Clinical trial NCT05248997
Conditions: Chronic Rhinosinusitis (CRS) With and Without Nasal Polyps
Keywords: Chronic Rhinosinusitis (CRS) Chronic Rhinosinusitis (CRS) with Nasal Polyps Chronic Rhinosinusitis (CRS) without Nasal Polyps
Sponsor: Pfizer
Start date: 2022-02-17; Completion date: 2024-04-02
Enrollment: 261 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy and safety of rimegepant versus placebo in the acute treatment of chronic rhinosinusitis (CRS) with and without nasal polyps.

Detailed description:

Arms: arm 1: One dose of rimegepant 75 mg ODT arm 2: One dose of matching placebo
Interventions: intervention 1: rimegepant 75 mg ODT intervention 2: Matching placebo
Intervention descriptions: intervention 1: One dose of rimegepant 75 mg ODT intervention 2: One dose of matching placebo

Protocol documents:
Prot_000.pdf: 
B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
D R U G:
B H V - 3 0 0 0 ( P F-0 7 8 9 9 8 0 1) (ri me ge pa nt)
S T U D Y N U M B E R( S):
B H V 3 0 0 0 - 3 1 6 ( C 4 9 5 1 0 1 5)
P R O T O C O L TI T L E:
A P hase 2 / 3, D o u ble-Bli n d, Ra n d o mize d, Place b o -
C o ntr olle d , Safet y a n d Efficac y Trial of B H V-3 0 0 0 
(ri me ge pa nt) Orally Disi nte grati n g Ta blet ( O D T) f or t he 
Ac ute Treat me nt of C hr o nic R hi n osi n usitis ( C R S) Wit h 
or Wit h o ut Nasal P ol y ps
I N D N U M B E R:
I ND 1 5 8 9 5 7
S P O N S O R:
Pfizer I nc. 
6 6 H u ds o n B o ule var d East
Ne w Y or k, N Y 1 0 0 0 1
O RI GI N A L P R O T O C O L D A T E:
2 1 Oct o ber 2 0 2 1
V E R SI O N N U M B E R:
4. 0
V E R SI O N D A T E:
1 4 J ul y 2 0 2 3
T his a me n d me nt i nc or p orates all re visi o ns t o date, i ncl u di n g a me n d me nts ma de at t he re q uest of 
c o u ntr y healt h a ut h orities a n d IR Bs/ E Cs, a n d a n y pr ot oc ol a d mi nistrati ve c ha n ge letter (s).
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E
Versi o n 4. 0 – A me n d me nt 3 ( 0 7 J ul y  2 0 2 3)
O ver all R ati o n ale f or t he A me n d me nt: C ha n ge i n s p o ns ors hi p fr o m Bi o ha ve n t o Pfizer wit h 
ali g n me nt of t he pr ot oc ol te m plate.
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n # a n d N a me
S u bst a nti al M o dific ati o n(s)
Refere nce d st u d y n u m ber 
B H V 3 0 0 0 -3 1 6 t o C 4 9 5 1 0 1 5 
a n d c o m p o u n d na me B H V-
3 0 0 0 t o P F -0 7 8 9 9 8 0 1 t o 
reflect i de ntificati o n c ha n ges 
b y  s p o ns or.
Reflects c ha n ge i n s p o ns ors hi p p r ot oc ol 
a n d c o m p o u n d i de ntificati o n n u m bers
S t u d y Sy n o psis
1. 1 Bac k gr o u n d 
1. 3 St u d y  Rati o nale
7. 1. 1 I n vesti gati o nal 
Pr o d uct Hea ders
Title pa ge
S p o ns or na me c ha n ge d
R eflects tra nsfer of s p o ns ors hi p fr o m 
Bi o ha ve n P har mace uticals H ol di n g 
C o m pa n y  Li mite d t o Pfizer I nc.
T hr o u g h o ut t he 
d oc u me nt
Refere nce d st u d y n u m ber 
B H V 3 0 0 0 -3 1 6 t o C 4 9 5 1 0 1 5 
a n d c o m p o u n d na me 
B H V 3 0 0 0 t o P F -0 7 8 9 9 8 0 1 t o 
reflect i de ntificati o n c ha n ges 
b y  sp o ns or
T o ref lect s p o ns ors hi p c ha n ge, pr ot oc ol
a n d c o m p o u n d i de ntificati o n n u m bers
Pr ot oc ol c o ver pa ge 
St u d y  sc he matic
1. 1 Bac k g r o u n d
1. 3 St u d y  rati o nale
4. 2 Sc he d ule of 
Assess me nts
Pla n ne d n u m ber of s u bjects 
ra n d o mize d i ncrease d (fr o m 
a p pr o xi matel y 2 5 0 t o 
a p pr o xi matel y 2 8 6)
T o acc o u nt f or t he perce nta ge of s u bjects 
n ot ha vi n g a facial pai n/ press ure/f ull ness 
w hic h reac hes pai n i nte nsit y  of ≥6 o n 
t he N R S ( 0- 1 0)
St u d y  S u m mar y 
( S yn o psis)
1. 3. 1 St u d y  desi g n 
rati o nale
5. 1 N u m ber of 
S u bjects
4. 2. 2 Ac ute 
treat me nt 
( Ra n d o mizati o n) 
p hase
9. 2 Sa m ple size
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L
I ncl usi o n criteri o n # 1 “ Si g ne d 
writter n I nf or me d C o nse nt” 
delete d
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
5. 2. I ncl usi o n 
Criteria
I ncl usi o n criteri o n # 2. b a n d 
E xcl usi o n criteri o n # 4.a f or 
re pr o d ucti ve stat us u p date d
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
5. 2. I ncl usi o n 
Criteria
5. 3. E xcl usi o n 
Criteria
A d diti o n of a n e xcl usi o n 
criteri o n # 7.i f or site staff, 
s p o ns or e m pl o yees a n d 
fa milies
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
5. 3. E xcl usi o n 
Criteria
A d diti o n o f a n e xcl usi o n 
criteri o n # 7.j “ S u bject u na ble 
t o c o m plete e Diar y 
i n de pe n de ntly i n t he o pi ni o n 
of t he I n vesti gat or . ”
T o e ns ure e Diar y  data is c ollecte d 
a p pr o priatel y
5. 3. E xcl usi o n 
Criteria
E xcl usi o n criteri o n # 2.a f or 
b o d y  mass i n de x c ha n ge d t o 
> 3 5. 0 k g/ m 2 (i nstea d of  ≥ 
3 3. 0 k g/ m 2)
T o ali g n wit h t he defi niti o n of all Class 1 
O besit y  s u bjects
5 . 3 E xcl usi o n 
Criteria
E xcl usi o n criteri o n # 2. b f or 
“ HI V disease” delete d
T o ali g n wit h ri me ge pa nt prescri bi n g 
i nf or mati o n w here t here is n o 
co ntrai n dicati o n f or use
5 . 3 E xcl usi o n 
Criteria
E xcl usi o n criteri o n # 2.j f or 
“ Hist or y of he mat ol o gic or 
s oli d mali g na nc y dia g n osis 
wit hi n 5 y ears pri or t o 
scree ni n g” delete d
E xcl usi o n criteri o n alrea d y  c o vere d i n 
a n ot her E xcl usi o n criteri o n a n d t o ali g n 
wit h ri me ge pa nt prescri bi n g i nf or mati o n 
w here t here is n o c o ntrai n dicati o n f or 
use
5 . 3 E xcl usi o n 
Criteria
E xcl usi o n criteri o n # 5.a f or 
e G F R criteria c ha n ge d t o <
3 0 ml/ mi n/ 1. 7 3 m 2
All o we d f or s u bjects wit h m o derate 
re nal i m pair me nt t o be i ncl u de d i n t he 
trial c o nsiste nt wit h t he prescri bi n g 
i nf or mati o n
5. 3 E xcl usi o n 
Criteria
E xcl usi o n criteria # 5. b-e f or 
“ Q Tc F, Left B u n dle Bra nc h 
Bl oc k, Ri g ht B u n dle Bra nc h 
Bl oc k a n d I ntra C o n d ucti o n 
defect” delete d 
T o ali g n wit h ri me ge pa nt prescri bi n g 
i nf or mati o n w here t here is n o 
co ntra i n dicati o n f or use
5 . 3 E xcl usi o n 
Criteria
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
E xcl usi o n criteri o n # 5. b f or 
“E C G a b n or malities t hat, i n 
t he In vesti gat or’s o pi ni o n, 
ma kes t he s u bject u ns uita ble 
f or partici pati o n i n t he st u d y” 
a d de d
T o i ncrease st u d y  i ncl usi vit y a n d t o ali g n 
wit h ri me ge pa nt pr escri bi n g i nf or mati o n 
w here t here is n o c o ntrai n dicati o n f or 
use
5 . 3 E xcl usi o n 
Criteria
E xcl usi o n criteri o n # 5.f f or 
li ver e nz ymes ( A L T a n d 
A S T) c ha n ge d t o > 2 x U L N 
(i nstea d > 1 x U L N) a n d # 5.c 
t otal bilir u bi n c ha n ge d t o 
> 1. 5 x U L N ( i nstea d > 1 x 
U L N). F or Gil bert’s 
s yn dr o me, direct bilir u bi n 
> U L N is e xcl usi o nar y .
T o ali g n wit h ri me ge pa nt prescri bi n g 
i nf or mati o n w here t here is n o 
c o ntrai n dicati o n f or use
5 . 3 E xcl usi o n 
Criteria
E xcl usi o n criteri o n # 5.e f or 
H b A 1c c ha n ge d t o > 7. 5 % 
(i nstea d of  ≥ 6. 5 %)
T o all o w t he i ncl usi o n of well c o ntr olle d 
dia betics, ali g ne d wit h ri m ge pa nt 
prescri bi n g i nf or mati o n w here t here is 
n o e xcl usi o n f or s u bjects wit h dia betes
5 . 3 E xcl usi o n 
Criteria
E xcl usi o n criteri o n # 6.f f or 
pri or m o n ocl o nal a nti b o d y  
use c ha n ge d fr o m 6 m o n t hs t o 
3 m o nt hs pri or t o scree ni n g
T o i ncrease st u d y  i ncl usi vit y a n d t o ali g n 
wit h ri me ge pa nt prescri bi n g i nf or mati o n 
w here t here is n o c o ntrai n dicati o n f or 
use
5 . 3 E xcl usi o n 
Criteria
5. 4 Pr o hi bite d 
Me dicati o ns
A d diti o n of a n e xcl usi o n 
criteri o n # 6.j “ Use of a n y 
pr o hi bite d c o nc o mita nt 
me dicati o n(s) as s pecifie d i n 
Secti o n 5. 4.”
T o ali g n wit h Secti o n 5. 4 Pr o hi bite d a n d 
Restricte d C o nc o mita nt Me dicati o ns
5. 3. E xcl usi o n 
Criteria
As piri n d ose all o we d c ha n ge d 
fr o m 8 1 m g t o u p t o 1 0 0 m g
T o ta ke i nt o acc o u nt c o m m o nl y 
prescri be d d ose i n car di o vasc ular 
pr o p h y la xis
5. 4 Pr o hi bite d a n d 
Restricte d 
C o nc o mita nt 
Me dicati o ns
G ui da nce relati ve t o W o me n 
of C hil beari n g P ote ntial 
re place d wit h C o ntrace pt i o n 
secti o n a n d A p pe n di x III
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
5. 6 C o ntrace pti o n
1 6. 3 A p pe n di x III : 
C o ntrace pti ve a n d 
Barrier G ui da nce
A d diti o n of g ui da nce relati ve 
t o a b n or mal la b orat or y tests
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
6. 2. 4 L a b orat or y 
assess me nts
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 of 1 0 4
P FI Z E R C O N FI D E N TI A L
A d diti o n of g ui da nce relati ve 
t o E C G ma na ge me nt a n d 
a d diti o n of a ne w a p pe n di x 
relati ve t o EC G fi n di n gs of 
P ote ntial Cli nical C o ncer n
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
6. 2. 2 E C G
1 6. 2: A P P E N DI X II: 
E C G fi n di n gs of 
P ote ntial Cli nical 
C o ncer n
State me nt re gar di n g a n y 
“ yes” res p o nses o n t he C-
S S R S q uesti o n naire u p date d
T o ali g n wit h E xcl usi o n criteri o n # 7.f 
6. 2. 5 C ol u m bia -
S uici de Se verit y  
Rati n g Scale ( C -
S S R S)
Re m o ve d N o n -I n vesti gati o nal 
Pr o d uct secti o n
N ot a p plica ble f or t his st u d y
7. 1. 2. N o n -
I n vesti gati o nal 
Pr o d uct
P ote ntial DI LI cases 
i de ntificati o n a n d 
ma na ge me nt u p date
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses 
8. 5 P ote ntial Dr u g 
I n d uce d Li ver I nj ur y 
( DI LI)
U p date d O ver d ose secti o n
T o clarif y  t hat o nly o ver d ose ass ociate d 
wit h a n S A E is re p orta ble t o Pfizer 
Safet y  
8. 3 O ver d ose
Re -scree ni n g p olic y u p date d
T o all o w a n d defi ne rescree ni n g criteria 
f or pre vi o usly scree n faile d s u bjects
4. 2. 1 Scree ni n g 
p hase
U p date d t he i nf or mati o n 
a b o ut t he k n o w n a n d 
e x pecte d be nefits a n d ris ks 
a n d reas o na bl y e x pecte d A Es 
of r i me ge pa nt a n d refere nce d 
t o t he In vesti gat or Br oc h ure
T o ali g n wit h I n vesti gat or br oc h ure
1. 2 Pr o d uct 
de vel o p me nt 
bac k gr o u n d
1. 3. 4 Be nefit/ Ris k 
assess me nt
D escri pti o n of pri mar y 
esti ma n d a d de d
Pri mar y  esti ma n d descri pti o n was n ot 
i ncl u de d i n earlier pr ot oc ol versi o ns
9. 3 P o p ulati o ns f or 
A nal y sis a n d 
Esti ma n ds
D elete d  “s u bject as r a n d o m 
effect “ a n d  c ha n ge d 
“ge ner alize d li ne ar mixe d 
effect m o del ” t o “li ne ar 
m o del ” fr o m t he m o del 
s pecificati o n of pri mar y a n d 
sec o n dar y a nalys is
A re peate d meas ure wit hi n s u bject is 
alrea d y c o nsi dere d i n M M R M a nal y sis 
t o a d dress wit hi n s u bject c orrelati o n. 
A d diti o nal s pecificati o n of ra n d o m effect 
f or s u bject is mislea di n g t o t he c o nte xt.
9. 4. Statistical 
met h o ds
A d diti o n of “ Se nsiti vit y  
a nal ys is”
R o b ust nes s of pri mar y esti ma n d ( M A R 
ass u m pti o n) will be verifie d t hr o u g h 
a d diti o nal se nsiti vit y a nal ysis
9. 4. 2 Pri mar y  
E n d p oi nt(s)
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B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Re place d “ str atifie d 
C oc hr a n- M a ntel -H ae nszel 
( C M H) test … str atific ati o n 
f act or as...” wit h “M a ntel -
H ae nszel risk esti m ati o n …. 
str atific ati o n by …"
C orrect refere nce t o test pr oce d ure
9. 4. 3. Sec o n dar y  
E n d p oi nts
A d diti o n of t he secti o n 
re gar di n g S p o ns or’s 
Me dicall y  Q ualifie d 
I n di vi d ual
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
1 0. 6 S p o ns or’s 
Me dicall y  Q ualifie d 
I n di vi d ual
D eleti o n of tacr oli m us
T o a li g n wit h n o ncli nical a n d cli nical 
dr u g t o dr u g i nteracti o n i nf or mati o n 
a vaila ble o n ri me ge pa nt
1 6. 1 A P P E N DI X I: 
Str o n g I n hi bit ors a n d 
Str o n g a n d M o derate 
I n d ucers of C Y P 3 A 4 
Pr otei n ( N ot all -
i ncl usi ve)
A d diti o n of m o derate 
C Y P 3 A 4 i n d ucers
T o ali g n wit h n o ncli nical a n d cli nical 
dr u g t o dr u g i nteracti o n i nf or mati o n 
a vaila ble o n ri me ge pa nt
1 6. 1 A P P E N DI X I: 
Str o n g I n hi bit ors a n d 
Str o n g a n d M o derate 
I n d ucers of C Y P 3 A 4 
Pr otei n ( N ot all -
i ncl usi ve)
A d diti o n of C o ntrace pti ve 
a n d Barrier Gui da nce
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
1 6. 3 A P P E N DI X III: 
C o ntrace pti ve a n d 
Barrier G ui da nce
Defi ne d E n d of St u d y
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
4. 1 St u d y  Desi g n 
a n d D urati o n
N o n -s u bst a nti al M o dific ati o n(s)
Clarifie d I P a d mi nistrati o n
T o ali g n wit h Secti o n 7. 2. 2 Selecti o n a n d 
Ti mi n g of D ose a n d A d mi nistrati o n
1. 3. 1 St u d y  Desi g n 
Rati o nale
4. 1 St u d y  Desi g n 
a n d D urati o n
U p date d t he Seri o us A d verse 
E ve nt ( S A E) a n d pre g na nc y  
re p orti n g desti nati o n a n d 
electr o nic re p orti n g s ys tem ; 
u p date d S A E re p orti n g 
re q uire me nts
T o i nc or p orate t he n o n -s u bsta ntial 
c ha n ges descri be d i n pre vi o us P A C L  
date d 2 8 A pr 2 0 2 3
8. 1. 2 C ollecti o n a n d 
re p orti n g Seri o us 
A d verse E ve nts 
8. 4 Pre g na nc y
A d diti o n of Pre g na nt Part ner 
Release of I nf or mati o n F or m
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
8. 4 Pre g na nc y
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B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 of 1 0 4
P FI Z E R C O N FI D E N TI A L
U p date d t he n o n -Seri o us 
A d verse E ve nts re p orti n g 
starti n g p oi nt
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses re gar di n g A E re p orti n g 
starti n g p oi nt
8. 2. 1 C ollecti o n a n d 
re p orti n g of n o n-
Seri o us A d verse 
E ve nts
Re p orti n g re q uire me nts 
a d de d f or :
E n vir o n me ntal E x p os ure, 
E x p os ure D uri n g 
B reastfee di n g, Occ u pati o nal 
E x p os ure ;
Lac k of E fficac y;
Me dicati o n E rr ors;
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
8. 7 E n vir o n me ntal 
E x p os ure, E x p os ure 
D uri n g 
Breastfee di n g a n d 
Occ u pati o nal 
E x p os ure
8. 8 L ac k of Efficac y
8. 9 Me dicati o n 
Err ors
A p pr o xi mati ve n u m ber of 
sites a n d st u d y d urati o n 
delete d
T o ali g n wit h Pfizer’s sta n dar ds
5. 1 N u m ber of 
s u bjects
Clarifie d t hat dail y  
me dicati o n d oses m ust be 
sta ble f or at least o ne m o nt h 
pri or t o t he Scree ni n g Visit 
a n d t hr o u g h o ut t he st u d y
C orrecti o n
5. 5 Dail y  a n d 
Resc ue Me dicati o ns
A d diti o n of refere nce t o 
Q ualit y  T olera nce Li mits a n d 
re na me d t he secti o n
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
5. 8 Pr ot oc ol 
de viati o ns a n d 
Q ualit y  T olera nce 
Li mits
A d diti o n of I n vesti gati o nal 
Pr o d uct ma n ual a n d P re g na nt 
Part ner Release of 
I nf or mati o n F or m; U p date d 
f or ms a n d re m o ve d refere nce 
t o e C R F f or S A E re p orti n g
T o ali g n wit h Pfizer’s pr ocesses
6. 1 St u d y  materials
Re place me nt of “ P har mac y  
Ma n ual” wit h 
“I n vesti gati o nal Pr o d uct 
Ma n ual”
a n d re m o val of 
“ h u mi dit y” fr o m 
e n vir o n me ntal c o n diti o n
re q uire me nts
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
7. 1. 2 Pac ka gi n g, 
S hi p me nt a n d 
St ora ge
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 of 1 0 4
P FI Z E R C O N FI D E N TI A L
State me nt re gar di n g p u blic 
re gistrati o n of P hase 1 trials 
i n p u blicl y accessi ble 
data base delete d. S tate me nt 
re gar di n g Pri nci pal 
I n vesti gat or a n d t he s p o ns or’s 
re prese ntati ve si g nat or y 
delete d. S p o ns or’s re g ulat or y  
a n d et hics res p o nsi bilities 
a d de d
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
1 0. 1 G o o d Cli nical 
Practice
Ne w secti o n re gar di n g 
Disse mi nati o n of Cli nical 
St u d y  Data
T o ali g n wit h Pfizer’s sta n dar ds 
re gar di n g disse mi nati o n of Cli nical 
St u d y  Data
1 0. 2 Disse mi nati o n 
of Cli nical St u d y  
Data
Clarifie d t hat s u bject m ust 
si g n a n d date a n I R B/I E C 
a p pr o ve d writte n i nf or me d 
c o nse nt f or m f or st u d y
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
1 0. 4 I nf or me d 
C o nse nt
Re m o ve d state me nt t hat 
I RB/I E C has t o be n otifie d at 
least 5 da ys pri or t o 
i m ple me nti n g pr ot oc ol 
c ha n ge
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
1 2 A me n d me nts
Secti o n 1 3 “ St u d y re p ort a n d 
P u blicati o ns p olic y ” re na me d 
t o “ P u blicati o n p olic y”; 
se nte nce re gar di n g C S R 
delete d
T o acc o u nt f or t he a d diti o n of Secti o n 
1 0. 2 Disse mi nati o n of Cli nical St u d y  
Data
1 3 P u bl icati o n 
p olic y
Secti o n 1 5 “ C o nfi de ntialit y ” 
re na me d t o “ Data Pr otecti o n” 
a n d u p date d
T o ali g n wit h Pfizer’s sta n dar ds a n d 
pr ocesses
1 5 Data pr otecti o n
M o ve d past pr ot oc ol 
a me n d me nts secti o n 
“ S u m mar y of C ha n ges” t o 
A p pe n di x 
T o ali g n wit h Pfizer’s e dit orial sta n dar ds
1 6. 3 A P P E N DI X IV:
Pr ot oc ol 
A me n d me nt Hist or y
Secti o ns “ C o nfi de ntialit y a n d 
I n vesti gat or state me nt” a n d 
“ Cli nical Pr ot oc ol A p pr o val 
f or m” re m o ve d
T o ali g n wit h Pfizer’s sta n dar ds
C o nfi de ntialit y  a n d 
I n vesti gat or 
state me nt
Cli nical Pr ot o c ol 
A p pr o val f or m
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Re place me nt of “ partici pa nt” 
wit h “s u bject”
F or c o nsiste nc y  t hr o u g h o ut t he pr ot oc ol
T hr o u g h o ut t he 
pr ot oc ol
Re n u m beri n g of I ncl usi o n
an d E xcl usi o n criteria
E dit orial c ha n ge
5 . 2 Incl usi o n criteria
5. 3 E xcl usi o n 
criteria
L ist of a b bre viati o ns u p date d 
T o reflect ne w a b bre viati o ns a d de d t o 
t he Pr ot oc ol a me n d me nt
L ist of a b bre viati o ns
Mi n or gra m matical a n d 
s pelli n g c orrecti o ns; Secti o n 
re n u m beri n g 
C orrecti o ns
T hr o u g h o ut t he 
d oc u me nt
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 0 of 1 0 4
P FI Z E R C O N FI D E N TI A L
S T U D Y S U M M A R Y ( S Y N O P SI S)
Title: 
A P hase 2 / 3, D o u ble-Bli n d, Ra n d o mize d, Place b o -C o ntr olle d, Safet y a n d 
Efficac y  Trial of B H V-3 0 0 0 ( P F-0 7 8 9 9 8 0 1) (ri me ge pa nt) Orally 
Disi nte grati n g Ta blet ( O D T) f or t he Ac ute Treat me nt of C hr o nic 
R hi n osi n usitis ( C R S) W it h or W it h o ut Nasal P ol y ps
R ati o n ale: 
C hr o nic r hi n osi n usitis ( C R S) is a s y m pt o matic i nfla m mati o n of t he para nasal 
si n uses a n d nasal ca vit y lasti n g m ore t ha n 1 2 wee ks. Br oa dly, it ca n be di vi de d 
i nt o t w o p he n ot ypes: C R S wit h a n d wit h o ut nasal p ol y ps. T y picall y, it prese nts 
wit h facial pai n/ pres s ure/f ull ness, nasal o bstr ucti o n (c o n gesti o n), nasal 
disc har ge, a n d/ or decrease d se nse of s mell. C R S affects a p pr o xi matel y 5-1 2 % 
of t he U S p o p ulati o n a n d is ass ociate d wit h re d uce d q ualit y  of life a n d 
si g nifica nt healt h care b ur de n. 1 - 3
T he mai nsta y  of treat me nt are t o pical nasal c ortic oster oi ds a n d sali ne 
irri gati o n; h o we ver, t he efficac y  is ver y li mite d lea vi n g ma n y patie nts wit h o ut 
ac hie vi n g desira ble relief. I n c o ntrast, oral c ortic oster oi ds, l o n g -ter m n o n-
ster oi dal a nti-i nfla m mat or y dr ugs ( N S AI Ds ), or a nti bi otics ma y pr o vi de m ore 
be nefits b ut are ass ociate d wit h si g nifica nt si de effects. Wit h li mite d treat me nt 
o pti o ns a n d i na de q uate disease ma na ge me nt, C R S re mai ns a n area of u n met 
me dical nee d pr o m pti n g de vel o p me nt of disease- s pecific i nter ve nti o ns.4 ,5
T he pr o p ose d st u d y is base d o n t he e v ol vi n g precli nical a n d cli nical e vi de nce 
s u g gesti ng a r ole f or calcit o ni n ge ne-relate d pe pti de (C G R P ) i n t he 
pat h o p h y si ol o g y of C R S. B H V- 3 0 0 0 ( P F-0 7 8 9 9 8 0 1) (ri me ge pa nt) is a s mall 
m olec ule C G R P rece pt or a nta g o nist t hat is bei n g de vel o pe d f or t he p ote ntial 
treat me nt of C R S. T he data fr o m t his st u d y will all o w c haracterizati o n of t he 
safety a n d efficac y of orall y  disi nte grati n g ta blet ( O D T) of ri me ge pa nt vers us 
place b o i n t he treat me nt of chr o nic rhi n osi n usitis wit h or wit h o ut p ol y ps.
T ar get 
P o p ul ati o n:
T he st u d y  will recr uit male a n d fe male s u bjects 1 8 years of a ge a n d ol der wit h 
a hist or y of c hr o nic r hi n osi n usitis wit h or wit h o ut nasal p ol y ps, dia g n ose d b y a 
healt hcare pr o vi der , t hat ha ve ha d at least a t wel ve wee k hist or y  of facial 
pai n / press ure/f ull ness a n d o ne or m ore of t he f oll o wi n g si g ns a n d s y m pt o ms: 
nasal disc har ge (a nteri or, p osteri or, or b ot h), nasal o bstr ucti o n (c o n gesti o n), 
a n d/or decrease d se nse of s mell. S u bjects m ust ha ve ha d i nfla m mati o n 
d oc u me nte d b y o ne or m ore of t he f oll o wi n g fi n di n gs : p ur ule nt ( n ot clear) 
m uc us or e de ma i n t he mi d dle meat us or a nteri or et h m oi d re gi o n ; p ol y ps i n 
nasal ca vit y or t he mi d dle meat us ; a n d/ or ra di o gra p hic i ma gi n g s h o wi n g 
i nfla m mati o n of t he para nasal si n uses.
S u bjects m ust ha ve ha d at least t w o i nsta nces of facial pai n / press ure/f ull ness 
t hat ha d reac he d a c urre nt i nte nsit y of m o derate or se vere o n a 4 -p oi nt rati n g 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
scale (0 = N o ne, 1 = M il d, 2 = M o derate, 3 = S e vere) wit hi n 3 0 da y s pri or t o 
t he Scree ni n g Visit. 
N u m ber of 
S u bjects:
A p pr o xi matel y 2 8 6 s u bjects will be ra n d o mize d t o res ult i n a p pr o xi matel y 2 0 0 
( 1 0 0 per ar m) e val ua ble s u bjects . T he s u bjects will be ra n d o mize d i n a 1: 1 
rati o t o t he ri me ge pa nt or place b o treat me nt gr o u ps. T he ra n d o mizati o n will be 
stratifie d b y t he prese nce of nasal p oly ps ( yes or n o).
O bjecti ves 
( Pri m ar y): 
T o e val uate t he efficac y  of ri me ge pa nt c o m pare d wit h place b o i n t he ac ute 
treat me nt of chr o nic r hi n osi n usitis wit h or wit h o ut p ol y ps o n mea n c ha n ge 
fr o m baseli ne of facial pai n/ press ure/f ull ness o n a N u merical Rati n g Scale 
(N R S ) ( 0-1 0) sc ore at 2 h o urs p ost-d ose.
O bjecti ves 
( Sec o n d ar y):
1.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m baseli ne i n 
T otal Nasal S y m pt o m Sc ore ( T N S S) at 2 h o urs p ost -d ose.
2.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m baseli ne i n
nasal o bstr ucti o n (c o n gesti o n) sc ore o n N R S ( 0-1 0) sc ore at 2 h o urs p ost -
d ose.
3.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m baseli ne i n 
nasal disc har ge sc ore o n N R S ( 0-1 0) sc ore at 2 h o urs p ost -d ose.
4.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n hea dac he pai n relief o n a 
4- p oi nt Li kert scale at 2 h o urs p ost -d ose c o m pare d t o baseli ne .
5.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n t he pr o ba bilit y of 
re q uiri n g resc ue me dicati o n wit hi n 2 4 h o urs of i nitial treat me nt.
E x pl or at or y O bjecti ves
1.
T o e val u ate ri me ge pa nt c o m pare d t o place b o o n ≥ 3 0 % re d ucti o n fr o m 
baseli ne of facial pai n/ press ure/f ull ness N R S ( 0- 1 0) sc ore at 2 h o urs p ost -
d ose .
2.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n ≥ 5 0 % re d ucti o n fr o m 
baseli ne of facial pai n/ press ure/f ull ness N R S ( 0- 1 0) sc ore at 2 h o urs p ost -
d ose .
3.
T o e val uate t he effect of ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m 
baseli ne of facial pai n/ press ure/f ull ness N R S ( 0- 1 0) sc ore at 1 5, 3 0, 4 5, 6 0, 
9 0 mi n utes a n d 2, 4, 8 a n d 2 4 h o urs p ost -d ose.
4.
T o e val uate t he effect of ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m 
baseli ne nasal o bstr ucti o n (c o n gesti o n) N R S ( 0 -1 0) sc ore at 1 5, 3 0, 4 5, 6 0, 
9 0 mi n utes a n d 2, 4, 8 a n d 2 4 h o urs p ost -d ose.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
5.
T o e val uate t he effect of ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m 
baseli ne of nasal disc har ge N R S ( 0 -1 0) sc ore at 1 5, 3 0, 4 5, 6 0, 9 0 mi n utes 
a n d 2, 4, 8 a n d 2 4 h o urs p ost- d ose.
6.
T o e val uate t he effect of ri me ge pa nt c o m pare d t o place b o hea dac he pai n 
relief at 1 5, 3 0, 4 5, 6 0, 9 0 mi n utes a n d 2, 4, 8 a n d 2 4 h o urs p ost-d ose
c o m pare d t o baseli ne.
7.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n t he P GI- C q uesti o n naire at 
2 4 h o urs p ost -d ose.
8.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n ≥ 3 0 % re d ucti o n of facial 
pai n/ press ure/f ull ness N R S ( 0 -1 0) sc ore at 2 4 h o urs p ost -d ose .
9.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n ≥ 5 0 % re d ucti o n of facial 
pai n/ press ure/f ull ness N R S ( 0 -1 0) sc ore at 2 4 h o urs p ost -d ose .
1 0. T o e val uate ri me ge pa nt c o m pare d t o place b o o n s ustai ne d relief of facial 
pai n/ press ure/f ull ness, as defi ne d b y  eac h of t he f oll o wi n g: 3 0 % re d ucti o n 
fr o m baseli ne o n N R S ( 0-1 0), 1. 5 -p oi nt re d ucti o n o n N R S ( 0 -1 0), a n d a 2 -
p oi nt re d ucti o n o n N R S ( 0- 1 0) t hr o u g h 2 4 h o urs p ost -d ose.
1 1. T o e x pl ore t he distri b uti o n of baseli ne disease se verit y  usi n g t he of Si n o-
Nasal O ut c o me Test ( S N O T-2 2).
1 2. T o e val uate ri me ge pa nt c o m pare d t o place b o o n t he Si n o -Nasal O utc o me 
Test ( S N O T -2 2) sc ore at 2 4 h o urs p ost -d ose.
1 3. T o e val uate t he safet y a n d t olera bilit y of ri me ge pa nt i n t he ac ute treat me nt 
of c hr o nic r hi n osi n usitis as meas ure d b y t he fre q ue nc y of a d verse e ve nts of 
m o derate or se vere i nte nsit y , seri o us a d verse e ve nts ( S A Es), cli nicall y 
rele va nt la b orat or y a b n or malities, a n d nasal i ns pecti o n a b n or malities.
1 4. T o e val uate ri me ge pa nt c o m pare d t o place b o f or t he C ol u m bia-S uici d e
Se verit y  Rati ng Scale ( C -S S R S).
St u d y Desi g n:
T his is a d o u ble -bli n d, ra n d o mize d, m ultice nter, o ut patie nt e val uati o n of t he 
safety a n d efficac y of ri me ge pa nt as c o m pare d t o place b o f or t he ac ute 
treat me nt of c hr o nic r hi n osi n usitis ( C R S) wit h or wit h o ut nasal p ol yps. T h e 
st u d y dr u g will be ri me ge pa nt prese nte d i n a 7 5 m g O D T or matc hi n g place b o.
S u bjects w h o ha ve c o nse nte d t o st u d y  partici pati o n will first partici pate i n t he 
scree ni n g p hase ( 3 t o 1 4 da y peri o d). S u bjects m ust re mai n o n t he sa me d ose 
of dail y  use of me dicati o ns t o treat C R S s ym pt o ms fr o m scree ni n g t hr o u g h t he 
d urati o n of t he st u d y  a n d ma y n ot start a n y ne w dail y me dicati o n. S u bjects 
meeti n g i nitial eli gi bilit y  criteria will be as ke d t o c o nti n ue t o a Baseli ne Visit.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L
At t he Baseli ne Visit, eli gi bilit y  f or c o nti n ue d partici pati o n i n t he st u d y will be 
assesse d bef ore ra n d o mizati o n occ urs a n d bef ore st u d y  me dicati o n is 
dis pe nse d. T he s u bject will be dis pe nse d a si n gle d ose of t he d o u ble -bli n d 
st u d y me dicati o n. T he s u bject will be i nstr ucte d t o ta ke t heir st u d y me dicati o n, 
as a n o ut patie nt, w he n (if) t he y ha ve a facial pai n/ press ure/f ull ness w hic h 
reac hes a c urre nt i nte nsit y of ≥6 o n t he N R S ( 0 -1 0). T he s u bject will c o m plete 
q uesti o n naires o n a n e Diar y  f or 2 4 h o urs after ta ki n g st u d y me dicati o n. T he 
s u bject will be i nstr ucte d t o tele p h o ne t he st u d y ce nter i m me diatel y if a se vere 
or seri o us a d verse e ve nt occ urs.
S u bjects will rec or d efficac y  data i n t heir e Diar y. T his i ncl u des t he f oll o wi n g: 
i nte nsit y of t he facial pai n/ press ure/f ull ness pri or t o a n d at ti me of ta ki n g st u d y 
me dicati o n. S u bject s h o ul d n ot d ose wit h st u d y  me dicati o n u ntil facial 
pai n/ press ure/f ull ness reac hes a c urre nt i nte nsit y of ≥6 o n t he N R S ( 0- 1 0). 
S u bjects will c o m plete Si n o -Nasal O utc o me Test ( S N O T -2 2) q uesti o n naire at 
t he Baseli ne Visit ( o n a pa per scale), a n d  at 2 4 h o urs p ost-d ose, s u bjects will 
c o m plete S N O T-2 2 ( o n t he e Diar y ). Facial pai n/ press ure/f ull ness se verity, 
nasal c o n gesti o n ( o bstr ucti o n) se verit y, a n d nasal disc har ge se verit y will be 
rec or de d usi n g a N R S ( 0 -1 0) j ust pri or t o ta ki n g st u d y  me dicati o n a n d at 1 5, 
3 0, 4 5, 6 0, a n d 9 0 mi n utes a n d 2, 4, 8 a n d 2 4 h o urs after d osi n g. T otal Nasal 
S y m pt o m Sc ore ( T N S S) will be calc ulate d as t he s u m of 3 s y m pt o m sc ores: ( 1) 
facial pai n/ press ure/f ull ness; ( 2) nasal o bstr ucti o n (c o n gesti o n); a n d ( 3) nasal 
disc har ge; rec or de d j ust pri or t o ta ki n g st u d y me dicati o n a n d after d osi n g at 
ti me p oi nts of 1 5, 3 0, 4 5, 6 0, a n d 9 0 mi n utes a n d 2, 4, 8 a n d 2 4 h o urs. S u bjects 
w h o e x perie nce c urre nt hea dac he pai n of m o derat e or se vere pai n i nte nsit y at 
t he ti me of q ualif yi n g facial pai n/ press ure/f ull ness will rec or d t heir hea dac he 
pai n se verit y usi n g a 4 -p oi nt L i kert scale ( 0 = N o ne; 1 = Mil d; 2 = M o derate; 3 
= Se vere) at ti me of ta ki n g st u d y me dicati o n a n d after d osi n g at t i me p oi nts of 
1 5, 3 0, 4 5, 6 0, a n d 9 0 mi n utes a n d 2, 4, 8 a n d 2 4 h o urs. S u bjects will c o m plete 
t he Patie nt Gl o bal Im pressi o n of C ha n ge ( P GI -C) q uesti o n naire 2 4 h o urs after 
d osi n g.
At t he e n d of 2 h o urs after d osi n g wit h st u d y me dicati o n (a n d after t he 2 -h o u r 
assess me nts ha ve bee n c o m plete d o n t he e Diar y ), s u bjects will be per mitte d t o 
use t he f oll o wi n g resc ue me dicati o n: aceta mi n o p he n ( u p t o 1 0 0 0 m g/ da y ), or 
as piri n, i b u pr ofe n, na pr o xe n ( or a n y  ot her ty pe of n o n -ster oi dal a nti-
i nfla m mat or y dr u g [ N S AI D]), oral a nti hista mi nes ( n o n-se dati n g), oral 
dec o n gesta nts, t o pical nasal dec o n gesta nts, t o pical nasal a ntic h oli ner gics (all 
u p t o t he dail y  rec o m me n de d d ose i n dicate d o n t he dr u g pac ka gi n g). T hese are 
t he o nl y me dicati o ns all o we d f or resc ue treat me nt after 2 h o urs p ost d ose of 
st u d y me dicati o n. At t he e n d of 2 4 h o urs after d osi n g wit h st u d y me dicati o n 
( b ut bef ore t he E n d of Treat me nt Visit), if nee de d, t he y ma y ta ke t heir 
prescri be d sta n dar d of care me dicati o ns pr o vi de d all of t he assess me nts ha ve 
bee n c o m plete d o n t he e Diar y . E xcl usi o nar y resc ue me dicati o n s uc h as o pi oi ds 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
a n d b utal bital c o m p o u n ds are n ot all o we d o n t his st u d y . 
Si milarl y , if t he facial pai n/ press ure/f ull ness is relie ve d b y st u d y me dicati o n at 
2 h o urs after d osi n g b ut t he n rec urs t o a i nte nsit y  of ≥6 o n t he N R S ( 0- 1 0) 
bet wee n 2 a n d 2 4 h o urs, t he s u bject will be per mitte d t o ta ke t he sa me resc ue 
t hera py as o utli ne d a b o ve. I n all circ u msta nces, t he s u bject will al wa ys 
c o nti n ue t o c o m plete his or her e Diar y  f or u p t o 2 4 h o urs after c o ns u mi n g t he 
st u dy me dicati o n. D uri n g t he 4 5 -d a y  treat me nt p hase, if t he s u bject has a n o n -
q u alif yi n g i nsta nce of facial pai n/ press ure/f ull ness (i.e., facial 
pai n/ press ure/f ull ness < 6 o n a N R S [ 0 - 1 0]), t he s u bject is per mitte d t o use 
o nl y  t he f oll o wi n g me dicati o ns t o treat t he s ym pt o ms: aceta mi n o p he n ( u p t o 
1 0 0 0 m g/ da y ), or as piri n, i b u pr ofe n, na pr o xe n ( or a n y ot her ty pe of n o n -
ster oi dal a nti-i nfla m mat or y dr u g [ N S AI D]), oral a nti hista mi nes ( n o n-se dati n g), 
oral dec o n gesta nts, t o pical nasal dec o n gesta nts , t o pical nasal a ntich oli ner gics
(all u p t o t he dail y rec o m me n de d d ose i n dicate d o n t he dr u g pac ka gi n g), t hat 
are n ot ot her wise pr o hi bite d b y  t he st u d y, see Secti o n 5. 4 .
S u bjects s h o ul d ha ve access t o s y ste mic c ortic oster oi ds a n d a nti bi otics d uri n g 
t he trial f or treat me nt of s ym pt o ms, if i n dicate d. H o we ver, s u bjects s h o ul d 
disc o nti n ue t he st u d y  if t he y recei ve t h ose t hera pies. 
S u bjects will ret ur n t o t he st u d y  site wit hi n 7 da ys ( + 2) after ta ki n g st u dy 
treat me nt f or re vie w of t he e Diar y, assess me nt of me dicati o n c o m plia nce, 
a n d m o nit ori n g of t olera bilit y a n d safet y. If a s u bject has N O T e x perie nce d 
a facial pai n/ press ure/f ull ness of s ufficie nt se verit y wit hi n 4 5 da y s after 
ra n d o mizati o n, t he y still are re q uire d t o c o m plete all E O T visit pr oce d ures. 
All s u bjects m ust ret ur n e m pt y  me dicati o n pac ka gi n g, a ny u n use d st u d y 
me dicati o n, a n d t he e Diar y  t o t he st u d y ce nter.  
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 5 of 1 0 4
P FI Z E R C O N FI D E N TI A L
S T U D Y S C H E M A TI C
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) Ac ute Tre at me nt of C hr o nic R hi n osi n usitis Wit h or Wit h o ut 
N as al P ol y ps St u d y
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 6 of 1 0 4
P FI Z E R 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
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E ...................................... 2
S T U D Y S U M M A R Y ( S Y N O P SI S) ............................................................................................ 1 0
S T U D Y S C H E M A TI C ................................................................................................................ 1 5
T A B L E O F C O N T E N T S ............................................................................................................ 1 6
LI S T O F T A B L E S ....................................................................................................................... 1 9
LI S T O F A B B R E V I A TI O N S ..................................................................................................... 2 0
1
I N T R O D U C TI O N A N D R A TI O N A L E ............................................................................. 2 4
1. 1
B ac k gr o u n d ...................................................................................................................... 2 4
1. 2
Pr o d uct De vel o p me nt B ac k gr o u n d ................................................................................ 2 5
1. 3
St u d y R ati o n ale ................................................................................................................ 2 5
1. 3. 1
St u d y Desi g n R ati o n ale ..............................................................................................2 6
1. 3. 2
D ose Selecti o n R ati o n ale ............................................................................................ 2 7
1. 3. 3
Rese arc h H y p ot hesis .................................................................................................. 2 7
1. 3. 4
Be nefit/ Ris k ................................................................................................................2 7
2
S T U D Y O B J E C TI V E S ........................................................................................................ 2 9
2. 1
Pri m ar y O bjecti ve(s) ....................................................................................................... 2 9
2. 2
Sec o n d ar y O bjecti ve(s) .................................................................................................... 2 9
2. 3
E x pl or at or y O bjecti ve(s) ................................................................................................. 2 9
3
S T U D Y E N D P OI N T S .......................................................................................................... 3 1
3. 1
Pri m ar y E n d p oi nt(s) ........................................................................................................ 3 1
3. 2
Sec o n d ar y E n d p oi nt(s) .................................................................................................... 3 1
3. 3
Me as ures of i nterest ......................................................................................................... 3 1
4
S T U D Y P L A N ....................................................................................................................... 3 2
4. 1
St u d y Desi g n a n d D ur ati o n ............................................................................................. 3 2
4. 2
Sc he d ule of Assess me nts .................................................................................................. 3 3
4. 2. 1
Scree ni n g P h ase ( 3 t o 1 4 d a ys) .................................................................................. 4 2
4. 2. 2
Ac ute Tre at me nt ( R a n d o miz ati o n) P h ase ............................................................... 4 2
4. 2. 2. 1
e Di ar y D at a C ollecti o n ........................................................................................ 4 2
4. 2. 3
E xte nsi o n P h ase.......................................................................................................... 4 4
4. 2. 4
W as h o ut P h ase................................ ...........................................................................4 4
4. 2. 5
E n d of Tre at me nt .......................................................................................................4 4
4. 3
P ost St u d y Access t o T her a p y ......................................................................................... 4 4
5
P O P U L A TI O N ......................................................................................................................4 5
5. 1  
N u m ber of S u bjects................................ ..........................................................................4 5
5. 2
I ncl usi o n Criteri a .............................................................................................................4 5
5. 3 
E xcl usi o n Criteri a................................ ............................................................................4 6
5. 4
Pr o hi bite d a n d Restricte d C o nc o mit a nt Me dic ati o ns .................................................. 5 1
5. 5
D ail y a n d Resc ue Me dic ati o ns ........................................................................................5 2
5. 6
C o ntr ace pti o n ...................................................................................................................5 4
5. 7
Ot her Restricti o ns a n d Prec a uti o ns ...............................................................................5 4
5. 8 
Pr ot oc ol De vi ati o ns a n d Q u alit y T oler a nce Li mits .......................................................5 4
6
S T U D Y C O N D U C T A N D D E S C RI P TI O N O F S T U D Y P R O C E D U R E S .....................5 5
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 7 of 1 0 4
P FI Z E R C O N FI D E N TI A L
6. 1
St u d y M ateri als ................................................................................................................ 5 5
6. 2
S afe t y Assess me nts........................................................................................................... 5 6
6. 2. 1
Vit al Si g ns a n d P h ysic al Me as ure me nts ( Hei g ht a n d Wei g ht).............................. 5 6
6. 2. 2
Electr oc ar di o gr a m ( E C G) ......................................................................................... 5 6
6. 2. 3
P h ysic al E x a m ............................................................................................................ 5 6
6. 2. 4
L a b or at or y Assess me nts ............................................................................................ 5 6
6. 2. 4. 1
S afet y L a b or at or y Testi n g .................................................................................. 5 7
6. 2. 4. 2
Pre g n a nc y Testi n g ................................................................................................ 5 8
