Clinical trial NCT03336619
Conditions: Influenza
Keywords: Influenza
Sponsor: Romark Laboratories L.C.
Start date: 2018-01-17; Completion date: 2019-04-17
Enrollment: 1030 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Trial to evaluate efficacy and safety of nitazoxanide (NTZ) in the treatment of uncomplicated influenza.

Detailed description:
A multicenter, randomized, double-blind, placebo controlled trial to evaluate efficacy and safety of nitazoxanide (NTZ) in the treatment of uncomplicated influenza.

Arms: arm 1: Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days arm 2: Two Placebo tablets orally twice daily (b.i.d.) 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 documents:
Prot_000.pdf: 
A Phase III, Randomized, Double-Blind, Placebo Controlled Trial 
to Evaluate the Efficacy and Safety ofNitazoxanide in the Treatment of 
Uncomplicated Influenza 
Protocol No. RM08-3004 
Study Sponsor: 
The Romark Institute for Medical Research 
Version: FINAL 1.5 
Janua1y 3, 2019 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
2 
 
 
T A B L E O F C O N T E N T S  
 
 
A P P R O V A L O F FI N A L P R O T O C O L  ..........................................................................................................................4 
 
P R O T O C O L S Y N O P S I S ...............................................................................................................................................5 
 
1  B A C K G R O U N D  ...........................................................................................................................................................6  
1. 1  
I nfl u e n za ...........................................................................................................................................................6  
1. 2  
Nitaz o x a ni d e ( N T Z)  .........................................................................................................................................6  
1. 2. 1  A cti vit y of N T Z A g ai nst I nfl u e n z a Vir us R e plic ati o n  ..........................................................................7  
1. 2. 2  P h ar m ac o ki n etics of N T Z i n H u m a ns  ...................................................................................................7  
1. 2. 3  P h ase 2 Cli nical Trials of N T Z i n S u bje cts wit h I nfl u e n z a -li k e Ill n ess: St u dies R M 0 2-2 0 2 2 a n d 
R M 0 1 -2 0 2 1  ............................................................................................................................................8  
1. 2. 4  P h ase 2 b/ 3 Cli nical Trial of N T Z i n U n c o m plic ate d I nfl u e n z a: St u d y R M 0 8 -3 0 0 1  .............................9  
1. 2. 5  R a n d o mize d 2 x 2 F act orial Trial of N T Z a n d O S T i n Tre ati n g U n c o m plic ate d I nfl u e n z a: St u d y 
R M 0 8 -3 0 0 2  ..........................................................................................................................................1 1  
1. 2. 6  R a n d o mize d D o u ble -Bli n d Plac e b o C o ntr olle d Trial of N T Z i n Tre ati n g U n c o m plic ate d I nfl u e n z a: 
S t u d y R M 0 8-3 0 0 3  ...............................................................................................................................1 2  
1. 2. 7  O v er vie w of Ot h er E x p erie n ce i n Cli nic al Trials a n d P ost -m ar k eti n g S ur v eilla n c e  ...........................1 3  
1. 3  
R ati o n ale f or t h e St u d y  ...................................................................................................................................1 3  
2  S T U D Y O B J E C TI V E S  ...............................................................................................................................................1 4  
3  S T U D Y D E SI G N  .........................................................................................................................................................1 4  
4  P A TI E N T S E L E C TI O N  ............................................................................................................................................1 7  
4. 1  
I n cl usi o n Criteria ............................................................................................................................................1 7  
4. 2  
E x cl usi o n Criteria  ...........................................................................................................................................1 8  
5  S T U D Y P R O C E D U R E S  ............................................................................................................................................1 9  
5. 1  
S cree ni n g E v al u ati o n ( d a y 1)  .........................................................................................................................1 9  
5. 2  
B aseli n e ( d a y 1, sa m e d a y as scree ni n g e v al u ati o n)  .......................................................................................1 9  
5. 3  
D a y 2 – D a y 2 2  ...............................................................................................................................................2 1  
5. 4  
D a y 2 -5 T ele p h o n e M o nit ori n g  ......................................................................................................................2 1  
5. 5  
D a y 2 a n d 3 E v al u ati o ns  .................................................................................................................................2 1  
5. 6  
D a y 7 F oll o w -u p ( +/ - 1 d a y)  ...........................................................................................................................2 1  
5. 7  
D a y 2 2 F oll o w -u p ( + 3 d a ys)  ..........................................................................................................................2 2  
5. 8  
U nsc h e d ule d Visit  ..........................................................................................................................................2 2  
5. 9  
St u d y Disc o nti n u ati o n  ....................................................................................................................................2 3  
5. 1 0  Electr o nic S u bject Diar y  .................................................................................................................................2 3  
5. 1 1  Pla n f or Vir ol o g y T esti n g a n d M o nit ori n g R esista n c e  ...................................................................................2 3  
5. 1 2  Pre g n a n c y  .......................................................................................................................................................2 4  
6  R A N D O MI Z A TI O N  ...................................................................................................................................................2 5  
7  D A T A M A N A G E M E N T  ............................................................................................................................................2 5  
7. 1  
Electr o nic D ata E ntr y  .....................................................................................................................................2 5  
7. 2  
Pr ot o c ol D e viati o ns  ........................................................................................................................................2 6  
7. 3  
D ata Q u alit y Ass ura n ce  ..................................................................................................................................2 6  
8  S T A TI S TI C A L C O N SI D E R A TI O N S  ......................................................................................................................2 6  
8. 1  
S a m ple Size C alc ulati o n  .................................................................................................................................2 6  


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 
 
8. 2  
Efficac y V aria bles  ..........................................................................................................................................2 7  
8. 3  
R es p o nse D efi niti o ns  ......................................................................................................................................2 8  
8. 4  
Statistical M et h o d ol o g y  ..................................................................................................................................2 9  
8. 4. 1  Efficac y A n al yses  ................................................................................................................................2 9  
8. 4. 2  I nfl u e n za A nti b o d y Titer A n al ysis ......................................................................................................3 1  
8. 4. 3  P o p ulati o n P h ar m ac o ki n etics A n al ysis  ................................................................................................3 1  
8. 4. 4  S afet y A n al yses  ...................................................................................................................................3 1  
9  I N V E S TI G A TI O N A L P R O DU C T S  .........................................................................................................................3 1  
9. 1  
Dr u g R e gi m e ns, A d mi nistrati o n a n d D urati o n  ...............................................................................................3 1  
9. 2  
I de ntit y of I n v esti g ati o n al Pr o d u cts  ................................................................................................................3 1  
9. 3  
P ac k a gi n g a n d L a b eli n g  .................................................................................................................................3 1  
9. 4  
Dr u g A cc o u nta bilit y  .......................................................................................................................................3 2  
9. 5  
S u bject C o m plia n ce  ........................................................................................................................................3 2  
9. 6  
Disall o w e d M e dicati o n  ...................................................................................................................................3 2  
1 0  A D V E R S E E V E N T S  ..................................................................................................................................................3 2  
1 0. 1  D efi niti o ns  ......................................................................................................................................................3 4  
1 0. 2  Cli nical A d v erse E v e nts  .................................................................................................................................3 4  
1 0. 3  R e p orti n g R e q uire m e nt  ..................................................................................................................................3 5  
1 0. 4  M e dicati o n M o dificati o n/ Wit h dra w al D u e t o a n A d v ers e E v e nt  ...................................................................3 5  
1 0. 5  M e dicati o n Err ors  ...........................................................................................................................................3 6  
1 1  DI S C O N TI N U A TI O N  ................................................................................................................................................3 6  
1 1. 1  St u d y Disc o nti n u ati o n:  ...................................................................................................................................3 6  
1 1. 2  S u bject Disc o nti n u ati o n:  ................................................................................................................................3 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  ......................................................................................3 6  
1 3  R E T E N TI O N O F R E C O R D S  ...................................................................................................................................3 7  
1 4  M O NI T O RI N G T H E S T U D Y  ...................................................................................................................................3 7  
1 5  I N F O R M E D C O N S E N T ............................................................................................................................................3 7  
1 6  E T HI C S   
 .................................................................................................................................................................3 8  
1 6. 1  St u d y -S p ecific D esi g n C o nsi d erati o ns  ...........................................................................................................3 8  
1 6. 2  I n v esti g at or R es p o nsi bilities ..........................................................................................................................3 8  
1 6. 3  I nstit uti o n al R e vie w B o ar d (I R B) ..................................................................................................................3 9  
1 6. 4  Pri v ac y of P ers o n al D ata  ................................................................................................................................4 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/P U B LI C A TI O N  .........................................................4 0  
1 8  D A T A/ R E P O R T R E Q UI R E M E N T S  .......................................................................................................................4 1  
1 9  C O N T A C T I N F O R M A TI O N  ....................................................................................................................................4 2  
2 0  R E F E R E N C E S  ............................................................................................................................................................4 3  
2 1  A P P E N DI C E S  .............................................................................................................................................................4 5  
2 1. 1  A p p e n di x I.    St u d y S c h e d ule  ........................................................................................................................4 6  
2 1. 2  A p p e n di x II. T o xicit y Gra di n g f or A d v erse E v e nts  .......................................................................................4 7  
2 1. 3  A p p e n di x III.  List of Esse ntial D o c u m e nts f or t h e I n v esti g ati v e Site  ...........................................................5 3  
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  .......................................................................................................5 5  
2 1. 5  A p p e n di x V.  D eclarati o n of H elsi n ki  ............................................................................................................5 8  
 
