Conditions: Rosacea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 667
Healthy volunteers: no

Brief summary:
To compare the bioequivalence of Perrigo's azelaic acid foam product to Finacea Foam for the treatment of Inflammatory Lesions of Rosacea

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Azelaic acid foam intervention 2: Azelaic acid foam intervention 3: Azelaic acid foam - Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 
 
 
NCT02800148 
 
10-04-2016 






Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 of 5 3  
 
T A BL E O F C O N T E N T S  
 
 
T A BL E O F C O N T E N T S  ........................................................................................................................... 3 
A B B R E VI A TI O N S  .................................................................................................................................. 8 
1.  B A C K G R O U N D  ............................................................................................................................... 9 
2.  S T U D Y O BJ E C TI V E S  ........................................................................................................................ 9 
3. S T U D Y D E SI G N  ................................................................................................................................ 1 0  
3. 1 T y p e/ D esi g n of St u dy  .................................................................................................................. 1 0  
3. 2 St u dy P o p ul ati o n  ......................................................................................................................... 1 0  
4. S EL E C TI O N A N D WI T H D R A W AL O F S T U D Y S U B J E C T S ........................................................................ 1 0  
4. 1 I ncl usi o n Crit eri a  ......................................................................................................................... 1 0  
4. 2 Ex cl usi o n Crit eri a ......................................................................................................................... 1 1  
4. 3 Pr o hi bit e d M e dic ati o ns  ............................................................................................................... 1 4  
4. 4 Pr ec a uti o ns  ................................................................................................................................. 1 5  
5.  P R O C E D U R E S  ................................................................................................................................ 1 6  
5. 1 S u bj ect Scr e e ni n g a n d E nr oll m e nt  .............................................................................................. 1 6  
5. 2 Assi g n m e nt of S u bj ect N u m b er  .................................................................................................. 1 6  
5. 3 D e m o gr a p hics/ M e dic al Hist ory  .................................................................................................. 1 7  
5. 4 C o nc o mit a nt M e dic ati o ns  ........................................................................................................... 1 7  
5. 5 P hysic al Ex a mi n ati o n  ................................................................................................................... 1 7  
5. 6 Uri n e Pr e g n a nc y T est  .................................................................................................................. 1 7  
5. 7 D er m at ol o gic al Ass ess m e nt ( Di a g n osis)  ..................................................................................... 1 8  
5. 8 I nv esti g at or’s Gl o b al Ass ess m e nt (I G A)  ...................................................................................... 1 8  
5. 9 Ev al u ati o n of Tr e at m e nt Ar e a  ..................................................................................................... 1 8  
5. 9. 1 I nfl a m m at ory L esi o n C o u nt ( P a p ul es a n d P ust ul es)  ........................................................... 1 9  
5. 9. 2 Er yt h e m a S ev erit y Ass ess m e nt  .......................................................................................... 1 9  
5. 9. 3 T el a n gi ect asi a E v al u ati o n  ................................................................................................... 1 9  
5. 1 0 A p plic ati o n Sit e R e acti o n Ass ess m e nt  ...................................................................................... 1 9  
5. 1 1 St u dy M e dic ati o n Us e, S u bj ect I nstr ucti o ns a n d Di ar y  ............................................................. 2 1  
5. 1 2 Visit S p ecific Pr oc e d ur es  ........................................................................................................... 2 2  
5. 1 2. 1 B a s eli n e Visit 1/ D ay 1 ...................................................................................................... 2 2  
5. 1 2. 2 T el e p h o n e C o nt act/ W e ek 2/ D a y 1 4 ( ± 4 d ays)  ................................................................ 2 3  
5. 1 2. 3 Visit 2/ W e e k 4/ D a y 2 8 ( ± 4 d a ys)  ..................................................................................... 2 3  
5. 1 2. 4 Visit 3/ W e e k 8/ D a y 5 6 ( ± 4 d a ys)  ........................................................................................... 2 4  
5. 1 2. 5 Visit 4/ W e e k 1 2/ D ay 8 4 ( ± 4 d ays) E n d of Tr e at m e nt/ E arly T er mi n ati o n Visit  ..................... 2 4  
5. 1 2. 6 U nsc h e d ul e d Visit  .................................................................................................................. 2 4  
5. 1 3 S u m m ary of Ass ess m e nts ......................................................................................................... 2 5  
5. 1 4 Scr e e n F ail ur es  .......................................................................................................................... 2 7  
5. 1 5 Pr ot oc ol D evi ati o ns/ Vi ol ati o ns  ................................................................................................. 2 7  
5. 1 6 S u bj ect/ Tr e at m e nt C o m pli a nc e  ................................................................................................ 2 7  
5. 1 7 Disc o nti n u ati o n/ Wit h dr a w al of St u dy 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 dy 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 bility  ................................................................................... 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 2  
7. 2 D efi niti o ns  ................................................................................................................................... 3 2  
7. 3 Eliciti n g a n d R e p orti n g of A dv ers e E v e nts  .................................................................................. 3 3  
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 dy C e nt er  ...................................................... 3 4  
7. 3. 2 S u b mitti n g a n Ex p e dit e d S af ety R e p ort t o t h e I R B  .................................................................. 3 4  
7. 4 S A E & A Es R e q uiri n g Disc o nti n u ati o n of St u dy Dr u g, i ncl u di n g Pr e g n a nci es  ............................. 3 5  
7. 4. 1 Pr e g n a nc y  ................................................................................................................................. 3 6  
7. 5 P ost St u dy A dv ers e E v e nts  .......................................................................................................... 3 7  
7. 5. 1 N o n -s eri o us A dv ers e E v e nts .................................................................................................... 3 7  
7. 5. 2 S eri o us A dv ers e E v e nts  ............................................................................................................ 3 7  
8. S T A TI S TI C AL A N AL Y SI S  ....................................................................................................... 3 7  
8. 1 St atistic al A n al ysis Pl a n  ............................................................................................................... 3 7  
8. 1. 1 A nal ysis P o p ulati o ns .................................................................................................... 3 7  
8. 1. 2 Pl a n n e d A n alysis  ...................................................................................................................... 3 8  
8. 1. 3 S a m pl e Siz e C o nsi d er ati o ns  ..................................................................................................... 3 9  
8. 1. 4 Efficac y Meas ures a n d A nal ysis .................................................................................. 3 9  
8. 1. 5 Safet y a n d A d verse E ve nts A nal ysis ............................................................................ 4 0  
8. 2 C o m p ar a bilit y of S u bj ects at B as eli n e  ......................................................................................... 4 0  
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 0  
9. 1 S u bj ect C o nfi d e nti ality  ................................................................................................................ 4 1  
1 0. 1 C o m pl eti o n of St u dy  ................................................................................................................. 4 2  
1 0. 2 Pr ot oc ol A m e n d m e nts  .............................................................................................................. 4 2  
1 1. R E C O R D S M A N A G E M E N T  ................................................................................................. 4 2  
1 1. 1 D at a C oll ecti o n  .......................................................................................................................... 4 2  
1 1. 2 S o urc e D oc u m e nts  .................................................................................................................... 4 3  
1 1. 3 Fil e M a n a g e m e nt at t h e St u dy Sit e  ........................................................................................... 4 4  
1 1. 4 R ec or ds R et e nti o n at t h e St u dy Sit e  ......................................................................................... 4 4  
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 4  
1 2. 1 M o nit ori n g  ................................................................................................................................ 4 4  
1 2. 2 A u diti n g  ….................................................................................................. ….. … … …. … … … … ….. … 4 4  
1 3. E T HI C S A N D R E S P O N SI BILI T Y  ............................................................................................ 4 4  
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 5  
I N V E S TI G A T O R A G R E E M EN T  .................................................................................................. 4 6  
1 5. A P P E N DI C E S  ..................................................................................................................... 4 7  
1 5. 1 A p p e n dix A: St u dy P ers o n n el C o nt acts  ..................................................................................... 4 7  


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P a g e 5 of 5 3  
 
1 5. 2 A P P E N DI X B:  I N S T R U C TI O N S F O R T H E S U BJ E C T  .............................................................. 4 8  
1 5. 3 A P P E N DI X C:  F A C E DI A G R A M  ......................................................................................... 5 2  
1 6. R E F E R E N C E S  ..................................................................................................................... 5 3  


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 6 of 5 3  
 
S T U D Y S Y N O P SI S  
 
Titl e:  
A  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 e d,  P ar all el -
Gr o u p St u d y t o C o m p ar e P erri g o U K FI N C O’s Az el aic Aci d F o a m, 1 5 % t o B a y er 
H e alt h C ar e P h ar m ac e utic als I nc., Fi n ac e a ® (Az el aic aci d) F o a m, 1 5 %, a n d B ot h 
Acti v e Tr e at m e nts t o a V e hicl e C o n tr ol i n t h e Tr e at m e nt of I nfl a m m at or y 
L esi o ns of R os ac e a  
St u d y P eri o d:  
1 2 w e e ks ( 8 4 D a ys)  
St u d y M e dic ati o n:  
1.  Az el aic Aci d F o a m, 1 5 %, o w n e d b y P erri g o U K FI N C O, m a n uf act ur e d b y  
P erri g o Isr a el P h ar m ac e utic als Lt d.  
 
2.  Fi n ac e a ® ( Az el aic A ci d F o a m ,  1 5 %) m a n uf act ur e d  b y  B a y er  H e alt h C ar e  
P h ar m ac e utic als I nc.  
3.  V e hicl e of t est pr o d uct, m a n uf act ur e d b y  P erri g o Isr a el P h ar m ac e utic als 
Lt d. 
St u d y O bj ecti v es:  
T o c o m p ar e t h e s af et y a n d effic acy pr ofil es of P erri g o U K FI N C O’s Az el aic Aci d 
F o a m, 1 5 %, t o B a y er H e alt h C ar e P h ar m ac e utic als I nc., Fi n ac e a ® ( Az el aic Aci d) 
F o a m,  1 5 %,  i n  or d er  t o  pr o v e  bi o e q ui v al e nc e  b et w e e n  t h e m  a n d  t o  
d e m o nstr at e t h e s u p eri or effic acy of t h e t w o activ e f or m ul ati o ns o v er t h at of 
t h e v e hicl e i n t h e tr e at m e nt of I nfl a m m at or y L esi o ns of R os ac e a. 
St u d y D esi g n:  
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 e d, 
p ar all el -gr o u p  st u d y  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.  M al e a n d f e m al e s u bj ects at l e ast 1 8 y e ars of a g e wit h 
m o d er at e  p a p ul o p ust ul ar 
r os ac e a  I G A  gr a d e  3 wit h  1 2  t o  5 0  f aci al  
i nfl a m m at or y l esi o ns ( p a p ul es a n d p ust ul es), at l e ast m o d er at e p ersist e nt  
er yt h e m a a n d pr es e nc e of t el a n gi ect asi a  will b e eli gi bl e f or e nr oll m e nt.  
St u d y P o p ul ati o n:  
A p pr oxi m at el y  
 h e alt h y m al es a n d f e m al es, at l e ast 1 8 y e ars of a g e, w h o 
m e et t h e i ncl usi o n/ excl usi o n cr it eri a, will b e e nr oll 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 ( mI T T) a n d  
 p er -pr ot oc ol ( P P) s u bj ects.  
D osi n g:  
S u bj ects  will  b e  r a n d o miz e d  i n  a   
 t o  eit h er  t h e  t est  pr o d uct,  
r ef er e nc e pr o d uct or v e hicl e tr e at m e nt gr o u p, r es p ecti v el y, a n d f or a si n gl e 
a p plic ati o n will a p pl y t h e s m all est a m o u nt of t h e st u d y m e dic ati o n n ec ess ar y 
t o a d e q u at el y c o v er e ac h ar e a  of t h e f ac e (c hi n, l eft c h e e k, ri g ht c h e e k, n os e, 
f or e h e a d) 
 a n d a v oi di n g c o nt act wit h t h e e y es ( u p p er a n d 
l o w er  e y eli ds),  li ps,  br o k e n  s ki n,  i nsi d e  t h e  n os e/ n ostrils,  a n d  m uc o us  
m e m br a n es t wic e d ail y , m or ni n g a n d e v e ni n g , (
 
) a p pr oxi m at el y t h e s a m e ti m e  f or 1 2 w e e ks. 
St u d y Visits:  
Cli nic al E v al u ati o ns will b e p erf or m e d at:  
1.  Visit 1/ D a y 1 ( B as eli n e)  
2.  Visit 2/ W e e k 4/ D a y 2 8 ( ± 4 d a ys)  (I nt eri m) 
3.  Visit 3/ W e e k 8/ D a y 5 6 ( ± 4 d a ys)  (I nt eri m) 
4.  Visit 4/ W e e k 1 2/ D a y 8 4 ( ± 4 d a ys)  ( E n d of tr e at m e nt/ E n d st u d y) 
S af et y will b e ass ess e d by m o nit ori n g a d v ers e  e v e nts at e ac h visit a n d at t h e 
W e e k 2/ D a y 1 4  ( ±4  d a ys) T el e p h o n e C o nt act.  


