , a n d electr ocar di o gra ms ( E C Gs ), as dee me d b y t he I n vesti gat or or desi g nee, i ncl u di n g t he 
f oll o wi n g:

Seate d bl o o d press ure is ≥9 0/ 4 0 m m H g a n d ≤ 1 4 0/ 9 0 m m H g at t he scree ni n g visit.

Seate d p ulse rate is ≥4 0 b p m  a n d ≤9 9 b p m at t he scree ni n g visit.

Q Tc F i nter val is ≤ 4 6 0 msec ( males) a n d ≤ 4 7 0 msec (fe males) a n d has E C G fi n di n gs c o nsi dere d 
n or m al or n ot cli nicall y si g nifica nt b y t he I n vesti gat or or desi g nee at t he scree ni n g visit.

Esti mate d creati ni ne cleara nce ≥ 8 0 m L/ mi n at t he scree ni n g visit.

Li ver -relate d tests i ncl u di n g ala ni ne a mi n otra nsferase ( A L T), as partate a mi n otra nsferase ( A S T), 
al kali ne p h os p hatase ( A L P), a n d t otal bilir u bi n ≤u p per li mit of n or mal ( U L N) at t he scree ni n g visit a n d 
at c hec k -i n.
6.
U n dersta n ds t he st u d y pr oce d ures i n t he i nf or me d c o nse nt f or m (I C F), a n d be willi n g a n d a ble t o c o m pl y 
wit h t he pr ot oc ol.
Criteri a f or E xcl usi o n:
Partici pa nts m ust n ot be e nr olle d i n t he st u d y if t he y meet a n y of t he f oll o wi n g criteria:
1.
Is me ntall y or le gall y i nca pacitate d or has si g nifica nt e m oti o nal pr o ble ms at t he ti me of t he scree ni n g visit or 
e x pecte d d uri n g t he c o n d uct of t he st u d y.
2.
Hist or y or prese nce of cli nicall y si g nifica nt me dical or ps yc hiatric c o n diti o n or disease i n t he o pi ni o n of t he 
I n vesti gat or or desi g nee.
3.
Hist or y of a n y ill ness t hat, i n t he o pi ni o n of t he I n vesti gat or or desi g nee, mi g ht c o nf o u n d t he res ults of t he 
st u d y or p oses a n a d diti o nal ris k t o t he partici pa nt b y t heir partici pati o n i n t he s t u d y.
4.
Prese nce of a n y acti ve i nfecti o n at t he scree ni n g visit or c hec k -i n.
5.
Hist or y or prese nce of alc o h ol or dr u g a b use wit hi n t he past 2 years pri or t o t he first d osi n g.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 9 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
6.
Hist or y or prese nce of h y perse nsiti vit y or i di os y ncratic reacti o n t o t he st u d y dr u g, i nacti ve i n gre die nts, or 
relate d c o m p o u n ds.
7. 
Fe m ale partici pa nt wit h a p ositi ve pre g na nc y test at t he scree ni n g visit or at c hec k -i n or w h o is lactati n g.
8.
P ositi ve uri ne dr u g or alc o h ol res ults at t he scree ni n g visit or c hec k -i n.
9.
P ositi ve res ults f or h u ma n i m m u n o deficie nc y vir us ( HI V), he patitis B s urface a nti ge n ( H Bs A g), or he patitis 
C vir us ( H C V) at t he scree ni n g visit.
1 0. U na ble t o refrai n fr o m or a ntici pates t he use of:

A n y dr u gs, i ncl u di n g prescri pti o n a n d n o n -prescri pti o n me dicati o ns, her bal re me dies, or v ita mi n 
s u p ple me nts be gi n ni n g 1 4 da ys pri or t o t he first d osi n g. Me dicati o n liste d as part of acce pta ble birt h 
c o ntr ol met h o ds (refer t o  A p pe n di x D ), h or m o ne re place me nt t hera p y, a n d t h yr oi d h or m o ne 
re place me nt me dicati o n (refer t o S ecti o n 7. 3 ) will be all o we d.

A n y dr u gs k n o w n t o be m o derate or str o n g i n d ucers of c yt oc hr o me P 4 5 0 (C Y P ) 3 A 4 e nz y mes a n d/ or 
P- gl yc o pr otei n ( P- g p), i ncl u di n g St. J o h n’s W ort, f or 2 8 da ys pri or t o t he firs t d osi n g. A p pr o priate 
s o urces (e g, Fl oc k hart Ta ble ™) will be c o ns ulte d t o c o nfir m lac k of P K/ p har mac o d y na mic i nteracti o n 
wit h t he st u d y dr u g.

A n y i njecta ble ster oi d w it hi n 1 2 wee ks pri or t o t he first d osi n g or a n y ot her f or m of ster oi ds 
(e g, i n hale d, nasal, oral) wit hi n 3 0 da ys pri or t o t he first d osi n g.
1 1. Has bee n o n a diet i nc o m pati ble w it h t he o n-st u d y diet, i n t he o pi ni o n of t he I n vesti gat or or desi g nee, wit hi n 
t he 3 0 da ys pri or t o t he first d osi n g.
1 2. Is lact ose i nt olera nt.
1 3. D o nati o n of bl o o d or si g nifica nt bl o o d l oss w it hi n 5 6 da ys pri or t o t he first d osi n g.
1 4. Plas ma d o nati o n wit hi n 7 d a y s pri or t o t he first d osi n g.
1 5. Partici pati o n i n a n ot her cli nical st u d y wit hi n 3 0 d a y s or 5 half-li ves, w hic he ver is later, pri or t o t he first 
d osi n g. T he 3 0 -d a y  ( or 5 half-li ves) wi n d o w will be deri ve d fr o m t he date of t he last bl o o d c ollecti o n or 
d osi n g, w hic he ver is later, i n t he pre vi o us st u d y t o Da y 1 of Peri o d 1 of t he c urre nt st u d y.
M ai n Criteri a f or E v al u ati o n a n d A n al yses:
Pri mar y e n d p oi nts :
T he f oll o w i n g pri mar y P K para m eters will be a nal yze d f or plas ma b u des o ni de :

Ma xi m u m o bser ve d c o nce ntrati o n ( C
ma x ).

Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n 
( A U Clast).

Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o i nfi nit y, calc ulate d usi n g t he o bser ve d val ue of t he 
last q ua ntifia ble c o nce ntrati o n ( A U C∞).
Sec o n dar y e n d p oi nts:
Safet y e n d p oi nts will i ncl u de :

I nci de nce of T E A Es a n d t heir se verit y, seri o us ness, a n d ca usalit y .

I nci de nce of cli nicall y si g nifica nt a b n or mal val ues f or vital si g ns, a n d cli nical la b orat or y e val uati o ns.
T he f oll o w i n g sec o n dar y P K para meters will be a nal yze d f or plas ma b u des o ni de:

Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 1 2 h o urs ( A U C 0- 1 2).

Area u n der t he c ur ve fr o m t he last q ua ntifia ble c o nce ntrati o n t o i nfi nit y, calc ulate d usi n g t he o bser ve d val ue 
of t he last q ua ntifia ble c o nce ntrati o n, e x presse d as a perce nta ge of A U C ∞( A U Ce xtra p%).

Ti m e of first occ urre nce of C ma x (tma x ).

La g ti me t o first q ua ntifia ble c o nce ntrati o n (tla g).

T er m i nal dis p ositi o n p hase half -life (t1/ 2z).

T er m i nal dis p ositi o n p hase rate c o nsta nt ( λz).

A p pare nt cleara nce after e xtra vasc ular a d mi nistrati o n, calc ulate d usi n g t he o bser ve d val ue of t he last 
q ua ntifia ble c o nce ntrati o n ( C L/ F).
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 1 0 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L

A p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal dis p ositi o n p hase after e xtra vasc ular a d mi nistrati o n, 
calc ulate d usi n g t he o bser ve d val ue of t he last q ua ntifia ble c o nce ntrati o n ( V z/ F).
St atistic al C o nsi der ati o ns:
P K a nal ysis:
Plas ma b u des o ni de c o nce ntrati o ns a n d P K para meters will be liste d b y partici pa nt a n d treat me nt, a n d 
s u m marize d usi n g a p pr o priate descri pti ve statistics t o be f ull y o utli ne d i n t he statistical a nal ysis pla n ( S A P).
P K para meters ( C ma x , A U Clast, A U C∞, A U C0- 1 2, A U Ce xtra p %, tma x , tl a g, t1/ 2z, λz, C L/ F, a n d Vz/ F) will be c o m p ute d 
usi n g sta n dar d n o n -c o m part me ntal a nal ysis ( N C A). I n di vi d ual plas ma c o nce ntrati o n/ti me c ur ves will be 
prese nte d i n li near/li near a n d l o g/li near scale .
T he a p pr o priate P K a nal ysis will be f ull y s pecifie d i n t he S A P.
Esti mati o n of f o o d -effect:
A li near mi xe d -effect s m o del will be a p plie d t o l o g -tra nsf or me d Cma x , A U Clast, a n d A U C∞wit h treat me nt, peri o d, 
a n d se q ue nce as fi xe d effects, a n d partici pa nt wit hi n se q ue nce as a ra n d o m effect. P oi nt esti mates a n d t heir 
ass ociate d 9 0 % c o nfi de nce i nter vals ( CIs) will be c o nstr ucte d f or t he differe nce bet wee n Treat me nt B (fe d ) 
mi n us Treat me nt A (fasti n g). T he p oi nt esti mates a n d t heir ass ociate d 9 0 % CIs will be t he n bac k tra nsf or me d t o 
pr o vi de p oi nt esti mates a n d 9 0 % CIs f or t he rati os of Treat me nt B (fe d) vers us Treat me nt A (fasti n g).
A nal ysis of t ma x a n d t l a g will be perf or me d b y n o n- para m etric Wilc o x o n si g ne d-ra n k test.
Safet y a nal ysis:
T E A Es will be ta b ulate d. S u m mar y statistics f or vital si g ns, a n d cli nical la b orat or y assess me nts will be 
c o m p ute d a n d pr o vi de d .
S a m ple Size J ustific ati o n: 
T w e nt y (2 0 ) partici pa nts will be e nr olle d t o acc o u nt f or p ossi ble dr o p o uts.
A t otal of a p pr o xi matel y 1 8 partici pa nts s h o ul d c o m plete all treat me nt peri o ds of t he st u d y.
F or plas ma b u des o ni de C ma x , A U C∞, a n d A U Clast, ass u mi n g t he tr ue mea n rati o of 1. 0 wit h i ntra-partici pa nt 
coefficie nt of varia nce ( C V) of 2 1. 8, 2 1. 0, a n d 2 1. 8 %, res pecti vel y, 1 8 c o m pleters will pr o vi de 8 0, 8 5, a n d 8 0 % 
p o w er t o test f or bi oe q ui vale nce bet w ee n d osi n g u n der fe d vers us fasti n g c o n diti o n usi n g t he criteria of a 9 0 % CI 
wit hi n (0. 8 0, 1. 2 5 ). C o nsi deri n g 1 0 % dr o p o ut rate, a t otal of 20 partici pa nts will be e nr olle d.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 1 1 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
2. 0
S T U D Y S C H E M A TI C
Fi g ure 2. a
O ver all St u d y Desi g n
a. 
I n eac h peri o d, partici pa nts will recei ve a si n gle oral d ose of B O S u n der fasti n g ( Treat me nt A) or fe d 
(hi g h -fat/ hi g h-cal orie meal; Tr e at m e nt B) c o n diti o ns o n Da y 1, acc or di n g t o t he ra n d o mizati o n sc he d ule.
b.
T here w ill be a was h o ut of at least 2 da ys bet w ee n d oses .
c.
All partici pa nts w h o recei ve d a n y B O S (i ncl u di n g partici pa nts w h o ter mi nate t he st u d y earl y) will ret ur n t o t he 
C R U a p pr o xi matel y 3 da ys after t he last d ose of B O S f or f oll o w-u p pr oce d ures, a n d t o deter mi ne if a n y A E has 
occ urre d si nce t he last st u d y visit .
A b bre viati o n s: C R U = cli nical researc h u nit, P K = p har mac o ki netic.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 1 4 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
4. 0
I N T R O D U C TI O N
4. 1
B ac k gr o u n d
B u des o ni de is a n a nti -i nfla m mat or y c ortic oster oi d t hat has p ote nt gl uc oc ortic oi d acti vit y, wea k 
mi neral oc ortic oi d acti vit y , a n d p ote nt l ocal a nti-i nfla m mat or y effects. Ta ke da is c urre ntl y  
de vel o pi n g b u des o ni de oral s us pe nsi o n ( B O S), t hr o u g h t he T A K-7 2 1 ( pre vi o usl y  S H P 6 2 1) 
cli nical de vel o p me nt pr o gra m, f or t he treat me nt of e osi n o p hilic es o p ha gitis (E o E ). B O S is 
desi g ne d t o i ncrease t he resi de nce ti me of b u des o ni de o n t he s urface of t he es o p ha g us after 
s wall o wi n g, as c o m pare d wit h ot her b u des o ni de f or m ulati o ns. F o ur differe nt f or m ulati o ns of 
B O S ( M B-7, M B -8, M B - 9, a n d S B-1 0) ha ve bee n e val uate d i n n o ncli nical a n d/ or cli nical st u dies 
t o date. I n t his st u d y, t he effect of f o o d will be e val uate d usi n g t he B O S S B -1 0 f or m ulati o n .
T he n o ncli nical p har mac ol o g y , t o xic ol o g y, cli nical p har mac ol o g y, a n d safet y of b u des o ni de are 
well st u die d as b u des o ni de is prese nt i n se veral U nite d States ( U S) F o o d a n d Dr u g 
A d mi nistrati o n ( F D A) -a p pr o ve d dr u g pr o d ucts. B u des o ni de has bee n s h o w n t o be t olerate d a n d 
effecti ve i n n u mer o us well -c o ntr olle d cli nical st u dies f or ot her i n dicati o ns. Vari o us a p pr o ve d 
f or m ulati o ns of b u des o ni de are c urre ntl y mar kete d f or t he ma na ge me nt of Cr o h n’s disease, f or 
ast h ma mai nte na nce, f or t he treat me nt of aller gic r hi nitis, a n d f or i n d ucti o n of re missi o n i n 
patie nts wit h acti ve, mil d t o m o derate ulcerati ve c olitis
Rece ntl y , b u des o ni de oral disi nte grati n g ta blet was a p pr o ve d f or use i n a d ults wit h E o E i n a 
n u m ber of c o u ntries i n E ur o pe. T here is a lar ge safet y data base i n h u ma ns wit h b u des o ni de i n a 
variet y of f or m ulati o ns gi ve n b y m ulti ple r o utes of a d mi nistrati o n ( oral, i n halati o n, rectal, a n d 
nasal s pra y s), w hic h f or ms t he pri mar y basis of s u p p ort f or t he safety assess me nt of B O S a n d t he 
pr o p ose d cl i nical st u dies.
Refer t o t he I n vesti gat or’s Br oc h ure (I B) f or detaile d bac k gr o u n d i nf or mati o n o n B O S.
4. 1. 1
Cli nic al P h ar m ac ol o g y
T he c urre nt cli nical pr o gra m f or t he de vel o p me nt of B O S f or t he treat me nt of E o E i n a d olesce nts
a n d a d ults i ncl u des o ne c o m plete d P h ase 1 st u d y ( S H P 6 2 1-1 0 1), t w o c o m plete d P hase 2 st u dies
( M PI 1 0 1-0 1 a n d M PI 1 0 1 -0 6), a n d t hree c o m plete d P hase 3 st u dies ( S H P 6 2 1 - 3 0 1, S H P 6 2 1 - 3 0 2, 
S H P 6 2 1 - 3 0 3).
St u d y  S H P 6 2 1- 1 0 1 utilize d t he S B -1 0 f or m ulati o n a n d de m o nstrate d t hat b u des o ni de is rea dil y 
a bs or be d fr o m t he B O S S B - 1 0 f or m ulati o n wit h a me dia n t ma x o bser ve d at 1. 5 h o urs w hile a 
dela y e d a bs or pti o n of b u des o ni de is de m o nstrate d f or E N T O C O R T E C ( b u des o ni de 
dela y e d-release ca ps ules) wit h a me dia n t ma x o bser ve d at 4 h o urs. T he oral bi oa vaila bilit y  of 
b u des o ni de fr o m t he B O S S B -1 0 f or m ulati o n is esti mate d at 1 4. 2 % i n healt h y  partici pa nts, 
c o nsiste nt wit h hi g h first - pass meta b olis m as o bser ve d wit h E N T O C O R T E C; h o we ver, 
esti mate d oral bi oa vaila bilit y was a p pr o xi matel y 5 7. 5 % hi g her t ha n t hat fr o m E N T O C O R T E C 
(esti mate d at 9 %). T he reas o n f or hi g her oral bi oa vaila bilit y of b u des o ni de fr o m t he B O S S B - 1 0 
f or m ulati o n as c o m pare d t o t he E N T O C O R T E C f or m ulati o n is u n k n o w n, b ut li kel y relate d t o 
re d uce d first-pass meta b olis m, n ot relate d t o t he e xte nt of a bs or pti o n.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 1 5 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
Alt h o u g h b u des o ni de is a p o orl y s ol u ble, hi g hly per mea ble Bi o p har mace utics Classificati o n 
S y ste m Class II c o m p o u n d , a bs or pti o n fr o m E N T O C O R T E C f oll o wi n g oral d osi n g a p pears t o 
be c o m plete. T he a bs or pti o n of b u des o ni de fr o m t he B O S f or m ulati o n is e x pecte d t o be c o m plete 
as well gi ve n t he B O S f or m ulati o n is a n i m me diate release f or m ulati o n tar geti n g dr u g release i n 
t he es o p ha g us.
B u des o ni de P K is d ose -pr o p orti o nal f oll o wi n g re peate d a d mi nistrati o n i n t he d ose r a n ge of 0. 5 t o 
2 m g base d o n t he p o p ulati o n P K a nal y sis w hic h de m o nstrate d d ose was n ot a si g nifica nt 
c o variate i n t he m o del. T his is s u p p orte d b y c o m plete a bs or pti o n a n d is als o c o nsiste nt wit h w hat 
is see n wit h E N T O C O R T E C w h ose P K were d ose-pr o p orti o nal f oll o wi n g re peate d 
a d mi nistrati o n i n t he d ose ra n ge of 3 t o 1 5 m g.
A s mall acc u m ulati o n ( ≤1 5 %) of b u des o ni de is esti mate d f oll o wi n g t wice dail y ( BI D) d osi n g b y  
t he met h o d of s u per p ositi o n usi n g P K data fr o m St u d y S H P 6 2 1-1 0 1. T his is c o nsiste nt wit h t he 
o b ser ve d t1/ 2 of 5. 0 5 h o urs.
F oll o wi n g oral a d mi nistrati o n, b u des o ni de is s u bject t o hi g h first -pass meta b olis m ( 8 0 -9 0 %) 
pri maril y  via C Y P 3 A 4 is oz ymes. B u des o ni de is a s u bstrate f or C Y P 3 A 4; t heref ore, c o nc o mita nt 
use wit h C Y P 3 A 4 i n hi bit ors (e g, ket oc o naz ole, itrac o naz ole, rit o na vir, i n di na vir, sa q ui na vir, 
er yt hr o m y ci n, c ycl os p ori ne, gra pefr uit j uice) s h o ul d be a v oi de d as t he y  ca n i ncrease s yste mic 
b u des o ni de c o nce ntrati o ns. C o -a d mi nistrati o n of ket oc o naz ole res ults i n a n 8-f ol d i ncrease i n t he 
A U C of oral b u d es o ni de. Gra pefr uit j uice, a n i n hi bit or of g ut m uc osal C Y P 3 A 4, a p pr o xi matel y  
d o u bles t he s y ste mic e x p os ure of oral b u des o ni de. Oral c o ntrace pti ves c o ntai ni n g et hi n yl 
estra di ol, w hic h is als o meta b olize d b y  C Y P 3 A 4, d o n ot affect t he P K of b u des o ni de. 
B u des o ni de d oes n ot affect t he plas ma le vels of oral c o ntrace pti ves (ie, et hi n y l estra di ol).
4. 1. 2
Cli nic al S afet y
I n St u dy S H P 6 2 1 -1 0 1 wit h healt h y  a d ult partici pa nts , n o n ota ble differe nces were a p pare nt wit h
res pect t o T E A Es or relate d T E A Es acr oss treat me nts, i ncl u di n g a c o m paris o n a m o n g all B O S
treat me nt ar ms a n d E N T O C O R T E C. O verall, 1 5 ( 6 8. 2 %) partici pa nts i n t he safety a nal ys is set 
ha d 1 9 T E A Es. Of t hese, 1 3 ( 5 9. 1 %) partici pa nts ha d 1 7 T E A Es t hat were c o nsi dere d b y t he 
In vesti gat or t o be relate d t o t he st u dy dr u g . T he syste m or ga n class wit h t he m ost partici pa nts
re p orti n g T E A Es i n t he safety a nal ysis set was ner v o us s yste m dis or ders wit h 8 ( 3 6. 4 %) 
partici pa nts re p orti n g 9 e ve nts, f oll o we d b y gastr oi ntesti nal dis or ders wit h 7 ( 3 1. 8 %) partici pa nts
re p orti n g 8 e ve nts. B y preferre d ter m, t he m ost c o m m o nl y re p orte d T E A E was hea dac he
( 7 [ 3 1. 8 %] partici pa nts re p orti n g 8 e ve nts) f oll o we d b y  dr y m o ut h ( 4 [ 1 8. 2 %] partici pa nts 
re p orti n g 4 e ve nts). All T E A Es were mil d i n se verit y . T here were n o se vere T E A Es, deat hs, or 
T E A Es res ulti n g i n disc o nti n uati o n re p orte d d uri n g t he st u dy. N o n ota ble differe nces i n T E A Es 
were a p pare nt acr oss treat me nts.
4. 2
R ati o n ale f or t he Pr o p ose d St u d y
T he p ur p ose of t his st u d y is t o deter mi ne if t he s ys temic e x p os ure t o t he pr o p ose d 
t o- be-mar kete d B O S S B - 1 0 pr o d uct will be altere d if d ose d wit h f o o d.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 1 6 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
C o -a d mi nistrati o n of a hi g h -fat meal dela ye d t he tma x of b u des o ni de ca ps ule ( E N T O C O R T E C 
dela y e d-release ca ps ules) b y 2. 3 h o urs b ut di d n ot si g nifica ntly affect t he A U C i n healt h y 
partici p a nts. A f o o d -effect st u d y i n v ol vi n g a d mi nistrati o n of b u des o ni de ta blets t o healt h y 
partici pa nts u n der fasti n g c o n diti o ns a n d wit h a hi g h -fat meal i n dicate d t hat t he Cma x decrease d 
b y  2 7 % w hile t here was n o si g nifica nt decrease i n A U C. A d diti o nall y, a mea n dela y  i n 
a bs or pti o n la g ti me of 2. 4 h o urs is o bser ve d u n der fe d c o n diti o ns.
As t he P K differe nce bet wee n E N T O C O R T E C a n d B O S is pri maril y  relate d t o t he rate a n d 
e xte nt of a bs or pti o n of b u des o ni de a n d n o si g nifica nt differe nces are e x pecte d i n t he distri b uti o n, 
meta b olis m, a n d e xcreti o n of b u des o ni de , a si milar effect b y f o o d is a ntici pate d f or t he B O S 
f or m ulati o n.
I n a d diti o n t o a f o o d effect assess me nt, res ults of t his st u d y will pr o vi de a n i m p orta nt safety a n d 
t olera bilit y c o m paris o n of pr o d uct perf or mance u n der fe d a n d fasti n g c o n diti o ns i n healt h y  a d ult 
partici pa nts .
4. 3
Be nefit/ Ris k Pr ofile
T he d ose of B O S a d mi nistere d i n t his st u d y is n ot a ntici pate d t o i n d uce a ny p ote ntial ris k t o 
partici pa nts , as it is a si n gle d ose a d mi nistere d acc or di n g t o t he d osi n g rec o m me n dati o ns f o u n d 
i n t he I B.
T here will be n o direct healt h be nefit f or st u d y  partici pa nts fr o m t he recei pt of B O S . A n i n direct 
healt h be nefit t o t he healt h y  partici pa nts e nr olle d i n t his st u d y is t he free me dical tests recei ve d at 
scree ni n g a n d d uri ng t he st u d y .
T he i ncl usi o n a n d e xcl usi o n criteria, scree ni n g, a n d safet y m o nit ori n g practices e m pl o ye d b y t his 
pr ot oc ol (ie, vital si g ns, cli nical la b orat or y  tests, A E q uesti o ni n g, a n d p hys ical e xa mi nati o ns) are 
a de q uate t o pr otect t he partici pa nt’s safety a n d s h o ul d detect all T E A Es.
5. 0
S T U D Y O B J E C TI V E S A N D E N D P OI N T S
5. 1
H y p ot hesis
N ot a p plica ble.
5. 2
St u d y O bjecti ves
5. 2. 1
St u d y Pri m ar y O bjecti ve
T o assess t he relati ve bi oa vaila bilit y of a si n gle d ose of B O S a d mi nistere d u n der fasti n g a n d fe d 
( hi g h-fat/ hi g h-cal orie meal) c o n diti o ns.
5. 2. 2
St u d y Sec o n d ar y O bjecti ve s
T o assess t he safet y a n d t olera bilit y of a si n gle d ose of B O S a d mi nistere d u n der fasti n g a n d fe d 
( hi g h-fat/ hi g h-cal orie meal) c o n diti o ns.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 1 7 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
T o e val uate ot her P K para meters of a si n gle d ose of B O S a d mi nistere d u n der fast i n g a n d fe d 
( hi g h-fat/ hi g h-cal orie meal) c o n diti o ns .
5. 3
E n d p oi nts
5. 3. 1
Pri m ar y E n d p oi nt
T he f oll o wi n g pri mar y  P K para meters will be a nal yze d f or plas ma b u des o ni de:

Ma xi m u m o bser ve d c o nce ntrati o n ( C
ma x ).

Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he last q ua ntifia ble 
c o nce ntrati o n ( A U C last).

Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o i nfi nit y, calc ulate d usi n g t he 
o bser ve d val ue of t he last q ua ntifia ble c o nce ntrati o n ( A U C ∞).
5. 3. 2
Sec o n d ar y E n d p oi nts
Safet y  e n d p oi nts will i ncl u de:

I nci de nce of T E A Es a n d t heir se verit y, seri o us ness, a n d ca usalit y.

I nci de nce of cli nicall y si g nifica nt a b n or mal val ues f or vital si g ns, a n d cli nical la b orat or y  
e val uati o ns .
T he f oll o wi n g sec o n dar y P K para meters will be a nal y ze d f or plas ma b u des o ni de:

Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 1 2 h o urs ( A U C0- 1 2).

Area u n der t he c ur ve fr o m t he last q ua ntifia ble c o nce ntrati o n t o i nfi nit y , calc ulate d usi n g t he 
o bser ve d val ue of t he last q ua ntifia ble c o nce ntrati o n, e x presse d as a perce nta ge of A U C ∞
( A U Ce xtra p %).

Ti me t o first occ urre nce of C ma x (tma x ).

La g ti me t o first q ua ntifia ble c o nce ntrati o n (t la g).

Ter mi nal dis p ositi o n p hase half -life (t1/ 2z).

Ter mi nal dis p ositi o n p hase rate c o nsta nt ( λ z).

A p pare nt cleara nce after e xtra vasc ular a d mi nistrati o n, calc ulate d usi n g t he o bser ve d val ue of 
t he last q ua ntifia ble c o nce ntrati o n ( C L/ F).

A p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal dis p ositi o n p hase after e xtra vasc ular 
a d mi nistrati o n, calc ulate d usi n g t he o bser ve d val ue of t he last q ua ntifia ble c o nce ntrati o n 
( Vz/ F).
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 1 8 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
6. 0 
S T U D Y D E SI G N A N D D E S C RI P TI O N
6. 1
St u d y Desi g n
T his is a n o pe n -la bel, si n gle-d ose, ra n d o mize d, 2 -peri o d, 2 -se q ue nce, 2-wa y  cr oss o ver st u d y i n 
healt h y  a d ult partici pa nts.
St u d y  sc he matic a n d d ose re gi me ns are s h o w n i n Fi g ure 2. a a n d Ta ble 6.a . T he sc he d ule of 
assess me nts is s h o w n i n t he Sc he d ule of St u d y Pr oce d ures ( Secti o n 3. 0 ).
O n Da y 1 of Peri o d 1, partici pa nts will be ra n d o ml y  assi g ne d t o 1 of 2 treat me nt se q ue nces.
O n Da y  1 of eac h peri o d, a si n gle oral d ose of B O S will be a d mi nistere d u n der fasti n g 
( Treat me nt A) or fe d (hi g h -fat/ hi g h-cal orie meal; Treat me nt B) c o n diti o ns . P K sa m ples will be 
c ollecte d pre d ose a n d u p t o 2 4 h o urs p ost d ose i n eac h peri o d.
T here will be a was h o ut of at least 2 d a y s bet wee n d oses.
Safet y  a n d t olera bilit y will be assesse d t hr o u g h o ut t he st u d y b y T E A Es, vital si g ns, a n d cli nical 
la b orat or y e val uati o ns.
All partici pa nts w h o recei ve d a n y B O S (i ncl u di n g partici pa nts w h o ter mi nate t he st u d y early) 
will ret ur n t o t he C R U a p pr o xi matel y  3 d a y s after t he last d ose of B O S f or f oll o w-u p pr oce d ures, 
a n d t o deter mi ne if a n y A E has occ urre d si nce t he last st u d y  visit.
T a ble 6. a
St u d y Tre at me nts
Tre at m e nt
St u d y Dr u g
D ose
D ose Re gi m e n
Treat me nt A
B u des o ni de oral 
s us pe nsi o n
2 m g 
( 1 0 m L of 0. 2 m g/ m L)
Si n gle d ose, oral, fasti n g
Treat me nt B
B u des o ni de oral 
s us pe nsi o n
2 m g 
( 1 0 m L of 0. 2 m g/ m L)
Si n gle d ose, oral, fe d: f oll o wi n g a 
hi g h -fat/ hi g h-cal orie meal
6. 2
D ose Esc al ati o n
N ot a p plica ble.
6. 3
St o p pi n g R ules
A n ur ge nt safet y re vie w will be c o n d ucte d b y t he S p o ns or if o ne or m ore of t he f oll o wi n g criteria 
are met:

Deat h t hat is c o nsi dere d relate d t o t he st u d y dr u g.

T w o S A Es of si milar t y pe ( defi ne d as sa me or si milar Me dical Dicti o nar y  f or Re g ulat or y
Acti vities ® (Me d D R A
® ) hi g her le vel gr o u p c o de), a n d c o nsi dere d relate d t o t he st u d y dr u g.
T he ur ge nt re vie w will be perf or me d b y a S p o ns or safet y re vie w gr o u p, w hic h will i ncl u de t he
st u d y Gl o bal Safet y Lea d, Gl o bal Cli nical Lea d, a n d Gl o bal Safet y T hera pe utic Area Hea d. 
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 1 9 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
F oll o wi n g t he S p o ns or’s re vie w of safet y data, o ne of t he f oll o wi n g acti o ns will be ta ke n wit h 
res pect t o st u dy stat us :

C o nti n ue st u d y  wit h pr ot oc ol u nc ha n ge d.

C o nti n ue st u d y  wit h m o dificati o ns t o t he pr ot oc ol.

Ter mi nate st u d y .
Partici pa nt safety will be m o nit ore d o n a c o nti n u o us basis d uri n g t his st u d y u ntil t he last 
partici pa nt c o m pletes his or her last sc he d ule d st u d y  visit/assess me nt.
6. 4
R ati o n ale f or St u d y Desi g n, D ose, a n d E n d p oi nts
6. 4. 1
R ati o n ale of St u d y Desi g n
T his st u d y is bei n g c o n d ucte d t o assess t he effect of f o o d o n t he P K pr ofile of b u des o ni de after a 
si n gle oral d ose.
T he c urre nt st u d y is desi g ne d i n acc or da nce wit h t he F D A g ui da nce [F D A 2 0 2 2 ] as a defi niti ve
f o o d-effect st u d y i n healt h y partici pa nts a n d will utilize a hi g h -fat a n d hi g h-cal orie test meal i n 
Treat me nt B.
Partici pa nts will be ra n d o mize d t o treat me nt se q ue nces t o mi ni mize assi g n me nt bias. A 
cr oss o ver desi g n is use d t o re d uce t he resi d ual varia bilit y  as e ver y partici pant acts as t heir o w n 
c o ntr ol.
T he was h o ut peri o d of at least 2 d a y s bet wee n d oses is m ore t ha n 7 x t he b u des o ni de t1/ 2z, w hic h 
is als o i n acc or da nce wit h F D A rec o m me n dati o ns [F D A 2 0 2 2 ] a n d is c o nsi dere d s ufficie nt t o 
pre ve nt carr y o ver effects of t he prece di n g treat me nt.
6. 4. 2
R ati o n ale f or D ose
T he 2 m g si n gle oral d ose of B O S was selecte d as it is t he rec o m me n de d cli nical d ose a n d is 
e x pecte d t o pr o vi de a safet y  mar gi n s h o ul d a f o o d effect occ ur.
Partici pa nts i n t he c o m plete d P hase 3 st u dies recei ve d oral BI D a d mi nistrati o n of B O S at 1 0 m L 
of 0. 2 m g/ m L ( dail y d ose of 2 m g BI D ) f or a t otal of 1 2 wee ks d uri n g t he c o m plete d i n d ucti o n 
st u d y ( S H P 6 2 1- 3 0 1), f or a n a d diti o nal 3 6 wee ks i n t he e xte nsi o n st u d y ( St u d y S H P 6 2 1 -3 0 2), a n d 
f or u p t o a n ad diti o nal 4. 5 ye ars at d oses u p t o 2 m g BI D i n t he S H P 6 2 1-3 0 3 o pe n -la bel 
c o nti n uati o n st u d y.
T he hi g hest t otal d ose of b u des o ni de i n t he P hase 3 st u dies is 4 m g/ da y  ( gi ve n as 2 m g BI D ), 
w hic h is l o wer t ha n t he c hr o nicall y a d mi nistere d oral d ose of b u des o ni de la bele d f or t he 
treat me nt of Cr o h n’s disease. T he a p pr o ve d dail y d osa ge of oral b u des o ni de ca ps ules is 
9 m g/ da y  f or t he treat me nt of Cr o h n’s disease ( E N T O C O R T E C) or oral b u des o ni de ta blets f or 
ulcerati ve c olitis ( U C E RI S) f oll o we d b y  l o n g-ter m mai nte na nce wit h 6 m g/ da y oral b u des o ni de 
ta blets f or t he treat me nt of Cr o h n’s disease. T he s yste mic e x p os ure of b u des o ni de, A U C, after 
i n gesti o n of 2 m g BI D of B O S is pre dicte d t o be 6 7 % of t hat fr o m E N T O C O R T E C 9 m g o nce a 
da y  a n d si milar t o t hat fr o m E N T O C O R T 6 m g o nce a da y .
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 0 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
6. 4. 3
R ati o n ale f or E n d p oi nts
6. 4. 3. 1
P h ar m ac oki netic E n d p oi nts
T he P K e n d p oi nts are sta n dar d f or t his t y pe of st u d y.
6. 4. 3. 2
S afety E n d p oi nts
T he ke y  safety e n d p oi nts are t y pical f or P hase 1 st u dies a n d will be assesse d t hr o u g h m o nit ori n g 
of A Es, vital si g ns, cli nical la b orat or y assess me nts, a n d p h ysical e xa mi nati o ns.
6. 4. 4
F ut ure Bi o me dic al Rese arc h
N o a d diti o nal a nal ys is is pla n ne d t o be perf or me d o n t he P K bl o o d sa m ples f or p ossi ble f ut ure 
researc h. A ny a d diti o nal researc h o n t hese sa m ples u ns pecifie d b y t his pr ot oc ol will re q uire 
a p pr o val fr o m t he partici pa nts.
6. 4. 5
Critic al Pr oce d ures B ase d o n St u d y O bjecti ves: Ti mi n g of Pr oce d ures
F or t his st u d y , t he critical c o m p o ne nt is t he bl o o d c ollecti o n f or plas ma c o nce ntrati o ns of 
b u des o ni de, a n d is t o be c ollecte d a s cl ose t o t he sc he d ule d ti mes defi ne d i n t his pr ot oc ol as 
p ossi ble.
6. 5
St u d y Desi g n/ D osi n g/ Pr oce d ures M o dific ati o ns Per mitte d Wit hi n Pr ot oc ol 
P ar a meters
T he d ose a n d a d mi nistrati o n of B O S t o a ny partici pa nt ma y  n ot be m o difie d. If necessar y, a 
partici pa nt ma y  be disc onti n ue d f or t he reas o ns descri be d i n Secti o n 7. 5 a n d Secti o n 7. 6 .
6. 6
St u d y Be gi n ni n g a n d E n d/ C o m pleti o n
6. 6. 1
Defi niti o n of Be gi n ni n g of t he St u d y
T he be gi n ni n g of t he st u d y  will be defi ne d as t he be gi n ni n g of t he scree ni n g (ie, si g ni n g of t he 
I CF) of t he first partici pa nt .
6. 6. 2
Defi niti o n of E n d of t he St u d y
T he e n d of st u d y is defi ne d as t he date of t he last sc he d ule d pr oce d ure ie, t he f oll o w- u p visit , as 
o utli ne d i n t he Sc he d ule of St u d y  Pr oce d ures ( Secti o n 3. 0 ).
A partici pa nt is c o nsi dere d t o ha ve c o m plete d t he st u d y  if t he partici pa nt has c o m plete d t he last 
sc he d ule d pr oce d ure ie, t he f oll o w-u p visit s h o w n i n t he Sc he d ule of St u d y  Pr oce d ures 
( Secti o n 3. 0 ).
6. 6. 3
Defi niti o n of St u d y Disc o nti n u ati o n
Celeri o n reser ves t he ri g ht t o ter mi nate t he st u d y  i n t he i nterest of partici pa nt welfare.
T he S p o ns or reser ves t he r i g ht t o s us pe n d or ter mi nate t he st u d y at a n y ti me.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 1 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
6. 6. 4
Criteri a f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of t he St u d y
T he st u d y  will be c o m plete d as pla n ne d u nless o ne or m ore of t he f oll o wi n g criteria are satisfie d 
t hat re q uire te m p orar y s us pe nsi o n or early t er mi nati o n of t he st u d y:

Ne w i nf or mati o n or ot her e val uati o n re gar di n g t he safet y or efficac y of t he st u d y  dr u g t hat 
i n dicates a c ha n ge i n t he k n o w n ris k/ be nefit pr ofile f or t he pr o d uct, s uc h t hat t he ris k is n o 
l o n ger acce pta ble f or partici pa nts partici pati n g i n t he st u d y.

Si g nifica nt vi olati o n of G o o d Cli nical Practice ( G C P) t hat c o m pr o mises t he a bilit y  t o ac hie ve 
t he pri mar y st u d y o bjecti ves or c o m pr o mises partici pa nt safety.
6. 6. 5
Criteri a f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of a Site
N ot a p plica ble.
7. 0 
S E L E C TI O N A N D DI S C O N TI N U A TI O N/ WI T H D R A W A L O F P A R TI CI P A N T S
7. 1 
I ncl usi o n Criteri a
Partici pa nts m ust f ulfill all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or partici pati o n i n 
t he st u d y:
1.
Healt h y, a d ult, male or fe male *, 1 9- 5 5 years of a ge, i ncl usi ve, at t he scree ni n g visit.
*
Fe males of c hil d beari n g p ote ntial are defi ne d as all fe males p h ys i ol o gicall y ca pa ble of 
bec o mi n g pre g na nt.
Fe males of n o n -c hil d beari n g p ote ntial are defi ne d as f oll o ws:

Fe males w h o ha ve u n der g o ne o ne of t he f oll o wi n g sterilizati o n pr oce d ures at least 
6 m o nt hs pri or t o t he first d osi n g:
–
H y ster osc o pic sterilizati o n.
–
Bilateral t u bal li gati o n or bilateral sal pi n gect o m y.
–
H y sterect o my.
–
Bilateral o o p h orect o m y.
or

Fe males w h o are p ost me n o pa usal wit h a me n orr hea f or at least 1 2 m o nt hs pri or t o t he 
first d osi n g a n d F S H ser u m le vels c o nsiste nt wit h p ost me n o pa usal stat us at t he 
scree ni n g visit .
2.
Fe male of c hil d beari n g p ote ntial a n d male partici pa nts m ust f oll o w pr ot oc ol s pecifie d 
c o ntrace pti o n g ui da nce as descri be d i n  A p pe n di x D.
3.
C o nti n u o us n o n -s m o ker w h o has n ot use d nic oti ne- a n d t o bacc o-c o ntai ni n g pr o d ucts f or at 
least 3 m o nt hs pri or t o t he first d osi n g base d o n partici pa nt self-re p orti n g.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 2 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
4.
B MI ≥1 8. 0 a n d ≤3 2. 0 k g/ m 2 at t he scree ni n g visit.
5.
Me dicall y  healt h y wit h n o cli nicall y si g nifica nt me dical hist or y, p h ysical e xa mi nati o n, 
la b orat or y pr ofiles, vital si g ns, a n d E C Gs, as dee me d b y t he I n vesti gat or or desi g nee, 
i ncl u di n g t he f oll o wi n g:

Seate d bl o o d press ure is ≥ 9 0/ 4 0 m m H g a n d ≤ 1 4 0/ 9 0 m m H g at t he scree ni n g visit.

Se ate d p ulse rate is ≥4 0 b p m a n d ≤ 9 9 b p m at t he scree ni n g visit.

Q Tc F i nter val is ≤ 4 6 0 msec ( males) a n d ≤ 4 7 0 msec (fe males) a n d has E C G fi n di n gs 
c o nsi dere d n or mal or n ot cli nicall y  si g nifica nt by t he I n vesti gat or or desi g nee at t he 
scree ni n g visit.

Esti m ate d creati ni ne cleara nce ≥ 8 0 m L / mi n at t he scree ni n g visit.

L i ver-relate d tests i ncl u di n g A L T, A S T, A L P, a n d t otal bilir u bi n ≤U L N at t he scree ni n g 
visit a n d at c hec k -i n.
6.
U n dersta n ds t he st u d y pr oce d ures i n t he I CF, a n d be willi n g a n d a ble t o c o m pl y  wit h t he 
pr ot oc ol.
7. 2 
E xcl usi o n Criteri a
Partici pa nts m ust n ot be e nr olle d i n t he st u d y  if t he y meet a n y of t he f oll o wi n g criteria:
1.
Is me ntall y or le gally i nca pacitate d or has si g nifica nt e m oti o nal pr o ble ms at t he ti me of t he 
scree ni n g visit or e x pecte d d uri n g t he c o n d uct of t he st u d y.
2.
Hist or y  or prese nce of cli nicall y si g nifica nt me dical or ps yc hiatric c o n diti o n or disease i n t he 
o pi ni o n of t he I nvesti gat or or desi g nee.
3.
Hist or y  of a n y ill ness t hat, i n t he o pi ni o n of t he I nvesti gat or or desi g nee, mi g ht c o nf o u n d t h e 
res ults of t he st u d y or p oses a n a d diti o nal ris k t o t he partici pa nt b y  t heir partici pati o n i n t he 
st u d y.
4.
Prese nce of a n y acti ve i nfecti o n at t he scree ni n g visit or c hec k -i n.
5.
Hist or y  or prese nce of alc o h ol or dr u g a b use wit hi n t he past 2 ye ars pri or t o t h e first d osi n g .
6.
Hist or y  or prese nce of hy perse nsiti vit y or i di os y ncratic reacti o n t o t he st u d y dr u g, i nacti ve 
i n gre die nts, or relate d c o m p o u n ds.
7.
Fe male partici pa nt wit h a p ositi ve pre g na nc y  test at t he scree ni n g visit or at c hec k-i n or w h o 
is lactati n g.
8.
P ositi ve uri ne dr u g or alc o h ol res ults at t he scree ni n g visit or c hec k -i n.
9.
P ositi ve res ults f or HI V, H Bs A g, or H C V at t he scree ni n g visit.
1 0. U na ble t o refrai n fr o m or a ntici pates t he use of:

A n y  dr u gs, i ncl u di n g prescri pti o n a n d n o n-prescri pti o n me dicati o ns, her bal re me dies, or 
vita mi n s u p ple me nts be gi n ni n g 1 4 d a y s pri or t o t he first d osi n g. Me dicati o n liste d as part 
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 3 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
of acce pta ble birt h c o ntr ol met h o ds (refer t o A p pe n di x D ), h or m o ne re place me nt t hera py, 
a n d t h yr oi d h or m o ne re place me nt me dicati o n (refer t o Secti o n 7. 3 ) will be all o we d.

A n y  dr u gs k n o w n t o be m o derate or str o n g i n d ucers of C Y P 3 A4 e nz ymes a n d/ or P - g p, 
i ncl u di n g St. J o h n’s W ort, f or 2 8 d a y s pri or t o t he first d osi n g. A p pr o priate s o urces 
(e g, Fl oc k hart Ta ble ™) will be c o ns ulte d t o c o nfir m lac k of P K/ p har mac o d y na mic 
i nteracti o n wit h t he st u d y dr u g.

