Clinical trial NCT02770365
Conditions: Atrophy
Sponsor: Padagis LLC
Start date: 2016-05-01; Completion date: 2016-11-01
Enrollment: 695 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare safety and efficacy of Perrigo's drug product compared to an FDA approved drug product in the treatment of vulvar and vaginal atrophy.

Detailed description:

Arms: arm 1: estradiol cream arm 2: estradiol cream arm 3: Placebo cream
Interventions: intervention 1: estrace cream (Perrigo) intervention 2: estrace cream (Reference) intervention 3: Placebo cream
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
NCT02770365 
 
02-08-2016 


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A R A N D O MI Z E D, D O U BL E -BLI N D E D , V E HI CL E-C O N T R OLL E D, P A R ALL EL -G R O U P, M UL TI C E N T E R 
S T U D Y T O C O M P A R E P E R RI G O U K F I N C O’ S E S T R A DI OL V A GI N AL C R E A M 0. 0 1 % T O E S T R A C E ® 
( ES T R A DI OL ) V A GI N AL C R E A M, U S P,  0. 0 1 %  (W A R N E R C HIL C O T T (U S ), LL C) A N D  B O T H A C TI V E 
T R E A T M E N T S T O A V E HI CL E C O N T R OL  I N T H E T R E A T M E N T O F V UL V A R A N D V A GI N AL 
A T R O P H Y  
 
 
 
 
 
P R O T O C OL N U M B E R: P R G -N Y - 1 5-0 0 7  
 
 
 
 
 
 
C o nf i d e nti al 
 
T h e c o nfi d e nti al i nf or m ati o n pr o vi d e d i n t his d oc u m e nt is f or us e b y p arti es dir ectl y i n v ol v e d 
i n t his i n v esti g ati o n.  B y acc e pti n g t his d oc u m e nt, y o u a gr e e t h at t h e i nf or m ati o n c o nt ai n e d 
h er ei n will n ot b e discl os e d t o a n y p ers o n n ot dir ectl y i n v ol v e d i n t his i n v esti g ati o n wit h o ut 
writt e n a ut h oriz ati o n fr o m P erri g o.  
 
 




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P a g e 3 of 5 1  
T A BL E O F C O N T E N T S  
1  B A C K G R O U N D A N D R A TI O N AL E  
1 2  
2  S T U D Y O BJ E C TI V E S  
1 3  
2. 1  
E n d p oi nts:  .................................................................................................................... 1 3  
2. 2  
S af et y:  ........................................................................................................................... 1 3  
3  S T U D Y D E SI G N  1 4  
3. 1  
T y p e/ D esi g n of st u d y  ................................................................................................... 1 4  
3. 2  
St u d y P o p ul ati o n:  ......................................................................................................... 1 5  
4  S U BJ E C T S EL E C TI O N  
1 6  
4. 1  
I ncl usi o n Crit eri a .......................................................................................................... 1 6  
4. 2  
Excl usi o n Crit eri a  .......................................................................................................... 1 7  
4. 3  
Pr ec a uti o ns  ................................................................................................................... 1 9  
5  S T U D Y P R O C E D U R E S  
1 9  
5. 1  
S u bj ect Scr e e ni n g a n d E nr oll m e nt  ............................................................................... 1 9  
5. 2  
Assi g n m e nt of S u bj ect N u m b er  ................................................................................... 2 0  
5. 3  
D e m o gr a p hics/ M e dic al Hist or y  ................................................................................... 2 0  
5. 4  
C o nc o mit a nt a n d Pr o hi bit e d M e dic ati o ns  ................................................................... 2 0  
5. 5  
Ass ess m e nt of V V A S y m pt o ms a n d M ost B ot h ers o m e S y m pt o m  ............................... 2 1  
5. 6  
P h ysic al Ex a mi n ati o n  .................................................................................................... 2 1  
5. 7  
P a p s m e ar  ..................................................................................................................... 2 2  
5. 8  
V a gi n al s m e ar cyt ol o g y  ................................................................................................ 2 2  
5. 9  
V a gi n al p H  .................................................................................................................... 2 2  
5. 1 0  
Cli nic al l a b or at or y t ests: ............................................................................................... 2 2  
5. 1 1  
V a gi n al ultr as o u n d  ....................................................................................................... 2 3  
5. 1 2  
M a m m o gr a p h y  ............................................................................................................. 2 3  
5. 1 3  
R a n d o miz ati o n a n d tr e at m e nt  ..................................................................................... 2 3  
5. 1 4  
St u d y m e dic ati o n us e, S u bj ect Di ar y a n d I nstr ucti o n S h e et:  ....................................... 2 3  
5. 1 5  
Visit S p ecific Pr oc e d ur es  .............................................................................................. 2 4  
5. 1 5. 1  
Visit 1/ Scr e e ni n g - ( D a y -1 4 t o D a y -1)  
2 4  
5. 1 5. 2  
Visit 2/ R a n d o miz ati o n - ( D a y 1) 
2 4  
5. 1 5. 3  
Visit 3/ E n d of St u d y/ E arly T er mi n ati o n - ( D a y 8 + 3 D a ys) 
2 5  
5. 1 5. 4  
U nsc h e d ul e d Visit  
2 5  
5. 1 6  
S u m m ar y of Ass ess m e nts  ............................................................................................ 2 6  
5. 1 7  
Pr ot oc ol D e vi ati o ns/ Vi ol ati o ns  .................................................................................... 2 7  
5. 1 8  
S u bj ect Tr e at m e nt/ C o m pli a nc e  ................................................................................... 2 7  
5. 1 9  
Disc o nti n u ati o n / Wit h dr a w al of St u d y S u bj ects  .......................................................... 2 8  
6  M A T E RI AL S A N D S U P PLI E S  
2 9  


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6. 1  
St u d y M e dic ati o n  ......................................................................................................... 2 9  
6. 2  
M e dic ati o n M a n a g e m e nt  ............................................................................................. 2 9  
6. 2. 1  L a b eli n g, P ac k a gi n g a n d Distri b uti o n 
2 9  
6. 2. 2  R et e nti o n S a m pl es  
3 0  
6. 2. 3  St or a g e a n d T est Articl e Acc o u nt a bilit y  
3 0  
6. 2. 4  R a n d o miz ati o n  
3 1  
6. 2. 5  Pr oc e d ur e f or Br e a ki n g t h e Bli n d  
3 1  
7  A D V E R S E R E A C TI O N S  
3 1  
7. 1  
D e p art ur e fr o m t h e Pr ot oc ol f or I n di vi d u al S u bj ects  .................................................. 3 3  
7. 2  
D efi niti o ns  .................................................................................................................... 3 3  
7. 3  
Eliciti n g a n d R e p orti n g of A d v ers e E v e nts  ................................................................... 3 4  
7. 3. 1  Ex p e dit e d R e p orti n g R es p o nsi biliti es of t h e St u d y C e nt er  
3 5  
7. 3. 2  S u b mitti n g a n Ex p e dit e d S af et y R e p ort t o t h e R e g ul at or y A ut h orit y  
3 6  
7. 4  
S A E & A Es R e q uiri n g Disc o nti n u ati o n of St u d y Dr u g, i ncl u di n g Pr e g n a nci es  .............. 3 7  
7. 4. 1  Pr e g n a ncy  
3 7  
7. 5  
P ost St u d y A d v ers e E v e nts  ........................................................................................... 3 8  
7. 5. 1  N o n -s eri o us P ost St u d y A d v ers e E v e nts 
3 8  
7. 5. 2  S eri o us P ost St u d y A d v ers e E v e nts  
3 8  
8  S T A TI S TI C AL A N AL Y SI S  
3 9  
8. 1  
St atistic al A n al ysis  ........................................................................................................ 3 9  
8. 1. 1  A n al ysis P o p ul ati o ns  
3 9  
8. 1. 2  Pl a n n e d A n al ysis  
3 9  
8. 1. 3  S a m p l e Siz e C o nsi d er ati o ns 
4 0  
8. 1. 4  Effic acy M e as ur es a n d A n al ysis  
4 0  
8. 1. 5  S af et y a n d A d v ers e E v e nts A n al ysis  
4 2  
8. 2  
C o m p ar a bilit y of S u bj ects at b as eli n e  .......................................................................... 4 2  
9  C O N S E N T C O N SI D E R A TI O N S A N D P R O C E D U R E S  
4 2  
9. 1  
S u bj ect C o nfi d e nti alit y  ................................................................................................. 4 3  
1 0  C O N D U C T O F S T U D Y  
4 4  
1 0. 1  
C o m pl eti o n of St u d y  ..................................................................................................... 4 4  
1 0. 2  
Pr ot oc ol A m e n d m e nts  ................................................................................................. 4 4  
1 1  R E C O R D S M A N A G E M E N T  
4 5  
1 1. 1  
D at a C oll ecti o n  ............................................................................................................. 4 5  
1 1. 2  
S o urc e D oc u m e nts  ....................................................................................................... 4 6  
1 1. 3  
Fil e M a n a g e m e nt at t h e St u d y Sit e  .............................................................................. 4 6  
1 1. 4  
R ec or ds R et e nti o n at t h e St u d y Sit e  ............................................................................ 4 6  
1 2  Q U ALI T Y C O N T R OL A N D Q U ALI T Y A S S U R A N C E  
4 6  


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P a g e 5 of 5 1  
1 2. 1  
M o nit ori n g  .................................................................................................................... 4 6  
1 2. 2  
A u diti n g  ........................................................................................................................ 4 7  
1 3  E T HI C S A N D R E S P O N SI BILI T Y  
4 7  
1 4  U S E O F I N F O R M A TI O N A N D P U BLI C A TI O N  
4 7  
1 5  R E F E R E N C E S  
5 0  
 
 


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S T U D Y S Y N O P SI S  
 
TI TL E:  
A
 R a n d o miz e d,
 D o u bl e -Bli n d e d,
 V e hicl e -C o ntr oll e d,
 P ar all el -Gr o u p 
M ultic e nt er St u d y T o C o m p ar e P erri g o U K F I N C O’s Estr a di ol V a gi n al Cr e a m 
0. 0 1 % T o E S T R A C E ® ( estr a di ol) V a gi n al Cr e a m, U S P, 0. 0 1 % (W ar n er C hilc ott 
( U S),  LL C)  A n d  B ot h  Acti v e  Tr e at m e nts  T o  A  V e hicl e  C o ntr ol  I n  T h e  
Tr e at m e nt Of V ul v ar A n d V a gi n al Atr o p h y   
 S T U D Y P E RI O D  
A p pr oxi m at el y 2 2  D a ys ; u p t o 1 4 d a ys  of  scr e e ni n g p eri o d f oll o w e d b y a 7 
d a y  tr e at m e nt p eri o d, a n d  o n e d a y p ost -tr e at m e nt f oll o w u p. 
S T U D Y 
M E DI C A TI O N  
•  T est Pr o d uct:  Estr a di ol V a gi n al Cr e a m 0. 0 1 % ,
 
 
  
  
  
  
•  R ef er e nc e Pr o d uct:  ES T R A C E ® ( estr a di ol) V a gi n al Cr e a m, U S P, 0. 0 1 %, 
m a n uf act ur e d b y W ar n er C hilc ott ( U S), LL C   
  
  
  
•  V e hicl e:  V e hicl e of t h e t est pr o d uct, 
 
 
  
  
 
S T U D Y 
O BJ E C TI V E S : 
T o d e m o nstr at e  bi o e q uiv al e nc e  of P erri g o U K F I N C O’s E str a di ol V a gi n al 
C r e a m 0. 0 1 % c o m p ar e d wit h E S T R A C E ( e str a di ol) Va gi n al Cr e a m, U S P,  
0. 0 1 % ( W ar n er C hilc ott ( U S ), LL C) i n t h e tr e at m e nt of v ul v ar a n d v a gi n al 
atr o p h y a n d t o d e m o nstr at e  s u p eri orit y of t h e t w o acti v e tr e at m e nts o v er 
V e hicl e . 
S T U D Y D E SI G N  
T his st u d y will f oll o w a r a n d o miz e d, d o u bl e -bli n d, v e hicl e -c o ntr oll e d, 
p ar all el -gr o u p d esi g n. 
 s u bj ects will b e r a n d o miz e d i n 
a p pr oxi m at el y 3 3 st u d y c e nt ers. S u bj ects will b e a d mitt e d i nt o t h e st u d y 
o nl y aft er writt e n i nf or m e d c o ns e nt h as b e e n o bt ai n e d a n d aft er all 
i ncl usi o n/ excl usi o n crit eri a h a v e b e e n m et.  Q u alifi e d s u bj ects will b e 
r a n d o ml y assi g n e d 
 t o t h e T est Pr o d uct, R ef er e nc e Pr o d uct, 
or V e hicl e f or a 7 -d a y, o nc e -d ail y tr e at m e nt r e gi m e n ( Tr e at m e nt P eri o d).  
 
S T U D Y VI SI T S:  
S u bj ects will visit t h e st u d y c e nt er at Visit 1/ Scr e e ni n g  ( D a y -1 4  t o D a y -1). 
At t his visit s u bj ect s will r e vi e w a n d si g n t h e st u dy s p ecific I C F, c o m pl et e a 
p h ysic al ex a m (i ncl u di n g br e ast a n d p el vic ex a m ).  T h e f oll o wi n g will als o b e 
c o n d uct e d: a n o n -f asti n g bl o o d s a m pl e, vit al si g ns, v a gi n al ultr as o u n d (f or 
all w o m e n wit h a n i nt act ut er us), v a gi n al cyt ol o g y, m a m m o gr a p h y (if o v er 
4 0 y e ars of a g e a n d n ot d o n e wit hi n t h e l ast 9 m o nt hs of st u d y e nr oll m e nt), 
P a p t est (if n ot c o n d uct e d wit hi n t h e l ast 1 2 m o nt hs), a n d v a gi n al p H will b e 
o bt ai n e d.  R e vi e w of i ncl usi o n/ excl usi o n crit eri a, r e vi e w of m e dic al hist ory 
r e vi e w, r e vi e w of pri or a n d c o nc o mit a nt m e dic ati o n r e vi e w, a n d a n 
ass ess m e nt of M ost B ot h ers o m e S y m pt o m of v a gi n al a n d v ul v ar atr o p h y 
( V V A) will b e p erf or m e d. S u bj ects w ill als o b e gi v e n i nstr ucti o ns f or st u d y 


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P a g e 7 of 5 1  
m e dic ati o n  a p plic ati o n a n d a s u bj ect di ar y t o c o m pl et e at h o m e.  
 
At Visit 2/ R a n d o miz ati o n ( D a y 1)  – T h e f oll o wi n g will b e c o n d uct e d: a 
r e vi e w of i ncl usi o n/ excl usi o n crit eri a , A E’s a n d c o nc o mit a nt m e dic ati o ns. 
V it al si g ns will b e o bt ai n e d  a n d  a n ass ess m e nt of M ost B ot h ers o m e 
S y m pt o m of v a gi n al a n d v ul v ar atr o p h y ( V V A) will b e p erf or m e d  a n d 
s u bj ects will b e assi g n e d t o o n e of t h e tr e at m e nt ar ms: T est Pr o d uct, 
R ef er e nc e Pr o d uct, or V e hicl e.  
 
At Visit 3/ E n d of St u d y 
 - Su bj ects will h a v e a p h ysic al ex a m 
(i ncl u di n g br e ast a n d p elvic ex a m), r o uti n e bl o o d t ests o bt ai n e d, vit al si g ns 
o bt ai n e d, v a gi n al p H, v a gi n al cyt ol o g y p erf or m e d; a n d a n ass ess m e nt of 
V V A s y m pt o ms i ncl u di n g  t h e Most B ot h ers o m e Sy m pt o m t h at w as 
i d e ntifi e d at b as eli n e will b e d o n e. Ad v ers e e v e nts ( A Es) a n d c o nc o mit a nt 
m e dic ati o ns will als o b e r ec or d e d. S u bj ect di ari es a n d r e m ai ni n g st u d y 
m e dic ati o n will b e c oll ect e d a n d s u bj ect s will b e disc h ar g e d fr o m t h e st u dy.  
S T U D Y 
P O P UL A TI O N:  
P ost -m e n o p a us al f e m al e s u bj ects t h at m e et t h e i ncl usi o n/ excl usi o n crit eri a 
will b e e nr oll e d i n t his tri al. P ost m e n o p a us al is d efi n e d as 1 2 m o nt hs of 
s p o nt a n e o us a m e n orr h e a, 6 m o nt hs of s p o nt a n e o us a m e n orr h e a wit h 
s er u m f ollicl e-sti m ul ati n g h or m o n e ( F S H) l ev els > 4 0 mI U/ ml , 6 w e e ks 
p osts ur gic al bil at er al o o p h or ect o my wit h or wit h o ut hyst er ect o my 2, or 
hyst er ect o my wit h o ut o o p h or ect o my wit h F S H l ev els >  4 0 mI U/ m l. 
 s u bj ects will b e r a n d o miz e d, i n or d er t o c o m pl et e at 
l e ast 
 m o difi e d  i nt e nt-t o-tr e at (m I T T) s u bj ects a n d  
 p er -pr ot oc ol ( P P) 
s u bj ects. 
D O SI N G & 
A D MI NI S T R A TI O N  
S u bj ects will b e r a n d o miz e d 
 t o r ec ei v e o n e of t h e t hr e e 
tr e at m e nts: Estr a di ol V a gi n al Cr e a m 0. 0 1 % ( P erri g o U K F I N C O); E S T R A C E® 
( estr a di ol) Va gi n al C r e a m, U S P, 0. 0 1 % (W ar n er C hilc ott ( U S), LL C ) or V e hicl e  
(P erri g o U K F I N C O). S u bj ects will a p pl y 2 gr a ms of t h e assi g n e d tr e at m e nt 
o nc e d ail y  i ntr a v a gi n all y at  b e d ti m e  f or 7 d a ys at a p pr oxi m at el y t h e s a m e 
ti m e e ac h d a y.  
K E Y I N CL U SI O N 
C RI T E RI A  
•  S u bj ect is a p ost m e n o p a us al f e m al e a n d ot h er wis e h e alt h y , 3 0 – 7 5 
y e ars of a g e, i ncl usi v e .    
•  H as ≤ 5 % s u p erfici al c ells o n v a gi n al s m e ar cyt ol o g y at Visit 
1/ Scr e e ni n g.  
•  H as a v a gi n al p H > 5. 0 at Visit 1/ Scr e e ni n g.  
•  S u bj ect s h o ul d h a v e at l e ast o n e s elf -ass e ss e d  m o d er at e t o s e v er e 
s y m pt o m of V V A fr o m t h e f oll o wi n g list t h at is i d e ntifi e d b y t h e 
s u bj ect as b ei n g t h e m ost b ot h ers o m e t o h er:  
1.  V a gi n al dr y n ess  
2.  V a gi n al a n d/ or v ul v ar irrit ati o n/itc hi n g  


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3.  D ys uri a  
4.  V a gi n al p ai n ass oci at e d wit h s ex u al acti vit y  
5.  V a gi n a l bl e e di n g ass oci at e d wit h s ex u al acti vit y (if i d e ntifi e d 
as M ost B ot h ers o m e S y m pt o m, t his  s y m pt o m is ass ess e d as 
pr es e nt)  
•  F or w o m e n wit h a n i nt act ut er us, v a gi n al ultr as o n o gr a p h y 
c o nfir m ati o n at Visit 1/ Scr e e ni n g of a n i n acti v e e n d o m etri al li ni n g 
wit h a n e n d o m etri al t hick n ess l ess t h a n 4 m m.  
•  S u bj ect s h o ul d h a v e s yst olic bl o o d pr ess ur e n o gr e at er t h a n 1 5 0 m m 
H g a n d di ast olic bl o o d pr ess ur e n o gr e at er t h a n 9 0 m m H g at Visit 
1/ Scr e e ni n g a n d at Visit 2/ R a n d o miz ati o n . 
K E Y E X CL U SI O N 
C RI T E RI A  
•  U n di a g n os e d v a gi n al  bl e e di n g or a hist or y of si g nific a nt ris k f act ors 
f or e n d o m etri al c a nc er. 
•  S u bj ect h as k n o w n, s us p ect e d, or hist or y of c a nc er of t h e br e ast or 
m a m m o gr a m i n dic ati n g a n y a b n or m aliti es or s u bj ect h as a hist or y 
of c er vic al c a nc er.  
•  V a gi n al ultr as o n o gr a p h y f or a ll w o m e n wit h a n i nt act ut er us 
c o nfir mi n g e n d o m etri al t hic k n ess of 4 m m or m or e  
•  S u bj ect h as a hist or y of hy p ers e nsiti vit y or all er g y t o estr a di ol or a n y 
of t h e ot h er st u d y m e dic ati o n i n gr e di e nts.  
•  
. 
•  
 
 
•  
 
. 
•  
. 
•  S u bj ect is c urr e ntl y r ec eivi n g tr e at m e nt wit h estr o g e ns or r ec ei v e d 
o n e m or e r ec e ntl y t h a n t h e p eri o ds list e d u n d er S ecti o n 4. 2 of t h e 
pr ot oc ol.  
E V AL U A TI O N S  
V a gi n al cyt ol o g y  a n d  v a gi n al p H, will b e e v al u at e d at D a y -1 4  t o -1 
( Scr e e ni n g) a n d D a y 8 ( E n d of St u d y).   
 
 M ost B ot h ers o m e S y m pt o m of V V A will b e e v al u at e d at  D a y -1 4 t o -1 
( Scr e e ni n g), D a y 1 ( R a n d o miz ati o n ) a n d D a y 8 ( E n d of St u d y).  
 