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 7 of 5 3  
 
E v al u ati o ns:  
T h e n u m b er of f aci al i nfl a m m at or y l esi o ns (p a p ul es  a n d p ust ul es ) will b e 
r ec or d e d at b as eli n e a n d e ac h s u bs e q u e nt visit ( Visits 2, 3 a n d 4).  Er yt h e m a 
s e v erit y, t h e I n v esti g at or Gl o b al Ass ess m e nt (I G A) a n d l oc al irrit ati o n will b e 
ass ess e d at B as eli n e a n d all s u bs e q u e nt visits. T h e pr es e nc e of T el a n gi ect asi a 
will b e r ec or d e d at B as eli n e.  
E n d p oi nts:  
T h e pri m ar y effic acy e n d p oi nt will b e t h e  m e a n p erc e nt c h a n g e fr o m b as eli n e 
t o Visit 4/ W e e k 1 2 ( D a y 8 4) i n t h e i nfl a m m at or y ( p a p ul es a n d p ust ul es) l esi o n 
c o u nt.  
 
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 cli nic al s ucc ess 
d efi n e d as a sc or e of cl e ar or al m ost cl e ar (sc or e of 0 or 1) o n t h e I n v esti g at or 
Gl o b al Ass ess m e nt (I G A) at Visit 4/ W e e k 1 2  ( D a y 8 4). 
S af et y:  
T h e  i nci d e nc e  of  all  a d v ers e  e v e nts  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.  S af et y of t h e t est a n d r ef er e nc e 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.   


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P a g e 8 of 5 3  
 
A B B R E VI A TI O N S  
 
A E  
A dv ers e E v e nt  
A N O V A  
A n al ysis of V ari a nc e  
C M H  
C oc hr a n – M a nt el – H a e nsz el t est  
C R F  
C as e R e p ort F or m  
D C F  
D at a C orr ecti o n 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  
G C P  
G o o d Cli nic al Pr actic es  
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 G A 
I nv esti g at or’s Gl o b al Ass ess m e nt 
I R B 
I nstit uti o n al R evi 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 ) 
I U 
I nt er n ati o n al U nit 
I U D 
I ntr a-Ut eri n e D evic e  
L O C F 
L ast O bs erv ati o n C arri e d F or w ar d 
M e d D R A  
M e dic al Dicti o n ary f or R e g ul at or y Activiti es  
mI T T  
M o difi e d I nt e nt -to -Tr e at (p o p ul ati o n ) 
N S AI D  
N o n -St er oi d al A nti -I nfl a m m at or y Dr u g  
O T C  
O v er t h e c o u nt er  
PI  
Pri nci p al I nv 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 dv ers e Ev e nt  
S A P  
St atistic al A n alysis Pl a n  
S P F  
S u n Pr ot ecti o n F act or  
S u b -I  
S u b -I nv esti g at or 
U P T  
Uri n e Pr e g n a nc y T est  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.  B A C K G R O U N D  
 
 
   
 
  
 
  
 
  
 
    
 
 
 
    
 
 
 
 
   
 
 
  
 
 
 
 
 
 
Fi n ac e a ® ( Az el aic Aci d f o a m, 1 5 %) is i n dic at e d f or t h e tr e at m e nt of I nfl a m m at or y L esi o ns of R os ac e a.5     
P erri g o U K FI N C O h as d ev el o p e d a g e n eric f or m ul ati o n of Az el aic Aci d f o a m, 1 5 %.  
 
2.  S T U D Y O BJ E C TI V E S  
T h e o bj ecti v es of t his st u d y ar e t o c o m p ar e t h e effic acy a n d s af et y pr ofil es of P erri g o U K FI N C O, Az el aic 
Aci d f o a m, 1 5 %, a n d Fi n ac e a ® ( Az el aic Aci d f o a m, 1 5 %), i n or d er t o s h o w bi o e q ui v al e nc e b et w e e n 
t h e m, a n d t o s h o w t h e s u p eri or effic acy of t h e t w o acti v e f or m ul ati o ns ov er t h at of t h e v e hicl e i n t h e 
tr e at m e nt of I nfl a m m at or y L esi o ns of R os ac e a. 
 
2. 1 E n d p oi nts  
T h e pri m ar y effic acy e n d p oi nt will b e t h e m e a n p erc e nt c h a n g e fr o m b as eli n e t o W e e k 1 2 ( D a y 8 4) i n 
t h e i nfl a m m at or y ( p a p ul es a n d p ust ul es) l esi o n c o u nt.  
 
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 cli nic al s ucc ess d efi n e d as a sc or e of 
cl e ar or al m ost cl e ar (sc or e of 0 or 1) o n t h e I n v esti g at or Gl o b al Ass ess m e nt (I G A) at Visit 4/ W e e k 1 2.  
 
2. 2 S af et y  
S af et y of 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 b y e v al u ati 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.  All a d v ers e e v e nts t h at occ ur d uri n g t h e st u d y will b e 


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V ersi o n 2. 0 D at e: Oct o b er 0 4, 2 0 1 6                                                                   A m e n d m e nt # 1  
 
P a g e 1 0  of 5 3  
 
r ec or d e d. D escri pti o ns of r e acti o ns or c o m pl ai nts will i nclu d e t h e a p pr oxi m at e d at e of o ns et, t h e d at e 
t h e a d v ers e e v e nt e n d e d, t h e s e v erit y of t h e a d v ers e e v e nt, a n d t h e o utc o m e.  C o m p aris o ns b et w e e n 
t h e tr e at m e nt gr o u ps will b e m a d e b y t a b ul ati n g t h e fr e q u e ncy of su bj ects wit h o n e or m or e a d v ers e 
e v e nts (cl assif i e d i nt o M e d D R A t er ms) d uri n g t h e st u d y. P e ars o n’s C hi-S q u ar e 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 n of s u bj ects i n e ac h 
tr e at m e nt gr o u p wit h a ny a d v ers e e v e nt.  T h e a dv ers e e v e nts 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 b e s u m m ariz e d d escri pti v el y. 
 
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 e d, p ar all el-gr o u p st u d y will 
b e assi g n e d i n a 
 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.  
 
 will b e a p pli e d t o pic all y 
as a t hi n l a y er  t o a d e q u at el y c o v er  e ac h ar e a of t h e f ac e (c hi n, l eft c h e e k, ri g ht c h e e k, n os e, a n d 
f or e h e a d), a v oi di n g c o nt act wit h t h e e y es ( u p p er a n d l o w er e y eli ds), li ps, br o k e n s ki n, i nsi d e t h e 
n os e/ n ostrils a n d m uc o us m e m br a n es , t wic e d aily m or ni n g a n d e v e ni n g (
 
) a p pr oxi mat el y t h e s a m e ti m e f or 1 2 w e e ks.   
 
Visits t o t h e st u d y sit e ar e sc h e d ul e d at B as eli n e ( D a y 1) a n d W e e ks 4, 8, a n d 1 2.  A t el e p h o n e c o nt act 
will b e m a d e at W e e k 2/ D a y 1 4.  
 
3. 2 St u d y P o p ul ati o n  
S u bj ects will b e m al es a n d f e m al es, at l e ast 1 8 y e ars of a g e, wit h at l e ast m o d er at e p a p ul o p ust ul ar 
f aci al r os ac e a wit h a n i nfl a m m at or y l esi o n ( p a p ul es a n d p ust ul es) 
, i ncl usi v e, o n t h e 
f ac e i ncl u di n g t h os e pr es e nt o n t h e n os e, at l e ast m od er at e er yt h e m a a n d pr es e nc e of t el a n gi ect asi a.   
 
4.  S EL E C TI O N A N D WI T H D R A W AL O F S T U D Y S U BJ E C T S  
 
4. 1 I ncl usi o n Crit eri a 
S u bj ects m ust  m e et all of t h e f oll o wi n g crit eri a:  
 
1.  S u bj ect m ust si g n a n I nstit uti o n al R e vi e w B o ar d (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 t his 
st u d y.  
 
 
2.  S u bj ects m ust b e  h e alt hy m al es or f e m al es  at l e ast 1 8  y e ars of a g e. S u bj ects m ust b e i n g e n er al 
g o o d h e alt h a n d fr e e fr o m a n y cli nic all y si g ni fic a nt dis e as e, ot h er t h a n r os ac e a, t h at mi g ht i nt erf er e 
wit h t h e st u d y e v al u ati o ns.  
3.  S u bj ects m ust h a v e a d efi nit e cli nic al di a g n osis of m o d er at e  f aci al p a p ul o p ust ul ar r os ac e a , d efi n e d 
as t h e pr es e nc e of:  
a)  A 
 i nfl a m m at or y l esi o ns ( p a p ul es a n d p ust ul es) 
i ncl u di n g t h os e pr es e nt o n t h e n os e. 


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P a g e 1 1  of 5 3  
 
b) At l e ast m o d er at e p ersist e nt er yt h e m a, A N D  
c) T el a n gi ect asi a. 
4.  
 
  
5.  
 
 
6.  
 
  
•  
 
 
 
 
 
 
 
 
 
 
 
 
. 
7.  S u bj ects m ust b e willi n g t o mi ni miz e c o ntr oll a bl e ext er n al f act ors t h at mi g ht tri g g er r os ac e a fl ar e -
u ps  (
 
) t hr o u g h o ut t h eir 
p artici p ati o n i n t h e  st u d y. 
8.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
. 
 
4. 2 E x cl usi o n Crit eri a 


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P a g e 1 2  of 5 3  
 
S u bj ects m a y n ot  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.  S u bj ects, w h o ar e pr e g n a nt, br e astf e e di n g, or pl a n ni n g a pr e g n a ncy wit hi n t h e  p eri o d of t h eir st u d y  
p artici p ati o n . 
2.  
. 
3.  C urr e nt  or p ast oc ul ar r os ac e a  ( e. g., c o nj u ncti vitis, bl e p h aritis, or k er atitis) of s uffici e nt  s e v erit y t o 
r e q uir e t o pic al or s yst e mic a nti bi otics. 
4.  S u bj ects wit h is ol at e d a n d/ or m o d er at e t o s e v er e r hi n o p h y m a, d e ns e t el a n gi ect as es or pl a q u e -li k e 
f aci al e d e m a. 
5.  Pr es e nc e of a n y ot h er f aci al s ki n c o n diti o n t h at mi g ht i nt erf er e wit h r os ac e a di a g n osis a n d / or 
ass ess m e nt 
 
 
 
 
 
 
. 
6.  A n y u nc o ntr oll e d, c hr o nic or s eri o us dis e as e or m e dic al c o n diti o n t h at w o ul d pr e v e nt p artici p ati o n 
i n a cli nic al tri al or, i n j u d g m e nt of t h e I n v esti g at or, w o ul d p ut t h e s u bj ect at u n d u e ris k or mi g ht 
c o nf o u n d t h e st u d y ass ess m e nts (s uc h as pl a n n e d h os pit aliz ati o ns d uri n g t h e st u d y).  
7.  Exc essi v e f aci al h air ( e. g., b e ar ds, si d e b ur ns, m o ust ac h es, etc.) t h at w o ul d i nt erf er e wit h di a g n osis 
or ass ess m e nt of r os ac e a.  
8.  
 
9.  
. 
1 0.  
 
1 1.  Hist or y of h y p ers e nsiti vity or all er g y t o a z el aic aci d , a n d/ or a n y i n gr e di e nt i n t h e st u d y m e dic ati o n  
( e. g., pr o p yl e n e gl yc ol) .  
1 2.  Us e wit hi n 6 m o nt hs  ( 1 8 0 d a ys) pri or t o b as eli n e or d uri n g t h e st u d y of or al r eti n oi ds ( e. g., 
Acc ut a n e ®)  or t h er a p e utic vit a mi n A s u p pl e m e nts of gr e at er t h a n 1 0, 0 0 0 u nits/ d a y ( m ulti vit a mi ns 
ar e all o w e d).  
1 3.  
 