A n y  i njecta ble ster oi d wit hi n 1 2 wee ks pri or t o t he firs t d osi n g or a ny ot her f or m of 
ster oi ds (e g, i n hale d, nasal, oral) wit hi n 3 0 d a y s pri or t o t he first d osi n g.
1 1. Has bee n o n a diet i nc o m pati ble wit h t he o n- st u d y diet, i n t he o pi ni o n of t he I nvesti gat or or 
desi g nee, wit hi n t he 3 0 d a y s pri or t o t he first d osi n g.
1 2. Is lact ose i nt olera nt.
1 3. D o nati o n of bl o o d or si g nifica nt bl o o d l oss wit hi n 5 6 da y s pri or t o t he first d osi n g.
1 4. Plas ma d o nati o n wit hi n 7 da y s pri or t o t he first d osi n g.
1 5. Partici pati o n i n a n ot her cli nical st u d y  wit hi n 3 0 da y s or 5 half -li ves, w hic he ver is later, pri or 
t o t he first d osi n g. T he 3 0-d a y  (or 5 half -li ves) wi n d o w will be deri ve d fr o m t he date of t he 
last bl o o d c ollecti o n or d osi n g, w hic he ver is later, i n t he pre vi o us st u d y t o Da y 1 of Peri o d 1 
of t he c urre nt st u d y .
7. 3
E xcl u de d Me dic ati o ns , S u p ple me nts, Diet ar y Pr o d ucts
Pri or c o nc o mita nt me dicati o ns (i ncl u di n g prescri pti o n a n d n o n-prescri pti o n me dicati o ns, her bal 
re me dies, or vita mi n s u p ple me nts) will be pr o hi bite d as liste d i n t he e xcl usi o n criteria i n 
Secti o n 7. 2 a n d t hr o u g h o ut t he st u d y (ie, u ntil t he f oll o w-u p visit) wit h t he e xce pti o n of 
acce pta ble birt h c o ntr ol met h o ds as descri be d i n  A p pe n di x D . H or m o ne re place me nt t hera py will 
be all o we d. T h yr oi d h or m o ne re place me nt me dicati o n, if t he partici pa nt has bee n o n t he sa me 
sta ble d ose f or at least t he i m me diate 3 m o nt hs pri or t o t he first d osi n g, will als o be all o we d.
After t he first d ose , aceta mi n o p he n ( u p t o 2 g per 2 4 h o urs ) m a y be a d mi nistere d at t he discreti o n 
of t he I n vesti gat or or desi g nee.
If de viati o ns occ ur, t he I n vesti gat or or desi g nee i n c o ns ultati o n wit h t he S p o ns or if nee de d will 
deci de o n a case -b y -case basis w het her t he partici pa nt ma y  c o nti n ue partici pati o n i n t he st u d y.
All me dicati o ns ta ke n b y partici pa nt s d uri n g t he c o urse of t he st u d y will be rec or de d.
Use of e xcl u de d a ge nts ( prescri pti o n or n o n -prescri pti o n) or dietar y  pr o d ucts is o utli ne d i n 
Ta ble 7.a.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 4 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
T a ble 7 .a
E xcl u de d Me dic ati o ns, S u p ple me nts, a n d Diet ar y Pr o d ucts
C ate g or y
Bet wee n Scree ni n g a n d First D osi n g 
( D a ys -2 8 t o pre d ose [ D a y 1])
After First D osi n g ( D a y 1) t o 
F oll o w -U p 
Alc o h ol
Pr o hi bite d fr o m 4 8 h o urs pri or t o first 
d osi n g
Pr o hi bite d fr o m first d osi n g u ntil t he 
last P K sa m ple c ollecti o n o n Da y 2 of 
Peri o d 2.
X a nt hi ne a n d/ or c affei ne
Pr o hi bite d fr o m 2 4 h o urs pri or t o first 
d osi n g a
Pr o hi bite d fr o m first d osi n g u ntil t he 
last P K sa m ple c ollecti o n o n Da y 2 of 
Peri o d 2. a
Me dic ati o ns 
See Secti o ns  7. 1 a n d 7. 2 .
See Secti o ns  7. 1 a n d 7. 2 .
Nic oti ne - a n d t o b acc o -
c o nt ai ni n g a n d/ or 
c a n n a bis pr o d ucts
Pr o hi bite d fr o m 3 m o nt hs pri or t o first 
d osi n g
Pr o hi bite d fr o m first d osi n g u ntil t he 
f oll o w-u p visit.
F o o d s u bst a nce
Gr a pefr uit/ Se ville or a n ge
Pr o hi bite d fr o m 1 4 da ys pri or t o first 
d osi n g
Pr o hi bite d fr o m first d osi n g u ntil t he 
f oll o w-u p visit.
(a) s mall a m o u nts of caffei ne deri ve d fr o m n or mal f o o dst uffs e g, 2 5 0 m L/ 8 oz/ 1 c u p decaffei nate d c offee or ot her 
decaffei nate d be vera ge, per da y, wit h t he e xce pti o n of es press o; 4 5 g/ 1. 5 oz c h oc olate bar, per da y, w o ul d n ot be 
c o nsi dere d a de viati o n t o t his restricti o n.
7. 4
Diet, Fl ui d, Acti vit y
7. 4. 1
Diet a n d Fl ui d
Water (e xce pt water pr o vi de d wit h eac h d osi n g) will be restricte d 1 h o ur pri or t o a n d 1 h o ur after 
eac h d osi n g, b ut will be all o we d a d li bit u m at all ot her ti mes. Ot her fl ui ds ma y be gi ve n as part 
of meals a n d s nac ks b u t will be restricte d at all ot her ti mes t hr o u g h o ut t he c o nfi ne me nt peri o d.
F or Treat me nt A, partici pa nts will be re q uire d t o fast o ver ni g ht f or at least 1 0 h o urs pri or t o 
d osi n g a n d will c o nti n ue t o fast f or at least 4 h o urs p ost d ose.
F or Treat me nt B, partici pa nts will be re q uire d t o fast o ver ni g ht f or at least 1 0 h o urs u ntil 
3 0 mi n utes pri or t o t heir sc he d ule d m or ni n g d ose, w he n t he y  will be gi ve n a hi g h-fat brea kfast 
( 8 0 0-1 0 0 0 cal ories a n d a p pr o xi matel y  5 0 % fat) [F D A 2 0 2 2] w hic h will be e ntirel y  c o ns u me d 
wit hi n 3 0 mi n utes. A n e xa m ple of a hi g h -fat brea kfast w o ul d be 2 slices of b uttere d t oast, 2 e g gs 
frie d i n b utter, 2 stri ps of bac o n, 4 oz of has h br o w n p otat oes, a n d 8 o u nces (a p pr o xi matel y  
2 4 0 m L ) of w h ole mil k [F D A 2 0 2 2] . Partici pa nts will fast f or at least 4 h o urs p ost d ose.
Eac h meal a n d/ or s nac k ser ve d at t he C R U will be sta n dar dize d a n d will be si milar i n cal oric 
c o nte nt a n d c o m p ositi o n (e xce pt f or t he meal ser ve d as part of Treat me nt B) a n d wi ll be ta ke n at 
a p pr o xi matel y t he sa me ti me i n eac h peri o d.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 5 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
W he n c o nfi ne d, sta n dar d meals a n d s nac ks will be pr o vi de d at a p pr o priate ti mes, e xce pt w he n 
partici pa nts are re q uire d t o fast. W he n c o nfi ne d i n t he C R U, partici pa nts will be re q uire d t o fast 
fr o m all f o o d a n d dri n k e xce pt water bet wee n meals a n d s nac ks.
7. 4. 2
Acti vit y
Partici pa nts will re mai n a m b ulat or y  or seate d u pri g ht f or t he first 4 h o urs p ost d ose, e xce pt w he n 
t he y are s u pi ne or se mi-recli ne d f or st u dy pr oce d ures.
S h o ul d A Es occ ur at a n y ti me, participa nts ma y  be place d i n a n a p pr o priate p ositi o n or will be 
per mitte d t o lie d o w n o n t heir ri g ht si de.
Partici pa nts will be i nstr ucte d t o refrai n fr o m stre n u o us p h y sical acti vit y w hic h c o ul d ca use 
m uscle ac hes or i nj ur y , i ncl u di n g c o ntact s p orts at a n y ti me fr o m t he scree ni n g visit u ntil 
c o m pleti o n of t he st u d y.
Acti vities s uc h as br us hi n g teet h or ot her ri nsi n g of t he m o ut h (e xce pt f or t he sc he d ule d m o ut h 
ri nse a p pr o xi matel y 3 0 mi n utes after eac h d osi n g) will n ot be all o we d f or 1 h o ur pri or t o a n d 
1 h o ur aft er eac h d osi n g.
7. 5
Criteri a f or Disc o nti n u ati o n or Wit h dr a w al of a P artici p a nt
T he pri mar y  reas o n f or disc o nti n uati o n or wit h dra wal of t he partici pa nt fr o m t he st u d y or st u d y 
dr u g s h o ul d be rec or de d i n t he case re p ort f or m ( C R F) usi n g t he f oll o wi n g cate g ori es:
1.
A E: T he partici pa nt has e x perie nce d a n A E t hat re q uires earl y ter mi nati o n beca use c o nti n ue d 
partici pati o n i m p oses a n u nacce pta ble ris k t o t he partici pa nt’s healt h or t he partici pa nt is 
u n willi n g t o c o nti n ue beca use of t he A E.
Li ver F u ncti o n Test ( L F T) A b n or malities: 
St u d y  dr u g s h o ul d be disc o nti n ue d i m me diatel y wit h a p pr o priate cli nical f oll o w- u p 
(i ncl u di n g re peat la b orat or y tests, u ntil a partici pa nt’s la b orat or y pr ofile has ret ur ne d t o 
n or mal/ ba seli ne stat us, see Secti o n 9. 2. 8 ), if t he f oll o wi n g circ u msta nces occ ur at a n y ti me 
d uri n g st u d y dr u g treat me nt: 

A L T or A S T > 8 × U L N, or 

A L T or A S T > 5 × U L N a n d persists f o r m ore t ha n 2 wee ks, or

A L T or A S T > 3 × U L N i n c o nj u ncti o n wit h ele vate d t otal bilir u bi n > 2 × U L N , or

A L T or A S T > 3 × U L N wit h a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or te n der ness, fe ver, ras h , a n d/ or e osi n o p hilia ( > 5 %).
2.
Si g nifi ca nt pr ot oc ol de viati o n: T he disc o ver y  p ost-e nr oll me nt t hat t he partici pa nt faile d t o 
meet pr ot oc ol e ntr y  criteria or di d n ot a d here t o pr ot oc ol re q uire me nts, a n d c o nti n ue d 
partici pati o n p oses a n u nacce pta ble ri s k t o t he partici pa nt’s healt h.
3.
L ost t o f oll o w- u p: Atte m pts t o c o ntact t he partici pa nts were u ns uccessf ul. Atte m pts t o 
c o ntact t he partici pa nt m ust be d oc u me nte d i n t he partici pa nt’s s o urce d oc u me nts.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 6 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
4.
V ol u ntar y  wit h dra wal: T he partici pa nt ( or partici pa nt’s le gally acce pta ble re prese ntati ve) 
wis hes t o wit h dra w fr o m t he st u d y . T he reas o n f or wit h dra wal, if pr o vi de d, s h o ul d be 
rec or de d i n the C R F.
N ote: All atte m pts s h o ul d be ma de t o deter mi ne t he u n derl yi n g reas o n f or t he wit h dra wal 
a n d, w here p ossi ble, t he pri mar y  u n derlyi n g reas o n s h o ul d be rec or de d ( ie, wit h dra wal d ue t o 
a n A E s h o ul d n ot be rec or de d i n t he “ v ol u ntar y  wit h dra wal” cate g or y). If a partici pa nt 
c h o oses t o wit h dra w fr o m st u d y partici pati o n d ue t o pers o nal c o ncer ns relate d t o t he 
C or o na vir us disease 2 0 1 9 ( C O VI D - 1 9) pa n de mic ( ot her t ha n a C O VI D - 1 9-relate d A E), t his 
s h o ul d be s pecifie d as t he reas o n f or partici pa nt wit h dra wal i n t he C R F.
5.
St u d y  ter mi nati o n: T he S p o ns or, instit uti o nal re vie w b oar d (I R B)/i n de pe n de nt et hics 
co m mittee (I E C), or re g ulat or y a ge nc y ter mi nates t he st u d y.
6.
Pre g na nc y : as descri be d i n A p pe n di x D.
7.
Partici pa nts ma y  be wit h dra w n fr o m t he st u d y b y t he In vesti gat or or desi g nee f or t he 
f oll o wi n g reas o ns: 

Di ffic ulties i n bl o o d c ollecti o n.

