Conditions: Enterovirus Rhinovirus
Keywords: Enterovirus Rhinovirus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1756
Healthy volunteers: no

Brief summary:
Trial to evaluate efficacy and safety of nitazoxanide in the treatment of colds due to Enterovirus/Rhinovirus infection

Detailed description:
Multicenter, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety of nitazoxanide in the treatment of colds due to Enterovirus/Rhinovirus infection

Arms:
arm 1: Two Nitazoxanide 300 mg tablets orally twice daily for 5 days arm 2: Two placebo tablets orally twice daily for 5 days

Interventions: intervention 1: Nitazoxanide intervention 2: Placebo
Intervention descriptions: intervention 1: Nitazoxanide 600 mg administered orally twice daily for five days intervention 2: Placebo administered orally twice daily for five days

Protocol document:
Prot_000.pdf: 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  2  of  7 2 
C O N FI D E N TI A L 
T A B L E  O F  C O N T E N T S 
P R O T O C O L  N O.  R M 0 8- 3 0 0 5 ........................................................................................................ 1  
I N V E S TI G A T O R’ S  A G R E EM E N T  ............................................................................................... 6 
S Y N O P SI S ...................................................................................................................................... 7  
1.   
I N T R O D U C TI O N ........................................................................................................ 9 
1. 1.   
E nt er o vir us es/ R hi n o vir us es .......................................................................................... 9  
1. 1. 1.   
A nti vir als  St u di e d f or  Tr e at m e nt  of  C ol ds  D u e t o  E V/ R V I nf e cti o n ......................... 1 0  
1. 2.   
Nit a z o x a ni d e ( N T Z) .................................................................................................... 1 1  
1. 2. 1.   
N T Z I n hi bits  Vir al  R e pli c ati o n  a n d  C yt o ki n e  S e cr eti o n ............................................ 1 1  
1. 2. 2.   
P h ar m a c o ki n eti cs  of  N T Z i n  H u m a ns ........................................................................ 1 2  
1. 2. 3.   
P h as e  2  Cli ni c al  Tri als  of  N T Z i n  S u bj e cts  wit h I nfl u e n z a-li k e Ill n ess:  St u di es 
R M 0 2- 2 0 2 2  a n d  R M 0 1- 2 0 2 1 ..................................................................................... 1 4  
1. 2. 4.   
P h as e  2 b/ 3  Cli ni c al  Tri al  of  N T Z i n  U n c o m pli c at e d I nfl u e n z a:  St u d y  R M 0 8- 3 0 0 1 .. 1 5  
1. 2. 5.   
R a n d o mi z e d  2 x 2  F a ct ori al  Tri al  of  N T Z  a n d  O S T i n  Tr e ati n g  U n c o m pli c at e d 
I nfl u e n z a:  St u d y  R M 0 8- 3 0 0 2 ..................................................................................... 1 6 
1. 2. 6.   
O v er vi e w  of  Ot h er  E x p eri e n c e i n  Cli ni c al  Tri als  a n d  P ost- m ar k eti n g  S ur v eill a n c e .. 1 9  
1. 3.   
R ati o n al e f or t h e  St u d y ............................................................................................... 2 0  
2.   
S T U D Y  O BJ E C TI V E S .............................................................................................. 2 0  
3.   
S T U D Y  D E SI G N ....................................................................................................... 2 1  
4.   
S U BJ E C T  S E L E C TI O N ............................................................................................. 2 4  
4. 1.   
I n cl usi o n  Crit eri a ........................................................................................................ 2 4 
4. 2.   
E x cl usi o n  Crit eri a ....................................................................................................... 2 5  
5.   
S T U D Y  P R O C E D U R E S ............................................................................................ 2 6  
5. 1.   
S cr e e ni n g  E v al u ati o n ( d a y  1) ...................................................................................... 2 6  
5. 2.   
B as eli n e ( d a y  1, s a m e  d a y  as s cr e e ni n g  e v al u ati o n) ................................................... 2 6  
5. 3.   
D a y  2  –  D a y  2 2 ........................................................................................................... 2 8  
5. 4.   
D a y  2- 5  T el e p h o n e  M o nit ori n g .................................................................................. 2 8  
5. 5.   
D a y  2  a n d  3  E v al u ati o ns ............................................................................................. 2 8  
5. 6.   
D a y  7  F oll o w- u p ( ± 1  d a y) .......................................................................................... 2 8  
5. 7.   
D a y  2 2  F oll o w- u p ( + 3  d a ys) ....................................................................................... 2 9  
5. 8.   
U ns c h e d ul e d  Visit ....................................................................................................... 2 9  
5. 9.   
St u d y  Dis c o nti n u ati o n ................................................................................................ 2 9  
5. 1 0.   
El e ctr o ni c  S u bj e ct  Di ar y ............................................................................................. 3 0  


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  3  of  7 2 
C O N FI D E N TI A L 
5. 1 1.   
Pl a n f or  L a b or at or y  S af et y  T ests ................................................................................ 3 0  
5. 1 2.   
Pl a n f or  Vir ol o g y  T esti n g  a n d  M o nit ori n g  R esist a n c e ............................................... 3 0  
5. 1 3.   
Pr e g n a n c y ................................................................................................................... 3 2  
6.   
R A N D O MI Z A TI O N .................................................................................................. 3 3  
7.   
D A T A  M A N A G E M E N T ........................................................................................... 3 3  
7. 1.   
El e ctr o ni c  D at a  E ntr y ................................................................................................. 3 3  
7. 2.   
Pr ot o c ol  D e vi ati o ns .................................................................................................... 3 4  
7. 3.   
D at a  Q u alit y  Ass ur a n c e .............................................................................................. 3 4  
8.   
S T A TI S TI C A L  C O N SI D E R A TI O N S ....................................................................... 3 5  
8. 1.   
S a m pl e  Si z e  C al c ul ati o ns ........................................................................................... 3 5  
8. 2.   
Effi c a c y  V ari a bl es ...................................................................................................... 3 6  
8. 3.   
R es p o ns e  D efi niti o ns .................................................................................................. 3 6  
8. 4.   
St atisti c al  M et h o d ol o g y .............................................................................................. 4 0  
8. 4. 1.   
Effi c a c y  A n al ys es ....................................................................................................... 4 0  
8. 4. 2.   
P o p ul ati o n  P h ar m a c o ki n eti cs  A n al ysis ....................................................................... 4 1  
8. 4. 3.   
S af et y  A n al ys es .......................................................................................................... 4 2  
9.   
I N V E S TI G A TI O N A L  P R O D U C T S .......................................................................... 4 2 
9. 1.   
Dr u g  R e gi m e ns,  A d mi nistr ati o n  a n d  D ur ati o n ........................................................... 4 2  
9. 2.   
I d e ntit y  of I n v esti g ati o n al  Pr o d u cts ............................................................................ 4 2 
9. 3.   
P a c k a gi n g  a n d  L a b eli n g .............................................................................................. 4 2  
9. 4.   
Dr u g  A c c o u nt a bilit y ................................................................................................... 4 3  
9. 5.   
S u bj e ct  C o m pli a n c e .................................................................................................... 4 3  
9. 6.   
Dis all o w e d  M e di c ati o n ............................................................................................... 4 3  
1 0.   
A D V E R S E  E V E N T S .................................................................................................. 4 3  
1 0. 1.   
D efi niti o ns .................................................................................................................. 4 4  
1 0. 2.   
Cli ni c al  A d v ers e  E v e nts ............................................................................................. 4 5  
1 0. 3.   
R e p orti n g  R e q uir e m e nt ............................................................................................... 4 5  
1 0. 4.   
M e di c ati o n  M o difi c ati o n/ Wit h dr a w al  D u e t o  a n  A d v ers e  E v e nt ............................... 4 6  
1 0. 5.   
M e di c ati o n  Err ors ....................................................................................................... 4 6  
1 1.   
DI S C O N TI N U A TI O N ............................................................................................... 4 6  
1 1. 1.   
St u d y  Dis c o nti n u ati o n ................................................................................................ 4 6  
1 1. 2.   
S u bj e ct  Dis c o nti n u ati o n .............................................................................................. 4 6  
1 2.   
E L E C T R O NI C  D A T A  C O L L E C TI O N ( E D C)  S Y S T E M ......................................... 4 7  


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  4  of  7 2 
C O N FI D E N TI A L 
1 3.   
R E T E N TI O N  O F  R E C O R D S .................................................................................... 4 7  
1 4.   
M O NI T O RI N G  T H E  S T U D Y ................................................................................... 4 7  
1 5.   
I N F O R M E D  C O N S E N T ............................................................................................ 4 8 
1 6.   
E T HI C S ...................................................................................................................... 4 8  
1 6. 1.   
St u d y- S p e cifi c  D esi g n  C o nsi d er ati o ns ....................................................................... 4 9  
1 6. 2.   
I n v esti g at or  R es p o nsi biliti es ....................................................................................... 4 9 
1 6. 3.   
I nstit uti o n al  R e vi e w  B o ar d (I R B) ............................................................................... 4 9 
1 6. 4.   
Pri v a c y  of  P ers o n al  D at a ............................................................................................ 5 0  
1 7.   
D A T A  C O N FI D E N TI A LI T Y,  DI S C L O S U R E  O F  D A T A,  A N D  P U B LI C A TI O N . 5 1  
1 8.   
D A T A  A N D  R E P O R T  R E Q UI R E M E N T S ............................................................... 5 1  
1 9.   
C O N T A C T I N F O R M A TI O N .................................................................................... 5 3  
2 0.   
LI S T  O F  R E F E R E N C E S ............................................................................................ 5 4  
2 1.   
A P P E N DI C E S ............................................................................................................ 5 7  
2 1. 1.   
A p p e n di x I:  St u d y  S c h e d ul e ....................................................................................... 5 8  
2 1. 2.   
A p p e n di x II:  T o xi cit y  Gr a di n g f or  A d v ers e  E v e nts ................................................... 5 9  
2 1. 3.   
A p p e n di x III:  List  of  Ess e nti al  D o c u m e nts f or t h e I n v esti g ati v e  Sit e ........................ 6 6  
2 1. 4.   
A p p e n di x I V:  Pr ot o c ol  R e visi o n  Hist or y ................................................................... 6 8  
2 1. 5.   
A p p e n di x  V:  D e cl ar ati o n  of  H elsi n ki ......................................................................... 7 2  
 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  5  of  7 2 
C O N FI D E N TI A L 
LI S T  O F  T A B L E S 
T a bl e  1:   
S u m m ar y  of  Ti z o x a ni d e  a n d  Ti z o x a ni d e  Gl u c ur o ni d e  P h ar m a c o ki n eti cs 
P ar a m et ers ................................................................................................................... 1 3  
T a bl e  2:   
S u m m ar y  of  Ti z o x a ni d e  a n d  Ti z o x a ni d e  Gl u c ur o ni d e  Tr o u g h  Pl as m a 
C o n c e ntr ati o ns ............................................................................................................ 1 3  
T a bl e  3:   
St u d y  R M 0 8- 3 0 0 1:  M e di a n (I Q R) ti m e ( hrs.) t o  all e vi ati o n  of  all s y m pt o ms f or 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n ......................................... 1 6  
T a bl e  4:   
St u d y  R M 0 8- 3 0 0 2:  M e di a n (I Q R) ti m e ( hrs.) t o  all e vi ati o n  of  all s y m pt o ms f or 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n ......................................... 1 7  
T a bl e  5:   
St u d y  R M 0 8- 3 0 0 2:  M e di a n (I Q R) ti m es ( hrs.) t o  all e vi ati o n  of  all s y m pt o ms f or 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n,  N T Z  vs.  pl a c e b o ............ 1 8  
T a bl e  6:   
St u d y  R M 0 8- 3 0 0 2:  M e di a n (I Q R) ti m es ( hrs.) t o  all e vi ati o n  of  all s y m pt o ms f or 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n ......................................... 1 8  
T a bl e  7:   
St u d y  R M 0 8- 3 0 0 2:  M e di a n (I Q R) ti m es ( hrs.) t o r et ur n t o  n or m al  a cti viti es f or 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n,  N T Z  vs.  pl a c e b o ............ 1 8  
T a bl e  8:   
St u d y  R M 0 8- 3 0 0 2:  M e di a n (I Q R) ti m es ( hrs.) t o r et ur n t o  n or m al  a cti viti es f or 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n ......................................... 1 9  
T a bl e  9:   
R M 0 8- 3 0 0 2:  M ost  c o m m o n  a d v ers e  e v e nts (r e p ort e d  b y  2 %  of s u bj e cts i n  a n y 
tr e at m e nt  gr o u p) r e g ar dl ess  of  c a us alit y ..................................................................... 1 9 
T a bl e  1 0:   Vir ol o g y t esti n g  of  n as o p h ar y n g e al s w a bs ................................................................. 3 1  
T a bl e  1 1:   St u d y  M e di c ati o n  L a b el .............................................................................................. 4 2  
T a bl e  1 2:   C o nt a ct I nf or m ati o n .................................................................................................... 5 3  
T a bl e  1 3:   S c h e d ul e  of  Ass ess m e nts ............................................................................................ 5 8  
T a bl e  1 4:   T a bl e f or  Cli ni c al  A b n or m aliti es:  Vit al  Si g ns ............................................................ 5 9  
T a bl e  1 5:   T a bl e f or  Cli ni c al  A b n or m aliti es:  S yst e mi c ( G e n er al) ............................................... 6 0  
T a bl e  1 6:   T a bl e f or  Cli ni c al  A b n or m aliti es:  S yst e mi c Ill n ess .................................................... 6 0  
T a bl e  1 7:   T a bl e f or  L a b or at or y  A b n or m aliti es:  S er u m .............................................................. 6 1  
T a bl e  1 8:   T a bl e f or  L a b or at or y  A b n or m aliti es:  H e m at ol o g y ..................................................... 6 4  
T a bl e  1 9:   T a bl e f or  L a b or at or y  A b n or m aliti es:  Uri n e ................................................................ 6 5  
T a bl e  2 0:   List  of  Ess e nti al  D o c u m e nts f or t h e I n v esti g ati v e  Sit e ............................................... 6 6  
T a bl e  2 1:   Pr ot o c ol  R e visi o n  Hist or y ........................................................................................... 6 8  
 
 




Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  7  of  7 2 
C O N FI D E N TI A L 
S Y N O P SI S  
Titl e:  
A   P h as e   3,    R a n d o mi z e d,    D o u bl e- Bli n d,   Pl a c e b o 
C o ntr oll e d  Tri al t o  E v al u at e t h e  Effi c a c y  a n d  S af et y  of 
Nit a z o x a ni d e   i n   t h e    Tr e at m e nt   of    C ol ds    D u e   t o 
E nt er o vir us/ R hi n o vir us  I nf e cti o n  
St u d y  N u m b e r:  
R M 0 8- 3 0 0 5 
I N D  N u m b e r: 
1 4 0, 4 4 5 
I n di c ati o n: 
Tr e at m e nt   of   c ol ds   d u e   t o  E nt er o vir us/ R hi n o vir us  
i nf e cti o n 
D esi g n:  
M ulti c e nt er,   r a n d o mi z e d,   d o u bl e- bli n d,   pl a c e b o-
c o ntr oll e d  tri al  t o   e v al u at e   effi c a c y   a n d   s af et y   of 
nit a z o x a ni d e  ( N T Z)  i n  t h e  tr e at m e nt  of  c ol ds  d u e  t o 
E nt er o vir us/ R hi n o vir us  i nf e cti o n 
N u m b e r  of  S u bj e cts:  
At l e ast  6 0 0 ( u p t o  m a xi m u m  of  7 0 0)  wit h  c ol ds  d u e t o 
l a b or at or y   
c o nfir m e d  
E nt er o vir us/ R hi n o vir us  
i nf e cti o n;  esti m at e d t o r e q uir e  u p t o  1, 7 5 0  s u bj e cts i n 
t ot al 
P o p ul ati o n:  
M al es  a n d f e m al es  ≥   1 2  y e ars  of  a g e  wit h  c ol ds  d u e t o 
E nt er o vir us/  R hi n o vir us  i nf e cti o n 
R a n d o mi z ati o n:  
1: 1  
St u d y  D os e  a n d  A d mi nist r ati o n:     
Gr o u p  1 ( N T Z):  T w o  N T Z  3 0 0  m g t a bl ets  or all y t wi c e 
d ail y ( b.i. d.) f or  5  d a ys. 
Gr o u p  2 ( Pl a c e b o):  T w o  pl a c e b o t a bl ets  or all y  b.i. d. f or 
5  d a ys.   
O bj e cti v e:  
E v al u at e t h e  eff e ct  of  N T Z  a d mi nist er e d  6 0 0  m g  or all y 
b.i. d. f or  5  d a ys i n r e d u ci n g t h e  d ur ati o n  of  s y m pt o ms 
c o m p ar e d t o t h at  of  a  pl a c e b o. 
P ri m a r y  Effi c a c y  P a r a m et e r:     
Ti m e  fr o m  first  d os e  t o  S y m pt o m   R es p o ns e  o v er  2 1 
d a ys   of   f oll o w   u p   b as e d   u p o n   t h e   F L U- P R O © 
i nstr u m e nt 
K e y  S e c o n d a r y  Effi c a c y  P a r a m et e r:     
Ti m e fr o m first  d os e t o  A bilit y t o  P erf or m  All  N or m al 
A cti viti es 
Ot h e r  S e c o n d a r y  Effi c a c y  P a r a m et e rs:    Pr o p orti o ns   of   s u bj e cts   e x p eri e n ci n g   o n e   or    m or e 
c o m pli c ati o ns  of  c ol ds  d u e t o  E nt er o vir us/ R hi n o vir us  
i nf e cti o n   i n cl u di n g   p n e u m o ni a,   otitis    m e di a, 
br o n c hitis,   si n usitis,   e x a c er b ati o ns   of   ast h m a   or 
C O P D,    w ors e ni n g  of  pr e- e xisti n g  h e alt h  c o n diti o ns, 
s e c o n d ar y i nf e cti o ns r e q uiri n g s yst e mi c  a nti bi oti c  us e, 
h os pit ali z ati o n  d u e  t o  c ol d  or  c o m pli c ati o ns  of  t h e 
c ol d,  a n d  d e at h  d u e t o  c o m pli c ati o ns  of t h e  c ol d 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  8  of  7 2 
C O N FI D E N TI A L 
S af et y  P a r a m et e rs:  
A d v ers e  e v e nts 
Bi ol o gi c al  S a m pl es:  
Bl o o d  s a m pl es    will  b e  c oll e ct e d  f or  all  s u bj e cts  at 
b as eli n e  a n d  D a y  7.  Uri n e s a m pl es  will  b e  c oll e ct e d  at 
b as eli n e  a n d    D a y  7.      N as o p h ar y n g e al  s w a bs    will  b e 
c oll e ct e d  at   b as eli n e,    D a ys   2,   3,   7  a n d   2 2  f or  all 
s u bj e cts.   A  bl o o d  s a m pl e  will  b e  c oll e ct e d  o n  D a y  3 
f or  p h ar m a c o ki n eti cs. 
St u d y  C e nt e rs:  
M ulti c e nt er  
T ri al  D u r ati o n:  
A u g ust  2 0 1 8  –  A pril  2 0 1 9 
 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  9  of  7 2 
C O N FI D E N TI A L 
1.   
I N T R O D U C TI O N 
1. 1.   E nt e r o vi r us es/ R hi n o v i r us es 
T h er e  ar e    m or e  t h a n  5 0 0    milli o n  n o n-i nfl u e n z a  vir al  r es pir at or y  i nf e cti o ns  or  “ c o m m o n 
c ol ds ”  e a c h  y e ar i n t h e  U nit e d  St at es,  wit h  a d ults  e x p eri e n ci n g  as  m a n y  as  2- 6 ill n ess es  p er 
y e ar  a n d  c hil dr e n  e x p eri e n ci n g  6- 8 ( F e n dri c k  et  al.  2 0 0 3 , T ur n er  1 9 9 7 , W orr all  2 0 1 1 ). 
C ol ds  h a v e  b e e n  r e p ort e d  t o  a c c o u nt  f or  as    m u c h  as  4 0 %  of  ti m e  l ost  fr o m   w or k  i n  t h e 
e m pl o y e d  p o p ul ati o n  a n d  3 0 %  of  s c h o ol  a bs e n c es ( Kir k p atri c k  1 9 9 6 ). I n  a  st u d y  c o n d u ct e d 
fr o m  N o v e m b er  of  2 0 0 0 t o  F e br u ar y  of  2 0 0 1, t h e t ot al  e c o n o mi c i m p a ct  of  n o n-i nfl u e n z a 
vir al r es pir at or y tr a ct i nf e cti o ns  w as  n e arl y  $ 4 0  billi o n ( F e n dri c k  et  al.  2 0 0 3 ).  A dj ust e d f or 
i nfl ati o n  ( F e br u ar y  2 0 0 1 t o  J a n u ar y  2 0 1 8), t h e  e c o n o mi c i m p a ct t o d a y  w o ul d  e x c e e d  $ 5 6 
billi o n ( U S D O L  B ur e a u  of  L a b or  St atisti cs  2 0 1 8 ). 
Fift y  ( 5 0)  t o  6 7 %  of  n o n-i nfl u e n z a  vir al  r es pir at or y  tr a ct  i nf e cti o ns  ar e  ass o ci at e d    wit h 
vir us es  fr o m  t h e   g e n us  E nt er o vir us  ( E V),    w hi c h   b el o n g  t o  t h e  Pi c or n a viri d a e   f a mil y 
(At ki ns o n  et  al.  2 0 1 6 ).  Wit hi n t h e  E V   g e n us, t h er e  ar e  pr es e ntl y  fift e e n  s p e ci es i n cl u di n g 
R hi n o vir us   A ,  R hi n o vir us   B ,  R hi n o vir us    C   a n d  E nt er o vir us   A   t hr o u g h  L  (T h e  Pir bri g ht 
I nstit ut e  2 0 1 8).   T h er e  ar e  h u n dr e ds  of   E V  s er ot y p es,  pr e v e nti n g  t h e  d e v el o p m e nt  of  a n 
eff e cti v e  v a c ci n e  or  pr o d u cti o n  of s uffi ci e nt i n di vi d u al i m m u nit y t o a v oi d  m ulti pl e i nf e cti o ns 
a n n u all y  ( J a c o bs  et  al.  2 0 1 3 ).    A  l ar g e    m aj orit y  of  r es pir at or y  tr a ct  i nf e cti o ns  c a us e d  b y 
vir us es  fr o m t h e  E nt er o vir us  g e n us  ar e  d u e t o  R hi n o vir us  s p e ci es,  a n d  R T- P C R  ass a ys  d o 
n ot  disti n g uis h  b et w e e n t h e  diff er e nt  s p e ci es  of  e nt er o vir us es.  T h er ef or e, i n t his  d o c u m e nt 
w e  will r ef er t o t h es e  vir us es  as  E nt er o vir us/ R hi n o vir us ( E V/ R V). 
E V/ R V   i nf e cti o n   h as   b e e n   d es cri b e d   as   a   “ c yt o ki n e   dis e as e ”   b e c a us e   i nf e cti o n   is 
c h ar a ct eri z e d   b y    m assi v e   u pr e g ul ati o n   of  I F N,  I L- 1,  I L- 6,  I L- 8,    T N F- α ,   gr a n ul o c yt e 
m a cr o p h a g e  c ol o n y-sti m ul ati n g  f a ct or  a n d    R A N T E S  ( At ki ns o n  et  al.   2 0 1 6 ).    C o m m o n 
s y m pt o ms  i n cl u d e  r hi n orr h e a,  n as al  c o n g esti o n,  s or e  t hr o at,  c o u g h,  h e a d a c h e,  f e v er,  a n d 
m al ais e.  A  n at ur al  hist or y  st u d y  of  E V/ R V i nf e cti o ns  d e m o nstr at e d t h at  p ati e nts  w er e  a bl e 
t o s elf- di a g n os e  a  c ol d i n l ess t h a n  a  d a y,  wit h  m ost  p ati e nts s elf- di a g n osi n g l ess t h a n  8  h o urs 
fr o m s y m pt o m  o ns et (Arr u d a  et  al.  1 9 9 7 ). 
C ol ds  d u e  t o    E V/ R V  i nf e cti o n  ar e  g e n er all y  c o nsi d er e d  s elf-li miti n g  a n d  d o  n ot  c a us e 
r es pir at or y  distr ess. Wit h   a d v a n c es i n  vir al  d et e cti o n  m et h o ds,  h o w e v er,  c ol ds  d u e t o  E V/ R V 
i nf e cti o n   h a v e   b e e n  li n k e d  t o   e x a c er b ati o ns   of    C O P D,   ast h m a   d e v el o p m e nt,   s e v er e 
br o n c hi olitis i n  p e di atri c  p ati e nts,  a n d f at al  p n e u m o ni a i n  el d erl y  a n d i m m u n o c o m pr o mis e d 
a d ults.    T h es e   s e v er e   o ut c o m es   ar e   i n   a d diti o n   t o   t h e    mil d er   c o m m o nl y   a c c e pt e d 
c o m pli c ati o ns  of t h e  c o m m o n  c ol d i n cl u di n g  s e c o n d ar y  otitis  m e di a,  si n usitis,  p n e u m o ni a, 
a n d, i n  p e di atri c  p ati e nts,  cr o u p  a n d  br o n c hi olitis ( J a c o bs  et  al.  2 0 1 3). 
B e c a us e t h er e  ar e  n o  F D A- a p pr o v e d  a nti vir al  dr u gs f or tr e at m e nt  of  c ol ds  d u e t o  E Vs, t h e 
st a n d ar d  of  c ar e  is  tr e at m e nt  of  s y m pt o ms    wit h  o v er-t h e- c o u nt er  ( O T C)  s y m pt o m  r eli ef 
m e di c ati o n i n cl u di n g  a nti hist a mi n es,  d e c o n g est a nts,  a n al g esi cs,  a ntit ussi v es,  N S AI Ds,  a n d 
c o m bi n ati o ns  t h er e of.    M ost  of  t h es e  tr e at m e nts  h a v e  n ot  s h o w n  cl e ar  b e n efit  ( All a n  a n d 
Arr oll  2 0 1 4 ).  A nti vir al  dr u gs t o  miti g at e t h e i m p a ct  of  E V/ R V i nf e cti o n ar e t h er ef or e  n e e d e d. 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
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1. 1. 1.   
A nti vi r als  St u di e d f o r  T r e at m e nt  of  C ol ds  D u e t o  E V/ R V I nf e cti o n 
I n t h e  p ast  2 5  y e ars,  o nl y t w o  a nti vir al  dr u gs f or t h e tr e at m e nt  of  c ol ds  d u e t o  E V/ R V 
i nf e cti o n  h a v e  b e e n  st u di e d i n  P h as e  2  or  3  cli ni c al tri als,  pl e c o n aril ( Vir o P h ar m a)  a n d 
v a p e n d a vir ( A vir a g e n).  
Pl e c o n aril 
Pl e c o n aril is  a  br o a d-s p e ctr u m  a nti- pi c or n a vir al  a g e nt t h at i nt e gr at es i nt o  h y dr o p h o bi c 
p o c k ets  wit hi n  V P 1  of t h e  c a psi d  of  pi c or n a vir us es.  T w o  P h as e  2  st u di es  of  pl e c o n aril 
c o n d u ct e d i n  1 9 9 8  a n d  1 9 9 9  e nr oll e d  ot h er wis e  h e alt h y  s u bj e cts  ≥ 1 4  y e ars  of  a g e  wit h 
m o d er at e  or s e v er e  a c ut e r es pir at or y ill n ess  wit hi n  3 6  h o urs  of s y m pt o m  o ns et.  S u bj e cts 
w er e  r e q uir e d  t o  gr a d e  s y m pt o ms  i n cl u di n g  r hi n orr h e a,  n as al  c o n g esti o n,  c o u g h,  s or e 
t hr o at,  m al ais e,  a n d  m y al gi a  as  a bs e nt,  mil d,  m o d er at e,  or  s e v er e  d ail y f or  2 1  d a ys.  T h e 
first  of  t h e  st u di es  ( n = 1 0 2 4,  4 1 %  pi c or n a vir us- p ositi v e)  e v al u at e d  ti m e  t o  c o m pl et e 
r es ol uti o n  of  s y m pt o ms,  d efi n e d  as  all  s y m pt o ms  gr a d e d  a bs e nt  f or  t w o  d a ys   wit h  n o 
s u bs e q u e nt r el a ps e.  T h e s e c o n d st u d y ( n = 8 7 5,  4 3 %  pi c or n a vir us- p ositi v e) e v al u at e d ti m e 
t o  all e vi ati o n  of  s y m pt o ms,  d efi n e d  as r hi n orr h e a  gr a d e d  a bs e nt  a n d  all  ot h er  s y m pt o ms 
gr a d e d  a bs e nt  or   mil d  f or  at  l e ast  4 8  h o urs.   N eit h er  st u d y  al o n e  a c hi e v e d  st atisti c all y 
si g nifi c a nt r es ults i n s pit e  of tr e n ds t o w ar d  effi c a c y,  b ut  pl e c o n aril-tr e at e d s u bj e cts  h a d  a 
1. 5  d a y ( 8. 5  vs.  1 0  d a ys)  m e di a n  b e n efit i n ti m e t o  all e vi ati o n  of  s y m pt o ms i n  a  p o ol e d 
a n al ysis  of t h e t w o st u di es ( P = 0. 0 2 9) ( H a y d e n  et  al.  2 0 0 2 ). 
B as e d  o n t h e  P h as e  2 st u di es, t w o  p ar all el  P h as e  3 st u di es  of  pl e c o n aril  w er e  d esi g n e d t o 
e v al u at e  effi c a c y  usi n g ti m e t o  all e vi ati o n  of s y m pt o ms  as  a  pri m ar y  e n d p oi nt.   S y m pt o m 
all e vi ati o n  w as  d efi n e d  as r hi n orr h e a  gr a d e d  a bs e nt  a n d t h e  ot h er fi v e s y m pt o ms  gr a d e d 
a bs e nt  or  mil d f or  4 8  h o urs  wit h o ut t h e  us e  of  s y m pt o m r eli ef  m e di c ati o n.   E nr oll m e nt 
w as  r estri ct e d  t o  s u bj e cts  pr es e nti n g  t o  t h e  cli ni c   wit hi n  2 4  h o urs  of  s y m pt o m  o ns et. 
Ot h er i m p ort a nt s u bj e ct s el e cti o n  crit eri a i n cl u d e d  ot h er wis e  h e alt h y s u bj e cts  at l e ast  1 8 
y e ars  of  a g e  wit h  m o d er at e t o s e v er e r hi n orr h e a  a n d  at l e ast  o n e  ot h er  m o d er at e  or s e v er e 
r es pir at or y s y m pt o m ( n as al  c o n g esti o n,  c o u g h,  or s or e t hr o at).  S u bj e cts  w er e  e x cl u d e d if 
t h e y  h a d f e v er, r e c e nt  hist or y  of  all er gi c r hi nitis, if t h e y  h a d r e c ei v e d  ast h m a tr e at m e nt 
wit hi n   t h e   pr e vi o us   t w o    m o nt hs,   or   if   t h e y   h a d   c hr o ni c   c o u g h,   a n y   k n o w n 
i m m u n o d efi ci e n c y,  or  a n y  u n d erl yi n g    m e di c al  c o n diti o n  t h at    w o ul d  c o nf o u n d  st u d y 
r es ults.   E nr oll m e nt    w as  str atifi e d  b as e d  o n  s m o ki n g  st at us  a n d  pr e-tr e at m e nt  us e  of 
s y m pt o m  r eli ef    m e di c ati o n,   a n d   s u bj e cts    w er e   all o w e d  t o  t a k e   a c et a mi n o p h e n   or 
d e xtr o m et h or p h a n  as  n e e d e d  f or  s y m pt o ms.   T h e  st u di es  w er e  c o n d u ct e d  fr o m  A u g ust 
t hr o u g h  N o v e m b er  2 0 0 0  a n d  e nr oll e d  a t ot al  of  2, 0 9 6  s u bj e cts i n cl u di n g  1, 3 6 3  ( 6 5 %) 
wit h l a b or at or y- c o nfir m e d  pi c or n a vir us i nf e cti o n.  Ti m e t o  all e vi ati o n  of  s y m pt o ms  w as 
si g nifi c a ntl y  s h ort er f or t h e  pl e c o n aril  gr o u p  c o m p ar e d t o  pl a c e b o i n  b ot h  st u di es,  wit h 
m e di a n tr e at m e nt  b e n efits  of  0. 6  d a ys ( 6. 6  c o m p ar e d t o  7. 2  d a ys,  P = 0. 0 3 7)  a n d  1. 5  d a ys 
( 6. 2  c o m p ar e d t o  7. 7  d a ys,  P = 0. 0 0 1)  s e p ar at el y  a n d  1. 0  d a ys ( 6. 3  c o m p ar e d t o  7. 3  d a ys, 
P < 0. 0 0 1) i n  a  p o ol e d  a n al ysis.  Pl e c o n aril-tr e at e d s u bj e cts  als o  h a d i m pr o v e m e nts i n ti m e 
t o r es ol uti o n  of i n di vi d u al s y m pt o ms  a n d ti m e t o s elf- ass ess e d  “ n o  c ol d ” st at us (H a y d e n 
et  al.  2 0 0 3 ).  S u bj e cts  w h o  us e d s y m pt o m r eli ef  m e di c ati o n  pri or t o  e nr oll m e nt  h a d l o n g er 
ti m es t o  all e vi ati o n  of  s y m pt o ms.  It is  u n cl e ar  w h et h er t h e  s y m pt o m  r eli ef  m e di c ati o n 
us e  w as t h e r es ult  of  m or e s e v er e s y m pt o ms  or if t h e  pr ol o n g e d s y m pt o ms  w er e t h e r es ult 


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of  s u p pr essi o n  of  c yt o ki n es  a n d  r es ulti n g  pr ol o n g e d  vir al  r e pli c ati o n  ( U S D H H S  F D A 
Di visi o n  of  A nti vir al  Dr u g  Pr o d u cts  2 0 0 3 ). 
V a p e n d a vir 
V a p e n d a vir is  a n  a nti vir al  c a psi d  bi n d er t h at  h as  b e e n st u di e d i n t w o  P h as e  2 st u di es f or 
t h e  tr e at m e nt  of  s y m pt o m ati c  h u m a n  r hi n o vir us  i nf e cti o n  i n  ast h m ati c  a d ults.    B ot h 
st u di es e nr oll e d s u bj e cts  wit h a  di a g n osis  of ast h m a a n d  pr es u m pti v e r hi n o vir us  q u alifi e d 
b y ( 1) r u n n y  n os e, s or e t hr o at,  a n d s cr at c h y t hr o at;  a n d ( 2)  a  mi ni m u m t ot al  W U R S S- 2 1 
s c or e  of  2 0;  or ( 3)  si g nifi c a nt f e v er.  T h e first  of t h e  st u di es  w as  c o n d u ct e d  A u g ust  2 0 1 0 
–  M ar c h  2 0 1 2  a n d  e nr oll e d  3 0 0  s u bj e cts i n cl u di n g  9 2 r hi n o vir us- i nf e ct e d.  T h e  pri m ar y 
e n d p oi nt    w as    A N C O V A  d ail y  c h a n g e  i n    W U R S S- 2 1  s e v erit y  s c or e  o v er  d a ys  2- 4. 
Tr e at m e nt  wit h  v a p e n d a vir r es ult e d i n a st atisti c all y si g nifi c a nt r e d u cti o n  of t h e  W U R S S-
2 1 s e v erit y s c or e i n t h e  pri m ar y  a n al ysis ( P = 0. 0 2 0) ( Cli ni c altri als. g o v  2 0 1 8 a ). 
T h e s e c o n d  P h as e  2 st u d y  of  v a p e n d a vir f urt h er r estri ct e d  eli gi bl e s u bj e cts t o t h os e  wit h 
m o d er at e t o  s e v er e  ast h m a  w h o  w er e  wit hi n  4 8  h o urs  of  s y m pt o m  o ns et.  T h e  pri m ar y 
e n d p oi nt  of t h e st u d y  w as  c o m p aris o n  of t w o  d os es  of  v a p e n d a vir t o  pl a c e b o  usi n g l e ast 
s q u ar es  m e a n  c h a n g e i n  A C Q- 6 t ot al  s c or e fr o m  b as eli n e t o  D a y  1 4 ( Cli ni c altri als. g o v 
2 0 1 8 b ).   T h e  st u d y  e nr oll e d  4 5 5  s u bj e cts  i n cl u di n g  1 6 8   wit h  r hi n o vir us  i nf e cti o n.   T h e 
st u d y  di d  n ot  d e m o nstr at e  a st atisti c all y si g nifi c a nt i m pr o v e m e nt  c o m p ar e d t o  pl a c e b o i n 
t h e  pri m ar y  a n al ysis,  b ut  v a p e n d a vir  t h er a p y    w as  r e p ort e d  t o  s h o w  “ e vi d e n c e  of  a n 
a nti vir al  eff e ct ” i n  s u bj e cts  w h o r e c ei v e d t h e  dr u g  wit hi n  2 4  h o urs  aft er  s y m pt o m  o ns et 
(G e n eti c  E n gi n e eri n g  &  Bi ot e c h n ol o g y  N e ws  2 0 1 7 ). 
1. 2.   Nit a z o x a ni d e ( N T Z) 
N T Z i s  a t hi a z oli d e  a nti-i nf e cti v e  wit h  i n  vitr o  a cti vit y  a g ai nst  p ar asit es,  a n a er o bi c  b a ct eri a, 
a n d  vir us es ( A n d ers o n  a n d  C urr a n  2 0 0 7). 
Ali ni a ®  ( N T Z)  f or   Or al  S us p e nsi o n  ( p ati e nts  1  y e ar  of  a g e  a n d  ol d er)  a n d   Ali ni a  ( N T Z) 
T a bl ets ( p ati e nts  1 2  y e ars  a n d  ol d er)  ar e  m ar k et e d i n t h e  U nit e d  St at es f or t h e tr e at m e nt  of 
di arr h e a  c a us e d  b y  Gi ar di a l a m bli a   or Cr y pt os p ori di u m  p ar v u m .   Ali ni a f or  Or al  S us p e nsi o n 
a n d  Ali ni a  T a bl ets  h a v e  n ot  b e e n s h o w n t o  b e s u p eri or t o  pl a c e b o f or t h e tr e at m e nt  of  di arr h e a 
c a us e d  b y  Cr y pt os p ori di u m  p ar v u m   i n   HI V-i nf e ct e d  or  i m m u n o d efi ci e nt  p ati e nts  (Ali ni a 
pr es cri bi n g i nf or m ati o n  2 0 1 7 ). 
1. 2. 1.   
N T Z I n hi bits  Vi r al  R e pli c ati o n  a n d  C yt o ki n e  S e c r eti o n 
Ti z o x a ni d e, t h e  a cti v e  m et a b olit e  of  N T Z,  h as  b e e n s h o w n t o  p oss ess  a nti vir al  a cti vit y i n 
c ell  c ult ur e  a g ai nst  a  br o a d  r a n g e  of  vir us es  i n cl u di n g  i nfl u e n z a    A  a n d    B  vir us es, 
p ar ai nfl u e n z a ( S e n d ai)  vir us, r es pir at or y  s y n c yti al  vir us ( R S V)  A- 2,  c a ni n e  c or o n a vir us 
S- 3 7 8, r ot a vir us,  n or o vir us,  h e p atitis  C  vir us  g e n ot y p es  1 a  a n d  1 b, J a p a n es e  e n c e p h alitis 
vir us,   d e n g u e   f e v er   vir us- 2,   y ell o w   f e v er   vir us,   h e p atitis    B   vir us,   a n d   h u m a n 
i m m u n o d efi ci e n c y  vir us ( HI V) (R ossi g n ol  2 0 1 4 ).  T h e  wi d e s p e ctr u m  of a nti vir al a cti vit y 
s u g g ests  a  c ell- m e di at e d  eff e ct r at h er t h a n  a s p e cifi c  vir al t ar g et. 
L a b or at or y  st u di es  t o  e v al u at e  t h e   p ot e nti al  f or  r esist a n c e   of  i nfl u e n z a    A   vir us  t o 
ti z o x a ni d e  h a v e  b e e n  u n a bl e t o  s el e ct f or r esist a nt  vir us ( R o m ar k  St u d y  R e p ort  R M 0 1-
0 4 1 7,  d at a  o n fil e).   T h es e st u di es s u g g est  a l o w  p ot e nti al f or r esist a n c e. 


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N o v e m b er  2 9,  2 0 1 8 
 
P a g e  1 2  of  7 2 
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E x p eri m e nts i n  H e L a  R 1 9  c ells  h a v e  s h o w n t h at  N T Z i n hi bits r e pli c ati o n  of  R hi n o vir us 
A  s er ot y p es  2  a n d  1 6  wit h  E C 5 0s  of  a p pr o xi m at el y  1 t o  5  µ M.   St u di es i n  P B M Cs  h a v e 
als o  s h o w n t h at ti z o x a ni d e  s u p pr ess es  s e cr eti o n  of  pr o-i nfl a m m at or y  c yt o ki n es t h at  ar e 
u pr e g ul at e d  b y  E V/ R V i nf e cti o n.   C o n c e ntr ati o ns r e q uir e d t o s u p pr ess c yt o ki n e s e cr eti o n 
b y  5 0 % f or I L- 2, I L- 4, I L- 5, I L- 6, I L- 8, I L- 1 0  a n d  T N F- α  r a n g e d fr o m  2. 0 t o  9. 8 µ M.  
( R o m ar k,  d at a  o n fil e)   Nit a z o x a ni d e  h as  als o  b e e n s h o w n t o s u p pr ess I L- 6  pr o d u cti o n i n 
T G -i nj e ct e d  mi c e (H o n g  et  al.  2 0 1 2 ). 
O n g oi n g st u di es  of t h e  m e c h a nis m  of a cti o n  of  N T Z  h a v e s h o w n t h at  N T Z a n d ti z o x a ni d e 
m o d ul at e  mit o c h o n dri al f u n cti o n  b y  u n c o u pli n g  o xi d ati v e  p h os p h or yl ati o n.   St u di es  h a v e 
s h o w n  t h at  ti z o x a ni d e  d e cr e as es  c ell ul ar   A T P  i n  a  d os e- d e p e n d e nt   m a n n er  i n    M D C K 
c ells  a n d i n  M D C K  c ells i nf e ct e d  wit h i nfl u e n z a  vir us es.   M a xi m u m i n hi biti o n  of  A T P 
i n  i nfl u e n z a-i nf e ct e d  or  u ni nf e ct e d    M D C K  c ells  r e a c h es  u p  t o  4 5 %  aft er  2 4  h o urs  of 
e x p os ur e t o  1 0 0  µ M ti z o x a ni d e.  I n t h es e  e x p eri m e nts,  a  1 0 % r e d u cti o n  of  A T P  a c hi e v e d 
b y  a d di n g l ess t h a n  1 0  µ M ti z o x a ni d e is  s uffi ci e nt t o i n hi bit i nfl u e n z a  vir us r e pli c ati o n 
b y  a p pr o xi m at el y  9 0 %.   T h e  d e cr e as e i n  c ell ul ar  A T P  d o es  n ot  aff e ct  c ell  vi a bilit y  a n d is 
r e v ersi bl e  aft er  eli mi n ati n g ti z o x a ni d e fr o m t h e  c ult ur e. ( R o m ar k,  d at a  o n fil e)   St u di es 
of  a  n u m b er  of  diff er e nt  vir us es  h a v e  s h o w n  t h at  vir al  r e pli c ati o n  is    A T P- d e p e n d e nt 
(Br a a k m a n  et  al.  1 9 9 2 , Br a a k m a n  et  al.  1 9 9 1 , D o ms  et  al.  1 9 8 7 , C h a n g  et  al.  2 0 0 9 , 
Mi r a zi mi  a n d  S v e nss o n  2 0 0 0). I n  a d diti o n, i n hi biti o n  of  A T P  a n d its  d o w nstr e a m  eff e ct 
o n    A M P- a cti v at e d   pr ot ei n   ki n as e  ( A M P K)  a cti v ati o n   h as   b e e n  s h o w n  t o  s u p pr ess 
s e cr eti o n  of  pr o-i nfl a m m at or y  c yt o ki n es  ( L e e  et  al.  2 0 1 7 , S a g  et  al.  2 0 0 8 , W a n g  et  al. 
2 0 0 3 ). 
T h e  a cti vit y  of  N T Z i n i n hi biti n g r e pli c ati o n  of  a  br o a d r a n g e  of r es pir at or y  vir us es  as 
w ell  as  s e cr eti o n  of  pr o-i nfl a m m at or y  c yt o ki n es  u pr e g ul at e d  d uri n g  r es pir at or y  vir us 
i nf e cti o n  h as  pr o m pt e d  cli ni c al  d e v el o p m e nt  of  N T Z  as  a tr e at m e nt  of  c ol ds  a n d fl u  d u e 
t o i nfl u e n z a  A  a n d  B  vir us es  a n d  e nt er o vir us es. 
1. 2. 2.   
P h a r m a c o ki n eti cs  of  N T Z i n  H u m a ns 
N T Z is  n ot  d et e ct a bl e i n t h e  pl as m a f oll o wi n g  or al  a d mi nistr ati o n  of t h e  dr u g.   T h e  m ai n 
m et a b olit es  of  N T Z i n  h u m a ns  ar e ti z o x a ni d e  a n d ti z o x a ni d e  gl u c ur o ni d e.   Ti z o x a ni d e is 
hi g hl y  b o u n d t o  pl as m a  pr ot ei ns ( > 9 9 %).   T h e  a bs or pti o n  of  N T Z i n i m m e di at e r el e as e 
t a bl ets is si g nifi c a ntl y e n h a n c e d ( Cm a x  a n d  A U C  of ti z o x a ni d e a n d ti z o x a ni d e  gl u c ur o ni d e 
i n  pl as m a  ar e  m or e t h a n  d o u bl e d)  w h e n it is  a d mi nist er e d  wit h  f o o d.  I n  f ast e d  h u m a n 
v ol u nt e ers r e c ei vi n g  a  si n gl e  5 0 0  m g  d os e  of 1 4C  N T Z,  a p pr o xi m at el y  o n e-t hir d  of t h e 
d os e  w as  e x cr et e d i n  uri n e  as ti z o x a ni d e  a n d ti z o x a ni d e  gl u c ur o ni d e,  a n d t w o-t hir ds  w as 
e x cr et e d  i n  f e c es   as  ti z o x a ni d e.      N o   ot h er   si g nifi c a nt    m et a b olit es    w er e   d et e ct e d. 
(I n v esti g at ors  Br o c h ur e f or  N T Z  3 0 0  m g  T a bl ets, J ul y  2 0 1 8) 
T h e  p h ar m a c o ki n eti cs  of  ti z o x a ni d e  a n d  ti z o x a ni d e  gl u c ur o ni d e  d uri n g  r e p e at e d  or al 
d osi n g  of  nit a z o x a ni d e  ( N T Z)  3 0 0    m g  e xt e n d e d  r el e as e  t a bl ets  a d mi nist er e d  6 0 0    m g 
t wi c e  d ail y  wit h f o o d  w er e e v al u at e d i n  h e alt h y  v ol u nt e ers.  T w el v e ( 1 2) s u bj e cts r e c ei v e d 
t w o    N T Z   c o ntr oll e d   r el e as e   t a bl ets   t wi c e   d ail y    wit h   f o o d   f or   7   d a ys.    T h e 
p h ar m a c o ki n eti cs  w er e st u di e d i n  pl as m a  u p t o  1 2  h o urs  p ost- d os e aft er t h e  m or ni n g  d os e 
o n  D a y  1  a n d  D a y  7,  a n d  b ef or e t h e  m or ni n g  d os e  o n  D a y  2- 6.  B as e d  o n  mi x e d  eff e ct 
a n al ysis  of  v ari a n c e,  t h e  st e a d y  st at e  ti z o x a ni d e  a n d  ti z o x a ni d e  gl u c ur o ni d e  pl as m a 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  1 3  of  7 2 
C O N FI D E N TI A L 
c o n c e ntr ati o ns  w as  r e a c h e d  b y  D a y  2,  aft er  o n e  d a y  of tr e at m e nt  wit h  N T Z  at  6 0 0  m g 
b.i. d.  T h e  m ai n  p h ar m a c o ki n eti cs  p ar a m et ers  of ti z o x a ni d e  a n d ti z o x a ni d e  gl u c ur o ni d e 
ar e s u m m ari z e d i n t h e t a bl e  b el o w: 
T a bl e  1:   S u m m a r y  of  Ti z o x a ni d e  a n d  Ti z o x a ni d e  Gl u c u r o ni d e  P h a r m a c o ki n eti cs 
P a r a m et e rs 
P K  P a r a m et e r ( u nit)  
Ti z o x a ni d e  
Ti z o x a ni d e  Gl u c u r o ni d e  
 
D a y  1  
N = 1 2  
D a y  7  
N = 1 2  
D a y  1  
N = 1 2  
D a y  7  
N = 1 2  
C m a x  (µ g/ m L)  
5. 2 3  ±  2. 7 1  
8. 1 6  ±  4. 1 6   
4. 8 8  ± 1. 7 2   
8. 9 6  ± 3. 4 8  
tm a x  ( h) 
6. 0 0 ( 4. 0 0 -9. 0 0)   
5. 0 0 ( 3. 0 0 -8. 0 0)   
6. 0 0 ( 5. 0 0 -1 1. 0 0)   5. 5 0 ( 0. 0 0- 7. 0 2)  
tl a g ( h) 
0. 0 0 ( 0. 0 0 -2. 0 0)   
0. 0 0 ( 0. 0 0 -0. 0 0)   
0. 5 0 ( 0. 0 0 -2. 0 0)   
0. 0 0 ( 0. 0 0 -0. 0 0)  
A U C 0- t (µ g. h/ m L)   
2 6. 9   ±  1 6. 1   
5 2. 5  ±  3 3. 7   
2 9. 5   ±  1 2. 1   
7 5. 0  ±  3 7. 8  
A U C 0-  Τ  (µ g. h/ m L)   
2 8. 6   ±  1 6. 3 a  
4 8. 3  ±  3 1. 9 b  
3 0. 5   ±  1 2. 2 c  
7 5. 2  ±  3 7. 9  
C  Τ  (µ g/ m L)  
0. 7 0 9  ±  0. 9 8 7   
1. 7 2  ±  2. 0 4   
1. 3 9  ±  0. 8 4 6   
3. 8 9  ±  2. 8 8  
A U C 0- ∞  (µ g. h/ m L)   
2 7. 8  ±  1 7. 8 b  
5 2. 3  ±  3 5. 6 b  
3 5. 3  ±  1 6. 5 d  
6 2. 1  ±  2 4. 2 e 
t1/ 2 ( h) 
1. 6 6  ±  0. 4 0 8 b  
2. 1 9  ±  0. 4 8 5 b  
2. 7 0  ±  0. 8 4 8 c  
4. 9 9  ±  5. 2 0  
λ z ( 1/ h) 
0. 4 4 1  ±  0. 1 0 6 b  
0. 3 3 1  ±  0. 0 7 3 3 b  
0. 2 8 2  ±  0. 0 9 0 2 c  
0. 2 0 1  ±  0. 0 8 1 3  
C a v g (µ g/ m L)  
N A   
4. 0 2  ±  2. 6 6 b  
N A   
6. 2 7  ±  3. 1 6  
C mi n  (µ g/ m L)  
N A   
1. 5 0  ±  1. 8 3   
N A   
3. 6 3  ±  3. 0 0  
P T F ( %)  
N A   
1 9 3  ±  3 9. 1 b  
N A   
1 0 1  ±  4 0. 7  
S wi n g ( %)  
N A   
1 0 3 9  ±  6 5 6   
N A  
2 6 8  ±  1 9 4  
V al u es  ar e  arit h m eti c  m e a n  ±  S D,  e x c e pt  m e di a n (r a n g e) f or t m a x  a n d t l a g 
N  =  n u m b er  of s u bj e cts  wit h  d at a;  N A  =  n ot  a p pli c a bl e  
a N = 1 0; b N = 1 1; c N = 1 1; d N = 8; e N = 7  
 
T a bl e  2:   S u m m a r y  of  Ti z o x a ni d e  a n d  Ti z o x a ni d e  Gl u c u r o ni d e  T r o u g h  Pl as m a 
C o n c e nt r ati o ns 
P K  P a r a m et e r ( u nit)  
T r o u g h  C o n c e nt r ati o ns ( µ g/ m L  
M e a n ( C V %)  
D os e  G r o u p  
Nit a z o x a ni d e  
D a y  
 
