Clinical trial NCT06268301
Conditions: Healthy Volunteers
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2023-02-06; Completion date: 2023-02-20
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main aim of this study is to check what the body of a healthy adult who either fasted or had eaten does to TAK-721 and how TAK-721 is distributed in and removed from the body. Other aims are to learn how safe the treatment with TAK-721 is and how suitable the TAK-721 is for healthy adults who either fasted or had eaten. All participants will receive TAK-721 but half will be assigned by chance to the participant group who are fasting first then getting the high-fat/high-calorie meal later or the group who gets meal first and fasts later. The group assignment will be switched once during the course of the study so that all participants will receive TAK-721 in both a fasted or fed condition.

Detailed description:
The drug being tested in this study is called budesonide. Budesonide oral suspension (BOS) is being tested in healthy adult participants. This study will determine whether the absorption of BOS will be altered if taken with food.

The study will enroll approximately 20 patients. The study will consist of two treatment sequences and two periods separated by a washout period of 2 days. Participants will be randomly assigned (by chance, like flipping a fair coin) to one of the two treatment sequences:

* Treatment Sequence 1: Participants will receive 2 mg BOS orally on Day 1 of Period 1 in fasted condition (Treatment A). Two days later, participants will receive 2 mg BOS orally on Day 1 of Period 2 in fed condition (Treatment B).
* Treatment Sequence 2: Participants will receive 2 mg BOS orally on Day 1 of Period 1 in fed condition (Treatment B). Two days later, participants will receive 2 mg BOS orally on Day 1 of Period 2 in fasted condition (Treatment A).

This single center trial will be conducted in the United States. Participation in the study is up to approximately 34 days. Participants will visit the clinic approximately three days after last dose of study drug for a follow-up assessment.

Arms: arm 1: Participants will receive 2 mg BOS, single dose, orally on Day 1 of Period 1 under fasted condition (Treatment A). Two days later, participants will receive 2 mg BOS single dose, orally on Day 1 of Period 2 under fed condition (Treatment B). arm 2: Participants will receive 2 mg BOS, single dose, orally on Day 1 of Period 1 under fed condition (Treatment B). Two days later, participants will receive 2 mg BOS single dose, orally on Day 1 of Period 2 under fasted condition (Treatment A).
Interventions: intervention 1: Budesonide
Intervention descriptions: intervention 1: Budesonide oral suspension

Protocol documents:
Prot_000.pdf: 


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

SAP_001.pdf: 
For non-commercial use only


STATISTICAL ANALYSIS PLAN
Study Number: TAK-721-1003
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: 1
Version: Final
Date: 18 January 2023
Prepared by: 
, MS
Data Management and Biometrics
Celerion
, MSc
, Clinical Pharmacology & Pharmacometrics
Data Management and Biometrics
Celerion
Based on:
Protocol Version: Final
Protocol Date: 22 November 2022
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda.
For non-commercial use only


TAK-721-1003
Celerion Study Number CA39504
18 Jan 2023
Statistical Analysis Plan Final
Page 2 of 21
CONFIDENTIAL
REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
Original version
18-Jan-2023
Not Applicable
For non-commercial use only