P ositi v e uri ne dr u g or alc o h ol test.
8.
Ot her . T he s pecific reas o ns f or disc o nti n uati o n s h o ul d be e ntere d i nt o t he C R F i ncl u di n g 
u na v oi da ble circ u msta nces s uc h as t he C O VI D -1 9 pa n de mic. Partici pa nts ma y  be wit h dra w n 
fr o m t he st u d y at a n y ti me at t he discreti o n of t he I n vesti gat or or S p o ns or f or safety reas o ns 
w hic h s h o ul d be e ntere d i nt o t he C R Fs.
7. 6
Pr oce d ures f or Disc o nti n u ati o n or Wit h dr a w al of a P artici p a nt
T he I n vesti gat or ma y  disc o nti n ue a partici pa nt’s st u d y partici pati o n at a n y ti me d uri n g t he st u d y 
w he n t he partici pa nt meets t he st u d y  ter mi nati on criteria descri be d i n Secti o n  7. 5 . In a d di ti o n, a 
partici pa nt ma y  disc o nti n ue his or her partici pati o n wit h o ut gi vi n g a reas o n at a n y ti me d uri n g
t he st u d y. S h o ul d a partici pa nt’s partici pati o n be disc o nti n ue d, t he pri mar y criteri o n f or 
ter mi nati o n m ust be rec or de d b y t he I n vesti gat or. I n a d diti o n, eff orts s h o ul d be ma de t o perf or m 
all pr oce d ures sc he d ule d f or t he e n d -of -st u d y or earl y ter mi nati o n as descri be d i n Secti o n  3. 0.
7. 7
P artici p a nt Re pl ace me nt
Re place me nt of disc o nti n ue d or wit h dra w n partici pa nts d ue t o a n y reas o n will be assesse d o n a 
case-b y - case basis by t he S p o ns or a n d I n vesti gat or.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 7 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
8. 0
C LI NI C A L S T U D Y M A T E R I A L M A N A G E M E N T
8. 1
Cli nic al St u d y Dr u g
Pr o d uct Na me:
B u des o ni de oral s us pe nsi o n ( B O S)
Stre n gt h:
0. 2 m g/ m L
D ose:
2 m g
D osa ge F or m/ F or m ulati o n:
Oral s us pe nsi o n
D osi n g re gi me n:
Si n gle d os e
R o ute of A d mi nistrati o n:
Oral
8. 1. 1
Cli nic al St u d y Dr u g L a beli n g
St u d y  dr u g c o ntai ners will be affi xe d wit h a cli nical la bel i n acc or da nce wit h l ocal re g ulat or y 
re q uire me nts.
8. 1. 2
Cli nic al St u d y Dr u g I n ve nt or y a n d St or a ge
T he S p o ns or will s u p pl y  s ufficie nt q ua ntities of t he st u d y dr u g t o all o w c o m pleti o n of t his st u d y.
T he sa me l ot n u m ber will be use d t hr o u g h o ut t he st u d y. T he l ot n u m bers a n d e x pirati o n dates 
( w here a vaila ble) of t he st u d y dr u g s u p plie d will be rec or de d i n t he fi nal re p ort. St u d y dr u g will 
be st ore d acc or di n g t o t he pr o d uct la bels pr o vi de d wit h t he pr o d uct.
Rec or ds will be ma de of t he recei pt, pre parati o n, dis pe nsi n g, a n d fi nal dis p ositi o n of t he st u d y  
dr u g s u p plie d.
8. 1. 3
Cli nic al St u d y Dr u g Bli n di n g
T his is a n o pe n -la bel st u d y.
8. 1. 4
R a n d o miz ati o n C o de Cre ati o n a n d St or a ge
A c o m p uterize d ra n d o mizati o n sc he me will be create d b y a Celeri o n statisticia n.
Treat me nts A a n d B will be ra n d o mize d t o 1 of 2 se q ue nces as i n dicate d i n Ta ble 8.a.
T a ble 8. a
R a n d o miz ati o n Se q ue nce
Se q ue nces
N u m ber of p artici p a nts ( N)
Peri o d 1
Peri o d 2
1
1 0
A
B
2
1 0
B
A
Treat me nt A = 2 m g B O S ( 1 0 m L of 0. 2 m g/ m L), fasti n g
Treat me nt B = 2 m g B O S ( 1 0 m L of 0. 2 m g/ m L), fe d, f oll o wi n g a hi g h -fat/ hi g h-cal orie meal.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 8 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
8. 1. 5
Cli nic al St u d y Bli n d M ai nte n a nce/ U n bli n di n g Pr oce d ure
N ot a p plica ble.
8. 1. 6
Acc o u nt a bilit y a n d Destr ucti o n of S p o ns or -S u p plie d Dr u gs
Rec or ds will be ma de of t he recei pt a n d dis pe nsi n g of t he st u d y dr u g s u p plie d. At t he c o ncl usi o n 
of t he st u d y, a n y u n use d st u d y dr u g will be retai ne d b y Celeri o n, ret ur ne d t o t he S p o ns or or 
desi g nee , or destr o ye d, as per S p o ns or i nstr ucti o ns. A n y  re mai ni n g s u p plies t hat were p urc hase d 
b y  Celeri o n will be destr o ye d, if a p pr o priate. If n o s u p plies re mai n, t his fact will be d oc u me nte d 
i n t he p har mac y pr o d uct acc o u nta bilit y rec or ds.
9. 0
S T U D Y P R O C E D U R E S
9. 1
A d mi nistr ati ve Pr oce d ures
9. 1. 1
I nf or me d C o nse nt Pr oce d ure
T he p ur p ose of t he st u d y , t he pr oce d ures t o be carrie d o ut a n d t he p ote ntial hazar ds will be 
descri be d t o t h e partici pa nts i n n o n-tec h nical ter ms. Partici pa nts will be re q uire d t o rea d, si g n, 
a n d date a n I CF s u m marizi n g t he disc ussi o n pri or t o scree ni n g, a n d will be ass ure d t hat t he y  ma y 
wit h dra w fr o m t he st u d y at a n y ti me wit h o ut je o par dizi n g t heir me dical care .
Partici pa nt s will be gi ve n a c o p y of t heir si g ne d I CF.
9. 1. 1. 1
Assi g n me nt of Scree ni n g a n d R a n d o miz ati o n N u m bers
Eac h partici pa nt will be assi g ne d a u ni q ue i de ntificati o n n u m ber u p o n t he scree ni n g visit . 
Partici pa nts w h o c o m plete t he st u d y  scree ni n g assess me nts a n d meet all t he eli gi bilit y criteria 
will be assi g ne d a u ni q ue ra n d o mizati o n i de ntificati o n n u m ber at t he ti me of t he first d osi n g, 
differe nt fr o m t he scree ni n g n u m ber, a n d will recei ve t he st u d y dr u g.
T he se q ue nces t o be use d i n t he ra n d o mizati o n will be A B a n d B A .
If re place me nt partici pa nts are use d , t he re place me nt partici pa nt n u m ber will be 1 0 0 m ore t ha n 
t he ori gi nal (e g, Partici pa nt N o. 1 0 1 will re place Partici pa nt N o. 1).
9. 1. 1. 2
St u dy Dr u g Assi g n me nt
All partici pa nts will recei ve t he treat me nts as detaile d i n Secti o n 9. 2. 6 .
9. 1. 2
I ncl usi o n a n d E xcl usi o n
Please refer t o Secti o n  7. 1 a n d Secti o n 7. 2.
9. 1. 3
Me dic al Hist or y/ De m o gr a p h y
Me dical hist or y  a n d de m o gra p hic data, i ncl u di n g na me, se x, a ge, race, et h nicit y, a n d hist or y of 
t o bacc o use will be rec or de d.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 2 9 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
9. 1. 4
C o nc o mit a nt M e dic ati o n s
C o nc o mita nt me dicati o ns will be pr o hi bite d as liste d i n Secti o n 7. 3 . All me dicati o ns ta ke n b y 
partici pa nts d uri n g t he c o urse of t he st u d y will be rec or de d.
9. 2
Cli nic al Pr oce d ures a n d Assess me nts
T he Sc he d ule of St u d y Pr oce d ures ( Secti o n 3. 0 ) s u m marizes t he cli nical pr oce d ures t o be 
perf or me d at eac h visit. I n di vi d ual cli nical pr oce d ures are descri be d i n detail bel o w. A d diti o nal 
e val uati o ns/testi n g ma y be dee me d necessar y b y t he In vesti gat or or desi g nee a n d/ or t he S p o ns or 
f or reas o ns relate d t o partici pa nt safety.
F or t his st u d y , c ollecti o n of bl o o d f or b u des o ni de P K is t he critical para meter a n d nee ds t o be 
c ollecte d as cl ose t o t he e xact ti me p oi nt as p ossi ble. All ot her pr oce d u res s h o ul d be c o m plete d 
as cl ose t o t he prescri be d/sc he d ule d ti me as p ossi ble, b ut ca n be perf or me d pri or t o or after t he 
prescri be d/sc he d ule d ti me.
A n y  n o n-sc he d ule d pr oce d ures re q uire d f or ur ge nt e val uati o n of safet y c o ncer ns ta ke prece de nce 
o ver all r o u ti ne sc he d ule d pr oce d ures.
9. 2. 1
F ull P h ysic al E x a m i n ati o n
F ull p h y sical e xa mi nati o ns will be perf or me d as o utli ne d i n t he Sc he d ule of St u d y Pr oce d ures 
( Secti o n 3. 0 ). A d diti o nal p h ysical e xa mi nati o ns ma y be perf or me d at ot her ti mes, if dee me d 
necessar y  b y t he I n vesti gat or or desi g nee.
9. 2. 2
Hei g ht a n d Wei g ht
B o d y hei g ht (c m) a n d wei g ht ( k g) will be re p orte d as o utli ne d i n t he Sc he d ule of St u d y 
Pr oce d ures ( Secti o n 3. 0 ).
9. 2. 3
B MI
B MI will be calc ulate d base d o n t he hei g ht a n d wei g ht meas ure d at t he scree ni n g visit.
9. 2. 4
Vit al Si g n s
Si n gle meas ure me nts of b o d y  te m perat ure, res pirat or y rate, bl o o d press ure, a n d p ulse rate will be 
meas ure d as o utli ne d i n t he Sc he d ule of St u d y Pr oce d ures ( Secti o n 3. 0 ). A d diti o nal vital si g ns 
ma y  be ta ke n at a n y ot her ti mes, if dee me d necessar y b y t he I n vesti gat or or desi g nee.
Bl o o d press ure a n d p ulse rate meas ure me nts will be perf or me d wit h partici pa nts i n a seate d 
p ositi o n, e xce pt w he n t he y are s u pi ne or se mi -recli ne d beca use of st u d y pr oce d ures a n d/ or A Es 
(e g, na usea, dizzi ness) or if dee me d necessar y  b y t he I n vesti gat or or desi g nee.
Vital si g ns will be meas ure d wit hi n 2 h o urs pri or t o d osi n g i n eac h peri o d. W he n sc he d ule d 
p ost d ose, vital si g ns will be perf or me d wit hi n a p pr o xi matel y 1 5 mi n ut es of t he sc he d ule d ti me 
p oi nt.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 0 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
9. 2. 5
1 2 - Le a d E C G
Si n gle 1 2 -lea d E C Gs will be perf or me d as o utli ne d i n t he Sc he d ule of St u d y Pr oce d ures 
( Secti o n 3. 0 ). A d diti o nal E C Gs ma y be ta ke n at a n y ot her ti mes, if dee me d necessar y b y t he 
I n vesti gat or or desi g nee.
E C Gs will be perf or me d wit h partici pa nts i n a s u pi ne p ositi o n. All E C G traci n gs will be 
re vie we d by t he I n vesti gat or or desi g nee.
9. 2. 6
St u d y D r u g A d mi nistr ati o n
B O S will be pr o vi de d as descri be d i n Secti o n 8. 1.
Treat me nts are descri be d i n  Ta ble 6.a.
T he p har mac y  at t he C R U will pr o vi de eac h d ose i n i n di vi d ual u nit d ose c o ntai ners f or eac h 
partici pa nt a n d f or eac h st u d y  peri o d, as per t he ra n d o mizati o n sc he d ule.
Eac h d ose of B O S will be a d mi nistere d o rall y wit h a p pr o xi matel y 2 4 0 m L  of water.
T he e xact cl oc k ti me of d osi n g will be rec or de d. H o ur 0 will be set as t he d osi n g ti me.
A q ualifie d desi g nee will be res p o nsi ble f or m o nit ori n g t he a d mi nistrati o n of t he ti me d oral 
d oses. A m o ut h c hec k will be perf or me d b y t he q ualifie d desi g nee t o e ns ure t hat t he partici pa nts 
ha ve s wall o we d t he st u d y dr u g. O nce a partici pa nt has fi nis he d t he d osi n g water, t he q ualifie d 
desi g nee will use a flas hli g ht a n d a t o n g ue de press or t o c hec k t he partici pa nt’s m o ut h.
A p pr o xi matel y  3 0 mi n utes after eac h d osi n g, all partici pa nts m ust ri nse t heir m o ut hs wit h 
a p pr o xi matel y 6 0 m L of r o o m te m perat ure water a n d s pit ( partici pa nts are n ot t o s wall o w t his 
ri nsi n g water).
9. 2. 7
A E M o nit ori n g
Partici pa nts will be m o nit ore d t hr o u g h o ut t he st u d y f or a d verse reacti o ns t o t he st u d y  dr u g a n d/ or 
pr oce d ures as descri be d i n Secti o n 1 0. 0.
9. 2. 8
L a b or at or y Pr oce d ures a n d Assess me nts
All tests liste d bel o w will be per f or me d as o utli ne d i n t he Sc he d ule of St u d y Pr oce d ures 
( Secti o n 3. 0 ). I n a d diti o n, la b orat or y safety tests ma y be perf or me d at vari o us u nsc he d ule d ti me 
p oi nts, if dee me d necessar y  b y t he I n vesti gat or or desi g nee.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 1 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
9. 2. 8. 1
Cli nic al L a b or at ory Tests
He m at ol o gy
He mat ol o g y  will c o nsist of t he f oll o wi n g tests:
H e m o gl o bi n
Re d bl o o d cell c o u nt
H e m at ocrit 
Platelet c o u nt
T otal a n d differe ntial le u k oc yte c o u nt
C he mistry
Ser u m c he mistr y  tests will be perf or me d after at least a n 8- h o ur fast; h o we ver, i n case of 
dr o p o uts or rec hec ks, partici pa nt s ma y  n ot ha ve faste d f or 8 h o urs pri or t o w he n t he ser u m 
c he mistr y sa m ple bei n g ta ke n.
Ser u m c he mistr y  e val uati o ns will co nsist of t he f oll o wi n g sta n dar d c he mistr y pa nel:
Al b u mi n
S o di u m
Bl o o d Urea Nitr o ge n
P otassi u m
Bilir u bi n (t otal a n d direct)
C hl ori de
A L P
Gl uc ose (fasti n g)
A S T
Creati ni ne *
A L T
* At scree ni n g, creati ni ne cleara nce will be calc ulate d usi n g t he C oc kcr oft -Ga ult f or m ula.
Uri n alysis
Uri nal y sis will c o nsist of t he f oll o wi n g tests:
p H
Bilir u bi n
S pecific gra vit y
Bl o o d *
Pr otei n *
Nitrite *
Gl uc ose
Ur o bili n o ge n
Ket o nes
Le u k oc yte esterase *
* If uri nal ysis is a b n or mal f or pr otei n, bl o o d, nitrite a n d/ or le u k oc yte esterase, a micr osc o pic e xa mi nati o n (f or re d 
bl o o d cells, w hite bl o o d cells, bacteria, casts, a n d e pit helial cells) will be perf or me d.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 2 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
Ot her
HI V test
Uri ne dr u g scree n
O piates (i ncl u des m or p hi ne, her oi n [ diacet yl m or p hi ne], 
c o dei ne, 6- acet yl m or p hi ne, di h y dr oc o dei ne, h y dr oc o d o ne, 
t he bai ne, a n d, h y dr o m or p h o ne)
A m p heta mi nes
Bar bit urates
Be nz o diaze pi nes
C ocai ne
Ca n na bi n oi ds
H Bs A g
H C V
Uri ne alc o h ol scree n
Ser u m pre g na nc y test (f or fe males o nl y)
F S H (f or p ost me n o pa usal fe males o nl y)
C O VI D -1 9 (se vere ac ute res pirat or y s y n dr o me -
c or o na vir us -2 p ol y merase c hai n reacti o n test or 
e q ui vale nt), t o be perf or me d as per C R U 
re q uire me nts
9. 3
P K S a m ples
Sa m ples f or b u des o ni de P K assess me nt will be c ollecte d as o utli ne d i n t he Sc he d ule of St u d y  
Pr oce d ures ( Secti o n 3. 0 ).
I nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, a n d s hi p pi n g will be pr o vi de d se paratel y.
Pri mar y  s peci me n c ollectio n para meters are pr o vi de d i n  Ta ble 9.a.
T a ble 9. a
Pri m ar y S peci me n C ollecti o ns
S peci me n N a me
Pri m ar y 
S peci me n
Pri m ar y 
S peci me n 
Deri v ati ve
Descri pti o n of I nte n de d Use
S a m ple 
C ollecti o n
Plas ma sa mple f or P K
Bl o o d
Plas ma
Plas ma sa m ple f or P K a nal ysis
Ma n dat or y
9. 3. 1
P K Me as ure me nts
Sa m ples fr o m all partici pa nts will be assa ye d e ve n if t he partici pa nts d o n ot c o m plete t he st u d y. 
Sa m ples f or deter mi nati o n of plas ma b u des o ni de will be a nal yz e d usi n g vali date d bi oa nal yt ical 
met h o ds.
P har mac o ki netic para meters of b u des o ni de will be calc ulate d fr o m t he i n di vi d ual 
c o nce ntrati o n -ti me pr ofiles fr o m all e val ua ble partici pa nts usi n g N C A met h o ds. Act ual sa m pli n g 
ti mes, rat her t ha n sc he d ule d sa m pli n g ti mes, will be use d i n all c o m p utati o ns i n v ol vi n g sa m pli n g 
ti mes.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 3 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
9. 3. 1. 1
Pl as m a f or P K Me as ure me nts
T he f oll o wi n g P K para meters will be calc ulate d fr o m plas ma c o nce ntrati o ns of b u des o ni de , 
u nless ot her wise s pecifie d:
A U C last:
Area u n der t he c o nce ntrati o n -ti me c ur ve, fr o m ti me 0 t o t he last 
q ua ntifia ble c o nce ntrati o n.
A U C :
Area u n der t he c o nce ntrati o n -ti me c ur ve, fr o m ti me 0 t o i nfi nit y , 
calc ulate d usi n g t he o bser ve d val ue of t he last q ua ntifia ble c o nce ntrati o n.
A U C 0- 1 2:
Area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 1 2 h o urs.
A U C e xtra p%:
Area u n der t he c ur ve fr o m t he last q ua ntifia ble c o nce ntrati o n t o i nfi nit y  
calc ulate d usi n g t he o bser ve d val ue of t he last q ua ntifia ble c o nce ntrati o n, 
e x presse d as a perce nta ge of A U C .
C L / F:
A p pare nt cleara nce after e xtra vasc ular a d mi nistrati o n, calc ulate d usi n g 
t he o bser ve d val ue of t he last q ua ntifia ble c o nce ntrati o n.
C ma x :
Ma xi m u m o bser ve d c o nce ntrati o n.
tma x :
Ti me of first occ urre nce of C ma x .
tla g:
La g ti me t o first q ua ntifia ble c o nce ntrati o n .
t1/ 2z:
Ter mi nal dis p ositi o n p hase half -life.
λ z:
Ter mi nal dis p ositi o n p hase rate c o nsta nt.
V z/ F:
A p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal dis p ositi o n p hase 
after e xtra vasc ular a d mi nistrati o n, calc ulate d usi n g t he o bser ve d val ue of 
t he last q ua ntifia ble c o nce ntrati o n.
N o val ue f or λ z, A U C, A U Ce xtra p%, C L / F, Vz/ F, or t1/ 2 z will be re p orte d f or cases t hat d o n ot 
e x hi bit a ter mi nal l o g -li near p hase i n t he c o nce ntrati o n-ti me pr ofile.
P K para meters will n ot be calc ulate d f or partici pa nt s wit h less t ha n 3 c o nsec uti ve p ost d ose ti me 
p oi nts wit h q ua ntifia ble c o nce ntrati o ns .
I n di vi d ual a n d mea n plas ma c o nce ntrati o n c ur ves ( b ot h li near a n d l o g- li near) will be i ncl u de d i n 
t he fi nal re p ort.
9. 3. 2
Bi o m ar ker Me as ure me nts
N ot a p plica ble.
9. 3. 3
P G x Me as ure me nts
N ot a p plica ble.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 4 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
9. 3. 4
C o nfi ne me nt
Partici pa nts will be h o use d o n Da y  -1 of Peri o d 1, at t he ti me i n dicate d b y  t he C R U, u ntil after 
t he 2 4- h o ur bl o o d dra w a n d/ or st u d y pr oce d ures o n Da y 2 of Peri o d 2. Partici pa nts ma y  be 
a d mitte d earlier t ha n D a y -1 of Peri o d 1 f or C O VI D -1 9 testi n g n ot relate d t o st u d y  pr ot oc ol as 
per C R U re q uire me nts.
At all ti mes, a partici pa nt ma y  be re q uire d t o re mai n at t he C R U f or l o n ger at t he discreti o n of 
t he In vesti gat or or desi g nee.
1 0. 0  
A D V E R S E E V E N T S
1 0. 1
Defi niti o ns a n d Ele me nts of A Es
A n A E is defi ne d as a n y u nt o war d me dical occ urre nce i n a cli nical i n vesti gati o n partici pa nt w h o 
has si g ne d i nf or me d c o nse nt t o partici pate i n a st u d y ; it d oes n ot necessaril y ha ve t o ha ve a 
ca usal relati o ns hi p wit h t he treat me nt.
A n A E ca n t heref ore be a n y  u nfa v ora ble a n d u ni nte n de d si g n (e g, a cli nicall y si g nifica nt 
a b n or mal la b orat or y fi n di n g), sy m pt o m, or disease te m p orall y ass ociate d wit h t he use of a dr u g, 
w het her or n ot it is c o nsi dere d relate d t o t he dr u g.
A n u nt o war d fi n di n g ge nerall y ma y:

I n dicate a ne w dia g n osis or u ne x pecte d w orse ni n g of a pree xisti n g c o n diti o n. (I nter mitte nt 
e ve nts f or pre-e xisti n g c o n diti o ns or u n derl y i n g disease s h o ul d n ot be c o nsi dere d A Es.)

Necessitate t hera pe utic i nter ve nti o n.

Re q uire a n i n vasi ve dia g n ostic pr oce d ure.

Re q uire disc o nti n uati o n or a c ha n ge i n d ose of st u d y  dr u g or a c o nc o mita nt me dicati o n.

Be c o nsi dere d u nfa v ora ble b y  t he In vesti gat or f or a n y  reas o n.
Dia g n oses v ers us si g ns a n d s ym pt o ms:

Eac h e ve nt s h o ul d be rec or de d t o re prese nt a si n gle dia g n osis. Acc o m pa n yi n g si g ns 
(i ncl u di n g a b n or mal la b orat or y val ues or E C G fi n di n gs) or sy m pt o ms s h o ul d N O T be 
rec or de d as a d diti o nal A Es. If a dia g n osis is u n k n o w n, si g n(s) or sy m pt o m(s) s h o ul d be 
rec or de d a p pr o priately as a n A E(s).
La b orat or y  val ues a n d E C G fi n di n gs:

C ha n ges i n la b orat or y  val ues or E C G para meters ma ybe c o nsi dere d A Es if t he y  are j u d ge d t o 
be cli nicall y  si g nifica nt (ie, if s o me acti o n or i nter ve nti o n is re q uire d or if t he In vesti gat or 
j u d ges t he c ha n ge t o be be yo n d t h e ra n ge of n or mal p h y si ol o gic fl uct uati o n). A la b orat or y 
re-test a n d/ or c o nti n ue d m o nit ori n g of a n a b n or mal val ue are n ot c o nsi dere d a n i nter ve nti o n. 
I n a d diti o n, re peate d or a d diti o nal n o n-i n vasi ve testi n g f or verificati o n, e val uati o n or 
m o nit ori n g of a n a b n or malit y is n ot c o nsi dere d a n i nter ve nti o n.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 5 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L

If a b n or mal la b orat or y val ues or E C G fi n di n gs are t he res ult of pat h ol o g y f or w hic h t here is 
a n o verall dia g n osis (e g, i ncrease d creati ni ne i n re nal fail ure), t he dia g n osis o nl y  s h o ul d be 
re p orte d a p pr o priately as a n A E.
Pre -e xisti n g c o n diti o ns:

A pre - e xisti n g c o n diti o n ( prese nt at t he ti me of si g ni n g of i nf or me d c o nse nt) is c o nsi dere d a 
c o nc urre nt me dical hist or y c o n diti o n a n d s h o ul d N O T be rec or de d as a n A E. A baseli ne 
e val uati o n (e g, la b orat or y test, X -ra y, etc.) s h o ul d N O T be rec or de d as a n A E u nless relate d 
t o a st u d y pr oce d ure. H o we ver, if t he partici pa nt e x perie nces a w orse ni n g or c o m plicati o n of 
s uc h a c o nc urre nt me dical hist or y c o n diti o n, t he w orse ni n g or c o m plicati o n s h o ul d be 
rec or de d a p pr o priately as a n A E ( w orse ni n g or c o m plicati o n occ urs after i nf or me d c o nse nt is 
si g ne d). I n vesti gat ors s h o ul d e ns ure t hat t he e ve nt ter m rec or de d ca pt ures t he c ha n ge i n t he 
c o n diti o n (e g, “ w orse ni n g of …”).

If a partici pa nt has a pre -e xisti n g e pis o dic c o n diti o n (e g, ast h ma  e pile ps y) , a n y occ urre nce of 
a n e pis o de s h o ul d o nl y be ca pt ure d as a n A E if t he e pis o des bec o me m ore fre q ue nt, seri o us, 
or se vere i n nat ure, t hat is, I n vesti gat ors s h o ul d e ns ure t hat t he A E ter m rec or de d ca pt ures t he 
c ha n ge fr o m b aseli ne i n t he c o n dit i o n (e g “ w orse ni n g of …”).

If a partici pa nt has a de ge nerati ve c o nc urre nt c o n diti o n (e g, cataracts, r he u mat oi d art hritis), 
w orse ni n g of t he c o n diti o n s h o ul d o nl y  be ca pt ure d as a n A E if occ urri n g t o a greater e xte nt 
t o t hat w hic h w o ul d be e x pecte d. A gai n, In vesti gat ors s h o ul d e ns ure t hat t he A E ter m 
rec or de d ca pt ures t he c ha n ge i n t he c o n diti o n (e g, “ w orse ni n g of …”).
W o rse ni n g of A Es:

If t he partici pa nt e x perie nces a w orse ni n g or c o m plicati o n of a n A E after t he first 
a d mi nistrati o n of st u d y dr u g or after a n y c ha n ge i n st u d y dr u g , t he w orse ni n g or 
c o m plicati o n s h o ul d be rec or de d as a ne w A E. I n vesti gat ors s h o ul d e ns ure t hat t he A E ter m 
rec or de d ca pt ures t he c ha n ge i n t he c o n diti o n (e g, “ w orse ni n g of …”).
C ha n ges i n se verit y of A Es:

If t he partici pa nt e x perie nce s a c ha n ge i n t he se verit y of a n A E t hat is n ot ass ociate d wit h a 
c ha n ge i n st u d y dr u g , t he e ve nt s h o ul d be ca pt ure d o nce wit h t he ma xi m u m se verity 
rec or de d.
Pre pla n ne d s ur geries or pr oce d ures:

Pre pla n ne d pr oce d ures (s ur geries or t hera pies) t hat were sc he d ule d pri or t o si g ni n g of 
i nf or me d c o nse nt are n ot c o nsi dere d A Es. H o we ver, if a pre pla n ne d pr oce d ure is perf or me d 
earl y (e g, as a n e mer ge nc y) d ue t o a w orse ni n g of t he pre -e xisti n g c o n diti o n, t he w orse ni n g 
of t he c o n diti o n s h o ul d be ca pt ure d a p pr o priatel y as a n A E. C o m plicati o ns res ulti n g fr o m 
a n y pla n ne d s ur ger y s h o ul d be re p orte d as A Es.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 6 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
Ele cti ve s ur geries or pr oce d ures:

Electi ve pr oce d ures perf or me d w here t here is n o c ha n ge i n t he partici pa nt’s me dical 
c o n diti o n s h o ul d n ot be rec or de d as A Es b ut s h o ul d b e d oc u me nte d i n t he partici pa nt’s
s o urce d oc u me nts. C o m plicati o ns res ulti n g fr o m a n electi ve s ur ger y s h o ul d be re p orte d as 
A Es.
O ve r d ose:

A n o ver d ose is defi ne d as a k n o w n deli berate or acci de ntal a d mi nistrati o n of st u d y dr u g, t o 
or b y  a st u d y partici pa nt , at a d ose a b o ve t hat w hic h is assi g ne d t o t hat i n di vi d ual partici pa nt
acc or di n g t o t he st u d y pr ot oc ol. I t is u p t o t he In vesti gat or or t he re p orti n g p h y sicia n t o 
deci de w het her a d ose is t o be c o nsi dere d a n o ver d ose, i n c o ns ultati o n wit h t he S p o ns or.

All cases of o ver d ose ( wit h or wit h o ut ass ociate d A Es) will be d oc u me nte d o n a n O ver d ose 
pa ge of t he C R F, i n or der t o ca pt ure t his i m p orta nt safet y i nf or mati o n c o nsiste ntl y i n t he 
data base. A Es ass ociate d wit h a n o ver d ose will be d oc u me nte d o n A E C R F(s) acc or d i n g t o 
Secti o n 1 0. 0 .

Seri o us a d verse e ve nts ( S A Es) of o ver d ose s h o ul d be re p orte d acc or di n g t o t he pr oce d ure 
o utli ne d i n Secti o n 1 0. 2. 8 .

I n t he e ve nt of dr u g o ver d ose, t he partici pa nt s h o ul d be treate d sy m pt o maticall y .
1 0. 1. 1 S A Es
A n S A E is defi ne d as a n y u nt o war d me dical occ urre nce t hat at a n y d ose:
1.
Res ults i n D E A T H.
2.
Is LI F E T H R E A T E NI N G.

T he ter m “life t hreate ni n g” refers t o a n e ve nt i n w hic h t he partici pa nt was at ris k of deat h 
at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat h y p ot heticall y mi g ht ha ve 
ca use d deat h if it were m ore se vere.
3.
Re q uires i n patie nt H O S PI T A LI Z A TI O N or p r ol o n gati o n of e xisti n g h os pitalizati o n.
4.
Res ults i n persiste nt or si g nifica nt DI S A BI LI T Y/I N C A P A CI T Y.
5.
Is a C O N G E NI T A L A N O M A L Y/ BI R T H D E F E C T.
6.
Is a n I M P O R T A N T M E DIC A L  E V E N T t hat satisfies a ny of t he f oll o wi n g:

Ma y  re q uire i nter ve nti o n t o pre ve nt ite ms 1 t hr o u g h 5 a b o ve.

Ma y  e x p ose t he partici pa nt t o da n ger, e ve n t h o u g h t he e ve nt is n ot i m me diatel y life 
t hreate ni n g or fatal or d oes n ot res ult i n h os pitalizati o n.

I ncl u des a n y e ve nt or s y n o n y m descri be d i n t he Ta ke da Me dicall y  Si g nifica nt A E List 
(Ta ble 1 0.a ).
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 7 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
T a ble 1 0 .a
T a ke d a Me dic all y Si g nific a nt A E List
Ter m
Ac ute res pirat or y fail ure/ac ute res pirat or y 
distress s y n dr o me
He patic necr osis
Ac ute li ver fail ure
T orsa de de p oi ntes / ve ntric ular fi brillati o n / 
ve ntric ular tac h ycar dia
A na p h ylactic s h oc k
Ac ute re nal fail ure
Mali g na nt h y perte nsi o n
P ul m o nar y h y perte nsi o n
C o n v ulsi ve seiz ures
P ul m o nar y fi br osis
A gra n ul oc yt osis
C o nfir me d or s us pecte d e n d ot o xi n s h oc k
A plastic a ne mia
C o nfir me d or s us pecte d tra ns missi o n of i nfecti o us a ge nt 
b y a me dici nal pr o d uct
T o xic e pi der mal necr ol ysis/
Ste ve ns -J o h ns o n s y n dr o me
Ne ur ole ptic mali g na nt s y n dr o me / ma li g na nt 
h y pert her mia
C O VI D -1 9 -relate d disease
C O VI D -1 9 p ne u m o nia
S p o nta ne o us a b orti o n / still birt h a n d fetal deat h
A b bre viati o ns: C O VI D -1 9 = C or o na vir us disease 2 0 1 9 .
A Es t hat f ulfill 1 or m ore of t he seri o us criteria a b o ve are t o be c o nsi dere d S A Es a n d s h o ul d be 
re p orte d a n d f oll o we d u p i n t he sa me ma n ner (see Secti o ns 1 0. 1 a n d 1 0. 1. 1 ).
1 0. 1. 2 A d verse E ve nts of S peci al I nterest
Si nce B O S is a gl uc oc ortic oster oi d, ge neral war ni n gs c o ncer ni n g gl uc oc ortic oi ds s h o ul d be 
f oll o we d.
I m p orta nt i de ntifie d ris ks i ncl u de:

H y perc ortis olis m a n d adre nal s u p pressi o n .