S af et y  will b e e v al u at e d b as e d o n s p o nt a n e o us a n d elicit e d r e p orts of 
a d v ers e e v e nts.   
E N D P OI N T S  
T h e pri m ar y e n d p oi nt  of t h e st u d y is t h e pr o p orti o n of s u bj ects i d e ntifi e d 
as r es p o n d ers at  Visit 3/ E n d of St u d y. A r es p o n d er is d efi n e d as a s u bj ect 
wit h at l e ast  a 2 5 % r e d ucti o n fr o m b as eli n e  ( Visit 1/ Scr e e ni n g) i n t h e s u m 
of % ( p erc e nt) b as al/ p ar a b as al + % ( p erc e nt) i nt er m e di at e c ells o n v a gi n al 


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cyt ol o g y A N D v a gi n al p H < 5. 0 wit h a c h a n g e fr o m Visit 1/ Scr e e ni n g   v a gi n al 
p H of at l e ast 0. 5.  
  
T h e s ec o n d ar y e n d p oi nt will b e t h e pr o p orti o n of s u bj ects wit h tr e at m e nt 
s ucc ess b as e d o n t h e i m pr o v e m e nt (c h a n g e fr o m b as eli n e ( Visit 
2/ R a n d o miz ati o n) ) of t h e M ost B ot h ers o m e S y m pt o m of V V A at Visit 3/ E n d 
of St u d y.  Tr e at m e nt s ucc ess is d efi n e d as a c h a n g e fr o m b as eli n e w hic h 
will r es ult i n a sc or e of 0 ( n o n e) or 1 ( mil d) at Visit 3 if t h e M ost 
B ot h ers o m e S y m pt o m is v a gi n al dr y n ess, v a gi n al or v ul v ar irrit ati o n or 
itc hi n g, d ys uri a a n d v a gi n al p ai n ass oci at e d wit h s ex u al acti vit y. If t h e M ost 
B ot h ers o m e S y m pt o m is v a gi n al bl e e di n g ass oci at e d wit h s ex u al acti vit y 
t h e n tr e at m e nt s ucc ess will b e a bs e nc e of v a gi n al bl e e di n g ass oci at e d wit h 
s ex u al acti vit y as r e p ort e d at t h e e n d of t h e st u d y.  
  
S af et y a n al ysis : T h e i nci d e nc e of all A Es r e p ort e d d uri n g t h e st u d y will b e 
s u m m ariz e d b y tr e at m e nt gr o u p. E q ui v al e nc e of t h e t est a n d r ef er e nc e 
wit h r e g ar d t o s af et y will b e e v al u at e d b y c o m p ari n g t h e n at ur e, s e v erit y 
a n d fr e q u e ncy of t h eir a d v ers e e v e nt pr ofil es.  
S T A TI S TI C AL 
M E T H O D S  
D at a S ets t o b e A n al yz e d:  
 
A n I T T  s af et y s u bj ect is a n y s u bj ect w h o: ( a) was r a n d o miz e d i nt o t h e st u dy 
a n d ( b) a p pli e d at l e ast 1 d os e of assi g n e d st u d y m e dic ati o n i ntr a v a gi n ally.  
 
A m o difi e d i nt e nt-t o-tr e at (m I T T) s u bj ect is a n y s u bj ect w h o: ( a) w as 
r a n d o miz e d i n t h e st u d y, ( b) a p pli e d at l e ast 1 d os e of assi g n e d st u d y 
m e dic ati o n i ntr a v a gi n ally, (c) c o m pl et e d at l e ast o n e p ost r a n d o miz ati o n 
ass ess m e nt , a n d ( d) m et eli gi bilit y crit eri a. 
 
A p er -pr ot oc ol ( P P) s u bj ect , is a n y s u bj ect w h o: ( a) w as  r a n d o miz e d i n t h e 
st u d y aft er m eet i n g all i ncl usi o n/ excl usi o n crit eri a, ( b) h a d n ot t a k e n a n y 
c o nc o mit a nt m e dic ati o ns pr o hi bit e d b y t h e pr ot oc ol n or h a d a n y ot h er 
si g nific a nt pr ot oc ol vi ol ati o ns; (c) r et ur n e d f or Visit 3/ E n d of St u d y wit hi n 
t h e d esi g n at e d visit wi n d o w  
 wit h d at a o n th e pri m ar y effic acy 
e n d p oi nt a n d , d) h a d a c o m pli a nc e r at e 
 O R 
disc o nti n u e d t h e st u d y d u e t o l ac k of tr e at m e nt eff ect
 
 
 
Effic acy A n al ysis:  
F or bi o e q ui v al e nc e, t h e diff er e nc e i n t h e pr o p orti o n of r es p o n d ers at Visit 
3/ E n d of St u d y will b e e v al u at e d usi n g a 2 -si d e d 9 0 % c o nfi d e nc e i nt er v al by 
W al d’s m et h o d wit h Y at es’ c o nti n uit y c orr ecti o n b as e d o n t h e d at a p o ol e d 
fr o m all cli nic al sit es f or t h e P P p o p ul ati o n. Th e t h er a p e utic e q ui v al e nc e of 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 1 0  of 5 1  
t h e T est pr o d uct a n d t h e R ef er e nc e pr o d uct will b e est a blis h e d if t h e 9 0 % 
c o nfi d e nc e i nt er v al is c o nt ai n e d wit hi n t h e li mits of – 0. 2 0 t o + 0. 2 0.  
 
T o ass ur e t h at t h e st u d y is s e nsiti v e e n o u g h t o s h o w a si g nific a nt diff er e nc e 
b et w e e n t h e acti v e pr o d ucts a n d t h e V e hicl e , t h e t est a n d r ef er e nc e 
pr o d ucts will b e  c o m p ar e d f or t h eir st atistic al s u p eri orit y t o V e hicl e  ( α 
= 0. 0 5, 2 -si d e d c o nti n uit y-c orr ect e d Z-t ests) f or pr o p orti o n of r es p o n d ers 
usi n g t h e m I T T p o p ul ati o n.  
 
S af et y A n al ysis:  
A d v ers e e v e nts will b e cl assifi e d o n t h e b asis of M e d D R A ( V ersi o n 1 8. 1 ) 
t er mi n ol o g y (s yst e m or g a n cl ass es a n d pr ef err e d t er ms) a n d s u m m ariz e d 
f or e ac h tr e at m e nt gr o u p . I nci d e nc e of a d v ers e ev e nts will b e s u m m ariz e d 
b y s yst e m or g a n cl ass a n d pr ef err e d t er m, a n d f urt h er b y s e v erit y a n d 
r el ati o ns hi p t o st u d y m e dic ati o n. Pr o p orti o ns of s u bj ects r e p orti n g a n y 
tr e at m e nt-e m er g e nt a d v ers e e v e nts will b e c o m p ar e d b et w e e n t h e 2 acti v e 
tr e at m e nts usi n g C hi-S q u ar e or Fis h er’s ex act t est if a p pr o pri at e.  
 
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 1 1  of 5 1  
 
A B B R E VI A TI O N S  
 
 
A C O G  
A m eric a n C oll e g e of O bst etrici a ns a n d G y n ec ol o gists  
A E  
A d v ers e E v e nt  
C R F  
C as e R e p ort F or m  
F D A  
U S F o o d a n d Dr u g A d mi nistr ati o n  
F S H  
F ollicl e Sti m ul ati o n Sti m ul ati n g H or m o n e  
G C P  
G o o d Cli nic al Pr actic e  
I C H 
I nt er n ati o n al C o nf er e nc e o n H ar m o niz ati o n  
I R B 
I nstit uti o n al R e vi e w B o ar d 
I T T 
I nt e nt T o Tr e at P o p ul ati o n  
LO C F  
L ast O bs er v ati o n C arri e d F or w ar d 
Mc g  
Micr o gr a m  
M e d D R A  
M e dic al Dicti o n ar y f or R e g ul at or y Acti viti es  
MI  
M at ur ati o n I n d ex  
O T C  
Ov er t h e C o u nt er  
PI  
Pri nci p al I n v esti g at or 
P P  
P er Pr ot oc ol P o p ul ati o n  
Rx  
Pr escri pti o n  
S A E  
S eri o us A d v ers e E v e nt  
S A P  
St atistic al A n al ysis Pl a n  
U TI  
Uri n ar y Tr act I nf ecti o n  
V V A  
V ul v ar  a n d V a gi n al Atr o p h y  






Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 1 4  of 5 1  
t est or Fis h er’s Ex act t est, w hic h e v er is m ost a p pr o pri at e, will b e us e d t o c o m p ar e t h e 
pr o p orti o ns of s u bj ects i n t h e t w o acti v e tr e at m e nt gr o u ps w h o r e p ort a ny a d v ers e e v e nts.  
 
 
3  
S T U D Y D E SI G N  
3. 1  
T y p e/ D esi g n of st u d y  
S u bj ects i n t his m ulti -c e nt er, d o u bl e-bli n d, r a n d o miz e d, v e hicl e -c o ntr oll ed, p ar all el -gr o u p st u d y 
will b e assi g n e d 
 t o t est pr o d uct, r ef er e nc e pr o d uct, or v e hicl e, r es p ecti v el y. 
S u bj ects will r ec ei v e o n e 
 t u b e of t h e r a n d o ml y assi g n e d st u d y m e dic ati o n , whic h 2 
gr a ms will b e a p pli e d o nc e d ail y i ntr a v a gi n all y f or 7 d a ys usi n g t h e pr o vi d e d a p plic at or  at b e d 
ti m e. S u bj ects will b e h e alt h y p ost m e n o p a us al f e m al es, 3 0 -7 5 y e ars of a g e, i ncl usi v e, s el ect e d 
o n v a gi n al cyt ol o g y crit eri a of l ess t h a n or e q u al t o 5 % s u p erfici al c ells a n d v a gi n al p H gr e ater 
t h a n 5. 0, w h o d o n ot h a v e c o ntr ai n dic ati o ns f or h or m o n e r e pl ac e m e nt t h er a p y wit h estr a di ol. 
S u bj ects will b e e v al u at e d at D a y 8 (aft er 7 d a ys of tr e at m e nt)  f or t h e c h a n g e i n v a gi n al 
cyt ol o g y, v a gi n al p H a n d M ost B ot h ers o m e S y m pt o m of V V A  fr o m b as eli n e. 
 
 s u bj ects will b e r a n d o miz e d t o o bt ai n a p pr oxi m at el y 
 m o difi e d i nt e nt-t o-
tr e at (m I T T) s u bj ects 
 a n d  
 p er -pr ot oc ol ( P P) s u bj ects.  E nr oll m e nt will 
c o nti n u e u ntil a s uffici e nt n u m b er of P P s u bj ects h a v e  b e e n o bt ai n e d .    
 
T o q u alif y f or e nr oll m e nt i n t h e st u d y , s u bj ects m ust b e h e alt h y p ost m e n o p a us al f e m al es, 
(P ost m e n o p a us al is d efi n e d as 1 2 m o nt hs of s p o nt a n e o us a m e n orr h e a or 6 m o nt hs of 
s p o nt a n e o us a m e n orr h e a wit h s er u m F S H l ev els > 4 0 mI U/ ml or 6 w e e ks p osts ur gic al bil at er al 
o o p h or ect o my wit h or wit h o ut hyst er ect o my 2 or hyst er ect o my wit h o ut o o p h or ect o my wit h F S H 
l ev els > 4 0 mI U/ ml), a n d b et w e e n t h e a g e of 3 0 -7 5, i ncl usi v e. All s u bj ects m ust r e vi e w a n d si g n 
t h e I R B-a p pr o v e d i nf or m e d c o ns e nt d oc u m e nt pri or t o t h e i niti ati o n of a n y st u d y -r el at e d 
pr oc e d ur es.   S u bj ects will b e r a n d o miz e d i nt o t h e st u d y aft er i nf or m e d c o ns e nt h as b e e n 
o bt ai n e d a n d aft er all i ncl usi o n/ excl usi o n crit eri a h a v e b e e n m et .  
 
T o b e eli gi bl e f or i ncl usi o n i n t h e st u d y , s u bj ects must h a v e l ess t h a n or e q u al t o 5 % s u p erfici al 
c ells o n v a gi n al s m e ar cyt ol o g y a n d a v a gi n al p H gr e at er t h a n 5. 0.  S u bj ects s h o ul d als o h a v e at 
l e ast o n e s elf-ass ess e d m o d er at e t o s e v er e s y m pt o m of v ul v ar a n d v a gi n al atr o p h y ( V V A) o n a 
sc al e of 0 – 3 fr o m t h e f oll o wi n g list t h at is i d e ntifi e d b y t h e s u bj ect as b ei n g m ost b ot h ers o m e 
t o h er ( M ost B ot h ers o m e S y m pt o m):  
 
•  V a gi n al dr y n ess  
•  V a gi n al a n d/ or v ul v ar irrit ati o n/itc hi n g  
•  D ys uri a  
•  V a gi n al p ai n ass oci at e d wit h s ex u al acti vit y  
•  V a gi n al bl e e di n g ass oci at e d wit h s ex u al ac ti vit y (if i d e ntifi e d as M ost B ot h ers o m e 
S y m pt o m  at b as eli n e , t his s y m pt o m is ass ess e d as pr es e nt) 
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 1 5  of 5 1  
T h e s elf -ass ess e d s y m pt o ms will b e e v al u at e d o n a sc al e  of  0 = n o n e , 1 = mil d, 2 = m o d er at e a n d 
3 =s e v er e , wit h t h e exc e pti o n of v a gi n al bl e e di n g ass oci at e d wit h s ex u al acti vit y, w hic h will b e 
n ot e d as pr es e nt or a bs e nt . 
 
S u bj ects will visit t h e st u d y c e nt er at Visit 1/ Scr e e ni n g – ( D a y -1 4  t o D a y -1). At t his visit, s u bj ects 
will r e vi e w a n d si g n t h e st u d y s p ecific I C F c o m pl et e a p h ysic al ex a m (i ncl u di n g br e ast a n d p el vic 
ex a m ), a uri n e pr e g n a ncy t est will b e p erf or m e d a n d Visit 2/ R a n d o miz ati o n  will b e sc h e d ul e d .  
A n o n -f asti n g bl o o d s a m pl e, vit al si g ns, v a gi n al ultr as o u n d  (f or all w o m e n wit h a n i nt act ut er us), 
v a gi n al cyt ol o g y, m a m m o gr a p h y (if o v er 4 0 y e ars of a g e a n d n ot d o n e wit hi n t h e l ast 9 m o nt hs 
of st u d y e nr oll m e nt), P a p t est (if n ot c o n d uct e d wit hi n t h e l ast 1 2 m o nt hs),  a n d v a gi n al p H  will 
als o b e o bt ai n e d.  R e vi e w of i ncl usi o n/ excl usi o n crit eri a, m e dic al hist or y, pri or a n d c o nc o mit a nt 
m e dic ati o n s will als o b e r e vi e w e d. T h e s u bj ect will als o b e gi v e n a di ar y t o b e us e d t hr o u g h o ut 
t h e st u d y.  I n a d diti o n, a n ass ess m e nt  of M ost B ot h ers o m e S y m pt o m of v a gi n al a n d v ul v ar 
atr o p h y ( V V A) will b e p erf or m e d.  
 
At Visit 2/ R a n d o miz ati o n ( D a y 1)  – T h e f oll o wi n g pr oc e d ur es  will b e c o n d uct e d:  
i ncl usi o n/ excl usi o n crit eri a, A E’s a n d c o nc o mit a nt m e dic ati o ns will b e ass ess e d  t hr o u g h r e vi e w 
of t h e s u bj ect di ar y gi v e n at Visit 1 , vit al si g ns will b e o bt ai n e d,  a n ass ess m e nt of t h e M ost 
B ot h ers o m e S y m pt o m will  b e c o m pl et e d, a n d t h e s u bj ect will b e assi g n e d t o o n e of t h e 
tr e at m e nt ar ms: T est Pr o d uct or R ef er e nc e Pr o d uct or V e hicl e. S u bj ect will  als o  b e gi v e n 
i nstr ucti o ns f or st u d y m e dic ati o n  a p plic ati o n .  
 
At Visit 3/ E n d of St u d y ( D a y 8 , + 3  d a ys)  -  Su bj ects will h a v e a p h ysic al ex a m  c o n d uct e d 
(i ncl u di n g br e ast a n d p elvic ex a m), vit al si g ns, cli nic al l a bs, v a gi n al p H, a n d v a gi n al cyt ol o g y  
c oll ect e d; a n d a n  ass ess m e nt of V V A s y m pt o ms i ncl u di n g M ost B ot h ers o m e S y m pt o m  
i d e ntifi e d.  A d v ers e e v e nts ( A Es) a n d c o nc o mit a nt m e dic ati o ns will b e r ec or d e d  I n a d diti o n, 
su bj ect di ari es a n d r e m ai ni n g st u d y m e dic ati o n will b e c oll ect e d  fr o m t h e s u bj ect pri or t o t h e 
s u bj ect b ei n g disc h ar g e d fr o m t h e st u d y.   
 
3. 2  
St u d y P o p ul ati o n:  
P ost -m e n o p a us al f e m al e s u bj ects t h at m e et t h e i ncl usi o n/ excl usi o n crit eri a will b e r a n d o miz e d 
i n t his tri al. P ost m e n o p a us al is d efi n e d as  1 2 m o nt hs of s p o nt a n e o us a m e n orr h e a , 6 m o nt hs of 
s p o nt a n e o us a m e n orr h e a wit h s er u m f ollicl e-sti m ul ati n g h or m o n e ( F S H) l ev els > 4 0 mI U/ ml, 6 
w e e ks p osts ur gic al bil at er al o o p h or ect o my wit h or wit h o ut hyst er ect o my 2, or hyst er ect o my 
wit h o ut o o p h or ect o my wit h F S H l ev els > 4 0 mI U/ ml . 
 
 s u bj ects will b e r a n d o miz e d, i n or d er t o c o m pl et e at l e ast 
 m o difi e d 
i nt e nt-t o-tr e at (m I T T) s u bj ects a n d 
 p er -pr ot oc ol ( P P) s u bj ects.  
 
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 1 6  of 5 1  
4  
S U BJ E C T S EL E C TI O N  
4. 1  
I ncl usi o n Crit eri a 
A s u bj ect M U S T  m e et all  of t h e f oll o wi n g crit eri a:  
1.  Willi n g a n d a bl e t o u n d erst a n d a n d pr o vi d e writt e n i nf or m e d c o ns e nt .  
2.  H e alt h y p ost m e n o p a us al f e m al e s, 3 0 – 7 5 y e ars of a g e, i ncl usi v e .  
 
 
  
 
 
 
  
 
 
 
 
  
3.  H a v e ≤ 5 % s u p erfici al c ells o n v a gi n al  s m e ar cyt ol o g y at Visit 1/ Scr e e ni n g. 
4.  H a v e a v a gi n al p H > 5. 0 at Visit 1/ Scr e e ni n g.  
5.  H a v e at l e ast o n e s elf -ass ess e d m o d er at e t o s e v er e s y m pt o m of V V A o n a sc al e of 0 
– 3 fr o m t h e f oll o wi n g list t h at is i d e ntifi e d b y t h e s u bj ect as b ei n g m ost b ot h ers o m e 
t o h er:  
•  V a gi n al dr y n ess  
•  V a gi n al a n d/ or v ul v ar irrit ati o n/itc hi n g  
•  D ys uri a  
•  V a gi n al p ai n ass oci at e d wit h s ex u al acti vit y  
•  V a gi n al  bl e e di n g  ass oci at e d  wit h  s ex u al  acti vit y  (if  i d e ntifi e d  as  M ost 
B ot h ers o m e  S y m pt o m  at  Visit  / Scr e e ni n g,  t his  s y m pt o m  is  ass ess e d  as  
pr es e nt  or a bs e nt ) 
6.  F or w o m e n wit h i nt act ut er us, v a gi n al ultr as o n o gr a p h y at Visit 1 / Scr e e ni n g of a n 
i n acti v e e n d o m etri al li ni n g, wit h a n e n d o m etri al t hic k n ess l ess t h a n 4 m m.  
7.  S yst olic bl o o d pr ess ur e is n o gr e at er t h a n 1 5 0 m m H g a n d di ast olic bl o o d pr ess ur e is 
n o gr e at er t h a n 9 0 m m H g at Visit 1/ Scr e e ni n g a n d at Visit 2/ R a n d o miz ati o n . 
8.  F or w o m e n o v er t h e a g e of 4 0, a n e g ati v e m a m m o gr a m or cli nic all y n ot si g nific a nt 
fi n di n gs o n m a m m o gr a m 
 
 
 
. 
9.  N or m al  or  n ot  cli nic all y si g nific a nt  fi n di n gs  o n  br e ast  ex a mi n ati o n  at  Visit  
1/ Scr e e ni n g.  
1 0.  D oc u m e nt e d  P a p  s m e ar  c o n d uct e d  wit hi n  t h e  pr e vi o us  1 2  m o nt hs  of  Visit  
1/ Scr e e ni n g/ or at Visit 1/ Scr e e ni n g wit h n o fi n di n gs t h at t h e I n v esti g at or b eli e v es 
w o ul d n ot all o w f or t h e us e of t o pic al v a gi n al estr a di ol.   Pr e vi o us P a p t est r es ults  
a n d d oc u m e nt ati o n m ust  b e a v ail a bl e  f or s u bj ects usi n g pr e vi o us r es ults. 
1 1.  I n g e n er al g o o d h e alt h wit h n o cli nic all y si g nific a nt dis e as e t h at mi g ht i nt erf er e wit h 
t h e tr e at m e nt or ass ess m e nts. 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 1 7  of 5 1  
1 2.  Willi n g a n d a bl e t o c o m pl y wit h t h e r e q uir e m e nts of t h e st u d y, p artic ul arl y wit h 
r es p ect t o tr e at m e nt d osi n g r e q uir e m e nts, visit sc h e d ul e, t h er a p y pr o hi biti o ns, di ary 
c o m pl eti o n, a n d m ust b e a bl e t o c o m pl et e t h e st u d y as s p ecifi e d i n t h e pr ot oc ol.  
 