 
 


The Romark Jnstitule for Medical Research 
CONFIDENTIALITY 
Protocol RM08-3004 Final v. 1.5 
January 3, 2019 
The information in this protocol is provided to you, as an Investigator or consultant, for review by you, your staff, 
and an applicable institutional review committee. By accepting this document, you agree that infom1ation contained 
herein will be considered confidential and will not be disclosed to others, without written authority from The 
Romark Institute for Medical Research, except to the extent necessary to obtain: (a) Institutional Review Board 
approval and (b) informed consent from those persons to whom the investigational medicinal product will be 
administered. 
APPROVAL OF FINAL PROTOCOL 
My signature below constitutes agreement with this protocol. I am providing the necessary assurances that this 
study will be conducted by me and my staff according to all stipulations of the protocol, including all statements 
regarding confidentiality, and in complete accordance with all applicable regulations including current Good 
Clinical Practice guidelines and the ethical guidelines set by the World Medical Assembly (Declaration of Helsinki, 
last amendment in Fortaleza, Brazil October 2013). 
Furthermore, my signature below indicates that source 
docmnents will be available for review by the Sponsor or their designated representative. 
Principal Investigator Signature: 
Principal Investigator 
Print name: _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ 
With the signature below, the Sponsor approves of this protocol. 
Sponsor Signature: 
Print name: 
4 
Date 
Date 
CONFIDENT JAL 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
5 
 
P R O T O C O L S Y N O P SI S  
 
Title:    
A  P h as e  III , R a n d o miz e 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  Nita z o x a ni d e  i n  t h e  Tre a t m e nt  of 
U n c o m plic ate d I nfl u e n z a  
St u d y N u m b er:  
R M 0 8 -3 0 0 4 
I N D N u m b er: 
1 0 7, 3 1 6  
I n dic ati o n: 
Tre at m e nt of u n c o m plic ate d i nfl u e n z a 
D esi g n:  
M ultic e nter , ra n d o miz e 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 effic a c y a n d safet y of nita z o x a ni d e ( N T Z) i n t h e tre at m e nt of 
u n c o m plic ate d i nfl u e n z a  
N u m b er of S u bjects:  
At  le ast 6 0 0  ( u p  t o  m a xi m u m  of 7 0 0 ) wit h  la b orat or y -c o nfir m e d 
i nfl u e n z a;  esti m ate d  t o  re q uire  a p pr o xi m atel y 8 0 0 -1 2 0 0  s u bje cts i n 
t otal 
P o p ul ati o n:  
M ales a n d fe m ales ≥ 1 2 y e ars of a g e wit h u n c o m pl ic ate d i nfl u e n z a  
R a n d o miz ati o n:  
1: 1  
St u d y D ose a n d 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 ail y ( b.i. d.) 
f or 5 d a ys. 
Gr o u p 2 ( Pla c e b o ): T w o pla c e b o ta blets orall y b.i. d. f or 5 d a ys.   
O bjecti v e:  
E v al u ate t h e effe ct of N T Z a d mi nistere d 6 0 0 m g orall y 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 c o m p are d t o t h at of a pla c e b o.  
P ri m a r y Effic a c y P a r a m eter:  
Ti m e fr o m first d ose t o S y m pt o m R es p o nse  o v er 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 ©  i nstr u m e nt 
K e y S ec o n d a r y Eff ic a c y P a r a m eter: 
Ti m e fr o m first d ose t o A bilit y t o P erf or m All N or m al A cti vit ies 
 
Ot h er S ec o n d a r y Effic a c y P a r a m eter s: 
(i) Pr o p orti o ns of s u bje cts e x p erie n ci n g o n e or m ore c o m plic ati o ns of 
i nfl u e n z a 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, 
w ors e ni n g of pre -e xisti n g h e alt h c o n diti o ns, s yste mic a nti bi otic use f or 
i nfe cti o ns se c o n d ar y t o i nfl u e n z a i nfe cti o n, h os pitaliz ati o n d u e t o 
i nfl u e n z a or c o m plic ati o ns of i nfl u e n z a, a n d d e at h 
 
(ii) Ti m e t o S y m pt o m R es p o ns e e x cl u di n g t h e F L U -P R O 
G astr oi nt esti n al a n d E y e d o m ai ns  
 
 
S afet y P a r a m eters:  
A d v ers e e v e nts  
Bi ol o gic al S a m ples:  
Bl o o d s a m ples will b e c olle cte d f or all s u bje cts at b as eli n e, d a y 7 a n d 
d a y 2 2 .  Uri n e  sa m ples  will  b e  c olle cte d  at  b aseli 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 olle cte d a t b aseli n e, d a ys 2, 3, 7 a n d 2 2 
f or  all  s u bje cts.  A  bl o o d  s a m ple  will  b e  c olle cte d  o n  d a y  3  f or 
p h ar m a c o ki n etics.  
St u d y C e nters : 
M ultic e nter   
T ri al D u r ati o n : 
D e c e m b er 2 0 1 7 – A pril 2 0 1 9  
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
6 
 
1  
B A C K G R O U N D  
 
1. 1  
I nfl u e n z a 
 
I nfl u e n za, a c o nta gi o us res pirat or y ill n ess c a use d b y i nfl u e n z a A, B or C vir uses , is of gl o b al c o n c er n wit h a n 
a n n u al attac k rate esti m ate d at 5 % t o 1 0 % i n a d ults a n d 2 0 % t o 3 0 % i n c hil dre n.  I nfe cti o n wit h i nfl u e n z a 
res ults i n a b o ut 3-5 milli o n cases of se v ere dise ase a n d 2 5 0, 0 0 0 -5 0 0, 0 0 0 d e at hs a n n u all y w orl d wi d e. 1  I n t h e 
U nite d  States,  seas o n al  i nfl u e n za  h as  b e e n  res p o nsi ble  f or  b et w e e n  9. 2  milli o n  a n d  3 5. 6  milli o n  ill n ess es, 
1 4 0, 0 0 0 a n d 7 1 0, 0 0 0 h os pitalizati o ns, a n d 1 2, 0 0 0 a n d 5 6, 0 0 0 d e at hs a n n u all y si n c e 2 0 1 0. 2  
 
P a n d e mics ca use d b y n e w i nfl u e n z a strai ns  h a v e t y pic all y o c c urre d e v er y 1 0 t o 5 0 y e ars t hr o u g h o ut re c or d e d 
hist or y  a n d  are  rec o g nize d  as  a  gl o b al  t hre at.    T h e  p a n d e mic  of  1 9 1 8  w as  p artic ularl y  se v ere , res ulti n g  i n 
a p pr o xi m atel y 4 0 milli o n d eat hs w orl d wi d e. 3 
 