I ncrease d ris k of i nfecti o n .

Ot her g l uc oc ortic oi d effects i ncl u di n g fract ures, h y perte nsi o n, dia betes mellit us, 
oste o p or osis, pe ptic ulcer, gla uc o ma , or cataracts .

Gastr oi ntesti nal s ym pt o ms relate d t o c ortic oster oi d use .
1 0. 2
A E Pr oce d ures
1 0. 2. 1 Assi g ni n g Se verit y/I nte nsit y of A Es
T he differe nt cate g ories of se verit y/ i nte nsit y are:
Mil d:
A n A E t hat is us uall y tra nsie nt a n d ma y re q uire o nl y mi ni mal treat me nt or 
t hera pe utic i nter ve nti o n. T he e ve nt d oes n ot ge nerall y i nterfere wit h us ual 
acti vities of dail y li vi n g.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 8 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
M o derate:
A n A E t hat is us uall y alle viate d wit h a d diti o nal s pecific t hera pe utic 
i nter ve nti o n. T he e ve nt i nterferes wit h us ual acti vities of dail y li vi n g, 
ca usi n g disc o mf ort b ut p oses n o si g nifica nt or per ma ne nt ris k of har m t o t he 
researc h partici pa nt.
Se vere:
A n A E t hat i nterr u pts us ual acti vities of dail y li vi n g, or si g nifica ntl y affects 
cli nical stat us, or ma y re q uire i nte nsi ve t hera pe utic i nter ve nti o n.
1 0. 2. 2 Assi g ni n g C a us alit y of A Es
T he relati o ns hi p of eac h A E t o st u d y  dr u g (s) will be assesse d usi n g t he f oll o wi n g cate g ories:
Relate d:
A n A E t hat f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of a 
dr u g (i ncl u di n g t he c o urse after wit h dra wal of t he dr u g), or f or w hic h a 
ca usal relati o ns hi p is at le ast a reas o na ble p ossi bilit y, ie, t he relati o ns hi p 
ca n n ot be r ule d o ut , alt h o u g h fact ors ot her t ha n t he dr u g, s uc h as u n derl yi n g 
dis eases, c o m plicati o ns, c o nc o mita nt dr u gs a n d c o nc urre nt treat me nts, ma y 
als o be res p o nsi ble.
N ot Relate d:
A n A E t hat d oes n ot f oll o w a reas o na ble te m p oral se q ue nce fr o m 
a d mi nistrati o n of a dr u g a n d/ or t hat ca n reas o na bl y be e x plai ne d b y  ot her 
fact ors, s uc h as u n derlyi n g diseases, c o m plicati o ns, c o nc o mita nt me dicati o ns
a n d c o nc urre nt treat me nts.
I n a d diti o n, relati o ns hi p (ca usalit y) t o C O VI D-1 9 s h o ul d be deter mi ne d f or all A Es. T he 
relati o ns hi p s h o ul d be assesse d as relate d if t he I n vesti gat or c o nsi ders t hat t here is reas o na ble 
p ossi bilit y  t hat a n e ve nt is d ue t o C O VI D-1 9. Ot her wise, t he relati o ns hi p s h o ul d be assesse d as 
n ot relate d.
Si milarl y , relati o ns hi p (ca usalit y) t o C O VI D-1 9 vacci nes s h o ul d be deter mi ne d f or all A Es. T he 
relati o ns hi p s h o ul d be assesse d as relate d if t he I n vesti gat or c o nsi ders t hat t here is reas o na ble 
p ossi bilit y  t hat a n e ve nt is d ue t o C OVI D- 1 9 vacci nes. Ot her wise, t he relati o ns hi p s h o ul d be 
assesse d as n ot relate d. If t he A E has relati o ns hi p t o vacci nati o n, s pecific ver bati m ter m s h o ul d 
be use d, e g, p ost - vacci nati o n fe ver, vacci nati o n site b ur ni n g.
I n a d diti o n, if t he ca usalit y assess me nt d o ne b y  t he I n vesti gat or deter mi nes t hat t he e ve nt or 
e ve nts ( A Es) are relate d or p ossi ble relate d t o C O VI D - 1 9 or t he C O VI D- 1 9 vacci ne, t he e ve nts 
s h o ul d be assesse d as n ot relate d t o t he st u dy dr u g. If t he A E is relate d t o C O VI D - 1 9 
vacci nati o n, s pecific ver bati m ter m(s) s h o ul d be use d, e g, p ost -vacci nati o n fe ver, vacci nati o n site 
b ur ni n g.
1 0. 2. 3 St art D ate
T he start date of t he A E is t he date t hat t he first si g ns/s y m pt o ms were n ote d b y  t he partici pa nt
a n d/ or I n vesti gat or.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 3 9 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1 0. 2. 4 E n d D ate
T he e n d date of t he A E is t he d ate at w hic h t he partici pa nt rec o vere d, t he e ve nt res ol ve d b ut wit h 
se q uelae or t he partici pa nt die d.
1 0. 2. 5 P atter n of A E ( Fre q ue nc y )
Si n gle A Es (e g, v o mit) are t h ose w hic h occ ur i nsta nta ne o usl y. E pis o dic A Es (e g, hea dac he) or 
t h ose w hic h occ ur re peate dl y o ver a peri o d of c o nsec uti ve da ys are i nter mitte nt. C o nti n u o us A Es 
(e g, si n us c o n gesti o n) occ ur wit h o ut i nterr u pti o n o ver a s pecifie d peri o d.
1 0. 2. 6 Acti o n T a ke n Wit h St u d y Tre at me nt

Dr u g wit h dra w n – a st u d y dr u g is st o p pe d d ue t o t he partic ular A E.

D ose n ot c ha n ge d – t he partic ular A E di d n ot re q uire st o p pi n g a st u d y dr u g.

U n k n o w n – o nl y  t o be use d if it has n ot bee n p ossi ble t o deter mi ne w hat acti o n has bee n 
ta ke n.

N ot a p plica ble – a st u d y dr u g was st o p pe d f or a reas o n ot her t ha n t he partic ular A E e g, t he 
st u d y has bee n ter mi nate d, t he partici pa nt die d, d osi n g wit h st u d y  dr u g ha d n ot y et starte d or 
d osi n g wit h st u d y dr u g was alre a d y st o p pe d bef ore t he o nset of t he A E.

D ose re d uce d – t he d ose was re d uce d d ue t o t he partic ular A E.

Dr u g i nterr u pte d – t he d ose was i nterr u pte d d ue t o t he partic ular A E.
1 0. 2. 7 O utc o me 

Rec o vere d/res ol ve d – partici pa nt ret ur ne d t o first assess me nt stat us wit h res pect t o t he A E.

Rec o veri n g/res ol vi n g – t he i nte nsit y is l o were d b y o ne or m ore sta ges: t he dia g n osis has or 
si g ns/s ym pt o ms ha ve al m ost disa p peare d; t he a b n or mal la b orat or y  val ue i m pr o ve d, b ut has 
n ot ret ur ne d t o t he n or mal ra n ge or t o t he baseli ne val ue ; t he partici pa nt die d fr o m a ca use 
ot h er t ha n t he partic ular A E wit h t he c o n diti o n re mai ni n g “rec o veri n g/res ol vi n g .”

N ot rec o vere d/ n ot res ol ve d – t here is n o c ha n ge i n t he dia g n osis, si g ns or s ym pt o ms; t he 
i nte nsit y of t he dia g n osis, si g ns/s ym pt o ms or la b orat or y  val ue o n t he last da y of t he o bser ve d 
st u d y peri o d has bec o me w orse t ha n w he n it starte d; is a n irre versi ble c o n ge nital a n o mal y;  
t he partici pa nt die d fr o m a n ot her ca use wit h t he partic ular A E state re mai ni n g “ N ot 
rec o vere d/ n ot res ol ve d.”

Rec o vere d/r es ol ve d wit h se q uelae – t he partici pa n t rec o vere d fr o m a n ac ute A E b ut was left 
wit h per ma ne nt/si g nifica nt i m pair me nt (e g, rec o vere d fr o m a car di o vasc ular acci de nt b ut 
wit h s o me persisti n g paresis ).

Fatal – a n A E t hat is c o nsi dere d as t he ca use of deat h.

U n k n o w n – t he c o urse of t he A E ca n n ot be f oll o we d u p d ue t o h os pital c ha n ge or resi de nce 
c ha n ge at t he e n d of t he partici pa nt’s partici pati o n i n t he st u d y .
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 0 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1 0. 2. 8
C ollecti o n a n d Re p orti n g of A Es, S A Es, S peci al I nterest A Es, a n d A b n or m al L F Ts
1 0. 2. 8. 1 C ollecti o n Peri o d
C ollecti o n of A Es (ie, A Es, S A Es, S pecial I nterest A Es, a n d a b n or mal L F Ts) will c o m me nce at 
t he ti me t he partici pa nt si g ns t he i nf or me d c o nse nt. R o uti ne c ollecti o n of A Es will c o nti n ue u ntil 
t he f oll o w-u p visit, a p pr o xi matel y  3 d a y s after t he last d ose of st u d y dr u g. F or partici pa nt s w h o 
disc o nti n ue pri or t o t he a d mi nistrati o n of st u d y dr u g , A Es will be f oll o we d u ntil t he partici pa nt 
di sc o nti n ues st u d y partici pati o n.
1 0. 2. 8. 2 Re p orti n g A E s
At eac h st u d y visit, t he In vesti gat or will assess w het her a n y s u bjecti ve A Es ha ve occ urre d. A 
ne utral q ues ti o n, s uc h as “ H o w ha ve yo u bee n feeli n g si nce y o ur last visit?” ma y  be as ke d. 
Partici pa nt s ma y  re p ort A Es occ urri n g at a n y ot her ti me d uri n g t he st u d y. Partici pa nt s 
e x perie nci n g an S A E pri or t o t he first e x p os ure t o t he st u d y dr u g m ust be m o nit ore d u ntil t he 
s ym pt o ms s u bsi de a n d a n y  cli nicall y rele va nt c ha n ges i n la b orat or y val ues ha ve ret ur ne d t o 
baseli ne or t here is a satisfact or y  e x pla nati o n f or t he c ha n ge. N o n-seri o us A Es t hat be gi n pri or t o 
t he first e x p os ure t o t he st u d y dr u g, relate d or u nrelate d t o t he st u d y pr oce d ure, nee d n ot be 
f oll o we d- u p f or t he p ur p oses of t he pr ot oc ol.
All partici pa nts e x perie nci n g A Es, w het her c o nsi dere d ass ociate d wit h t he use of t he st u d y  dr u g 
or n ot, m ust be m o nit ore d u ntil t he s y m pt o ms s u bsi de a n d a n y  cli nically rele va nt c ha n ges i n 
la b orat or y val ues ha ve ret ur ne d t o baseli ne or u ntil t here is a satisfact or y e x pla nati o n f or t he 
c ha n ges o bser ve d. All A Es will be d oc u me nte d i n t he A E pa ge of t he C R F, w het her or n ot t he 
I n vesti gat or c o ncl u des t hat t he e ve nt is relate d t o t he st u d y dr u g. T he f oll o w i n g i nf or mati o n will 
be d oc u me nte d f or eac h e ve nt:

E ve nt ter m .

Start a n d e n d date a n d ti me .

Patter n of A E (fre q ue nc y).

Se verit y /Inte nsit y .

Ca usalit y  (I n vesti gat or’s o pi ni o n of t he ca usal relati o ns hi p bet wee n t he e ve nt a n d 
a d mi nistrati o n of st u d y  dr u g).

Relati o ns hi p t o C O VI D- 1 9.

Relati o ns hi p t o C O VI D- 1 9 vacci ne.

Acti o n ta ke n wit h st u d y  dr u g.

O utc o me of e ve nt .

Seri o us ness .
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 1 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1 0. 2. 8. 3 Re p orti n g S A Es
W he n a n S A E occ urs t hr o u g h t he A E c ollecti o n peri o d it s h o ul d be re p orte d acc or di n g t o t he
pr oce d ure o utli ne d bel o w:
A Ta ke da S A E f or m m ust be c o m plete d, i n E n glis h a n d si g ne d b y  t he In vesti gat or i m me diatel y 
or wit hi n 2 4 h o urs of first o nset or n otificati o n of t he e ve nt. T he i nf or mati o n s h o ul d be 
c o m plete d as f ull y as p ossi ble b ut c o ntai n, at a mi ni m u m:

A s h ort descri pti o n of t he e ve nt a n d t he reas o n w h y t he e ve nt is cate g orize d as seri o us.

P artici pa nt i de ntificati o n n u m ber.

I n vesti gat or’s na me.

Na me of t he st u d y dr u g (s).