4. 2  
E xcl usi o n Crit eri a  
A s u bj ect m a y N O T b e s el ect e d if a n y  of t h e f oll o wi n g crit eri a exist:  
 
1.  
. 
2.  H as u n di a g n os e d  v a gi n al bl e e di n g. 
3.  F e m al es wit h a n i nt act ut er us, h a vi n g a n e n d o m etri al t hic k n ess of 4 m m or m or e 
d uri n g t h e scr e e ni n g visit vi a v a gi n al ultr as o n o gr a p h y.  
4.  Hist or y  of  h y p ers e nsitivit y  or  all er g y  t o  estr a di ol  or  a n y  of  t h e  ot h er  st u d y  
m e dic ati o n i n gr e di e nts. 
5.  
 
 
 
6.  
 
7.  
. 
8.  
 
9.  
 
 
 
1 0.  A b n or m al P a p s m e ar wit hi n t h e pr e vi o us 1 2 m o nt hs of Visit 1/ Scr e e ni n g or o bt ai n e d 
d uri n g Visit 1/ Scr e e ni n g  a n d d e e m e d cli nic all y si g nific a nt b y t h e i n v esti g at or.  A n y 
e vi d e nc e  of  m ali g n a ncy  or  pr e m ali g n a nt  c h a n g es;  or  At y pic al  S q u a m o us  C ell  of  
U n d et er mi n e d Si g nific a nc e ( A S C -U S) P a p wit h p ositi v e hi g h ris k H P V.  
1 1.  
 
 
1 2.  
 
 
1 3.  H as k n o w n  ac ut e or c hr o nic h e p atic dis e as e or d ysf u ncti o n.  
1 4.  
  
1 5.  
. 
1 6.  S u bj ect c o ns u m es exc essi v e alc o h ol, a b us es dr u gs, or h as a c o n diti o n t h at c o ul d 
c o m pr o mis e t h e s u bj ect’s a bilit y t o c o m pl y wit h st u d y r e q uir e m e nts a n d/ or h a v e 
dr u g or alc o h ol a d dicti o n r e q uiri n g tr e at m e nt i n t h e p ast 1 2 m o nt hs . 
1 7.  A n y cli nic all y si g nific a nt c o n diti o n or sit u ati o n (i ncl u di n g l a b or at or y v al u es) or us e of 
a n y m e dic ati o n w hic h, i n t h e o pi ni o n of t h e I n v esti g at or, mi g ht i nt erf er e wit h t h e 
c o n d uct or r es ults of t h e st u d y or pl ac e t h e pr os p ecti v e s u bj ect at i ncr e as e d ris k . 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 1 8  of 5 1  
1 8.  S u bj ect is c o nc urr e ntl y p artici p ati n g i n a n ot h er i n v esti g ati o n al st u d y i nv ol vi n g a ny 
i n v esti g ati o n al dr u g, bi ol o gic, or d e vic e or usi n g a n y  i n v esti g ati o n al dr u g, bi ol o gic, or 
d e vic e wit hi n t h e 3 0 d a ys pri or t o Visit 1/ Scr e e ni n g.  
1 9.  S u bj ect h as pr e vi o usl y e n r oll e d i n t his st u d y r e g ar dl ess of l oc ati o n. 
2 0.  
 
 
2 1.  S u bj ect is u n willi n g t o si g n t h e i nf or m e d c o ns e nt f or m  or u n willi n g t o c o m pl y wit h 
t h e pr ot oc ol r e q uir e m e nts. 
2 2.   S u bj ect is pr e g n a nt or b ec o m es pr e g n a nt d uri n g t h e c o urs e of t h e tri al.  
2 3.  S u bj ect is r ec ei vi n g a n y tr e at m e nt list e d i n t h e t a bl e b el o w m or e r ec e ntly t h a n t h e 
i n dic at e d p eri o d pri or t o Visit 1/ Scr e e ni n g a n d Visit 2/ R a n d o miz ati o n will excl u d e 
t h e s u bj ect i n t his st u d y: 
 
Pr o hi bit e d M e dic ati o ns  
Pr o hi bit e d P eri o d Pri or t o 
Visit 1/ Scr e e ni n g a n d Visit 
2/ R a n d o miz ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 1 9  of 5 1  
4. 3  
Pr ec a uti o ns  
T h e f oll o wi n g pr ec a uti o ns ar e t o b e t a k e n d uri n g t his st u d y:  
1.  
S u bj ects s h o ul d a v oi d c o nt act of t h e st u d y m e dic ati o n wit h ot h er p arts of t h e b o d y 
ot h er t h a n t h e i nt e n d e d tr e at m e nt ar e a .  
2.  
W as h h a n ds b ef or e a n d aft er a p pl yi n g st u d y m e dic ati o n . Su bj ect s s h o ul d b e i nstr uct e d 
t h at t h e pr o d uct is o nl y f or i ntr a v a gi n al us e.  
3.  
St or e st u d y m e dic ati o n at c o ntr oll e d r o o m t e m p er at ur e 1 5° -3 0° C ( b el o w 8 6° F). D o n ot 
r efri g er at e or fr e ez e.  
4.  
K e e p t his m e dic ati o n o ut of t h e r e ac h of c hil dr e n.  
5.  
S u bj ects  s h o ul d  c o ns ult  t h e  In v esti g at or  wit h  a n y  q u esti o ns  r e g ar di n g  c o nc o mit a nt  
m e dic ati o ns.  
6.  
T h e pr o d uct s h o ul d n ot b e a p pli e d m or e t h a n o nc e d ail y  a n d s u bj ects s h o ul d n ot us e 
m or e t h a n t h e r ec o m m e n d e d a m o u nt.  
7.  
S u bj ects s h o ul d i m m e di at el y n otif y t h e st u d y sit e st aff if t h e y ex p eri e nc e a n y u n us u al 
v a gi n al bl e e di n g d uri n g t h e st u d y.   
8.  
 S u bj ects s h o ul d  b e i nf or m e d t h at estr o g e n i ncr e as es t h e ris k of g all bl a d d er dis e as e or 
li v er pr o bl e ms.  S u bj ects s h o ul d n otif y t h e st u d y st aff if t h e y ex p eri e nc e a b d o mi n al p ai n, 
y ell o wi n g of t h e s ki n, e y es or n ail b e ds.  
9.  
S u bj ects s h o ul d b e i nf or m e d t h at estr o g e ns m a y i ncr e as e t h e c h a nc es of g etti n g c ert ai n 
t y p es of c a nc ers, i ncl u di n g c a nc er of t h e br e ast or ut er us. 
1 0.  
S u bj ects s h o ul d b e i nf or m e d t h at estr o g e n -al o n e t h er a p y i ncr e as es t h e ris k of str o k e, 
d e e p -v ei n t hr o m b osis ( D V T), pr o b a bl e d e m e nti a.  S u bj ects s h o ul d n otify st u d y st aff if 
t h e y ex p eri e nc e c h a n g es i n s p e ec h, s h ort n ess of br e at h, p ai n i n l e gs. 
1 1.  
If s u d d e n p arti al or c o m pl et e l oss of visi o n occ urs, s u bj ects s h o ul d n otif y st u d y st aff 
i m m e di at el y a n d disc o nti n u e st u d y m e dic ati o n.  
1 2.  
S u bj ects  s h o ul d  b e  i nf or m e d  t h at  s u bst a nti al i ncr e as e  i n  bl o o d  pr ess ur e  a n d  
h y p ertri gl yc eri d e mi a h as  b e e n r e p ort e d wit h estr o g e n t h er a p y.  
 
 
5  
S T U D Y P R O C E D U R E S  
5. 1  
S u bj ect Scr e e ni n g a n d E nr oll m e nt  
T h e st u d y p ers o n n el will r e vi e w t h e I R B a p pr o v e d i nf or m e d c o ns e nt f or m wit h e ac h s u bj ect a n d 
gi v e t h e s u bj ect a n o p p ort u nit y t o h a v e all q u esti o ns a ns w er e d b ef or e pr oc e e di n g.  T h e 
i nf or m e d c o ns e nt f or m m ust b e si g n e d b y e ac h s u bj ect a n d wit n ess e d b ef or e a n y st u d y r el at e d 
pr oc e d ur es ar e p erf or m e d or t h e s u bj ect is e nr oll e d i nt o t h e st u d y.  A c o py of t h e si g n ed 
c o ns e nt will b e gi v e n t o e v er y s u bj ect a n d t h e ori gi n al will b e m ai nt ai n e d b y t h e I n v esti g at or 
wit h t h e p artici p a nt’s r ec or ds.   
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 2 0  of 5 1  
5. 2  
Assi g n m e nt of S u bj ect N u m b er  
 
 
 
 
 
  
 
5. 3  
D e m o gr a p hics/ M e dic al Hist or y  
A d e m o gr a p hic pr ofil e  will b e o bt ai n e d at Visit 1/ Scr e e ni n g, w hic h i ncl u d e s d at e of birt h, r ac e 
a n d et h nicit y.  A  m e dic al hist or y will b e r ec or d e d at Visit 1/ Scr e e ni n g, w hic h  will i ncl u d e a 
c o m pl et e  r e vi e w  of  all  p ast  a n d  c urr e nt  si g nific a nt m e dic al  c o n diti o ns/ dis e as es  a n d  t h eir  
r es p ecti v e tr e at m e nts. A d et ail e d o bst etric a n d g y n ec ol o gic al m e dic al hist or y will b e o bt ai n e d 
fr o m all s u bj ects i ncl u di n g c o nfir m ati o n of p ost m e n o p a us al st at us. 
 
5. 4  
C o nc o mit a nt a n d Pr o hi bit e d M e dic ati o ns  
C o nc o mit a nt m e dic ati o ns a n d a n y m e dic ati o ns t ak e n 
 pri or t o si g ni n g i nf or m e d 
c o ns e nt will b e r ec or d e d as pri or/c o nc o mit a nt m e dic ati o ns ( usi n g t h eir g e n eric n a m e, if k n o w n) 
wit h t h e c orr es p o n di n g i n dic ati o n. T h e m e dic ati o ns t o b e r ec or d e d will i ncl u d e pr escri pti o n ( Rx) 
a n d o v er -t h e-c o u nt er ( O T C) m e dic ati o ns a n d di et ar y s u p pl e m e nts.  All m e dic ati o ns t a k e n o n 
eit h er a r e g ul ar or as n e e d e d  b asis, i ncl u di n g vit a mi ns, as piri n a n d ac et a mi n o p h e n, s h o ul d b e 
r ec or d e d pri or t o c o m m e nci n g t h e us e of t h e st u d y m e dic ati o n.  A r ec or d of m e dic ati o n t a k e n 
b y t h e s u bj ect d uri n g t h e st u d y is t o b e o bt ai n e d at e ac h st u d y visit i ncl u di n g Visit 3/ E n d of 
St u d y/ D a y 8 .   
 
M e dic ati o ns/ Pr o d ucts  ( Pr escri pti o n a n d Ov er-t he- C o u nt er) pr o hi bit e d  at a n y ti m e  d uri n g t h e 
st u d y ar e list e d i n t h e f oll o wi n g t a bl e:  
 
 
 
 
  
  
 
 
 
 
 
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 2 1  of 5 1  
T h e m e dic ati o ns pr o hi bit e d pri or t o Visit  1 a n d t h eir pr o hi bit e d ti m e p eri o d s ar e list e d i n 
S ecti o n 4. 3. 
 
. 
 
5. 5  
Ass ess m e nt of V V A S y m pt o ms a n d M ost B ot h ers o m e S y m pt o m  
S u bj ects will s elf -r e p ort s y m pt o ms of V V A a n d t h e p erc ei v e d s e v erit y of t h e m ost b ot h ers o m e 
s y m pt o m at  Visit  1/ Scr e e ni n g,  Visit  2/ R a n d o miz ati o n  a n d  Visit  3/ E n d  of  St u d y/ D a y  8.   
S y m pt o ms t o b e e v al u at e d i ncl u d e:  
•  V a gi n al dr y n ess  
•  V a gi n al a n d/ or v ul v ar irrit ati o n/itc hi n g  
•  D ys uri a  
•  V a gi n al p ai n ass oci at e d wit h s ex u al acti vit y  
•  V a gi n al bl e e di n g ass oci at e d wit h s ex u al acti vit y ( a bs e nc e vs. pr es e nc e)  
 
E ac h s y m pt o m ( wit h t h e exc e pti o n of v a gi n al bl e e di n g ass oci at e d wit h s ex u al acti vit y) will b e 
sc or e d o n a sc al e of 0 t o 3, i n w hic h: 
 t 
S C O R E  
A S S E S S M E N T  
D E S C RI P TI O N  
0 
N o n e  
A bs e nt  
1 
Mil d  
 
2 
M o d er at e  
 
3  
S e v er e  
  
 
T h e s y m pt o m of v a gi n al bl e e di n g ass oci at e d wit h s ex u al acti vit y will b e ass ess e d as eit h er b ei n g 
pr es e nt  or  a bs e nt.   S u bj ects  will  b e  as k e d  t o  d efi n e  o n e  of  t h e  fi v e  s y m pt o ms  as  m ost  
b ot h ers o m e  t o  h er.  T h e
 
  
 
5. 6  
P h ysic al E x a mi n ati o n  
T h e ex a m will i ncl u d e 
 
 
 
 
.  
 
 
  
 
 
 
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 2 2  of 5 1  
5. 7  
P a p s m e ar  
F or  s u bj ects  wit h  a n  i nt act  ut er us  a  p a p  s m e ar,  usi n g  a  st a n d ar diz e d  pr oc e d ur e  will  b e  
p erf or m e d  at  Visit  1/ Scr e e ni n g  if  o n e  h as  n ot  b e e n  d o n e  
 a n d/ or  
d oc u m e nt ati o n c a n n ot b e r etri e v e d  a n d pr o vi d e d t o t h e st u d y c e nt er.  
 
5. 8  
V a gi n al s m e ar c yt ol o g y  
V a gi n al cyt ol o g y will b e p erf or m e d at Visit 1/ Scr e e ni n g a n d Visit 3/ D a y 8/ E n d of St u d y. V a gi n al 
s m e ars will b e c oll ect e d 
 a n d e v al u at e d 
 
. B as al/ P ar a b as al, I nt er m e di at e a n d S u p erfici al c ells will b e c o u nt e d i n a 
fi el d u p t o 1 0 0 t ot al c ells a n d pr es e nt e d as p erc e nt a g e s.  W o m e n wit h e q u al or l ess t h a n 5 % 
s u p erfici al c ells will b e i ncl u d e d i n t his st u d y. 
 
5. 9  
V a gi n al p H  
V a gi n al  p H usi n g s m e ars 
 will b e m e as ur e d  at Visit 
1/ Scr e e ni n g a n d Visit 3/ D a y 8/ E n d of St u d y.  T h e In v esti g at or or q u alifi e d d esi g n e e will us e 
st a n d ar diz e d p H p a p er f or ass ess m e nt of v a gi n al p H. W o m e n wit h v a gi n al p H gr e at er t h a n 5 . 0 
at Visit 1/ Scr e e ni n g will b e e nr oll e d i n t his st u d y.  
 
5. 1 0  Cli nic al l a b or at or y t ests:  
N o n -f asti n g cli nic al l a b or at or y t ests will b e o bt ai n e d at Visit 1/ Scr e e ni n g a n d at Visit 3/ E n d of 
St u d y/ D a y 8 f or h e m at ol o g y 
 bi oc h e mistr y, i ncl u di n g li v er p a n el t ests a n d 
F S H 
 
A b n or m al  v al u es  will  b e  ass ess e d  b y  t h e  i nv esti g at or,  s u b -i n v esti g at or  or  a p pr o pri at el y  
d el e g at e d  a n d  q u alifi e d  d esi g n e e.  Cli nic a ll y  si g nific a nt  a b n or m aliti es  m a y b e  r e p e at e d  p er  
i n v esti g at or discr eti o n a n d t h e s u bj ect excl u d e d fr o m e nr oll m e nt if t h e a b n or m aliti es p ersist. 
 
Cli nic al L a b or at or y T ests  
H e m at ol o g y  
C h e mistr y  
 
  
 
 
  
 
 
  
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 2 3  of 5 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
   
 
5. 1 1  V a gi n al ultr as o u n d  
B as eli n e v a gi n al ultr as o n o gr a p h y will b e p erf or m e d f or all w o m e n wit h a n i nt act ut er us   
. S u bj ects wit h a n e n d o m etri al t hic k n ess 
of 4 m m or m or e will n ot b e e nr oll e d i n t h e st u d y.  
 
5. 1 2  M a m m o g r a p h y 
All s u bj ects o v er t h e a g e of 4 0 y e ars, eli gi bl e f or e nr oll m e nt, s h o ul d h a v e a n e g ati v e scr e e ni n g 
m a m m o gr a m.  
 
.  If t h e s u bj ect di d 
n ot h a v e   a m a m m o gr a m i n t h e l ast 9 m o nt hs, t h e s u bj ect will r ec ei v e a m a m m o gr a m at a n 
a p pr o pri at e f acilit y as dir ect e d b y t h e st u d y c e nt er, d uri n g t h e scr e e ni n g p eri o d a n d r es ults 
m ust b e a v ail a bl e pri or t o Visit 2/ R a n d o miz ati o n . S u bj ects wit h cli nic ally si g nific a nt a b n or m al 
fi n di n gs o n t h e m a m m o gr a m will n ot b e e nr oll e d i n t h e st u d y. 
 
5. 1 3  R a n d o miz ati o n a n d tr e at m e nt  
W o m e n w h o q u alif y f or st u d y p artici p ati o n will b e r a n d o ml y assi g n e d t o T est, R ef er e nc e, or 
V e hicl e . If p ossi bl e, a n i n d e p e n d e nt t hir d -p art y dis p e ns er or d esi g n e e will dis p e ns e o n e t u b e of 
st u d y m e dic ati o n a n d a p plic at or t o t h e s u bj ect.  If a n i n d e p e n d e nt t hir d-p art y dis p e ns er is n ot 
a v ail a bl e, a n i n di vi d u al t h at is n ot a n In v esti g at or c o n d ucti n g e v al u ati o ns of t h e st u d y will 
dis p e ns e   on e t u b e of st u d y m e dic ati o n a l o n g wit h t h e acc o m p a n yi n g a p plic at or acc or di n g  t o 
t h e r a n d o miz ati o n sc h e d ul e. S u bj ects will b e i nstr uct e d t o a d mi nist er 2 gr a ms of t h e st u dy 
m e dic ati o n i ntr a v a gi n ally o nc e d ail y   
, pr ef er a bl e at t h e s a m e ti m e d uri n g t h e d a y f or 
7 d a ys .  
 
5. 1 4  St u d y m e dic ati o n us e, S u bj ect Di ar y a n d I nstr ucti o n S h e et:  
At Visit 2/ R a n d o miz ati o n ( D a y 1), o n e  
 t u b e of st u d y m e dic ati o n will b e dis p e ns e d t o 
t h e e nr oll e d s u bj ects 
 
.  S u bj ects will b e gi v e n i nstr ucti o ns h o w t o d eliv er 2 gr a ms  usi n g t h e 
a p plic at or. S u bj ects will b e a d vis e d t o a p pl y i ntr av a gi n all y 2 gr a ms of t h e st u d y m e dic ati o n o nc e 
d ail y   
 f or 7 d a ys. E ac h s u bj ect will als o r ec ei v e a c o p y of writt e n i nstr ucti o ns, w hic h 
d et ail  t h e  pr o p er  a p plic ati o n  m et h o d,  a n d  g e n er al  i nstr ucti o ns  r e g ar di n g  t h e  st u d y  a n d  a  




Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 2 5  of 5 1  
5. 1 5. 3  Visit 3/ E n d of St u d y/ E arl y T er mi n ati o n - ( D a y 8 + 3 D a ys) 
 
 
 
 
   
 
  
 
 
 
 
 
5. 1 5. 4  U nsc h e d ul e d Visit  
A n u nsc h e d ul e d visit is all o w e d at a n y ti m e  if i n t h e i n v esti g at or’s o pi ni o n it is w arr a nt e d.  If t h e 
i n v esti g at or ass ess es t h e s u bj ect’s c o n diti o n a n d d et er mi n es t h at t h e s u bj ect’s c o n diti o n h as 
w ors e n e d t o t h e d e gr e e t h at it is u ns af e f or t h e s u bj ect t o c o nti n u e i n t h e st u d y, t h e s u bj ect 
m a y b e d isc o nti n u e d fr o m t h e st u d y as a tr e at m e nt f ail ur e, a n d a st a n d ar d of c ar e tr e at m e nt 
m a y b e a d vis e d at t h e i nv esti g at or’s discr eti o n. T h e f oll o wi n g pr oc e d ur es m a y b e p erf or m e d at 
t h e U nsc h e d ul e d Visit if r e q uir e d: 
 
 
 
 
 
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 2 6  of 5 1  
5. 1 6  S u m m ar y of Ass ess m e nts  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        
  
          
 
      
 
 
                                       
  


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 2 7  of 5 1  
Scr e e n F ail ur es:  
Scr e e n f ail ur es will n ot b e i ncl u d e d i n a n y d at a a n al ys es.  A scr e e n f ail ur e is a s u bj ect w h o 
r ec ei v e d i nf or m ati o n  a b o ut  t h e  st u d y,  i ncl u di n g  si g ni n g  a n  i nf or m e d  c o ns e nt,  b ut  n e v er  
r ec ei v e d m e dic ati o n. 
 