For non-commercial use only


TAK-721-1003
Celerion Study Number CA39504
18 Jan 2023
Statistical Analysis Plan Final
Page 4 of 21
CONFIDENTIAL
TABLE OF CONTENTS
REVISION HISTORY.....................................................................................................................2
APPROVAL SIGNATURES...........................................................................................................3
TABLE OF CONTENTS.................................................................................................................4
LIST OF IN-TEXT TABLES ..........................................................................................................5
LIST OF IN-TEXT FIGURES.........................................................................................................5
ABBREVIATIONS .........................................................................................................................6
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................8
1.1
Objectives ......................................................................................................................8
1.1.1
Primary Objective..................................................................................................8
1.1.2
Secondary Objectives ............................................................................................8
1.2
Endpoints .......................................................................................................................8
1.2.1
Primary Endpoints.................................................................................................8
1.2.2
Secondary Endpoints.............................................................................................8
1.2.3
Additional Endpoints.............................................................................................9
1.3
Estimands.......................................................................................................................9
2.0
STUDY DESIGN.................................................................................................................9
3.0
STATISTICAL HYPOTHESES AND DECISION RULES.............................................11
3.1
Statistical Hypotheses ..................................................................................................11
3.2
Statistical Decision Rules ............................................................................................11
3.3
Multiplicity Adjustment...............................................................................................11
4.0
SAMPLE-SIZE DETERMINATION................................................................................11
5.0
ANALYSIS SETS .............................................................................................................11
5.1
Safety Set .....................................................................................................................11
5.2
PK Set ..........................................................................................................................11
6.0
STATISTICAL ANALYSIS .............................................................................................12
6.1
General Considerations................................................................................................12
6.1.1
Handling of Treatment Misallocations................................................................13
6.2
Study Information........................................................................................................13
6.3
Disposition of Participants...........................................................................................14
6.4
Demographic and Other Baseline Characteristics .......................................................14
6.4.1
Demographics......................................................................................................14
6.4.2
Medical History and Concurrent Medical Conditions.........................................14
6.5
Medication History and Concomitant Medications.....................................................14
6.6
Efficacy Analysis.........................................................................................................15
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6.7
Safety Analysis ............................................................................................................15
6.7.1
Adverse Events....................................................................................................15
6.7.2
Adverse Events of Special Interest......................................................................16
6.7.3
Clinical Laboratory Evaluation ...........................................................................17
6.7.4
Vital Signs ...........................................................................................................18
6.7.5
12-Lead ECG.......................................................................................................18
6.7.6
Physical Examinations.........................................................................................18
6.7.7
Overdose..............................................................................................................18
6.7.8
Extent of Exposure and Compliance ...................................................................19
6.8
Pharmacokinetic Analysis............................................................................................19
6.9
Patient Reported Outcomes and Health Care Utilization Endpoints Analysis ............20
6.10
Interim Analysis...........................................................................................................20
6.11
Preliminary Analysis....................................................................................................20
6.12
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees].................................................................................................................20