1 4.  
 
 
 
1 5.  
 
 
 
 
 
  
1 6.  Us e of m e dic at e d m a k e -u p  (
) t hr o u g h o ut t h e st u d y a n d si g nific a nt 
c h a n g e i n t h e us e of c o ns u m er pr o d ucts wit hi n 3 0 d a ys  of st u d y e ntr y a n d t hr o u g h o ut t h e st u d y.  


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P a g e 1 3  of 5 3  
 
1 7.  
 
 
 
1 8.  Us e wit hi n 3 0 d a ys  ( 1 m o nt h) pri or t o b as eli n e or d uri n g t h e st u d y of 1) s yst e mic st er oi ds * * , 2) 
t o pic al r eti n oi ds t o t h e f ac e, 3) s yst e mic ( e. g., or al or i nj ect a bl e) a nti bi otics k n o w n t o i m p act o n 
t h e s e v erit y of f aci al r os ac e a ( e. g., cycli n es a n d its d eri v ati v es, t etr acycli n e a n d its d eri v ati v es , 
er yt hr o m yci n  a n d its d eriv ati v es , d oxycycli n e a n d its d eri v ati v es, mi n ocycli n e a n d its d eri v ati v es,  
m acr oli d es  a n d its d eri v ati v es,  azit hr o m yci n a n d its d eri v ati v es, cl arit hr o m yci n a n d its d eri v ati v es,  
m etr o ni d az ol e a n d its d eri v ati v es,   s ulf a m et h ox a d ol e, b actri m or tri m et h o pri m ); s h ort t er m 
tr e at m e nt of all ot h er a nti bi otics ( n ot aff ecti n g r os ac e a  f or) ≤ 1 4 d a ys f or n o n -r os ac e a r el at e d 
c o n diti o ns is acc ept a bl e , 4) i m m u n os u p pr essi v e a g e nts, or i m m u n o m o d ul at ors. 
•  
 
 
•  
 
 
•  
. 
•  
 
1 9.  
 
 
 
 
 
2 0.  
 
 
 
 
 
 
2 1.  
 
.  
2 2.  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 ply 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. 
2 3.  
  
 
 
2 4.  
 
  
2 5.  P artici p ati o n i n a ny cli nic al st u dy i nv olvi n g a n i n v esti g ati o n al pr o d uct, a g e nt or d evic e  t h at mi g ht 
i nfl u e nc e t h e i nt e n d e d eff ects or m as k t h e si d e eff ects of st u d y m e dic ati o n i n t h e 1 m o nt h ( 3 0 
d a ys) pri or Visit 1/ D a y 1 ( B as eli n e) or t hr o u g h o ut t h e st u d y.  
2 6.  
 
 


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P a g e 1 4  of 5 3  
 
2 7.  
 
  
2 8.  
 
 
2 9.  
 
 
 
3 0.  
.  
3 1.  S u bj ects w h o i n t h e o pi ni o n of t h e i n v esti g at or, ar e u nli k el y t o b e a bl e t o f oll o w t h e r estricti o ns of 
t h e pr ot oc ol a n d c o m pl et e t h e st u d y.  
 
4. 3 Pr o hi bit e d M e dic ati o ns  
T h e f oll o wi n g m e dic ati o ns/ pr oc e d ur es ar e p r o hi bit e d d uri n g t his st u d y: 
1.  Us e of a n y tr e at m e nt f or r os ac e a ot h er t h a n t h e assi g n e d st u d y tr e at m e nt . 
2.  
 
.  
•  
 
 
 
 
 
.  
3.  Us e  of  s yst e mic a nti -r os ac e a dr u gs,  s yst e mic  r eti n oi ds,  s yst e mic  c ortic ost er oi ds,  or  
i m m u n os u p pr essi v e dr u gs or i m m u n o m o d ul at ors , t h er a p e utic vit a mi n A s u p pl e m e nts of gr e at er 
t h a n 1 0, 0 0 0 u nits/ d a y ar e pr o hi bit e d d uri n g t his st u d y.  
4.  
 
•  
d.  
•  
 
. 
•  
 
5.  Us e of s yst e mic a nti bi otics  ( e. g., or al or i nj ect a bl e) k n o w n t o i m p act o n t h e s e v erit y of r os ac e a 
i ncl u di n g,  b ut  n ot  li mit e d  t o,  cycli n es  a n d  its  d eri v ati v es,  t etr acycli n e  a n d  its  d eri v ati v es,  
er yt hr o m yci n a n d its d eri v ati v es, d oxycli n e a n d its d eri v ati v es, mi n ocycli n e a n d its d eri v ati v e, 
m acr oli d es a n d  its d eri v ati v es, azit hr o m yci n a n d its d eri v ati v es, cl arit hr o myci n a n d its d eri v ati v es, 
m etr o niz a d ol e a n d its d eri v ati v es, s ulf a m et h ox a d ol e, b actri m a n d tri m et h o pri m ar e pr o hi bit e d 
d uri n g t his st u d y.  S h ort t er m tr e at m e nt of all ot h er a nti bi otics ≤ 1 4 d a ys f or n o n-r os ac e a r el at e d 
c o n diti o ns is acc e pt a bl e. 
6.  Us e of t o pic al a nti bi otics, ot h er r os ac e a dr u gs, r eti n oi ds or c ortic ost er oi ds a p pli e d t o t h e f ac e ar e 
pr o hi bit e d d uri n g t his st u d y.  
7.  Us e of or al r eti n oi ds is pr o hi bit e d d uri n g t h e st u dy.  
8.  A p plic ati o n  of  t o pic al  astri n g e nts  or  a br asi v es  e. g.,  r u bs,  exf oli ati n g  cl e a ns ers  a n d  pr o d ucts  


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P a g e 1 5  of 5 3  
 
c o nt ai ni n g S alicylic aci d a n d/ or alc o h ol b as e d t o n ers, astri n g e nts; t o pic al pr e p ar ati o ns t h at c o nt ai n 
s pic es or li m e, or m e dic at e d t o pic al pr e p ar ati o ns ( pr escri pti o n a n d O T C pr o d ucts) t o t h e f ac e.  
9.  Us e of a br asi v e cl e a ns ers or w as h es ( e. g., exf oli ati n g f aci al scr u bs) a n d a d h esi v e cl e a nsi n g stri ps 
( e. g., Bi or é ® P or e Stri ps) o n t h e f ac e.  
1 0.  
 
 
 
 
 
 
  
1 1.  
 
 
1 2.  Us e of t a n ni n g b o ot hs, s u n l a m ps, s a u n a, s u n b at hi n g or ot h er exc essi v e ex p os ur e t o s u nli g ht 
s h o ul d b e a v oi d e d. 
1 3.  M e dici n es  a n d/ or  pr o d ucts  t h at  m a y  i ncr e as e  s e nsiti vit y  t o  s u nli g ht  ( a p art  fr o m  t h e  st u d y  
m e dic ati o n) s h o ul d b e us e d d uri n g t his st u d y o nl y aft er c o ns ult ati o n wit h t h e I n v esti g at or.  
1 4.  Us e of h or m o n al c o ntr ac e pti v es s h o ul d n ot b e i niti at e d or c h a n g e d d uri n g t h e st u d y.  
 
 
4. 4 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 t h e e y es  ( u p p er a n d l o w er e y eli ds), 
i nsi d e t h eir n os e/ n ostrils, m uc o us m e m br a n es a n d  li ps, or o n a n y c uts or br o k e n s ki n. I n c as e of 
acci d e nt al ex p os ur e, t h e e y es s h o ul d b e ri ns e d wit h pl e nt y of w at er a n d a p h ysici a n s h o ul d b e 
c o ns ult e d if e y e irrit ati o n p ersists. 
2.  A v oi d fir e, fl a m e, or s m oki n g d uri n g a n d i m m e di at el y f oll o wi n g a p plic ati o n of t h e  st u d y m e dic ati o n 
si nc e t h e pr o p ell a nt i n t h e st u d y m e dic ati o n is fl a m m a bl e. 
3.  T h e a er os ol c a nist er s h o ul d n ot b e p u nct ur e d or i nci n er at e d. 
4.  T h e pr o d uct s h o ul d n ot b e a p pli e d t o c uts, a br asi o ns, ecz e m at o us or s u n b ur n e d s ki n, or sit es ot h er 
t h a n t h e tr e at m e nt ar e a.  
5.  S u bj ects s h o ul d w as h t h eir h a n ds b ef or e a n d i m m e di at el y aft er a p pl yi n g st u d y m e dic ati o n.  
6.  
 
 
s.  
7.  
 
 
8.  T h e st u d y m e dic ati o n s h o ul d b e s pr e a d s m o ot hl y a n d 
 o n t h e f ac e (f or e h e a d, 
c hi n, a n d n os e, l eft a n d ri g ht c h e e k); exc essi v e r u b bi n g m ust b e a v oi d e d.  
9.  T h e st u d y m e dic ati o n s h o ul d n ot b e a p pli e d m or e t h a n t wic 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 o n t h e e ntir e f ac e (
 
). 


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P a g e 1 6  of 5 3  
 
1 0.  
. 
1 1.  S u bj ects s h o ul d n ot a p pl y m oist uriz ers  (
), 
m e dic at e d m a k e -u p ( i ncl u di n g n e w br a n ds), cr e a ms, l oti o ns, p o w d ers or a n y t o pic al pr o d uct ot h er 
t h a n t h e st u d y m e dic ati o n t o t h e f ac e. 
1 2.  
 
  
1 3.  S u bj ects s h o ul d li mit s u n ex p os ur e, i ncl u di n g s u nl a m ps ( n o n -pr escri pti o n U V li g ht s o urc es); a v oi d 
t a n ni n g b e ds/ b o ot hs/ p arl ors a n d s a u n a w hil e usi n g t h e pr o d uct. 
1 4.  S u bj ect s h o ul d us e a n y ty p e of s u nscr e e n a n d pr ot ecti v e a p p ar el ( e. g. , wi d e -bri m m e d h at) w h e n 
o ut d o ors. W e at h er  extr e m es,  s uc h  as  wi n d  or  c ol d,  m a y  b e  irr it ati n g  t o  s u bj ects  r ec ei vi n g  
tr e at m e nt. 
1 5.  
.  
1 6.  
 
 
 
 
1 7.  
 
. 
1 8.  S u bj ects s h o ul d c o ns ult t h e i n 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.  
1 9.  
 
 
2 0.  
. 
2 1.  
 
.   
2 2.  S u bj ect s h o ul d a v oi d a n y f o o ds a n d b e v er a g es t h at mi g ht pr o v o k e er yt h e m a, fl us hi n g, a n d bl us hi n g 
 
 t hr o u g h o ut t h e st u d y. 
 
5.  
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 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 t h e s u bj ect is e nr oll e d i nt o t h e st u d y.  T h e wit n ess c a n 
b e a n y o n e pr es e nt d uri n g t h e si g ni n g of t h e c o ns e nt f or m ot h er t h a n t h e i n di vi d u al ex pl ai ni n g t h e 
c o ns e nt.  A c o p y of t h e si g n e d c o ns e nt will  b e gi v e n t o e v er y p artici p a nt ( or l e g all y a ut h oriz e d 
r e pr es e nt ativ e ) a n d t h e ori gi n al will b e m ai nt ai n e d wit h t h e p artici p a nt’s r ec or ds.    
 
 
 
 
5. 2 Assi g n m e nt of S u bj ect N u m b er  


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P a g e 1 7  of 5 3  
 
 
  T h e s u bj ect n u m b er will c orr es p o n d 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 d ul e assi g ni n g t h e n u m b er t o o n e of t h e t hr e e st u d y tr e at m e nt gr o u ps.  
 
O nc e t h e s u bj ect h as c o ns e nt e d  a n d  m et i ncl usi o n/ excl us i o n crit eri a, t h e y will b e assi g n e d a s u bj ect 
n u m b er. T h e s u bj ect n u m b er will b e t a k e n fr o m t h e st u d y m e dic ati o n kit dis p e ns e d t o t h e s u bj ect at 
e ac h sit e.  
 
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  a n d  c o m pl et e  m e dic al  hist or y  will  b e  r ec or d e d pri or  t o  st arti n g  st u d y  
m e dic ati o n .  T h e m e dic al hist or y will i ncl u d e a c o m pl et e r e vi e w of all c urr e nt dis e as es a n d t h eir 
r es p ecti v e tr e at m e nts. 
 