T h e g e n o m e of i nfl u e n za A vir uses c o nsists of ei g ht si n gle -stra n d e d R N A se g m e nts t h at e n c o d e 1 1 pr otei ns, 
i n cl u di n g  t h e m ai n  s urface  gl y c o pr otei ns,  h e m a g gl uti ni n  ( H A)  a n d  n e ura mi ni d ase  ( N A),  of  w hic h  1 6  H A 
( H 1– H 1 6) a n d ni n e N A ( N A 1 – N A 9) s u bt y p es h a v e b e e n i d e ntifie d s o far. 4 I nfl u e n z a vir us  i nfe cti o n i n v ol v es 
a  series  of  ste ps:  t h e  vir us  attac h es  t o  h ost  sial ylate d  gl y c o pr otei ns  via  t h e  viral  H A  a n d  e nters t h e  c ell  b y 
e n d o c yt osis, f oll o w e d b y p H -d e p e n d e nt f usi o n a n d  rele ase of viral g e n o mic ri b o n u cle o-pr otei n c o m ple x es i n 
t h e c yt o plas m .  Ri b o n u cle o pr otei ns t h e n tra nsl o c ate t o t h e n u cle us  w h ere tra ns cri pti o n a n d re plic ati o n of viral 
R N A  o cc urs.  D uri n g  t h e  re plicati o n  c y cle , s o m e  viral  pr otei ns  tra nsl o c ate  t o  t h e n u cle us  f or  pr o g e n y 
ri b o n u cle o pr otei n f or m ati o n, w h ereas t h e viral H A, N A, a n d M 2 pr otei ns re a c h t h e plas m a m e m bra n e via  t h e 
secret or y  p at h w a y,  a n  e v e nt  t h at  is  esse ntial  f or  viral  p article f or m ati o n  a n d  b u d di n g  fr o m  h ost  c ells.5 I n 
h u m a ns,  i nfl u e n za  A  vir us  re plicates  t hr o u g h o ut  t h e  res pirat or y  tra ct,  w h ere  t h e  viral  a nti g e n  is f o u n d 
pre d o mi n a ntl y  i n  t h e  e pit h elial  cells.    T h e  t y pic al  c o urs e  of  i nfl u e n z a  is  s elf -li miti n g  a n d  lasts  f or a b o ut  a 
w ee k;  h o w e v er,  cli nical  o utc o m es  ra n g e  fr o m  mil d  dis e as e  t o  fatal  viral  p n e u m o nia. 6, 7 Alt h o u g h  t h e 
m ec h a nis ms  u n d erl yi n g  t h e  e x pressi o n  of s y m pt o ms  a n d  t h e  d e v el o p m e nt  of se c o n d ar y  c o m plic ati o ns  t h at 
m a y res ult i n res pirat or y fail ure  are still n ot w ell u n d erst o o d, e x c essi v e i nfla m m ati o n c a use d b y  o v era b u n d a nt 
pr o d u cti o n of pr o -i nfla m m at or y c yt o ki n es a n d l u n g i nfla m m at or y i nfiltrates, dri v e n in p art b y o n g oi n g viral 
re plicati o n, is c o nsi d ere d a n i m p orta nt fa ct or i n dise ase p at h o g e n esis.8- 1 0  
 
H A a n d N A gl y c o pr otei ns, w hic h are t h e m ai n tar g ets of  t h e pr ote cti v e i m m u n e res p o nse, v ar y c o nti n u o usl y 
as a  res ult of a nti g e nic drift a n d less ofte n a nti g e nic s hift.  M aj or c h a n g es  fr o m a nti g e nic s hift are c a use d b y 
differe nt  H A  a n d  N A  s u bt y p es  d eri v e d  fr o m  vir uses  circ ulati n g  i n  bir ds  a n d  ot h er  a ni m als  t h at  cre ate  a  
reser v oir  of  i nfl u e n za  A  g e n es  a v aila ble  f or  g e n etic  re ass ort m e nt  wit h  t h e  circ ulati n g  h um a n vir uses. 1 1 T h e 
lac k of pr otecti v e i m m u nit y i n t h e h u m a n p o p ulati o n a g ai nst n e w  H A wit h or wit h o ut n e w N A pr otei ns c a n 
res ult  i n  ra pi d  gl o b al  s prea d  of t h e  vir us.  I n re c e nt  hist or y,  t h e  e m er g e n c e  of  hi g h  p at h o g e nicit y  a via n 
i nfl u e n za  vir uses  i n  d o m estic  p o ultr y  a n d  t h e  i n cre asi n g  n u m b er  of  c ases  of  dire ct  tra ns missi o n  of  a via n 
i nfl u e n za vir uses  t o  h u m a ns  re prese nt  a  m aj or  ris k,  as  i n dic ate d  b y  t h e  o n g oi n g  o ut bre a k  of  hi g h 
p at h o g e nicit y a via n i nfl u e n za H 5 N 1  vir uses i n t h e bir d p o p ulati o n a n d b y a n a p pr o x i m ate 5 0 % c ase fatalit y 
rate a m o n g t h e p e o ple i nfecte d.1 2, 1 3 I n a d diti o n, t h e hi g hl y c o nta gi o us p a n d e mic 2 0 0 9 A( H 1 N 1) vir us d eri v e d 
fr o m  s wi n e  rece ntl y  e m er g e d i n  M e xic o  a n d  ra pi dl y  s pre a d  w orl d wi d e  c a usi n g  a n  esti m ate d  2 0 1, 2 0 0 
res pirat or y d eat hs (ra n g e 1 05, 7 0 0 -3 9 5, 6 0 0) a n d a n a d diti o n al 8 3, 3 0 0 c ar di o v asc ular d e at hs ( 4 6, 0 0 0 -1 7 9, 9 0 0), 
8 0 %  of  w hic h  w ere  i n  p e o ple  y o u n g er  t h a n  6 5  y e ars  i n  its  first  y e ar  of  circ ulati o n. 1 4 N o v el  a nti viral  dr u gs 
effecti v e  a g ai nst differe nt strai ns of i nfl u e n z a vir uses are t h eref o re gre atl y n e e d e d.  
 
1. 2  
Nit a z o x a ni d e ( N T Z)  
 
N T Z is a t hiaz oli d e a nti -i nfecti v e wit h i n vitr o a cti vit y a g ai nst p arasites, a n a er o bic b a cteria, a n d vir uses. 1 5   
 
Ali nia ®  ( N T Z) f or Oral S us p e nsi o n ( p atie nts 1 y e ar of a g e a n d ol d er) a n d Ali nia ( N T Z) T a blets ( p atie nts 1 2 
y ears a n d ol d er) are m ar k ete d i n t h e U nite d States f or t h e tre at m e nt of diarr h e a c a use d b y Gi ar di a l a m bli a  or 
Cry pt os p ori di u m p arv u m .  Ali nia f or Oral S us p e nsi o n a n d Ali nia T a blets h a v e n ot b e e n s h o w n t o b e s u p eri or 


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t o  place b o  f or  t h e  treat m e nt  of  diarr h e a  c a use d  b y Cr y pt os p ori di u m  p ar v u m  i n  HI V-i nfe cte d  or 
i m m u n o d eficie nt p atie nts.1 6 
 
1. 2. 1  
A cti vit y of N T Z A g ai nst I nfl u e n z a Vir us R e plic ati o n 
 
T h e a nti -i nfl u e n za acti vit y of nitaz o x a ni d e a n d its circ ulati n g m eta b olite, tiz o x a ni d e, h as b e e n i n v esti g ate d i n 
h u m a n ( M o n o c ytic U 9 3 7, T -l y m p h o c ytic J ur k at, a n d Al v e olar t y p e II-li k e A 5 4 9) a n d c a ni n e ( M D C K) c ells 
after  i nfecti o n  wit h  m ulti ple  differe nt  strai ns  of  i nfl u e n z a  A  vir us  i n cl u di n g  oselta mi vir -resista nt  a n d 
a m a nta di n e -resista nt strai ns.1 7- 1 9 ( R o m ar k L a b orat ories, d ata o n file) 
 
A st u d y of t h e s usce pti bilit y of 2 1 0 circ ulati n g se as o n al i nfl u e n z a vir uses t o tiz o x a ni d e d e m o nstrate d m e dia n 
E C 5 0 v al u es ( ±I Q R) of 0. 4 8 µ M ( 0. 3 3 -0. 7 1), 0. 6 2 µ M ( 0. 5 6 -0. 7 5), 0. 6 6 µ M ( 0. 6 2 -0. 6 9), a n d 0. 6 0 µ M ( 0. 5 1 -
0. 6 7) f or A( H 1 N 1) p d m 0 9,  A( H 3 N 2), B( Vict oria li n e a g e) a n d B( Y a m a g ata li n e a g e) , res p e cti v el y.2 0  
 