Ca usalit y  assess me nt.
T he S A E f or m s h o ul d be tra ns mitte d wit hi n 2 4 h o urs t o t he atte nti o n of t he c o ntact liste d i n 
Secti o n 1 4. 1. 1 .
A n y  S A E s p o nta ne o usl y re p orte d t o t he In vesti gat or f oll o wi n g t he A E c ollecti o n peri o d s h o ul d 
be re p orte d t o t he S p o ns or if c o nsi dere d relate d t o st u d y partici pati o n.
Re p orti n g of S A Es t hat be gi n bef ore first a d mi nistrati o n of st u d y  dr u g will f oll o w t he sa me 
pr oce d ure f or S A Es occ urri n g o n treat me nt.
S A E F ol l o w-U p
If i nf or mati o n is n ot a vaila ble at t he ti me of t he first re p ort bec o mes a vaila ble at a later date, t he 
In vesti gat or s h o ul d c o m plete a f oll o w -u p S A E f or m or pr o vi de ot her writte n d oc u me ntati o n a n d 
fa x it i m me diatel y wit hi n 2 4 h o urs of recei pt. C o pies of a n y rele va nt data fr o m t he h os pital n otes 
(e g, E C Gs, la b orat or y tests, disc har ge s u m mar y, p ost m orte m res ults) s h o ul d be se nt t o t he 
a d dressee, if re q ueste d.
All S A Es s h o ul d be f oll o we d u p u ntil res ol uti o n or per ma ne nt o utc o me of t he e ve nt. T he 
ti meli nes a n d pr oce d ure f or f oll o w- u p re p orts are t he sa me as t h ose f or t he i nitial re p ort.
1 0. 2. 8. 4 Re p orti n g S peci al I nterest A Es
R o uti ne c ollecti o n of A Es of s pecial i nterest is n ot ma n dat or y  f or t he p ur p oses of t his st u d y.
1 0. 2. 8. 5 Re p orti n g of A b n or m al L F Ts
If a partici pa nt is n ote d t o ha ve A L T or A S T ele vate d > 3 × U L N o n 2 c o nsec uti ve occasi o ns, t he 
a b n or malit y s h o ul d be rec or de d as a n A E. I n a d diti o n, a n L F T I ncreases C R F m ust be c o m plete d 
pr o vi di n g a d diti o nal i nf or mati o n o n rele va nt rece nt hist or y , ris k fact ors, cli nical si g ns a n d 
s ym pt o ms a n d res ults of a n y  a d diti o nal dia g n ostic tests perf or me d.
If a p artici pa nt is n ote d t o ha ve A L T or A S T > 3 × U L N a n d t otal bilir u bi n > 2 × U L N f or w hic h a n 
alter nati ve eti ol o g y has n ot bee n i de ntifie d, t he e ve nt s h o ul d be rec or de d as a n S A E a n d re p orte d 
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 2 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
as per Secti o n  1 0. 2. 8. 3 . T he I n vesti gat or m ust c o ntact t he Me dical M o nit or f or disc ussi o n of t he 
rele va nt partici pa nt details a n d p ossi ble alter nati ve eti ol o gies, s uc h as ac ute viral he patitis A or B 
or ot her ac ute li ver disease. F oll o w- u p la b orat or y  tests as descri be d i n Secti o n 9. 2. 8 m ust als o be 
perf or me d. I n a d diti o n, a n L F T I ncreases C R F m ust be c o m plete d a n d tra ns mitte d wit h t he 
Ta k e da S A E f or m (as per Secti o n 1 0. 2. 9 ).
1 0. 2. 9 S afet y Re p orti n g t o I n vesti g at ors, I R Bs or I E Cs, a n d Re g ul at or y A ut h orities 
T he S p o ns or will be res p o nsi ble f or re p orti n g all s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
( S U S A Rs) a n d a ny ot her a p plica ble S A Es t o re g ulat or y a ut h orities, In vesti gat ors a n d I R Bs or 
I E Cs, as a p plica ble, i n acc or da nce wit h nati o nal re g ulati o ns i n t he c o u ntries w here t he st u d y is 
c o n d ucte d. Relati ve t o t he first a ware ness of t he e ve nt b y / or f urt her pr o visi o n t o t he S p o ns or or 
S p o ns or ’s desi g nee, S U S A Rs will be s u b mitte d wit hi n 7 da ys f or fatal a n d life-t hreate ni n g 
e ve nts a n d 1 5 d a y s f or ot her seri o us e ve nts, u nless ot her wise re q uire d b y nati o nal re g ulati o ns. 
T he S p o ns or will als o pre pare a n e x pe dite d re p ort f or ot her safet y iss ues w here t hese mi g ht 
materiall y  alter t he c urre nt be nefit-ris k assess me nt of a n i n vesti gati o nal me dici nal pr o d uct or t hat 
w o ul d be s uffici e nt t o c o nsi der c ha n ges i n t he i n vesti gati o nal me dici nal pr o d ucts a d mi nistrati o n 
or i n t he o verall c o n d uct of t he st u d y. T he i n vesti gati o nal site als o will f or war d a c o p y of all 
e x pe dite d re p orts t o his or her I R B or I E C i n acc or da nce wit h nati o nal re g ulat i o ns.
1 1. 0 
S T A TI S TI C A L M E T H O D S
1 1. 1 
St atistic al a n d A n al ytic al Pl a ns
Detaile d met h o d ol o g y  f or s u m mar y a n d statistical a nalys es of t he data c ollecte d i n t his st u d y  will 
be d oc u me nte d i n a S A P . T he SA P will be pre pare d b y  Celeri o n a n d a gree d u p o n wit h t he 
S p o ns or. T hi s d oc u me nt ma y m o dif y t he pla ns o utli ne d i n t he pr ot oc ol; h o we ver, a n y maj or 
m o dificati o ns of t he pri mar y  e n d p oi nts defi niti o n a n d/ or its a nalys is will als o be reflecte d i n a 
pr ot oc ol a me n d me nt. A d diti o nal statistical a nal y ses ot her t ha n t h ose descri be d i n t his secti o n 
ma y  be perf or me d if dee me d a p pr o priate.
1 1. 1. 1 A n al ysis Sets
1 1. 1. 1. 1 S afety Set
All partici pa nts w h o recei ve d a n y st u d y dr u g will be i ncl u de d i n t he safety e val uati o ns.
1 1. 1. 1. 2 P K Set
All partici pa nts w h o c o m pl y  s ufficie ntl y wit h t he pr ot oc ol a n d dis pla y a n e val ua ble P K pr ofile 
(e g, e x p os ure t o treat me nt, a vaila bilit y of meas ure me nts, a n d a bse nce of maj or pr ot oc ol 
vi olati o ns) will be i ncl u de d i n t he P K a nal ys es.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 3 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1 1. 1. 2 A n al ysis of De m o gr a p h y a n d Ot her B aseli ne C h ar acteristics
C o nti n u o us de m o gra p hic data (ie, a ge, wei g ht, h ei g ht, a n d B MI) will be liste d a n d s u m marize d 
usi n g a p pr o priate s u m mar y  statistics. Cate g orical de m o gra p hic data (ie, se x, race, a n d et h nicity) 
will als o be liste d a n d ta b ulate d.
1 1. 1. 3
P K A n al ysis
Statistical a nal y sis of P K data will be base d o n t he P K Set.
Plas ma b u des o ni de c o nce ntrati o ns a n d P K para meters will be liste d b y partici pa nt a n d treat me nt, 
a n d s u m marize d usi n g a p pr o priate descri pti ve statistics t o be f ull y  o utli ne d i n t he S A P.
P K para meters ( C ma x , A U Clast, A U C∞, A U C0- 1 2, A U Ce xtra p %, tma x , tla g, t1/ 2 z, λz, C L/ F, a n d Vz/ F) 
will be c o m p ute d usi n g sta n dar d N C A. I n di vi d ual plas ma c o nce ntrati o n/ti me c ur ves will be 
prese nte d i n li near/li near a n d l o g/li near scale.
T he a p pr o priate P K a nal ysis will be f ull y  s pecifie d i n t he S A P .
1 1. 1. 3. 1 Esti m ati o n of F o o d- E ffect
A li near mi xe d -effect s m o del will be a p plie d t o l o g-tra nsf or me d Cma x , A U Clast, a n d A U C∞wit h 
treat me nt, peri o d, a n d se q ue nce as fi xe d effects, a n d partici pa nt wit hi n se q ue nce as a ra n d o m 
effect. P oi nt esti mates a n d t heir ass ociate d 9 0 % CIs will be c o nstr ucte d f or t he differe nce 
bet wee n Treat me nt B ( fe d) mi n us Treat me nt A (fasti n g). T he p oi nt esti mates a n d t heir ass ociate d 
9 0 % CI s will be t he n bac k tra nsf or me d t o pr o vi de p oi nt esti mates a n d 9 0 % CIs f or t he rati os of 
Treat me nt B ( fe d) vers us Treat me nt A (fasti ng).
1 1. 1. 3. 2 N o n -P ar a metric A n alysis
A nal y sis of tma x a n d t la g will be perf or me d b y n o n - para metric Wilc o x o n si g ne d-ra n k test.
1 1. 1. 4
P D A n al ysis
N ot a p plica ble .
1 1. 1. 5 S afet y A n al ysis
All safet y data will be liste d.
T E A Es will be ta b ulate d. T he re mai ni n g q ua ntitati ve safet y data as well as t he differe nce t o 
baseli ne, w he n a p pr o priate, will be s u m marize d usi n g t he a p pr o priate descri pti ve statistics.
1 1. 1. 5. 1 A Es
A Es will be c o de d usi n g t he m ost c urre nt versi o n of Me d D R A
® a vaila ble at Celeri o n a n d 
s u m marize d b y treat me nt f or t he n u m ber of p artici pa nt s re p orti n g t he T E A E a n d t he n u m ber of 
T E A Es re p orte d. 
A n A E will be c o nsi dere d treat me nt -e mer ge nt (ie, a T E A E) if t he o nset date a n d ti me is at t he 
ti me of or after first a d mi nistrati o n of st u d y  dr u g.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 4 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
A b y -partici pa nt A E data listi n g i ncl u di n g ver bati m ter m, c o de d ter m, treat me nt, se verit y, a n d 
relati o ns hi p t o treat me nt will be pr o vi de d.
1 1. 1. 5. 2 Cli nic al L a b or at ory Ev al u ati o n
Cli nical la b orat or y  res ults will be s u m marize d b y  treat me nt a n d p oi nt of ti me of c ollecti o n a n d a 
s hift ta ble descri bi n g o ut of nor mal ra n ge s hifts will be pr o vi de d.
M ore detail will be pr o vi de d i n t he S A P .
1 1. 1. 5. 3 Vit al Si g ns
Vital si g ns assess me nts will be s u m marize d b y  treat me nt a n d p oi nt of ti me of c ollecti o n.
M ore detail will be pr o vi de d i n t he S A P .
1 1. 1. 5. 4 Ot her S afety P ar a meters
Me dical hist or y , a n d c o nc urre nt c o n diti o ns will be c o de d usi n g t he Me d D R A® a n d c o nc o mita nt 
me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) dr u g dicti o nar y  a n d will 
be liste d b y  partici pa nt.
M ore detail will be pr o vi de d i n t he S A P.
1 1. 2
I nteri m A n al ysis a n d Criteri a f or E arl y Ter mi n ati o n
N ot a p plica ble.
1 1. 3  
Deter mi n ati o n of S a m ple Size
T we nt y  ( 2 0) partici pa nts will be e nr olle d t o acc o u nt f or p ossi ble dr o p o uts.
A t otal of a p pr o xi matel y 1 8 partici pa nts s h o ul d c o m plete all treat me nt peri o ds of t he st u d y .
F or plas ma b u des o ni de C ma x , A U C∞, a n d A U Clast, ass u mi n g t he true mea n rati o of 1. 0 wit h 
i ntra-partici pa nt C V of 2 1. 8, 2 1. 0, a n d 2 1. 8 %, res pecti vel y, 1 8 c o m pleters will pr o vi de 8 0, 8 5, 
a n d 8 0 % p o wer t o test f or bi oe q ui vale nce bet wee n d osi n g u n der fe d vers us fasti n g c o n diti o n 
usi n g t he criteria of a 9 0 % CI  wit hi n ( 0. 8 0, 1. 2 5). C o nsi deri n g 1 0 % dr o p o ut rate, a t otal of 
2 0 partici pa nts will be e nr olle d.
1 2. 0
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E
1 2. 1
St u d y -Site M o nit ori n g Visits
M o nit ori n g visits t o t he st u d y site will be ma de peri o dicall y  d uri n g t he st u d y t o e ns ure t hat all 
as pects of t he pr ot oc ol are f oll o we d. D ue t o C O VI D- 1 9, m o nit ori n g visits ma y  als o be c o n d ucte d 
re m otel y. S o urce d oc u me nts will be re vie we d f or verificati o n of data rec or de d o n t he C R Fs. 
S o urce d oc u me nts are defi ne d as ori gi nal d oc u me nts, data, a n d rec or ds. T he I n vesti gat or a n d 
st u d y site g uara ntee access t o s o urce d oc u me nts b y t he S p o ns or or its desi g nee (cli nical researc h 
or ga nizati o n ) a n d by t he I R B or I E C.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 5 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
All as pects of t he st u d y a n d its d oc u me nta ti o n will be s u bject t o re vie w by t he S p o ns or or t he 
S p o ns or’s desi g nee, i ncl u di n g b ut n ot li mite d t o t he I n vesti gat or’s Bi n der, st u d y  dr u g, partici pa nt
me dical rec or ds, i nf or me d c o nse nt d oc u me ntati o n, a n d re vie w of C R Fs a n d ass ociate d s o urce 
d oc u me nts. I t is i m p orta nt t hat t he In vesti gat or a n d ot her st u d y  pers o n nel are a vaila ble d uri n g t he 
m o nit ori n g visits a n d t hat s ufficie nt ti me is de v ote d t o t he pr ocess.
1 2. 2 
Pr ot oc ol De vi ati o ns
T he In vesti gat or s h o ul d n ot de viate fr o m t he pr ot oc ol, e xce pt w here necessar y  to eli mi nate a n 
i m me diate hazar d t o st u d y partici pa nts . S h o ul d ot her u ne x pecte d circ u msta nces arise t hat will 
re q uire de viati o n fr o m pr ot oc ol-s pecifie d pr oce d ures, t he In vesti gat or s h o ul d c o ns ult wit h t he 
s p o ns or or desi g nee (a n d I R B or I E C, as re q uire d) t o deter mi ne t he a p pr o priate c o urse of acti o n. 
T here will be n o e xe m pti o ns (a pr os pecti vel y  a p pr o ve d de viati o n) fr o m t he i ncl usi o n or 
e xcl usi o n criteria.
F or C O VI D - 1 9-relate d pr ot oc ol de viati o ns, t he s pecific pr ot oc ol de viati o n, t he reas o n f or t he 
de viati o n, a n d t he relati o ns hi p t o C O VI D- 1 9 s h o ul d be d oc u me nte d usi n g C R U sta n dar d 
pr ocesses.
Si g nifica nt de viati o ns i ncl u de, b ut are n ot li mite d t o, t h ose t hat i n v ol ve fra u d or misc o n d uct, 
i ncrease t he healt h ris k t o t he partici pa nt , or c o nf o u n d i nter pretati o n of pri mar y  st u d y 
assess me nt.
1 2. 3
Q u alit y Ass ur a nce A u dits a n d Re g ul at or y A ge nc y I ns pecti o ns
T he st u d y  site als o ma y be s u bject t o q ualit y ass ura nce a u dits b y t he S p o ns or or desi g nees. I n 
t his circ u msta nce, t he S p o ns or - desi g nate d a u dit or will c o ntact t he site i n a d va nce t o arra n ge a n 
a u diti n g visit. T he a u dit or ma y as k t o visit t he facilities w here la b orat or y  sa m ples are c ollecte d, 
w here t he me dicati o n is st ore d a n d pre pare d, a n d a n y  ot her facilit y use d d uri n g t he st u dy. I n 
a d diti o n, t here is t he p ossi bilit y t hat this st u d y  ma y be i ns pecte d by re g ulat or y  a ge ncies, 
i ncl u di n g t h ose of f orei g n g o ver n me nts (e g, t he F D A, t he U nite d Ki n g d o m Me dici nes a n d 
Healt hcare pr o d ucts Re g ulat or y  A ge nc y, t he P har mace uticals a n d Me dical De vices A ge nc y of 
Ja pa n). If t he st u dy site is c o ntacte d f or a n i ns pecti o n b y  a re g ulat or y b o d y, t he S p o ns or s h o ul d 
be n otifie d i m me diatel y . T he In vesti gat or g uara ntee s access f or q ualit y ass ura nce a u dit ors t o all 
st u d y d oc u me nts as descri be d i n Secti o n 1 2. 1 .
1 3. 0
E T HI C A L A S P E C T S O F T H E S T U D Y
T his st u d y  will be c o n d ucte d wit h t he hi g hest res pect f or t he i n di vi d ual partici pa nts (ie, s u bjects) 
acc or di n g t o t he pr ot oc ol, t he et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of 
Helsi n ki, a n d t he I nter nati o nal C o nfere nce o n Har m o nisati o n (I CH) Har m o nise d Tri partite 
G ui deli ne f or G C P. Eac h In vesti gat or will c o n d uct t he st u d y  acc or di n g t o a p plica ble l ocal or 
re gi o nal re g ulat or y re q uire me nts a n d alig n his or her c o n d uct i n acc or da nce wit h t he 
“Res p o nsi bilities of t he I n vesti gat or ” t hat are liste d i n A p pe n di x A . T he pri nci ples of Helsi n ki 
are a d dresse d t hr o u g h t he pr ot oc ol a n d t hr o u g h a p pe n dices c o ntai ni n g re q uire me nts f or i nf or me d 
c o nse nt a n d In vesti gat or res p o nsi bilities.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 6 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1 3. 1 
I R B a n d/ or I E C A p pr o v al
I RBs a n d I E Cs m ust be c o nstit ute d acc or di n g t o t he a p plica ble state a n d fe deral/l ocal 
re q uire me nts of eac h partici pati n g re gi o n. T he S p o ns or or desi g nee will re q uire d oc u me ntati o n 
n oti n g all na mes a n d titles of me m bers w h o ma ke u p t he res pecti ve I R B or I E C . If a n y me m ber 
of t he I R B or I E C has direct partici pati o n i n t his st u d y , writte n n otificati o n re gar di n g his or her 
a bsti ne nce fr o m v oti n g m ust als o be o btai ne d. T h ose A mericas sites u n willi n g t o pr o vi de na mes 
a n d titles of all me m bers d ue t o pri vac y  a n d co nflict of i nterest c o ncer ns s h o ul d i nstea d pr o vi de a 
Fe deral Wi de Ass ura nce N u m ber or c o m para ble n u m ber assi g ne d b y t he De part me nt of Healt h 
a n d H u ma n Ser vices.
T he S p o ns or or desi g nee will s u p pl y  rele va nt d oc u me nts f or s u b missi o n t o t he res pecti ve I R B or
I E C f or t he pr ot oc ol’s re vie w a n d a p pr o val. T his pr ot oc ol, t he I B, a c o p y of t he I CF , a n d, if 
a p plica ble, partici pa nt recr uit me nt materials a n d/ or a d vertise me nts a n d ot her d oc u me nts re q uire d 
b y  all a p plica ble la ws a n d re g ulati o ns, m ust be s u b mitte d t o a ce ntral or l ocal I R B or I E C f or 
a p pr o val. T he I RB’ s or I E C’s writte n a p pr o val of t he pr ot oc ol a n d partici pa nt i nf or me d c o nse nt 
m ust be o btai ne d a n d s u b mitte d t o t he S p o ns or or desi g nee bef ore c o m me nce me nt of t he st u d y 
(ie, bef ore s hi p me nt of t he S p o ns or -s u pplie d dr u g or st u d y  s pecific scree ni n g acti vit y). T he I R B 
or I E C a p pr o val m ust refer t o t he st u d y  b y e xact pr ot oc ol title, n u m ber, a n d versi o n date; i de ntif y 
versi o ns of ot her d oc u me nts (e g, I CF ) re vie we d; a n d state t he a p pr o val date. T he S p o ns or will 
s hi p dr u g/ n otif y  site o nce t he S p o ns or has c o nfir me d t he a de q uac y  of site re g ulat or y 
d oc u me ntati o n a n d, w he n a p plica ble, t he S p o ns or has recei ve d per missi o n fr o m c o m pete nt 
a ut h orit y t o be gi n t he st u d y. U ntil t he site recei ves dr u g/ n otificati o n n o pr ot oc ol activities, 
i ncl u di n g scree ni n g, ma y occ ur.
Sites m ust a d here t o all re q uire me nts sti p ulate d b y  t heir res pecti ve I R B or I E C. T his ma y i ncl u de 
n otificati o n t o t he I R B or I E C re gar di n g pr ot oc ol a me n d me nts, u p dates t o t he I CF, recr uit me nt 
materials i nte n de d f or vie wi n g b y partici pa nt s, l ocal safet y re p orti n g re q uire me nts, re p orts a n d 
u p dates re gar di n g t he o n g oi n g re vie w of t he st u d y at i nter vals s pecifie d b y t he res pecti ve I R B or 
I E C, a n d s u b missi o n of t he I n vesti gat or’s fi nal stat us re p ort t o IR B or I E C. All I R B a n d I E C 
a p pr o vals a n d rele va nt d oc u me ntati o n f or t hese ite ms m ust be pr o vi de d t o t he S p o ns or or its 
desi g nee.
Partici pa nt i nce nti ves s h o ul d n ot e xert u n d ue i nfl ue nce f or partici pati o n. Pa y me nts t o 
partici pa nts m ust be a p pr o ve d b y t he I R B or I E C a n d S p o ns or .
1 3. 2 
P artici p a nt I nf or m ati o n, I nf or me d C o nse nt, a n d P artici p a nt A ut h oriz ati o n
Writte n c o nse nt d oc u me nts will e m b o d y  t he ele me nts of i nf or me d c o nse nt as descri be d i n t he 
Declarati o n of Helsi n ki a n d t he I C H G ui deli nes f or G C P a n d will be i n acc or da nce wit h all 
a p plica ble la ws a n d re g ulati o ns. T he I CF, partici pa nt a ut h orizati o n f or m (if a p plica ble), a n d 
partici pa nt i nf or mati o n s heet (if a p plica ble) descri be t he pla n ne d a n d per mitte d uses, tra nsfers, 
a n d discl os ures of t he par tici pa nt’s pers o nal a n d pers o nal healt h i nf or mati o n f or p ur p oses of 
c o n d ucti n g t he st u d y. T he I CF a n d t he partici pa nt i nf or mati o n s heet (if a p plica ble) f urt her 
e x plai n t he nat ure of t he st u d y , its o bjecti ves, a n d p ote ntial ris ks a n d be nefits, as well as t he date 
i nf or me d c o nse nt is gi ve n. T he I C F will detail t he re q uire me nts of t he partici pa nt a n d t he fact 
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 7 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
t hat he or s he is free t o wit h dra w at a ny ti me wit h o ut gi vi n g a reas o n a n d wit h o ut prej u dice t o his 
or her f urt her me dical care.
T he In vesti gat or is res p o nsi ble f or t he pre parati o n, c o nte nt, a n d I R B or I E C a p pr o val of t he I CF
a n d, if a p plica ble, t he partici pa nt a ut h orizati o n f or m. T he I CF, partici pa nt a ut h orizati o n f or m (if 
a p plica ble), a n d partici pa nt i nf or mati o n s heet (if a p plica ble) m ust be a p pr o ve d b y b ot h t he I R B 
or I E C a n d t he S p o ns or pri or t o use.
T he I CF, partici pa nt a ut h orizati o n f or m (if a p plica ble), a n d partici pa nt i nf or mati o n s heet (if 
a p plica ble) m ust be writte n i n a la n g ua ge f ull y  c o m pre he nsi ble t o t he pr os pecti ve partici pa nt . It 
is t he res p o nsi bilit y of t he In vesti gat or t o e x plai n t he detaile d ele me nts of t he I CF, partici pa nt 
a ut h orizati o n f or m (if a p plica ble), a n d partici pa nt i nf or mati o n s heet (if a p plica ble) t o t he 
partici pa nt . I nf or mati o n s h o ul d be gi ve n i n b ot h oral a n d writte n f or m w he ne ver p ossi ble a n d i n 
t he ma n ner dee me d a p pr o priate b y t he I R B or I E C. In t he e ve nt t he partici pa nt is n ot ca pa ble of 
re n deri n g a de q uate writte n i nf or me d c o nse nt, t he n t he partici pa nt ’s le gall y acce pta ble 
re prese ntati ve ma y pr o vi de s uc h c o nse nt f or t he partici pa nt i n acc or da nce wit h a p plica ble la ws 
a n d re g ulati o ns.
T he partici pa nt , or t he partici pa nt ’s le gally acce pta ble re prese ntati ve, m ust be gi ve n a m ple 
o p p ort u nit y  t o: ( 1) i n q uire a b o ut details of t he st u d y, a n d ( 2) deci de w het her or n ot t o partici pat e 
i n t he st u d y. If t he partici pa nt , or t he partici pa nt ’s le gall y acce pta ble re prese ntati ve, deter mi nes 
he or s he will partici pate i n t he st u d y , t he n t he I CF a n d partici pa nt a ut h orizati o n f or m (if 
a p plica ble) m ust be si g ne d a n d date d b y t he partici pa nt , or t he partici pa nt ’s le gall y acce pta ble 
re prese ntati ve, at t he ti me of c o nse nt a n d pri or t o t he partici pa nt e nteri n g i nt o t he st u d y. T he 
partici pa nt or t he partici pa nt ’s le gally acce pta ble re prese ntati ve s h o ul d be i nstr ucte d t o si g n 
usi n g t heir le gal na mes, n ot nic k na mes, usi n g bl ue or blac k ball p oi nt i n k. T he I n vesti gat or m ust 
als o si g n a n d date t he I CF a n d partici pa nt a ut h orizati o n (if a p plica ble) at t he ti me of c o nse nt a n d 
pri or t o partici pa nt e nteri n g i nt o t he st u d y; h o we ver, t he S p o ns or m a y  all o w a desi g nee of t he 
In vesti gat or t o si g n t o t he e xte nt per mitte d b y  a p plica ble la w.
O nce si g ne d, t he ori gi nal I CF, partici pa nt a ut h orizati o n f or m (if a p plica ble), a n d partici pa nt 
i nf or mati o n s heet (if a p plica ble) will be st ore d i n t he I n vesti gat or’s site file. T he In vesti gat or 
m ust d oc u me nt t he date t he partici pa nt si g ns t he i nf or me d c o nse nt i n t he partici pa nt ’s me dical 
rec or d. C o pies of t he si g ne d I CF , t he si g ne d partici pa nt a ut h orizati o n f or m (if a p plica ble), a n d 
partici pa nt i nf or mati o n s heet (if a p plica ble) s hall be gi ve n t o t he partici pa nt .
All re vise d I C Fs m ust be re vie we d a n d si g ne d b y rele va nt partici pa nt s or t he rele va nt 
partici pa nt ’s le gally acce pta ble re prese ntati ve i n t he sa me ma n ner as t he ori gi nal i nf or me d 
c o nse nt. T he date t he re vise d c o nse nt was o btai ne d s h o ul d be rec or de d i n t he partici pa nt ’s 
me dical rec or d, a n d t he partici pa nt s h o ul d recei ve a c o py of t he re vise d I CF.
1 3. 3
P artici p a nt C o nfi de nti alit y
T he S p o ns or a n d desi g nees affir m a n d u p h ol d t he pri nci ple of t he partici pa nt ’s ri g ht t o pr otecti o n 
a gai nst i n vasi o n of pri vac y. T hr o u g h o ut t his st u d y, a partici pa nt ’s s o urce data will o nl y be li n ke d 
t o t he S p o ns or’ s cli nical st u d y database or d oc u me ntati o n via a u ni q ue i de ntificati o n n u m ber. As 
per mitte d b y  all a p plica ble la ws a n d re g ulati o ns, li mite d partici pa nt attri b utes, s uc h as se x, a ge, 
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 8 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
or date of birt h, a n d partici pa nt i nitials ma y be use d t o verif y t he partici pa nt a n d acc urac y of t he 
partici pa nt ’s u ni q ue i de ntificati o n n u m ber.
T o c o m pl y  wit h I C H G ui deli nes f or G C P a n d t o verif y c o m plia nce wit h t his pr ot oc ol, t he 
S p o ns or re q uires t he I n vesti gat or t o per mit its m o nit or or desi g nee’s m o nit or, re prese ntati ves 
fr o m a ny re g ulat or y  a ut horit y  (e g, F D A, Me dici nes a n d Healt hcare pr o d ucts Re g ulat or y A ge nc y, 
P har mace uticals a n d Me dical De vices A ge nc y ), t he S p o ns or’ s desi g nate d a u dit ors, a n d t he 
a p pr o priate I RBs a n d I ECs t o re vie w t he partici pa nt’s ori gi nal me dical rec or ds (s o urce data or 
d oc u me nts), i ncl u di n g, b ut n ot li mite d t o, la b orat or y  test res ult re p orts, E C G re p orts, a d missi o n 
a n d disc har ge s u m maries f or h os pital a d missi o ns occ urri n g d uri n g a partici pa nt ’s st u d y 
partici pati o n, a n d a ut o ps y  re p orts. Access t o a partici pa nt ’s ori gi nal me di cal rec or ds re q uires t he 
s pecific a ut h orizati o n of t he partici pa nt as part of t he i nf or me d c o nse nt pr ocess (see 
Secti o n 1 3. 2 ).
C o pies of a n y partici p a nt s o urce d oc u me nts t hat are pr o vi de d t o t he S p o ns or m ust ha ve certai n 
pers o nall y i de ntifia ble i nf or mati o n re m o ve d (ie, partici pa nt na me, a d dress, a n d ot her i de ntifier 
fiel ds n ot c ollecte d o n t he partici pa nt ’s C R F).
1 3. 4 
P u blic ati o n, Discl os ure, a n d Cli nic al St u d y Re gistr ati o n P olic y
1 3. 4. 1 P u blic ati o n a n d Discl os ure
T he In vesti gat or is o bli ge d t o pr o vi de t he S p o ns or wit h c o m plete test res ults a n d all data deri ve d 
b y  t he In vesti gat or fr o m t he st u d y. D uri n g a n d after t he st u d y, o nly t he S p o ns or ma y  ma ke st u d y 
i nf or mati o n a vaila ble t o ot her st u d y In vesti gat ors or t o re g ulat or y  a ge ncies, e xce pt as re q uire d by 
la w or re g ulati o n. E xce pt as ot her wise all o wa ble i n t he cli nical st u d y site a gree me nt, a ny p u blic 
discl os ure (i ncl u di n g p u blicl y  accessi ble we bsites) relate d t o t he pr ot oc ol or st u d y  res ults, ot her 
t ha n st u d y recr uit me nt materials a n d/ or a d vertise me nts, is t he s ole res p o nsi bilit y of t he S p o ns or .
T he S p o ns or m a y  p u blis h a n y data a n d i nf or mati o n fr o m t he st u d y (i ncl u di n g data a n d 
i nf or mati o n ge nerate d by t he In vesti gat or) wit h o ut t he c o nse nt of t he In vesti gat or. Ma n uscri pt 
a ut h ors hi p f or a n y peer -re vie we d p u blicati o n will a p pr o priatel y reflect c o ntri b uti o ns t o t he 
pr o d ucti o n a n d re vie w of t he d oc u me nt. All p u blicati o ns a n d prese ntati o ns m ust be pre pare d i n 
acc or da nce wi t h t his secti o n a n d t he Cli nical St u d y Site A gree me nt. I n t he e ve nt of a n y 
discre pa nc y  bet wee n t he pr ot oc ol a n d t he Cli nical St u d y  Site A gree me nt, t he Cli nical St u d y  Site 
A gree me nt will pre vail.
1 3. 4. 2 Cli nic al St u d y Re gistr ati o n
I n or der t o e ns ure t hat i nf or matio n o n cli nical trials reac hes t he p u blic i n a ti mel y  ma n ner a n d t o 
c o m pl y wit h a p plica ble la ws, re g ulati o ns a n d g ui da nce, Ta ke da will, at a mi ni m u m re gister all 
i nter ve nti o nal cli nical trials it S p o ns ors a n yw here i n t he w orl d o n Cli nical Trials. g o v a n d/ or o t her 
p u blicl y  accessi ble we bsites bef ore start of st u d y, as defi ne d i n Ta ke da P olic y/ Sta n dar d. Ta ke da 
c o ntact i nf or mati o n, al o n g wit h I n vesti gat or’s cit y, state (f or A mericas I n vesti gat ors), c o u ntr y, 
a n d recr uiti n g stat us will be re gistere d a n d a vaila ble f or p u blic vie wi n g. 
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 4 9 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
F or s o me re gistries, Ta ke da will assist callers i n l ocati n g st u d y sites cl osest t o t heir h o mes b y 
pr o vi di n g t he I n vesti gat or na me, a d dress, a n d p h o ne n u m ber t o t he callers re q uesti n g st u d y 
i nf or mati o n. O nce partici pa nt s recei ve I n vesti gat or c o ntact i nf or mati o n, t he y m a y call t he site 
re q uesti n g e nr oll me nt i nt o t he st u d y. T he i n vesti gati ve sites are e nc o ura ge d t o ha n dle t he st u d y 
i n q uiries acc or di n g t o t heir esta blis he d partici pa nt scree ni n g pr ocess. If t he caller as ks a d diti o nal 
q uesti o n s be yo n d t he t o pic of st u d y  e nr oll me nt, t he y s h o ul d be referre d t o t he S p o ns or.
A n y  In vesti gat or w h o o bjects t o t he S p o ns or pr o vi di n g t his i nf or mati o n t o callers m ust pr o vi de 
t he S p o ns or wit h a writte n n otice re q uesti n g t hat t heir i nf or mati o n n ot be liste d o n t he re gistr y  
site.
1 3. 4. 3 Cli nic al St u d y Res ults Discl os ure
Ta ke da will p ost t he res ults of cli nical st u dies o n Cli nical Trials. g o v or ot her p u blicl y  accessi ble 
we bsites, as re q uire d b y Ta ke da P olic y / Sta n dar d, a p plica ble la ws a n d/ or re g ulati o ns.
1 3. 5
I ns ur a nce a n d C o m pe ns ati o n f or I nj ur y
Eac h partici pa nt i n t he st u d y m ust be i ns ure d i n acc or da nce wit h t he re g ulati o ns a p plica ble t o t he 
site w here t he partici pa nt is partici pati n g. If a l ocal u n der writer is re q uire d, t he n t he S p o ns or or 
S p o ns or ’s desi g nee will o btai n cli nical st u d y i ns ura nce a gai nst t he ris k of i nj ur y t o st u d y 
partici pa nt s. Refer t o t he st u d y site a gree me nt re gar di n g t he S p o ns or ’s p olic y o n partici pa nt
c o m pe nsati o n a n d treat me nt f or i nj ur y . If t he In vesti gat or has q uesti o ns re ga r di n g t his p olic y, he 
or s he s h o ul d c o ntact t he S p o ns or or S p o ns or’s desi g nee.
1 4. 0
A D MI NI S T R A TI V E A N D R E F E R E N C E I N F O R M A TI O N
1 4. 1  
A d mi nistr ati ve I nf or m ati o n
1 4. 1. 1 St u d y C o nt act I nf or m ati o n
C o nt act T y pe / R ole
C o nt act
Seri o us a d verse e ve nt a n d pre g na nc y re p orti n g
P har m ac o vi gila nce
Ta ke da De vel o p me nt Ce nter A mericas, I nc.
Fa x: + 1 2 2 4 -5 5 4 -1 0 5 2
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 0 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1 4. 1. 2 I n vesti g at or A gree me nt
I c o nfir m t hat I ha ve rea d a n d t hat I u n dersta n d t his pr ot oc ol, t he I B, pac ka ge i nsert , a n d a n y 
ot her pr o d uct i nf or mati o n pr o vi de d b y t he S p o ns or . I a gree t o c o n d uct t his st u d y i n acc or da nce 
wit h t he re q uire me nts of t his pr ot oc ol a n d als o t o pr otect t he ri g hts, safet y , pri vac y, a n d 
well -bei n g of st u d y partici pa nt s i n acc or da nce wit h t he f oll o wi n g:

T he et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.

I C H, E 6[ R 2] G o o d Cli nical Practice: C o ns oli date d G ui deli ne.

All a p plica ble la ws a n d re g ulati o ns, i ncl u di n g, wit h o ut li mitati o n, data pri vac y  la ws a n d 
re g ulati o ns.

Re g ulat or y  re q uire me nts f or re p orti n g S A Es defi ne d i n Secti o n 1 0. 2. 9 of t his pr ot oc ol.

Ter ms o utli ne d i n t he st u d y site a gree me nt.

Res p o nsi bilities of t he I nvesti gat or (A p pe n di x A ).
I f urt her a ut h orize t hat m y pers o nal i nf or mati o n ma y be pr ocesse d a n d tra nsferre d i n acc or da nce 
wit h t he uses c o nte m plate d i n  A p pe n di x C of t his pr ot oc ol .
Si g nat ure of I n vesti gat or
Date
I n vesti gat or Na me ( pri nt or t ype)
I n vesti gat or’s Title
L ocati o n of Facilit y  ( Cit y, State/ Pr o vince)
L ocati o n of Facilit y  ( C o u ntr y)
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 1 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1 4. 1. 3 St u d y -Rel ate d Res p o nsi bilities
T he S p o ns or will perf or m all st u d y -relate d acti vities wit h t he e xce pti o n of t h ose i de ntifie d i n t he 
St u d y -Relate d Res p o nsi bilities te m plate. T he ve n d ors i de ntifie d f or s pecific st u d y -relate d 
acti vities will perf or m t hese acti vities i n f ull or i n part ners hi p wit h t he S p o ns or.
1 4. 1. 4 List of A b bre vi ati o ns
A E
A d verse e ve nt
A L P
Al kali ne p h os p hatase
A L T
Ala ni ne a mi n otra nsferase
A S T
As partate a mi n otra nsferase
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve
A U C 
Area u n der t he c o nce ntrati o n -ti me c ur ve, fr o m ti me 0 t o i nfi nit y
A U C e xtra p%
Area u n der t he c ur ve fr o m t he last q ua ntifia ble c o nce n trati o n t o i nfi nit y
A U C 0- 1 2
Area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 1 2 h o urs
A U C last
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he last q ua ntifia ble 
c o nce ntrati o n
BI D
T w ice dail y
B MI
B o d y  mass i n de x
B O S
B u des o ni de oral s us pe nsi o n
b p m
Beats per mi n ute
C F R
C o de of Fe deral Re g ulati o ns
CI
C o nfi de nce i nter val
C L/ F
A p pare nt cleara nce after e xtra vasc ular a d mi nistrati o n
c m
Ce nti meter
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n
C O VI D -1 9
C or o na vir us disease 2 0 1 9
C R F
Case re p ort f or m
C R U
Cli nical researc h unit
C V
C oefficie nt of varia nce
C Y P
C y t oc hr o me P 4 5 0
E C G
Electr ocar di o gra m
E o E
E osi n o p hilic es o p ha gitis
F D A
F o o d a n d Dr u g A d mi nistrati o n
F S H
F ollicle -sti m ulati n g h or m o ne
g
Gra m
G C P
G o o d Cli nical Practice
H Bs A g
He patitis B s urface a nti ge n
h C G
H u ma n c h ori o nic g o na d otr o pi n
H C V
He patitis C vir us 
HI V
H u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or’s Br oc h ure
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 2 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
I C F
I nf or me d co nse nt for m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I D
I de ntificati o n
I E C
I n de pe n de nt et hics co m mittee
I R B
I nstit uti o nal re vie w b oar d
I U
I nter nati o nal u nit
k g
Kil o gra m
L
Liter
L F T
Li ver f u ncti o n test
λ z
T er m i nal dis p ositi o n p hase rate c o nsta nt
m 2
Meters s q uare d
Me d D R A
®
Me dical Dicti o nar y f or Re g ulat or y Acti vities
®
m g
Milli gra m
mi n
Mi n ute
m L
Milliliter
m m H g
Milli meter of merc ur y
msec
Millisec o n d
N C A
N o n -c o mpart me ntal a nal ysis
P- g p
P- gl yc o pr otei n
P G x
P har m ac o ge n o mics(s)
P K
P har m ac o ki netic(s)
Q Tc F
Q T i nter val c orrecte d f or p ulse rate usi n g Fri dericia’s f or m ula
S A E
Seri o us a d verse e ve nt
S A P
Statistical a nal ysis pla n
S D
Sta n dar d de viati o n
S U S A R
S us pecte d u ne x pecte d seri o us a d verse reacti o n
t1/ 2z
T er m i nal dis p ositi o n p hase half-life
T D C A
Ta ke da De vel o p me nt Ce nter A mericas , I nc.
T E A E
Treat me nt- e mer ge nt a d verse e ve nt
tla g
La g ti me t o first q ua ntifia ble c o nce ntrati o n
tma x
Ti m e of first occ urre nce of C ma x
U L N
U p per li mit of n or mal
U S
U nite d States
U S A
U nite d States of A merica
V z/ F
A p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal dis p ositi o n p hase after 
e xtra vasc ular a d mi nistrati o n
W H O
W orl d Healt h Or ga nizati o n
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 3 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1 5. 0
D A T A H A N D LI N G A N D R E C O R D K E E PI N G
T he f ull details of pr oce d ures f or data ha n dli n g will be d oc u me nte d i n t he Data Ma na ge me nt 
Pla n. A Es, me dical hist or y, a n d c o nc urre nt c o n diti o ns will be c o de d usi n g t he Me d D R A ® . Dr u gs 
will be c o de d usi n g t he W H O
Dr u g Dicti o nar y .
1 5. 1  
C R Fs ( Electr o nic a n d P a per)
Celeri o n sta n dar d C R Fs will be s u p plie d. Eac h C R F will be re vie we d a n d si g ne d b y t he 
I n vesti gat or. T he fi nal si g ne d C R Fs will be arc hi ve d electr o nically at t he e n d of st u d y i n a 
d oc u me nt re p osit or y  sys te m. Fi nal C R Fs will be pr o vi de d t o t he S p o ns or i n t he f or mat a n d 
tra nsfer met h o d as deci de d bet wee n Celeri o n a n d t he S p o ns or.
After c o m pleti o n of t he e ntr y  pr ocess, c o m p uter l o gic c hec ks will be r u n t o i de ntif y ite ms, s uc h 
as i nc o nsiste nt dates, missi n g data, a n d q uesti o na ble val ues. Q ueries ma y  be iss ue d b y Ta ke da 
pers o n nel ( or desi g nees) a n d will be a ns were d b y t he site.
C orrecti o ns are rec or de d i n a n a u dit trail t hat ca pt ures t he ol d i nf or mati o n, t he ne w i nf or mati o n, 
i de ntificati o n of t he pers o n ma ki n g t he c orrecti o n, t he date t he c orrecti o n was ma de, a n d t he 
reas o n f or c ha n ge. Reas o ns f or si g nifica nt c orrecti o ns s h o ul d a d diti o nall y  be i ncl u de d.
T he I n vesti gat or m ust re vie w t he C R Fs f or c o m plete ness a n d acc urac y  a n d m ust si g n a n d date 
t he a p pr o priate C R Fs as i n dicate d. F urt her m ore, t he I n vesti gat or m ust retai n f ull res p o nsi bilit y  
f or t he acc urac y a n d a ut he nticit y of all data e ntere d o n t he C R Fs .
After t he loc k of t he cli nical st u d y data base, a n y c ha n ge of, m o dificati o n of, or a d diti o n t o t he 
data o n t he C R Fs s h o ul d be ma de b y t he In vesti gat or wit h use of c ha n ge a n d m o dificati o n 
rec or ds of t he C R Fs. T he In vesti gat or m ust re vie w t he data c ha n ge f or c o m plete ness a n d 
acc urac y, a n d m ust si g n a n d date
C R Fs will be re vie we d f or c o m plete ness a n d acce pta bilit y at t he st u d y site d uri n g peri o dic visits 
b y  st u d y m o nit ors. T he S p o ns or or its desi g nee will be per mitte d t o re vie w t he partici pa nt’s
me dical a n d h os pital rec or ds perti ne nt t o t he st u d y t o e ns ur e acc urac y of t he C R Fs. T he
c o m plete d C R Fs are t he s ole pr o pert y of t he S p o ns or a n d s h o ul d n ot be ma de a vaila ble i n a n y 
f or m t o t hir d parties, e xce pt f or a ut h orize d re prese ntati ves of a p pr o priate g o ver n me ntal healt h or 
re g ulat or y a ut h orities, wit h o ut writte n per missi o n of t he S p o ns o r.
1 5. 2
Rec or d Rete nti o n
T he In vesti gat or a grees t o kee p t he rec or ds sti p ulate d i n Secti o n  1 5. 1 a n d t h ose d oc u me nts t hat 
i ncl u de ( b ut are n ot li mite d t o) t he st u d y-s pecific d oc u me nts, t he i de ntificati o n l o g of all 
partici pati n g partici pa nts, me dical rec or ds, te m p orar y  me dia s uc h as t her mal se nsiti ve pa per, 
s o urce w or ks heets, all ori gi nal si g ne d a n d date d I CFs , partici pa nt a ut h orizati o n f or ms re gar di n g 
t he use of pers o nal healt h i nf or mati o n (if se parate fr o m t he I C Fs), electr onic c o p y  of C R Fs, 
i ncl u di n g t he a u dit trail, a n d detaile d rec or ds of dr u g dis p ositi o n t o e na ble e val uati o ns or a u dits 
fr o m re g ulat or y a uth orities, t he S p o ns or or its desi g nees. A n y s o urce d oc u me ntati o n pri nte d o n 
de gra da ble t her mal se nsiti ve pa per s h o ul d be p h ot oc o pie d b y t he site a n d file d wit h t he ori gi nal 
i n t he partici pa nt’s c hart t o e ns ure l o n g-ter m le gi bilit y. F urt her m ore, I C H E 6 Sect i o n 4. 9. 5 
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 4 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
re q uires t he I n vesti gat or t o retai n esse ntial d oc u me nts s pecifie d i n I C H E 6 ( Secti o n 8) u ntil at 
least 2 years after t he last a p pr o val of a mar keti n g a p plicati o n f or a s pecifie d dr u g i n dicati o n 
bei n g i n vesti gate d or, if a n a p plicati o n is n ot a p pr o ve d, u ntil at least 2 ye ars after t he 
i n vesti gati o n is disc o nti n ue d a n d re g ulat or y a ut h orities are n otifie d. I n a d diti o n, IC H E 6 
Secti o n 4. 9. 5 states t hat t he st u d y  rec or ds s h o ul d be retai ne d u ntil a n a m o u nt of ti me s pecifie d b y 
a p plica ble re g ulat or y re q uire me nts or f or a ti me s pecifie d i n t he Cli nical St u d y Site A gree me nt 
bet wee n t he In vesti gat or a n d S p o ns or .
Refer t o t he Cli nical St u d y Site A gree me nt f or t he S p o ns or’ s re q uire me nts o n rec or d rete nti o n. 
T he In vesti gat or a n d t he hea d of t he i nstit uti o n s h o u l d c o ntact a n d recei ve writte n a p pr o val fr o m 
t he S p o ns or bef ore dis p osi n g of a n y s uc h d oc u me nts.
1 6. 0
R E F E R E N C E S
1.
F o o d a n d Dr u g A d mi nistrati o n. Ce nter f or Dr u g E val uati o n a n d Researc h ( C D E R). G ui da nce 
f or I n d ustr y: Assessi n g t he Effects of F o o d o n Dr u gs i n I N Ds a n d N D As – Cli nical 
P har mac ol o g y  C o nsi derati o ns. J u n 2 0 2 2 . A vaila ble at:
htt ps:// w w w.f da. g o v/ me dia/ 1 2 1 3 1 3/ d o w nl oa d.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K-7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 5 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
1 7. 0
A P P E N DI C E S
A p pe n di x A
Res p o nsi bilities of t he I n vesti g at or
Cli nical researc h st u dies s p o ns ore d b y  t he S p o ns o r are s u bject t o IC H G C P a n d all t he a p plica ble 
l ocal la ws a n d re g ulati o ns. T he res p o nsi bilities i m p ose d o n I n vesti gat ors b y  t he F D A are 
s u m marize d i n t he “ State me nt of I n vesti gat or” ( F or m F D A 1 5 7 2), w hic h m ust be c o m plete d a n d 
si g ne d bef ore t he I n vesti gator ma y  partici pate i n t his st u d y.
T he In vesti gat or a grees t o ass u me t he f oll o wi n g res p o nsi bilities b y  si g ni n g a F or m F D A 1 5 7 2:
1.
C o n d uct t he st u d y  i n acc or da nce wit h t he pr ot oc ol.
2.
Pers o nall y  c o n d uct or s u per vise t he staff t hat will assist i n t he pr ot oc ol.
3.
If t he In vesti gat or/i nstit uti o n retai ns t he ser vices of a n y  i n di vi d ual or party t o perf or m st u d y-
relate d d uties a n d f u ncti o ns, t he In vesti gat or/i nstit uti o n s h o ul d e ns ure t hat t his i n di vi d ual or 
part y  is q ualifie d t o perf or m t h ose st u d y-relate d d uties a n d f u ncti o ns a n d s h o ul d i m ple me nt 
pr oce d ures t o e ns ure t he i nte grit y of t he st u d y-relate d d uties a n d f u ncti o ns perf or me d a n d 
a n y data ge nerate d.
4.
E ns ure t hat st u d y  relate d pr oce d ures, i ncl u di n g st u d y s pecific ( n o n-r o uti ne/ n o n-sta n dar d 
pa nel ) scree ni n g assess me nts are N O T perf or me d o n p ote ntial partici pa nts , pri or t o t he 
recei pt of writte n a p pr o val fr o m rele va nt g o ver ni n g b o dies/a ut h orities.
5.
E ns ure t hat all c ollea g ues a n d e m pl o y ees assisti n g i n t he c o n d uct of t he st u d y  are i nf or me d 
of t hese o bli gati o ns.
6.
Sec ure pri or a p pr o val of t he st u d y  a n d a n y c ha n ges b y a n a p pr o priate I R B/I E C t hat c o nf or m 
t o 2 1 C F R Part 5 6, IC H, a n d l ocal re g ulat or y  re q uire me nts.
7.
E ns ure t hat t he I R B/I E C will be res p o nsi ble f or i nitial re vie w, c o nti n ui n g re vie w, a n d 
a p pr o val of t he pr ot oc ol. Pr o m ptl y  re p ort t o t he I R B/I E C all c ha n ges i n researc h acti vit y a n d 
all a ntici pate d ris ks t o partici pa nt s. Ma ke at least yearly re p orts o n t he pr o gress of t he st u d y 
t o t he IR B/I E C, a n d iss ue a fi nal re p ort wit hi n 3 m o nt hs of st u d y  c o m pleti o n.
8.
E ns ure t hat re q uire me nts f or i nf or me d c o nse nt, as o utli ne d i n 2 1 C F R Part 5 0, I C H a n d l ocal 
re g ulati o ns, are met.
9.
O btai n vali d i nf or me d c o nse nt fr o m eac h partici pa nt w h o partici pates i n t he st u d y , a n d 
d oc u me nt t he date of c o nse nt i n t he partici pa nt’s me dical c hart. Vali d i nf or me d c o nse nt is t he 
m ost c urre nt versi o n a p pr o ve d b y t he I R B/I E C. Eac h I C F s h o ul d c o ntai n a partici pa nt 
a ut h orizati o n secti o n t hat descri bes t he uses a n d discl os ures of a partici pa nt’s pers o nal 
i nf or mati o n (i ncl u di n g pers o nal healt h i nf or mati o n) t hat will ta ke place i n c o n necti o n wit h 
t he st u d y. If a n I CF d oes n ot i ncl u de s uc h a partici pa nt a ut h orizati o n, t he n t he In vesti gat or 
m ust o btai n a se parate partici pa nt a ut h orizati o n f or m fr o m eac h partici pa nt or t he 
partici pa nt’s le gally ac ce pta ble re prese ntati ve.
1 0. Pre pare a n d mai ntai n a de q uate case hist ories of all pers o ns e ntere d i nt o t he st u d y , i ncl u di n g 
C R Fs, h os pital rec or ds, la b orat or y  res ults, etc., a n d mai ntai n t hese data f or a mi ni m u m of 
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 6 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
2 ye ars f oll o wi n g n otificati o n b y  t he S p o ns or t hat all i n vesti gati o ns ha ve bee n disc o nti n ue d 
or t hat t he re g ulat or y  a ut h orit y has a p pr o ve d t he mar keti n g a p plicati o n. T he In vesti gat or 
s h o ul d c o ntact a n d recei ve writte n a p pr o val fr o m t he S p o ns or bef ore dis p osi n g of a n y s uc h 
d oc u me nts.
1 1. All o w p ossi ble i ns pecti o n a n d c o p yi n g b y  t he re g ulat or y a ut h orit y of G C P-s pecifie d esse ntial 
d oc u me nts.
1 2. Mai ntai n c urre nt rec or ds of t he recei pt, a d mi nistrati o n, a n d dis p ositi o n of S p o ns or -s u p plie d 
dr u gs, a n d ret ur n all u n use d S p o ns or -s u p plie d dr u gs t o t he S p o ns or .
1 3. Re p ort a d verse reacti o ns t o t he S p o ns or pr o m ptl y . I n t he e ve nt of a n S A E, n otif y t he S p o ns or
wit hi n 2 4 h o urs.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 7 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
A p pe n di x B
Ele me nts of t he P artici p a nt I nf or me d C o nse nt
I n see ki n g i nf or me d c o nse nt, t he f oll o wi n g i nf or mati o n s hall be pr ovi de d t o eac h partici pa nt :
1.
A state me nt t hat t he st u d y i n v ol ves researc h.
2.
A n e x pla nati o n of t he p ur p oses of t he researc h.
3.
T he e x pecte d d urati o n of t he partici pa nt’s partici pati o n.
4.
A descri pti o n of t he pr oce d ures t o be f oll o we d, i ncl u di n g i n vasi ve pr oce d ures .
5.
T he i de ntificati o n of a n y pr oce d ures t hat are e x peri me ntal.
6.
T he esti mate d n u m ber of partici pa nts i n v ol ve d i n t he st u d y.
7.
A descri pti o n of t he partici pa nt’s res p o nsi bilities.
8.
A descri pti o n of t he c o n d uct of t he st u d y.
9.
A state me nt descri bi n g t he treat me nt(s) a n d t he pr o ba bilit y f or ra n d o m assi g n me nt t o eac h 
treat me nt.
1 0. A descri pti o n of t he p ossi ble si de effects of t he treat me nt t hat t he partici pa nt ma y  recei ve.
1 1. A descri pti o n of a n y reas o na bl y f oreseea ble ris ks or disc o mf orts t o t he partici pa nt a n d, w he n 
a p plica ble, t o a n e m br yo, fet us, or n ursi n g i nfa nt.
1 2. A descri pti o n of a n y be nefits t o t he partici pa nt or t o ot hers t hat reas o na bl y  ma y be e x pecte d 
fr o m t he researc h. W he n t here is n o i nte n de d cli nical be nefit t o t he partici pa nt , t he partici pa nt 
s h o ul d be ma de a ware of t his.
1 3. Discl os ures of a p pr o priate alter nati ve pr oce d ures or c o urses of treat me nt, if a n y, t hat mi g ht 
be a d va nta ge o us t o t he partici pa nt a n d t heir i m p orta nt p ote ntial ris ks a n d be nefits.
1 4. A state me nt descri bi n g t he e xte nt t o w hic h c o nfi de nti alit y of rec or ds i de ntif yi n g t he 
partici pa nt will be mai ntai ne d, a n d a n ote of t he p ossi bilit y  t hat re g ulat or y a ge ncies, 
a u dit or(s), I R B/I E C, a n d t he m o nit or ma y  i ns pect t he rec or ds. B y si g ni n g a writte n I CF , t he 
partici pa nt or t he partici pa nt’s le gall y ac ce pta ble re prese ntati ve is a ut h orizi n g s uc h access.
1 5. F or researc h i n v ol vi n g m ore t ha n mi ni mal ris k, a n e x pla nati o n as t o w het her a n y 
c o m pe nsati o n a n d a n e x pla nati o n as t o w het her a n y  me dical treat me nts are a vaila ble if i nj ur y 
occ urs a n d, if s o, w hat t he y  c onsist of or w here f urt her i nf or mati o n ma y  be o btai ne d.
1 6. T he a ntici pate d pr orate d pa y me nt(s), if a n y , t o t he partici pa nt f or partici pati n g i n t he st u d y.
1 7. T he a ntici pate d e x pe nses, if a n y , t o t he partici pa nt f or partici pati n g i n t he st u d y.
1 8. A n e x pla nati o n of w h o m t o c o ntact f or a ns wers t o perti ne nt q uesti o ns a b o ut t he researc h 
(I n vesti gat or), partici pa nt’s ri g hts, a n d I RB/I E C a n d w h o m t o c o ntact i n t he e ve nt of a 
researc h-relate d i nj ur y t o t he partici pa nt .
1 9. A state me nt t hat partici pati o n is v ol u ntar y , t hat ref usal t o partici pate will i n v ol ve n o pe nalty 
or l oss of be nefits t o w hic h t he partici pa nt ot her wise is e ntitle d, a n d t hat t he partici pa nt or t he 
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 8 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
partici pa nt’s le gally acce pta ble re prese ntati ve ma y disc o nt i n ue partici pati o n at a ny ti me 
wit h o ut pe nalt y  or l oss of be nefits t o w hic h t he partici pa nt is ot her wise e ntitle d.
2 0. T he c o nse q ue nces of a partici pa nt’s decisi o n t o wit h dra w fr o m t he researc h a n d pr oce d ures 
f or or derl y ter mi nati o n of partici pati o n b y t he par tici pa nt.
2 1. A state me nt t hat t he partici pa nt or t he partici pa nt’s le gally acce pta ble re prese ntati ve will be 
i nf or me d i n a ti mel y ma n ner if i nf or mati o n bec o mes a vaila ble t hat ma y be rele va nt t o t he 
partici pa nt’s willi n g ness t o c o nti n ue partici pati o n i n t he st u d y .
2 2. T he f oreseea ble circ u msta nces or reas o ns u n der w hic h t he partici pa nt’s partici pati o n i n t he 
st u d y ma y be ter mi nate d.
2 3. A writte n partici pa nt a ut h orizati o n (eit her c o ntai ne d wit hi n t he I C F or pr o vi de d as a se parate 
d oc u me nt) descri bi n g t o t he partici pa nt t he c o nte m plate d a n d per missi ble uses a n d 
discl os ures of t he partici pa nt’s pers o nal i nf or mati o n (i ncl u di n g pers o nal healt h i nf or mati o n) 
f or p ur p oses of c o n d ucti n g t he st u dy. T he partici pa nt a ut h orizati o n m ust c o ntai n t he 
f oll o wi n g state me nts re gar di n g t he uses a n d discl os ures of t he partici pa nt’s pers o nal 
i nf or mati o n:
a)
t hat pers o nal i nf or mati o n (i ncl u di n g pers o nal healt h i nf or mati o n) ma y be pr ocesse d by or 
tra nsferre d t o ot her parties i n ot her c o u ntries f or cli nical researc h a n d safet y re p orti n g 
p ur p oses, i ncl u di n g, wit h o ut li mitati o n, t o t he f oll o wi n g: ( 1) Ta ke da, its affiliates, a n d 
lice nsi n g part ners; ( 2) b usi ness part ners assisti n g Ta ke da, its affiliates, a n d lice nsi n g 
part ners; ( 3) re g ulat or y  a ge ncies a n d ot her healt h a ut h orities; a n d ( 4) I R Bs/I E Cs;
b)
it is p ossi ble t hat pers o nal i nf or mati o n (i ncl u di n g pers o nal healt h i nf or mati o n) ma y be 
pr ocesse d a n d tra nsferre d t o c o u ntries t hat d o n ot ha ve data pr otecti o n la ws t hat offer 
partici pa nt s t he sa me le vel of pr otecti o n as t he data pr otecti o n la ws wit hi n t his co u ntr y ; 
h o we ver, Ta ke da will ma ke e ver y eff ort t o kee p y o ur pers o nal i nf or mati o n c o nfi de ntial, 
a n d yo ur na me will n ot be discl ose d o utsi de t he cli nic u nless re q uire d b y  la w;
c)
t hat pers o nal i nf or mati o n (i ncl u di n g pers o nal healt h i nf or mati o n) ma y be a d de d t o 
Ta ke da’s researc h data bases f or p ur p oses of de vel o pi n g a better u n dersta n di n g of t he 
safety a n d effecti ve ness of t he st u d y dr u g(s), st u d yi n g ot her t hera pies f or patie nts, 
de vel o pi n g a better u n dersta n di n g of disease, a n d i m pr o vi n g t he efficie nc y  of f ut ure 
cli nical st u dies;
d)
t hat partici pa nt s a gree n ot t o restrict t he use a n d discl os ure of t heir pers o nal i nf or mati o n 
(i ncl u di n g pers o nal healt h i nf or mati o n) u p o n wit h dra wal fr o m t he st u d y t o t he e xte nt t hat 
t he restricte d use or discl os ure of s uc h i nf or mati o n may i m pact t he scie ntific i nte grit y of 
t he researc h; a n d
e)
t hat t he partici pa nt’s i de ntit y will re mai n c o nfi de ntial i n t he e ve nt t hat st u d y res ults are 
p u blis he d.
2 4. Fe male partici pa nts of c hil d beari n g p ote ntial (e g, n o n -sterilize d, pre-me n o pa usal fe male 
partici p a nts) w h o are se x uall y acti ve m ust use hi g hl y effecti ve c o ntrace pti o n (as defi ne d i n 
t he i nf or me d c o nse nt) fr o m si g ni n g t he i nf or me d c o nse nt a n d t hr o u g h o ut t he d urati o n of t he 
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 5 9 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
st u d y, a n d f or at least 2 8 da ys after t he last d ose of st u d y dr u g. Re g ular pre g na nc y tests will 
be perf or me d t hr o u g h o ut t he st u d y  f or all fe male partici pa nts of c hil d beari n g p ote ntial. If a 
partici pa nt is f o u n d t o be pre g na nt d uri n g st u d y, st u d y dr u g will be disc o nti n ue d a n d t he 
I n vesti gat or will offer t he partici pa nt t he c h oice t o recei ve treat me nt i nf or mati o n .
2 5. Male partici pa nts m ust use hi g hl y effecti ve c o ntrace pti o n (as defi ne d i n t he i nf or me d 
c o nse nt) fr o m si g ni n g t he i nf or me d c o nse nt t hr o u g h o ut t he d urati o n of t he st u d y a n d f or at 
least 9 0 d a y s after t he last d ose of st u d y dr u g. If t he part ner of t he partici pa nt is f o u n d t o be 
pre g na nt d uri n g t he st u d y , t he In vesti gat or will offer t he partici pa nt t he c h oice t o recei ve 
treat me nt i nf or mati o n.
2 6. A state me nt t hat cli nical trial i nf or mati o n fr o m t his st u d y  will be p u blicl y discl ose d i n a
p u blicl y  accessi ble we bsite, s uc h as Cli nical Trials. g o v.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 6 0 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
A p pe n di x C
I n vesti g at or C o nse nt t o t he Use of Pers o n al I nf or m ati o n 
Ta ke da will c ollect a n d retai n pers o nal i nf or mati o n of In vesti gat or, i ncl u di n g his or her na me, 
a d dress, a n d ot her pers o nall y i de ntifia ble i nf or mati o n. In a d diti o n, In vesti gat or ’s pers o nal 
i nf or mati o n ma y be tra nsferre d t o ot her parties l ocate d i n c o u ntries t hr o u g h o ut t he w orl d (e g, t he 
U nite d Ki n g d o m, U nite d States, a n d Ja pa n), i ncl u di n g t he f oll o wi n g:

Ta ke da, its affiliates, a n d lice nsi n g part ners.

B usi ness part ners assisti n g Ta ke da, its affiliates, a n d lice nsi n g part ners.

Re g ulat or y  a ge ncies a n d ot her healt h a ut h orities.

I RBs a n d I E Cs.
I n vesti gat or’s pers o nal i nf or mati o n ma y be retai ne d, pr ocesse d, a n d tra nsferre d by Ta ke da a n d 
t hese ot her parties f or researc h p ur p oses i ncl u di n g t he f oll o wi n g:

Assess me nt of t he s uita bilit y  of In vesti gat or f or t he st u d y  a n d/ or ot her cli nical st u dies.

Ma na ge me nt, m o nit ori n g, i ns pecti o n, a n d a u dit of t he st u d y .

A nal y sis, re vie w, a n d verificati o n of t he st u d y res ults.

Safet y  re p orti n g a n d p har mac o vi gila nce relati n g t o t he st u d y.

Pre parati o n a n d s u b missi o n of re g ulat or y  fili n gs, c orres p o n de nce, a n d c o m m u nicati o ns t o 
re g ulat or y a ge ncies relati n g t o t he st u d y

Pre parati o n a n d s u b missi o n of re g ulat or y  fili n gs, c orres p o n de nce, a n d c o m m u nicati o ns t o 
re g ulat or y a ge ncies relati n g t o ot her me dicati o ns use d i n ot her cli nical st u dies t hat ma y 
c o ntai n t he sa me c he mical c o m p o u n d prese nt i n t he st u d y  dr u g .

I ns pecti o ns a n d i n vesti gati o ns b y re g ulat or y a ut h orities relati n g t o t he st u d y.

Self -i ns pecti o n a n d i nter nal a u dit wit hi n Ta ke da, its affiliates, a n d lice nsi n g part ners.

Arc hi vi n g a n d a u dit of st u d y  rec or ds.

P osti n g In vesti gat or site c o ntact i nf or mati o n, st u d y  details a n d res ults o n p u blicl y accessi ble 
cli nical trial re gistries, data bases, a n d we bsites.
I n vesti gat or’s pers o nal i nf or mati o n ma y be tra nsferre d t o ot her c o u ntries t hat d o n ot ha ve data 
pr otecti o n la ws t hat offer t he sa me le vel of pr otecti o n as data pr otecti o n l a ws i n In vesti gat or ’s 
o w n c o u ntr y .
I n vesti gat or ac k n o wle d ges a n d c o nse nts t o t he use of his or her pers o nal i nf or mati o n b y Ta ke da 
a n d ot her parties f or t he p ur p oses descri be d a b o ve.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 6 1 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
A p pe n di x D
Pre g n a nc y a n d C o ntr ace pti o n
C o n tr ace pti o n a n d Pre g n a nc y A v oi d a nce Pr oce d ure
M ale P artici p a nts
Fr o m si g ni n g of i nf or me d c o nse nt, t hr o u g h o ut t he d urati o n of t he st u d y, a n d f or at least 9 0 d a y s 
after t he last d ose of st u d y dr u g , n o n-sterilize d * * male partici pa nts w h o are se x uall y  acti ve wit h 
a fe male part ner of c hil d beari n g p ote ntial * m ust use barrier c o ntrace pti o n (e g, c o n d o m wit h or 
wit h o ut s per mici dal crea m or jell y ). I n a d diti o n, t he y m ust be a d vise d n ot t o d o nate s per m d uri n g 
t his peri o d.
Fe m ale P artici p a nts a n d T heir M ale P art ners
F r o m si g ni n g of i nf or me d c o nse nt, t hr o u g h o ut t he d urati o n of t he st u d y, a n d f or 2 8 da ys after t he 
last d ose of st u d y dr u g , fe male partici pa nts of c hil d beari n g p ote ntial * w h o are se x uall y acti ve 
wit h a n o n -sterilize d male part ner * * m ust use a hi g hl y effecti v e met h o d of c o ntrace pti o n (fr o m 
t he list bel o w).
I n a d diti o n t he y m ust be a d vise d n ot t o d o nate o va d uri n g t his peri o d.
Defi niti o ns a n d Pr oce d ures f or C o ntr ace pti o n a n d Pre g n a ncy Av oi d a nce
T he f oll o wi n g defi niti o ns a p ply f or c o ntr ace pti o n a n d pre g n a ncy av o i d a nce pr oce d ures.
* A w o ma n is c o nsi dere d a w o ma n of c hil d beari n g p ote ntial , ie, 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. Per ma ne nt sterilizati o n met h o ds 
i ncl u de h ys ter osc o pic sterilizati o n, bilateral t u bal li gati o n, bilateral sal pi n gect o m y , h y sterect o my, 
a n d bilateral o o p h orect o m y . A p ost me n o pa usal state 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 ( F S H 
> 4 0 I U/ L) ma y be use d t o c o nfir m a p ost-me n o p a usal state i n yo u n ger w o me n (e g, t h ose 
< 4 5 ye ar ol d) or w o me n w h o are n ot usi n g h or m o nal c o ntrace pti o n or h or m o nal re place me nt 
t hera py. H o we ver, i n t he a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H meas ure me nt is 
i ns ufficie nt.
* * Sterilize d males s h o ul d be at least 1 ye ar p ost-bilateral vasect o m y  a n d ha ve c o nfir me d t hat 
t he y ha ve o btai ne d d oc u me ntati o n of t he a bse nce of s per m i n t he ejac ulate or ha ve ha d bilateral 
orc hi dect o m y.
T he f oll o wi n g pr oce d ures a p ply f or c o ntr ace pti o n a n d p re g n a ncy av oi d a nce.
1.
Hi g hl y effecti ve met h o ds of c o ntrace pti o n are defi ne d as “t h ose, al o ne or i n c o m bi nati o n, 
t hat res ult i n a l o w fail ure rate (ie, less t ha n 1 % fail ure rate per ye ar w he n use d c o nsiste ntl y 
a n d c orrectl y). I n t his st u d y , w here me dicati o ns a n d de vices c o ntai ni n g h or m o nes are 
i ncl u de d, t he o nl y acce pta ble met h o ds of c o ntrace pti o n are: 

N o n -H or m o nal Met h o ds:
–
I ntra uteri ne de vice.
–
Bilateral t u bal occl usi o n .
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 6 2 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
–
Vasect o mi ze d part ner ( pr o vi de d t hat part ner is t he s ole se x ual part ner of t he st u d y
parti ci pa nt a n d t hat t he vasect o mi ze d part ner has recei ve d me dical ass ess me nt of t he 
s ur gical s uccess).
–
Tr ue se x ual a bsti ne nce, o nl y  if t his is i n li ne wit h t he preferre d a n d us ual lifest yle of 
t he partici pa nt . Tr ue a bsti ne nce is defi ne d as refrai ni n g fr o m heter ose x ual i nterc o urse 
d uri n g t he e ntire peri o d of t he st u d y , fr o m at least 2 8 da y s pri or t o t he first d ose u ntil 
at least 2 8 d a y s after t he last d ose.

H or m o nal Met h o ds:
–
C o m bi ne d (estr o ge n a n d pr o gest o ge n) or pr o gest o ge n -o nl y  h or m o nal c o ntrace pti o n 
ass ociated wit h i n hi biti o n of o v ulati o n i nitiate d at least 3 m o nt hs pri or t o t he first 
d ose of st u d y  dr u g a n d c o m bi ne d wit h a p h ysical (e g, male c o n d o m, fe male c o n d o m, 
dia p hra g m) or a c he mical (e g, s per mici de) barrier met h o d fr o m t he scree ni n g visit 
u ntil at least 2 8 da y s after t he last d ose;

Oral .

I ntra va gi nal (e g, ri n g).

Tra ns der mal.
–
De p ot/i m pla nta ble h or m o ne (e g, De p o -Pr o vera ® , I m pla n o n® ) f or at least 3 m o nt hs 
pri or t o t he first d os e u ntil at least 2 8 d a y s after t he last d ose.

O ral.

I njecta ble.

I m pla nta ble.
9.
U nacc e pta ble met h o ds of c o ntrace pti o n are:

Peri o dic a bsti ne nce (e g , cale n dar, o v ulati o n, s y m pt ot her mal, p ost- o v ulati o n met h o ds).

S per mici des o nl y .

Wit h dra wal.

N o met h o d at all.

Use of fe male a n d male c o n d o ms t o get her.

Ca p/ dia p hra g m/s p o n ge wit h o ut s per mici de a n d wit h o ut c o n d o m.

Se x ual a bsti ne nce is N O T a n acce pta ble met h o d of c o ntrace pti o n , u nless it is tr ue se x ual 
a bsti ne nce as descri be d a b o ve.
2.
Partici pa nts will be pr o vi de d wit h i nf or mati o n o n hi g hl y effecti ve met h o ds of c o ntrace pti o n 
as part of t he partici pa nt i nf or me d c o nse nt pr ocess a n d will be as ke d t o si g n a c o nse nt f or m 
stati n g t hat t he y u n dersta n d t he re q uire me nts f or a v oi da nce of pre g na nc y, d o nati o n of o va, 
a n d s per m d o nati o n d uri n g t he c o urse of t he st u d y.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 6 3 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
3.
D uri n g t he c o urse of t he st u d y , re g ular ser u m h uma n c h ori o nic g o na d otr o pi n ( h C G) 
pre g na nc y  tests will be perf or me d o nly f or w o me n of c hil d beari n g p ote ntial a n d all 
partici pa nt s ( male a n d fe male) will recei ve c o nti n ue d g ui da nce wit h res pect t o t he a v oi da nce 
of pre g na nc y  a n d s per m d o nati o n as part of t he st u d y pr oce d ures. S uc h g ui da nce s h o ul d 
i ncl u de a re mi n der of t he f oll o wi n g:
a)
c o ntrace pti ve re q uire me nts of t he st u d y .
b) reas o ns f or use of barrier met h o ds (ie, c o n d o m) i n males wit h pre g na nt part ners.
c)
assess me nt of partici pa n t c o m plia nce t hr o u g h q uesti o ns s uc h as
i. Ha ve y o u use d t he c o ntrace pti o n c o nsiste ntl y a n d c orrectl y si nce t he last visit?
ii. H a ve y o u f or g otte n t o use c o ntrace pti o n si nce t he last visit?
iii. Are y o ur me nses late (e ve n i n w o me n wit h irre g ular or i nfre q ue nt me nstr ual c y cles a 
pre g na nc y  test m ust be perf or me d if t he a ns wer is “ y es”)
i v. Is t here a c ha nce y o u c o ul d be pre g na nt ?
4.
I n a d diti o n t o a ne gati ve ser u m h C G pre g na nc y  test at t he scree ni n g visit , fe male partici pa nts 
of c hil d beari n g p ote ntial m ust als o ha ve c o nfir me d me nses i n t he m o nt h bef ore first d o si n g 
( n o dela ye d me nses ; wit h t he e xce pti o n of fe male partici pa nts usi n g a pr ot oc ol acce pta ble 
c o ntrace pti o n met h o d t hat has a k n o w n si de effect of dela y e d or irre g ular me nses) . I n 
a d diti o n, partici pa nts m ust als o ha ve a ne gati ve ser u m h C G pre g na nc y  test wit h 2 4 h o urs 
pri or t o recei vi n g first d ose of st u d y dr u g as cl ose as p ossi ble a n d pri or t o first d ose of st u d y  
dr u g, prefera bl y o n t he sa me da y.
Ge ner al G ui d a nce Wit h Res pect t o t he Av oi d a nce of Pre g n a ncy
S uc h g ui da nce s h o ul d i ncl u de a re mi n der of t he f oll o wi n g:

c o ntrace pti ve re q uire me nts of t he st u d y .

reas o ns f or use of barrier met h o ds (ie, c o n d o m) i n males wit h pre g na nt part ners.

assess me nt of partici pa nt c o m plia nce t hr o u g h q uesti o ns s uc h as:
–
Ha ve y o u use d t he c o ntrace pti o n c o nsiste ntl y a n d c orrectl y si nce t he last visit?
–
H a ve y o u f or g otte n t o use c o nt race pti o n si nce t he last visit?
–
Are y o ur me nses late (e ve n i n w o me n wit h irre g ular or i nfre q ue nt me nstr ual c y cles a 
pre g na nc y  test m ust be perf or me d if t he a ns wer is “ yes”)
–
Is t here a c ha nce y o u c o ul d be pre g na nt ?
Pre g n a nc y
If a ny fe male partici pa nt is f o u n d t o be pre g na nt d uri n g t he st u dy s he s h o ul d be wit h dra w n a n d 
a n y S p o ns or-s u p plie d st u d y dr u g s h o ul d be i m me diatel y disc o nti n ue d. I n a d diti o n, a n y 
pre g na ncies i n t he part ner of a male partici pa nt d uri n g t he st u d y or f or at least 9 0 da y s after t he 
last d ose, s h o ul d als o be rec or de d f oll o wi n g a ut h orizati o n fr o m t he partici pa nt’s part ner.
F or n o n- c o m m er ci al u s e o nl y

B u des o ni de Or al S us pe nsi o n ( T A K -7 2 1)
St u d y N o. T A K -7 2 1 -1 0 0 3
P a ge 6 4 of 6 4
Pr ot oc ol
2 2 N o ve m ber 2 0 2 2
C O N FI D E N TI A L
If t he fe male partici pa nt a n d/ or fe male part ner of a male partici pa nt a grees t o t he pri mar y care 
p h y sicia n bei n g i nf or me d, t he In vesti gat or s h o ul d n otif y  t he pri mar y care p h ysicia n of her or her 
male part ner (ie, male partici pa nt) partici pati o n i n a cli nical st u d y  at t he ti me s he beca me 
pre g na nt a n d pr o vi de details of t he st u d y dr u g t he fe male partici pa nt or her male part ner
(ie, male partici pa nt) recei ve d.
All pre g na ncies, i ncl u di n g fe male part ners of male partici pa nt s, i n partici pa nt s o n acti ve st u d y  
dr u g (i ncl u di n g c o m parat or , if a p plica ble) will be f oll o we d u p t o fi nal o utc o me, usi n g t he 
pre g na nc y  f or m. T he o utc o me, i ncl udi n g a n y pre mat ure ter mi nati o n, m ust be re p orte d t o t he 
S p o ns or. A n e val uati o n after t he birt h of t he c hil d will als o be c o n d ucte d.
F or n o n- c o m m er ci al u s e o nl y