5. 1 7  Pr ot oc ol D e vi ati o ns/ Vi ol ati o ns  
T his st u d y will b e c o n d uct e d as d escri b e d i n t his pr ot oc ol exc e pt f or a n e m er g e ncy sit u ati o n i n 
w hic h t h e pr ot ecti o n, s af et y,  a n d w ell -b ei n g  of t h e s u bj ect r e q uir es i m m e di at e i nt er v e nti o n, 
b as e d  o n  t h e  j u d g m e nt  of  t h e  i n v esti g at or  or  a  r es p o nsi bl e,  a p pr o pri at el y  tr ai n e d  a n d  
cr e d e nti al e d  pr of essi o n al(s)  d esi g n at e d  b y  t h e  i n v esti g at or.   I n  t h e  e v e nt  of  a  si g nific a nt  
d e vi ati o n fr o m  t h e pr ot oc ol d u e t o a n e m er g e ncy, acci d e nt or mist a k e, t h e i n v esti g at or or 
d esi g n e e m ust c o nt act P erri g o / 
 c o nt acts at t h e e arli est p ossi bl e ti m e.  
 
 
 
 
 
 
  
 
 
 
 
 
 
. 
 
 
5. 1 8  S u bj ect  Tr e at m e nt /C o m pli a nc e  
S u bj ect s wi ll s elf-a d mi nist er  i ntr a v a gi n all y  
 s u p pli e d st u d y m e dic ati o n o nc e d ail y f or 7 
d a ys   
. S u bj ect will b e i nstr uct e d t o r ec or d all a p plic ati o ns m a d e or miss e d i n a di ar y 
c ar d. C o m pli a nc e will b e d et er mi n e d fr o m t h e di ar y c ar d o n Visit 3/ E n d of St u d y /D a y 8. S u bj ects  
will b e c o nsi d er e d c o m pli a nt if t h e y a p pl y 
 
 st u d y m e dic ati o n. 
 
 
 T h e t ot al n u m b er of st u d y m e dic ati o n d os es a p pli e d a n d/ or miss e d will b e 
d et er mi n e d b as e d u p o n t h e first d os e a p pli e d t hr o u g h a n d i ncl u di n g t h e l ast d os e a p pli e d. T h e 
first a n d l ast d at es of tr e at m e nt s h o ul d b e r ec or d e d o n t h e C R F. T h e t ot al of a p pli e d a n d miss e d 
st u d y m e dic ati o n a p plic ati o ns s h o ul d als o b e r ec or d e d.  By d efi niti o n t h er e ar e n o miss e d 
a p plic ati o ns b ef or e t h e first d at e of tr e at m e nt or aft er t h e l ast d at e of tr e at m e nt.   T h e n u m b er 


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P a g e 2 8  of 5 1  
of a p plic ati o ns will b e t ot al e d b y t h e st u d y c o or di n at or a n d r ec or d e d o n t h e di ar y c ar d a n d o n 
t h e c o m pli a nc e p a g e of t h e c as e r e p ort f or m ( C R F). U n us e d a n d p arti ally us e d t u b es of st u d y 
m e dic ati o n  will  b e  c oll ect e d  b y  t h e  st u d y  sit e  at  Visit  3/ E n d  of  St u d y/  D a y  8  or  e arly  
t er mi n ati o n. 
 
5. 1 9  Disc o nti n u ati o n / Wit h dr a w al of St u d y S u bj ects  
S u bj ects m a y b e r e m o v e d fr o m t h e st u d y f or a n y of t h e f oll o wi n g r e as o ns:  
•  T h e s u bj ect wit h dr a ws h er c o ns e nt f or a n y r e as o n.  
•  T h e s u bj ect’s c o n diti o n h as w ors e n e d t o t h e d e gr e e t h at  t h e i n v esti g at or f e els it is u ns af e 
f or t h e s u bj ect t o c o nti n u e i n t h e st u d y. 
•  T h e s u bj ect’s m e dic ati o n c o d e is u n bli n d e d.  
•  A n a d v ers e e v e nt occ urs f or w hic h t h e s u bj ect d esir es t o disc o nti n u e tr e at m e nt or t h e 
i n v esti g at or d et er mi n es t h at it is i n t h e s u bj ect’s b est i nt er est t o b e disc o nti n u e d. 
•  T h e s u bj ect is l ost t o f oll o w -u p.  T h e i n v esti g at or will d oc u m e nt eff orts t o att e m pt t o r e ac h 
t h e s u bj ect t wic e b y t el e p h o n e a n d will s e n d a c ertifi e d f oll o w-u p l ett er b ef or e c o nsi d eri n g 
t h at s u bj ect l ost t o f oll o w-u p . All att e m pts m ust b e t h or o u g hl y r ec or d e d. 
•  T h er e is a si g nific a nt pr ot oc ol vi ol ati o n  as d escri b e d i n S ecti o n 5. 1 8 . 
•  A c o nc o mit a nt t h er a p y is r e p ort e d or r e q uir e d t h at is li k el y t o i nt erf er e wit h t h e r es ult of 
t h e st u d y. 
•  I ns uffici e nt t h er a p e utic r es p o ns e 
 
 
T h e r e as o ns f or a s u bj ect b ei n g disc o nti n u e d will b e d oc u m e nt e d i n t h e C R F  a n d t h e e nr oll m e nt  
l o g.  If a s u bj ect is disc o nti n u e d fr o m t h e st u dy f or a n y r e as o n, t h e E arl y T er mi n ati o n Visit 
pr oc e d ur es s h o ul d b e c o m pl et e d a n d a n y o utst a n di n g d at a a n d st u d y m e dic ati o n s h o ul d b e 
c oll ect e d.  D at a, i n a d diti o n t o t h e r e as o n f or disc o nti n u ati o n a n d t h e d a t e of r e m o v al, will b e 
r ec or d e d o n t h e E n d of St u d y C R F . 
 
I n t h e e v e nt t h at a s u bj ect disc o nti n u es fr o m t h e st u d y at a n y ti m e d u e t o a n a d v ers e e v e nt, t h e 
r e as o n  f or  disc o nti n u ati o n,  t h e  n at ur e  of  t h e  e v e nt  a n d  its  cli nic al  c o urs e  m ust  b e  f ull y  
d oc u m e nt e d.   F or s uc h a s u bj ect, t h e i n v esti g at or m ust stri v e t o f oll o w t h e s u bj ect u ntil t h e 
a d v ers e e v e nt h as r es ol v e d, b ec o m e cli nic all y i nsi g nific a nt, is st a biliz e d, or t h e s u bj ect is l ost t o 
f oll o w-u p.  
 
 
 
 
 
 
 


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P a g e 2 9  of 5 1  
6  
M A T E RI AL S A N D S U P PLI E S  
6. 1  
St u d y M e dic ati o n  
T h e st u d y m e dic ati o n s u p pli e d b y P erri g o will c o nsist of:  
 
T est Pr o d uct :   
Estr a di ol V a gi n al Cr e a m 0. 0 1 %   
  
  
 
   
                                       
  
  
  
 
 
           R ef er e nc e Pr o d uct : 
E S T R A C E ® (Estr a di ol ) V a gi n al Cr e a m, U S P, 0. 0 1 %  
M a n uf act ur e d b y: W ar n er C hilc ott ( U S), LL C  
 
V e hicl e :  
 
Estr a di ol V a gi n al Cr e a m 0. 0 1 % – V e hicl e    
   
 
6. 2  
M e di c ati o n M a n a g e m e nt  
6. 2. 1  L a b eli n g, P ac k a gi n g a n d Distri b uti o n 
T h e st u d y m e dic ati o n assi g n e d t o e ac h s u bj ect n u m b er will b e d et er mi n e d b y a c o m p ut er -
g e n er at e d r a n d o miz ati o n sc h e d ul e.   St u d y m e dic ati o n is l a b el e d a n d p ac k a g e d, acc or di n g t o t h e 
r a n d o miz ati o n c o d e, s o t h at n eit h er t h e s u bj ect n or t h e i n v esti g at or c a n i d e ntif y t h e tr e at m e nt.  
 
 
 
 
 
  
 
 
T h e t e ar -off p orti o n of e ac h kit l a b el c o nt ai ns t h e i de ntit y of t h e m e dic ati o n i n t h e t u b e. T h e 
i n v esti g at or will n ot r e m o v e t h e occl u di n g l a y er of t h e l a b el u nl ess a bs ol ut el y n ec ess ar y t o 
pr o vi d e m e dic al tr e at m e nt t o a s u bj ect i n a n e m er g e ncy a n d pr ef er a bl y wit h pri or a ut h oriz ati o n 
fr o m  P erri g o  or  d esi g n e e.  If  t h e  occl u d e d  p orti o n  of  t h e  l a b el  is  r e m o v e d,  e ac h  i n v ol v e d 
s u bj ect(s) will b e disc o nti n u e d fr o m t h e st u d y a n d t h e r e as o n will b e n ot e d o n t h e s o urc e 
d oc u m e nt a n d C R F.  
 
T h e t e ar -off p orti o n h as a n a d h esi v e b ac ki n g t o affix t o t h e st u d y m e dic ati o n dis p e nsi n g l o g t h at 
will b e m ai nt ai n e d at t h e i n v esti g at or sit e. T h e i n di vi d u al b ox es ar e n u m b er e d s e q u e nti all y a n d 
s h o ul d b e dis p e ns e d i n or d er. 
 
 
 


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P a g e 3 0  of 5 1  
 
 
T h e dis p e ns er will i nstr uct t h e s u bj ect i n st u d y m e dic ati o n a p plic ati o n a n d i nstr uct t h e s u bj ect 
i n di ar y c ar d c o m pl eti o n. ( N ot e: S u bj ect  d at a d o es n ot i ncl u d e t h e c oll ecti o n of i niti al b as eli n e 
m e dic al hist or y, c o nt act i nf or m ati o n, or i nf or m e d c o ns e nt, etc., o nl y t h os e it e ms/ acti viti es t h at 
m a y r es ult i n t h e i n d e p e n d e nt t hir d p art y dis p e ns er b ec o mi n g bi as e d s h o ul d b e a v oi d e d).   T h e 
i n v esti g at or p erf or mi n g t h e cli nic al e v al u ati o ns will n ot dis p e ns e or c oll ect st u d y m e dic ati o n.  
 
T h e  I n v esti g at or  m ust  n ot  u nc o v er  t h e  bli n d e d  pr o d uct  i d e ntific ati o n  u nl ess  a bs ol ut el y  
n ec ess ar y t o s u p p ort m e dic al tr e at m e nt i n a n e m er g e ncy. T h e M e dic al M o nit or or  S p o ns or 
s h o ul d b e c o nt act e d pri or t o br e a ki n g t h e bli n d, or as s o o n as p ossi bl e t h er e aft er, if s uc h a n 
e v e nt occ urs. If t h e st u d y bli n d is br o k e n f or a n y s u bj ect, f or a n y r e as o n, t h e s u bj ect will b e 
disc o nti n u e d fr o m t h e st u d y a n d t h e r e as o n r ec or d e d.  
  
6. 2. 2  R et e nti o n S a m pl es  
E ac h i n v esti g ati o n al sit e w h er e st u d y m e dic ati o n is dis p e ns e d t o at l e ast o n e s u bj ect will b e 
r e q uir e d t o r a n d o ml y s el ect o n e bl oc k of st u d y m e dic ati o n 
 
 t o  b e  m ai nt ai n e d  as  r et ai n  s a m pl es.   T h e  i n v esti g at or  will  m ai nt ai n  o n e  r a n d o mly  
s el ect e d bl oc k of st u d y m e dic ati o n f or e ac h s hi p m e nt of st u d y m e dic ati o n r ec ei v e d.  As p er t h e 
C o d e of F e d er al R e g ul ati o ns P art 2 1, S ecti o n 3 2 0. 3 8( e), “ E ac h r es er v e s a m pl e s h all b e st or e d 
u n d er c o n diti o ns c o nsist e nt wit h pr o d uct l a b eli n g a n d i n a n ar e a s e gr e g at e d fr o m t h e ar e a 
w h er e t esti n g is c o n d uct e d a n d wit h acc ess li mit e d t o a ut h oriz e d p ers o n n el. E ac h r es er v e 
s a m pl e s h all b e r et ai n e d f or a p eri o d of at l e ast 5 y e ars f oll o wi n g t h e d at e o n w hic h t h e 
a p plic ati o n or s u p pl e m e nt al a p plic ati o n is a p pr o v e d, or, if s uc h a p plic ati o n or s u p pl e m e nt al 
a p plic ati o n  is  n ot  a p pr o v e d,  at  l e ast  5  y e ars  f oll o wi n g  t h e  d at e  of  c o m pl eti o n  of  t h e  
bi o a v ail a bilit y st u d y i n w hic h t h e s a m pl e fr o m w hic h t h e r es er v e s a m pl e w as o bt ai n e d w as 
us e d.”  T h e  i n v esti g at or  will  st or e  t h e  r et ai n  s a m pl e  st u d y  m e dic ati o n  u ntil  s uc h  ti m e  as  
n otific ati o n is r ec ei v e d fr o m P erri g o t h at t h e s a m pl es ar e n o l o n g er r e q uir e d.  
 
6. 2. 3  St or a g e a n d T est Articl e Acc o u nt a bilit y  
St u d y articl es us e d t o c o n d uct t his st u d y will b e m ai nt ai n e d u n d er a d e q u at e s ec urit y b y t h e 
i n v esti g at or. St u d y t est articl es s h o ul d b e st or e d i n a s ec ur e d ar e a wit h li mit e d acc ess.  St u d y 
t est articl es will b e st or e d at r o o m t e m p er at ur e a n d s h o ul d b e pr ot ect e d fr o m t e m p er at ur e i n 
exc ess  of  4 0° C  ( 1 0 4° F).  E ac h  i n v esti g at or  si t e  will  e ns ur e  t h at  t h e  t e m p er at ur e  of  st u d y  
m e dic ati o n is m o nit or e d a n d r ec or d e d t hr o u g h o ut t h e st u d y. T h e m e dic ati o n s h o ul d n ot b e 
fr oz e n, s h o ul d b e pr ot ect e d fr o m h e at a n d k e pt ti g htl y cl os e d.  T h e i n v esti g at or will n ot s u p ply 
st u d y t est articl es t o a ny p ers o n n ot e nr oll e d i n t his st u d y, or t o a n y p h ysici a n or sci e ntist 
exc e pt t h os e n a m e d as s u b -i n v esti g at ors.  
 
T h e cli nic p ers o n n el will k e e p a r u n ni n g i n v e nt or y of st u d y t est articl es dis p e ns e d t h at will 
i ncl u d e s u bj ect n u m b ers assi g n e d a n d t h e d at e e ac h is dis p e ns e d a n d us e d.  A st u d y m e dic ati o n 


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P a g e 3 1  of 5 1  
acc o u nt a bilit y f or m will b e pr o vi d e d t o t h e i n v esti g at or t o d oc u m e nt all m e dic ati o ns r ec ei v e d, 
dis p e ns e d b y a n d us e d b y e ac h s u bj ect.  At t h e c o ncl usi o n of t h e st u d y all u n us e d, p arti all y 
us e d, a n d e m pt y c o nt ai n ers m ust b e i n v e nt ori e d b y t h e m o nit or a n d r et ur n e d t o P erri g o, or 
d esi g n e e, f or d estr ucti o n.  
 
6. 2. 4  R a n d o miz ati o n  
R a n d o miz ati o n will b e p erf or m e d acc or di n g t o a c o m p ut er g e n er at e d r a n d o miz ati o n sc h e m e 
w h er e t h e tr e at m e nt gr o u p d esi g n ati o n h as b e e n assi g n e d t o a s u bj ect n u m b er.  T h e tr e at m e nt 
d esi g n ati o n will r e m ai n bli n d e d u ntil t h e fi n al d at a b as e is  l oc k e d.  A n i n d e p e n d e nt t hir d p art y 
will h ol d t h e r a n d o miz ati o n c o d e t hr o u g h o ut t h e st u d y.  T h e r a n d o miz ati o n sc h e m e will b e a 
bl oc k r a n d o miz ati o n, 
 assi g n e d t o T est: R ef er e nc e: V e hicl e  
 
. 
 
6. 2. 5  Pr oc e d ur e f or Br e a ki n g t h e Bli n d  
T h e s p o ns or, i n v esti g at or, st aff at t h e st u d y sit e, st u d y m o nit ors, a n d d at a 
a n al ysis/ m a n a g e m e nt p ers o n n el ar e bli n d e d t o t h e s u bj ect assi g n m e nt. I n t h e e v e nt of a n 
e m er g e ncy, t h e s p ecific s u bj ect tr e at m e nt m a y b e i d e ntifi e d b y r e m o vi n g t h e o v erl a y of t h e 
bli n d e d l a b el , w hic h is att ac h e d t o t h e st u d y m e dic ati o n l o g; h o w e v er, e v er y eff ort s h o ul d b e 
m a d e t o m ai nt ai n t h e bli n d.  T h e i n v esti g at or m ust n ot scr atc h off t h e occl u di n g l a y er of t h e 
l a b el u nl ess a bs ol ut el y n ec ess ar y t o pr o vi d e m e dic al tr e at m e nt t o a s u bj ect i n a n e m er g e nc y 
sit u ati o n o nl y a n d s h o ul d s e e k pri or a ut h oriz ati o n b y P erri g o or d esi g n e e w h e n p ossi bl e.  T h e 
r e as o n f or br e a ki n g t h e bli n d m ust b e cl e arl y d oc u m e nt e d i n t h e s o urc e d oc u m e nt ati o n a n d 
C R F a n d t h e s u bj ect m ust b e disc o nti n u e d fr o m t h e st u d y .  
 
7  
A D V E R S E R E A C TI O N S  
T h e r ef er e nc e s af et y i nf or m ati o n f or ass essi n g t h e ex p ect e d n ess of a n a d v ers e e v e nt f or t his 
st u d y is t h e p ac k a g e i ns ert f or Estr ac e ® ( Estr a di ol) V a gi n al Cr e a m, 0. 0 1 %.   
 
T h e p ot e nti al a d v ers e r e acti o ns of g e n eric estr a di ol v a gi n al cr e a m 0. 0 1 % ar e a ntici p at e d t o b e 
si mil ar t o t h os e o bs er v e d wit h Estr ac e ® ( Estr a di ol) V a gi n al Cr e a m, 0. 0 1 %. A d v ers e r e acti o ns 
r el at e d t o tr e at m e nt wit h Estr ac e ® ( Estr a di ol) V a gi n al Cr e a m 0. 0 1 % i ncl u d e b ox e d w ar ni n g s f or: 
•  I ncr e as e d ris k of e n d o m etri al c a nc er,  
•  C ar di o v asc ul ar a n d ot h er ris ks: m y oc ar di al i nf arcti o n, str o k e, i n v asi v e br e ast c a nc er, 
p ul m o n ar y e m b oli, a n d d e e p v e n o us t hr o m b osis i n p ost m e n o p a us al w o m e n ( 5 0 t o 7 9 
y e ars of a g e) d uri n g 5 y e ars of tr e at m e nt wit h or al  c o nj u g at e d estr o g e ns ( C E 0. 6 2 5 m g) 
c o m bi n e d wit h m e dr oxy pr o g est er o n e ac et at e ( M P A 2. 5 m g) r el ati v e t o V e hicl e . 
•  I ncr e as e d ris k of d e v el o pi n g pr o b a bl e d e m e nti a i n p ost m e n o p a us al w o m e n 6 5 y e ars of 
a g e  or  ol d er  d uri n g  4  y e ars  of  tr e at m e nt  wit h  or al  c o nj u g at e d  estr o g e ns -pl us -
m e dr oxy pr o g est er o n e ac et at e r el ati v e t o V e hicl e . 
 


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P a g e 3 2  of 5 1  
S yst e mic a bs or pti o n m a y occ ur wit h t h e us e of E S T R A C E ® (Estr a di ol ) V a gi n al Cr e a m,  U S P, 0. 0 1 %. 
T h e  w ar ni n gs,  pr ec a uti o ns,  a n d  a d v ers e  r e acti o ns  ass oci at e d  wit h  or al  estr o g e n  tr e at m e nt  
s h o ul d b e t a k e n i nt o acc o u nt. 
 
T h e f oll o wi n g a d diti o n al a d v ers e r e acti o ns h a v e b e e n r e p ort e d wit h estr o g e n a n d/ or pr o g esti n 
t h er ap y:  
 
G e nit o uri n ar y s yst e m  
C h a n g es i n v a gi n al bl e e di n g p att er n a n d a b n or m al wit h dr a w al bl e e di n g or fl o w; br e a kt hr o u g h 
bl e e di n g; s p otti n g; d ys m e n orr h e a, i ncr e as e i n siz e of ut eri n e l ei o m y o m at a; v a gi nitis, i ncl u di n g 
v a gi n al  c a n di di asis;  c h a n g e  i n  a m o u nt  of  c er vic al  s ecr eti o n;  c h a n g es  i n  c er vic al  ectr o pi o n;  
a p plic ati o n sit e r e acti o ns of v ul v o v a gi n al disc o mf ort i ncl u di n g b ur ni n g a n d irrit ati o n; g e nit al 
pr urit us; o v ari a n c a nc er; e n d o m etri al h y p er pl asi a; e n d o m etri al c a nc er.  
 
Br e asts  
T e n d er n ess,  e nl ar g e m e nt,  p ai n,  ni p pl e  disc h ar g e,  g al act orr h e a;  fi br ocystic  br e ast  c h a n g es;  
br e ast c a nc er.  
 
C ar di o v asc ul ar  
D e e p a n d s u p erfici al v e n o us t hr o m b osis; p ul m o n ar y e m b olis m; t hr o m b o p hl e bitis; m y oc ar di al 
i nf arcti o n; str o k e; i ncr e as e i n bl o o d pr essur e.  
 
G astr oi nt esti n al  
N a us e a, v o miti n g;  a b d o mi n al cr a m ps, bl o ati n g; c h ol est atic j a u n dic e; i ncr e as e d  i nci d e nc e of 
g all bl a d d er dis e as e; p a ncr e atitis, e nl ar g e m e nt of h e p atic h e m a n gi o m as.  
 