6. 2. 5
C ol u m bi a -S uici de Se verit y R ati n g Sc ale ( C -S S R S) ................................................ 5 8
6. 2. 6
Wee kl y C o nt act
.......................................................................................................... 5 8
6. 3
Effic ac y Assess me nts ....................................................................................................... 5 8
6. 3. 1
F aci al p ai n/ press ure/f ull ness ..................................................................................... 5 8
6. 3. 2
N as al o bstr ucti o n (c o n gesti o n).................................................................................. 5 8
6. 3. 3
N as al disc h ar ge ........................................................................................................... 5 9
6. 3. 4
He a d ac he p ai n ............................................................................................................ 5 9
6. 3. 5
Resc ue Me dic ati o n ..................................................................................................... 5 9
6. 3. 6
P atie nt Gl o b al I m pressi o n of C h a n ge ( P GI-C) Q uesti o n n aire .............................. 5 9
6. 3. 7
Si n o -N as al O utc o me Test ( S N O T -2 2)...................................................................... 5 9
6. 4
E arl y Disc o nti n u ati o n fr o m t he St u d y........................................................................... 5 9
6. 5
L ost t o F oll o w U p ............................................................................................................. 6 0
7
S T U D Y D R U G M A N A G E M E N T....................................................................................... 6 1
7. 1
Descri pti o n of St u d y Dr u g ..............................................................................................6 1
7. 1. 1
I n vesti g ati o n al Pr o d uct ............................................................................................. 6 1
7. 1. 2
P ac k a gi n g, S hi p me nt a n d St or a ge ............................................................................ 6 1
7. 2
D ose a n d A d mi nistr ati o n ................................................................................................. 6 1
7. 2. 1
Met h o d of Assi g ni n g S u bject I de ntific ati o n............................................................ 6 1
7. 2. 2
Selecti o n a n d Ti mi n g of D ose a n d A d mi nistr ati o n................................................. 6 2
7. 2. 3
D ose M o dific ati o ns ..................................................................................................... 6 2
7. 3
Bli n di n g a n d U n bli n di n g ................................................................................................. 6 2
7. 4
Tre at me nt C o m pli a nce.................................................................................................... 6 3
7. 5
Destr ucti o n a n d Ret ur n of St u d y Dr u g .......................................................................... 6 3
8
A D V E R S E E V E N T S ............................................................................................................ 6 4
8. 1
Seri o us A d verse E ve nts ................................................................................................... 6 5
8. 1. 1
Defi niti o n of Seri o us A d verse E ve nt ( S A E) .............................................................6 5
8. 1. 2
C ollecti o n a n d Re p orti n g Seri o us A d verse E ve nts .................................................6 7
8. 2
N o n -seri o us A d verse E ve nts............................................................................................6 8
8. 2. 1
C ollecti o n a n d Re p orti n g of N o n -Seri o us A d verse E ve nts ....................................6 8
8. 2. 2
L a b or at or y Test A b n or m alities ................................................................................ 6 8
8. 3
O ver d ose ...........................................................................................................................6 8
8. 4
Pre g n a nc y .........................................................................................................................6 8
8. 5 
P ote nti al Dr u g I n d uce d Li ver I nj ur y ( DI LI) ................................ ................................6 9
8. 6
A d verse E ve nts of S peci al I nterest .................................................................................7 0
8. 7
E n vir o n me nt al E x p os ure, E x p os ure D uri n g Bre astfee di n g, a n d Occ u p ati o n al 
E x p os ure ........................................................................................................................... 7 1
8. 7. 1
E x p os ure D uri n g Bre astfee di n g ................................................................................ 7 1
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 8 of 1 0 4
P FI Z E R C O N FI D E N TI A L
8. 7. 2
Occ u p ati o n al E x p os ure ............................................................................................. 7 1
8. 8
L ac k of Effic ac y ................................................................................................................ 7 2
8. 9
Me dic ati o n Err ors ............................................................................................................ 7 2
9
S T A TI S TI C S ......................................................................................................................... 7 3
9. 1
Ge ner al Pr oce d ures ......................................................................................................... 7 3
9. 2
S a m ple Size ....................................................................................................................... 7 3
9. 3
P o p ul ati o ns f or A n al ysis a n d Esti m a n ds ....................................................................... 7 3
9. 4
St atistic al Met h o ds ........................................................................................................... 7 4
9. 4. 1
De m o gr a p hic a n d B aseli ne C h ar acteristics ............................................................. 7 4
9. 4. 2
Pri m ar y E n d p oi nt(s) .................................................................................................. 7 5
9. 4. 3
Sec o n d ar y E n d p oi nt(s) ..............................................................................................7 5
9. 4. 4
A dj ust me nt f or M ulti plicit y...................................................................................... 7 6
9. 4. 5
Missi n g D at a ............................................................................................................... 7 7
9. 4. 6
Resc ue Me dic ati o n ..................................................................................................... 7 7
9. 4. 7
A n al ysis of S afet y ....................................................................................................... 7 8
9. 5
Sc he d ule of A n al yses ........................................................................................................ 7 8
1 0
E T HI C S A N D R E S P O N SI B I LI TI E S ................................................................................. 7 9
1 0. 1
G o o d Cli nic al Pr actice..................................................................................................... 7 9
1 0. 2
Disse mi n ati o n of Cli nic al St u d y D at a ............................................................................ 8 0
1 0. 3
I nstit uti o n al Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee....................................... 8 1
1 0. 4
I nf or me d C o nse nt ............................................................................................................ 8 1
1 0. 5
C ase Re p ort F or ms .......................................................................................................... 8 2
1 0. 6
S p o ns or’s Me dic all y Q u alifie d I n di vi d u al..................................................................... 8 2
1 1
R E C O R D S M A N A G E M E N T ..............................................................................................8 4
1 1. 1
S o urce D oc u me nt ati o n ..................................................................................................... 8 4
1 1. 2
St u d y Files a n d Rec or d Rete nti o n ..................................................................................8 5
1 2
A M E N D M E N T S ................................................................................................................... 8 6
1 3
P U B LI C A TI O N P O LI C Y .................................................................................................... 8 7
1 4
S T U D Y DI S C O N TI N U A TI O N ........................................................................................... 8 8
1 5
D A T A P R O T E C TI O N ......................................................................................................... 8 9
1 6
A P P E N DI C E S ....................................................................................................................... 9 0
1 6. 1
A P P E N DI X I: Str o n g I n hi bit ors a n d Str o n g a n d M o der ate I n d ucers of 
C Y P 3 A 4 Pr otei n ( N ot all- i ncl usi ve) ............................................................................... 9 0
1 6. 2
A P P E N DI X II: E C G Fi n di n gs of P ote nti al Cli nic al C o ncer n .....................................9 2
1 6. 3  
A P P E N DI X III: C o ntr ace pti ve a n d B arrier G ui d a nce................................ ................9 4
1 6. 3. 1
M ale S u bject Re pr o d ucti ve I ncl usi o n Criteri a
.......................................................9 4
1 6. 3. 2
Fe m ale S u bject Re pr o d ucti ve I ncl usi o n Criteri a ....................................................9 4
1 6. 3. 3
W o m a n of C hil d be ari n g P ote nti al ............................................................................ 9 4
1 6. 3. 4
C o ntr ace pti o n Met h o ds................................ .............................................................9 5
1 6. 4
A P P E N DI X I V: Pr ot oc ol A me n d me nt Hist or y .............................................................9 7
1 7
R E F E R E N C E S ...................................................................................................................1 0 3
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 9 of 1 0 4
P FI Z E R C O N FI D E N TI A L
LI S T O F T A B L E S
T a ble 1
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) Sc he d ule of Assess me nts ........................................ 3 3
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 0 of 1 0 4
P FI Z E R C O N FI D E N TI A L
LI S T O F A B B R E VI A TI O N S
A C S
Ac ute C or o nar y  S yn dr o me
A D H D
Atte nti o n -Deficit/ H y peracti vit y  Dis or der
A E R D
As piri n E xacer bate d Res pirat or y  Disease
A E
A d verse E ve nt
A L T
Ala ni ne A mi n otra nsferase
A S T
As partate A mi n otra nsferase
A V
Atri o ve ntric ular
b p m
Beats Per Mi n ute
B U N
Bl o o d Urea Nitr o ge n
C B D
Ca na bi di ol
C G R P
Calcit o ni n Ge ne Relate d Pe pti de
CI
C o nfi de nce I nter val
C K
Creati ne Ki nase
C M H
C oc hra n -Ma ntel -Hae nszel
C O P D
C hr o nic O bstr ucti ve P ul m o nar y  Disease
C R F
Case Re p ort F or m
C R O
Cli nical Researc h Or ga nizati o n
C R S
C hr o nic R hi n osi n usitis
C R S w N P
C hr o nic R hi n osi n usitis Wit h Nasal P ol y ps
C S R
Cli nical St u d y  Re p ort
C -S S R S
C ol u m bia -S uici de Se verit y  Rati n g Scale
C T
Cli nical Trial
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C TI S
Cli nical Trial I nf or mati o n S y ste m
C Y P
C y t oc hr o me P-4 5 0
D AI D S
Di visi o n of AI D S
DI LI
Dr u g -I n d uce d Li ver I nj ur y
D S M -V
Dia g n ostic a n d Statistical ma n ual of Me ntal Dis or ders, Fift h e diti o n
D S U
Dr u g Safet y U nit
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
E C
Et hics C o m mittee
E C C
E mer ge nc y  C o ntact Car d
E C G
Electr ocar di o gra m
e C R F
Electr o nic Case Re p ort F or m
E D B
E x p os ure D uri n g Breastfee di n g
E D C
Electr o nic Data Ca pt ure
e Diar y
Electr o nic Diar y
E D P
E x p os ure D uri n g Pre g na nc y
E F D
E m br y o -Fetal De vel o p me nt
e G F R
Esti mate d Gl o mer ular Filtrati o n Rate
E O D
E ver y  Ot her Da y
E O T
E n d of Treat me nt
e P R O
Electr o nic Patie nt Re p orte d O utc o mes
e T M F
Electr o nic Trial Master File
E U
E ur o pea n U ni o n
E u dra C T
E ur o pea n U ni o n Dr u g Re g ulati n g A ut h orities Cli nical Trials ( E ur o pea n 
Cli nical Trials Data base)
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 C P
G o o d Cli nical Practice
G G T
Ga m ma -Gl uta m yl  Tra nsferase
G L P
G o o d La b orat or y  Practice
H b A 1c
He m o gl o bi n A 1 C
H C P
Healt hcare Pr o vi der
H D L
Hi g h -De nsit y  Li p o pr otei n
HI V
H u ma n I m m u n o deficie nc y  Vir us
H R
Heart h Rate
H R T
H or m o ne Re place me nt T hera p y
I B
I n vesti gat or’s Br oc h ure
I CF
I nf or me d C o nse nt F or m
I C H
I nter nati o nal C o nfere nce o n Har m o nizati o n of Tec h nical Re q uire me nts 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
f or P har mace uticals f or H u ma n Use
I C H D-3
T he I nter nati o nal Classificati o n of Hea dac he Dis or ders, 3r d e diti o n
I D
I de ntificati o n
I E C
I n de pe n de nt Et hics C o m mittee
I ND
I n vesti gati o nal Ne w Dr u g
I N R
I nter nati o nal N or malize d Rati o
I RB
I nstit uti o nal Re vie w B oar d
I W R S
I nteracti ve We b Res p o nse S yste m
L B B B
Left B u n dle Bra nc h Bl oc k
L D H
Lactate De h y dr o ge nase
L D L
L o w -De nsit y Li p o pr otei n
L F T
Li ver F u ncti o n Test
M A R
Missi n g at Ra n d o m
M D R D
M o dificati o n of Diet i n Re nal Disease
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 T T
M o difie d I nte nt T o Treat
m m
Milli meter
M M R M
Mi xe d M o del Re peate d Meas ures
mi n
Mi n ute
MI
M y ocar dial I nfarcti o n
M QI
Me dicall y  Q ualifie d I n di vi d ual
N O A E L
N o O bser ve d A d verse Effect Le vel
N R S
N u merical Rati n g Scale
N S AI D
N o n - Ster oi dal A nti-I nfla m mat or y Dr u g
O D T
Orall y  Disi nte grati n g Ta blet
P A C L
Pr ot oc ol A d mi nistrati ve C ha n ge Letter
P CI
Perc uta ne o us C or o nar y  I nter ve nti o n
P C P
P he nc y cli di ne
P GI -C
Patie nt Gl o bal I m pressi o n of C ha n ge
P R N
Pr o Re Nata
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L
P S S A
Pfizer S A E S u b missi o n Assista nt
P V C
Pre mat ure Ve ntric ular C o ntracti o n
R B C
Re d Bl o o d Cell
Q Tc F
Q Tc c orrecte d usi n g Fri dericia’s f or m ula
Q T L
Q ualit y  T olera nce Li mit
S A E
Seri o us A d verse E ve nt
S A P
Statistical A nal y sis Pla n
S G O T
Ser u m Gl uta mic -O xal oacetic Tra nsa mi nase
S G P T
Ser u m Gl uta mic -P y r u vic Tra nsa mi nase
S N O T -2 2
Si n o -Nasal O utc o me Test – 2 2
S R S D
Si n gle Refere nce Safet y D oc u me nt
T Bili
T otal Bilir u bi n
TI A
Tra nsie nt Isc he mic Attac k
T N F -α
T u m or Necr osis Fact or - Al p ha
T N S S
T otal Nasal S y m pt o m Sc ore
T M F
Trial Master File
U L N
U p per Li mit of N or mal
U K
U nite d Ki n g d o m
U S
U nite d States
W B C
W hite Bl o o d Cell
W O C B P
W o me n of C hil d -Beari n g P ote ntial
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1
I N T R O D U C TI O N A N D R A T I O N AL E
1. 1
B a c k gr o u n d
C hr o nic r hi n osi n usitis ( C R S) is a n i nfla m mat or y disease of t he para nasal si n uses a n d nasal 
ca vit y lasti n g m ore t ha n 1 2 wee ks. Br oa dly, it ca n be di vi de d i nt o t w o p he n ot y pes, C R S wit h a n d 
wit h o ut nasal p ol y ps, wit h a p pr o xi matel y  2 0 % of patie nts ha vi n g nasal p ol yp osis. 6
It is esti mate d t hat C R S affects bet wee n 5-1 2 % of t he ge neral p o p ulati o n, h o we ver, w he n t his is 
c o m bi ne d wit h d oc u me nte d i nfla m mati o n, t he pre vale nce is re d uce d t o 3 -6 %. I t pre d o mi na ntly 
affects t he a d ult p o p ulati o n a n d has si g nifica nt i m pact o n t he q ualit y of life. C R S is c o nsi dere d 
o ne of t he t o p 1 0 m ost c ostl y  healt h c o n diti o ns i n t he U S wit h estimate d i n direct c osts e xcee di n g 
$ 2 2 billi o n per y ear. 7
T he e xact u n derl yi n g mec ha nis ms i n C R S pat h o p h y si ol o g y are u n k n o w n a n d are m ost li kel y 
m ultifact orial. T he disease is belie ve d t o arise fr o m c hr o nic i nfla m mat i o n of t he nasal ca vit y a n d 
para nasal si n uses. Pre dis p osi n g fact ors i ncl u de e n vir o n me ntal (e. g, p oll uti o n, aller ge ns, vir uses, 
bacteria), s ys te mic (e. g., ge netic, c ystic fi br osis, ciliar y defects), a n d l ocal (e. g., a nat o mic, 
p ol y ps, t u m ors) fact ors. 8 C R S is ofte n acc o m pa nie d b y  ot her m or bi dities, s uc h as aller gic
r hi nitis, ast h ma, a n d as piri n e xacer bate d res pirat or y disease ( A E R D).3 ,9
T he dia g n osis re q uires prese nce of at least t w o of t he f o ur car di nal s y m pt o ms (i.e., facial 
pai n/ press ure/f ull ness, nasal o bstr ucti o n (c o n gesti o n), nasal disc har ge, decrease d se nse of s mell) 
a n d c o nfir me d prese nce of i nfla m mati o n b y  ra di o gra p hic i ma gi n g or nasal e n d osc o p y.1 Car di nal 
s ym pt o ms var y  i n pre vale nce, wit h nasal o bstr ucti o n or c o n gesti o n re p orte d as t he m ost c o m m o n 
i n b ot h patie nts wit h or wit h o ut nasal p ol yps. 7
T he g oal of treat me n t is t o re d uce t he i nfla m mati o n, rest ore m uc ociliar y cleara nce a n d si n us 
drai na ge, a n d pre ve nt i nfecti o ns. 8 T he first -li ne treat me nt t ypicall y  i ncl u des t o pical i ntra nasal 
ster oi ds a n d nasal sali ne irri gati o n, h o we ver, t he efficac y is li mite d. M ore effecti ve t hera pies 
i ncl u de s yste mic c ortic oster oi ds a n d l o n g-ter m a nti bi otics, t h o u g h t he y are ass ociate d wit h 
si g nifica nt si de effects.4 ,5 O ne st u d y  f o u n d t hat i n patie nts wit h C R S w N P a n d se veral oral 
c ortic oster oi d b ursts per year, 4 3 % of patie nts de vel o pe d oste o p or osis a n d 4 9 % de vel o pe d
seco n dar y  a dre nal i ns ufficie nc y.1 0 A p pr o xi matel y  half of t he C R S patie nts will e ve nt uall y 
u n der g o e n d osc o pic s ur ger y  i n or der t o c o ntr ol t heir s ym pt o ms, h o we ver, t he maj orit y  will still 
ha ve i na de q uate s y m pt o m relief a n d ~ 3 7 % will nee d at least o ne re visi o n s ur ger y.2 ,4
B H V -3 0 0 0 ( P F-0 7 8 9 9 8 0 1) (ri me ge pa nt) is a calcit o ni n ge ne-relate d pe pti de ( C G R P) rece pt or 
a nta g o nist i n de vel o p me nt f or t he ac ute treat me nt of C R S. T he C G R P rece pt or i s l ocate d wit hi n 
pai n -si g nali n g pat h wa ys, i ntracra nial arteries a n d t he tri ge mi nal ga n gli o n, a n d its acti vati o n is 
t h o u g ht t o pla y a ca usal r ole i n C R S pat h o p h ysi ol o g y. 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 5 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Treat me nt wit h a C G R P rece pt or a nta g o nist is belie ve d t o e xert m ulti ple d o w nstrea m eff ects t hat 
ma y  pr o vi de be nefits i n treat me nt of C R S t hr o u g h t he f oll o wi n g p ossi ble mec ha nis ms:
Bl oc ki n g Ne ur o ge nic I nfl a m m ati o n : Bi n di n g of C G R P rece pt or a nta g o nists t o C G R P rece pt ors 
l ocate d o n satellite glial cells w o ul d i n hi bit i nfla m mati o n ca use d by tri ge mi nal ner ve release of 
C G R P o nt o satellite glial cells a n d cell b o dies of a- delta fi bers i n t he tri ge mi nal ga n gli o n.
Decre asi n g Arter y Dil ati o n : B y bl oc ki n g t he C G R P rece pt ors l ocate d i n s m o ot h m uscle cells 
wit hi n vessel walls, C G R P rece pt or a nta g o nists w o ul d i n hi bit t he pat h ol o gic dilati o n of arteries 
wit h o ut t he u n wa nte d effect of acti ve vas oc o nstricti o n.
I n hi biti n g P ai n Tr a ns missi o n: Bi n di n g of C G R P rece pt or a nta g o nists t o C G R P rece pt ors 
w o ul d s u p press t he tra ns missi o n of pai n b y  i n hi biti n g t he ce ntral rela y of pai n si g nals fr o m t he 
tri ge mi nal ner ve t o t he ca u dal tri ge mi nal n ucle us.
1. 2
Pr o d u ct D e v el o p m e nt B a c k gr o u n d
Details of t he cli nical a n d precli nical st u dies are pr o vi de d i n t he m ost c urre nt I n vesti gat or 
Br oc h ure. A s u m mar y  of t he rele va nt data t o t he st u d y are prese nte d bel o w.
Ri me ge pa nt is a p pr o ve d f or t he ac ute treat me nt a n d pre ve nti o n of e pis o dic mi grai ne i n t he 
U nite d S tates ( U S), Unite d K i n g d o m ( U K), a n d E ur o pea n U ni o n ( E U) a n d is well t olerate d i n 
h u ma ns w he n gi ve n as a si n gle oral d ose of 7 5 m g f or t he ac ute treat me nt of mi grai ne a n d at a 
d ose of 7 5 m g e ver y ot her da y (E O D ) f or t he pre ve nti o n of e pis o dic mi grai ne. T he efficac y , 
safety, a n d t olera bilit y of ri me ge pa nt f or t he ac ute a n d pre ve nti ve treat me nt of mi grai ne i n t he 
pe diatric p o p ulati o n is c urre ntl y bei n g e val uate d.
As of 2 6 A u g ust 2 0 2 2, m ore t ha n 8 9 0 0 u ni q ue s u bjects ha ve partici pate d i n P hase 1 st u dies i n 
healt h y  s u bjects or P hase 2 a n d 3 st u dies i n s u bjects wit h mi grai ne or refract or y tri ge mi nal 
ne ural gia, chr o nic r hi n osi n usitis , or te mp or o ma n di b ular dis or ders ; of t hese, a p pr o xi matel y 6 0 3 6 
u ni q ue s u bjects ha ve recei ve d ri me ge pa nt at a n y d ose. C ollecti vel y , t he c urre nt data 
de m o nstrates a fa v ora ble be nefit-ris k pr ofile f or ri me ge pa nt i n t he ac ute a n d pre ve nti ve treat me nt 
of mi grai ne .
Please refer t o t he m ost u p -t o- date I n vesti gat or’s Br oc h ure f or a d diti o nal i nf or mati o n.
1. 3
St u d y R ati o n al e
C hr o nic r hi n osi n usitis ( C R S) is a s y m pt o matic i nfla m mati o n of t he para nasal si n uses a n d nasal 
ca vit y lasti n g m ore t ha n 1 2 wee ks. T y picall y , it ma nifest s as facial pai n/ press ure/f ull ness, nasal 
o bstr ucti o n (c o n gesti o n), nasal disc har ge, a n d/ or decrease d se nse of s mell. 1- 3
T he nasal ca vit y  a n d para nasal si n uses recei ve sens or y  a n d n ocice pti ve i n ner vati o n fr o m distal 
bra nc hes of t he tri ge mi nal ner ve. Alt h o u g h t he u n derl yi n g mec ha nis ms of C R S ha ve n ot bee n 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 6 of 1 0 4
P FI Z E R C O N FI D E N TI A L
f ull y el uci date d, n u mer o us st u dies ha ve i m plicate d tri ge mi nal ner ve a n d C G R P i n t he 
pat h o p h y si ol o g y of t he disease a n d su g geste d t hera pe utic be nefits of C G R P a nta g o nis m. C G R P + 
fi bers are pre d o mi na ntly f o u n d i n t he ma xillar y si n uses a n d t o lesser e xte nt i n ot her si n uses.
Pre vi o us st u dies ha ve s u g geste d t hat C G R P c o nt ri b utes t o nasal secreti o n b y i n d uci n g s ustai ne d 
arterial vas o dilati o n, i ncreasi n g nasal bl o o d fl o w, a n d p ossi bl y  b y i ncreasi n g plas ma fl u x acr oss 
fe nestrate d ca pillaries.1 3 - 1 8 I n a cli nical st u d y, i ntra nasal a d mi nistrati o n of C G R P i n healt h y 
v ol u nteers res ulte d i n i ncreases i n bl o o d fl o w, t he se nsati o ns of o bstr ucti o n, hea dac he, a n d mil d 
s neezi n g.1 3
A n ot her st u d y f o u n d t hat in patie nts wit h c hr o nic r hi n osi n usitis, nasal m uc osa C G R P le vels 
c orrelated wit h s y m pt o m i nte nsit y  a n d t he n u m ber of i nfla m mat or y cells.1 9 M ore o ver,
i n a st u d y
wit h aller gic r hi n osi n usitis, t he baseli ne sali var y C G R P le vels were ele vate d i n bet wee n 
attac ks. 2 0 Intra nasal ca psaici n a p plicati o n has bee n s h o w n t o re d uce p ol y p rec urre nce f oll o wi n g 
s ur ger y a n d decrease t he i nte nsit y of nasal o bstr ucti o n i n C R S .2 1 I n a precli nical st u d y i n pi g 
nasal m uc osa, C G R P a nta g o nists atte n uate d ca psaici n- , hista mi ne-, a n d bra d yki ni n -i n d uce d 
vas o dilati o n. 2 2 I n a n ot her st u d y, C G R P 8 -3 7 atte n uate d t he ca psaici n -i n d uce d vas o dilati o n a n d 
decrease i n nasal ca vit y v ol u me w hi c h was u naffecte d b y N K 1 -a nta g o nists. T his s u g gests t hat 
C G R P, b ut n ot s u bsta nce P, is a n i m p orta nt me diat or of nasal vasc ular c ha n ges res ulti n g fr o m 
acti vati o n of C-fi ber affere nts.2 3
B H V - 3 0 0 0 ( P F-0 7 8 9 9 8 0 1) (ri me ge pa nt) is a calcit o ni n ge ne-relate d pe pti de ( C G R P) rece pt or 
a nta g o nist i n de vel o p me nt f or t he ac ute treat me nt of C R S . T he C G R P rece pt or is l ocate d wit hi n 
pai n -si g nali n g pat h wa ys, i ntracra nial arteries a n d t he tri ge mi nal ga n gli o n, a n d its acti vati o n is 
t h o u g ht t o pla y a ca usal r ole i n C R S pat h o p h y si ol o g y. 
T his st u d y  is bei n g c o n d ucte d t o e val uate t he efficac y, safety, a n d t olera bilit y  of ri me ge pa nt f or 
t he ac ute treat me nt of C R S . It will als o f urt her defi ne t he safet y pr ofile of ri me ge pa nt 
a d mi nistrati o n i n t his patie nt p o p ulati o n, se paratel y fr o m t he a p pr o ve d i n dicati o n of ac ute a n d 
pre ve nti ve treat me nt of mi grai ne.
1. 3. 1
St u d y D e si g n R ati o n al e
T his is a d o u ble - bli n d, ra n d o mize d, m ultice nter, o ut patie nt e val uati o n of t he safety a n d efficac y 
of ri me ge pa nt as c o m pare d t o place b o i n t he ac ute treat me nt of c hr o nic r hi n osi n usitis ( C R S) wit h 
or wit h o ut p ol y ps . T he st u d y dr u g will be ri me ge pa nt f or m ulate d i n a 7 5 m g O D T (place d o n or 
u n der t he t o n g ue ) or a matc hi n g place b o. T he s u bjects will be i nstr ucte d t o ta ke t heir st u d y 
me dicati o n, as a n o ut patie nt, w he n (if) t he y  ha ve a facial pai n/ press ure/f ull ness w hic h reac hes 
i nte nsit y of ≥6 o n t he N R S ( 0 -1 0). 
T he st u d y  will ra n d o mize a p pr o xi matel y 2 8 6 s u bjects t o res ult i n a p pr o xi matel y 2 0 0 e val ua ble 
s u bjects. T he s u bjects will be ra n d o mize d i n a 1: 1 rati o t o t he ri me ge pa nt or place b o treat me nt 
gr o u ps. T he ra n d o mizati o n will be stratifie d b y  t he prese nce of nasal p oly p s ( yes or n o).
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 7 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1. 3. 2
D o s e S el e cti o n R ati o n al e
T he P hase 2 b d ose -ra n gi n g st u dy, C N 1 7 0 0 0 3 , esta blis he d t hat ri me ge pa nt 7 5 m g is t he mi ni m u m 
effecti ve d ose f or t he ac ute treat me nt of mi grai ne. T he t hree P hase 3 st u dies , B H V 3 0 0 0 - 3 0 1, 
B H V 3 0 0 0 -3 0 2, a n d B H V 3 0 0 0 - 3 0 3, c o nfir me d t his efficac y usi n g t he c urre nt re gistrati o nal 
e n d p oi nts f or ac ute treat me nt of mi grai ne. T his o bser vati o n a n d t he flat d ose- res p o nse wit h 
ri me ge pa nt a n d ot her C G R P rece pt or a nta g o nists s u g gest t hat ri me ge pa nt 7 5 m g ma y be a n 
effecti ve d ose f or t he ac ute treat me nt of c hr o nic r hi n osi n usitis wit h or wit h o ut p ol yps . T he 
p har mac o ki netic pr ofile of ri me ge pa nt s u p p orts t his st u d y’s a d mi nistrati o n of a si n gle d ose.
Please refer t o t he c urre nt versi o n of I n vesti gat or’ s Br oc h ure f or a s u m mar y of t he cli nical safety 
pr ofile.
1. 3. 3
R e s e ar c h H y p ot h e si s
Ri me ge pa nt will ha ve efficac y s u peri or t o place b o i n t he ac ute treat me nt of c hr o nic 
r hi n osi n usitis ( C R S) wit h or wit h o ut p ol y ps wit h a fa v ora ble safet y  pr ofile.
1. 3. 4
B e n efit/ Ri s k
Ri me ge pa nt re prese nts a n a d va nce me nt i n mi grai ne t hera pe utics, pr o vi di n g t he first C G R P 
a nta g o nist t o de m o nstr ate be nefit f or b ot h t he ac ute treat me nt a n d pr o p h yl a xis of mi grai ne.
Ri me ge pa nt a p pears t o be ge nerall y safe a n d well t olerate d i n h u ma ns w he n gi ve n as si n gle oral 
d oses fr o m 7 5 m g u p t o t he ma xi m u m d ose of 1 5 0 0 m g a n d m ulti ple oral d oses u p t o t he 
ma xi m u m dail y  d ose of 6 0 0 m g f or 1 4 da ys. 
Br oa d a n d s ustai ne d efficac y of ri me ge pa nt 7 5 m g was de m o nstrate d i n 3 pre vi o usl y  c o m plete d 
P hase 3 st u dies ( B H V 3 0 0 0 -3 0 1, B H V 3 0 0 0 - 3 0 2, a n d B H V 3 0 0 0 -3 0 3). Statisticall y  si g nifica nt 
efficac y was de m o nstrate d o n t he c o-pri m ar y e n d p oi nts of free d o m fr o m pai n, a n d free d o m fr o m 
m ost b ot hers o me s y m pt o m at 2 h o urs p ost -d ose. Si milar res ults were de m o nstrate d i n t he 
B H V 3 0 0 0 -3 1 0 st u d y  rece ntl y c o m plete d i n C hi na a n d K orea. I n t he P hase 2/ 3 place b o-c o ntr olle d 
st u d y ( B H V 3 0 0 0-3 0 5) f or t he pre ve nti ve treat me nt of mi grai ne, ri me ge pa nt at a d ose of 7 5 m g 
e ver y ot her da y ( E O D) de m o nstrate d statisticall y si g nifica nt s u peri orit y t o place b o o n t he 
pri mar y  e n d p oi nt of c ha n ge fr o m t he o bser vati o n peri o d i n t he mea n n u m ber of mi grai ne da ys 
per m o nt h o n treat me nt i n t he last m o nt h of t he d o u ble - bli n d treat me nt p hase.
A m ultice nter o pe n -la bel, l o n g-ter m st u d y ( B H V 3 0 0 0-2 0 1) was c o n d ucte d t o e val uate t he safet y 
a n d t olera bilit y of ri me ge pa nt 7 5 m g ta blet ta ke n as nee de d ( u p t o o ne ta blet per da y u p o n o nset 
of a mi grai ne of mil d, m o derate, or se vere i nte nsit y ) f or t he ac ute treat me nt of mi grai ne f or u p t o 
5 2 wee ks. T his m ulti ple -d ose, l o n g -ter m st u d y of ri me ge pa nt 7 5 m g a d mi nistere d f or u p t o 5 2 
wee ks c o nfir me d t he fa v ora ble safet y pr ofile acr oss a var iety of safet y e n d p oi nts, i ncl u di n g A E 
assess me nts, cli nical la b orat or y  testi n g i ncl u di n g li ver f u ncti o n tests (L F Ts ), vital si g ns a n d 
electr ocar di o gra ms ( E C Gs) . Safety data fr o m t he d o u ble - bli n d treat me nt a n d t he o pe n-la bel 
e xte nsi o n p hases of t he pi v otal P hase 2/ 3, ra n d o mize d, d o u ble- bli n d, place b o -c o ntr olle d 
pre ve nti ve treat me nt of mi grai ne st u d y ( B H V 3 0 0 0 -3 0 5) s u p p ort a fa v ora ble safet y pr ofile of 
ri me ge pa nt 7 5 m g a d mi nistere d E O D f or t he pre ve nti ve treat me nt of mi grai ne. Ri me ge pa nt 7 5 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 8 of 1 0 4
P FI Z E R C O N FI D E N TI A L
m g a d mi nistere d E O D + P R N f or u p t o 5 2 wee ks i n t he o pe n- la bel p hase is well t olerate d, wit h 
n o ne w safet y  si g nals o bser ve d i n t he o pe n-la bel-e xte nsi o n p hase.
Acr oss ri me ge pa nt cli nical de vel o p me nt pr o gra m, l o w fre q ue nc y  of e ve nts of h yperse nsiti vit y  
(i ncl u di n g urticaria, an gi oe de ma, a na p h yl actic reacti o n a n d ras h) were o bser ve d. N o A Es 
re prese nti n g seri o us c uta ne o us ma nifestati o n of h y perse nsiti vit y (e. g., Ste ve ns -J o h ns o n 
s yn dr o me) were o bser ve d.
Acr oss t he ri me ge pa nt cli nical de vel o p me nt pr o gra m, n o cases of H y ’s La w were i de ntifie d, a n d
t here was n o si g nal of DI LI d ue t o ri me ge pa nt w he n a d mi nistere d u p t o o nce daily P R N f or u p t o
5 2 wee ks of treat me nt.
T here are n o a de q uate data o n t he de vel o p me ntal ris k ass ociate d wit h t he use of ri me ge pa nt i n 
pre g na nt w o me n. B ot h w o me n of c hil d beari n g p ote ntial, as well as t h ose w h o are of 
n o n- c hil d beari n g p ote ntial, ma y be e nr olle d gi ve n t he a vaila bilit y of e m br y o-fetal de vel o p me nt
(E F D ) n o ncli nical t o xicit y  st u dies wit h ri me ge pa nt. C o ntrace pti o n met h o d is re q uire d, a n d 
meas ures will be ta ke n t o li mit t he ris k of pre g na nc y i n t he fe male p o p ulati o n of c hil d beari n g 
p ote ntial e nr olle d ( See Secti o n 1 6. 3 ). T he p ote ntial ris k of e x p os ure t o ri me ge pa nt i n a se x ual 
part ner of a male s u bjects i n t his st u d y via ejac ulate is l o w, a n d t heref ore n o c o ntrace pti o n 
(c o n d o m) use i n male s u bjects is warra nte d. T he calc ulate d safety mar gi n is ≥1 0 0- f ol d bet wee n 
t he esti mate d part ner e x p os ure d ue t o se mi nal tra nsfer a n d t he N O A E L f or seri o us ma nifestati o ns 
of de vel o p me ntal t o xicit y  i n n o ncli nical st u dies. T he safety mar gi n of 1 0 0 -f ol d is base d o n 
a p pl yi n g a 1 0-f ol d safety fact or f or i nters pecies e xtra p olati o n a n d a 1 0 -f ol d safety fact or f or 
s usce pti ble p o p ulati o ns. 2 8
S u bjects u n der g o re g ular pre g na nc y  testi n g t hr o u g h o ut t he d urati o n of t he st u d y. Alt h o u g h n o 
safety iss ues i n cli nical trials of ri me ge pa nt were o bser ve d, car di o v asc ular e ve nts, 
cere br o vasc ular e ve nts, h y perte nsi ve e ve nts, a n d seri o us gastr oi ntesti nal e ve nts ass ociate d wit h 
c o nsti pati o n are re vie we d i n eac h a g gre gate re p ort per T he U nite d States F o o d a n d Dr u g 
A d mi nistrati o n ( F D A ) re q uest. N o ne of t hese re vie ws ha ve detecte d a n y  safet y si g nal ass ociate d 
wit h t hese e ve nts. S u bjects are e xcl u de d if t here is u nc o ntr olle d, u nsta ble, or rece ntl y  dia g n ose d 
car di o vasc ular disease or h y perte nsi o n. S u bjects are m o nit ore d t hr o u g h m ulti ple safet y  
e n d p oi nts, i ncl u di n g A E assess m e nts, cli nical la b orat or y testi n g, vital si g ns a n d E C Gs.
Re vie w of all data a vaila ble, i ncl u di n g p ost -mar keti n g i nf or mati o n, n o ncli nical, cli nical, a n d 
scie ntific literat ure data, de m o nstrates a fa v ora ble be nefit-ris k pr ofile f or t he use of ri me ge pa nt 
i n this st u d y . M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d 
reas o na bly e x pecte d A E s of ri me ge pa nt m a y  be f o u n d i n t he I nvesti gat or Br oc h ure , w hic h is t he 
S R S D f or t his st u d y . 
I n vesti gat ors are t o m o nit or c ha n ges i n he mat ol o g y, c he mistr y, a n d ot her la b orat or y meas ures 
(see Secti o n 8. 5 ). I n a d diti o n, In vesti gat ors are re q uire d t o m o nit or all re p orte d A Es, c ha n ges o n 
p h y sical e xa mi nati o n, E C G, a n d e mer ge nt la b a b n or malities, etc. (see Ta b le 1).
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 2 9 of 1 0 4
P FI Z E R C O N FI D E N TI A L
2
S T U D Y O B J E C TI V E S
2. 1
Pri m ar y O bj e cti v e( s)
T o e val uate t he efficac y  of ri me ge pa nt c o m pare d wit h place b o i n t he ac ute treat me nt of chr o nic 
r hi n osi n usitis wit h o r wit h o ut p ol y ps o n mea n c ha n ge fr o m baseli ne of facial
pai n/ press ure/f ull ness o n N R S ( 0 -1 0) sc ore at 2 h o urs p ost d ose .
2. 2
S e c o n d ar y O bj e cti v e( s)
1.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m baseli ne i n T otal Nasal 
S y m pt o m Sc ore ( T N S S) at 2 h o urs p ost -d ose.
2.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m baseli ne i n nasal o bstr ucti o n
(c o n gesti o n) sc ore o n N R S ( 0-1 0) sc ore at 2 h o urs p ost -d ose.
3.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m baseli ne i n nasal disc har ge
sc ore o n N R S ( 0-1 0) s c ore at 2 h o urs p ost -d ose.
4.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n hea dac he pai n relief o n a 4 -p oi nt Li kert
scale at 2 h o urs p ost -d ose c o m pare d t o baseli ne.
5.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n t he pr o ba bilit y of re q uiri n g resc ue 
me dicati o n wit hi n 2 4 h o urs of i nitial treat me nt.
2. 3
E x pl or at or y  O bj e cti v e( s) 
1.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n ≥ 3 0 % re d ucti o n fr o m baseli ne of facial
pai n/ press ure/f ull ness N R S ( 0- 1 0) sc ore at 2 h o urs.
2.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n ≥ 5 0 % re d ucti o n fr o m baseli ne of facial
pai n/ press ure/f ull ness N R S ( 0 -1 0) sc ore at 2 h o urs.
3.
T o e val uate t he effect of ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m baseli ne of facial
pai n/ press ure/f ull ness N R S ( 0 -1 0) sc ore at 1 5, 3 0, 4 5, 6 0, 9 0 mi n utes a n d 2, 4, 8 a n d 2 4 
h o urs p ost -d ose.
4.
T o e val uate t he effect of ri me ge pa nt c o m pare d t o place b o o n c ha n ge fr o m baseli ne of nasal 
o bstr ucti o n (c o n gesti o n) N R S ( 0 - 1 0) sc ore at 1 5, 3 0, 4 5, 6 0, 9 0 mi n utes a n d 2, 4, 8 a n d 2 4 
h o urs p ost -d ose.
5.
T o e val uate t he effect of ri me ge p a nt c o m pare d t o place b o o n c ha n ge fr o m baseli ne of nasal 
disc har ge N R S ( 0 -1 0) sc ore at 1 5, 3 0, 4 5, 6 0, 9 0 mi n utes a n d 2, 4, 8 a n d 2 4 h o urs p ost -d ose.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 0 of 1 0 4
P FI Z E R C O N FI D E N TI A L
6.
T o e val uate t he effect of ri me ge pa nt c o m pare d t o place b o o n hea dac he pai n relief usi n g a 4 -
p oi nt Li kert scale at 1 5, 3 0, 4 5, 6 0, 9 0 mi n utes a n d 2, 4, 8 a n d 2 4 h o urs p ost- d ose c o m pare d 
t o baseli ne.
7.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n t he P GI- C q uesti o n naire at 2 4 h o urs p ost-
d ose.
8.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n ≥ 3 0 % re d ucti o n fr o m baseli ne of facial 
pai n/ press ure/f ull ness N R S ( 0 -1 0) sc ore at 2 4 h o urs.
9.
T o e val uate ri me ge pa nt c o m pare d t o place b o o n ≥ 5 0 % re d ucti o n fr o m baseli ne of facial 
pai n/ press ure/f ull ness N R S ( 0 -1 0) sc ore at 2 4 h o urs.
1 0. T o e val uate ri me ge pa nt c o m pare d t o place b o o n s ustai ne d relief of facial 
pai n/ press ure/f ull ness, as defi ne d b y eac h of t he f oll o wi n g: 3 0 % re d ucti o n fr o m baseli ne o n 
N R S ( 0 -1 0), 1. 5 -p oi nt re d ucti o n o n N R S ( 0 - 1 0), a n d a 2-p oi nt re d ucti o n o n N R S ( 0 -1 0) 
t hr o u g h 2 4 h o urs p ost-d ose.
1 1. T o e x pl ore t he distri b uti o n of baseli ne disease se verit y usi n g t he of Si n o -Nasal O utc o me Test 
( S N O T-2 2).
1 2. T o e val uate ri me ge pa nt c o m pare d t o place b o o n t he Si n o -Nasal O utc o me Test ( S N O T -2 2) 
sc ore at 2 4 h o urs p ost-d ose.
1 3. T o e val uate t he safet y a n d t olera bilit y of ri me ge pa nt i n t he acute treat me nt of c hr o nic 
r hi n osi n usitis as meas ure d b y t he fre q ue nc y of a d verse e ve nts of m o derate or se vere 
i nte nsit y, seri o us a d verse e ve nts ( S A Es), cli nically rele va nt la b orat or y a b n or malities, a n d 
nasal i ns pecti o n a b n or malities.
1 4. T o e val uate ri me ge pa nt c o m pare d t o place b o f or t he C ol u m bia -S uici d e Se verit y  Rati n g Scale 
( C-S S R S).
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
3 
S T U D Y E N D P OI N T S 
3. 1
Pri m ar y E n d p oi nt( s)
C ha n ge fr o m baseli ne facial pai n/ press ure/f ull ness will be assesse d usi n g t he n u m ber of 
e val ua ble s u bjects t hat re p ort facial pai n/ press ure/f ull ness ≥6 o n N R S ( 0 -1 0) at baseli ne a n d 
w h o als o re p ort pai n le vel at 2 h o urs p ost -d ose rec or de d i n t he e Diar y.
3. 2
S e c o n d ar y E n d p oi nt( s)
1.
C ha n ge fr o m baseli ne of T ot al N as al S y m pt o m Sc ore ( T N S S) will be assesse d usi n g t he 
n u m ber of e val ua ble s u bjects t hat re p ort facial pai n/ press ure/f ull ness, nasal o bstr ucti o n
(c o n gesti o n), a n d nasal disc har ge sc ores at baseli ne a n d at 2 h o urs p ost -d ose i n t he e Diar y.
2.
C ha n ge fr o m baseli ne of n as al o bstr ucti o n (c o n gesti o n ) will be assesse d usi n g t he n u m ber 
of e val ua ble s u bjects t hat re p ort nasal o bstr ucti o n (c o n gesti o n) sc ore o n N R S ( 0 -1 0) sc ore at 
baseli ne a n d 2 h o urs p ost -d ose i n t he e Diar y.
3.
C ha n ge fr o m baseli ne of n as al disc h ar ge will be assesse d usi n g t he n u m ber of e val ua ble 
s u bjects t hat re p ort nasal disc har ge sc ore o n N R S ( 0 -1 0) sc ore at baseli ne a n d 2 h o urs p ost -
d ose i n t he e Diar y.
4.
H e a d ac he p ai n relief will be assesse d usi n g t he n u m ber of e val ua ble s u bjects t hat re p ort a 
hea dac he pai n le vel of m o derate or s e vere i nte nsit y at baseli ne a n d t he n re p o rt a pai n le vel of 
n o ne or mil d at 2 h o urs p ost -d ose i n t he e Diar y usi n g a 4 -p oi nt L i kert scale.
5.
T he pr o b a bilit y of re q uiri n g resc ue me dic ati o n will be assesse d usi n g t he n u m ber of 
s u bjects t hat ta ke resc ue me dicati o n wit hi n 2 4 h o urs after a d mi nistrati o n of st u d y  me dicati o n 
(ri me ge pa nt or place b o).
3. 3
M e a s ur e s of i nt er e st
Safet y  a n d Ot her assess me nts:

A d verse E ve nts

E C G assess me nts

Vital Si g n s a n d P h y sical Meas ure me nts

R o uti ne L a b orat or y Tests

C ol u m bia -S uici de Se verit y  Rati n g Scale ( C-S S R S) 

Assess me nt of C R S Pai n a n d S y m pt o ms

Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI -C)

Si n o -Nasal O utc o me Test ( S N O T - 2 2)
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
4
S T U D Y P L A N
4. 1
St u d y D e si g n a n d D ur ati o n
T his is a d o u ble - bli n d, ra n d o mize d, m ultice nter, o ut patie nt e val uati o n of t he safety a n d efficac y 
of ri me ge pa nt as c o m pare d t o place b o i n t he ac ute treat me nt of c hr o nic r hi n osi n usitis wit h or 
wit h o ut p ol y ps . S u bjects will be dis pe nse d o ne d ose of st u d y me dicati o n c o nsisti n g of a 
ri me ge pa nt 7 5 m g O D T (place d o n or u n der t he t o n g ue ) or a matc hi n g place b o. T he t otal 
d urati o n of s u bject’s st u d y partici pati o n will be u p t o a p pr o xi matel y 6 6 da ys. T his i ncl u des a 3 t o 
1 4 da y  ( + 2 da ys f or sc he d uli n g p ur p oses, if nee de d) Scree ni n g Peri o d, a n Ac ute Treat me nt P hase 
t hat ca n last u p t o 4 5 da ys or u ntil t he s u bject has a facial pai n / press ure/f ull ness t hat reac hes a 
c urre nt i nte nsity of ≥6 o n t he N R S ( 0 -1 0), f oll o we d b y  a n E n d of Treat me nt Visit ( E O T) wit hi n
7 da y s ( + 2 d a y s f or sc he d uli n g p ur p oses, if nee de d) after t he a d mi nistrati o n of t he st u d y  
me dicati o n .
If a s u bject has N O T e x perie nce d a facial pai n/ press ure/f ull ness of s ufficie nt se verit y wit hi n 4 5 
da y s after ra n d o mizati o n, t he y still are re q uire d t o c o m plete all EO T visit pr oce d ures. 
All s u bjects m ust ret ur n e m pt y me dicati o n c o ntai ners or u n use d st u d y  me dicati o n a n d t he e Diar y 
t o t he st u d y ce nter.
T he e n d of t he st u d y is defi ne d as t he date of t he last visit of t he last s u bject.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L
4. 2
S c h e d ul e of A s s e s s m e nt s
T a bl e 1
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) S c h e d ul e of A s s e s s m e nt s
Pr oce d ure
Scree ni n g 
Visit 
( 3- 1 4 
d a ys)
B aseli ne Visit 
( R a n d o miz ati o n)
Wee kl y 
bet w ee n 
B aseli ne 
Visit 
a n d 
D osi n g
F aci al 
p ai n/ press ure/f ull ness 
≥6 o n N R S ( 0- 1 0)
D uri n g 
Tre at me nt 
1 5, 3 0, 4 5, 
6 0 a n d 9 0 
mi n utes 
P ost -D ose
D uri n g 
Tre at me nt 
2, 4, 8 
h o urs  
P ost -D ose
D uri n g 
Tre at me nt 
2 4 h o urs 
P ost -D ose
E n d of Tre at me nt 
Visit ( wit hi n 7 ( + 2) 
d a ys of tre ati n g f aci al 
p ai n/ press ure/f ull ness)
C o m me nts
Eli gi bilit y Assess m e nts
I nf or me d 
C o nse nt
X
I ncl usi o n/ 
E xcl usi o n 
Criteria
X
X
Me dical Hist or y
X
C ollect Dail y 
Use of 
Me dicati o ns t o 
Re d uce 
I nte nsit y of 
C R S S y m pt o ms 
/ C o nc o mita nt 
Me dicati o ns
X
X
X
S u bjects will be 
gi ve n pa per diaries t o 
use t o kee p trac k of 
t heir c o nc o mita nt 
me dicati o ns a n d 
resc ue me dicati o ns 
t hr o u g h o ut t he st u d y. 
All me dicati o ns 
ta ke n f or a n y reas o n 
s h o ul d be 
d oc u me nte d.  Site 
staff s h o ul d i nstr uct 
s u bjects o n pr o per 
use of t he pa per 
diaries a n d i nstr uct 
s u bjects t hat t he 
diaries will be 
c ollecte d, re vie we d, 
a n d disc usse d wit h 
t he s u bject at eac h 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T a bl e 1
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) S c h e d ul e of A s s e s s m e nt s
Pr oce d ure
Scree ni n g 
Visit 
( 3- 1 4 
d a ys)
B aseli ne Visit 
( R a n d o miz ati o n)
Wee kl y 
bet w ee n 
B aseli ne 
Visit 
a n d 
D osi n g
F aci al 
p ai n/ press ure/f ull ness 
≥6 o n N R S ( 0- 1 0)
D uri n g 
Tre at me nt 
1 5, 3 0, 4 5, 
6 0 a n d 9 0 
mi n utes 
P ost -D ose
D uri n g 
Tre at me nt 
2, 4, 8 
h o urs  
P ost -D ose
D uri n g 
Tre at me nt 
2 4 h o urs 
P ost -D ose
E n d of Tre at me nt 
Visit ( wit hi n 7 ( + 2) 
d a ys of tre ati n g f aci al 
p ai n/ press ure/f ull ness)
C o m me nts
visit.
Ass ess me nt of 
C R S Hist or y)
X
P a per s o urce 
d oc u me nt will be 
use d t o ca pt ure C R S 
Hist or y a n d e ntere d 
i n e C R F
S afet y Assess me nts
P h ysical 
E xa mi nati o n
X
X
Vital 
Si g ns/ P h ysical 
Meas ure me nts
X
X
X
Vital Si g ns c o nsist of 
sitti n g arterial 
s yst olic a n d diast olic 
bl o o d press ure, heart 
rate, oral b o d y 
te m perat ure, b o d y 
wei g ht a n d hei g ht.  
Hei g ht a n d wei g ht 
will o nl y be 
meas ure d at 
Scree ni n g.
Cli nical Safet y 
La b orat or y 
Testi n g
X
X
All Scree ni n g visit
la b orat or y test res ults 
m ust be recei ve d 
pri or t o Baseli ne 
Visit (ra n d o mizati o n)
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 5 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T a bl e 1
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) S c h e d ul e of A s s e s s m e nt s
Pr oce d ure
Scree ni n g 
Visit 
( 3- 1 4 
d a ys)
B aseli ne Visit 
( R a n d o miz ati o n)
Wee kl y 
bet w ee n 
B aseli ne 
Visit 
a n d 
D osi n g
F aci al 
p ai n/ press ure/f ull ness 
≥6 o n N R S ( 0- 1 0)
D uri n g 
Tre at me nt 
1 5, 3 0, 4 5, 
6 0 a n d 9 0 
mi n utes 
P ost -D ose
D uri n g 
Tre at me nt 
2, 4, 8 
h o urs  
P ost -D ose
D uri n g 
Tre at me nt 
2 4 h o urs 
P ost -D ose
E n d of Tre at me nt 
Visit ( wit hi n 7 ( + 2) 
d a ys of tre ati n g f aci al 
p ai n/ press ure/f ull ness)
C o m me nts
F S H
X
F S H le vels will be 
meas ure d o n p ost -
me n o pa usal w o me n 
t o c o nfir m p ost-
me n o pa usal stat us. 
F S H le vel testi n g is 
n ot re q uire d f or 
w o me n greater t ha n 
or e q ual t o 6 2 years 
ol d wit h a me n orr hea 
of greater t ha n or 
e q ual t o 1 year.
H b A 1c
X
Li pi d Pa nel
X
Tri gl yceri des, t otal 
c h olester ol, H D L, 
a n d L D L
Uri ne dr u g 
scree n f or dr u gs 
of a b use
X
X
E C G
X
X
Pre g na nc y Test
X
X
X
X
A ser u m pre g na nc y 
test will be 
c o m plete d at 
Scree ni n g a n d E n d of 
Treat me nt Visits as 
part of t he sta n dar d 
la b orat or y tests (if 
a p pr o priate). 
C o nfir mat or y uri ne 
pre g na nc y test f or 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 6 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T a bl e 1
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) S c h e d ul e of A s s e s s m e nt s
Pr oce d ure
Scree ni n g 
Visit 
( 3- 1 4 
d a ys)
B aseli ne Visit 
( R a n d o miz ati o n)
Wee kl y 
bet w ee n 
B aseli ne 
Visit 
a n d 
D osi n g
F aci al 
p ai n/ press ure/f ull ness 
≥6 o n N R S ( 0- 1 0)
D uri n g 
Tre at me nt 
1 5, 3 0, 4 5, 
6 0 a n d 9 0 
mi n utes 
P ost -D ose
D uri n g 
Tre at me nt 
2, 4, 8 
h o urs  
P ost -D ose
D uri n g 
Tre at me nt 
2 4 h o urs 
P ost -D ose
E n d of Tre at me nt 
Visit ( wit hi n 7 ( + 2) 
d a ys of tre ati n g f aci al 
p ai n/ press ure/f ull ness)
C o m me nts
W O C B P s h o ul d be 
c o m plete d o n site at 
t he Baseli ne Visit 
a n d a n y s u bse q ue nt 
visits f or 
c o nfir mati o n at t he 
I n vesti gat or’s 
discreti o n. H o me 
pre g na nc y test will 
be pr o vi de d t o 
W O C B P after 
c o m pleti o n of 
baseli ne visit. 
W O C B P s u bjects 
m ust c o m plete t he 
uri ne pre g na nc y test 
at h o me, a n d t hat test 
res ult m ust be 
ne gati ve pri or t o 
ta ki n g st u d y 
me dicati o n.
A d verse E ve nt 
a n d Seri o us 
A d verse E ve nt 
Assess me nt
X
X
X
X
X
X
X
S A Es a n d n o n -
seri o us AEs are 
re p orte d fr o m t he 
ti me of i nf or me d 
c o nse nt. See Secti o n
8 of t he pr ot oc ol f or 
f urt her i nf or mati o n.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 7 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T a bl e 1
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) S c h e d ul e of A s s e s s m e nt s
Pr oce d ure
Scree ni n g 
Visit 
( 3- 1 4 
d a ys)
B aseli ne Visit 
( R a n d o miz ati o n)
Wee kl y 
bet w ee n 
B aseli ne 
Visit 
a n d 
D osi n g
F aci al 
p ai n/ press ure/f ull ness 
≥6 o n N R S ( 0- 1 0)
D uri n g 
Tre at me nt 
1 5, 3 0, 4 5, 
6 0 a n d 9 0 
mi n utes 
P ost -D ose
D uri n g 
Tre at me nt 
2, 4, 8 
h o urs  
P ost -D ose
D uri n g 
Tre at me nt 
2 4 h o urs 
P ost -D ose
E n d of Tre at me nt 
Visit ( wit hi n 7 ( + 2) 
d a ys of tre ati n g f aci al 
p ai n/ press ure/f ull ness)
C o m me nts
C ol u m bia -
S uici de 
Se verit y Rati n g 
Scale ( C -S S R S)
X
X
X
T his scale will be 
cli nicia n 
a d mi nistere d, 
c o m plete d o n site, 
a n d will be i n pa per. 
T he s o urce d oc u me nt 
will be pr o vi de d b y 
Pf izer. See Secti o n 
6. 2. 5 f or f urt her 
details.  
Cli nic al Dr u g S u p plies/ St u d y S u p plies
Ra n d o mize
X
S u bjects will be 
ra n d o mize d i n t he 
I W R S s yste m at t he 
Baseli ne Visit 
(ra n d o mizati o n)
Dis pe nse St u d y 
Me dicati o n
X
Wee kl y C o ntact 
(e. g. via p h o ne, 
te xt, e mail)
X
S u bjects s h o ul d be 
c o ntacte d at least 
wee kl y a n d 
q uesti o ne d a b o ut 
t heir s yste mic 
c ortic oster oi d a n d 
a nti bi otics ( ot her 
t ha n t o pical nasal 
a nti bi otics) use a n d 
re m o ve d fr o m t he 
st u d y acc or di n g t o 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 8 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T a bl e 1
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) S c h e d ul e of A s s e s s m e nt s
Pr oce d ure
Scree ni n g 
Visit 
( 3- 1 4 
d a ys)
B aseli ne Visit 
( R a n d o miz ati o n)
Wee kl y 
bet w ee n 
B aseli ne 
Visit 
a n d 
D osi n g
F aci al 
p ai n/ press ure/f ull ness 
≥6 o n N R S ( 0- 1 0)
D uri n g 
Tre at me nt 
1 5, 3 0, 4 5, 
6 0 a n d 9 0 
mi n utes 
P ost -D ose
D uri n g 
Tre at me nt 
2, 4, 8 
h o urs  
P ost -D ose
D uri n g 
Tre at me nt 
2 4 h o urs 
P ost -D ose
E n d of Tre at me nt 
Visit ( wit hi n 7 ( + 2) 
d a ys of tre ati n g f aci al 
p ai n/ press ure/f ull ness)
C o m me nts
t he re q uire me nts i n 
Secti o n 6. 2. 6 .
A d mi nister 1 
d ose of st u d y 
me dicati o n
X
S u bjects will use 
e Diar y t o a ns wer 
q uesti o ns a b o ut t heir 
C R S s y m pt o ms u p o n 
e x perie nci n g a facial 
pai n/ press ure/f ull ness 
of ≥ 6 o n N R S ( 0 -
1 0). T he s u bject will 
a d mi nister pre -
dis pe nse d st u d y dr u g 
if 1) t he facial 
pai n/ press ure/f ull ness 
re mai ns ≥ 6 o n N R S 
( 0-1 0); 2) t he s u bject 
has c o m plete d all 
re q uire d C R S 
assess me nt q uesti o ns 
i n t he e Diar y, a n d 3) 
t he s u bject h as n ot 
alre a dy t ake n 
pr o hi bite d 
me dic ati o ns (see 
pr ot oc ol S ecti o n 5. 4 ). 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 3 9 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T a bl e 1
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) S c h e d ul e of A s s e s s m e nt s
Pr oce d ure
Scree ni n g 
Visit 
( 3- 1 4 
d a ys)
B aseli ne Visit 
( R a n d o miz ati o n)
Wee kl y 
bet w ee n 
B aseli ne 
Visit 
a n d 
D osi n g
F aci al 
p ai n/ press ure/f ull ness 
≥6 o n N R S ( 0- 1 0)
D uri n g 
Tre at me nt 
1 5, 3 0, 4 5, 
6 0 a n d 9 0 
mi n utes 
P ost -D ose
D uri n g 
Tre at me nt 
2, 4, 8 
h o urs  
P ost -D ose
D uri n g 
Tre at me nt 
2 4 h o urs 
P ost -D ose
E n d of Tre at me nt 
Visit ( wit hi n 7 ( + 2) 
d a ys of tre ati n g f aci al 
p ai n/ press ure/f ull ness)
C o m me nts
T he e Di ar y will 
pr o m pt t he s u bject 
t o t a ke st u d y 
me dic ati o n.
Ret ur n u n use d 
st u d y 
me dicati o n
X
e Diar y 
ret ur ne d/ 
re vie we d f or 
c o m plete ness
X
Staff t o re vie w a n d 
c o nfir m e Diar y 
e ntries wit h s u bjects, 
c o nfir m all data 
p oi nts are tra nsferre d 
t o t he s yste m, a n d 
reset e Diar y f or 
f ut ure s u bject use, 
P RI O R t o t he s u bject 
lea vi n g t he cli nic 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 0 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T a bl e 1
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) S c h e d ul e of A s s e s s m e nt s
Pr oce d ure
Scree ni n g 
Visit 
( 3- 1 4 
d a ys)
B aseli ne Visit 
( R a n d o miz ati o n)
Wee kl y 
bet w ee n 
B aseli ne 
Visit 
a n d 
D osi n g
F aci al 
p ai n/ press ure/f ull ness 
≥6 o n N R S ( 0- 1 0)
D uri n g 
Tre at me nt 
1 5, 3 0, 4 5, 
6 0 a n d 9 0 
mi n utes 
P ost -D ose
D uri n g 
Tre at me nt 
2, 4, 8 
h o urs  
P ost -D ose
D uri n g 
Tre at me nt 
2 4 h o urs 
P ost -D ose
E n d of Tre at me nt 
Visit ( wit hi n 7 ( + 2) 
d a ys of tre ati n g f aci al 
p ai n/ press ure/f ull ness)
C o m me nts
Effic ac y Assess me nts
± wi n d o ws f or 
ti mefra me ar o u n d 
efficac y assess me nts 
( 1 5, 3 0, 4 5, 6 0, 9 0 
mi n, 2, 4, 8, a n d 2 4 
h o urs) will be 
a ut o mate d a n d 
ca pt ure d i n t he 
e Diar y.
Assess me nt of 
facial 
pai n/ press ure/ 
f ull ness
X
X
X
X
T his scale is ca pt ure d 
i n t he e Diar y
Assess me nt of 
nasal 
o bstr ucti o n 
(c o n gesti o n)
X
X
X
X
T his scale is ca pt ure d 
i n t he e Diar y.
Assess me nt of 
nasal disc har ge
X
X
X
X
T his scale is ca pt ure d 
i n t he e Diar y
Hea dac he Pai n
X
X
X
X
T his scale is ca pt ure d 
i n t he e Diar y f or 
s u bjects w h o re p ort 
c urre nt hea dac he 
pai n of m o derate or 
se vere at t he ti me of 
q ualif yi n g facial 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T a bl e 1
B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) S c h e d ul e of A s s e s s m e nt s
Pr oce d ure
Scree ni n g 
Visit 
( 3- 1 4 
d a ys)
B aseli ne Visit 
( R a n d o miz ati o n)
Wee kl y 
bet w ee n 
B aseli ne 
Visit 
a n d 
D osi n g
F aci al 
p ai n/ press ure/f ull ness 
≥6 o n N R S ( 0- 1 0)
D uri n g 
Tre at me nt 
1 5, 3 0, 4 5, 
6 0 a n d 9 0 
mi n utes 
P ost -D ose
D uri n g 
Tre at me nt 
2, 4, 8 
h o urs  
P ost -D ose
D uri n g 
Tre at me nt 
2 4 h o urs 
P ost -D ose
E n d of Tre at me nt 
Visit ( wit hi n 7 ( + 2) 
d a ys of tre ati n g f aci al 
p ai n/ press ure/f ull ness)
C o m me nts
pai n/ press ure/f ull ness
Patie nt Gl o bal 
I m pressi o n of 
C ha n ge      
( P GI-C)
X
T his scale is ca pt ure d 
i n t he e Diar y
Si n o -Nasal 
O utc o me Test 
( S N O T-2 2)
X
X
T his scale is ca pt ure d 
o n pa per at t he 
Baseli ne Visit a n d i n 
t he e Diar y at 2 4-
h o urs p ost -d ose. 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
4. 2. 1 
S cr e e ni n g P h a s e ( 3 t o 1 4 d a y s)
T he Scree ni n g P hase will be 3 t o 1 4 da y s ( + 2 da ys if nee de d f or sc he d uli n g p ur p oses). All 
s u bjects w h o si g ne d I nf or me d C o nse nt will be e ntere d i nt o t he I nteracti ve We b Res p o nse S yste m 
(IW R S)
a n d assi g ne d a s u bject i de ntifier. After o btai ni n g i nf or me d c o nse nt, s u bjects will 
u n der g o all scree ni n g pr oce d ures as detaile d i n Ta ble 1 . After all scree ni n g pr oce d ures are 
c o m plete, t he s u bject meets t he I ncl usi o n/ E xcl usi o n Criteria a n d la b test res ults ha ve bee n 
re vie we d by t h e I n vesti gat or, t he Baseli ne Visit will be sc he d ule d. 
S u bjects w h o were c o nsi dere d scree n fail ures ma y  be c o nsi dere d f or re-scree ni n g pr o vi de d t he 
i neli gi bilit y was d ue t o o ne of t he eli gi bilit y criteria t hat ma y ha ve c ha n ge d d ue t o me dical 
i nter ve nti o n or o ne of t he eli gi bilit y criteria m o difie d i n a pr ot oc ol a me n d me nt. A de q uate 
d oc u me ntati o n i n s o urce rec or ds m ust s u p p ort t he pre vi o usl y  faile d criteria. I n all p ossi ble re-
scree ni n g circ u msta nces, t he sit uati o n m ust be disc usse d wit h t he sp o ns or pri or t o re-scree ni n g, 
wit h a p pr o val i n writi n g fr o m t he sp o ns or pri or t o re -scree ni n g.  If a s u bject is a p pr o ve d f or re-
scree ni n g, a ne w s u bject n u m ber m ust be o btai ne d fr o m t he a p pr o priate st u d y-relate d sys te m. 
Re -scree ni n g will o nl y be per mitte d o ne ti me.
4. 2. 2
A c ut e Tr e at m e nt ( R a n d o mi z ati o n) P h a s e
It is esti mate d t hat a p pr o xi matel y 2 8 6 s u bjects will be ra n d o mize d t o res ult i n a p pr o xi matel y 2 0 0 
e val ua ble s u bjects . If t he s u bject meets all eli gi bilit y criteria, t he y will be ra n d o mize d at t he 
Baseli ne Visit via t he I W R S. S u bjects will be pr o vi de d wit h a n e Diar y. S t u d y pers o n nel will 
e d ucate t he s u bject o n t he pr o per use of t he e Diar y, acc urate re p orti n g a n d place b o res p o nse 
pri or t o t he s u bject lea vi n g t he office . 
After ra n d o mizati o n via t he I W R S, t he s u bject will be dis pe nse d a si n gle d ose of t he d o u ble -
bli n d st u d y  me dicati o n t o ta ke h o me. T he s u bject will be i nstr ucte d t o ta ke t heir st u d y 
me dicati o n wit hi n 4 5 da ys , as a n o ut patie nt, w he n (if) t he y ha ve facial pai n/ press ure/f ull ness 
w hic h reac hes a c urre nt i nte nsit y of ≥6 o n t he N R S ( 0 -1 0) a n d after t he y a ns wer e Diar y 
q uesti o ns a b o ut t heir c urre nt pai n a n d s y m pt o ms. T he s u bject will c o m plete q uesti o n naires i n
t heir e Diar y, at vari o us ti me p oi nts, f or 2 4 h o urs after ta ki n g st u d y me dicati o n t o rec or d efficac y 
a n d ot her q ualit y of life meas ures.
S u bjects i n t his st u d y  ma y be ra n d o mize d o nl y o nce. U n der n o circ u msta nces ma y a s u bject be 
re-ra n d o mize d.
4. 2. 2. 1
e Di ar y  D at a C oll e cti o n
S u bjects will rec or d t he date a n d ti me of d osi n g, pre-d ose a n d p ost -d ose efficac y assess me nts, 
a n d ot her q ualit y of life meas ures i n t heir e Diar y. S u bjects s h o ul d n ot d ose wit h st u d y  
me dicati o n u ntil t he facial pai n/ press ure/f ull ness reac hes a c urre nt i nte nsity of ≥6 o n t he N R S 
( 0-1 0) a n d t he y ha ve c o m plete d t he pre-d ose assess me nts i n t he e Diar y . Efficac y a n d q uality of 
life meas ure me nts i ncl u de t he f oll o wi n g: o nset ti me of facial pai n/ press ure/f ull ness at ti me of 
ta ki n g st u dy me dicati o n a n d after d osi n g at ti mes liste d i n Ta ble 1 . Nasal o bstr ucti o n 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L
(c o n gesti o n) se verit y a n d Nasal disc har ge se verit y a n d will be rec or de d usi n g a N R S ( 0 -1 0) at 
t he o nset of t he facial pai n/ press ure/f ull ness ≥6 o n t he N R S ( 0 - 1 0) a n d after d osi n g at ti me s 
liste d i n Ta ble 1 . Hea dac he pai n se verit y will be rec or de d usi n g a 4-p oi nt Li kert scale (0 = N o ne; 
1 = Mil d; 2 = M o derate; 3 = Se vere) at t he o nset of t he facial pai n/ press ure/f ull ness ≥6 o n t he 
N R S ( 0 -1 0) a n d after d osi n g at ti mes liste d i n Ta ble 1 .
T he Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI -C) will be c o m plete d b y t he s u bject 2 4 h o urs 
after d osi n g. T he Si n o -Nasal O utc o me Test ( S N O T -2 2) q uesti o n naire will be c o m plete d o n 
pa per at t he Baseli ne Visit a n d o n t he e Diar y  at 2 4 h o urs after d osi n g.
After d osi n g wit h st u d y  me dicati o n, all ot her me dicati o n t o treat C R S s ym pt o ms is pr o hi bite d 
d uri n g t he 2 h o urs p ost -d ose. A t t he e n d of 2 h o urs after d osi n g wit h st u d y  me dicati o n (a n d after 
t he 2- h o ur assess me nts ha ve bee n c o m plete d o n t he e Diar y ) s u bjects will be per mitte d t o use t he 
f oll o wi n g resc ue me dicati o n: aceta mi n o p he n ( u p t o 1 0 0 0 m g/ da y), or as piri n, i b u pr ofe n, 
na pr o xe n ( or a n y ot her t y pe of n o nster oi dal a nti -i nfla m mat or y dr u g [N S AI D ]), oral 
a nti hista mi nes ( n o n-se dati n g), oral dec o n gesta nts, t o pical nasal dec o n gesta nts, t o pical nasal 
a ntic h oli ner gics (all u p t o t he dail y rec o m me n de d d ose i n dicate d o n t he dr u g pac ka gi n g). T hese 
are t he o nl y me dicati o ns all o we d f or resc ue treat me nt after 2 h o urs p ost -d ose of st u d y  
me dicati o n. H o we ver, if nee de d, after 2 4 h o urs of a d mi nisteri n g t he o ne d ose of st u d y  
me dicati o n (a n d bef ore ret ur ni n g f or t he E n d of Treat me nt Visit) s u bject ma y  ta ke t heir 
prescri be d sta n dar d of care me dicati o ns f or treat me nt of C R S s y m pt o ms pr o vi de d all t he 
assess me nts ha ve bee n c o m plete d o n t he e Diar y . E xcl usi o nar y resc ue me dicati o n s uc h as, 
o pi oi ds a n d b utal bital c o m p o u n ds, are n ot all o we d o n t his st u d y. Si milarl y, if t he facial 
pai n/ press ure/f ull ness is relie ve d b y st u d y me dicati o n at 2 h o urs after d osi n g b ut t he n rec urs t o 
i nte nsit y le vel of ≥6 o n t he N R S ( 0 -1 0) bet wee n 2 a n d 2 4 h o urs, t he s u bject will be per mitte d t o 
ta ke t he sa me resc ue t hera p y as o utli ne d a b o ve.
S u bjects s h o ul d be e nc o ura ge d t o treat t he first q ualif y i n g facial pai n/ press ure/f ull ness (i nte nsit y 
le vel of ≥6 o n t he N R S ( 0 - 1 0)) t hat occ urs d uri n g t he treat me nt p hase. If s u bjects are u na ble t o 
treat t heir first q ualif yi n g facial pai n/ press ure/f ull ness d ue t o sc he d uli n g, etc., t he sa me 
me dicati o n restricti o ns w o ul d still a p pl y  (i.e., s u bjects w o ul d o nl y be per mitte d t o ta ke 
aceta mi n o p he n ( u p t o 1 0 0 0 m g/ da y ), or as piri n, i b u pr ofe n, na pr o xe n ( or a n y  ot her ty p e of 
n o nster oi dal a nti -i nfla m mat or y dr u g [N S AI D ]), oral a nti hista mi nes ( n o n-se dati n g), oral 
dec o n gesta nts, t o pical nasal dec o n gesta nts, t o pical nasal a ntic h oli ner gics [all u p t o t he dail y 
rec o m me n de d d ose i n dicate d o n t he dr u g pac ka gi n g]).
Si milarl y , f or treat me nt of n o n-q ualif y i n g facial pai n/ press ure/f ull ness (i.e., i nte nsit y le vel of < 6 
o n t he N R S ( 0- 1 0 )) that occ ur d uri n g t he ra n d o mizati o n peri o d bef ore a q ualif y i n g facial 
pai n/ press ure/f ull ness is re p orte d, s u bject will o nly be per mitte d t o use t he me dicati o ns liste d 
a b o ve. A ceta mi n o p he n ( o ver 1 0 0 0 m g / da y) is pr o hi bite d after ra n d o mizati o n e xce pt as resc ue
me dicati o n as descri be d i n Secti o n 5. 5 . In all circ u msta nces, t he s u bject will c o nti n ue t o 
c o m plete his or her e Diar y f or u p t o 2 4 h o urs after c o ns u mi n g t he st u d y me dicati o n.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
S u bjects s h o ul d ha ve access t o s y ste mic c ortic oster oi ds a n d a nti bi otics d uri n g t he trial f or 
treat me nt of sy m pt o ms if i n dicate d. H o we ver, s u bjects s h o ul d disc o nti n ue t he st u d y  if t he y 
recei ve t h ose t hera pies. 
4. 2. 3
E xt e n si o n P h a s e
N ot a p plica ble. 
4. 2. 4
W a s h o ut P h a s e
N ot a p plica ble. 
4. 2. 5
E n d of Tr e at m e nt
S u bjects will ret ur n t o t he st u d y  site wit hi n 7 da ys of st u d y treat me nt ( + 2 da ys) f or re vie w of t he 
e Diar y assess me nt, of me dicati o n c o m plia nce, a n d m o nit ori n g of t olera bilit y  a n d safety 
(i ncl u di n g vital si g ns, la b orat or y tests, a n d electr ocar di o gra p h y).  If a s u bject has N O T 
e x perie nce d a facial pai n/ press ure/f ull ness of s ufficie nt se verit y wit hi n 4 5 d a y s after 
ra n d o mizati o n, t he y still are re q uire d t o c o m plete all E O T visit pr oce d ures. All s u bjects m ust 
ret ur n u n use d st u dy me dicati o n or e m pt y pac ka gi n g a n d t he e Diar y t o t he st u d y ce nter.
4. 3
P o st St u d y  Ac c e s s t o T h er a p y
At t he e n d of t he st u d y t he sp o ns or will n o t c o nti n ue t o s u p pl y st u d y dr u g t o 
su bjects/ In vesti gat ors. T he I n vesti gat or s h o ul d e ns ure t hat t he s u bject recei ves t he a p pr o priate 
sta n dar d of care t o treat t he c o n diti o n u n der st u dy.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 5 of 1 0 4
P FI Z E R C O N FI D E N TI A L
5
P O P U L A TI O N
I n di vi d uals e ntere d i n t his trial will be s u bjects w h o s uffer fr o m c hr o nic r hi n osi n usitis wit h or 
wit h o ut nasal p ol y ps as s pecifie d u n der S ecti o n 5. 2 . T he treat me nt setti n g f or t hese s u bjects ma y 
i ncl u de cli nics, i nstit uti o ns, or pri vate office practices. S u bjects ma y  be recr uite d t hr o u g h a 
variet y of s o urces, i ncl u di n g referral fr o m p h ysicia ns a n d ot her healt h care pr ofessi o nals.
5. 1
N u m b er of S u bj e ct s
T he st u d y  will ra n d o mize a p pr o xi matel y 2 8 6 s u bjects t o res ult i n a p pr o xi matel y 2 0 0 e val ua ble 
s u bjects.. T he su bjects will be ra n d o mize d i n a 1: 1 rati o t o t he ri me ge pa nt or place b o treat me nt 
gr o u ps.
5. 2
I n cl u si o n Crit eri a
1.
Tar get p o p ulati o n
At t he Scree ni n g Visit, t he s u bject ha s a mi ni m u m 3- m o nt h hist or y of c hr o nic r hi n osi n usitis 
( C R S) wit h or wit h o ut p ol yps, dia g n os e d b y a healt hcare pr o vi der , i ncl u di n g all of t he 
f oll o wi n g:
a.
F aci al p ai n/ press ure/f ull ness A N D o ne or m ore of t he f oll o wi n g si g ns a n d s y m pt o ms: 
nasal disc har ge (a nteri or, p osteri or, or b ot h), nasal o bstr ucti o n (c o n gesti o n), or decrease d 
se nse of s mell.
b.
I nfl a m m ati o n is d oc u me nte d b y at least o ne of t hese t hree fi n di n gs:
i.
E n d osc o pic fi n di n g s of m uc o p ur ule nt drai na ge ( n ot clear) or e de ma i n t he mi d dle or 
s u peri or meat us , or a nteri or et h m oi d re gi o n
ii. P ol y ps i n nasal ca vit y or t he mi d dle or s u peri or meat us
iii R a di o gra p hic i ma gi n g s h o wi n g i nfla m mati o n of t he para nasal si n uses wit h partial 
o pacificati o n of at least t w o si n uses or c o m plete o pacificati o n of at least o ne si n us.
R es ults fr o m hist oric i ma gi n g, dia g n ostic or hist oric e n d osc o p y bef ore t he Scree ni n g 
Visit , b ut n ot ol der t ha n 1 2 m o nt hs , ca n be c o nsi dere d f or c o nfir mati o n of i nfla m mati o n.
c.
At least t w o e pis o des of facial pai n/ press ure/f ull ness of m o derate or se vere i nte nsit y o n a 
4- p oi nt rati n g scale ( 0 = N o ne, 1 = M il d, 2 = M o derate, 3 = S e vere) i n t he past 3 0 da ys 
pri or t o t he Scree ni n g Visit.
d.
S u bject wit h dail y  use of me dicati o ns liste d i n Secti o n 5. 5 is per mitte d t o re mai n o n 
t hera py if t he y ha ve bee n o n a sta ble d ose f or at least 1 m o nt h pri or t o t he Scree ni n g 
Visit , a n d t he d ose is n ot e x pecte d t o c ha n ge d uri n g t he c o urse of t he st u d y.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 6 of 1 0 4
P FI Z E R C O N FI D E N TI A L
e.
S u bje ct a grees t o n ot c o m me nce ne w t hera p y or a n y pai n ma na ge me nt tec h ni q ues t o treat 
t heir C R S d uri n g t he c o urse of t he st u d y.
2.
A ge a n d Re pr o d ucti ve Stat us
a.
Male a n d Fe male s u bjects ≥ 1 8 ye ars a n d ol der.
b.
S u bject meets re pr o d ucti ve criteria. Refer t o Secti o n 1 6. 3 f or re pr o d ucti ve criteria f or 
male (Secti o n 1 6. 3. 1 ) a n d fe male (Secti o n 1 6. 3. 2 ) s u bjects. 
c.
At t he Baseli ne Visit pri or t o dis pe nsi n g I n vesti gati o nal St u d y  Me dicati o n, W O C B P m ust 
ha ve a ne gati ve uri ne pre g na nc y  test.
3.
N o cli nicall y  si g nifica nt a b n or malit y i de ntifie d o n t he me dical or la b orat or y  e val uati o n. A 
s u bject wit h a cli nical a b n or malit y or la b orat or y para meters o utsi de t he refere nce ra n ge ma y 
be i ncl u de d o nl y if t he I n vesti gat or c o nsi ders t hat t he fi n di n g is n ot cli nicall y si g nifica nt a n d 
will n ot i ntr o d uce a d diti o na l ris k fact ors a n d will n ot i nterfere wit h t he st u d y pr oce d ures.
5. 3
E x cl u si o n Crit eri a
1.
Disease Tar get E xcl usi o n
a.
S u bject has a hist or y  of pri mar y hea dac he dis or der (e. g., mi grai ne, te nsi o n-t ype 
hea dac he, cl uster hea dac he), or M O H , dia g n ose d b y  a healt hcare pr o vi der , c o nsiste nt 
wit h dia g n ostic criteria acc or di n g t o t he I nter nati o nal Classificati o n of Hea dac he 
Dis or ders, 3 r d E diti o n (IC H D - 3). I nfre q ue nt te nsi o n-t ype hea dac he c o nsiste nt wit h 
dia g n ostic criteria acc or di n g t o t he I C H D-3 is n ot e xcl usi o nar y .
b.
S u bject has a hist or y  of nasal or facial s ur ger y wit hi n t he 6 m o nt hs pri or t o t he Scree ni n g 
Visit.
c.
S u bject has o n g oi n g r hi nitis me dica me nt osa (re b o u n d c o n gesti o n).
d.
S u bject has a hist or y  of nasal or u p per res pirat or y  i nfecti o n wit hi n t he 2 wee ks pri or t o 
t he Scree ni n g Visit.
e.
S u bject has a hist or y of i n vasi ve f u n gal r hi n osi n usitis.
f.
S u bject has dia g n ose d ac ute bacterial/ viral r hi n osi n usitis or has s y m pt o ms s u g gesti ve of 
a n ac ute e xacer bati o n of t heir c hr o nic r hi n osi n usitis (e. g., c o u g hi n g, fe ver, p ur ule nt 
disc har ge) wit hi n t he 2 wee ks pri or t o t he Scree ni n g Visit . If t he s u bject has dia g n ose d 
ac ute bacterial/ viral r hi n osi n usitis or has s y m pt o ms s u g gesti ve of a n ac ute e xacer bati o n 
of t heir c hr o nic r hi n osi n usitis bet wee n scree ni n g a n d d osi n g wit h st u d y dr u g, t he s u bject 
s h o ul d be disc o nti n ue d fr o m t he st u d y.
g.
S u bject has a dia g n osis of c y stic fi br osis.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 7 of 1 0 4
P FI Z E R C O N FI D E N TI A L
h.
S u bject has a dia g n osis of p ri mar y ciliar y d ys ki nesia (i m m otile-cilia s yn dr o me) .
i.
S u bject is c urre ntl y recei vi n g as piri n dese nsitizati o n or mai nte na nce t hera p y f or Sa mter’s 
Tria d.
j.
S u bject has a hist or y  of h yp o ga m ma gl o b uli ne mia.
k.
S u bject has a hist or y  of i m m u n o deficie nc y sy n dr o me .
l.
S u bject has a hist or y  of gra n ul o mat o us diseases.
m.
S u bject has a hist or y  of rec urre nt ac ute si n usitis (f o ur or m ore e pis o des per year of ac ute 
bacterial r hi n osi n usitis ( A B R S) wit h o ut si g ns or s y m pt o ms of r hi n osi n usitis bet wee n 
e pis o des).
n.
S u bject has a hist or y  of si n us m uc ocele wit hi n 1 year pri or t o t he Scree ni n g Visit.
o.
S u bject has a hist or y  of mali g na nt nasal or para nasal t u m or.
p.
S u bject has a hist or y  of o d o nt o ge nic si n usitis wit hi n 1 y ear pri or t o t he Scree ni n g Visit.
2.
Me dical Hist or y  a n d C o nc urre ntDiseases
a.
B o d y Mass I n de x 3 5. 0 k g/ m 2
b.
S u bject hist or y  wit h c urre nt e vi de nce of u nc o ntr olle d, u nstable or rece ntl y dia g n ose d 
car di o vasc ular disease, s uc h as isc he mic heart disease, c or o nar y  arter y vas os pas m, a n d 
cere bral isc he mia. S u bjects wit h M y ocar dial I nfarcti o n ( MI), Ac ute C or o nar y  Sy n dr o me 
( A C S), Perc uta ne o us C or o nar y Inter ve nti o n ( P CI), car diac s ur ger y , str o ke or tra nsie nt 
isc he mic attac k ( TI A) d uri n g t he 6 m o nt hs pri or t o t he Scree ni n g Visit .
c.
S u bject has u nc o ntr olle d h y perte nsi o n ( hi g h bl o o d press ure), or u nc o ntr olle d dia betes 
( h o we ver s u bjects ca n be i ncl u de d w h o ha ve sta ble h yperte nsi o n a n d/ or dia betes f or at 
least 3 m o nt hs pri or t o t he Scree ni n g Visit). A si n gle bl o o d press ure meas ure me nt of 
greater t ha n 1 5 0 m m H g s y st olic or 1 0 0 m m H g diast olic after 1 0 mi n utes of rest is 
e xcl usi o nar y.
d.
S u bject has a c urre nt dia g n osis of maj or de pressi o n, ot her pai n s y n dr o mes, ps yc hiatric 
c o n diti o ns (e. g., sc hiz o p hre nia), de me ntia, or si g nifica nt ne ur ol o gical dis or ders t hat, i n 
t he In vesti gat or’s o pi ni o n, mi g ht i nterfere wit h st u d y assess me nts.
e.
S u bject has a hist or y  of gastric, or s mall i ntesti nal s ur ger y (i ncl u di n g Gastric B ypass, 
Gastric Ba n di n g, Gastric Slee ve, Gastric Ball o o n, etc.), or has a disease t hat ca uses
mala bs or pti o n .
f.
S u bject has a hist or y  or c urre nt e vi de nce of a n y si g nifica nt a n d/ or u nsta ble me dical 
c o n diti o ns (e. g., hist or y of c o n ge nital heart disease or arr hyt h mia, k n o w n s us pecte d 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 8 of 1 0 4
P FI Z E R C O N FI D E N TI A L
i nfecti o n, he patitis B or C, or ca ncer) t hat, i n t he In vesti gat or’s o pi ni o n, w o ul d e x p ose 
t he m t o u n d ue ris k of a si g nifica nt a d verse e ve nt ( A E) or i nterfere wit h assess me nts of 
safety or efficac y d uri n g t he c o urse of t he trial. Se vere he patic i m pair me nt ( C hil d -P u g h 
C) is e xcl usi o nar y  i n all cases.
g.
S u bject has a h ist or y of, treat me nt f or, or e vi de nce of, alc o h ol or dr u g a b use or w h o ha ve 
met D S M -V criteria 2 4 f or a n y si g nifica nt s u bsta nce use dis or der wit hi n t he 1 2 m o nt hs 
pri or t o t he S cree ni n g V isit.
h.
S u bject s h o ul d be e xcl u de d if t he y  ha ve a p ositi ve dr u g scree n f or dr u gs of a b use t hat i n 
t he In vesti gat or’s j u d g me nt is me dicall y  si g nifica nt, i n t hat it w o ul d i m pact t he safety of 
t he s u bject or t he i nter pretati o n of t he st u d y res ults. In a d diti o n:
i.
Detecta ble le vels of c ocai ne, a m p heta mi ne, a n d p he nc y cli di ne ( P C P) i n t he dr u g 
scree n are e xcl usi o nar y. S u bjects w h o are p ositi ve f or a m p heta mi nes, a n d w h o are o n 
a prescri be d a m p heta mi ne me dicati o n f or a n a p pr o ve d i n dicati o n ( e. g., A D H D) will 
be all o we d i nt o t he st u d y at t he I n vesti gat or’s discreti o n.  T his deter mi nati o n b y t he 
I n vesti gat or must be well d oc u me nte d i n t he s u bject’s s o urce me dical rec or ds.  T he 
sti m ula nt d ose m ust be sta ble fr o m 3 m o nt hs pri or t o t he Scree ni n g Visit u ntil t he e n d 
of treat me nt visit occ urs.   
ii. Detecta ble le vels of ca n na bi n oi ds (e. g., marij ua na, C B D) i n t he dr u g scree n at t he 
Scree ni n g Visit are n ot e xcl usi o nar y, if i n t he In vesti gat or’s d oc u me nte d o pi ni o n t he 
s u bject d oes n ot meet D S M- V criteria 2 4 f or s u bsta nce use dis or der, a n d t he p ositi ve 
test d oes n ot si g nal a cli nical c o n diti o n t hat w o ul d i m pact t he safety of t he s u bject or 
i nter pretati o n of t he st u d y res ults.
3.
Aller gies a n d A d verse Dr u g Reacti o ns
a.
S u bject has a h ist or y of dr u g or ot her aller g y w hic h, i n t he o pi ni o n of t he In vesti gat or, 
ma kes t he s u bject u ns uita ble f or partici pati o n i n t he st u d y.
4.
Se x a n d Re pr o d ucti ve Stat us
a.
Fe males of c hil d - beari n g p ote ntial w h o are u n willi n g or u na ble t o use a n acce pta ble 
c o ntrace pti ve met h o d or a bsti ne nce t o a v oi d pre g na nc y  f or t he e ntire st u dy peri o d a n d f or 
2 8 da y s after d osi n g wit h st u d y  dr u g.
b.
W o me n w h o are pre g na nt , lactati n g or breastfee di n g.
c.
W o me n wit h a p ositi ve pre g na nc y  test o n e nr oll me nt or pri or t o st u d y dr u g
a d mi nistrati o n.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 4 9 of 1 0 4
P FI Z E R C O N FI D E N TI A L
5.
E C G a n d La b orat or y  TestFi n di n gs
a.
Esti mate d gl o mer ular filtrati o n rate (e G F R) acc or di n g t o t he re -e x presse d a b bre viate d 
(f o ur-varia bl e) M o dificati o n of Diet i n Re nal Disease ( M D R D) St u d y  e q uati o n < 3 0
ml/ mi n/ 1. 7 3 m 2
b.
E C G a b n or malities t hat , i n t he In vesti gat or’s o pi ni o n , ma kes t he s u bject u ns uita ble f or 
partici pati o n i n t he st u d y .
c.
T ota l ser u m bilir u bi n > 1. 5 x U L N ( O nl y a b n or mal val ues wit h cli nical j ustificati o n m ay 
be re pe ate d o nce f or c o nfir m ati o n d uri n g t he scree ni n g peri o d) . F or Gil bert’s 
s yn dr o me, direct bilir u bi n > 1 x U L N is e xcl usi o nar y .
d.
Ne utr o p hil c o u nt ≤ 1 0 0 0/ µ L  ( ore q ui vale nt).
e.
H b A 1c > 7 . 5 %
f.
A S T ( S G O T) or A L T ( S G P T) > 2 x U L N ( O nl y a b n or mal val ues wit h cli nical 
j ustificati o n m ay be re pe ate d o nce f or c o nfir m ati o n d uri n g t he scree ni n g peri o d ).
6.
E xcl u de d C urre nt or Rece nt Treat me nts
a.
S u bject has a hist or y  of a nti bi otics ( ot her t ha n t o pical nasal a nti bi otics) use wit hi n t he 1 4 
da ys  pri or t o Scree ni n g Visit.
b.
S u bject has a hist or y  of s yste mic c ortic oster oi ds use wit hi n t he 3 0 da y s pri or t o Scree ni n g 
Visit.
c.
S u bject has a hist or y  of c ortic oster oi d el uti n g si n us i m pla nts wit hi n t he 3 m o nt hs of date 
of i m pla nt (P R O P E L ®) or 6 m o nt hs of date of i m pla nt ( SIN U V A ® ) pri or t o Scree ni n g 
Visit.
d.
S u bject has a hist or y  of n o n -ster oi d i m m u n os u p pressa nts (i.e., calci ne uri n i n hi bit ors, 
i nterle u ki n i n hi bit ors, selecti ve i m m u n os u p pressa nts, T N F-i n hi bit ors, ot her 
i m m u n os u p pressa nts) use wit hi n t he 6 0 da y s pri or t o Scree ni n g Visit.
e.
S u bject has a hist or y of ne w or rece ntl y m o difie d aller ge n i m m u n ot hera p y wit hi n t he 3 
m o nt hs pri or t o Scree ni n g Visit.
f.
S u bject has a hist or y  of m o n ocl o nal a nti b o d y t hera p y (e. g., d u pil u ma b, me p oliz u ma b, 
o maliz u ma b, be nraliz u ma b , resliz u ma b) wit hi n t he 3 m o nt hs pri or t o Scree ni n g Visit.
g.
S u bject has a hist or y  of ne w or rece ntly m o difie d le u k otrie ne m o difiers t hera p y wit hi n 
t he 1 m o nt h pri or t o Scree ni n g Visit.
h.
S u bject has a hist or y of ne w or rece ntl y m o difie d β -a dre n oce pt or a g o nists t hera p y wit hi n 
t he 1 m o nt h pri or t o Scree ni n g Visit.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 0 of 1 0 4
P FI Z E R C O N FI D E N TI A L
i.
S u bject has ha d ast h ma e xacer bati o n re q uiri n g s ys te mic c ortic oster oi d treat me nt, 
e mer ge nc y de part me nt visit, or h os pitalizati o n w it hi n t he 3 m o nt hs pri or t o Scree ni n g 
Visit.
j.
U se of a ny pr o hi bite d c o nc o mita nt me dicati o n(s) as s pecifie d i n Secti o n 5. 4 .
7.
Ot her E xcl usi o n Criteria
a.
Pr is o ners or s u bjects w h o are i n v ol u ntar y i ncarcerate d.
b.
S u bjects w h o are c o m p uls oril y  detai ne d f or treat me nt of eit her a ps yc hiatric or p h ysical 
(e. g., i nfecti o us disease) ill ness.
c.
S u bject p artici pati o n i n cli nical trial wit h n o n -bi ol o gical i n vesti gati o nal a ge nts or 
i n vesti gati o nal i nter ve nti o nal treat me nts wit hi n t he 3 0 da ys pri or t o Scree ni n g Visit.
d.
S u bjects w h o ha ve pre vi o usl y  partici pate d i n a ny B H V -3 0 0 0/ B M S -9 2 7 7 1 1/ ri me ge pa nt 
st u d y.
e.
S u bject p artici pati o n i n cli nical trial wit h bi ol o gical i n vesti gati o nal a ge nts wit hi n t he 3 
m o nt hs pri or t o t he Scree ni n g Visit .
f.
S u bjects w h o meet criteria f or C -S S R S S uici dal I deati o n I te ms 4 or 5 wit hi n t he last 1 2 
m o nt hs pri or t o scree ni n g, O R s u bjects w h o e n d or se a ny of t he fi ve C -S S R S S uici dal 
Be ha vi or Ite ms (act ual atte m pt, i nterr u pte d atte m pt, a b orte d atte m pt, pre parat or y  acts, or 
be ha vi or) wit hi n t he last 1 0 y ears pri or t o scree ni n g, O R s u bjects w h o, i n t he o pi ni o n of 
t he In vesti gat or, prese nt a seri o us ris k of s uici de ( See Secti o n 6. 2. 5 ).
g.
Pla n ne d p artici pati o n i n a n y ot her i n vesti gati o nal cli nical trial w hile partici pati n g i n t his 
cli nical trial.
h.
S u bjects e n ga ge d i n, or wit h pla ns t o e n ga ge i n, liti gati o n or W or ker’s C o m pe nsati o n i n 
w hic h m o netar y  gai n or l oss ( or ot her c o m pe nsati o n) ma y affect t heir o bjecti ve 
partici pati o n i n t he trial.
i.
I n vesti gat or site staff directl y i n v ol ve d i n t he c o n d uct of t he st u d y a n d t heir fa mil y 
me m bers, site staff ot her wise s u per vi se d by t he i n vesti gat or, a n d s p o ns or a n d s p o ns or 
dele gate e m pl o y ees directl y i n v ol ve d i n t he c o n d uct of t he st u d y a n d t heir fa mil y 
me m bers.
j.
S u bject u na ble t o c o m plete e Diar y i n de pe n de ntly i n t he o pi ni o n of t he I n vesti gat or.
Please see Secti o n 5. 4 f or Pr o hi bite d a n d Restricte d C o nc o mita nt Me dicati o ns a n d Secti o n 5. 5
f or Dail y a n d Resc ue Me dicati o ns .
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
5. 4
Pr o hi bit e d a n d R e stri ct e d C o n c o mit a nt M e di c ati o n s
T he bel o w me dicati o ns are pr o hi bite d pri or t o ra n d o mizati o n a n d d uri n g t he c o urse of t his st u d y  
or as s pecifie d. 
1.
Hist or y  of n o n-narc otic a nal gesic i nta ke o n ≥ 1 5 da y s per m o nt h f or greater ≥ 3 m o nt h ( e. g.,
aceta mi n o p he n, N S AI Ds, ga ba pe nti n etc.). ( Please refer t o Secti o n 5. 5 f or resc ue 
me dicati o n s). 
2.
Use of all aceta mi n o p he n or aceta mi n o p he n c o ntai ni n g pr o d ucts m ust be disc o nti n ue d at 
least 2 da ys pri or t o ra n d o mizati o n (aceta mi n o p he n ≤1 0 0 0 m g/ da y  is all o we d as resc ue 
me dicati o n, see Secti o n 5. 5 ). D uri n g t he scree ni n g p hase ( 3 t o 1 4 da y s) a n d t hr o u g h o ut t he 
st u d y, t he use of aceta mi n o p he n or aceta mi n o p he n c o ntai ni n g pr o d ucts at dail y  d osi n g le vels 
of greater t ha n 1 0 0 0 m g / da y is pr o hi bite d. 
3.
S y ste mic cortic oster oi ds (e. g., pre d nis o ne, pre d nis ol o ne, met h yl pre d nis ol o ne, 
beta met has o ne, de xa met has o ne, tria mci n ol o ne, h y dr oc ortis o ne, c ortis o ne) s h o ul d n ot be 
ta ke n 3 0 da y s pri or t o t he Scree ni n g Visit a n d t hr o u g h o ut t he st u d y. S u bjects s h o ul d ha ve 
access t o s yste mic c ortic oster oi ds d uri n g t he trial f or treat me nt of s ym pt o ms , if i n dicate d. 
H o we ver, s u bjects s h o ul d disc o nti n ue t he st u d y  if t he y recei ve t his t hera p y. 
4.
A nti bi otics, ot her t ha n t o pical nasal a nti bi otics, s h o ul d n ot b e ta ke n 1 4 da ys pri or t o t he 
Scree ni n g Visit a n d t hr o u g h o ut t he st u d y . S u bjects s h o ul d ha ve access t o a nti bi otics d uri n g 
t he trial f or treat me nt of s ym pt o ms , if i n dicate d. H o we ver, s u bjects s h o ul d disc o nti n ue t he 
st u d y if t he y recei ve t his t hera p y.
5.
M o n ocl o nal a nti b o d y  t hera p y (e. g., d u pil u ma b, me p oliz u ma b, o maliz u ma b, be nraliz u ma b, 
resliz u ma b) s h o ul d n ot be ta ke n 3 m o nt hs pri or t o t he Scree ni n g Visit a n d t hr o u g h o ut t he 
st u d y.
6.
St. J o h n’s W ort s h o ul d n ot be ta ke n 1 4 da y s pri or t o t he Baseli ne Visit a n d t hr o u g h o ut t he 
st u d y. 
7.
Bar bit urate -c o ntai ni n g pr o d ucts ( e. g., Fi oricet, Fi ori nal, b utal bital, p he n o bar bital) s h o ul d n ot 
be ta ke n 1 4 da y s pri or t o t he Baseli ne Visit a n d t hr o u g h o ut t he st u d y. 
8.
M o dafi nil ( P R O VI GI L ®) s h o ul d n ot be ta ke n 1 4 da y s pri or t o the Baseli ne Visit a n d 
t hr o u g h o ut t he st u dy.
9.
T he use of C G R P a nta g o nists ( bi ol o gic [e. g., Ai m o vi g® (ere n u ma b-a o oe), Aj o v y ®
(fre ma nez u ma b-vfr m), E m galit y ® ( galca nez u ma b-g nl m), V y e pti ® (e pti nez u ma b-jj mr)] or 
s mall m olec ule) ot her t ha n ri me ge pa nt is pr o hi bite d d uri n g t he st u d y. C G R P a nta g o nist 
bi ol o gics m ust be disc o nti n ue d 3 m o nt hs pri or t o t he Baseli ne Visit . C G R P s mall m olec ule 
a nta g o nists m ust be disc o nti n ue d 1 4 da y s pri or t o t he Baseli ne Visit a n d t hr o u g h o ut t he 
st u d y.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 0. Use of narc otic me dicati o n, s uc h as o pi oi ds ( e. g., m or p hi ne, c o dei ne, o x yc o d o ne a n d 
h y dr oc o d o ne) s h o ul d n ot be ta ke n 2 da y s pri or t o t he Baseli ne Visit a n d t hr o u g h o ut t he st u d y.
1 1. Use of ca n na bi n oi ds (e. g., marij ua na , C B D) is pr o hi bite d fr o m t he Baseli ne Visit a n d 
t hr o u g h o ut t he st u dy.
1 2. C o nc o mita nt use of str o n g C Y P 3 A 4 i n hi bit ors, s uc h as HI V Pr otease I n hi bit ors, He patitis C 
pr otease i n hi bit ors, certai n az ole a ntif u n gals, or clarit hr o m y ci n, is pr o hi bite d d uri n g t he 
st u d y. Str o n g C Y P 3 A 4 i n hi bit ors m ust be disc o nti n ue d 1 4 da y s pri or t o t he Baseli ne Visit 
a n d t hr o u g h o ut t he c o urse of t he st u d y. Please see Secti o n 1 6. 1 f or a d diti o nal res o urces.
1 3. C o nc o m ita nt use of m o derate t o str o n g C Y P 3 A 4 i n d ucers, s uc h as car ba maze pi ne, 
p he n y t oi n, or rifa m pi n, is pr o hi bite d d uri n g t he st u d y.  M o derate or str o n g C Y P 3 A 4 i n d ucers 
m ust be disc o nti n ue d 1 4 da y s pri or t o t he Baseli ne Vi sit a n d t hr o u g h o ut t he c o urse of t he 
stu d y . Please see Secti o n 1 6. 1 f or a d diti o nal res o urces.
1 4. A t ypical a nti ps y c h otics s uc h as A bilif y (ari pi praz ole), Z ypre xa ( ola nza pi ne), Ser o q uel 
( q uetia pi ne), Ge o d o n (zi prasi d o ne), or Ris per dal (ris peri d o ne) or De pa k ote/ De pa ke ne 
( val pr oic aci d/ val pr oate) s h o ul d n ot be ta ke n 9 0 da y s pri or t o t he Baseli ne Visit a n d 
t hr o u g h o ut t he st u dy.
1 5. L A M I CT A L (la m otri gi ne) s h o ul d n ot be ta ke n 9 0 da y s pri or t o t he Baseli ne Visit a n d 
t hr o u g h o ut t he st u dy.
1 6. T o pical nasal dec o n gesta nts s h o ul d n ot be ta ke n m ore t ha n 3 ti mes per wee k.
S u bjects wit h dail y  use of me dicati o ns liste d i n Secti o n 5. 5 are per mitte d t o re mai n o n t hera p y 
pr o vi de d t he y  ha ve bee n o n a sta ble d ose f or at least 1 m o nt h pri or t o t he Scree ni n g Visit .
L o w d ose as piri n ( e. g., u p t o 1 0 0 m g) f or d oc u me nte d car di o va sc ular pr o p h yla xis is all o we d.
5. 5
D ail y a n d R e s c u e M e di c ati o n s
Me dicati o n d oses m ust be st a ble f or at le ast o ne m o nt h pri or t o t he Scree ni n g Visit a n d 
t hr o u g h o ut t he st u dy. S u bjects ma y  use:

Sali ne a n d ot her n o n -me dicate d s pra y /ri nse (a d diti ves s uc h as deter ge nts, m oist urizers, 
m uc ol y tics are per mitte d) – mai ntai n d osi n g re gi me n esta blis he d pri or t o t he Scree ni n g Visit
A N D u p t o t w o of t he t o pic al n as al me dic ati o ns (st a ble d osi n g, n ot P R N, a n y i n dic ati o n):

T o pical nasal cortic oster oi ds (s pra y or ri nse)

T o pical nasal a nti bi otics a n d a ntif u n gal me dicati o ns (s pra y or ri nse)

T o pical nasal a nti hista mi nes ( n o n-se dati n g)
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L

T o pical nasal cr o m ol yn
A N D a n y of t he f oll o wi n g me dicati o ns (st a ble d osi n g, n ot P R N ):

Le u k otrie ne m o difiers 

Cr o m ol y n ( oral or i n halati o n)

Met h y l xa nti nes (e. g., t he o p h ylli ne, a mi n o p h ylli nes) 

M uc o acti ve a ge nts (e. g., g uaife nesi n, acet yl c ystei ne)
S u bjects wit h c o nc o mita nt ast h ma or C O P D ma y  re mai n o n t heir baseli ne S o C treat me nt if t he y 
ha ve bee n o n a sta ble d ose f or at least 1 m o nt h pri or t o t he Scree ni n g Visit a n d if n ot s pecificall y
liste d i n Secti o n 5. 4 Pr o hi bite d a n d Restricte d C o nc o mita nt Me dicati o ns , a n d t he d ose is n ot 
e x pecte d t o c ha n ge d uri n g t he c o urse of t he st u d y . S u bjects ma y  use t heir resc ue i n halers a n d/ or 
ne b ulizers as directe d b y t heir healt hcare pr o vi der ( H C P).
After d osi n g wit h st u d y me dic ati o n, all ot her C R S me dic ati o n is pr o hi bite d d uri n g t he 2 
h o urs p ost -d ose . A t t he e n d of 2 h o urs after d osi n g wit h st u d y  me dicati o n (a n d after t he 2- h o ur
assess me nts ha ve bee n c o m plete d o n t he e Diar y ), s u bjects will be per mitte d t o use t he f oll o wi n g 
resc ue me dicati o n: aceta mi n o p he n ( u p t o 1 0 0 0 m g/ da y ), or as piri n, i b u pr ofe n, na pr o xe n ( or a n y 
ot her t y pe of n o n -ster oi dal a nti-i nfla m mat or y dr u g ( N S AI D)), oral a nti hista mi nes ( n o n-se dati n g), 
oral dec o n gesta nts, t o pical nasal dec o n gesta nts , t o pical nasal a ntic h oli ner gics (all u p t o t he daily 
rec o m me n de d d ose i n dicate d o n t he dr u g pac ka gi n g). T hese are t he o nly m e dicati o ns all o we d f or 
resc ue treat me nt after 2 h o urs p ost d ose of st u d y me dicati o n.  
H o we ver, if nee de d, after 2 4 h o urs of a d mi nisteri n g t he o ne d ose of st u d y me dicati o n (a n d 
bef ore c o mi n g i n f or t he E n d of Treat me nt Visit) s u bject ma y  ta ke t heir prescri be d sta n dar d of 
care me dicati o ns f or treat me nt of C R S s y m pt o ms pr o vi de d all t he assess me nts ha ve bee n 
c o m plete d o n t he e Diar y. E xcl usi o nar y  resc ue me dicati o n s uc h as o pi oi ds, b utal bital c o m p o u n ds, 
are n ot all o we d o n t his st u d y . Si milarl y , if t he facial pai n/ press ure/f ull ness is relie ve d b y st u d y 
me dicati o n at 2 h o urs after d osi n g b ut t he n rec urs t o i nte nsit y le vel of ≥6 o n N R S ( 0 -1 0) 
bet wee n 2 a n d 2 4 h o urs, t he s u bject will be per mitte d t o ta ke t he sa me resc ue t hera p y as o utli ne d 
a b o ve. I n all circ u msta nces, t he s u bject will al wa ys c o nti n ue t o c o m plete his or her e Diar y  
e ntries t hr o u g h t he 2 4-h o ur assess me nt after c o ns u mi n g t he st u d y  me dicati o n. 
Use of c o nc o mita nt me dicati o n after ra n d o mizati o n, i ncl u di n g resc ue me dicati o n, will be 
rec or de d by t he s u bject o n a pa per diar y a n d re p orte d t o t he site. T he site will rec or d all 
me dicati o ns t hat were ta ke n fr o m 1 4 da ys bef ore t he Scree ni n g Visit t hr o u g h t he e n d of t he E n d 
of Treat me nt Visit. 
D uri n g t he 4 5- d a y  Treat me nt P hase , if t he s u bject has a n o n -q u alif yi n g facial 
pai n/ press ure/f ull ness (i.e., facial pai n/ press ure/f ull ness < 6 o n a N R S ( 0- 1 0)), t he s u bject is 
per mitte d t o use o nl y  t he f oll o wi n g me dicati o ns: aceta mi n o p he n ( u p t o 1 0 0 0 m g/ da y ), or as piri n, 
i b u pr ofe n, na pr o xe n ( or a n y ot her ty p e of n o nster oi dal a nti -i nfla m mat or y dr u g [N S AI D ]), oral 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
a nti hista mi nes ( n o n-se dati n g), oral dec o n gesta nts, t o pical nasal dec o n gesta nts, t o pical nasal 
a ntic h oli ner gics (all u p t o t he dail y rec o m me n de d d ose i n dicate d o n t he dr u g pac ka gi n g).
S u bjects s h o ul d ha ve access t o s y ste mic c ortic oster oi ds a n d a nti bi otics duri n g t he trial f or 
treat me nt of sy m pt o ms , if i n dicate d. H o we ver, s u bjects s h o ul d disc o nti n ue t he st u d y if t he y 
recei ve t h ose t hera pies. 
5. 6
C o ntr a c e pti o n
T he i n vesti gat or or t heir desi g nee, i n c o ns ultati o n wit h t he s u bject, will c o nfir m t hat t he s u bject
is utilizi n g a n a p pr o priate met h o d of c o ntrace pti o n f or t he i n di vi d ual s u bject fr o m t he per mitte d 
list of c o ntrace pti o n met h o ds (see Secti o n 1 6. 3. 4 ) a n d will c o nfir m t hat t he s u bject has bee n 
i nstr ucte d i n its c o nsiste nt a n d c orrect use. 
T he i n vesti gat or or desi g nee will i nf or m t he s u bject of t he nee d t o use acce pta ble effecti ve
c o ntrace pti o n c o nsiste ntl y a n d c orrectl y a n d d oc u me nt t he c o n versati o n a n d t he s u bject’s 
affir mati o n i n t he s u bject’s c hart. S u bject s nee d t o affir m t heir c o nsiste nt a n d c orrect use of at 
least 1 of t he selecte d met h o ds of c o ntrace pti o n, c o nsi deri n g t hat t heir ris k f or pre g na nc y ma y 
ha ve c ha n ge d si nce t he last visit. 
I n a d diti o n, t he i n vesti gat or or desi g nee will i nstr uct t he s u bject t o call i m me diately if t he 
selecte d c o ntrace pti o n met h o d is disc o nti n ue d a n d d oc u me nt t he re q uire me nt t o use a n alter nate 
pr ot oc ol -s pecifie d met h o d, i ncl udi n g if t he s u bject will n o l o n ger use a bsti ne nce as t he selecte d 
c o ntrace pti o n met h o d, or if pre g na nc y  is k n o w n or s us pecte d i n t he s u bject or part ner.
5. 7
Ot h er R e stri cti o n s a n d Pr e c a uti o n s
N ot a p plica ble. 
5. 8
Pr ot o c ol D e vi ati o n s a n d Q u alit y  T ol er a n c e Li mits
A n y  si g nifica nt e ve nt t hat d oes n ot c o m pl y wit h t he i ncl usi o n/e xcl usi o n criteria, st u dy c o n d uct, 
or st u d y  pr oce d ures will be d oc u me nte d as a de viati o n. De viati o ns will be d oc u me nte d a n d 
re p orte d t hr o u g h t he cli nical m o nit ori n g of t he trial. De viati o ns will be re p orte d t o t he I R B/ E C at 
t he fre q ue nc y re q uire d b y yo ur I R B/ E C. Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o 
recr uit me nt a n d e nr oll me nt criteria, als o k n o w n as pr ot oc ol wai vers or e xe m pti o ns, is n ot 
per mitte d . See Secti o n 1 0. 1 f or m ore i nf or mati o n o n pr ot oc ol de viati o ns.
I n a d diti o n, Q ualit y T olera nce Li mits ( Q T Ls) are pre defi ne d para meters t hat are m o nit ore d 
d uri n g t he st u d y. I m p orta nt de viati o ns fr o m t he Q T L s a n d a n y re me dial acti o ns ta ke n will be 
s u m marize d i n t he C S R.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 5 of 1 0 4
P FI Z E R C O N FI D E N TI A L
6
S T U D Y C O N D U C T A N D D E S C RI P TI O N O F S T U D Y P R O C E D U R E S
6. 1
St u d y M at eri al s
T he f oll o wi n g st u d y materials m a y  be pr o vi de d:

I n vesti gat or File/ Re g ulat or y  Bi n der

P har mac y  Bi n der

I n vesti gati o nal Pr o d uct Ma n ual

Dr u g Acc o u nta bilit y  Lo gs

Sa m ple s o urce d oc u me nts, w here a p plica ble

Pa per diar y  t o rec or d C o nc o mita nt a n d Resc ue Me dicati o n (ta ke h o me f or s u bject) 

I n vesti gat or’s Br oc h ure

I nteracti ve We b-base d Res p o nse S y ste m (IW R S)
Ma n ual

Electr o nic Diar y  (e Diar y): 1 will be gi ve n t o eac h ra n d o mize d s u bject

I nstr ucti o ns f or t he e Diar y de vice a n d access t o t he p ortal

Si n o -Nasal O utc o me Test ( S N O T -2 2)

La b orat or y  Kits a n d La b orat or y Ma n ual

H o me Pre g na nc y  Test

E C G Mac hi ne a n d I nstr ucti o ns

C ol u m bia -S uici de Se verit y  Rati n g Scale 

Seri o us A d verse E ve nt ( S A E) f or ms (t o be use d o nl y if P S S A is n ot a vaila ble)