7.0
REFERENCES ..................................................................................................................20
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES...................................................20
9.0
APPENDIX........................................................................................................................21
9.1
Changes From the Previous Version of the SAP.........................................................21
9.2
Data Handling Conventions.........................................................................................21
9.3
Analysis Software........................................................................................................21
LIST OF IN-TEXT TABLES
Table 2.a
Study Treatments ...................................................................................................10
Table 6.a
Collection of Laboratory Samples .........................................................................17
Table 6.b
Collection of Vital Signs........................................................................................18
Table 6.c
Collection of Blood Samples for Pharmacokinetic Analysis.................................19
LIST OF IN-TEXT FIGURES
Figure 2.a
Overall Study Design.............................................................................................10
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ABBREVIATIONS
z
terminal disposition phase rate constant
AE
adverse event
AESI
adverse event of special interest
AUC0-12
area under the concentration-time curve from time 0 to 12 hours
AUC∞_obs
area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value of the last quantifiable concentration
AUC∞_pred
area under the concentration-time curve from time 0 to infinity, calculated using the predicted
value of the last quantifiable concentration
AUCextrap%_obs
area under the curve from the last quantifiable concentration to infinity, calculated using the 
observed value of the last quantifiable concentration, expressed as a percentage of AUC∞_obs
AUCextrap%_pred
area under the curve from the last quantifiable concentration to infinity, calculated using the 
predicted value of the last quantifiable concentration, expressed as a percentage of AUC∞_pred
AUClast
area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration
BLQ
below the lower limit of quantitation
BOS
budesonide oral suspension
CI
confidence interval
CL/F_obs
apparent clearance after extravascular administration, calculated using the observed value of 
the last quantifiable concentration
CL/F_pred
apparent clearance after extravascular administration, calculated using the predicted value of 
the last quantifiable concentration
Cmax
maximum observed concentration
COVID-19
coronavirus disease 2019 
CPAP
clinical pharmacology analysis plan
CRF
case report form
CRU
clinical research unit
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variance
DMP
data management plan
ECG
electrocardiogram
ET
early termination
Geom
geometric
GMR
geometric least-squares mean ratio
ICF
informed consent form
LLN
lower limit of normal
LSM
least-squares mean
Mean
arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
n
number of observations
PK
pharmacokinetic
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SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SEM
standard error of the mean
SOC
System Organ Class
t1/2z
terminal disposition phase half-life
TEAE 
treatment-emergent adverse event
TFL
table, figure, and listing
tlag
lag time to first quantifiable concentration
tmax
time to first occurrence of Cmax
Vz/F_obs
apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration
Vz/F_pred
apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the predicted value of the last quantifiable concentration
WHO
World Health Organization
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1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objective
To assess the relative bioavailability of a single dose of budesonide oral suspension (BOS) 
administered under fasting and fed (high-fat/high-calorie meal) conditions.
1.1.2
Secondary Objectives
To assess the safety and tolerability of a single dose of BOS administered under fasting and fed 
(high-fat/high-calorie meal) conditions.
To evaluate other pharmacokinetic (PK) parameters of a single dose of BOS administered under 
fasting and fed (high-fat/high-calorie meal) conditions.
1.2
Endpoints
1.2.1
Primary Endpoints
The following primary PK parameters will be analyzed for plasma budesonide:
•
Maximum observed concentration (Cmax).
•
Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast).
•
Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞_obs).
1.2.2
Secondary Endpoints 
Safety endpoints will include:
•
Incidence of treatment-emergent adverse events (TEAEs) and their severity, seriousness, and 
causality.
•
Incidence of clinically significant abnormal values for vital signs, and clinical laboratory 
evaluations.
The following secondary PK parameters will be analyzed for plasma budesonide:
•
Area under the concentration-time curve from time 0 to 12 hours (AUC0-12).
•
Area under the curve from the last quantifiable concentration to infinity, calculated using the 
observed value of the last quantifiable concentration, expressed as a percentage of AUC∞_obs
(AUCextrap%_obs).
•
Time to first occurrence of Cmax (tmax).
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•
Lag time to first quantifiable concentration (tlag).
•
Terminal disposition phase half-life (t1/2z).
•
Terminal disposition phase rate constant (λz).
•
Apparent clearance after extravascular administration, calculated using the observed value of 
the last quantifiable concentration (CL/F_obs).
•
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration 
(Vz/F_obs).
1.2.3
Additional Endpoints 
The following additional PK parameters will be analyzed for plasma budesonide:
•
Area under the concentration-time curve from time 0 to infinity, calculated using the 