St u dies  i n  cell  c ult ures  h a v e  s h o w n  t h at  c o m bi n ati o ns  of  nita z o x a ni d e  a n d  oselta mi vir  or  nita z o x a ni d e  a n d 
za n a mi vir act s y n er gisticall y i n i n hi biti n g re plic ati o n of t h e i nfl u e n z a vir u ses.  Strai ns use d i n t h ese st u dies 
i n cl u d e d  A/ P u ert o  Ric o/ 8/ 1 9 3 4  ( H 1 N 1),  A/ W S N/ 1 9 3 3  a n d  t h e  a via n  A/c hic k e n/Ital y/ 9 0 9 7/ 1 9 9 7  ( H 5 N 9) 
strai ns. 2 1 A  c o nfir m at or y  st u d y  s h o w e d  s y n er gistic  a cti vit y  wit h  os elta mi vir  usi n g  A/ C alif or nia/ 0 7/ 2 0 0 9 
( p H 1 N 1),  A/ Vict oria/3 6 1/ 2 0 1 1  ( H 3 N 2),  A/ N ort h  C ar oli n a/ 3 9/ 2 0 0 9  oselta mi vir -resista nt  ( p H 1 N 1),  a n d 
B/ N e v a d a/ 3/ 2 0 1 1 strai ns . ( R o mar k L a b orat ories, d ata o n file)  
 
M ec h a nis m st u dies d e m o nstrate t h at tiz o x a ni d e i n hi bits t h e re plic ati o n of H 1 N 1 a n d ot h er strai ns of i nfl u e n z a 
A vir us  b y a n o v el m ec h a nis m. 1 7 It acts at t h e p ost-tra nslati o n al le v el b y sele cti v el y bl o c ki n g t h e m at urati o n 
of  t h e  viral  h e m a g gl uti ni n  at  a  sta g e  pre c e di n g  resista n c e  t o  e n d o gl y c osi d ase  H  di g esti o n,  t h us  i m p airi n g 
h e m a g gl uti ni n  i ntracell ular  traffic ki n g  a n d  i n serti o n  i nt o  t h e  h ost  plas m a  m e m bra n e,  a  k e y  ste p  f or  c orre ct 
asse m bl y  a n d  e xit  of  t h e  vir us  fr o m  t h e  h ost  c ell. 1 7 W h et h er  t h e  alterati o n  of  h e m a g gl uti ni n  m at urati o n  is 
ca use d b y direct bi n di n g of tiz o x a ni d e t o t h e viral gl y c o pr otei n or is d u e t o a c ell -m e diate d effe ct re m ai ns t o 
b e esta blis h e d. 1 7  Tiz o x a ni d e h as b ee n s h o w n t o p oss ess a nti viral a cti vit y i n c ell c ult ure a g ai nst a br o a d ra n g e 
of  ot h er  vir uses  i n cl u di n g  p arai nfl u e n z a  ( S e n d ai)  vir us,  res pirat or y  s y n c ytial  vir us  ( R S V)  A -2,  c a ni n e 
c or o n a vir us S - 37 8, r ota 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, Ja p a n ese e n c e p h alitis vir us, 
d e n g u e fe v er vir us -2, y ell o w fe 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 eficie n c y vir us ( HI V). 2 2 T h e 
wi d e s p ectr u m of a nti viral acti vit y s u g g ests a c ell -m e d iate d effe ct rat h er t h a n a s p e cific viral tar g et. 
 
L a b orat or y st u dies t o e v al u ate t h e p ote ntial f or resista n c e of i nfl u e n z a A vir us t o tiz o x a ni d e h a v e b e e n u n a ble 
t o  select  f or  resista nt  vir us  ( R o m ar k  L a b orat ories  St u d y  R e p ort  R M 0 1-0 4 1 7,  d ata  o n  file).    T h ese  st u dies  
s u g g est a l o w p ote ntial f or resista n ce. 
 
1. 2. 2  
P h a r m a c o ki n etics of N T Z i n H u m a ns  
 
N T Z is n ot d etecta ble i n t h e plas m a f oll o wi n g oral a d mi nistrati o n of t h e dr u g.  T h e m ai n m eta b olites of N T Z 
i n h u m a n s are 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.  Tiz o x a ni d e is hi g hl y b o u n d t o plas m a pr otei ns ( > 9 9 %).  
T h e a bs or pti o n of N T Z i n i m m e diate rele as e ta blets is si g nific a ntl y e n h a n c e d ( C ma x  a n d A U C of 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  i n  plas m a  are m ore  t h a n d o u ble d)  w h e n  it  is  a d mi nistere d  wit h  f o o d.  I n  fast e d 
h u m a n  v ol u nteers  recei vi n g  a  si n gle  5 0 0  m g  d ose  of 1 4C  N T Z,  a p pr o xi m atel y  o n e -t hir d  of  t h e  d ose  w as 
e x crete d  i n  uri n e  as  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,  a n d  t w o -t hir ds  w as  e x crete d  i n  fe c es  as 
tiz o x a ni d e.  N o ot h er si g nifica nt m eta b olites w ere d ete cte d. (I n v esti g at ors Br o c h ure f or N T Z 3 0 0 m g T a blets, 
N o v e m b er 2 0 1 7) 
 
T h e p h ar m ac o ki n etics of 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 d uri n g re p e ate d oral d osi n g of nita z o x a ni d e 
( N T Z) 3 0 0 m g e xte n d e d release ta blets a d mi nistere d 6 0 0 m g t wic e d ail y wit h f o od w ere e v al u ate d i n h e alt h y 
v ol u nte ers.  T w el v e ( 1 2) s u bjects recei v e d t w o N T Z c o ntr olle d rele as e ta blets t wic e d ail y wit h f o o d f or 7 d a ys. 
T h e p h ar m ac o ki n etics w ere st u die d i n plas m a u p t o 1 2  ho urs  p ost -d ose after t h e m or ni n g d ose o n D a y  1 a n d 
D a y  7, a n d b ef ore t h e m or ni n g d ose o n D a y 2 -6. B ase d o n mi x e d -effe ct a n al ysis of v aria n c e, t h e ste a d y state 
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 plas m a  c o n c e ntrati o ns  w as  re a c h e d  b y  D a y  2,  after  o n e  d a y  of 


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treat 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 etics  p ara m eters  of  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  are s u m m arize d i n t h e ta ble b el o w:  
 
S u m m a r y of Tiz o x a ni d e a n d Tiz 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 etics P a r a m ete rs  
P K P a r a m eter  ( u nit) 
Tiz o x a ni d e  
Tiz 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 ma 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  
tma 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)  
tla 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 are arit h m etic m ea n ± S D, e x ce pt m e dia n (ra n g e) f or t ma x  a n d t la g 
N = n u m b er of s u bjects wit h d ata ; N A = n ot a p plica ble  
a N = 1 0; b N = 1 1; c N = 1 1; d N = 8; e N = 7  
 
S u m m a r y of Tiz o x a ni d e a n d Tiz 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 ntr ati o ns  
D ose  
G r o u p  
Nitaz o x a ni d e  
T r o u g h c o n ce ntr ati o ns ( µ g/ m L)  
M e a n ( C V %)  
D a y  
1 ( a)  
2 
3 
4 
5 
6 
7 ( b)  
Tiz 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) 
Tiz o x a ni d e 
Gl u c u r 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) 
 
 
1. 2. 3  
P h ase 2  Cli nic al T ri als of N T Z i n S u bje cts wit h I nfl u e n z a-li k e Ill n ess: St u dies R M 0 2-2 0 2 2 a n d 
R M 0 1 -2 0 2 1  
 
T w o ra n d o mize d, d o u ble -bli n d, place b o c o ntr olle d cli nic al trials w ere c o n d u cte d i n s u bje cts wit h s y m pt o ms 
of viral res pirat or y i nfecti o n ( V RI) i n C aja m arc a, P er u.   
 