S ki n  
C hl o as m a  or  m el as m a,  t h at  m a y  p ersist  w h e n  dr u g  is  disc o nti n u e d;  er yt h e m a  m ultif or m e; 
er yt h e m a n o d os u m; h e m orr h a gic er u pti o n; l oss of sc al p h air; hirs utis m; pr urit us, r as h.  
 
E y es  
R eti n al v asc ul ar t hr o m b osis, i nt ol er a nc e t o c o nt act l e ns es.  
 
C e ntr al n er v o us s yst e m  
H e a d ac h e; mi gr ai n e; dizzi n ess; m e nt al d e pr essi o n; c h or e a; n er v o us n ess; m o o d dist ur b a nc es; 
irrit a bilit y; ex ac er b ati o n of e pil e ps y, d e m e nti a.  
 
Misc ell a n e o us  
I ncr e as e  or d ecr e as e  i n w ei g ht; r e d uc e d c ar b o h y dr at e t ol er a nc e; a g gr a v ati o n of p or p h yri a; 
e d e m a;  art hr al gi as;  l e g  cr a m ps;  c h a n g es  i n  li bi d o;  urtic ari a,  a n gi o e d e m a,  h y p ers e nsiti vit y,  
a n a p h yl act oi d/ a n a p h yl actic r e acti o ns;  h y p oc alc e mi a;  ex ac er b ati o n  of  ast h m a;  i ncr e as e d  
tri gl yc eri d es.  
 


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7. 1  
D e p art ur e fr o m t h e Pr ot oc ol f or I n di vi d u al S u bj ects  
W h e n a n e m er g e ncy occ urs r e q uiri n g a d e p art ur e fr o m t h e pr ot oc ol f or a s u bj ect, d e p art ur e 
will b e o nl y f or t h at s u bj ect.  I n s uc h circ u mst a nc es, t h e In v esti g at or or ot h er p h ysici a n i n 
att e n d a nc e will c o nt act t h e M e dic al M o nit or or P erri g o b y t el e p h o n e a n d f oll o w u p wit h a 
writt e n d escri pti o n as s o o n as p ossi bl e.  T h e o v ers e ei n g I R B s h o ul d als o b e n otifi e d.  
 
7. 2  
D efi niti o ns  
A n a d v ers e e v e nt ( A E) is d efi n e d as a n y u nt o w ar d m e dic al occ urr e nc e i n a s u bj ect a d mi nist er e d 
a m e dici n al pr o d uct a n d w hic h d o es n ot n ec ess a ril y h a v e t o h a v e a c a us al r el ati o ns hi p wit h t his 
tr e at m e nt.  A n  a d v ers e  e v e nt  c a n  t h er ef or e  b e  a n y  u nf a v or a bl e  a n d  u ni nt e n d e d  si g n  (f or  
ex a m pl e, a n a b n or m al l a b or at or y fi n di n g), s y m pt o m, or dis e as e t e m p or ally ass oci at e d wit h t h e 
us e of a m e dici n al pr o d uct,  w h et h er or n ot c o nsi d er e d r el at e d t o t his m e dici n al pr o d uct.  
 
A s eri o us a d v ers e e v e nt ( S A E) is a n a d v ers e e v e nt t h at r es ults i n a n y of t h e f oll o wi n g o utc o m es:  
 
•  d e at h  
•  lif e-t hr e at e ni n g  e v e nt  (i. e.,  t h e  s u bj ect  w as,  i n  t h e  o pi ni o n  of  t h e  i n v esti g at or,  at  
i m m e di at e ris k of d e at h fr o m t h e e v e nt as it occ urr e d.  It d o es n ot i ncl u d e a n e v e nt t h at, 
h a d it occ urr e d i n a m or e s e v er e f or m, mi g ht h a v e c a us e d d e at h)  
•  r e q uir es i n-s u bj ect h os pit aliz ati o n or pr ol o n gs h os pit aliz ati o n 
•  a p ersist e nt or si g nific a nt dis a bilit y/i nc a p acit y or s u bst a nti al disr u pti o n of t h e a bilit y t o 
c o n d uct n or m al lif e f u ncti o ns 
•  c o n g e nit al a n o m al y/ birt h d ef ect 
•  ot h er a d v ers e e v e nts t h at m a y b e c o nsi d er e d s eri o us w h e n, b as e d u p o n a p pr o pri at e 
m e dic al j u d g m e nt, t h e y m a y j e o p ar diz e t h e s u bj ect or s u b j ect or m a y r e q uir e m e dic al or 
s ur gic al i nt er v e nti o n t o pr e v e nt o n e of t h e pr e vi o usl y list e d o utc o m es. 
 
I m m e di at el y R e p ort a bl e A d v ers e E v e nts (I R A E): A n y s eri o us A E or a n y A E t h at n ec essit at es 
disc o nti n u ati o n of st u d y m e dic ati o n, i ncl u di n g pr e g n a ncy.  
 
U n ex p ect e d A d v ers e E v e nt : A n u n ex p ect e d e v e nt is a n y a d v ers e dr u g ex p eri e nc e, t h e s p ecificit y 
or s e v erit y of w hic h is n ot c o nsist e nt wit h t h e c urr e nt a p pr o v e d pr o d uct l a b eli n g ( p ac k a g e 
i ns ert) f or t h e st u d y m e dic ati o n, or as d escri b e d i n t h e cli nic al pr ot oc ol a n d c o ns e nt m at eri als.    
 
I nt e nsit y of A d v ers e E v e nts: T h e m axi m u m i nt e nsit y of a n A E d uri n g a d ay s h o ul d b e r ec or d e d 
o n t h e C R F. If t h e i nt e nsit y of a n A E c h a n g es ov er a n u m b er of d a ys, t h e n s e p ar at e e ntri es 
s h o ul d b e m a d e h a vi n g disti nct o ns et d at es f or t h e c h a n g es i n s e v erit y. 
 
Mil d - A Es ar e us u all y tr a nsi e nt, r e q uiri n g n o s p eci al tr e at m e nt, a n d d o n ot i nt erf er e 
wit h s u bj ect’s d ail y acti viti es.  
 


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P a g e 3 4  of 5 1  
M o d er at e 
- A Es  t y pic all y  i ntr o d uc e a  l o w  l e v el of  i nc o n v e ni e nc e or  c o nc er n  t o  t h e 
s u bj ect a n d m a y i nt erf er e wit h d ail y acti viti es, b ut ar e us u all y a m eli or at e d b y si m pl e 
t h er a p e utic m e as ur es. 
 
S e v er e - A Es i nt err u pt a s u bj ect’s us u al d ail y acti vit y a n d tr a diti o n all y r e q uir e s yst e mic 
dr u g t h er a p y or ot h er tr e at m e nt.  
 
 
C a us al R el ati o ns hi p t o St u d y M e dic ati o n:   
T h e f oll o wi n g crit eri a s h o ul d b e us e d i n ass essi n g t h e a p p ar e nt c a us al r el ati o ns hi p of a n A E t o 
st u d y m e dic ati o n.  
 
D efi nit el y - T h e A E:  
• 
f oll o ws a r e as o n a bl e t e m p or al s e q u e nc e fr o m st u d y m e dic ati o n a d mi nistr ati o n 
• 
a b at es u p o n disc o nti n u ati o n of t h e st u d y m e dic ati o n ( d ec h all e n g e)  
• 
is c o nfir m e d b y r e a p p e ar a nc e of t h e r e acti o n o n r e p e at ex p os ur e 
 
Pr o b a bl y - T h e A E:  
• 
f oll o ws a r e as o n a bl e t e m p or al s e q u e nc e fr o m st u d y m e dic ati o n a d mi nistr ati o n 
• 
a b at es u p o n disc o nti n u ati o n of t h e st u d y m e dic ati o n ( d ec h all e n g e).  
• 
c a n n ot b e r e as o n a bl y ex pl ai n e d b y t h e k n o w n c h ar act eristics of t h e s u bj ect’s st at e.  
 
P ossi bl e - T h e A E:  
• 
f oll o ws a r e as o n a bl e t e m p or al s e q u e nc e fr o m st u d y m e dic ati o n a d mi nistr ati o n 
• 
b ut t h at c o ul d r e a dil y b e pr o d uc e d b y a n u m b er of ot h er f act ors . 
 
U nli k el y - T h e A E:  
• f oll o ws a r e as o n a bl e t e m p or al s e q u e nc e fr o m st u d y m e dic ati o n a d mi nistr ati o n. 
• c o ul d h a v e b e e n pr o d uc e d b y eit h er t h e s u bj ect’s cli nic al st at e or b y st u d y m e dic ati o n 
a d mi nistr ati o n.  
 
N ot r el at e d - T h e A E:  
• d o es  n ot  h a v e  a  r e as o n a bl e  t e m p or al  ass oci ati o n  wit h  t h e  a d mi nistr ati o n  of  st u d y  
m e dic ati o n  
• 
h as s o m e ot h er o b vi o us ex pl a n ati o n f or t h e e v e nt  
 
7. 3  
Eliciti n g a n d R e p orti n g of A d v ers e E v e nts  
T h e i n v esti g at or will p eri o dic all y ass ess s u bj ects f or t h e occ urr e nc e of a d v ers e e v e nts.  I n or d er 
t o a v oi d bi as i n eliciti n g a d v ers e e v e nts, t h e s u bj ect s h o ul d b e as k e d a n o n-s p ecific q u esti o n 
( e. g., “ H o w h a v e y o u b e e n f e eli n g si nc e y o ur l ast visit ?”) t o ass ess w h et h er a n y A E h as b e e n 
ex p eri e nc e d si nc e t h e l ast visit.  All a d v ers e e v e nts ( as d efi n e d i n S ecti o n 7. 2 ), eit h er o bs er v e d 
b y t h e I n v esti g at or or o n e of his/ h er m e dic al c oll a b or at ors, or r e p ort e d b y t h e p artici p a nt 
s p o nt a n e o usl y, or i n r es p o ns e t o dir ect q u esti o ni n g, will b e r e p ort e d a n d d oc u m e nt e d i n t h e 




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P a g e 3 6  of 5 1  
fr o m t h e st u d y m e dic ati o n s h o ul d al w a ys b e i ncl u d e d wit h a f oll o w u p r e p ort.  Ass ess a n d 
r e p ort t h e c a us alit y of t h e e v e nt. 
 
T h e n otific ati o n a b o ut a n y s eri o us a d v ers e e v e nt s h o ul d b e dir ect e d t o:  
 
: 
 
 
 
 
 
 
 
 
 
 
 
 
 
S p o ns or c o nt act d et ails:  
 
 
 
 
  
 
 
7. 3. 2  S u b m itti n g a n E x p e dit e d S af et y R e p ort t o t h e R e g ul at or y A ut h orit y  
O nc e   
 r ec ei v es  all  s u p p orti n g  d oc u m e nt ati o n  f or  t h e  r e p ort e d  e v e nt,  t h e  M e dic al  
M o nit or, i n c o nj u ncti o n wit h t h e s p o ns or, will d et er mi n e if t h e s af et y r e p ort is eli gi bl e f or 
ex p e dit e d r e vi e w.  
 will l o g t h e i niti al e v e nt a n d will n otif y t h e s p o ns or t h at a n e v e nt h as 
b e e n r e p ort e d wit hi n 1 b usi n ess d a y aft er i niti al r ec ei pt.  
 will c o m pl et e t h e r e vi e w of t h e 
e v e nt, e nt er i nf or m ati o n i nt o t h eir s af et y d at a b as e a n d f or w ar d t h e S A E r e p ort t o t h e S p o ns or. 
T his f or m, as w ell as ot h er s u p p orti n g d oc u m e nt ati o n, will b e f or w ar d e d t o  
 M e dic al 
M o nit or f or r e vi e w.   
 will fi n aliz e t h e r e p ort a n d distri b ut e it t o t h e s p o ns or wit hi n 2 4 
h o urs  aft er i niti al r ec ei pt.  W h e n ex p e dit e d s af ety r e p orti n g t o r e g u lat ory a ut h oriti es is i n d e e d 
r e q uir e d, t h e I n v esti g at or s h o ul d r e vi e w a n d u p d at e a n y n e wl y a v ail a bl e m at eri als at o nc e.  
F oll o w -u p q u eri es m a y b e s e nt t o t h e st u d y c e nt er t o f urt h er cl arif y t h e e v e nt.  
 
E ac h ex p e dit e d s af et y r e p ort will r o uti n el y i ncl u d e a b ri ef c o v er m e m or a n d u m, t h e c o m pl et e d 
r e p ort, a n d a n y a d diti o n al p erti n e nt i nf or m ati o n r ec o m m e n d e d b y  
, t h e s p o ns or, or 
st u d y M e dic al M o nit or. O nc e t h e r e p ort is ass e m bl e d, t h e Pri nci p al I n v esti g at or m ust s u b mit 
t h e ex p e dit e d s af et y r e p ort t o t h e I R B wit hi n t h e r e q uir e d r e p orti n g ti m efr a m e. F oll o w -u p 
r e p orts  s h o ul d  b e  s u b mitt e d  w h e n  r e q u est e d  or  w h e n  p erti n e nt  i nf or m ati o n  b ec o m es  
a v ail a bl e.  


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P a g e 3 7  of 5 1  
 
W h e n a Pri nci p al I n v esti g at or r ec ei v es a n ex p e dit e d s af et y r e p ort fr o m  
 or t h e s p o ns or 
d et aili n g  a d v ers e  e v e nts  occ urri n g  at  ot h er  st u d y  c e nt ers  u n d er  t his  pr ot oc ol,  it  m ust  b e  
pr o m ptl y s u b mitt e d t o t h e st u d y c e nt er’s I R B.  T h e Pri nci p al I n v esti g at or m ust r et ai n a c o p y of 
s uc h r e p orts as s u b mitt e d t o t h eir I R B i n t h e sit e’s st u d y R e g ul at or y Bi n d er. 
7. 4  
S A E & A Es R e q uiri n g Disc o nti n u ati o n of St u d y Dr u g, i ncl u di n g Pr e g n a nci es  
A N Y S A E, W HI C H O C C U R S A F T E R A S U BJ E C T H A S E N T E R E D T H E S T U D Y, W H E T H E R O R N O T 
R EL A T E D T O S T U D Y M E DI C A TI O N, M U S T B E R E P O R T E D T O  
 I M M E DI A T EL Y ( WI T HI N 2 4 
H O U R S) VI A T EL E P H O N E O R F A C SI MIL E. I F I NI TI ALL Y R E P O R T E D VI A T EL E P H O N E, T HI S M U S T B E 
F OLL O W E D- U P B Y A F A C SI MIL E O F T H E W RI T T E N S A E R E P O R T WI T HI N 2 4 H O U R S O F T H E C ALL 
T O  
.  
 
A  s u bj ect  w h o  ex p eri e nc es  a  s eri o us  a d v ers e  e v e nt  r el at e d  t o  st u dy  m e dic ati o n  will  b e  
disc o nti n u e d fr o m t h e st u d y.  
 
N o n -s eri o us  e v e nts t h at  r e q uir e  disc o nti n u ati o n  of  st u d y  m e dic ati o n  (i ncl u di n g  l a b or at or y  
a b n or m aliti es)  s h o ul d  b e  r e p ort e d  t o  t h e  s p o ns or  i m m e di at el y  a n d  wit hi n  1 w or ki n g  d a y.   
S u bj ects w h o disc o nti n u e d u e t o ex p eri e nci n g a dv ers e e v e nts s h o ul d b e f oll o w e d  cli nic all y u ntil 
t h eir h e alt h h as r et ur n e d t o b as eli n e st at us, or u ntil all p ar a m et ers h a v e r et ur n e d t o n or m al.  It 
is ex p ect e d t h at t h e i n v esti g at or will pr o vi d e or arr a n g e a p pr o pri at e s u p p orti v e c ar e f or t h e 
s u bj ect. 
 
7. 4. 1  Pr e g n a nc y  
At t h e ti m e a Pri nci p al I n v esti g at or or sit e p ers o n n el b ec o m es a w ar e t h at a st u d y p artici p a nt 
b ec a m e  pr e g n a nt  f oll o wi n g  st u d y  p artici p ati o n,  t h e  Pri nci p al  I n v esti g at or  or  d esi g n e e  will  
r e p ort t h e pr e g n a ncy i m m e di at el y b y p h o n e a n d/ or b y f axi n g a c o m pl et e d Pr e g n a ncy R e p ort t o 
 wit hi n o n e w or ki n g d a y of b ei n g n otifi e d of t h e pr e g n a ncy r e p ort. 
 
T h e r e p ort will i ncl u d e t h e f oll o wi n g el e m e nts:  
•  P artici p a nt ( m ot h er’s) c o d e d st u d y i d e ntifi er;  
•  D at e of p artici p a nt’s l ast m e nstr u al p eri o d;  
•  T ot al acc u m ul at e d d os e of st u d y tr e at m e nt a d mi nist er e d t o d at e;  
•  D at e of st u d y m e dic ati o n a d mi nistr ati o n.  
 
T h e i n v esti g at or will f oll o w t h e s u bj ect u ntil c o m pl eti o n of t h e pr e g n a ncy a n d m ust ass ess t h e 
o utc o m e i n t h e s h ort est p ossi bl e ti m e b ut n ot m or e t h a n 3 0 d a ys wit hi n c o m pl eti o n of t h e 
pr e g n a ncy.  
 
U p o n d eli v er y, misc arri a g e or a b orti o n, t h e Pri nci p al I n v esti g at or or d esi g n e e m ust f or w ar d a 
f oll o w-u p Pr e g n a ncy R e p ort wit h a n y r el e v a nt i nf or m ati o n o n t h e pr es e nt c o n diti o n of t h e f et us 
t o t h e  
, i ncl u di n g: 
•  M ot h er’s c o d e d st u d y i d e ntifi er(s);  


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P a g e 3 8  of 5 1  
•  G est a ti o n al a g e at d eli v er y, misc arri a g e or a b orti o n; 
•  Birt h w ei g ht, g e n d er, l e n gt h a n d h e a d circ u mf er e nc e, if a v ail a bl e;  
•  A p g ar sc or es r ec or d e d aft er birt h, if a v ail a bl e;  
•  A n y a b n or m aliti es.  
 
If t h e o utc o m e of t h e pr e g n a ncy m e ets t h e crit eri a f or i m m e di at e cl assific ati o n of a n S A E ( e. g., 
s p o nt a n e o us or t h er a p e utic a b orti o n [ a n y c o n g e nit al a n o m al y d et ect e d i n a n a b ort e d f et us is t o 
b e d oc u m e nt e d], still birt h, n e o n at al d e at h, or c o n g e nit al a n o m al y), t h e i n v esti g at or will r e p ort 
t h e e v e nt b y p h o n e a n d b y f axi n g a c o m pl et e d S A E r e p ort f or m t o  
 wit hi n o n e w or ki n g 
d a y of b ei n g n otifi e d of t h e pr e g n a ncy r e p ort.  
 
If t h e tri al is c o m pl et e d b ef or e t h e o utc o m e of t h e pr e g n a ncy is k n o w n,  
 will ass u m e t h e 
r es p o nsi bilit y f or f oll o wi n g u p o n t h e pr e g n a ncy.    
 will c o nt act t h e I n vesti g at or or St u d y 
c o or di n at or o n or ar o u n d t h e p ot e nti al ex p ect e d d at e of d eli v er y t o f oll o w -u p o n t h e o utc o m e 
of pr e g n a ncy a n d will als o c h ec k o n t h e st at us of t h e i nf a nt 8 w e e ks p ost -d eli v er y.  U p o n 
a w ar e n ess of t h e pr e g n a ncy o utc o m e a n d k n o w n st at us of  t h e i nf a nt f oll o wi n g 8 w e e ks of 
d eli v er y, t h e i n v esti g at or will c o m pl et e t h e a p plic a bl e pr e g n a ncy r e p ort f or ms a n d f ax t o 
 wit hi n 1 d a y of b ei n g n otifi e d. 
 
 
7. 5  
P ost St u d y A d v ers e E v e nts  
7. 5. 1   N o n -s eri o us P ost St u d y A d v ers e E v e nts 
A d v ers e e v e nts t h at ar e i d e ntifi e d at t h e l ast ass ess m e nt visit ( or t h e e arl y t er mi n ati o n visit) 
m ust b e r ec or d e d o n t h e A E C R F wit h t h e st at us of t h e A E n ot e d.  All e v e nts t h at ar e o n g oi n g at 
t his ti m e will b e r ec or d e d as o n g oi n g o n t h e C R F. 
 
7. 5. 2  S eri o us P ost St u d y A d v ers e E v e nts  
S eri o us a d v ers e e v e nts t h at ar e i d e ntifi e d o n t h e l ast ass ess m e nt visit ( or t h e e arl y t er mi n ati o n 
visit) m ust b e r ec or d e d o n t h e A E C R F p a g e a n d r e p ort e d t o t h e M e dic al M o nit or acc or di n g t o 
t h e pr oc e d ur es o utli n e d a b o v e.  S u bj ects wit h u nr es ol v e d pr e vi o usl y r e port e d s eri o us a d v ers e 
e v e nts, or a n y n e w s eri o us a d v ers e e v e nts i d e ntifi e d o n t h e l ast ass ess m e nt visit, s h o ul d b e 
f oll o w e d b y t h e i n v esti g at or u ntil t h e e v e nts ar e r es ol v e d, or t h e s u bj ect is l ost t o f oll o w-u p.  
R es ol uti o n m e a ns t h e s u bj ect h as r et ur n e d t o t h e b as eli n e st at e of h e alt h, or t h e i n v esti g at or 
d o es n ot ex p ect a n y f urt h er i m pr o v e m e nt or w ors e ni n g of t h e a d v ers e e v e nt.  T h e i n v esti g at or 
s h o ul d c o nti n u e t o r e p ort a n y si g nific a nt f oll o w-u p i nf or m ati o n t o P erri g o u p t o t h e p oi nt t h at 
t h e e v e nt h as r es ol v e d.  A n y s eri o us a d v ers e e v e nt r e p ort e d b y t h e s u bj ect t o t h e i n v esti g at or 
t h at occ urs aft er t h e l ast ass ess m e nt, a n d is d et er mi n e d b y t h e i n v esti g at or t o b e r e as o n a bl y 
ass oci at e d wit h t h e us e of t h e st u d y m e dic ati o n, s h o ul d b e r e p ort e d t o P erri g o a n d  f oll o we d -u p  
u p as n ot e d a b o v e.   
 