1 ( a)   
2  
3  
4  
5  
6  
7 ( b)  
Ti z o x a ni d e  
0. 7 0 9  
( 1 3 9) 
1. 5 5  
( 1 0 0) 
2. 3 6  
( 1 0 1) 
3. 2 4  
( 9 9. 7) 
3. 8 0  
( 1 4 6) 
3. 2 6  
( 1 1 9) 
3. 0 2  
( 9 8. 6) 
Ti z o x a ni d e 
Gl u c ur o ni d e  
1. 3 9  
( 6 1. 0) 
3. 6 8  
( 7 2. 3) 
4. 3 8  
( 7 2. 8) 
5. 3 5  
( 7 7. 2) 
5. 8 3  
( 9 8. 8) 
5. 9 4  
( 9 1. 2) 
5. 6 5  
( 6 8. 7) 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  1 4  of  7 2 
C O N FI D E N TI A L 
1. 2. 3.   
P h as e  2  Cli ni c al  T ri als  of  N T Z i n  S u bj e cts  wit h I nfl u e n z a-li k e Ill n ess:  St u di es 
R M 0 2- 2 0 2 2  a n d  R M 0 1- 2 0 2 1 
T w o  r a n d o mi z e d,  d o u bl e- bli n d,  pl a c e b o  c o ntr oll e d  cli ni c al  tri als    w er e  c o n d u ct e d  i n 
s u bj e cts  wit h s y m pt o ms  of  vir al r es pir at or y i nf e cti o n ( V RI) i n  C aj a m ar c a,  P er u.  F or t h es e 
st u di es,  s u bj e cts  w er e  e nr oll e d  b as e d  u p o n  s y m pt o ms  wit h  v er y li mit e d  vir ol o g y t esti n g 
b ei n g  c o n d u ct e d  b y r a pi d  dir e ct i m m u n ofl u or es c e n c e  ass a y.   
St u d y  R M 0 2- 2 0 2 2:   O n e- h u n dr e d ( 1 0 0) c hil dr e n a g e d  1 2  m o nt hs t hr o u g h  1 1  y e ars  of a g e 
wit h  f e v er,  at  l e ast  o n e  r es pir at or y  s y m pt o m  ( c o u g h,  n as al  dis c h ar g e  or  c o n g esti o n, 
s n e e zi n g  or  s or e  t hr o at)  a n d  at  l e ast  o n e  c o nstit uti o n al  s y m pt o m  ( m y al gi a,    m al ais e, 
f ati g u e,  h e a d a c h e, c hills/s w e at)  of l ess t h a n  7 2  h o urs  d ur ati o n  w er e r a n d o mi z e d t o r e c ei v e 
N T Z  1 0 0  m g/ 5  m L  s us p e nsi o n  or  a  m at c hi n g  pl a c e b o  s us p e nsi o n  b.i. d. f or  5  d a ys.   T h e 
d os e  of t h e s us p e nsi o n  w as  5  m L f or  c hil dr e n  a g e d  1 2 t hr o u g h  4 7  m o nt hs  a n d  1 0  m L f or 
c hil dr e n  a g e d  4 8    m o nt hs  t hr o u g h  1 1  y e ars.     A  n as o p h ar y n g e al  s w a b   w as  o bt ai n e d  at 
b as eli n e a n d s u bj e ct e d t o r a pi d  dir e ct i m m u n ofl u or es c e n c e ass a y f or r es pir at or y s y n c yti al 
vir us ( R S V), i nfl u e n z a  A, i nfl u e n z a  B,  p ar ai nfl u e n z a  1,  2 a n d  3, a n d a d e n o vir us.   P h ysi c al 
e x a mi n ati o ns  w er e  p erf or m e d  at  b as eli n e  a n d  o n  st u d y  D a y  7.   S u bj e cts  or t h eir  p ar e nts 
or  g u ar di a ns  m ai nt ai n e d  a  d ail y  di ar y t o r e c or d  a d mi nistr ati o n  of  st u d y  m e di c ati o n  a n d 
a d v ers e  e v e nts  a n d t o  gr a d e  e a c h  of t h eir  s y m pt o ms  o n  a  4- p oi nt  s c al e:  0 =  a bs e nt,  1 = 
mil d,  2 =    m o d er at e,  3 =  s e v er e.      A  st u d y  n urs e  visit e d  e a c h  s u bj e ct  d ail y  d uri n g  t h e 
tr e at m e nt  p eri o d t o  e ns ur e  c o m pli a n c e  wit h t h e st u d y  a n d t o  c oll e ct  pl asti c  zi p p er st or a g e 
b a gs  c o nt ai ni n g tiss u e  us e d  d uri n g t h e  pr e c e di n g  d a y.   T h e  pri m ar y  e n d p oi nt  of t h e st u d y 
w as  ti m e  fr o m  first  d os e  t o  all e vi ati o n  of  s y m pt o ms  ( all  s y m pt o ms  a bs e nt  or    mil d) 
c o m p ar e d  usi n g  a  s ur vi v al  a n al ysis (l o g r a n k t est).   T h e  m e di a n ti m es fr o m first  d os e t o 
all e vi ati o n  of s y m pt o ms  w er e  4  d a ys (I Q R  2- 7) f or t h e  N T Z tr e at m e nt  gr o u p  a n d  > 7  d a ys 
(I Q R  3-  > 7) f or t h e  pl a c e b o  gr o u p ( P < 0. 0 0 1, l o g r a n k t est).   T his  a n al ysis  w as s u p p ort e d 
b y  s e c o n d ar y  a n al ys es.   S u bj e cts r a n d o mi z e d t o t h e  pl a c e b o tr e at m e nt  gr o u p  w er e  m or e 
li k el y t o  h a v e  at l e ast  o n e ill n ess-r el at e d  p h ysi c al  e x a m  a b n or m alit y  at  D a y  7 f oll o w  u p 
( 8 1 %  vs.  2 8 %,  P < 0. 0 0 0 1),  a n d t h e y  w er e  m or e li k el y t o r e q uir e  a nti bi oti c tr e at m e nt  at 
t h e  D a y  7 f oll o w  u p ( 6 4 %  vs.  9 %,  P < 0. 0 0 0 1) t h a n s u bj e cts tr e at e d  wit h  N T Z.   T h e  m ost 
c o m m o n  ill n ess-r el at e d   p h ysi c al  e x a m  fi n di n gs  at  t h e    D a y   7  f oll o w- u p   visit    w er e 
er yt h e m at o us  or o p h ar y n x ( 7 2 %  vs.  2 0 %,  P < 0. 0 0 0 1),  h y p ertr o p hi c t o nsils ( 7 4 %  vs.  1 7 %, 
P < 0. 0 0 0 1),  n as al  c o n g esti o n ( 4 9 %  vs.  9 %,  P < 0. 0 0 0 1), r o n c hi ( 4 0 %  vs.  7 %,  P = 0. 0 0 0 6) 
a n d  a d e n o m e g al y  ( 2 6 %  vs.  7 %,  P = 0. 0 2).   Tr e at m e nt  wit h  N T Z  w as  ass o ci at e d  wit h  a 
si g nifi c a nt  d e cli n e  i n    w ei g ht  of  d ail y  tiss u e  c oll e cti o ns  d uri n g  t h e  tr e at m e nt  p eri o d 
( P = 0. 0 3 4 7).      B y  r a pi d   dir e ct  i m m u n ofl u or es c e n c e   ass a y,  r es pir at or y   vir us es    w er e 
i d e ntifi e d i n  1 7 %  of t h e s u bj e cts,  1 2 s u bj e cts  wit h  a d e n o vir us,  2  wit h i nfl u e n z a  A,  2  wit h 
p ar ai nfl u e n z a  1,  a n d  1  wit h  R S V.   T h e s m all  n u m b er  of s u bj e cts  wit h i d e ntifi e d  V RI  di d 
n ot  all o w f or  a n al ys es f or  s u bs ets  wit h  s p e cifi c  V RIs.  N ot a bl y, t h e r a pi d  ass a y  di d  n ot 
i n cl u d e  a t est f or  E V/ R V.   Gi v e n t h at  E V/ R Vs  ar e t h e  m ost  c o m m o n  c a us e  of  V RIs, it is 
li k el y t h at  m ost  of t h e s u bj e cts  w er e i nf e ct e d  wit h  E V/ R V.  T h er e  w er e  n o s eri o us a d v ers e 
e v e nts.   All  a d v ers e  e v e nts  w er e  mil d t o  m o d er at e i n s e v erit y.   T h e  n at ur e  a n d fr e q u e n c y 
of  a d v ers e  e v e nts r e p ort e d  b y s u bj e cts i n t h e  a cti v e  a n d  pl a c e b o  gr o u ps  w er e si mil ar, t h e 
o nl y  e x c e pti o n  b ei n g  a  hi g h er i n ci d e n c e  of  c hr o m at uri a ( y ell o w  dis c ol or ati o n  of  uri n e), 
w hi c h  w as  r e p ort e d  b y  6 4 %  of  s u bj e cts i n t h e  N T Z  gr o u p  a n d  2 8 %  of  s u bj e cts i n t h e 
pl a c e b o  gr o u p ( P = 0. 0 0 0 6). 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  1 5  of  7 2 
C O N FI D E N TI A L 
St u d y  R M 0 1- 2 0 2 1:  I n  a s e c o n d  cli ni c al tri al,  8 6  a d ults  a n d  a d ol es c e nts ≥ 1 2  y e ars  of  a g e 
wit h  f e v er,  at  l e ast  o n e  r es pir at or y  s y m pt o m  ( c o u g h,  n as al  dis c h ar g e  or  c o n g esti o n, 
s n e e zi n g  or  s or e  t hr o at)  a n d  at  l e ast  o n e  c o nstit uti o n al  s y m pt o m  ( m y al gi a,    m al ais e, 
f ati g u e,  h e a d a c h e, c hills/s w e at)  of l ess t h a n  7 2  h o urs  d ur ati o n  w er e r a n d o mi z e d t o r e c ei v e 
N T Z  5 0 0  m g t a bl ets  or  a  pl a c e b o  b.i. d. f or  5  d a ys.   A  n as o p h ar y n g e al s w a b  w as  o bt ai n e d 
at  b as eli n e  a n d  s u bj e ct e d  t o  r a pi d  dir e ct  i m m u n ofl u or es c e n c e  ass a y  f or  r es pir at or y 
s y n c yti al  vir us ( R S V), i nfl u e n z a  A, i nfl u e n z a  B,  p ar ai nfl u e n z a  1,  2 a n d  3, a n d a d e n o vir us.  
P h ysi c al  e x a mi n ati o ns    w er e  p erf or m e d  at  b as eli n e  a n d  o n  st u d y    D a y  7.     S u bj e cts 
m ai nt ai n e d  a  d ail y  di ar y t o r e c or d  a d mi nistr ati o n  of st u d y  m e di c ati o n  a n d  a d v ers e  e v e nts 
a n d t o  gr a d e  e a c h  of t h eir s y m pt o ms  o n  a  4- p oi nt s c al e:  0 =  a bs e nt,  1 =  mil d,  2 =  m o d er at e, 
3 = s e v er e.   A st u d y  n urs e  visit e d  e a c h s u bj e ct  d ail y  d uri n g t h e tr e at m e nt  p eri o d t o  e ns ur e 
c o m pli a n c e   wit h  t h e  st u d y  a n d  t o  c oll e ct  pl asti c  zi p p er  st or a g e  b a gs  c o nt ai ni n g  tiss u e 
us e d  d uri n g t h e  pr e c e di n g  d a y.   T h e  pri m ar y  e n d p oi nt  of t h e  st u d y  w as ti m e fr o m first 
d os e t o  all e vi ati o n  of s y m pt o ms ( all s y m pt o ms  a bs e nt  or  mil d)  c o m p ar e d  usi n g  a s ur vi v al 
a n al ysis (l o g r a n k t est).   T h e  m e di a n ti m e fr o m first  d os e t o  all e vi ati o n  of  V RI s y m pt o ms 
w as  4  d a ys (I Q R  3- 5) f or t h e  N T Z tr e at m e nt  gr o u p  a n d  7  d a ys (I Q R  3- > 7) f or t h e  pl a c e b o 
gr o u p  ( P = 0. 0 3 6 5,  l o g  r a n k  t est).     T his  a n al ysis   w as  s u p p ort e d  b y  s e c o n d ar y  effi c a c y 
a n al ys es.   S u bj e cts r a n d o mi z e d t o t h e  pl a c e b o tr e at m e nt  gr o u p  w er e  m or e li k el y t o  h a v e 
at l e ast  o n e ill n ess-r el at e d  p h ysi c al  e x a m  a b n or m alit y  at t h e  D a y  7 f oll o w  u p ( 7 1 %  vs. 
3 7 %,  P = 0. 0 0 3 2),  a n d t h e y  w er e  m or e li k el y t o r e q uir e  a nti bi oti c tr e at m e nt  at t h e  D a y  7 
f oll o w  u p ( 3 6 %  vs.  1 8 %,  P = 0. 1 3 2) t h a n  s u bj e cts tr e at e d  wit h  N T Z.   T h e  m ost  c o m m o n 
ill n ess-r el at e d  p h ysi c al  e x a m  fi n di n gs  at t h e  D a y  7  f oll o w  u p  visit  w er e  er yt h e m at o us 
or o p h ar y n x  ( 6 9 %  vs.  2 6 %,  P < 0. 0 0 1)  a n d  h y p ertr o p hi c t o nsils  ( 5 0 %  vs.  2 1 %,  P = 0. 0 1).  
T h e  m e a n  w ei g ht  of tiss u e c oll e ct e d  o v er t h e tr e at m e nt  p eri o d  w as als o  hi g h er f or s u bj e cts 
i n t h e  pl a c e b o  gr o u p t h a n f or  s u bj e cts tr e at e d  wit h  N T Z ( 1 4. 2 3  gr a ms  vs.  1 0. 5 8  gr a ms, 
P = 0. 2 0),  wit h t h e  diff er e n c e  arisi n g  pri m aril y  d uri n g t h e  first t w o t o t hr e e  d a ys  of t h e 
st u d y.   B y r a pi d  dir e ct i m m u n ofl u or es c e n c e  ass a y, r es pir at or y  vir us es  w er e i d e ntifi e d i n 
1 2 %  of t h e  s u bj e cts,  4  s u bj e cts  wit h  a d e n o vir us,  5  wit h  R S V  a n d  1  wit h i nfl u e n z a  A. 
N ot a bl y, t h e r a pi d  ass a y  di d  n ot i n cl u d e  a t est f or  E V/ R V.   Gi v e n t h at  E V/ R Vs  ar e t h e 
m ost  c o m m o n  c a us e  of  V RIs, it is li k el y t h at  m ost  of t h e  s u bj e cts  w er e i nf e ct e d  wit h 
E V/ R V.   T h er e  w er e  n o s eri o us a d v ers e e v e nts.   All a d v ers e e v e nts  w er e  mil d t o  m o d er at e 
i n s e v erit y.   T h e  n at ur e  a n d fr e q u e n c y  of  a d v ers e  e v e nts r e p ort e d  b y s u bj e cts i n t h e  a cti v e 
a n d   pl a c e b o   gr o u ps    w er e  si mil ar,  t h e   o nl y  e x c e pti o n   b ei n g  a   hi g h er  i n ci d e n c e   of 
c hr o m at uri a ( y ell o w  dis c ol or ati o n  of  uri n e),  w hi c h  w as r e p ort e d  b y  6 0 %  of  s u bj e cts i n 
t h e  N T Z  gr o u p  a n d  1 9 %  of s u bj e cts i n t h e  pl a c e b o  gr o u p ( P = 0. 0 0 0 1). 
1. 2. 4.   
P h as e  2 b/ 3  Cli ni c al  T ri al  of  N T Z i n  U n c o m pli c at e d I nfl u e n z a:  St u d y  R M 0 8- 3 0 0 1 
A r a n d o mi z e d,  d o u bl e- bli n d,  pl a c e b o  c o ntr oll e d  d os e-r a n g e fi n di n g st u d y  w as  c o n d u ct e d 
t o  c o m p ar e t h e  effi c a c y  of  3 0 0  m g  N T Z t wi c e  d ail y f or  5  d a ys,  6 0 0  m g  N T Z t wi c e  d ail y 
f or  5  d a ys  or  a  pl a c e b o f or t h e tr e at m e nt  of  u n c o m pli c at e d i nfl u e n z a i n s u bj e cts  1 2 t o  6 5 
y e ars  of  a g e.   T h e  st u d y   w as  c o n d u ct e d  i n  7 4  o ut p ati e nt  pri m ar y  c ar e  c e nt ers  l o c at e d 
t hr o u g h o ut t h e  U nit e d  St at es  d uri n g t h e  2 0 1 0- 2 0 1 1 i nfl u e n z a  s e as o n.  6 2 4  s u bj e cts  w er e 
e nr oll e d i n t h e st u d y  b as e d  u p o n s y m pt o ms  a n d  pr es e n c e  of i nfl u e n z a i n t h e  c o m m u nit y 
wit hi n  4 8  h o urs  of s y m pt o m  o ns et.  N as o p h ar y n g e al s w a bs  w er e  c oll e ct e d  at  b as eli n e f or 
i d e ntifi c ati o n   of   1 9   diff er e nt   vir al   r es pir at or y   i nf e cti o ns   b y    R T- P C R.      S u bj e cts 
m ai nt ai n e d  di ari es t o r e c or d ti m e  of  m e di c ati o n i nt a k e,  or al t e m p er at ur e, t h e  s e v erit y  of 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  1 6  of  7 2 
C O N FI D E N TI A L 
e a c h  of  9 s y m pt o ms (r u n n y  n os e,  n as al  c o n g esti o n, s or e t hr o at,  c o u g h,  h e a d a c h e,  m us cl e 
a c h es, tir e d n ess/f ati g u e,  f e v eris h n,  a n d  s w e ats/ c hills)  gr a d e d  as  a bs e nt,  mil d,  m o d er at e 
or  s e v er e),  a bilit y t o  p erf or m  n or m al  a cti viti es  (s c al e  of  0- 1 0), ti m e l ost  fr o m  w or k  or 
s c h o ol,  c o n c o mit a nt    m e di c ati o ns  a n d  a d v ers e  e v e nts.     Di ar y  d at a   w as  r e c or d e d  t wi c e 
d ail y t hr o u g h  st u d y  D a y  7  or, if l o n g er,  u ntil t h e  s u bj e ct  n o l o n g er  h a d  a n y  m o d er at e  or 
s e v er e i nfl u e n z a  s y m pt o ms.  S u bj e cts r et ur n e d t o t h e  cli ni c f or f oll o w- u p  o n  D a y  7  a n d 
D a y  2 8.   Bl o o d  a n d  uri n e  s a m pl es  w er e  c oll e ct e d  at  b as eli n e  a n d  D a y  7 f or l a b or at or y 
s af et y  t ests,  a n d  bl o o d  s a m pl es    w er e  c oll e ct e d  at  b as eli n e  a n d    D a y  2 8  f or  i nfl u e n z a 
a nti b o d y tit er.  T h e  pri m ar y  effi c a c y  e n d p oi nt  w as ti m e fr o m first  d os e t o  all e vi ati o n  of 
s y m pt o ms  ( all  9  s y m pt o ms  a bs e nt  or    mil d  a n d  r e m ai n e d  s o  f or  at  l e ast  2 4  h o urs)  i n 
s u bj e cts   wit h  l a b or at or y- c o nfir m e d  i nfl u e n z a.  I n  a c c or d a n c e   wit h  t h e  st u d y  st atisti c al 
a n al ysis  pl a n, t h e  pri m ar y  effi c a c y  a n al ysis  w as r e p e at e d f or t h e  s u bs et  of  s u bj e cts  wit h 
E V/ R V i nf e cti o n. 
Ei g ht y- ei g ht ( 8 8)  s u bj e cts  e nr oll e d  w er e  di a g n os e d  wit h  E V/ R V  as t h e  s ol e i nf e cti o n  at 
b as eli n e.  A  vir us  s p e ci es  w as i d e ntifi e d  b y  s e q u e n ci n g f or  8 3 %  of t h es e  s u bj e cts.  Si xt y-
f o ur  p er c e nt  ( 6 4 %)  w er e  R hi n o vir us  A ,  4 % R hi n o vir us  B ,  2 9 %  R hi n o vir us  C,  a n d  3 % 
w er e  E nt er o vir us  C .  Wit hi n  e a c h  s p e ci es t h er e  w as  a  wi d e r a n g e  of  s er ot y p es.  A n al ys es 
of ti m e fr o m first  d os e t o  all e vi ati o n  of  all  s y m pt o ms f or t h es e  s u bj e cts  ar e  pr es e nt e d i n 
T a bl e  3   b el o w.  D u e t o t h e  s m all  s a m pl e  si z e  f or  a  vir us  wit h  si g nifi c a nt  v ari a bilit y i n 
pr es e nt ati o n,  as  w ell  as i n a d e q u at e  st u d y  d esi g n f or t h es e  vir us es,  n o tr e at m e nt  b e n efit 
w as  e x p e ct e d  or  o bs er v e d  i n  t his  s u bs et.    W hil e  n o  a p p ar e nt  tr e at m e nt  b e n efit    w as 
o bs er v e d f or t h e  N T Z  6 0 0  m g tr e at e d  s u bj e cts  c o m p ar e d t o  pl a c e b o-tr e at e d  s u bj e cts i n 
t his s u bs et, it is i m p ort a nt t o  n ot e t h at t h e s a m pl e si z e  w as s m all ( n = 2 9  a n d  n = 2 6 f or  N T Z 
6 0 0   m g  a n d  pl a c e b o  gr o u ps,  r es p e cti v el y)  f or  a n  ill n ess   wit h  si g nifi c a nt  v ari a bilit y  i n 
pr es e nt ati o n, t h e  m e di a n ti m e t o s y m pt o m all e vi ati o n f or t h e  pl a c e b o-tr e at e d s u bj e cts  w as 
r el ati v el y  s h ort  ( 9 0. 8  h o urs),  t h e  p ati e nt-r e p ort e d  o ut c o m es  i nstr u m e nt  h as  n ot  b e e n 
v ali d at e d  a c c or di n g  t o  c urr e nt  F D A  st a n d ar ds,  a n d  t h e  pri m ar y  e n d p oi nt  us e d  f or  t his 
st u d y  h as  b e e n s h o w n t o  b e r el ati v el y i ns e nsiti v e i n  d et e cti n g tr e at m e nt  b e n efit i n st u di es 
of  a p pr o v e d i nfl u e n z a  a nti vir al  m e di c ati o ns. 
T a bl e  3:   St u d y  R M 0 8- 3 0 0 1:  M e di a n (I Q R) ti m e ( h rs.) t o  all e vi ati o n  of  all s y m pt o ms f o r 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n 
G r o u p  
N T Z  6 0 0  m g   
N T Z  3 0 0  m g   
Pl a c e b o  
N ( c e ns or e d)  
2 9 ( 1)  
3 3 ( 3)  
2 6 ( 2)  
M e di a n (I Q R)  
1 0 5. 1 ( 6 0 -1 5 9)   
8 6. 7 ( 7 0 -1 1 9)   
9 0. 8 ( 5 9 -1 3 4)  
Diff er e n c e  vs.  pl a c e b o  
+ 1 4. 3 ( + 1,  + 2 5)   
-4. 1 ( + 1 1,  -1 5)  
- 
P  v al u e  vs.  pl a c e b o,  Wil c o x o n   
0. 4 3 6 4  
0. 8 8 4 9  
- 
P  v al u e  vs.  pl a c e b o,  L o g -R a n k   
0. 5 1 9 6  
0. 8 6 9 9  
- 
1. 2. 5.   
R a n d o mi z e d  2 x 2  F a ct o ri al  T ri al  of  N T Z  a n d  O S T i n  T r e ati n g  U n c o m pli c at e d 
I nfl u e n z a:  St u d y  R M 0 8- 3 0 0 2 
A  r a n d o mi z e d,  d o u bl e- bli n d,  f a ct ori al  tri al  of    N T Z  a n d    O S T    w as  c o n d u ct e d  i n  1 3 0 
o ut p ati e nt  pri m ar y  c ar e  cli ni cs i n t h e  U nit e d  St at es,  C a n a d a,  B el gi u m,  A ustr ali a  a n d  N e w 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  1 7  of  7 2 
C O N FI D E N TI A L 
Z e al a n d  b et w e e n  M ar c h  2 0 1 3  a n d  A pril  2 0 1 5.  1, 9 4 1 s u bj e cts  1 3 t o  6 5  y e ars  of  a g e  w er e 
e nr oll e d  b as e d  u p o n s y m pt o ms  a n d t h e  pr es e n c e  of i nfl u e n z a i n t h e  c o m m u nit y.  S u bj e cts 
w er e  e nr oll e d  wit hi n  4 8  h o urs  of  s y m pt o m  o ns et  a n d  r a n d o mi z e d t o  r e c ei v e  N T Z  6 0 0 
m g,  O S T  7 5  m g,  N T Z  6 0 0  m g  pl us  O S T  7 5  m g  or  pl a c e b o t wi c e  d ail y  f or  fi v e  d a ys.  
N as o p h ar y n g e al  s w a bs  w er e  c oll e ct e d  at  b as eli n e f or i d e ntifi c ati o n  of  1 9  diff er e nt  vir al 
r es pir at or y  i nf e cti o ns   b y    R T- P C R.     S u bj e cts    m ai nt ai n e d   di ari es  t o  r e c or d  ti m e   of 
m e di c ati o n i nt a k e,  or al t e m p er at ur e, t h e  s e v erit y  of  e a c h  of  7  s y m pt o ms  ( c o u g h,  n as al 
o bstr u cti o n,  s or e  t hr o at,  f ati g u e,  h e a d a c h e,    m y al gi a  or  f e v eris h n ess  gr a d e d  as  a bs e nt, 
mil d,  m o d er at e  or  s e v er e),  a bilit y t o  p erf or m  n or m al  a cti viti es (s c al e  of  0- 1 0), ti m e l ost 
fr o m    w or k  or  s c h o ol,  c o n c o mit a nt    m e di c ati o ns  a n d  a d v ers e  e v e nts.      Di ar y  d at a    w as 
r e c or d e d t wi c e  d ail y t hr o u g h  st u d y  D a y  1 4  or, if l o n g er,  u ntil t h e  s u bj e ct  n o l o n g er  h a d 
a n y  m o d er at e  or  s e v er e i nfl u e n z a  s y m pt o ms.  S u bj e cts r et ur n e d t o t h e  cli ni c f or f oll o w-
u p  o n  D a y  7,  D a y  1 4  a n d  D a y  2 8.   Bl o o d  a n d  uri n e  s a m pl es  w er e  c oll e ct e d  at  b as eli n e 
a n d  D a y  7 f or l a b or at or y  s af et y t ests,  a n d  bl o o d  s a m pl es  w er e  c oll e ct e d  at  b as eli n e  a n d 
D a y  2 8 f or i nfl u e n z a  a nti b o d y tit er.  T h e  pri m ar y  effi c a c y  e n d p oi nt  w as ti m e fr o m first 
d os e t o  all e vi ati o n  of  s y m pt o ms ( all  7  s y m pt o ms  a bs e nt  or  mil d  a n d r e m ai n e d  s o f or  at 
l e ast  2 4  h o urs).    I n  a c c or d a n c e    wit h  t h e  st u d y  st atisti c al  a n al ysis  pl a n,  t h e  pri m ar y 
effi c a c y  a n al ysis  w as r e p e at e d f or t h e s u bs et  of s u bj e cts  wit h  E V/ R V i nf e cti o n.  
T w o  h u n dr e d t w e nt y- ei g ht  ( 2 2 8)  s u bj e cts  e nr oll e d  w er e  di a g n os e d  wit h  E V/ R V  as t h e 
s ol e i nf e cti o n  at  b as eli n e.  A  vir us s p e ci es  w as i d e ntifi e d  b y s e q u e n ci n g f or  8 6 %  of t h es e 
s u bj e cts.   Si xt y-f o ur   p er c e nt   ( 6 4 %)    w er e  R hi n o vir us    A ,   1 2 %  R hi n o vir us    B ,   2 3 % 
R hi n o vir us  C ,  a n d  1 %  w er e  eit h er E nt er o vir us  A  or  E nt er o vir us  B .  Wit hi n  e a c h  s p e ci es 
t h er e   w as  a   wi d e  r a n g e  of  s er ot y p es.  A n al ys es  of  r es p o ns e  d at a  f or  t h es e  s u bj e cts  ar e 
pr es e nt e d  b el o w  as  b a c k gr o u n d  a n d s er v e i n  p art  as t h e  b asis f or  h y p ot h es es t est e d i n t h e 
pr es e nt st u d y ( R M 0 8- 3 0 0 5). 
I n  s u bj e cts   wit h   E V/ R V  i d e ntifi e d  as  t h e  s ol e  c a us e  of  r es pir at or y  ill n ess  at  b as eli n e, 
tr e at m e nt  wit h  N T Z  w as  ass o ci at e d  wit h  a r e d u cti o n  of ti m e t o  all e vi ati o n  of  s y m pt o ms 
c o m p ar e d t o tr e at m e nt  wit h  pl a c e b o  or  O S T.   
T a bl e  4:   St u d y  R M 0 8- 3 0 0 2:  M e di a n (I Q R) ti m e ( h rs.) t o  all e vi ati o n  of  all s y m pt o ms f o r 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n 
G r o u p  
N T Z   
O S T   
N T Z + O S T   
Pl a c e b o  
N ( c e ns or e d)  
5 5 ( 1)   
5 1 ( 5)   
6 1 ( 5)   
6 1 ( 7)  
M e di a n (I Q R)  
1 1 5. 6 ( 6 9 -2 1 0)   1 3 8. 8 ( 8 3 -3 0 9)   
1 1 3. 7 ( 6 5 -1 7 9)   
1 4 6. 5 ( 9 2 -2 9 8)  
Diff er e n c e  vs.  pl a c e b o   
-3 0. 9 ( -2 3,  -8 8)   -7. 7 ( -9,  + 1 1)   
-3 2. 8 ( -2 7  -1 1 9)   
 
P  v al u e  vs.  pl a c e b o,  Wil c o x o n   
0. 0 3 9 0   
0. 7 0 1 5   
0. 0 2 0 5  
 
P  v al u e  vs.  pl a c e b o,  L o g  R a n k   
0. 0 1 2 8   
0. 9 1 4 1   
0. 0 6 6 0 1 
 
1P  v al u e  vs.  pl a c e b o is s h o w n f or t his s e nsiti vit y  a n al ysis  b e c a us e  O S T is  n ot  eff e cti v e  a g ai nst  E V/ R V.  
 
A n al ysis  of ti m e t o all e vi ati o n  of all s y m pt o ms c o m p ari n g all  N T Z-tr e at e d s u bj e cts ( N T Z 
a n d  N T Z + O S T  gr o u ps) t o  pl a c e b o-tr e at e d s u bj e cts is  pr es e nt e d  b el o w. 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  1 8  of  7 2 
C O N FI D E N TI A L 
T a bl e  5:   St u d y  R M 0 8- 3 0 0 2:  M e di a n (I Q R) ti m es ( h rs.) t o  all e vi ati o n  of  all s y m pt o ms f o r 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n,  N T Z  vs.  pl a c e b o 
G r o u p  
N T Z  
Pl a c e b o  
N ( c e ns o r e d) 
1 1 6  ( 6)  
6 1 ( 7)  
M e di a n (I Q R)  
1 1 4. 1 ( 6 5 -1 8 7)  
1 4 6. 5 ( 9 2 -2 9 8)  
Diff er e n c e  vs.  pl a c e b o  
-3 2. 4 ( -2 7,  -1 1 1)  
 
P  v al u e  vs.  pl a c e b o,  Wil c o x o n  
0. 0 1 3 3  
 
P  v al u e  vs.  pl a c e b o,  L o g  R a n k  
0. 0 1 6 1  
 
T h e  m a g nit u d e  of tr e at m e nt  b e n efit  w as l ar g er i n s u bj e cts tr e at e d  e arli er i n t h e  c o urs e  of 
ill n ess.   T h e f oll o wi n g t a bl e  pr es e nts  a n  a n al ysis  of ti m e t o  all e vi ati o n  of  s y m pt o ms f or 
s u bj e cts  e nr oll e d  wit hi n  2 4  h o urs  of  s y m pt o m  o ns et  a n d  f or t h os e  e nr oll e d  > 2 4  h o urs 
aft er s y m pt o m  o ns et. 
T a bl e  6:   St u d y  R M 0 8- 3 0 0 2:  M e di a n (I Q R) ti m es ( h rs.) t o  all e vi ati o n  of  all s y m pt o ms f o r 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n 
 
E n r o ll e d ≤ 2 4  H o u rs f r o m 
S y m pt o m  O ns et  
E n r oll e d  > 2 4  H o u rs  aft e r 
S y m pt o m  O ns et  
G r o u p  
N T Z   
Pl a c e b o   
N T Z   
Pl a c e b o  
N ( c e ns or e d)  
4 7 ( 4)   
2 3 ( 3)   
6 9 ( 2)   
3 8 ( 4)  
M e di a n (I Q R)  
1 0 3. 5 ( 6 3 -2 1 2)   1 7 4. 2 ( 1 1 4 -3 0 9)   1 2 4. 7 ( 7 2 -1 8 1)   1 3 7. 5 ( 7 9 -2 6 1)  
Diff er e n c e  vs.  pl a c e b o   
-7 0. 7 ( -5 1,  -9 7)   
  
-1 2. 8 ( -7,  -8 0)   
 
P  v al u e  vs.  pl a c e b o,  Wil c o x o n   
0. 0 1 0 3  
 
0. 3 0 0 4  
 
P  v al u e  vs.  pl a c e b o,  L o g  R a n k   
0. 0 4 9 3  
 
0. 1 2 3 5  
 
 
Tr e at m e nt  wit h  N T Z als o s h o w e d  b e n efit i n a n al ysis  of ti m e t o r et ur n t o a bilit y t o  p erf or m 
all  n or m al  a cti viti es  wit h t h e  m e di a n i m pr o v e m e nt  b ei n g  a p pr o xi m at el y  4. 6 9  d a ys ( 1 1 2. 5 
h o urs).   S e e t h e t a bl e  b el o w. 
T a bl e  7:   St u d y  R M 0 8- 3 0 0 2:  M e di a n (I Q R) ti m es ( h rs.) t o  r et u r n t o  n o r m al  a cti viti es f o r 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n,  N T Z  vs.  pl a c e b o 
G r o u p  
N T Z  
Pl a c e b o  
N ( c e ns or e d)  
1 1 5 ( 2 9)  
6 0 ( 2 2)  
M e di a n (I Q R)  
1 8 9. 5 ( 1 0 9 -4 0 2)  
3 0 2. 0 ( 1 3 5 -6 4 3)  
Diff er e n c e  vs.  pl a c e b o  
-1 1 2. 5 ( -2 6,  -2 4 1)  
 
P  v al u e  vs.  pl a c e b o,  Wil c o x o n  
0. 0 4 5 2  
 
P  v al u e  vs.  pl a c e b o,  L o g  R a n k  
0. 0 3 2 6  
 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  1 9  of  7 2 
C O N FI D E N TI A L 
T h e  m a g nit u d e  of tr e at m e nt  b e n efit f or ti m e t o r et ur n t o  n or m al  a cti viti es  w as  als o l ar g er 
f or  s u bj e cts  e nr oll e d   wit hi n  2 4  h o urs  of  s y m pt o m  o ns et:    m e di a n  b e n efit  =  7. 4 4  d a ys 
( 1 7 8. 6  h o urs) f or  s u bj e cts  e nr oll e d  wit hi n  2 4  h o urs  of  s y m pt o m  o ns et  c o m p ar e d t o  2. 6 8 
d a ys  ( 6 4. 2  h o urs)  f or  s u bj e cts  e nr oll e d  > 2 4  h o urs  aft er  s y m pt o m  o ns et.  S e e  t h e  t a bl e 
b el o w. 
T a bl e  8:   St u d y  R M 0 8- 3 0 0 2:  M e di a n (I Q R) ti m es ( h rs.) t o  r et u r n t o  n o r m al  a cti viti es f o r 
s u bj e cts i nf e ct e d  wit h  E V/ R V  as s ol e i d e ntifi e d  p at h o g e n 
 
E n r oll e d  ≤ 2 4  H o u rs f r o m  S y m pt o m 
O ns et  
E n r oll e d  > 2 4  H o u rs  aft e r  S y m pt o m 
O ns et  
G r o u p  
N T Z  
Pl a c e b o  
N T Z  
Pl a c e b o  
N ( c e ns or e d)  
4 6 ( 1 0)  
2 2 ( 8)  
6 9 ( 1 9)   
3 8 ( 1 4)  
M e di a n (I Q R)   
1 6 5. 1 ( 1 0 5 -3 0 9)   3 4 3. 7 ( 2 4 1 -> 7 0 0)   2 1 4. 3 ( 1 1 2 -4 3 1)   
2 7 8. 5 ( 1 1 9 -> 7 0 0)  
Diff er e n c e  vs.  pl a c e b o   
-1 7 8. 6   
(-1 3 6,  > -3 9 1)  
 
-6 4. 2   
(-8,  < -2 6 9)  
 
P  v al u e  vs.  pl a c e b o, 
Wil c o x o n  
0. 0 0 5 1  
 
0. 7 7 3 8  
 
P  v al u e  vs.  pl a c e b o, 
L o g  R a n k  
0. 0 1 1 6  
 
0. 4 8 1 6  
 
 
Tr e at m e nt  wit h  N T Z  6 0 0  m g t wi c e  d ail y f or fi v e  d a ys  as  m o n ot h er a p y  or i n  c o m bi n ati o n 
wit h  O S T  w as  w ell t ol er at e d  b y all s u bj e cts.  T h e  m ost c o m m o nl y r e p ort e d a d v ers e e v e nts 
(r e p ort e d  b y ≥ 2 %  of s u bj e cts i n  a n y tr e at m e nt  gr o u p) r e g ar dl ess  of  c a us alit y  w er e: 
T a bl e  9:    R M 0 8- 3 0 0 2:  M ost  c o m m o n  a d v e rs e  e v e nts ( r e p o rt e d  b y  2 %  of s u bj e cts i n  a n y 
t r e at m e nt  g r o u p)  r e g a r dl ess  of  c a us alit y 
A d v e rs e  e v e nt ( ≥ 2 %)   
N T Z ( %)   
O S T ( %)   
N T Z + O S T ( %)   
Pl a c e b o ( %)  
N a us e a  
3. 9  
4. 4  
6. 4  
5. 3  
V o miti n g  
2. 5  
4. 2  
6. 4  
2. 7  
Di arr h e a  
6. 2  
2. 5  
3. 9  
4. 9  
A b d o mi n al  p ai n  u p p er   
2. 1  
0. 8  
2. 3  
1. 2  
C hr o m at uri a  
5. 2  
- 
5. 5  
0. 4  
Di z zi n es s 
2. 5  
3. 1  
3. 1  
1. 0  
 
T h er e  w er e  n o s eri o us  a d v ers e  e v e nts r el at e d t o  a n y  of t h e tr e at m e nts. 
1. 2. 6.   
O v e r vi e w  of  Ot h e r  E x p e ri e n c e i n  Cli ni c al  T ri als  a n d  P ost- m a r k eti n g  S u r v eill a n c e 
N T Z  h as  b e e n  m ar k et e d f or  di arr h e al  dis e as e  c a us e d  b y  Gi ar di a   or Cr y pt os p ori di u m  i n 
t h e  U nit e d  St at es si n c e  2 0 0 3  a n d i n  L ati n  A m eri c a si n c e  1 9 9 6.  It is  esti m at e d t h at  m or e 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  2 0  of  7 2 
C O N FI D E N TI A L 
t h a n  2 5 0  milli o n  p ati e nts  h a v e  b e e n  e x p os e d t o  N T Z  w orl d wi d e.   N o  dr u g-r el at e d s eri o us 
a d v ers e  e v e nts  h a v e  b e e n r e p ort e d  d uri n g  p ost- m ar k eti n g  e x p eri e n c e  wit h  N T Z. 
P h as e  2  a n d  3  cli ni c al  st u di es  h a v e  b e e n  c o n d u ct e d i n  a p pr o xi m at el y  5, 6 0 0  s u bj e cts t o 
e v al u at e t h e s af et y a n d effi c a c y  of  N T Z i n tr e ati n g  p ar asiti c,  b a ct eri al a n d  vir al i nf e cti o ns.  
D uri n g t h es e  st u di es,  n o  dr u g-r el at e d  s eri o us  a d v ers e  e v e nts  h a v e  b e e n  o bs er v e d.   T h e 
si d e  eff e cts  h a v e  b e e n  us u all y  of  a  mil d tr a nsi e nt  n at ur e,  a n d l ess t h a n  1 %  of  s u bj e cts 
h a v e  dis c o nti n u e d  t h er a p y  b e c a us e  of  a n  a d v ers e  e v e nt.     T h e    m ost  c o m m o n  a d v ers e 
e v e nts r e p ort e d i n cli ni c al tri als i n cl u d e a b d o mi n al  p ai n, c hr o m at uri a,  di arr h e a,  di z zi n ess, 
h e a d a c h e,  n a us e a  a n d  v o miti n g  a n d  di d  n ot  diff er  si g nifi c a ntl y  fr o m  t h os e  of  pl a c e b o 
e x c e pt  f or  c hr o m at uri a  w hi c h  w as  r e p ort e d  b y  4 t o  5 %  of  s u bj e cts  a n d is  attri b ut e d t o 
uri n ar y  e x cr eti o n  of    N T Z    m et a b olit es.      Cli ni c al  c h e mistr y  a n d  h e m at ol o g y  o bt ai n e d 
b ef or e  a n d  aft er  tr e at m e nt  h a v e  n ot  r e v e al e d  a n y  a b n or m aliti es  attri b ut a bl e  t o  t h e  t est 
dr u g ( Cli ni c altri als. g o v  2 0 1 8 b ). 
1. 3.   R ati o n al e f o r t h e  St u d y 
T h er e is a n i m p ort a nt  n e e d f or a tr e at m e nt f or c ol ds  d u e t o  E V/ R V i nf e cti o n t h at c o ul d r e d u c e 
t h e  d ur ati o n  of s y m pt o ms, t h e ti m e  u ntil  p ati e nts  ar e  a bl e t o  p erf or m t h eir  n or m al  a cti viti es, 
a n d  p ot e nti all y t h e ris k  of  c o m pli c ati o ns.  T his  pr o d u ct s h o ul d  h a v e  a f a v or a bl e s af et y  pr ofil e 
a n d l o w ris k f or r esist a n c e. 
T his  st u d y is  a  m ulti c e nt er  r a n d o mi z e d,  d o u b l e- bli n d,  pl a c e b o- c o ntr oll e d tri al  d esi g n e d t o 
e v al u at e  effi c a c y  a n d  s af et y  of  N T Z  6 0 0  m g  a d mi nist er e d  or all y t wi c e  d ail y  f or  fi v e  d a ys 
c o m p ar e d t o  a  pl a c e b o i n t h e tr e at m e nt  of  c ol ds  d u e t o  E V/ R V i nf e cti o n. 
2.   
S T U D Y  O B J E C TI V E S 
T h e  pri m ar y  o bj e cti v e  of t his st u d y is t o  e v al u at e t h e  eff e ct  of  N T Z  a d mi nist er e d  or all y  6 0 0 
m g  b.i. d. f or  5  d a ys i n r e d u ci n g t h e  d ur ati o n  of  s y m pt o ms  of  c ol ds  d u e t o  E V/ R V i nf e cti o n 
c o m p ar e d  t o  t h at  of  a  pl a c e b o  d uri n g  2 1  d a ys  of  f oll o w- u p  b as e d  u p o n  t h e  F L U- P R O © 
p ati e nt-r e p ort e d  o ut c o m e i nstr u m e nt. 
A  k e y s e c o n d ar y  effi c a c y  o bj e cti v e is t o  e v al u at e t h e  eff e ct  of  N T Z  c o m p ar e d t o  pl a c e b o  o n 
ti m e t o r et ur n t o  a bilit y t o  p erf or m  all  n or m al  a cti viti es. 
A n ot h er  s e c o n d ar y  effi c a c y  o bj e cti v e is t o  e v al u at e t h e  eff e ct  of  N T Z  c o m p ar e d t o  pl a c e b o 
o n t h e  pr o p orti o n  of s u bj e cts  e x p eri e n ci n g  o n e  or  m or e  c o m pli c ati o ns  of  c ol ds  d u e t o  E V/ R V 
i nf e cti o n i n cl u di n g  p n e u m o ni a,  otitis  m e di a,  br o n c hitis, si n usitis,  e x a c er b ati o ns  of  ast h m a  or 
C O P D,  w ors e ni n g  of  pr e- e xisti n g  h e alt h  c o n diti o ns, s e c o n d ar y i nf e cti o ns r e q uiri n g s yst e mi c 
a nti bi oti c  us e,  h os pit ali z ati o n  d u e t o  c ol d  or  c o m pli c ati o ns  of t h e  c ol d,  a n d  d e at h  d u e t o  c ol d 
or  c o m pli c ati o ns  of t h e  c ol d. 
E x pl or at or y  effi c a c y  o bj e cti v es i n cl u d e  e v al u ati n g t h e  eff e ct  of tr e at m e nt  wit h  N T Z  o n t h e 
ti m e t o r es p o ns e f or  e a c h  F L U- P R O s y m pt o m, ti m e t o r es p o ns e f or  e a c h  F L U- P R O  d o m ai n, 
ti m e t o r et ur n t o  us u al  h e alt h,  c h a n g es i n  vir al tit ers fr o m  b as eli n e t o  e a c h  of  D a ys  2,  3  a n d 
7,  ti m e  t o  s y m pt o m  r es p o ns e  f or  all  s u bj e cts  tr e at e d,  a n d  ti m e  t o  s y m pt o m  r es p o ns e  f or 
s u bj e cts  wit h i n di vi d u al  n o n- E V/ R V  vir us i nf e cti o ns. 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  2 1  of  7 2 
C O N FI D E N TI A L 
Ot h er i m p ort a nt  o bj e cti v es i n cl u d e  e v al u ati o n  of t h e  s af et y  of  N T Z  b y  a n al ysis  of  a d v ers e 
e v e nts  a n d  e v al u ati o n  of  r el ati o ns hi ps  b et w e e n  p h ar m a c o ki n eti cs  a n d  cli ni c al  or  vir ol o gi c 
r es p o ns es. 
3.   
S T U D Y  D E SI G N  
T h e  st u d y  will  b e  a  m ulti c e nt er,  r a n d o mi z e d,  d o u bl e- bli n d tri al t o  e v al u at e t h e  effi c a c y  of 
N T Z  c o m p ar e d t o  pl a c e b o i n tr e ati n g  c ol ds  d u e t o  E V/ R V i nf e cti o n.  
S u bj e cts  will  b e r a n d o mi z e d  1: 1 t o  o n e  of t h e f oll o wi n g  gr o u ps:  
•   Gr o u p  1 ( N T Z):    
T w o  N T Z  3 0 0  m g t a bl ets  b.i. d. f or  5  d a ys 
•   Gr o u p  2 ( Pl a c e b o):    T w o  pl a c e b o t a bl ets  b.i. d. f or  5  d a ys 
E nr oll m e nt  a n d  t h e  pri m ar y  effi c a c y  a n al ysis   will  b e  str atifi e d  b y  ( 1)  ti m e  fr o m  o ns et  of 
ill n ess t o st u d y  e nr oll m e nt ( 0- 2 4,  > 2 4-≤ 3 6,  or  > 3 6  h o urs fr o m  o ns et), ( 2)  pr e- e nr oll m e nt  us e 
of  s y m pt o m  r eli ef    m e di c ati o n,  a n d  ( 3)  pr es e n c e  of  u n d erl yi n g  l u n g  c o n diti o n  i n cl u di n g 
ast h m a,  C O P D,  or  p ast  or  pr es e nt  hist or y  of s m o ki n g. 
T his st u d y is  e x p e ct e d t o r u n fr o m  A u g ust  2 0 1 8 t hr o u g h  A pril  2 0 1 9. 
R ati o n al e f or i m p ort a nt iss u es i n t h e st u d y  d esi g n is  d es cri b e d  b el o w: 
•   C h oi c e  of  N T Z  d os e  a n d  d ur ati o n  of tr e at m e nt.   T h e  d os e  of  N T Z  us e d f or t his  cli ni c al 
tri al  ( 6 0 0    m g  b.i. d.  f or  5  d a ys)    w as  ass o ci at e d    wit h  a  r e d u cti o n  of  t h e  d ur ati o n  of 
s y m pt o ms  a n d ti m e t o  a bilit y t o  p erf or m  all  n or m al  a cti viti es i n  s u bj e cts  wit h  E V/ R V 
i nf e cti o n i n  a  pr e vi o us tri al  of  N T Z f or t h e tr e at m e nt  of i nfl u e n z a ( St u d y  R M 0 8- 3 0 0 2).  
I n  cli ni c al tri als i n v ol vi n g  2, 8 8 6  s u bj e cts,  a d v ers e  e v e nts r e p ort e d  b y  s u bj e cts r e c ei vi n g 
6 0 0  m g  N T Z  b.i. d.  f or  5  d a ys  w er e  si mil ar t o t h os e  of  s u bj e cts  r e c ei vi n g t h e  pl a c e b o, 
wit h t h e  e x c e pti o n  of  a  hi g h er r at e  of  di arr h e a ( 8. 1 %  c o m p ar e d t o  5. 8 % f or t h e  pl a c e b o).  
St u di es  of  N T Z  at  hi g h er  d os es  h a v e  s h o w n  d os e- d e p e n d e nt i n cr e as es i n t h e fr e q u e n c y 
of  r e p ort e d  di arr h e a  a n d  ot h er  g astr oi nt esti n al  si d e  eff e cts, t h er ef or e  n o  hi g h er  d os e is 
pl a n n e d f or t his st u d y. 
•   C h oi c e  of  c o ntr ol  gr o u ps.   A  pl a c e b o  c o ntr ol is  a p pr o pri at e f or t h e  st u d y  d u e t o l a c k  of 
a n y  a p pr o v e d  a cti v e  c o ntr ol.  
•   C h oi c e   of   p ati e nt   p o p ul ati o n.     T h e   p o p ul ati o n  t o   b e  st u di e d  i n cl u d es   a d ults   a n d 
a d ol es c e nts  at l e ast  1 2  y e ars  of  a g e  wit h  E V/ R V i nf e cti o n.   T his is  a  p o p ul ati o n  si mil ar 
t o t h os e  s el e ct e d f or  st u di es  R M 0 8- 3 0 0 1,  R M 0 8- 3 0 0 2,  R M 0 8- 3 0 0 3  a n d  R M 0 8- 3 0 0 4  of 
t h e  N T Z  3 0 0  m g  e xt e n d e d r el e as e t a bl ets i n  m or e t h a n  3, 0 0 0 s u bj e cts  wit h i nfl u e n z a-li k e 
ill n ess.   N o s af et y  c o n c er ns  h a v e  b e e n i d e ntifi e d fr o m t h es e  cli ni c al tri als. 
F or t h e  pr es e nt  st u d y,  s o m e  s u bj e cts ( e. g.,  s u bj e cts  > 6 5  y e ars  of  a g e,  u n d erl yi n g  ast h m a 
or    C O P D,  di a b et es    m ellit us  if  n ot  p o orl y  c o ntr oll e d,  et c.  –  s e e  I n cl usi o n/ E x cl usi o n 
crit eri a i n s e cti o ns   4. 1  a n d 4. 2 )  w h o  ar e  at  hi g h er ris k  of  c o m pli c ati o ns  or  e x a c er b ati o ns 
of   u n d erl yi n g  c o n diti o ns    will   b e  all o w e d  t o   p arti ci p at e  if,  i n  t h e  j u d g m e nt   of  t h e 
i n v esti g at or, t h e y  ar e  a bl e t o  c o m pl y  wit h  pr ot o c ol r e q uir e m e nts  a n d  ar e  n ot  e x p e ct e d t o 
r e q uir e  h os pit ali z ati o n.   T h er e  is  n o  a p pr o v e d  a nti vir al  f or  c ol ds  d u e  t o   E V/ R V,  a n d 
s u bj e cts    will   n ot   b e   pr e v e nt e d   fr o m   b ei n g   pr es cri b e d   r es c u e    m e di c ati o n   f or 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  2 2  of  7 2 
C O N FI D E N TI A L 
c o m pli c ati o ns.   T h er ef or e,  p arti ci p ati o n i n t h e  st u d y  will  n ot  p os e  u nr e as o n a bl e ris k t o 
a n y  eli gi bl e  s u bj e ct.    E nr oll m e nt    will   b e  str atifi e d   b y   pr es e n c e   of   u n d erl yi n g  l u n g 
c o n diti o n i n cl u di n g  ast h m a,  C O P D,  a n d  hist or y  of s m o ki n g. 
D at a fr o m  p h ar m a c o ki n eti cs  st u di es i n  h e alt h y  v ol u nt e ers  1 2 t o  1 7  y e ars  of  a g e  or  1 8 t o 
6 5  y e ars  of  a g e  i n di c at e  t h at  t h e  p h ar m a c o ki n eti cs  of  t h e    m aj or    N T Z    m et a b olit es, 
ti z o x a ni d e  a n d ti z o x a ni d e  gl u c ur o ni d e, f oll o wi n g  or al  a d mi nistr ati o n  of  a  N T Z  5 0 0  m g 
t a bl et  ar e  si mil ar f or t h es e  a g e  gr o u ps.   S af et y  d at a is  als o  si mil ar f or t h es e  a g e  gr o u ps.  
T h er ef or e, t h e  a d ult  d os e is  d e e m e d  a p pr o pri at e f or  p e di atri c  p ati e nts  d o w n t o  1 2  y e ars 
of  a g e.    I nf or m e d  c o ns e nt   will  b e  r e q uir e d  f or  s u bj e ct  p arti ci p ati o n  i n  t his  st u d y  (s e e 
Pr ot o c ol  s e cti o n  1 5 ).   A  si g n e d  ass e nt f or m  will  b e r e q uir e d f or  a n y  mi n ors  e nr oll e d (≤  
1 8  y e ars  of  a g e  or  as l o c al r e g ul ati o ns  a p pl y)  as  w ell  as  si g n e d  p ar e nt al/l e g al  g u ar di a n 
c o ns e nt  b y t h eir  p ar e nt/l e g al  g u ar di a n  all o wi n g f or t h e  mi n or’s  p arti ci p ati o n.   
•   C h oi c e   of   I n cl usi o n    Crit eri a.    I n   n o n- ast h m ati c  i n di vi d u als,   s y m pt o ms   of    E V/ R V 
i nf e cti o n  ar e  g e n er all y  li mit e d  t o  t h e  u p p er  r es pir at or y  tr a ct.      R hi n orr h e a  a n d  n as al 
o bstr u cti o n   ar e  t h e    m ost   pr o mi n e nt  s y m pt o ms  i n   u n c o m pli c at e d   c as es   of    E V/ R V 
i nf e cti o n.      L o w er  r es pir at or y  s y m pt o ms  i n cl u di n g  c o u g h,  s h ort n ess  of  br e at h,  c h est 
ti g ht n ess,  a n d    w h e e zi n g    m a y  b e  t h e    m ost  pr o mi n e nt  s y m pt o m  i n  p ati e nts    w h o  h a v e 
u n d erl yi n g ast h m a  or  ot h er c hr o ni c l u n g  dis e as e.    R hi n orr h e a r at e d as  m o d er at e  or s e v er e 
w as t h e  m ai n i n cl usi o n  crit eri o n f or t w o  P h as e  3 st u di es  of  pl e c o n aril i n t h e tr e at m e nt  of 
pi c or n a vir us- ass o ci at e d  vir al  r es pir at or y  i nf e cti o n,  a c c o m p a ni e d  b y  n as al  c o n g esti o n, 
c o u g h,  or  s or e t hr o at,  r es ulti n g i n  a  pi c or n a vir us- p ositi v e  r at e  of  6 2 %  a n d  6 8 %  ( All a n 
a n d    Arr oll   2 0 1 4 ).    T h e  s a m e  crit eri a   h a v e   b e e n   us e d  t o  e nr oll   n at ur al   hist or y  a n d 
e pi d e mi ol o g y  st u di es  of  E V/ R V i nf e cti o n  wit h  u p t o  a n  8 2 %  pi c or n a vir us- p ositi v e r at e 
(Arr u d a  et  al.  1 9 9 7 ). 
F e v er,   es p e ci all y   a   l o w- gr a d e   f e v er,   is   c o nsist e nt    wit h    E V/ R V   i nf e cti o n   i n 
e pi d e mi ol o gi c al   st u di es,    wit h   pr es e nt ati o n   g ui d eli n es   f or   p h ysi ci a ns,   a n d    wit h 
pr es e nt ati o n  of  m or e t h a n  3 0 0  E V/ R V-i nf e ct e d  s u bj e cts  e nr oll e d i n  P h as e  3  st u di es  of 
N T - 3 0 0 f or tr e at m e nt  of i nfl u e n z a (C h u g ht ai et al.  2 0 1 7 , R ot b art a n d  H a y d e n  2 0 0 0,  Ari n g 
2 0 1 6 ).  E x cl usi o n  of s u bj e cts  wit h f e v er is li k el y t o e x cl u d e  E V/ R V-i nf e ct e d s u bj e cts  wit h 
s e v er e  c yt o ki n e r es p o ns e.   T h er ef or e, t h e  pr es e nt  st u d y  will r e q uir e  a  n e g ati v e r es ult f or 
i nfl u e n z a  b y  a r a pi d  di a g n osti c t est if t h e s u bj e ct  h as  a n  or al t e m p er at ur e  > 1 0 0° F  or  w h e n 
l o c al i nfl u e n z a  a cti vit y  h as  b e e n  c o nfir m e d i n  or d er t o  mi ni mi z e t h e  n u m b er  of  s u bj e cts 
e nr oll e d  wit h i nfl u e n z a i nf e cti o n. 
H u m a n  c h all e n g e  st u di es  i n di c at e  t h at  t h e  o ns et  of  s y m pt o ms  of   R hi n o vir us  i nf e cti o n 
o c c urs a p pr o xi m at el y  2 4  h o urs  p ost-i n o c ul ati o n ( p.i.); s y m pt o ms  p e a k a p pr o xi m at el y  4 8-
7 2  h o urs  p.i.;  a n d  vir us  tit er  p e a ks  a p pr o xi m at el y  9 6  h o urs  p.i.  ( F ull e n  et  al.  2 0 1 6 ). 
E nr oll m e nt  wit hi n  4 0  h o urs  of s y m pt o m  o ns et  will  m a xi mi z e  p ot e nti al tr e at m e nt  b e n efit 
b y i niti ati n g tr e at m e nt  b ef or e  s y m pt o m  s e v erit y  a n d  vir us tit er  p e a k.   S e e  s e cti o ns   1. 1. 1 
a n d  1. 2. 4   a b o v e f or  pr es e nt ati o n  of  d at a i n di c ati n g i m pr o v e d  effi c a c y  of i n v esti g ati o n al 
a nti vir al   dr u gs  a n d    N T Z  i n  s u bj e cts  e nr oll e d  e arli er   d uri n g  t h e  c o urs e   of    E V/ R V 
i nf e cti o n. 
•   C h oi c e  of   P ati e nt- R e p ort e d    O ut c o m e  I nstr u m e nt.     T his  cli ni c al  tri al    will  us e  a  n e w, 
r e c e ntl y  r el e as e d  p ati e nt-r e p ort e d  o ut c o m e  q u esti o n n air e,  I n F L U e n z a  P ati e nt- R e p ort e d 
O ut c o m e  Q u esti o n n air e ( F L U- P R O ©).  