E x p os ure d uri n g Pre g na nc y  S u p ple me ntal F or ms

Pre g na nt Part ner Release of I nf or mati o n F or m
All sites will use a n Electr o nic Data Ca pt ure ( E D C) t o ol t o s u b mit st u d y  data t o t he sp o ns or ’s 
C R O. Electr o nic Patie nt Re p orte d O utc o mes (e P R O) will be use d f or all patie nt -rate d scales a n d 
will be ca pt ure d o n a n e Diar y . A ny assess me nt c o m plete d b y t he s u bject i n t he e Di ar y will be 
tra nsferre d fr o m t he site/s u bject t o t he ve n d or a n d fr o m t he ve n d or t o t he C R O a n d/ or sp o ns or. 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 6 of 1 0 4
P FI Z E R C O N FI D E N TI A L
N o a d diti o nal s o urce d oc u me nts are re q uire d f or scales a n d assess me nts c o m plete d b y  t he 
s u bject i n e Diar y.
Safet y  la b orat or y, plas ma, ser u m, i nstr ucti o ns f or all s peci me ns c ollecte d will be pr o vi de d b y a 
desi g nate d ce ntral la b orat or y . E C G e q ui p me nt, s u p plies, i nstr ucti o ns, a n d trai ni n g materials will 
be s u p plie d b y  a ce ntralize d E C G ve n d or.
6. 2 
S af et y  As s e s s m e nt s
6. 2. 1
Vit al Si g n s a n d P h y si c al M e a s ur e m e nt s ( H ei g ht a n d W ei g ht)
Sitti n g arterial s ys t olic a n d diast olic bl o o d press ure a n d p ulse rate, hei g ht, wei g ht a n d oral b o d y  
te m perat ure will be meas ure d at Scree ni n g a n d E n d of Treat me nt. Hei g ht a n d wei g ht will be 
meas ure d at Scree ni n g o nl y see Ta ble 1 .
6. 2. 2
El e ctr o c ar di o gr a m ( E C G)
A sta n dar d 1 2 -lea d E C G will be rec or de d d uri n g t he Scree ni n g P hase a n d at t he sc he d ule d visits 
as o utli ne d i n Ta ble 1 . E C G data will be s u b mitte d t o a ce ntral E C G ve n d or f or meas ure me nt 
a n d i nter pretati o n. T he fi nal E C G re p ort fr o m t he ce ntral ve n d or s h o ul d be mai ntai ne d i n t he 
s u bject’s s o urce d oc u me ntati o n a n d be use d f or t he fi nal i nter pretati o n of t he E C G rec or di n g. 
Base d o n t he ce ntral E C G ve n d or re p ort, t he I n vesti gat or will deter mi ne if s u bject is eli gi ble a n d 
if a n y a b n or malities are cli nicall y si g nifica nt or n ot. A n y cli nicall y si g nifica nt c ha n ges fr o m t he 
Scree ni n g E C G ma y  p ote ntiall y be AE s (Secti o n 1 6. 2 ) a n d s h o ul d be e val uate d f urt her, as 
cli nicall y warra nte d.
6. 2. 3
P h y si c al E x a m 
S u bjects will u n der g o a r o uti ne p h y sical e xa mi nati o n d uri n g t he Scree ni n g P hase a n d at t he 
sc he d ule d visits as o utli ne d i n Ta ble 1 . P h y sical e xa mi nati o ns i ncl u de e xa mi nati o n of t he heart, 
a b d o me n, l u n gs, a n d a n y ot her b o d y s ys te m t o be g ui de d by s y m pt o ms.
6. 2. 4
L a b or at or y  As s e s s m e nt s 
All pr ot oc ol -re q uire d la b orat or y assess me nts m ust be c o n d ucte d i n acc or da nce wit h t he 
la b orator y  ma n ual a n d t he Sc he d ule of Assess me nts (Ta ble 1 ). U nsc he d ule d cli nical la b orat or y  
meas ure me nts ma y  be o btai ne d at a n y ti me d uri n g t he st u d y t o assess a n y percei ve d safet y 
iss ues.
T he i n vesti gat or m ust re vie w t he la b orat or y  re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he C R F. T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d oc u me nts. Cli nicall y si g nifica nt a b n or mal 
la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he u n derlyi n g disease, u nless j u d ge d 
b y  t he i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he s u bject’s c o n diti o n.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 7 of 1 0 4
P FI Z E R C O N FI D E N TI A L
6. 2. 4. 1
S af et y  L a b or at or y T e sti n g
Bl o o d a n d uri ne sa m ples will be o btai ne d as o utli ne d i n Ta ble 1 f or cli nical la b orat or y 
e val uati o ns. A ce ntral la b orat or y ve n d or will be utilize d f or t his st u d y a n d a la b orat or y ma n ual 
will be pr o vi de d t o eac h site. If p ossi ble, s u bjects s h o ul d be f asti n g f or a mi ni m u m of 8 h o urs 
pri or t o all bl o o d dr a ws. H o we ver, if a s u bject is n ot fasti n g at a gi ve n visit, t he bl o o d dra w 
s h o ul d still be perf or me d, a n d t he n o n-fasti n g stat us s h o ul d be d oc u me nte d.
He m at ol o g y : He m o gl o bi n, he mat ocrit, re d bl o o d cell ( R B C) c o u nt, w hite bl o o d cell ( W B C)
c o u nt wit h differe ntial, a n d platelets.
Bl o o d c he mistr y/electr ol yte : S o di u m, p otassi u m, c hl ori de, bicar b o nate, calci u m; gl uc ose, B U N 
( urea), ser u m creati ni ne, uric aci d, A L T, A S T, al kali ne p h os p hatase, L D H, t otal pr otei n, 
al b u mi n, t otal bilir u bi n, direct bilir u bi n, i n direct bilir u bi n, C K. E n d of Treat me nt Visit –
ele vati o ns i n C K ( > 5 x U L N) ma y  ha ve f urt her C K fracti o nati o n tests perf or me d t hr o u g h t he 
ce ntral la b.  
Esti m ate d gl o mer ul ar filtr ati o n r ate : e G F R usi n g t he esti mate d M D R D f or m ula will be 
calc ulate d a n d re p orte d b y t he ce ntral la b at eac h visit t hat cli nical la b orat or y tests are c ollecte d 
as o utli ne d i n Ta ble 1 .
Uri n al ysis: p H, s pecific gra vit y , ket o nes, nitrites, ur o bili n o ge n, le u k oc yte esterase, pr otei n, 
gl uc ose a n d bl o o d. If bl o o d, pr otei n or le u k oc y tes are p ositi ve, refle x t o micr osc o pic 
e xa mi nati o n.
Uri ne Dr u g Scree n : F or dru gs of a b use.
F S H : F S H le vels will be meas ure d at t he Scree ni n g Visit o n p ost-me n o pa usal w o me n t o c o nfir m 
p ost -me n o pa usal stat us. F S H le vel testi n g is n ot re q uire d f or w o me n greater t ha n or e q ual t o 6 2 
ye ars ol d wit h a me n orr hea of greater t ha n or e q ual t o 1 y ear.
H b A 1c at scree ni n g.
Li pi d P a nel (tri gl yceri des, t otal c h olester ol, H D L, a n d L D L) will be meas ure d at t he Scree ni n g 
Visit.
Refle x tests: 
If A L T or A S T ≥ 3 x U L N O R t otal bilir u bi n ≥ 2 x U L N at a n y visit after t he baseli ne visit, t he 
ce ntral la b orat or y will perf or m refle x tests t hat ma y i ncl u de: C K, G G T, a n d a nti-viral ser ol o gies. 
S u bjects ma y  ha ve t o ret ur n t o t he st u d y site t o pr o vi de a d diti o nal bl o o d sa m ples f or t hese 
la b orat or y tests. 
A d diti o nal la b orat or y  tests ma y be o btai ne d t o e val uate la b orat or y  a b n or malities a n d/ or a d verse 
e ve nts. 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 8 of 1 0 4
P FI Z E R C O N FI D E N TI A L
6. 2. 4. 2
Pr e g n a n c y  T e sti n g
Pre g na nc y  tests will be c o n d ucte d (ser u m, uri ne, or h o me pre g na nc y test), if a p pr o priate pri or t o 
ra n d o mizati o n, a n d as o utli ne d i n Ta ble 1 .
6. 2. 5
C ol u m bi a- S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S) 
T he C ol u m bia -S uici de Se verit y Rati n g Scale ( C -S S R S) is a q uesti o n naire use d f or s uici de 
Assess me nt. 2 5 T he C -S S R S “ Scree ni n g versi o n” will be use d at t he Scree ni n g Visit a n d t he 
“ Si nce Last Visit versi o n” 2 6 will be use d at s u bse q ue nt visits i n t his st u d y.
T he C -S S R S Assess me nt is i nte n de d t o hel p esta blis h a pers o n’s i m me diate ris k of s uici de. T he 
C- S S R S is a cli nicia n a d mi nistere d scale t hat s h o ul d be a d mi nistere d b y a certifie d rater. T his 
scale will be c ollecte d o n site wit h a pa per f or m. T he C- S S R S s h o ul d be re vie we d b y t he 
I n vesti gat or or desi g nee bef ore t he s u bject is all o we d t o lea ve cli nic.
At t he Scree ni n g Visit, t he recall peri o d f or c o m pleti n g is 1 2 m o nt hs f or s uici dal i deati o n a n d 1 0 
ye ars f or s uici dal be ha vi or; at all ot her visits, t he recall peri o d f or c o m pleti n g t he C -S S R S is 
si nce t he last visit (Ta ble 1 ).
A n y  “ Yes” res p o nses m ust be i m me diatel y e val uate d b y t he i n vesti gat or. If t he In vesti gat or 
deter mi nes t hat a s u bject is at ris k of s uici de, self -har m, a p pr o priate meas ures t o e ns ure t he 
s u bject’s safety a n d o btai n me ntal healt h e val uati o n m ust be i m ple me nte d. I n s uc h 
circ u msta nces, t he s u bject m ust i m me diatel y  be disc o nti n ue d fr o m t he st u d y. T he e ve nt s h o ul d 
be rec or de d as eit her a n A E or S A E as deter mi ne d b y  t he I n vesti gat or a n d re p orte d wit hi n 2 4 
h o urs t o t he sp o ns or.  
6. 2. 6
W e e kl y  C o nt a ct
S u bject s s h o ul d be c o ntacte d (e. g., via p h o ne, te xt, e mail) at least wee kl y b y st u d y staff t o 
m o nit or (a n d re mi n d t he m t o re p ort) a n y s yste mic c ortic oster oi d a n d / or a nti bi otics ( ot her t ha n 
t o pical nasal a nti bi otics) use. If a s u bject re p orts ta ki n g o ne of t hese t hera pies bef ore d osi n g, 
st u d y staff s h o ul d wit h dra w t he s u bject fr o m t he st u d y, i nf or m t he s u bject t hat t he y s h o ul d n ot 
d ose wit h st u d y  me dicati o n, a n d sc he d ule an E n d of Treat me nt visit.
6. 3
Effi c a c y  As s e s s m e nt s
6. 3. 1
F a ci al p ai n/ pr e s s ur e/f ull n e s s
S u bjects will rec or d i n t heir e Diar y t heir c urre nt facial pai n/ press ure/f ull ness sc ore, o n a N R S ( 0 -
1 0) at t he ti me p oi nts i n dicate d i n Ta ble 1 .
6. 3. 2
N a s al o b str u cti o n ( c o n g e sti o n)
S u bjects will rec or d i n t heir e Diar y t heir c urre nt nasal o bstr ucti o n (c o n gesti o n) sc ore, o n a N R S 
( 0- 1 0) at t he ti me p oi nts i n dicate d i n Ta ble 1 .
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 5 9 of 1 0 4
P FI Z E R C O N FI D E N TI A L
6. 3. 3
N a s al di s c h ar g e
S u bjects will rec or d i n t heir e Diar y  t heir c urre nt nasal disc har ge (a nteri or, p osteri or, or b ot h)
sc ore, o n a N R S ( 0-1 0) at t he ti me p oi nts i n dicate d i n Ta ble 1 .
6. 3. 4
H e a d a c h e p ai n
S u bjects w h o re p ort m o derate or se vere hea dac he pai n at t he ti me of q ualif yi n g facial 
pai n/ press ure/f ull ness will rec or d i n t heir e Diar y  t heir c urre nt hea dac he pai n sc ore o n a 4 -p oi nt 
Li kert scale ( 0 = N o ne ; 1 = M il d; 2 = M o derate ; 3 = S e vere ) at t he ti me p oi nts i n dicate d i n Ta ble 
1.
6. 3. 5
R e s c u e M e di c ati o n
T he s u bject’s use of resc ue me dicati o n is rec or de d b y  t he s u bject o n a pa per diar y  a n d re vie we d 
b y  site staff.
6. 3. 6
P ati e nt Gl o b al I m pr e s si o n of C h a n g e ( P GI- C) Q u e sti o n n air e
T he P GI -C is a patie nt -rate d scale w hic h assesses h o w t he s u bject’s c urre nt ill ness state has 
c ha n ge d relati ve t o t he baseli ne visit. T he s u bject is as ke d t o rate a c ha n ge i n t heir o verall disease 
c o n diti o n o n a 7 -p oi nt L i kert scale, wit h t he f oll o wi n g res p o nse o pti o ns: 1 = ver y  m uc h 
i m pr o ve d, 2 = m uc h i m pr o ve d, 3 = mi ni mall y  i m pr o ve d, 4 = n o c ha n ge, 5 = mi ni mall y w orse, 6 
= m uc h w orse, a n d 7 = ver y  m uc h w orse. T he P GI -C is a gl o bal i n de x scale t hat ma y  be use d t o 
rate t he res p o nse of a c o n diti o n t o a t hera p y. T he e Diar y  is use d t o e val uate t he P GI - C
Q uesti o n naire at t he ti me p oi nts i n dicate d i n Ta ble 1 .
6. 3. 7
Si n o -N a s al O ut c o m e T e st ( S N O T -2 2)
S N O T -2 2 is a vali date d s ym pt o m - base d o utc o me meas ure t o assess t he b ur de n of C R S 
s ym pt o mat ol o g y . It is a 2 2 -ite m i nstr u me nt t hat i ncl u des b ot h nasal a n d e xtra-nasal s ym pt o ms 
s uc h as p o or slee p a n d m o o d dist ur ba nce. T he S N O T - 2 2 will be c ollecte d o n pa per at t he 
Baseli ne Visit a n d o n t he e Diar y at 2 4 h o urs p ost -d ose (see Ta ble 1 ).
6. 4
E arl y  Di s c o nti n u ati o n fr o m t h e St u d y
S u bjects M U S T disc o nti n ue i n vesti gati o nal pr o d uct (a n d n o n -i n vesti gati o nal pr o d uct at t he 
discreti o n of t he In vesti gat or) f or a n y  of t he f oll o wi n g reas o ns:

Wit h dra wal of i nf or me d c o nse nt (s u bject’s decisi o n t o wit h dra w f or a n y  reas o n).

A n y  cli nical a d verse e ve nt ( A E), la b orat or y a b n or malit y or i nterc urre nt ill ness w hic h, i n 
t he o pi ni o n of t he In vesti gat or or sp o ns or, i n dicates t hat c o nti n ue d partici pati o n i n t he 
st u d y is n ot i n t he best i nterest of t he s u bject.

Pre g na nc y
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 0 of 1 0 4
P FI Z E R C O N FI D E N TI A L

Ter mi nati o n of t he st u d y b y  Pfizer I nc .

L oss of a bilit y  t o freely pr o vi de c o nse nt t hr o u g h i m pris o n me nt or i n v ol u ntar y 
i ncarcerati o n f or treat me nt of eit her a psyc hi atric or p h ysical (e. g., i nfecti o us disease) 
ill ness.

Use of s ys te mic c ortic oster oi ds.

Use of a nti bi otics ( ot her t ha n t o pical nasal a nti bi otics). 
All s u bjects w h o disc o nti n ue s h o ul d c o m pl y  wit h pr ot oc ol s pecifie d E n d of Treat me nt 
pr oce d ures as o utli ne d i n Ta ble 1 . T he o nly e xce pti o n t o t his re q uire me n t is w he n a s u bject 
wit h dra ws c o nse nt f or all st u d y  pr oce d ures or l oses t he a bilit y t o c o nse nt freely (i.e., is 
i nca pacitate d, i m pris o ne d, or i n v ol u ntaril y  i ncarcerate d f or t he treat me nt of eit her a psyc hiatric 
or p h y sical ill ness).
6. 5
L o st t o F oll o w U p
A s u bject will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y  fails t o ret ur n f or sc he d ule d 
visits a n d is u na ble t o be c o ntacte d b y t he st u d y site.
T he f oll o wi n g acti o ns m ust be ta ke n a n d d oc u me nte d if a s u bject fails t o ret ur n t o t he cli nic f or a 
re q uire d st u dy visit:
T he site m ust atte m pt t o c o ntact t he s u bject a n d resc he d ule t he misse d visit as s o o n as p ossi ble 
a n d c o u nsel t he s u bject o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit sc he d ule a n d 
ascertai n whet her or n ot t he s u bject wis hes t o a n d/ or s h o ul d c o nti n ue i n t he st u d y .
Bef ore a s u bject is dee me d l ost t o f oll o w u p, t he In vesti gat or or desi g nee m ust ma ke e ver y  eff ort 
t o re gai n c o ntact wit h t he s u bject ( w here p ossi ble, 3 tele p h o ne calls a n d, if necessar y, a certifie d 
letter t o t he s u bject’s last k n o w n maili n g a d dress or l ocal e q ui vale nt met h o ds). T hese c o ntact 
atte m pts s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or d.
S h o ul d t he s u bject c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve w it h dra w n fr o m 
t he st u d y.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
7
S T U D Y D R U G M A N A G E M E N T
7. 1
D e s cri pti o n of St u d y  Dr u g
7. 1. 1
I n v e sti g ati o n al Pr o d u ct
A n i n vesti gati o nal pr o d uct, als o k n o w n as i n vesti gati o nal me dici nal pr o d uct i n s o me re gi o ns, is 
defi ne d as f oll o ws:
A p har mace utical f or m of a n acti ve s u bsta nce or place b o bei n g teste d or use d as a refere nce i n a 
cli nical st u d y, i ncl u di n g pr o d ucts alrea d y wit h a mar keti n g a ut h orizati o n b ut use d or asse m ble d 
(f or m ulate d or pac ka ge d) i n a wa y differe nt fr o m t he a ut h orize d f or m, or use d f or a n 
u na ut h orize d i n dicati o n, or w he n use d t o gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.
T he i n vesti gati o nal pr o d uct s h o ul d be st ore d i n a sec ure area acc or di n g t o l ocal re g ulati o ns. It is 
t he res p o nsi bilit y of t he I n vesti gat or t o e ns ure t hat i n vesti gati o nal pr o d uct is o nl y dis pe nse d t o 
st u d y s u bjects. T he i n vesti gati o nal pr o d uct m ust be dis pe nse d o nly fr o m official st u d y sites b y 
a ut h orize d pers o n nel acc or di n g t o l ocal re g ulati o ns.
I n t his pr ot oc ol, i n vesti g ati o n al pr o d uct is/ are:
Ri me ge pa nt O D T a n d matc hi n g place b o.  T he ri me ge pa nt O D T a n d t he matc hi n g place b o a p pear 
i de ntical vis uall y, via t o uc h, s mell a n d taste.  
7. 1. 2
P a c k a gi n g, S hi p m e nt a n d St or a g e
T he pr o d uct st ora ge ma na ger s h o ul d e ns ure t hat t he st u d y  dr u g is st ore d i n acc or da nce wit h t he 
e n vir o n me ntal c o n diti o ns (te m perat ure a n d li g ht) as deter mi ne d b y t he sp o ns or. Please see t he 
I n vesti gati o nal Pr o d uct Ma n ual/I n vesti gat or ’s Br oc h ure f or s pecific c o n diti o ns. I f c o ncer ns 
re gar di n g t he q ualit y or a p peara nce of t he st u d y dr u g arise, d o n ot dis pe nse t he st ud y  dr u g a n d 
c o ntact t he sp o ns or/ C R O i m me diatel y .
7. 2
D o s e a n d A d mi ni str ati o n
O ne d ose of ri me ge pa nt O D T ( 7 5 m g) or matc hi n g place b o will be dis pe nse d t o t he s u bject a n d 
will be ta ke n at t he ti me t he s u bject has a facial pai n/ press ure/f ull ness t hat reac hes i ntensit y of ≥
6 o n t he N R S ( 0- 1 0) a n d after c o m pleti n g t he e Diar y q uesti o ns. 
7. 2. 1
M et h o d of A s si g ni n g S u bj e ct I d e ntifi c ati o n
At t he ti me of e nr oll me nt, i m me diatel y  after writte n i nf or me d c o nse nt is o btai ne d a n d bef ore 
perf or mi n g a n y st u d y -relate d pr oce d ures, eac h s u bject will be assi g ne d, t hr o u g h a n i nteracti ve 
we b res p o nse s y ste m (I W R S), a u ni q ue s u bject n u m ber f or i de ntificati o n t hr o u g h o ut t he st u d y.
T his s u bject n u m ber m ust n ot be re use d f or a n y ot her s u bject i n t he st u d y. T he 
p h y sicia n/c o or di nat or m ust c o ntact t he IW R S t o e nr oll eac h s u bject i nt o a ce ntralize d data base at 
t he ti me of si g ni n g c o nse nt.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
After c o m pleti o n of all scree ni n g e val uati o ns all eli gi ble s u bjects will be ra n d o mize d i n a 1: 1 
rati o t o t he ri me ge pa nt or matc hi n g place b o treat me nt gr o u ps. T he ra n d o mizati o n will be 
stratifie d b y t he prese nce of nasal p oly ps ( yes or n o). It is i m p orta nt t o c orrectl y e nter s u bjects 
w h o ha ve nasal p ol y ps i n t he I W R S s y ste m. O nce a s u bject is stratifie d i n t he IW R S, t his ca n n ot 
be c ha n ge d a n d will be c o nsi dere d a de viati o n.
Ra n d o mizati o n sc he d ules will be ge nerate d a n d ke pt b y  t he I WR S ve n d or i n a sec ure net w or k 
f ol der wit h access li mite d t o o nl y u n bli n de d tea m me m bers. Eac h s u bject w h o is q ualifie d f or 
treat me nt will be ra n d o mize d via t he IW R S ra n d o mizati o n o pt i o n. S u bjects will mai ntai n t heir 
s u bject n u m ber assi g ne d at scree ni n g t hr o u g h o ut t he trial. T he I W R S will pr o vi de t he d o u ble-
bli n d treat me nt assi g n me nts.
T he ra n d o mizati o n will tri g ger dis pe nsati o n f or t he s u bject a n d assi g n a b ottle n u m ber f or t he 
a p pr o priate ra n d o mize d treat me nt ty pe. T he dr u g is dis pe nse d at t he ti me of ra n d o mizati o n.
7. 2. 2
S el e cti o n a n d Ti mi n g of D o s e a n d A d mi ni str ati o n
St u d y  me dicati o n ( o ne 7 5 m g O D T or matc hi n g place b o) will be pac ka ge d i n a si n gle blister u nit 
i n a s u bject-s pecific b ottle. T here are n o d ose a dj ust me nts i n t his st u d y a n d s u bjects will recei ve 
o ne d ose t o treat o ne facial pai n/ press ure/f ull ness t hat reac hes i nte nsit y of ≥6 o n t he N R S ( 0- 1 0) 
wit hi n 4 5 da y s of ra n d o mizati o n ( Baseli ne Visit). S u bjects will be dis pe nse d t he st ud y  
me dicati o n at ra n d o mizati o n ( Baseli ne Visit) a n d will ta ke t he O D T fr o m t he blister/ b ottle at t he 
ti me of o nset of facial pai n/ press ure/f ull ness ≥6 o n t he N R S ( 0 -1 0) O N L Y after a ns weri n g 
q uesti o ns re gar di n g t heir C R S s ym pt o ms i n t he e Diar y  de vice. T he O D T s h o ul d be place d o n or 
u n der t he t o n g ue u ntil f ull y  diss ol ve d t he n s wall o we d.  S u bjects s h o ul d be i nstr ucte d t o use dr y 
ha n ds w he n ha n dli n g t he st u d y  me dicati o n.  
7. 2. 3  
D o s e M o difi c ati o n s
T here will be n o d ose a dj ust me nts i n t his st u d y .
7. 3
Bli n di n g a n d U n bli n di n g
Bli n di n g is critical t o t he i nte grit y of t his cli nical st u d y .  H o we ver, i n t he e ve nt of a me dical 
e mer ge nc y or pre g na nc y i n a n i n di vi d ual s u bject, i n w hic h k n o wle d ge of t he i n vesti gati o nal 
pr o d uct is critical t o t he s u bject’s ma na ge me nt, t he bl i n d f or t hat s u bject ma y be br o ke n b y t he 
treati n g p hys icia n. 
Bef ore brea ki n g t he bli n d of a n i n di vi d ual s u bject’s treat me nt, t he I n vesti gat or s h o ul d ha ve 
deter mi ne d t hat t he i nf or mati o n is necessar y , (i.e., t hat it will alter t he s u bject’s i m me diate 
ma na ge me nt). I n ma ny cases, partic ularl y w he n t he e mer ge nc y is clearl y n ot i n vesti gati o nal 
pr o d uct relate d, t he pr o ble m ma y  be pr o perly ma na ge d b y ass u mi n g t hat t he s u bject is recei vi n g 
acti ve pr o d uct wit h o ut t he nee d f or u n bli n di n g.  
I n cases of acci de ntal un bli n di n g, c o ntact t he Pfizer Me dical M o nit or a n d e ns ure e ver y  atte m pt 
t o preser ve t he bli n d is ma de.    
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L
7. 4
Tr e at m e nt C o m pli a n c e
Res p o nsi ble st u d y  pers o n nel will dis pe nse t he st u d y dr u g.  Acc o u nta bilit y a n d c o m plia nce 
verificati o n s h o ul d be d oc u me nte d i n t he s u bject’s st u d y  rec or ds.  
S u bjects ha ve t o be c o u nsele d o n t he i m p orta nce of ta ki n g t he st u d y dr u g as directe d w he n a 
facial pai n/ press ure/f ull ness occ urs a n d reac hes i nte nsit y of ≥6 o n t he N R S ( 0 - 1 0).  If t he s u bject 
d oes n ot ha ve a facial pai n/ press ure/f ull ness ≥6 o n t he N R S ( 0 - 1 0) or ta ke t heir st u d y  
me dicati o n wit hi n 4 5 da ys of t he Baseli ne Visit, t he y  s h o ul d ret ur n t o t he cli nic f or t heir E n d of 
St u d y  Visit a n d ret ur n t heir st u d y me dicati o n.
7. 5
D e str u cti o n a n d R et ur n of St u d y Dr u g
All u n use d st u d y  dr u g ca n be se nt bac k t o t he dr u g de p ot f or destr ucti o n o nl y after bei n g 
i ns pecte d a n d rec o ncile d b y t he res p o nsi ble St u d y m o nit or or t he sp o ns or’s desi g nee. If it is site 
p olic y  t o destr oy st u d y dr u g o n site, it is t he I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat 
arra n ge me nts ha ve bee n ma de f or t he dis p osal, pr oce d ures f or pr o per dis p osal ha ve bee n 
esta blis he d acc or di n g t o t he a p pl ica ble re g ulati o ns, g ui deli nes a n d i nstit uti o nal pr oce d ures, a n d 
a p pr o priate rec or ds of t he dis p osal ha ve bee n d oc u me nte d. T he u n use d st u d y  dr u gs ca n o nly be 
destr o y e d after bei n g i ns pecte d a n d rec o ncile d b y t he res p o nsi ble St u d y M o nit or or t he sp o ns or’s 
d esi g nee.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
8
A D V E R S E E V E N T S
A n A d verse E ve nt ( A E) is defi ne d as a n y ne w u nt o war d me dical occ urre nce or w orse ni n g of a 
pre -e xisti n g me dical c o n diti o n i n a s u bject or cli nical i n vesti gati o n s u bject a d mi nistere d a n 
i n vesti gati o nal ( me dici nal) pr o d uct a n d t hat d oes n ot necessarily ha ve a ca usal relati o ns hi p wit h 
t his treat me nt.  A n A E ca n t heref ore be a ny u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g f or e xa m ple) s ym pt o m, or disease te m p orall y  ass ociate d wit h t he 
use of t he i n vesti gati o n al pr o d uct, w het her or n ot c o nsi dere d relate t o t he i n vesti gati o nal pr o d uct. 
A d verse e ve nts ca n be s p o nta ne o usl y  re p orte d or elicite d d uri n g a n o pe n-e n de d q uesti o ni n g, 
e xa mi nati o n, or e val uati o n of a s u bject. I n or der t o pre ve nt re p orti n g bias, s u bjects s h o ul d n ot be 
q uesti o ne d re gar di n g t he s pecific occ urre nce of o ne or m ore A Es.
If a s pecific dia g n osis or s yn dr o me is i de ntifie d b y t he I n vesti gat or, t his s h o ul d be rec or de d as 
t he A E, rat her t ha n rec or di n g (as se parate A Es) t he i n di vi d ual si g ns/s ym pt o ms or cli nicall y 
si g nifica nt la b orat or y a b n or malities k n o w n t o be ass ociate d wit h, a n d c o nsi dere d b y t he 
I n vesti gat or t o be a c o m p o ne nt of, t he disease/sy n dr o me.
Defi niti o n of ter ms rel ate d t o all A d verse E ve nts (seri o us a n d n o n -seri o us):
Mil d : Is us uall y transie nt a n d ma y  re q uire o nly 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.
M o derate : 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 s u bject.
Se vere : I nterr u pts us ual acti vities of dail y li vi n g, si g nifica ntly affects cli nical stat us, or ma y 
re q uire i nte nsi ve t hera pe utic inter ve nti o n.
Life t hreate ni n g A Es t hat are c o nsi dere d life t hreate ni n g s h o ul d be c o nsi dere d S A Es.  A n A E is 
life t hreate ni n g if t he s u bject was at i m me diate ris k of deat h fr o m t he e ve nt as it occ urre d, i.e., it 
d oes n ot i ncl u de a reacti o n t hat if it ha d occ urre d i n a m ore seri o us f or m mi g ht ha ve ca use d 
deat h. F or e xa m ple, dr u g i n d uce d he patitis t hat res ol ve d wit h o ut e vi de nce of he patic fail ure 
w o ul d n ot be c o nsi dere d life t hreate ni n g e ve n t h o u g h dr u g i n d uce d he patitis ca n be fatal.
H os pitalizati o n : A Es re q uiri n g h os pitalizati o n s h o ul d be c o nsi dere d S A Es. H os pitalizati o n f or 
electi ve s ur ger y or r o uti ne cli nical pr oce d ures t hat are n ot t he res ult of A E (e. g., electi ve s ur ger y 
f or a pre-e xisti n g c o n diti o n t hat has n ot w orse ne d) nee d n ot be c o nsi dere d A Es or S A Es. If 
a n yt hi n g u nt o war d is re p orte d d uri n g t he pr oce d ure, t hat occ urre nce m ust be re p orte d as a n A E, 
eit her 'seri o us' or ' n o n -seri o us' acc or di n g t o t he us ual criteria.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 5 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Assess me nt f or Deter mi ni n g Rel ati o ns hi p of A E t o St u d y Dr u g :
T he relate d ness of eac h A E t o st u d y  dr u g m ust be classifie d base d o n me dical j u d ge me nt a n d 
acc or di n g t o t he f oll o wi n g cate g ories. T he defi niti o ns are as f oll o ws:
Relate d : T his cate g or y a p plies t o A Es t hat are c o nsi dere d, wit h a hi g h de gree of certai nt y , t o be 
relate d t o t he st u d y dr u g. A n A E ma y be c o nsi dere d relate d w he n it f oll o ws a te m p oral se q ue nce 
fr o m t he a d mi nistrati o n of st u d y dr u g, it ca n n ot reas o na bl y be e x plai ne d b y t he k n o w n 
c haracteristics of t he s u bject’s cli nical s tate, e n vir o n me nt, or t o xic fact ors, or ot her m o des of 
t hera py a d mi nistere d t o t he s u bject. A n A E ma y be c o nsi dere d relate d w he n it f oll o ws a k n o w n 
patter n of res p o nse t o t he st u d y  dr u g, or if t he A E rea p pears u p o n re-c halle n ge. T his cate g or y 
als o a p plies t o A Es t hat are c o nsi dere d t o ha ve a n u nli kel y c o n necti o n t o st u d y dr u g, b ut a 
relati o ns hi p ca n n ot be r ule d o ut wit h certai nty.
U nrelate d: T his cate g or y  a p plies t o A Es t hat are c o nsi dere d wit h a hi g h de gree of certai nt y t o be 
d ue o nl y  t o e xtra ne o us ca uses (e. g., s u bject’s cli nical state, e n vir o n me nt, t o xic fact ors, disease 
u n der st u d y , etc.) a n d d oes n ot meet t he criteria of ot her cate g ories a b o ve.
T here are t w o t y pes of a d verse e ve nts, Seri o us A d verse E ve nts ( S A E) a n d N o n -Seri o us A d verse 
E ve nts ( A Es).
8. 1
S eri o u s A d v er s e E v e nt s
8. 1. 1
D efi niti o n of S eri o u s A d v er s e E v e nt ( S A E )
A n S A E is a n y  e ve nt t hat meets a n y of t he f oll o wi n g criteria at a n y d ose:

Deat h

Life -t hreate ni n g

I n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n

Persiste nt or si g nifica nt disa bilit y /i nca pacity

C o n ge nital a n o mal y/ birt h defect i n t he offs pri n g of a s u bject w h o recei ve d ri me ge pa nt

Ot her: I m p orta nt me dical e ve nts t hat ma y  n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n, ma y  be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical j u d g me nt, 
t he y ma y je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he o utc o mes liste d i n t his defi niti o n. E xa m ples of s uc h e ve nts are ( b ut n ot li mite d t o):
○
I nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m
○
Bl o o d d ys crasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 6 of 1 0 4
P FI Z E R C O N FI D E N TI A L
○
De vel o p me nt of dr u g de pe n de nc y  or dr u g a b use
○
P ote ntial dr u g i n d uce d li ver i nj ur y  (see Secti o n 8. 5 )
○
A b use or O ver d ose of me dicati o n
▪
P ote ntial st u d y  me dicati o n a b use (i ncl u di n g cases of e xcessi ve n o n-c o m plia nce wit h 
st u d y me dicati o n d osi n g i nstr ucti o ns or s u bjects w h o disc o nti n ue treat me nt wit h o ut 
ret ur ni n g st u d y me dicati o n) s h o ul d be d oc u me nte d i n t he s o urce rec or d a n d re p orte d 
as a n A E or S A E as a p pr o priate. I n vesti gat ors m ust m o nit or s u bjects f or p ossi ble 
cases of a b use of st u d y me di cati o n (s u bjects ta ki n g st u d y dr u g f or n o n -t hera pe utic 
p ur p oses, e. g., f or ps yc h oacti ve effects s uc h as hi g h or e u p h oria). I n vesti gat ors s h o ul d 
o btai n m ore i nf or mati o n a n d e x pla nati o n fr o m s u bjects w he n t here are st u d y  dr u g 
acc o u nta bilit y discre pa ncies
▪
P ot e ntial st u d y me dicati o n o ver d ose is defi ne d i n Secti o n 8. 3
I n ge neral, h os pitalizati o n si g nifies t hat t he s u bject has bee n detai ne d ( us uall y  i n v ol vi n g at least 
a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n a n d/ or treat me nt t hat w o ul d 
n ot ha ve bee n a p pr o priate i n t he p h y sicia n's office or o ut patie nt setti n g. W he n i n d o u bt as t o 
w het her ' h os pitalizati o n' occ urre d or was necessar y, t he A E s h o ul d be c o nsi dere d seri o us.
T he f oll o wi n g h os pitalizati o ns are n ot c o nsi dere d S A Es i n Pfizer cli nical st u dies ( b ut ma y be 
c o nsi dere d n o n -seri o us A Es):

A visit t o t he e mer ge nc y  r o o m or ot her h os pital de part me nt < 2 4 h ours t hat d oes n ot res ult i n 
a n a d missi o n ( u nless c o nsi dere d “i m p orta nt me dical e ve nt” or e ve nt t hat is life t hreate ni n g) .

Electi ve s ur ger y  pla n ne d pri or t o si g ni n g c o nse nt.

A d missi o ns as per pr ot oc ol f or a pla n ne d me dical/s ur gical pr oce d ure.

R o uti ne healt h assess me nt re q uiri n g a d missi o n (i.e., r o uti ne c ol o n osc o p y ).

A d missi o n e nc o u ntere d f or a n ot her life circ u msta nce t hat carries n o beari n g o n healt h a n d 
re q uires n o me dical i nter ve nti o n (i.e., lac k of h o usi n g, care-gi ver res pite, fa mil y  
circ u msta nces).
Dis a b ilit y/i nc a p acit ati n g: A n A E is i nca pacitati n g or disa bli n g if t he e x perie nce res ults i n a 
s u bsta ntial a n d/ or per ma ne nt disr u pti o n of t he s u bject’s a bilit y t o carr y o ut n or mal life f u ncti o ns.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 7 of 1 0 4
P FI Z E R C O N FI D E N TI A L
8. 1. 2
C oll e cti o n a n d R e p orti n g S eri o u s A d v er s e E v e nt s
F oll o wi n g t he s u bject’s writte n c o nse nt t o partici pate i n t he st u d y, all S A Es, w het her relate d or 
n ot relate d t o st u d y  dr u g, m ust be c ollecte d, i ncl u di n g t h ose t h o u g ht t o be ass ociate d wit h 
pr ot oc ol -s pecific pr oce d ures. All S A Es m ust be c ollecte d t hat occ ur fr o m t he ti me t he s u bject
pr o vi des i nf or me d c o nse nt , t hr o u g h o ut t he c o urse of t he st u d y, a n d u p t o 3 0 da y s after last d ose. 
T he I n vesti gat or s h o ul d re p ort a ny S A E occ urri n g after t his ti me peri o d t hat is belie ve d t o be 
relate d t o st u dy dr u g or pr ot oc ol -s pecific pr oce dures.  
All S A Es s h o ul d be f oll o we d t o res ol uti o n or sta bilizati o n.
A n S A E re p ort s h o ul d be c o m plete d f or a n y e ve nt w here d o u bt e xists re gar di n g its stat us of 
seri o us ness.
If t he In vesti gat or belie ves t hat a n S A E is n ot relate d t o t he st u d y  dr u g, b ut is p ote ntiall y relate d 
t o t he c o n diti o ns of t he st u d y (s uc h as a wit h dra wal of pre vi o us t hera py or a c o m plicati o n relate d 
t o st u d y pr oce d ure), t he relati o ns hi p s h o ul d be s pecifie d i n t he narrati ve secti o n of t he S A E 
Re p ort. 
S A Es, w het her relate d or n ot relate d t o st u d y dr u g, o ver d ose w he n ass ociate d wit h a n S A E (see 
Secti o n 8. 3 ), p ote ntial dr u g i n d uce d li ver i nj ur y (see Secti o n 8. 5 ) a n d pre g na ncies (see 
Secti o n 8. 4 ) m ust be re p orte d wit hi n 2 4 h o urs of t he I n vesti gat or bec o mi n g a ware of t he e ve nt. 
T he I n vesti gat or is res p o nsi ble f or s u b mitti n g all a p plica ble e ve nts t o t he I n de pe n de nt Re vie w 
B oar d (I R B) as per t he I R B’s re p orti n g re q uire me nts . A d diti o nall y , t he I n vesti gat or, or 
desi g nate d staff, is res p o nsi ble f or e nteri n g t he S A E i nf or mati o n i nt o t he Case Re p ort F or m 
( C R F) a n d safety re p orti n g s yste m (i.e., e ve nt ter m, start/st o p dates, ca usalit y, a n d se verit y).
A n y  seri o us a d verse e ve nt m ust be re p orte d i m me diately or n o later t ha n 2 4 h o urs after 
a ware ness of t he e ve nt t o Pfizer D S U eit her via t he Pfizer S A E S u b missi o n Assista nt ( P S S A)
t o ol or as a writte n descri pti o n, usi n g t he Pfizer C T S A E re p ort f or m, t hat m ust be se nt b y  
facsi mile (fa x or e Fa x ) t o t he Pfizer D S U at 1- 8 6 6- 9 9 7- 8 3 2 2.
If o nl y li mite d i nf or mati o n is i nitiall y a vaila ble, f oll o w-u p re p orts are re q uire d. If a n o n g oi n g 
S A E c ha n ges i n its i nte nsit y or relati o ns hi p t o st u d y dr u g or if ne w i nf or mati o n bec o mes 
a vaila ble, a f oll o w- u p S A E re p ort s h o ul d be se nt wit hi n 2 4 h o urs of t he I n vesti gat or bec o mi n g 
a ware of t he u p date d i nf or mati o n usi n g t he sa me pr oce d ure use d f or t he tra ns missi o n of t he 
i nitial S A E a n d t he sa me e ve nt ter m s h o ul d be use d.
T he mi ni m u m i nf or mati o n re q uire d f or a n i nitial S A E re p ort is:

Se n der of re p ort ( Site n u m ber, I n vesti gat or na me)

S u bject i de ntificati o n ( s u bject n u m ber)

Pr ot oc ol n u m ber
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 8 of 1 0 4
P FI Z E R C O N FI D E N TI A L

S A E ter m (if a n S A E is bei n g re p orte d)
8. 2
N o n -s eri o u s A d v er s e E v e nt s
A n o n -seri o us a dverse eve nt is a n A E n ot classifie d as seri o us. 
8. 2. 1
C oll e cti o n a n d R e p orti n g of N o n- S eri o u s A d v er s e E v e nt s
T he c ollecti o n of n o n -seri o us A E i nf or mati o n s h o ul d be gi n at t he ti me t he s u bject pr o vi des 
i nf or me d c o nse nt t hr o u g h t he E n d of Treat me nt Visit.  
N o n -seri o us a d verse e ve nts s h o ul d be f oll o we d u ntil c o ncl usi o n or sta bilizati o n, or re p orte d as 
S A Es if t he y  bec o me seri o us.  F oll o w -u p is als o re q uire d f or n o n -seri o us A Es t hat ca use 
i nterr u pti o n or disc o nti n uati o n of st u d y dr u g or t h ose t hat are prese nt at t he e n d of st u d y 
treat me nt. 
8. 2. 2
L a b or at or y  T e st A b n or m aliti e s
T he f oll o wi n g la b orat or y test a b n or malities s h o u l d be ca pt ure d o n t he n o n-seri o us A E C R F pa ge 
or S A E Re p ort F or m ( pa per or electr o nic) as a p pr o priate:

A n y  la b orat or y test res ult t hat is cli nicall y si g nifica nt or meets t he defi niti o n of a n S A E.

A n y  la b orat or y a b n or malit y t hat re q uire d t he s u bject t o ha ve t he st u d y dr u g disc o nti n ue d or 
i nterr u pte d.

A n y  la b orat or y a b n or malit y t hat re q uire d t he s u bject t o recei ve s pecific c orrecti ve t hera p y.
8. 3
O v er d o s e
A n o ver d ose is defi ne d as t he acci de ntal or i nte nti o nal a d mi nistrati o n of a n y d ose of a
pr o d uct t hat is c o nsi dere d b ot h e xcessi ve a n d me dic all y i m p ort a nt.
O ver d ose is re p orta ble t o Pfizer Safet y  o nly w he n ass ociate d wit h a n S A E. Details of a n y si g ns 
or s y m pt o ms a n d t heir ma na ge me nt s h o ul d be rec or de d i ncl u di n g details of a n y  treat me nts 
a d mi nistere d.
As y m pt o matic d osi n g err ors ( e. g., acci de ntall y ta ki n g t w o ta blets i nstea d of prescri be d d ose of 
o ne ta blet i n o ne cale n dar da y ) s h o ul d be re p orte d as de viati o ns.
8. 4
Pr e g n a n c y
If, f oll o wi n g t he B aseli ne V isit, it is s u bse q ue ntl y disc o vere d t hat a st u d y s u bject is pre g na nt or 
ma y  ha ve bee n pre g na nt at t he ti me of t he i n vesti gati o nal pr o d uct e x p os ure, i ncl u di n g d uri n g at 
least 6 half-li ves after t he pr o d uct a d mi nistrati o n, t he i n vesti gati o nal pr o d uct will be per ma ne ntly 
disc o nti n ue d i n a n a p pr o priate ma n n er (i.e., d ose ta peri n g if necessar y f or s u bject safety).  
Pr ot oc ol -re q uire d pr oce d ures f or st u dy disc o nti n uati o n a n d f oll o w -u p m ust be perf or me d o n t he 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 6 9 of 1 0 4
P FI Z E R C O N FI D E N TI A L
s u bject u nless c o ntrai n dicate d by t he pre g na nc y  (i.e., x-ra y st u dies). Ot her a p pr o priate pre g na nc y 
f ollo w- u p pr oce d ures s h o ul d be c o nsi dere d if i n dicate d.  
Sites s h o ul d i nstr uct patie nts t o c o ntact t he I n vesti gat or if t he y  bec o me pre g na nt d uri n g t he 
c o urse of t he st u d y. T he In vesti gat or m ust i m me diatel y  n otif y t he Pfizer Me dical M o nit or
( or 
desi g nee) a n d re p ort t he e ve nt b y  eit her usi n g t he P S S A t o ol or b y  c o m pleti n g a n E x p os ure
D uri n g Pre g na nc y ( E D P) S u p ple me ntal F or m f oll o wi n g t he S A E re p orti n g pr oce d ures as 
descri be d i n Secti o n 8. 1. 2 . 
F oll o w -u p i nf or mati o n re gar di n g t he c o urse of t he pre g na nc y , i ncl u di n g peri natal a n d ne o natal 
o utc o me a n d, w here a p plica ble offs pri n g i nf or mati o n m ust als o be re p orte d o n a n E D P 
S u p ple me ntal F or m.
A n y  pre g na nc y t hat occ urs i n a fe male part ner of a male st u d y s u bject s h o ul d be re p orte d t o t he 
Pfizer D S U . Inf or mati o n o n t his pre g na nc y  will be c ollecte d o n a n E D P S u p ple me ntal F or m, as 
a p pr o priat e. I n t he case of pater nal e x p os ure, t he i n vesti gat or will pr o vi de t he s u bject wit h t he 
Pre g na nt Part ner Release of I nf or mati o n F or m t o deli ver t o his part ner. T he i n vesti gat or m ust 
d oc u me nt i n t he s o urce d oc u me nts t hat t he s u bject was gi ve n t he Pre g na nt P art ner Release of 
I nf or mati o n F or m t o pr o vi de t o his part ner.
8. 5
P ot e nti al Dr u g I n d u c e d Li v er I nj ur y ( DI LI)
H u ma ns e x p ose d t o a dr u g w h o s h o w n o si g n of li ver i nj ur y  (as deter mi ne d b y ele vati o ns i n 
tra nsa mi nases) are ter me d “t olerat ors,” w hile t h ose w h o s h o w tra nsie nt li ver i nj ur y b ut a da pt are 
ter me d “a da pt ors.” I n s o me s u bjects, tra nsa mi nase ele vati o ns are a har bi n ger of a m ore seri o us 
p ote ntial o utc o me. T hese s u bjects fail t o a da pt a n d t heref ore are “s usce pti ble” t o pr o gressi ve a n d 
seri o us li ver i nj ur y, c o m m o nl y referre d t o as DI LI. S u bject s w h o e x perie nce a tra nsa mi nase 
ele vati o n a b o ve 3 × U L N s h o ul d be m o nit ore d m ore fre q ue ntl y t o deter mi ne if t he y  are 
“a da pt ors” or are “s usce pti ble.”
I n t he maj orit y of DI LI cases, ele vati o ns i n A S T a n d/ or A L T prece de T bili ele vati o ns ( > 2 × 
U L N) b y se veral da ys or wee ks. T he i ncrease i n T bili t y picall y  occ urs w hile A S T/ A L T is/are 
still ele vate d a b o ve 3 × U L N (ie, A S T/ A L T a n d T bili val ues will be ele vate d wit hi n t he sa me 
la b orat or y sa m ple). I n rare i nsta nces, b y t he ti me T bili ele vati o ns are detecte d, A S T/ A L T val ues 
mi g ht ha ve decrease d. T his occ urre nce is still re gar de d as a p ote ntial DI LI. T heref ore, a b n or mal 
ele vati o ns i n eit her A S T  O R A L T i n a d diti o n t o T bili t hat meet t he criteria o utli ne d bel o w are 
c o nsi dere d p ote ntial DI LI (assesse d per H y ’s la w criteria) cases a n d s h o ul d al wa ys be c o nsi dere d 
i m p orta nt me dical e ve nts, e ve n bef ore all ot her p ossi ble ca uses of li ver i nj ur y ha ve bee n 
e xcl u de d.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 0 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T he t hres h ol d of la b orat or y  a b n or malities f or a p ote ntial DI LI case de pe n ds o n t he s u bject’s 
i n di vi d ual baseli ne val ues a n d u n derlyi n g c o n diti o ns. S u bject s w h o prese nt wit h t he f oll o wi n g 
la b orat or y a b n or malities s h o ul d be e val uate d f urt her as p ote ntial DI LI ( H y’s la w) cases t o 
defi niti vel y  deter mi ne t he eti ol o g y of t he a b n or mal la b orat or y val ues:

S u bject s wit h A S T/ A LT a n d T bili baseli ne val ues wit hi n t he n or mal ra n ge w h o 
s u bse q ue ntl y prese nt wit h A S T O R A LT val ues ≥3 × U L N A N D a T bili val ue ≥2 × U L N 
wit h n o e vi de nce of he m ol y sis a n d a n al kali ne p h os p hatase val ue < 2 × U L N or n ot a vaila ble.

F or s u bjects wit h baseli ne A S T O R A L T O R T bili val ues a b o ve t he U L N, t he f oll o wi n g 
t hres h ol d val ues are use d i n t he defi niti o n me nti o ne d a b o ve, as nee de d, de pe n di n g o n w hic h 
val ues are a b o ve t he U L N at baseli ne:

Pree xisti n g A S T or A L T baseli ne val ues a b o ve t he n or mal ra n ge: A S T or A L T val ues 
≥2 ti mes t he baseli ne val ues A N D ≥3 × U L N; or ≥8 × U L N ( w hic he ver is s maller).

Pree xisti n g val ues of T bili a b o ve t he n or mal ra n ge: T bili le vel i ncrease d fr o m baseli ne 
val ue b y a n a m o u nt of ≥1 × U L N or if t he val ue reac hes ≥3 × U L N ( w hic he ver is 
s maller).
Rises i n A S T/ A L T a n d T bili se parate d b y m ore t ha n a fe w wee ks s h o ul d be assesse d
in di vi d uall y  base d o n cli nical j u d g me nt; a n y case w here u ncertai nt y re mai ns as t o w het her it 
re prese nts a p ote ntial H y’s la w case s h o ul d be re vie we d wit h t he s p o ns or. T he s u bject s h o ul d 
ret ur n t o t he i n vesti gat or site a n d be e val uate d as s o o n as p ossi ble, prefera bl y wit hi n 4 8 h o urs 
fr o m a ware ness of t he a b n or mal res ults. T his e val uati o n s h o ul d i ncl u de la b orat or y tests, detaile d 
hist or y, a n d p h ysical assess me nt.
If a ny p ote ntial DI LI is i de ntifie d a n d meets t he criteria a b o ve, t he Pfizer Me dical M o nit or ( or 
desi g nee) s h o ul d i m me diatel y  be c o ntacte d f or f urt her i nstr ucti o n o n w het her t he s u bject m ust 
disc o nti n ue fr o m t he trial a n d a p pr o priate f oll o w- u p re q uire me nts . 
All cases de m o nstrate d o n re peat testi n g as meeti n g t he la b orat or y  criteria of A S T/ A L T a n d T bili 
ele vati o n defi ne d a b o ve s h o ul d be c o nsi dere d p ote ntial DI LI ( H y ’s la w) cases if n o ot her reas o n 
f or t he L F T a b n or malities has yet bee n f o u n d. S uc h p ote nti a l DI LI ( H y’s l a w) c ases are t o be 
re p orte d as S A Es, irres pecti ve of a v ail a bilit y of all t he res ults of t he i n vesti g ati o ns 
perf or me d t o deter mi ne eti ol o g y of t he L F T a b n or m alities.
A p ote ntial DI LI ( H y ’s la w) case bec o mes a c o nfir me d case o nly after all re s ults of reas o na ble 
i n vesti gati o ns ha ve bee n recei ve d a n d ha ve e xcl u de d a n alter nati ve eti ol o g y.
8. 6
A d v er s e E v e nt s of S p e ci al I nt er e st
N o ne
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
8. 7
E n vir o n m e nt al E x p o s ur e, E x p o s ur e D uri n g Br e a stf e e di n g, a n d 
O c c u p ati o n al E x p o s ur e
E n vir o n me ntal e x p os ure occ urs w he n a pers o n n ot e nr olle d i n t he st u d y as a s u bject recei ves 
u n pla n ne d direct c o ntact wit h or e x p os ure t o t he st u d y  i nter ve nti o n. S uc h e x p os ure ma y or ma y 
n ot lea d t o t he occ urre nce of a n A E or S A E. Pers o ns at ris k f or e n vir o n me ntal e x p os ure i ncl u de 
healt hcare pr o vi ders, fa mil y  me m bers, a n d ot hers w h o ma y be e x p ose d. A n e n vir o n me ntal 
e x p os ure ma y i ncl u de E D P, e x p os ure d uri n g breastfee di n g ( E D B ), a n d occ u pati o nal e x p os ure.
A n y  s uc h e x p os ures t o t he st u d y i nter ve nti o n u n der st u dy are re p orta ble t o Pfizer Safet y wit hi n 
2 4 h o urs of i n vesti gat or a ware ness.
8. 7. 1
E x p o s ur e D uri n g Br e a stf e e di n g
A n E D B occ urs if:

A fe male s u bject is f o u n d t o be breastfee di n g w hile recei vi n g or after disc o nti n ui n g st u d y 
i nter ve nti o n.