St u d y R M 0 2 -2 0 2 2:  O n e -h u n dre d ( 1 0 0) c hil dre 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 fe v er, at le ast 
o n e  res pirat or y  s y m pt o m  (c o u g h,  n asal  disc h ar g e  or  c o n g esti o n,  s n e e zi n g  or  s ore  t hr o at)  a n d  at  le ast  o n e 
c o nstit uti o n al  s y m pt o m  ( m y al gia,  m alaise,  fati g u e,  h e a d a c h e,  c hills/s w e at)  of  less  t h a n  7 2  h o urs  d urati o n 
w ere  ra n d o mize d  t o  recei v e  N T Z  1 0 0  m g/ 5  m L  s us p e nsi o n  or  a  m atc hi n g  pla c e b o  s us p e nsi o n  b.i. d.  f or  5 
d a ys.  T h e d ose of t h e s us p e nsi o n w as 5 m L f or c hil dre 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 dre n 
a g e d 4 8 m o nt hs t hr o u g h 1 1 y ears.  A n as o p h ar y n g e al s w a b w as o btai n e d at b aseli n e a n d s u bje cte d t o ra pi d 
direct  i m m u n ofl u oresce n ce  assa y  f or  res pirat or y  s y n c ytial  vir us  ( R S V),  i nfl u e n z a  A,  i nfl u e n z a  B, 
p arai nfl u e n za 1, 2 a n d 3, a n d a d e n o vir us.  P h ysic al e x a mi n ati o ns w ere p erf or m e d at b aseli n e a n d o n st u d y d a y 
7.   S u bjects or  t h eir  p are nts  or  g u ar dia ns  m ai ntai n e d  a  d ail y  diar y  t o  re c or d  a d mi nistrati o n  of  st u d y 
m e dica ti o n a n d a d v erse e v e nts a n d t o gra d e e a c h of t h eir s y m pt o ms o n a 4 p oi nt sc ale: 0 = a bse nt, 1 = mil d, 2 = 
m o d erate,  3 =  se v ere.    A  st u d y  n urse  visite d  e a c h  s u bje ct  d ail y  d uri n g  t h e  tre at m e nt  p eri o d  t o  e ns ure 
c o m plia n ce  wit h  t h e  st u d y  a n d  t o  c olle ct  plastic  zi p p er  st ora g e  b a gs  c o ntai ni n g  tiss u e  use d  d uri n g  t h e 
prece 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 ose t o alle viati o n of s y m pt o ms (all 
s y m pt o ms a bse nt or mil d) c o m p are d usi n g a s ur vi v al a n al ysis (l o g ra n k test).  T h e m e dia n ti m es fr o m first 


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d ose t o alle viati o n of s y m pt o ms w ere 4 d a ys (I Q R 2 -7) f or t h e N T Z tre 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 place b o gr o u p (P < 0. 0 0 1, l o g ra n k test).  T his a n al ysis w as s u p p orte d b y se c o n d ar y a n al yses.  S u bje cts 
ra n d o mize d t o t h e place b o treat me nt gr o u p w ere m ore li k el y t o h a v e at le ast o n e ill n ess -relate d p h ysic 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 ere  m ore  li k el y  t o  re q uire  a nti bi otic 
treat 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 bje cts tre ate d wit h N T Z.  T h e m ost c o m m o n 
ill n ess-relate d  p h ysical  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 ere 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 hic t o nsils ( 7 4 % vs. 1 7 %, P < 0 . 0 0 0 1), n asal 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).  Tre at m e nt  wit h  N T Z  w as 
ass o ciate d  wit h  a  si g nifica nt  d ecli n e  i n  w ei g ht  of  d ail y  tiss u e  c olle cti o ns  d uri n g  t h e  tre at m e nt  p eri o d 
(P = 0. 0 3 4 7).    B y  ra pi d  direct  i m m u n ofl u oresc e n c e  assa y,  res pirat or y  vir uses  w ere  i d e ntifie d  i n  1 7 %  of  t h e 
s u bjects, 1 2 s u bjects wit h a d e n o vir us, 2 wit h i nfl u e n z a A, 2 wit h p arai 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 bjects wit h i d e ntifie d V RI di d n ot all o w f or a n al yses f or s u bsets wit h s p e cific V RIs.  T h ere w ere 
n o seri o us a d v erse e v e nts.  All a d v erse e v e nts w ere mil d t o m o d erate i n se v erit y.  T h e n at ure a n d fre q u e n c y 
of a d v erse e v e nts re p orte d b y s u bjects i n t h e a cti v e a n d pla c e b o gr o u ps w ere si milar, 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 ce of c hr o m at uria ( y ell o w di sc ol orati o n of uri n e), w hic h w as re p orte d b y 6 4 % of s u bje cts i n 
t h e N T Z gr o u p a n d 2 8 % of s u bjects i n t h e pla c e b o gr o u p (P = 0 . 0 0 0 6). 
 
St u d y R M 0 1 -2 0 2 1:  I n a sec o n d cli nic al trial, 8 6 a d ults a n d a d olesc e nts ≥1 2 y e ars of a g e wit h fe v er, at le ast 
o n e  res pirat or y  s y m pt o m  (c o u g h,  n asal  disc h ar g e  or  c o n g esti o n,  s n e e zi n g  or  s ore  t hr o at)  a n d  at  le ast  o n e 
c o nstit uti o n al  s y m pt o m  ( m y al gia,  m alaise,  fati g u e,  h e a d a c h e ,  c hills/s w e at)  of  less  t h a n  7 2  h o urs  d urati o n 
w ere ra n d o mize d t o recei v e N T Z 5 0 0 m g ta blets or a pla 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 btai n e d  at  b aseli n e  a n d  s u bjecte d  t o  ra pi d  dire ct  i m m u n ofl u oresc e n c e  assa y  f or  res pirat or y  s y n c ytial  vi r us 
( R S V),  i nfl u e n za  A,  i nfl u e n za  B,  p arai nfl u e n z a  1,  2  a n d  3,  a n d  a d e n o vir us.    P h ysic al  e x a mi n ati o ns  w ere 
p erf or m e d at b aseli n e a n d o n st u d y d a y 7.  S u bje cts m ai ntai n e d a d ail y diar y t o re c or d a d mi nistrati o n of st u d y 
m e dicati o n a n d a d v erse e v e nts a n d t o g ra d e e a c h of t h eir s y m pt o ms o n a 4 p oi nt sc ale: 0 = a bse nt, 1 = mil d, 2 = 
m o d erate,  3 =  se v ere.    A  st u d y  n urse  visite d  e a c h  s u bje ct  d ail y  d uri n g  t h e  tre at m e nt  p eri o d  t o  e ns ure 
c o m plia n ce  wit h  t h e  st u d y  a n d  t o  c olle ct  plastic  zi p p er  st ora g e  b a gs  c o ntai ni n g  tiss u e  use d  d uri n g  t h e 
prece 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 ose t o alle viati o n of s y m pt o ms (all 
s y m pt o ms  a bse nt  or  mil d)  c o m p are d  usi n g  a  s ur vi v al  a n al ysis  (l o g  ra n k  test).    T h e  m e dia n  ti m e  fr o m  first 
d ose t o alle viati o n of V R I 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 tre 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  place b o  gr o u p  ( P = 0. 0 3 6 5,  l o g  ra n k  test).    T his  a n al ysis  w as  s u p p orte d  b y  se c o n d ar y  effic a c y 
a n al yses.  S u bjects ra n d o mize d t o t h e pla c e b o tre at m e nt gr o u p w ere m ore li k el y t o h a v e at le ast o n e ill n ess -
relate d  p h ysical  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 ere  m ore 
li k el y t o re q uire a nti bi otic treat 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 bje cts tre ate d wit h 
N T Z.    T h e  m ost  c o m m o n  ill n ess -relate d  p h ysic 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 ere 
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 hic  t o nsils  ( 5 0 %  vs.  2 1 %, P = 0. 0 1).    T h e 
m ea n w ei g ht of tiss u e c ollecte d o v er t h e tre at m e nt p eri o d w as als o hi g h er f or s u bje cts i n t h e pla c e b o gr o u p 
t h a n  f or  s u bjects  treate d  wit h  N T Z  ( 1 4. 2 3  gra ms  vs.  1 0. 5 8  gra ms, P = 0. 2 0),  wit h  t h e  differe n c e  arisi n g 
pri m aril y  d uri n g  t h e  first  t w o  t o  t hre e  d a ys  of  t h e  st u d y.    B y  ra pi d  dire ct  i m m u n ofl u oresc e n c e  assa y, 
res pirat or y vir uses w ere i d e ntifie d i n 1 2 % of t h e s u bje cts, 4 s u bje 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 za A.  T h ere w ere n o seri o us a d v ers e e v e nts.  All a d v ers e e v e nts w ere mil d t o m o d erate i n s e v erit y.  
T h e  n at ure  a n d  fre q u e n c y  of  a d v erse  e v e nts  re p orte d b y  s u bje cts  i n  t h e  a cti v e  a n d  pla c e b o  gr o u ps  w ere 
si milar,  t h e  o nl y  e x ce 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 uria  ( y ell o w  disc ol orati o n  of  uri n e),  w hic h 
w as re p orte d b y 6 0 % of s u bjects i n t h e N T Z gr o u p a n d 1 9 % of s u bje cts i n t h e pla c e b o gr o u p ( P = 0 . 0 0 0 1). 
 