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  2 3  of  7 2 
C O N FI D E N TI A L 
F L U - P R O  w as  d e v el o p e d  wit h t h e s u p p ort  of t h e  U. S.  D e p art m e nt  of  H e alt h  a n d  H u m a n 
S er vi c es t hr o u g h t h e  N ati o n al  C a n c er I nstit ut e  a n d t h e  N ati o n al I nstit ut es  of  All er g y  a n d 
I nf e cti o us  Dis e as es,  N ati o n al I nstit ut es  of  H e alt h, i n r es p o ns e t o t h e  n e e d f or i m pr o v e d 
m etri cs t o e v al u at e tr e at m e nt eff e ct i n cli ni c al tri als  of  dr u gs f or t h e tr e at m e nt  of i nfl u e n z a 
a n d  ot h er r es pir at or y tr a ct  vir al  dis e as es.  It  w as  d e v el o p e d  a n d  v ali d at e d i n  a c c or d a n c e 
wit h  F D A’s  g ui d a n c e,  “ P ati e nt- R e p ort e d   O ut c o m e    M e as ur es:   Us e  i n    M e di c al  Pr o d u ct 
D e v el o p m e nt  t o  S u p p ort   L a b eli n g   Cl ai ms. ”    It  h as  als o  b e e n  v ali d at e d  f or  us e  o n  a n 
el e ctr o ni c  d e vi c e  as  p art  of  a n  el e ctr o ni c  di ar y  ( “ e Di ar y ”)  t h at  c a n  ti m e  st a m p  di ar y 
e ntri es t o  e ns ur e ti m el y r e c or di n g, t h er e b y  miti g ati n g ris ks  of r e c all  bi as.   W e  will  us e  a n 
el e ctr o ni c  di ar y  f or  t his  cli ni c al  tri al.  F L U- P R O   w as  s e p ar at el y  v ali d at e d  f or  us e  i n  a 
p o p ul ati o n  wit h  n o n-i nfl u e n z a I LI ( P o w ers  et  al.  2 0 1 8 ). 
P R O  i nstr u m e nts  us e d  i n  pr e vi o us  st u di es  of    E V/ R V- ass o ci at e d  ill n ess  i n cl u d e  t h e 
m o difi e d J a c ks o n i n d e x, t h e  Wis c o nsi n  U p p er  R es pir at or y  S y m pt o m  S ur v e y ( W U R S S), 
a n d  a  si x-s y m pt o m  s c al e  i n cl u di n g  r hi n orr h e a,  n as al  c o n g esti o n,  s or e  t hr o at,    m al ais e, 
c o u g h,  a n d  m y al gi a.   T h e  J a c ks o n  s c al e is t h e  ol d est  P R O  f or  e v al u ati o n  of  c ol ds  a n d 
i nfl u e n z a,  b ut it  w as  n ot  d e v el o p e d  or  v ali d at e d i n  a c c or d a n c e  wit h  F D A  g ui d a n c e  o n 
P R Os, t h er ef or e c o nt e nt  v ali dit y a n d  m e as ur e m e nt  pr o p erti es  m a y  b e i n c o m pl et e ( B arr ett 
et  al.  2 0 0 9 , J a c ks o n  a n d  D o wli n g  1 9 5 9 ).  T h e  W U R S S  w as  d e v el o p e d  a n d  v ali d at e d f or 
p ati e nts  wit h s elf- di a g n os e d  c ol ds i n  g e n er al  a c c or d a n c e  wit h  pr a cti c es r e c o m m e n d e d i n 
t h e  F D A  g ui d a n c e  o n  P R Os (B arr ett  et  al.  2 0 0 2 ).  H o w e v er, t h e  W U R S S is i nt e n d e d t o 
m e as ur e t h e  o v er all i m p a ct  of I LI  o n a  p ati e nt, as e vi d e n c e d  b y  pr es e n c e  of  b ot h s y m pt o m 
a n d  q u alit y  of lif e  ass ess m e nts  wit hi n t h e  s ur v e y.   B e c a us e t h e  p ur p os e  of t h e  pr es e nt 
st u d y is t o  m e as ur e  h o w  a  p ati e nt f e els  d u e t o  E V/ R V i nf e cti o n ( c o n c e pt  m e as ur e d),  us e 
of t h e  W U R S S s c al e is  n ot  a p pr o pri at e f or  m e as ur e m e nt  of  effi c a c y  d at a.   T h e  F L U- P R O 
s c al e    m e as ur es  t h e  a p pr o pri at e  c o n c e pt  a n d    w as   v ali d at e d  f or   us e  i n  t h e  i nt e n d e d 
p o p ul ati o n ( P o w ers  2 0 1 8 ). 
I n  a n  o n g oi n g  st u d y    R M 0 8- 3 0 0 4  e nr olli n g  s u bj e cts    wit h  i nfl u e n z a  or  i nfl u e n z a-li k e 
ill n ess,  di ar y  c o m pli a n c e,  b as e d  u p o n  el e ctr o ni c  d at e  a n d ti m e-st a m p e d  d at a,  h as  b e e n 
8 7 %  wit h a n a v er a g e ti m e t o c o m pl et e t h e  F L U- P R O  of l ess t h a n f o ur  mi n ut es, i n di c ati n g 
p ati e nt  a c c e pt a bilit y  a n d l a c k  of  p ati e nt  b ur d e n.   T h er ef or e,  us e  of  F L U- P R O is  e x p e ct e d 
t o  pr o vi d e  r o b ust  a n d  r eli a bl e  d at a  f or  a n al ysis  of  t h e  s y m pt o ms  c a us e d  b y   E V/ R V 
i nf e cti o n. 
•   C h oi c e  of  E n d p oi nts.   T h e  effi c a c y  e n d p oi nts t o  b e  a n al y z e d  s e q u e nti all y f or t his  st u d y 
ar e ( 1)  Ti m e t o  S y m pt o m  R es p o ns e  b as e d  u p o n t h e  F L U- P R O © i nstr u m e nt, ( 2)  Ti m e t o 
A bilit y t o  P erf or m  All  N or m al  A cti viti es,  a n d ( 3)  pr o p orti o ns  of  s u bj e cts  e x p eri e n ci n g 
c o m pli c ati o ns  of  E V/ R V i nf e cti o n. 
T h e  pri m ar y  effi c a c y  e n d p oi nt f or t his  st u d y  will  b e  Ti m e t o  S y m pt o m  R es p o ns e  b as e d 
u p o n  t h e  F L U- P R O ©  i nstr u m e nt.     T his  is  dir e ct e d  t o  t h e    w a y  t h e  p ati e nt  “f e els ”  as 
m e as ur e d  b y  his/ h er  s y m pt o ms.      A  S y m pt o m   R es p o ns e  d efi niti o n    will  b e  d e v el o p e d 
b as e d  u p o n  a  bli n d e d  r e vi e w  of  F L U- P R O  s y m pt o m  s c or es  ( p o ol e d  f or  all  s u bj e cts 
wit h o ut r e g ar d t o tr e at m e nt  gr o u p  assi g n m e nt s o  as t o  m ai nt ai n  bli n di n g)  a n d  c orr el ati o n 
of t h os e s c or es t o t h e ti m e  at  w hi c h s u bj e cts r e p ort t h at t h e y  h a v e r et ur n e d t o t h eir  us u al 
st at e  of  h e alt h ( a  “ y es ”  or  “ n o ”  q u esti o n i n c or p or at e d i nt o t h e  d ail y  Q u esti o n n air e).  T w o 
S y m pt o m  R es p o ns e  d efi niti o ns  will  b e  d et er mi n e d i n t his  m a n n er:  o n e f or s u bj e cts  wit h 


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P a g e  2 4  of  7 2 
C O N FI D E N TI A L 
u n d erl yi n g l u n g  c o n diti o ns i n cl u di n g  ast h m a,  C O P D  or  hist or y  of  s m o ki n g;  a n d  o n e f or 
s u bj e cts  wit h  n o  u n d erl yi n g l u n g  c o n diti o n.  T his  m et h o d ol o g y  will  all o w f or  a n al ysis  of 
all s u bj e cts t o g et h er  w hil e  a c c o u nti n g f or  diff er e n c es  e x p e ct e d i n t h e  us u al st at e  of  h e alt h 
f or s u bj e cts  wit h l u n g  c o n diti o ns ( e. g.,  c hr o ni c  c o u g h).  T h e  Ti m e t o  S y m pt o m  R es p o ns e 
us e d f or  e v al u ati n g t h e  pri m ar y  e n d p oi nt  will  b e  c al c ul at e d  b as e d  u p o n t h es e  S y m pt o m 
R es p o ns e  d efi niti o ns  a n d  pr o gr a m m e d  pri or  t o  d at a b as e  u n bli n di n g  f or  t h e  pri m ar y 
a n al ysis.   T his  a n c h or- b as e d  a p pr o a c h t o  d efi ni n g r es p o n d ers  e ns ur es t h at t h e  S y m pt o m 
R es p o ns e  d efi niti o n is  v ali d  a n d  m e a ni n gf ul f or t h e  s u bj e cts  p arti ci p ati n g i n  e a c h  gi v e n 
cli ni c al tri al. 
T h e  k e y  s e c o n d ar y  e n d p oi nt t o  b e  a n al y z e d  s e c o n d i n  s e q u e n c e  will  b e  Ti m e t o  A bilit y 
t o  P erf or m  All  N or m al  A cti viti es.   T his e n d p oi nt  will  pr o vi d e i m p ort a nt i nf or m ati o n  wit h 
r es p e ct t o t h e  w a y  a  p ati e nt  “f u n cti o ns. ”   E a c h  of t h e  pr e vi o us  cli ni c al tri als  of  N T Z i n 
s u bj e cts  wit h i nfl u e n z a  h a v e i n di c at e d i m pr o v e m e nt i n t his e n d p oi nt  w hil e  d at a c oll e cti o n 
fr o m t h os e  st u di es  h as t y pi c all y  n ot  e xt e n d e d  o ut l o n g  e n o u g h t o f ull y  c h ar a ct eri z e t h e 
b e n efit.   As  n ot e d i n  s e cti o n   1. 2. 4  a b o v e,  s u bj e cts  wit h  E V/ R V i nf e cti o n  as t h eir  s ol e 
i d e ntifi e d  c a us e  of  r es pir at or y  ill n ess  at  b as eli n e  als o  s h o w e d  i m pr o v e m e nt  i n  t his 
e n d p oi nt  f or  s u bj e cts tr e at e d  wit h  nit a z o x a ni d e  c o m p ar e d t o  pl a c e b o.  T his  e n d p oi nt is 
m or e  m e a ni n gf ul t h a n ti m e t o r et ur n t o  w or k  or  s c h o ol  b e c a us e t h e  d e cisi o n t o r et ur n t o 
w or k  or  s c h o ol is i nfl u e n c e d  b y f a ct ors i n d e p e n d e nt  of  h o w t h e  p ati e nt f e els  or  his/ h er 
a bilit y t o  p erf or m  w or k  or s c h o ol  a cti viti es ( Mit c h ell  2 0 1 1 ). 
A n ot h er  s e c o n d ar y  e n d p oi nt  will  b e  pr o p orti o ns  of  s u bj e cts  e x p eri e n ci n g  c o m pli c ati o ns 
of    E V/ R V   i nf e cti o n,   i n cl u di n g   p n e u m o ni a,   otitis    m e di a,   br o n c hitis,   si n usitis, 
e x a c er b ati o ns   of   ast h m a   or    C O P D,    w ors e ni n g   of   pr e- e xisti n g   h e alt h   c o n diti o ns, 
s e c o n d ar y  i nf e cti o ns  r e q uiri n g  s yst e mi c  a nti bi oti c  us e,  h os pit ali z ati o n  d u e  t o  c ol d  or 
c o m pli c ati o ns  of t h e  c ol d,  a n d  d e at h  d u e t o  c ol d  or  c o m pli c ati o ns  of t h e  c ol d.   W e  d o  n ot 
e x p e ct t o s e e e n o u g h c o m pli c ati o ns i n t his  p o p ul ati o n t o  d e m o nstr at e  diff er e n c es  b et w e e n 
tr e at m e nt  gr o u ps,  a n d t h er ef or e, t his  e n d p oi nt is l ess er i n  pri orit y  c o m p ar e d t o  Ti m e t o 
A bilit y t o  P erf or m  All  N or m al  A cti viti es.   All  ot h er effi c a c y e n d p oi nts  will  b e c o nsi d er e d 
e x pl or at or y. 
4.   
S U B J E C T  S E L E C TI O N 
T h e  crit eri a f or i n cl usi o n  a n d  e x cl usi o n  ar e  d efi n e d  b el o w: 
4. 1.   I n cl usi on  C rit e ri a 
1.   M al e  a n d f e m al e s u bj e cts  at l e ast  1 2  y e ars  of  a g e 
2.   Pr es e n c e  of  cli ni c al  si g ns  a n d/ or  s y m pt o ms  c o nsist e nt  wit h  a n  a c ut e ill n ess  c o m p ati bl e 
wit h  E V/ R V i nf e cti o n ( e a c h  of t h e f oll o wi n g is r e q uir e d): 
a.   Pr es e n c e  of   m o d er at e  or  s e v er e  r hi n orr h e a  d efi n e d  as  “ att e m pti n g  t o  r eli e v e  n as al 
s y m pt o ms  b y  bl o wi n g,  wi pi n g,  or  s niffli n g  at l e ast t wi c e  p er  h o ur f or  a n y  o n e  h o ur 
wit hi n  1 2  h o urs  pr e c e di n g st u d y  e ntr y, ”  A N D  
b.   Pr es e n c e  of  c o u g h, s or e t hr o at  or  n as al  o bstr u cti o n. 


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N o v e m b er  2 9,  2 0 1 8 
 
P a g e  2 5  of  7 2 
C O N FI D E N TI A L 
3.   N e g ati v e  r a pi d  i nfl u e n z a   di a g n osti c  t est  (r e q uir e d   o nl y  if  t h e  s u bj e ct   h as   a n   or al 
t e m p er at ur e  > 1 0 0° F  i n  t h e  cli ni c  or  if  t h e  l at est   C D C   w e e kl y  i nfl u e n z a  r e p ort  s h o ws 
i nfl u e n z a  pr e v al e n c e  “ R e gi o n al ”  or  hi g h er  f or  t h e  i nstit uti o n’s  st at e).   A  r es ult  fr o m  a 
r a pi d  i nfl u e n z a  di a g n osti c  t est  p erf or m e d  o n  t h e  s a m e  d a y  t h at  i nf or m e d  c o ns e nt  is 
o bt ai n e d    will  b e  s uffi ci e nt  t o    m e et  t his  crit eri o n  if  d o c u m e nt ati o n  of  t est  r es ults  is 
a v ail a bl e  as  p art  of  m e di c al  hist or y. 
4.   O ns et  of ill n ess  n o  m or e t h a n  4 0  h o urs  b ef or e  e nr oll m e nt i n t h e tri al.  O ns et  of ill n ess is 
d efi n e d  as t h e first ti m e  at  w hi c h t h e  s u bj e ct  e x p eri e n c e d r hi n orr h e a,  c o u g h,  s or e t hr o at 
or  n as al  o bstr u cti o n. 
5.   Willi n g  a n d  a bl e t o  pr o vi d e  writt e n i nf or m e d  c o ns e nt (i n cl u di n g  ass e nt  b y l e g al  g u ar di a n 
if  u n d er  1 8  y e ars  of  a g e)  a n d  c o m pl y  wit h t h e  r e q uir e m e nts  of t h e  pr ot o c ol, i n cl u di n g 
c o m pl eti o n  of t h e s u bj e ct  di ar y 
4. 2.   E x cl usi o n  C rit e ri a 
1.   P ers o ns r e q uiri n g  or  a nti ci p at e d t o r e q uir e i n- h os pit al  c ar e 
2.   C ysti c fi br osis  
3.   C ar di a c  arr h yt h mi a  
4.   I m m u n ol o gi c  dis or d ers  or r e c ei vi n g i m m u n os u p pr essi v e t h er a p y ( e. g., f or  or g a n  or  b o n e 
m arr o w tr a ns pl a nts, i m m u n o m o d ul at or y t h er a pi es f or  c ert ai n  a ut oi m m u n e  dis e as es) 
5.   U ntr e at e d  HI V i nf e cti o n  or tr e at e d  HI V i nf e cti o n  wit h a  C D 4 c o u nt  b el o w  3 5 0 c ells/ m m 3 
i n t h e l ast  6  m o nt hs 
6.   P ers o ns  wit h si c kl e  c ell  a n e mi a  or  ot h er  h e m o gl o bi n o p at hi es 
7.   P o orl y  c o ntr oll e d i ns uli n- d e p e n d e nt  di a b et es  m ellit us ( H b A 1 C  > 8. 0 %) 
8.   C o n c urr e nt i nf e cti o n  at t h e  s cr e e ni n g  e x a mi n ati o n t h at  r e q uir es  s yst e mi c  a nti mi cr o bi al 
t h er a p y 
9.   F e m al es  of  c hil d b e ari n g  p ot e nti al  w h o  ar e  eit h er  pr e g n a nt  or s e x u all y  a cti v e  wit h o ut t h e 
us e  of  birt h  c o ntr ol.   F e m al e  s u bj e cts  of  c hil d- b e ari n g  p ot e nti al t h at  ar e  s e x u all y  a cti v e 
m ust  h a v e  a  n e g ati v e  b as eli n e  pr e g n a n c y t est  a n d  m ust  a gr e e t o  c o nti n u e  a n  a c c e pt a bl e 
m et h o d  of  birt h  c o ntr ol f or t h e  d ur ati o n  of t h e  st u d y  a n d f or  1  m o nt h  p ost-tr e at m e nt.   A 
d o u bl e  b arri er  m et h o d,  or al  birt h  c o ntr ol  pills  a d mi nist er e d f or  at l e ast  2  m o nt hl y  c y cl es 
pri or t o st u d y  dr u g a d mi nistr ati o n, a n I U D,  or  m e dr o x y pr o g est er o n e a c et at e a d mi nist er e d 
i ntr a m us c ul arl y  f or  a    mi ni m u m  of  o n e    m o nt h  pri or  t o  st u d y  dr u g  a d mi nistr ati o n  ar e 
a c c e pt a bl e   m et h o ds  of  birt h  c o ntr ol  f or  i n cl usi o n  i nt o  t h e  st u d y.    F e m al e  s u bj e cts  ar e 
c o nsi d er e d   of   c hil d b e ari n g   p ot e nti al   u nl ess  t h e y   ar e   p ost m e n o p a us al   ( a bs e n c e   of 
m e nstr u al  bl e e di n g  f or  1  y e ar  -  or  6    m o nt hs  if  l a b or at or y  c o nfir m ati o n  of  h or m o n al 
st at us),  or  h a v e  h a d  a  h yst er e ct o m y,  bil at er al t u b ul ar li g ati o n  or  bil at er al  o o p h or e ct o m y. 
1 0.  F e m al es  w h o  ar e  br e astf e e di n g 
1 1.  R e c ei pt  of  a n y  d os e  of  N T Z  wit hi n  3 0  d a ys  pri or t o s cr e e ni n g 
1 2.  Pri or tr e at m e nt  wit h  a n y i n v esti g ati o n al  dr u g t h er a p y  wit hi n  3 0  d a ys  pri or t o s cr e e ni n g 


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P a g e  2 6  of  7 2 
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1 3.  S u bj e cts    wit h  a cti v e  r es pir at or y  all er gi es  or  s u bj e cts  e x p e ct e d  t o  r e q uir e  a nti- all er g y 
m e di c ati o ns  d uri n g t h e st u d y  p eri o d f or r es pir at or y  all er gi es 
1 4.  K n o w n s e nsiti vit y t o  N T Z  or  a n y  of t h e  e x ci pi e nts  c o m prisi n g t h e  N T Z t a bl ets 
1 5.  S u bj e cts  u n a bl e t o t a k e  or al  m e di c ati o ns 
1 6.  S u bj e cts  w h o, i n t h e j u d g m e nt  of t h e  I n v esti g at or,  will  b e  u nli k el y t o  c o m pl y  wit h t h e 
r e q uir e m e nts  of t his  pr ot o c ol i n cl u di n g  c o m pl eti o n  of t h e s u bj e ct  di ar y 
5.   
S T U D Y  P R O C E D U R E S 
5. 1.   S c r e e ni n g  E v al u ati o n ( d a y  1) 
B ef or e s cr e e ni n g, s u bj e cts  a n d t h eir  p ar e nts/ g u ar di a n(s)  will  b e i nf or m e d  of t h e  n at ur e  of 
st u d y,  a n d  writt e n  c o ns e nt  m ust  b e  o bt ai n e d  pri or t o  p arti ci p ati o n.   Aft er  gi vi n g i nf or m e d 
c o ns e nt, t h e s u bj e ct  will  b e  assi g n e d  a s u bj e ct  n u m b er,  a n d t h e f oll o wi n g  pr o c e d ur es  will 
b e  c arri e d  o ut: 
1.   C o m pl et e  m e di c al  hist or y. 
2.   F ull  p h ysi c al  e x a mi n ati o n i n cl u di n g  b o d y  w ei g ht  a n d  vit al  si g ns ( bl o o d  pr ess ur e,  p uls e, 
r es pir at or y r at e a n d  or al t e m p er at ur e  usi n g st a n d ar d el e ctr o ni c  or al t h er m o m et er  pr o vi d e d 
b y  S p o ns or). 
3.   C oll e cti o n  of  d e m o gr a p hi c i nf or m ati o n  a n d s m o ki n g  hist or y. 
4.   Uri n e  pr e g n a n c y t est f or  all f e m al es  of  c hil d b e ari n g  p ot e nti al. 
5.   R e c or di n g  of ti m e  of  o ns et  of r es pir at or y s y m pt o ms. 
6.   E v al u ati o n  a c c or di n g t o  eli gi bilit y ( i n cl usi o n  a n d e x cl usi o n )  crit eri a. 
5. 2.   B as eli n e ( d a y  1, s a m e  d a y  as s c r e e ni n g  e v al u ati o n) 
At  b as eli n e, t h e f oll o wi n g  pr o c e d ur es  will  b e  c arri e d  o ut: 
1.   C oll e cti o n  of t w o  n as o p h ar y n g e al s w a bs ( o n e fr o m  e a c h  n ostril)  usi n g  n yl o n fl o c k e d  dr y 
s w a bs ( C o p a n  Di a g n osti cs) f or  R T- P C R  a n d  c ult ur e. 
2.   C oll e cti o n  of  bl o o d s a m pl e f or l a b or at or y s af et y t ests. 
3.   C oll e cti o n  of  a  uri n e s a m pl e f or r o uti n e  uri n al ysis ( gl u c os e,  pr ot ei n  a n d  bl o o d). 
4.   R e vi e w  a n d r e c or di n g  of  a n y  c o n c o mit a nt  m e di c ati o ns. 
5.   Pr o visi o n  of  a n  el e ctr o ni c  di ar y t o  s u bj e ct  vi a  his/ h er  o w n  s m art p h o n e  or  a  pr o visi o n e d 
d e vi c e,  a n d  s u bj e ct  c o m pl eti o n   of   b as eli n e  el e ctr o ni c   di ar y   u n d er  s u p er visi o n  a n d 
i nstr u cti o n   of   st u d y   sit e   p ers o n n el,   i n cl u di n g   t h e   Pr a cti c e    Di ar y,   F L U- P R O 
Q u esti o n n air e,  A cti vit y  Di ar y,  a n d  St u d y  Dr u g I nt a k e  a n d  T e m p er at ur e  Di ar y. 
6.   R a n d o mi z ati o n  a n d  dis p e nsi n g  of  st u d y  m e di c ati o n  ( m e di c ati o n  assi g n e d i n  s e q u e nti al 
or d er). 


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7.   A d mi nistr ati o n  of t h e first  d os e  of st u d y  m e di c ati o n  wit h f o o d ( <  1  h o ur aft er f o o d i nt a k e) 
u n d er  o bs er v ati o n  of I n v esti g at or  or  a  m e m b er  of I n v esti g at or’s st aff,  a n d  e ntr y i n  St u d y 
Dr u g I nt a k e  a n d  T e m p er at ur e  Di ar y. 
8.   I nstr u ct s u bj e ct r e g ar di n g: 
a.   A d mi nistr ati o n  of st u d y  m e di c ati o n.    S u bj e cts  will  b e i nstr u ct e d t o t a k e t h e st u d y 
m e di c ati o n (t w o t a bl ets) t wi c e  d ail y  wit h f o o d ( <  1  h o ur  aft er f o o d i nt a k e, 
pr ef er a bl y  a  hi g h-f at  m e al  b ut  at  a  mi ni m u m  a  c er e al  b ar).   T h e s u bj e ct s h o ul d t a k e 
his/ h er s e c o n d  d os e  as  cl os e  as  p ossi bl e t o  1 2  h o urs  aft er t h e first  d os e.   T h e n  h e/s h e 
will t a k e t h e st u d y  m e di c ati o n  e v er y  1 2  h o urs f or t h e r e m ai ni n g  4  d a ys. 
b.   C o m pl eti o n  of s u bj e ct  di ar y.    S u bj e cts  will  b e i nstr u ct e d  o n  c o m pl eti o n  of t h e 
el e ctr o ni c  di ar y. 
c.   Us e  of  birt h  c o ntr ol.    F e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al, if s e x u all y  a cti v e, 
will  b e i nstr u ct e d t o  c o nti n u e  a n  a c c e pt a bl e  m et h o d  of  birt h  c o ntr ol f or t h e  d ur ati o n 
of t h e st u d y  a n d f or  1  m o nt h  p ost-tr e at m e nt.   A c c e pt a bl e  m et h o ds  of  birt h  c o ntr ol 
i n cl u d e  a  d o u bl e  b arri er  m et h o d,  or al  birt h  c o ntr ol  pills,  a n I U D,  or 
m e dr o x y pr o g est er o n e  a c et at e  a d mi nist er e d i ntr a m us c ul arl y. 
d.   F oll o w- u p  visits:    S u bj e cts  will  b e i nstr u ct e d t o r et ur n t o t h e  cli ni c f or f oll o w- u p  o n 
D a y  7  a n d  D a y  2 2. 
e.   S e e ki n g  e m er g e n c y  c ar e  or  c o nt a cti n g t h e st u d y  p h ysi ci a n  or  n urs e :   S u bj e cts  m ust 
b e i nf or m e d t o s e e k  e m er g e n c y  m e di c al  c ar e  or  c o nt a ct t h e st u d y  p h ysi ci a n  or  n urs e 
if t h e y  d e v el o p  a n y  of t h e f oll o wi n g s y m pt o ms list e d  b el o w  d uri n g t h e f ull  2 2- d a y 
st u d y  a n d f oll o w- u p  p eri o d. 
C A L L  9 1 1  ( U nit e d  St at es)    O R    L O C A L    E M E R G E N C Y  S E R VI C E S  ( o utsi d e  of 
U nit e d  St at es)  O R  H O S PI T A L  O R  C O N T A C T  S T U D Y  P H Y SI CI A N, I F:  
•   Tr o u bl e  br e at hi n g i n cl u di n g s h ort n ess  of  br e at h 
•   S e v er e  h e a d a c h e, stiff  n e c k,  c o nf usi o n  or  e x c essi v e s o m n ol e n c e 
C A L L  S T U D Y  N U R S E  O R  P H Y SI CI A N, I F:  
•   E xtr e m el y  hi g h f e v er  > 1 0 4° F ( 4 0° C) 
•   F e v er ( ≥ 1 0 0. 4° F  or  ≥ 3 8° C) l asts f or l o n g er t h a n  3  d a ys 
•   I n cr e as e d  diffi c ult y  br e at hi n g 
•   W h e e zi n g  d e v el o ps 
•   N e w  p ai n  d e v el o ps  or  p ai n l o c ali z es t o  o n e  ar e a, s u c h  as  a n  e ar, t h e t hr o at, t h e 
c h est,  or t h e si n us es 
•   S y m pt o ms  b e c o m e  m or e s e v er e  or fr e q u e nt 
•   F e v er ( ≥ 1 0 0. 4° F  or  ≥ 3 8° C) r et ur ns  aft er  b ei n g  a bs e nt f or  2 4  h o urs 
•   S y m pt o ms r e c ur  or  a n y  diffi c ult y  br e at hi n g f oll o wi n g  5- 1 0  d a ys r es ol uti o n  of 
ill n ess 
•   A n  all er gi c-li k e r e a cti o n  o c c urs  or is s us p e c t e d 
•   A b n or m al  b e h a vi or 
9.   R e vi e w  a n d r e c or d  a d v ers e  e v e nts 


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5. 3.  D a y  2  –  D a y  2 2  
A  st u d y  p h ysi ci a n,  n urs e  or  ot h er  sit e  p ers o n n el  will r e vi e w  e a c h  s u bj e ct’s  el e ctr o ni c  di ar y 
e ntri es  d ail y  t o  e ns ur e  c o m pli a n c e    wit h  c oll e cti o n  of  di ar y  d at a.    If  a  s u bj e ct  h as  n ot 
c o m pl et e d  his/ h er  di ar y  or if err ors ar e s us p e ct e d, t h e st u d y  p ers o n n el  will c o nt a ct t h e s u bj e ct 
t o i m pl e m e nt  a p pr o pri at e  c orr e cti v e  a cti o ns. 
5. 4.   D a y  2- 5  T el e p h o n e  M o nit o ri n g 
A  st u d y  p h ysi ci a n,  n urs e  or  ot h er  sit e  p ers o n n el  will  m a k e  d ail y t el e p h o n e  c alls t o  s u bj e c ts 
o n  e a c h  of  D a ys  2,  3,  4  a n d  5  of  d osi n g t o  s cr e e n  f or  p ot e nti al  c o m pli c ati o ns  a n d  r e vi e w 
a d v ers e  e v e nts.   S u bj e cts    will   b e  r ef err e d  f or  i m m e di at e  c ar e  as   n e e d e d   b as e d   o n  t h e 
s cr e e ni n g.  All i nf or m ati o n  g ai n e d fr o m t el e p h o n e  m o nit ori n g  will  b e i n cl u d e d i n t h e  E D C 
s yst e m f or  e a c h s u bj e ct.  [ N ot e: I n li e u  of  a t el e p h o n e  c all, t his i nf or m ati o n  m a y  b e  o bt ai n e d 
d uri n g t h e  D a y  2  a n d  3  h o m e  or  offi c e  visits (s e e  b el o w).] 
5. 5.   D a y  2  a n d  3  E v al u ati o ns 
A  st u d y  p h ysi ci a n,  n urs e  or  ot h er  st u d y  p ers o n n el  will  visit  e a c h  s u bj e ct  at  h o m e ( or  at t h e 
cli ni c  or  a n ot h er l o c ati o n  as  a gr e e d  wit h t h e  s u bj e ct)  o n  e a c h  of  D a ys  2  a n d  3 t o (i)  c oll e ct 
t w o  n as o p h ar y n g e al s w a bs f or  d et e cti n g  a n d  q u a ntif yi n g  E V/ R V,  a n d (ii) s cr e e n f or  p ot e nti al 
c o m pli c ati o ns  a n d  a d v ers e  e v e nts.   S u bj e cts  will  b e r ef err e d f or i m m e di at e  c ar e  as  n e e d e d 
b as e d  o n t h e s cr e e ni n g.   All i nf or m ati o n  g ai n e d fr o m t h es e  visits  will  b e i n cl u d e d i n t h e  c as e 
r e p ort  f or ms  f or  e a c h  s u bj e ct.    I n  a d diti o n,  a  bl o o d  s a m pl e  f or  p h ar m a c o ki n eti cs   will  b e 
c oll e ct e d  o n  D a y  3.   T h e  D a y  2  a n d  D a y  3  visits  will  o c c ur  at  a p pr o xi m at el y t h e  s a m e ti m e 
of  d a y t h at t h e  p ati e nt t o o k  his/ h er first  d os e  of  st u d y  m e di c ati o n ( a p pr o xi m at el y  2 4  a n d  4 8 
h o urs aft er t h e first  d os e).   O n  D a y  3, t h e  bl o o d s a m pl e f or  p h ar m a c o ki n eti cs  will  b e c oll e ct e d 
b ef or e t h e first  d os e  of t h at  d a y. 
St u d y sit es  or s u bj e cts  m a y  o pt  o ut  of t h es e  D a y  2 a n d  D a y  3  visits  d u e t o sit e st affi n g, s u bj e ct 
a v ail a bilit y  or  ot h er  pr a cti c al  c o nsi d er ati o ns  or  pr ef er e n c es;  n e v ert h el ess  at  l e ast  7 5 %  of 
s u bj e cts  e nr oll e d i n t h e tri al  ar e  e x p e ct e d t o  c o m pl et e t h e  D a y  2  a n d  D a y  3  visits  a n d r el at e d 
pr o c e d ur es (f or  vir al  ki n eti cs  a n d  p h ar m a c o ki n eti cs). 
5. 6.  D a y  7  F oll o w- u p ( ± 1  d a y)  
S u bj e cts  will r et ur n t o t h e  cli ni c  o n  D a y  7,  a n d t h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d: 
1.   Bri ef   p h ysi c al   e x a mi n ati o n   ( b o d y    w ei g ht   a n d   vit al   si g ns    wit h   n ursi n g   p h ysi c al 
ass ess m e nt) i n cl u di n g  s y m pt o m  dir e ct e d  p h ysi ci a n  p h ysi c al  e x a mi n ati o n  as r e q uir e d  b y 
s u bj e ct  s y m pt o ms.   Vit al  si g ns  will i n cl u d e  bl o o d  pr ess ur e,  p uls e,  r es pir at or y  r at e  a n d 
or al t e m p er at ur e ( us e st a n d ar d  el e ctr o ni c  or al t h er m o m et er  pr o vi d e d  b y  S p o ns or). 
2.   C oll e cti o n   of  t w o   n as o p h ar y n g e al   s w a bs   usi n g   n yl o n   fl o c k e d   dr y   s w a bs   ( C o p a n 
Di a g n osti cs) f or  R T- P C R  a n d  c ult ur e. 
3.   C oll e cti o n  of  bl o o d s a m pl e f or l a b or at or y s af et y t ests. 
4.   C oll e cti o n  of  uri n e s a m pl e f or r o uti n e  uri n al ysis. 
5.   R e vi e w  of  c o m pli a n c e  wit h  st u d y  m e di c ati o n,  c oll e cti o n  of  m e di c ati o n  b ottl e  wit h  a n y 
u n us e d  m e di c ati o ns,  a n d  c o m pl eti o n  of t h e  pill  c o u nt l o g f or m. 


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6.   R e vi e w  a n d r e c or di n g  of  c o n c o mit a nt  m e di c ati o ns. 
7.   R e vi e w  a n d r e c or di n g  of  a d v ers e  e v e nts/si d e  eff e cts  a n d  c o m pli c ati o ns. 
5. 7.   D a y  2 2  F oll o w- u p ( + 3  d a ys) 
S u bj e cts  will r et ur n t o t h e  cli ni c  o n  D a y  2 2,  a n d t h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d: 
1.   Bri ef   p h ysi c al   e x a mi n ati o n   ( b o d y    w ei g ht   a n d   vit al   si g ns    wit h   n ursi n g   p h ysi c al 
ass ess m e nt) i n cl u di n g  s y m pt o m  dir e ct e d  p h ysi ci a n  p h ysi c al  e x a mi n ati o n  as r e q uir e d  b y 
s u bj e ct  s y m pt o ms.   Vit al  si g ns  will i n cl u d e  bl o o d  pr ess ur e,  p uls e,  r es pir at or y  r at e  a n d 
or al t e m p er at ur e ( us e st a n d ar d  el e ctr o ni c  or al t h er m o m et er  pr o vi d e d  b y  S p o ns or). 
2.   C oll e cti o n   of  t w o   n as o p h ar y n g e al   s w a bs   usi n g   n yl o n   fl o c k e d   dr y   s w a bs   ( C o p a n 
Di a g n osti cs) f or  R T- P C R a n d c ult ur e (t o  b e t est e d f or  pr es e n c e  of  vir us  o nl y if t h e s a m pl e 
c oll e ct e d  at t h e  pr e c e di n g ti m e  p oi nt  h a d  d et e ct a bl e  vir us). 
3.   R e vi e w  a n d r e c or di n g  of  c o n c o mit a nt  m e di c ati o ns. 
4.   R e vi e w  a n d  r e c or di n g  of  a d v ers e  e v e nts/si d e  eff e cts  a n d  c o m pli c ati o ns.   N ot e t h at  all 
a d v ers e  e v e nts  a n d  c o m pli c ati o ns  m ust  b e f oll o w e d  u ntil t h eir r es ol uti o n  or st a bili z ati o n 
e v e n  b e y o n d t h e  2 2- d a y st u d y  p eri o d. 
5. 8.   U ns c h e d ul e d  Visit 
S u bj e cts  r et ur ni n g  t o  t h e  cli ni c  f or  a n  u ns c h e d ul e d  visit  d u e  t o    w ors e ni n g  s y m pt o ms  or 
a d v ers e  e v e nts    will   b e  e v al u at e d  at  t h e   dis cr eti o n   of  t h e  I n v esti g at or  as  is    m e di c all y 
w arr a nt e d.   T ests  a n d/  or  pr o c e d ur es  p erf or m e d  at t his  visit  m a y i n cl u d e,  b ut  ar e  n ot li mit e d 
t o, t h e f oll o wi n g: 
1.   Bri ef   p h ysi c al   e x a mi n ati o n   ( b o d y    w ei g ht   a n d   vit al   si g ns    wit h   n ursi n g   p h ysi c al 
ass ess m e nt) i n cl u di n g  s y m pt o m  dir e ct e d  p h ysi ci a n  p h ysi c al  e x a mi n ati o n  as r e q uir e d  b y 
s u bj e ct  s y m pt o ms.   Vit al  si g ns  will i n cl u d e  bl o o d  pr ess ur e,  p uls e,  r es pir at or y  r at e  a n d 
or al t e m p er at ur e ( us e st a n d ar d  el e ctr o ni c  or al t h er m o m et er  pr o vi d e d  b y  S p o ns or). 
2.   C oll e cti o n   of  t w o   n as o p h ar y n g e al   s w a bs   usi n g   n yl o n   fl o c k e d   dr y   s w a bs   ( C o p a n 
Di a g n osti cs) f or  R T- P C R  a n d  c ult ur e. 
3.   C oll e cti o n  of  bl o o d s a m pl e f or l a b or at or y s af et y t ests. 
4.   C oll e cti o n  of  uri n e s a m pl e f or r o uti n e  uri n al ysis. 
5.   R e vi e w  of  c o m pli a n c e  wit h st u d y  m e di c ati o n. 
6.   R e vi e w  a n d r e c or di n g  of  c o n c o mit a nt  m e di c ati o ns. 
7.   R e vi e w  a n d r e c or di n g  of  a d v ers e  e v e nts/si d e  eff e cts. 
5. 9.   St u d y  Dis c o nti n u ati o n 
R ul es f or  dis c o nti n u ati o n  of  a  s u bj e ct  or f or  dis c o nti n ui n g t h e  st u d y  ar e  pr o vi d e d i n  s e cti o n 
1 1. 2 .      All  s u bj e cts  dis c o nti n u e d  fr o m  t h e  st u d y  b ef or e    D a y  7    will  b e  e v al u at e d  at  st u d y 
dis c o nti n u ati o n  usi n g t h e  pr o c e d ur es  d es cri b e d  a b o v e f or  D a y  7.   All  s u bj e cts  dis c o nti n u e d 
fr o m t h e  st u d y  aft er  D a y  7  will  b e  e v al u at e d  at  st u d y  dis c o nti n u ati o n  usi n g t h e  pr o c e d ur es 
d es cri b e d  a b o v e f or  D a y  2 2. 


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N o v e m b er  2 9,  2 0 1 8 
 
P a g e  3 0  of  7 2 
C O N FI D E N TI A L 
5. 1 0.  El e ct r o ni c  S u bj e ct  Di a r y  
El e ctr o ni c  s u bj e ct  di ari es   will  b e  c o m pl et e d  t wi c e  d ail y  t hr o u g h   D a y  2 1.     T h e  el e ctr o ni c 
di ari es  will  c a pt ur e t h e f oll o wi n g i nf or m ati o n: 
1.   M e di c ati o n i nt a k e (t wi c e  d ail y  at ti m e  of  m e di c ati o n i nt a k e). 
2.   Or al t e m p er at ur e (t wi c e  d ail y  at ti m e  of  m e di c ati o n i nt a k e).   Us e st a n d ar d  el e ctr o ni c 
or al t h er m o m et er  pr o vi d e d  b y  S p o ns or. 
3.   Us e  of  ot h er  m e di c ati o ns t a k e n  b y t h e s u bj e ct  n ot  pr e vi o usl y  c a pt ur e d i n t h e s u bj e ct’s 
m e di c ati o n  hist or y.   D o c u m e nt i n  d et ail i n cl u di n g  d os e i n  milli gr a ms  or  ot h er 
a p pli c a bl e  u nits, ti m e  of i n g esti o n,  a n d t h e r e as o n f or  us e  of t h e  m e di c ati o n ( at ti m e  of 
m e di c ati o n i nt a k e). 
4.   F L U - P R O  Q u esti o n n air e ( o n c e  d ail y  b et w e e n  7  p m  a n d  1 1  p m) t o  c h ar a ct eri z e 
s y m pt o ms. 
5.   A cti vit y  ass ess m e nt  usi n g  a n  1 1- p oi nt  vis u al  a n al o g s c al e ( 0 =  u n a bl e t o  p erf or m  n or m al 
a cti vit y,  1 0 = f ull y  a bl e t o  p erf or m  n or m al  a cti vit y) ( o n c e  d ail y  b et w e e n  7  p m  a n d  1 1 
p m). 
6.   A d v ers e  e x p eri e n c es ( o n c e  d ail y  b et w e e n  7  p m  a n d  1 1  p m). 
5. 1 1.  Pl a n f o r  L a b o r at o r y  S af et y  T ests 
A  c e ntr al  l a b or at or y    will  b e  us e d  f or  l a b or at or y  s af et y  t esti n g.    Bl o o d  t ests    will  i n cl u d e 
h e m o gl o bi n,  h e m at o crit, c o m pl et e  bl o o d c o u nt (t ot al a n d  diff er e nti al),  pl at el et c o u nt, r a n d o m 
bl o o d s u g ar, t ot al  c h ol est er ol,  H D L,  L D L, tri gl y c eri d es,  al b u mi n,  A S T,  A L T,  G G T,  al k ali n e 
p h os p h at as e,  bilir u bi n (t ot al/ dir e ct),  B U N,  cr e ati ni n e,  s o di u m,  p ot assi u m,  c hl ori d e.  R o uti n e 
uri n al ysis  will i n cl u d e  gl u c os e,  pr ot ei n,  a n d  bl o o d. 
5. 1 2.  Pl a n f o r  Vi r ol o g y  T esti n g  a n d  M o nit o ri n g  R esist a n c e 
Vir ol o g y  t esti n g  of  n as o p h ar y n g e al  s w a b  s a m pl es   will  b e  c o n d u ct e d  as  d es cri b e d  o n  t h e 
f oll o wi n g  p a g es. 
 