A fe male n o n s u bject is f o un d t o be breastfee di n g w hile bei n g e x p ose d or ha vi n g bee n 
e x p ose d t o st u d y i nter ve nti o n (i.e., e n vir o n me ntal e x p os ure). A n e xa m ple of e n vir o n me ntal 
E D B is a fe male fa mil y  me m ber or healt hcare pr o vi der w h o re p orts t hat s he is breastfee di n g 
after ha vi n g bee n e x p ose d t o t he st u d y i nter ve nti o n b y  i n gesti o n.   
T he i n vesti gat or m ust re p ort E D B t o Pfizer Safet y wit hi n 2 4 h o urs of t he i n vesti gat or’s 
a ware ness, irres pecti ve of w het her a n S A E has occ urre d. T he i nf or mati o n m ust be re p orte d via 
P S S A t o ol or b y  c o m pleti n g t he C T S A E Re p ort F or m . W he n E D B occ urs i n t he setti n g of 
e n vir o n me ntal e x p os ure, t he e x p os ure i nf or mati o n d oes n ot pertai n t o t he s u bject e nr olle d i n t he 
st u d y, s o t he i nf or mati o n is n ot rec or de d o n a C R F. H o we ver, a c o p y of t he c o m plete d re p ort is 
mai ntai ne d i n t he i n vesti gat or site file.
A n E D B re p ort is n ot create d w he n a Pfizer dr u g s pecificall y a p pr o ve d f or use i n breastfee di n g 
w o me n (e . g., vita mi ns) is a d mi nistere d i n acc or da nce wit h a ut h orize d use. H o we ver, if t he i nfa nt 
e x perie nces a n S A E ass ociate d wit h s uc h a dr u g, t he S A E is re p orte d t o get her wit h t he E D B.
8. 7. 2
O c c u p ati o n al E x p o s ur e
T he i n vesti gat or m ust re p ort a n y  i nsta nce of occ u pati o nal e x p os ure t o Pfizer Safety wit hi n 2 4 
h o urs of t he i n vesti gat or ’s a ware ness via P S S A t o ol or b y  c o m pleti n g t he C T S A E Re p ort F or m
re gar dless of w het her t here is a n ass ociate d S A E. Si nce t he i nf or mati o n a b o ut t he occ u pati o nal 
e x p os ure d oes n ot pertai n t o a s u bject e nr olle d i n t he st u d y, t he i nf or mati o n is n ot rec or de d o n a 
C R F; h o we ver , a c o p y of t he c o m plete d re p ort is mai ntai ne d i n t he i n vesti gat or site file.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
8. 8
L a c k of E ffi c a c y
T he i n vesti gat or m ust re p ort si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m lac k of 
efficac y.  Lac k of efficac y or fail ure of e x pecte d p har mac ol o gical acti o n is re p orta ble t o Pfizer 
Safet y  o nl y if ass oci ate d wit h a n S A E .
8. 9
M e di c ati o n E rr or s
Me dicati o n err ors ma y  res ult fr o m t he a d mi nistrati o n or c o ns u m pti o n of t he st u d y i nter ve nti o n 
b y  t he wr o n g s u bject, or at t he wr o n g ti me, or at t he wr o n g d osa ge stre n gt h.
Me dicati o n err ors are rec or de d a n d re p orte d as f oll o ws:
Rec or de d o n t he Me dic ati o n 
Err or P a ge 
of t he C R F
Rec or de d o n t he 
A d verse E ve nt P a ge 
of t he C R F
Re p orte d o n C T S A E 
Re p ort F or m / vi a P S S A t o 
Pfizer S afet y Wit hi n 2 4 
H o urs of A w are ness
All (re gar dless of w het her 
ass ociate d wit h a n A E)
A n y  A E or S A E ass ociate d 
wit h t he me dicati o n err or
O nl y  if ass ociate d wit h a n 
S A E
Me dicati o n err ors i ncl u de:

Me dicati o n err ors i n v ol vi n g s u bject e x p os ure t o t he st u d y i nter ve nti o n

P ote ntial me dicati o n err ors or uses o utsi de of w hat is f oresee n i n t he pr ot oc ol t hat d o or d o 
n ot i n v ol ve t he st u d y  s u bject.
W het her or n ot t he me dicati o n err or is acc o m pa nie d b y  a n A E, as deter mi ne d b y  t he i n vesti gat or, 
s uc h me dicati o n err ors occ urri n g t o a st u dy s u bject are rec or de d o n t he me dicati o n err or pa ge of 
t he C R F, w hic h is a s pecific versi o n of t he A E pa ge a n d, if a p plica ble, a n y  ass ociate d seri o us a n d 
n o nseri o us A E(s) are rec or de d o n t he A E pa ge of t he C R F .
I n t he e ve nt of a me dicati o n d osi n g err or, t he s p o ns or s h o ul d be n otifie d wit hi n 2 4 h o urs. 
Me dicati o n err ors s h o ul d be re p orte d t o Pfizer Safet y wit hi n 2 4 h o urs via P S S A t o ol or b y  
c o m pleti n g t he C T S A E Re p ort F or m o nl y w he n ass oci ate d wit h a n S A E.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L
9
S T A TI S TI C S
C o m plete details o n t he statistical met h o ds f or t his st u d y  ma y be f o u n d t he Statistical A nal ysis 
Pla n ( S A P).
9. 1
G e n er al Pr o c e d ur e s
Cate g orical varia bles are ta b ulate d wit h c o u nts a n d perce nta ges. C o nti n u o us varia bles are 
s u m marize d wit h u ni variate statistics (e. g., n, mea n, sta n dar d err or, me dia n, mi ni m u m a n d 
ma xi m u m).
F or t he calc ulati o n of descri pti ve statistics of o bser ve d data, s u bjects m ust ha ve a baseli ne val ue 
t o be e val ua ble f or e n d p oi nts base d o n val ues a n d c ha n ges fr o m baseli ne o ver ti me.
Ta b ulati o n s of t he f oll o wi n g e n d p oi nts prese nt t he n u m ber of u ni q ue s u bjects wit h a n e ve nt: 
pr ot oc ol de viati o ns; i nterr u pti o ns of st u d y  t hera p y; n o nst u d y me dicati o ns; a d verse e ve nts; a n d 
la b orat or y a b n or malities. T h us, f or t hese e n d p oi nts, m ulti ple occ urre nces of t he sa me e ve nt are 
c o u nte d o nl y o nce per s u bject.
9. 2
S a m pl e Si z e
If 7 0 % of t he 2 8 6 ra n d o mize d (1 4 3 per treat me nt ar m) ha ve a facial pai n/ press ure/f ull ness w hic h 
reac hes pai n i nte nsit y of ≥6 o n t he N R S ( 0- 1 0) i n t he all otte d ti me peri o d, a n d c o m plete t heir 
e Diar y i n t he 2 4 h o urs f oll o wi n g, we e x pect r o u g hl y 2 0 0 t otal or 1 0 0 per treat me nt gr o u p i n t he 
m o difie d i nte nt t o treat ( mI T T) p o p ulati o n f or a nal y sis. 
Ass u mi n g ri me ge pa nt pr o vi des a 2 -p oi nt re d ucti o n i n N R S pai n, a n d a 1. 3 5- p oi nt a d va nta ge o ver 
place b o o n t he pri mar y  e n d p oi nt, a n d a c o m m o n sta n dar d de viati o n of 3. 0, t he n t he st u d y will 
ha ve r o u g hl y 8 8 % p o wer o n t he pri mar y e n d p oi nt. T he esti mates f or c ha n ge fr o m baseli ne i n 
N R S a n d c o m m o n sta n dar d de viati o n are c o nsiste nt wit h a m o dest re d ucti o n i n pai n o ver place b o 
a n d a c o nser vati ve sta n dar d de viati o n esti mate, as t hese varie d wi del y i n pre vi o us st u dies
e xa mi ni n g C R S .2 7
9. 3
P o p ul ati o n s f or A n al y si s a n d E sti m a n d s
T he set of e nr olle d s u bjects c o nsists of all s u bjects w h o si g ne d t he i nf or me d c o nse nt f or m a n d 
were assi g ne d a s u bject i de ntificati o n n u m ber.
T he set of ra n d o mize d s u bjects c o nsists of e nr olle d s u bjects w h o were assi g ne d a ra n d o mize d 
treat me nt gr o u p .
T he set of treate d s u bjects c o nsists of e nr olle d s u bjects w h o ta ke st u d y t hera p y ( ri me ge pa nt or 
place b o) . 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T he M o difie d I nte nt t o Treat ( mI T T) set c o nsists of ra n d o mize d s u bjects t hat ta ke st u d y  t hera p y, 
ha ve a facial pai n/ press ure/f ull ness w hic h reac hes pai n i nte nsit y of ≥6 o n t he N R S ( 0 - 1 0) pri or 
t o a d mi nistrati o n of treat me nt, a n d pr o vi de at least o ne p ost -baseli ne efficac y  data p oi nt.  
Esti m a n d s
T he esti ma n d is a s ys te matic descri pti o n of t he treat me nt effect t o be q ua ntifie d i n or der t o
a ns wer t he trial's researc h o bjecti ve. T he esti ma n d c o nsists of t he f oll o wi n g 5 attri b utes: 
Treat me nt, P o p ulati o n, Varia ble, P o p ulati o n- Le vel S u m mar y , a n d Ha n dli n g of I nterc urre nt 
E ve nts (I C Es). Esti ma n d f or pri mar y  o bjecti ve is disc usse d bel o w.
Pri mar y  Esti ma n d:

Treat me nt: Ri me ge pa nt f or m ulate d i n a 7 5 m g O D T (place d o n or u n der t he t o n g ue) or a 
matc hi n g place b o

P o p ulati o n : S u bject s as defi ne d by i ncl usi o n/ e xcl usi o n criteria of t he st u d y.  

Varia ble: C ha n ge fr o m baseli ne of facial pai n/ press ure/f ull ness o n N R S ( 0 -1 0) sc ore at 2 
h o urs p ost -d ose.

P o p ulati o n -Le v el S u m mar y: Differe nce i n mea ns a n d 9 5 % CI, i n c ha n ge fr o m baseli ne of 
facial pai n/ press ure/f ull ness o n N R S ( 0-1 0) sc ore at 2 h o urs p ost -d ose, bet wee n 
Ri me ge pa nt a n d place b o.

I nterc urre nt E ve nt:
o
Use of n o nst u d y resc ue me dicati o ns o n or bef ore 2 h o urs p ost -d ose         
H y p ot hetical strate g y : I n t he e ve nt a s u bject uses a n o nst u d y resc ue me dicati o n o n 
or bef ore 2 h o urs p ost -d ose, all data p oi nts after resc ue me dicati o n was 
a d mi nistere d are set t o missi n g.  It is ass u me d t hat, if t he i nterc urre nt e ve nt ha d 
n ot occ urre d a n d s u bject ha d f oll o we d t he patter n of ot her s u bjects w h o c o nti n ue d 
f oll o w-u p wit h o ut n o nst u d y  resc ue me dicati o n, t heir efficac y w o ul d ha ve bee n 
li ke t he efficac y of s u bjects fr o m t he sa me treat me nt gr o u p w h o di d n ot use resc ue 
me dicati o n.  T his is li ke missi n g at ra n d o m ( M A R) strate g y .
o
All ot her i nterc urre nt e ve nts
   
Treat me nt p olic y  strate g y: All a vaila ble assess me nts o n t he s u bject are use d 
re gar dless of ot her i nterc urre nt e ve nts.
                        
Si milarl y , esti ma n ds f or ot her o bjecti ves will be disc usse d i n detail i n t he statistical a nal ysis 
pla n.
9. 4
St ati sti c al M et h o d s
9. 4. 1
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s
Ta b ulati o ns of de m o gra p hic a n d baseli ne c haract eristics are ma de f or: s u bjects ra n d o mize d b ut 
n ot treate d; s u bjects ra n d o mize d a n d treate d; a n d o verall. A se parate set of ta b ulati o ns are ma de 
f or s u bjects e nr olle d b ut n ot ra n d o mize d.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 5 of 1 0 4
P FI Z E R C O N FI D E N TI A L
9. 4. 2
Pri m ar y  E n d p oi nt( s)
Pri mar y  e n d p oi nt will be a nalyz e d acc or di n g t o pr i mar y esti ma n d. T he c ha n ge fr o m baseli ne 
efficac y e n d p oi nt is a nal yze d o n t he mI T T p o p ulati o n usi n g a  li near  m o del t hat i ncl u des t he 
baseli ne N R S ( 0 - 1 0) val ue f or facial pai n/ press ure/f ull ness as a c o variate, a n d fi xe d effects f or 
treat me nt gr o u p, stratificati o n fact or ( prese nce of nasal p ol y ps ; yes or n o ), sc he d ule d ti me p oi nt, 
a n d ti me p oi nt b y-treat me nt gr o u p i nteracti o n. Ti me p oi nts i ncl u de d i n t he m o del are n o mi nally 
at 1 5, 3 0, 4 5, 6 0, 9 0 a n d 1 2 0 mi n utes p ost -d ose. 
Re peate d meas ures wit hi n s u bject will be m o dele d usi n g t he u nstr uct ure d c o varia nce str uct ure 
f or wit hi n s u bject err or. I n t he case t he m o del fails t o c o n ver ge, a H uy n h -Fel dt err or str uct ure 
will be utilize d, f oll o we d b y a n A R( 1) str uct ure. Err or de grees of free d o m will be calc ulate d 
usi n g t he Ke n war d - R o gers a p pr o xi mati o n if a n u nstr uct ure d c o varia nce str uct ure fits 
a p pr o priatel y;  ot her wise, a sa n d wic h esti mat or will be utilize d t o esti mate t he c o varia nce 
str uct ure, a n d t he de grees of free d o m will be calc ulate d usi n g t he bet wee n-wit hi n met h o d.  
T he differe nce esti mate (ri me ge pa nt - place b o), sta n dar d err or, 9 5 % c o nfi de nce i nter val, a n d p-
val ue will be re p orte d f or 2 h o urs p ost -d ose.
I n t he e ve nt a s u bject uses a n o nst u d y resc ue me dicati o n o n or bef ore 2 h o urs p ost-d ose, all data 
p oi nts after resc ue me dicati o n was a d mi nistere d will be set t o missi n g ( R M = M: Resc ue 
me dicati o n use = Missi n g). Li ke wise, if a s u bject fails t o l o g t heir pai n sc ore after st u d y  dr u g is 
a d mi nistere d, t hr o u g h 2 h o urs p ost- d ose, t his d ata will be c o nsi dere d missi n g ( N C = M: N o n -
c o m pleters = Missi n g).
Se nsiti vit y A n al ysis: T he a nal ys is of t he pri mar y e n d p oi nt ass u mes a h yp ot hetical strate g y  f or 
i nterc urre nt e ve nt of pr o hi bite d resc ue me dicati o n use o n or bef ore 2 h o urs p ost -d ose . It f urther 
ass u mes t hat ha d t he s u bjects n ot use d a resc ue me dicati o n, t heir efficac y  w o ul d ha ve bee n 
si milar t o t he efficac y of s u bjects fr o m t he sa me treat me nt gr o u p w h o di d n ot .  As a res ult, t he 
pr i mar y a nalys is uses a missi n g at ra n d o m ( M A R) strate g y. T he p u r p ose of t hese se nsiti vit y 
a nal ys es is t o i n vesti gate de part ures fr o m t hese ass u m pti o ns.
T he f oll o wi n g se nsiti vit y a nal ys es are pla n ne d:

J u m p t o refere nce

Ti p pi n g P oi nt
All se nsiti vit y  a nalys es are c o n d ucte d o n t he mI T T p o p ulati o n. Details of t hese a nal ys es will be 
disc usse d i n statistical a nal y sis pla n.
9. 4. 3
S e c o n d ar y  E n d p oi nt( s)
Esti ma n ds f or sec o n dar y  e n d p oi nts will be defi ne d i n S A P. A nal y sis of sec o n dar y e n d p oi nts
w o ul d f oll o w t he res pecti ve esti ma n d strate g y .
If t he pri mar y e n d p oi nt test is si g nifica nt, t he n t he sec o n dar y e n d p oi nts are e val uate d usi n g a 
hierarc hical gate -kee pi n g pr oce d ure, wit h eac h test i n t he hierarc h y c o n d ucte d at p = 0. 0 5.  T hese 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 6 of 1 0 4
P FI Z E R C O N FI D E N TI A L
sec o n dar y e n d p oi nts will be teste d i n t he or der s h o w n i n t he Stu d y  O bjecti ves secti o n of t his 
pr ot oc ol. Sec o n dar y e n d p oi nts will be a nal y ze d o n t he mIT T p o p ulati o n. 
T he a nal ys is t o e val uate c ha n ge fr o m baseli ne i n t he T N S S will be d o ne usi n g a  li near  m o del 
t hat i ncl u des t he baseli ne T N S S val ue as a c o variate, a n d fi xe d effects f or treat me nt gr o u p, 
sc he d ule d ti me p oi nt, a n d ti me p oi nt b y-treat me nt gr o u p i nteracti o n. Ti me p oi nts i ncl u de d i n t he 
m o del are n o mi nall y at 1 5, 3 0, 4 5, 6 0, 9 0 a n d 1 2 0 mi n utes p ost -d ose. T he differe nce esti mate 
(ri me ge pa nt - place b o), sta n dar d err or, 9 5 % c o nfi de nce i nter val, a n d p- val ue will be re p orte d f or 
2 h o urs p ost -d ose.
T he a nal ys is t o e val uate c ha n ge fr o m baseli ne i n t he nasal o bstr ucti o n (c o n gesti o n) sc ore o n t he 
N R S ( 0 -1 0) will be d o ne i n t he sa me ma n ner as t he first sec o n dar y  e n d p oi nt, wit h baseli ne nasal 
o bstr ucti o n (c o n gesti o n) sc ore fr o m t he N R S as a c o variate i nstea d of baseli ne T N S S.
T he a nal ys is t o e val uate c ha n ge fr o m baseli ne i n t he nasal disc har ge sc ore o n t he N R S ( 0-1 0) 
will be d o ne i n t he sa me ma n ner as t he first sec o n dar y  e n d p oi nt, wit h baseli ne nasal disc har ge 
sc ore fr o m t he N R S as a c o variate i nstea d of baseli ne T N S S.
T he n u m ber of s u bjects t hat e x perie nce hea dac he pai n relief at 2 h o urs p ost -d ose will be 
a nal yz e d after first i m p uti n g missi n g data at 2 h o urs t o be fail ure (i.e., N C = F: N o n- C o m pleters 
= Fail ure). A d diti o nall y, s u bjects w h o use resc ue me dicati o n o n or bef ore assess me nt of pai n at 2 
h o urs will als o be assi g ne d as fail ures ( R M = F: Resc ue me dicati o n use = Fail ure). T he a nal ys is 
will be d o ne usi n g Ma ntel -Hae ns zel ris k esti mati o n  after i m p utati o n is d o ne, wit h stratificati o n 
b y prese nce of nasal p ol y ps ( y es or n o) . Hea dac he pai n is defi ne d usi n g a 4 -p oi nt scale of n o ne, 
mil d, m o derate, a n d se vere. Hea dac he pai n relief is defi ne d as a hea dac he pai n le vel of n o ne or 
mil d at 2 h o urs p ost -d ose, wit h a hea dac he pai n le vel of m o derate or se vere at baseli ne. N ote t hat 
o nl y  s u bjects wit h a hea dac he pai n le vel of m o derate or se vere at baseli ne will be i ncl u de d i n t his 
a nal ys is. 
T he n u m ber of s u bjects t hat use resc ue me d icati o n at 2 4 p ost-d ose will be a nal yz e d after first 
i m p uti n g missi n g data at 2 4 h o urs t o be fail ure ( N C = F). T he a nalys is will be d o ne usi n g 
M a ntel-Hae nszel ris k esti mati o n after t he missi n g data are i m p ute d as fail ures, wit h stratificati o n 
b y prese nce of nasal p ol y ps ( yes or n o) .
9. 4. 4
A d j u st m e nt f or M ulti pli cit y
T y pe 1 err or is c o ntr olle d t hr o u g h t he use of hierarc hical testi n g.  T he si g nifica nce of t he pri mar y  
e n d p oi nt is e val uate d at t he t w o- si de d al p ha le vel of 0. 0 5.  If t he pri mar y e n d p oi nt is si g nifica nt, 
t he n t he f oll o wi n g sec o n dar y e n d p oi nts will be teste d hierarc hically i n t he or der s pecifie d i n t he 
sec o n dar y o bjecti ves secti o n (Secti o n 2. 2 ), eac h at t he 0. 0 5 le vel. 
T h us, a sec o n dar y  e n d p oi nt will be teste d o nl y if t he prece di n g sec o n dar y e n d p oi nt i n t he 
hierarc h y is deter mi ne d t o be si g nifica nt.  Descri pti ve p -val ues will be pr o vi de d f or a n y n o n -
si g nifica nt sec o n dar y e n d p oi nts a n d c o m parati ve e x pl orat or y e n d p oi nts.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 7 of 1 0 4
P FI Z E R C O N FI D E N TI A L
N o atte m pt will be ma de t o a dj ust f or m ulti plicit y  w he n testi n g t he e x pl orat or y e n d p oi nts. A n y 
e x pl orat or y e n d p oi nts s u bjecte d t o si g nifica nce testi n g are e val uate d at a n u na dj uste d t w o-si de d 
al p ha le vel of 0. 0 5. 
9. 4. 5
Mi s si n g D at a
F or t he pri mar y  e n d p oi nt of c ha n ge i n N R S o n si n us pai n/ press ure/f ull ness fr o m baseli ne, 
s u bjects w h o fail t o rec or d t heir pai n at 2 h o urs p ost-d ose will be c o nsi dere d missi n g ( N C = M); 
t he M M R M a nal ysis m o del will be use d, w hic h ass u mes missi n g data are missi n g at ra n d o m 
( M A R).
T his is t he a p pr oac h f or ha n dli n g missi n g data t hat will als o be use d f or t he first, sec o n d, a n d 
t hir d sec o n dar y e n d p oi nts of c ha n ge fr o m baseli ne i n T N S S, i n N R S f or nasal o bstr ucti o n 
(c o n gesti o n), a n d N R S f or nasal disc har ge, res pecti vel y .
F or t he sec o n dar y  e n d p oi nt of pr o p orti o n of s u bjects wit h hea dac he pai n relief fr o m baseli ne at 2 
h o urs p ost -d ose, missi n g data at 2 h o urs p ost - d ose will be i m p ute d as a fail ure ( N C = F).
F or t he sec o n dar y  e n d p oi nt of pr o p orti o n of s u bjects w h o use resc ue me dicati o n at 2 4 h o urs 
p ost -d ose, missi n g data at 2 4 h o urs p ost -d ose will be i m p ute d as a fail ure ( N C = F).
A d diti o nal met h o ds f or ha n dli n g of missi n g data, i ncl u di n g se nsiti vit y  a nal yses, will be 
des cri be d i n detail i n t he S A P. 
9. 4. 6
R e s c u e M e di c ati o n 
F or t he pri mar y  e n d p oi nt of c ha n ge i n N R S o n si n us pai n/ press ure/f ull ness fr o m baseli ne, t he 
i nterc urre nt e ve nt of use of n o nst u d y resc ue me dicati o ns o n or bef ore t he ti me p oi nt of i nterest ( 2 
h o urs p ost - d ose) will be ha n dle d wit h a h y p ot hetical strate g y . S pecifically,  t he ass u m pti o n will 
be t hat ha d t he s u bject n ot use d a resc ue me dicati o n, t heir efficac y  w o ul d ha ve bee n si milar t o 
t he efficac y of s u bjects fr o m t he sa me treat me nt gr o u p w h o di d n ot use resc ue me dicati o n. T hese 
data p oi nts after resc ue me dicati o n was a d mi nistere d will be set t o missi n g ( R M = M). 
T his is t he a p pr oac h t hat will als o be use d f or ha n dli n g resc ue me dicati o n use o n or bef ore 2 
h o urs p ost - d ose f or t he first, sec o n d, a n d t hir d sec o n dar y e n d p oi nts of c ha n ge fr o m baseli ne i n 
T N S S, i n N R S f or nasal o bstr ucti o n (c o n gesti o n), a n d N R S f or nasal disc har ge, res pecti vel y.
F or t he sec o n dar y  e n d p oi nt of pr o p orti o n of s u bjects wit h hea dac he pai n relief fr o m baseli ne at 2 
h o urs p ost -d ose, s u bjects t hat ta ke resc ue me dicati o n o n or bef ore 2 h o urs p ost-d ose will be 
c o nsi dere d as fail ures ( R M = F). 
Resc ue me dicati o ns are descri be d i n m ore detail i n Secti o n 5. 5.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 8 of 1 0 4
P FI Z E R C O N FI D E N TI A L
9. 4. 7
A n al y si s of S af et y
T he In vesti gat ors deter mi ne t he i n te nsit y of A Es a n d t he relati o ns hi p of A Es t o st u d y t hera p y. 
T he In vesti gat ors’ ter ms are c o de d a n d gr o u pe d b y  s yste m or ga n class usi n g t he latest versi o n of 
t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) a vaila ble. A Es are prese nte d by 
s yste m or ga n class a n d preferre d ter m, or dere d by t he o verall fre q ue nc y  of e ve nts. If a s u bject 
ha d a n a d verse e ve nt wit h differe nt i nte nsities o ver ti me, t he n o nl y  t he greatest i nte nsit y is 
re p orte d.
A Es are ta b ulate d i n all treate d s u bjects. S A Es occ urri n g i n s ubjects e nr olle d b ut n ot treate d are 
liste d. Deat hs are liste d f or e nr olle d s u bjects wit h o ut re gar d t o o nset.
T he fre q ue ncies of t he f oll o wi n g safet y  e ve nts are s u m marize d b y treat me nt re gi me n, a n d 
o verall, f or treate d s u bjects:  S A Es; all A Es, A Es b y  i nte nsit y; a n d A Es b y relate d ness.
Cli nicall y  si g nifica nt la b orat or y test a b n or malities will be i de ntifie d as Gra de 3 t o 4 la b orat or y 
test res ults gra de d acc or di n g t o n u meric la b orat or y test criteria i n C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts ( C T C A E) Versi o n 5. 0 ( 2 0 1 7), if a vaila ble. Ot her wise, if C T C A E gra des are 
n ot a vaila ble, t he n res ults will be gra de d acc or di n g t o n u meric la b orat or y  test criteria i n Di visi o n 
of AI D S ( D AI D S) Ta ble f or Gra di n g t he Se verit y of A d ult a n d Pe diatric A d verse E ve nts 
C orrecte d Versi o n 2. 1 ( 2 0 1 7). If a s u bject has a la b orat or y  test a b n or malit y wit h differe nt 
t o xicit y gra des o ver ti me, t he n o nl y t he hi g hest t o xicit y gra de will be re p orte d.
F urt her safet y a nal ys es will be descri be d i n t he statistical a nal ysis pla n.
9. 5
S c h e d ul e of A n al y s e s
T he data fr o m t his st u d y  ma y be l oc ke d a n d a nalyze d at a n y p oi nt after t he last s u bject c o m pletes 
t heir e n d of treat me nt visit a n d a de q uate ti me has bee n all o we d f or f oll o w- u p.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 7 9 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 0
E T HI C S A N D R E S P O N SI B I LI TI E S
1 0. 1
G o o d Cli ni c al Pr a cti c e
T his st u d y  will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, G o o d Cli nical Practice ( G C P), 
G o o d La b orat or y  Practice ( G L P), Inter nati o nal C o nfere nce o n Har m o nizati o n g ui deli nes , a n d all 
a p plica ble re g ulati o ns, i ncl u di n g t he F e deral F o o d, Dr u g a n d C os metic Act, U. S. a p plica bl e 
C o de of Fe deral Re g ulati o ns (title 2 1), a n y  In de pe n de nt Et hics C o m mittee (I E C) re q uire me nts 
relati ve t o cli nical st u dies. T he st u d y will als o be c o n d ucte d i n c o m plia nce wit h t he 
rec o m me n dati o ns lai d d o w n i n t he m ost rece nt versi o n of t he Declarati o n of Helsi n ki.
T his st u d y  will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol. T he pr ot oc ol a n d a ny a me n d me nts 
a n d t he s u bject i nf or me d c o nse nt will recei ve I nstit uti o nal Re vie w B oar d/ I nde pe n de nt Et hics 
C o m mittee (I R B/ I E C) a p pr o val/fa v ora ble o pi ni o n pri or t o i nitiati o n of t he st u d y.   
T he sp o ns or is res p o nsi ble f or e ns uri n g t hat all u p date d rele va nt i nf or mati o n relate d t o t he 
pr ot oc ol be s u b mitte d t o re g ulat or y  a ut h orities a n d In de pe n de nt Et hics C o m mittees i n 
acc or da nce wit h l ocal la ws a n d re g ulati o ns. T his i ncl u d es e x pe dite d re p orti n g of s us pecte d 
u ne x pecte d seri o us a d verse reacti o ns per re g ulat or y  g ui deli nes.
All seri o us breac hes m ust be re p orte d t o Pfizer ( or desi g nee) i m me diately.  A Seri o us breac h is a 
breac h of t he c o n diti o ns a n d pri nci ples of G C P i n c o n necti o n wit h t he st u d y or pr ot oc ol, w hic h is 
li kel y t o affect, t o a si g nifica nt de gree, t he safety or p h y sical or me ntal i nte grity of t he s u bjects 
of t he st u d y  or t he scie ntific val ue of t he st u d y. E xa m ples i ncl u de ( b ut are n ot li mite d t o):

Missi n g, i na de q uate,
or deli n q ue nt i nf or me d c o nse nt.

Ra n d o mizati o n of a s u bject t hat d oes n ot meet ke y eli gi bilit y  criteria.

Fail ure t o wit h dra w a s u bject meeti n g disc o nti n uati o n criteria.

U nre p orte d seri o us a d verse e ve nts.

I m pr o per brea ki n g of t he bli n d.

C o n d ucti n g t he st u d y wit h o ut I R B a p pr o val. 

W or ki n g u n der a n e x pire d me dical lice nse, or a de barre d or dis q ualifie d stat us.

Falsif y i n g researc h or me dical rec or ds.
St u d y  pers o n nel i n v ol ve d i n c o n d ucti n g t his st u d y will be q ualifie d b y e d ucati o n, trai ni n g, a n d 
e x perie nce t o pe rf or m t heir res pecti ve tas k(s). 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 0 of 1 0 4
P FI Z E R C O N FI D E N TI A L
T his st u d y  will n ot use t he ser vices of st u d y pers o n nel w here sa ncti o ns ha ve bee n i n v o ke d or 
w here t here has bee n scie ntific misc o n d uct or fra u d (e. g., l oss of me dical lice ns ure, de bar me nt).
It is t he sp o ns or’s res p o nsi bili t y t o s u b mit t he pr ot oc ol a n d its a me n d me nts (if a n y), a n d t he I C Fs 
t o re g ulat or y a ut h orities w he n necessar y. 
1 0. 2
Di s s e mi n ati o n of Cli ni c al St u d y  D at a
Pfizer f ulfills its c o m mit me nt t o p u blicl y  discl ose cli nical st u d y res ults t hr o u g h p osti n g t he 
res ults of stu dies o n w w w .cli nicaltrials. g o v ( Cli nical Trials. g o v), t he E u dra C T/ C TIS, a n d/ or 
w w w . pfizer.c o m, a n d ot her p u blic re gistries a n d we bsites i n acc or da nce wit h a p plica ble l ocal 
la ws/re g ulati o ns. I n a d diti o n, Pfizer re p orts st u d y res ults o utsi de of t he re q uire ments of l ocal 
la ws/re g ulati o ns p urs ua nt t o its S O Ps.
I n all cases, st u dy res ults are re p orte d b y Pfizer i n a n o bjecti ve, acc urate, bala nce d, a n d c o m plete 
ma n ner a n d are re p orte d re gar dless of t he o utc o me of t he st u d y  or t he c o u ntr y i n w hic h t he st u d y 
was c o n d ucte d.
w w w.cli nicaltrials. g o v
Pfizer p osts cli nical trial res ults o n w w w .cli nicaltrials. g o v f or Pfizer-s p o ns ore d i nter ve nti o nal 
st u dies (c o n d ucte d i n patie nts) t hat e val uate t he safet y a n d/ or efficac y of a pr o d uct, re gar dless of 
t he ge o gra p hical l ocati o n i n w hic h t he st u d y is c o n d ucte d. T hese res ults are s u b mitte d f or p osti n g 
i n acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y U S la w.
E u dra C T/ C TI S
Pfizer p osts cli nical trial res ults o n E u dra C T/ C TI S f or Pfizer -s p o ns ore d i nter ve nti o nal st u dies i n 
acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y  E U re q uire me nts.
w w w. pfizer.c o m
Pfizer p osts C S R s y n o pses a n d plai n -la n g ua ge st u d y res ults s u m maries o n w w w. pfizer.c o m f or 
Pfizer -s p o ns ore d i nter ve nti o nal st u dies at t he sa me ti me t he c orres p o n di n g st u d y res ults are 
p oste d t o w w w.cli nicaltrials. g o v . C S R s yn o pses will ha ve pers o nall y i de ntifia ble i nf or mati o n 
a n o n ymize d.
D oc u me nts wit hi n mar keti n g a p plicati o ns
Pfizer c o m plies wit h a p plica ble l ocal la ws/re g ulati o ns t o p u blis h cli nical d oc u me nts i ncl u de d i n 
mar keti n g a p plicati o ns. Cli nical d oc u me nts i ncl u de s u m mar y  d oc u me nts a n d C S Rs i ncl u di n g t he 
pr ot oc ol a n d pr ot oc ol a me n d me nts, sa m ple C R Fs, a n d S A Ps. Cli nical d oc u me nts will ha ve 
pers o nall y i de ntifia ble i nf or mati o n a n o n y m ize d.
Data s hari n g
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Pfizer pr o vi des researc hers sec ure access t o s u bject-le vel data or f ull C S Rs f or t he p ur p oses of 
“ b o na-fi de scie ntific researc h” t hat c o ntri b utes t o t he scie ntific u n dersta n di n g of t he disease, 
tar get, or c o m p o u n d class. Pfizer will ma ke data fr o m t hese trials a vaila ble 1 8 m o nt hs after st u d y  
c o m pleti o n. S u bject -le vel data will be a n o ny m ize d i n acc or da nce wit h a p plica ble pri vac y la ws 
a n d re g ulati o ns. C S Rs will ha ve pers o nall y i de ntifia ble i nf or m ati o n a n o n y mize d.
Data re q uests are c o nsi dere d fr o m q ualifie d researc hers wit h t he a p pr o priate c o m pete ncies t o 
perf or m t he pr o p ose d a nal y ses. Researc h tea ms m ust i ncl u de a bi ostatisticia n. Data will n ot be 
pr o vi de d t o a p plica nts wit h si g nifica nt c o nflicts of i nterest, i ncl u di n g i n di vi d uals re q uesti n g 
access f or c o m mercial/c o m petiti ve or le gal p ur p oses.
1 0. 3
I n stit uti o n al R e vi e w B o ar d/I n d e p e n d e nt Et hi c s C o m mitt e e
T he I n vesti gat ors a gree t o pr o vi de t he I R B/I E C wit h all a p pr o priate d oc u me nts, i ncl u di n g a c o py 
of t h e pr ot oc ol/a me n d me nts, IC Fs, a d vertisi n g te xt (if a n y ), I n vesti gat or’s br oc h ure (if a ny) a n d 
a n y ot her writte n i nf or mati o n pr o vi de d t o st u d y s u bjects. T he trial will n ot be gi n u ntil t he 
I n vesti gat ors ha ve o btai ne d t he I R B/I E C fa v ora ble writte n a p pr o vals f or t he a b o ve-me nti o ne d 
st u d y d oc u me nts. 
I n t he e ve nt t hat t he pr ot oc ol is a me n de d, t he re vise d pr ot oc ol m ust be a p pr o ve d b y t he I RB/ I E C 
pri or t o its i m ple me ntati o n, u nless t he c ha n ges i n v ol ve o nl y  l o gistical or a d mi nistrati ve as pects 
of t he trial. 
1 0. 4
I nf or me d C o n s e nt
I n vesti gat ors m ust e ns ure t hat s u bjects, or, i n t h ose sit uati o ns w here c o nse nt ca n n ot be gi ve n by 
s u bjects, t heir le gally acce pta ble re prese ntati ves, are clearl y a n d f ull y i nf or me d a b o ut t he 
p ur p ose, p ote ntial ris ks, a n d ot her critical iss ues re gar di n g cli nical st u dies i n w hic h t he y  
v ol u nteer t o partici pate. 
Pfizer ( or desi g nee) will pr o vi de t he In vesti gat or wit h a n a p pr o priate (i.e., Gl o bal or L ocal) 
sa m ple i nf or me d c o nse nt f or m w hic h will i ncl u de all ele me nts re q uire d by I C H, G C P a n d 
a p plica bl e re g ulat or y re q uire me nts.  T he sa m ple i nf or me d c o nse nt f or m will a d here t o 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.
Bef ore t he p ote ntial s u bject has u n der g o ne a n y st u d y -relate d scree ni n g pr oce d ures, t he nat ure of 
t he st u d y a n d t he p ote ntial ris ks ass ociate d wit h it will be e x plai ne d t o t he s u bject, a n d t he 
s u bject will be gi ve n a n o p p ort u nit y t o as k q uesti o ns t o his or her satisfacti o n. After t he 
q uesti o ns are a ns were d, b ut bef ore pr ocee di n g f urt her, t he s u bject m ust si g n a n d date an 
I RB/I E C a p pr o ve d writte n i nf or me d c o nse nt f or m f or st u d y . T he si g ne d a n d date d I C F will be 
retai ne d at t he I n vesti gat or’s site, wit h a c o p y pr o vi de d t o t he st u d y s u bject a n d date will be 
e ntere d i n his or her C R F or a p pr o priate s ys te m. T he IR B/I E C m ust re vie w a n d a p pr o ve all 
pr ot oc ol versi o ns a n d i nf or me d c o nse nt f or m versi o ns a n d a c o p y of eac h versi o n of t he I R B/I E C 
a p pr o ve d pr ot oc ol a n d i nf or me d c o nse nt f or m is t o be retai ne d i n t he St u d y  Master file. A n y 
re visi o ns t o t he pr ot oc ol or IC F will be re vie we d a n d a p pr o ve d b y  t he I R B/IE C a n d s u bjects will 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
be i nf or me d of I CF c ha n ge s a n d d oc u me nt c o nti n ui n g c o nse nt b y si g ni n g a n d dati n g t he re vise d 
versi o n of t he I C F.
If a re vise d I C F is i ntr o d uce d d uri n g t he st u dy, eac h s u bject’s f urt her c o nse nt m ust be o btai ne d. 
T he ne w versi o n of t he I C F m ust be a p pr o ve d b y t he IR B/I E C, pri or t o s u bse q ue ntl y  o btai ni n g 
eac h s u bject’s c o nse nt. 
If i nf or me d c o nse nt is i nitiall y gi ve n by a s u bject’s le gal g uar dia n or le gall y acce pta ble 
re prese ntati ve, a n d t he s u bject s u bse q ue ntly bec o mes ca pa ble of ma ki n g a n d c o m m u nicati n g 
t heir i nf or me d c o nse nt d uri n g t he st u d y, t he n t he c o nse nt m ust a d diti o nall y be o btai ne d fr o m t he 
s u bject. 
T he i nf or me d c o nse nt f or m m ust als o i ncl u de a state me nt t hat Pfizer a n d its re prese ntati ves a n d 
re g ulat or y a ut h orities ma y ha ve direct access t o s u bject rec or ds.  
1 0. 5
C a s e R e p ort F or m s
A n In vesti gat or is re q uire d t o pre pare a n d mai ntai n a de q uate a n d acc urate case hist ories desi g ne d 
t o rec or d all o bser vati o ns a n d ot her data perti ne nt t o t he i n vesti gati o n of eac h st u d y patie nt. Data 
re p orte d o n t he C R F t hat are deri ve d fr o m s o urce d oc u me nts m ust be c o nsiste nt wit h t he s o urce 
d oc u me nts or t he discre pa ncies m ust be e x plai ne d.
Electr o nic C R Fs will be pre pare d f or all data c ollecti o n fiel ds w he n E D C is bei n g use d.   
T he c o nfi de ntialit y of rec or ds t hat c o ul d i de ntif y patie nts m ust be pr otec te d, res pecti n g t he 
pri vac y  a n d c o nfi de ntialit y r ules i n acc or da nce wit h t he a p plica ble re g ulat or y re q uire me nt(s). 
T he In vesti gat or m ust retai n a c o p y of t he C R Fs i ncl u di n g rec or ds of c ha n ges a n d c orrecti o ns.   
If E D C is bei n g use d, si g nat ures will be o btai ne d electr o nicall y a n d a c o py of t he electr o nic 
C R Fs will be pr o vi de d ( or t he data fr o m t he C R Fs) f or f ut ure refere nce.
1 0. 6
S p o n s or’ s M e di c all y  Q u alifi e d I n di vi d u al 
T he c o ntact i nf or mati o n f or t he s p o ns or’s M QI f or t he st u d y  is d oc u me nte d i n t he st u d y c o ntact 
list l ocate d i n t he I nvesti gat or Site File.
T o facilitate access t o t heir i n vesti gat or a n d t he s p o ns or’s M QI f or st u d y relate d me dical 
q uesti o ns or pr o ble ms fr o m n o nst u d y  healt hcare pr ofessi o nals, s u bjects are pr o vi de d wit h a n 
E C C at t he ti me of i nf or me d c o nse nt. T he E C C c o ntai ns, at a mi ni m u m, (a) pr ot oc ol a n d st u d y 
i nter ve nti o n i de ntifiers, ( b) s u bject’s st u d y i de ntificati o n n u m ber, (c) site e mer ge nc y  p h o ne 
n u m ber acti ve 2 4 h o urs/ da y , 7 da ys per wee k, a n d ( d) Pfizer Call Ce nter n u m ber.T he E C C is 
i nte n de d t o a u g me nt, n ot re place, t he esta blis he d c o m m u nicati o n pat h wa ys bet wee n t he s u bject
a n d t heir i n vesti gat or a n d site staff, a n d bet wee n t he i n vesti gat or a n d s p o ns or st u d y  tea m. T he 
E C C is o nl y  t o be use d b y healt hcare pr ofessi o nals n ot i n v ol ve d i n t he researc h st u d y, as a mea ns 
of reac hi n g t he i n vesti gat or or site staff relate d t o t he car e of a s u bject. T he Pfizer Call Ce nter 
n u m ber is t o be use d w he n t he i n vesti gat or a n d site staff are u na vaila ble. T he Pfizer Call Ce nter 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L
n u m ber is n ot f or use b y t he s u bject directl y;  if a s u bject calls t hat n u m ber directl y, t he y will be 
directe d bac k t o t he i n vesti gat or site.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 1
R E C O R D S M A N A G E M E N T
I n acc or da nce wit h t he pri nci ples of G C P a n d G LP, t he st u d y  ma y be i ns pecte d b y re g ulat or y 
a ut h orities, t he sp o ns or a n d C R O. T he s p o ns or is e ntitle d t o access i nf or mati o n a b o ut t he stat us 
of t he st u d y a n d t o re vie w t he ori gi nal d oc u me nts of t he st u d y.
T he In vesti gat or m ust retai n all st u d y  rec or ds a n d s o urce d oc u me nts f or t he ma xi m u m ti me 
peri o d re q uire d b y t he a p plica ble re g ulati o ns a n d g ui deli nes, or i nstit uti o n pr oce d ures or f or t he 
peri o d of ti me s pecifie d b y  t he sp o ns or, w hic he ver is l o n ger.  T he In vesti gat or m ust c o ntact t he 
sp o ns or pri or t o destr o yi n g a n y rec or ds ass ociate d wit h t his st u d y. 
Pfizer will n otif y  t he i n vesti gat ors w he n t he st u d y files f or t his st u d y are n o l o n ger nee de d. 
If t he In vesti gat or wit h dra ws fr o m t he st u d y (i.e., retire me nt, rel ocati o n), t he rec or ds s hall be 
tra nsferre d t o a m ut ually a gree d u p o n desi g nee.  N otice of s uc h tra nsfer will be gi ve n i n writi n g 
t o Pfizer. 
It is t he res p o nsi bilit y of t he In vesti gat or t o e ns ure t hat t he c urre nt dis p ositi o n rec or d of 
i n vesti gati o nal pr o d uct ( ma y be s u p plie d b y t he sp o ns or) is mai ntai ne d at eac h st u d y site w here 
t he st u d y dr u g is i n ve nt orie d a n d dis pe nse d.  Rec or ds or l o gs m ust c o m ply wit h a p plica ble 
re g ulati o ns a n d g ui deli nes a n d s h o ul d i ncl u de:

am o u nt of st u d y  dr u g recei ve d a n d place d i n st ora ge area

la bel I D n u m ber or batc h n u m ber or Kit n u m ber as s pecifie d f or t he pr ot oc ol

a m o u nt dis pe nse d t o a n d ret ur ne d fr o m eac h patie nt

a m o u nt tra nsferre d t o a n ot her area or site f or dis pe nsi n g or st ora ge if a p plica ble

a m o u nt of dr u g l ost or waste d

a m o u nt destr o ye d at t he site if a p plica ble

a m o u nt ret ur ne d t o t he sp o ns or, if a p plica ble

retai n sa m ples f or bi oa vaila bilit y/ bi oe q ui vale nce, if a p plica ble

rec or d of dates a n d i nitials of pers o n nel res p o nsi ble f or I P dis pe nsi n g a n d acc o u nta bilit y    
1 1. 1
S o ur c e D o c u m e nt ati o n
A n I n vesti gat or is re q uire d t o pre pare a n d mai ntai n a de q uate a n d acc urate case hist ories desi g ne d 
t o rec or d all o bser vati o ns a n d ot her data perti ne nt f or all s u bjects o n st u d y.  
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 5 of 1 0 4
P FI Z E R C O N FI D E N TI A L
If s o urce d oc u me nts are create d t o s u p p ort t he c ollecti o n of st u d y  i nf or mati o n, t his m ust be 
retai ne d wit h t he ot her perti ne nt me dical rec or ds f or eac h s u bject f or verificati o n of data p oi nts, 
u nless ot her wise i nstr ucte d b y  t he sp o ns or or desi g nee t o e nter data directl y o n t he e C R F.
St u d y  m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d i nt o 
t he C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m s o urce 
d oc u me nts; t hat t he safet y a n d ri g hts of s u bjects are bei n g pr otecte d; a n d t hat t he st u d y  is bei n g 
c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y  a gree me nts, 
I C H G C P, a n d all a p plica ble re g ulat or y re q uire me nts.
T he In vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d re g ulat or y 
a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts.
1 1. 2
St u d y Fil e s a n d R e c or d R et e nti o n
T he sp o ns or d oes n ot re q uire ori gi nal d oc u me nts t hat ha ve alrea d y bee n sca n ne d a n d e ntere d i nt o 
t he e T M F sys te m t o be f or war de d to t he sp o ns or. A n y  ori gi nal d oc u me nts (i.e., 1 5 7 2, si g ne d 
fi na ncial discl os ure, si g ne d IC F, etc.) will be retai ne d i n t he re g ulat or y  bi n der at t he st u d y site. 
T he C R O will c o n d uct a fi nal T M F rec o nciliati o n t o e ns ure all st u d y  files a n d re g ulat or y 
d oc u me nt s ha ve bee n c orrectly u pl oa de d t o t he T M F pri or t o t he cl ose or ter mi nati o n of t he 
st u d y. A ny materials or d oc u me nts t o s u p p ort t he cli nical trial o utsi de of t he e T M F (i.e., rater 
trai ni n g ta pes) s h o ul d be mai ntai ne d b y t he C R O. T he s p o ns or will be c o ntacte d t o deter mi ne 
w het her t he st u d y d oc u me nts/ materials t hat are retai ne d o utsi de of t he T M F will be f or war de d t o 
t he sp o ns or, destr o ye d or ke pt at t he C R O or at a n ot her facilit y f or a l o n ger peri o d of ti me at t he 
sp o ns or ’s e x pe nse.
T he C R O will mai ntai n a de q uate st u d y rec or ds after c o m pleti o n or ter mi nati o n of st u d y. After 
t hat peri o d, t he sp o ns or will be c o ntacte d t o deter mi ne w het her t he st u d y  rec or ds will be 
f or war de d t o t he sp o ns or, destr o y e d or ke pt at C R O or at a n ot her facilit y f or a l o n ger peri o d of 
ti me at t he sp o ns or ’s e x pe nse.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 6 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 2
A M E N D M E N T S
Pr ot oc ol m o dificati o ns, e xce pt t h ose i nte n de d t o re d uce i m me diate ris k t o st u d y  s u bjects, ma y be 
ma de o nl y  b y Pfizer ( or s pecifie d desi g nee). A pr ot oc ol c ha n ge i nte n de d t o eli mi nate a n a p pare nt 
i m me diate hazar d t o su bjects ma y  be i m ple me nte d i m me diatel y.
A n y  per ma ne nt c ha n ge t o t he pr ot oc ol m ust be ha n dle d as a pr ot oc ol a me n d me nt. T he writte n 
a me n d me nt m ust be s u b mitte d t o t he I R B/I E C a n d t he In vesti gat or m ust a wait a p pr o val bef ore 
i m ple me nti n g t he c ha n ges. Pfizer or s pecifie d desi g nee will s u b mit pr ot oc ol a me n d me nts t o t he 
a p pr o priate re g ulat or y a ut h orities f or a p pr o val.
If i n t he j u d g me nt of t he I R B/I E C, t he In vesti gat or, a n d/ or Pfizer , t he a me n d me nt t o t he pr ot oc ol 
s u bsta ntiall y c ha n ges t he st u d y desi g n a n d/ or increases t he p ote ntial ris k t o t he s u bject a n d/ or has 
a n i m pact o n t he s u bject ’s i n v ol ve me nt as a st u d y s u bject, t he c urre ntl y a p pr o ve d writte n 
i nf or me d c o nse nt f or m will re q uire si milar m o dificati o n. I n s uc h cases, i nf or me d c o nse nt will be 
re ne we d f or s u bjects e nr olle d i n t he st u d y bef ore c o nti n ue d partici pati o n.
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B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 7 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 3
P U B LI C A TI O N P O LI C Y
T he p u blicati o n p olic y  of Pfizer is disc usse d i n t he In vesti gat or ’s Cli nical Researc h A gree me nt.
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B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 8 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 4
S T U D Y DI S C O N TI N U A TI O N 
B ot h Pfizer a n d t he Pri nci pal In vesti gat or reser ve t he ri g ht t o ter mi nate t he st u d y at t he 
In vesti gat or’s site at a n y  ti me. S h o ul d t his be necessar y, Pfizer or a s pecifie d desi g nee will 
i nf or m t he a p pr o priate re g ulat or y a ut h orities of t he ter mi nati o n of t he st u d y a n d t he reas o ns f or 
its ter mi nati o n, a n d t he Pri nci pal I n vesti gat or will i nf or m t he IR B/I E C of t he sa me. I n 
ter mi nati n g t he st u dy, Pfizer a n d t he Pri nci pal I n vesti gat or will ass ure t hat a de q uate 
c o nsi derati o n is gi ve n t o t he pr otecti o n of t he s u bjects’ i nterests.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 8 9 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 5
D A T A  P R O T E C TI O N
All parties will c o m pl y wit h all a p plica ble la ws, i ncl u di n g la ws re gar di n g t he i m ple me ntati o n of 
or ga nizati o nal a n d tec h nical meas ures t o e ns ure pr otecti o n of s u bject data.
S u bject s’ pers o nal data will be st ore d at t he st u d y site i n e ncr ypte d electr o nic a n d/ or pa per f or m 
a n d will be pass w or d pr otecte d or sec ure d i n a l oc ke d r o o m t o e ns ure t hat o nl y a ut h orize d st u d y 
staff ha ve access. T he st u d y site will i m ple me nt a p pr o priate tec h nical a n d or ga nizati o nal 
meas ures t o e ns ure t hat t he pers o nal data ca n be rec o vere d i n t h e e ve nt of disaster. I n t he e ve nt of 
a p ote ntial pers o nal data breac h, t he st u d y  site will be res p o nsi ble f or deter mi ni n g w het her a 
pers o nal data breac h has i n fact occ urre d a n d, if s o, pr o vi di n g breac h n otificati o ns as re q uire d b y 
la w.
To  pr otect t he ri g hts a n d free d o ms of s u bjects wit h re gar d t o t he pr ocessi n g of pers o nal data, 
s u bjects will be assi g ne d a si n gle, s u bject-s pecific n u merical c o de. A n y s u bject rec or ds or data 
sets t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he n u merical c o de; s u bject n a mes will n ot be 
tra nsferre d. All ot her i de ntifia ble data tra nsferre d t o t he s p o ns or will be i de ntifie d b y  t his si n gle, 
s u bject-s pecific c o de. T he st u d y  site will mai ntai n a c o nfi de ntial list of s u bjects w h o partici pate d 
i n t he st u d y, li n ki n g eac h s u bject’s n u merical c o de t o t heir act ual i de ntit y a n d me dical rec or d I D. 
I n case of data tra nsfer, t he s p o ns or will pr otect t he c o nfi de ntiality of s u bjects’ pers o nal data 
c o nsiste nt wit h t he cli nical st u d y  a gree me nt a n d a p plica ble pri vac y la ws.
I nf or mati o n tec h n olo g y  s yste ms use d t o c ollect, pr ocess, a n d st ore st u d y-relate d data are sec ure d 
b y  tec h nical a n d or ga nizati o nal sec urit y meas ures desi g ne d t o pr otect s uc h data a gai nst 
acci de ntal or u nla wf ul l oss, alterati o n, or u na ut h orize d discl os ure or access.
T he s p o ns o r mai ntai ns S O Ps o n h o w t o res p o n d i n t he e ve nt of u na ut h orize d access, use, or 
discl os ure of s p o ns or i nf or mati o n or s y ste ms.
W he n s u bject data are t o be delete d, t he i n vesti gat or will e ns ure t hat all c o pies of s uc h data are 
pr o m ptl y  a n d irre v oca bl y deleted fr o m all s y ste ms.
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B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 0 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 6
A P P E N DI C E S
1 6. 1
A P P E N DI X I : Str o n g I n hi bit or s a n d Str o n g a n d M o d e rat e I n d u c er s of 
C Y P 3 A 4 P r ot ei n ( N ot all-i n cl u si v e)
T he f oll o wi n g me dicati o ns a n d me dicati o n c o m bi nati o ns are s o me of t he str o n g i n hi bit ors of 
C Y P 3 A 4). T his list s h o ul d n ot be c o nsi dere d all -i ncl usi ve. As descri be d i n t he st u d y pr ot oc ol, 
c o nc o mita nt use of str o n g C Y P 3 A 4 i n hi bit ors is pr o hi bite d. I n di vi d ual dr u g la bels s h o ul d be 
re vie we d f or s pecific i nf or mati o n o n pr o pe nsit y t o i n hi bit C Y P 3 A 4 e nz ymes f or a s pecific 
c o m p o u n d.
Str o n g C Y P 3 A 4 i n hi bit ors
b oce pre vir, c o bicistat, c o ni va pta n, da n o pre vir a n d rit o na vir, el vite gra vir a n d rit o na vir, 
i n di na vir a n d rit o na vir, itrac o naz ole, ket oc o naz ole, l o pi na vir a n d rit o na vir, parita pre vir a n d 
rit o na vir a n d ( o m bitas vir a n d/ or dasa b u vir), p osac o naz ole, rit o na vir, sa q ui na vir a n d rit o na vir, 
tela pre vir, ti pra na vir a n d rit o na vir, tr olea n d o myci n, v oric o naz ole, clarit hr o m yci n, 
nefaz o d o ne, nelfi na vir , mife prist o ne, mi befra dil.  
T he f oll o wi n g me dicati o ns a n d s u p ple me nts are m o derate t o str o n g i n d ucers of C Y P 3 A 4. As 
descri be d i n t he st u d y pr ot oc ol, c o nc o mita nt use of m o derate t o str o n g C Y P 3 A 4 i n d ucers is 
pr o hi bite d. T his list s h o ul d n ot be c o nsi dere d all-i ncl usi ve. I n di vi d ual pr o d uct la bels s h o ul d be 
re vie we d f or s pecific i nf or mati o n o n pr o pe nsit y t o ca use m o derate t o str o n g i n d ucti o n of t he 
C Y P 3 A 4 e nz y me f or a s pecific c o m p o u n d.
Str o n g C Y P 3 A 4 i n d ucers
a pal uta mi de, car ba maze pi ne, p he n o bar bital, p he n yt oi n, rifa m pi n, rifa pe nti ne, St. J o h n’s W ort
M o der ate C Y P 3 A 4 i n d ucers
B ose nta n, rifa b uti n, m o dafi nil, nafcilli n, efa vire nz, etra viri ne, l o pi na vir
Res o urces: 
htt ps:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti
o ns L a beli n g/ uc m 0 9 3 6 6 4. ht m #ta ble 3 - 2
htt ps:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt R es o urces/ Dr u gI nteracti
o ns L a beli n g/ uc m 0 9 3 6 6 4. ht m #ta ble 3 - 3
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Hac ha d H, Ra g ue nea u -Majlessi I , Le v y R H. A usef ul t o ol f or dr u g i nteracti o n e val uati o n: t he 
U ni versit y  of Was hi n gt o n Meta b olis m a n d Tra ns p ort Dr u g I nteracti o n Data base. H u m 
Ge n o mics. 2 0 1 0 Oct; 5( 1): 6 1- 7 2. 
U ni versit y  of Was hi n gt o n Meta b olis m a n d Tra ns p ort Dr u g I nteracti o n Data base accessi ble at 
htt ps:// w w w. dr u gi nteracti o ni nf o. or g/
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 6. 2
A P P E N DI X II: E C G Fi n di n g s of P ot e nti al Cli ni c al C o n c er n
E C G Fi n di n gs T h at M a y
Q u alif y as A Es

Mar ke d si n us bra d yc ar dia (rate < 4 0 b p m) lasti n g mi n utes.

Ne w P R i nter val pr ol o n gati o n > 2 8 0 ms.

Ne w pr ol o n gati o n of Q Tc F t o > 4 8 0 ms (a bs ol ute).

Ne w pr ol o n gati o n of Q Tc F b y > 6 0 ms fr o m baseli ne.

Ne w -o nset atrial fl utter or fi brillati o n, wit h c o ntr olle d ve ntric ular res p o nse rate: ie,
rate < 1 2 0 b p m.

Ne w -o nset t y pe I sec o n d-de gree ( We nc ke bac h) A V bl oc k of > 3 0 -sec o n d d urati o n.