predicted value of the last quantifiable concentration (AUC∞_pred).
•
Area under the curve from the last quantifiable concentration to infinity, calculated using the 
predicted value of the last quantifiable concentration, expressed as a percentage of AUC∞_pred
(AUCextrap%_pred).
•
Apparent clearance after extravascular administration, calculated using the predicted value of 
the last quantifiable concentration (CL/F_pred).
•
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the predicted value of the last quantifiable concentration 
(Vz/F_pred).
1.3
Estimands
Not applicable.
2.0
STUDY DESIGN
This is an open-label, single-dose, randomized, 2-period, 2-sequence, 2-way crossover study in 
healthy adult participants. A study schematic of the overall study design is shown in Figure 2.a
and the dose regimens are shown in Table 2.a. 
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Figure 2.a
Overall Study Design
AE=adverse event; BOS=budesonide oral suspension; CRU=clinical research unit; PK=pharmacokinetic
a.
In each period, participants will receive a single oral dose of BOS under fasting (Treatment A) or fed 
(high-fat/high-calorie meal; Treatment B) conditions on Day 1, according to the randomization schedule.
b.
There will be a washout of at least 2 days between doses.
c.
All participants who received any BOS (including participants who terminate the study early) will return to the 
CRU approximately 3 days after the last dose of BOS for follow-up procedures, and to determine if any AE has 
occurred since the last study visit.
Table 2.a
Study Treatments
Treatment
Study Drug
Dose
Dose Regimen
Treatment A
Budesonide oral 
suspension
2 mg 
(10 mL of 0.2 mg/mL)
Single dose, oral, fasting
Treatment B
Budesonide oral 
suspension
2 mg 
(10 mL of 0.2 mg/mL)
Single dose, oral, fed: following a 
high-fat/high-calorie meal
On Day 1 of Period 1, participants will be randomly assigned to 1 of 2 treatment sequences.
On Day 1 of each period, a single oral dose of BOS will be administered under fasting 
(Treatment A) or fed (high-fat/high-calorie meal; Treatment B) conditions. PK samples will be 
collected predose and up to 24 hours postdose in each period. There will be a washout of at least 
2 days between doses.
Safety and tolerability will be assessed throughout the study by TEAEs, vital signs, and clinical 
laboratory evaluations. All participants who received any BOS (including participants who 
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terminate the study early) will return to the clinical research unit (CRU) approximately 3 days 
after the last dose of BOS for follow-up procedures, and to determine if any adverse event (AE) 
has occurred since the last study visit.
3.0
STATISTICAL HYPOTHESES AND DECISION RULES 
3.1
Statistical Hypotheses
Not applicable.
3.2
Statistical Decision Rules
Not applicable.
3.3
Multiplicity Adjustment
Not applicable.
4.0
SAMPLE-SIZE DETERMINATION
Twenty (20) participants will be enrolled to account for possible dropouts.
A total of approximately 18 participants should complete all treatment periods of the study.
For plasma budesonide Cmax, AUC∞_obs, and AUClast, assuming the true mean ratio of 1.0 with 
intra-participant coefficient of variance (CV) of 21.8, 21.0, and 21.8%, respectively, 
18 completers will provide 80, 85, and 80% power to test for bioequivalence between dosing 
under fed versus fasting condition using the criteria of a 90% confidence interval (CI) within 
(0.80, 1.25). Considering 10% dropout rate, a total of 20 participants will be enrolled.
5.0
ANALYSIS SETS
5.1
Safety Set
All participants who received any study drug will be included in the safety evaluations.
5.2
PK Set 
All participants who comply sufficiently with the protocol and display an evaluable PK profile 
(eg, exposure to treatment, availability of measurements, and absence of major protocol 
violations) will be included in the PK analyses.
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6.0
STATISTICAL ANALYSIS
6.1
General Considerations
All PK analyses will be conducted using Phoenix® WinNonlin® Version 8.3.4, or higher. All 
statistical analyses will be conducted using SAS® Version 9.4. All data recorded on the case 
report form (CRF) will be listed by participant and treatment. All table, figure, and listing (TFL) 
shells and numbering list will be included and specified in the TFL Shells document. 
The number of observations (n) will be presented as an integer (no decimal places), arithmetic 
mean (mean), median, and geometric mean (geom mean) values will be presented to 1 more 
level of precision than the individual values. Standard deviation (SD) and standard error of the 
mean (SEM) will be presented to 2 more levels of precision than the individual values. Minimum 
and maximum values will be presented to the same precision as the individual values. Arithmetic 
percent coefficient of variation (CV%) and geometric percent coefficient of variation (geom 
CV%) will be presented to 1 decimal place.
Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
individual data. Geometric LSM ratios (GMRs) and 90% confidence intervals (CIs) for the 
GMRs will be reported to 2 decimal places. Intra-participant CVs will be reported to 1 decimal 
place.
Noncompartmental analyses of PK parameters will be used in this study. Concentration values 
below the lower limit of quantitation (BLQ) will be presented as ‘BLQ’ in the concentration 
table listings and footnoted accordingly. BLQ values will be treated as zero for the calculation of 
summary statistics, the generation of concentration plots, and the calculation of PK parameters, 
unless they are deemed questionable (eg, BLQ value between measurable values), in which case 
they will be treated as missing and excluded from the concentration summary statistics and the
PK analysis. Values of 0 are not included in the calculation of geom mean and geom CV%. 
A participant’s PK parameter data will be included in the listings but may be excluded from the 
descriptive and inferential statistics if one or more of the following criteria are met:

A predose (0 hour) concentration is greater than 5% of that participant’s Cmax value for the 
same treatment

A participant did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Pharmacology Lead and Celerion Pharmacokinetic Scientist)

A participant deviates substantially from the protocol defined study procedures including but 
not limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist) 

A participant may be excluded due to vomiting >2 times within the median tmax of 
budesonide (2 × 1.5 hours = 3 hours)
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The details on PK parameter calculations and TFLs will be outlined in the clinical pharmacology 
and analysis plan (CPAP) and TFL Shells document including specifics on the following:

Insufficient data to determine a reliable t1/2z value and other λz-dependent parameters 

PK parameters presented by treatment, including the units, precision, and summary statistics 
that will be presented in in-text and end-of-text tables

Concentration data presented by treatment, including the units, precision, and summary 
statistics that will be presented in end-of-text tables

Concentration data file used for PK analysis

PK parameter Phoenix® WinNonlin® output file used to generate the TFLs

PK parameter ratios for Cmax, AUClast, AUC∞_obs, and AUC∞_pred presented in end-of-text 
tables.

Linear mixed-effect model and non-parametric statistical analysis results presented in in-text 
and end-of-text tables

Arithmetic mean concentration-time figures presented as in-text and end-of-text figures

Listings of concentration data for individual participants in Appendix 16.2.5.