 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  3 1  of  7 2 
C O N FI D E N TI A L 
T a bl e  1 0:    Vi r ol o g y t esti n g  of  n as o p h a r y n g e al s w a bs 
 
D a y  1   
D a y  2   
D a y  3   
D a y  7   
D a y  2 2  
R T -P C R  b y  e Pl e x  R P P f or  Vir us 
D et e c ti o n 
X  
X 1  
X 2  
X 3  
X 4 
S e q u e n ci n g f or  E V/ R V  T y pi n g  
X 5  
 
 
 
 
Q u a ntit ati v e  P C R  
X 6  
X 6  
X 6  
X 7  
 
C ult ur e  &  S us c e pti bilit y  T esti n g f or 
R esist a n c e  M o nit ori n g  
X 8  
 
  
X 8  
X 8 
N u cl e oti d e  S e q u e n ci n g  
X 9  
 
  
X 9  
X 9 
1  If  D a y  1 s a m pl e is  n e g ati v e f or  E V/ R V  b y  R T-P C R  
2  If  D a y  2 s a mpl e is  n e g ati v e f or  E V/ R V  b y  R T -P C R  
3  O nl y if  o n e  of  D a y  1,  2,  or  3 s a m pl es is  p ositi v e f or  E V/ R V f or  R T -P C R  
4  If  D a y  7 s a m pl e is  p ositi v e f or  E V/ R V  b y  R T-P C R  
5  O nl y  t h e  e arli est  s a m pl e  p ositi v e  f or   E V/ R V  b y   R T -P C R  of  t h os e  c oll e ct e d  at    D a ys  1,  2,  a n d  3    wi ll  b e 
s e q u e n c e d f or  E V/ R V t y p e  
6  A s a m pl e  will  o nl y  b e s u bj e ct e d t o  q u a ntit ati v e  P C R if  o n e  of t h e  D a y  1,  2,  or  3 s a m pl es is  p ositi v e f or  E V/ R V 
b y  R T -P C R  
7  T h e  D a y  7  s a m pl e  will  b e  s u bj e ct e d t o  q u a ntit ati v e  P C R  o nl y if  o n e  of t h e  D a y  1,  2,  or  3  s a m pl es  A N D  t h e 
D a y  7 s a m pl e is  p ositi v e f or  E V/ R V  b y  R T -P C R  
8  If t h e  D a y  1  a n d  D a y  7  or  D a y  1,  7,  a n d  2 2  s a m pl es  ar e  p ositi v e f or  E V/ R V  b y  R T-P C R  e a c h  s a m pl e  will  b e 
c ult ur e d  a n d t est e d f or  s us c e pti bilit y t o ti z o x a ni d e.  R es ults  o bs er v e d f or t h e  D a y  7  a n d  D a y  2 2  s a m p l es  will 
b e  c o m p ar e d t o t h e r es ults  o bs er v e d f or t h e  D a y  1 s a m pl e.  
9  S a m pl e  p airs  e x hi biti n g r esist a n c e t o ti z o x a ni d e  will  b e s u bj e ct e d t o s e q u e n ci n g.  
1.   C oll e cti o n  of s a m pl es: 
T w o  n as o p h ar y n g e al  s w a bs  will  b e  c oll e ct e d fr o m  e a c h  s u bj e ct  at  B as eli n e ( D a y  1)  a n d 
D a ys  2,  3,  7  a n d  2 2. 
2.   T esti n g  of  bi ol o gi c al s a m pl es: 
a.   E a c h  B as eli n e  s a m pl e  will  b e  s u bj e ct e d t o  R T- P C R  usi n g t h e  e Pl e x  ®  R es pir at or y 
P at h o g e n  P a n el ( G e n M ar k,  C arls b a d,  C A) t o  d et e ct i nfl u e n z a  A ( n o n-s p e cifi c  as t o 
s u bt y p e);  i nfl u e n z a    A    H 1,    H 1 N 1  ( 2 0 0 9),    H 3  s u bt y p es;  i nfl u e n z a    B;  r es pir at or y 
s y n c yti al  vir us  A  a n d  B ( R S V);  p ar ai nfl u e n z a  1,  2,  3  a n d  4;  h u m a n  m et a p n e u m o vir us 
( h M P V);  a d e n o vir us;  h u m a n  E V/ R V;  c or o n a vir us  N L 6 3,  H K U 1,  2 2 9 E  a n d  O C 4 3; 
h u m a n   b o c a vir us;  C hl a m y d o p hil a   p n e u m o ni a e ;  L e gi o n ell a   p n e u m o p hil a ;   a n d 
M y c o pl as m a  p n e u m o ni a e . 
b.   If  a s u bj e ct’s  B as eli n e s a m pl e is  n e g ati v e f or  E V/ R V  b y  R T- P C R,  his/ h er  D a y  2  a n d 
D a y  3 s a m pl es  will  b e s u bj e ct e d t o  R T- P C R  usi n g t h e  e Pl e x ®  R es pir at or y  P at h o g e n 
P a n el t o  d et e ct r es pir at or y  p at h o g e ns. 
c.   If  t h e   B as eli n e  s a m pl e  or  t h e   D a y  2  or   D a y  3  s a m pl e  is  p ositi v e  f or   E V/ R V,  t h e 
e arli est  p ositi v e  s a m pl e  will  b e  s e q u e n c e d t o  d et er mi n e  vir us t y p e  a n d  e a c h  of t h e 
B as eli n e,  D a y  2  a n d  D a y  3  s a m pl es  will  b e  s u bj e ct e d t o  q u a ntit ati v e  P C R t esti n g t o 
q u a ntif y  vir al s h e d di n g. 
d.   All    D a y  7  s a m pl es    will  b e  s u bj e ct e d  t o    R T- P C R  usi n g  t h e  e Pl e x ®    R es pir at or y 
P at h o g e n   P a n el.    D a y   7  s a m pl es   p ositi v e  f or    E V/ R V    will  als o   b e  s u bj e ct e d  t o 






Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  3 4  of  7 2 
C O N FI D E N TI A L 
Q u eri es  e m er gi n g  d uri n g  d at a  cl e a ni n g   will  b e  g e n er at e d  b y  d at a   m a n a g e m e nt  or  cli ni c al 
r es e ar c h ass o ci at es i n 
   T h e I n v esti g at or  or  his/ h er  d esi g n e e  will a ns w er 
t h e  q u eri es  a n d  u p d at e t h e s o ur c e  d at a, if  n e e d e d.  
A d v ers e  e v e nts  will  b e  c o d e d  b y  d at a  m a n a g e m e nt  usi n g t h e l at est  v ersi o n  of t h e  M e di c al 
Di cti o n ar y  f or    R e g ul at or y    A cti viti es  ( M e d D R A);    m e di c ati o ns    will   b e   c o d e d   b y   d at a 
m a n a g e m e nt  usi n g t h e  W orl d  H e alt h  Or g a ni z ati o n ( W H O)  D R U G  di cti o n ar y.  
Aft er t h e  L ast  S u bj e ct  L ast  Visit  ( L S L V)  h as t a k e n  pl a c e, t h e  d at a b as e  will  b e  cl e a n e d  as 
n e c ess ar y.   As s o o n as t h e  d at a b as e is c o nsi d er e d cl e a n, it  will  b e l o c k e d.  T h e l o c k e d  d at a b as e 
will  b e  us e d i n t h e fi n al st atisti c al  a n al ysis f or st u d y r e p orti n g.   M e as ur es  will  b e  u n d ert a k e n 
t o  pr ot e ct  s u bj e ct  d at a  h a n dl e d  d uri n g i ns p e cti o ns  a g ai nst  dis cl os ur e t o  u n a ut h ori z e d t hir d 
p arti es.   S u bj e ct  c o nfi d e nti alit y  will  b e  m ai nt ai n e d  at  all ti m es. 
All listi n gs,  s u m m ari es  a n d  a n al ys es  will  b e  pr o d u c e d  usi n g  S A S  St atisti c al  S oft w ar e ( S A S 
I nstit ut e, I n c.,  C ar y,  N C). 
7. 2.   P r ot o c ol  D e vi ati o ns 
Pr ot o c ol  d e vi ati o ns    will  b e  d o c u m e nt e d  b y  t h e  I n v esti g at or,  r e p ort e d  t o  t h e  i nstit uti o n al 
r e vi e w  b o ar d  (I R B)  as  a p pr o pri at e,  a n d  als o  r e vi e w e d  b y  t h e  assi g n e d  cli ni c al  r es e ar c h 
ass o ci at e ( C R A).  D e vi ati o ns  will  b e r e p ort e d i n t h e  cli ni c al tri al  m a n a g e m e nt  s yst e m.  E a c h 
d e vi ati o n  will  b e  cl assifi e d  as  m aj or  or  mi n or  a c c or di n g t o t h e f oll o wi n g  d efi niti o ns: 
M aj or  pr ot o c ol  d e vi ati o n:    
A   d e vi ati o n   t h at   h as   a n   i m p a ct   o n   s u bj e ct   s af et y,    m a y 
s u bst a nti all y  alt er ris ks t o  s u bj e cts,  m a y  h a v e  a n  eff e ct  o n t h e 
i nt e grit y   of   t h e   st u d y   d at a,   or    m a y   aff e ct   t h e   s u bj e ct’s 
willi n g n ess t o  p arti ci p at e i n t h e st u d y  
Mi n or  pr ot o c ol  d e vi ati o n:    All  ot h er  pr ot o c ol  d e vi ati o ns. 
7. 3.  D at a  Q u alit y  Ass u r a n c e  
T h e  a c c ur a c y  a n d r eli a bilit y  of t h e  st u d y  d at a  will  b e  ass ur e d  b y t h e  s el e cti o n  of  q u alifi e d 
I n v esti g at ors   a n d   a p pr o pri at e   st u d y   c e nt ers,   r e vi e w   of   pr ot o c ol   pr o c e d ur es    wit h  t h e 
I n v esti g at or  a n d  ass o ci at e d  p ers o n n el  pri or t o t h e st u d y,  a n d  b y  p eri o di c  m o nit ori n g  visits  b y 
t h e  S p o ns or.   Writt e n i nstr u cti o ns  will  b e  pr o vi d e d f or  c oll e cti o n,  pr e p ar ati o n,  a n d s hi p m e nt 
of s a m pl es. 
T h e    m o nit or    will   r e vi e w   t h e   s o ur c e   d at a   f or   a c c ur a c y   a n d   c o m pl et e n ess,   a n d   a n y 
dis cr e p a n ci es  will  b e r es ol v e d  wit h t h e I n v esti g at or  or  d esi g n e e,  as  a p pr o pri at e.  
T h e  S p o ns or    will  b e  e ntitl e d  t o  i ns p e ct  a n d  a u dit  t h e  f a ciliti es  us e d  i n  t h e  cli ni c al  a n d 
l a b or at or y  p arts  of  t h e  st u d y,  as   w ell  as  t o    m a k e  a n o n y mi z e d  c o pi es  of  all  t h e  d at a  fil es 
p ert ai ni n g  t o  t h e  st u d y.     Si mil ar  pr o c e d ur es    m a y  als o  b e  c o n d u ct e d  b y  a g e nts  of  a n y 
r e g ul at or y  b o d y,  eit h er  as  p art  of  a  n ati o n al  G C P  c o m pli a n c e  pr o gr a m  or t o r e vi e w t h e r es ults 
of t his  st u d y i n  s u p p ort  of  a  r e g ul at or y  s u b missi o n.   T h e  I n v esti g at or  s h o ul d i m m e di at el y 
n otif y  t h e  S p o ns or  if  t h e y  h a v e  b e e n  c o nt a ct e d  b y  a  r e g ul at or y  a g e n c y  c o n c er ni n g  a n 
u p c o mi n g i ns p e cti o n. 




Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  3 6  of  7 2 
C O N FI D E N TI A L 
8. 2.   Effi c a c y  V a ri a bl es 
Pri m ar y  Effi c a c y  P ar a m et er:    
Ti m e fr o m first  d os e  u ntil  S y m pt o m  R es p o ns e  
S e c o n d ar y  Effi c a c y  P ar a m et ers:  
i.    Ti m e  fr o m  first   d os e   u ntil  s u bj e cts  ar e  a bl e  t o 
p erf or m  1 0 0 %  of  n or m al  a cti viti es (i. e.,  a  s c or e  of 
1 0  o n t h e s c al e  of  0- 1 0) 
ii.   Pr o p orti o ns  of  s u bj e cts  e x p eri e n ci n g  o n e  or  m or e 
c o m pli c ati o ns  of  c ol ds  d u e  t o    E V/ R V  i nf e cti o n 
i n cl u di n g   p n e u m o ni a,   otitis    m e di a,   br o n c hitis, 
si n usitis,   e x a c er b ati o ns   of   ast h m a   or    C O P D, 
w ors e ni n g   of   pr e- e xisti n g   h e alt h   c o n diti o ns, 
s e c o n d ar y i nf e cti o ns  r e q uiri n g  s yst e mi c  a nti bi oti c 
us e,  h os pit ali z ati o n  d u e t o  c ol d  or  c o m pli c ati o ns  of 
t h e  c ol d,  a n d  d e at h  d u e t o  c ol d  or  c o m pli c ati o ns  of 
t h e  c ol d 
E x pl or at or y  Effi c a c y  P ar a m et ers:  
i.    Ti m e t o I n di vi d u al  S y m pt o m  R es p o ns e 
ii.    Ti m e t o  F L U- P R O  D o m ai n  R es p o ns e 
i v.    Ti m e t o  R et ur n t o  Us u al  H e alt h 
v.    C h a n g e  i n   vir us  tit er  ( q u a ntit ati v e   P C R)  fr o m 
b as eli n e  t o    D a y  2,  fr o m  b as eli n e  t o    D a y  3,  a n d 
fr o m  b as eli n e t o  D a y  7 
vi.   Pr o p orti o ns   of  s u bj e cts    wit h   vir us   d et e ct e d  i n 
n as o p h ar y n g e al  s w a bs  c oll e ct e d  at  e a c h  of   D a ys 
2,  3  a n d  7  b y  c ult ur e  a n d  b y  R T- P C R 
vii.    Ti m e   t o   S y m pt o m    R es p o ns e   f or   all   s u bj e cts 
tr e at e d (I T T  p o p ul ati o n) 
viii.  Ti m e t o  S y m pt o m  R es p o ns e f or  s u bj e cts i nf e ct e d 
wit h i n di vi d u al  n o n- E V/ R V  vir us es 
8. 3.   R es p o ns e  D efi niti o ns 
S y m pt o m  R es p o ns e:    
T o  b e  d efi n e d  b as e d  u p o n  a  bli n d e d  r e vi e w  of  s y m pt o m 
s c or es  ( p o ol e d  f or  all    E V/ R V-i nf e ct e d  s u bj e cts    wit h o ut 
r e g ar d t o tr e at m e nt  gr o u p  assi g n m e nt) t h at  c orr el at e t o t h e 
ti m e  at    w hi c h  s u bj e cts  r e p ort  t h at  t h e y  r et ur n  t o  us u al 
h e alt h ( a  d ail y  gl o b al  ass ess m e nt  q u esti o n).   M et h o d ol o g y 
f or   t h e   c orr el ati o n    will   b e   d efi n e d   i n   t h e   St atisti c al 
A n al ysis  Pl a n.   S y m pt o m s c or es  m ust  b e  m ai nt ai n e d  at t h e 
d efi n e d l e v el f or  at l e ast  2  d ail y  di ar y  p eri o ds  wit h o ut  a n y 
s y m pt o m  r eli ef    m e di c ati o n   d uri n g  t h os e   2   d ail y   di ar y 
p eri o ds. 
Ti m e  of  S y m pt o m  R es p o ns e:    
T h e st art  of t h e first  d ail y  di ar y  p eri o d i n  w hi c h  S y m pt o m 
R es p o ns e is  a c hi e v e d  a n d is  m ai nt ai n e d f or  at l e ast  2  d ail y 


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C O N FI D E N TI A L 
di ar y   p eri o ds    wit h o ut   a n y   s y m pt o m  r eli ef    m e di c ati o n 
d uri n g t h os e  2  d ail y  di ar y  p eri o ds. 
Ti m e t o  S y m pt o m  R es p o ns e:    
Ti m e  ( h o urs)  fr o m  first  d os e  t o  t h e    Ti m e  of  S y m pt o m 
R es p o ns e. 
A bilit y t o  P erf or m  All  N or m al 
A cti viti es: 
S u bj e ct r e p orts  a  s c or e  of  1 0  o n t h e  0- 1 0  s c al e f or  a bilit y 
t o  p erf or m  n or m al  a cti viti es,   w hi c h  is    m ai nt ai n e d  f or  at 
l e ast   2   d ail y   di ar y   p eri o ds    wit h o ut   s y m pt o m   r eli ef 
m e di c ati o n  d uri n g t h os e  2  d ail y  di ar y  p eri o ds 
Ti m e  of  A bilit y t o  P erf or m  
All  N or m al  A cti viti es:    
T h e st art  of t h e first  d ail y  di ar y  p eri o d i n  w hi c h t h e s u bj e ct 
r e p orts a s c or e  of  1 0  o n t h e  0- 1 0 s c al e f or a bilit y t o  p erf or m 
n or m al  a cti viti es,  w hi c h is  m ai nt ai n e d f or  at l e ast  2  d ail y 
di ar y  p eri o ds   wit h o ut  s y m pt o m  r eli ef    m e di c ati o n  d uri n g 
t h os e  2  d ail y  di ar y  p eri o ds 
 
Ti m e t o  A bilit y t o  P erf or m  All 
N or m al  A cti viti es: 
Ti m e  ( h o urs)  fr o m  first  d os e  t o  t h e   Ti m e  of    A bilit y  t o 
P erf or m  All  N or m al  A cti viti es 
I n di vi d u al  S y m pt o m  R es p o ns e:   F or  e a c h  i n di vi d u al  s y m pt o m  ( n = 3 2),  a  s c or e  of  ≤   t h e 
m a xi m u m   r es p o ns e   v al u e   s p e cifi e d   i n   t h e   S y m pt o m 
R es p o ns e  d efi niti o n   m ai nt ai n e d  f or  at  l e ast  2  d ail y  di ar y 
p eri o ds  wit h o ut s y m pt o m r eli ef  m e di c ati o n  d uri n g t h os e  2 
d ail y  di ar y  p eri o ds 
Ti m e  of I n di vi d u al  S y m pt o m  
R es p o ns e: 
T h e  st art   of  t h e  first   d ail y   di ar y   p eri o d  i n    w hi c h  t h e 
I n di vi d u al   S y m pt o m    R es p o ns e   is   a c hi e v e d   a n d   is 
m ai nt ai n e d  f or   at  l e ast   2   d ail y   di ar y   p eri o ds    wit h o ut 
s y m pt o m  r eli ef    m e di c ati o n   d uri n g  t h os e   2   d ail y   di ar y 
p eri o ds 
Ti m e t o I n di vi d u al  S y m pt o m  
R es p o ns e: 
Ti m e   ( h o urs)   fr o m   first   d os e   t o    Ti m e   of   I n di vi d u al 
S y m pt o m  R es p o ns e 
F L U - P R O  D o m ai n  R es p o ns e:   
F or  e a c h i n di vi d u al  d o m ai n ( n = 6),  e a c h it e m  s c or e d  ≤  t h e 
m a xi m u m   r es p o ns e   v al u e   s p e cifi e d   i n   t h e   S y m pt o m 
R es p o ns e  d efi niti o n   m ai nt ai n e d  f or  at  l e ast  2  d ail y  di ar y 
p eri o ds  wit h o ut s y m pt o m r eli ef  m e di c ati o n  d uri n g t h os e  2 
d ail y  di ar y  p eri o ds 
Ti m e  of  F L U- P R O  D o m ai n  
R es p o ns e: 
F or  e a c h  d o m ai n, t h e st art  of t h e first  d ail y  di ar y  p eri o d i n 
w hi c h t h e  F L U- P R O  D o m ai n  R es p o ns e is  a c hi e v e d  a n d is 
m ai nt ai n e d  f or   at  l e ast   2   d ail y   di ar y   p eri o ds    wit h o ut 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  3 8  of  7 2 
C O N FI D E N TI A L 
s y m pt o m  r eli ef    m e di c ati o n   d uri n g  t h os e   2   d ail y   di ar y 
p eri o ds 
Ti m e t o  F L U- P R O  D o m ai n  
R es p o ns e: 
Ti m e   ( h o urs)   fr o m   first   d os e   t o   F L U- P R O    D o m ai n 
R es p o ns e f or  e a c h  d o m ai n 
R et ur n t o  Us u al  H e alt h:   
“ Y es ” r es p o ns e t o t h e  d ail y  F L U- P R O  gl o b al  ass ess m e nt 
q u esti o n,  “ H a v e  y o u r et ur n e d t o  y o ur  us u al  h e alt h t o d a y ? ” 
m ai nt ai n e d  f or   at  l e ast   2   d ail y   di ar y   p eri o ds    wit h o ut 
s y m pt o m  r eli ef    m e di c ati o n   d uri n g  t h os e   2   d ail y   di ar y 
p eri o ds 
Ti m e  of  R et ur n t o  Us u al  H e alt h:    T h e  st art  of  t h e  first  d ail y  di ar y  p eri o d  i n    w hi c h    Us u al 
H e alt h  is  a c hi e v e d  a n d  is   m ai nt ai n e d  f or  at  l e ast  2  d ail y 
di ar y  p eri o ds   wit h o ut  s y m pt o m  r eli ef    m e di c ati o n  d uri n g 
t h os e  2  d ail y  di ar y  p eri o ds 
Ti m e t o  R et ur n t o  Us u al  H e alt h:    Ti m e  ( h o urs)  fr o m  first  d os e t o  Ti m e  of  R et ur n t o  Us u al 
H e alt h  
C o m pli c ati o n  of  C ol ds:    
C o m pli c ati o ns  of  c ol ds  d u e  t o   E V/ R V  i nf e cti o n  i n cl u d e 
p n e u m o ni a,   
otitis    
m e di a,   
br o n c hitis,   
si n usitis, 
e x a c er b ati o ns   of   ast h m a   or    C O P D,    w ors e ni n g   of   pr e-
e xisti n g  h e alt h  c o n diti o ns,  s e c o n d ar y i nf e cti o ns r e q uiri n g 
s yst e mi c   a nti bi oti c   us e,   h os pit ali z ati o n   d u e  t o   c ol d   or 
c o m pli c ati o ns   of  t h e   c ol d,   a n d   d e at h   d u e  t o   c ol d   or 
c o m pli c ati o ns   of   t h e   c ol d.    E x a c er b ati o ns   of   ast h m a, 
e x a c er b ati o ns   of    C O P D,   b a ct eri al   p n e u m o ni a,   a c ut e 
b a ct eri al  otitis  m e di a  a n d  a c ut e  b a ct eri al  si n usitis  will  b e 
r e p ort e d  as  c o m pli c ati o ns  of  c ol ds  d u e t o  E V/ R V i nf e cti o n 
o nl y if  e a c h  of t h e f oll o wi n g  crit eri a  ar e s atisfi e d: 
E x a c er b ati o n  of  ast h m a: 
1.   E pis o d e   
r e q uir es   
tr e at m e nt    
wit h   
s yst e mi c 
c orti c ost er oi ds,  a n d 
2.   E pis o d e is  c o nsi d er e d  b y t h e I n v esti g at or t o  b e r el at e d 
t o  vir al r es pir at or y i nf e cti o n 
E x a c er b ati o n  of  C O P D: 
1.   E pis o d e r e q uir es  a  c h a n g e i n r e g ul ar  m e di c ati o n ( e. g., 
a d diti o n  of  a nti bi oti cs  a n d/ or  or al  c orti c ost er oi ds),  a n d 
2.   E pis o d e is  c o nsi d er e d  b y t h e I n v esti g at or t o  b e r el at e d 
t o  vir al r es pir at or y i nf e cti o n 
B a ct eri al  p n e u m o ni a: 


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N o v e m b er  2 9,  2 0 1 8 
 
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C O N FI D E N TI A L 
1.   At  l e ast  t w o  of  t h e  f oll o wi n g  s y m pt o ms:  diffi c ult y 
br e at hi n g,  c o u g h,  pr o d u cti o n  of  p ur ul e nt s p ut u m,  c h est 
p ai n,  a n d 
2.   At l e ast t w o  of t h e f oll o wi n g  vit al  si g n  a b n or m aliti es: 
f e v er,  h y p ot e nsi o n, t a c h y c ar di a, t a c h y p n e a,  a n d 
3.   At  l e ast  o n e  of  t h e  f oll o wi n g  fi n di n gs:  h y p o x e mi a, 
cli ni c al  e vi d e n c e  of  p ul m o n ar y  c o ns oli d ati o n,  el e v at e d 
w hit e  bl o o d  c ell  c o u nt  or l e u k o p e ni a,  a n d 
4.   C h est r a di o gr a p h fi n di n gs  of  n e w i nfiltr at es i n  a l o b ar 
or  m ultil o b ar  distri b uti o n,  a n d 
5.   Mi cr o bi ol o gi c  crit eri a:  a p pr o pri at e  s p ut u m  s p e ci m e n 
wit h f e w er t h a n  1 0 s q u a m o us  e pit h eli al  c ells  a n d  m or e 
t h a n  2 5  p ol y m or p h o n u cl e ar  c ells  p er l o w  p o w er fi el d 
A c ut e  b a ct eri al  otitis  m e di a: 
1.   S y m pt o ms   of   e ar   p ai n   or   e ar a c h e,   e ar  f ull n ess   or 
d e cr e as e d  h e ari n g,  a n d  
2.   O n e   or    m or e   of  t h e   f oll o wi n g   ot os c o pi c   fi n di n gs 
p erf or m e d  b y  a  cli ni ci a n  e x p eri e n c e d i n  ot os c o p y: 
•   B ul gi n g   or  f ull n ess   of  t h e  t y m p a ni c    m e m br a n e 
( c o n v e xit y  of t h e  pl a n e  of t h e  e ar dr u m),  wit h l oss 
of  a n at o mi c l a n d m ar ks  o n  vis u ali z ati o n,  
•   O p a cifi c ati o n   of   t h e   t y m p a ni c    m e m br a n e 
r e g ar dl ess  of  c ol or,  
•   Er yt h e m a  of t h e t y m p a ni c  m e m br a n e,  or  
•   A b n or m al   t y m p a ni c    m e m br a n e    m o bilit y   o n 
bi p h asi c   p n e u m ati c   ot os c o p y;   a   t y m p a ni c 
m e m br a n e i n t h e  n e utr al  p ositi o n  or r etr a ct e d is  n ot 
s uffi ci e nt  e vi d e n c e  of  a c ut e  b a ct eri al  otitis  m e di a 
b e c a us e t h es e  fi n di n gs  ar e  n ot  s p e cifi c  e n o u g h t o 
disti n g uis h  t h e   dis e as e   fr o m   otitis    m e di a    wit h 
eff usi o n  
B a ct eri al si n usitis: 
1.   At l e ast t w o  of t h e f oll o wi n g s y m pt o ms:  
•   M a xill ar y  t o ot h  p ai n  ( u nil at er al  fi n di n gs  c a n  b e 
m or e s p e cifi c)  
•   F a ci al   p ai n   ( u nil at er al   fi n di n gs   c a n   b e    m or e 
s p e cifi c)  
•   Fr o nt al  h e a d a c h e  


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N o v e m b er  2 9,  2 0 1 8 
 
P a g e  4 0  of  7 2 
C O N FI D E N TI A L 
•   P ur ul e nt  n as al  dis c h ar g e ( u nil at er al fi n di n gs  c a n  b e 
m or e s p e cifi c)  
•   N e w  o ns et f et or  oris ( b a d  br e at h)  
•   M or ni n g  c o u g h  
•   N as al  o bstr u cti o n,  a n d 
2.   At l e ast  o n e  of t h e f oll o wi n g si g ns:  
•   P ur ul e nt   s e cr eti o ns   fr o m   si n us   osti a   o n 
e x a mi n ati o n  
•   A b n or m al si n us tr a nsill u mi n ati o n  
•   P ai n  o n  p al p ati o n  o v er si n us es  
•   F a ci al s w elli n g,  a n d 
3.   R a di o gr a p hi c fi n di n gs  c o nsist e nt  wit h  a c ut e si n usitis 
8. 4.   St atisti c al  M et h o d ol o g y 
T h e  st atisti c al  m et h o d ol o g y is  d es cri b e d  bri efl y  b el o w  a n d  will  b e  d es cri b e d i n  d et ail i n t h e 
St atisti c al  A n al ysis  Pl a n. 
8. 4. 1.   
Effi c a c y  A n al ys es 
Effi c a c y  a n al ys es  will  b e  b as e d  o n  a  p o p ul ati o n  c o nsisti n g  of  all s u bj e cts t h at r e c ei v e d  at 
l e ast  o n e  d os e  of  st u d y  dr u g  a n d  h a d l a b or at or y- d o c u m e nt e d  E V/ R V i nf e cti o n (i nf e ct e d 
i nt e nt-t o-tr e at  or I T TI  p o p ul ati o n).   L a b or at or y- d o c u m e nt e d  E V/ R V i nf e cti o n is  d efi n e d 
b y i d e ntifi c ati o n  of  E V/ R V i n  n as o p h ar y n g e al s e cr eti o ns  b y  R T- P C R  at  b as eli n e,  D a y  2 
or  D a y  3.  F or ti m e t o  e v e nt  a n al ys es  a t est  of si g nifi c a n c e ( as  d es cri b e d i n t h e f oll o wi n g) 
will  b e  p erf or m e d  wit h  d es cri pti v e st atisti cs  pr o vi d e d i n cl u di n g t h e  us e  of  K a pl a n- M ei er 
fi g ur es.  
T h er e  will  b e  o n e  pri m ar y  effi c a c y  a n al ysis: 
•   Ti m e t o  S y m pt o m  R es p o ns e f or t h e  N T Z tr e at m e nt  gr o u p  will  b e  c o m p ar e d t o t h at 
of t h e  pl a c e b o tr e at m e nt  gr o u p  usi n g  a  str atifi e d  G e h a n- Wil c o x o n t est  ( α   = 0. 0 5) 
w h er e  str atifi c ati o n   will  f oll o w  t h at  us e d  f or  r a n d o mi z ati o n.    S u bj e cts   wit h o ut  a 
S y m pt o m  R es p o ns e  b ei n g r e c or d e d  will  b e tr e at e d  as  c e ns or e d  as  of t h eir l ast  di ar y 
wit h o ut  a  d o c u m e nt e d  S y m pt o m  R es p o ns e. 
If t h e  pri m ar y  a n al ysis is  si g nifi c a nt  at t h e  0. 0 5 l e v el,  a  k e y  s e c o n d ar y  effi c a c y  a n al ysis 
will  b e f or m all y  e v al u at e d  at t h e  0. 0 5 l e v el  as f oll o ws: 
•   Ti m e t o  A bilit y t o  P erf or m  All  N or m al  A cti viti es f or t h e t w o tr e at m e nt  gr o u ps  will 
b e  c o m p ar e d  usi n g  a  str atifi e d  G e h a n- Wil c o x o n t est ( α   = 0. 0 5)  w h er e  str atifi c ati o n 
will f oll o w t h at  us e d f or r a n d o mi z ati o n.   S u bj e cts  wit h o ut  a n  A bilit y t o  P erf or m  All 
N or m al  A cti viti es r es p o ns e  b ei n g r e c or d e d  will  b e tr e at e d  as  c e ns or e d  as  of t h eir 
l ast  di ar y  wit h o ut  a  d o c u m e nt e d  A bilit y t o  P erf or m  All  N or m al  A cti viti es r es p o ns e. 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  4 1  of  7 2 
C O N FI D E N TI A L 
If  b ot h t h e  pri m ar y  a n al ysis  a n d t h e  k e y s e c o n d ar y  effi c a c y  a n al ysis  ar e si g nifi c a nt  at t h e 
0. 0 5  l e v el,  a n ot h er  s e c o n d ar y  effi c a c y  a n al ysis   will  b e  f or m all y  e v al u at e d  at  t h e  0. 0 5 
l e v el  as f oll o ws: 
•   Pr o p orti o ns  of  s u bj e cts  e x p eri e n ci n g  o n e  or    m or e  c o m pli c ati o ns  of  c ol ds  d u e  t o 
E V/ R V i nf e cti o n  will  b e  c o m p ar e d  b et w e e n t h e tr e at m e nt  gr o u ps  usi n g  a  C o c hr a n-
M a nt el- H a e ns z el t est str atifi e d  b y t h e r a n d o mi z ati o n str at a ( α   = 0. 0 5). 
E x pl or at or y  a n al ys es  will  b e  p erf or m e d  as f oll o ws: 
•   F or  e a c h  of t h e  3 2 i n di vi d u al  F L U- P R O  s y m pt o ms,  Ti m e t o I n di vi d u al  S y m pt o m 
R es p o ns e  f or t h e  N T Z  a n d  pl a c e b o tr e at m e nt  gr o u ps  will  b e  c o m p ar e d  usi n g t h e 
G e h a n- Wil c o x o n t est. 
•   F or  e a c h  of t h e  6  F L U- P R O  d o m ai ns,  Ti m e t o  F L U- P R O  D o m ai n  R es p o ns e f or t h e 
N T Z  a n d  pl a c e b o tr e at m e nt  gr o u ps  will  b e  c o m p ar e d  usi n g t h e  G e h a n- Wil c o x o n 
t est. 
•   Ti m e t o  R et ur n t o  Us u al  H e alt h f or t h e  N T Z  a n d  pl a c e b o tr e at m e nt  gr o u ps  will  b e 
c o m p ar e d  usi n g t h e  G e h a n- Wil c o x o n t est. 
•   C h a n g es i n  vir al tit ers fr o m  b as eli n e t o  D a y  2, fr o m  b as eli n e t o  D a y  3,  a n d fr o m 
b as eli n e t o  D a y  7 f or t h e  N T Z a n d  pl a c e b o tr e at m e nt  gr o u ps  will  b e c o m p ar e d  usi n g 
a t- t est. 
•   F or  s u bj e cts  wit h l a b or at or y- c o nfir m e d  E V/ R V, t h e  pr o p orti o ns  of  s u bj e cts  wit h 
E V/ R V  d et e ct e d  b y  c ult ur e i n  n as o p h ar y n g e al s w a bs  c oll e ct e d  at  e a c h  of  D a ys  2,  3 
a n d  7  will  b e  c o m p ar e d f or t h e t w o tr e at m e nt  gr o u ps  usi n g  a  Fis h er’s  e x a ct t est. 
•   F or  t h e  I T T  p o p ul ati o n,   Ti m e  t o  S y m pt o m   R es p o ns e  f or  t h e    N T Z  a n d  pl a c e b o 
tr e at m e nt  gr o u ps  will  b e  c o m p ar e d  usi n g t h e  G e h a n- Wil c o x o n t est. 
•   F or   s u bs ets   of   s u bj e cts   i nf e ct e d    wit h   i n di vi d u al   n o n- E V/ R V   vir us es   ( e. g., 
c or o n a vir us),   Ti m e  t o  S y m pt o m    R es p o ns e  f or  t h e    N T Z  a n d  pl a c e b o  tr e at m e nt 
gr o u ps  will  b e  c o m p ar e d  usi n g t h e  G e h a n- Wil c o x o n t est.   
S e nsiti vit y  a n al ys es f or t h e  pri m ar y  e n d p oi nt  will i n cl u d e: 
•   R e p e at t h e  pri m ar y  effi c a c y  a n al ysis,  assi g ni n g  a  Ti m e t o  S y m pt o m  R es p o ns e  of 
2 1  d a ys f or  s u bj e cts t h at  dis c o nti n u e  pri or t o  D a y  2 1  wit h o ut  a c hi e vi n g  S y m pt o m 
R es p o ns e. 
•   R e p e at t h e  pri m ar y  effi c a c y  a n al ysis f or  a  “ p er  pr ot o c ol ” s u bs et. 
•   R e p e at t h e  pri m ar y  effi c a c y  a n al ysis  e x cl u di n g  N T Z-tr e at e d s u bj e cts  w h o r e p ort e d 
e x p eri e n ci n g  c hr o m at uri a. 
8. 4. 2.   
P o p ul ati o n  P h a r m a c o ki n eti cs  A n al ysis 
O n  D a y  3, t h e  pl as m a s a m pl es  will  b e  c oll e ct e d  b ef or e t h e  m or ni n g  d os e ( at t h e tr o u g h).  
T h es e  d at a  will  all o w f or  a n al ysis  of r el ati o ns hi ps  b et w e e n tr o u g h  pl as m a  c o n c e ntr ati o ns 
a n d  cli ni c al  a n d  vir ol o gi c r es p o ns e. 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  4 2  of  7 2 
C O N FI D E N TI A L 
D a y  3  tr o u g h  pl as m a  c o n c e ntr ati o ns  of  ti z o x a ni d e  a n d  ti z o x a ni d e  gl u c ur o ni d e   will  b e 
s u m m ari z e d  d es cri pti v el y f or  e a c h  of t h e tr e at m e nt  gr o u ps.   E x pl or at or y  a n al ys es  will  b e 
c o n d u ct e d  t o  e v al u at e  t h e  r el ati o ns hi ps  b et w e e n  pl as m a  c o n c e ntr ati o ns  a n d  a g e,  r a c e, 
g e n d er,  b o d y  w ei g ht,  b o d y  m ass i n d e x,  c o n c o mit a nt  m e di c ati o ns,  c h a n g es i n  vir al tit er 
o v er ti m e, ti m e fr o m first  d os e t o  S y m pt o m  R es p o ns e  a n d  a d v ers e  e v e nts. 
8. 4. 3.   
S af et y  A n al ys es 
All  r a n d o mi z e d  s u bj e cts   w h o  r e c ei v e  t h e  st u d y   m e di c ati o n   will  b e  e v al u at e d  f or  dr u g 
s af et y.   S af et y  a n al ys es  will  b e  d o n e  d es cri pti v el y. 
9.   
I N V E S TI G A TI O N A L  P R O D U C T S 
9. 1.   D r u g  R e gi m e ns,  A d mi nist r ati o n  a n d  D u r ati o n 
Gr o u p  1 ( N T Z):   
S u bj e cts  will r e c ei v e t w o  N T Z  3 0 0  m g t a bl ets  b.i. d.  wit h f o o d ( <  1  h o ur 
aft er f o o d i nt a k e) f or  5  d a ys. 
Gr o u p  2 ( Pl a c e b o):   S u bj e cts  will r e c ei v e t w o  pl a c e b o t a bl ets  b.i. d.  wit h f o o d ( <  1  h o ur aft er 
f o o d i nt a k e) f or  5  d a ys. 
T h e f o o d  pri or t o  dr u g i nt a k e s h o ul d  pr ef er a bl y  b e  a  hi g h-f at  m e al,  b ut  at  mi ni m u m  a  c er e al 
b ar. 
9. 2.   I d e ntit y  of I n v esti g ati o n al  P r o d u cts 
N T Z  3 0 0  m g  a n d  pl a c e b o t a bl ets  w er e  m a n uf a ct ur e d f or  R o m ar k  L a b or at ori es,  L. C.  b y   
 
 i n t h e  U nit e d  St at es.   T h e  a cti v e f or m ul ati o n f or 
t his st u d y is  a  y ell o w, fil m- c o at e d t a bl et t h at  c o nt ai ns  3 0 0  m g  N T Z  pl us st a n d ar d  e x ci pi e nts.  
T h e  pl a c e b o t a bl et  will  h a v e t h e s a m e a p p e ar a n c e a n d i n a cti v e i n gr e di e nts as t h e a cti v e t a bl et. 
9. 3.   P a c k a gi n g  a n d  L a b eli n g 
N T Z  or  pl a c e b o  t a bl ets   will  b e  p a c k a g e d  f or  e a c h  s u bj e ct  i n  a   w hit e   H D P E  b ottl e,  e a c h 
c o nt ai ni n g  2 0  t a bl ets.     T h e  s u bj e cts   will  t a k e  t w o  t a bl ets  at  e a c h  d osi n g  ti m e  p oi nt.     T h e 
b ottl es    will   b e  st or e d   at  r o o m  t e m p er at ur e   a n d    will   b e ar   a  l a b el    wit h  t h e  f oll o wi n g 
i nf or m ati o n: 
T a bl e  1 1:   St u d y  M e di c ati o n  L a b el 
 
2 0  T a bl ets 
St u d y  N°  R M 0 8- 3 0 0 5    
Tr e at m e nt  N°:   X X X X 
L ot: 
P ri n ci p al I n v esti g at o r:  
 
T a k e  2  T a bl ets  b y  M o ut h  wit h  F o o d  T wi c e  D ail y 
C a uti o n:  N e w  Dr u g- Li mit e d  b y  F e d er al  L a w t o I n v esti g ati o n al  Us e 
S T O R E  A T  R O O M  T E M P E R A T U R E •  D O  N O T  U S E  B E Y O N D  E N D  O F  S T U D Y 
K E E P  O U T  O F  R E A C H  O F  C HI L D R E N 
St u d y  S p o ns or:  T h e  R o m ar k I nstit ut e f or  M e di c al  R es e ar c h 
 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  4 3  of  7 2 
C O N FI D E N TI A L 
9. 4.   D r u g  A c c o u nt a bilit y 
M e di c ati o n  will  b e  dis p e ns e d at  b as eli n e.   M e di c ati o n c o m pli a n c e  will  b e r e vi e w e d  wit h e a c h 
s u bj e ct  d uri n g t h e  D a y  2- 5  T el e p h o n e  M o nit ori n g.   At t h e  D a y  7  visit, s u bj e cts  will  b e  as k e d 
t o r et ur n t h e  b ottl e i n  w hi c h t h e  m e di c ati o n  w as  dis p e ns e d al o n g  wit h a n y  u n us e d  m e di c ati o n.  
T h e I n v esti g at or  or  d esi g n e e is r e q uir e d t o  m ai nt ai n  a d e q u at e r e c or ds  of t h e  dis p ositi o n  of 
all  st u d y  dr u g,  i n cl u di n g  d at es,  q u a ntit y  a n d  us e  b y  s u bj e ct.      U n us e d  s u p pli es    m ust  b e 
r et ur n e d t o t h e  S p o ns or. 
9. 5.   S u bj e ct  C o m pli a n c e 
S u bj e ct  c o m pli a n c e  wit h t h e  pr ot o c ol  will  b e  c h e c k e d  b y t h e I n v esti g at or  a n d r e c or d e d i n t h e 
E D C s yst e m  at  e a c h  visit. 
S u bj e cts  will  b e  c o nsi d er e d  n o n- c o m pli a nt  ( m aj or  pr ot o c ol  vi ol ati o n) if t h e y  h a v e  miss e d 
m or e t h a n t w o  d os es  of t h e  st u d y  m e di c ati o n  d uri n g t h e first t hr e e  d a ys  of t h e  st u d y.   N o n-
c o m pli a n c e  will  n ot  b e  c a us e f or  dis c o nti n u ati o n  of s u bj e ct  p arti ci p ati o n i n t h e st u d y. 
9. 6.   Dis all o w e d  M e di c ati o n 
T h e  f oll o wi n g    m e di c ati o ns    will   n ot   b e   all o w e d   d uri n g  t h e  st u d y:  t o pi c al   or  s yst e mi c 
d e c o n g est a nts,  n as al  c orti c ost er oi ds,  a n d  a n y  pr es cri pti o n  or  n o n- pr es cri pti o n    m e di c ati o ns 
cl assifi e d  as (i)  e x p e ct or a nts  a n d  c o u g h  pr e p ar ati o ns, (ii)  a n al g esi cs  a n d  a nti p yr eti cs  or (iii) 
a nti hist a mi n es   ( A m eri c a n    H os pit al   F or m ul ar y   S er vi c e   ( A H F S)   cl assifi c ati o n).    As   a n 
e x c e pti o n t o t his r ul e, s u bj e cts  will  b e all o w e d t o  us e a c et a mi n o p h e n a n d/ or  d e xtr o m et h or p h a n 
as  n e c ess ar y f or  dis a bli n g s y m pt o ms . 
M e di c ati o ns f or  pr e- e xisti n g  c o n diti o ns t h at  ar e  n ot  e x cl u d e d (s e e  e x cl usi o n  crit eri a)  s h o ul d 
b e  c o nti n u e d  as  pr es cri b e d.  T h e  us e  of s u c h  m e di c ati o n  will  b e r e c or d e d i n t h e  E D C s yst e m. 
1 0.   A D V E R S E  E V E N T S 
T h e t er m  “ a d v ers e  e v e nt ” is  d efi n e d  f or  p ur p os es  of t his  st u d y  as  a n y  u n w a nt e d  p h ysi c al, 
ps y c h ol o gi c al  or  b e h a vi or al  c h a n g e  e x p eri e n c e d  b y  a  s u bj e ct  d uri n g t h e  c o urs e  of t h e  st u d y 
a n d  aft er t a ki n g t h e first  d os e  of st u d y  m e di c ati o n r e g ar dl ess  of its s e v erit y  or r el ati o n t o t h e 
st u d y.   A d v ers e  e v e nts  m a y i n cl u d e s y m pt o ms, si g ns,  u n e x p e ct e d  w ors e ni n g  of  pr e- e xisti n g 
c o n diti o ns,  cli ni c all y  si g nifi c a nt  c h a n g es i n l a b or at or y  v al u es,  dis e as es  a n d  s y n dr o m es,  a n d 
si g nifi c a nt   a n d   u n e x p e ct e d   f ail ur es   of   p h ar m a c ol o gi c al   a cti o n   of   ot h er    m e di c ati o ns.  
S y m pt o ms  of  c ol ds  d u e t o  E V/ R V i nf e cti o n ( c o u g h,  s or e t hr o at,  n as al  o bstr u cti o n, f ati g u e, 
h e a d a c h e,  m y al gi a, f e v eris h n ess)  a n d  c o m pli c ati o ns  of  c ol ds  will  n ot  b e r e p ort e d  as  a d v ers e 
e v e n ts. 
A d v ers e  e v e nts  will  b e r e c or d e d  o n t h e  a p pr o pri at e  E D C f or ms t hr o u g h o ut t h e st u d y,  a n d t h e 
s e v erit y  of  e a c h  a d v ers e  e v e nt  will  b e  gr a d e d  o n  a f o ur- p oi nt  s c al e:  mil d,  m o d er at e,  s e v er e, 
or lif e-t hr e at e ni n g ( S e e  A p p e n di x II ).   T h e  d ur ati o n  of t h e  a d v ers e  e v e nt  a n d r el ati o ns hi p t o 
t h e  st u d y  dr u g    will  als o  b e  r e c or d e d.      All  a d v ers e  e v e nts    m ust  b e  f oll o w e d  u ntil  t h eir 
r es ol uti o n  or st a bili z ati o n  e v e n  b e y o n d t h e  pl a n n e d st u d y  p eri o d. 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  4 4  of  7 2 
C O N FI D E N TI A L 
1 0. 1.  D efi niti o ns 
T h e f oll o wi n g  d efi niti o ns  will  a p pl y t o t h e r e p orti n g  of  a d v ers e  e v e nts: 
1.   S eri o us  A d v ers e  E v e nt:  A n y  a d v ers e  e x p eri e n c e  o c c urri n g  at  a n y  d os e t h at is f at al  or lif e 
t hr e at e ni n g;   r e q uir es   i n- p ati e nt   h os pit ali z ati o n   or   pr ol o n g ati o n   of   a n   e xisti n g 
h os pit ali z ati o n; is  a  p ersist e nt  si g nifi c a nt  dis a bilit y/i n c a p a cit y; is  a  c o n g e nit al  a n o m al y 
or  birt h  d ef e ct;  or  is  a n  i m p ort a nt   m e di c al  e v e nt  t h at   m a y  n ot  r es ult  i n  d e at h,  b e  lif e-
t hr e at e ni n g,  or  r e q uir e  h os pit ali z ati o n  b ut,  b as e d  u p o n  a p pr o pri at e    m e di c al  j u d g m e nt, 
m a y j e o p ar di z e t h e  s u bj e ct  a n d  m a y r e q uir e  m e di c al  or  s ur gi c al i nt er v e nti o n t o  pr e v e nt 
o n e  of t h e  o ut c o m es list e d  a b o v e. 
2.   U n e x p e ct e d    A d v ers e   E v e nt:    A n y  a d v ers e  e x p eri e n c e  t h at  is  n ot  i d e ntifi e d  i n  n at ur e, 
s e v erit y,  or fr e q u e n c y i n t h e I n v esti g at or's  Br o c h ur e f or  N T Z. 
3.   S e v erit y  of a d v ers e e v e nts  will  b e ass ess e d  b y t h e I n v esti g at or  usi n g t h e  T o xi cit y  Gr a di n g 
S c al e  T a bl es  pr o vi d e d i n  A p p e n di x II  ( d eri v e d  a n d  a d a pt e d fr o m  “ G ui d a n c e f or I n d ustr y: 
T o xi cit y    Gr a di n g   S c al e  f or    H e alt h y    A d ult  a n d    A d ol es c e nt    V ol u nt e ers    E nr oll e d  i n 
Pr e v e nti v e  V a c ci n e  Cli ni c al  Tri als ”,  U S  D e pt.  of  H H S,  F D A,  C D E R,  S e pt e m b er  2 0 0 7 
a n d t h e  N ati o n al  I nstit ut es  of  H e alt h,  N ati o n al  C a n c er  I nstit ut e  C o m m o n  T er mi n ol o g y 
Crit eri a f or  A d v ers e  E v e nts ( C T C A E)  v ersi o n  4. 0). 
4.   C a us alit y (r el ati o ns hi p t o tr e at m e nt)  will  b e  ass ess e d  as f oll o ws: 
•   D efi nit el y  R el at e d:   T h e  a d v ers e  e v e nt is  cl e arl y r el at e d t o t h e i n v esti g ati o n al  a g e nt(s) 
or  r es e ar c h  i nt er v e nti o n:  t h e   a d v ers e   e v e nt   h as   a  t e m p or al  r el ati o ns hi p  t o  t h e 
a d mi nistr ati o n  of  t h e  i n v esti g ati o n al  a g e nt(s)  or  r es e ar c h  i nt er v e nti o n,  f oll o ws  a 
k n o w n  p att er n  of r es p o ns e,  a n d  n o  alt er n ati v e  c a us e is  pr es e nt. 
•   Pr o b a bl y  R el at e d:   T h e  a d v ers e  e v e nt is li k el y r el at e d t o t h e i n v esti g ati o n al  a g e nt(s) 
or i nt er v e nti o n: t h e  a d v ers e  e v e nt  h as  a t e m p or al r el ati o ns hi p t o t h e  a d mi nistr ati o n  of 
t h e i n v esti g ati o n al  a g e nt(s)  or  r es e ar c h i nt er v e nti o n,  f oll o ws  a  k n o w n  or  s us p e ct e d 
p att er n  of r es p o ns e,  b ut  a n  alt er n ati v e  c a us e  m a y  b e  pr es e nt. 
•   P ossi bl y   R el at e d:    T h er e  is  a  r e as o n a bl e  p ossi bilit y  t h at  t h e  e v e nt    m a y  h a v e  b e e n 
c a us e d  b y  or is li n k e d i n  a  si g nifi c a nt  w a y t o t h e r es e ar c h; t h e  a d v ers e  e v e nt  h as  a 
t e m p or al r el ati o ns hi p t o t h e  a d mi nistr ati o n  of t h e i n v esti g ati o n al  a g e nt(s)  or r es e ar c h 
i nt er v e nti o n,  f oll o ws  a  s us p e ct e d  p att er n  of  r es p o ns e,  b ut  a n  alt er n ati v e  c a us e  is 
pr es e nt. 
•   U nr el at e d  ( or    N ot    R el at e d):     T h e   a d v ers e   e v e nt  is   cl e arl y    N O T  r el at e d  t o  t he 
i n v esti g ati o n al   a g e nt(s)   or   i nt er v e nti o n:   t h e   a d v ers e   e v e nt   h as   n o   t e m p or al 
r el ati o ns hi p   t o   t h e   a d mi nistr ati o n   of   t h e   i n v esti g ati o n al   a g e nt(s)   or   r es e ar c h 
i nt er v e nti o n, f oll o ws  n o  k n o w n  or  s us p e ct e d  p att er n  of r es p o ns e,  a n d  a n  alt er n ati v e 
c a us e is  pr es e n t. 
U n d er  d o u bl e- bli n d tr e at m e nt  c o n diti o ns, it  s h o ul d  b e  ass u m e d t h at  all  s u bj e cts  ar e t a ki n g 
t h e t est  dr u g. 






Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
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C O N FI D E N TI A L 
1 2.   E L E C T R O NI C  D A T A  C O L L E C TI O N ( E D C)  S Y S T E M 
A n  E D C  s yst e m  will  b e  us e d f or t his  st u d y (
).  
Pri or t o st u d y i niti ati o n, sit e st aff  a n d  a ut h ori z e d  R o m ar k  p ers o n n el  will  b e tr ai n e d t o  us e t his 
s yst e m.  
All  el e ctr o ni c  s o ur c e f or ms  ar e t o  b e fill e d  o ut  c o m pl et el y  b y t h e  e x a mi ni n g  sit e  st aff  a n d 
r e vi e w e d  a n d  si g n e d  off  o n  b y t h e I n v esti g at or(s).   El e ctr o ni c  di ari es  will  b e  c o m pl et e d  b y 
t h e st u d y s u bj e cts  a n d r e vi e w e d  b y st u d y  p ers o n n el  a n d  a ut h ori z e d  S p o ns or r e pr es e nt ati v es. 
1 3.   R E T E N TI O N  O F  R E C O R D S 
Ess e nti al    D o c u m e nts   ( E Ds)   ar e   d o c u m e nts   t h at   i n di vi d u all y   a n d   c oll e cti v el y   p er mit 
e v al u ati o n  of t h e  c o n d u ct  of  a tri al  a n d  q u alit y  of t h e  d at a  pr o d u c e d.   T h e y  d e m o nstr at e t h e 
c o m pli a n c e  of t h e I n v esti g at or,  S p o ns or,  a n d  m o nit or  wit h t h e  G C P  st a n d ar ds  a n d  wit h  all 
a p pli c a bl e r e g ul at or y r e q uir e m e nts. 
I n  c o m pli a n c e   wit h  t h e  I C H/ G C P  g ui d eli n es,  t h e  I n v esti g at or/i nstit uti o n   will   m ai nt ai n  all 
e C R Fs  a n d  all  E D C s o ur c e f or ms  a n d s o ur c e  d o c u m e nts t h at s u p p ort t h e  d at a  c oll e ct e d fr o m 
e a c h  s u bj e ct,  as  w ell  as  all  st u d y  d o c u m e nts  as  s p e cifi e d i n I C H/ G C P  S e cti o n  8,  Ess e nti al 
D o c u m e nts f or t h e  C o n d u ct  of  a  Cli ni c al  Tri al,  a n d  all  st u d y  d o c u m e nts  as  s p e cifi e d  b y t h e 
a p pli c a bl e  r e g ul at or y  r e q uir e m e nt(s).   A list  of t h es e  d o c u m e nts is  f o u n d i n  A p p e n di x  III: 
List  of  Ess e nti al  D o c u m e nt f or t h e I n v esti g ati v e  Sit e .   T h e I n v esti g at or/i nstit uti o n  will t a k e 
m e as ur es t o  pr e v e nt  a c ci d e nt al  or  pr e m at ur e  d estr u cti o n  of t h es e  d o c u m e nts. 
Ess e nti al  d o c u m e nts  list e d  i n  A p p e n di x  III     m ust  b e  r et ai n e d  f or  t h e  d ur ati o n  r e q uir e d  b y 
a p pli c a bl e  r e g ul at or y  a ut h oriti es  or  u ntil  t h e  S p o ns or  i nf or ms  t h e  I n v esti g at or/i nstit uti o n 
t h es e  d o c u m e nts  ar e  n o l o n g er  n e e d e d. 
If it  b e c o m es  n e c ess ar y f or t h e  S p o ns or  or t h e  a p pr o pri at e r e g ul at or y  a ut h orit y t o r e vi e w  a n y 
d o c u m e nt ati o n r el ati n g t o t his st u d y, t h e I n v esti g at or  m ust  p er mit  a c c ess t o s u c h r e p orts. 
T h e  S p o ns or is r es p o nsi bl e f or  or g a ni zi n g  a n d  m ai nt ai ni n g t h e  Tri al  M ast er  Fil e  w hi c h is  a 
cl e ar  d o c u m e nt ati o n  of t h e  c o urs e  of t h e st u d y. 
1 4.   M O NI T O RI N G  T H E  S T U D Y 
M o nit ori n g  will  b e  c o n d u ct e d  b y t h e  S p o ns or  a n d/ or  a  c o ntr a ct r es e ar c h  or g a ni z ati o n ( C R O) 
a c c or di n g t o t h e  S p o ns or’s  st a n d ar d  o p er ati n g  pr o c e d ur es.   Sit e  visits  will  b e  c o n d u ct e d  b y 
t h e  S p o ns or  at r e g ul ar i nt er v als t o  c o n d u ct i ns p e cti o ns. 
A n y  d at a tr a ns cri b e d i nt o t h e  E D C s yst e m  will  b e  1 0 0 % s o ur c e  v erifi e d.   
T h e  I n v esti g at or    will  gr a nt  r e pr es e nt ati v es  of  t h e  S p o ns or's  cli ni c al  o p er ati o ns  t e a m  a n d 
q u alit y t e a m, as  w ell as r e g ul at or y a g e n ci es a n d et hi c al c o m mitt e es a c c ess t o i ns p e ct f a ciliti es 
a n d r e c or ds (i n cl u di n g s u bj e ct  c h arts) r el e v a nt t o t his st u d y  a n d  a gr e es t o  assist t h e  m o nit ors 
i n t h eir  a cti viti es, if r e q u est e d. 
Gi v e n  t h e  s h ort  d ur ati o n  of  t his  st u d y,  t h e  l ar g e  cli ni c al  e x p eri e n c e    wit h    N T Z,  a n d  t h e 
p o p ul ati o n  b ei n g  st u di e d, t h e  d at a fr o m t his  st u d y  will  n ot  b e  m o nit or e d  b y  a n i n d e p e n d e nt 
d at a  m o nit ori n g  c o m mitt e e.   