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8  
S T A TI S TI C AL A N AL Y SI S  
8. 1  
St atistic al A n al ysis  
T h e s ecti o ns t h at f oll o w hi g hli g ht s a m pl e siz e d et er mi n ati o n a n d t h e pl a n n e d a n al ys es f or t his 
st u d y.  A st atistic al a n al ysis pl a n ( S A P) will b e pr e p ar e d s e p ar at el y fr o m t his pr ot oc ol a n d it will 
d escri b e  st atistic al m et h o ds, m o d els, h y p ot h es es a n d s u bj ect p o p ul ati o ns t o b e a n al yz e d.  T h e 
S A P will b e c o m pl et e d a n d a p pr o v e d b ef or e l oc ki n g t h e d at a b as e a n d u n bli n di n g t h e st u d y a n d 
will s er v e as d oc u m e nt ati o n of t h e pl a n n e d st atistic al m et h o ds  a n d will s erv e as a c o m p a ni o n t o 
t h e pr ot oc ol a n d t h e d e f act o  d oc u m e nt ati o n of t h e pr o p os e d st atistic al e v al u ati o n.  T h e S A P 
will b e c o m pl et e d a n d fi n aliz e d pri or t o br e a ki n g t h e bli n d.  
 
8. 1. 1  A n al ysis P o p ul ati o ns  
I nt e nt-t o-tr e at (I T T) p o p ul ati o n:  a n y s u bj ect w h o: ( a) w as r a n d o miz e d i nt o t h e st u d y a n d ( b) 
a p pli e d at l e ast 1 d os e of assi g n e d st u d y m e dic ati o n i ntr a v a gi n all y.  
 
 
M o difi e d I nt e nt-t o-tr e at (m I T T) p o p ul ati o n: a n y s u bj ect w h o ( a) w as r a n d o miz e d i n t h e st u d y 
( b) a p pli e d at l e ast 1 d os e of assi g n e d st u d y m e dic ati o n i ntr a v a gi n all y, (c) c o m pl et e d at l e ast 
o n e p ost r a n d o miz ati o n ass ess m e nt , a n d ( d) m et eli gi bilit y crit eri a.  
 
P er Pr ot oc ol ( P P) p o p ul ati o n ; a n y s u bj ect w h o ( a) w as r a n d o miz e d  i n t h e st ud y a n d m et all 
i ncl usi o n/ excl usi o n crit eri a, ( b) h a d n ot t a k e n a n y c o nc o mit a nt m e dic ati o ns pr o hi bit e d b y t h e 
pr ot oc ol or h a d a n y ot h er si g nific a nt pr ot oc ol vi ol ati o ns; (c)  r et ur n e d f or Visit 3/ E n d of St u d y 
wit hi n t h e d esi g n at e d visit wi n d o w 
 wit h  d at a o n t h e pri m ar y effic acy e n d p oi nt a n d; d) 
h a d a st u d y m e dic ati o n a p plic ati o n c o m pli a nc e r at e 
 
O R w as disc o nti n u e d fr o m t h e st u d y d u e t o l ac k of tr e at m e nt eff ect
 
   
 
 
 
 
 
 
 
 
 
 
. 
 
8. 1. 2  Pl a n n e d A n al ysis  
All r a n d o miz e d s u bj ects w h o r ec ei v e d st u d y m e dic ati o n will b e e v al u at e d f or s af et y.  T h e 
effic acy a n al ysis will b e c o n d uct e d o n b ot h t h e P P a n d t h e m I T T p o p ul ati o ns.  T w o-si d e d 
h y p ot h esis t esti n g will b e c o n d uct e d.  R es ulti n g p -v al u es ≤ 0. 0 5 will b e c o nsi d er e d st atistic all y 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 4 0  of 5 1  
si g nific a nt.  N o a dj ust m e nts of p-v al u es f or m ulti pl e c o m p aris o ns will b e m a d e.  N o i nt eri m 
a n al ys es ar e pl a n n e d.  S A S s oft w ar e  V ersi o n 9. 1. 3  will b e us e d f or all d at a a n al ys es a n d 
t a b ul ati o ns. 
 
T h e tr e at m e nt r es p o ns e will b e s u m m ariz e d b y tr e at m e nt gr o u p f or Visit 3/ E n d of St u d y 
e v al u ati o n.  T h e pri m ar y effic acy e n d p oi nt will b e t h e pr o p orti o n of s u bj ects t h at ar e i d e ntifi e d 
as r es p o n d ers at V isit 3/ E n d of St u d y.  A r es p o n d er is d efi n e d as a s u bj ect wit h at l e ast a 2 5 % 
r e d ucti o n fr o m b as eli n e i n t h e s u m of % ( p erc e nt) b as al/ p ar a b as al + % ( p erc e nt) i nt er m e di at e 
c ells o n v a gi n al cyt ol o g y A N D v a gi n al p H < 5. 0 wit h a c h a n g e fr o m Visit 1/ Scr e e ni n g  va gi n al p H 
of at l e ast 0. 5.  
 
T h e s ec o n d ar y e n d p oi nt will b e t h e pr o p orti o n of s u bj ects wit h tr e at m e nt s ucc ess b as e d o n t h e 
i m pr o v e m e nt (c h a n g e fr o m b as eli n e) of t h e m ost b ot h ers o m e s y m pt o m of V V A at Visit 3/ E n d 
of st u d y. Tr e at m e nt s ucc ess is d efi n e d as a c h a n g e fr o m b as eli n e w hic h will r es ult i n a sc or e of 0 
( n o n e) or 1 ( mil d) at Visit 3 if t h e M ost B ot h ers o m e S y m pt o m is v a gi n al dr y n ess, v a gi n al or 
v ul v ar irrit ati o n or itc hi n g, d ys uri a  a n d v a gi n al p ai n ass oci at e d wit h s ex u al acti vit y. If t h e M ost 
B ot h ers o m e S y m pt o m is v a gi n al bl e e di n g ass oci at e d wit h s ex u al acti vit y t h e n tr e at m e nt 
s ucc ess will b e a bs e nc e of v a gi n al bl e e di n g ass oci at e d wit h s ex u al acti vit y as r e p ort e d at t h e 
e n d of t h e st u d y . Th e s a m e m et h o d of a n al ysis as f or t h e pri m ar y e n d p oi nt will b e us e d  f or t h e 
s ec o n d ar y e n d p oi nt.  
  
 
. 
 
8. 1. 3  S a m pl e Siz e C o nsi d er ati o ns  
 
 
 
 
 
 
  
 
 
 
 
  
8. 1. 4  Effic ac y M e as ur es a n d A n al ysis  
Cli nic al e n d p oi nts  


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 4 1  of 5 1  
 
T h e pri m ar y e n d p oi nt of t h e st u d y is t h e pr o p orti o n of s u bj ects i n e ac h tr e at m e nt gr o u p t h at 
ar e i d e ntifi e d as r es p o n d ers at t h e e n d of t h e tr e at m e nt p eri o d. A r es p o n d er is d efi n e d as a 
s u bj ect wit h at l e ast a 2 5 % r e d ucti o n fr o m b as eli n e i n t h e s u m of % b a s al/ p ar a b as al + % 
i nt er m e di at e  c ells  o n  v a gi n al  cyt ol o g y  A N D  v a gi n al  p H  <  5. 0  wit h  a  c h a n g e  fr o m  Visit 
1/ Scr e e ni n g/ B as eli n e  v a gi n al p H of at l e ast 0. 5.  
E q ui v al e nt effic acy  
 
T h e cli nic al e q ui v al e nc e of t h e t est a n d r ef er e nc e tr e at m e nts will b e b as e d o n t h e  pr o p orti o n of 
s u bj ects i d e ntifi e d as r es p o n d ers at Visit 3/ E n d of St u d y ( D a y 8).  T h e 9 0 % W al d’s c o nfi d e nc e 
i nt er v al, usi n g Y at es’ c o nti n uit y c orr ecti o n, will b e c o nstr uct e d o n t h e diff er e nc e b et w e e n t h e 
t est a n d r ef er e nc e r es p o n d er pr o p orti o ns.  If t h e co nfi d e nc e i nt er v al is e ntir el y c o nt ai n e d 
wit hi n t h e i nt er v al – 2 0 % t o + 2 0 %, t h e n t h e t est pr o d uct will b e c o nsi d er e d t o b e cli nic all y 
e q ui v al e nt t o t h e r ef er e nc e pr o d uct.  T h e a n al ysis will b e c o n d uct e d o n b ot h t h e P er -Pr ot oc ol 
( P P) p o p ul ati o n a n d t h e m o dif i e d I nt e nt-T o -Tr e at ( m I T T) p o p ul ati o n.  T h e e v al u ati o n i n t h e P P 
p o p ul ati o n will b e c o nsi d er e d d efi niti v e, wit h t h at i n t h e m I T T p o p ul ati o n as s u p p orti v e. 
 
S u p eri orit y  
 
E ac h  acti v e  tr e at m e nt’s  r es p o n d er  pr o p orti o n  will  b e  c o m p ar e d  t o  t h at  of  t h e  V e hicl e , 
in d e p e n d e ntl y ( T est vs. V e hicl e, R ef er e nc e vs. V e hicl e ), usi n g a t w o-si d e d, α  = 0. 0 5 , c o nti n uit y-
c orr ect e d Z-t est.  If e ac h acti v e tr e at m e nt’s r es p o n d er pr o p orti o n at Visit 3/ E n d of St u d y will b e  
st atistic all y gr e at er t h a n t h at of t h e V e hicl e  ( p< 0. 0 5) , t h e n s u p eri orit y will b e c o nsi d er e d t o 
h a v e b e e n d e m o nstr at e d. S u p eri orit y a n al ys es will b e c o n d uct e d o n b ot h t h e P P a n d t h e m I T T 
p o p ul ati o n s.  T h e a n al ys es i n t h e m I T T p o p ul ati o n will b e c o nsi d er e d pri m ar y, whil e  t h os e i n t h e 
P P as s u p p orti v e.  
 
I n t h e m I T T p o p ul ati o n, a L ast-O bs er v ati o n -C arri e d -F or w ar d a p pr o ac h will b e us e d t o i m p ut e 
missi n g effic acy r es ults.  F or s u bj ects w h o disc o nti n u e d u e t o tr e at m e nt f ail ur e, t h e y will b e 
i ncl u d e d i n t h e P P p o p ul ati o n as n o n-r es p o n d ers f or t h e pri m ar y a n al ys es.  N o f or m al st atistic al 
a n al ys es ar e pl a n n e d t o e v al u at e t h e c o nsist e ncy of effic acy r es ults acr oss t h e m ulti pl e c e nt ers 
f or t h e pri m ar y effic acy v ari a bl e.  T h es e r es ults, h o w e v er, will b e t a b ul at e d a n d, if a c e nt er’s 
r es p o ns e is o b vi o usl y i nc o nsist e nt wit h t h os e of t h e ot h er c e nt ers, t his will b e ex pl or e d a n d 
a d dr ess e d i n t h e fi n al st u d y r e p ort.  
 
S ec o n d ar y A n al ys es  
 
T h e s ec o n d ar y e n d p oi nt will b e t h e pr o p orti o n of s u bj ects wit h tr e at m e nt s ucc ess b as e d o n t h e 
i m pr o v e m e nt (c h a n g e fr o m b as eli n e) of t h e M ost B ot h ers o m e S y m pt o m of V V A at Visit 3/ E n d 
of St u d y.  Tr e at m e nt s ucc ess is d efi n e d as a c h a n g e fr o m b as eli n e w hic h will r es ult i n a sc or e of 
0 ( n o n e) or 1 ( mil d) at Visit 3 if t h e M ost B ot h ers o m e S y m pt o m is v a gi n al dr y n ess, v a gi n al or 
v ul v ar irrit ati o n or itc hi n g,  d ys uri a a n d v a gi n al p ai n ass oci at e d wit h s ex u al acti vit y . If t h e M ost 
B ot h ers o m e S y m pt o m is v a gi n al bl e e di n g ass oci at e d wit h s ex u al acti vit y t h e n tr e at m e nt 
s ucc ess will b e a bs e nc e of v a gi n al bl e e di n g ass oci at e d wit h s ex u al acti vit y as r e p ort e d at t h e 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 4 2  of 5 1  
e n d of t h e st u d y.  T h e s a m e m et h o ds of a n al ysis as f or t h e pri m ar y e n d p oi nt will b e us e d f or t h e 
s ec o n d ar y e n d p oi nt c h a n g e fr o m b as eli n e i n t h e sc or e of m ost b ot h ers o m e s y m pt o m of V V A at 
Visit 3/ E n d of st u d y. T h e s e v erit y of M ost B ot h ers o m e S y m pt o m of V V A will b e ass ess e d b as e d 
o n t h e sc ori n g sc al e: 0 ( n o n e ), 1 ( mil d ), 2( m o d er at e) a n d 3 (s e v er e) as d efi n e d i n S ecti o n 5. 5.  
 
8. 1. 5  S af et y a n d A d v ers e E v e nts A n al ysis  
A Es will b e c o d e d usi n g t h e M e dic al Dicti o n ar y f or R e g ul at or y Acti viti es ( M e d D R A), V ersi o n  1 8. 1  
.  T h e n u m b er a n d p erc e nt of s u bj ects r e p orti n g A Es will b e t a b ul at e d by tr e at m e nt gr o u p f or 
t h e s af et y p o p ul ati o n o nl y.  S u m m ari es will b e pr es e nt e d b y b o d y s yst e m a n d pr ef err e d t er m, 
a n d f urt h er b y  s e v erit y a n d r el ati o ns hi p t o st u dy m e dic ati o n.  I n s u m mari es of s e v erit y a n d 
r el ati o ns hi p, s u bj ects w h o r e p ort m or e t h a n 1 e v e nt t h at ar e m a p p e d t o t h e s a m e pr ef err e d 
t er m will b e c o u nt e d o nly o nc e u n d er t h e str o n g est s e v erit y a n d r el ati o ns hi p, acc or di n gl y.  T h e 
a d v ers e e v e nt r e p ort e d b y at l e ast fi v e p erc e nt of t h e s u bj ects i n a n y tr e at m e nt gr o u p will als o 
b e t a b ul at e d.  T h e c o m p ar a bl e s af et y of t h e T est a n d R ef er e nc e tr e at m e nts will b e e v al u at e d b y 
st atistic al c o m p aris o n of t h e pr o p orti o n of s u bj ect w h o r e p ort e d a n y a d v ers e e v e nts usi n g C hi -
S q u ar e or Fis h er’s  ex act t est if a p pr o pri at e.    
 
S A Es will b e disc uss e d wit hi n t h e cli nic al st u d y r e p ort.  D at a c oll ect e d p ert ai ni n g t o S A Es will b e 
pr es e nt e d i n d at a listi n gs.  
 
C o nc o mit a nt m e dic ati o ns will b e cl assifi e d acc or di n g t o t h e W orl d H e alt h Or g a niz ati o n ( W H O) 
Dr u g  Dicti o n ar y, t h e S e pt e m b er 2 0 1 5 v ersi o n, a n d will b e pr es e nt e d i n d at a listi n gs.  
 
8. 2  
C o m p ar a bilit y of S u bj ects at b as eli n e  
B as eli n e v ari a bl es will b e c o m p ar e d b et w e e n tr e at m e nt gr o u ps t o i d e ntif y diff er e nc es w hic h 
m a y n ot h a v e b e e n eli mi n at e d b y r a n d o miz ati o n.  A n y si g nific a nt b as eli n e diff er e nc es will b e 
r e vi e w e d f or t h eir p ot e nti al i m p act o n t h e effic acy fi n di n gs. 
 
9  
C O N S E N T C O N SI D E R A TI O N S A N D P R O C E D U R E S  
It will b e m a d e cl e ar t o t h e s u bj ects t h at, f or t h e p ur p os es of t h e st u d y, t h e y ar e c o ns e nti n g 
o nl y  f or  t h e  a p plic ati o n  of  st u d y  m e dic ati o n  or  v e hicl e.   I n v esti g at ors  m a y  disc uss  t h e  
a v ail a bilit y of t h e st u d y a n d t h e p ossi bilit y f or e ntr y wit h a p ot e nti al s u bj ect wit h o ut first 
o bt ai ni n g c o ns e nt. H o w e v er, i nf or m e d c o ns e nt m ust b e o bt ai n e d a n d d oc u m e nt e d pri or t o 
i niti ati o n of a n y pr oc e d ur es t h at ar e p erf or m e d s ol el y f or t h e p ur p os e of d et er mi ni n g eli gi bilit y 
f or  r es e arc h,  i ncl u di n g  wit h dr a w al  fr o m  c urr e nt  m e dic ati o n(s).   W h e n  t his  is  d o n e  i n  
a ntici p ati o n of, or i n pr e p ar ati o n f or, t h e r es e arc h, it is  c o nsi d er e d t o b e p art of t h e r es e arc h. 
 
T h e st u d y m ust b e a p pr o v e d i n writi n g b y a n a p pr o pri at e I R B as d efi n e d b y F D A r e g ul ati o ns.  A 
c o p y of t h e L ett er of A p pr o v al fr o m t h e I R B, w hic h als o c o nt ai ns s p ecific i d e ntific ati o n of t h e 
d oc u m e nts a p pr o v e d, m ust b e r ec ei v e d b y P erri g o, pri or t o st u d y c o m m e nc e m e nt.  
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 4 3  of 5 1  
P eri o dic st at us r e p orts m ust b e s u b mitt e d t o t h e I R B at l e ast a n n u all y as r e q uir e d b y t h e sit e’s 
I R B, as w ell as n otific ati o n of c o m pl eti o n of t h e st u d y a n d a fi n al r e p ort wit hi n t hr e e m o nt hs of 
st u d y c o m pl eti o n or t er mi n ati o n.  A c o p y of all r e p orts s u b mitt e d t o t h e I R B m ust b e s e nt t o 
P erri g o  
 
T h e i n v esti g at or(s) h as b ot h et hic al a n d l e g al r es p o nsi bilit y t o e ns ur e t h at e ac h s u bj ect b ei n g 
c o nsi d er e d f or i ncl usi o n i n t his st u d y is gi v e n a f ull ex pl a n ati o n of t h e pr ot oc ol.  T his s h all b e 
d oc u m e nt e d  o n  a  writt e n  i nf or m e d  c o ns e nt  f or m,  w hic h  s h all  b e  a p pr o v e d  b y  t h e  s a m e  
I nstit uti o n al  R e vi e w  B o ar d  (I R B)  r es p o nsi bl e  f or  a p pr o v al  of  t his  pr ot oc ol.  E ac h  i nf or m e d  
c o ns e nt f or m s h all i ncl u d e t h e el e m e nts r e q uir e d  b y F D A r e g ul ati o ns i n 2 1 C F R P art 5 0.  T h e 
i n v esti g at or a gr e es t o o bt ai n a p pr o v al fr o m P erri g o of a n y writt e n i nf or m e d c o ns e nt f or m us e d 
i n t h e st u d y, pr ef er a bl y pri or t o s u b missi o n t o t h e I R B. 
 
O nc e  t h e  a p pr o pri at e  ess e nti al  i nf or m ati o n  h as  b e e n  pr o vi d e d  t o  t h e  s u bj ect  a n d  f ull y  
ex pl ai n e d  b y  t h e  i n v esti g at ors  ( or  a  q u alifi e d  d esi g n e e)  a n d  it  is  f elt  t h at  t h e  s u bj ect  
u n d erst a n ds t h e i m plic ati o ns of p artici p ati n g, t h e I R B -a p pr o v e d writt e n i nf or m e d c o ns e nt f or m 
s h all b e si g n e d b y t h e s u bj ect  a n d t h e p ers o n o bt ai ni n g c o ns e nt (i n v esti g at or or d esi g n e e).  T h e 
s u bj ect s h all b e gi v e n a c o p y of t h e si g n e d i nf or m e d c o ns e nt/ ass e nt f or m a n d t h e i n v esti g at or 
s h all k e e p t h e ori gi n al o n fil e. 
 
If t h e s u bj ect f ails t o m e et t h e i ncl usi o n/ excl usi o n crit eri a at t h e c o ncl usi o n of t h e scr e e ni n g 
p h as e, t h e s u bj ect will b e wit h dr a w n fr o m scr e e ni n g.  I n t h e e v e nt t h at t h e s u bj ect is r e -
scr e e n e d f or st u d y p artici p ati o n, a n e w i nf or m e d c o ns e nt/ ass e nt f or m m ust b e si g n e d. 
 