1. 2. 4  
P h ase 2 b/ 3  Cli nic al T ri al of N T Z i n U n c o m plic ate d I nfl u e n z a : St u d y R M 0 8-3 0 0 1  
 
A  ra n d o mize d,  d o u ble -bli n d,  place b o  c o ntr olle d  d ose -ra n g e  fi n di n g  st u d y  w as  c o n d u cte d  t o  c o m p are  t h e 
efficac y  of  3 0 0  m g  N T Z  t wice  d ail y  f or  5  d a ys,  6 0 0  m g  N T Z  t wic e  d ail y  f or  5  d a ys  or  a  pla c e b o  f or  t h e 
treat m e nt  of  u n c o m plicate d  i nfl u e n za  i n  s u bje 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 cte d  i n  7 4 
o ut p atie nt pri m ar y care ce nters l o cate d t hr o u g h o ut t h e U nite d States d uri n g t h e 2 0 1 0 -2 0 1 1 fl u se as o n.  6 2 4 
s u bjects w ere e nrolle d i n t h e st u d y wit hi n 4 8 h o urs of s y m pt o m o nset.  S u bje cts w ere e nr olle d b ase d u p o n 
s y m pt o ms a n d t h e prese n ce of i nfl u e n z a i n t h e c o m m u nit y.  U p o n e nr oll m e nt, s u bje cts w ere ra n d o miz e d t o 
o n e of t h e t hree treat m e nt gr o u ps.  N as o p h ar y n g e al s w a bs w ere c ol le cte d at b aseli n e f or i d e ntific ati o n of 1 9 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
1 0  
 
differe nt viral res pirat or y i nfecti o ns b y R T -P C R.  S u bje cts m ai ntai n e d diaries t o  re c or d  ti m e  of  m e dic ati o n 
i nta k e, oral te m p erat ure, t h e se v erit y of e a c h of 9 s y m pt o ms (c o u g h, s ore t hr o at, n asal c o n g esti o n, r u n ny n ose, 
h ea d ac h e,  m uscle  ac h es,  tire d n ess/fati g u e,  fe v eris h,  s w e ats  or  c hills  gra d e d  as  a bse nt,  mil d,  m o d erate  or 
se v ere),  a bilit y  t o  p erf or m  n or m al  acti vities  (sc ale  of  0 -1 0),  ti m e  l ost  fr o m  w or k  or  sc h o ol,  c o n c o mita nt 
m e dicati o ns a n d a d v erse e v e nts.  Dia r y d ata w as re c or d e d t wic 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 bject n o  l o n g er  h a d  a n y  m o d erate  or  se v ere  i nfl u e n z a  s y m pt o ms.  S u bje cts  ret ur n e d  t o  t h e  cli nic  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 sa m ples w ere c olle cte d at b as eli n e a n d d a y 7 f or la b orat or y  
safet y tests, a n d bl o o d sa m ples w ere c olle cte d at b aseli 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 titer.  A s u bset of 
s u bjects fr o m a p pr o xi m atel y 2 0 % of t h e st u d y sites w ere visite d b y t h e st u d y te a m t o c olle ct n as o p h ar y n g e al 
s w a bs o n d a ys 2, 3, 4 a n d 5 f or q u a ntitati v e i nfl u e n z a viral titer d eter mi n ati o n.  N as o p h ar y n g e al s w a bs w ere 
c ollecte d fr o m all s u bjects at d a y 7 f or i d e ntific ati o n of vir uses a n d f or q u a ntitati v e i nfl u e n z a viral titer.  T h e 
pri m ar y efficac y e n d p oi nt w as ti m e fr o m first d ose t o alle viati o n of s y m pt o ms (all s y m pt o ms a bse nt or mil d 
a n d re m ai n e d s o f or at least 2 4 h o urs).  
 
2 5 7 s u bjects ( 4 1 %) e nr olle d i n t his st u d y w ere i nfe cte d wit h i nfl u e n z a A or i nfl u e n z a B b ase d u p o n R T -P C R 
a n d  viral  c ult ures  p erf or m e d  o n  n as o p h ar y n g e al  s w a bs  c olle cte d  at  b aseli n e.    1 7 %  w ere  i nfe cte d  wit h 
i nfl u e n za A s u bt y p e 2 0 0 9 H 1 N 1, 8 % wit h i nfl u e n z a A H 3 N 2, 4 % wit h i nfl u e n z a A s u bt y p e u n d eter mi n e d, 
a n d 1 2 % wit h i nfl u e n za B.  2 2 % w ere i nfe cte d wit h ot h er vir uses, t h e m ost c o m m o n b ei n g r hi n o vi r us ( 1 4 % 
of all s u bjects e nr olle d) f oll o w e d b y c or o n a vir uses ( 3 % of all s u bje cts e nr olle d).  W hile R T -P C R w as use d t o 
i d e ntif y vir uses i n t h e b aseli n e n as o p h ar y n g e al sa m ple, n o c a use of ill n ess w as i d e ntifie d f or 3 7 % of s u bje cts 
e nr olle d i n t h e st u d y.  
 
Ti m e  fr o m  first  d ose  t o  alle viati o n  of  s y m pt o ms  w as  si g nific a ntl y  l o w er  ( P = 0. 0 0 8 4 ,  Wilc o x o n  test)  f or 
i nfl u e n za-i nfecte d  s u bjects  ra n d o mize d  t o  t h e  6 0 0  m g  N T Z  tre at m e nt  gr o u p  ( m e dia n  9 5. 5  ho u rs,  I Q R:  7 1-
1 2 6) t h a n f or s u bjects ra n d o mize d t o t h e pla c e b o tre at m e nt gr o u p ( m e dia n 1 1 6. 7 h o u rs, I Q R: 9 1-1 4 4).  Ti m e 
fr o m first d ose t o alle viati o n  of s y m pt o ms f or t h e 3 0 0 m g N T Z tre at m e nt gr o u p ( m e dia n 1 0 9. 1 h o u rs, I Q R: 
8 2 -1 5 2) w as l o w er t h a n f or t h e place b o gr o u p, b ut t h e differe n c e w as n ot statistic all y si g nific a nt ( P = 0. 5 2 0 8).  
S e nsiti vit y a n al yses c o nfir m e d t h e effect i n t h e 6 0 0 m g N T Z d ose gr o u p c o m p are d t o t h e pla c e b o re g ar dless 
of  (i) a ceta mi n o p h e n  use,  (ii)  e x cl usi o n  of  s u bje cts  t h at  faile d  t o  c o m plete  t h e  st u d y  or  h a d  m aj or  pr ot o c ol 
d e viati o ns, or (iii) treati n g s u bjects wit h missi n g d ata as h a vi n g res ol v e d s y m pt o ms at d a y 2 8.  A n al ysis of all 
s u bjects treate d (re g ar dless of ca use of ill n ess) als o s h o w e d a statistic all y si g nific a nt re d u cti o n ( P = 0. 0 0 2 6) of 
ti m es fr o m first d ose t o alle viati o n  of s y m pt o ms f or t h e 6 0 0  m g N T Z tre at m e nt gr o u p ( m e dia n 9 4. 9 h o u rs, 
I Q R: 6 2-1 2 6) c o m p are d t o t h e place b o gr o u p ( m e dia n 1 0 8. 2 h o u rs, I Q R: 8 2-1 5 2).   
 