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1 5.   I N F O R M E D  C O N S E N T 
E a c h  s u bj e ct  m ust  gi v e  writt e n  c o ns e nt  a c c or di n g t o l o c al r e q uir e m e nts  aft er t h e  n at ur e  of 
t h e st u d y  h as  b e e n f ull y  e x pl ai n e d.   T h e i nf or m e d  c o ns e nt f or m (I C F)  m ust  b e si g n e d  b ef or e 
p erf or m a n c e  of  a n y  st u d y-r el at e d  a cti vit y.   T h e i nf or m e d  c o ns e nt f or m  will  b e  a p pr o v e d  b y 
b ot h t h e  S p o ns or  a n d  b y t h e r e vi e wi n g I R B.   T h e y  will  b e i n  a c c or d a n c e  wit h  pri n ci pl es t h at 
ori gi n at e d  i n  t h e  D e cl ar ati o n  of    H elsi n ki ,  c urr e nt  I C H  a n d    G C P  g ui d eli n es,  a p pli c a bl e 
r e g ul at or y r e q uir e m e nts,  a n d  S p o ns or  p oli c y. 
B ef or e   e nr oll m e nt   i n   t h e   st u d y,   t h e   I n v esti g at or   or   a n   a ut h ori z e d    m e m b er   of   t h e 
i n v esti g ati o n al  st aff    m ust   e x pl ai n  t o   p ot e nti al  s u bj e cts  t h e   ai ms,    m et h o ds,  r e as o n a bl y 
a nti ci p at e d  b e n efits,  a n d  p ot e nti al  h a z ar ds  of t h e  st u d y,  a n d  a n y  dis c o mf ort  p arti ci p ati o n i n 
t h e st u d y  m a y  e nt ail.   S u bj e cts  will  b e i nf or m e d t h at t h eir  p arti ci p ati o n is  v ol u nt ar y  a n d t h at 
t h e y  m a y  wit h dr a w  c o ns e nt t o  p arti ci p at e  at  a n y ti m e.   T h e y  will  b e i nf or m e d t h at  c h o osi n g 
n ot t o  p arti ci p at e  will  n ot  aff e ct t h e  c ar e  h e/s h e  will r e c ei v e.   Fi n all y, t h e y  will  b e t ol d t h at 
t h e I n v esti g at or  will  m ai nt ai n  a  s u bj e ct i d e ntifi c ati o n r e gist er f or t h e  p ur p os es  of l o n g-t er m 
f oll o w- u p  if  n e e d e d  a n d  t h at  t h eir  r e c or ds    m a y  b e  a c c ess e d  b y  h e alt h  a ut h oriti es  a n d 
a ut h ori z e d  S p o ns or  st aff   wit h o ut  vi ol ati n g  t h e  c o nfi d e nti alit y  of  t h e  s u bj e ct,  t o  t h e  e xt e nt 
p er mitt e d  b y  t h e  a p pli c a bl e  l a w(s)  or  r e g ul ati o ns.      B y  si g ni n g  t h e  I C F  t h e  s u bj e ct  is 
a ut h ori zi n g  s u c h  a c c ess,  a n d  a gr e es  t o  all o w  his  or  h er  st u d y  p h ysi ci a n  t o  r e- c o nt a ct  t h e 
s u bj e ct f or t h e  p ur p os e  of  o bt ai ni n g  c o ns e nt f or  a d diti o n al s af et y  e v al u ati o ns, if  n e e d e d. 
T h e s u bj e ct  will  b e  gi v e n s uffi ci e nt ti m e t o r e a d t h e I C F  a n d t h e  o p p ort u nit y t o  as k  q u esti o ns.  
Aft er  t his  e x pl a n ati o n  a n d  b ef or e  e ntr y  i nt o  t h e  st u d y,  c o ns e nt  s h o ul d  b e  a p pr o pri at el y 
r e c or d e d  b y  m e a ns  of t h e  s u bj e ct's  p ers o n all y  d at e d  si g n at ur e.   Aft er  h a vi n g  o bt ai n e d t h e 
c o ns e nt,  a  c o p y  of t h e I C F  m ust  b e  gi v e n t o t h e s u bj e ct. 
If t h e s u bj e ct is  u n a bl e t o r e a d  or  writ e,  a n i m p arti al  wit n ess s h o ul d  b e  pr es e nt f or t h e  e ntir e 
i nf or m e d  c o ns e nt  pr o c ess  ( w hi c h i n cl u d es  r e a di n g  a n d  e x pl ai ni n g  all  writt e n i nf or m ati o n) 
a n d s h o ul d  p ers o n all y  d at e  a n d si g n t h e I C F  aft er t h e  or al  c o ns e nt  of t h e s u bj e ct is  o bt ai n e d, 
if  p er mitt e d  b y l o c al l a w. 
Ass e nt  fr o m  a n y  mi n or  ( ≤   1 8  y e ars  of  a g e  or  as l o c al  r e g ul ati o ns  a p pl y)  e nr oll e d i nt o t h e 
st u d y  will  b e  o bt ai n e d  al o n g  wit h  d o c u m e nt e d  c o ns e nt  fr o m t h eir  p ar e nt/l e g al  g u ar di a n t o 
all o w t h e  mi n or t o  p arti ci p at e i n t h e  st u d y.   T h e  ass e nt  a n d  c o ns e nt  f or ms  m ust  b e  si g n e d 
pri or t o t h e  p erf or m a n c e  of  a n y st u d y r el at e d  a cti vit y.   
Si g n e d  I C Fs    m ust  r e m ai n  i n  t h e  s u bj e ct's  fil e(s)  a n d   b e  a v ail a bl e  f or   v erifi c ati o n   b y 
r e pr es e nt ati v es  of  R o m ar k, t h e I R B,  a n d  F D A/r el e v a nt r e g ul at or y  a g e n ci es  at  a n y ti m e.   
1 6.   E T HI C S 
T h e  cli ni c al  tri al    will  b e  p erf or m e d  i n  a c c or d a n c e    wit h  t h e  g ui d eli n es  s et  b y  t h e    W orl d 
M e di c al  Ass e m bl y  ( D e cl ar ati o n  of  H elsi n ki , l ast  a m e n d m e nt i n  F ort al e z a,  Br a zil,  O ct o b er 
2 0 1 3).   Pri or  writt e n  a p pr o v al  of t h e st u d y  pr ot o c ol  a n d  of t h e i nf or m e d  c o ns e nt f or m  will  b e 
o bt ai n e d fr o m t h e  a p pr o pri at e l o c al  M e di c al  Et hi cs  R e vi e w  B o ar d. 


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1 6. 1.  St u d y- S p e cifi c  D esi g n  C o nsi d e r ati o ns 
P ot e nti al s u bj e cts  will  b e f ull y i nf or m e d  of t h e ris ks a n d r e q uir e m e nts  of t h e st u d y a n d  d uri n g 
t h e  st u d y  s u bj e cts    will  b e  gi v e n  a n y  n e w  i nf or m ati o n  t h at    m a y  aff e ct  t h eir  d e cisi o n  t o 
c o nti n u e  p arti ci p ati o n.     T h e y   will  b e  t ol d  t h at  t h eir  c o ns e nt  t o  p arti ci p at e  i n  t h e  st u d y  is 
v ol u nt ar y  a n d  m a y  b e  wit h dr a w n  at  a n y ti m e  wit h  n o r e as o n  gi v e n  a n d  wit h o ut  p e n alt y  or 
l oss  of  b e n efits t o  w hi c h t h e y  w o ul d  ot h er wis e  b e  e ntitl e d.   O nl y s u bj e cts  w h o  ar e f ull y  a bl e 
t o  u n d erst a n d t h e ris ks,  b e n efits,  a n d  p ot e nti al  A Es  of t h e  st u d y,  a n d  pr o vi d e t h eir  c o ns e nt 
v ol u nt aril y  will  b e  e nr oll e d. 
1 6. 2.  I n v esti g at o r  R es p o nsi biliti es 
T h e I n v esti g at or is r es p o nsi bl e f or e ns uri n g t h at t h e cli ni c al st u d y is  p erf or m e d i n a c c or d a n c e 
wit h t h e  pr ot o c ol,  c urr e nt I nt er n ati o n al  C o nf er e n c e  o n  H ar m o ni z ati o n (I C H)  g ui d eli n es  o n 
G o o d  Cli ni c al  Pr a cti c e ( G C P),  a n d  a p pli c a bl e r e g ul at or y  a n d  c o u ntr y s p e cifi c r e q uir e m e nts. 
G o o d    Cli ni c al   Pr a cti c e  is   a n  i nt er n ati o n al   et hi c al   a n d   s ci e ntifi c   q u alit y   st a n d ar d  f or 
d esi g ni n g,  c o n d u cti n g,  r e c or di n g,  a n d  r e p orti n g  st u di es  t h at  i n v ol v e  t h e  p arti ci p ati o n  of 
h u m a n  s u bj e cts.   C o m pli a n c e  wit h t his  st a n d ar d  pr o vi d es  p u bli c  ass ur a n c e t h at t h e  ri g hts, 
s af et y,  a n d    w ell b ei n g  of  st u d y  s u bj e cts  ar e  pr ot e ct e d,  c o nsist e nt    wit h  t h e  pri n ci pl es  t h at 
ori gi n at e d i n t h e  D e cl ar ati o n  of  H elsi n ki ,  a n d t h at t h e  cli ni c al st u d y  d at a  ar e  cr e di bl e. 
1 6. 3.  I nstit uti o n al  R e vi e w  B o a r d (I R B) 
B ef or e t h e  st art  of t h e  st u d y, t h e I n v esti g at or ( or  S p o ns or  w h er e r e q uir e d)  will  pr o vi d e t h e 
I R B  wit h  c urr e nt  a n d  c o m pl et e  c o pi es  of t h e f oll o wi n g  d o c u m e nts: 
•   Fi n al  pr ot o c ol  a n d, if  a p pli c a bl e,  a m e n d m e nts 
•   S p o ns or- a p pr o v e d I C F ( a n d  a n y  ot h er  writt e n  m at eri als t o  b e  pr o vi d e d t o t h e s u bj e cts) 
•   I n v esti g at or’s  Br o c h ur e ( or  e q ui v al e nt i nf or m ati o n)  a n d  a d d e n d a 
•   S p o ns or- a p pr o v e d s u bj e ct r e cr uiti n g  m at eri als 
•   I nf or m ati o n   o n  c o m p e ns ati o n  f or  st u d y-r el at e d  i nj uri es   or   p a y m e nt  t o  s u bj e cts  f or 
p arti ci p ati o n i n t h e st u d y, if  a p pli c a bl e 
•   I n v esti g at or’s   c urri c ul u m   vit a e   or   e q ui v al e nt  i nf or m ati o n  ( u nl ess   n ot  r e q uir e d,   as 
d o c u m e nt e d  b y I R B) 
•   I nf or m ati o n  r e g ar di n g  f u n di n g,  n a m e  of  t h e  S p o ns or,  i nstit uti o n al  affili ati o ns,  ot h er 
p ot e nti al  c o nfli cts  of i nt er est,  a n d i n c e nti v es f or s u bj e cts 
•   A n y  ot h er  d o c u m e nts t h at t h e I R B r e q u ests t o f ulfill its  o bli g ati o n 
T his st u d y  will  b e  u n d ert a k e n  o nl y  aft er t h e I R B  h as  gi v e n f ull  a p pr o v al  of t h e fi n al  pr ot o c ol, 
a m e n d m e nts  (if  a n y),  t h e  I C F,  a p pli c a bl e  r e cr uiti n g    m at eri als,  a n d  s u bj e ct  c o m p e ns ati o n 
pr o gr a ms,  a n d t h e  S p o ns or  h as r e c ei v e d  a  c o p y  of t his  a p pr o v al.   T his  a p pr o v al l ett er  m ust 
b e  d at e d  a n d  m ust  cl e arl y i d e ntif y t h e I R B  a n d t h e  d o c u m e nts  b ei n g  a p pr o v e d. 
D uri n g  t h e  st u d y,  t h e  I n v esti g at or  ( or  S p o ns or    w h er e  r e q uir e d)    will  s e n d  t h e  f oll o wi n g 
d o c u m e nts  a n d  u p d at es t o t h e I R B f or t h eir r e vi e w  a n d  a p pr o v al,  w h er e  a p pr o pri at e:  


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•   Pr ot o c ol  a m e n d m e nts 
•   R e visi o n(s) t o I C F  a n d  a n y  ot h er  writt e n  m at eri als t o  b e  pr o vi d e d t o s u bj e cts 
•   If  a p pli c a bl e,  n e w  or r e vis e d s u bj e ct r e cr uiti n g  m at eri als  a p pr o v e d  b y t h e  S p o ns or 
•   R e visi o ns   t o   c o m p e ns ati o n   f or   st u d y-r el at e d   i nj uri es   or   p a y m e nt   t o   s u bj e cts   f or 
p arti ci p ati o n i n t h e st u d y, if  a p pli c a bl e 
•   I n v esti g at or’s  Br o c h ur e  a d d e n d a  or  n e w  e diti o n(s) 
•   S u m m ari es  of t h e  st at us  of t h e  st u d y  at i nt er v als  sti p ul at e d i n  g ui d eli n es  of t h e I R B ( at 
l e ast  a n n u all y) 
•   R e p orts  of  A Es t h at  ar e s eri o us,  u nlist e d,  a n d  ass o ci at e d  wit h t h e i n v esti g ati o n al  dr u g 
•   N e w i nf or m ati o n t h at  m a y  a d v ers el y  aff e ct t h e  s af et y  of t h e  s u bj e cts  or t h e  c o n d u ct  of 
t h e st u d y 
•   D e vi ati o ns fr o m  or c h a n g es t o t h e  pr ot o c ol t o eli mi n at e i m m e di at e  h a z ar ds t o t h e s u bj e cts 
•   R e p ort  of  d e at hs  of s u bj e cts  u n d er t h e I n v esti g at or’s  c ar e 
•   N otifi c ati o n if  a  n e w I n v esti g at or is r es p o nsi bl e f or t h e st u d y  at t h e sit e 
•   A n n u al  I N D    U p d at e    R e p ort,  S h ort    T er m  St u d y  S p e cifi c  S af et y  S u m m ar y  a n d    Li n e 
Listi n gs,  w h er e  a p pli c a bl e 
•   A n y  ot h er r e q uir e m e nts  of t h e I R B 
F or  all  pr ot o c ol  a m e n d m e nts  ( e x cl u di n g  t h e  o n es  t h at  ar e  p ur el y  a d mi nistr ati v e,   wit h  n o 
c o ns e q u e n c es f or  s u bj e cts,  d at a  or  st u d y  c o n d u ct), t h e  a m e n d m e nt  a n d  a p pli c a bl e i nf or m e d 
c o ns e nt f or m  a n d  ass e nt f or m r e visi o ns  m ust  b e  s u b mitt e d  pr o m ptl y t o t h e I R B f or r e vi e w 
a n d  a p pr o v al  b ef or e i m pl e m e nt ati o n  of t h e  c h a n g e(s),  e x c e pt  w h e n  n e c ess ar y t o  eli mi n at e 
i m m e di at e  h a z ar d t o t h e st u d y s u bj e cts.  If  a  d e vi ati o n fr o m,  or  a  c h a n g e t o t h e  pr ot o c ol  w as 
i m pl e m e nt e d  t o  eli mi n at e  a n  i m m e di at e  h a z ar d  t o  st u d y  s u bj e cts,  t h e n  t h e  i m pl e m e nt e d 
d e vi ati o n  or  c h a n g e, t h e r e as o ns f or it,  a n d, if  a p pr o pri at e, t h e  pr ot o c ol  a m e n d m e nt  s h o ul d 
b e s u b mitt e d t o t h e I R B  as s o o n  as  p ossi bl e. 
T h e r e- a p pr o v al  of t h e  cli ni c al st u d y  b y t h e I R B s h o ul d  b e  d o c u m e nt e d i n  writi n g. 
At t h e  e n d  of t h e  st u d y, t h e  I n v esti g at or  ( or  S p o ns or  w h er e  r e q uir e d)  will  n otif y t h e  I R B 
a b o ut t h e st u d y  c o m pl eti o n. 
1 6. 4.  P ri v a c y  of  P e rs o n al  D at a 
T h e  c oll e cti o n  a n d  pr o c essi n g  of  p ers o n al  d at a fr o m  s u bj e cts  e nr oll e d i n t his  st u d y  will  b e 
li mit e d t o t h os e  d at a t h at  ar e  n e c ess ar y t o i n v esti g at e t h e  s af et y,  q u alit y,  a n d  utilit y  of t h e 
i n v esti g ati o n al st u d y  dr u g(s)  us e d i n t his st u d y. 
T h es e   d at a    m ust   b e   c oll e ct e d   a n d   pr o c ess e d    wit h   a d e q u at e   pr e c a uti o ns   t o   e ns ur e 
c o nfi d e nti alit y  a n d  c o m pli a n c e  wit h  a p pli c a bl e  d at a  pri v a c y  pr ot e cti o n l a ws  a n d r e g ul ati o ns.  
A p pr o pri at e  t e c h ni c al  a n d  or g a ni z ati o n al    m e as ur es  t o  pr ot e ct  t h e  p ers o n al  d at a  a g ai nst 
u n a ut h ori z e d  dis cl os ur es  or  a c c ess,  a c ci d e nt al  or  u nl a wf ul  d estr u cti o n,  or  a c ci d e nt al l oss  or 


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alt er ati o n  m ust  b e  p ut i n  pl a c e.   S p o ns or  p ers o n n el  w h os e r es p o nsi biliti es r e q uir e  a c c ess t o 
p ers o n al  d at a  a gr e e t o  k e e p t h e i d e ntit y  of st u d y s u bj e cts  c o nfi d e nti al. 
T h e i nf or m e d  c o ns e nt  o bt ai n e d fr o m t h e s u bj e ct i n cl u d es  e x pli cit  c o ns e nt f or t h e  pr o c essi n g 
of  p ers o n al  d at a  a n d f or t h e I n v esti g at or t o  all o w  dir e ct  a c c ess t o  his  or  h er  ori gi n al  m e di c al 
r e c or ds  f or  st u d y-r el at e d    m o nit ori n g,  a u dit,  I R B  r e vi e w,  a n d  r e g ul at or y  i ns p e cti o n.     T his 
c o ns e nt  als o  a d dr ess es t h e tr a nsf er  of t h e  d at a t o  ot h er  e ntiti es  a n d t o  ot h er  c o u ntri es. 
1 7.   D A T A  C O N FI D E N TI A LI T Y,  DI S C L O S U R E  O F  D A T A,  A N D  P U B LI C A TI O N 
D at a  g e n er at e d f or t h e st u d y s h o ul d  b e st or e d  b y t h e I n v esti g at or i n  a li mit e d- a c c ess fil e  ar e a 
a n d   b e   a c c essi bl e   o nl y  t o   r e pr es e nt ati v es   of  t h e   st u d y   sit e,    R o m ar k,  t h e   I R B,   a n d 
F D A/r el e v a nt   r e g ul at or y   a g e n ci es.       M e di c al   i nf or m ati o n   r es ulti n g   fr o m   a   s u bj e ct’s 
p arti ci p ati o n  i n  t his  st u d y    m a y  b e  gi v e n  t o  t h e  s u bj e ct’s  p ers o n al  p h ysi ci a n  or  t o  t h e 
a p pr o pri at e  m e di c al  p ers o n n el r es p o nsi bl e f or t h e s u bj e ct’s  w elf ar e.   
N o i nf or m ati o n t h at  c a n  b e r el at e d t o  a s p e cifi c i n di vi d u al s u bj e ct  m a y  b e r el e as e d  or  us e d i n 
a n y   f as hi o n    wit h o ut   t h e   si g n e d    writt e n   c o ns e nt   of   t h at   s u bj e ct.       All   r e p orts   a n d 
c o m m u ni c ati o ns r el ati n g t o  st u d y  s u bj e cts  will i d e ntif y  s u bj e cts  o nl y  b y i niti als  a n d  s u bj e ct 
i d e ntifi c ati o n   n u m b er.      T h e  I n v esti g at or    will   k e e p   c o m pl et e  s u bj e ct  i d e ntifi c ati o n  f or 
p ur p os es  of  l o n g-t er m  f oll o w- u p,  if  n e e d e d.     T his  i nf or m ati o n   will  b e  tr e at e d   wit h  stri ct 
a d h er e n c e t o  pr of essi o n al st a n d ar ds  of  c o nfi d e nti alit y. 
Sit e  p ers o n n el  will  e nt er  d at a  r el ati n g t o  e a c h  s u bj e ct’s  p arti ci p ati o n i n t h e  st u d y i nt o t h e 
E D C s yst e m  pr o vi d e d  b y t h e  S p o ns or.  I n t h e  E D C s yst e m, i d e ntifi c ati o n  n u m b ers a n d i niti als 
will  b e  us e d t o i d e ntif y s u bj e cts.   S u bj e ct  n a m es  will  n ot  b e  us e d i n t h e  C R Fs.   M a n a g e m e nt 
of  d at a  fr o m  t h e   E D C  s yst e m  a n d  t h e  pr o d u cti o n  of  t h e  cli ni c al  st u d y  r e p ort   will  b e  t h e 
r es p o nsi bilit y  of t h e  S p o ns or.   A c c ess t o t h e  d at a b as e  will  b e r estri ct e d t o  e m pl o y e es  w h o 
h a v e  b e e n tr ai n e d t o  us e t h e  s yst e m.   A c c ess t o t h e  E D C  s yst e m  a n d  st u d y  r e p ort  will  b e 
li mit e d t o t h e I R B,  F D A  or  ot h er r e g ul at or y  a g e n ci es  a n d t h e  S p o ns or. 
Pr es e nt ati o n  a n d/ or  p u bli c ati o n  of t h e r es ults  of t h e  st u d y is  e n c o ur a g e d  pr o vi d e d t h at  T h e 
R o m ar k  I nstit ut e  f or  M e di c al  R es e ar c h is  n otifi e d i n  a d v a n c e  of t h e  a ut h or's i nt e nt  a n d is 
gi v e n t h e  o p p ort u nit y t o r e vi e w t h e  m a n us cri pt  or  a bstr a ct  4 5  d a ys  pri or t o its s u b missi o n f or 
pr es e nt ati o n   at   a   s ci e ntifi c    m e eti n g   or   f or   p u bli c ati o n  i n   a   s ci e ntifi c  j o ur n al.      T h e 
I n v esti g at ors    will  h a v e  c o m pl et e  a ut o n o m y  r e g ar di n g  t h e  c o nt e nt  a n d    w or di n g  of  a n y 
a bstr a cts,  pr es e nt ati o ns,  a n d  s ci e ntifi c  p u bli c ati o ns  arisi n g  fr o m  t his  st u d y,  i n cl u di n g  t h e 
d e cisi o n  of  w h et h er  or  n ot t o  p u blis h.  
1 8.   D A T A  A N D  R E P O R T  R E Q UI R E M E N T S 
D at a r e q uir e d  b y  T h e  R o m ar k I nstit ut e f or  M e di c al  R es e ar c h  pri or t o  a p pr o v al  a n d i niti ati o n 
of t h e st u d y  ar e  as f oll o ws: 
1.   C urri c ul u m  vit a e  of t h e  Pri n ci p al I n v esti g at or  a n d  all  C o-I n v esti g at ors.  
2.   C o p y  of t h e I R B- a p pr o v e d I nf or m e d  C o ns e nt  a n d s u bj e ct i nf or m ati o n f or ms.  
3.   C o p y  of t h e I R B  a p pr o v al f or t h e  c o n d u ct  of t h e st u d y.  


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D at a  a n d  m at eri als r e q uir e d  b y  T h e  R o m ar k I nstit ut e f or  M e di c al  R es e ar c h  b ef or e t h e st u d y 
c a n  b e  c o nsi d er e d  c o m pl et e  a n d t er mi n at e d  ar e  as f oll o ws:  
1.   Pr e-  a n d  p ost-tr e at m e nt  hist or y,  p h ysi c al  e x a mi n ati o n  a n d s u bj e ct  e v al u ati o ns.  
2.   Pr e-  as  w ell  as i nt eri m  a n d  p ost-tr e at m e nt l a b or at or y fi n di n gs  a n d  all s p e ci al t est r es ults. 
3.   E D C f or ms  pr o p erl y  c o m pl et e d  a n d si g n e d  b y t h e  Pri n ci p al I n v esti g at or.  
4.   Dr u g I n v e nt or y  L o gs i n di c ati n g  dr u g  dis p e ns e d  a n d r et ur n  of t h e  u n us e d  s u p pli es t o t h e 
S p o ns or  or  d estr u cti o n  b y st u d y sit e.  
5.   Si g n e d I nf or m e d  C o ns e nt/ Ass e nt fr o m  e a c h s u bj e ct. 




Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
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P a g e  5 4  of  7 2 
C O N FI D E N TI A L 
2 0.   LI S T  O F  R E F E R E N C E S 
1.   F e n dri c k  A M,  M o nt o  A S,  Ni g ht e n g al e  B,  S a m es  M.  T h e  e c o n o mi c  b ur d e n  of  n o n-i nfl u e n z a-
r el at e d  vir al r es pir at or y i nf e cti o n i n t h e  U nit e d  St at es. Ar c h I nt er n  M e d  2 0 0 3;  1 6 3( 4): 4 8 7- 9 4.  
2.   T ur n er    R B.   E pi d e mi ol o g y,  P at h o g e n esis,  a n d   Tr e at m e nt  of  t h e    C o m m o n    C ol d.  A n n als  of 
All er g y,  Ast h m a  & I m m u n ol o g y   1 9 9 7;  7 8( 6): 5 3 1- 5 4 0.  
3.   W orr all  G.  C o m m o n  c ol d.  C a n  F a m  P h ysi ci a n   2 0 1 1;  5 7( 1 1): 1 2 8 9- 1 2 9 0.  
4.   Kir k p atri c k    G L.    T h e    C o m m o n    C ol d.  Pri m ar y    C ar e:    Cli ni cs  i n    Offi c e    Pr a cti c e    1 9 9 6; 
2 3( 4): 6 5 7- 6 7 5. 
5.   U nit e d  St at es   D e p art m e nt  of   L a b or  –   B ur e a u  of   L a b or  St atisti cs.   C PI  I nfl ati o n   C al c ul at or. 
A v ail a bl e  at:  htt ps:// w w w. bls. g o v/ d at a/i nfl ati o n _ c al c ul at or. ht m 
6.   At ki ns o n  S K,  S a d ofs k y  L R,  M ori c e  A H.  H o w  d o es r hi n o vir us  c a us e t h e  c o m m o n  c ol d  c o u g h ? 
B M J  O p e n  R es pir at or y  R es e ar c h   2 0 1 6; 3: e 0 0 0 1 1 8. 
7.   T h e   
Pir bri g ht   
I nstit ut e,    
U K.   
( 2 0 1 8).    
E nt er o vir us.    
R etri e v e d   
fr o m: 
htt p:// w w w. pi c or n a viri d a e. c o m/ e nt er o vir us/  e nt er o vir us. ht m 
8.   J a c o bs  S E,   L a ms o n   D M,  St.   G e or g e   K,    W als h   TJ.   H u m a n   R hi n o vir us es.  Cli n    Mi cr o b   R e v  
2 0 1 3;  2 6( 1): 1 3 5- 1 5 2. 
9.   Arr u d a  E,  Pit k ar a nt a  A,  Wit e k  TJ,  D o yl e  C,  H a y d e n  F G.  Fr e q u e n c y  a n d  N at ur al  Hist or y  of 
R hi n o vir us I nf e cti o ns i n  A d ults  d uri n g  A ut u m n.  J  Cli n  Mi cr o bi o   N o v  1 9 9 7;  2 8 6 4- 2 8 6 8. 
1 0.  All a n    G M,    Arr oll   B.  Pr e v e nti o n  a n d  tr e at m e nt  of  t h e  c o m m o n  c ol d:    m a ki n g  s e ns e  of  t h e 
e vi d e n c e.  C M A J   2 0 1 4  F e b  1 8;  1 8 6( 3):  1 9 0- 1 9 9. 
1 1.  H a y d e n  F G,   C o ats   T,   Ki m   K,   H ass m a n   H A,   Bl att er    M M,   Z h a n g   B,   Li u  S.   Or al  pl e c o n aril 
tr e at m e nt  of  pi c or n a vir us- ass o ci at e d  vir al r es pir at or y ill n ess i n  a d ults:  effi c a c y  a n d t ol er a bilit y 
i n  P h as e II  cli ni c al tri als. A nti vir al  T h er a p y   2 0 0 2; 7: 5 3- 6 5. 
1 2.  H a y d e n  F G,   H erri n gt o n   D T,   C o ats   T L,   Ki m   K,   C o o p er   E C,   Vill a n o  S A,   Li u  S,   H u ds o n  S, 
P e v e ar  D C,  C oll ett  M,  M c Ki nl a y  M,  Pl e c o n aril  R es pir at or y I nf e cti o n  St u d y  Gr o u p.  Effi c a c y 
a n d  S af et y  of  Or al  Pl e c o n aril f or  Tr e at m e nt  of  C ol ds  D u e t o  Pi c or n a vir us es i n  A d ults:  R es ults 
of   2    D o u bl e- Bli n d,    R a n d o mi z e d,   Pl a c e b o- C o ntr oll e d    Tri als.  Cli n   I nf e ct    Dis    2 0 0 3; 
3 6( 1 5): 1 5 2 3- 1 5 3 2. 
1 3.  D e p art m e nt  of    H e alt h  a n d    H u m a n  S er vi c es,  F o o d  a n d    Dr u g    A d mi nistr ati o n,    Di visi o n  of 
A nti vir al    Dr u g  Pr o d u cts.    B a c k gr o u n d  P a c k a g e  f or    N D A  2 1- 2 4 5:  Pi c o vir T M  ( pl e c o n aril). 
A v ail a bl e  at:  htt ps:// w a y b a c k. ar c hi v e-it. or g/ 7 9 9 3/ 2 0 1 7 0 4 0 5 1 5 2 4 5 1/ htt ps:// w w w.f d a. g o v/ 
o hr ms/ d o c k ets/ a c/ 0 2/ bri efi n g/ 3 8 4 7 b 1 _ 0 2 _ F D A. ht m 
1 4.  Cli ni c al Tri als. g o v.    A  P h as e  2  St u d y  of   B T A  7 9 8  i n    Ast h m ati c    A d ults    Wit h  S y m pt o m ati c 
H u m a n    R hi n o vir us   I nf e cti o n   ( R HI N O).    Bi ot a   S ci e ntifi c    M a n a g e m e nt   Pt y    Lt d. 
Cli ni c al Tri als. g o v I d e ntifi er:  N C T 0 1 1 7 5 2 2 6. 
1 5.  Cli ni c al Tri als. g o v.  A  P h as e  2  St u d y  of  V a p e n d a vir i n  Ast h m ati c  A d ults  Wit h  S y m pt o m ati c 
H u m a n    R hi n o vir us  I nf e cti o n  ( S PI RI T U S).    Bi ot a   P h ar m a c e uti c als,  I n c.    Cli ni c al Tri als. g o v 
I d e ntifi er:  N C T 0 2 3 6 7 3 1 3. 


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1 6.  G e n eti c  E n gi n e eri n g  &  Bi ot e c h n ol o g y  N e ws. ( F e br u ar y  1 4,  2 0 1 7).  A vir a g e n  A nti vir al  Dr u g 
V a p e n d a vir   F ails   P h as e   II b   St u d y   i n    Ast h m a   P ati e nts.    R etri e v e d   fr o m: 
htt ps:// w w w. g e n e n g n e ws. c o m/ g e n- n e ws- hi g hli g hts/ a vir a g e n- a nti vir al- dr u g- v a p e n d a vir-f ails-
p h as e- ii b-st u d y-i n- ast h m a- p ati e nts/ 8 1 2 5 3 8 7 3 
1 7.  A n d ers o n    V R,    C urr a n    M P.    N T Z:    A  r e vi e w  of  its  us e  i n  t h e  tr e at m e nt  of  g astr oi nt esti n al 
i nf e cti o ns. Dr u gs   2 0 0 7; 6 7: 1 9 4 7- 1 9 6 7. 
1 8.  Ali ni a ( nit a z o x a ni d e)  pr es cri bi n g i nf or m ati o n.  R o m ar k,  L. C.,  T a m p a,  F L,  A pril  2 0 1 7. 
1 9.  R ossi g n ol  J F.    Nit a z o x a ni d e:    A  first- i n- cl ass  br o a d-s p e ctr u m  a nti vir al  a g e nt.  A nti vir al   R es  
2 0 1 4;  1 1 0: 9 4- 1 0 3. 
2 0.  H o n g  S K,    Ki m    HJ,  S o n g    C S,    C h oi  I S,    L e e  J B,  P ar k  S Y.    Nit a z o x a ni d e  s u p pr ess es  I L- 6 
pr o d u cti o n   i n    L P S-sti m ul at e d    m o us e    m a cr o p h a g es   a n d    T G-i nj e ct e d    mi c e.  
I nt 
I m m u n o p h ar m a c ol,  2 0 1 2;  1 3: 2 3- 2 7. 
2 1.  Br a a k m a n I.,  H el e ni us J,  H el e ni us  A.  R ol e  of  A T P a n d  dis ul p hi d e  b o n ds  d uri n g  pr ot ei n f ol di n g 
i n t h e  e n d o pl as mi c r eti c ul u m. N at ur e   1 9 9 2;  3 5 6: 2 6 0- 2 6 2. 
2 2.  Br a a k m a n I,  H o o v er- Litt y  H,  W a g n er  K R,  H el e ni us  A.  F ol di n g  of i nfl u e n z a  h e m a g gl uti ni n i n 
t h e  e n d o pl as mi c r eti c ul u m J  C ell  Bi ol   1 9 9 1;  1 1 4: 4 0 1- 4 1 1. 
2 3.  D o ms  R W,  K ell er  D S,  H el e ni us  A,  B al c h  W E.  R ol e  of  a d e n osi n e tri p h os p h at e i n r e g ul ati n g 
t h e  ass e m bl y  a n d tr a ns p ort  of  v esi c ul ar  st o m atitis  vir us  G  pr ot ei n tri m ers. J  C ell  Bi ol   1 9 8 7; 
1 0 5: 1 0 9 5 7- 1 9 6 9. 
2 4.  C h a n g  C W,  Li  H C,  Hs u  C F,  C h a n g  C Y,  L o  S Y. I n cr e as e d  A T P  g e n er ati o n i n t h e  h ost  c ell is 
r e q uir e d f or  effi ci e nt  v a c ci ni a  vir us  pr o d u cti o n. J  Bi o m e d  S ci   2 0 0 9;  1 6: 8 0. 
2 5.  Mir a zi mi   A,  S v e nss o n   L.   A T P  is  r e q uir e d  f or  c orr e ct  f ol di n g  a n d  dis ulfi d e  b o n d  f or m ati o n 
r ot a vir us  V P 7. J  Vir ol   2 0 0 0;  7 4: 8 0 4 8- 5 2. 
2 6.  L e e  J H,  Z h a n g  Y,  Z h a o  Z,  Y e  X,  Z h a n g  X,  W a n g  H,  Y e  J. I ntr a c ell el ul ar  A T P i n  b al a n c e  of 
pr o-i nfl a m m at or y  a n d  a nti-i nfl a m m at or y  c yt o ki n es i n  a di p os e tiss u e  wit h  a n d  wit h o ut tiss u e 
e x p a nsi o n.  I nt  J  O b es ( L o n d)  2 0 1 7;  4 1: 6 4 5- 6 5 1. 
2 7.  S a g  D,  C arli n g  D,  St o ut  R D,  S uttl es  J.  A M P- a cti v at e d  pr ot ei n  ki n as e  pr o m ot es  m a cr o p h a g e 
p ol ari z ati o n  t o  a n  a nti-i nfl a m m at or y  f u n cti o n al  p h e n ot y p e.  J  I m m u n ol   2 0 0 8;  1 8 1( 1 2): 8 6 3 3-
8 6 4 1. 
2 8.  W a n g  W,  Y a n g  X,  d e  Sil a n es I L,  C arli n g  D,  G or os p e  M. I n cr e as e d  A M P: A T P  R ati o a n d  A M P-
a cti v at e d   Pr ot ei n    Ki n as e    A cti vit y   d uri n g    C ell ul ar   S e n es c e n c e    Li n k e d  t o    R e d u c e d    H u R 
F u n cti o n.  J  of  Bi ol o gi c al  C h e mistr y   2 0 0 3;  2 7 8: 2 7 0 1 6- 2 7 0 2 3. 
2 9.  K e n n e d y  J L,   T ur n er   R B,   Br a ci al e   T,    H e y m a n n  P Q,   B oris h   L.  P at h o g e n esis  of   R hi n o vir us 
I nf e cti o n. C urr  O pi n  Vir ol .  2 0 1 2 J u n;  2( 3):  2 8 7- 2 9 3.  
3 0.  C h u g ht ai    A A,    W a n g    Q,    D u n g    T C,    M a ci nt yr e    C R.    T h e  pr es e n c e  of  f e v er  i n  a d ults    wit h 
i nfl u e n z a  a n d  ot h er  vir al r es pir at or y i nf e cti o ns. E pi d e mi ol I nf e ct   2 0 1 7 J a n;  1 4 5( 1):  1 4 8- 1 5 5.  
3 1.  R ot b art   H A,   H a y d e n  F G.  Pi c or n a vir us  I nf e cti o ns:   A  Pri m er  f or  t h e  Pr a ctiti o n er.  Ar c h   F a m 
M e d   2 0 0 0; 9: 9 1 3- 9 2 0.  


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3 2.  Ari n g  A M,  C h a n  M M.  C urr e nt  C o n c e pts i n  A d ult  A c ut e  R hi n osi n usitis.  A m  F a m  P h ysi ci a n  
2 0 1 6 J ul  1 5; 9 4( 2): 9 7- 1 0 5.  
3 3.  F ull e n    DJ,  et  al.    A    T o ol  f or  I n v esti g ati n g    Ast h m a  a n d    C O P D    E x a c er b ati o ns:    A    N e wl y 
M a n uf a ct ur e d  a n d    W ell   C h ar a ct eris e d    G M P    Wil d- T y p e    H u m a n   R hi n o vir us  f or    Us e  i n  t h e 
H u m a n  Vir al  C h all e n g e  M o d el.  P L o S  O N E   D e c e m b er  9,  2 0 1 6; 1 1( 1 2): e 0 1 6 6 1 1 3. 
3 4.  P o w ers J H  et  al.  P erf or m a n c e  of t h e i n F L U e n z a  P ati e nt- R e p ort e d  O ut c o m e ( F L U- P R O)  di ar y 
i n  p ati e nts  wit h i nfl u e n z a-li k e ill n ess (I LI). P L o S  O N E   2 0 1 8  1 3( 3): d 0 1 9 4 1 8 0.  
3 5.  B arr ett  B,  Br o w n  R L,  M u n dt  M P,  T h o m as  G R,  B arl o w  S K,  Hi g hstr o m  A D,  B a hr ai ni a n  M. 
V ali d ati o n  of  a  s h ort  f or m    Wis c o nsi n    U p p er    R es pir at or y  S y m pt o m  S ur v e y  ( W U R S S- 2 1). 
H e alt h  Q u al  Lif e  O ut c o m es   2 0 0 9;  7: 7 6. 
3 6.  J a c ks o n  G G,  D o wli n g  H F.  Tr a ns missi o n  of t h e  C o m m o n  C ol d t o  V ol u nt e ers  U n d er  C o ntr oll e d 
C o n diti o ns. I V.  S p e cifi c I m m u nit y t o t h e  C o m m o n  C ol d.  J  Cli n I n v est   1 9 5 9;  3 8( 5): 7 6 2- 7 6 9. 
3 7.  B arr ett   B,   L o c k e n    K,    M a b err y   R,  S c h a m m a n  J,   Br o w n   R,   B o b ul a  J,  St a uff a c h er   E A.   T h e 
Wis c o nsi n    U p p er   R es pir at or y  S y m pt o m  S ur v e y  ( W U R S S):  a  n e w  r es e ar c h  i nstr u m e nt  f or 
ass essi n g t h e  c o m m o n  c ol d.  J  F a m  Pr a ct   2 0 0 2;  5 1( 3): 2 6 5. 
3 8.    Mit c h ell    RJ,    B at es   P.    M e as uri n g    H e alt h- R el at e d   Pr o d u cti vit y    L oss.  P o p ul ati o n    H e alt h 
M a n a g e m e nt   2 0 1 1;  1 4( 2): 9 3- 9 8 


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2 1.   A P P E N DI C E S 
A p p e n di x I:   
St u d y  S c h e d ul e  
A p p e n di x II:    T o xi cit y  Gr a di n g f or  A d v ers e  E v e nts 
A p p e n di x III:     List  of  Ess e nti al  D o c u m e nts f or t h e I n v esti g ati v e  Sit e 
A p p e n di x I V:   Pr ot o c ol  R e visi o n  Hist or y 
A p p e n di x  V:     D e cl ar ati o n  of  H elsi n ki 
 
 


Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  5 8  of  7 2 
C O N FI D E N TI A L 
2 1. 1.  A p p e n di x I:  St u d y  S c h e d ul e 
T a bl e  1 3:  S c h e d ul e  of  Ass ess m e nts 
 
S c r e e ni n g 
( D a y  1) 
B as eli n e 
( D a y  1) 
D a ys 
2- 2 2  
D a ys 
2- 5 
D a ys 
2,  3  
D a y 
7 ± 1  
D a y 
2 2 + 3  
U ns c h e d ul e d 
Visit  
Si g n e d i nf or m e d  c o ns e nt  
X  
  
  
  
  
  
  
 
C o m pl et e  m e di c al  hist or y  
X  
  
  
  
  
  
  
 
P h ysi c al  e x a mi n ati o n/ w ei g ht/ vit al si g ns   
X  
  
  
  
  
X 1  
X 1  
X 
D e m o gr a p hi cs/s m o ki n g  hist or y  
X  
  
  
  
  
  
  
 
Uri n e  pr e g n a n c y t est  
X  
  
  
  
  
  
  
 
R e c or d  or al t e m p er at ur e  
X  
  
  
  
  
X  
X  
X 
R e c or d s y m pt o m s  a n d ti m e  of  o ns et    
X  
  
  
  
  
  
  
 
E v al u at e  a c c or di n g t o i n cl usi o n/ e x cl usi o n 
crit eri a  
X  
  
  
  
  
  
  
 
C oll e ct  n as o p h ar y n g e al s w a bs   
  
X  
  
  
X 2  
X 3  
X 4  
X 
Bl o o d s a m pl e f or  p h ar m a c o ki n eti cs   
  
  
  
  
X 5  
  
  
 
Bl o o d s a m pl e f or l a b or at or y s af et y t ests 6  
  
X  
  
  
  
X  
  
X 
Uri n e s a m pl e f or r o uti n e  uri n al ysis 6  
  
X  
  
  
  
X  
  
X 
R e c or d  c o n c o mit a nt  m e di c ati o ns  
  
X  
  
  
  
X  
X  
X 
C o m pl et e  b as eli n e s y m pt o m s  i n  di ar y  a n d 
dis p e ns e  di ar y  
  
X  
  
  
  
  
  
 
R a n d o mi z ati o n/ dis p e ns e st u d y 
m e di c ati o n  
  
X  
  
  
  
  
  
 
First  d os e i n  offi c e  a n d  e nt er i n  di ar y   
  
X  
  
  
  
  
  
 
I nstr u cti o ns r e:  d osi n g,  c o n c o mit a nt 
m e di c ati o ns, s u bj e ct  di ar y,  birt h  c o ntr ol, 
f oll o w-u p  visits  a n d s e e ki n g  e m er g e n c y 
c ar e  
  
X  
  
X  
  
X  
  
X 
R e vi e w/r e c or d  a d v ers e  e v e nts  
  
X  
  
X  
X  
X  
X  
X 
R e vi e w  el e ctr o ni c s u bj e ct  di ar y  e ntri es   
  
  
X 7  
  
  
  
  
X 7 
S cr e e n f or  E V -r el at e d  c o m pli c ati o ns  
  
  
  
X  
X  
  
  
 
R e vi e w  c o m pli a n c e  wit h st u d y 
m e di c ati o n,  c oll e ct  c o nt ai n er  wit h  u n us e d 
m e di c ati o n,  c o m pl et e  pill  c o u nt l o g f or m  
  
  
  
  
X  
X  
  
X 8 
1   D a y  7  a n d  2 2  p h ysi c al  e x a m is  a  bri ef  p h ysi c al  e x a m ( vit al si g ns  a n d  n ursi n g  p h ysi c al  ass ess m e nt) i n cl u di n g s y m pt o m  dir e ct e d 
p h ysi ci a n  p h ysi c al  e x a mi n ati o n  as r e q uir e d  b y s u bj e ct s y m pt o ms.  Vit al si g ns i n cl u d e  bl o o d  pr ess ur e,  p uls e, r es pir at or y r at e  a n d 
or al t e m p er at ur e.  
2   N as o p h ar y n g e al s w a bs  o n  d a ys  2  a n d  3  will  b e  c oll e ct e d  at t h e s u bj e ct’s  h o m e ( or  cli ni c  or  a n ot h er l o c ati o n  as  a gr e e d  wit h t h e 
s u bj e ct).   
3   N as o p h ar y n g e al s w a bs  c oll e ct e d  o n  d a y  7  will  o nl y  b e t est e d f or t h e  pr es e n c e  of  vir us if  a  s a m pl e fr o m  d a y  1,  2  or  3  w as 
p ositi v e f or  e nt er o vir us/r hi n o vir us.  
4 N as o p h ar y n g e al s w a bs  c oll e ct e d  o n  d a y  2 2  will  o nl y  b e t est e d f or t h e  pr es e n c e  of  vir us if t h e s a m pl e fr o m  d a y  7  w as  p ositi v e 
f or  e nt er o vir us/r hi n o vir us. 
5     Bl o o d s a m pl e  c oll e ct e d  pr e-d os e  o n  d a y  3.  
6   L a b or at or y s af et y t ests i n cl u d e  h e m o gl o bi n,  h e m at o crit,  c o m pl et e  bl o o d  c o u nt (t ot al  a n d  diff er e nti al),  pl at el et  c o u nt, r a n d o m  
bl o o d s u g ar, t ot al  c h ol est er ol,  H D L,  L D L, tri gl y c eri d es,  al b u mi n,  A S T,  A L T,  G G T,  al k al i n e  p h os p h at as e,  bilir u bi n 
(t ot al/ dir e ct),  B U N,  cr e ati ni n e, s o di u m,  p ot assi u m,  c hl ori d e  a n d r o uti n e  uri n al ysis ( gl u c os e,  pr ot ei ns  a n d  bl o o d).  
7   All s u bj e cts  will  m ai nt ai n  a n  el e ctr o ni c  di ar y  u ntil  d a y  2 2 ( + 3).   Sit e st aff  will  c o nt a ct s u bj e cts  as  n e e d e d  d uri n g st u d y t o 
e ns ur e ti m el y  c o m pl eti o n  of  el e ctr o ni c  di ar y.  
8   C oll e cti o n  of  u n us e d I M P  a n d  c o m pl eti o n  of  pill  c o u nt l o g f or m  will  b e  p erf or m e d  at  u ns c h e d ul e d  visit if  a p pli c a bl e.  
 
 
























Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
P a g e  7 0  of  7 2 
C O N FI D E N TI A L 
S u m m a r y  of  C h a n g e s 
C h a n g e  9:   
P a g e  2 1,  S e cti o n  3. 0,  “ St u d y  D esi g n ” 
U p d at e d  C h oi c e  of I n cl usi o n  Crit eri a  t o  cl arif y t h at  a  n e g ati v e r es ult f or i nfl u e n z a  b y  a r a pi d  di a g n osti c t est  will  b e r e q uir e d if 
t h e s u bj e ct  h as  a n  or al t e m p er at ur e  > 1 0 0 ° F. 
C h a n g e  1 0:   
P a g e  2 4,  S e c ti o n  4. 1,  “I n cl usi o n  Crit eri a” 
U p d at e d I n cl usi o n  3 fr o m   “N e g ati v e r a pi d i nfl u e nz a  di a g n osti c t est ( n ot r e q uir e d if l at est  C D C  w e e kl y i nfl u e nz a r e p ort s h o ws 
i nfl u e nz a  pr e v al e n c e l ess t h a n  “ R e gi o n al ” f or t h e i nstit uti o n’s st at e).”  T o   “N e g ati v e r a pi d i nfl u e nz a  di a g n osti c t est (r e q uir e d 
o nl y if t h e  s u bj e ct  h as  a n  or al t e m p er at ur e  > 1 0 0 ° F i n t h e  cli ni c  or if t h e  l at est  C D C  w e e kl y i nfl u e nz a r e p ort s h o ws i nfl u e nz a 
pr e v al e n c e  “ R e gi o n al ”  or  hi g h er f or t h e i nstit uti o n’s st at e). ”  
C h a n g e  1 1:   
P a g e  3 4,  S e cti o n  8. 1,  “ S a m p l e  Siz e  C al c ul ati o ns” 
C orr e ct e d  n u m b er  of s u bj e cts  p er  gr o u p fr o m   “2 8 5 ” t o  “ 2 6 5 ” 
C h a n g e  1 2:   
P a g e  3 5,  S e cti o n  8. 2,  “ Effi c a c y  V ari a bl es ” 
A d d e d  e x pl or at or y  a n al ys es:   “vii.  Ti m e t o  S y m pt o m  R es p o ns e f or  all s u bj e cts tr e at e d (I T T  
p o p ul ati o n)  viii.  Ti m e t o  S y m pt o m  R es p o ns e f or s u bj e cts i nf e ct e d  wit h  i n di vi d u al  n o n-E V/ R V  vir us es ” 
C h a n g e  1 3:   
P a g e  4 0,  S e cti o n  8. 4. 1,  “ Effi c a c y  A n al ys es ” 
A d d e d  e x pl or at or y  a n al ys es:  
•  “ F or t h e I T T  p o p ul ati o n,  Ti m e t o  S y m pt o m  R es p o ns e f or t h e  N T Z  a n d  pl a c e b o tr e at m e nt  gr o u ps  will  b e  c o m p ar e d 
usi n g t h e  G e h a n- Wil c o x o n t est. 
•  F or s u bs ets  of s u bj e cts i nf e ct e d  wit h i n di vi d u al  n o n- E V/ R V   vir us es ( e. g.,  c or o n a vir us),  Ti m e t o  S y m pt o m 
R es p o ns e f or t h e  N T Z  a n d  pl a c e b o tr e at m e nt  gr o u ps  will  b e  c o m p ar e d  usi n g t h e  G e h a n- Wil c o x o n t est. ” 
A d d e d s e nsiti vit y  a n al ysis:   “R e p e at t h e  pri m ar y  effi c a c y  a n al ysis  e x cl u di n g  N T Z -tr e at e d s u bj e cts  w h o r e p ort e d  e x p eri e n ci n g 
c hr o m at uri a. ” 
C h a n g e  1 4:   
P a g e  4 2,  S e cti o n  9. 6,  “ Dis all o w e d  M e di c ati o n ” 
A d d e d s e cti o n t o  o utli n e  dis all o w e d  m e di c ati o n.  
A cti o n:   
A r e vis e d  pr ot o c ol  v e rsi o n  1. 2  d at e d  A u g ust  3 1,  2 0 1 8  w as  g e n er at e d. 