9. 1  
S u bj ect C o nfi d e nti alit y  
All p artici p a nts ar e c o nc er n e d f or t h e i n di vi d u al s u bj ect’s pri v acy a n d, t h er ef or e, all s u bj ect 
d at a will b e i d e ntifi e d o nl y b y a s u bj ect i d e ntific ati o n n u m b er a n d s u bj ect i niti als. H o w e v er, i n 
c o m pli a nc e wit h f e d er al g ui d eli n es r e g ar di n g t h e m o nit ori n g of  cli nic al st u di es a n d i n f ulfill m e nt 
of his/ h er o bli g ati o ns t o P erri g o, it is r e q uir e d t h at t h e i n v esti g at or p er mit t h e st u d y m o nit or, 
a n y S p o ns or a ut h oriz e d r e pr es e nt ati v e, a n d/ or F D A r e pr es e nt ati v e t o r e vi e w t h at p orti o n of t h e 
s u bj ect’s m e dic al r ec or d th at is dir ectl y r el at e d t o t h e st u d y.  T his s h all i ncl u d e all st u d y r el e v a nt 
d oc u m e nt ati o n i ncl u di n g s u bj ect m e dic al hist ori es t o v erif y eli gi bilit y, l a b or at or y t est r es ult 
r e p orts  t o  v erif y  tr a nscri pti o n  acc ur acy,  a d missi o n/ disc h ar g e  s u m m ari es  f or  h os pit al  st a ys  
occ urri n g w hil e t h e s u bj ect is e nr oll e d i n t h e st u d y a n d a ut o ps y r e p orts f or d e at hs occ urri n g 
d uri n g t h e st u d y.  
 
As p art of t h e r e q uir e d c o nt e nt of i nf or m e d c o ns e nt, t h e s u bj ect m ust b e i nf or m e d t h at his/ h er 
m e dic al  c h art  m a y  b e  r e vi e w e d  b y  P erri g o  or  t h eir  a ut h oriz e d  r e pr es e nt ati v e,  or  a  
r e pr es e nt ati v e of t h e F D A.  S h o ul d acc ess t o t h e m e dic al r ec or d r e q uir e a s e p ar at e w ai v er or 
a ut h oriz ati o n, it is t h e i nv esti g at or’s r es p o nsi bility t o o bt ai n s uc h p er missi o n fr o m t h e s u bj ect i n 
writi n g b ef or e t h e s u bj ect is e nt er e d i nt o t h e st u dy.  
 


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P a g e 4 4  of 5 1  
T o  pr es er v e  t h e  s u bj ect's  c o nfi d e nti alit y,  t h e  d at a  c oll ect e d  will  b e  a v ail a bl e  o nl y  t o  t h e  
i n v esti g at ors of t h e st u d y, t h eir s u p p ort st aff, P erri g o or t h eir a ut h oriz e d r e pr es e nt ati v e a n d 
p ossi bl y t h e F D A.  
 
All r e p orts a n d c o m m u nic ati o ns r el ati n g t o t h e s u bj ect i n t h e st u d y will i d e ntif y e ac h s u bj ect 
o nl y b y t h e s u bj ect’s i niti als a n d b y t h e s u bj ect n u m b er. T h e i n v esti g at or a gr e es t o f ur nis h 
P erri g o wit h c o m pl et e s u bj ect i d e ntific ati o n, if n ec ess ar y o n a c o nfi d e nti al f oll o w- u p f or m, 
w hic h will b e us e d f or t h e p ur p os e of a l o n g -t er m f oll o w-u p, if n e e d e d.  T his will b e tr e at e d wit h 
strict a d h er e nc e t o pr of essi o n al st a n d ar ds of c o nfi d e nti alit y a n d will b e fil e d at P erri g o u n d er 
a d e q u at e s ec urit y a n d r estrict e d acc essi bilit y  
 
1 0  C O N D U C T O F S T U D Y  
T h e i n v esti g ati o n al sit e is t o m ai nt ai n c o m pl et e d oc u m e nt ati o n of all e v e nts a n d t h e ti m es at 
w hic h t h e y occ ur.  
 
1 0. 1  C o m pl eti o n of St u d y  
T h e i n v esti g ati o n al sit e will c o m pl et e t h e st u d y a n d c o m pl et e all d oc u m e nt ati o n r e q uir e d, i n 
s atisf act or y co m pli a nc e wit h t h e pr ot oc ol, wit hi n 3. 5 m o nt hs  of e nr oll m e nt of t h e l ast s u bj ect 
a n d ext e n di n g b e y o n d as n e e d e d t o c o m pl et e n ec ess ar y d at a q u eri es.  
 
It is a gr e e d t h at, f or r e as o n a bl e c a us e, eit h er t h e i n v esti g at or or P erri g o m a y t er mi n at e t his 
st u d y b ef or e c o m pl eti o n pr o vi d e d writt e n n otic e is s u b mitt e d at a r e as o n a bl e ti m e i n a d v a nc e 
of i nt e n d e d t er mi n ati o n.  A n y ext e nsi o n of t his st u d y m ust b e m ut u all y a gr e e d u p o n i n writi n g 
b y b ot h t h e i n v esti g at or a n d P erri g o.  
 
1 0. 2  Pr ot oc ol A m e n d m e nts  
T h e I n v esti g at or will n ot m a k e a n y c h a n g es t o t his pr ot oc ol wit h o ut pri or writt e n c o ns e nt fr o m 
P erri g o a n d s u bs e q u e nt a p pr o v al b y t h e I R B.  A n y p er m a n e nt c h a n g e t o t h e pr ot oc ol, w h et h er 
it is a n o v er all c h a n g e or a c h a n g e f or s p ecific st u d y c e nt er(s), m ust b e h a n dl e d as a pr ot o c ol 
a m e n d m e nt. A n y a m e n d m e nt t o t h e pr ot oc ol t h at a p p e ars i n dic at e d as t h e st u d y pr o gr ess es 
will b e f ull y disc uss e d b et w e e n  
 a n d P erri g o. If a gr e e m e nt is r e ac h e d r e g ar di n g t h e 
n e e d f or a n a m e n d m e nt, t h e a m e n d m e nt will b e writt e n b y P erri g o. T h e w ritt e n a m e n d m e nt 
m ust b e s u b mitt e d t o t h e c h air m a n of t h e I R B i d e ntifi e d wit h t his r es p o nsi bilit y.  Exc e pt f or 
‘ a d mi nistr ati v e a m e n d m e nts’, i n v esti g at ors m ust a w ait I R B a p pr o v al of pr ot oc ol a m e n d m e nts 
b ef or e i m pl e m e nti n g t h e c h a n g e(s). A d mi nistr ati v e a m e n d m e nts ar e d efi n e d t o h a v e n o eff ect 
o n  t h e  s af et y  of  t h e  r es e arc h  s u bj ects,  sc o p e  of  t h e  i n v esti g ati o n,  or  q u alit y  of  t h e  tri al.   
H o w e v er, a pr ot oc ol c h a n g e i nt e n d e d t o eli mi n at e a n a p p ar e nt i m m e di at e h az ar d t o s u bj ects 
s h o ul d b e i m pl e m e nt e d i m m e di at el y, a n d t h e I R B n otifi e d wit hi n fi v e d ays.  P erri g o will s u b mit 
pr ot oc ol a m e n d m e nts t o t h e F D A or ot h er r e g ul at or y a g e nci es.  
 


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P a g e 4 5  of 5 1  
W h e n, i n t h e j u d g m e nt of t h e r e vi e wi n g I R B, t h e i n v esti g at ors a n d/ or P erri g o, t h e a m e n d m e nt 
t o t h e pr ot oc ol s u bst a nti all y alt ers t h e stu d y d esi g n a n d/ or i ncr e as es t h e p ot e nti al ris k t o t h e 
s u bj ect,  t h e  c urr e ntl y  a p pr o v e d  writt e n  i nf or m e d  c o ns e nt  f or m  will  r e q uir e  si mil ar  
m o dific ati o n.  I n s uc h c as es, r e p e at i nf or m e d c o ns e nt will b e o bt ai n e d fr o m s u bj ects e nr oll e d i n 
t h e st u d y b ef or e ex p ecti n g c o nti n u e d p artici p ati o n. 
 
1 1  R E C O R D S M A N A G E M E N T  
1 1. 1  D at a C oll ecti o n  
 
All  d at a  c oll ect e d  i n  t his  st u d y  will  b e  e nt er e d  o nt o  c as e r e p ort  f or ms  ( C R Fs),  v erifi e d  b y 
m o nit ori n g, a n d s u b mitt e d f or st atistic al e v al u ati o n as d escri b e d b el o w.  C h ec ks will b e r u n o n 
t h e d at a a n d q u eri es iss u e d as n e e d e d. O nc e all d at a is cl e a n e d, f ull q u alit y c o ntr ol v erific ati o n 
will b e d o n e pri or t o br e a ki n g t h e bli n d. Aft er all d at a ar e c orr ectl y e nt er e d, t h e d at a b as e will 
b e l oc k e d a n d s u b mitt e d f or a p pr o pri at e Q u ality Ass ur a nc e v erific ati o ns b ef or e t h e tr e at m e nt 
assi g n m e nt c o d e is br o k e n.  All d at a c oll ect e d i n t h e C R Fs will b e d oc u m e nt e d i n s u bj ect d at a 
listi n gs a n d s u m m ariz e d i n t a bl es, as a p pr o pri at e. 
 
D uri n g e ac h s u bj ect’s visit t o t h e cli nic, a d esi g n e e p artici p ati n g i n t h e st u dy will r ec or d pr o gr ess 
n ot es t o d oc u m e nt all si g nific a nt o bs er v ati o ns.  At a mi ni m u m, t h es e n ot es will c o nt ai n:  
 
a)  D oc u m e nt ati o n of t h e i nf or m e d c o ns e nt pr oc ess;  
b)  T h e d at e of t h e visit a n d t h e c orr es p o n di n g Visit or W e e k i n t h e st u d y sc h e d ul e;  
c) G e n er al s u b j ect st at us r e m ar ks, i ncl u di n g a n y si g nific a nt m e dic al fi n di n gs.  T h e s e v erit y, 
fr e q u e ncy, a n d d ur ati o n of a n y a d v ers e e v e nts a n d t h e i n v esti g at or's ass ess m e nt of 
r el ati o ns hi p t o st u d y m e dic ati o n m ust als o b e r ec or d e d. 
d)  A n y c h a n g es i n c o nc o mit a nt m e dic ati o n s or d os a g es; 
e)  A g e n er al r ef er e nc e t o t h e pr oc e d ur es c o m pl et e d; a n d  
f) T h e si g n at ur e ( or i niti als) a n d d at e of all cli nici a ns w h o m a d e a n e ntr y i n t h e pr o gr ess 
n ot es.  
 
I n a d diti o n, a n y c o nt act wit h t h e s u bj ect vi a t el e p h o n e or ot h er m e a ns t h at pr o vi d es si g nific a nt 
cli nic al i nf or m ati o n will als o b e d oc u m e nt e d i n t h e pr o gr ess n ot es as d escri b e d a b o v e.  
 
A n y c h a n g es t o i nf or m ati o n i n t h e st u d y pr o gr ess n ot es a n d ot h er s o urc e d oc u m e nts, will b e 
e nt er e d  i n  bl ac k  i n k , i niti al e d a n d 
d at e d 
b y  t h e  a ut h oriz e d  p ers o n  m a ki n g  t h e  
c orr ecti o n/ a d diti o n.  C h a n g es will b e m a d e b y striki n g a si n gl e li n e t hr o u g h err o n e o us d at a, a n d 
cl e arl y e nt eri n g t h e c orr ect d at a.  ( e. g., wr o n g d at a  ri g ht d at a).  E ntri es m a y n ot b e er as e d or 
m as k e d wit h w hit e -o ut fl ui d.  If t h e r e as o n f or t h e c h a n g e is n ot a p p ar e nt, a bri ef ex pl a n ati o n 
f or t h e c h a n g e will b e writt e n a dj ac e nt t o t h e c h a n g e b y t h e cli nici a n. 
 
F or  tr a ns missi o n  t o  P erri g o,  i nf or m ati o n  fr o m  t h e  st u d y  pr o gr ess  n ot es  a n d  ot h er  s o urc e  
d oc u m e nts will b e pr o m ptl y e nt er e d i nt o t h e d at a b as e.  T h e d at a b as e  als o c o nt ai ns a c o m pl et e 


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P a g e 4 6  of 5 1  
a u dit tr ail t o c a pt ur e all r e g ul at or y c o m p o n e nts of d at a c orr ecti o ns ( e. g. i niti al e ntr y, n e w v al u e, 
i niti als a n d d at e of t h e c h a n g e). 
 
1 1. 2  S o urc e D oc u m e nts  
S o urc e d oc u m e nts ar e d efi n e d as t h e r es ults of ori gi n al o bs er v ati o ns a n d acti viti es of a cli nic al 
i n v esti g ati o n.   S o urc e  d oc u m e nts  will  i ncl u d e,  b ut  ar e  n ot  li mit e d  t o,  pr o gr ess  n ot es  a n d  
scr e e ni n g  l o gs.   All  s o urc e  d oc u m e nts  p ert ai ni n g  t o  t his  st u d y  will  b e  m ai nt ai n e d  b y  t h e  
i n v esti g at ors a n d m a d e a v ail a bl e f or i ns p ecti o n b y a ut h oriz e d p ers o ns.  T h e ori gi n al si g n e d 
i nf or m e d c o ns e nt f or m f or e ac h p artici p ati n g s u bj ect s h all b e fil e d wit h r ec or ds k e pt b y t h e 
i n v esti g at ors a n d a c o p y gi v e n t o t h e s u bj ect. 
 
1 1. 3   Fil e M a n a g e m e nt at t h e St u d y Sit e 
It is t h e r es p o nsi bilit y of t h e i n v esti g at or t o e ns ur e t h at t h e st u d y c e nt er fil e is m ai nt ai n e d i n 
acc or d a nc e wit h S ecti o n 8 of t h e I nt er n ati o n al C o nf er e nc e o n H ar m o niz ati o n (I C H) G ui d eli n e f or 
G o o d Cli nic al Pr actic es ( G C P) . 
 
1 1. 4   R ec or ds R et e nti o n at t h e St u d y Sit e  
F D A  r e g ul ati o ns  r e q uir e  all  i n v esti g at ors  p artici p ati n g  i n  cli nic al  dr u g  st u di es  t o  m ai nt ai n  
d et ail e d cli nic al d at a f or o n e of t h e f oll o wi n g p eri o ds:  
 
a)  A p eri o d of at l e ast t w o y e ars f oll o wi n g t h e d at e o n w hic h a N e w Dr u g A p plic ati o n is 
a p pr o v e d b y t h e F D A;  
b)  A p eri o d of t w o y e ars aft er P erri g o n otifi es t h e i nv esti g at or t h at n o f urt h er a p plic ati o n is 
t o b e fil e d wit h t h e F D A. 
 
T h e i n v esti g at or m ust n ot dis p os e of a n y r ec or ds r el e v a nt t o t his st u dy wit h o ut eit h er ( 1) 
writ t e n p er missi o n fr o m P erri g o or ( 2) pr o vi di n g a n o p p ort u nit y f or P erri g o t o c oll ect s uc h 
r ec or ds.   T h e  i n v esti g at or  s h all  t a k e  r es p o nsi bilit y  f or  m ai nt ai ni n g  a d e q u at e  a n d  acc ur at e  
el ectr o nic or h ar d c o p y s o urc e d oc u m e nts of all o bs er v ati o ns a n d d at a g e n er at e d d uri n g t his 
st u d y,  i ncl u di n g  a n y  d at a  c orr ecti o n f or ms  ( D C Fs)  r ec ei v e d  fr o m  
.  S uc h  
d oc u m e nt ati o n is s u bj ect t o i ns p ecti o n b y P erri g o a n d t h e F D A.  
 
1 2  Q U ALI T Y C O N T R OL A N D Q U ALI T Y A S S U R A N C E  
1 2. 1  M o nit ori n g  
P erri g o h as et hic al, l e g al a n d sci e ntific o bli g ati o ns t o c ar ef ull y f oll o w t his st u d y i n a d et ail e d a n d 
or d erl y m a n n er i n acc or d a nc e wit h est a blis h e d r es e arc h pri nci pl es a n d F D A r e g ul ati o ns.  All 
m e dic al  r ec or ds  (s o urc e  d oc u m e nts)  of  t h e  s u bj ects  p artici p ati n g  i n  t his  st u d y  m ust  b e  
pr es e nt e d f or r e vi e w  a n d v erific ati o n of C R Fs.  


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P a g e 4 7  of 5 1  
1 2. 2  A u diti n g  
P erri g o  ( or r e pr es e nt ativ e) m a y c o n d uct a u dits at t h e st u d y c e nt er(s).  A u dits will i ncl u d e, b ut 
ar e n ot b e li mit e d t o, dr u g s u p pl y, pr es e nc e of r e q uir e d d oc u m e nts, t h e i nf or m e d c o ns e nt 
pr oc ess, a n d c o m p aris o n of C R F s wit h s o urc e d oc u m e nts.  T h e i n v esti g at or a gr e es t o p artici p at e 
wit h a u dits c o n d uct e d at a r e as o n a bl e ti m e i n a r e as o n a bl e m a n n er.  
 
R e g ul at or y a ut h oriti es w orl d wi d e m a y als o a u dit t h e i n v esti g at or d uri n g or aft er t h e st u d y. T h e 
i n v esti g at or s h o ul d c o nt act P erri g o i m m e di at el y if n otifi e d of s uc h a n a u dit, a n d m ust f ull y 
c o o p er at e wit h t h e a u dits c o n d uct e d at a r e as o n a bl e ti m e i n a r e as o n a bl e m a n n er.  
 
1 3  E T HI C S A N D R E S P O N SI B ILI T Y 
T his st u d y m ust b e c o n d uct e d i n c o m pli a nc e wit h t h e pr ot oc ol, t h e U nit e d St at es F o o d a n d 
Dr u g  A d mi nistr ati o n  ( F D A)  r e g ul ati o ns,  a n y  ot h er  c o u ntri es  r e g ul ati o ns,  a n d  I C H  G C P  
G ui d eli n es.  
 
1 4  U S E O F I N F O R M A TI O N A N D P U BLI C A TI O N  
All i nf or m ati o n s u p pli e d b y P erri g o  i n c o n n ecti o n wit h t his st u d y a n d n ot pr e vi o usl y p u blis h e d, 
is c o nsi d er e d c o nfi d e ntial i nf or m ati o n.  T his i nf or m ati o n i ncl u d es, b ut is n ot li mit e d t o, d at a, 
m at eri als  (i. e.  t h e  cli nic al  pr ot oc ol,  C R Fs ),  e q ui p m e nt,  ex p eri e nc e  ( w h et h er  of  a  sci e ntific,  
t ec h nic al, e n gi n e eri n g, o p er ati o n al, or c o m m erci al n at ur e), d esi g ns, s p ecific ati o ns, k n o w-h o w, 
pr o d uct  us es, pr oc ess es, f or m ul a e, c osts, fi n a nci al d at a, m ar k eti n g pl a ns a n d  dir ect  s elli n g 
s yst e ms, c ust o m er lists a n d t ec h nic al a n d c o m m erci al i nf or m ati o n r el ati n g t o c ust o m ers or 
b usi n ess  pr oj ecti o ns  us e d  b y  P erri g o  i n  its  b usi n ess.  A n y  d at a,  i n v e nti o ns,  or  disc o v eri es  
c oll ect e d or d e v el o p e d, as a r es ult of t his st u dy is c o nsi d er e d c o nfi d e nti al. T his c o nfi d e nti al 
i nf or m ati o n  s h all  r e m ai n  t h e  s ol e  pr o p ert y  of  P erri g o,  s h all  n ot  b e  discl os e d  t o  a n y  
u n a ut h oriz e d p ers o n or us e d i n a n y u n a ut h oriz e d m a n n er wit h o ut writt e n c o ns e nt of P erri g o, 
a n d s h all n ot b e us e d exc e pt i n t h e p erf or m a nc e of t h e st u d y.  As s uc h, c o nfi d e nti al st u d y -
r el at e d  i nf or m ati o n  s h o ul d  n ot  b e  i ncl u d e d  o n  t h e  c urric ul u m  vit a e  of  a n y  p artici p ati n g  
i n v esti g at or or st u d y st aff. 
 
T h e  i nf or m ati o n  d e v el o p e d  d uri n g  t h e  c o urs e  of  t his  cli nic al  st u dy  is  als o  c o nsi d er e d  
c o nfi d e nti al, a n d will b e us e d b y P erri g o i n c o n n ecti o n wit h t h e d e v el o p m e nt of t h e dr u g.  T h e 
i nf or m ati o n  m a y  b e  discl os e d  as  d e e m e d  n ec ess ar y  b y  P erri g o  t o  all o w  t h e  us e  of  t he 
i nf or m ati o n d eri v e d fr o m t his cli nic al st u d y, t h e i n v esti g at or is o bli g e d t o pr o vi d e P erri g o wit h 
c o m pl et e t est r es ults a n d all d at a d e v el o p e d i n t h e st u d y. T h e i nf or m ati o n o bt ai n e d d uri n g t his 
st u d y m a y b e m a d e a v ail a bl e t o ot h er i n v esti g at ors w h o ar e c o n d ucti n g si mil ar st u di es. 
 
T h e  i n v esti g at or  s h all  n ot  m a k e  a n y  p u blic ati o n  r el at e d  t o  t his  st u d y  wit h o ut  t h e  ex pr ess  
writt e n p er missi o n of P erri g o. 
 