F urt h er vir ol o g y testi n g usi n g a n u p d ate d R T -P C R m et h o d w as u n d erta k e n t o i n v esti g ate t h e c a use of ill n ess 
f or  t h ose  p atie nts  wit h n o  vir us  i d e ntifie d  at  b aseli n e,  a n d  p atie nts  w ere  re -classifie d  i nt o  n e w  a n al ysis 
p o p ulati o ns  b ase d  o n  p ositi v e  R T -P C R  or  c ult ure  res ults  at  a n y  ti m e  d uri n g  t h e  tre at m e nt  p eri o d  ( b aseli n e 
t hr o u g h  d a y  7).  I n  t h ese  n e w  a n al ysis  p o p ulati o ns,  4 6 %  w ere  i nfe cted  wit h  i nfl u e n z a  A  or  B,  2 8 %  w ere 
i nfecte d wit h ot h er vir uses, a n d 2 6 % h a d n o c a use of ill n ess i d e ntifie d. 
 
I n t h e retr os p ecti v e a n al ysis of p atie nts wit h la b orat or y-c o nfir m e d i nfl u e n z a fr o m sa m ples c olle cte d b et w e e n 
b aseli n e a n d d a y 7, ti m es fr o m first d o se t o res ol uti o n of s y m pt o ms w ere si g nific a ntl y l o w er ( P = 0. 0 0 0 6) f or 
i nfl u e n za-i nfecte d p atie nts ra n d o mize d t o t h e 6 0 0 m g N T Z tre at m e nt gr o u p ( m e dia n 9 5. 5 hrs, I Q R: 6 5-1 2 4) 
t h a n  f or  p atie nts  ra n d o mize d  t o  t h e  pla c e b o  tre at m e nt  gr o u p  ( m e dia n  1 1 7. 3  hrs,  I Q R: 9 3 -1 5 2). Ti m es fr o m 
first d ose t o res ol uti o n of s y m pt o ms f or t h e 3 0 0 m g N T Z tre at m e nt gr o u p ( m e dia n 1 0 8. 6 hrs, I Q R: 8 1-1 4 4) 
w ere l o w er t h a n f or t h e place b o gr o u p, b ut t h e differe n c e w as n ot statistic all y si g nific a nt ( P = 0. 1 9 3 0).  
 
A n al yses  of  d ail y  T CI D 5 0  viral  titers  of  s u bje cts  wit h  d ail y  n as o p h ar y n g e al  s w a b  c olle cti o ns  s h o w e d 
statisticall y si g nifica nt re d u cti o ns of viral titer f or t h e 6 0 0 m g N T Z tre at m e nt gr o u p c o m p are d t o t h e pla c e b o 
treat m e nt  gr o u p  (P = 0. 0 0 0 6).    R e d u cti o ns  of  viral  titer  c o m p are d  t o  t h e pla c e b o  w ere  o bser v e d  at  t h e  first 
n as o p h ar y n g eal  s w a b  c ollecti o n  f oll o wi n g  i nitiati o n  of  tre at m e nt  ( ~ 2 4  h o urs  after  i nitiati n g  tre at m e nt)  a n d 
w ere m ai ntai n e d u ntil d a y 5, b y w hic h ti m e t h e viral titers f or s u bje cts i n t h e pla c e b o tre at m e nt gr o u p h a d 
d ecli n e d t o le v els a p pr o xi m ati n g t h ose of s u bje cts i n t h e N T Z tre at m e nt gr o u ps.  As o bser v e d i n t h e a n al ysis 
of ti m e t o res ol uti o n of s y m pt o ms, treat m e nt wit h 3 0 0 m g N T Z t wic e d ail y f or 5 d a ys w as ass o ciate d wit h a n 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
1 1  
 
i nter m e diate  viral  titer  res p o nse  b et w e e n  t h at  of  t h e  6 0 0  m g  N T Z  tre at m e nt  gr o u p  a n d  t h e  pla c e b o  gr o u p.  
Differe n ces i n viral titers b et w ee n t his l o w d os e tre at m e nt gr o u p a n d t h e pla c e b o tre at m e nt gr o u p w ere n ot 
statisticall y si g nifica nt (P = 0. 1 5 5 3).  
 
Treat m e nt  wit h  N T Z  di d  n ot  i m p air  t h e  n or m al  h u m o ral  a nti b o d y  res p o nse  t o  i nfe cti o n.    T h ere  w ere  n o 
si g nific a nt differe n ces b et w ee n t h e treat m e nt gr o u ps i n a nti b o d y titer i n cre ases fr o m b aseli n e t o st u d y d a y 2 8.  
 
A d v erse e v e nts w ere si milar t o t h ose re p orte d b y s u bje cts re c ei vi n g pla c e b o, wit h t h e e x c e pt i o n of a gre ater 
fre q u e n c y  of  diarr h ea  i n  t h e  6 0 0  m g  N T Z  tre at m e nt  gr o u p  ( 1 7/ 2 1 1,  8. 1 %)  c o m p are d  t o  t h e  pla c e b o  gr o u p 
( 7/ 2 1 2,  3. 3 %)  (P = 0. 0 3 7 3).    N o n e  of  t h ese  a d v erse  e v e nts  res ulte d  i n  i nterr u pti o n  or  disc o nti n u ati o n  of 
t h era p y.2 3 
 
1. 2. 5  
R a n d o mize d 2 x 2 F a ct o ri a l 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 plic ate d I nfl u e n z a: St u d y 
R M 0 8 -3 0 0 2  
 
A ra n d o mize d, d o u ble-bli n d, fact orial  trial of N T Z a n d O S T w as c o n d u cte d i n 1 3 0 o ut p atie nt pri m ar y c are 
cli nics  i n t h e  U nite d  States,  C a n a d a,  B el gi u m,  A ustralia  a n d  N e w  Z e ala n d  b et w e e n  M arc h  2 0 1 3  a n d  A pril 
2 0 1 5. 1, 9 4 1 s u bjects 1 3 t o 6 5 y ears of a g e w ere e nr olle d b as e d u p o n s y m pt o ms a n d t h e pres 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 bjects w ere e nr olle d wit hi n 4 8 h o urs of s y m pt o m o nset a n d ra n d o miz e d t o re 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 pla c e b o t wic 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 ere  c ollecte d  at  b aseli n e  f or  i d e ntific ati o n  of  1 9  differe nt  viral  res pirat or y  i nfe cti o ns  b y  R T -P C R.  
S u bjects m ai ntai n e d diaries t o rec or d ti m e of m e dic ati o n i nta k e, o ral te m p erat ure, t h e se v erit y of e a c h of 7 
s y m pt o ms (c o u g h, n asal o bstr u cti o n, s ore t hr o at, fati g u e, h e a d a c h e, m y al gia  or  fe v eris hn ess  gra d e d as a bse nt, 
mil d, m o d erate or se v ere), a bilit y t o p erf or m n or m al a cti vities (sc ale of 0 -1 0), ti m e l ost fr o m w or k or  sc h o ol, 
c o n c o mita nt m e dicati o ns a n d a d v erse e v e nts.  Diar y d ata w as re c or d e d t wic 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 bject n o l o n g er h a d a n y m o d erate or se v ere i nfl u e n z a s y m pt o ms. S u bje cts ret ur n e d t o t h e 
cli nic 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 sa m ples w ere c olle cte d at b aseli n e a n d d a y 
7 f or la b orat or y  safet y tests, a n d bl o o d sa m ples w ere c olle cte d at b aseli 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 
titer.  A s u bset of s u bjects fr o m selecte d st u d y sites (a p pr o xi m atel y 3 3 % of t h e s u bje cts e nr olle d) w ere visite d 
b y t h e st u d y tea m t o c ollect n as o p h ar y n g e al s w a bs o n d a ys 2, 3, 4 a n d 5 f or q u a ntitati v e i nfl u e n z a viral titer 
d eter mi n ati o n.  F or  t h e  s u bjects,  bl o o d  sa m ples  w ere  als o  c olle cte d  o n  d a ys  3  a n d  5  f or  p o p ulati o n 
p h ar m ac o ki n etics. N as o p h ar y n g eal s w a bs w ere c olle cte d fr o m all s u bje cts at d a y s 7 a n d 1 4 f or i d e ntific ati o n 
of vir uses a n d f or q u a ntitati v e i nfl u e n za viral titer.  T h e pri m ar y effic a c y e n d p oi nt w as ti m e fr o m first d ose t o 
alle viati o n of s y m pt o ms (all 7 s y mpt o ms a bse nt or mil d a n d re m ai n e d s o f or at le ast 2 4 h o urs).   T h ere w ere 
t w o pri m ar y efficac y a n al yses: ( 1) c o m p aris o n of ti m e t o s y m pt o m alle viati o n f or t h e N T Z tre at m e nt gr o u p 
a n d  t h e  place b o,  a n d  ( 2)  c o m p aris o n  of  ti m e  t o  s y m pt o m  alle viati o n  f or  t h e  N T Z + O S T  tre at m e nt  gr o u p  t o 
eac h of t h e ot h er treat m e nt gr o u ps.  
 