Pr ot o c ol  R M 0 8- 3 0 0 5  FI N A L  v 1. 3 
 
N o v e m b er  2 9,  2 0 1 8 
 
 
P a g e  7 2  of  7 2 
C O N FI D E N TI A L 
2 1. 5.   
A p p e n di x  V:  D e cl a r ati o n  of  H elsi n ki 




C o p yri g ht  2 0 1 3  A m eri c a n  M e di c al  A s s o ci ati o n.  All ri g ht s r e s er v e d.
1 3.   Gr o u p s t h at ar e u n d err e pr e s e nt e d i n   m e di c al r e s e ar c h s h o ul d
b e pr o vi d e d a p pr o pri at e a c c e s s t o p arti ci p ati o n i n r e s e ar c h.
1 4.  P h y si ci a n s   w h o c o m bi n e   m e di c al r e s e ar c h   wit h   m e di c al c ar e
s h o ul d i n v ol v e t h eir p ati e nt s i n r e s e ar c h o nl y t o t h e e xt e nt t h at
t hi s i s j u stifi e d b y it s p ot e nti al pr e v e nti v e, di a g n o sti c or t h er a-
p e uti c v al u e a n d if t h e p h y si ci a n h a s g o o d r e a s o n t o b eli e v e t h at
p arti ci p ati o n i n t h e r e s e ar c h st u d y   will n ot a d v er s el y aff e ct t h e
h e alt h of t h e p ati e nt s   w h o s er v e a s r e s e ar c h s u bj e ct s.
1 5.   A p pr o pri at e c o m p e n s ati o n a n d tr e at m e nt f or s u bj e ct s   w h o ar e
h ar m e d  a s  a r e s ult  of  p arti ci p ati n g i n r e s e ar c h   m u st  b e  e n-
s ur e d.
Ri s k s, B ur d e n s a n d B e n efit s
1 6.  I n   m e di c al pr a cti c e a n d i n   m e di c al r e s e ar c h,   m o st i nt er v e nti o n s
i n v ol v e ri s k s a n d b ur d e n s.
M e di c al r e s e ar c h i n v ol vi n g  h u m a n s u bj e ct s   m a y  o nl y  b e c o n-
d u ct e d if t h e i m p ort a n c e of t h e o bj e cti v e o ut w ei g hs t h e ris ks a n d
b ur d e n s t o t h e r e s e ar c h s u bj e ct s.
1 7.   All   m e di c al r e s e ar c h i n v ol vi n g  h u m a n s u bj e ct s   m u st  b e  pr e-
c e d e d  b y c ar ef ul a s s e s s m e nt of  pr e di ct a bl e ri s k s a n d  b ur d e n s
t o t h e i n di vi d u al s a n d gr o u p s i n v ol v e d i n t h e r e s e ar c h i n c o m-
p ari s o n   wit h f or e s e e a bl e b e n efit s t o t h e m a n d t o ot h er i n di vi d u-
al s or gr o u p s aff e ct e d b y t h e c o n diti o n u n d er i n v e sti g ati o n.
M e a s ur e s t o   mi ni mi s e t h e ri s k s   m u st b e i m pl e m e nt e d. T h e ri s k s
m u st b e c o nti n u o u sl y   m o nit or e d, a s s e s s e d a n d d o c u m e nt e d b y
t h e r e s e ar c h er.
1 8.  P h y si ci a n s   m a y n ot b e i n v ol v e d i n a r e s e ar c h st u d y i n v ol vi n g h u-
m a n s u bj e ct s u nl e s s t h e y ar e c o nfi d e nt t h at t h e ri s k s h a v e b e e n
a d e q u at el y a s s e s s e d a n d c a n b e s ati sf a ct oril y   m a n a g e d.
W h e n t h e ri s k s ar e f o u n d t o o ut w ei g h t h e p ot e nti al b e n efit s or
w h e n t h er e i s c o n cl u si v e  pr o of  of  d efi niti v e  o ut c o m e s,  p h y si-
ci a n s   m u st a s s e s s   w h et h er t o c o nti n u e,   m o dif y or i m m e di at el y
st o p t h e st u d y.
V ul n er a bl e   Gr o u p s a n d I n di vi d u al s
1 9.  S o m e gr o u ps a n d i n di vi d u als ar e p arti c ul arl y v ul n er a bl e a n d   m a y
h a v e a n i n cr e as e d li k eli h o o d of b ei n g  wr o n g e d or of i n c urri n g a d-
diti o n al h ar m.
All  v ul n er a bl e  gr o u p s a n d i n di vi d u al s s h o ul d r e c ei v e s p e cifi-
c all y c o n si d er e d pr ot e cti o n.
2 0.   M e di c al r e s e ar c h   wit h a v ul n er a bl e gr o u p i s o nl y j u stifi e d if t h e
r e s e ar c h i s r e s p o n si v e t o t h e  h e alt h  n e e d s  or  pri oriti e s  of t hi s
gr o u p  a n d t h e r e s e ar c h  c a n n ot  b e  c arri e d  o ut i n  a  n o n-
v ul n er a bl e gr o u p. I n a d diti o n, t hi s gr o u p s h o ul d st a n d t o  b e n-
efit fr o m t h e k n o wl e d g e, pr a cti c e s or i nt er v e nti o n s t h at r e s ult
fr o m t h e r e s e ar c h.
S ci e ntifi c R e q uir e m e nt s a n d R e s e ar c h Pr ot o c ol s
21.   M e di c al r es e ar c h i n v ol vi n g h u m a n s u bj e cts   m ust c o nf or m t o g e n-
er all y a c c e pt e d s ci e ntifi c  pri n ci pl e s,  b e  b a s e d  o n a t h or o u g h
k n o wl e d g e of t h e s ci e ntifi c lit er at ur e, ot h er r el e v a nt s o ur c e s of
i nf or m ati o n, a n d a d e q u at e l a b or at or y a n d, a s a p pr o pri at e, a ni-
m al e x p eri m e nt ati o n. T h e   w elf ar e of a ni m al s u s e d f or r e s e ar c h
m u st b e r e s p e ct e d.
2 2.  T h e  d e si g n a n d  p erf or m a n c e of e a c h r e s e ar c h st u d y i n v ol vi n g
h u m a n s u bj e ct s   m u st b e cl e arl y d e s cri b e d a n d j u stifi e d i n a r e-
s e ar c h pr ot o c ol.
T h e pr ot o c ol s h o ul d c o nt ai n a st at e m e nt of t h e et hi c al c o n si d-
er ati o n s i n v ol v e d a n d s h o ul d i n di c at e h o w t h e pri n ci pl e s i n t hi s
D e cl ar ati o n h a v e b e e n a d dr e s s e d. T h e pr ot o c ol s h o ul d i n cl u d e
i nf or m ati o n r e g ar di n g f u n di n g, s p o n s or s, i n stit uti o n al affili a-
ti o n s, p ot e nti al c o nfli ct s of i nt er e st, i n c e nti v e s f or s u bj e ct s a n d
i nf or m ati o n r e g ar di n g  pr o vi si o n s f or tr e ati n g a n d/ or c o m p e n-
s ati n g s u bj e ct s   w h o ar e h ar m e d a s a c o n s e q u e n c e of p arti ci p a-
ti o n i n t h e r e s e ar c h st u d y.
I n cli ni c al tri al s, t h e pr ot o c ol   m u st al s o d e s cri b e a p pr o pri at e ar-
r a n g e m e nt s f or p o st-tri al pr o vi si o n s.
R e s e ar c h Et hi c s C o m mitt e e s
2 3.  T h e r es e ar c h pr ot o c ol   m ust b e s u b mitt e d f or c o nsi d er ati o n, c o m-
m e nt, g ui d a n c e a n d a p pr o v al t o t h e c o n c er n e d r e s e ar c h et hi c s
c o m mitt e e  b ef or e t h e st u d y  b e gi n s.  T hi s c o m mitt e e   m u st  b e
tr a n s p ar e nt i n it s f u n cti o ni n g,   m u st b e i n d e p e n d e nt of t h e r e-
s e ar c h er, t h e s p o n s or a n d a n y ot h er u n d u e i nfl u e n c e a n d   m u st
b e d ul y q u alifi e d. It   m u st t a k e i nt o c o n si d er ati o n t h e l a w s a n d
r e g ul ati o n s of t h e c o u ntr y or c o u ntri e s i n   w hi c h t h e r e s e ar c h i s
t o b e p erf or m e d a s   w ell a s a p pli c a bl e i nt er n ati o n al n or m s a n d
st a n d ar d s b ut t h e s e   m u st n ot b e all o w e d t o r e d u c e or eli mi n at e
a n y of t h e pr ot e cti o n s f or r e s e ar c h s u bj e ct s s et f ort h i n t hi s  D e c-
l ar ati o n.
T h e c o m mitt e e   m u st  h a v e t h e ri g ht t o   m o nit or  o n g oi n g st u d-
i e s. T h e r e s e ar c h er   m u st pr o vi d e   m o nit ori n g i nf or m ati o n t o t h e
c o m mitt e e, e s p e ci all y i nf or m ati o n a b o ut a n y s eri o u s a d v er s e
e v e nt s.   N o a m e n d m e nt t o t h e pr ot o c ol   m a y b e   m a d e   wit h o ut
c o n si d er ati o n a n d a p pr o v al b y t h e c o m mitt e e.  Aft er t h e e n d of
t h e st u d y, t h e r e s e ar c h er s   m u st s u b mit a fi n al r e p ort t o t h e c o m-
mitt e e c o nt ai ni n g a s u m m ar y  of t h e st u d y’s fi n di n g s a n d c o n-
cl u si o n s.
Pri v a c y a n d C o nfi d e nti alit y
2 4.  E v er y  pr e c a uti o n   m u st  b e t a k e n t o  pr ot e ct t h e  pri v a c y  of r e-
s e ar c h s u bj e ct s a n d t h e c o nfi d e nti alit y of t h eir p er s o n al i nf or-
m ati o n.
I nf or m e d C o n s e nt
2 5.  P arti ci p ati o n b y i n di vi d u al s c a p a bl e of gi vi n g i nf or m e d c o n s e nt
a s s u bj e ct s i n   m e di c al r e s e ar c h   m u st b e v ol u nt ar y.   Alt h o u g h it
Cli ni c al R e vi e w   & E d u c ati o n S p e ci al C o m m u ni c ati o n
W orl d   M e di c al  A s s o ci ati o n   D e cl ar ati o n of   H el si n ki
21 9 2  
J A M A 
N o v e m b er 2 7, 2 01 3  V ol u m e 31 0,   N u m b er 2 0
j a m a. c o m
C o p yri g ht  2 0 1 3  A m eri c a n  M e di c al  A s s o ci ati o n.  All ri g ht s r e s er v e d.
D o w nl o a de d Fr o m: htt p://j a m a.j a m a net w or k.c o m/ b y a A meric a n Me dic al Ass oci ati o n User  o n 0 9/ 2 3/ 2 0 1 5


C o p yri g ht  2 0 1 3  A m eri c a n  M e di c al  A s s o ci ati o n.  All ri g ht s r e s er v e d.
m a y  b e a p pr o pri at e t o c o n s ult f a mil y   m e m b er s or c o m m u nit y
l e a d er s, n o i n di vi d u al c a p a bl e of gi vi n g i nf or m e d c o n s e nt   m a y
b e e nr oll e d i n a r e s e ar c h st u d y u nl e s s h e or s h e fr e el y a gr e e s.
2 6. I n   m e di c al r e s e ar c h i n v ol vi n g h u m a n s u bj e ct s c a p a bl e of gi vi n g
i nf or m e d c o n s e nt, e a c h  p ot e nti al s u bj e ct   m u st  b e a d e q u at el y
i nf or m e d  of t h e ai m s,   m et h o d s, s o ur c e s  of f u n di n g, a n y  p o s-
si bl e c o nfli ct s  of i nt er e st, i n stit uti o n al affili ati o n s  of t h e r e-
s e ar c h er, t h e a nti ci p at e d b e n efits a n d p ot e nti al ris ks of t h e st u d y
a n d t h e di s c o mf ort it   m a y e nt ail, p o st- st u d y pr o vi si o n s a n d a n y
ot h er r el e v a nt a s p e ct s of t h e st u d y. T h e p ot e nti al s u bj e ct   m u st
b e i nf or m e d of t h e ri g ht t o r ef u s e t o p arti ci p at e i n t h e st u d y or
t o   wit h dr a w c o n s e nt t o  p arti ci p at e at a n y ti m e   wit h o ut r e pri-
s al. S p e ci al att e nti o n s h o ul d  b e gi v e n t o t h e s p e cifi c i nf or m a-
ti o n n e e d s of i n di vi d u al p ot e nti al s u bj e ct s a s  w ell a s t o t h e   m et h-
o d s u s e d t o d eli v er t h e i nf or m ati o n.
Aft er e n s uri n g t h at t h e p ot e nti al s u bj e ct h a s u n d er st o o d t h e i n-
f or m ati o n, t h e p h y si ci a n or a n ot h er a p pr o pri at el y q u alifi e d i n-
di vi d u al   m u st t h e n s e e k t h e p ot e nti al s u bj e ct’s fr e el y- gi v e n i n-
f or m e d c o n s e nt, pr ef er a bl y i n   writi n g. If t h e c o n s e nt c a n n ot b e
e x pr e s s e d i n   writi n g, t h e n o n- writt e n c o n s e nt   m u st b e f or m all y
d o c u m e nt e d a n d   wit n e s s e d.
All   m e di c al r es e ar c h s u bj e cts s h o ul d b e gi v e n t h e o pti o n of b ei n g
i nf or m e d a b o ut t h e g e n er al o ut c o m e a n d r e s ult s of t h e st u d y.
2 7.   W h e n s e e ki n g i nf or m e d c o n s e nt f or p arti ci p ati o n i n a r e s e ar c h
st u d y t h e p h y si ci a n   m u st b e p arti c ul arl y c a uti o u s if t h e p ot e n-
ti al s u bj e ct i s i n a d e p e n d e nt r el ati o n s hi p   wit h t h e p h y si ci a n or
m a y c o n s e nt u n d er d ur e s s. I n s u c h sit u ati o n s t h e i nf or m e d c o n-
s e nt   m ust b e s o u g ht b y a n a p pr o pri at el y q u alifi e d i n di vi d u al  w h o
i s c o m pl et el y i n d e p e n d e nt of t hi s r el ati o n s hi p.
2 8.  F or a  p ot e nti al r e s e ar c h s u bj e ct   w h o i s i n c a p a bl e  of gi vi n g i n-
f or m e d c o ns e nt, t h e p h ysi ci a n   m ust s e e k i nf or m e d c o ns e nt fr o m
t h e l e g all y a ut h oris e d r e pr es e nt ati v e. T h es e i n di vi d u als   m ust n ot
b e i n cl u d e d i n a r e s e ar c h st u d y t h at h a s n o li k eli h o o d of b e n efit
f or t h e m u nl e s s it i s i nt e n d e d t o pr o m ot e t h e h e alt h of t h e gr o u p
r e pr e s e nt e d  b y t h e  p ot e nti al s u bj e ct, t h e r e s e ar c h c a n n ot i n-
st e a d  b e  p erf or m e d   wit h  p er s o n s  c a p a bl e  of  pr o vi di n g i n-
f or m e d c o n s e nt, a n d t h e r e s e ar c h e nt ail s o nl y   mi ni m al ri s k a n d
mi ni m al b ur d e n.
2 9.   W h e n a p ot e nti al r e s e ar c h s u bj e ct   w h o i s d e e m e d i n c a p a bl e of
gi vi n g i nf or m e d c o n s e nt i s a bl e t o gi v e a s s e nt t o d e ci si o n s a b o ut
p arti ci p ati o n i n r e s e ar c h, t h e p h y si ci a n   m u st s e e k t h at a s s e nt i n
a d diti o n t o t h e c o n s e nt  of t h e l e g all y a ut h ori s e d r e pr e s e nt a-
ti v e. T h e p ot e nti al s u bj e ct’s di s s e nt s h o ul d b e r e s p e ct e d.
3 0.  R e s e ar c h i n v ol vi n g s u bj e ct s   w h o ar e p h y si c all y or   m e nt all y i n-
c a p a bl e of gi vi n g c o n s e nt, f or e x a m pl e, u n c o n s ci o u s  p ati e nt s,
m a y b e d o n e o nl y if t h e p h y si c al or   m e nt al c o n diti o n t h at pr e-
v e nts gi vi n g i nf or m e d c o ns e nt is a n e c ess ar y c h ar a ct eristi c of t h e
r e s e ar c h gr o u p. I n s u c h cir c u m st a n c e s t h e p h y si ci a n   m u st s e e k
i nf or m e d c o n s e nt fr o m t h e l e g all y a ut h ori s e d r e pr e s e nt ati v e. If
n o s u c h r e pr e s e nt ati v e i s a v ail a bl e a n d if t h e r e s e ar c h c a n n ot b e
d el a y e d, t h e st u d y   m a y pr o c e e d   wit h o ut i nf or m e d c o n s e nt pr o-
vi d e d t h at t h e s p e cifi c r e a s o n s f or i n v ol vi n g s u bj e ct s   wit h a c o n-
diti o n t h at r e n d er s t h e m u n a bl e t o gi v e i nf or m e d c o n s e nt h a v e
b e e n st at e d i n t h e r e s e ar c h pr ot o c ol a n d t h e st u d y h a s b e e n a p-
pr o v e d b y a r es e ar c h et hi c s c o m mitt e e. C o ns e nt t o r e m ai n i n t h e
r e s e ar c h   m u st b e o bt ai n e d a s s o o n a s p o s si bl e fr o m t h e s u bj e ct
or a l e g all y a ut h ori s e d r e pr e s e nt ati v e.
31.  T h e p h ysi ci a n   m ust f ull y i nf or m t h e p ati e nt  w hi c h as p e cts of t h eir
c ar e ar e r el at e d t o t h e r e s e ar c h. T h e r ef u s al of a p ati e nt t o p ar-
ti ci p at e i n a st u d y or t h e p ati e nt’s d e ci si o n t o   wit h dr a w fr o m t h e
st u d y   m u st  n e v er a d v er s el y aff e ct t h e  p ati e nt- p h y si ci a n r el a-
ti o n s hi p.
3 2.  F or   m e di c al r e s e ar c h u si n g i d e ntifi a bl e h u m a n   m at eri al or d at a,
s u c h a s r e s e ar c h  o n   m at eri al  or  d at a c o nt ai n e d i n  bi o b a n k s  or
si mil ar r e p o sit ori e s, p h y si ci a n s   m u st s e e k i nf or m e d c o n s e nt f or
it s c oll e cti o n, st or a g e a n d/ or r e u s e.  T h er e   m a y  b e e x c e pti o n al
sit u ati o n s   w h er e c o n s e nt   w o ul d  b e i m p o s si bl e  or i m pr a cti-
c a bl e t o  o bt ai n f or s u c h r e s e ar c h. I n s u c h sit u ati o n s t h e r e-
s e ar c h   m a y b e d o n e o nl y aft er c o n si d er ati o n a n d a p pr o v al of a
r e s e ar c h et hi c s c o m mitt e e.
U s e of Pl a c e b o
3 3.  T h e  b e n efit s, ri s k s,  b ur d e n s a n d eff e cti v e n e s s  of a  n e w i nt er-
v e nti o n   m u st b e t e st e d a g ai n st t h o s e of t h e b e st pr o v e n i nt er-
v e nti o n( s), e x c e pt i n t h e f oll o wi n g cir c u m st a n c e s:
W h er e n o pr o v e n i nt er v e nti o n e xi st s, t h e u s e of pl a c e b o, or n o
i nt er v e nti o n, i s a c c e pt a bl e; or
W h er e f or c o m p elli n g a n d s ci e ntifi c all y s o u n d   m et h o d ol o gi c al
r e a s o n s t h e u s e of a n y i nt er v e nti o n l e s s eff e cti v e t h a n t h e b e st
pr o v e n o n e, t h e u s e of pl a c e b o, or n o i nt er v e nti o n i s n e c e s s ar y
t o d et er mi n e t h e effi c a c y or s af et y of a n i nt er v e nti o n
a n d t h e p ati e nts  w h o r e c ei v e a n y i nt er v e nti o n l ess eff e cti v e t h a n
t h e b e st pr o v e n o n e, pl a c e b o, or n o i nt er v e nti o n   will n ot b e s u b-
j e ct t o a d diti o n al ri s k s of s eri o u s or irr e v er si bl e h ar m a s a r e s ult
of n ot r e c ei vi n g t h e b e st pr o v e n i nt er v e nti o n.
E xtr e m e c ar e   m u st b e t a k e n t o a v oi d a b u s e of t hi s o pti o n.
P o st- Tri al Pr o vi si o n s
3 4. I n a d v a n c e of a cli ni c al tri al, s p o ns ors, r es e ar c h ers a n d h ost c o u n-
tr y g o v er n m e nt s s h o ul d   m a k e pr o vi si o n s f or p o st-tri al a c c e s s f or
all p arti ci p a nt s   w h o still n e e d a n i nt er v e nti o n i d e ntifi e d a s b e n-
efi ci al i n t h e tri al. T hi s i nf or m ati o n   m u st al s o b e di s cl o s e d t o p ar-
ti ci p a nt s d uri n g t h e i nf or m e d c o n s e nt pr o c e s s.
R e s e ar c h R e gi str ati o n a n d P u bli c ati o n a n d   Di s s e mi n ati o n
of R e s ult s
3 5.  E v er y r e s e ar c h st u d y i n v ol vi n g h u m a n s u bj e ct s   m u st b e r e gi s-
t er e d i n a p u bli cl y a c c e s si bl e d at a b a s e b ef or e r e cr uit m e nt of t h e
fir st s u bj e ct.
W orl d   M e di c al  A s s o ci ati o n   D e cl ar ati o n of   H el si n ki
S p e ci al C o m m u ni c ati o n Cli ni c al R e vi e w   & E d u c ati o n
j a m a. c o m
J A M A N o v e m b er 2 7, 2 01 3  V ol u m e 31 0,   N u m b er 2 0 
21 9 3
C o p yri g ht  2 0 1 3  A m eri c a n  M e di c al  A s s o ci ati o n.  All ri g ht s r e s er v e d.
D o w nl o a de d Fr o m: htt p://j a m a.j a m a net w or k.c o m/ b y a A meric a n Me dic al Ass oci ati o n User  o n 0 9/ 2 3/ 2 0 1 5


C o p yri g ht  2 0 1 3  A m eri c a n  M e di c al  A s s o ci ati o n.  All ri g ht s r e s er v e d.
3 6.  R e s e ar c h er s, a ut h or s, s p o n s or s, e dit or s a n d p u bli s h er s all h a v e
et hi c al o bli g ati o n s   wit h r e g ar d t o t h e p u bli c ati o n a n d di s s e mi-
n ati o n of t h e r es ults of r es e ar c h. R es e ar c h ers h a v e a d ut y t o   m a k e
p u bli cl y a v ail a bl e t h e r e s ult s  of t h eir r e s e ar c h  o n  h u m a n s u b-
j e ct s a n d ar e a c c o u nt a bl e f or t h e c o m pl et e n e s s a n d a c c ur a c y of
t h eir r e p ort s.   All p arti e s s h o ul d a d h er e t o a c c e pt e d g ui d eli n e s
f or et hi c al r e p orti n g.   N e g ati v e a n d i n c o n cl u si v e a s   w ell a s p o si-
ti v e r e s ult s   m u st b e p u bli s h e d or ot h er wi s e   m a d e p u bli cl y a v ail-
a bl e. S o ur c e s of f u n di n g, i n stit uti o n al affili ati o n s a n d c o nfli ct s
of i nt er e st   m u st  b e  d e cl ar e d i n t h e  p u bli c ati o n.  R e p ort s  of r e-
s e ar c h n ot i n a c c or d a n c e   wit h t h e pri n ci pl e s of t hi s  D e cl ar ati o n
s h o ul d n ot b e a c c e pt e d f or p u bli c ati o n.
U n pr o v e n I nt er v e nti o n s i n Cli ni c al Pr a cti c e
3 7.  I n t h e tr e at m e nt  of a n i n di vi d u al  p ati e nt,   w h er e  pr o v e n i nt er-
v e nti o n s d o n ot e xi st or ot h er k n o w n i nt er v e nti o n s h a v e b e e n
i n eff e cti v e, t h e p h y si ci a n, aft er s e e ki n g e x p ert a d vi c e,   wit h i n-
f or m e d c o n s e nt fr o m t h e p ati e nt or a l e g all y a ut h ori s e d r e pr e-
s e nt ati v e,   m a y  u s e a n  u n pr o v e n i nt er v e nti o n if i n t h e  p h y si-
ci a n' s j u d g e m e nt it  off er s  h o p e  of s a vi n g lif e, r e- e st a bli s hi n g
h e alt h or all e vi ati n g s uff eri n g. T hi s i nt er v e nti o n s h o ul d s u b s e-
q u e ntl y  b e   m a d e t h e o bj e ct of r e s e ar c h,  d e si g n e d t o e v al u at e
it s s af et y a n d effi c a c y. I n all c a s e s, n e w i nf or m ati o n   m u st b e r e-
c or d e d a n d,   w h er e a p pr o pri at e,   m a d e p u bli cl y a v ail a bl e.
A R TI C L E I N F O R M A TI O N
C orr e s p o n di n g   A ut h or: W orl d   M e di c al
A s s o ci ati o n, 1 3, c h. d u L e v a nt, CI B - B âti m e nt  A,
01 21 0 F er n e y- V olt air e, Fr a n c e;   w m a @ w m a. n et.
P u bli s h e d   O nli n e: O ct o b er 1 9, 2 01 3.
d oi:1 0.1 0 01/j a m a. 2 01 3. 2 81 0 5 3.
Di s cl ai m er: © 2 01 3   W orl d   M e di c al  A s s o ci ati o n, I n c.
All Ri g ht s R e s er v e d.  All i nt ell e ct u al pr o p ert y ri g ht s
i n t h e   D e cl ar ati o n of   H el si n ki ar e v e st e d i n t h e
W orl d   M e di c al  A s s o ci ati o n. T h e   W M A h a s gr a nt e d
J A M A e x cl u si v e ri g ht s t o p u bli s h t h e
E n gli s h-l a n g u a g e v er si o n of t h e   D e cl ar ati o n
t hr o u g h   D e c e m b er 31, 2 01 3.
O nli n e- O nl y C o nt e nt: A u di o p o d c a st i s a v ail a bl e at
w w w.j a m a. c o m.
Cli ni c al R e vi e w   & E d u c ati o n S p e ci al C o m m u ni c ati o n
W orl d   M e di c al  A s s o ci ati o n   D e cl ar ati o n of   H el si n ki
21 9 4  
J A M A 
N o v e m b er 2 7, 2 01 3  V ol u m e 31 0,   N u m b er 2 0
j a m a. c o m
C o p yri g ht  2 0 1 3  A m eri c a n  M e di c al  A s s o ci ati o n.  All ri g ht s r e s er v e d.
D o w nl o a de d Fr o m: htt p://j a m a.j a m a net w or k.c o m/ b y a A meric a n Me dic al Ass oci ati o n User  o n 0 9/ 2 3/ 2 0 1 5

SAP_001.pdf: 








R M 0 8 -3 0 0 5 S A P FI N A L  v 1. 4 
 
J ul y 1, 2 0 1 9  
 
P a g e 5 of 4 6  
C O N FI D E N TI A L  
3.  
T E C H NI C A L S U M M A R Y R E P O R T  
N a m e of S p o ns o r/ C o m p a n y  
T h e R o m ar k I nstit ute f or M e dical 
R esearc h  
I n di vi d u al St u d y T a ble 
R efe r ri n g t o P a rt of t h e 
D ossie r:  
V ol u m e:  
( F or N ati o n al A ut h ority Use 
O nly) : 
N a m e of Fi nis h e d P r o d u ct:  
Nitaz o x a ni d e 3 0 0 m g T a blets  
P a g e:  
 
N a m e of A cti v e I n g re die nt:  
Nitaz o x a ni d e  
 
 
Title Of St u d y:  A P h ase 3, R a n d o mize d, D o u ble -Bli n d, Pla c e b o C o ntr olle d Trial t o E v al u ate t h e Effic a c y a n d 
S afet y of Nitaz o x a ni d e i n t h e Tre at m e nt of C ol ds D u e t o E nter o vir us/ R hi n o vir us  I nfe cti o n 
I n v esti g at o rs: M ultice nter  
St u die d p eri o d : A u g ust 2 0 1 8 – A pril 2 0 1 9  
P h as e of d e v el o p m e nt:  3  
O bjecti v es:  
T h e pri m ar y o bjecti v e of t h e st u d y is t o e v al u ate t h e effe ct of nita z o x a ni d e ( N T Z ) a d mi nistere d orall y 6 0 0 m g b.i. d. 
f or  5  d a ys  i n  re d u ci n g  t h e  d urati o n  of  s y m pt o ms  of  c ol ds  d u e  t o E nter o vir us / R hi n o vir us  (E V / R V) i nfe cti o n 
c o m p are d t o place b o d uri n g 2 1 d a ys of f oll o w -u p b ase d u p o n t h e F L U -P R O ©  p atie nt -re p orte d o utc o m e i nstr u m e nt. 
A k e y sec o n d ar y efficac y o bjecti v e is t o e v al u ate t h e effe ct of N T Z c o m p are d t o pla c e b o o n ti m e t o ret ur n t o a bilit y 
t o p erf or m all n or m al acti vities. 
A n ot h er sec o n d ar y efficac y o bjecti v e is t o e v al u ate t h e effe ct of N T Z c o m p are d t o pla c e b o o n t h e pr o p orti o n of 
s u bjects  e x p erie n ci n g  o n e  or  m ore  c o m plicati o ns  of  c ol ds  d u e  t o  E V/ R V  i nfe cti o n  i n cl u di n g  p n e u m o nia,  otitis 
m e dia,  br o n c hitis,  si n usitis,  e x acer b ati o ns  of  ast h m a  or  C O P D,  w orse ni n g  of  pre -e xisti n g  h e alt h  c o n diti o ns, 
sec o n d ar y i nfecti o ns re q uiri n g s yste mic a nti bi otic use, h os pitaliz ati o n d u e t o c ol d or c o m plic ati o ns of t h e c ol d, a n d 
d eat h d u e t o c ol d or c o m plicati o ns of t h e c ol d.  
E x pl orat or y efficac y o bjecti v es i n cl u d e e v al u ati n g t h e effe ct of tre at m e nt wit h N T Z o n t h e ti m e t o res p o nse f or 
eac h F L U -P R O s y m pt o m ; ti m e t o res p o nse f or e a c h F L U-P R O d o m ai n ; ti m e t o ret ur n t o us u al h e alt h; c h a n g es i n 
viral titers fr o m B aseli n e  t o eac h of D a ys 2, 3 a n d 7; ti m e t o s y m pt o m res p o nse, ti m e t o a bilit y t o p erf or m all n or m al 
acti vities, a n d pr o p orti o ns e x p erie n ci n g c o m plic ati o ns  f or all s u bje cts tre ate d (I T T p o p ulati o n); ti m e t o s y m pt o m 
res p o nse f or s u bjects i nfecte d wit h i n di vi d u al n o n-E V/ R V vir us es ; a n d ti m e t o s y m pt o m res p o nse f or s u bje cts w h o 
recei v e d t h e first d ose of st u d y m e dicati o n 0-2 4, > 2 4 -≤3 6, or > 3 6 h o urs fr o m s y m pt o m o nset. A fi n al e x pl orat or y 
o bjecti v e is t o e v al u ate t h e i m p act of s y m pt o m relief m e dic ati o n use o n ti m e t o s y m pt o m res p o nse, ti m e t o ret ur n 
t o a bilit y t o p erf or m all n or m al acti vities , a n d pr o p orti o ns e x p erie n ci n g c o m plic ati o ns of c ol ds f or pla c e b o-tre ate d 
s u bjects. 
Ot h er i m p orta nt o bjecti v es i n cl u d e e v al u ati o n of t h e s afet y of N T Z b y a n al ysis of a d v ers e e v e nts a n d e v al u ati o n of 
relati o ns hi ps b et w ee n p h ar m ac o ki n etics a n d cli nic al or vir ol o gic res p o nses. 
N u m b er of S u bject s: 5 3 0 s u bjects wit h la b orat o r y-c o nfir m e d E V/ R V i nfe cti o n  a n d c o m plete d ata f or a n al ysis 
p ur p oses, esti m ate d t o re q uire at least 6 0 0 ( u p t o m a xi m u m of 7 0 0) wit h c ol ds d u e t o la b orat or y-c o nfir m e d 
E V/ R V  i nfecti o n 
St u d y D esi g n:  
M ultice nter,  ra n d o mize d,  d o u ble -bli n d , plac e b o  c o ntr olle d  trial  t o  e v al u ate  effic a c y  a n d  safet y  of  N T Z  i n  t h e 
treat m e nt of c ol ds d u e t o E V/ R V i nfecti o n 
 P o p ul ati o n:  M ales a n d fe m ales ≥1 2 y ears of a g e wit h E V / R V i nfe cti o n 
St u d y  d ose a n d m o d e of a d mi nistr ati o n:  
Gr o u p 1 ( N T Z):  
T w o N T Z 3 0 0 m g ta blets orall y t wic e d aily ( b.i. d.) wit h f o o d f or 5 d a ys  
Gr o u p 2 ( Place b o):  
T w o place b o ta blets orall y b.i. d. wit h f o o d f or 5 d a ys  


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St atistic al m et h o ds:  
L et S 0(t) a n d S1(t) b e t h e u n d erl yi n g s ur vi v al f u n cti o ns re g ar di n g t h e ti m e t o S y m pt o m R es p o nse f or pla c e b o a n d 
N T Z, res p ecti v el y. T h e n ull a n d alter n ati v e h y p ot h es es f or t h e pri m ar y o bje cti v e are d efi n e d as f oll o ws:  
 
H 0: S1(t) = S0(t) 
H A : S1(t) ≠ S0(t) 
T h e ti m e t o S y m pt o m R es p o nse f or s u bjects wit h la b orat or y -c o nfir m e d E V/ R V i nfe cti o n (I T TI p o p ulati o n) will b e 
c o m p are d usi n g a G e h a n -Wilc o x o n test  at t h e α = 0. 0 5 le v el  (t w o-taile d) stratifie d b y ( 1) ti m e fr o m o nset of ill n ess 
t o  ti m e  of  first  d ose  of  st u d y  m e dicati o n ( 0-2 4,  > 2 4 -≤3 6,  or  > 3 6  h o urs  fr o m  o ns et),  ( 2)  pre -e nr oll m e nt  use  of 
s y m pt o m relief m e dicatio n, a n d ( 3) prese n ce of u n d erl yi n g l u n g c o n diti o n i n cl u di n g ast h m a, C O P D, or p ast or 
prese nt hist or y of s m o ki n g.  
 


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4.  
T A B L E O F C O N T E N T S 
1.  
R E VI SI O N HI S T O R Y ....................................................................................................... 2  
2.  
SI G N A T U R E P A G E .......................................................................................................... 4  
3.  
T E C H NI C A L S U M M A R Y R E P O R T ............................................................................... 5  
4.  
T A B L E O F C O N T E N T S ................................................................................................... 7  
5.  
LI S T O F T A B L E S ........................................................................................................... 1 0  
6.  
LI S T O F A B B R E VI A TI O N S .......................................................................................... 1 1  
7.  
I N T R O D U C TI O N ............................................................................................................ 1 2 
8.  
S T U D Y D E S C RI P TI O N .................................................................................................. 1 2  
8. 1.  
St u d y O bjecti ves ............................................................................................................... 1 2  
8. 2.  
St u d y Desi g n .................................................................................................................... 1 3  
8. 3.  
Sa m ple Size J ustificati o n .................................................................................................. 1 4  
8. 4.  
Data C ollecti o n ................................................................................................................. 1 5  
9.  
D A T A D E FI NI TI O N S A N D C O N V E N TI O N S .............................................................. 1 5  
9. 1.  
A nal ysis P o p ulati o ns ........................................................................................................ 1 5  
9. 2.  
Data Prese ntati o n C o n ve nti o ns ........................................................................................ 1 6  
9. 3.  
Ha n dli n g of U nsc he d ule d Assess me nts ........................................................................... 1 6  
9. 4.  
Ha n dli n g of Missi n g Data ................................................................................................ 1 7  
1 0.  
G E N E R A L C H A R A C T E RI S TI C S .................................................................................. 1 8  
1 0. 1.  
Ge neral C haracteristics Ta bles a n d Fi g ures ..................................................................... 1 8  
1 0. 1. 1.  Dis p ositi o n of S u bjects ..................................................................................................... 1 8  
1 0. 1. 2.  Pr ot oc ol De viati o ns .......................................................................................................... 1 8  
1 0. 1. 3.  De m o gra p hics ................................................................................................................... 1 8  
1 0. 1. 4.  Dise ase C haracteristics ..................................................................................................... 1 8  
1 0. 1. 5.  Pri or a n d C o nc o mita nt Me dicati o n .................................................................................. 1 9  
1 0. 1. 6.  Me dical Hist or y a n d C o nc o mita nt Diseases .................................................................... 1 9  
1 0. 1. 7.  Treat me nt E x p os ure ......................................................................................................... 1 9  
1 0. 2.  
Ge neral C haracteristics Listi n gs ....................................................................................... 1 9  
1 1.  
E F FI C A C Y ....................................................................................................................... 2 0  
1 1. 1.  
Ge neral ............................................................................................................................. 2 0  
1 1. 2.  
Pri mar y Efficac y A nal ysis: Ti me t o S y m pt o m Res p o nse ................................................ 2 1  
1 1. 2. 1.  Deri vati o n of t he S y m pt o m Res p o nse Defi niti o n ............................................................ 2 2  
1 1. 2. 2.  A nal ysis of t he Pri mar y Efficac y Para meter .................................................................... 2 4  


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1 1. 3.  
Se nsiti vit y A nal yses of t he Pri mar y Efficac y A nal ysis .................................................... 2 5  
1 1. 3. 1.  Se nsiti vit y A nal ysis Ass u mi n g Ti me of S y m pt o m Res p o nse of 2 1 Da ys f or 
Disc o nti n ue d S u bjects ...................................................................................................... 2 5  
1 1. 3. 2.  Se nsiti vit y A nal ysis f or a “ Per Pr ot oc ol” S u bset ............................................................. 2 5  
1 1. 3. 3.  Se nsiti vit y A nal ysis E xcl u di n g S u bjects Re p orti n g C hr o mat uria .................................... 2 5  
1 1. 4.  
Sec o n dar y Efficac y A nal yses ........................................................................................... 2 5  
1 1. 4. 1.  Ti me t o A bilit y t o Perf or m All N or mal Acti vities ........................................................... 2 5  
1 1. 4. 2.  Pr o p orti o n of S u bjects E x perie nci n g C o m plicati o ns of C ol ds ......................................... 2 7  
1 1. 5.  
E x pl orat or y Efficac y A nal yses ......................................................................................... 2 7  
1 1. 5. 1.  Ti me t o I n di vi d ual S y m pt o m Res p o nse ........................................................................... 2 7  
1 1. 5. 2.  Ti me t o F L U- P R O D o mai n Res p o nse .............................................................................. 2 9  
1 1. 5. 3.  Ti me t o Ret ur n t o Us ual Healt h ....................................................................................... 3 0  
1 1. 5. 4.  C ha n ge i n Vir us Titer fr o m Baseli ne t o Da y 2, 3, a n d 7 .................................................. 3 2  
1 1. 5. 5.  Pr o p orti o ns of S u bjects wit h Detecta ble Vir us at Da y 2, Da y 3, or Da y 7 ...................... 3 2  
1 1. 5. 6.  Ti me t o S y m pt o m Res p o nse f or All S u bjects Treate d (I T T P o p ulati o n) ......................... 3 3  
1 1. 5. 7.  Ti me t o A bilit y t o Perf or m All N or mal Acti vities f or All S u bjects Treate d (I T T 
P o p ulati o n) ....................................................................................................................... 3 3  
1 1. 5. 8.  A nal ysis of Pr o p orti o ns E x perie nci n g C o m plicati o ns, All S u bjects Treate d (I T T 
P o p ulati o n) ....................................................................................................................... 3 3  
1 1. 5. 9.  Ti me t o S y m pt o m Res p o nse f or S u bjects I nfecte d wit h I n di vi d ual n o n- E V/ R V Vir uses 
or N o Pat h o ge n Detecte d .................................................................................................. 3 3  
1 1. 5. 1 0.  A nal ysis of Ti me t o S y m pt o m Res p o nse f or S u bjects D ose d Wit hi n 2 4 H o urs of 
S y m pt o m O nset ................................................................................................................ 3 4  
1 1. 5. 1 1.  A nal ysis of Ti me t o S y m pt o m Res p o nse f or S u bjects D ose d > 2 4- ≤3 6 H o urs after 
S y m pt o m O nset ................................................................................................................ 3 4  
1 1. 5. 1 2.  A nal ysis of Ti me t o S y m pt o m Res p o nse f or S u bjects D ose d > 3 6 H o urs after S y m pt o m 
O nset ................................................................................................................................. 3 4  
1 1. 6.  
Ot her E x pl orat or y A nal yses ............................................................................................. 3 5  
1 1. 6. 1.  P o p ulati o n P har mac o ki netics A nal ysis ............................................................................ 3 5  
1 1. 6. 2.  A nal ysis of Ti me t o S y m pt o m Res p o nse b y S y m pt o m Relief Me dicati o n Use f or 
Pl ace b o- Treate d S u bjects ................................................................................................. 3 5  
1 1. 6. 3.  A nal ysis of Ti me t o A bilit y t o Perf or m All N or mal Acti vities b y S y m pt o m Relief 
Me dicati o n Use f or Place b o- Treate d S u bjects ................................................................. 3 6  
1 1. 6. 4.  Pr o p orti o n of S u bjects E x perie nci n g C o m plicati o ns of C ol ds b y S y m pt o m Relief 
Me dicati o n Use f or Place b o- Treate d S u bjects ................................................................. 3 6  
1 1. 7.  
Efficac y Listi n gs ............................................................................................................... 3 6  


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1 2.  
S A F E T Y  ........................................................................................................................... 3 7 
1 2. 1.  
Safet y Ta bles a n d Fi g ures ................................................................................................ 3 7  
1 2. 1. 1.  S u m mar y of All Treat me nt E mer ge nt A d verse E ve nts ( T E A Es) .................................... 3 8  
1 2. 1. 2.  S u m maries of T E A Es b y S O C a n d Preferre d Ter m ......................................................... 3 8  
1 2. 1. 3.  La b orat or y Res ults a n d C ha n ges fr o m Baseli ne .............................................................. 3 8  
1 2. 1. 4.  S u m maries of Vital Si g ns Res ults a n d C ha n ges fr o m Baseli ne ....................................... 3 9  
1 2. 1. 5.  S u m maries of P h ysical E xa mi nati o n Res ults a n d C ha n ges fr o m Baseli ne ...................... 3 9  
1 2. 2.  
Safet y Listi n gs .................................................................................................................. 3 9  
A P P E N DI X 1.  S C H E D U L E O F A S S E S S M E N T S  .................................................................... 4 1 
A P P E N DI X 2.  D A T A DI S P L A Y S ............................................................................................ 4 2  
 


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5.  
LI S T O F T A B L E S 
Ta ble 1:  
S u m mar y of Re visi o n Hist or y ...................................................................................... 2  
Ta ble 2:  
Defi niti o n of A nal ysis P o p ulati o ns ............................................................................. 1 6  
Ta ble 3:  
Data Prese ntati o n C o n ve nti o ns ................................................................................... 1 6  
Ta ble 4:  
Ha n dli n g of Missi n g Data ........................................................................................... 1 7  
Ta ble 5:  
Data Prese nte d i n Ge neral Listi n gs ............................................................................. 1 9  
Ta ble 6:  
Varia bles Use d f or t he Pri mar y Efficac y A nal ysis ..................................................... 2 1  
Ta ble 7:  
Varia bles Use d f or A nal ysis of Ti me t o A bilit y t o Perf or m All N or mal Acti vities ... 2 6  
Ta ble 8:  
Varia bles Use d f or A nal ysis of C o m plicati o ns of C ol ds ............................................ 2 7  
Ta ble 9:  
Varia bles Use d f or A nal ysis of Ti me t o I n di vi d ual S y m pt o m Res p o nse ................... 2 8  
Ta ble 1 0:  Varia bles Use d f or A nal ysis of Ti me t o F L U- P R O D o mai n Res p o nse ..................... 2 9  
Ta ble 1 1:  Varia bles Use d f or A nal ysis of Ti me t o Ret ur n t o Us ual Healt h ............................... 3 1  
Ta ble 1 2:  Varia bles Use d f or A nal ysis of C ha n ge i n Vir us Titer ............................................... 3 2  
Ta ble 1 3:  Varia bles Use d f or A nal ysis of Pr o p orti o ns of S u bjects wit h Detecta ble Vir us at Da y 
2, Da y 3, or Da y 7 ....................................................................................................... 3 2  
Ta ble 1 4:  Varia bles Use d f or A nal ysis of Plas ma C o nce ntrati o ns ............................................. 3 5  
Ta ble 1 5:  Data Prese nte d i n Efficac y Listi n gs ............................................................................ 3 6  
Ta ble 1 6:  Data Prese nte d i n Safet y Listi n gs ............................................................................... 3 9  
Ta ble 1 7:  Sc he d ule of Assess me nts ............................................................................................ 4 1  
Ta ble 1 8:  Data Dis pla ys .............................................................................................................. 4 2  
 


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6.  
LI S T O F A B B R E VI A TI O N S 
 
A b b r e vi ati o n  
D efi niti o n  
A L T  
Ala ni n e a mi n otra nsferase  
A S T  
As p artate a mi n otra nsferase  
b.i. d.  
bis i n die (t wic e d ail y)  
B U N  
Bl o o d ure a nitr o g e n  
C O P D  
C hr o nic o bstr u cti v e p ul m o n ar y dise ase  
C R F  
C ase re p ort f or m  
C S R  
Cli nic al st u d y re p ort  
E D C  
Ele ctr o nic d ata c a pt ure  
E V/ R V  
E nter o vir us/ R hi n o vir us  
F D A  
U. S. F o o d a n d Dr u g A d mi nistrati o n  
F L U -P R O  
i n F L U e n z a P atie nt-R e p orte d O utc o m es  
G G T  
G a m m a -gl uta m yltra nsferase  
H D L  
Hi g h -d e nsit y li p o pr otei n  
h M P V  
H u m a n m eta p n e u m o vir us  
I T T 
I nte nt t o tre at 
I T TI 
I nte nt t o tre at i nfe cte d 
L D L  
L o w -d e nsit y li p o pr otei n  
M e d D R A  
M e dic al Dicti o n ar y f or R e g ulat or y A cti vities  
N T Z  
Nita z o x a ni d e  
R S V  
R es pirat or y s y n c ytial vir us  
R T -P C R  
R e al ti m e p ol y m erase c h ai n re a cti o n  
S A P  
Statistic al a n al ysis pla n  
S O C  
S yste m Or g a n Class  
T 
Tiz o x a ni d e  
T E A E  
Tre at m e nt -e m er g e nt a d v erse e v e nt  
T G  
Tiz o x a ni d e Gl u c ur o ni d e  
W H O Dr u g  
W orl d H e alt h Or g a niz ati o n Dr u g dicti o n ar y  


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C O N FI D E N TI A L  
7.  
I N T R O D U C TI O N 
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o descri be t he pla n ne d a nal yses a n d data 
dis pla ys t o be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R) f or Pr ot oc ol R M 0 8- 3 0 0 5. 
All decisi o ns re gar di n g fi nal a nal ysis as defi ne d i n t his S A P will be ma de pri or t o data base l oc k 
a n d u n bli n di n g of t he st u d y data. F urt her i nf or mati o n ca n be f o u n d i n t he pr ot oc ol. 
T he S A P is base d o n: 
•  Pr ot oc ol R M 0 8- 3 0 0 5, Fi nal Versi o n 1. 3, N o ve m ber 2 9, 2 0 1 8 
•  I nter nati o nal C o nfere nce o n Har m o nisati o n G ui deli nes E 4 a n d E 9; a n d 
•  
Disc ussi o ns wit h t he U. S. F o o d a n d Dr u g A d mi nistrati o n ( F D A). 
T his d oc u me nt will descri be a nal ysis p o p ulati o ns a n d detail met h o d ol o g y f or deri vi n g varia bles, 
ha n dli n g missi n g data, a n d a nal yzi n g efficac y a n d safet y data. 
T he  S A P  ma y  be  re vise d  or  a me n de d  t o  reflect  t he  re q uire me nts  of  pr ot oc ol  a me n d me nts  or 
re g ulat or y  re q uests,  b ut  m ust  be  fi nalize d,  a p pr o ve d  a n d  place d  o n  file  bef ore  t he  data base  is 
l oc ke d. De viati o ns fr o m t he S A P will be n ote d i n t he C S R. 
8.  
S T U D Y D E S C RI P TI O N 
8. 1.  St u d y O bjecti ves 
T he pri mar y o bjecti ve of t his st u d y is t o e val uate t he effect of N T Z a d mi nistere d orall y 6 0 0 
m g b.i. d. f or 5 da ys i n re d uci n g t he d urati o n of s y m pt o ms of c ol ds d ue t o E V/ R V i nfecti o n 
c o m pare d  t o  t hat  of  a  place b o  d uri n g  2 1  da ys  of  f oll o w- u p  base d  u p o n  t he  F L U- P R O ©  
patie nt-re p orte d o utc o me i nstr u me nt. 
A ke y sec o n dar y efficac y o bjecti ve is t o e val uate t he effect of N T Z c o m pare d t o place b o o n 
ti me t o ret ur n t o a bilit y t o perf or m all n or mal acti vities. 
A n ot her sec o n dar y efficac y o bjecti ve is t o e val uate t he effect of N T Z c o m pare d t o place b o 
o n t he pr o p orti o n of s u bjects e x perie nci n g o ne or m ore c o m plicati o ns of c ol ds d ue t o E V/ R V 
i nfecti o n i ncl u di n g p ne u m o nia, otitis me dia, br o nc hitis, si n usitis, e xacer bati o ns of ast h ma or 
C O P D, w orse ni n g of pre-e xisti n g healt h c o n diti o ns, sec o n dar y i nfecti o ns re q uiri n g s yste mic 
a nti bi otic use, h os pitalizati o n d ue t o c ol d or c o m plicati o ns of t he c ol d, a n d deat h d ue t o c ol d 
or c o m plicati o ns of t he c ol d. 
E x pl orat or y efficac y o bjecti ves i ncl u de e val uati n g t he effect of treat me nt wit h N T Z o n t he 
ti me t o res p o nse f or eac h F L U- P R O s y m pt o m; ti me t o res p o nse f or eac h F L U- P R O d o mai n; 
ti me t o ret ur n t o us ual healt h; c ha n ges i n viral titers fr o m Baseli ne t o eac h of Da ys 2, 3 a n d 
7;  ti me  t o  s y m pt o m  res p o nse  f or  all  s u bjects  treate d  (I T T  p o p ulati o n);  ti me  t o  s y m pt o m 
res p o nse  f or  s u bjects  i nfecte d  wit h  i n di vi d ual  n o n- E V/ R V  vir uses;  a n d  ti me  t o  s y m pt o m 
res p o nse f or s u bjects w h o recei ve d t he first d ose of st u d y me dicati o n 0- 2 4, > 2 4-≤3 6, or > 3 6 
h o urs  fr o m  s y m pt o m  o nset.  A  fi nal  e x pl orat or y  o bjecti ve  is  t o  e val uate  t he  i m pact  of 
s y m pt o m  relief  me dicati o n  use  o n  ti me  t o  s y m pt o m  res p o nse,  ti me  t o  ret ur n  t o  a bilit y  t o 
perf or m  all  n or mal  acti vities,  a n d  pr o p orti o ns  e x perie nci n g  c o m plicati o ns  of  c ol ds  f or 
place b o-treate d s u bjects. 