Fre q ue nt P V Cs, tri plets, or s h ort i nter vals ( < 3 0 sec o n ds) of c o nsec uti ve ve ntric ular 
c o m ple xes.
E C G Fi n di n gs T h at M a y
Q u alif y as S A Es

Q Tc F pr ol o n gati o n > 5 0 0 ms.

A bs ol ute val ue of Q Tc F > 4 5 0 ms A N D Q Tc F c ha n ge fr o m baseli ne > 6 0 ms.

Ne w S T -T c ha n ges s u g gesti ve of m y ocar dial isc he mia.

Ne w -o nset L B B B ( Q R S c o m ple x > 1 2 0 ms).

Ne w -o nset ri g ht b u n dle bra nc h bl oc k ( Q R S c o m ple x > 1 2 0 ms).

S y m pt o matic bra d y car dia. 

As y st ole
o
I n a wa ke, s y m pt o m -free s u bjects i n si n us r h yt h m, wit h d oc u me nte d asys t olic 
pa uses ≥3 sec o n ds or a n y esca pe rate < 4 0 b p m, or wit h a n esca pe r h yt h m t hat 
is bel o w t he A V n o de;
o
I n a wa ke, sy m pt o m -free s u bjects wit h atrial fi brillati o n a n d bra dyc ar dia wit h 
1 or m or e as ys t olic pa uses of at least 5 sec o n ds or l o n ger. 

Atrial fl utter or fi brillati o n, wit h ra pi d ve ntric ular res p o nse rate: ra pi d = rate 
> 1 2 0 b p m.

S ustai ne d s u pra ve ntric ular tac h yc ar dia (rate > 1 2 0 b p m) (“s ustai ne d” = s h ort d urati o n 
wit h rele va nt s y m pt o ms or lasti n g > 1 mi n ute).

Ve ntric ular r h yt h ms > 3 0 sec o n d d urati o n, i ncl u di n g i di o ve ntric ular r h y t h m ( H R < 4 0 
b p m), accelerate d i di o ve ntric ular r h yt h m ( H R 4 0 b p m t o < 1 0 0 b p m), a n d 
m o n o m or p hic/ p ol y m or p hic ve ntric ular tac h y car dia ( H R > 1 0 0 b p m [s uc h as t orsa des 
de p oi ntes]).

T y pe II sec o n d- de gree ( M o bitz II) A V bl oc k.

C o m plete (t hir d -de gree) heart bl oc k.
E C G Fi n di n gs T h at Q u alif y as S A Es

C ha n ge i n patter n s u g gesti ve of ne w m y ocar dial i nfarcti o n. 

S ustai ne d ve ntric ular tac h y arr h yt h mias ( > 3 0-sec o n d d urati o n).

Sec o n d - or t hir d -de gree A V bl oc k re q uiri n g pace ma ker place me nt.

As y st olic pa uses re q uiri n g pace ma ker place me nt.

Atrial fl utter or fi brillati o n wit h ra pi d ve ntric ular res p o nse re q uiri n g car di o versi o n.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L

Ve ntric ular fi brillati o n/fl utter.

At t he discreti o n of t he i n ve sti gat or, a ny arr h yt h mia classifie d as a n a d verse 
e x perie nce.
T he maj or e ve nts of p ote ntial cli nical c o ncer n liste d a b o ve are rec o m me n de d as “alerts” or n otificati o ns fr o m 
t he c ore E C G la b orat or y t o t he i n vesti gat or a n d Pfizer st u d y tea m, a n d n ot t o be c o nsi dere d as all -i ncl usi ve of 
w hat is t o be re p orte d as A Es/ S A Es.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 6. 3
A P P E N DI X III : C o ntr a c e pti v e a n d B arri er G ui d a n c e 
1 6. 3. 1
M al e S u bj e ct R e pr o d u cti v e I n cl u si o n Crit eri a
N o c o ntrace pti o n met h o ds are re q uire d f or male s u bjects i n t his st u d y, as t he calc ulate d safety 
mar gi n is ≥1 0 0 f ol d bet wee n t he esti mate d mater nal e x p os ure d ue t o se mi nal tra nsfer a n d t he 
N O A E L  f or seri o us ma nifestati o ns of de vel o p me ntal t o xicit y i n n o ncli nical st u dies.
1 6. 3. 2
F e m al e S u bj e ct R e pr o d u cti v e I n cl u si o n C rit eri a
T he criteria bel o w are part of I ncl usi o n Criteri o n 2. b ( A ge a n d Se x; Secti o n 5. 2 ) a n d s pecif y t he 
repr o d ucti ve re q uire me nts f or i ncl u di n g fe male s u bjects. Refer t o Secti o n 1 6. 3. 4 f or a c o m plete 
list of c o ntrace pti ve met h o ds per mitte d i n t he st u d y. 
A fe male s u bject is eli gi ble t o partici pate if s he is n ot pre g na nt or breastfee di n g a n d at least 1 of 
t he f oll o wi n g c o n diti o ns a p plies:

Is n ot a W O C B P (see defi niti o ns bel o w i n Secti o n 1 6. 3. 3 ).
O R

Is a W O C B P a n d a grees t o use a n acce pta ble c o ntrace pti ve met h o d d uri n g t he 
i nter ve nti o n peri o d (f or a mi ni m u m of 2 8 da y s after t he last d ose of st u d y i nter ve nti o n).  
T he i n vesti gat or s h o ul d e val uate t he effecti ve ness of t he c o ntrace pti ve met h o d i n 
relati o ns hi p t o t he first d ose of st u d y i nter ve nti o n.
T he i n vesti gat or is res p o nsi ble f or re vie w of me dical hist or y , me nstr ual hist or y, a n d rece nt 
se x ual acti vit y t o decrease t he ris k f or i ncl usi o n of a w o ma n wit h a n early u n detecte d pre g na nc y .
1 6. 3. 3
W o m a n of C hil d b e ari n g P ot e nti al
A w o ma n is c o nsi dere d 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 (see bel o w).
If fertilit y is u nclear (e g, a me norr hea or oli g o me n orr hea) a n d a me nstr ual c y cle ca n n ot be 
c o nfir me d bef ore t he first d ose of st u d y  i nter ve nti o n, a d diti o nal e val uati o n s h o ul d be c o nsi dere d.
Wo me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d W O C B P:
1.
Pre me narc hal.
2.
Pre me n o pa usal fe male wit h 1 of t he f oll o wi n g: 

D oc u me nte d h ys terect o m y

D oc u me nte d bilateral sal pi n gect o m y
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 5 of 1 0 4
P FI Z E R C O N FI D E N TI A L

D oc u me nte d bilateral o o p h orect o m y
F or i n di vi d uals wit h per ma ne nt i nfertilit y  d ue t o a me dical ca use ot her t ha n t he a b o ve (e g, 
m ulleria n a ge nesis, a n dr o ge n i nse nsiti vit y ), i n vesti gat or discreti o n s h o ul d be a p plie d t o 
deter mi ni n g st u d y e ntr y.
N ote: D oc u me ntati o n f or a n y  of t he a b o ve cate g ories ca n c o me fr o m t he site pers o n nel’s re vie w 
of t he s u bject ’s me dical rec or ds, me dical e xa mi nati o n, or me dical hist or y i nter vie w. T he met h o d
of d oc u me ntati o n s h o ul d be rec or de d i n t he s u bject’s me dical rec or d f or t he st u d y.
3.
P ost me n o pa usal fe male:

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. I n a d diti o n:

A hi g h F S H le vel i n t he p ost me n o pa usal ra n ge m ust be use d t o c o nfir m a 
p ost me n o pa usal state i n w o me n u n der 6 0 ye ars of a ge a n d n ot usi n g h or m o nal 
c o ntrace pti o n or H R T. 

A fe male o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use 
o ne of t he hi g hl y effecti ve n o nestr o ge n h or m o nal c o ntrace pti o n met h o ds if s he 
wis hes t o c o nti n ue her H R T d uri n g t he st u d y. Ot her wise, s he m ust disc o nti n ue H R T 
t o all o w c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y e nr oll me nt.
1 6. 3. 4
C o ntr a c e pti o n M et h o d s
C o ntrace pt i ve use by me n or w o me n s h o ul d be c o nsiste nt wit h l ocal a vaila bilit y /re g ulati o ns 
re gar di n g t he use of c o ntrace pti ve met h o ds f or t h ose partici pati n g i n cli nical trials.
T he f oll o wi n g c o ntrace pti ve met h o ds are a p pr o priate f or t his st u d y :
Hi g hl y Effecti ve Met h o ds T hat Ha ve L o w User De pe n de nc y  
1.
I m pla nta ble pr o gest o ge n-o nl y  h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n.
2.
I ntra uteri ne de vice.
3.
I ntra uteri ne h or m o ne-releasi n g sys te m.
4.
Bilateral t u bal occl usi o n.
5.
Vasect o mize d part ner:

Vasect o mize d par t ner is a hi g hl y effecti ve c o ntrace pti ve met h o d pr o vi de d t hat t he 
part ner is t he s ole se x ual part ner of t he W O C B P a n d t he a bse nce of s per m has bee n 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 6 of 1 0 4
P FI Z E R C O N FI D E N TI A L
c o nfir me d. If n ot, a n a d diti o nal hi g hl y  effecti ve met h o d of c o ntrace pti o n s h o ul d be 
use d. T he s per mat o ge nesi s c ycle is a p pr o xi matel y 9 0 da ys.
Hi g hl y Effecti ve Met h o ds T hat Are User De pe n de nt 
6.
C o m bi ne d (estr o ge n - a n d pr o gest o ge n -c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n:

Oral

I ntra va gi nal

Tra ns der mal
7.
Pr o gest o ge n - o nly h or m o ne c o ntr ace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n:

Oral

I njecta ble
8.
Se x ual A bsti ne nce

Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y  if 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 ris k ass ociate d 
wit h t he st u d y  i nter ve nti o n. T he relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d 
i n relati o n t o t he d urati o n of t he st u d y a n d t he preferre d a n d us ual lifestyl e of t he 
s u bject.
Ot her Effecti ve Met h o ds
9.
Pr o gest o ge n - o nly oral h or m o nal c o ntrace pti o n w here i n hi biti o n of o v ulati o n is n ot t he 
pri mar y  m o de of acti o n.
1 0. Male or fe male c o n d o m, wit h or wi t h o ut s per mici de.
1 1. Cer vical ca p, dia p hra g m, or s p o n ge wit h s per mici de.
1 2. A c o m bi nati o n of male c o n d o m wit h eit her cer vical ca p, dia p hra g m, or s p o n ge wit h 
s per mici de ( d o u ble-barrier met h o ds).
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 7 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 6. 4
A P P E N DI X I V: Pr ot o c ol Am e n d m e nt Hi st or y
T he pr ot oc ol a me n d me nt s u m mar y  of c ha n ges ta ble f or t he c urre nt a me n d me nt is l ocate d 
directl y  bef ore t he St u d y s u m mar y. T he pr ot oc ol a me n d me nt s u m mar y of c ha n ges ta bles f or past 
a me n d me nt(s) ca n be f o u n d bel o w:
Versi o n N u m ber
Brief Descri pti o n S u m m ar y of C h a n ges
D ate
Versi o n 1. 0 – Ori gi nal 
N ot A p plica ble
2 1 Oct 2 0 2 1
Versi o n 2. 0 –
A me n d me nt 1
C orrecte d t he re q uire me nt:  S u bjects m ust ha ve ha d at least t w o 
i nsta nces of facial pai n/ press ure/f ull ness t hat ha d reac he d a c urre nt 
i nte nsit y of m o derate or se vere o n a 4-p oi nt rati n g scale ( 0 = N o ne, 1 
= Mil d, 2 = M o derate, 3 = Se vere) w it hi n 3 0 da ys pri or t o t he 
Scree ni n g Visit.  T his was c orrecte d i n t w o places t hat it a p pears i n 
t he pr ot oc ol b y a d di n g “ or se vere” f oll o wi n g t he w or d “ m o derate”.  
T his w as u p date d i n t he s y n o ps is a n d i n I ncl usi o n 1c.
U p date d t he p o w er calc ulati o n/sa m ple size i n Secti o n 9. 2  t o i ncrease 
t he n u m ber of e val ua ble s u bjects fr o m 1 6 0 t o 2 0 0.
Pri mar y, sec o n dar y, a n d e x pl orat or y o bjecti ves were u p date d t o 
e ns ure c o nsiste nc y i n t he wa y t he y are writte n i n t he s y n o psis a n d 
b o d y of t he pr ot oc ol.
T h e w or d “ac ute” was i nserte d i nt o t he descri pti o n of t he st u d y desi g n 
a n d pri mar y o bjecti ve t o pr o vi de clarit y.  T he st u d y desi g n n o w  rea ds: 
T his is a d o u ble -bli n d, ra n d o mize d, m ultice nter, o ut patie nt e val uati o n 
of t he safet y a n d efficac y of ri me ge pa nt as c o m pare d t o place b o f or 
t he ac ute treat me nt of c hr o nic r hi n osi n usitis ( C R S) wit h or wit h o ut 
nasal p ol y ps.
F oll o w i n g fee d bac k fr o m t he F D A, t he f oll o wi n g se nte nce was a d de d 
t o t he pr ot oc ol: S u bjects s h o ul d ha ve access t o s yste mic 
c ortic oster oi ds a n d a nti bi otics d uri n g t he trial f or treat me nt of 
s y m pt o ms, if i n dicate d. H o we ver, s u bjects s h o ul d disc o nti n ue t he 
st u d y if t he y recei ve t h ose t hera pies. T his was a d de d t o t he pr ot oc ol 
s y n o psis, Secti o n 4. 2. 2. 1, a n d Secti o n 5.5.
T he te xt “sta ble d osi n g, n ot P R N” was a d de d t o Secti o n 5. 5 f or 
Le u k otrie ne m o difiers a n d Cr o m ol y n.
T he st u d y sc he matic was u p date d t o be m ore c o ncise t o t he st u d y a n d 
f or f or matti n g p ur p oses. Refere nces t o pai n were c ha n ge d t o 
pai n/ press ure/f ull ness.
I n Secti o n 6. 1, Electr o nic C R F I nstr ucti o ns were re m o ve d fr o m t he 
list of st u d y materials.  C R F i nstr ucti o ns are e m be d de d i n t he e C R F.
Wee kl y c o ntact (e. g., p h o ne, te xt, e mail) w as a d de d t o t he st u d y 
bet w ee n t he Baseli ne Visit a n d d osi n g t o m o nit or (a n d re mi n d s u bjects 
2 1 Ja n 2 0 2 1
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 8 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Versi o n N u m ber
Brief Descri pti o n S u m m ar y of C h a n ges
D ate
t o re p ort) a n y s yste mic c ortic oster oi d a n d/ or a nti bi otics ( ot her t ha n 
t o pical nasal a nti bi otics) use. T his was a d de d t o Ta ble 1 B H V 3 0 0 0 -
3 1 6 Sc he d ule of Assess me nts a n d Secti o n 6. 2. 6.
F S H, H b A 1c a n d Li pi d pa nel were a d de d t o Ta ble 1 B H V 3 0 0 0 -3 1 6 
Sc he d ule of Assess me nts a n d Secti o n 6. 2. 4. 1.  
Ta ble 1 B H V 3 0 0 0 -3 1 6 Sc he d ule of Assess me nts was u p date d t o 
clarif y a n d c orrect t he c o m me nts f or t he C -S S R S a n d t he S N O T -2 2 
pr oce d ures.
T he f oll o w i n g e xcl usi o n criteria were u p date d t o eit her c orrect or 
clarif y w hat was writte n or t o a d d c o nsiste nc y wit h ot her as pects of 
t he pr ot oc ol: 1f, 4a, 6a, a n d 6i.
I n Secti o n 5. 4 Pr o hi bite d a n d Restricte d C o nc o mita nt Me dicati o ns 
wa s u p date d.  N u m ber 3 i n t he list descri bi n g s yste mic c ortic oster oi ds 
wa s u p date d a n d a descri pti o n of pr o hi bite d a nti bi otics was a d de d t o 
be c o nsiste nt wit h t he F D A’s fee d bac k.  
I n Secti o n 6. 4 Earl y Disc o nti n uati o n fr o m t he St u d y, use of s yste mic 
c ortic oster oi ds a n d use of a nti bi otics ( ot her t ha n t o pical nasal 
a nti bi otics) were a d de d t o t he list of reas o ns a s u bject m ust 
disc o nti n ue t he st u d y.
I n secti o n 8. 2. 1 C ollecti o n a n d Re p orti n g of N o n-Seri o us A d verse 
E ve nts, t he se nte nce “ N o n seri o us A E i nf or mati o n s h o ul d als o be 
c ollecte d fr o m t he start of a place b o lea d -i n p hase or ot her o bser vati o n 
peri o d i nte n de d t o esta blis h a baseli ne stat us f or a s u bject.” 
Versi o n 3. 0 –
A me n d me nt 2
T o pical nasal a ntic h oli ner gics were a d de d t o t he list of all o we d resc ue 
me dicati o ns a n d me dicati o ns t hat ma y be ta ke n f or n o n -q ualif yi n g 
C R S ass ociate d facial pai n/ press ure/f ull ness.  T his has bee n a d de d i n 
t he St u d y Desi g n secti o n of t he s y n o psis; Secti o n 4. 2. 2. 1, a n d Secti o n 
5. 5.
Secti o n 5. 2, I ncl usi o n 2. b. w as f urt her clarifie d wit h a d diti o nal te xt:  
Ori gi nal te xt:  Ra di o gra p hic i ma gi n g s h o wi n g i nfla m mati o n of t he 
para nasal si n uses.  Ne w Te xt: Ra di o gra p hic i ma gi n g s h o wi n g 
i nfla m mati o n of t he para nasal si n uses wit h p arti al o p acific ati o n of at 
le ast t w o si n uses or c o m plete o p acific ati o n of at le ast one si n us .
Secti o n 5. 2, I ncl usi o n 2. d. w as u p date d t o clarif y re q uire me nts f or 
dail y use of me dicati o ns.  Ori gi nal Te xt:  S u bject w it h dail y use of 
me dicati o ns t o treat C R S sy m pt o ms ( ple ase refer t o Secti o n 5. 5) is 
per mitte d t o re mai n o n t hera p y if t he y ha v e bee n o n a sta ble d ose f or 
at least 3 m o nt hs pri or t o t he Scree ni n g Visit, a n d t he d ose is n ot 
e x pecte d t o c ha n ge d uri n g t he c o urse of t he st u d y.  Ne w Te xt:  S u bject 
wit h dail y use of me dicati o ns liste d i n Secti o n 5. 5 is per mitte d t o 
r e mai n o n t hera p y if t he y ha ve bee n o n a sta ble d ose f or at least 1 
1 5 Mar 2 0 2 2
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 9 9 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Versi o n N u m ber
Brief Descri pti o n S u m m ar y of C h a n ges
D ate
m o nt h pri or t o t he Scree ni n g Visit, a n d t he d ose is n ot e x pecte d t o 
c ha n ge d uri n g t he c o urse of t he st u d y.
Secti o n 5. 3, E xcl usi o n 1a w as u p date d t o clarif y t hat i nfre q ue nt 
te nsi o n-t ype hea dac he is n ot e xcl usi o nar y.  T he f oll o w i n g se nte nce 
wa s a d de d:  I nfre q ue nt te nsi o n-t ype hea dac he c o nsiste nt wit h 
dia g n ostic criteria acc or di n g t o t he I C H D -3 is n ot e xcl usi o nar y.
Secti o n 5. 3, E xcl usi o n 1e., n., o., a n d p. w ere u p date d t o clarif y 
e xcl usi o nar y c o nc o mita nt ill nesse s:  
1.e. w as c ha n ge d fr o m S u bject has di a g n ose d or s us pecte d i n vasi ve 
f u n gal r hi n osi n usitis. t o S u bject has a hist ory of i n vasi ve f u n gal 
r hi n osi n usitis.
1. n. w as c ha n ge d fr o m S u bject has a di a g n osis of si n us m uc ocele. t o
S u bject has a hist ory of si n us m ucocele wit hi n 1 ye ar pri or t o t he 
Scree ni n g Visit.
1. o. w as c ha n ge d fr o m S u bject has a di a g n osis of nasal or para nasal 
t u m or. t o S u bject has a hist ory of m ali g n a nt nasal or para nasal t u m or.
1. p. w as c ha n ge d fr o m S u bject has a di a g n osis of o d o nt o ge nic 
si n usitis. t o S u bject has a hist ory of o d o nt o ge nic si n usitis wit hi n 1 
ye ar pri or t o t he Scree ni n g Visit.
Secti o n 5. 3 E xcl usi o n 2. d. clarifies t he defi niti o n of u nc o ntr olle d 
h y perte nsi o n.  T he f oll o wi n g se nte nce was a d de d: A si n gle bl o o d 
press ure me as ure me nt of g re ater t h a n 1 5 0 m m H g syst olic or 1 0 0 
m m H g di ast olic after 1 0 mi n utes of rest is excl usi o n ary.
Secti o n 5. 3 E xcl usi o n 2. g. was u p date d t o a d d t hat s u bjects wit h 
se vere he ptic i m pair me nt ( C hil d-P u g h C) are t o be e xcl u de d. T he 
f oll o wi n g se nte nce was a d de d t o Excl usi o n 2. g: Severe he p atic 
i m p air me nt ( C hil d-P u g h C) is excl usi o n ary i n all c ases .
Secti o n 5. 3 E xcl usi o n 6. g. u p date d t he hist or y of ne w or rece ntl y 
m o difie d le u k otrie ne m o difiers t hera p y. Te xt was c ha n ge d fr o m 
S u bject has a hist or y of ne w or rece ntl y m o difie d le u k otrie ne 
m o difiers t hera p y wit hi n t he 3 m o nt hs pri or t o Scree ni n g Visit. t o
S u bject has a hist or y of ne w or rece ntl y m o difie d le u k otrie ne 
m o difiers t hera p y wit hi n t he 1 m o nt h pri or t o Scree ni n g Visit.
Secti o n 5. 3 E xcl usi o n 6. h. u p date d t he hist or y of ne w or rece ntl y 
m o difie d le u k otrie ne m o difiers t hera p y. Te xt was c ha n ge d fr o m 
S u bject has a hist or y of ne w or rece ntl y m o difie d β -a dre n oce pt or 
a g o nists t hera p y wit hi n t he 3 m o nt hs pri or t o Scree ni n g Visit. t o 
S u bject has a hist or y of ne w or rece ntl y m o difie d β -a dre n oce pt or 
a g o nists t hera p y wit hi n t he 1 m o nt h pri or t o Scree ni n g Visit.
Secti o n 5. 4 Pr o hi bite d a n d Restricte d C o nc o mita nt Me dicati o ns:  # 1 6 
wa s a d de d t o rea d T o pic al n as al dec o n gest a nts s h o ul d n ot b e t ake n 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 0 0 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Versi o n N u m ber
Brief Descri pti o n S u m m ar y of C h a n ges
D ate
m ore t h a n 3 ti mes per week.
Secti o n 5. 4 Pr o hi bite d a n d Restricte d C o nc o mita nt Me dicati o ns:  
N u m bers 3, 4 a n d 5 w ere u p date d t o be restricte d pri or t o t he 
Scree ni n g Visit.  F or merl y t he y were restricte d pri or t o t he Baseli ne 
Visit.  See te xt bel o w .
3. S yste mic c ortic oster oi ds (e. g., pre d nis o ne, pre d nis ol o ne, 
met h yl pre d nis ol o ne, beta met has o ne, de xa met has o ne, tria mci n ol o ne, 
h y dr oc ortis o ne, c ortis o ne) s h o ul d n ot be ta ke n 3 0 da ys pri or t o t he 
Scree ni n g Visit a n d t hr o u g h o ut t he st u d y. S u bjects s h o ul d ha ve access 
t o s yste mic c ortic oster oi ds d uri n g t he trial f or treat me nt of s y m pt o ms, 
if i n dicate d. H o we ver, s u bjects s h o ul d disc o nti n ue t he st u d y if t he y 
recei ve t his t hera p y. 
4. A nti bi otics, ot her t ha n t o pical nasal a nti bi otics, s h o ul d n ot be ta ke n 
1 4 da ys pr i or t o t he Scree ni n g Visit a n d t hr o u g h o ut t he st u d y. S u bjects 
s h o ul d ha ve access t o a nti bi otics d uri n g t he trial f or treat me nt of 
s y m pt o ms, if i n dicate d. H o we ver, s u bjects s h o ul d disc o nti n ue t he 
st u d y if t he y recei ve t his t hera p y.
5. M o n ocl o nal a nti b o d y t h era p y (e. g., d u pil u ma b, me p oliz u ma b, 
o m aliz u ma b, be nraliz u ma b, resliz u ma b) s h o ul d n ot be ta ke n 6 m o nt hs 
pri or t o t he Scree ni n g Visit a n d t hr o u g h o ut t he st u d y.
Secti o n 5. 4:  Para gra p h w as u p date d t o f urt her clarif y t he criteria f or 
dail y use me dicati o ns.  T e xt was u p date d fr o m S u bjects wit h dail y use 
of me dicati o ns t o tre at C R S sy m pt o ms are per mitte d t o re mai n o n 
t hera p y pr o vi de d t he y ha ve bee n o n a sta ble d ose f or at least 3 m o nt hs
pri or t o t he B aseli ne Visit (see Secti o n 5. 5). t o S u bjects wit h dail y use 
of me dicati o ns liste d i n Secti o n 5. 5 are per mitte d t o re mai n o n t hera p y 
pr o vi de d t he y ha ve bee n o n a sta ble d ose f or at least 1 m o nt h pri or t o 
t he Scree ni n g Visit. 
Secti o n 5. 5 Dail y a n d Resc ue Me dicati o ns was u p date d t o re d uce t he 
ti me me dicati o ns m ust be sta ble a n d t o clarif y t hat sali ne, as s pecifie d 
i n t he ne w te xt, ma y be use d wit h u p t o t wo t o pical nasal me dicati o ns.  
I n a d diti o n, t he list of me dicati o ns was u p date d a n d clarifie d. 
Secti o n was u p date d fr o m: S u bjects m ay n ot use m ore t h a n 1 of t he 
f oll o wi n g me dic ati o ns. Me dicati o n d oses m ust be st a ble wit hi n 3 
m o nt hs pri or t o t he B aseli ne Visit a n d t hr o u g h o ut t he st u d y. 
D aily me dic ati o ns t h at are per mitte d d uri n g t he st u dy i ncl u de:

D aily me dic ati o ns t h at are per mitte d d uri n g t he st u dy i ncl u de:

T o pic al n a s al c ortic oster oi ds (s pr ay or ri nse; st a ble d osi n g, n ot 
P R N)

T o pic al n as al a nti bi otics a n d a ntif u n g al me dic ati o ns (s pr ay or 
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 0 1 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Versi o n N u m ber
Brief Descri pti o n S u m m ar y of C h a n ges
D ate
ri nse; st a ble d osi n g, n ot P R N)

T o pic al n as al a ntic h oli ner gics (s pr ay or ri nse; st a ble d osi n g, n ot 
P R N)

T o pic al a n d or al a nti hist a mi n es ( n o n -se d ati n g; st a ble d osi n g, n ot 
P R N)

S ali ne (s pr ay or ri nse, a d ditives s uc h as deter ge nts or 
m oist urizers are ok)

Or al dec o n gest a nts (st a ble d osi n g, n ot P R N)

Le uk otrie ne m o difiers (st a ble d osi n g, n ot P R N)

Cr o m oly n (st a ble d osi n g, n ot P R N)

M uc olytics (e. g., acetylcystei ne) (st a ble d osi n g, n ot P R N)
After d osi n g wit h st u d y me dicati o n, all ot her p ai n me dicati o n is 
pr o hi bite d d uri n g t he 2 h o urs p ost -d ose. At t he e n d of 2 h o urs after 
d osi n g wit h st u d y me dicati o n (a n d after t he 2 -h o ur assess me nts ha ve 
bee n c o m plete d o n t he e Diar y), s u bjects w ill be per mitte d t o use t he 
f oll o wi n g resc ue me dicati o n: aceta mi n o p he n ( u p t o 1 0 0 0 m g/ da y), or 
as piri n, i b u pr ofe n, na pr o xe n ( or a n y ot her t y pe of n o n -ster oi dal a nti-
i nfla m mat or y dr u g ( N S AI D)), oral a nti hista mi nes ( n o n-se dati n g), oral 
dec o n gesta nts, t o pical nasal dec o n gesta nts (all u p t o t he dail y 
rec o m me n de d d ose i n dicate d o n t he dr u g pac ka gi n g). T hese are t he 
o nl y me dicati o ns all o we d f or resc ue treat me nt after 2 h o urs p ost d ose 
of st u d y me dicati o n.  
T o: Me dicati o n d oses m ust be st a ble wit hi n o ne m o nt h pri or t o t he 
Scree ni n g Visit a n d t hr o u g h o ut t he st u d y. S u bjects ma y use:

S ali ne a n d ot her n o n -me dic ate d s pr ay/ri nse ( a d ditives s uc h as 
deter ge nts, m oist urizers, m uc olytics are per mitte d) - m ai nt ai n 
d osi n g re gi me n est a blis he d pri or t o t he Scree ni n g Visit
A N D u p t o t w o of t he t o pic al n as al me dic ati o ns (st a ble d osi n g, n ot 
P R N, a ny i n dic ati o n ):

T o pic al n as al c ortic oster oi ds (s pr ay or ri nse)

T o pic al n as al a nti bi otics a n d a ntif u n g al me dic ati o ns (s pr ay or 
ri nse)

T o pic al n as al a nti hist a mi nes ( n o n -se d ati n g)

T o pic al n as al cr o m oly n
A N D a ny of t he f oll o wi n g me dic ati o ns (st a ble d osi n g, n ot P R N):
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 0 2 of 1 0 4
P FI Z E R C O N FI D E N TI A L
Versi o n N u m ber
Brief Descri pti o n S u m m ar y of C h a n ges
D ate

Le uk otrie ne m o difiers 

Cr o m oly n ( or al or i n h al ati o n)

Met hylx a nti nes (e. g., t he o p hylli ne, a mi n o p hylli nes) 

M uc o active a ge nts (e. g., g u aife nesi n, acetylcystei ne) 
S u bjects wit h c o nc o mit a nt ast h m a or C O P D m ay re m ai n o n t heir 
b aseli ne S o C tre at me nt if t hey h ave bee n o n a st a ble d ose f or at le ast 
1 m o nt h pri or t o t he Scree ni n g Visit a n d if n ot s pecific ally liste d i n 
S ecti o n 5. 4 Pr o hi bite d a n d Restricte d C o nc o mit a nt Me dic ati o ns, a n d 
t he d ose is n ot ex pecte d t o c h a n ge d uri n g t he c o urse of t he st u dy. 
S u bjects m ay use t heir resc ue i n h alers a n d/ or ne b ulizers as directe d 
by t heir H C P.
After d osi n g wit h st u d y m e dic ati o n, all ot her C R S me dic ati o n is 
pr o hi bite d d uri n g t he 2 h o urs p ost -d ose. At t he e n d of 2 h o urs after 
d osi n g wit h st u d y me dicati o n (a n d after t he 2 -h o ur assess me nts ha ve 
bee n c o m plete d o n t he e Diar y), s u bjects w ill be per mitte d t o use t he 
f oll o wi n g resc ue me dicati on: aceta mi n o p he n ( u p t o 1 0 0 0 m g/ da y), or 
as piri n, i b u pr ofe n, na pr o xe n ( or a n y ot her t y pe of n o n -ster oi dal a nti-
i nfla m mat or y dr u g ( N S AI D)), oral a nti hista mi nes ( n o n-se dati n g), oral 
dec o n gesta nts, t o pical nasal dec o n gesta nts, t o pic al n as al 
a ntic h oli ner gics (all u p t o t he dail y rec o m me n de d d ose i n dicate d o n 
t he dr u g pac ka gi n g). T hese are t he o nl y me dicati o ns all o we d f or 
resc ue treat me nt after 2 h o urs p ost d ose of st u d y me dicati o n.  
Secti o n 8. 4 Pre g na nc y: T his secti o n i nstr ucti n g w here t o e mail t he 
Pre g na nc y F or m  has a t y p o gra p hical err or.  B H V 3 0 0 0-3 1 4 was 
u p date d t o B H V 3 0 0 0 -3 1 6.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 0 3 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 7
R E F E R E N C E S
1. 
R ose nfel d R M, Piccirill o J F, C ha n drase k har S S, et al. Cli nical practice g ui deli ne 
( u p date): a d ult si n usitis. Ot olar yn g ol Hea d Nec k S ur g 2 0 1 5; 1 5 2: S 1 -S 3 9.
2. 
B hattac har y ya N, Orla n di R R, Gre b ner J, Marti ns o n M. C ost b ur de n of c hr o nic 
r hi n osi n usitis: a clai ms-base d st u d y . Ot olar yn g ol Hea d Nec k S ur g 2 0 1 1; 1 4 4: 4 4 0 - 5.
3.
Se da g hat A R. C hr o nic R hi n osi n usitis. A m Fa m P h ysicia n 2 0 1 7; 9 6: 5 0 0 - 6.
4.
Bac h ert C, Ge vaert P, Helli n gs P. Bi ot hera pe utics i n C hr o nic R hi n osi n usitis wit h a n d 
wit h o ut Nasal P ol y ps. J Aller g y  Cli n I m m u n ol Pract 2 0 1 7; 5: 1 5 1 2- 6.
5.
S ha h S A, I s hi na ga H, Ta ke uc hi K. Pat h o ge nesis of e osi n o p hilic c hr o nic r hi n osi n usitis. J 
I nfla m m ( L o n d) 2 0 16; 1 3: 1 1.
6.
Ha mil os D L . C hr o nic r hi n osi n usitis: e pi de mi ol o g y a n d me dical ma na ge me nt. J Aller g y 
Cli n I m m u n ol 2 0 1 1; 1 2 8: 6 9 3 -7 0 7; q uiz 8 - 9.
7.
F o k ke ns WJ, L u n d VJ, H o p ki ns C, et al. E ur o pea n P ositi o n Pa per o n R hi n osi n usitis a n d 
Nasal P ol y ps 2 0 2 0. R hi n ol o g y  2 0 20; 5 8: 1 -4 6 4.
8.
S u h J D, Ke n ne d y  D W. Treat me nt o pti o ns f or c hr o nic r hi n osi n usitis. Pr oc A m T h orac S oc 
2 0 1 1; 8: 1 3 2 - 4 0.
9.
Ste ve ns W W, Sc hlei mer R P. As piri n -E xacer bate d Res pirat or y  Disease as a n E n d ot ype of 
C hr o nic R hi n osi n usitis. I m m u n ol Aller g y  Cli n N ort h A m 2 0 1 6; 3 6: 6 6 9 - 8 0.
1 0.
B o nfils P, Hali mi P, Mali n va u d D. A dre nal s u p pressi o n a n d oste o p or osis after treat me nt 
of nasal p ol y p osis. Acta Ot olar y n g ol 2 0 0 6; 1 2 6: 1 1 9 5 - 2 0 0.
1 1.
Sat o I , I m ura K, Mi wa Y, Y os hi da S, S u n o hara M. Distri b uti o ns of calcit o ni n ge ne-
relate d pe pti de a n d s u bsta nce P i n t he h u ma n ma xillar y  si n us of Ja pa nese ca da vers. J 
Cra ni o ma xill ofac S ur g 2 0 1 2; 4 0:e 2 4 9 - 5 2.
1 2.
Sat o T, Sasa hara N, Ka n da N, et al. Distri b uti o n of C G R P a n d T R P V 2 i n H u ma n 
Para nasal Si n uses. Cells Tiss ues Or ga ns 2 0 1 7; 2 0 3: 5 5- 6 4.
1 3.
Ra n gi S P, Sa m ple S, Ser w o ns ka M H, Le na ha n G A, G oetzl EJ. Me diati o n of pr ol o n ge d 
i ncreases i n nasal m uc osal bl o o d fl o w b y calcit o ni n ge ne-relate d pe pti de ( C G R P). J Cli n 
I m m u n ol 1 9 9 0; 1 0: 3 0 4-1 0.
1 4.
Bara ni u k J N, Kali ner M A. Ne ur o pe pti des a n d nasal secreti o n. J Aller g y Cli n Im m u n ol 
1 9 9 0; 8 6: 6 2 0 - 7.
1 5.
Bara ni u k J N, L u n d gre n J D, G off J, et al. Calcit o ni n ge ne-relate d pe pti de i n h u ma n nasal 
m uc osa. A m J P h y si ol 1 9 9 0; 2 5 8: L8 1- 8.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


B H V 3 0 0 0 ( P F -0 7 8 9 9 8 0 1) (ri me ge pa nt)
Pr ot oc ol B H V 3 0 0 0 -3 1 6 ( C 4 9 5 1 0 1 5) 
Fi nal Pr ot oc ol Versi o n 4. 0, A me n d me nt 3, 1 4 J ul y 2 0 2 3
Pa ge 1 0 4 of 1 0 4
P FI Z E R C O N FI D E N TI A L
1 6.
Br o ka w JJ, W hite G W. Calcit o ni n ge ne -relate d pe pti de p ote ntiates s u bsta nce P-i n d uce d 
plas ma e xtra vasati o n i n t he rat trac hea. L u n g 1 9 9 2; 1 7 0: 8 5 - 9 3.
1 7.
Ca m bri d ge H, Brai n S D. Calcit o ni n ge ne -relate d pe pti de i ncreases bl o o d fl o w a n d 
p ote ntiates plas ma pr otei n e xtra vasati o n i n t he rat k nee j oi nt. Br J P har mac ol 1 9 9 2; 1 0 6: 7 4 6 - 5 0.
1 8.
G uar naccia S, Bara ni u k J N, Bella nti J, D ui na M. Calcit o ni n ge ne-relate d pe pti de nasal 
pr o v ocati o n i n h u ma ns. A n n Aller g y  1 9 9 4; 7 2: 5 1 5- 9.
1 9.
Lacr oi x J S, K urt A M, P oc h o n N, Brett o n C, L u n d ber g J M, Des h usses J. Ne utral 
e n d o pe pti dase acti vit y a n d c o nce ntrati o n of se ns ory ne ur o pe pti de i n t he h u ma n nasal m uc osa. 
E ur Arc h Ot or hi n olar y n g ol 1 9 9 5; 2 5 2: 4 6 5 - 8.
2 0.
Bella m y J L,  Ca dy R K, D ur ha m P L . Sali var y le vels of C G R P a n d VIP i n r hi n osi n usitis 
a n d mi grai ne patie nts. Hea dac he 2 0 0 6; 4 6: 2 4 - 3 3.
2 1.
Z he n g C, Wa n g Z, Lacr oi x J S. Effect of i ntra nasal treat me nt wit h ca psaici n o n t he 
rec urre nce of p oly ps after p ol y pect o m y  a n d et h m oi dect o m y. Acta Ot olar y n g ol 2 0 0 0; 1 2 0: 6 2- 6.
2 2.  
Malis D D, Rist B, Nic o ucar K, Bec k- Sic ki n ger A G, M orel D R, Lacr oi x J S. M o d ulat or y  
effect of t w o n o vel C G R P rece pt or a nta g o nists o n nasal vas o dilatat or y res p o nses t o e x o ge n o us 
C G R P, ca psaici n, bra d y k i ni n a n d hista mi ne i n a naest hetise d pi gs. Re g ul Pe pt 2 0 0 1; 1 0 1: 1 0 1- 8.
2 3.
Ri n der J, L u n d ber g J M. Effects of h C G R P 8 - 3 7 a n d t he N K 1-rece pt or a nta g o nist S R 
1 4 0. 3 3 3 o n ca psaici n -e v o ke d vas o dilati o n i n t he pi g nasal m uc osa i n vi v o. Acta P h ysi ol Sca n d 
1 9 9 6; 1 5 6: 1 1 5 - 2 2.
2 4.
A P A. Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders, 5t h E diti o n: D S M -5 5t h 
E diti o n. 5t h e d: A merica n Ps y c hiatric P u blis hi n g; 2 0 1 3.
2 5.
P os ner K, Br o w n G K, Sta nle y  B, et al. T he C ol u m bia-S uici de Se verit y Rati n g Scale: 
i nitial vali dit y a n d i nter nal c o nsiste nc y fi n di n gs fr o m t hree m ultisite st u dies wit h a d olesce nts a n d 
a d ults. A m J Ps y c hiatr y 2 0 1 1; 1 6 8: 1 2 6 6- 7 7.
2 6.
P os ner K, Bre nt D, L ucas C, et al. C ol u m bia -S uici de Se verit y  Rati n g Scale. T he 
Researc h F o u n dati o n f or Me ntal H y gi e ne, i nc 2 0 0 9; Versi o n 1/ 1 4/ 0 9.
2 7.
Salaffi F, Sta ncati A, Sil vestri C A, Cia petti A, Grassi W. Mi ni mal cli nicall y i m p orta nt 
c ha n ges i n c hr o nic m usc ul os keletal pai n i nte nsit y meas ure d o n a n u merical rati n g scale. E ur J 
Pai n 2 0 0 4; 8: 2 8 3 - 9 1.
2 8.  
Ba n h olzer M L, Wa n del C, Barr o w P, et al. Cli nical trial c o nsi derati o ns o n male 
c o ntrace pti o n a n d c ollecti o n of pre g na nc y  i nf or mati o n fr o m fe male part ner: u p date. Cli n Tra nsl 
Me d. 2 0 1 6; 5( 1)( Dec): 1 - 1 4.
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)


D o c u m e nt A p pr o v al R e c or d
D o c u m e nt N a m e:
D o c u m e nt Titl e:
Si g n e d B y:
D at e( G M T)
Si g ni n g C a p a cit y
0 9 0 1 7 7 e 1 9 e 2 9 2 2 5 8\ A p pr o v e d\ A p pr o v e d O n: 2 8- J ul- 2 0 2 3 1 5: 5 7 ( G M T)
P P D
P P D

SAP_001.pdf: 
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Statistical Analysis Plan for Protocol BHV3000-316 (C4951015)
Page 1 of 64
Confidentiality 
This document is confidential and proprietary property of Pfizer Inc. and to be used only as authorized by Pfizer 
Inc.  No part is to be reproduced, disclosed to others, or quoted without prior written authorization from Pfizer Inc.. 
 
Pfizer Inc. 
 
Protocol BHV3000-316 (C4951015) 
 
A Phase 2/3, Double-Blind, Randomized, Placebo- 
Controlled, Safety and Efficacy Trial of BHV-3000 
(rimegepant) Orally Disintegrating Tablet (ODT) for 
the Acute Treatment of Chronic Rhinosinusitis (CRS) 
With or Without Nasal Polyps  
 
 
Statistical Analysis Plan 
 
 
Version 3.0 
Date: 29-Feb-2024 
 
 
 
 
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This document is confidential and proprietary property of Pfizer Inc. and to be used only as authorized by Pfizer 
Inc.  No part is to be reproduced, disclosed to others, or quoted without prior written authorization from Pfizer Inc..
SIGNATURE PAGE
Protocol Title:
A Phase 2/3, Double-Blind, Randomized, Placebo-
Controlled, Safety and Efficacy Trial of BHV-3000 
(rimegepant) Orally Disintegrating Tablet (ODT) for the 
Acute Treatment of Chronic Rhinosinusitis (CRS) With or 
Without Nasal Polyps
Sponsor:
Pfizer Inc.
Document Version:
V3.0
Date:
29 February 2024
Author:
Rho, Inc.
Signature:_
__
Date:_____
__
Sponsor 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study/project, are in accordance with the study/project objectives, and are 
consistent with the statistical methodology described in the protocol, clinical development 
plan, and all applicable regulatory guidelines.
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author.
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the Clinical Study Report (CSR).
Sponsor Signatories:
Edward P Whalen
Sr. Director Statistics (Group 
Lead),
Pfizer Inc.
Signature:_
_
Date:_____
_
PPD
PPD
PPD


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Statistical Analysis Plan for Protocol BHV3000-316 (C4951015)
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TABLE OF CONTENTS 
SIGNATURE PAGE ..........................................................................................................2 
LIST OF TABLES .............................................................................................................6 
LIST OF FIGURES ...........................................................................................................7 
REVISION HISTORY ......................................................................................................8 
ABBREVIATIONS ..........................................................................................................10 
1 
BACKGROUND AND RATIONALE ....................................................................12 
1.1 
RESEARCH HYPOTHESIS ..............................................................................12 
1.2 
SCHEDULE OF ANALYSES .............................................................................12 
2 
STUDY DESCRIPTION ..........................................................................................13 
2.1 
STUDY DESIGN ..................................................................................................13 
2.2 
TREATMENT ASSIGNMENT ..........................................................................14 
2.3 
BLINDING AND UNBLINDING .......................................................................14 
2.4 
PROTOCOL AND PROTOCOL AMENDMENTS .........................................15 
3 
STUDY OBJECTIVES AND ESTIMANDS ..........................................................15 
3.1 
OBJECTIVES ......................................................................................................15 
3.1.1 
PRIMARY OBJECTIVES ............................................................................15 
3.1.2 
SECONDARY OBJECTIVES ......................................................................15 
3.1.3 
EXPLORATORY OBJECTIVES ................................................................15 
3.2 
ESTIMANDS ........................................................................................................17 
3.2.1 
PRIMARY OBJECTIVE ESTIMAND .......................................................17 
3.2.2 
SECONDARY OBJECTIVE ESTIMANDS ...............................................17 
3.2.3 
EXPLORATORY OBJECTIVE ESTIMANDS..........................................19 
4 
ANALYSIS SETS, TREATMENT GROUPS, AND SUBGROUPS ....................21 
4.1 
ANALYSIS SETS.................................................................................................21 
4.2 
TREATMENT GROUPS ....................................................................................22 
4.3 
SUBGROUPS .......................................................................................................22 
5 
SAMPLE SIZE, POWER, AND TYPE I ERROR ................................................22 
5.1 
HIERARCHICAL TESTING STRATEGY ......................................................23 
6 
STATISTICAL ANALYSES ...................................................................................24 
6.1 
GENERAL ............................................................................................................24 
6.1.1 
PROGRAMMED OUTPUT .........................................................................24 
6.1.1.1 
TABLES ....................................................................................................25 
6.1.1.2 
LISTINGS .................................................................................................25 
6.1.2 STATISTICAL METHODS ...............................................................................25 
6.1.3 HANDLING OF MISSING DATA ....................................................................25 
6.2 
STUDY POPULATION ......................................................................................26 
6.2.1 
ANALYSIS SETS...........................................................................................26 
6.2.2 
ENROLLMENT .............................................................................................26 
6.2.3 
SUBJECT DISPOSITION ............................................................................26 
6.2.3.1 
SUBJECT DISPOSITION AT STUDY MILESTONES ......................26 
6.2.3.2 
OVERALL PREMATURE STUDY TERMINATION DUE TO 
COVID-19 .................................................................................................27 
6.2.4 PROTOCOL DEVIATIONS ..............................................................................27 
6.2.4.1 
RELEVANT PROTOCOL DEVIATIONS ...........................................27 
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6.2.4.2 
SIGNIFICANT PROTOCOL DEVIATIONS .......................................28 
6.2.5 BASELINE CHARACTERISTICS ...................................................................28 
6.2.5.1 
DEMOGRAPHICS AND OTHER RELEVANT BASELINE 
CHARACTERISTICS .............................................................................28 
6.2.5.2 
BASELINE DISEASE CHARACTERISTICS .....................................29 
6.2.5.3 
MEDICAL HISTORY .............................................................................31 
6.2.5.4 
NON-STUDY PRIOR MEDICATIONS ................................................32 
6.2.6 
EXPOSURE ....................................................................................................32 
6.2.6.1 
STUDY THERAPY .................................................................................32 
6.2.6.2 
MEASUREMENTS OF TREATMENT COMPLIANCE ...................33 
6.2.6.3 
CONCOMITANT AND RESCUE MEDICATIONS ...........................34 
6.3 
EFFICACY ...........................................................................................................35 
6.3.1 
OVERALL EFFICACY SUMMARY ..........................................................35 
6.3.2 
RESCUE MEDICATION .............................................................................38 
6.3.3 
PRIMARY EFFICACY ENDPOINT ..........................................................38 
6.3.3.1 
PRIMARY ANALYSIS ...........................................................................38 
6.3.3.2 
SENSITIVITY ANALYSES ...................................................................39 
6.3.3.2.1 
JUMP TO REFERENCE ........................................................................39 
6.3.3.2.2 
TIPPING POINT .....................................................................................40 
6.3.4 
SECONDARY EFFICACY ENDPOINTS ..................................................41 
6.3.4.1 
TOTAL NASAL SYMPTOM SCORE (TNSS) .....................................41 
6.3.4.2 
NASAL OBSTRUCTION (CONGESTION) .........................................42 
6.3.4.3 
NASAL DISCHARGE .............................................................................42 
6.3.4.4 
HEADACHE PAIN RELIEF ..................................................................42 
6.3.4.5 
RESCUE MEDICATION USE WITHIN 24 HOURS ..........................43 
6.3.5 
EXPLORATORY EFFICACY ENDPOINTS ............................................43 
6.3.5.1 
PAIN/PRESSURE/FULLNESS NRS (0-10) SCORE AT 2 HOURS ..44 
6.3.5.2 
PAIN/PRESSURE/FULLNESS NRS (0-10) SCORE AT 2 HOURS ..45 
6.3.5.3 
CHANGE FROM BASELINE OF FACIAL 
PAIN/PRESSURE/FULLNESS NRS (0-10) SCORE AT 15, 30, 45, 60, 
90 MINUTES AND 2, 4, 8 AND 24 HOURS POST-DOSE ..................45 
6.3.5.4 
CHANGE FROM BASELINE OF NASAL OBSTRUCTION 
(CONGESTION) NRS (0-10) SCORE AT 15, 30, 45, 60, 90 MINUTES 
AND 2, 4, 8 AND 24 HOURS POST-DOSE ..........................................45 
6.3.5.5 
CHANGE FROM BASELINE OF NASAL DISCHARGE NRS (0-10) 
SCORE AT 15, 30, 45, 60, 90 MINUTES AND 2, 4, 8 AND 24 HOURS 
POST-DOSE .............................................................................................45 
6.3.5.6 
HEADACHE PAIN RELIEF AT 15, 30, 45, 60, 90 MINUTES AND 2, 
4, 8 AND 24 HOURS POST-DOSE ........................................................46 
6.3.5.7 
PGI-C AT 24 HOURS POST-DOSE ......................................................46 
6.3.5.8 
PAIN/PRESSURE/FULLNESS NRS (0-10) SCORE AT 24 HOURS 46 
6.3.5.9 
PAIN/PRESSURE/FULLNESS NRS (0-10) SCORE AT 24 HOURS 47 
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6.3.5.10 
SUSTAINED RELIEF OF FACIAL PAIN/PRESSURE/FULLNESS47 
6.3.5.11 
SINO-NASAL OUTCOME TEST (SNOT-22) ......................................48 
6.4 
SAFETY ................................................................................................................48 
6.4.1 
ADVERSE EVENTS .....................................................................................49 
6.4.1.1 
DEATHS ...................................................................................................49 
6.4.1.2 
AE OVERVIEW ......................................................................................50 
6.4.1.3 
ON-TREATMENT AES BY SOC AND PT ..........................................50 
6.4.2 
LABORATORY TESTS ...............................................................................50 
6.4.2.1 
LABORATORY TEST ABNORMALITIES ........................................51 
6.4.2.2 
LIVER FUNCTION TEST ELEVATIONS ..........................................51 
6.4.2.3 
LFT PLOTS ..............................................................................................52 
6.4.2.4 
LABORATORY TEST CHANGES FROM BASELINE TABLE ......52 
6.4.2.5 
LABORATORY TEST LISTINGS ........................................................52 
6.4.3 
VITAL SIGNS AND PHYSICAL MEASUREMENTS .............................53 
6.4.3.1 
VITAL SIGN CHANGES FROM BASELINE .....................................53 
6.4.3.2 
VITAL SIGNS ABNORMALITIES ......................................................53 
6.4.4 
ELECTROCARDIOGRAM .........................................................................53 
6.4.4.1 
ECG CHANGES FROM BASELINE ....................................................53 
6.4.4.2 
ECG ABNORMALITIES .......................................................................54 
6.4.5 
PROCEDURES ..............................................................................................54 
6.4.6 
SUICIDALITY ...............................................................................................54 
6.4.7 
SAFETY NARRATIVE SUBJECT IDENTIFIERS LISTING .................54 
7 
CONVENTIONS.......................................................................................................55 
7.1 
DERIVED DATES ...............................................................................................55 
7.1.1 
ANALYSIS PERIOD REFERENCE DATES .............................................55 
7.1.1.1 
STUDY DRUG DATES ...........................................................................55 
7.1.2 
IMPUTED DATES ........................................................................................56 
7.1.3 
LAST CONTACT DATE ..............................................................................56 
7.1.4 
COVID-19 VISIT DATE ...............................................................................56 
7.1.5 
OTHER DERIVED/IMPUTED DATES .....................................................56 
7.2 
ANALYSIS PERIODS.........................................................................................57 
7.3 
ANALYSIS VISIT WINDOWS ..........................................................................57 
7.4 
SUBGROUPS .......................................................................................................59 
7.5 
BASELINE VALUE ............................................................................................59 
8 
CONTENT OF REPORTS ......................................................................................60 
9 
APPENDICES ...........................................................................................................60 
9.1 
RELEVANT PROTOCOL DEVIATIONS .......................................................60 
9.2 
CHANGES TO PLANNED ANALYSES IN THE PROTOCOL ...................63 
10 REFERENCES .........................................................................................................64 
 
 
 
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LIST OF TABLES 
Table 1: 
Primary Objective Estimand ..................................................................17 
Table 2: 
Secondary Objective Estimands .............................................................17 
Table 3: 
Exploratory Objective Estimands ..........................................................19 
Table 4: 
Sample Size and Power Considering Different Drop Out Rates .........22 
Table 5: 
Efficacy Endpoints and Analysis Methods ............................................36 
Table 6: 
Analysis Visit Windows for Safety Parameters.....................................58 
Table 7: 
Evaluation Intervals for Efficacy Analyses ...........................................58 
 
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LIST OF FIGURES 
Figure 1: Study Schematic ..............................................................................................14 
Figure 2: Hierarchical Gate Keeping Procedure ..........................................................23 
 
 
 
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REVISION HISTORY 
 
 
Version 
Description of Change 
1.0 
Original version based on Protocol Version 3.0 and BHV3000-3500 Core SAP v 1.0 
2.0 
Updated version based on BHV3000-3500 Core SAP v 2.0 and CSR TLF guidance for 
3000/3500 studies 
3.0 
Updated version based on Protocol Version 4.0, BHV3000-3500 Core SAP v 3.0, and 
BHV3000-3500 Core SAP v 4.0 
Updated version based on sponsor feedback. 
Clarified Section 2.3 regarding ineligible subjects. Clarified secondary and exploratory 
objectives regarding the type of objective (safety or efficacy). Updated section 
numbering. Clarified Section 6.2.6.2 regarding cross-tabulation. Added overall efficacy 
summary section and table. Updated Jump to Reference sensitivity analysis. Proposed 
update to definition of rescue medication in Section 6.3.4.5. Updated PGI-C analysis in 
Section 6.3.5.7. Added PGI-C, SNOT-22, vital signs, and ECG listing. Updated relevant 
protocol deviations in Section 9.1. 
Updated sponsor signatory to Edward P Whalen. 
Updated Section 4.3 for subgroup analysis by stratification factor. 
Updated Section 6.2.3.1 randomization to treatment disposition table to include the 
number and percentage of subjects who completed the study without being treated and 
the reason. Added treatment to completion/discontinuation table for mITT analysis set 
to align with mocks. 
Updated Section 6.2.4.1 to present relevant protocol deviation tables for full, mITT, and 
safety analysis sets. 
Updated Section 6.2.5.1 to add exception to core SAP. Also added randomization 
stratum frequency table for mITT analysis set, and noted a deviation from the core SAP 
-
 
Updated Section 6.2.6.1 to align with mock, removing rows for n(%) subjects who 
reported or never reported a qualifying facial pain/pressure/fullness NRS score >=6.  
-tabulation if it is 
applicable. Added details for by-subject listing. 
Updated Section 6.3.3.1 to include repeating the primary analysis for the subgroup of 
the stratification factor. 
Updated Sections 6.3.4.1-6.3.4.3 to clarify that the subgroup analysis is included in the 
repeat analysis. 
Updated Section 6.3.4.4 to include headache pain listing. 
Updated Section 6.3.4.5 to reference the Core SAP. 
Updated Section 6.4.1.2 to report AE leading to study discontinuation instead of AE 
leading to study drug discontinuation. 
Updated Section 6.4.1.3 to remove local irritation AEs by intensity, add AEs leading to 
study discontinuation, and clarify AEs by maximum relationship. 
Updated Section 6.4.2.2 to note the addition of elevations of >2xULN in tabulations for 
ALT and AST. Also clarified how to determine evidence of hemolysis. 
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Updated Section 6.4.7 to change from AE leading to discontinuation of study drug to 
 
Updated Section 7.4 to add details regarding stratification factor subgroup. 
Updated Appendix 9.1 to remove post-baseline C-SSRS criteria and surgical history of 
polyps to presence of polyps in looking for discrepancies between IWRS and CRF data. 
Updated Section 5 for new sample size and hierarchical testing strategy. 
Updated Population for all estimands in Section 3. 
Removed baseline SNOT-22 reference from Table 5 as well as from estimand section in 
Table 3. 
Removed outdated text from Section 5. 
Removed stray links from Sections 6.3.4.5 and 6.3.5. 
Updated Section 9.1 for formatting issue, updated baseline/screening out of range 
and antibiotic PDs. 
Updated Section 9.2 for protocol v4 and removed text regarding change from Section 
9.3 of the protocol, as it no longer applies. 
 