Individual concentration-time figures presented in Appendix 16.2.6.
Continuous demographic and safety data will be summarized descriptively. For categorical 
variables, the count and percentages of each reported value will be tabulated, where applicable. 
The denominator for the percent calculation will be the number of participants in the safety set 
for overall summaries, and the number of participants dosed with each treatment in by-treatment 
summaries. For continuous variables, n, mean, SD, minimum, median, and maximum values will 
be tabulated. The level of precision will be presented as follows: minimum/maximum in the 
same precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be presented 
as an integer. Counts and percentages will be presented as integers. Baseline is defined as the last 
observation prior to dosing.
6.1.1
Handling of Treatment Misallocations
Participants with any treatment misallocations will be analyzed based on the treatment the 
participants actually received.
6.2
Study Information
A study information table will be generated including the following items: date of first 
participant’s signed informed consent form (ICF), date of first dose of BOS, date of last dose of 
BOS, date of last participant’s last visit/contact, date of last participant’s last procedure for 
collection of data for primary endpoint, the version of Medical Dictionary for Regulatory 
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Activities (MedDRA®), the version of World Health Organization (WHO) Drug Dictionary, and 
SAS version used for creating the datasets.
6.3
Disposition of Participants
Disposition of all randomized participants (number of participants dosed, completed the study, 
discontinued from the study and/or BOS, and reason(s) for discontinuation(s)) will be 
summarized by randomized treatment sequence and overall. Treatment sequence, study 
completion status, date of completion, and whether BOS was discontinued will be listed by 
participant. Reasons for discontinuation of BOS and/or study and dates of discontinuation will be 
listed, if applicable. 
A listing of participants with major protocol deviations will also be provided by the clinic.
6.4
Demographic and Other Baseline Characteristics
6.4.1
Demographics
Demographic and baseline characteristics will be summarized by randomized treatment sequence 
and overall based on the safety set. Summary statistics (n, mean, SD, minimum, median, and 
maximum) will be generated for continuous variables (age, weight, height, and body mass index 
[BMI]) and the number and percentages of participants within each category will be presented 
for categorical variables (sex, race, and ethnicity). The last height, weight, and BMI measured 
prior to dosing will be used in the summaries. All demographic data will be listed by participant 
as recorded on the CRF, including date of informed consent and protocol version.
6.4.2
Medical History and Concurrent Medical Conditions
Medical history will include determining whether the participant has any significant conditions 
or diseases that resolved at or before signing the ICF. All medical history reported by the 
participant will be recorded regardless of when it may have occurred. Concurrent medical 
conditions are those significant ongoing conditions or diseases that are present at signing the 
ICF. Medical history and concurrent medical conditions will be listed based on safety set.
Any medical condition starting or worsening after taking the first dose of BOS will be classified 
as a TEAE. All medical history will be coded using MedDRA® version specified in the data 
management plan (DMP). If available, the medical history and concurrent medical condition 
listings will include the coded term (preferred term and system organ class [SOC]), start date (if 
known) and end date (if known) or whether the condition was ongoing, and a description of the 
condition or event. No summaries or statistical analysis will be performed for these data.
6.5
Medication History and Concomitant Medications 
Medication history includes any relevant medication stopped at or within 28 days before signing 
the ICF. Concomitant medication includes any medication other than BOS taken at any time 
between screening and the end of the study (including follow-up contact). All medication history 
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and concomitant medications recorded during the study will be coded with the WHO Drug 
Dictionary version specified in the DMP and listed based on the safety set. If available, the 
listings will include the medication name, coded term, dosage, route of administration, start date 
and time (if known), end date and time (if known), or whether it continued after study 
completion, and indication for use. No summaries or statistical analysis will be performed for 
these data. 
6.6
Efficacy Analysis
Not applicable.
6.7
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, severity and relationship(s) of TEAEs, and 
changes from baseline in the participants’ clinical laboratory results, vital signs, and 12-lead 
ECGs using the safety set. Clinically significant laboratory values and vital signs will be reported 
as AEs, as applicable. All safety data will be listed by participant, treatment, and assessment time 
points, including rechecks, unscheduled assessments, and early termination (ET), 
chronologically.
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators. Postdose recheck, unscheduled, or ET results will 
not be used in summaries.
Tables summarizing safety data by assessment time point will only include summaries for 
baseline and post-baseline time points.
6.7.1
Adverse Events
All AEs captured in the database will be listed in by-participant data listings including verbatim 
term, coded term, severity (mild, moderate, severe), relationship to BOS (related or not related), 
relationship to COVID-19 and COVID-19 vaccine, frequency, and action relative to the AE as 
recorded in the CRF. Study procedure taken due to AE will also be listed. All AEs occurring 
during this study will be coded using the MedDRA® version specified in the DMP. Only TEAEs 
will be summarized.
A TEAE is defined as an AE that is starting or worsening at the time of or after the first dose of 
BOS administered in the study, and until the follow up visit approximately 3 days after the last 
dose of BOS. Each TEAE will be attributed to the treatment prior to and the closest to the AE 
based on the AE onset date and time.
If the onset time of an AE is missing and the onset date is the same as a treatment dosing date, 
then the AE will be counted under the treatment given on the same day. If onset time of an AE is 
missing and the onset date does not fall on a dosing date, then the AE will be considered 
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treatment emergent for the most recent treatment administered. If the onset date of an AE is 
missing, then the AE will be considered treatment emergent and attributed to the first treatment 
received. If severity is missing, the AE will be counted as severe, and if relationship is missing, 
the AE will be counted as related. 
TEAEs will be tabulated by treatment (including overall), SOC, and preferred term. Summary 
tables will include number of participants reporting the TEAE as percent of safety set by 
treatment and overall. The most commonly reported non-serious TEAEs (i.e., those events 
reported by >1 participant in any treatment, excluding serious adverse events (SAEs) will also be 
summarized. The denominators for percent calculations will be the number of participants dosed 
for each treatment. In addition, TEAEs will be summarized as number of TEAEs and percentage 
of TEAEs for each treatment and overall. 
Additional TEAE summary tables will be presented by severity and relationship to BOS. If a 
participant has multiple TEAEs with different severity levels within the same preferred term, the 
participant will be counted in the most severe category only. For relationship to BOS, if a 
participant has both related and unrelated TEAEs with the same preferred term, the participant 
will be counted as having related TEAEs.
An overview summary of TEAEs table, including number of participants with TEAEs, 
treatment-emergent SAEs, treatment-related TEAEs, treatment-related SAEs, TEAEs by 
severity, and AEs leading to discontinuation will be provided.
Should any SAEs (including all-cause mortalities) occur, they will be summarized the same way 
as TEAEs. All AEs will be displayed in the data listings and TEAEs will be discussed in the text 
of the clinical study report (CSR).
6.7.2
Adverse Events of Special Interest 
Since BOS is a glucocorticosteroid, general warnings concerning glucocorticoids should be
followed:

Hypercortisolism and adrenal suppression.

Increased risk of infection.

Other glucocorticoid effects including fractures, hypertension, diabetes mellitus, 
osteoporosis, peptic ulcer, glaucoma, or cataracts.