5. 4 C o nc o mit a nt 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 i n t h e  
 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 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 “ pr n” 
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 o n t his p a g e pri or t o st arti n g 
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 t h e W e e k 2/ D a y 1 4 ( ± 4  d a ys) t el e p h o n e c o nt act.  
 
5. 5 P h ysic al E x a mi n ati o n  
T h e i n v esti g at or, s u b -i n v esti g at or or a p pr o pri at ely d el e g at e d a n d q u alifi e d d esi g n e e will p erf or m a 
bri ef p h ysic al ex a mi n ati o n pri or t o t h e s u bj ect st arti n g st u d y m e dic ati o n o n B as eli n e/ D a y 1 .
 
 
 
 
 
5. 6 Uri n e Pr e g n a nc y T est  
A uri n e pr e g n a ncy t est will b e c o n d uct e d at Visit 1/ B as eli n e ( b ef or e t h e s u bj ect a p pli es t h e first d os e 
of t h e  st u d y m e dic ati o n at t h e sit e) a n d at  e ac h s u bs e q u e nt visit . A n i n v esti g at or m a y r e p e at t h e 
pr e g n a ncy t est a n yti m e d uri n g t h e st u d y if t h er e is a n y s us pici o n or p ossi bilit y t h at t h e s u bj ect m a y b e 
pr e g n a nt. 
 
 
 
 
 
 
 
 
 
 
 


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P a g e 1 8  of 5 3  
 
 
 
 
  
 
5. 7 D er m at ol o gic al Ass ess m e nt ( Di a g n osis)  
T h e I n v esti g at or or s u b-i n v esti g at or will ex a mi n e t h e s u bj ect t o est a blis h t h e cli nic al di a g n osis of 
p a p ul o p ust ul ar  f aci al  r os ac e a  
 
. 
 
5. 8 I n v esti g at or’s Gl o b al Ass ess m e nt (I G A) 
T o t h e gr e at est ext e nt p ossi bl e, t h e s a m e i n v esti g at or w h o m a d e b as eli n e ( D a y 1) ass ess m e nts will 
p erf or m a Gl o b al Ass ess m e nt of t h e s u bj ect’s o v er all r os ac e a c o n diti o n at e ac h s u bs e q u e nt visit.  
 
At Visit 1/ B as eli n e ( D a y 1), t h e i n v esti g at or s h o ul d p erf or m t h e I G A b ef or e t h e s u bj ect a p pli es t h e first 
d os e of t h e st u d y m e dic ati o n at t h e sit e.  
 
 
 
 
.  
 
T h e f oll o wi n g sc al e will b e us e d f or t h e I n v esti g at or’s Gl o b al Ass ess m e nt:  
 
Gr a d e  
C at e g or y  
D escri pti o n  
0 
Cl e ar  
Cl e ar s ki n wit h n o i nfl a m m at or y  l esi o ns ( p a p ul es or p ust ul es) or 
n o d ul es ; at m ost, mil d eryt h e m a.  
1 
Al m ost 
Cl e ar  
V er y f e w s m all p a p ul es or p ust ul es . V er y mil d er yt h e m a pr es e nt . 
2 
Mil d  
S e v erit y  
S e v er al s m all p a p ul es or p ust ul es . Mil d er yt h e m a 
3 
M o d er at e  
S e v erit y  
S e v er al s m all or l ar g e p a p ul es or p ust ul es, a n d u p t o 2 n o d ul es . 
M o d er at e er yt h e m a.  
4  
S e v er e  
N u m er o us s m all a n d/ or l ar g e p a p ul es or p ust ul es, u p t o s e v er al 
n o d ul es . S e v er e er yt h e m a. 
 
5. 9 E v al u ati o n of Tr e at m e nt Ar e a  
T h e i n v esti g at or s h o ul d e v al u at e  t h e tr e at m e nt ar e a b ef or e a s u bj ect a p pli es t h e first d os e of st u d y 
m e dic ati o n. E ac h s u bj ect’s i niti al c o n diti o n a n d c o urs e of r os ac e a will b e ass ess e d b y t h e f oll o wi n g: 1) 
c o u nti n g t h e i nfl a m m at or y ( p a p ul es a n d p ust ul es ) a n d n o d ul es i ncl u di n g t h os e pr es e nt o n t h e n os e 
a n d d oc u m e nti n g o n t h e f aci al di a gr a m ( 
 as p art of t h e s o urc e d oc u m e nt ati o n, 2) r ati n g 
t h e s e v erit y of er yt h e m a, 3) pr es e nc e/ a bs e nc e of t el a n gi ect asi a ( e v al u at e d at Visit 1/ B as eli n e o nly), 
a n d 4) e v al u ati o n of t h e a p plic at i o n sit e r e acti o n. 
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 1 9  of 5 3  
 
 
 
 
 
5. 9. 1 I nfl a m m at or y L esi o n C o u nt ( P a p ul es a n d P ust ul es) 
T h e n u m b ers of i nfl a m m at or y l esi o ns (f aci al p a p ul es a n d  p ust ul es ) a n d n o d ul es , l oc at e d a b o v e t h e j a w 
li n e t o t h e h airli n e i ncl u di n g t h ose pr es e nt o n t h e n os e, ar e t o b e c o u nt e d at b as eli n e  ( b ef or e t h e 
s u bj ect a p pli es t h e first d os e of t h e st u d y m e dic ati o n at t h e sit e) a n d at e ac h s u bs e q u e nt visit. T h e 
t y p e a n d n u m b er of e ac h l esi o n is t o b e r ec or d e d o n t h e s o urc e d oc u m e nt at e ac h visit a nd t h e t ot al 
c o u nt of p a p ul es a n d p ust ul es r ec or d e d ( excl u di n g n o d ul es).  
 
P a p ul e = s oli d p al p a bl e i nfl a m m at or y l esi o n ≤ 5 m m di a m et er  
 
P ust ul e = p us -fill e d i nfl a m m at or y l esi o n ≤ 5 m m i n di a m et er 
 
N o d ul e  = p al p a bl e s oli d or s oft l esi o n > 5 m m i n di a m et er  
 
C o u nts of n o d ul es s h o ul d b e r e p ort e d s e p ar at el y a n d n ot i ncl u d e d i n i nfl a m m at or y l esi o n c o u nts.  
S u bj ects wit h m or e t h a n 2 f aci al n o d ul es at b as eli n e s h o ul d b e excl u d e d fr o m t h e st u d y.   
 
5. 9. 2 Er yt h e m a S e v erit y Ass ess m e nt  
 
At Visit 1/ B as eli n e ( D a y 1), t h e i n v esti g at or s h o ul d p erf or m t h e er yt h e m a ass ess m e nt b ef or e t h e 
s u bj ect a p pli es t h e first d os e of t h e st u d y m e dic ati o n at t h e sit e. 
 
T h e s e v erit y of er yt h e m a is t o b e r at e d as f oll o ws:  
 
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  
N o r e d n ess pr es e nt  
1  
Mil d  
Sli g ht pi n k n ess t o li g ht r e d 
2  
M o d er at e  
D efi nit e r e d n ess, e asil y r ec o g niz e d  
3  
S e v er e  
M ar k e d er yt h e m a; fi er y r e d  
 
5. 9. 3 T el a n gi ect asi a E v al u ati o n  
 
T h e pr es e nc e or a bs e nc e of t el a n gi ect asi a is t o b e e v al u at e d at Visit  1/ B as eli n e o nl y  pri or t o first st u d y 
d os e m e dic ati o n a p plic ati o n . 
 
5. 1 0 A p plic ati o n Sit e R e acti o n Ass ess m e nt  
 
At Visit 1/ B as eli n e ( D a y 1) a n d e ac h s u bs e q u e nt visit, a p plic ati o n sit e r e acti o ns s uc h as  dr y n ess, 
b ur ni n g/sti n gi n g, pr urit us  a n d sc ali n g/ p e eli n g, a n d p ai n ar e t o b e r ec or d e d o n t h e s o urc e d oc u m e nt . 
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 2 0  of 5 3  
 
At Visit 1/ B as eli n e ( D a y 1), t h e i n v esti g at or s h o ul d p erf or m t h e a p plic ati o n sit e r e acti o n ass ess m e nt 
b ef or e a n d 
 aft er t h e s u bj ect a p pli es t h e first d os e of t h e st u d y m e dic ati o n 
at t h e sit e.  
 
T h e A p plic ati o n Sit e R e acti o n Ass ess m e nt  m ust b e c o n d uct e d b y q u alifi e d i n v esti g at ors list e d o n t h e 
F or m F D A 1 5 7 2 w h o h av e b e e n d el e g at e d t h es e t as ks b y t h e PI. 
 
 
.  
 
 
 
•  
.  
•  
. 
•  
. 
 
 
 
 
T h e i n v esti g at or will ass ess a s u bj ect’s a p plic ati o n sit e r e acti o n b y r ati n g t h e f oll o wi n g s y m pt o ms 
acc or di n g t o t h e sc al es pr o vi d e d b el o w .  Pr urit us a n d sti n gi n g/ b ur ni n g s y m pt o ms will b e ass ess e d b y 
disc ussi o n wit h t h e s u bj ect a n d will b e r e p ort e d as t h e s e v erit y ex p eri e nc e d wit hi n 2 4 h o urs of t h e 
st u d y visit.     
 
Dr y n ess : Mil d sc ali n g, r o u g h n ess, f e eli n g of ti g ht n ess, a n d p ossi bl y itc hi n g  
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  
 
1  
Mil d  
 
2  
M o d er at e  
 
3  
S e v er e  
 
 
Sc ali n g/ P e eli n g:  S ki n d es q u a m ati o n; s h e d di n g of t h e o ut er l a y ers of t h e s ki n  
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  
 
1 
Mil d  
 
2  
M o d er at e  
 
3  
S e v er e  
 
 
Pr urit us:  Itc hi n g 
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  
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 2 1  of 5 3  
 
1  
Mil d  
 
2 
M o d er at e  
 
 
3 
S e v er e  
 
 
 
Sti n gi n g/ B ur ni n g:   Sti n gi n g/ti n gli n g s e ns ati o n  
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  
 
1  
Mil d  
 
2 
M o d er at e  
 
. 
3 
S e v er e  
 
 
 
P ai n:   P ai n, u n pl e as a nt s e ns ati o n c a usi n g disc o mf ort s uc h as ti n gli n g, pric ki n g  ( pi ns a n d n e e dl es) 
a n d/ or t e n d er n ess  
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  
 
1  
Mil d  
 
2  
M o d er at e  
 
3  
S e v er e  
 
 
5. 1 1 St u d y M e dic ati o n Us e, S u bj ect I nstr ucti o ns a n d Di ar y  
At t h e b as eli n e visit, o n e  ( 1), 
 a er os ol  c a nist er of st u d y m e dic ati o n fr o m t h e s u bj ect kit b ox will 
b e dis p e ns e d , b y t h e t hir d p art y dis p e ns er (if p ossi bl e) or d esi g n e e , t o e nr oll e d s u bj ects al o n g wit h a 
di ar y c ar d.  E ac h s u bj ect will als o r ec ei v e a c o py 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  (
). At  Visit  
1/ B as eli n e/ D a y 1, t h e t hir d p art y dis p e ns e r (if p ossi bl e) or d esi g n e e s h o ul d e ns ur e t h at all s u bj ects m et 
eli gi bilit y  crit eri a  a n d  all  effic aci es  (I G A,  Er yt h e m a,  T el a n gi ect asi a)  a n d  s af et y  ( a p plic ati o n  sit e  
r e acti o ns) ass ess m e nts ar e c o n d uct e d b y t h e i n v esti g at or b ef or e t h e s u bj ects p erf or m t h e i niti al 
a p plic ati o n.  T h e i niti al a p plic ati o n o n D a y 1 will b e p erf or m e d b y t h e s u bj ect a n d o bs er v e d b y st u d y 
st aff at t h e st u d y sit e d uri n g t h e st u d y visit t o e ns ur e s u bj ects u n d erst a n d t h e i nstr ucti o ns  a n d ar e 
a p pl yi n g t h e m e dic ati o n a p pr o pri at el y .  
 