 
 
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ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ASE 
asymptotic standard error 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
CI 
Confidence interval 
CK 
Creatine kinase 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case report form 
CRS 
Chronic Rhinosinusitis 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DILI 
Drug-induced liver injury 
ECG 
electrocardiogram 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
EOT 
End of Treatment 
FESS 
functional endoscopic sinus surgery 
ICH 
International Conference on Harmonization 
IP 
investigational product 
IWRS 
Interactive web response system 
LFT 
Liver function test 
LS 
Least squares 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCMC 
Markov Chain Monte Carlo 
MI 
Multiple imputation 
MNAR 
Missing not at random 
NRS 
Numerical Rating Scale 
PGI-C 
Patient Global Impression of Change 
PT 
Preferred term 
REML 
Restricted maximum likelihood 
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SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SI 
Systeme Internationale 
SNOT-22 
Sino-Nasal Outcome Test  22 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TBL 
Total bilirubin 
TLF 
Table listing figure 
TNSS 
Total Nasal Symptom Score 
ULN 
Upper limit of normal 
US 
United States 
WHO-DD 
World Health Organization-Drug Dictionary 
 
 
 
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1 BACKGROUND AND RATIONALE 
This document presents the statistical analysis plan (SAP) for Pfizer Inc., Protocol BHV3000-
316 (C4951015): A phase 2/3, double-blind, randomized, placebo-controlled, safety and efficacy 
trial of BHV-3000 (rimegepant) orally disintegrating tablet (ODT) for the acute treatment of 
chronic rhinosinusitis (CRS) with or without nasal polyps. 
This SAP contains the analysis details and methodology to answer the study objectives, 
including planned tables, listings, and figures (TLFs), which provide the basis for the results 
section of the clinical study report (CSR).  
The Rimegepant (BHV3000/C495)/Zavegepant (BHV3500/C530) Core Statistical Analysis Plan, 
v4
Core SAP
 analysis details and methodologies common to the BHV3000 
(PF-07899801) program and is incorporated by reference.  The Core SAP assumes primacy for 
any matter where this SAP is silent (and the relevant content of the Core SAP could feasibly 
apply) or where the Core SAP is directly referenced as applicable.  Otherwise, should any 
discrepancy exist between the Core SAP and this SAP, this SAP assumes primacy.  
For purposes of applying the Core SAP, the following applies: 
 BHV3000-316 (C4951015) is a single-dose study 
 BHV3000-316 (C4951015) is not a study with a follow-up phase 
 
-
will not 
necessarily apply to BHV3000-316 (C4951015).  COVID-19 impact will be addressed as 
specified in this SAP. 
1.1 
Research Hypothesis   
Rimegepant will have efficacy superior to placebo in the acute treatment of CRS with or without 
polyps with a favorable safety profile. 
1.2 
Schedule of Analyses 
During the course of this study, safety and exposure data are monitored on an ongoing basis.  
The CSR is produced after the last patient last visit and final database lock.  All analyses 
described in this SAP are performed after the final database lock.  No interim unblinded analyses 
are planned.    
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2 STUDY DESCRIPTION 
2.1 
Study Design 
This is a Phase 2/3, double-blind, randomized, multicenter, outpatient evaluation of the safety 
and efficacy of rimegepant as compared to placebo for the acute treatment of CRS with or 
without nasal polyps.  The study drug will be rimegepant presented in a 75 mg ODT (placed on 
or under the tongue) or matching placebo. 
Subjects who have consented to study participation will first participate in the screening phase (3 
to 14 day period).  Subjects must remain on the same dose of daily use of medications to treat 
CRS symptoms from screening through the duration of the study and may not start any new daily 
medication.  Subjects meeting initial eligibility criteria will be asked to continue to a Baseline 
Visit. Subjects who were considered screen failures may be considered for re-screening provided 
the ineligibility was due to one of the eligibility criteria that may have changed due to medical 
intervention or one of the eligibility criteria modified in a protocol amendment. In all possible re-
screening circumstances, the situation must be discussed with the sponsor prior to re-screening, 
with approval in writing from the sponsor prior to re-screening. If a subject is approved for re-
screening, a new subject number must be obtained from the appropriate study-related system. 
Re-screening will only be permitted one time. 
At the Baseline Visit, eligibility for continued participation in the study will be assessed before 
randomization occurs and before study medication is dispensed.  After randomization, the 
subject will be dispensed a single dose of the double-blind study medication to take home for up 
to 45 days.  The subject will be instructed to take their study medication, as an outpatient, when 
(if) they have a facial pain/pressure/fullness which reaches a current intensity of  6 on the 
Numerical Rating Scale (NRS) (0-10); they should not dose until facial pain/pressure/fullness 
reaches a current intensity of  6. The subject will complete questionnaires on an eDiary for 24 
hours after taking study medication.  The subject will be instructed to telephone the study center 
immediately if a severe or serious adverse event occurs. 
Subjects will record efficacy data in their eDiary.  Subjects will complete Sino-Nasal Outcome 
Test (SNOT-22) questionnaire at the Baseline Visit (on a paper scale), and at 24 hours post-dose, 
subjects will complete SNOT-22 (on the eDiary).  Facial pain/pressure/fullness severity, nasal 
congestion (obstruction) severity, and nasal discharge severity will be recorded using an NRS (0-
10) just prior to taking study medication and at 15, 30, 45, 60, and 90 minutes and 2, 4, 8 and 24 
hours after dosing. Total Nasal Symptom Score (TNSS) will be calculated as the sum of 3 
symptom scores: (1) facial pain/pressure/fullness; (2) nasal obstruction (congestion); and (3) 
nasal discharge; recorded just prior to taking study medication and after dosing at time points of 
15, 30, 45, 60, and 90 minutes and 2, 4, 8 and 24 hours.  Subjects who experience current 
headache pain of moderate or severe pain intensity at the time of qualifying facial 
pain/pressure/fullness will record their headache pain severity using a 4-point Likert scale (0 = 
None; 1 = Mild; 2 = Moderate; 3 = Severe) at time of taking study medication and after dosing at 
time points of 15, 30, 45, 60, and 90 minutes and 2, 4, 8 and 24 hours.  Subjects will complete 
the Patient Global Impression of Change (PGI-C) questionnaire 24 hours after dosing. 
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Subjects will return to the study site within 7 days (+2) after taking study treatment for review of 
the eDiary, assessment of medication compliance, and monitoring of tolerability and safety.  If a 
subject has NOT experienced a facial pain/pressure/fullness of sufficient severity within 45 days 
after randomization, they still are required to complete all end of treatment (EOT) visit 
procedures.  All subjects must return empty medication packaging, any unused study medication, 
and the eDiary to the study center.   
The end of the study will be defined as the date of the last visit of the last subject. 
Figure 1: Study Schematic 
 
2.2 
Treatment Assignment 
After completion of all screening evaluations all eligible subjects will be randomized in a 1:1 
ratio to the rimegepant or matching placebo treatment groups.  The randomization will be 
stratified by the presence of nasal polyps (yes or no)  Further detail is provided in the 
Randomization Plan v1.0, dated 01 December 2021.  Subjects will be randomized via the 
Interactive Web Response System (IWRS).  
2.3 
Blinding and Unblinding 
The study is double-blinded. 
Randomization schedules are generated and kept by the IWRS vendor in a secure network folder 
with access limited to only unblinded team members.  Each eligible subject (as per 
inclusion/exclusion criteria) is randomized via the IWRS randomization option.  Randomization 
of any ineligible subjects will be a protocol deviation.  Subjects maintain their subject number 
assigned at screening throughout the trial.  The IWRS provides the double-blind treatment 
assignments.  Further detail is provided in the BHV3000-316 (C4951015) Unblinding Plan v1.0 
(as amended).  
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Dummy coding of treatment groups are used for purposes of blinded statistical programming and 
data review.  Blinding of subjects is maintained until the database has been locked and 
unblinding has been approved.  
Unblinding of individual subject(s) may occur in events of medical emergencies or pregnancies 
as specified in Section 7.3 of the protocol.  
2.4 
Protocol and Protocol Amendments 
The current version of the SAP is based on Version 4.0 of the protocol (14 July 2023). 
3 STUDY OBJECTIVES AND ESTIMANDS 
3.1 
Objectives 
3.1.1 
Primary Objectives 
To evaluate the efficacy of rimegepant compared with placebo in the acute treatment of chronic 
rhinosinusitis with or without polyps on mean change from baseline of facial 
pain/pressure/fullness on NRS (0-10) score at 2 hours post-dose. 
3.1.2 
Secondary Objectives 
1. To evaluate rimegepant compared to placebo on change from baseline in Total Nasal 
Symptom Score (TNSS) at 2 hours post-dose. (Efficacy) 
2. To evaluate rimegepant compared to placebo on change from baseline in nasal obstruction 
(congestion) score on NRS (0-10) score at 2 hours post-dose. (Efficacy) 
3. To evaluate rimegepant compared to placebo on change from baseline in nasal discharge 
score on NRS (0-10) score at 2 hours post-dose. (Efficacy) 
4. To evaluate rimegepant compared to placebo on headache pain relief on a 4-point Likert 
scale at 2 hours post-dose compared to baseline. (Efficacy) 
5. To evaluate rimegepant compared to placebo on the probability of requiring rescue 
medication within 24 hours of initial treatment. (Efficacy) 
3.1.3 
Exploratory Objectives 
1. 
pain/pressure/fullness NRS (0-10) score at 2 hours post-dose. (Efficacy) 
2. 
pain/pressure/fullness NRS (0-10) score at 2 hours post-dose. (Efficacy) 
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3. To evaluate the effect of rimegepant compared to placebo on change from baseline of facial 
pain/pressure/fullness NRS (0-10) score at 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 
hours post-dose. (Efficacy) 
4. To evaluate the effect of rimegepant compared to placebo on change from baseline of nasal 
obstruction (congestion) NRS (0-10) score at 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 
hours post-dose. (Efficacy) 
5. To evaluate the effect of rimegepant compared to placebo on change from baseline of nasal 
discharge NRS (0-10) score at 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 hours post-dose. 
(Efficacy) 
6. To evaluate the effect of rimegepant compared to placebo on headache pain relief using a 4-
point Likert scale at 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 hours post-dose compared 
to baseline. (Efficacy) 
7. To evaluate rimegepant compared to placebo on the PGI-C questionnaire at 24 hours post-
dose. (Efficacy) 
8. 
30% reduction from baseline of facial 
pain/pressure/fullness NRS (0-10) score at 24 hours post-dose. (Efficacy) 
9. 
pain/pressure/fullness NRS (0-10) score at 24 hours post-dose. (Efficacy) 
10. To evaluate rimegepant compared to placebo on sustained relief of facial 
pain/pressure/fullness, as defined by each of the following: 30% reduction from baseline on 
NRS (0-10), 1.5-point reduction on NRS (0-10), and a 2-point reduction on NRS (0-10) 
through 24 hours post-dose. (Efficacy) 
11. To explore the distribution of baseline disease severity using the Sino-Nasal Outcome Test 
(SNOT-22). (Efficacy) 
12. To evaluate rimegepant compared to placebo on the Sino-Nasal Outcome Test (SNOT-22) 
score at 24 hours post-dose. (Efficacy) 
13. To evaluate the safety and tolerability of rimegepant in the acute treatment of chronic 
rhinosinusitis as measured by the frequency of adverse events of moderate or severe 
intensity, serious adverse events (SAEs), clinically relevant laboratory abnormalities, and 
nasal inspection abnormalities. (Safety) 
14. To evaluate rimegepant compared to placebo for the Columbia Suicide Severity Rating Scale 
(C-SSRS). (Safety) 
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3.2 
Estimands 
An estimand is the target of estimation to address the scientific question of interest posed by a 
study objective. The five attributes of an estimand include the treatment, population of interest, 
variable of interest, population-level summary of the variable, and specification of how 
intercurrent events are reflected in the scientific question of interest. 
For all objectives, the population of interest is defined through appropriate inclusion/exclusion 
criteria to reflect the targeted patient population for approval.  Refer to the protocol for 
inclusion/exclusion criteria. 
Intercurrent Events 
Intercurrent events are those that occur after treatment initiation and either preclude observation 
of the endpoint or affect its interpretation.  Use of non-study rescue medications on or before the 
time point of interest is considered an intercurrent event; intercurrent events are discussed in 
Table 1, Table 2 and Table 3 as applicable. 
Refer to the specific sections below for additional detail on estimands for each endpoint.  Refer 
to Section 4.1 for analysis sets that are used to assess endpoints. The treatment for all estimands 
is Rimegepant formulated in a 75 mg ODT (placed on or under the tongue) or a matching 
placebo. 
3.2.1 
Primary Objective Estimand 
Table 1: 
Primary Objective Estimand 
Population  
CRS with and without nasal polyps. 
Variable 
Change from baseline in facial pain/pressure/fullness NRS score to 2 hours post-dose. 
Population-Level 
Summary 
Difference in mean change from baseline and 95% CI in the pain/pressure/fullness 
NRS score between the rimegepant and placebo groups at 2 hours post-dose.   
Intercurrent Events 
1)  Use of non-study rescue medications on or before 2 hours post-dose 
Hypothetical strategy: In the event a subject uses a non-study rescue medication on or 
before 2 hours post-dose, all data points after rescue medication was administered are 
set to missing.  It is assumed that, had the subject not used a non-study rescue 
medication, their efficacy would have been similar to the efficacy of subjects from the 
same treatment group who did not use rescue medication.   
2) All other intercurrent events 
Treatment policy strategy:  All available assessments on the subject are used 
regardless of other intercurrent events. 
3.2.2 
Secondary Objective Estimands 
Table 2: 
Secondary Objective Estimands 
1 
Population  
CRS with and without nasal polyps. 
 
Variable 
Change from baseline in TNSS to 2 hours post-dose. 
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Population-Level 
Summary 
Same as that of primary estimand, with respect to TNSS. 
 
Intercurrent 
Events 
Same as that of primary estimand. 
2 
Population  
CRS with and without nasal polyps. 
 
Variable 
Change from baseline of nasal obstruction (congestion) NRS score to 2 hours post-dose. 
 
Population-Level 
Summary 
Same as that of primary estimand, with respect to nasal obstruction (congestion) NRS 
score. 
 
Intercurrent 
Events 
Same as that of primary estimand. 
3 
Population  
CRS with and without nasal polyps. 
 
Variable 
Change from baseline of nasal discharge NRS score to 2 hours post-dose. 
 
Population-Level 
Summary 
Same as that of primary estimand, with respect to nasal discharge NRS score. 
 
Intercurrent 
Events 
Same as that of primary estimand. 
4 
Population  
CRS with and without nasal polyps. 
 
Variable 
Percentage of subjects reporting a pain level of moderate or severe at baseline in the 
eDiary that experience headache pain relief at 2 hours post-dose.  
Headache pain relief is defined as a headache pain level of none or mild at 2 hours post-
dose for subjects who reported a baseline pain level of moderate or severe at baseline. 
 
Population-Level 
Summary 
The difference and 95% CI in the percentage of subjects that experience headache pain 
relief at 2 hours post-dose between the rimegepant and placebo groups.   
 
 
Intercurrent 
Events 
1)  Use of non-study rescue medications on or before 2 hours post-dose 
Composite strategy: Subjects who use rescue medication on or before assessment of 
pain at 2 hours are imputed as a failure.   
2) Failure to report eDiary assessments at 2-hours post-dose 
Composite strategy: Subjects with missing data at 2 hours post-dose are imputed as a 
failure.   
3) All other intercurrent events: 
Treatment policy strategy:  All available assessments on the subject are used regardless 
of other intercurrent events. 
5 
Population  
CRS with and without nasal polyps. 
 
Variable 
Percentage of subjects that use rescue medication within 24 hours after administration 
of study drug.    
Subjects who do not report rescue medication use between 0 and 24 hours post-dose are 
deemed successes; subjects who report rescue medication use between 0 and 24 hours 
post-dose are deemed failures. 
 
Population-Level 
Summary 
Same as that of secondary endpoint #4 (headache pain relief), except analysis is not 
limited to subjects who reported a baseline pain level of moderate or severe at baseline.  
Subjects who fail to include rescue medication time on all reported rescue medications 
are excluded from the analysis.  
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Intercurrent 
Events 
Treatment policy strategy:  All available assessments on the subject are used regardless 
of intercurrent events.  
 
3.2.3 
Exploratory Objective Estimands 
Table 3: 
Exploratory Objective Estimands 
1 
Population  
CRS with and without nasal polyps. 
 
Variable 
The percentage 
pain/pressure/fullness NRS (0-10) score at 2 hours post-dose. 
-10) 
score at 2 hours post-dose. 
 
Population-Level 
Summary 
Same methodology as secondary endpoint #4 (headache pain relief), and analysis is not 
limited to subjects who reported a baseline pain level of moderate or severe at baseline.  
 
Intercurrent 
Events 
Same as that of secondary endpoint #4 (headache pain relief). 
2 
Population  
CRS with and without nasal polyps. 
 
Variable 
The percentage 
50% reduction from baseline of facial 
pain/pressure/fullness NRS (0-10) score at 2 hours post-dose. 
reduction from baseline in facial pain/pressure/fullness NRS (0-10) 
score at 2 hours post-dose
 
Population-Level 
Summary 
Same as that of secondary endpoint #4 (headache pain relief), and analysis is not limited 
to subjects who reported a baseline pain level of moderate or severe at baseline.  
 
Intercurrent 
Events 
Same as that of secondary endpoint #4 (headache pain relief). 
3 
Population  
CRS with and without nasal polyps. 
 
Variable 
Change from baseline in facial pain/pressure/fullness NRS score to 15, 30, 45, 60, 90 
minutes and 2, 4, 8 and 24 hours post-dose in evaluable subjects. 
 
Population-Level 
Summary 
Same as that of the primary endpoint, except all scheduled time points are included in 
the model and reported.  
 
Intercurrent 
Events 
1)  Use of non-study rescue medications on or before 24 hours post-dose 
Hypothetical strategy: In the event a subject uses a non-study rescue medication on or 
before 24 hours post-dose, all data points after rescue medication was administered are 
set to missing.  It is assumed that, had the subject not used a non-study rescue 
medication, their efficacy would have been similar to the efficacy of subjects from the 
same treatment group who did not use rescue medication.   
2) All other intercurrent events: 
Treatment policy strategy:  All available assessments on the subject are used regardless 
of other intercurrent events. 
4 
Population  
CRS with and without nasal polyps. 
 
Variable 
Change from baseline in nasal obstruction (congestion) NRS (0-10) score to 15, 30, 45, 
60, 90 minutes and 2, 4, 8 and 24 hours post-dose in evaluable subjects.  
 
Population-Level 
Summary 
Same as that of exploratory endpoint #3, with respect to nasal obstruction (congestion) 
NRS score.  
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Intercurrent 
Events 
Same as that of exploratory endpoint #3. 
5 
Population  
CRS with and without nasal polyps. 
 
Variable 
Change from baseline in nasal discharge NRS score to 15, 30, 45, 60, 90 minutes and 2, 
4, 8 and 24 hours post-dose in evaluable subjects.  
 
Population-Level 
Summary 
Same as that of exploratory endpoint #3, with respect to nasal discharge NRS score.  
 
Intercurrent 
Events 
Same as that of exploratory endpoint #3. 
6 
Population  
CRS with and without nasal polyps. 
 
Variable 
Percentage of subjects reporting a pain level of moderate or severe at baseline in the 
eDiary that experience headache pain relief, at each post-dose time point. 
 
Population-Level 
Summary 
The difference in the percentage of subjects that experience headache pain relief at each 
post-dose time point between the rimegepant and placebo groups, using Mantel-
Haenszel risk estimation, for subjects with a headache pain level of moderate or severe 
at baseline.  Headache pain relief is defined as a headache pain level of none or mild at 
the time point in question for evaluable subjects.  
 
Intercurrent 
Events 
1)  Use of non-study rescue medications on or before the time point in question: 
Composite strategy: Subjects who use rescue medication on or before assessment of 
pain at the time point in question are imputed as a failure.   
2) Failure to report eDiary assessments at the time point in question:  
Composite strategy: Subjects with missing data at the time point in question are 
imputed as a failure.   
3) All other intercurrent events: 
Treatment policy strategy:  All available assessments on the subject are used regardless 
of other intercurrent events. 
7 
Population  
CRS with and without nasal polyps. 
 
Variable 
Number and percentage of subjects in each of the 7 PGI-C improvement categories 
(very much improved to very much worse) relative to the baseline visit at 24 hours post-
dose.  
 
Population-Level 
Summary 
Frequency at 24 hours post-dose in PGI-C score by treatment group with PGI-C data, 
along with 2-sided exact Clopper-Pearson 95% CIs for each percentage. 
 
Intercurrent 
Events 
Treatment policy strategy:  All available assessments on the subject are used regardless 
of intercurrent events. 
8 
Population  
CRS with and without nasal polyps. 
 
Variable 
Same as that of exploratory endpoint #1, with respect to 24 hours post-dose. 
 
Population-Level 
Summary 
Same as that of exploratory endpoint #1, with respect to 24 hours post-dose. 
 
Intercurrent 
Events 
Same as exploratory endpoint #1, except subjects with missing data at 24 hours post-
dose and subjects who used rescue medication prior to the assessment at 24 hours post-
dose are deemed failures. 
9 
Population  
CRS with and without nasal polyps. 
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Variable 
Same as that of 
pain/pressure/fullness on NRS (0-10) score at 24 hours post-dose. 
 
Population-Level 
Summary 
Same as that of exploratory endpoint #1, with respect to 
 facial 
pain/pressure/fullness on NRS (0-10) score at 24 hours post-dose. 
 
Intercurrent 
Events 
Same as that of exploratory endpoint #1, except subjects with missing data at 24 hours 
post-dose and subjects who used rescue medication prior to the assessment at 24 hours 
post-dose are deemed failures. 
10 
Population  
CRS with and without nasal polyps. 
 
Variable 
The percentage of subjects that achieve sustained relief of facial pain/pressure/fullness. 
 
Population-Level 
Summary 
Same as that of exploratory endpoint #1, separately with respect to each component of 
sustained relief of facial pain/pressure/fullness. 
 
Intercurrent 
Events 
Same as that of exploratory endpoint #1, separately with respect to each component of 
sustained relief of facial pain/pressure/fullness.  
11 
Population  
CRS with and without nasal polyps. 
 
Variable 
Change from baseline in the SNOT-22 total score and domain scores. 
 
Population-Level 
Summary 
Difference in change from baseline in the SNOT-22 total score between the rimegepant 
and placebo treatment groups, and separately for each domain score, using an analysis 
of covariance (ANCOVA) model.  
 
Intercurrent 
Events 
Treatment policy strategy:  All available assessments on the subject are used regardless 
of intercurrent events. 
12 
Population  
CRS with and without nasal polyps. 
 
Variable 
Number and percentage of subjects with C-SSRS responses in the C-SSRS categories 
and sub-categories.  
 
Population-Level 
Summary 
Frequency by treatment group as outlined in the Core SAP. 
 
Intercurrent 
Events 
Treatment policy strategy:  All available assessments on the subject are used regardless 
of intercurrent events. 
 
4 ANALYSIS SETS, TREATMENT GROUPS, AND SUBGROUPS 
4.1 
Analysis Sets 
The following analysis sets are evaluated and used for presentation and analysis of the data and 
estimands: 
Enrolled: Subjects who signed the informed consent form and were assigned a subject 
identification number by the IWRS; i.e., nonmissing informed consent date.  This analysis set 
is used mainly to assess study population and in by-subject listings. 
Full: Enrolled subjects who were assigned a randomized treatment group; i.e., nonmissing IWRS 
randomization date. This analysis set is used mainly to assess study population. 
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Safety: Enrolled subjects who took study therapy (rimegepant or placebo); i.e., nonmissing study 
drug start date.  This analysis set is used to assess study population, exposure, and on-
treatment safety, and produce select by-subject listings. 
Modified Intent to Treat (mITT): Randomized subjects that take study therapy, have a facial 
pain/pressure/fullness which reaches pain intensity of  6 on the NRS (0-10) prior to 
administration of treatment, and provide at least one post-baseline efficacy data point in the 
eDiary.   
For clarity, subjects who mistakenly dose (see Section 6.2.6.1) are not included in the mITT 
analysis set but are included in the safety analysis set.  
4.2 
Treatment Groups 
The two treatment groups are rimegepant 75 mg and placebo. The safety analysis set is assessed 
by the as-treated treatment group (i.e., actual treatment received); the full and mITT analysis sets 
are assessed by as-randomized treatment group; and the enrolled analysis set is assessed overall.  
If there are non-
 
4.3 
Subgroups 
Stratification factor (presence of nasal polyps; yes or no), as randomized, is a subgroup of 
interest for the mITT analysis set. Refer to Sections 6.3.3.1 for more detail. All p-values from the 
subgroup analyses will be considered nominal.  For the subgroup analysis by stratification 
factor, stratification factor will be removed as a covariate from the model as appropriate.     
5 SAMPLE SIZE, POWER, AND TYPE I ERROR 
If 72% of the 250 randomized (125 per treatment arm) have a facial pain/pressure/fullness which 
-10) in the allotted time period, and complete their 
eDiary in the 24 hours following, we expect roughly 180 total or 90 per treatment group in the 
modified intent to treat (mITT) population for analysis. 
Assuming rimegepant provides a 2-point reduction in NRS pain, and a 1.35-point advantage over 
placebo on the primary endpoint, and a common standard deviation of 3.0, then the study will 
have roughly 85% power on the primary endpoint. The estimates for change from baseline in 
NRS and common standard deviation are consistent with a modest reduction in pain over placebo 
and a conservative standard deviation estimate, as these varied widely in previous studies 
examining CRS. 
Table 4: 
Sample Size and Power Considering Different Drop Out Rates 
Drop Out  
Rate* (%)
Randomized 
Subjects
Evaluable (mITT) 
Subject 
Power (%) 
25 
214
160
80.8
228
170
83.1
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240 
180 
85.1 
254 
190 
87.0 
268 
200 
88.6 
30 
230 
160 
80.8 
244 
170 
83.1 
258 
180 
85.1 
272 
190 
87.0 
286 
200 
88.6 
* Drop out rate: Percentage of randomized subjects who failed to move to mITT analysis set. 
5.1 
Hierarchical Testing Strategy 
 
If the primary endpoint test is significant, then secondary endpoints are evaluated using a 
hierarchical gate keeping procedure, with each test in the hierarchy conducted at 5% level (or 
one sided 2.5% level). For hierarchical testing, the p-
over entire population for each objective will be used (i.e., p-value from sub-groups will not be 
considered). All analyses will be conducted on the mITT population. 
 
The order of the endpoints in the hierarchy is shown below through a schematic diagram: 
 
Figure 2: Hierarchical Gate Keeping Procedure 
 
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Thus, a secondary endpoint is tested only if the preceding secondary endpoint in the hierarchy is 
determined to be significant.  Descriptive p-values are provided for any non-significant 
secondary endpoints and comparative exploratory endpoints. 
No attempt is made to adjust for multiplicity when testing the exploratory endpoints.  Any 
exploratory endpoints subjected to significance testing are evaluated at an unadjusted two-sided 
alpha level of 5% (or one sided 2.5%).  
 
6 STATISTICAL ANALYSES 
All statistical analyses are performed using SAS statistical software (Version 9.4 or higher).  
6.1 
General 
6.1.1 
Programmed Output 
A list of TLFs and corresponding templates, attributes, and programming notes are presented 
separately in a mock TLF document corresponding to this SAP. 
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Refer to the Core SAP for additional details about programmed output.    
Adverse event (AE), medical history, medications, and procedures are coded using Medical 
Dictionary for Regulatory Activities (MedDRA) v. 26.1 and World Health Organization-Drug 
Dictionary (WHO-DD) version September 2023 B3.      
6.1.1.1 
Tables 
Treatment Group Presentation 
Tables present results by treatment group (i.e., rimegepant 75 mg and placebo) with the 
following exceptions: 
 Results for the enrolled analysis set are presented only by overall, without treatment group. 
 Results for study population parameters (see Section 6.2) and pre-treatment safety also 
include overall. 
6.1.1.2 
Listings 
In general, by-subject listings are sorted by randomization status (randomized, not randomized), 
which is not displayed, followed by site-subject ID and visit and/or date/time, as applicable.  
Unless specified otherwise, listings of significant protocol deviations, safety parameters, efficacy 
parameters, and COVID-19 visit impact include the following: analysis visit or assessment in 
which the measurement was slotted (where applicable); event or finding date/time (where 
applicable); and study day and/or treatment day derived using the event or finding date/time (see 
Section 7.2 of the Core SAP).  Listings of significant protocol deviations, safety parameters, and 
COVID-19 visit impact also include the abbreviated name of the analysis period in which the 
measurement was slotted (i.e., PRETRT for pre-treatment and ONTRT for on-treatment; see 
Section 7.2).  
Refer to the Core SAP for additional details about listings.  The footnote for race abbreviations is 
provided in Section 3.6.2 of the Biohaven Pharmaceuticals Holding Company Limited 
Biostatistics Global TLF Standards
. 
6.1.2 Statistical Methods 
Refer to the Core SAP for descriptive statistics in summary tables, counting rules in frequency 
tables, and rounding rules.  
Notwithstanding Section 7.6 of the Core SAP, age in all instances is age recorded on the case 
report form (CRF).  
6.1.3 Handling of Missing Data 
All safety analyses are based on observed data without using imputation, except that partial or 
missing start and stop dates or datetimes for non-study medications and AEs are imputed solely 
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for purposes of categorizing the events.  See Section 7.1.2 for the imputation of partial or 
missing non-study medications and AE dates (except rescue medications). 
The number and percentage of subjects in the mITT analysis set with missing efficacy data at 
each relevant time point will be tabulated for the following endpoints: facial 
pain/pressure/fullness NRS, nasal obstruction (congestion) NRS, nasal discharge NRS, TNSS, 
headache pain relief, SNOT-22 total score, and PGI-C. 
Missing efficacy data are handled in the respective subsections of Section 6.3.  
6.2 
Study Population 
6.2.1 
Analysis Sets 
The number of subjects in each analysis set described in Section 4.1 is tabulated by treatment 
group (as-randomized for the full and mITT analysis sets; as-treated for the safety analysis set), 
not randomized, and overall.  
A by-subject listing of analysis sets is provided for the enrolled analysis set, and an 
administrative listing of randomization scheme and codes is provided for the full analysis set. 
Refer to the Core SAP for listing contents. 
6.2.2 
Enrollment 
Enrollment by country and site is tabulated for the enrolled analysis set.  Refer to the Core SAP 
for additional details. 
6.2.3 
Subject Disposition 
6.2.3.1 
Subject Disposition at Study Milestones 
Subject disposition is based on the Disposition CRF, unless noted otherwise.  
A separate subject disposition table is provided for study milestones and analysis 
sets, as specified below: 
 Enrollment to randomization for the enrolled analysis set.  This includes the number and 
percentage of enrolled subjects randomized, not randomized (i.e. screen failures) with 
reasons for screen failure, and re-screened (including randomized following re-screening 
and screen failures following re-screening).  For subjects whose reason is screen failure 
due to inclusion/exclusion criteria, the reason(s) for screen failure from the 
Inclusion/Exclusion Criteria CRF are also included as subcategories, and for this display, 
subjects may be counted in more than one category of inclusion/exclusion criteria. 
Subjects who have re-screened and were later randomized are included in the number of 
randomized subjects and are not counted under the number of screen failures. 
 
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 Randomization to treatment for the full analysis set. This includes the number and 
percentage of subjects who took study drug and did not take study drug with reasons for 
discontinuation. In addition, the number and percentage of subjects who completed the 
study without being treated, and the derived reason, are summarized.  
 
 Treatment to completion/discontinuation for the safety and mITT analysis sets.  
This includes the number and percentage of treated subjects completing the 
Disposition CRF) and not 
completing the study with reasons for non-completion, including whether or not 
the subject discontinued due to COVID-19. 
A by-subject listing of subject disposition is provided for the enrolled analysis set based on the 
Disposition CRF and includes the following: date randomized (as applicable), an indication 
whether the subject was re-screened, previous subject ID, date/time the study drug was 
administered (as applicable), an indication whether the subject completed the study (yes, no), 
reason for discontinuation if applicable (including an indication if the subject discontinued due to 
COVID-19), and last contact date (see Section 7.1.3).  Notwithstanding Section 6.2.3 of the Core 
SAP, disposition listings will not be provided separately for each phase, and study milestone 
parameters will not be included. 
A listing would be provided for all visits and assessments impacted by COVID-19 for the 
enrolled analysis set.  The listing would include the visits and assessments that were impacted by 
COVID-19, impact (e.g. missed), and relationship to COVID-19 (e.g. subject diagnosed with 
COVID-19).    
6.2.3.2 
Overall Premature Study Termination due to COVID-19 
 
Notwithstanding Section 6.2.3.2 of the Core SAP, a frequency table of overall premature study 
termination due to COVID-19 will not be produced.  
 
6.2.4 Protocol Deviations 
6.2.4.1 
Relevant Protocol Deviations 
A relevant protocol deviation is a deviation from the protocol which is programmed from the 
database and which could potentially affect the interpretability of the study results.  This type of 
deviation includes but is not limited to:  
 Eligibility 
 Subject management 
For purposes of identifying relevant protocol deviations related to medication use, partial or 
missing non-study medication dates are imputed as set forth in Section 7.1.2.  Medical history 
dates are not imputed; however, ongoing medications with partial start dates will be considered 
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ongoing for purposes of categorizing relevant protocol deviations related to medical history if the 
partial date(s) are consistent with the medication being ongoing at the time of Screening, or as 
specified in the relevant protocol deviation criteria (see Section 9.1 for further detail).  
Relevant Protocol Deviation Frequency Table 
The frequency table of relevant protocol deviations displays the number and percentage of 
subjects in deviation categories and subcategories by deviation type (e.g., eligibility, subject 
management) for the full, mITT, and safety analysis sets. Categories and subcategories are 
displayed in the order provided in specified in Section 9.1.  Results are displayed for all 
deviations, even those with 0 counts, unless otherwise specified.  See Section 6.2.4.1 of the Core 
SAP for further details. 
Relevant Protocol Deviation Listing 
The by-subject listing of relevant protocol deviations is provided for the enrolled analysis set. 
This includes deviation type, category, and subcategories, which are additional sorting variables. 
Footnotes describe the medical dictionary and the drug dictionary as applicable. 
6.2.4.2 
Significant Protocol Deviations 
Significant protocol deviations are those with major severity reported by sites in the clinical trial 
management system. 
The by-subject listing of significant protocol deviations is provided for the enrolled analysis set. 
This includes the date of deviation, date identified, whether the deviation is IRB reportable, date 
reported to IRB, study day, treatment day, category, subcategory, description, and resolution.  
 
6.2.5 Baseline Characteristics 
Baseline characteristics include (1) demographics and other relevant baseline characteristics, (2) 
baseline disease characteristics (i.e., CRS History, CRS/Nasal Polyp surgical history), (3) 
medical history, and (4) prior non-study medications.  These are tabulated for the safety and 
mITT analysis sets.  
By-subject listings are provided for the enrolled analysis set for the following: demographics, 
medical history, CRS history, and CRS/Nasal Polyp surgical history.  Alcohol use and smoking 
history will be listed for the enrolled analysis set.  
See Section 7.5 for the derivation of the baseline value for a parameter (e.g., weight). 
6.2.5.1 
Demographics and Other Relevant Baseline Characteristics 
Refer to the Core SAP (Section 6.2.5.1) for the table of demographics and other relevant baseline 
characteristics, with the following adjustments: 
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Experiences menstrual periods, if female  is not tabulated, as this data is not collected. 
 Country is not tabulated. 
 Triptan non-responders and cardiovascular risk factors contraindicating triptans are not 
tabulated, as these data are not directly collected. 
 
is not included as a race category. 
 Previous study participation is not tabulated, as this does not apply to these study 
subjects. 
Randomization Stratum Frequency Table 
A frequency table of randomization stratum displays the number and percentage of subjects in 
each randomization stratum for the full and mITT analysis sets to confirm whether balance was 
achieved across treatment groups.  
Demographics Listing 
Refer to Section 6.2.5.1 of the Core SAP for specifications on the demographics listings, with the 
following adjustment: 
 
-
 is not included in the listings. 
6.2.5.2 
Baseline Disease Characteristics 
With respect to reporting baseline disease characteristics, Section 6.2.5.2 Baseline Disease 
Characteristics
Core SAP does not apply in its entirety; the following applies instead. 
CRS/Nasal Polyp Surgical History 
 
Results are based on the Chronic Rhinosinusitis/Nasal Polyp Surgical History CRF.   
 
CRS/nasal polyp surgical history is tabulated and includes the following parameters summarized 
as categorical or continuous variables, as applicable.  The table includes 
For each category, the denominator is the number of subjects in the relevant 
population. 
 History of functional endoscopic sinus surgery (FESS)  
o Number of FESS  for subjects with a history of at least one (categorical) 
 History of nasal polyp surgery 
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o Number of nasal polyp surgeries for subjects with a history of at least one 
(categorical) 
 History of prior steroid eluting sinus stent placement  
 History of nasal septum surgery  
o Number of nasal septum surgeries for subjects with a history of at least one 
(categorical) 
 History of rhinoplasty surgery 
o Number of rhinoplasty surgeries for subjects with a history of at least one 
(categorical) 
 
A by-subject listing of CRS/nasal polyp surgical history is provided for enrolled subjects 
and includes the date of most recent surgery for the applicable surgeries. 
  
CRS History 
 
Results are based on the Chronic Rhinosinusitis (CRS) History CRF.   
 
CRS history is tabulated and includes the following parameters summarized as categorical or 
continuous variables, as applicable.  The table includes 
For each high-
level category listed below (e.g. the denominator for history of aspirin-exacerbated respiratory 
disease), the denominator is the number of subjects in the population.  For each low-level 
category listed below, the denominato
corresponding high-level category.  (For example, the denominator for each subtype of aspirin-
-
exacerbated respiratory disease).  
 History of aspirin-exacerbated respiratory disease  
o Subtype of aspirin-exacerbated respiratory disease (Class 1, Class 2, Class 3, 
Class 4, unknown) 
o Prior desensitization therapy   
 History of asthma (yes/no) 
o Active or inactive asthma 
o Severity (intermittent, mild, moderate, severe) 
 Prior history (not current) of invasive fungal sinusitis  
 Current allergic rhinitis 
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 Inadequate response to vaccines 
 Sinus CT scan in the past 12 months 
o Most recent Lund-MacKay CT score (if available) 
o Most recent Lund-MacKay score not available 
 Nasal endoscopy in the past 12 months 
o Nasal endoscopic polyp score (if applicable): 
o Nasal endoscopic polyp score is not applicable 
 Treated with systemic corticosteroid courses in the past 12 months for treatment of CRS-
associated symptoms 
o Number of courses of treatment in the past 12 months (categorical) 
 CRS diagnosis met (yes/no) 
o Facial pain/pressure/fullness  3 month history 
o Nasal obstruction (congestion)  3 month history 
o Nasal discharge (anterior, posterior, or both)  3 month history 
o Decreased sense of smell  3 month history 
o Endoscopic findings of mucopurulent drainage (not clear) or edema in the middle 
or superior meatus, or anterior ethmoid region  within 12 months 
o Polyps in nasal cavity or the middle or superior meatus  within 12 months 
o Radiographic imaging showing inflammation of the paranasal sinuses with partial 
opacification of at least two sinuses or complete opacification of at least one 
sinus  within 12 months 
 Number of instances CRS-associated facial pain/pressure/fullness reached moderate or 
severe intensity on a 4-point rating scale (0 = None, 1 = Mild, 2 = Moderate, 3 = Severe) 
in the past 30 days. 
 
A by-subject listing of CRS history is provided for enrolled subjects and includes date(s) 
of applicable procedures if available; CRS diagnostic criteria are separately listed. 
6.2.5.3 
Medical History 
Refer to the Core SAP (Section 6.2.5.3) for medical history.   
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6.2.5.4 
Non-Study Prior Medications  
The following prior non-study medications are tabulated by therapeutic class and preferred name 
for the safety analysis set: 
 Previous medications 
 Current medications 
 Stable CRS medications through completion or discontinuation of the study  
The definitions of medication types in Section 6.2.6.3 of the Core SAP, as applicable to single-
dose studies, applies.  For clarity, prior (previous and current) medications do not include rescue 
medications (see Section 6.2.6.3).   
Medications are displayed in descending order of overall frequency within therapeutic class and 
preferred name.  See Section 6.2.6.3 for further detail on medication types. 
Stable CRS medications through Screening are defined as CRS medications taken > 1 month 
before informed consent and through completion or discontinuation of the study, with no change 
in dose amount or frequency, i.e., (1) informed consent date  imputed medication start date > 30 
days, and (2) completion or discontinuation  imputed medication stop date, with no change in 
dose amount or frequency.  For purposes of this analysis, CRS medications is defined as follows: 
 Saline and other non-medicated spray/rinse (additives such as detergents, moisturizers, 
and mucolytics)  
 Topical nasal corticosteroids (spray or rinse) 
 Topical nasal antibiotics and antifungal medications (spray or rinse) 
 Topical nasal antihistamines (non-sedating) 
 Topical nasal cromolyn 
 Leukotriene modifiers 
 Cromolyn (oral or inhalation) 
 Methylxantines (e.g., theophylline, aminophyllines) 
 Mucoactive agents (e.g., guaifenesin, acetylcysteine) 
 Any medication indicated for asthma or chronic obstructive pulmonary disease (COPD)  
6.2.6 
Exposure 
6.2.6.1 
Study Therapy 
Study drug is dispensed in a subject-specific bottle containing one blister unit of drug. Exposure 
is measured by subjects providing self-reported study drug exposure information (see Section 
7.1).  As a check on this exposure data, study drug accountability data are provided on the Drug 
Accountability CRF. 
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The date/time of exposure is defined in Section 7.1.  
The self-reported study drug exposure data are tabulated by treatment group and overall for 
subjects in the full analysis set and includes: 
 The number (and percentage) of subjects in the full analysis set that took study 
medication 
o The number and percentage who mistakenly took drug.  A medication is deemed 
taken mistakenly if 
 
Initial facial pain/pressure/fullness  eDiary, or 
if the subject reported having mistakenly taken drug to the site without interacting 
with the eDiary.   
o The number and percentage that took study medication immediately after 
providing a qualifying facial pain/pressure/fullness NRS score (  6) (i.e. the 
Please confirm you took your Study 
Medication
 eDiary. 
 The number and percentage of subjects in the full analysis set who never reported taking 
study medication 
Subjects who mistakenly take drug are included in safety analyses but excluded from efficacy 
analyses. 
An administrative listing of investigational product (IP) batch numbers is provided for the 
randomized analysis set.  Refer to the Core SAP for listing contents. 
6.2.6.2 
Measurements of Treatment Compliance  
Section 6.2.6.2 of the Core SAP does not apply. 
The study drug accountability data are tabulated by treatment group and overall for subjects in 
the full analysis set and includes: 
 The number and percentage of randomized subjects to whom kits were dispensed 
 The number and percentage of randomized subjects who returned kits 
o The number and percentage of subjects with returned kits from which the IP was 
used 
o The number and percentage of subjects with returned kits from which the IP was 
not used 
o The number and percentage of subjects with returned kits from which IP use not 
reported (i.e., missing) 
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 The number and percentage of subjects who did not return kits 
 The number and percentage of subjects who did not report returning kit (i.e., missing) 
A cross-tabulation of exposure and accountability data is prepared.  This is done overall for 
subjects in the full analysis set and separately for subjects in the mITT analysis set who had a 
qualifying facial pain/pressure/fullness NRS score.  For the accountability data, the categories 
are: took IP, did not take IP, and unknown (if applicable); for the exposure data, the categories 
are: took IP, did not take IP, and unknown (if applicable). 
A by-subject listing is prepared that indicates the study drug exposure and accountability status 
for the full analysis set; this listing includes study drug start date/time and study day, whether or 
not the exposure was recorded in the eDiary or drug was mistakenly taken, drug accountability 
kit dispensed date, kit returned date, kit ID, and IP used status (IP taken, IP not taken), and 
number of tablets dispensed and returned. A patient identifier listing is prepared if subjects had 
unknown exposure data, unknown accountability data, or for whom the exposure and 
accountability data did not match. 
6.2.6.3 
Concomitant and Rescue Medications  
Concomitant non-study medications are tabulated by therapeutic class and preferred name for the 
safety analysis set.  The definition of concomitant medication in Section 6.2.6.3 of the Core SAP, 
as applicable to single-dose studies, applies.  For clarity, concomitant medications include both 
medications recorded on the Concomitant Medications CRF that meet the definition of 
Core SAP) and all rescue medications (defined below).  
Sites are instructed to exclude medications reported on the Rescue Medication CRF from the 
Concomitant Medications CRF.    
Medications are displayed in descending order of overall frequency within therapeutic class and 
preferred name.  Refer to the Sections 6.2.6.3 of the Core SAP for non-study medication 
counting rules in frequency tables.  
A by-subject listing of non-study concomitant medications is provided for the enrolled analysis 
set.   
Rescue medications include any non-study medication recorded on the Rescue Medication CRF 
with complete medication dates, and either (1) medication date/time is after the study drug start 
date/time if the medication time and study drug start time are both not missing, or (2) medication 
date is on or after study drug start date if the medication time or study drug start time is missing. 
Rescue medication dates and times are not imputed.  Rescue medications are separately tabulated 
and displayed in descending order of overall frequency within therapeutic class and preferred 
name for the safety analysis set and separately for the mITT analysis set.  Any medication 
recorded on the Rescue Medication CRF that 
treated as a current or concomitant medication, as appropriate, based on the 
imputed medication start date. 
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A by-subject listing of non-study rescue medications is provided for the enrolled analysis set.  
The listing displays medication type and treatment days derived from the imputed start date.  For 
purposes of this listing, the start date/time of rescue medication use is the date/time of rescue 
medication use, and rescue medications are identified.  Refer to the Core SAP for additional 
listing contents, except AE and medical history terms are not included.   
Non-study medications are classified according to the World Health Organization Drug 
Dictionary (WHO-DD) and Anatomical Therapeutic Chemical (ATC) classification system B3 
global format (September 2023).  
6.3 
Efficacy 
Unless otherwise noted, all efficacy analyses are conducted using the mITT analysis set as 
outlined below.  Efficacy tabulations present results by as-randomized treatment group only 
(excluding overall), unless specified otherwise.  All efficacy data are included in listings by 
subject, treatment group, and time point (as applicable). 
Summary statistics (n, mean, median, SD, minimum, maximum) are reported for continuous 
variables (i.e. NRS scores, SNOT-22 scores, and PGI-C scores) at each time point, along with 
change from baseline, as applicable.   
6.3.1 
Overall Efficacy Summary 
Table 5 provides a summary of the statistical methods used for the primary, secondary, and 
exploratory endpoints.  
Unless otherwise noted, all efficacy analyses will be conducted using the mITT population.   
A by-subject listing of eDiary NRS results is provided for the full analysis set. 
 
 
 
 
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Table 5: 
Efficacy Endpoints and Analysis Methods 
 
 
 
Efficacy Endpoints 
 
Linear 
model 
 
Mantel-
Haenszel 
Cumulative 
logit model 
Descriptive 
only 
Primary 
 
 
 
 
 
Change from baseline in facial pain/pressure/fullness NRS 
score to 2 hours post-dose. 
 
X 
 
 
 
Secondary 
 
 
 
 
Change from baseline in TNSS to 2 hours post-dose 
X 
 
 
 
Change from baseline of nasal obstruction (congestion) NRS 
score to 2 hours post-dose 
X 
 
 
 
Change from baseline of nasal discharge NRS score to 2 hours 
post-dose. 
X 
 
 
 
Percentage of subjects reporting a pain level of moderate or 
severe at baseline in the eDiary that experience headache pain 
relief at 2 hours post-dose 
 
X 
 
 
Percentage of subjects that use rescue medication within 24 
hours after administration of study drug. 
 
X 
 
 
Exploratory 
 
 
 
 
reduction from baseline 
of facial pain/pressure/fullness NRS (0-10) score at 2 hours 
post-dose. 
 
 
X 
 
 
of facial pain/pressure/fullness NRS (0-10) score at 2 hours 
post-dose. 
 
X 
 
 
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Change from baseline in facial pain/pressure/fullness NRS 
score to 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 hours 
post-dose in evaluable subjects. 
X 
 
 
 
Change from baseline in nasal obstruction (congestion) NRS 
(0-10) score to 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 
hours post-dose in evaluable subjects. 
X 
 
 
 
Change from baseline in nasal discharge NRS score to 15, 30, 
45, 60, 90 minutes and 2, 4, 8 and 24 hours post-dose in 
evaluable subjects. 
X 
 
 
 
Percentage of subjects reporting a pain level of moderate or 
severe at baseline in the eDiary that experience headache pain 
relief, at each post-dose time point. 
 
X 
 
 
Number and percentage of subjects in each of the 7 PGI-C 
improvement categories (very much improved to very much 
worse) relative to the baseline visit at 24 hours post-dose. 
 
 
X 
 
of facial pain/pressure/fullness NRS (0-10) score at 24 hours 
post-dose. 
 
X 
 
 
50% reduction from baseline 
of facial pain/pressure/fullness NRS (0-10) score at 24 hours 
post-dose. 
 
 
X 
 
 
The percentage of mITT subjects that achieve sustained relief 
of facial pain/pressure/fullness. 
 
X 
 
 
Change from baseline in the SNOT-22 total score and domain 
scores. 
X 
ANCOVA 
 
 
 
Number and percentage of subjects with C-SSRS responses in 
the C-SSRS categories and sub-categories. 
 