 
 


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Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 4 9  of 5 1  
I N V E S TI G A T O R A G R E E M E N T 
 
P R O T O C OL N U M B E R:  P R G -N Y - 1 5-0 0 7  
 
P R O T O C OL TI TL E:  A R a n d o miz e d, D o u bl e -Bli n d e d, V e hicl e -C o ntr oll e d, P ar all el -Gr o u p 
M ultic e nt er St u d y T o C o m p ar e P erri g o U K FI N C O’s Estr a di ol V a gi n al Cr e a m 0. 0 1 % T o E S T R A C E ® 
( estr a di ol) V a gi n al Cr e a m, U S P, 0. 0 1 % (W ar n er C hilc ott ( U S),  LL C) A n d B ot h Acti v e Tr e at m e nts 
T o A V e hicl e C o ntr ol I n T h e Tr e at m e nt Of V ul v ar A n d V a gi n al Atr o p h y  
 
 
I  h a v e  c ar ef ull y  r e a d  t h e  f or e g oi n g  pr ot oc ol  a n d  a gr e e  t h at  it  c o nt ai ns  all t h e  n ec ess ar y  
i nf or m ati o n f or c o n d ucti n g t his st u d y s af el y.  I will c o n d uct t his st u d y i n strict acc or d a nc e wit h 
t his pr ot oc ol, I C H G ui d eli n es f or G o o d Cli nic al Pr actic es, t h e C o d e of F e d er al R e g ul ati o ns, t h e 
H e alt h  I ns ur a nc e  P ort a bilit y  a n d  Acc o u nt a bilit y  Act  ( HI P A A)  a n d  a n y  l oc al  r e g ul at or y  
r e q uir e m e nts a n d will att e m pt t o c o m pl et e t h e st u d y wit hi n t h e ti m e d esi g n at e d.  I will pr o vi d e 
acc ess t o c o pi es of t h e pr ot oc ol a n d all ot h er i nf or m ati o n r el ati n g t o pr e -cli nic al a n d pri or 
cli nic al ex p eri e nc e s u b mitt e d b y P erri g o t o all p ers o n n el r es p o nsi bl e t o m e w h o p artici p at e i n 
t h e st u d y.  I will disc uss t his i nf or m ati o n wit h t h e m t o ass ur e t h at t h e y ar e a d e q u at el y i nf or m e d 
r e g ar di n g t h e dr u g a n d c o n d uct of t h e st u d y.  I a gr e e t o k e e p r ec or ds o n all s u bj ect i nf orm ati o n 
i n acc or d a nc e wit h F D A r e g ul ati o ns. 
 
 
 
  
 
 
 
   Pri nci p al I n v esti g at or’s Pri nt e d N a m e  
 
 
 
  
 
 
 
   Pri nci p al I n v esti g at or’s Si g n at ur e  
 
 
  
 
 
 
   D at e  
 
 


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 5 0  of 5 1  
1 5  R E F E R E N C E S  
1.  U. S. F o o d a n d Dr u g A d mi nistr ati o n. Dr aft G ui d a nc e o n Estr a di ol. ( Estr a di ol Cr e a m 0. 0 1 % 
V a gi n al) – R ec o m m e n d e d A u g 2 0 0 9 ; R e vis e d S e p 2 0 1 4  
2.  U. S. F o o d a n d Dr u g A d mi nistr ati o n. G ui d a nc e f or t h e I n d ustr y. Estr o g e n a n d 
Estr o g e n/ Pr o g esti n Dr u g Pr o d ucts t o Tr e at V as o m ot or S y m pt o ms a n d V ul v ar a n d 
V a gi n al Atr o p h y S y m pt o ms — R ec o m m e n d ati o ns f or Cli nic al E v al u ati o n  
3.  N ort h A m eric a n M e n o p a us e S oci et y. T h e r ol e of l oc al v a gi n al estr o g e n f or tr e at m e nt of 
v a gi n al atr o p h y i n p ost m e n o p a us al w o m e n: 2 0 0 7 p ositi o n st at e m e nt of T h e N ort h 
A m eric a n M e n o p a us e S oci et y. M e n o p a us e. 2 0 0 7; 1 4( 3 Pt 1): 3 5 5 -3 6 9  
4.  N ort h A m eric a n M e n o p a us e S oci et y. Estr o g e n a n d pr o g est o g e n us e i n p ost m e n o p a us al 
w o m e n: 2 0 1 0 p ositi o n st at e m e nt of T h e N ort h A m eric a n M e n o p a us e S oci et y. 
M e n o p a us e 2 0 0 7; 1 4( 2): 1 6 8 -1 8 2  
5.  N ort h A m eric a n M e n o p a us e S oci et y. T h e 2 0 1 2 h or m o n e t h er a p y p ositi o n st at e m e nt of 
T h e N ort h A m eric a n M e n o p a us e S oci et y. M e n o p a us e. 2 0 1 2 M ar; 1 9  ( 3): 2 5 7-7 1.  
6.  B ac h m a n n G A, L o b o R A, G ut R, N ac hti g all L, N ot el o vitz M: Effic acy of l o w -d os e Estr a di ol 
v a gi n al t a bl ets i n t h e tr e at m e nt of atr o p hic v a gi nitis. O bst etrics & G y n ec ol o g y V ol. 1 1 1, 
N o 1, J a n 2 0 0 8: 6 7 -7 6  
7.  B ac h m a n n G A, E b ert G A, B ur d I D. V ul v o v a gi n al c o m pl ai nts. I n: L o b o R A, e d. Tr e at m e nt 
of t h e P ost m e n o p a us al W o m a n: B asic a n d Cli nic al As p ects. P hil a d el p hi a, P A: Li p pi nc ott 
Willi a ms & Wil ki ns, 1 9 9 9: 1 9 5 -2 0 1.  
8.  N ac hti g all L, N ac hti g all M, G or e n J, L o e w e nst ei n J: U p d at e o n v a gi n al atr o p h y. 
M e n o p a us e, S e p/ Oct 2 0 0 5  
9.  Pi n k ert o n,J V. V a gi n al i m p act of m e n o p a us e -r el at e d estr o g e n d efici e ncy, s u p pl e m e nt t o 
O B G m a n a g e m e nt - M a n a gi n g v a gi n al atr o p h y a n d its s y m pt o ms i n m e n o p a us e, N o v 
2 0 1 0  
1 0.  Tri n k a us M, C hi n S, W olf m a n W, Si m m o ns C, Cl e m o ns M. S h o ul d ur o g e nit al atr o p h y i n 
br e ast c a nc er s ur vi v ors b e tr e at e d wit h t o pic al estr o g e ns ? O nc ol o gist 2 0 0 8; 1 3( 3): 2 2 2 -2 3 1  
1 1.  G ol dst ei n I. R ec o g nizi n g a n d tr e ati n g ur o g e nit al atr o p h y i n p ost m e n o p a us al w o m e n, J 
W o m e n’s H e alt h  (L ars h mt). 2 0 1 0; 1 9( 3): 4 2 5-4 3 2  
1 2.  L y nc h C. V a gi n al estr o g e n t h er a p y f or t h e tr e at m e nt of atr o p hic v a gi nitis. J W o m e n’s 
H e alt h, 2 0 0 9; 1 8( 1 0): 1 5 9 5 -1 6 0 6  
1 3.  Si m o n J, N ac hti g all L, G ut R, L a n g E, Arc h er D F, Uti a n W. Eff ecti v e tr e at m e nt of v a gi n al 
atr o p h y wit h a n ultr a -l o w-d os e estr a di ol v a gi n al t a bl et. O bst et G y n ec ol. 2 0 0 8 N o v;  1 1 2  
( 5): 1 0 5 3-6 0.  
1 4.   S uc kli n g J, L et h a b y A, K e n n e d y R. L oc al o estr o g e n f or v a gi n al atr o p h y i n 
p ost m e n o p a us al w o m e n. C o hr a n e D at a b as e S yst e m atic R e vi e w 2 0 0 3/ 2 0 0 5( 4)  
1 5.  Brizz ol ar a S, Kill e e n J, S ev eri n o R. V a gi n al p H a n d p ar a b as al c ells i n p ost m e n o p a us al 
w o m e n. O bst et G y n ec ol. 1 9 9 9 N o v; 9 4  ( 5 Pt 1): 7 0 0-3.  
1 6.  Nilss o n K, Ris b er g B, H ei m er G. T h e v a gi n al e pit h eli u m i n t h e p ost m e n o p a us e — cyt ol o g y, 
hist ol o g y a n d p H as m et h o ds of ass ess m e nt. M at urit as 1 9 9 5;  2 1: 5 1 – 6.  
1 7.   S p er off L. Effic acy a n d t ol er a bilit y of a n o v el estr a di ol v a gi n al ri n g f or r eli ef of 
m e n o p a us al s y m pt o ms. O bst et G y n ec ol. 2 0 0 3 Oct;  1 0 2  ( 4): 8 2 3-3 4.  
1 8.  J a n et A C h oll et Effic acy a n d s af et y of ultr a-l o w-d os e V a gif e m( 1 0 mc g). 2 0 1 1; 5: 5 7 1 – 5 7 4.  


Pr ot oc ol: P R G -N Y -1 5 -0 0 7  
 
 
P a g e 5 1  of 5 1  
1 9.  N ac hti g all L E. C o m p ar ativ e st u d y: R e pl e ns v ers us l oc al estr o g e n i n m e n o p a us al w o m e n. 
F ertil St eril 1 9 9 4;  6 1: 1 7 8 -1 8 0.  
2 0.  A yt o n R A, D arli n g G M, M ur ki es AL, et al. A c o m p ar ati v e st u d y of s af et y a n d effic acy of 
c o nti n u o us l o w d os e o estr a di ol r el e as e d fr o m a v a gi n al ri n g c o m p ar e d wit h c o nj u g at e d 
e q ui n e o estr o g e n v a gi n al cr e a m i n t h e tr e at m e nt of p ost m e n o p a us al ur o g e nit al 
atr o p h y. BJ O G 1 9 9 6; 1 0 3: 3 5 1 -3 5 8.  
2 1.  N ac hti g all L. Cli nic al tri al of t h e estr a di ol v a gi n al ri n g i n t h e U. S. M at urit as 1 9 9 5;  
2 2( S u p pl): S 4 3 -S 4 7. 2 6.  
2 2.  M a n o n ai J, T h e p pis ai U, S ut h ut v or a v u t S, U d o ms u b p a y a k ul U, C hitt ac h ar o e n A. T h e 
eff ect of estr a di ol v a gi n al t a bl et a n d c o nj u g at e d estr o g e n cr e a m o n ur o g e nit al 
s y m pt o ms i n p ost m e n o p a us al w o m e n: a c o m p ar ati v e st u d y. J O bst et G y n a ec ol R es 
2 0 0 1;  2 7: 2 5 5 -2 6 0.  
2 3.  Ri o ux J E, D e vli n M C, G elf a n d M M, St ei n b er g W M, H e p b ur n D S. 1 7 A - estr a di ol v a gi n al 
t a bl et v ers us c o nj u g at e d e q ui n e estr o g e n v a gi n al cr e a m t o r eli e v e m e n o p a us al atr o p hic 
v a gi nitis. M e n o p a us e 2 0 0 0; 7: 1 5 6 -1 6 1.  
2 4.  B ar e nts e n R, v a n d e W eij er P H, Sc hr a m J H. C o nti n u o us l o w d os e estr a di ol r el e as e d fr o m 
a v a gi n al ri n g v ers us estri ol v a gi n al cr e a m f or ur o g e nit al atr o p h y. E ur J O bst et G y n ec ol 
R e pr o d Bi ol 1 9 9 7;  7 1: 7 3 -8 0.  
2 5.  Cr a n d all C. V a gi n al estr o g e n pr e p ar ati o ns: a r e vi e w of s af et y a n d effic acy f or v a gi n al 
atr o p h y. J W o m e n’s H e alt h 2 0 0 2; 1 1: 8 5 7 -8 7 7  
2 6.  Eri ks e n P S, R as m uss e n H. L o w -d os e 1 7 β -estr a di ol v a gi n al t a bl ets i n t h e tr e at m e nt of 
atr o p hic v a gi nitis: a d o u bl e -bli n d pl ac e b o c o ntr oll e d st u d y. E ur J O bst et Gy n ec ol R e pr o d 
Bi ol 1 9 9 2; 4 4: 1 3 7 -1 4 4  
2 7.  C as p er F, P etri E. L oc al tr e at m e nt of ur o g e nit al atr o p h y wit h Estr a di o l-r el e asi n g v a gi n al 
ri n g: a c o m p ar ati v e a n d a pl ac e b o c o ntr oll e d m ultic e nt er st u d y. V a gi n al Ri n g St u d y 
Gr o u p. I nt Ur o g y n ec ol J 1 9 9 9: 1 0: 1 7 1 -1 7 6  
2 8.  J o h nst o n SL, F arr ell S A, B o uc h ar d C, F arr ell S A, B ec k ers o n L A, C o m e a u M, J o h nst o n SL, 
L ef e b vr e G, P a p ai o a n n o u A. T h e d et ecti o n a n d m a n a g e m e nt of v a gi n al atr o p h y. S O G C 
J oi nt C o m mitt e e-Cli nic al Pr actic e G y n a ec ol o g y a n d Ur o g y n a ec ol o g y. J O bst et G y n a ec ol 
C a n. 2 0 0 4 M a y; 2 6( 5): 5 0 3 -1 5  
2 9.  C h e n L, M o h -J e e N, Vl u gt T, Pric e P, Or e nci a A. St atistic al c o nsi d er ati o ns f or t h e effic acy 
ass ess m e nt of cli nic al st u di es of v ul v ar a n d v a gi n al atr o p h y. Dr u g I nf or m ati o n J, 
2 0 1 0; 4 4: 5 8 1 -5 8 8  
3 0.  N ac hti g all L, n ac hti g all M, G or e n J, L o e w e nst ei n J – U p d at e o n v a gi n al atr o p h y, 
M e n o p a us e m a n a g e m e nt 2 0 0 5  
3 1.  Estr ac e v a gi n al cr e a m 0. 0 1 % p ac k a g e i ns ert d at e d J u l y 2 0 1 1 
3 2.  Cli nic al Tri als. g o v I d e ntifi er: N C T 0 2 1 9 5 9 8 6: A C o m p aris o n of Estr a di ol V a gi n al Cr e a m t o 
Estr ac e ® Cr e a m i n 3 5 0 P ost m e n o p a us al F e m al es wit h Atr o p hic V a gi nitis; L ast v erifi e d 
d at e: J ul y 2 0 1 4  

SAP_001.pdf: 
 
 
 
 
NCT02770365 
 
02-08-2016 






P erri g o Ne w Y or k, I nc.                                                                                                                  Pr ot oc ol: P R G -N Y -1 5 -0 0 7                           
 
3  
C O N FI D E N TI A L  
List of A b bre viati o ns 
 
A E  
A d verse E ve nt  
A N O V A  
A nal ysis of Varia nce  
CI  
C o nfi de nce I nter val  
C M H  
C oc hra n – Ma ntel – Hae nszel T est  
I T T 
I nte nt-to -Treat ( P o p ulati o n)  
L O C F  
Last O bser vati o n Carrie d F or war d  
M B S  
M ost B ot hers o me S y m pt o m 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
mI T T  
M o difie d I nte nt -to -Treat ( P o p ulati o n)  
P D  
Pr ot oc ol De viati o n  
P P  
Per -Pr ot oc ol ( P o p ulati o n)  
P V  
Pr ot oc ol Vi olati o n  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A nal ysis Pla n  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
T E S A E  
Treat me nt -E mer ge nt Seri o us A d verse E ve nt  
W H O Dr u g  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
V V A  
V ul var a n d Va gi nal Atr o p h y  
 
 
 
 
 
 
 












P erri g o Ne w Y or k, I nc.                                                                                                                  Pr ot oc ol: P R G -N Y -1 5 -0 0 7                           
 
9  
C O N FI D E N TI A L  
fr o m baseli ne w hic h res ults i n a sc ore of 0 ( n o ne) or 1 ( mil d) at Visit 3 if t he M B S  is va gi nal 
dr y n ess, va gi nal or v ul var irritati o n or itc hi n g, d ys uria a n d va gi nal p ai n ass ociate d wit h se x ual 
acti vit y. If t he M B S  is v a gi n al blee di n g ass ociate d wit h se x ual acti vit y t he n treat me nt s uccess 
will be a bse nce of va gi nal blee di n g ass ociat e d wit h s e x ual acti vit y as re p orte d at t he e n d of t he 
st u d y. T he  sa me  met h o ds of a nal ysis as  f or  t he  pri mar y  a nal yses  will  be  c o n d ucte d  f or  t he 
sec o n dar y e n d p oi nt. 
5. 6  
Safet y Vari a bles a n d A n al yses  
D urati o n of Tr eat me nt a n d Me dicati o n C o m plia nce  
N u m ber  of  a p plicati o ns,  da ys  of  e x p os ure,  a n d  c o m plia nce  rate  will  be  s u m marize d  b y 
treat me nt gr o u p usi n g descri pti ve statistics. F or eac h s u bject, t he o verall d urati o n of treat me nt 
( da ys) will be calc ulate d usi n g t he f oll o wi n g f or m ula: 
( Date of l ast a p plicati o n of st u d y me dicati o n) - ( D ate of first a p plicati o n of st u d y me dicati o n) 
+ 1.  
Me dicati o n c o m plia nce r ate ( %) will be calc ul ate d f or eac h s u bject as f oll o ws:  
( T otal n u m ber of a p plicati o ns use d) / ( E x pecte d n u m ber of a p plicati o ns) * 1 0 0 %. 
S u bjects  w h o  c o m plete t he  st u d y  are  ex pecte d  t o  ha ve  7   a p plicati o ns. F or  pre mat urel y 
disc o nti n ue d  s u bjects,  e x pecte d  n u m ber  of  a p plicati o ns  will  be  deter mi ne d  base d  o n  t he 
e x pecte d  n u m ber  of  a p plicati o ns  b y  t he  ti me  of  disc o nti n uati o n,  i.e.  t he  o verall  d urati o n  of 
treat me nt. D escri pti ve  s u m ma ries  of  e x p os ure  a n d  me di cati o n  c o m plia nce  rate  will  be 
pr o vi de d b y treat me nt gr o u p f or t he I T T s u bjects. 
A d verse E v e nts  
A d verse e ve nts ( A Es) will be c o de d i n Me d D R A, versi o n 1 8. 1. Treat me nt -E mer ge nt A d v erse 
E ve nt ( T E A E) is defi ne d as a n y  A E o cc urs  o n  or  a fter a p plicati o n of t h e first d ose of st u d y 
dr u g. N u m ber a n d perce nt of s u bjects re p orti n g T E A Es will be ta b ulate d b y treat me nt gr o u p. 
S u m maries will be prese nte d b y b o d y s yste m a n d preferre d ter m  f or t he I T T p o p ulati o n, a n d 
f urt her  b y  s e verit y  a n d  relati ons hi p  t o  st u d y  m e dicati o n.  T E A Es  re p ort e d  b y  5 %  or  m ore 
s u bjects f or a n y tr eat me nt gr o u p  will als o be s u m marize d . I n t he s u m maries of i nci de nce rat es 
(fre q u e ncies a n d perce nt a ges) b y  s e verit y a n d rel ati o ns hi p t o st u d y dr u g, s u bjects w h o re p ort 
m ore  t ha n  o ne  e ve nt  t hat  are  ma p pe d  t o  t he  sa m e  preferre d  ter m  will  be  c o u nte d  o nl y  o nce 
u n der  t he  str o n gest  se verit y  a n d  relati o ns hi p,  acc or di n gl y. C hi- S q uare  or Fis her’s ex act  test 
will  be  use d  t o  c o m pare  t he  pr o p orti o ns  of  s u bjects  of  t he  t w o  acti ve  treat me nt  gr o u p s  w h o 
re p ort a n y T E A E . 
Treat me nt -E mer ge nt Seri o us A d verse E ve nts ( T E S A Es) will be dis c usse d wit hi n t he cli nical 
st u d y r e p ort. T E A Es, T E S A Es a n d T E A Es t hat le d t o treat me nt i nterr u pti o n or disc o nti n uati o n 
will be prese nte d i n dat a listi n gs.  
 
C o nc o mita nt Me d icati o ns, La b orat or y V al ues, a n d Vitals Si g ns 
C o nc o mita nt me dicati o ns will be c o de d usi n g t he W H O Dr u g Dicti o nar y, versi o n Se pte m ber 
2 0 1 5 ,  a n d  will  be  pr ese nte d  i n  data  listi n gs. All  la b orat or y  d ata  a n d  vital  si g ns  data  will  be 
dis pla ye d i n listi n gs.  
 
Safe t y c o m paris o ns will be perf or me d o nl y f or t h e I T T p o p ulati o n. 


P erri g o Ne w Y or k, I nc.                                                                                                                  Pr ot oc ol: P R G -N Y -1 5 -0 0 7                           
 
1 0   
C O N FI D E N TI A L  
6  
A p pe n dices  
6. 1  
Ha n dli n g of Missi n g or I nc o m plete Dates f or A d v erse E ve nts a n d C o nc o mita nt Me dicati o ns 
A d verse E v e nts  
Ha n dli n g of p artial dat es is o nl y c o nsi dere d f or t he start d ate. A n a d v erse e ve nt  wit h a p artial 
start date is c o nsi der e d tr eat me nt e mer ge nt if: 
- o nl y t he da y is missi n g  a n d t he start m o nt h/ year is t he sa me or after t he m o nt h/ year of t h e 
first d ose 
- t he da y a n d m o nt h are missi n g a n d t he start year is t he sa me or grea ter t ha n t he year of t he 
first d ose date 
- t he start date is c o m plet el y missi n g 
C o nc o mita nt Me dicati o ns  
Ha n dli n g of partial dates is o nl y c o nsi dere d f or t he st o p date. A me dicati o n wit h a partial st o p 
date is c o nsi dere d c o nc o mita nt if:  
- 
o nl y t he da y is missi n g a n d t he st o p m o nt h/ year is t he sa me or after t he m o nt h/ year of t he 
first d ose 
- 
t he da y a n d m o nt h ar e missi n g a n d t he st o p year is t he sa m e or greater t ha n t he year of t h e 
first d ose date 
- 
t he st o p date is c o m pletel y missi n g or t he me dicati o n is o n g oi n g 
6. 2  
S u m mar y of Ass ess me nts  
T he  sc he d ule  of  visits  a n d  pr oce d ures  t o  be  c o n d ucte d  at  eac h  visit  are  s u m marize d  i n  t he 
Sc he d ule of St u d y Pr o ce d ures.