 T h e p u m p of t h e a er os ol c a n ist er s h o ul d b e d e pr ess e d g e ntl y t o dis p e ns e t h e s m allest  
a m o u nt of t h e f o a m n ec ess ar y t o c o v er e ac h f aci al ar e a (c hi n, l eft c h e e k, ri g ht c h e e k, n os e, a n d 
f or e h e a d) f or e ac h si n gl e a p plic ati o n. T h e pr o p ell a nt i n t h e st u d y m e dic ati o n is fl a m m a bl e. T h er ef or e, 
fir e, fl a m e or s m o ki n g d uri n g a n d i m m e di at el y f oll o wi n g t h e a p plic ati o n of t h e st u d y m e dic ati o n s h o ul d 
b e a v oi d e d.  
 
. S u bs e q u e nt a p plic ati o ns of st u d y m e dic ati o n s h o ul d b e a p pli e d as 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 2 2  of 5 3  
 
i nstr uct e d b y t h e s u bj ect at h o m e m or ni n g a n d e v e ni n g (
).  T h e 
st u d y st aff s h o ul d i nstr uct t h e s u bj ect t o a p pl y all s u bs e q u e nt d os es of t h e st u d y m e dic ati o n t wic e 
d ail y , m or ni n g a n d e v e ni n g  
 b ef or e b e dti m e . S u bj ects will a p pl y t h e s ec o n d d os e of 
t h e m e dic ati o n i n t h e ev e ni n g o n D a y 1 if first d os e w as a p pli e d i n t h e m or ni n g o n D a y 1 or i n t h e 
m or ni n g of D a y 2 if first d os e w as a p pli e d i n t h e aft er n o o n/ e v e ni n g o n D a y 1 .  At all s u bs e q u e nt st u d y 
visits t h e st u d y m e dic ati o n will b e c oll ect e d t o ass ess  c o m pli a nc e a n d st u dy m e dic ati o n acc o u nt a bilit y.  
Aft er t h e c o m pli a nc e e v al u ati o n, e m pt y a e r os ol c a nist er will b e c oll ect e d a n d k e pt b y t h e sit e.  A er os ol 
c a nist ers wit h  r e m ai ni n g m e dic ati o n will b e  r e dis p e ns e d t o t h e s u bj ect. 
 
 
 
 
 
 
. T h e st u d y m e dic ati o n kits m ust b e 
st or e d (i n a n u pri g ht p ositi o n) i n a s ec ur e d ar e a wit h li mit e d acc ess, at 2 5° C ( 7 7° F); exc ursi o ns 
p er mitt e d b et w e e n 1 5° C t o 3 0° C ( 5 9° F t o 8 6° F) u ntil dis p e ns e d t o t h e s u bj ect.  O nc e dis p e ns e d t o t h e 
s u bj ect t h e st u d y m e dic ati o n will b e st or e d i n a n u pri g ht p ositi o n at 2 5° C ( 7 7° F) .  
 
S u bj ects will cl e a ns e t h eir f ac e wit h a mil d cl e a ns er usi n g o nl y t h eir h a n ds a n d p at dr y wit h a s oft cl e a n 
t o w el.   
. F or a si n gl e 
a p plic ati o n, t h e  “s m all est” a m o u nt of t h e st u d y m e dic ati o n n ec ess ar y will  b e a p pli e d 
 t o 
a d e q u at el y c o v er e ac h ar e a of t h e f ac e (c hi n, l eft c h e e k, ri g ht c h e e k, n os e, f or e h e a d) a n d a v oi di n g 
c o nt act wit h t h e e y es ( u p p er a n d l o w er e y eli ds), li ps, br o k e n s ki n, i nsi d e t h e n os e/ n ostril a n d m uc o us 
m e m br a n es, t wic e  d ail y  i n  t h e  m or ni n g  a n d  ev e ni n g  (
),  at  
a p pr oxi m at el y t h e s a m e ti m e f or 1 2 w e e k s.  (
 
) S u bj ects 
s h o ul d b e i nstr uct e d t o w as h h a n ds i m m e di at el y aft er a p pl yi n g t h e st u d y m e dic ati o n.  S u bj ects  s h o ul d 
c o nti n u e t o us e a mil d cl e a ns er t o w as h t h e f ac e f or t h e d ur ati o n of t h e st u d y. S u bj ects will b e 
i nstr uct e d t o n ot us e a n y ot h er t o pic al tr e at m e nts or pr o d ucts (a n y t y p e of s u nscr e e n is all o w e d) ot h er 
t h a n t h e st u d y m e dic ati o n o n t h eir f ac e.  
 
A di ar y c ar d will b e dis p e ns e d t o e ac h e nr oll e d s u bj ect at Visits 1, 2 & 3.  T h e s u bj ects will b e i nstr uct e d 
t o c o m pl et e t h e di ar y c ar d aft er a p pl yi n g e ac h d os e of st u d y m e dic ati o n  i n t h e m or ni n g a n d e v e ni n g 
d ail y .  At e ac h s u bs e q u e nt visit, st u d y p ers o n n el will r e vi e w a n d c oll ect t h e di ar y c ar d, d et er mi n e 
w h et h er t h e s u bj ect r e q uir es c o u ns eli n g f or d os a g e c o m pli a nc e, c o nfir m a n d r ec or d us e of a n y 
pr o hi bit e d m e dic ati o ns, ass ess A Es, dis p e ns e a d diti o n al st u d y m e dic ati o n a n d a n e w di ar y  as r e q uir e d .  
I n a d diti o n, e ac h st u d y s u bj ect will b e r e mi n d e d t o bri n g wit h t h e m all pr e vi o usl y dis p e ns e d a er os ol 
c a nist ers (r e g ar dl ess of c o nt e nt) a n d t h e c o m pl et e d di ar y c ar d at t h e n ext visit.  St u d y p ers o n n el will 
sc h e d ul e t h e s u bj ect’s n ext visit pri or t o t h e s u bj ect’s d ep art ur e.  
 
5. 1 2 Visit S p ecific Pr oc e d ur es  
T h e f oll o wi n g s ecti o ns o utli n e t h e pr oc e d ur es r e q uir e d at e ac h visit.  
 
5. 1 2. 1 B as eli n e Visit  1/ D a y 1 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 2 3  of 5 3  
 
Pr os p ecti v e s u bj ects will visit t h e st u d y c e nt er a n d b e ex a mi n e d b y t h e st u d y p h ysici a n  w h o will 
p erf or m t h e pr oc e d ur es b el o w at t his visit .  
 
T h e f oll o wi n g pr oc e d ur es : I nf or m e d C o ns e nt, I ncl usi o n/ Excl usi o n Crit eri a, M e dic al 
Hist or y/ D e m o gr a p hics, c oll ecti o n a n d r e vi e w of C o nc o mit a nt m e dic ati o ns, P h ysic al ex a m, Vit al si g ns, 
d er m at ol o gic al ass ess m e nt  ( di a g n osis), e v al u ati o n of t h e tr e at m e nt ar e a, I G A, er yt h e m a ass ess m e nt,  
e v al u ati o n  t el a n gi ect asi a a n d Uri n e pr e g n a ncy t est m ust b e c o m pl et e d a n d d oc u m e nt e d o n t h e 
s o urc e d oc u m e nt b ef or e a s u bj ect is r a n d o miz e d o n t h e st u d y. 
 
 
 
 
 
•  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 1 2. 2 T el e p h o n e C o nt act/ W e e k 2/ D a y 1 4 ( ± 4 d a ys)  
•  
 
 
 
 
 
 
 
 
 
5. 1 2. 3 Visit 2/ W e e k 4/ D a y 2 8 ( ± 4 d a ys)  
•  
 
 
 
 
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 2 4  of 5 3  
 
•  
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 1 2. 4 Vi sit 3/ W e e k 8/ D a y 5 6 ( ± 4 d a ys) 
•  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 1 2. 5 Visit 4/ W e e k 1 2/ D a y 8 4 ( ± 4 d a ys) E n d of Tr e at m e nt/ E arl y T er mi n ati o n Visit  
•  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 1 2. 6 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 disc 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 E arl y T er mi n ati o n Visit c o n d uct e d, a n d a st a n d ar d of c ar e 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 2 5  of 5 3  
 
tr e at m e nt m a y b e a d vis e d at t h e i n v esti g at or’s discr eti o n. T h e
 
 
 
•  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 1 3 S u m m ar y  of Ass ess m e nts  
T h e sc h e d ul e of visits a n d pr oc e d ur es t o b e c o n d uct e d at e ac h visit ar e s u m m ariz e d i n t h e Sc h e d ul e 
of St u d y Pr oc e d ur es.  
 
Visit 1/ B as eli n e/ D a y 1  
 
 Th e f oll o wi n g pr oc e d ur es :  I nf or m e d C o ns e nt, I ncl usi o n/ Excl usi o n Crit eri a, M e dic al Hist or y  
/ D e m o gr a p hics, c oll ecti o n a n d r e vi e w of C o nc o mit a nt m e dic ati o ns, P h ysic al ex a m, Vit al si g ns, 
d er m at ol o gic al ass ess m e nt  ( di a g n osis), e v al u ati o n of t h e tr e at m e nt ar e a, I G A, er yt h e m a ass ess m e nt,  
e v al u ati o n t el a n gi ect asi a  a n d Uri n e pr e g n a ncy t est  m ust b e c o m pl et e d a n d d oc u m e nt e d o n t h e 
s o urc e d oc u m e nt b ef or e a s u bj ect is r a n d o miz e d o n t h e st u d y. 
 
T h e s af et y ( a p plic ati o n sit es r e acti o ns ) ass ess m e nts m ust b e c o m pl et e d pri or t o  a n d 
 
aft er  t h e first st u d y m e dic ati o n a p plic ati o n .   
 
 
 
 
 
 
 
 
 
 
 
 




Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 2 7  of 5 3  
 
eSt u d y m e dic ati o n t o b e c oll ect e d a n d/ or dis p e ns e d, if n ec ess ar y  
 fU P T  t o b e c o n d uct e d at U nsc h e d ul e d Visit, if a p plic a bl e 
* *  A p plic ati o n sit es r e acti o ns m ust b e c o m pl et e d pri or t o a n d a p pr oxi m at el y t hirt y ( 3 0) mi n ut es aft er t h e first st u d y m e dic ati o n 
a p plic ati o n  
* * * O nc e t h e a er os ol c a nist er is o p e n e d a n d us e d at l e ast o nc e , it ex pir es 8 w e eks l at er 
 
 
5. 1 4 Scr e e n F ail ur es  
Scr e e n f ail ur es will n ot b e e nt er e d i n t h e d at a b as e n or  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, a n d 
p ossi bl y p erf or mi n g s o m e st u d y r el at e d pr oc e d ur es, b ut w as n ot e nr oll e d, dis p e ns e d a n d a p pli e d t h e 
i n v esti g ati o n al pr o d uct. 
 
5. 1 5  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 
ju 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 es i g n e e m ust c o nt act P erri g o / 
 c o nt acts 
i n S ecti o n 1 5 ( A p p e n dix A) at t h e e arli est p ossi bl e ti m e. 
 
 
 
 
 
 
  
 
 
 
 
 
 
.  
 
5. 1 6 S u bj ect/ Tr e at m e nt C o m pli a nc e  
S u bj ects will a p pl y t h e s m all est a m o u nt of t h e st u d y m e dic ati o n o n e ac h ar e a of t h e f ac e (c hi n, l eft 
c h e e k, ri g ht c h e e k, n os e, a n d f or e h e a d) i n t h e m or ni n g a n d  e v e ni n g (
 
) t wic e d ail y f or 1 2 w e e ks. O n D a y 1, s u bj ects will a p pl y t h eir i niti al d os e of st u d y m e dic ati o n 
a t t h e st u d y sit e
 
 
. O n W e ek 2/ D a y 1 4 ( ± 4 d a ys), c o m pli a nc e will b e ass ess e d vi a t el e p h o n e c o nt act. T h e 
st u d y c o or di n at or, or d esi g n e e, will r e vi e w t h e S u bj ect I nstr ucti o n S h e et a n d Di ar y wit h t h e s u bj ect o n 
t h e p h o n e. 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 wi ll 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 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 2 8  of 5 3  
 
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 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 
miss e d 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.
 
 
  All us e d a n d 
u n us e d a er os ol c a nist ers 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 a p pr o pri at e visits or 
e arl y t er mi n ati o n.  
 