Gastrointestinal symptoms related to corticosteroid use.
However, identification of AESI is not mandatory for the purposes of this study.
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6.7.8
Extent of Exposure and Compliance
The dates, times, and doses of BOS will be listed by participant and study period.
6.8
Pharmacokinetic Analysis
Blood samples for assessment of plasma budesonide concentrations will be collected as outlined 
in Table 6.c below: 
Table 6.c
Collection of Blood Samples for Pharmacokinetic Analysis
Analyte
Matrix
Scheduled Time (Hours)*
Budesonide
Plasma
Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 24 hours postdose. 
*The actual date and time of sample collection will be recorded on the source document in the case report form. 
Plasma concentrations of budesonide will be listed and summarized descriptively by PK 
sampling time and treatment using the following descriptive statistics: n, mean, SD, CV%, SEM, 
minimum, median, and maximum. Excluded concentrations will be presented and footnoted as 
such in the concentration table listings, and those values will be excluded from the descriptive 
statistics. 
Individual participant concentration-time curves will be plotted by treatment on linear and 
semi-log scales. The arithmetic mean profiles of the concentration-time data will be plotted by 
treatment on linear (with and without SD) and semi-log scales. For summary statistics and 
arithmetic mean plots by sampling time, the nominal PK sampling time will be used. For 
individual participant plots by time, the actual PK sampling time will be used.
The PK parameters will be calculated from plasma budesonide concentration-time profiles using 
non-compartmental analysis methods where all calculations will be based on actual sampling 
times after dosing. The PK parameters will be summarized by treatment using the following 
descriptive statistics: n, mean, SD, CV%, SEM, minimum, median, maximum, geom mean, and 
geom CV%. Excluded parameters will be presented and footnoted as such in the PK parameter 
table listings, and those values will be excluded from descriptive statistics.
Estimation of Food-Effect
A linear mixed-effects model will be applied to natural log-transformed Cmax, AUClast, AUC∞_obs, 
and AUC∞_pred with treatment, period, and sequence as fixed effects, and participant within 
sequence as a random effect. Point estimates and their associated 90% CIs will be constructed for 
the difference between Treatment B (fed) minus Treatment A (fasting). The point estimates and 
their associated 90% CIs will be then back transformed to provide point estimates and 90% CIs 
for the ratios of Treatment B (fed) versus Treatment A (fasting).
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The following SAS code will be used to perform the food-effect analysis:
PROC MIXED;
CLASS TREAT PERIOD SEQUENCE PARTICIPANT;
MODEL LN<Parameter> = TREAT PERIOD SEQUENCE / DDFM = KR;
RANDOM PARTICIPANT(SEQUENCE);
ESTIMATE “Treatment B (Fed) vs Treatment A (Fasted)” TREAT -1 1 / CL ALPHA=0.1 E;
RUN;
Non-Parametric Analysis
Analysis of tmax and tlag will be performed by non-parametric Wilcoxon signed-rank test. The 
median difference (fed versus fasted) and 90% CI will be estimated using the Hodges-Lehmann 
method and Walsh averages. The tmax and tlag parameters will not be ln-transformed. The 
comparison of interest is the same as in the linear mixed-effects model.
6.9
Patient Reported Outcomes and Health Care Utilization Endpoints Analysis
Not applicable.
6.10
Interim Analysis
Not applicable.
6.11
Preliminary Analysis
Two preliminary PK analyses, the first based on quality-controlled data and the second based on 
quality-assured data, will be completed as described in the CPAP and Section 6.8 of the 
statistical analysis plan (SAP), with the following changes: 1) nominal times (not actual 
sampling times) will be used to calculate PK parameters; 2) tables and figures will be created 
using Phoenix® WinNonlin® Version 8.3.4 or higher.
6.12
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees]
Not applicable.
7.0
REFERENCES
Not applicable.
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES
The following PK parameters not specified in the protocol will also be calculated for plasma 
budesonide: AUC∞_pred, AUCextrap%_pred, CL/F_pred, and Vz/F_pred.
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TAK-721-1003
Celerion Study Number CA39504
18 Jan 2023
Statistical Analysis Plan Final
Page 21 of 21
CONFIDENTIAL
9.0
APPENDIX 
9.1
Changes From the Previous Version of the SAP
Not applicable.
9.2
Data Handling Conventions 
Not applicable.
9.3
Analysis Software 
SAS® Version 9.4 or higher will be used for all statistical analysis provided in the CSR.
For non-commercial use only