 
 
X 
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6.3.2 
Rescue Medication 
Rescue medications are defined in Section 6.2.6.3.  For efficacy evaluations (except for the 
analysis set forth in Section 6.3.4.5), a rescue medication is considered used as of a given time 
point if the date/time of first rescue medication use is on or prior to the date/time of the efficacy 
evaluation or, if the eDiary assessment is missing at that time point, if the date/time of first 
Table 7.  For instance, if a subject receives rescue medication 2 hours and 5 minutes post-dose 
conducted at the 2 hours and 10 minute time point 
(within the protocol window), the subject is treated as having used rescue medication prior to the 
-
the subject is treated as having used rescue medication prior to the 
-
 (end of protocol 
window for 2 hour post-dose time point).  If the time of first rescue medication is missing, the 
rescue medication is considered used as of a given time point if the date of rescue medication is 
on or prior to the date of the efficacy evaluation.     
For efficacy evaluations, the first rescue medication date/time is defined as the earliest rescue 
medication date/time, where missing time is considered to be earlier than non-missing time on 
the same date. 
For clarity, assessments after rescue medication administration are not set to missing for 
purposes of calculating summary statistics, even when the assessments are set to missing for 
model evaluation, as specified in Sections 6.3.3, 6.3.4, or 6.3.5.  
6.3.3 
Primary Efficacy Endpoint 
6.3.3.1 
Primary Analysis 
Facial pain/pressure/fullness is assessed using an NRS score ranging in integers from 0 to 10, 
o facial pain/pressure/fullness
orst imaginable facial 
pain/pressure/fullness
     
Change from baseline in facial pain/pressure/fullness NRS score is analyzed on the mITT 
population using a linear model that includes the baseline NRS (0-10) value for facial 
pain/pressure/fullness as a covariate, and fixed effects for treatment group, stratification factor 
(presence of nasal polyps; yes or no), scheduled time point, and time point by-treatment group 
interaction.  Time points included in the model are nominally at 15, 30, 45, 60, 90, and 120 
minutes post-dose.  
Repeated measures within subject are modeled using the unstructured covariance structure for 
within subject error. In the case the model fails to converge, a Huynh-Feldt error structure is 
utilized, followed by an autoregressive (1) structure. Error degrees of freedom are calculated 
using the Kenward-Rogers approximation if an unstructured covariance structure fits 
appropriately; otherwise, a sandwich estimator is utilized to estimate the covariance structure, 
and the degrees of freedom are calculated using the between-within method.   
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Restricted maximum likelihood (REML) estimation is utilized; should the model fail to converge 
under REML, maximum likelihood estimation is utilized.  
The model will be repeated for the subgroup of the stratification factor, presence of nasal polyps 
(yes/no), excluding the stratification factor from the model. Only the overall p-value will be 
considered in hierarchical testing. 
Least squares (LS) means, standard errors (SE), 95% confidence interval (CI) are reported for 
each treatment group at 2 hours post-dose, along with LS mean difference estimate (rimegepant - 
placebo) and associated SE, 95% CI and p-value. The LS mean change from baseline is also 
plotted over time. 
In the event a subject uses a non-study rescue medication prior to or at 2 hours post-dose, all 
assessments after rescue medication administration are set to missing (RM = M: Rescue 
medication use = Missing).  If the time of first rescue medication is missing but the date of 
rescue medication is the same as the date of dosing, all data points after baseline are set to 
missing (i.e. the subject is excluded from the analysis as they will not have evaluable post-
baseline data available).   
Likewise, if a subject fails to log their pain score after study drug is administered, through 2 
hours post-dose, this data is considered missing (NC = M: Non-completers = Missing). 
6.3.3.2 
Sensitivity Analyses 
The primary analysis of the primary endpoint assumes data are missing at random (MAR).  It 
further assumes that had the subjects not used a rescue medication, their efficacy would have 
been similar to the efficacy of subjects from the same treatment group who did.  The purpose of 
these sensitivity analyses is to investigate departures from these assumptions. 
The following sensitivity analyses are planned: 
 Jump to reference 
 Tipping Point 
Sensitivity analyses are not repeated by subgroup.  All sensitivity analyses are conducted on the 
mITT population. 
6.3.3.2.1 
Jump to Reference  
The purpose of this sensitivity analysis is to investigate the departure from the MAR assumption 
for the treatment group.  A reference-based multiple imputation (MI) approach is applied to 
missing data.  It assumes the treatment effect observed in rimegepant subjects with missing data, 
including subjects with missing data due to use of rescue medication, immediately trends 
towards the estimated mean in the placebo group. 
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Missing values in the placebo group and intermittent missing values in the rimegepant group (ie, 
due to subjects failing to log their pain score at one or more timepoints but resuming entering 
scores at a later timepoint) are assumed to be MAR, while terminal missing values in the 
rimegepant group (ie, due to subjects who ceased entering pain scores entirely, or who used 
rescue medication prior to 2 hours and have scores set to missing through 2 hours as described in 
Section 6.3.3.1) are assumed to be missing not at random (MNAR).  Specifically, it is assumed 
that subjects in the rimegepant group with terminal missing scores, including those who took 
rescue medication prior to 2 hours post-dose, would have had similar subsequent NRS scores to 
those in the placebo arm.  Terminal missing values in the rimegepant group are multiply imputed 
based on a distribution with estimated mean values at missing time points similar to that of 
subjects in the placebo group.  
The MI procedure includes the following steps:  
 Intermittent missing values are first imputed using the Markov Chain Monte Carlo 
(MCMC) method with the SAS MI procedure, which is appropriate for non-
monotonic missing data.   
 For rimegepant subjects, monotone missing values are then multiply imputed with the 
SAS MI procedure using the monotone regression method.  The MNAR option in 
PROC MI is used and references the placebo group for informing the imputation.  
The placebo arm subjects use the profile under MAR. 
 For each stage, MI is performed with covariates baseline NRS score, stratification 
factor, and non-missing NRS scores.  MI is performed within treatment group for the 
first stage. 
 Twenty imputations are performed.  
 The primary analysis described in Section 6.3.3.1 is implemented for each imputed 
dataset.   
 Results are combined to generate an overall estimate and associated variance using 
 (Rubin 1987). 
LS means, SEs, 95% CI are reported for each treatment group at 2 hours post-dose, along with 
LS mean difference estimate (rimegepant - placebo) and associated SE, 95% CI and p-value. 
6.3.3.2.2 
Tipping Point  
The purpose of this sensitivity analysis is to investigate the departure from the MAR assumption. 
Missing data in the placebo group and all intermittent missing data are assumed to be MAR, 
while terminal missing data from the rimegepant group are multiply imputed assuming that 
subjects with missing data have missing data 
subjects with observed data.  Missing values are multiply imputed via this method with 
 The primary efficacy outcome analysis methodology is applied to the 
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s rules (Rubin, 1987), and repeated until statistical 
significance no longer holds.   
The same MI methods in Section 6.3.3.2.1 are applied, except at the second stage, rather than 
implementing the MNAR option in PROC MI for the rimegepant group, monotone missing 
values are multiply imputed separately by treatment group under MAR.  However, a shift 
parameter is progressively added to imputed rimegepant scores to decrease the treatment 
difference until the p-value is >0.05.  The shift parameter starts at 0 and increases in increments 
of an absolute value of 0.25 points.  The increment(s) may be determined at the time of analysis, 
with the intent to refine the grid around the tipping points. 
The tipping point analysis is only performed if statistical significance is achieved in the primary 
analysis, in favor of rimegepant.  If the p-value is >0.05 with a shift parameter of 0, the analysis 
stops there.  
LS means, SEs, 95% CI are reported for each treatment group at 2 hours post-dose, along with 
LS mean difference estimate (rimegepant - placebo) and associated SE, 95% CI and p-value.  
Values are reported for each shift parameter until the p-value is >0.05.  
6.3.4 
Secondary Efficacy Endpoints 
If the primary endpoint test is significant, then the secondary endpoints are evaluated using a 
hierarchical gate-keeping procedure, with each test in the hierarchy conducted at p=0.05.  These 
secondary endpoints are tested in the following order. 
1. Change from baseline of TNSS at 2 hours post-dose  
2. Change from baseline of nasal obstruction (congestion) at 2 hours post-dose 
3. Change from baseline of nasal discharge at 2 hours post-dose  
4. Headache pain relief at 2 hours post-dose  
5. The probability of requiring rescue medication within 24 hours after administration of 
study medication  
Should any test in the hierarchy fail to achieve statistical significance, nominal p-values are 
reported for any subsequent tests. 
No sensitivity analyses are performed for secondary endpoints. 
6.3.4.1 
Total Nasal Symptom Score (TNSS) 
TNSS is calculated at each time point as the sum of 3 symptom scores: (1) facial 
pain/pressure/fullness; (2) nasal obstruction (congestion); and (3) nasal discharge, at the 
applicable time point. 
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The analysis in Section 6.3.3.1, including the subgroup analysis, is repeated for TNSS, except 
baseline TNSS value is included as covariate instead of baseline NRS score (facial 
pain/pressure/fullness).  
6.3.4.2 
Nasal Obstruction (Congestion) 
The analysis in Section 6.3.3.1, including the subgroup analysis, is repeated for the nasal 
obstruction (congestion) NRS score, except baseline nasal obstruction (congestion) NRS score is 
included as covariate instead of baseline facial pain/pressure/fullness NRS score.  
6.3.4.3 
Nasal Discharge 
The analysis in Section 6.3.3.1, including the subgroup analysis, is repeated for the nasal 
discharge NRS score, except baseline nasal discharge NRS score is included as covariate instead 
of baseline facial pain/pressure/fullness NRS score.  
6.3.4.4 
Headache Pain Relief 
The number and percentage of subjects that experience headache pain relief at 2 hours post-dose 
are analyzed after first imputing missing data at 2 hours to be failure (i.e., NC = F: Non-
Completers = Failure).  Additionally, subjects who use rescue medication on or before 
assessment of pain at 2 hours are also assigned as failures (RM = F: Rescue medication use = 
Failure).  If the time of first rescue medication is missing, subjects are considered as failures if 
the date of rescue medication is the same as the date of dosing.  
The analysis is done using Mantel-Haenszel risk estimation after imputation is done, with 
stratification by presence of nasal polyps (yes or no).  If one category of stratification factor has 
sparse data (less than 5 subjects), then the stratification factor is removed from the analysis.   
Headache pain is defined using a 4-point scale (0 = None; 1 = Mild; 2 = Moderate; 3 = Severe).  
Headache pain relief is defined as a headache pain level of none or mild at 2 hours post-dose, 
with a headache pain level of moderate or severe at baseline.  Note that only subjects with a 
headache pain level of moderate or severe at baseline are included in this analysis. 
Results presented from the analysis includes the following: 
 
asymptotic standard error (ASE), and 95% CI 
by randomization stratum for each treatment group 
 
 
 Percentage difference between treatment groups (rimegepant  placebo), ASE, 95% CI, 
and p-value by randomization stratum 
 Stratified percentage difference between treatment groups (rimegepant  placebo), ASE, 
95% CI, and p-value* 
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* P-value for comparison of stratified percentage difference between treatment groups will be 
used in hierarchical testing procedure.  
A forest plot is produced depicting the risk difference for headache pain relief at 2 hours post 
dose. The risk difference for each strata will be presented, as well as the overall common risk 
difference.  
A by-subject listing of headache pain is provided for the randomized analysis set. 
6.3.4.5 
Rescue Medication Use within 24 Hours 
The number and percentage of subjects that use rescue medication within 24 hours post-dose are 
analyzed.  Subjects who used rescue medication as of 24 hours post-dose are deemed failures, 
and subjects who did not use rescue medication as of 24 hours are deemed successes.  For 
clarity, failure is the event being modeled (i.e. rescue medication use within 24 hours) in this 
analysis. The p-value for comparison of stratified percentage difference between treatment 
groups will be used in hierarchical testing procedure.  
Refer to Section 6.2.6.3 for the definition of rescue medication.  A rescue medication would be 
deemed used as of 24 hours post-dose if the date/time of first rescue medication use is strictly  
24 hours after the date/time of dosing, notwithstanding Section 6.3.2 of the SAP.  If time of first 
rescue medication use is missing, a rescue medication would be deemed used as of 24 hours 
post-
+ one day).  This is 
handled analogously to Section 8.7 of the Core SAP.  
No analysis window around the 24-hour post dose time point is used. 
The analysis follows the same methodology set forth in Section 6.3.4.4.  A forest plot is 
produced depicting the risk difference for rescue medication use within 24 hours post dose. The 
risk difference for each strata will be presented, as well as the overall common risk difference.  
6.3.5 
Exploratory Efficacy Endpoints 
The following efficacy-related exploratory endpoints are planned.  Any p-values reported for 
exploratory endpoints are nominal.  
1. 
pain/pressure/fullness NRS (0-10) score at 2 hours. 
2. 
pain/pressure/fullness NRS (0-10) score at 2 hours. 
3. To evaluate the effect of rimegepant compared to placebo on change from baseline of facial 
pain/pressure/fullness NRS (0-10) score at 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 
hours post-dose. 
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4. To evaluate the effect of rimegepant compared to placebo on change from baseline of nasal 
obstruction (congestion) NRS (0-10) score at 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 
hours post-dose. 
5. To evaluate the effect of rimegepant compared to placebo on change from baseline of nasal 
discharge NRS (0-10) score at 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 hours post-dose. 
6. To evaluate the effect of rimegepant compared to placebo on headache pain relief using a 4-
point Likert scale at 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 hours post-dose compared 
to baseline. 
7. To evaluate rimegepant compared to placebo on the PGI-C questionnaire at 24 hours post-
dose. 
8. 
pain/pressure/fullness NRS (0-10) score at 24 hours. 
9. 
pain/pressure/fullness NRS (0-10) score at 24 hours. 
10. To evaluate rimegepant compared to placebo on sustained relief of facial 
pain/pressure/fullness, as defined by each of the following: 30% reduction from baseline on 
NRS (0-10), 1.5-point reduction on NRS (0-10), and a 2-point reduction on NRS (0-10) 
through 24 hours post-dose. 
11. To explore the distribution of baseline disease severity using the Sino-Nasal Outcome Test 
(SNOT-22). 
12. To evaluate rimegepant compared to placebo on the Sino-Nasal Outcome Test (SNOT-22) 
score at 24 hours post-dose. 
The following exploratory endpoints are discussed in Section 6.4. 
1. To evaluate the safety and tolerability of rimegepant in the acute treatment of chronic 
rhinosinusitis as measured by the frequency of adverse events of moderate or severe 
intensity, serious adverse events (SAEs), clinically relevant laboratory abnormalities, and 
nasal inspection abnormalities. 
2. To evaluate rimegepant compared to placebo for the Columbia Suicide Severity Rating Scale 
(C-SSRS). 
6.3.5.1 
Reduction from Baseline of Facial Pain/Pressure/Fullness NRS (0-
10) Score at 2 Hours 
The percentage 
of facial pain/pressure/fullness 
NRS score at 2 hours is analyzed using the methodology set forth in Section 6.3.4.4, with the 
following adjustments.  
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pain/pressure/fullness NRS (0-10) score at 2 hours post-dose are deemed successes.  Subjects 
with < 30% reduction from baseline in facial pain/pressure/fullness NRS (0-10) score at 2 hours 
post-dose are deemed failures.  Subjects with missing data at 2 hours post-dose and subjects who 
use rescue medication prior to the assessment at 2 hours post-dose are deemed failures as well.  
Figures will not be produced.  
6.3.5.2 
-
10) Score at 2 Hours 
The percentage 
of facial pain/pressure/fullness 
NRS score at 2 hours is analyzed and tabulated using the methodology set forth in Section 
6.3.5.1, with respect to  50% reduction from baseline. 
6.3.5.3 
Change from baseline of facial pain/pressure/fullness NRS (0-10) score at 
15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 hours post-dose  
Change from baseline in facial pain/pressure/fullness NRS (0-10) score is analyzed using the 
methodology set forth in Section 6.3.3.1, except time points 15, 30, 45, 60, 90 minutes and 2, 4, 
8 and 24 hours post-dose are included in the model.  Estimates from the model are reported for 
each time point.   
If a subject uses a rescue medication, all data points after rescue medication use is set to missing. 
A line graph is produced depicting the LS mean change from baseline in facial 
pain/pressure/fullness NRS score with 95% CI bars by planned timepoint .   
6.3.5.4 
Change from baseline of nasal obstruction (congestion) NRS (0-10) score 
at 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 hours post-dose  
Change from baseline in nasal obstruction (congestion) NRS (0-10) score at 15, 30, 45, 60, 90 
minutes and 2, 4, 8 and 24 hours post-dose is analyzed using the same methodology set forth in 
Section 6.3.5.3. 
A line graph is produced depicting the LS mean change from baseline in nasal obstruction 
(congestion) NRS score with 95% CI bars by planned timepoint .   
6.3.5.5 
Change from baseline of nasal discharge NRS (0-10) score at 15, 30, 45, 
60, 90 minutes and 2, 4, 8 and 24 hours post-dose  
Change from baseline in nasal discharge NRS (0-10) score at 15, 30, 45, 60, 90 minutes and 2, 4, 
8 and 24 hours post-dose is analyzed using the same methodology set forth in Section 6.3.5.3. 
A line graph is produced depicting the LS mean change from baseline in nasal discharge NRS 
score with 95% CI bars by planned timepoint .   
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6.3.5.6 
Headache pain relief at 15, 30, 45, 60, 90 minutes and 2, 4, 8 and 24 
hours post-dose     
The percentage of subjects achieving headache pain relief is separately evaluated at 15, 30, 45, 
60, 90 minutes and 2, 4, 8 and 24 hours post-dose, following the same methodology set forth in 
Section 6.3.4.4 separately for each time point.  Figures will not be produced. 
The number of subjects that experience headache pain relief at each specified time point is 
analyzed after first imputing missing data at that time point to be failure (i.e., NC = F: Non-
Completers = Failure).  Additionally, subjects who use rescue medication on or before 
assessment of pain at that time point are also assigned as failures (RM = F: Rescue medication 
use = Failure).  If the time of first rescue medication is missing, subjects are considered as 
failures 1) if the date of rescue medication is the same as the date of dosing or 2) only with 
respect to the 24 hours post-dose analysis, if the date of rescue medication is the same as or one 
day after the date of dosing.   
Headache pain level at each time point will also be summarized for mITT subjects with a 
headache pain level of moderate or severe at baseline. 
6.3.5.7 
PGI-C at 24 hours post-dose 
The PGI-C is a patient-
changed relative to the baseline visit.  The subject is asked to rate a change in their overall 
disease condition on a 7-point Likert scale, with the following response options: 1 = very much 
improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 
= much worse, and 7 = very much worse. The PGI-C is a global index scale that may be used to 
rate the response of a condition to a therapy. The eDiary is used to evaluate the PGI-C 
Questionnaire at 24 hours post-dose. 
PGI-C score at 24 hours post-dose is tabulated as the number and percentage of subjects in each 
category by treatment group, with response options 1-
category, 
and response options 5-7 combined into a single 
. Percentages are based on subjects with non-missing PGI-C data at the 24 
hour time point.  A cumulative logit model will be used to investigate the effect of treatment on 
PGI-C score. The number of observations (i.e. frequency) in each category will be modelled with 
treatment group and nasal polyps (yes or no) as covariates. 
group as reference. Odds ratio (Treatment vs Placebo), 95% Wald CI, and predicted probabilities 
in each response group for treatment and placebo group will be reported. A by-subject listing of 
PGI-C results is provided for the full analysis set. 
6.3.5.8 
-
10) Score at 24 Hours 
The percentage 
of facial pain/pressure/fullness NRS 
score at 24 hours post dose is analyzed using the methodology set forth in Section 6.3.5.1, with 
30% reduction from baseline at 24 hours.  Subjects with missing data at 24 hours 
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post-dose and subjects who use rescue medication prior to the assessment at 24 hours post-dose 
are deemed failures.  
6.3.5.9 
-
10) Score at 24 Hours 
The percentage of subjects 
of facial pain/pressure/fullness NRS 
score at 24 hours post dose is analyzed using the methodology set forth in Section 6.3.5.1, with 
respect to 50% reduction from baseline at 24 hours.  Subjects with missing data at 24 hours 
post-dose and subjects who use rescue medication prior to the assessment at 24 hours post-dose 
are deemed failures. 
6.3.5.10 
Sustained Relief of Facial Pain/Pressure/Fullness  
Sustained relief of facial pain/pressure/fullness is assessed separately for each of the following 
criterion:  
1) 30% reduction from baseline on NRS (0-10), achieved for each time point from 2 hours 
to 24 hours post-dose  
2) 1.5-point reduction on NRS (0-10), achieved for each time point from 2 hours to 24 hours 
post-dose 
3) 2-point reduction on NRS (0-10) through 24 hours post-dose, achieved for each time 
point from 2 hours to 24 hours post-dose 
Subjects who meet all of the following criteria are classified as responders: 
 Achieving pain relief as defined in (1), (2), or (3) above at all time points from 2 to 24 
hours post-dose, respectively for each of the 3 criteria 
 Missing facial pain/pressure/fullness at  1 timepoint from 4 to 8 hours post-dose 
 No rescue medication taken at or before 24 hours post-dose  
Subjects who have any of the following are classified as failures: 
 Rescue medication taken at or before 24 hours post-dose (RM=F) 
 Did not achieve pain relief as defined in (1), (2), or (3) above for at least one time point 
from 2 to 24 hours post-dose, respectively for each of the 3 criteria 
 Missing facial pain/pressure/fullness at 2 or 24 hours post-dose 
 Missing facial pain/pressure/fullness at > 1 time point from 4 to 8 hours post-dose 
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Sustained relief (separately for each of the above 3 criteria) is analyzed following the same 
methodology set forth in Section 6.3.4.4.  Figures will not be produced. 
6.3.5.11 
Sino-Nasal Outcome Test (SNOT-22) 
SNOT-22 is a validated symptom-based outcome measure to assess the burden of CRS 
symptomatology. It is a 22-item instrument that includes both nasal and extra-nasal symptoms 
such as poor sleep and mood disturbance. The questionnaire consists of 22 items across 5 
domains: Nasal, Ear/Facial, Sleep, Function, and Emotional.  Items are categorized as specified 
by Khan et. al. (2022).  A scale ranging from 0 (no problem) to 5 (problem as bad as it can be) is 
used to respond to each item in the questionnaire. The total scores range from 0 to 110 with 
higher total scores implying greater impact on quality of life.  The SNOT-22 is collected on 
paper at the Baseline Visit and on the eDiary at 24 hours post-dose.  
Total and domain scores are derived by taking the sum of the non-missing item responses at each 
assessment (baseline and 24 hours post-dose).  Any missing responses are imputed with the 
mean value of non-missing answers; however, if at least half of the answers were missing for 
each domain or the entire questionnaire, the given domain or entire questionnaire, respectively, is 
set to missing.   
Summary statistics are reported for the total score and separately for each domain.  
Change from baseline in the total SNOT-22 score, and separately for each domain score, are 
evaluated using an analysis of covariance (ANCOVA) model with baseline SNOT-22 score as a 
covariate and fixed effects for treatment group and stratification factor (presence of nasal polyps; 
yes or no).   
LS means, SE, 95% CI are reported for each treatment group, and LS mean difference estimate 
(rimegepant - placebo), SE, 95% CI and p-value are reported.   
A by-subject listing of SNOT-22 results is provided for the full analysis set. 
6.4 
Safety 
Safety analyses are based on the safety analysis set by as-treated treatment group (i.e., the actual 
treatment received). Results for the overall treatment group are also presented in pre-treatment 
safety summaries.   
Safety parameters include deaths, AEs, and the following findings: laboratory tests; vital signs; 
physical measurements; electrocardiograms (ECGs); procedures; and C-SSRS.  
Analysis periods are pre-treatment and on-treatment (see Section 7.2). Refer to the Core SAP for 
slotting safety parameters into analysis periods. 
Values and changes from baseline in safety findings (e.g., laboratory tests, vital signs and 
physical measurements, ECGs) and C-SSRS endpoints are tabulated as continuous variables 
descriptively at baseline and the EOT visit.  These analyses are based on observed data without 
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imputation and regardless of rescue medication use. In these tables of safety parameters, if a 
subject has multiple values in the EOT analysis visit window (see Section 7.3), then the last non-
missing value measured in the analysis period is used. See Sections 6.3.4.1, 6.4.4.1, and 6.4.2.4 
for further handling of ties on the same measurement date or time. 
By-subject listings of safety parameters are described in subsections, and identify on-treatment 
data. 
6.4.1 
Adverse Events 
AEs are displayed in tables and listings by system organ class (SOC) and preferred term (PT), 
unless specified otherwise. 
Refer to the Core SAP for AE start date imputation, AE counting rules and frequency table 
specifications, definition of related to study drug, definition of treatment-emergent adverse 
events (TEAEs), definition of AEs of significant interest, reporting of deaths, and AE listing 
contents.  Exposure-adjusted multiple occurrences of unique AEs (Section 6.4.1.5 of the Core 
SAP) does not apply.   
For purposes of applying Section 6.4.1.2 of the Core SAP (definition of TEAE), an AE with non-
missing start time is considered pretreatment if the start date/time of the AE is prior to treatment 
start date/time.  Furthermore, the 
date or earliest start date/time, where an AE with non-missing start date/time is deemed prior to 
an AE with missing start time and an imputed start date on the same date. 
A by-subject AE listing is provided for the enrolled analysis set. Notwithstanding Section 6.4.1.7 
  
6.4.1.1 
Deaths 
Deaths are identified from any the following sources: 
 AE CRF with any of the following: PT of 
any death-
Is a death certificate available?
Is an autopsy report available?
partially complete death date (see Section 7.1)   
 Disposition CRF: subject status of 
eath.  
The by-subject listing of deaths is provided for the enrolled analysis set, and displays all CRF 
sources of death, safety analysis period, death date (see Section 7.1), study day derived from the 
death date, treatment day derived from the death date, and the following AE parameters: non-
imputed start date and end date; SOC; PT; verbatim term; outcome; and response to the question 
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6.4.1.2 
AE Overview 
An AE overview without SOC and PT presents the number and percentage of subjects with any 
of the following AEs: any AE; mild AE; moderate AE; severe AE; moderate or severe AE; AE 
related to study drug; SAE; SAE related to study drug; AE leading to study discontinuation; 
hepatic-related AE; cardiovascular AE; and suicidality AE.  
An AE overview is produced for each analysis period (pre-treatment, on-treatment) for the safety 
analysis set. 
6.4.1.3 
On-treatment AEs by SOC and PT 
On-treatment AEs are tabulated by SOC and PT for the safety analysis set for the following 
endpoints: 
 AEs by intensity 
 AEs related to study drug by intensity 
 AEs by maximum relationship to study drug (related, not related, not reported) 
 SAEs  
 AEs leading to study discontinuation 
 Hepatic-related AEs by intensity * 
 Cardiovascular AEs * 
 Suicidality AEs * 
AEs of significant 
AEs are displayed in descending order of 
rimegepant frequency within SOC and PT. 
6.4.2 
Laboratory Tests 
Laboratory tests are analyzed using results from a central laboratory and are collected at the 
following visits: Screening, EOT and Unscheduled.  Laboratory tests are slotted into safety 
analysis periods (pre-treatment and on-treatment) according to the laboratory collection date and 
time, as available.  Some tabulations are provided for the on-treatment period only, as specified 
below. 
Fasting time is not collected; therefore, cholesterol and triglycerides are analyzed as separate 
laboratory test parameters according to fasting status (last 8 hours): fasting; non-fasting; overall 
(see Section 6.4.2 of the Core SAP).     
Clinically significant laboratory abnormalities are identified as grade 3 to 4 laboratory test 
results. Refer to Section 6.4.2.1 of the Core SAP for laboratory tests of clinical interest for 
analyses, including identification of those with toxicity grades.  If a toxicity grade depends on 
age, then age is defined as age recorded on the CRF. 
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Estimated glomerular filtration rate (eGFR) is derived by the central laboratory using the 
modification of diet in renal disease (MDRD) formula.  eGFR is not separately derived but is 
provided as reported by the central laboratory.  
Laboratory test groups of clinical interest includes hematology, serum chemistry, and urinalysis. 
TLFs show data in the Systeme Internationale (SI) unit system, if applicable.  Tables present 
results by treatment group and overall, and laboratory tests alphabetically within laboratory test 
group, as applicable. 
6.4.2.1 
Laboratory Test Abnormalities 
Laboratory test abnormalities are tabulated as the number and percentage of subjects in the safety 
analysis set in the frequency tables specified in Section 6.4.2.2 of the Core SAP.  This is 
provided for the on-treatment period only. 
6.4.2.2 
Liver Function Test Elevations 
Liver function test (LFT) elevations are tabulated for laboratory tests as specified in Section 
6.4.2.3 of the Core SAP (as applicable to single-dose studies). Elevations of >2 x ULN are also 
tabulated for ALT and AST. In addition, LFT elevations which are potential cases of drug-
induced liver injury (DILI) per Section 8.5 of the protocol will be tabulated. Potential DILI cases 
will be defined as the following: 
 Subjects with aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and total 
bilirubin (TBL) baseline values within the normal range who subsequently present with 
upper limit of normal (ULN) AND a TBL 
with no evidence of hemolysis and an alkaline phosphatase (ALP) value <2 × ULN or not 
available. Evidence of hemolysis will be determined by the presence of the text string 
 in the comments field of the laboratory record, including any variations in 
capitalization or spelling/typos which are clearly intended to represent hemolysis. 
Hemolysis records will also be confirmed by the medical advisor. 
 For subjects with baseline AST OR ALT OR TBL values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on 
which values are above the ULN at baseline: 
o Preexisting AST or ALT baseline values above the normal range: AST or ALT 
smaller). 
o Preexisting values of TBL above the normal range: TBL level increased from 
(whichever is smaller).  
LFT Elevations: Cumulative, Mutually Exclusive, and Composite 
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The number and percentage of subjects with LFT elevations are tabulated separately for each 
analysis period (pre-treatment, on-treatment) for the safety analysis set.  LFT elevations are 
based on fold changes above ULN.  
LFT ULN Shifts from Baseline to Worst Elevation 
LFT ULN shifts from baseline to the worst (highest) on-treatment LFT elevation are tabulated as 
the number and percentage of subjects in the safety analysis set in pre-specified elevation 
categories.  
6.4.2.3 
LFT Plots 
An evaluation of drug-induced serious hepatotoxicity (eDISH) scatter plot is produced, as 
specified in Section 6.4.2.4 of the Core SAP, separately for each analysis period (pre-treatment, 
on-treatment).  By-subject longitudinal LFT plots are not produced.    
6.4.2.4 
Laboratory Test Changes from Baseline Table 
Values and changes from baseline in laboratory tests are tabulated descriptively as continuous 
variables over time at baseline and EOT.   
The table displays results by laboratory tests alphabetically within laboratory test group.  
Multiple values in analysis visit windows are handled as set forth in Section 7.3. 
6.4.2.5 
Laboratory Test Listings 
All laboratory test listings will be based on the enrolled analysis set. 
By-subject Listings of Laboratory Test Results 
All laboratory test listings will be based on the enrolled analysis set. 
A by-subject listing of the following select laboratory tests is provided for subjects with at least 
one laboratory assessment of grade 3 or 4 abnormality or a positive pregnancy test result: 
hematology results, serum chemistry results, and urinalysis results. If there is a positive 
pregnancy test, defined as a serum or urine pregnancy test 
value, or (2) numeric value  25 U/L. the listing will also include all pregnancy test results over 
time. 
Refer to Section 6.4.2.6 of the Core SAP for listing contents as applicable to this study. 
By-subject Listing of LFT Values and Ratios to ULN 
LFT values and ratios to ULN (i.e., ALT, AST, TBL and ALP) for SI units. The listing displays 
all LFT results over time for subjects with select LFT elevations (ALT or AST > 3x ULN; ALP 
or TBL > 2x ULN) at any time point.  Refer to Section 6.4.2.6 of the Core SAP for listing 
contents as applicable to this study. 
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6.4.3 
Vital Signs and Physical Measurements 
Vital signs include systolic blood pressure, diastolic blood pressure, heart rate, and temperature.  
These parameters are measured at Screening, Baseline, and EOT.  Vital signs are slotted into 
safety analysis periods (pre-treatment, on-treatment) according to the measurement date.  Vital 
signs are tabulated for the on-treatment analysis period (see Section 7.2) for the safety analysis 
set. 
Physical measurements include height, weight, and body mass index (where height and weight 
are measured at Screening only).  Physical measurements are slotted into safety analysis periods 
(pre-treatment, on-treatment) according to the measurement date. 
A by-subject listing of vital signs and physical measurements is provided for the enrolled 
analysis set. 
6.4.3.1 
Vital Sign Changes from Baseline 
Values and changes from baseline in vital signs are tabulated descriptively as continuous 
variables at baseline and EOT.  Physical measurements (i.e. weight, height, and BMI) are not 
included in this display.  
Multiple values in analysis visit windows are as set forth in Section 7.3. 
6.4.3.2 
Vital Signs Abnormalities 
Vital sign abnormalities are tabulated as the number and percentage of subjects in the safety 
analysis set meeting categories specified in Section 6.4.3.2 of the Core SAP during the on-
treatment analysis period, except weight change from baseline is not calculated.  Analyses are 
based on the subset of subjects with non-missing data in the on-treatment analysis period for a 
given parameter. 
6.4.4 
Electrocardiogram 
ECG parameters include RR, QRS, PR, QT, QTcF, and ventricular heart rate.  ECGs are 
measured at the following visits: Screening and EOT.  ECG parameters are slotted into safety 
analysis periods (pre-treatment, on-treatment) according to the measurement date and time, as 
available.  ECGs are tabulated for the on-treatment analysis period (see Section 7.2) for the 
safety analysis set. A by-subject listing of ECG results is provided for the enrolled analysis set. 
6.4.4.1 
ECG Changes from Baseline 
Values and changes from baseline in ECG parameters are tabulated descriptively as continuous 
variables at baseline and EOT in the on-treatment analysis period for the safety analysis set.   
Multiple values in analysis visit windows are handled as follows as set forth in Section 7.3. 
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6.4.4.2 
ECG Abnormalities 
On-treatment ECG abnormalities are tabulated as the number and percentage of subjects with on-
treatment ECG abnormalities in the categories specified in Section 6.4.4.2 of the Core SAP.   
Analyses are based on the subset of subjects with non-missing data in the on-treatment analysis 
period. 
ECG abnormalities are presented together with vital sign abnormalities in the same tables (see 
Section 6.4.3.2). 
6.4.5 
Procedures 
Procedures are listed for the enrolled analysis set using the Concomitant Procedures CRF.  The 
listing includes the name of the procedure/surgery, SOC and PT, the date of the 
procedure/surgery, and analysis periods.   See Section 6.4.5 of the Core SAP for further details.   
Procedures are slotted into safety analysis periods according to the procedure date.  Note that 
procedures are slotted like AEs, but without date imputation (see Section 7.2).  
6.4.6 
Suicidality 
The C-SSRS is a clinician administered questionnaire used for suicide assessment.  The C-SSRS 
Screening version is used at the Screening Visit and the Since Last Visit version is used at 
subsequent visits.  C-SSRS is measured at Screening, Baseline and EOT.  The C-SSRS 
 
At the Screening Visit, the recall period for completing the C-SSRS is past 12 months for 
ideation, and 10 years for attempt and behavior; at all other visits, the recall period for 
completing the C-SSRS is since the last visit. 
Refer to the Core SAP for the definitions of C-SSRS parameters and specifications for 
tabulation.  However, notwithstanding Section 6.4.6.2 of the Core SAP, C-SSRS results are not 
separately tabulated by analysis periods but instead tabulated by visit (Screening, Baseline Visit, 
and EOT).  Unscheduled or early termination visits following treatment are reassigned as 
specified in Section 7.3; unscheduled or early termination visits prior to treatment are not 
reassigned or tabulated.  
6.4.7 
Safety Narrative Subject Identifiers Listing 
A by-subject listing of safety narrative subject identifiers is provided for the following select 
events and analysis sets as columns:  
 All deaths on-treatment or during follow-up, regardless of treatment 
 SAEs on-treatment or during follow-up for rimegepant-treated subjects, regardless of 
relationship to study drug  
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 Any AE leading to discontinuation of study for rimegepant-treated subjects, regardless of 
relationship to study drug  
 On-treatment events of significant interest for rimegepant-treated subjects: 
o ALT or AST > 3x ULN 
o ALT or AST > 3x ULN concurrent with TBL > 2x ULN 
o TBL > 2x ULN 
o Select hepatic-related AE, i.e., PT containing cirrhosis, hepatic failure, hepatitis, 
jaundice, or liver failure 
o Suicidality AE 
 Any event of significant interest 
 Refer to the Core SAP for additional details. The listing flags subjects with select events.   
Should the criteria in the study Safety Narrative Plan conflict with the criteria above, the Safety 
Narrative Plan will take precedence.  
7 CONVENTIONS 
7.1 
Derived Dates 
Refer to Section 7.1 of the Core SAP for the definition of complete dates, partially complete 
 
7.1.1 
Analysis Period Reference Dates 
Analysis periods are determined by analysis period reference date/times.  The analysis period 
reference date/time for the pre-treatment and on-treatment analysis periods are the date of 
informed consent and the study drug date/time (see Section 7.2). 
Derived dates (or date/time values) are defined as follows. 
7.1.1.1 
Study Drug Dates 
 Study drug date/time: 
o For subjects who indicated that they took study medication (not mistakenly) on the 
Initial facial pain/pressure/fullness Diary
Initial facial 
pain/pressure/fullness Diary
 
o 
Initial 
facial pain/pressure/fullness Diary
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Initial facial pain/pressure/fullness Diary
n
When did 
  (Note that if the subject indicated that they dosed 
on the same day, only time is manually entered.)  
o For subjects who reported to the site that they took study medication without 
interacting with eDiary, the date/time recorded by the site and transmitted to the 
electronic patient-reported outcome vendor. 
7.1.2 
Imputed Dates 
Refer to Section 7.1.2 of the Core SAP for the imputation of non-study medication start dates 
(except rescue medications), non-study medication end dates, AE start dates, and AE end dates, 
with the following adjustment: with respect to the use of birth date in the imputation logic, the 
complete birth date is assumed to be January 1st of the birth year if the birth year is non-missing. 
7.1.3 
Last Contact Date 
The last contact date is used to determine select parameters (i.e., time on study, imputed non-
study medication end dates, and death date), and is typically defined using non-imputed dates as 
follows:  
1. Earliest complete death date from all sources that collect death dates (e.g., AE CRF), if it 
exists.  
2. Otherwise, the maximum complete date of the following CRF or external data sources, as 
applicable: AE start or end; COVID-19 visit where the COVID-19 visit impact type is not a 
missed visit; ECG; efficacy assessment; informed consent; IWRS randomization; laboratory 
test collection; non-study medication start or end; physical exam; physical measurement; 
protocol deviation; questionnaire; study drug start; subject disposition 
completion/discontinuation; visit; vital sign. 
3. If the last contact date is after the most recent raw database creation date, then it is set to the 
most recent raw database creation date.  
7.1.4 
COVID-19 Visit Date 
COVID-19 visit dates are not derived and are not displayed on listings.  
7.1.5 
Other Derived/Imputed Dates 
Additional derived dates include. 
 Date/time of eDiary assessments: The date/time of a given assessment collected in the eDiary 
is the datetime the diary for that time point is saved (e.g., the date/time of all assessments 
collected on the 15 minute diary is the datetime the 15 minute diary is saved).     
 Rescue medication start date/time: Earliest rescue medication date/time. Missing time is 
considered to be earlier than non-missing time on the same date. Refer to Section 6.2.6.3. 
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 Death date: Last contact date (see Section 7.1.3), derived only for subjects who died (see 
Section 6.4.1.1). 
No imputations are performed on these derived dates, except as specifically mentioned in this 
Section 7.1.5.  Complete dates are those with valid, non-missing day, month, and year. 
7.2 
Analysis Periods 
Measurements are slotted into analysis periods by comparing both measurement date and time to 
analysis period reference date and time (i.e., study drug start date and time; see Section 7.1.1). 
Otherwise, if (1) time is missing or not available for either the measurement or the analysis 
period reference, or (2) time is not required for slotting, then only the measurement date is 
compared to the analysis period reference date.  
Note that the measurement date must be complete for the measurement to be slotted into an 
analysis period (see Section 7.1).  Exceptions are noted for the pre-treatment analysis period for 
subjects in the enrolled analysis set who are not in the safety analysis set, and for AEs, where 
imputed start dates are used if start date is incomplete.  
Analysis periods are defined as follows.   
 Pre-treatment: measurement date/time at or before the study drug dose date/time. This period 
is used to derive baseline values and to assess pre-treatment endpoints. Note that all 
measurements are pre-treatment for subjects in the enrolled analysis set with missing study 
drug dose date and that AEs with imputed start date prior to study drug dose date are 
included in this analysis period (or start date/time < study drug dose date/time if AE start 
time is non-missing).  
 On-treatment: measurement date/time after the study drug dose date/time. This period is used 
to assess safety endpoints on treatment. Note that AEs with imputed start date equal to study 
drug dose date are included in this analysis period, unless start time is non-missing and start 
date/time is < study drug dose date/time.  Baseline assessments are not counted 
are 
 
See Section 7.1 for derived dates for determining analysis periods.   
7.3 
Analysis Visit Windows 
Refer to Protocol Section 4.2 for the schedule of assessments.  
Study days are calculated from the randomization date as follows: 
 Measurement date  randomization date + 1, if measurement date  randomization date 
 Measurement date  randomization date, if measurement date < randomization date. 
Treatment days are calculated from the study drug dose date as follows: 
 Measurement date  study drug dose date + 1, if measurement date  study drug dose date 
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 Measurement date  study drug dose date, if measurement date < study drug dose date. 
Analysis visit windows for safety parameters are presented in Table 6.  
Table 6: 
Analysis Visit Windows for Safety Parameters 
 
Analysis Visit 
Analysis-Specified Interval 
Screening  
 
 Study day  1 or both study day and treatment day missing 
 
 
 Treatment day  1 * 
Baseline  
Study day 1 
End of treatment 
 
 Study day 2 
 
 Treatment day * 
*Applies only to subjects who took study drug but were not randomized 
Notwithstanding Section 6.4.3.1 of the Core SAP, multiple values in analysis visit windows are 
handled as follows: 
 The scheduled visit takes priority over unscheduled or early termination visits. 
 If a subject does not have a scheduled visit, the unscheduled or early termination visit 
closest to the target date takes priority. 
 If there are still multiple values on the same measurement date, then the last value 
collected timewise takes priority (if time is collected); if ties remain, the value with the 
highest ECG reference identifier, vital signs identifier, or laboratory barcode is used, as 
applicable.   
For clarity, displays that tabulate baseline values tabulate the baseline value as defined in Section 
7.5, rather than the value that maps to the Baseline Visit, unless otherwise explicitly noted (see 
Section 6.4.6). 
For efficacy assessments collected on the eDiary, windows are imposed by the eDiary, as shown 
in Table 7.  The anchor point for the windows is the date/time of exposure, as defined in Section 
7.1.  
Table 7: 
Evaluation Intervals for Efficacy Analyses 
 
Post-dose Evaluation 
Analysis-Specified Interval  
Target Time 
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15 min diary  
10-20 min 
Study medication start time + 15 min 
30 min diary  
25-35 min 
Study medication start time + 30 min 
45 min diary  
40-50 min 
Study medication start time + 45 min 
60 min diary 
55-65 min 
Study medication start time + 60 min 
90 min diary  
85-95 min (1 hr 25 min  1 hr 35 min) 
Study medication start time + 90 min 
2 hr diary 
115-135 min (1 hr 55 min  2 hr 15 min) 
Study medication start time + 2 hr 
4 hr diary 
225-255 min (3 hr 45 min  4 hr 15 min) 
Study medication start time + 4 hr 
8 hr diary 
465-495 min (7 hr 45 min  8 hr 15 min) 
Study medication start time + 8 hr 
24 hr diary 
1380-1500 min (23 hr  25 hr ) 
Study medication start time + 24 hr 
 
7.4 
Subgroups 
 
Section 7.4 of the Core SAP does not apply in its entirety. The stratification factor subgroup is as 
noted in Section 4.3. The hierarchical testing strategy will always follow the overall p-values 
rather than the subgroup p-values. 
7.5 
Baseline Value 
The baseline value for a safety parameter collected with a measurement date/time (e.g., weight), 
is defined according to analysis set as follows: 
Enrolled analysis set but not in the full analysis set: Last nonmissing value 
 
Full analysis set but not in the safety analysis set: Last nonmissing value at or before the IWRS 
randomization date 
mITT and safety analysis sets: Last nonmissing value in the pre-treatment analysis period 
 
The baseline value for SNOT-22 is defined as the last nonmissing value in the pre-treatment 
analysis period. 
 
complete measurement date/time. See Section 7.1 for complete 
dates, Section 7.2 for analysis periods, and Sections 6.4.2.4, 6.4.3.1, and 6.4.4.1 for handling 
multiple values on the same measurement date.  
 
Initial facial 
pain/pressure/fullness
in the same session where the subject confirmed having dosed 
(not 
Initial 
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facial pain/pressure/fullness
Section 6.2.6), baseline NRS and headache pain scores are missing. 
 
8 CONTENT OF REPORTS 
The final CSR is produced after the final database lock, which occurs after last subject last visit. 
All TLFs described in this SAP are produced for the final CSR. No interim analyses are planned. 
9 APPENDICES 
9.1 
Relevant Protocol Deviations 
Relevant eligibility protocol deviations include the following categories:  
 CRS history not aligned with eligibility requirements as any of the following: 
o Subject has been treated with systemic corticosteroids within 30 days prior to 
Screening 
o CRS onset less than 3 months prior to Screening 
 Inflammation documentation older than 12 months 
 Finding out of range at Screening (or at Baseline, as applicable), defined as any of the 
following:  
o ALT/AST/Direct Bilirubin/Indirect Bilirubin/TBL > ULN if originally consented to 
protocol version 3 or lower 
o TBL > 1.5 x ULN if originally consented to protocol version 4 or higher 
o For subjects consented to protocol version 4 or higher 
syndrome, Direct Bilirubin > 1 x ULN 
o AST or ALT > 2 x ULN if originally consented to protocol version 4 or higher 
o ECG abnormalities as follows if originally consented to protocol version 3 or lower: 
 Corrected QT interval > 470 msec (QTc by method of Frederica) 
 Left Bundle Branch block 
 
 
 
 
o 
 
o 
6.5% if originally consented to protocol version 3 or lower 
o HbA1c > 7.5% if originally consented to protocol version 4 or higher 
o Systolic blood pressure > 150 mmHg after 10 mins of rest if originally consented to 
protocol version 3 or higher 
o Diastolic blood pressure > 100 mmHg after 10 mins of rest if originally consented to 
protocol version 3 or higher 
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o eGFR according to the MDRD Study equation  40 mL/min/1.73m2 if originally 
consented to protocol version 3 or lower 
o eGFR according to the MDRD Study equation  30 mL/min/1.73m2 if originally 
consented to protocol version 4 or higher 
o BMI  33 kg/m2 if originally consented to protocol version 3 or lower 
o BMI > 35 kg/m2 if originally consented to protocol version 4 or higher 
o Positive for cocaine or PCPs   
o Females with a positive pregnancy test at Screening or Baseline  
o CSSRS suicidal ideation with active intent or plan to act, or suicidal behavior present 
during screening through 
following CSSRS questions at Screening Visit or Baseline Visit: 
 Suicidal ideation question 4 (active suicidal ideation with some intent to act, 
without specific) or 5 (active suicidal ideation with specific plan and intent) 
 Suicidal behavior question 1 (actual attempt), 3 (interrupted attempt), 4 
(aborted attempt), 5 (preparatory acts or behavior), or 6 (suicidal behavior). 
 
Relevant subject management protocol deviations include the following:  
 eDiary assessment compliance 
o Subject has missed a 2-hour endpoint assessment. 
o Subject has mistakenly taken dose 
 Prohibited non-study medications, procedures, or therapies defined as any of the following: 
o Daily CRS medications with dose change (see Section 6.2.5.4 for the definition of 
CRS medication) 
o Excluded current or recent treatments (Section 5.3.6 of the protocol) prior to the 
Screening Visit or throughout the study as follows: 
 Non-steroid immunosuppressants (i.e., calcineurin inhibitors, interleukin 
inhibitors, selective immunosuppressants, TNF-  inhibitors, other 
immunosuppressants) use within the 60 days prior to Screening Visit or 
throughout the study.  
 New or recently modified allergen immunotherapy within the 3 months prior 
to Screening Visit or throughout the study.  
 Monoclonal antibody therapy (e.g., dupilumab, mepolizumab, omalizumab, 
benralizumab, reslizumab) within the 6 months prior to Screening Visit or 
throughout the study (Protocol version 3 or lower).  
 Monoclonal antibody therapy (e.g., dupilumab, mepolizumab, omalizumab, 
benralizumab, reslizumab) within the 3 months prior to Screening Visit or 
throughout the study (Protocol version 4 or higher).  
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 New or recently modified leukotriene modifiers therapy within the 3 months 
prior to Screening Visit or throughout the study (Protocol version 2 or lower).  
 New or recently modified leukotriene modifiers therapy within the 1 month 
prior to Screening Visit or throughout the study (Protocol version 3 or higher).  
 
-adrenoceptor agonists therapy within the 3 
months prior to Screening Visit or throughout the study (Protocol version 2 or 
lower).  
 
-adrenoceptor agonists therapy within the 1 month 
prior to Screening Visit or throughout the study (Protocol version 3 or higher).  
o Non-
the Screening Visit 
o Acetaminophen or acetaminophen containing products taken within 2 days before 
randomization.  
o Use of acetaminophen during the screening phase (3 to 14 days) or throughout the 
study at daily dosing levels of greater than 1000 mg/day  
o Systemic corticosteroids taken up to 30 days prior to the Screening Visit or afterward  
(specifically, 1) if the subject dosed after taking systemic corticosteroid or 2) if the 
subject did not discontinue the study).  
o Antibiotics, other than topical nasal antibiotics, taken up to 14 days prior to the 
Screening Visit or afterward (specifically, 1) if the subject dosed after taking the 
antibiotics or 2) if the subject did not discontinue the study). 
o Monoclonal antibody therapy taken during the study. 
o Barbiturate-containing products taken up to 14 days prior to the Baseline Visit or 
afterward 
o Narcotic medication, such as opioids, taken up to 2 days prior to the Baseline Visit or 
afterward  
o Strong CYP3A4 inhibitors taken up to 14 days prior to the Baseline Visit or afterward 
o Moderate or strong CYP3A4 inducers taken up to 14 days prior to the Baseline Visit 
or afterward 
o Atypical antipsychotics such as Abilify (aripiprazole), Zyprexa (olanzapine), 
Seroquel (quetiapine), Geodon (ziprasidone), or Risperdal (risperidone) or 
Depakote/Depakene (valproic acid/valproate) taken up to 90 days prior to the 
Baseline Visit or afterward  
 
Note: Medications taken up to X days before a reference date or afterward are defined 
as those with medication start date or stop date  reference date  X.  Refer to the 
Core SAP for additional details about prohibited non-study medications.  
 Finding out of range during the study, defined as any of the following: 
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o Positive for cocaine, cannabinoids or PCPs at any post-baseline visit, including EOT 
visit  
 
 Medical history, defined as any of the following subcategories: 
o Ongoing rhinitis medicamentosa* 
o Nasal or upper respiratory infection starting/ending less than or equal to 2 weeks prior 
to Screening Visit** 
o Acute bacterial/viral rhinosinusitis starting/ending less than or equal to 2 weeks prior 
to Screening Visit** 
 Presence of polyps discrepant between IWRS and CRF data, for the following subcategories: 
o IWRS randomization stratum of no, but presence of polyps or prior history of nasal polyp 
surgery 
 
* In the case of partial start and/or end dates, rhinitis medicamentosa is 
if 
1) the month and year of the partial start date is on or before the month and year of the Screening 
Visit AND 2) the month and year of the end date is after the month and year of the Screening 
Visit.  It is not considered ongoing if the start and end date are both completely missing. 
** In the case of partial start and/or end dates, the medical history is considered having 
started/ended than or equal to 2 weeks prior to Screening Visit if: 
1) If the date of the Screening Visit is less than the 14th of the month, the month and year of 
the partial start date is on or before the month and year of the Screening Visit AND (the 
month and year of the partial end date is on or before the month and year of the Screening 
Visit, the complete date of the end date is less than 14 days before the Screening Visit, 
OR the end date is missing) 
2) If the date of the Screening Visit is greater than the 14th of the month, the month and year 
of the partial start date is before the month and year of the Screening Visit AND (the 
month and year of the partial end date is before the month and year of the Screening 
Visit, the complete date of the end date is less than 14 days before the Screening Visit, 
OR the end date is missing) 
 
In the case of repeat Screening assessments, for purposes of identifying whether a medication 
was used or medical history occurred prior to the Screening Visit, the first Screening visit is 
used.  
 
9.2 
Changes to Planned Analyses in the Protocol 
The following changes to v4.0 of the Protocol are made in this SAP: 
 Section 3.1 of the protocol 
hange from baseline facial 
pain/pressure/fullness will be assessed using the number of evaluable subjects that report 
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facial pain/pressure/fullness  6 on NRS (0-10) at baseline and who also report pain level 
at 2 hours post-dose recorded in the eDiary.
is not limited to subjects who 
report pain level at 2 hours post-dose. 
 
Subjects will record the date and time of 
dosing
they mistakenly dosed, the date/time of dosing in general will be imputed as the date/time 
the applicable eDiary is saved (see Section 7.1). 
 Section 9.4.3 of the protocol states, 
at 24 post-dose will be analyzed after first imputing missing data at 24 hours to be failure 
the eDiary, subjects with missing eDiary data at 24 hours are not imputed as failures for 
purposes of analyzing rescue medication use within 24 hours (see Section 6.3.4.5)  
10 REFERENCES 
Khan A, Reaney M, Guillemin I, et al. Development of Sinonasal Outcome Test (SNOT-22) 
domains in chronic rhinosinusitis with nasal polyps. Laryngoscope 2022 May;132(5):933-941.  
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York, NY USA, 
John Wiley & Sons Inc. 
Salaffi F, Stancati A, Silvestri CA, Ciapetti A, Grassi W. Minimal clinically important changes 
in chronic musculoskeletal pain intensity measured on a numerical rating scale. Eur J Pain 
2004;8:283-91. 
 
 
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Timestamp
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Certified Delivery Events
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Timestamp
Carbon Copy Events
Status
Timestamp
Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
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Envelope Sent
Hashed/Encrypted
2/29/2024 2:36:58 PM
Certified Delivered
Security Checked
2/29/2024 2:37:06 PM
Signing Complete
Security Checked
2/29/2024 2:37:23 PM
Completed
Security Checked
3/9/2024 12:07:28 PM
Payment Events
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Electronic Record and Signature Disclosure
090177e1a0abd2f2\Approved\Approved On: 14-May-2024 06:18 (GMT)


ELECTRONIC RECORD AND SIGNATURE DISCLOSURE  
From time to time, Rho, Inc. (we, us or Company) may be required by law to provide to you 
certain written notices or disclosures. Described below are the terms and conditions for providing 
to you such notices and disclosures electronically through the DocuSign system. Please read the 
information below carefully and thoroughly, and if you can access this information electronically 
to your satisfaction and agree to this Electronic Record and Signature Disclosure (ERSD), please 
confirm your agreement by selecting the check-
 
 
Getting paper copies  
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. You will have the ability to download and print documents we send 
to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a 
$0.00 per-page fee. You may request delivery of such paper copies from us by following the 
procedure described below. 
 
Withdrawing your consent  
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind  
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically  
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Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact Rho, Inc.:  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: rho-css@rhoworld.com 
 
To advise Rho, Inc. of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at rho-css@rhoworld.com and in the 
body of such request you must state: your previous email address, your new email address.  We 
do not require any other information from you to change your email address.  
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from Rho, Inc.  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to rho-css@rhoworld.com and in the body 
of such request you must state your email address, full name, mailing address, and telephone 
number. We will bill you for any fees at that time, if any. 
 
To withdraw your consent with Rho, Inc.  
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 
090177e1a0abd2f2\Approved\Approved On: 14-May-2024 06:18 (GMT)


i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to rho-css@rhoworld.com and in the body of such request you must state 
your email, full name, mailing address, and telephone number. We do not need any other 
information from you to withdraw consent..  The consequences of your withdrawing consent for 
online documents will be that transactions may take a longer time to process.. 
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-
 
 
By selecting the check-
that: 
 
You can access and read this Electronic Record and Signature Disclosure; and 
 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
 
Until or unless you notify Rho, Inc. as described above, you consent to receive 
exclusively through electronic means all notices, disclosures, authorizations, 
acknowledgements, and other documents that are required to be provided or made 
available to you by Rho, Inc. during the course of your relationship with Rho, Inc.. 
090177e1a0abd2f2\Approved\Approved On: 14-May-2024 06:18 (GMT)


Document Approval Record
Document Name:
Document Title:
Signed By:
Date(GMT)
Signing Capacity
090177e1a0abd2f2\Approved\Approved On: 14-May-2024 06:18 (GMT)
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