5. 1 7 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 his or 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 or r e q uir es a n alt er n ati v e t h er a py . 
•  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.  
•  S u bj ect di d n ot m e et , or n o l o n g er m e ets , t h e e ntr y crit eri a. 
•  A n a d v ers e e v e nt , i ncl u di n g i nt erc urr e nt ill n ess, 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 ec t 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 e s u bj ect 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.  
•  L ac k of effic acy (tr e at m e nt f ail ur e) aft er 1 m o nt h ( 3 0 d a ys) of tr e at m e nt wit h a c o m pli a nc e 
r at e of  
 (i n v esti g at or r e m o v al fr o m st u d y). 
•  I n v esti g at or discr eti o n ( e. g., n o n-c o m pli a nt t o st u d y pr ot oc ol r e q uir e m e nts). 
 
Aft er a s u bj ect h as b e e n disc o nti n u e d, h e/s h e will n ot b e all o w e d t o r e -e nr oll i n t h e st u d y at a n y 
f acilit y.  
 
T h e r e as o n(s) f or a s u bj ect b ei n g disc o nti n u e d fr o m t h e st u d y 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 d y f or a n y r e as o n, t h e Visit 4 ( D a y 8 4)/ E n d of St u d y Visit/ 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 at e of r e m o v al, will 
b e r ec or d e d o n t h e S o urc e D oc u m e nt a n d 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.  
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 2 9  of 5 3  
 
 
 
 
  
 
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 :  Az el aic Aci d F o a m, 1 5 %,  
P erri g o
 
 
 
R ef er e nc e  Pr o d uct :   Fi n ac e a® ( Az el aic  aci d  f o a m,  1 5 %)  M a n uf act ur e d  b y  B a y er  H e alt h C ar e 
P h ar m ac e utic als I nc.  
 
V e hicl e :  V e hicl e of t est pr o d uct  
(
.) 
 
6. 2 M e dic 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 e r 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 d e ntit y of t h e m e dic ati o n i n t h e a er os ol c a nist er. 
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, w h e n e v er p ossi bl 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 olv 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 Fs . 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 0  of 5 3  
 
 
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 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.  
 
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 ra 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 ml y s el ect e d bl oc k of st u d y 
m e dic ati o n fr o m 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  ( at r o o m t e m p er at ur e, 2 5° C ( 7 7° F); exc ursi o ns p er mitt e d b et w e e n 
1 5° C t o 3 0° C ( 5 9° F a n d 8 6° F) e v e n aft er t h e st u d y h as c o ncl u d e d. 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 or 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 ne d  s a m pl e st u d y 
m e dic ati o n u ntil s uc h ti m e of 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 m e dic ati o n  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 or d esi g n e e. E ac h i n v esti g at or sit 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 st u d y m e dic ati o n s h o ul d n ot b e fr oz e n,  ex p os e d 
to h e at , or st or e d at t e m p er at ur es a b o v e 1 2 0° F ( 4 9 ° C). T h e st u d y m e dic ati o n s h o ul d b e st or e d at r o o m 
t e m p er at ur e i n a s ec ur e d ar e a wit h li mit e d acc ess, 2 5° C ( 7 7° F); exc ursi o ns p er mitt e d b et w e e n 1 5° C t o 
3 0° C ( 5 9° F t o 8 6° F) a n d a er os ol c a nist er s k e pt i n a n u pri g ht p ositi o n a n d ti g htl y cl os e d. T h e i n v esti g at or 
or d esi g n e e will i nstr uct s u bj ects t o st or e t h e st u d y m e dic ati o n i n a s ec ur e ar e a at r o o m t e m p er at ur e 
at 2 5° C ( 7 7°F), o ut of r e ac h of c hil dr e n, a er os ol c a nist er s ar e n ot t o b e ex p os e d t o h e at  or t e m p er at ur e 
a b o v e 1 2 0° F ( 4 9° C) , p u nct ur e d or i nci n er at e d. T h e i n v esti g at or will n ot s u p pl y st u d y m e dic ati o n t o a n y 
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.  
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 1  of 5 3  
 
T h e cli nic p ers o n n el at e ac h i n v esti g at or sit e will k e e p a r u n ni n g i n v e nt or y of st u d y m e dic ati o n  
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 a er os ol c a nist er of st u d y 
m e dic ati o n is dis p e ns e d a n d r et ur n e d.  A st u d y m e dic ati o n 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 a er os ol c a nist er s 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, wit h t h e exc e pti o n of r et e nti o n 
s a m pl es w hic h s h all r e m ai n at t h e I n v esti g at or sit e. 
 
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 t h e 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 he m e will b e a bl oc k r a n d o miz ati o n, 
wit h e ac h bl oc k 
. 
 
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 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 f or e ac h s u bj ect at e ac h i n v esti g at or sit e, 
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. P erri g o m ust b e n otifi e d i m m e di at el y u p o n all u n bli n di n g sit u ati o ns.  
 
7.  A D V E R S E R E A C TI O N S  
T h e p ot e nti al a d v ers e r e acti o ns of g e n eric  Az el aic Aci d F o a m , 1 5 % 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 i n Fi n ac e a ® (Az el aic Aci d ) F o a m, 1 5 %.  
 
T h e f oll o wi n g a d v ers e r e acti o ns occ urr e d i n gr e at er t h a n  0. 5 % of p ati e nts tr e at e d wit h Az el aic Aci d 
F o a m, 1 5 %,  a p plic ati o n sit e p ai n ( 6. 2 % ) , d escri b e d as b ur ni n g, sti n gi n g, “ pi ns a n d n e e dl es”, a n d/ or 
t e n d er n ess , a p plic ati o n sit e er yt h e m a ( 0. 7 %), a p plic a ti o n sit e dr y n ess ( 0. 7 %), a n d a p plic ati o n sit e 
pr urit us ( 2. 5 %).  
 
Is ol at e d r e p orts of l oss of s ki n c ol or ( h y p o pi g m e nt ati o n) h a v e b e e n  r e p ort e d f oll o wi n g t o pic al us e of 
Fi n ac e a ®.  Fi n ac e a ® h as n ot b e e n w ell st u di e d i n p ati e nts wit h d ar k c o m pl exi o n. T h er ef or e,  s u bj ects 
wit h d ar k er c o m pl exi o n s h o ul d b e m o nit or e d cl os el y f or e arl y si g ns of l oss of s ki n c ol or b y t h e 
i n v esti g at ors  a n d  i nstr uct e d  t o  r e p ort  i m m e di at el y  a n y  a b n or m al  c h a n g es  i n  s ki n c ol or  t o  t h e  
i n v esti g at ors.  W h e n si g nific a nt h y p o pi g m e nt ati o n ar e r e p ort e d b y s u bj ects, st u d y m e dic ati o n s h o ul d 
b e disc o nti n u e d.   
 
Az el aic aci d h as b e e n r e p ort e d t o c a us e irrit ati o n of t h e e y es a n d m uc o us m e m br a n e irrit ati o n. C o nt act 
wit h t h e st u d y pr o d uct s h o ul d b e a v oi d e d o n t h e  e y es, m o ut h a n d ot h er m uc o us m e m br a n es a n d if 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 2  of 5 3  
 
t h er e is c o nt act wit h t h e e y es, l ar g e a m o u nts of w at er s h o ul d b e us e d t o w as h t h e e y es a n d s u bj ects 
s h o ul d b e i nstr uct e d t o c o ns ult a p h ysici a n if e y e irrit ati o n p ersists.  
 
Hy p ers e nsiti vit y , r as h a n d w ors e ni n g of ast h m a  h a v e  b e e n r e p ort e d i n p ost -m ar k eti n g us e of pr o d ucts 
c o nt ai ni n g Az el aic aci d -c o nt ai ni n g f or m ul ati o ns.   
 
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 i n 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 aril 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 ev e nt c a nist er 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 all y  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 i t 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  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, m a y j e o p ar diz e t h e s u bj ect a n d 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 o utc o m es list e d a b o v e.  
 
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, t h e I n v esti g at or’s Br oc h ur e, or as d escri b e d i n t h e cli nic al pr ot o c 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 o v 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.  
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 3  of 5 3  
 
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. 
 
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:   Th 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 d ic 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 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. 
 
 
 
 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 s o urc e 
a n d t h e s t u d y r e p orti n g f or ms. W h e n r e p orti n g a n a d v ers e e v e nt, t h e I n v esti g at or m ust assi g n a 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 4  of 5 3  
 
s e v erit y gr a d e t o e ac h ev e nt a n d d ecl ar e a n o pi ni o n o n t h e r el at e d n ess of t h e e v e nt t o t h e st u d y 
m e dic ati o n or pr oc e d ur e.  S eri o us or u n ex p ect e d a d v ers e e v e nts m ust b e r e p ort e d t o P erri g o wit hi n 
2 4 h o urs  of w h e n t h e I n v esti g at or first l e ar ns of t h e occ urr e nc e of t h e e v e nt.  
 
A d v ers e e v e nts will b e d oc u m e nt e d i n t h e s o urc e d oc u m e nt a n d r ec or d e d i n a ti m el y m a n n er o n c as e 
r e p ort f or ms ( C R Fs).  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.  
 
A d v ers e e v e nt r e p orti n g b e gi ns fr o m t h e si g ni n g of i nf or m e d c o ns e nt. A d v ers e e v e nts s h o ul d b e 
f oll o w e d u ntil r es ol v e d or 3 0 d a ys aft er t h e fi n al st u d y tr e at m e nt.  I n a n y c as e, s eri o us a d v ers e e v e nts 
t h at ar e n ot r es ol v e d or c o nsi d er e d t o b e c hr o nic wit hi n 3 0 d a ys of t h e fi n al st u d y tr e at m e nt m ust 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 y b ec o m e r es ol v e d or ar e c o nsi d er e d t o b e c hr o nic (st a biliz e d f or 
at l e ast 3 0 d a ys).  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. 3. 1 E x 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  
F or a n y s eri o us or u n ex p ect e d a d v ers e e v e nt, t h e s p o ns or m ust b e n otifi e d wit hi n 2 4 h o urs  of w h e n 
t h e I n v esti g at or first l e ar ns of t h e occ urr e nc e of t h e e v e nt. Ex p e dit e d r e p orti n g r e q uir e m e nts f or 
s eri o us a d v ers e e v e nts ar e d escri b e d b el o w. A d e q u at e i nf or m ati o n m ust b e c oll ect e d wit h s u p p orti n g 
d oc u m e nt ati o n t o c o m pl et e a st a n d ar d r e p ort f or s u b missi o n t o P erri g o. T h e a d v ers e e v e nt t er m o n 
t h e A E C R F a n d t h e S A E r e p ort s h o ul d a gr e e ex actl y. S p eci al att e nti o n s h o ul d b e gi v e n t o r ec or di n g 
h os pit aliz ati o ns a n d c o nc o mit a nt m e dic ati o ns.   
 
S u bj ects wit h u nr es ol v e d a d v ers e e v e nt(s) or s eri o us a d v ers e  e v e nt(s) 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, e v e nt(s) d et er mi n e d t o b e c hr o nic 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 ow- u p i nf or m ati o n t o t h e s p o ns or 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 ec t  t o  t h e  
i n v esti g at or  t h at  occ urs  wit hi n  3 0  d a ys  aft er  t h e  l ast  ass ess m e nt,  a n d  ar e  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 
t h e s p o ns or wit hi n 2 4 h o urs of w h e n t h e I n v esti g at or first l e ar ns of t h e occ urr e nc e of t h e e v e nt.   
 
W h e n r e p orti n g a s eri o us a d v ers e e v e nt ( S A E) t h e I n v esti g at or ( or t h e St u d y C o or di n at or) will pr o m ptl y 
r e p ort a n y s eri o us a d v ers e e v e nt or pr e g n a ncy b y t el e p h o n e t o 
 i m m e di at el y aft er t h e i n v esti g at or b ec o m es a w ar e of t h e 
e v e nt.  A n S A E f or m s h o ul d b e c o m pl et e d a n d s e nt b y f ax, e m ail, or o v er ni g ht c o uri er t o  
 wit hi n 
2 4 h o urs of k n o wl e d g e of t h e e v e nt b y t h e sit e.  I n m a n y c as es, o nl y pr eli mi n ar y i nf or m ati o n will b e 
a v ail a bl e.  A p pr o pri at e  f oll o w  u p  i nf or m ati o n  s h o ul d  b e  s o u g ht  ( h os pit al  disc h ar g e  s u m m ari es,  
o p er ati v e r e p orts , etc.) a n d a f oll o w u p S A E r e p ort f or m s u b mitt e d.  A d esi g n ati o n of c a us alit y 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. 
 