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Ot her i m p orta nt o bjecti ves i ncl u de e val uati o n of t he safet y of N T Z b y a nal ysis of a d verse 
e ve nts a n d e val uati o n of relati o ns hi ps bet wee n p har mac o ki netics a n d cli nical or vir ol o gic 
res p o nses. 
8. 2.  St u d y Desi g n 
T he st u d y will be a m ultice nter, ra n d o mize d, d o u ble- bli n d trial t o e val uate t he efficac y of 
N T Z c o m pare d t o place b o i n treati n g c ol ds d ue t o E V/ R V i nfecti o n. S u bjects will be selecte d 
acc or di n g t o t he i ncl usi o n a n d e xcl usi o n criteria liste d i n t he pr ot oc ol. 
I m me diatel y after c o m pleti o n of i nf or me d c o nse nt, scree ni n g, a n d e nr oll me nt i n t he st u d y, 
t w o Baseli ne nas o p har y n geal s wa bs will be c ollecte d f or R T- P C R. Bl o o d a n d uri ne sa m ples 
will be c ollecte d f or la b orat or y safet y tests. S u bjects will recei ve i nstr ucti o n o n c o m pleti n g 
t heir electr o nic diaries, rec or di n g c o nc o mita nt me dicati o ns a n d atte n di n g f oll o w- u p visits.  
S u bjects will be ra n d o mize d 1: 1 t o o ne of t he f oll o wi n g gr o u ps:  
•  Gr o u p 1 ( N T Z):    
T w o N T Z 3 0 0 m g ta blets b.i. d. f or 5 da ys 
•  Gr o u p 2 ( Place b o):   T w o place b o ta blets b.i. d. f or 5 da ys 
Ra n d o mizati o n will be stratifie d b y ( 1) ti me fr o m o nset of ill ness t o ti me of first d ose of 
st u d y  me dicati o n  ( 0- 2 4,  > 2 4-≤3 6,  or  > 3 6  h o urs  fr o m  o nset),  ( 2)  pre-e nr oll me nt  use  of 
s y m pt o m relief me dicati o n, a n d ( 3) prese nce of u n derl yi n g l u n g c o n diti o n i ncl u di n g ast h ma, 
C O P D, or past or prese nt hist or y of s m o ki n g. 
St u d y me dicati o n will be ta ke n i n t he m or ni n g a n d e ve ni n g wit h f o o d. T he first d ose will be 
ta ke n wit h f o o d i n t he p h ysicia n’s office u n der t he o bser vati o n of t he Pri nci pal I n vesti gat or 
or a me m ber of t he I n vesti gat or’s staff. T he sec o n d d ose will be ta ke n b y t he patie nt as cl ose 
as p ossi ble t o 1 2 h o urs after t he first d ose. 
A  n urse  or  ot her  st u d y  pers o n nel  will  visit  eac h  s u bject  ( or  t he  s u bject  will  ret ur n  t o  t he 
cli nic) o n st u d y Da ys 2 a n d 3 t o c ollect t w o nas o p har y n geal s wa bs, t o re vie w patie nt diaries, 
a n d  t o  re vie w  s y m pt o ms  a n d  scree n  f or  c o m plicati o ns  of  c ol ds.  A  bl o o d  sa m ple  f or 
p har mac o ki netics will als o be c ol lecte d pri or t o t he first d ose of st u d y me dicati o n o n st u d y 
Da y 3. T hese Da y 2 a n d 3 visits will occ ur at a p pr o xi matel y t he sa me ti me of da y t hat t he 
s u bject t o o k his/ her first d ose of st u d y me dicati o n (r o u g hl y 2 4 a n d 4 8 h o urs p ost-first d ose). 
T he nas o p har y n geal s wa bs will be use d t o e val uate q ua ntitati ve c ha n ges i n viral s he d di n g. 
T he  bl o o d  sa m ple  will  be  use d  t o  e val uate  relati o ns hi ps  bet wee n  p har mac o ki netics  a n d 
vir ol o gic or cli nical res p o nse. St u d y sites or s u bjects ma y o pt o ut of t he Da y 2 a n d Da y 3 
visits d ue t o site staffi n g, patie nt a vaila bilit y or ot her practical c o nsi derati o ns or prefere nces; 
ne vert heless, at least 7 5 % of s u bjects e nr olle d i n t he trial are e x pecte d t o c o m plete t he Da y 
2 a n d Da y 3 visits a n d relate d pr oce d ures (f or viral ki netics a n d p har mac o ki netics). 
A st u d y p h ysicia n, n urse or ot her site pers o n nel will ma ke dail y tele p h o ne calls t o s u bjects 
f or t he first fi ve da ys of d osi n g t o re vie w s y m pt o ms a n d scree n f or c o m plicati o ns of c ol ds. 
[ N ote: I n lie u of a tele p h o ne call, t his i nf or mati o n ma y be o btai ne d d uri n g t he Da y 2 or 3 
office or h o me visits (see t he prece di n g para gra p h).] 
S u bjects will ret ur n t o t he cli nic o n Da ys 7 a n d 2 2 f or p ost-treat me nt f oll o w- u p, i ncl u di n g 
t w o  nas o p har y n geal  s wa bs,  dr u g  acc o u nta bilit y,  a n d  re p orti n g  of  a d verse  e ve nts  a n d 
c o m plicati o ns of c ol d. Bl o o d a n d uri ne sa m ples f or la b orat or y safet y tests will be c ollecte d 


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at Da y 7. S u bjects will mai ntai n t he electr o nic patie nt diaries t hr o u g h st u d y Da y 2 1. A n y 
visits t hat d o n ot occ ur o n t he prescri be d date, or wit hi n 1 da y of t hat date i n t he case of t he 
Da y 7 visit or wit hi n 3 da ys after i n t he case of t he Da y 2 2 visit will be rec or de d as pr ot oc ol 
de viati o ns. 
A ce ntral la b orat or y will be use d f or la b orat or y safet y tests a n d vir ol o g y testi n g. La b orat or y 
safet y  tests  will  i ncl u de  he m o gl o bi n,  he mat ocrit,  c o m plete  bl o o d  c o u nt  (t otal  a n d 
differe ntial), platelet c o u nt, ra n d o m bl o o d s u gar, t otal c h olester ol, H D L, L D L, tri gl yceri des, 
al b u mi n, A S T, A L T, G G T, al kali ne p h os p hatase, bilir u bi n (t otal/ direct), B U N, creati ni ne, 
s o di u m, p otassi u m, c hl ori de a n d r o uti ne uri nal ysis ( gl uc ose, pr otei n a n d bl o o d). Vir ol o g y 
testi n g  will  i ncl u de  R T- P C R  assa y  t o  i de ntif y  i nfl ue nza  A  ( n o n-s pecific  as  t o  s u bt y pe); 
i nfl ue nza A H 1, H 1 N 1 ( 2 0 0 9), a n d H 3 s u bt y pes; i nfl ue nza B; res pirat or y s y nc ytial vir us A 
a n d B ( R S V); parai nfl ue nza 1, 2, 3 a n d 4; h u ma n meta p ne u m o vir us ( h M P V); a de n o vir us; 
h u ma n  E V/ R V;  c or o na vir us  N L 6 3,  H K U 1,  2 2 9 E  a n d  O C 4 3;  h u ma n  b oca vir us; 
C hl a my d o p hil a  p ne u m o ni ae ; Le gi o nell a  p ne u m o p hil a ;  a n d Myc o pl as m a  p ne u m o ni ae . 
( Baseli ne a n d Da y 7 nas o p har y n geal s wa bs), a n d q ua ntitati o n of E V/ R V b y q ua ntitati ve P C R 
( Baseli ne a n d Da ys 2, 3 a n d 7 nas o p har y n geal s wa bs). F oll o w- u p sa m ples ( Da ys 2, 3 a n d 7) 
c ollecte d fr o m s u bjects w h o d o n ot test p ositi ve f or E V/ R V at Baseli ne, Da y 2 or Da y 3 will 
n ot be a nal yze d f or q ua ntitati ve vir us titer. 
T his st u d y is e x pecte d t o r u n fr o m A u g ust 2 0 1 8 t hr o u g h A pril 2 0 1 9. 
8. 3.  S a m ple Size J ustific ati o n 
T he S y m pt o m Res p o nse defi niti o ns f or t his st u d y will be deri ve d fr o m t he s u bjects’ F L U-
P R O  q uesti o n naire  res p o nses  as  descri be d  i n Secti o n  1 1. 2. 1 .  T he  F L U- P R O- deri ve d 
e n d p oi nt  is  e x pecte d  t o  trac k  ver y  cl osel y  t o  ret ur n  t o  us ual  healt h  stat us  (a  dail y  yes/ n o 
q uesti o n i n t he F L U- P R O q uesti o n naire), w hic h i n t ur n is e x pecte d t o trac k ver y cl osel y t o 
a bilit y  t o  perf or m  1 0 0 %  of  n or mal  acti vities.  We  ass u me,  t heref ore,  t hat  t he  c u m ulati ve 
distri b uti o ns  of  ti me  t o  S y m pt o m  Res p o nse  f or  t he  place b o  treat me nt  gr o u p  will  cl osel y 
reflect  hist orical  data  fr o m  R o mar k  St u d y  R M 0 8- 3 0 0 2  f or  ti me  fr o m  first  d ose  u ntil  t he 
E V/ R V-i nfecte d s u bjects re p ort t hat t he y are a ble t o perf or m 1 0 0 % of us ual acti vities (see 
place b o c ur ve i n c hart bel o w). T he n, t o calc ulate sa m ple size, we ass u me t hat treat me nt wit h 
N T Z treat me nt s h o ul d res ult i n re d ucti o n of at least 4 8 h o urs i n me dia n ti me t o s y m pt o m 
res p o nse. T he f oll o wi n g c ur ves ha ve bee n de vel o pe d f or deter mi ni n g sa m ple size. 




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T a ble 2:  Defi niti o n of A n al ysis P o p ul ati o ns 
T a ble  A n al ysis P o p ul ati o n  
D efi niti o n  
I nte nt t o Tre at (I T T) 
All s u bje cts w h o re c ei v e at le ast o n e d ose of st u d y m e dic ati o n  
I nte nt t o Tre at I nfe cte d (I T TI) T h e s u bset of t h e I T T p o p ulati o n w h o are p ositi v e f or E V/ R V b y 
R T -P C R at a n y of t h e B aseli n e , D a y 2 or D a y 3 visits 
P er Pr ot o c ol  
T h e s u bset of t h e I T TI p o p ulati o n wit h n o m aj or pr ot o c ol 
d e viati o ns t h at m a y h a v e a n effe ct o n t h e i nte grit y of t h e d ata or 
t h e e v al u ati o n of effe cti v e n ess 
9. 2.  D at a Prese nt ati o n C o n ve nti o ns 
T he f oll o wi n g c o n ve nti o ns are a p plie d t o all data prese ntati o ns a n d s u m maries. 
T a ble 3:  D at a Prese nt ati o n C o n ve nti o ns 
D at a  
P r ese nt ati o n C o n v e nti o n  
D es cri pti v e  statistics  f or  c o nti n u o us 
v aria bles  
I n cl u d e t h e n u m b er of s u bje cts wit h a v aila ble d ata, m e a n, 
sta n d ar d  d e viati o n,  m e dia n, first  q u artile,  t hir d  q u artile, 
mi ni m u m a n d m a xi m u m v al u es  
D es cri pti v e  statistics  f or  c ate g oric al 
v aria bles  
I n cl u d e  a  c o u nt  of  s u bje cts  wit h  e a c h  res p o nse  a n d 
p erc e nta g e of s u bje cts wit h e a c h res p o nse o ut  of t h e t otal 
n u m b er of s u bje cts p er p o p ulati o n or tre at m e nt gr o u p, as 
a p plic a ble  
M e a ns  a n d  m e dia ns  f or  c o nti n u o us 
v aria bles  
F or m at t o o n e m ore d e ci m al pla c e t h a n t h e m e as ure d v al u e  
Sta n d ar d  d e viati o ns  f or  c o nti n u o us 
v aria bles  
F or m at  t o  t w o  m ore  d e ci m al pla c es  t h a n  t h e  m e as ure d 
v al u e  
Mi ni m u ms  
a n d  
m a xi m u ms  
f or 
c o nti n u o us v aria bles  
F or m at  t o  t h e  sa m e  n u m b er  of  d e ci m al  pla c es  as  t h e 
m e as ure d v al u e  
N u m b er  a n d  p erc e nt  f or  c ate g oric al 
v aria bles  
X X ( X X. X %)  
D ate v aria bles  
D D M M M Y Y Y Y  
Ti m e v aria bles  
H H: M M ( 2 4 -h o ur cl o c k)  
P- v al u es  
Prese nt fi v e d e ci m al pla c es  
 
If less t h a n 0. 0 0 0 0 1, prese nt as < 0. 0 0 0 0 1 
 
If r o u n d e d res ult is 1. 0 0 0 0 0, prese nt as > 0. 9 9 9 9 9 
All  d e ci m al -c o ntai ni n g  d ata,  w h ere 
p ossi ble  
Prese ntati o n s h o ul d b e d e ci m al -ali g n e d  
9. 3.  H a n dli n g of U nsc he d ule d Assess me nts 
Res ults  of  u nsc he d ule d  assess me nts  will  be  i ncl u de d  i n  listi n gs,  b ut  will  n ot  be  use d  i n 
descri pti ve statistics. 


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9. 4.  H a n dli n g of Missi n g D at a 
Missi n g data will be ha n dle d as f oll o ws: 
T a ble 4:  H a n dli n g of Missi n g D at a 
D at a  
H a n dli n g C o n v e nti o n  
A d v erse e v e nt o nset d ate  
If o nset d ate is c o m pletel y missi n g, i m p ute wit h t h e d ate of first 
d ose.  
If y e ar is missi n g, i m p ute wit h t h e y e ar of e nr oll m e nt. 
If o nl y y e ar or if y e ar a n d d a y are prese nt: 
•  If y e ar = y e ar of first d ose, t h e n set m o nt h a n d d a y t o t h e d ate of 
t h e first d ose. 
•  If y e ar < y e ar of first d ose, t h e n set m o nt h a n d d a y t o D e c e m b er 
3 1.  
•  If y e ar > y e ar of first d ose, t h e n set m o nt h a n d d a y t o Ja n u ar y 1. 
If m o nt h a n d y e ar are prese nt, b ut d a y is missi n g: 
•  If y e ar = y e ar of first d ose a n d  
-  If m o nt h = m o nt h of first d ose, t h e n set d a y t o d a y of first d ose. 
-  If m o nt h < m o nt h of first d ose, t h e n set d a y t o t h e last d a y of 
t h e m o nt h. 
-  If m o nt h > m o nt h of first d ose, t h e n set d a y t o t h e first d a y of 
t h e m o nt h. 
•  If y e ar < y e ar of first d ose, t h e n set d a y t o t h e last d a y of t h e 
m o nt h.  
•  If y e ar > y e ar of first d ose, t h e n set d a y t o t h e first d a y of t h e 
m o nt h.  
•  F or all ot h er c ases, set o nset d ate t o t h e d ate of first d ose.  
A d v erse e v e nt e n d d ate  
If t h e e n d d ate is p artiall y or c o m pletel y missi n g, set t o t h e last d ate 
t h e s u bje ct w as k n o w n t o b e i n t h e st u d y. 
C o n c o mita nt m e dic ati o ns 
start d ate 
If start d ate is c o m pletel y missi n g, it will n ot b e i m p ute d. 
If o nl y y e ar or if y e ar a n d d a y are prese nt, set t h e m o nt h a n d d a y t o 
Ja nu ar y 1.  
If y e ar a n d m o nt h are prese nt a n d d a y is missi n g, set d a y t o t h e first 
d a y of t h e m o nt h.  
 
 


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C o n c o mita nt m e dic ati o ns 
e n d d ate  
If e n d d ate is c o m pletel y missi n g, it will n ot b e i m p ute d. 
If o nl y y e ar or if y e ar a n d d a y are prese nt, set t h e m o nt h a n d da y t o 
D e c e m b er 3 1.  
If y e ar a n d m o nt h are prese nt a n d d a y is missi n g, set d a y t o t h e last 
d a y of t h e m o nt h.  
C o n c o mita nt m e dic ati o ns 
ti m e of d osi n g 
If ti m e of d osi n g is missi n g f or s y m pt o m relief m e dic ati o n, it will 
b e i m p ute d as t h e ti m e of t h e F L U -P R O Q u esti o n n aire c o m pleti o n 
f or t h at d ate. 
1 0.  G E N E R A L C H A R A C T E RI S T I C S 
1 0. 1.  Ge ner al C h ar acteristics T a bles a n d Fi g ures 
All ta bles will prese nt data f or t he o verall st u d y a n d b y treat me nt gr o u p. 
1 0. 1. 1.  Dis p ositi o n of S u bjects 
T he  dis p ositi o n  ta bles  will  s u m marize  t he  c o u nt  a n d  perce nta ge  of  s u bjects  w h o 
c o m plete d  or  disc o nti n ue d  fr o m  t he  st u d y  a n d  t he  mea n  ( S D),  me dia n  (I Q R),  a n d 
mi ni m u m a n d ma xi m u m n u m ber of da ys i n t he st u d y. 
A nal ysis P o p ulati o n(s):  
I T T, I T TI 
Deri ve d Varia bles:  
N u m ber of da ys i n st u d y = date of st u d y c o m pleti o n/earl y 
ter mi nati o n – date of ra n d o mizati o n + 1 
1 0. 1. 2.  Pr ot oc ol De vi ati o ns 
T he de viati o ns ta bles will s u m marize t he c o u nt a n d perce nta ge of s u bjects wit h pr ot oc ol 
de viati o ns b y de viati o n classificati o n ( maj or or mi n or) a n d t he c o m m o n de viati o n ter m. 
A nal ysis P o p ulati o n(s):  
I T T, I T TI 
Deri ve d Varia bles:  
N o ne 
1 0. 1. 3.  De m o gr a p hics 
T he de m o gra p hics ta bles will s u m marize se x, a ge at scree ni n g ( years), race, hei g ht (c m), 
wei g ht ( k g), B MI ( k g/ m 2), a n d s m o ki n g stat us as c ollecte d at scree ni n g/ Baseli ne usi n g 
descri pti ve st atistics. 
A nal ysis P o p ulati o n(s):  
I T T, I T TI 
Deri ve d Varia bles:  
A ge i n years at scree ni n g = date of scree ni n g – date of birt h 
 
B MI = wei g ht i n k g / ( hei g ht i n c m / 1 0 0) 2 
1 0. 1. 4.  Dise ase C h ar acteristics 
T he  disease  c haracteristics  ta bles  will  s u m marize  ti me  si nce  o nset  of  s y m pt o ms  a n d 
baseli ne vir us i nfecti o n(s) usi n g descri pti ve statistics. 
A nal ysis P o p ulati o n(s):  
I T T, I T TI 


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Deri ve d Varia bles:  
N o ne  
1 0. 1. 5.  Pri or a n d C o nc o mit a nt Me dic ati o n 
T he pri or a n d c o nc o mita nt me dicati o n ta bles will s u m marize t he n u m ber a n d perce nta ge 
of  s u bjects  recei vi n g  eac h  me dicati o n  b y  Le vel  4  A nat o mical  T hera pe utic  C he mical 
( A T C) classificati o n a n d sta n dar dize d me dical na me. 
A nal ysis P o p ulati o n(s):  
I T T, I T TI 
Deri ve d Varia bles:  
Pri or me dicati o n classificati o n = me dicati o ns wit h st o p dates 
pri or t o scree ni n g date 
 
C o nc o mita nt  me dicati o n  classificati o n  =  me dicati o ns  wit h 
a d mi nistrati o n  occ urri n g  o n  or  after  t he  date  of  t he  first 
a d mi nistrati o n of st u d y dr u g u ntil t he e n d of t he st u d y 
1 0. 1. 6.  Me dic al Hist or y a n d C o nc o mit a nt Dise ases 
T he  me dical  hist or y  a n d  c o nc o mita nt  diseases  ta bles  will  s u m marize  t he  n u m ber  a n d 
perce nta ge of s u bjects re p orti n g eac h me dical hist or y e ve nt b y Me d D R A preferre d ter m 
a n d s yste m or ga n class. 
A nal ysis P o p ulati o n(s):  
I T T, I T TI 
Deri ve d Varia bles:  
Me dical hist or y classificati o n = e ve nts wit h st o p dates pri or 
t o scree ni n g date 
 
C o nc o mita nt disease classificati o n = e ve nts wit h st o p dates 
o n or after t he date of t he first a d mi nistrati o n of st u d y dr u g 
u ntil t he e n d of t he st u d y 
1 0. 1. 7.  Tre at me nt E x p os ure 
T he treat me nt e x p os ure ta bles will s u m marize t he t otal n u m ber of da ys o n t hera p y a n d 
n u m ber of ta blets ta ke n usi n g descri pti ve statistics. 
A nal ysis P o p ulati o n(s):  
I T T, I T TI 
Deri ve d Varia bles:  
N u m ber of ta blets ta ke n = n u m ber of d oses re p orte d t o ha ve 
bee n ta ke n i n t he case re p ort f or m ( C R F) * 2 
1 0. 2.  Ge ne r al C h ar acteristics Listi n gs 
Ge neral  c haracteristics  listi n gs  will  i ncl u de  data  s pecifie d  i n Ta ble  5   f or  all  s u bjects 
prese nte d b y s u bject n u m ber a n d treat me nt gr o u p. 
T a ble 5:  D at a Prese nte d i n Ge ner al Listi n gs 
Listi n g  
D at a P r ese nte d  
Dis c o nti n u e d S u bje cts  
D ate of disc o nti n u ati o n  
R e as o n f or disc o nti n u ati o n  


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Listi n g  
D at a P r ese nte d  
S u bje cts wit h Pr ot o c ol D e viati o ns  
D ate of d e viati o n  
C o m m o n d e viati o n ter m  
Classific ati o n ( M aj or/ Mi n or ) 
S u bje cts E x cl u d e d fr o m Effic a c y A n al ysis 1 
R e as o n f or e x cl usi o n  
D e m o gra p hic D ata  
S u bje ct i nitials  
D ate/ti m e of i nf or m e d c o nse nt  
D ate of birt h  
A g e  
S e x  
R a c e  
H ei g ht (c m)  
W ei g ht ( k g)  
B MI ( k g/ m 2)  
S m o ki n g stat us  
N u m b er of y e ars s m o k e d  
N u m b er of ci g arettes s m o k e d p er d a y  
B as eli n e  Dise ase C h ara cteristics  
Ti m e fr o m o nset of ill n ess t o first st u d y dr u g 
i nta k e ( h o urs) 
Vir us i nfe cti o n(s)  
Pri or M e dic ati o n  
C o n c o mita nt M e dic ati o n  
R e p orte d m e dic ati o n ter m  
Sta n d ar d m e dic al n a m e  
L e v el 4 A T C ter m  
I n dic ati o n 
Start d ate  
St o p d ate  
D ose  
D ose U nit  
Fre q u e n c y  
R o ute  
M e dic al Hist or y  
C o n c o mita nt Dise ases  
R e p orte d dise ase, c o n diti o n or s ur g er y ter m  
Sta n d ar d m e dic al n a m e  
S yste m or g a n class  
Y e ar of dia g n osis  
A cti v e at scre e ni n g ( Y/ N)  
M e dic ati o n t h era p y ( Y/ N)  
Tre at m e nt E x p os ure D ata  
T otal n u m b er of d a ys o n t h era p y  
N u m b er of ta blets ta k e n  
N u m b er of ta blets dis p e nse d  
N u m b er of ta blets ret ur n e d  
N u m b er of ta blets misse d  
1 S u bje cts w h o are n ot i n cl u d e d i n t h e I T TI p o p ulati o n d u e t o n e g ati v e R T -P C R ass a y will n ot b e 
c o nsi d ere d e x cl u d e d fr o m effic a c y a n al ysis  
1 1.  E F FI C A C Y 
1 1. 1.  Ge ner al 
U nless ot her wise s pecifie d, all statistical tests will use t w o-si de d tests at t he α = 0. 0 5 le vel.  


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T he f oll o wi n g defi niti o ns will a p pl y t o m ulti ple efficac y a nal yses: 
Dail y Diar y Peri o d  
Eac h dail y diar y peri o d will be gi n 2 4 h o urs pri or t o t he ti me 
of diar y assess me nt a n d e n d at t he ti me of diar y assess me nt. 
S y m pt o m Relief Me dicati o n  
A n y me dicati o n ta ke n f or a s y m pt o m of c ol ds as i n dicate d 
b y t he s u bject d uri n g t he st u d y peri o d. 
1 1. 2.  Pri m ar y Effic ac y A n al ysis: Ti me t o S y m pt o m Res p o nse 
T he pri mar y efficac y a nal ysis will be t he c o m paris o n of t he ti me fr o m first d ose of st u d y 
me dicati o n t o S y m pt o m Res p o nse bet wee n treat me nt gr o u ps usi n g Ka pla n- Meier s ur vi val 
c ur ves a n d a Ge ha n- Wilc o x o n test stratifie d b y ( 1) ti me fr o m o nset of ill ness t o ti me of first 
d ose of st u d y me dicati o n ( 0- 2 4, > 2 4- ≤3 6, or > 3 6 h o urs fr o m o nset), ( 2) pre-e nr oll me nt use 
of  s y m pt o m  relief  me dicati o n,  a n d  ( 3)  prese nce  of  u n derl yi n g  l u n g  c o n diti o n  i ncl u di n g 
ast h ma,  C O P D,  or  past  or  prese nt  hist or y  of  s m o ki n g.  Se parate  S y m pt o m  Res p o nse 
defi niti o ns will be deter mi ne d f or I T TI s u bjects wit h n o u n derl yi n g l u n g c o n diti o n a n d f or 
I T TI  s u bjects  wit h  u n derl yi n g  l u n g  c o n diti o ns.  Ti me  t o  S y m pt o m  Res p o nse  will  be 
calc ulate d i n t he sa me wa y f or t he t w o gr o u ps a n d all I T TI s u bjects will be a nal yze d t o get her. 
Defi niti o ns: 
S y m pt o m Res p o nse  
T he set of criteria t o be defi ne d base d u p o n a bli n de d re vie w 
of  s y m pt o m  sc ores  ( p o ole d  f or  all  I T TI  s u bjects  wit h o ut 
re gar d t o treat me nt gr o u p assi g n me nt) t hat c orrelate t o t he 
ti me at w hic h s u bjects re p ort t hat t he y ret ur n t o us ual healt h 
(a  dail y  gl o bal  assess me nt  q uesti o n).    Met h o d ol o g y  t o  be 
use d f or t he deri vati o n of t he S y m pt o m Res p o nse defi niti o n 
is descri be d i n Secti o n 1 1. 2. 1  bel o w.  S y m pt o m sc ores m ust 
be mai ntai ne d at t he defi ne d le vel f or at least 2 dail y diar y 
peri o ds  wit h o ut  a n y  s y m pt o m  relief  me dicati o n  d uri n g  or 
bet wee n t h ose 2 dail y diar y peri o ds.  
Ti me of S y m pt o m Res p o nse  
T he start of t he first dail y diar y peri o d i n w hic h S y m pt o m 
Res p o nse is ac hie ve d a n d is mai ntai ne d f or at least t w o dail y 
diar y peri o ds wit h o ut a n y s y m pt o m relief me dicati o n d uri n g 
or bet wee n t h ose t w o dail y diar y peri o ds. 
Ti me t o S y m pt o m Res p o nse  
Ti me ( h o urs) fr o m t he first d ose of st u d y me dicati o n t o t he 
Ti me of S y m pt o m Res p o nse. 
Varia bles Use d f or t he A nal ysis 
T he pri mar y efficac y a nal ysis will re q uire t he f oll o wi n g varia bles: 
T a ble 6:  V ari a bles Use d f or t he Pri m ar y Effic ac y A n al ysis 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
D ate a n d ti m e of first 
m e dic ati o n i nta k e  
C R F  
 


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V a ri a ble  
S o u r c e  
F o r m at/ N otes  
D ate a n d ti m e of c o m pleti o n 
f or e a c h s y m pt o m assess m e nt 
re c or d 
S u bje ct 
diar y  
 
S y m pt o m sc ore assess m e nt 
f or e a c h s y m pt o m f or e a c h 
diar y re c or d  
S u bje ct 
diar y  
T h e  or di n al  s y m pt o m  se v erit y,  i nte nsit y  or 
fre q u e n c y  sc ore  assess m e nt  f or  e a c h  of  t h e  3 2 
s y m pt o ms will b e c o d e d t o n u m eric al v al u es 0-4.  
It will n ot b e p ossi ble f or a n y i n di vi d u al s y m pt o m 
assess m e nt  t o  b e  missi n g  wit hi n  a  diar y  re c or d, 
t h eref ore  n o  i n di vid u al  ite m  i m p utati o n  will  b e 
re q uire d. 
I n t h e e v e nt t h at t h e diar y w as n ot c o m plete d at a 
s p e cifie d ti m e p oi nt (e. g., D a y 2), t h e missi n g d ata 
will n ot b e i m p ute d.  
D ate a n d ti m e of s y m pt o m 
relief m e dic ati o n i nta k e 
S p o ns or -
pr o vi d e d 
listi n g 
T h e  list  of  s y m p t o m  relief  m e dic ati o ns  will  b e 
sele cte d  fr o m  t h e  listi n g  of  all  c o n c o mita nt 
m e dic ati o ns pri or t o u n bli n di n g.  
1 1. 2. 1.  Deri v ati o n of t he S y m pt o m Res p o nse Defi niti o n 
T w o  S y m pt o m Res p o nse defi niti o ns will be deri ve d base d u p o n a nal ysis of bli n de d dail y 
F L U - P R O s y m pt o m sc ores a n d res p o nses t o t he dail y F L U- P R O q uesti o n, “ Ha ve y o u 
ret ur ne d t o y o ur us ual healt h t o da y?”  f or ( 1) t he I T TI p o p ulati o n wit h u n derl yi n g l u n g 
c o n diti o ns a n d ( 2) f or t he I T TI p o p ulati o n wit h o ut u n derl yi n g l u n g c o n diti o ns. 
T he S y m pt o m Res p o nse defi niti o n will c o nsist of a ma xi m u m res p o nse criteri o n ( 0, ≤1, 
≤2, ≤3 or ≤4) f or eac h of t he 3 2 F L U- P R O ite ms.  
T he  o bjecti ve  of  t his  pr oce d ure  is  t o  i de ntif y  t he  S y m pt o m  Res p o nse  defi niti o n  t hat 
mi ni mizes t he diar y-le vel misclassificati o n rate bet wee n S y m pt o m Res p o nse a n d Us ual 
Healt h stat us as re p orte d b y t he E V/ R V- p ositi ve s u bjects e nr olle d i n t his st u d y.   
Pr oce d ure: 
1.  E val uate  w het her  eac h  dail y  diar y  rec or d  has  ac hie ve d  ret ur n  t o  us ual  healt h 
(re q uiri n g 2 c o nsec uti ve dail y diar y assess me nts wit h “ yes” res p o nse t o t he “ us ual 
healt h” q uesti o n i n F L U- P R O wit h o ut use of s y m pt o m relief me dicati o n d uri n g or 
bet wee n t h ose dail y diar y peri o ds). T his ste p will create a “ Ret ur ne d” varia ble wit h 
p ossi ble  val ues  of  “ Y”  f or  eac h  dail y  diar y  rec or d  t hat  c o nstit utes  ret ur n  t o  us ual 
healt h a n d “ N” f or eac h dail y diar y rec or d t hat d oes n ot. 
2.  Deter mi ne  t he  set  of  S y m pt o m  Res p o nse  defi niti o ns  t o  be  e val uate d  b y  selecti n g 
p ote ntial ma xi m u m res p o nse criteria t hat are li kel y t o c orrelate well wit h ret ur n t o 
us ual healt h. 
a. E xa mi ne t he c u m ulati ve distri b uti o n of or di nal s y m pt o m assess me nt res p o nses 
f or  t he  first  t w o  c o nsec uti ve  diar y  rec or ds  at  w hic h  s u bjects  ret ur n  t o  Us ual 
Healt h.  


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b.  Ma xi m u m  res p o nse  criteria  will  be  selecte d  f or  c o nsi derati o n  as  part  of  t he 
S y m pt o m  Res p o nse  defi niti o n  if  t he y  are  i ncl u de d  i n  t he ≥9 0 %  - ≤9 5 % 
c u m ulati ve  distri b uti o n  of  s y m pt o m  assess me nts  at  t he  ti me  of  ret ur n  t o  us ual 
healt h. If a ma xi m u m res p o nse criteri o n i ncl u des t he 9 5 t h perce ntile a n d e xcee ds 
t he  9 5 %  c u m ulati ve  distri b uti o n,  t he  criteri o n  will  still  be  selecte d  f or 
c o nsi derati o n.  
F or e xa m ple, c o nsi der t he f oll o wi n g c u m ulati ve distri b uti o n of s y m pt o m rati n gs f or 
t he t w o c o nsec uti ve diar y rec or ds at w hic h a ficti o nal p o p ulati o n of s u bjects ret ur n 
t o us ual healt h: 
 
 
R ec o r ds 
R e p o rti n g  
0 
R e c o r ds 
R e p o rti n g 
≤1 
R e c o r ds 
R e p o rti n g 
≤2 
R e c o r ds 
R e p o rti n g 
≤3 
R e c o r ds 
R e p o rti n g 
≤4 
C o u g hi n g  
N 
3 0 0  
4 5 5 
4 7 8  
4 8 5  
5 0 0  
% 
6 0. 0 %  
9 1 . 0 % 
9 5. 6 %  
9 7 %  
1 0 0 %  
F elt c ol d  
N 
4 8 0  
4 9 9  
5 0 0  
5 0 0  
5 0 0  
% 
9 6. 0 %  
9 9. 8 %  
1 0 0 %  
1 0 0 %  
1 0 0 %  
(t a ble w o ul d i n cl u d e all 3 2 F L U-P R O s y m pt o ms f or m a xi m u m res p o nse criteri a sele cti o n 
p ur p oses)  
F or  “c o u g hi n g”,  t he  ma xi m u m  s y m pt o m  res p o nse  criteria  of ≤1  a n d ≤2  w o ul d  be 
selecte d  beca use  t he  9 0 t h  perce ntile  of  res p o nses  is  i ncl u de d  i n ≤1  a n d  t he  9 5 t h 
perce ntile  is  i ncl u de d  i n ≤2.  F or  “felt  c ol d”,  t he  ma xi m u m  s y m pt o m  res p o nse 
criteri o n of 0 w o ul d be selecte d beca use b ot h t he 9 0 t h a n d 9 5t h perce ntiles are i ncl u de d 
i n 0. 
P ossi ble S y m pt o m Res p o nse defi niti o ns will be deter mi ne d fr o m t he set of ma xi m u m 
res p o nse criteria selecte d. 
3.  F or eac h p ossi ble S y m pt o m Res p o nse defi niti o n, e val uate w het her eac h dail y diar y 
rec or d  has  ac hie ve d  S y m pt o m  Res p o nse  (t w o  c o nsec uti ve  diar y  e ntries  wit h  all 
s y m pt o ms  assesse d ≤  t he  ma xi m u m  res p o nse  val ues  wit h  n o  s y m pt o m  relief 
me dicati o n i nta ke d uri n g or bet wee n t h ose t w o dail y diar y peri o ds). T his ste p will 
create a “ Res p o n de d” varia ble wit h p ossi ble val ues of “ Y” f or eac h dail y diar y rec or d 
t hat has ac hie ve d S y m pt o m Res p o nse a n d “ N” f or eac h dail y diar y rec or d t hat has 
n ot ac hie ve d S y m pt o m Res p o nse.   T his ste p will be perf or me d o n a data st ora ge/ V M 
i nfrastr uct ure  t hat  ca n  s u p p ort  e val uati o n  of  4. 2  billi o n  dail y  diar y  rec or ds  wit h 
differe nt  p ossi ble  S y m pt o m  Res p o nse  defi niti o ns.  If  t he  n u m ber  of  diar y  rec or d 
e val uati o ns re q uire d ( n u m ber of p ossi ble S y m pt o m Res p o nse defi niti o ns m ulti plie d 
b y n u m ber of dail y diar y rec or ds t o be e val uate d) e xcee ds 4. 2 billi o n, g o bac k t o ste p 
2 b  a b o ve,  a n d  i ncrease  t he ≥9 0 %  c u m ulati ve  distri b uti o n  t hres h ol d  b y  0. 1 % 
i ncre me nts u ntil t he n u m ber of p ossi ble ma xi m u m res p o nse criteria is re d uce d t o a 
n u m ber t hat will res ult i n e val uati o n of ≤4. 2 billi o n dail y diar y rec or ds. 
4.  F or  eac h  p ossi ble  S y m pt o m  Res p o nse  defi niti o n,  deter mi ne  t he  defi niti o n’s 
misclassificati o n rate b y c o m pari n g t he “ Res p o n de d” a n d “ Ret ur ne d” varia bles f or 
eac h  dail y  diar y  rec or d.  T he  perce nta ge  of  dail y  diar y  rec or ds  wit h  mis matc he d 
“ Res p o n de d”  a n d  “ Ret ur ne d”  val ues  (e. g.,  “ Y”  a n d  “ N”)  will  c o nstit ute  t hat 
S y m pt o m Res p o nse defi niti o n’s misclassificati o n rate. 


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5.  T he S y m pt o m Res p o nse defi niti o n ret ur ni n g t he l o west misclassificati o n rate will be 
selecte d  as  t he  S y m pt o m  Res p o nse  defi niti o n  f or  t he  st u d y  a n d  will  be  use d  t o 
calc ulate  t he  pri mar y  efficac y  para meter  (ti me  t o  S y m pt o m  Res p o nse)  f or  eac h 
s u bject.  
6.  If t w o or m ore S y m pt o m Res p o nse defi niti o ns pr o d uce t he l o west misclassificati o n 
rate (a “tie”), t he S y m pt o m Res p o nse defi niti o n wit h t he l o wer s u m of sc ores will be 
selecte d. I n t he e ve nt t hat t he s u m of sc ores are als o e q ual, t he S y m pt o m Res p o nse 
defi niti o n  wit h  t he  s mallest  a bs ol ute  differe nce  bet wee n  t he  pr o p orti o n  of  false 
p ositi ves (“ Res p o n de d” b ut n ot “ Ret ur ne d”) a n d false ne gati ves (“ Ret ur ne d” b ut n ot 
“ Res p o n de d”) will be selecte d.  If t here is still a tie, t he defi niti o n wit h t he l o west 
s u m of ma xi m u m res p o nse val ues f or t he B o d y/ S yste mic d o mai n will be selecte d, 
a n d  if  t hat  is  still  a  tie,  t he  defi niti o n  wit h  t he  l o west  s u m  of  ma xi m u m  res p o nse 
val ues f or t he E ye d o mai n will be selecte d, a n d s o o n f or t he Gastr oi ntesti nal, T hr oat, 
N ose a n d C hest/ Res pirat or y d o mai ns.  If t here is still a tie, list t he ite ms u n der t he 
B o d y/ S yste mic, E ye, Gastr oi ntesti nal, T hr oat, N ose a n d C hest/ Res pirat or y d o mai ns 
i n al p ha betical or der a n d c o m pare t he ma xi m u m res p o nse val ues u ntil a defi niti o n 
wit h t he l o west ite m sc ore ca n be selecte d. 
T he  S y m pt o m  Res p o nse  Defi niti o n  selecte d  i n  t his  ste p  will  be  a p plie d  f or  a n y 
s u bse q ue nt  a nal ysis  t hat  calls  f or  t he  pri mar y  efficac y  a nal ysis  t o  be  re peate d  u nless 
ot her wise s pecifie d. 
1 1. 2. 2.  A n al ysis of t he Pri m ar y Effic ac y P ar a meter 
T he pri mar y efficac y para meter, ti me t o S y m pt o m Res p o nse, will be deri ve d as f oll o ws: 
E ve nt:   Ti me of S y m pt o m Res p o nse – ti me of t he first d ose 
Ce ns ore d:   Ti me of last s y m pt o m assess me nt – ti me of t he first d ose 
If  S y m pt o m  Res p o nse  is  ac hie ve d  at  t he  ti me  of  t he  first  s y m pt o m  assess me nt  diar y 
rec or d, t he s u bject will be e xcl u de d fr o m t he a nal ysis. 
If S y m pt o m Res p o nse is n ot ac hie ve d pri or t o a s u bject’s last a vaila ble diar y assess me nt, 
b ut t he criteria are met at t he last a vaila ble diar y assess me nt wit h n o e vi de nce of s y m pt o m 
relief  me dicati o n  i nta ke  d uri n g  t hat  diar y  peri o d,  ti me  of  S y m pt o m  Res p o nse  will  be 
c o nsi dere d t o ha ve occ urre d at t he start of t he last dail y diar y peri o d. 
Ti me t o S y m pt o m Res p o nse f or t he N T Z treat me nt gr o u p will be c o m pare d t o t hat of t he 
place b o treat me nt gr o u p usi n g a Ge ha n- Wilc o x o n test stratifie d b y ( 1) ti me fr o m o nset 
of ill ness t o ti me of first d ose of st u d y me dicati o n ( 0- 2 4, > 2 4- ≤3 6, or > 3 6 h o urs fr o m 
o nset),  ( 2)  pre-e nr oll me nt  use  of  s y m pt o m  relief  me dicati o n,  a n d  ( 3)  prese nce  of 
u n derl yi n g  l u n g  c o n diti o n  i ncl u di n g  ast h ma,  C O P D,  or  past  or  prese nt  hist or y  of 
s m o ki n g. T he c o m paris o n will be gra p hicall y de picte d usi n g Ka pla n- Meier c ur ves. 
A nal ysis P o p ulati o n(s): I T TI 
Deri ve d Varia bles:  
E ve nt: Ti me of S y m pt o m Res p o nse – ti me of first d ose 
 
Ce ns ore d: Ti me of last s y m pt o m assess me nt – ti me of first d ose 


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1 1. 3.  Se nsiti vit y A n al yses of t he Pri m ar y Effic ac y A n al ysis 
1 1. 3. 1.  Se nsiti vit y A n al ysis Ass u mi n g Ti me of S y m pt o m Res p o nse of 2 1 D a ys f or 
Disc o nti n ue d S u bjects 
Re peat t he pri mar y efficac y a nal ysis ass u mi n g a ti me of S y m pt o m Res p o nse of 2 1 da ys 
( 5 0 4 h o urs fr o m first d ose of st u d y me dicati o n) f or s u bjects w h o disc o nti n ue d t he st u d y 
pri or t o ac hie vi n g S y m pt o m Res p o nse. 
A nal ysis P o p ulati o n(s): I T TI 
Deri ve d Varia bles: 
See Secti o n 1 1. 2: Pri mar y Efficac y A nal ysis  
1 1. 3. 2.  Se nsiti vit y A n al ysis f or a “ Per Pr ot oc ol ” S u bset 
Re peat t he pri mar y efficac y a nal ysis f or t he Per Pr ot oc ol p o p ulati o n. 
A nal ysis P o p ulati o n(s): I T TI 
Deri ve d Varia bles: 
See Secti o n 1 1. 2: Pri mar y Efficac y A nal ysis 
1 1. 3. 3.  Se nsi ti vit y A n al ysis E xcl u di n g S u bjects Re p orti n g C hr o m at uri a 
Re peat  t he  pri mar y  efficac y  a nal ysis  f or  t he  I T TI  p o p ulati o n  e xcl u di n g  N T Z-treate d 
s u bjects w h o re p orte d c hr o mat uria as a n a d verse e ve nt d uri n g t he st u d y. 
A nal ysis P o p ulati o n(s): I T TI e xcl u di n g N T Z -treate d s u bjects w h o re p orte d c hr o mat uria 
Deri ve d Varia bles: 
See Secti o n 1 1. 2: Pri mar y Efficac y A nal ysis 
1 1. 4.  Sec o n d ar y Effic ac y A n al yses 
If t he pri mar y a nal ysis is si g nifica nt at t he 0. 0 5 le vel, t he sec o n dar y efficac y a nal ysis of Ti me 
t o A bilit y t o Perf or m All N or mal Acti vities will be f or mall y e val uate d at t he 0. 0 5 le vel.  If 
t he  pri mar y  a nal ysis  a n d  t he  sec o n dar y  efficac y  a nal ysis  of  Ti me  t o  Ret ur n  t o  N or mal 
Acti vities are b ot h si g nifica nt at t he 0. 0 5 le vel, t he sec o n dar y efficac y a nal ysis of Pr o p orti o ns 
of S u bjects E x perie nci n g C o m plicati o ns of C ol ds will be f or mall y e val uate d at t he 0. 0 5 le vel.  
If a n y of t hese a nal yses is n ot si g nifica nt at t he 0. 0 5 le vel, t he s u bse q ue nt a nal yses or a nal ysis 
will be perf or me d as e x pl orat or y. 
1 1. 4. 1.  Ti me t o A bilit y t o Perf or m All N or m al Acti vities 
Defi niti o ns: 
A bilit y t o Perf or m All  
N or mal Acti vities  
S u bject re p orts a sc ore of 1 0 o n t he 0- 1 0 scale f or a bilit y 
t o perf or m n or mal acti vities a n d mai ntai ns t he sc ore f or 
at  least  t w o  c o nsec uti ve  dail y  diar y  peri o ds  wit h o ut 
s y m pt o m relief me dicati o n d uri n g or bet wee n t h ose t w o 
dail y diar y peri o ds 
 
Ti me of A bilit y t o Perf or m  


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J ul y 1, 2 0 1 9  
 
P a g e 2 6  of 4 6  
C O N FI D E N TI A L  
All N or mal Acti vities  
T he ti me of t he first dail y diar y e ntr y i n w hic h t he s u bject 
ac hie ves A bilit y t o Perf or m All N or mal Acti vities 
 
Ti me t o A bilit y t o Perf or m 
All N or mal Acti vities  
Ti me  ( h o urs)  fr o m  first  d ose  t o  t he  Ti me  of  A bilit y  t o 
Perf or m All N or mal Acti vities 
 
Varia bles Use d f or t he A nal ysis 
T he a nal ysis will re q uire t he f oll o wi n g varia bles: 
T a ble 7:  V ari a bles Use d f or A n al ysis of Ti me t o A bilit y t o Perf or m All N or m al 
Acti vities 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
D ate a n d ti m e of first 
m e dic ati o n i nta k e  
C R F  
 
D ate a n d ti m e of c o m pleti o n f or 
e a c h a bilit y assess m e nt re c or d  
S u bje ct 
diar y  
 
A bilit y t o p erf or m n or m al 
a cti vities sc ore 
S u bje ct 
diar y  
T h e  a bilit y  t o  p erf or m  n or m al  a cti vities  sc ore 
will b e re c or d e d b y t h e s u bje ct o n a 0 -1 0 sc ale.  
I n t h e e v e nt t h at t h e sc ore w as n ot re c or d e d at a 
s p e cifie d  ti m e  p oi nt  (e. g.,  D a y  2),  t h e  missi n g 
d ata will n ot b e i m p ute d . 
D ate a n d ti m e o f s y m pt o m 
relief m e dic ati o n i nta k e 
S p o ns or -
pr o vi d e d 
listi n g 
T h e list of s y m pt o m relief m e dic ati o ns will b e 
sele cte d  fr o m  t h e  listi n g  of  all  c o n c o mita nt 
m e dic ati o ns pri or t o u n bli n di n g.  
A nal ysis 
T he efficac y para meter, Ti me t o A bilit y t o Perf or m All N or mal Acti vities, will be deri ve d 
as f oll o ws: 
E ve nt:   
Ti me of A bilit y t o Perf or m All N or mal Acti vities – ti me of t he first d ose 
Ce ns ore d:   
Ti me of last a bilit y assess me nt – ti me of t he first d ose 
If  A bilit y  t o  Perf or m  All  N or mal  Acti vities  is  ac hie ve d  at  t he  ti me  of  t he  first  a bilit y 
assess me nt diar y rec or d, t he s u bject will be e xcl u de d fr o m t he a nal ysis. 
If  t he  s u bject  d oes  n ot  ac hie ve  A bilit y  t o  Perf or m  All  N or mal  Acti vities  pri or  t o  t he 
s u bject’s  last  a vaila ble  diar y  assess me nt,  b ut  rec or ds  a  “ 1 0”  f or  a bilit y  t o  perf or m  all 
n or mal  acti vities  at  t he  last  a vaila ble  diar y  assess me nt  wit h  n o  e vi de nce  of  s y m pt o m 
relief me dicati o n i nta ke d uri n g t hat diar y peri o d, ti me of A bilit y t o Perf or m All N or mal 
Acti vities  will  be  c o nsi dere d  t o  ha ve  occ urre d  at  t he  ti me  of  t he  last  a vaila ble  diar y 
assess me nt. 
Ti me t o A bilit y t o Perf or m All N or mal Acti vities f or t he N T Z treat me nt gr o u p will be 
c o m pare d t o t hat of t he place b o treat me nt gr o u p usi n g a Ge ha n- Wilc o x o n test stratifie d 


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J ul y 1, 2 0 1 9  
 
P a g e 2 7  of 4 6  
C O N FI D E N TI A L  
b y ( 1) ti me fr o m o nset of ill ness t o ti me of first d ose of st u d y me dicati o n ( 0- 2 4, > 2 4- ≤3 6, 
or > 3 6 h o urs fr o m o nset), ( 2) pre-e nr oll me nt use of s y m pt o m relief me dicati o n, a n d ( 3) 
prese nce of u n derl yi n g l u n g c o n diti o n i ncl u di n g ast h ma, C O P D, or past or prese nt hist or y 
of s m o ki n g. T he c o m paris o n will be gra p hicall y de picte d usi n g Ka pla n- Meier c ur ves. 
A nal ysis P o p ulati o n(s): I T TI 
Deri ve d Varia bles:  
E ve nt: Ti me of A bilit y t o Perf or m All N or mal Acti vities – ti me 
of first d ose 
 
Ce ns ore d: Ti me of last a bilit y assess me nt – ti me of first d ose 
1 1. 4. 2.  Pr o p orti o n of S u bjects E x perie nci n g C o m plic ati o ns of C ol ds 
Varia bles Use d f or t he A nal ysis 
T he a nal ysis will re q uire t he f oll o wi n g varia bles: 
T a ble 8:  V ari a bles Use d f or A n al ysis of C o m plic ati o ns of C ol ds 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
C o m plic ati o ns of c ol ds  
C R F  
I n v esti g at ors will d esi g n ate a n a d v erse e v e nt 
as a c o m plic ati o n if t h e e v e nt m e ets pr ot o c ol -
s p e cifie d criteria. 
A nal ysis 
Pr o p orti o ns  of  s u bjects  e x perie nci n g  o ne  or  m ore  c o m plicati o ns  of  c ol ds  will  be 
c o m pare d bet wee n t he treat me nt gr o u ps usi n g a Fis her’s e xact test. 
A nal ysis P o p ulati o n(s): I T TI 
Deri ve d Varia bles:  
N o ne 
1 1. 5.  E x pl or at or y Effic ac y A n al yses 
1 1. 5. 1.  Ti me t o I n di vi d u al S y m pt o m Res p o nse 
Defi niti o ns: 
I n di vi d ual S y m pt o m Res p o nse  
F or eac h i n di vi d ual s y m pt o m ( n = 3 2), a sc ore of ≤ t he 
ma xi m u m res p o nse val ue s pecifie d b y t he S y m pt o m 
Res p o nse  defi niti o n  mai ntai ne d  f or  at  least  t w o 
c o nsec uti ve  dail y  diar y  peri o ds  wit h o ut  s y m pt o m 
relief me dicati o n d uri n g or bet wee n t h ose dail y diar y 
peri o ds. 
Ti me of I n di vi d ual S y m pt o m  
Res p o nse 
T he  start  of  t he  first  dail y  diar y  peri o d  i n  w hic h 
I n di vi d ual  S y m pt o m  Res p o nse  is  ac hie ve d  a n d  is 
mai ntai ne d f or at least t w o dail y diar y peri o ds wit h o ut 
a n y  s y m pt o m  relief  me dicati o n  d uri n g  or  bet wee n 
t h ose t w o dail y diar y peri o ds. 