7. 3. 2 S u b mitti n g a n E x p e dit e d S af et y R e p ort t o t h e I R B  


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 5  of 5 3  
 
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 P erri g o, 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 g e n er at e t h e r e p ort. 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 evi 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 1 ( o n e)  d a y aft er i niti al r ec ei pt. W h e n ex p e dit e d s af et y r e p orti n g t o r e g ul at or y 
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 bri 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  
, P erri g o, 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.  
 
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  
 A N D  P E R RI G 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 
. 
 
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 P erri g o 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 a ll 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. 
 
A s u bj ect w h o ex p eri e nc es a s e v er e a d v ers e e v e nt r el at e d t o st u d y dr u g will b e disc o nti n u e d fr o m t h e 
st u d y. 
 
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:  
 
 
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 6  of 5 3  
 
 
                                        
 
 
 
 
 
 
 
 
 
 
7. 4. 1 Pr e g n a nc y  
At t h e ti m e a Pri nci p al I nv 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 
S y m bi o, 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);  
•  G est ati 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 m f 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.  
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 7  of 5 3  
 
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 eliv 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 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 nt ifi 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.   
 
7. 5. 2 S eri o us 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 P erri g o 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 p ort e d s e ri o us a d v ers e ev 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  ar e  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 dr u g, s h o ul d b e r e p ort e d t o P erri g o. 
 
8. S T A TI S TI C AL  A N AL Y SI S  
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 w hic h gi v es 
d escri pti o ns of t h e st atistic al m et h o ds, m o d els, hy 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 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 St atistic al A n al ysis Pl a n  
 
8. 1. 1 A n al ysis P o p ul ati o ns  
T h e f oll o wi n g p o p ul ati o ns ar e d efi n e d f or t h e p ur p os e of a n al ys es:  
•  I nt e nt-t o-Tr e at (I T T) (s af et y p o p ul ati o n):  A n y s u bj ect t h at w as r a n d o miz e d, r ec ei v e d a n d us e d 
st u d y m e dic ati o n. 
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 8  of 5 3  
 
•  M o difi e d I nt e nt -t o-Tr e at ( mI T T):  A n y s u bj ect, w h o m et t h e i ncl usi o n/ excl usi o n crit eri a, w as 
r a n d o miz e d, r ec ei v e d a n d us e d t h e st u d y m e dic ati o n, a n d r et ur n e d f or at l e ast o n e p ost -
b as eli n e effic acy ass ess m e nt.  
 
•  P er Pr ot oc ol ( P P) :  A n y s u bj ect: 
•  W h o m et i ncl usi o n/ excl usi o n crit eri a,  
•  W h o w as r a n d o miz e d a n d r ec ei v e d a n d us e d st u dy m e dic ati o n,  
•  W h o m et t h e pr ot oc ol crit eri a f or c o m pli a nc e 
  
 
a n d  
•  W h o c o m pl et e d Visit 4/ W e e k 1 2/ D a y 8 4 ( E n d of Tr e at m e nt/ E arl y T er mi n ati o n Visit) wit hi n 
wi n d o w 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 tr e at m e nt f ail ur e. 
•  Wit h o ut si g nific a nt pr ot oc ol vi ol ati o ns t h at c o ul d h a v e i nt erf er e d wit h t h e a d mi nistr ati o n 
of t h e tr e at m e nt or t h e pr ecis e e v al u ati o n of tr e at m e nt effic acy.  
 
 
 
 
 
 
 
 
 
 
 
. 
 
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 / us 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 mI T T s u bj ect 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 - val u es l ess t h a n 0. 0 5 will b e c o nsi d er e d st atistic all y 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 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 t h e e n d -of -tr e at m e nt 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 m e a n p erc e nt c h a n g e fr o m b as eli n e t o Visit 4/ W e e k 1 2 ( D a y 
8 4) i n t h e i nfl a m m at or y ( p a p ul es a n d p ust ul es) l esi o n c o u nt.  
 
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 cli nic al s ucc ess d efi n e d as a sc or e of 
cl e ar or al m ost cl e ar (sc or e of 0 or 1) o n t h e I n v esti g at or Gl o b al Ass ess m e nt (I G A) at Visit 4/ W e ek 1 2  
( D a y 8 4). 
 
 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 3 9  of 5 3  
 
 
8. 1. 3 S a m pl e Siz e C o nsi d er ati o ns  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
8. 1. 4 Ef fic ac y M e as ur es a n d A n al ysis 
 
Cli nic al e n d p oi nts  
T h e pri m ar y effic acy m e as ur e will b e t h e m e a n p erc e nt c h a n g e fr o m b as eli n e t o Visit 4/ W e e k 1 2  ( D a y 
8 4)  i n t h e i nfl a m m at or y ( p a p ul es a n d p ust ul es) l esi o n c o u nts. T h e s ec o n d ar y effic acy m e as ur e will b e 
t h e pr o p orti o n of s u bj ects wit h cli nic al s ucc ess d efi n e d as a sc or e of cl e ar or al m ost cl e ar (sc or e of 0 
or 1) o n t h e I n v esti g at or Gl o b al Ass ess m e nt (I G A) at Visit 4/ W e e k 1 2  ( D a y 8 4). 
 
E q ui v al e nt effic acy  
F or t h e m e a n p erc e nt c h a n g e fr o m b as eli n e i n t h e i nfl a m m at or y l esi o n c o u nt, t h e T est tr e at m e nt will 
b e c o nsi d er e d t o b e t h er a p e utic all y e q ui v al e nt t o t h e R ef er e nc e tr e at m e nt if t h e 9 0 % c o nfi d e nc e 
i nt er v al o n t h e T est-t o-R ef er e nc e r ati o of m e a ns, c alc ul at e d b y Fi ell er’s M et h o d, f alls wit hi n t h e 
i nt er v al 0. 8 0 t o 1. 2 5. T h e tr e at m e nt m e a ns a n d esti m at e of r esi d u al v ari a nc e f or t h e c o nfi d e nc e 
i nt er v al c alc ul ati o n will c o m e fr o m a n A n al ysis of V ari a nc e of t h e T est a n d R ef er e nc e r es ults usi n g a 
st atistic al m o d el c o nt ai ni n g t er ms f or Tr e at m e nt a n d Sit e . 
 
F or t h e pr o p orti o n of s u bj ects wit h cli nic al s ucc ess, t h e T est tr e at m e nt will b e c o nsi d er e d t o b e 
t h er a p e utic all y e q ui v al e nt t o t h e R ef er e nc e tr e at m e nt if t h e 9 0 % c o nfi d e nc e i nt er v al o n t h e diff er e nc e 
b et w e e n T est a n d t h e R ef er e nc e pr o p orti o ns  is 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 
c o nfi d e nc e i nt er v al will b e c o nstr uct e d usi n g 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.  
 
T h er a p e utic e q ui v al e nc e e v al u ati o ns i n t h e p er -pr ot oc ol ( P P) p o p ul ati o n will b e c o nsi d er e d d efi niti v e 
a n d t h os e i n t h e mI T T will b e c o nsi d er e d s u p p ortiv e.  


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 4 0  of 5 3  
 
 
S u p eri orit y  
F or t h e m e a n p erc e nt c h a n g e fr o m b as eli n e i n t h e i nfl a m m at or y l esi o n c o u nt, e ac h acti v e tr e at m e nt 
will b e e v al u at e d t o d et er mi n e if it h as s u p eri or effic acy t o t h at of t h e V e hicl e at Visit 4/ W e e k 1 2 ( D a y 
8 4)  vi a a n A n al ysis of V ari a nc e usi n g Pr oc Mix e d of S A S wit h Tr e at m e nt a n d Sit e  as f act ors .  
 
T h e pr o p orti o n of s u bj ects wit h cli nic al s ucc ess f or e ac h acti v e tr e at m e nt will b e c o m p ar e d t o t h at of 
t h e V e hicl e usi n g Z- t est wit h Y at e’s c o nti n uit y c orr ecti o n. 
 
S u p eri orit y t ests will b e t w o -si d e d at a si g nific a nc e l e v el of α = 0. 0 5. S u p eri orit y a n al ys es i n t h e mI T T 
p o p ul ati o n will b e c o nsi d er e d d efi niti v e a n d t h os e i n t h e P P will b e c o nsi d er e d s u p p orti v e  
 
8. 1. 5 S af et y a n d A d v ers e E v e nts A n al ysis  
T h e fr e q u e ncy a n d p erc e nt of s u bj ects wit h a d v ers e e v e nts will b e s u m m ariz e d b y M e d D R A s yst e m 
or g a n cl ass a n d pr ef err e d t er m a n d b y s e v erit y a n d r el ati o ns hi p t o st u d y dr u g f or all t hr e e tr e at m e nt 
gr o u ps. 
 
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 ects w h o r e p ort e d a n y a d v ers e e v e nts.  S af ety 
c o m p aris o ns will b e p erf or m e d o nl y f or t h e s af ety i nt e nt -t o-tr e at p o p ul ati o n. 
 
8. 2 C o m p ar a bilit y of S u bj ects at B as eli n e  
D escri pti v e st atistics will b e pr es e nt e d, b y tr e at m e nt gr o u p, f or s u bj ect b as eli n e c h ar act eristics. T h e 
si g nific a nc e of a n y o b vi o us tr e at m e nt gr o u p diff er e nc es will b e disc uss e d i n t h e C S R. 
 
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 ect 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 o pic al a p plic ati o n of 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 bility 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 ov 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 eiv 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.  
 
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 a s 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 u r 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 


Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 4 1  of 5 3  
 
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 ov 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 o r 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 ov 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 by 
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 ( or t h eir 
p ar e nt/l e g all y a ut h oriz e d r e pr es e nt ati v e) 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 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 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 P erri g o a ut h oriz e d 
r epr 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 t h 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 ays 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 by 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 n v esti g at or’s 
r es p o nsi bilit y 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 d y. 
 
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 ees 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 nf i 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. 
 


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P a g e 4 2  of 5 3  
 
9.  
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 c o 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 oc 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 writt 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 fiv e 
d a ys.  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.  
 
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 st u 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  
  
C R Fs f or i n di vi d u al s u bj ects will b e pr o vi d e d 
. C R Fs m ust b e l e gi bl e a n d c o m pl et e.  C R Fs 
f or t his st u d y will b e m ai nt ai n e d i n a st u d y bi n d er a n d d at a r ec or d e d o n 2-p art N C R p a p er.  O n e c o p y 
will b e k e pt b y t h e i n v esti g at or a n d t h e ot h er c o py will  b e s u b mitt e d t o t h e C R O d at a m a n a g e m e nt 
gr o u p.  All f or ms s h o ul d b e c o m pl et e d usi n g a bl ack b all p oi nt p e n. Err ors s h o ul d b e li n e d o ut, b ut n ot 
o blit er at e d, a n d t h e c orr ecti o n i ns ert e d, i niti al e d, a n d d at e d b y d esi g n at e d st u d y p ers o n n el. F urt h er 


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P a g e 4 3  of 5 3  
 
d at a c orr ec ti o ns will b e p erf or m e d o n d at a c orr ecti o n f or ms ( D C Fs) t h at will b e pr o vi d e d b y t h e C R O 
t o t h e i n v esti g at or i n c as e of err o n e o us or u ncl e ar d at a. T h e i n v esti g at or will m a k e t h e c orr ecti o n o n 
t h e D C F a n d si g n t h e D C F. T h e si g n e d D C F will b e s u b mitt e d t o t h e C R O d at a m a n a g e m e nt gr o u p f or 
pr oc essi n g a n d a c o p y r et ai n e d wit h t h e C R Fs.  
A C R F m ust b e c o m pl et e d a n d si g n e d b y t h e i n v esti g at or f or e ac h s u bj ect e nr oll e d, i ncl u di n g t h os e 
disc o nti n u e d fr o m t h e st u d y f or a n y r e as o n. T h e r e as o n f or disc o nti n u ati o n m ust b e n ot e d o n a 
s u bj ect’s st u d y t er mi n ati o n f or m. 
C R Fs m ust b e k e pt c urr e nt t o r efl ect t h e s u bj ect’s st at us at e ac h p h as e d uri n g t h e c o urs e of t h e 
st u d y. S u bj ects ar e n ot t o b e i d e ntifi e d o n C R Fs by n a m e; a p pr o pri at el y c o d e d i d e ntific ati o n a n d t h e 
s u bj ect’s i niti als m ust b e us e d. T h e i n v esti g at or m ust k e e p a s e p ar at e l o g of t h e s u bj ect’s n a m es a n d 
a d dr ess es.  
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 bj 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 ns 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 stri ki 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 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 n ( 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 a s 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 a t 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 


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P a g e 4 4  of 5 3  
 
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 2 1 C F R § 3 1 2. 5 7 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) w ritt 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. 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.  
 
1 2. 2 A u diti n g  
P erri g o ( or r e pr es e nt ati v 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 Fs  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.  


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P a g e 4 5  of 5 3  
 
 
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 nti al 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 erie 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 al l 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 ate 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 d y 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 w it 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 h e 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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1 5. A P P E N DI C E S  
 
1 5. 1 A p p e n di x A: St u d y P ers o n n el C o nt acts  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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P a g e 4 8  of 5 3  
 
1 5. 2 A P P E N DI X B:  I N S T R U C TI O N S F O R T H E S U BJ E C T 
 
C h ec k Visit Dis p e ns e d: Visit 1:  
   Visit 2:   
        Visit 3:      
    U nsc h e d ul e d visit:   
     D at e: _ _ _ _ _ _ _ _  
 
S U BJ E C T I NI TI AL S: _ _ _ _ _ _ _ _ _ _ _    S U BJ E C T N U M B E R: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ SI T E N U M B E R: _ _ _ _ _ _ _ _  
 
1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
3.  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
  
 
  
 
 




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P a g e 5 0  of 5 3  
 
9.  
 
 
 
 
 
 
 
 
 
 
1 7.  
 
  
 
 
 
 
   
 
  
  
 
  
  
 
 
  
 
 
  
   
 
 
 
 
  


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P a g e 5 1  of 5 3  
 
2 9.  
 
 
 
 
 
 
 
 
 
Y o ur c all is sc h e d ul e d f or:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ( W e e k 2)  
  
  
  
 
          ( D at e) 
Y o u ar e sc h e d ul e d t o r et ur n at:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ o n _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ( Visit 2, St u d y W e e k 4)    
( Ti m e) 
( D at e) 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ o n _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ( Visit 3, St u d y W e e k 8)  
( Ti m e)   
  
  
 
( D at e) 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ o n _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ( Visit 4, St u d y W e e k 1 2)  
( Ti m e)  
  
  
 
( D at e)  
 
ALL A P P OI N T M E N T S A R E I M P O R T A N T! I F Y O U N E E D T O R E -S C H E D UL E Y O U R A P P OI N T M E N T, PL E A S E    
C ALL Y O U R S T U D Y D O C T O R’ S O F FI C E I M M E DI A T EL Y.  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
N a m e a n d T el e p h o n e N u m b er of St u dy C o or di n at or/ St u dy Sit e  
 




Pr ot oc ol  N o: P R G -N Y - 1 6-0 0 9  
 
                                                                   
 
 
P a g e 5 3  of 5 3  
 
1 6. R E F E R E N C E S  
1.  C o h e n A. F, Ti e mstr a J. D: Dis e as e a n d Tr e at m e nt of R os ac e a . J o ur n al of A m eric a n B o ar d of 
F a mil y Pr actic e. M a y -J u n e 2 0 0 2 V ol 1 5. N o 3: 2 1 4 - 2 1 7  
2.  Z u b er TJ. R os ac e a. D er m at ol o g y. Pri m C ar e 2 0 0 0; 2 7: 3 0 9 -1 8  
3.  Kli g m a n A M. Oc ul ar R os ac e a. C urr e nt C o nc e pts a n d T h er a p y. Arc D er m at ol 1 9 9 7; 1 3 3: 8 9 -9 0.  
4.  htt ps:// w w w. a a d. or g/ d er m at ol o g y - a-t o-z/ dis e as es-a n d -tr e at m e nts 
5.  P ac k a g es i ns ert Fi n ac e a ® F o a m 1 5 % ( Az el aic Aci d, F o a m 1 5 %) d at e d J ul y 2 0 1 5 4.  
6.  w w w.fi n ac e a.c o m  
7.  O G D Dr aft G ui d a nc e o n  M etr o niz a d ol e   Cr e a m 0. 7 5 % ; M ar 2 0 1 0 a n d Az el aic Aci d G el; M a y 
2 0 1 0 a n d R e vis e d S e p 2 0 1 2  
8.  Fi n ac e a ® F o a m. htt ps:// w w w. dr u gs .c o m/ pr o/fi n ac e a-f o a m. ht ml. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
 
NCT02800148 
 
10-04-2016 




Table of Contents 
1 
Purpose of Statistical Analysis Plan ........................................................................................................ 3 
2 
Study Objectives ....................................................................................................................................... 3 
3 
Study Design and Sample Size ................................................................................................................ 3 
3.1 
Study Design ..................................................................................................................................................... 3 
3.2 
Sample Size ....................................................................................................................................................... 4 
4 
Populations To Be Analyzed .................................................................................................................... 4 
5 
Planned Analyses ...................................................................................................................................... 5 
5.1 
Methodological Considerations ........................................................................................................................ 5 
5.2 
Handling of Dropouts or Missing Data ............................................................................................................. 5 
5.3 
Demographics and Baseline Characteristics ..................................................................................................... 5 
5.4 
Subject Accountability ...................................................................................................................................... 6 
5.5 
Efficacy Variables and Analyses ...................................................................................................................... 6 
5.5.1 
Primary Endpoint ................................................................................................................................. 6 
5.5.2 
Secondary Endpoints............................................................................................................................ 7 
5.5.3 
Additional Efficacy Variables .............................................................................................................. 9 
5.6 
Safety Variables and Analyses .......................................................................................................................... 9 
6 
Appendices .............................................................................................................................................. 10 
6.1 
Handling of Missing or Incomplete Dates for Adverse Events and Concomitant Medications ...................... 10 
6.2 
Summary of Assessments ............................................................................................................................... 11 


List of Abbreviations 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
CI 
Confidence Interval 
CMH 
Cochran–Mantel–Haenszel Test 
IGA 
Investigator’s Global Assessment 
ITT 
Intent-to-Treat (Population) 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat (Population) 
PD 
Protocol Deviation 
PP 
Per-Protocol (Population) 
PV 
Protocol Violation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
WHO Drug 
World Health Organization Drug Dictionary 
 
 
 
 
 
 
 










PROC GLM DATA=inf_pp; 
CLASS trt site; 
MODEL pchg_inf = trt site; 
ESTIMATE 'ratio=c' intercept (1-c) trt 1 -c; 
RUN; 
Where the ESTIMATE statement is run targeting at two-sided p=0.10 to locate the c value 
(our Test/RLD) for the 90% CI.  
Superiority 
For the percent change from baseline in the inflammatory lesion counts, each active treatment 
will be evaluated to determine if it has superior efficacy to that of the Vehicle at Visit 4/Week 
12 (Day 84) via an ANOVA model containing terms for treatment and site. The compound 
hypothesis to be tested for superiority of test and reference over Vehicle is:  
H0: μT ≤ μV or μR ≤ μV versus 
HA: μT > μV and μR > μV 
Where μT, μR and μV are the mean percent change from baseline to Visit 4/Week 12 (Day 84) in 
inflammatory lesions counts for the test, the reference and the vehicle treatments, respectively. 
The null hypothesis is rejected when both p-values from the ANOVA are less than 0.05 (two-
sided test). Rejection of the null hypothesis supports the conclusion of superiority of test and 
reference products over the vehicle product for the primary efficacy variable. 
A skewness test (SAS® PROC UNIVARIATE) will be performed using the residuals from the 
ANOVA of the primary efficacy variable. If the skewness statistic is greater than 2 or less than 
-2, the analysis will be performed on the ranked mean percent change from baseline to Visit 
4/Week 12 (Day 84) in inflammatory lesion counts. 
Superiority analyses in the mITT population will be considered definitive and those in the PP 
will be considered supportive. 
Analysis for superiority will be performed based on the following SAS code (SAS Institute 
v.9.1.3): 
The key procedure used to compare mean values of an active treatment arm to vehicle: 
PROC GLM DATA=inf_pp; 
CLASS trt site; 
MODEL pchg_inf = trt site /ss3; 
RUN; 
5.5.2  Secondary Endpoints 
The secondary efficacy endpoint is the proportion of subjects with clinical success defined as a 
score of clear or almost clear (score of 0 or 1) on the Investigator Global Assessment (IGA) at 
Visit 4/Week 12 (Day 84).   


Equivalent Efficacy 
The compound hypothesis to be tested for clinical equivalence between test and reference is:  
H0: pT- pR < -0.20 or pT- pR > 0.20 versus 
HA: -0.20 ≤ pT- pR ≤ 0.20.  
Where pT and pR are the proportions of subjects with clinical success at Visit 4/Week 12 (Day 
84) for the test and reference products, respectively. The test product will be considered to be 
therapeutically equivalent to the reference product if the 90% CI on the difference in their 
proportions of subjects with clinical success, calculated by Wald’s method with Yates’ 
continuity correction, is contained within the limits -0.20 to +0.20. Rejection of the null 
hypothesis supports the conclusion of therapeutic equivalence between the test and reference 
products for the secondary efficacy variable.  
The result of the analysis in the PP population will be considered definitive and that in the mITT 
population as supportive. 
Analysis for therapeutic equivalence will be performed based on the following SAS code 
(SAS Institute v.9.1.3): 
P-value is chosen from Continuity Adj. Chi-Square test. 
The SAS code for 90% confidence interval (trt=1 for Test, trt=2 for Reference): 
proc freq data=XX ; 
where trt in (1,2); 
tables trt* success / alpha=0.10 riskdiff; 
output out=CIDIFF (keep= l_rdif2 u_rdif2 ) riskdiff; 
run; 
For the final 90% continuity-corrected CI, the lower limit = (l_rdif2 - yates) and the upper 
limit = (u_rdif2 + yates), where yates, the Yates' continuity-correction factor, is derived as 
(1/n1+1/n2)/2, n1=number of subjects in Test arm and n2=number of subjects in Reference 
arm. 
Superiority 
The hypotheses to be tested for superiority of the test and reference products over Vehicle are:  
H0: pT ≤ pV versus HA: pT > pV  
H0: pR ≤ pV versus HA: pR > pV 
Where pT, pR and pV are the proportions of subjects with clinical success at Visit 4/Week 12 
(Day 84) for the test, reference and Vehicle products, respectively. The tests will be conducted 
independently for the test product vs. vehicle and the reference product vs. vehicle using 
two-sided, α = 0.05, continuity-corrected Z-tests. Superiority will be established if the 




further by severity and relationship to study medication. TEAEs reported by 5% or more 
subjects for any treatment group will also be summarized. In the summaries of incidence rates 
(frequencies and percentages), severity and relationship to study drug, subjects who report 
more than one event that are mapped to the same preferred term will be counted only once 
under the strongest severity and relationship, accordingly. The difference between Test and 
Reference treatments with regard to the severity and frequency of their dermatological adverse 
events will be statistically evaluated. Chi-Square or Fisher’s exact test will be used to compare 
the proportions of subjects of the two active treatment groups who report any TEAE. 
Treatment-Emergent Serious Adverse Events (TESAEs) will be discussed within the clinical 
study report. TEAEs, TESAEs and TEAEs that led to treatment interruption or discontinuation 
will be presented in data listings. 
Concomitant Medications, Laboratory Values, and Vitals Signs 
Concomitant medications will be coded using the WHO Drug Dictionary, version September 
2015, and will be presented in data listings. All vital signs data will be displayed in listings. 
Erythema Severity and Application Site Reaction Assessments 
Frequency and distribution of erythema severity assessment and application site reactions of 
dryness, scaling/peeling, pruritus, burning/stinging, pain and will be summarized and 
compared descriptively by visit. 
Safety comparisons will be performed only for the ITT population. 
6 
Appendices 
6.1 
Handling of Missing or Incomplete Dates for Adverse Events and Concomitant 
Medications 
Adverse Events 
Handling of partial dates is only considered for the start date. An adverse event with a partial 
start date is considered treatment emergent if: 
- 
only the day is missing and the start month/year is the same or after the month/year of 
the first dose 
- 
the day and month are missing and the start year is the same or greater than the year 
of the first dose date 
- 
the start date is completely missing 
Concomitant Medications 
Handling of partial dates is only considered for the stop date. A medication with a partial stop 
date is considered concomitant if: 
- 
only the day is missing and the stop month/year is the same or after the month/year of 
the first dose 
- 
the day and month are missing and the stop year is the same or greater than the year 
of the first dose date 


- 
the stop date is completely missing or the medication is ongoing 
6.2 
Summary of Assessments 
The schedule of visits and procedures to be conducted at each visit are summarized in the 
Schedule of Study Procedures.