R M 0 8 -3 0 0 5 S A P FI N A L  v 1. 4 
 
J ul y 1, 2 0 1 9  
 
P a g e 2 8  of 4 6  
C O N FI D E N TI A L  
Ti me t o I n di vi d ual S y m pt o m  
Res p o nse 
Ti me ( h o urs) fr o m t he first d ose of st u d y me dicati o n 
t o t he Ti me of I n di vi d ual S y m pt o m Res p o nse. 
Varia bles Use d f or t he A nal ysis 
T he a nal ysis will re q uire t he f oll o wi n g varia bles: 
T a ble 9:  V ari a bles Use d f or A n al ysis of Ti me t o I n di vi d u al S y m pt o m Res p o nse 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
D ate a n d ti m e of first 
m e dic ati o n i nta k e  
C R F  
 
D ate a n d ti m e of c o m pleti o n f or 
e a c h s y m pt o m assess m e nt 
re c or d 
S u bje ct 
diar y  
 
S y m pt o m sc ore assess m e nt f or 
e a c h s y m pt o m f or e a c h diar y 
re c or d 
S u bje ct 
diar y  
T h e  or di n al  s y m pt o m  se v erit y,  i nte nsit y  or 
fre q u e n c y sc ore assess m e nt f or e a c h of t h e 3 2 
s y m pt o ms will b e c o d e d t o n u m eric al v al u es 0-
4.  
It  will  n ot  b e  p ossi ble  f or  a n y  i n di vi d u al 
s y m pt o m  assess m e nt  t o  b e  missi n g  wit hi n  a 
diar y re c or d,  t h eref ore  n o  i n di vi d u al  ite m 
i m p utati o n will b e re q uire d. 
I n t h e e v e nt t h at t h e diar y w as n ot c o m plete d 
at a s p e cifie d ti m e p oi nt (e. g., D a y 2), t h e 
missi n g d ata will n ot b e i m p ute d.  
D ate a n d ti m e of s y m pt o m 
relief m e dic ati o n i nta k e 
S p o ns or -
pr o vi d e d 
listi n g 
T h e list of s y m pt o m relief m e dic ati o ns will b e 
sele cte d fr o m t h e listi n g of all c o n c o mita nt 
m e dic ati o ns pri or t o u n bli n di n g.  S u bje cts will 
re p ort t h e re as o n f or ta ki n g e a c h s y m pt o m 
relief m e dic ati o n, a n d t his d ata will b e use d t o 
assi g n c o n c o mita nt m e dic ati o ns t o rele v a nt 
c ol d s y m pt o ms re p orte d i n t h e F L U -P R O 
q u esti o n n aire.  
A nal ysis 
T he  efficac y  para meter,  ti me  t o  I n di vi d ual  S y m pt o m  Res p o nse,  will  be  deri ve d  as 
f oll o ws: 
E ve nt:   
Ti me of I n di vi d ual S y m pt o m Res p o nse – ti me of t he first d ose 
Ce ns ore d:   Ti me of last s y m pt o m assess me nt – ti me of t he first d ose 
If I n di vi d ual S y m pt o m Res p o nse is ac hie ve d at t he ti me of t he first s y m pt o m assess me nt 
diar y rec or d, t he s u bject will be e xcl u de d fr o m t he a nal ysis. 
If t he I n di vi d ual S y m pt o m Res p o nse is n ot ac hie ve d pri or t o a s u bject’s last a vaila ble 
diar y assess me nt, b ut t he criteria are met at t he last a vaila ble diar y assess me nt wit h n o 
e vi de nce  of  s y m pt o m  relief  me dicati o n  i nta ke  d uri n g  t hat  diar y  peri o d,  Ti me  of 


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J ul y 1, 2 0 1 9  
 
P a g e 2 9  of 4 6  
C O N FI D E N TI A L  
I n di vi d ual S y m pt o m Res p o nse will be c o nsi dere d t o ha ve occ urre d at t he start of t he last 
dail y diar y peri o d. 
Ti me t o I n di vi d ual S y m pt o m Res p o nse f or t he N T Z treat me nt gr o u p will be c o m pare d 
t o t hat of t he place b o treat me nt gr o u p usi n g a Ge ha n- Wilc o x o n test stratifie d b y ( 1) ti me 
fr o m o nset of ill ness t o ti me of first d ose of st u d y me dicati o n ( 0- 2 4, > 2 4-≤3 6, or > 3 6 
h o urs fr o m o nset), ( 2) pre-e nr oll me nt use of s y m pt o m relief me dicati o n, a n d ( 3) prese nce 
of  u n derl yi n g  l u n g  c o n diti o n  i ncl u di n g  ast h ma,  C O P D,  or  past  or  prese nt  hist or y  of 
s m o ki n g. T he c o m paris o n will be gra p hicall y de picte d usi n g Ka pla n- Meier c ur ves. 
A nal ysis P o p ulati o n(s): I T TI 
Deri ve d Varia bles:  
E ve nt:  Ti me  of  I n di vi d ual  S y m pt o m  Res p o nse  –  ti me  of  first 
d ose 
 
Ce ns ore d: Ti me of last s y m pt o m assess me nt – ti me of first d ose 
1 1. 5. 2.  Ti me t o F L U- P R O D o m ai n Res p o nse 
Defi niti o ns: 
F L U - P R O D o mai n Res p o nse  
F or eac h F L U- P R O d o mai n ( n = 6), eac h ite m/s y m pt o m 
sc ore d ≤ t he ma xi m u m res p o nse val ue s pecifie d b y t he 
S y m pt o m  Res p o nse  defi niti o n  a n d  mai ntai ne d  f or  at 
least  t w o  c o nsec uti ve  dail y  diar y  peri o ds  wit h o ut 
s y m pt o m  relief  me dicati o n  d uri n g  or  bet wee n  t h ose 
dail y diar y peri o ds 
Ti me of F L U- P R O D o mai n  
Res p o nse 
T he start of t he first dail y diar y peri o d i n w hic h F L U-
P R O D o mai n Res p o nse is ac hie ve d a n d is mai ntai ne d 
f or  at  least  t w o  dail y  diar y  peri o ds  wit h o ut  a n y 
s y m pt o m relief me dicati o n d uri n g or bet wee n t h ose t w o 
dail y diar y peri o ds. 
Ti me t o F L U- P R O D o mai n 
Res p o nse 
Ti me ( h o urs) fr o m t he first d ose of st u d y me dicati o n t o 
t he Ti me of F L U- P R O D o mai n Res p o nse. 
Varia bles Use d f or t he A nal ysis 
T he a nal ysis will re q uire t he f oll o wi n g varia bles: 
T a ble 1 0:  
V ari a bles Use d f or A n al ysis of Ti me t o F L U- P R O D o m ai n Res p o nse 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
D ate a n d ti m e of first 
m e dic ati o n i nta k e  
C R F  
 
D ate a n d ti m e of c o m pleti o n f or 
e a c h s y m pt o m assess m e nt 
re c or d 
S u bje ct 
diar y  
 


R M 0 8 -3 0 0 5 S A P FI N A L  v 1. 4 
 
J ul y 1, 2 0 1 9  
 
P a g e 3 0  of 4 6  
C O N FI D E N TI A L  
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
S y m pt o m sc ore assess m e nt f or 
e a c h s y m pt o m f or e a c h diar y 
re c or d 
S u bje ct 
diar y  
T h e  or di n al  s y m pt o m  se v erit y,  i nte nsit y  or 
fre q u e n c y sc ore assess m e nt f or e a c h of t h e 3 2 
s y m pt o ms will b e c o d e d t o n u m eric al v al u es 0-
4.  
I n t h e e v e nt t h at t h e diar y w as n ot c o m plete d 
at a s p e cifie d ti m e p oi nt (e. g., D a y 2), t h e 
missi n g d ata will n ot b e i m p ute d.  
D ate a n d ti m e of s y m pt o m 
relief m e dic ati o n i nta k e 
S p o ns or -
pr o vi d e d 
listi n g 
T h e list of s y m pt o m relief m e dic ati o ns will b e 
sele cte d fr o m t h e listi n g of all c o n c o mita nt 
m e dic ati o ns pri or t o u n bli n di n g.  S u bje cts will 
re p ort t h e re as o n f or ta ki n g e a c h s y m pt o m 
relief m e dic ati o n, a n d t his d ata will b e use d t o 
assi g n c o n c o mita nt m e dic ati o ns t o rele v a nt 
d o m ai ns c a pt ure d i n t h e F L U -P R O 
q u esti o n n aire.  
A nal ysis 
T he efficac y para meter, Ti me t o F L U- P R O D o mai n Res p o nse, will be deri ve d as f oll o ws: 
E ve nt:   Ti me of F L U- P R O D o mai n Res p o nse – ti me of t he first d ose 
Ce ns ore d:   Ti me of last s y m pt o m assess me nt – ti me of t he first d ose 
If F L U- P R O D o mai n Res p o nse is ac hie ve d at t he ti me of t he first s y m pt o m assess me nt 
diar y rec or d, t he s u bject will be e xcl u de d fr o m t he a nal ysis. 
If t he F L U- P R O D o mai n Res p o nse is n ot ac hie ve d pri or t o a s u bject’s last a vaila ble diar y 
assess me nt, b ut t he criteria are met at t he last a vaila ble diar y assess me nt wit h n o e vi de nce 
of s y m pt o m relief me dicati o n i nta ke d uri n g t hat diar y peri o d, Ti me of F L U- P R O D o mai n 
Res p o nse will be c o nsi dere d t o ha ve occ urre d at t he start of t he last dail y diar y peri o d. 
Ti me t o F L U- P R O D o mai n Res p o nse f or t he N T Z treat me nt gr o u p will be c o m pare d t o 
t hat of t he place b o treat me nt gr o u p usi n g a Ge ha n- Wilc o x o n test stratifie d b y ( 1) ti me 
fr o m o nset of ill ness t o ti me of first d ose of st u d y me dicati o n ( 0- 2 4, > 2 4-≤3 6, or > 3 6 
h o urs fr o m o nset), ( 2) pre-e nr oll me nt use of s y m pt o m relief me dicati o n, a n d ( 3) prese nce 
of  u n derl yi n g  l u n g  c o n diti o n  i ncl u di n g  ast h ma,  C O P D,  or  past  or  prese nt  hist or y  of 
s m o ki n g. T he c o m paris o n will be gra p hicall y de picte d usi n g Ka pla n- Meier c ur ves. 
A nal ysis P o p ulati o n(s): I T TI 
Deri ve d Varia bles:  
E ve nt: Ti me of F L U- P R O D o mai n Res p o nse – ti me of first d ose 
 
Ce ns ore d: Ti me of last s y m pt o m assess me nt – ti me of first d ose 
1 1. 5. 3.  Ti me t o Ret ur n t o Us u al He alt h 
Defi niti o ns: 
Ret ur n t o Us ual Healt h  
“ Yes”  res p o nse  t o  t he  dail y  F L U- P R O  gl o bal 
assess me nt  q uesti o n,  “ Ha ve  y o u  ret ur ne d  t o  y o ur 
us ual  healt h  t o da y?”  mai ntai ne d  f or  at  least  t w o 


R M 0 8 -3 0 0 5 S A P FI N A L  v 1. 4 
 
J ul y 1, 2 0 1 9  
 
P a g e 3 1  of 4 6  
C O N FI D E N TI A L  
c o nsec uti ve  dail y  diar y  peri o ds  wit h o ut  s y m pt o m 
relief me dicati o n d uri n g or bet wee n t h ose t w o dail y 
diar y peri o ds 
Ti me of Ret ur n t o Us ual Healt h  
T he ti me of t he first diar y e ntr y i n w hic h t he s u bject 
ac hie ves Ret ur n t o Us ual Healt h 
 
Ti me t o Ret ur n t o Us ual Healt h  
Ti me ( h o urs) fr o m first d ose t o t he Ti me of Ret ur n t o 
Us ual Healt h 
Varia bles Use d f or t he A nal ysis 
T he a nal ysis will re q uire t he f oll o wi n g varia bles: 
T a ble 1 1:  
V ari a bles Use d f or A n al ysis of Ti me t o Ret ur n t o Us u al He alt h 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
D ate a n d ti m e of first 
m e dic ati o n i nta k e  
C R F  
 
D ate a n d ti m e of c o m pleti o n f or 
e a c h s y m pt o m assess m e nt 
re c or d 
S u bje ct 
diar y  
 
R et ur n t o us u al h e alt h gl o b al 
assess m e nt q u esti o n res p o nse  
S u bje ct 
diar y  
T h e ret ur n t o us u al h e alt h q u esti o n will h a v e 
p ossi ble res p o nse v al u es of “ Y es” or “ N o ”.  
I n t h e e v e nt t h at t h e res p o nse w as n ot 
re c or d e d at a s p e cifie d ti m e p oi nt (e. g., D a y 
2), t h e missi n g d ata will n ot b e i m p ute d . 
D ate a n d ti m e of s y m pt o m 
relief m e dic ati o n i nta k e 
S p o ns or -
pr o vi d e d 
listi n g 
T h e list of s y m pt o m relief m e dic ati o ns will b e 
sele cte d fr o m t h e listi n g of all c o n co mita nt 
m e dic ati o ns pri or t o u n bli n di n g.  
A nal ysis 
T he efficac y para meter, Ti me t o Ret ur n t o Us ual Healt h, will be deri ve d as f oll o ws: 
E ve nt:   
Ti me of Ret ur n t o Us ual Healt h – ti me of t he first d ose 
Ce ns ore d:   Ti me of last diar y assess me nt – ti me of t he first d ose 
If Ret ur n t o Us ual Healt h is ac hie ve d at t he ti me of t he first s y m pt o m assess me nt diar y 
rec or d, t he s u bject will be e xcl u de d fr o m t he a nal ysis. 
If t he s u bject d oes n ot ac hie ve Ret ur n t o Us ual Healt h pri or t o t he s u bject’s last a vaila ble 
diar y assess me nt, b ut rec or ds a “ Yes” f or t he ret ur n t o us ual healt h gl o bal assess me nt 
q uesti o n  at  t he  last  a vaila ble  diar y  assess me nt  wit h  n o  e vi de nce  of  s y m pt o m  relief 
me dicati o n  i nta ke  d uri n g  t hat  diar y  peri o d,  ti me  of  Ret ur n  t o  Us ual  Healt h  will  be 
c o nsi dere d t o ha ve occ urre d at t he ti me of t he last a vaila ble diar y assess me nt. 
Ti me t o Ret ur n t o Us ual Healt h f or t he N T Z treat me nt gr o u p will be c o m pare d t o t hat of 
t he  place b o  treat me nt  gr o u p  usi n g  a  Ge ha n- Wilc o x o n  test  stratifie d  b y  ( 1)  ti me  fr o m 


R M 0 8 -3 0 0 5 S A P FI N A L  v 1. 4 
 
J ul y 1, 2 0 1 9  
 
P a g e 3 2  of 4 6  
C O N FI D E N TI A L  
o nset of ill ness t o ti me of first d ose of st u d y me dicati o n ( 0- 2 4, > 2 4- ≤3 6, or > 3 6 h o urs 
fr o m o nset), ( 2) pre-e nr oll me nt use of s y m pt o m relief me dicati o n, a n d ( 3) prese nce of 
u n derl yi n g  l u n g  c o n diti o n  i ncl u di n g  ast h ma,  C O P D,  or  past  or  prese nt  hist or y  of 
s m o ki n g. T he c o m paris o n will be gra p hicall y de picte d usi n g Ka pla n- Meier c ur ves. 
A nal ysis P o p ulati o n(s): I T TI 
Deri ve d Varia bles:  
E ve nt: Ti me of Ret ur n t o Us ual Healt h – ti me of first d ose 
 
Ce ns ore d: Ti me of last us ual healt h gl o bal assess me nt – ti me of 
first d ose 
1 1. 5. 4.  C h a n ge i n Vir us Titer fr o m B aseli ne t o D a y 2, 3, a n d 7 
Varia bles Use d f or t he A nal ysis 
T he a nal ysis will re q uire t he f oll o wi n g varia bles: 
T a ble 1 2:  
V ari a bles Use d f or A n al ysis of C h a n ge i n Vir us Titer 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
Q u a ntitati v e P C R vir us titer  
L a b orat or y 
D ata  
Q u a ntitati v e P C R v al u es s h o ul d b e l o g -
tra nsf or m e d f or a n al ysis p ur p oses.  
A nal ysis 
Mea n c ha n ges i n viral titers fr o m Baseli ne t o Da y 2, fr o m Baseli ne t o Da y 3, a n d fr o m 
Baseli ne t o Da y 7 f or t he N T Z a n d t he place b o treat me nt gr o u ps will be c o m pare d usi n g 
a t-test. 
S u bjects wit h u n detecta ble vir us b y q ua ntitati ve P C R at Baseli ne will be e xcl u de d fr o m 
t his a nal ysis. A n y u n detecta ble res ult o n Da y 2, Da y 3 or Da y 7 will be i m p ute d wit h t he 
l o wer li mit of detecti o n f or t he q ua ntitati ve P C R assa y. A n y p ositi ve res ult t hat is bel o w 
t he li mit of q ua ntitati o n will be i m p ute d wit h t he li mit of q ua ntitati o n f or t he q ua ntitati ve 
P C R assa y. 
A nal ysis P o p ulati o n(s): I T TI 
Deri ve d Varia bles:  
E ve nt: Ti me of Ret ur n t o Us ual Healt h – ti me of first d ose 
1 1. 5. 5.  Pr o p orti o ns of S u bjects wit h Detect a ble Vir us at D a y 2, D a y 3, or D a y 7 
Varia bles Use d f or t he A nal ysis 
T he a nal ysis will re q uire t he f oll o wi n g varia bles: 
T a ble 1 3:  
V ari a bles Use d f or A n al ysis of Pr o p orti o ns of S u bjects wit h 
Detect a ble Vir us at D a y 2, D a y 3, or D a y 7 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
e Ple x R P P R T -P C R  or 
q u a ntitati v e P C R  res ult f or 
E nter o vir us/ R hi n o vir us  
L a b orat or y 
D ata  
 
A nal ysis 


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T he pr o p orti o n of s u bjects wit h a p ositi ve res ult f or E V/ R V b y e Ple x R P P R T- P C R or 
q ua ntitati ve P C R at eac h of Da ys 2, 3, a n d 7 will be c o m pare d acr oss treat me nt gr o u ps 
usi n g a Fis her’s e xact test. 
A nal ysis P o p ulati o n(s): I T TI 
Deri ve d Varia bles:  
Pr o p orti o n of s u bjects wit h detecta ble vir us at Da y 2, 3, or 7 = 
n u m ber of s u bjects wit h “ p ositi ve” res ult f or E V/ R V b y e Ple x 
R P P R T- P C R or q ua ntitati ve P C R o n Da y 2, 3, or 7 di vi de d b y 
t he t otal n u m ber of E V/ R V-i nfecte d (I T TI) s u bjects wit h at least 
o ne test res ult f or t he ti me p oi nt f or eac h treat me nt gr o u p. 
N O T E:  Da y  2  a n d  3  visits  were  o pti o nal  acc or di n g  t o  t he 
pr ot oc ol s o it is e x pecte d t hat t he n u m ber of s u bjects wit h test 
res ults at t hese ti me p oi nts will be less t ha n t he n u m ber of I T TI 
s u bjects. 
1 1. 5. 6.  Ti me t o S y m pt o m Res p o nse f or All S u bjects Tre ate d (I T T P o p ul ati o n) 
Ti me t o S y m pt o m Res p o nse will be s u m marize d f or all s u bjects w h o recei ve d at least 
o ne  d ose  of  st u d y  me dicati o n  re gar dless  of  viral  i nfecti o n  (I T T  p o p ulati o n).  A 
p o p ulati o n-s pecific  S y m pt o m  Res p o nse  defi niti o n  will  be  deri ve d  i n  acc or da nce  wit h 
Secti o n 1 1. 2. 1 f or ( 1) t he I T T p o p ulati o n wit h u n derl yi n g l u n g c o n diti o ns a n d ( 2) f or t he 
I T T p o p ulati o n wit h o ut u n derl yi n g l u n g c o n diti o ns. Ti me t o S y m pt o m Res p o nse will be 
a nal yze d i n acc or da nce wit h Secti o n 1 1. 2. 2 . 
1 1. 5. 7.  Ti me t o A bilit y t o Perf or m All N or m al Acti vities f or All S u bjects Tre ate d (I T T 
P o p ul ati o n) 
Ti me t o A bilit y t o Perf or m All N or mal Acti vities as descri be d i n Secti o n 1 1. 4. 1  will be 
re peate d f or all s u bjects w h o recei ve d at least o ne d ose of st u d y me dicati o n re gar dless of 
viral i nfecti o n (I T T p o p ulati o n). 
1 1. 5. 8.  A n al ysis of Pr o p orti o ns E x perie nci n g C o m plic ati o ns, All S u bjects Tre ate d (I T T 
P o p ul ati o n) 
A nal ysis of Pr o p orti o ns E x perie nci n g C o m plicati o ns as descri be d i n Secti o n 1 1. 4. 2  will 
be re peate d f or all s u bjects w h o recei ve d at least o ne d ose of st u d y me dicati o n re gar dless 
of viral i nfecti o n (I T T p o p ulati o n). 
1 1. 5. 9.  Ti me t o S y m pt o m Res p o nse f or S u bjects I nfecte d wit h I n di vi d u al n o n- E V/ R V 
Vir uses  or N o P at h o ge n Detecte d 
Ti me t o S y m pt o m Res p o nse will be s u m marize d f or s u b gr o u ps of s u bjects i nfecte d wit h 
t he  vir uses  s h o w n  bel o w  or  wit h  n o  pat h o ge n  detecte d  pr o vi de d  t hat  t he  s u b gr o u p 
i ncl u des at least 1 0 0 s u bjects. 
P ossi ble S u b gr o u ps:  
I nfl ue nza-i nfecte d 
Parai nfl ue nza-i nfecte d 
h M P V-i nfecte d 
A de n o vir us-i nfecte d 


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C or o na vir us-i nfecte d 
B oca vir us-i nfecte d 
N o  pat h o ge n detecte d 
A s u b gr o u p-s pecific S y m pt o m Res p o nse defi niti o n will be deri ve d i n acc or da nce wit h 
Secti o n  1 1. 2. 1  f or ( 1)  t he  s pecific  vir us-i nfecte d  p o p ulati o n  wit h  u n derl yi n g  l u n g 
c o n diti o ns  a n d  ( 2)  f or  t he  s pecific  vir us-i nfecte d  p o p ulati o n  wit h o ut  u n derl yi n g  l u n g 
c o n diti o ns.  Ti me  t o  S y m pt o m  Res p o nse  will  be  a nal yze d  i n  acc or da nce  wit h Secti o n 
1 1. 2. 2 . 
1 1. 5. 1 0.  A n al ysis of Ti me t o S y m pt o m Res p o nse f or S u bjects D ose d Wit hi n 2 4 H o urs of 
S y m pt o m O nset 
Re peat t he pri mar y efficac y a nal ysis f or t he I T TI p o p ulati o n i ncl u di n g o nl y s u bjects 
w h o t o o k t he first d ose of st u d y me dicati o n wit hi n 2 4 h o urs ( ≤ 2 4 h o urs) fr o m s y m pt o m 
o nset. Ti me fr o m o nset of ill ness will n ot be use d as a fact or i n t his a nal ysis si nce all 
s u bjects will be fr o m t he sa me o nset cate g or y. 
A nal ysis P o p ulati o n(s): I T TI s u bjects wit h ti me of first d ose of st u d y me dicati o n ≤ 2 4 
h o urs fr o m s y m pt o m o nset 
Deri ve d Varia bles: 
See Secti o n 1 1. 2: Pri mar y Efficac y A nal ysis 
1 1. 5. 1 1.  A n al ysis of Ti me t o S y m pt o m Res p o nse f or S u bjects D ose d > 2 4- ≤3 6 H o urs after 
S y m pt o m O nset 
Re peat t he pri mar y efficac y a nal ysis f or t he I T TI p o p ulati o n i ncl u di n g o nl y s u bjects 
w h o t o o k t he first d ose of st u d y me dicati o n m ore t ha n 2 4 h o urs a n d less t ha n or e q ual 
t o 3 6 h o urs ( > 2 4-≤3 6 h o urs) fr o m s y m pt o m o nset. Ti me fr o m o nset of ill ness will n ot 
be use d as a fact or i n t his a nal ysis si nce all s u bjects will be fr o m t he sa me o nset 
cate g or y. 
A nal ysis P o p ulati o n(s): I T TI s u bjects wit h ti me of first d ose of st u d y me dicati o n > 2 4 
a n d ≤ 3 6 h o urs fr o m s y m pt o m o nset 
Deri ve d Varia bles: 
See Secti o n 1 1. 2: Pri mar y Efficac y A nal ysis 
1 1. 5. 1 2.  A n al ysis of Ti me t o S y m pt o m Res p o nse f or S u bjects D ose d > 3 6 H o urs after 
S y m pt o m O nset 
Re peat t he pri mar y efficac y a nal ysis f or t he I T TI p o p ulati o n i ncl u di n g o nl y s u bjects 
w h o t o o k t he first d ose of st u d y me dicati o n m ore t ha n 3 6 h o urs ( > 3 6 h o urs) fr o m 
s y m pt o m o nset. Ti me fr o m o nset of ill ness will n ot be use d as a fact or i n t his a nal ysis 
si nce all s u bjects will be fr o m t he sa me o nset cate g or y. 
A nal ysis P o p ulati o n(s): I T TI s u bjects wit h ti me of first d ose of st u d y me dicati o n > 3 6 
h o urs fr o m s y m pt o m o nset 
Deri ve d Varia bles: 
See Secti o n 1 1. 2: Pri mar y Efficac y A nal ysis 


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1 1. 6.  Ot her E x pl or at or y A n al yses 
1 1. 6. 1.  P o p ul ati o n P h ar m ac o ki netics A n al ysis 
Varia bles Use d f or t he A nal ysis 
T he a nal ysis will re q uire t he f oll o wi n g varia bles: 
T a ble 1 4:  
V ari a bles Use d f or A n al ysis of Pl as m a C o nce ntr ati o ns 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
D a y 3 tiz o x a ni d e ( T) a n d 
tiz o x a ni d e gl u c ur o ni d e ( T G) 
v al u es  
L a b orat or y 
d ata  
 
D e m o gra p hic d ata  
C R F  
 
C o n c o mita nt m e dic ati o ns use  
C R F  
 
A d v erse e v e nts  
C R F  
 
A nal ysis 
Plas ma c o nce ntrati o ns of T a n d T G will be s u m marize d descri pti vel y f or b ot h treat me nt 
gr o u ps. E x pl orat or y a nal yses will be c o n d ucte d t o e val uate relati o ns hi ps bet wee n plas ma 
c o nce ntrati o ns  a n d  a ge,  race,  ge n der,  b o d y  wei g ht,  b o d y  mass  i n de x,  c o nc o mita nt 
me dicati o ns ( yes/ n o), c ha n ges i n viral titer o ver ti me, Ti me t o S y m pt o m Res p o nse, a n d 
a d verse  e ve nts  ( yes/ n o).  F or  c o nti n u o us  fact ors,  t he  relati o ns hi p  wit h  plas ma 
c o nce ntrati o ns  will  be  assesse d  b y  S pear ma n’s  c orrelati o n  a nal ysis  a n d  Pears o n’ s 
c orrelati o n  a nal ysis.  F or  cate g orical  fact ors,  plas ma  c o nce ntrati o ns  will  be  c o m pare d 
a m o n g gr o u ps usi n g t he Kr us kal- Wallis test. 
A nal ysis P o p ulati o n(s): I T TI, N T Z-treate d o nl y 
Deri ve d Varia bles:  
C o nc o mita nt me dicati o n use: if a n y c o nc o mita nt me dicati o n is 
use d, t he n “ yes”, ot her wise “ n o” 
 
A d verse  e ve nts:  if  a n y  a d verse  e ve nt  is  re p orte d,  t he n  “ yes”, 
ot her wise “ n o” 
 
C ha n ges i n viral titer o ver ti me: see Secti o n 1 1. 5. 5  
 
Ti me t o S y m pt o m Res p o nse: see Secti o n 1 1. 2 
1 1. 6. 2.  A n al ysis of Ti me t o S y m pt o m Res p o nse b y S y m pt o m Relief Me dic ati o n Use f or 
Pl ace b o- Tre ate d S u bjects 
Re peat  t he  pri mar y  efficac y  a nal ysis  f or  t he  I T TI  a n d  I T T  p o p ulati o ns  c o m pari n g 
place b o-treate d s u bjects w h o di d n ot use s y m pt o m relief me dicati o n t o place b o-treate d 
s u bjects w h o di d use s y m pt o m relief me dicati o n. S u m of baseli ne F L U- P R O s y m pt o m 
assess me nts  ( < 4 2  or ≥4 2)  will  be  i ncl u de d  as  a  fact or  i n  t he  a nal ysis.  Pre-e nr oll me nt 
s y m pt o m relief me dicati o n use will n ot be use d as a fact or i n t he a nal ysis si nce t he gr o u ps 
bei n g c o m pare d are classifie d b y s y m pt o m relief me dicati o n use. 
A nal ysis P o p ulati o n(s): I T TI place b o-treate d s u bjects, I T T place b o-treate d s u bjects 


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Deri ve d Varia bles: 
See Secti o n 1 1. 2: Pri mar y Efficac y A nal ysis 
1 1. 6. 3.  A n al ysis of Ti me t o A bilit y t o Perf or m All N or m al Acti vities b y S y m pt o m Relief 
Me dic ati o n Use f or Pl ace b o- Tre ate d S u bjects 
Re peat t he a nal ysis of ti me t o a bilit y t o perf or m all n or mal acti vities f or t he I T TI a n d I T T 
p o p ulati o ns  c o m pari n g  place b o-treate d  s u bjects  w h o  di d  n ot  use  s y m pt o m  relief 
me dicati o n t o place b o-treate d s u bjects w h o di d use s y m pt o m relief me dicati o n. S u m of 
baseli ne F L U- P R O s y m pt o m assess me nts ( < 4 2 or ≥4 2) will be i ncl u de d as a fact or i n t he 
a nal ysis. Pre-e nr oll me nt s y m pt o m relief me dicati o n use will n ot be use d as a fact or i n 
t he a nal ysis si nce t he gr o u ps bei n g c o m pare d are classifie d b y s y m pt o m relief me dicati o n 
use. 
A nal ysis P o p ulati o n(s): I T TI place b o-treate d s u bjects, I T T place b o-treate d s u bjects 
Deri ve d Varia bles: 
See Secti o n  1 1. 4. 1  Ti me  t o  A bilit y  t o  Perf or m  All  N or mal 
Acti vities 
1 1. 6. 4.  Pr o p orti o n of S u bjects E x perie nci n g C o m plic ati o ns of C ol ds b y S y m pt o m Relief 
Me dic ati o n Use f or Pl ace b o- Tre ate d S u bjects 
Re peat t he a nal ysis of pr o p orti o n of s u bjects e x perie nci n g c o m plicati o ns of c ol ds f or t he 
I T TI a n d I T T p o p ulati o ns c o m pari n g place b o-treate d s u bjects w h o di d n ot use s y m pt o m 
relief  me dicati o n  t o  place b o-treate d  s u bjects  w h o  di d  use  s y m pt o m  relief  me dicati o n 
usi n g a Fis her’s e xact test. 
A nal ysis P o p ulati o n(s): I T TI place b o-treate d s u bjects, I T T place b o-treate d s u bjects 
Deri ve d Varia bles:  
N o ne 
 
1 1. 7.  Effic ac y Listi n gs 
Efficac y listi n gs will i ncl u de data s pecifie d i n Ta ble 1 5  f or all s u bjects prese nte d b y s u bject 
n u m ber a n d treat me nt gr o u p. 
T a ble 1 5:  
D at a Prese nte d i n Effic ac y Listi n gs 
Listi n g  
D at a P r ese nte d  
Ti m e t o S y m pt o m R es p o nse  
D ate/ti m e of first d ose  
D ate/ti m e of S y m pt o m R es p o nse  
E v e nt ti m e ( h o urs)  
C e ns ore d ti m e ( h o urs)  
Ti m e t o A bilit y t o P erf or m All 
N or m al A cti vities  
D ate/ti m e of first d ose  
D ate/ti m e of A bilit y t o P erf or m All N or m al A cti vities  
E v e nt ti m e ( h o urs)  
C e ns ore d ti m e ( h o urs)  


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Listi n g  
D at a P r ese nte d  
C o m plic ati o ns of C ol ds  
M e d D R A S O C  
M e d D R A preferre d ter m  
R e p orte d ter m  
O nset d ate  
E n d d ate  
S e v erit y  
O utc o m e  
C h a n g e i n st u d y dr u g d osa g e  
Tre at m e nt re q uire d  
Ti m e t o I n di vi d u al S y m pt o m 
R es p o nse  
D ate/ti m e of first d ose  
D ate/ti m e of I n di vi d u al S y m pt o m R es p o nse 
E v e nt ti m e ( h o urs)  
C e ns ore d ti m e ( h o urs)  
Ti m e t o F L U -P R O D o m ai n R es p o nse  
D ate/ti m e of first d ose  
D ate/ti m e of F L U -P R O D o m ai n R es p o nse  
E v e nt ti m e ( h o urs)  
C e ns ore d ti m e ( h o urs)  
Ti m e t o R et ur n t o Us u al H e alt h  
D ate/ti m e of first d ose  
D ate/ti m e of R et ur n t o Us u al H e alt h  
E v e nt ti m e ( h o urs)  
C e ns ore d ti m e ( h o urs)  
Vir ol o g y D ata  
St u d y d a y  
R T -P C R res ult  
Q u a ntitati v e P C R res ult  
1 2.  S A F E T Y 
1 2. 1.  S afet y T a bles a n d Fi g ures 
U nless ot her wise s pecifie d, all safet y ta bles will be base d o n t he I T T p o p ulati o n a n d prese nt 
data b y treat me nt gr o u p. 
A d verse  e ve nts  s u m mar y  ta bles  will  use  t he  f oll o wi n g  al g orit h ms  f or  c o u nti n g  s u bject 
e ve nts: 
•  Preferre d ter m: Eac h s u bject will be c o u nte d o nce wit hi n eac h u ni q ue preferre d ter m at 
t he ma xi m u m gra de.  
•  S yste m or ga n class: Eac h s u bject is c o u nte d o nl y o nce at t he ma xi m u m gra de at eac h 
s yste m or ga n class le vel. 
•  A n y e ve nt: Eac h s u bject wit h a n e ve nt is c o u nte d o nl y o nce at t he ma xi m u m gra de. 


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1 2. 1. 1.  S u m m ar y of All Tre at me nt E mer ge nt A d verse E ve nts ( T E A Es) 
T he s u m mar y of all T E A Es will s u m marize t he f oll o wi n g: 
•  T he t otal n u m ber of T E A Es; 
•  T he n u m ber a n d perce nta ge of s u bjects wit h at least o ne T E A E; 
•  T he n u m ber a n d perce nta ge of s u bjects wit h at least o ne S A E; 
•  T he n u m ber a n d perce nta ge of s u bjects wit h a T E A E b y t he ma xi m u m se verit y gra de; 
a n d 
•  T he n u m ber a n d perce nta ge of s u bjects wit h a T E A E b y t he cl osest relati o ns hi p t o t he 
st u d y dr u g. 
1 2. 1. 2.  S u m m aries of T E A Es b y S O C a n d Preferre d Ter m 
T he  n u m ber  a n d  perce nt  of  s u bjects  wit h  T E A Es  will  be  s u m marize d  b y  S O C  a n d 
preferre d ter m wit h t he f oll o wi n g variati o ns i n prese ntati o n 
•  N u m ber a n d perce nt of s u bjects wit h T E A Es will be s u m marize d b y S O C a n d preferre d 
ter m; 
•  N u m ber a n d perce nt of s u bjects wit h T E A Es will be s u m marize d b y S O C, preferre d 
ter m a n d se verit y; 
•  N u m ber a n d perce nt of s u bjects wit h gra de ≥3 T E A Es b y S O C a n d preferre d ter m; 
•  N u m ber a n d perce nt of s u bjects wit h T E A Es b y S O C, preferre d ter m a n d relati o ns hi p 
t o st u d y me dicati o n; 
•  N u m ber a n d perce nt of s u bjects wit h u ne x pecte d T E A Es b y S O C a n d preferre d ter m 
( N ote: u ne x pecte d T E A Es are t h ose n ot liste d i n t he I n vesti gat or’s Br oc h ure f or t he 
st u d y); 
•  N u m ber a n d perce nt of s u bjects wit h S A Es b y S O C a n d preferre d ter m; a n d 
•  N u m ber a n d perce nt of T E A Es lea di n g t o st u d y wit h dra wal b y S O C a n d preferre d ter m. 
1 2. 1. 3.  L a b or at or y Res ults a n d C h a n ges fr o m B aseli ne 
N u merical he mat ol o g y a n d ser u m bi oc he mistr y val ues will be c o n verte d t o SI u nits a n d 
classifie d as N or mal, Gra de 1, Gra de 2, Gra de 3 or Gra de 4 acc or di n g t o refere nce ra n ges 
i n dicate d  i n  t he  pr ot oc ol  t o xicit y  gra di n g  scale  ta bles  (see  Pr ot oc ol  A p pe n di x  II). 
Uri nal ysis res ults will be classifie d as N or mal or A b n or mal base d o n refere nce ra n ges 
pr o vi de d b y t he ce ntral la b orat or y. 
He mat ol o g y,  ser u m  bi oc he mistr y,  a n d  uri nal ysis  la b orat or y  res ults  a n d  c ha n ge  fr o m 
Baseli ne will be s u m marize d usi n g descri pti ve statistics f or eac h visit.  
S hift ta bles will dis pla y s hifts fr o m Baseli ne i n la b orat or y res ults classificati o n ( Gra de 
1/ 2/ 3/ 4 or N or mal/ A b n or mal) b y st u d y da y. 


R M 0 8 -3 0 0 5 S A P FI N A L  v 1. 4 
 
J ul y 1, 2 0 1 9  
 
P a g e 3 9  of 4 6  
C O N FI D E N TI A L  
1 2. 1. 4.  S u m m aries of Vit al Si g ns Res ults a n d C h a n ges fr o m B ase li ne 
Vital si g ns data will be classifie d as N or mal, Gra de 1, Gra de 2, Gra de 3 or Gra de 4 base d 
o n  t he  refere nce  ra n ges  i n dicate d  i n  t he  pr ot oc ol  t o xicit y  gra di n g  scale  ta bles  (see 
Pr ot oc ol  A p pe n di x  II).  If  t w o  vital  si g ns  val ues  are  a vaila ble  i n  t he  data base  f or  o ne 
a nal ysis ti me p oi nt (e. g., Da y 7 Visit), t he later val ue will be use d f or t he a nal ysis. 
Vital  si g ns  res ults  a n d  c ha n ge  fr o m  Baseli ne  will  be  s u m marize d  usi n g  descri pti ve 
statistics f or eac h visit.  
S hift ta bles will dis pla y s hifts fr o m Baseli ne i n vital si g ns classificati o n ( Gra de 1/ 2/ 3/ 4) 
b y st u d y da y. 
1 2. 1. 5.  S u m m aries of P h ysic al E x a mi n ati o n Res ults a n d C h a n ges fr o m B aseli ne 
T he n u m ber a n d perce nt of s u bjects wit h a b n or mal p h ysical e xa mi nati o n fi n di n gs will be 
s u m marize d b y b o d y s yste m f or eac h visit. 
A  s hift  ta ble  will  dis pla y  c ha n ges  i n  p h ysical  e xa mi nati o n  classificati o n 
( N or mal/ A b n or mal) at eac h visit b y b o d y s yste m. 
1 2. 2.  S afet y Listi n gs 
Safet y listi n gs will i ncl u de data s pecifie d i n Ta ble 1 6  f or all s u bjects prese nte d b y s u bject 
n u m ber a n d treat me nt gr o u p. 
T a ble 1 6:  
D at a Prese nte d i n S afet y Listi n gs 
Listi n g  
D at a P r ese nte d  
A d v erse E v e nts  
M e d D R A S O C  
M e d D R A preferre d ter m  
R e p orte d ter m  
O nset d ate  
E n d d ate  
S e v erit y  
S eri o us ( Y/ N)  
R elati o n t o st u d y dr u g  
O utc o m e  
C h a n g e i n st u d y dr u g d osa g e  
Tre at m e nt re q uire d  
H e m at ol o g y L a b orat or y R es ults  
S er u m Bi o c h e mistr y L a b orat or y R es ults  
Uri n al ysis L a b orat or y R es ults  
Visit  
D ate of visit  
L a b orat or y test  
R es ult  
R es ult u nits  
L o w er li mit of n or m al  
U p p er li mit of n or m al  
Classific ati o n ( L/ N/ H)  


R M 0 8 -3 0 0 5 S A P FI N A L  v 1. 4 
 
J ul y 1, 2 0 1 9  
 
P a g e 4 0  of 4 6  
C O N FI D E N TI A L  
Listi n g  
D at a P r ese nte d  
Plas m a Tiz o x a ni d e a n d Tiz o x a ni d e 
Gl u c ur o ni d e R es ults  
Visit  
D ate of visit  
Tiz o x a ni d e c o n c e ntrati o n ( µ g/ m L)  
Tiz o x a ni d e gl u c ur o ni d e c o n c e ntrati o n ( µ g/ m L)  
Vital Si g ns D ata  
Visit  
D ate of visit  
W ei g ht ( k g)  
S yst olic bl o o d press ure ( m m H g)  
Diast olic bl o o d press ure ( m m H g)  
P ulse ( b p m)  
R es pirat or y rate ( b p m)  
Oral te m p erat ure (° F)  
P h ysic al E x a mi n ati o n D ata  
Visit  
D ate of visit  
B o d y s yste m  
R es ult ( N or m al/ A b n or m al/ N ot D o n e)  
A b n or m alit y  


R M 0 8 -3 0 0 5 S A P FI N A L  v 1. 4 
 
J ul y 1, 2 0 1 9  
 
P a g e 4 1  of 4 6  
C O N FI D E N TI A L  
A P P E N DI X 1.  S C H E D U L E O F A S S E S S M E N T S 
T a ble 1 7:  
Sc he d ule of Assess me nts 
 
S cree ni n g 
( D a y 1) 
B as eli n e  
( D a y 1) 
D a ys 
2- 2 2  
D a ys 
2- 5 
D a ys 
2, 3  
D a y 
7 ± 1  
D a y 
2 2 + 3  
U ns c h e d ule d 
Visit  
Si g n e d i nf or m e d c o nse nt  
X 
 
 
 
 
 
 
 
C o m plete m e dical hist or y  
X 
 
 
 
 
 
 
 
P h ysical e x a mi n ati o n/ w ei g ht/ vital si g ns  
X 
 
 
 
 
X 1 
X 1 
X 
D e m o gra p hics/s m o ki n g hist or y  
X 
 
 
 
 
 
 
 
Uri n e pre g n a n c y test  
X 
 
 
 
 
 
 
 
R ec or d oral te m p erat ure  
X 
 
 
 
 
X 
X 
X 
R ec or d s y m pt o ms a n d ti m e of o nset  
X 
 
 
 
 
 
 
 
E v al u ate acc or di n g t o 
i n cl usi o n/e x cl usi o n criteria  
X 
 
 
 
 
 
 
 
C ollect n as o p h ar y n g eal s w a bs  
 
X 
 
 
X 2 
X 3 
X 4 
X 
Bl o o d sa m ple f or p h ar m ac o ki n etics  
 
 
 
 
X 5 
 
 
 
Bl o o d sa m ple f or la b orat or y safet y tests 6 
 
X 
 
 
 
X 
 
X 
Uri n e sa m ple f or r o uti n e uri n al ysis 6 
 
X 
 
 
 
X 
 
X 
R ec or d c o n c o mita nt m e dicati o ns  
 
X 
 
 
 
X 
X 
X 
C o m plete B aseli n e  s y m pt o ms i n diar y 
a n d dis p e nse diar y  
 
X 
 
 
 
 
 
 
R a n d o mizati o n/ dis p e nse st u d y 
m e dicati o n  
 
X 
 
 
 
 
 
 
First d ose i n office a n d e nter i n diar y  
 
X 
 
 
 
 
 
 
I nstr u cti o ns re: d osi n g, c o n c o mita nt 
m e dicati o ns, s u bject diar y, birt h c o ntr ol, 
f oll o w-u p  visits a n d see ki n g e m er g e n c y 
care  
 
X 
 
X 
 
X 
 
X 
R e vie w/rec or d a d v erse e v e nts  
 
X 
 
X 
X 
X 
X 
X 
R e vie w electr o nic s u bject diar y e ntries  
 
 
X 7 
 
 
 
 
X 7 
S cree n f or E V -relate d c o m plicati o ns 
 
 
 
X 
X 
 
 
 
R e vie w c o m plia n ce wit h st u d y 
m e dicati o n, c ollect c o ntai n er wit h 
u n use d m e dicati o n, c o m plete pill c o u nt 
l o g f or m 
 
 
 
 
X 
X 
 
X 8 
1 D a y 7 a n d 2 2 p h ysical e x a m is a brief p h ysical e x a m ( vital si g ns a n d n ursi n g p h ysic al ass ess m e nt) i n cl u di n g s y m pt o m 
directe d p h ysicia n p h ysical e x a mi n ati o n as re q uire d b y s u bje ct s y m pt o ms. Vital si g ns i n cl u d e bl o o d press ure, p uls e, 
res pirat or y rate a n d oral te m p erat ure. 
2 N as o p h ar y n g eal s w a bs o n d a ys 2 a n d 3 will b e c olle cte d at t h e s u bje ct’s h o m e ( or cli nic or a n ot h er l o c ati o n as a gre e d 
wit h t h e s u bject).  
3 N as o p h ar y n g eal s w a bs c ollecte d o n d a y 7 will o nl y b e teste d f or t h e prese n c e of vir us if a sa m ple fr o m d a y 1, 2 or 3 
w as p ositi v e f or e nter o vir us/r hi n o vir us.  
4N as o p h ar y n g eal s w a bs c ollecte d o n d a y 2 2 will o nl y b e teste d f or t h e pres e n c e of vir us if t h e s a m ple fr o m d a y 7 w as 
p ositi v e f or  e nter o vir us/r hi n o vir us.  
5 Bl o o d sa m ple c ollecte d pre -d ose o n d a y 3.  
6 L a b orat or y safet y tests i n cl u d e h e m o gl o bi n, h e m at o crit, c o m plete bl o o d c o u nt (t otal a n d differe ntial), platelet c o u nt, 
ra n d o m bl o o d s u g ar, t otal c h olester ol, H D L, L D L, tri gl y c eri d es, alb u mi n, A S T, A L T, G G T, al k ali n e p h os p h atase, 
bilir u bi n  (t otal/ direct),  B U N,  creati ni n e,  s o di u m,  p otassi u m,  c hl ori d e  a n d  r o uti n e  uri n al ysis  ( gl u c ose,  pr otei ns  a n d 
bl o o d).  
7 All s u bjects will m ai ntai n a n electr o nic diar y u ntil d a y 2 2 ( + 3).  Site staff will c o nta ct s u bje cts as n e e d e d d uri n g 
st u d y t o e ns ure ti m el y c o m pleti o n of electr o nic diar y. 
8 C ollecti o n of u n use d I M P a n d c o m pleti o n of pill c o u nt l o g f or m will b e p erf or m e d at u nsc h e d ule d visit if a p plic a ble  
 




R M 0 8 -3 0 0 5 S A P FI N A L  v 1. 4 
 
J ul y 1, 2 0 1 9 
 
P a g e 4 3  of 4 6  
C O N FI D E N TI A L  
Dis pl a y 
N u m b e r  
Title  
T y p e  
A n al ysis 
P o p ul ati o n  
1 4. 2. 2. 2. 2  
Gra p hic al R e prese ntati o n of S e nsiti vit y A n al ysis of Ti m e t o S y m pt o m R es p o nse f or t h e P er Pr ot o c ol 
P o p ulati o n  
Fi g ure  
P er Pr ot o c ol  
1 4. 2. 2. 3. 1  
S e nsiti vit y A n al ysis of Ti m e t o S y m pt o m R es p o nse E x cl u di n g N T Z -tre ate d S u bje cts R e p orti n g 
C hr o m at uria  
T a ble  
I T TI 
1 4. 2. 2. 3. 2  
Gra p hic al R e prese ntati o n of S e nsiti vit y A n al ysis of Ti m e t o S y m pt o m R es p o nse E x cl u di n g N T Z -tre ate d 
S u bje cts R e p orti n g C hr o m at uria  
Fi g ure  
I T TI 
1 4. 2. 3. 1  
A n al ysis of Ti m e t o A bilit y t o P erf or m All N or m al A cti vities 
T a ble  
I T TI 
1 4. 2. 3. 2  
Gra p hic al R e prese ntati o n of Ti m e t o A bilit y t o P erf or m All N or m al A cti vities  
Fi g ure  
I T TI 
1 4. 2. 4  
A n al ysis of Pr o p orti o ns E x p erie n ci n g C o m plic ati o ns of C ol ds  
T a ble  
I T TI 
1 4. 2. 5 . 1. x 
A n al ysis of Ti m e t o I n di vi d u al S y m pt o m R es p o nse 
T a ble  
I T TI 
1 4. 2. 5 . 2. x 
Gra p hic al R e prese ntati o n of Ti m e t o I n di vi d u al S y m pt o m R es p o nse  
Fi g ure  
I T TI 
1 4. 2. 6 . 1. x 
A n al ysis of Ti m e t o F L U -P R O D o m ai n R es p o nse  
T a ble  
I T TI 
1 4. 2. 6 . 2. x 
Gra p hic al R e prese ntati o n of Ti m e t o F L U -P R O D o m ai n  R es p o nse  
Fi g ure  
I T TI 
1 4. 2. 7 . 1 
A n al ysis of Ti m e t o R et ur n t o Us u al H e alt h  
T a ble  
I T TI 
1 4. 2. 7 . 2 
Gra p hic al R e prese ntati o n of Ti m e t o R et ur n t o Us u al H e alt h  
Fi g ure  
I T TI 
1 4. 2. 8 
A n al ysis of C h a n g es i n E V/ R V Vir us Titer  
T a ble  
I T TI 
1 4. 2. 9 
Pr o p orti o ns of S u bje cts wit h D ete cta ble E V/ R V  o n D a ys 2, 3, a n d 7  
T a ble  
I T TI 
1 4. 2. 1 0. 1  
E x pl orat or y E v al u ati o n of S y m pt o m R es p o nse D efi niti o ns f or All S u bje cts Tre ate d  
T a ble  
I T T 
1 4. 2. 1 0. 2 . 1 
A n al ysis of Ti m e t o S y m pt o m R es p o nse f or All S u bje cts Tre ate d  
T a ble  
I T T 
1 4. 2. 1 0. 2. 2  
A n al ysis of Ti m e t o A bilit y t o P erf or m All N or m al A cti vities f or All S u bje cts Tre ate d  
T a ble  
I T T 
1 4. 2. 1 0. 2. 3  
A n al ysis of Pr o p orti o ns E x p erie n ci n g C o m plic ati o ns of C ol ds, All S u bje cts Tre ate d  
T a ble  
I T T 
1 4. 2. 1 0. 3 . 1 
Gra p hic al R e prese ntati o n of Ti m e t o S y m pt o m R es p o nse f or All S u bje cts Tre ate d  
Fi g ure  
I T T 
1 4. 2. 1 0. 3. 2  
Gra p hic al R e prese ntati o n of Ti m e t o A bilit y t o P erf or m All N or m al A cti vities f or All S u bje cts Tre ate d  
Fi g ure  
I T T 
1 4. 2. 1 1. x. 1  
E x pl orat or y E v al u ati o n of S y m pt o m R es p o nse D efi niti o ns f or S p e cific Vir us S u b gr o u ps  
T a ble  
I T T 
1 4. 2. 1 1. x. 2  
A n al ysis of Ti m e t o S y m pt o m R es p o nse f or S p e cific Vir us S u b gr o u ps  
T a ble  
I T T 
1 4. 2. 1 1. x. 3  
Gra p hic al R e prese ntati o n of Ti m e t o S y m pt o m R es p o nse f or S p e cific Vir us S u b gr o u ps  
Fi g ure  
I T T 
1 4. 2. 1 2 . 1. 1 
A n al ysis of Ti m e t o S y m pt o m R es p o nse f or S u bje cts D ose d  ≤2 4 H o urs fr o m S y m pt o m O nset  
T a ble  
I T TI 
1 4. 2. 1 2. 1. 2  
Gra p hic al R e prese ntati o n of Ti m e t o S y m pt o m R es p o nse f or S u bje cts D ose d  ≤2 4 H o urs fr o m S y m pt o m 
O nset  
Fi g ure  
I T TI 
1 4. 2. 1 2. 2. 1  
A n al ysis of Ti m e t o S y m pt o m R es p o nse f or S u bje cts D ose d  > 2 4 - ≤3 6 H o urs fr o m S y m pt o m O nset  
T a ble  
I T TI 
1 4. 2. 1 2. 2. 2  
Gra p hic al R e prese ntati o n of Ti m e t o S y m pt o m R es p o nse f or S u bje cts D ose d  > 2 4 - ≤3 6 H o urs fr o m 
S y m pt o m O nset  
Fi g ure  
I T TI 
1 4. 2. 1 2. 3. 1  
A n al ysis of Ti m e t o S y m pt o m R es p o nse f or S u bje cts D ose d  > 3 6 H o urs fr o m S y m pt o m O nset  
T a ble  
I T TI 






R M 0 8 -3 0 0 5 S A P FI N A L  v 1. 4 
 
J ul y 1, 2 0 1 9 
 
P a g e 4 6  of 4 6  
C O N FI D E N TI A L  
Dis pl a y 
N u m b e r  
Title  
T y p e  
A n al ysis 
P o p ul ati o n  
1 6. 2. 6. 8  
Listi n g of Ti m e t o S y m pt o m R es p o nse f or S p e cific Vir us S u b gr o u ps  
Listi n g  
I T T 
1 6. 2. 6. 9  
Listi n g of Vir ol o g y D ata  
Listi n g  
I T T 
1 6. 2. 7  
Listi n g of A d v erse E v e nts  
Listi n g  
I T T 
1 6. 2. 8. 1  
Listi n g of H e m at ol o g y L a b orat or y R es ults  
Listi n g  
I T T 
1 6. 2. 8. 2  
Listi n g of S er u m Bi o c h e mistr y L a b orat or y R es ults  
Listi n g  
I T T 
1 6. 2. 8. 3  
Listi n g of Uri n al ysis L a b orat or y R es ults  
Listi n g  
I T T 
1 6. 2. 8. 4  
Listi n g of Plas m a Tiz o x a ni d e a n d Tiz o x a ni d e Gl u c ur o ni d e R es ults  
Listi n g  
I T T 
1 6. 2. 9. 1  
Listi n g of Vital Si g ns D ata  
Listi n g  
I T T 
1 6. 2. 9. 2  
Listi n g of P h ysic al E x a mi n ati o n D ata  
Listi n g  
I T T