7 3 7  s u bjects (3 8 %) e nr olle d i n t his st u d y w ere i nfe cte d wit h i nfl u e n z a A or i nfl u e n z a B b as e d u p o n R T -P C R 
a n d  viral  c ult ures  p erf or m e d  o n  n as o p h ar y n g e al  s w a bs  c olle cte d  at  b aseli n e.  2 5 %  w ere  i nfe cte d  wit h 
i nfl u e n za A s u bt y p e 2 0 0 9 H 1 N 1, 8 % wit h i nfl u e n z a A H 3 N 2, 1 % wit h i nfl u e n z a A s u bt y p e u n d eter mi n e d, 
a n d 4 % wit h i nfl u e n za B.  2 3 % w ere i nfe cte d wit h ot h er vir us es, t h e m ost c o m m o n b ei n g r hi n o vir us ( 1 2 % of 
all  s u bjects  e nr olle d)  f oll o w e d  b y  c or o n a v ir uses ( 6 %  of  all  s u bje cts  e nr olle d).  No  c a use  of  ill n ess  w as 
i d e ntifie d f or 3 9 % of s u bjects e nr olle d i n t h e st u d y.  
 
I n t h e pri m ar y a n al ysis, ti m es fr o m first d ose t o alle viati o n of 7 s y m pt o ms w ere n ot si g nific a ntl y differe nt f or 
a n y  of  t h e  treat m e nt  gr o u p s. E ac h  of  t h e  t hre e  a cti v e  tre at m e nt  gr o u ps  s h o w e d  i m pr o v e m e nt  i n  ti m e  t o 
alle viati o n  of  a  c o m p osite  e n d p oi nt  m a d e  u p  of fe v er,  fe v eris h n ess  a n d  m y al gia  (a c ute  fe brile  ill n ess) 
c o m p are d t o t h e place b o  (n o mi n al p < 0. 0 5) , a n d e a c h of t h e t hre e a cti v e tre at m ent gr o u ps s h o w e d m e a ni n gf ul 
( u p t o a p pr o xi m atel y 2 d a ys) i m pr o v e m e nt i n ti m e fr o m first d ose u ntil s u bje cts w ere a ble t o p erf or m all of 
t h eir n or m al acti vities c o m p are d t o t h e pla c e b o ( N S).  N o si g nific a nt differe n c es  (i.e., n o mi n al p-v al u e < 0. 0 5) 
i n ti m e t o alle viatio n of t h e res pirat or y s y m pt o ms w ere o bser v e d b et w e e n gr o u ps . 
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
1 2  
 
U n d er t h ese e x p eri m e ntal c o n diti o ns, t h e p ositi v e c o ntr ol, O S T, di d n ot s h o w t h e e x p e cte d effe ct o n ti m e t o 
alle viati o n  of 7 s y m pt o ms.  T h e i n a bilit y t o d ete ct tre at m e nt effe ct i n t h e pri m ar y a n al ysis w as attri b ute d t o 
m et h o d ol o g y use d t o c ollect p atie nt -re p orte d o utc o m e/s y m pt o m d ata.   
 
Treat m e nt  wit h  N T Z  as  m o n ot h era p y  or  i n  c o m bi n ati o n  wit h  O S T  di d  n ot  i m p air  t h e  n or m al  h u m oral 
a nti b o d y  res p o nse  t o  i nfecti o n.  T h ere  w ere  n o  si g nific a nt  differe n c es  b et w e e n  t h e  tre at m e nt  gr o u ps  i n 
a nti b o d y titer i n creases fr o m b aseli n e t o st u d y d a y 2 8.  
 
Treat m e nt wit h N T Z 6 0 0 m g t wice d ail y f or fi v e d a ys as m o n ot h era p y or i n c o m bi n ati o n wit h O S T w as w ell 
t olerate d  b y  s u bjects.   T h e  m ost  c o m m o nl y  re p ort e d  a d v erse  e v e nts  (re p orte d  b y ≥2 %  of  s u bje cts  i n  a n y 
treat m e nt gr o u p) re g ar dless of ca usalit y w ere: 
 
A d v erse 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 usea  
3. 9  
4. 4  
6. 4  
5. 3  
V o miti n g  
2. 5  
4. 2  
6. 4  
2. 7  
Diarr h o ea  
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 uria  
5. 2  
- 
5. 5  
0. 4  
Dizzi n ess  
2. 5  
3. 1  
3. 1  
1. 0  
 
T h ere w ere n o seri o us a d v erse e v e nts relate d t o a n y of t h e tre at m e nts.  
 
1. 2. 6  
R a n d o mize d D o u ble -Bli n d Pl a c e b o C o ntr olle d T ri al of N T Z i n T r e ati n g U n c o m plic ate d 
I nfl u e n z a: St u d y R M 0 8-3 0 0 3 
 
A  P h ase  3  ra n d o mize d,  d o u ble -bli n d,  pla c e b o  c o ntr olle d  trial  w as  c o n d u cte d  i n  2 5  o ut p atie nt  pri m ar y  c are 
cli nics  i n  t h e  U nite d  States,  P u ert o  Ric o  a n d  A ustralia  b et w e e n  D e c e m b er  2 0 1 5  a n d  A u g ust  2 0 1 6.  T hre e 
h u n dre d t w e nt y -f o ur s u bjects 1 2 t o 6 5 y e ars of a g e w ere e nr olle d b ase d u p o n s y m pt o ms a n d t h e prese n c e of 
i nfl u e n za  i n  t h e  c o m m u nit y.  S u bjects  w ere  e nr olle d  wit hi n  4 0  h o urs  of  s y m pt o m  o nset  a n d  ra n d o miz e d  t o 
recei v e N T Z 6 0 0 m g or place b o t wice 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 ere c olle cte d at b aseli n e 
f or  i d e ntificati o n  of  res pirat or y  p at h o g e ns  b y  R T-P C R.    All  s u bje cts  eit h er  ret ur n e d  t o  t h e  cli nic  or  w ere 
visite d  d ail y  b y  t h e  st u d y  tea m  t o  c olle ct  n as o p h ar y n g e al  s w a bs  o n  d a ys  2,  3,  4  a n d  5  f or  q u a ntitati v e 
i nfl u e n za  viral  titer  d eter mi n ati o n. Bl o o d  s a m ples  w ere  c olle cte d  o n  d a ys  3  a n d  5  f or  p o p ulati o n 
p h ar m ac o ki n etics.  S u bjects  m ai ntai n e d  diaries  t o  re c or d  ti m e  of  m e dic ati o n  i nta k e,  oral  te m p erat ure,  t h e 
se v erit y  of  eac h  of  7  s y m pt o ms  (c o u g h,  n asal  o bstr u cti o n,  s ore  t hr o at,  fati g u e,  h e a d a c h e, m y al gia  or 
fe v eris h n ess gra d e d as a bse nt, mil d, m o d erate or se v ere), a bilit y t o p erf or m n or m al a cti vities (sc ale of 0-1 0), 
ti m e l ost fr o m w or k or sc h o ol, c o n c o mita nt m e dic ati o ns a n d a d v erse e v e nts.  Diar y d ata w as re c or d e d t wic 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 bje ct  n o  l o n g er  h a d  a n y  m o d erate  or  se v ere  i nfl u e n z a 
s y m pt o ms.  S u bjects  ret ur n e d  t o  t h e  cli nic  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 
sa m ples w ere c ollecte d at b aseli n e a n d d a y 7 f or la b safet y tests, a n d bl o o d sa m ples w ere c olle cte d at b aseli n e 
a n d d a y 2 8 f or i nfl u e n za a nti b o d y titer. N as o p h ar y n g e al s w a bs w ere c olle cte d fr o m all s u bje cts at d a ys 7 a n d 
1 4 f or i d e ntificati o n of vir uses a n d f or q u a ntitati v e i nfl u e n z a viral titer.  T h e pri m ar y effic a c y e n d p oi nt w as 
ti m e fr o m first d ose t o alle viati o n of s y m pt o ms (all 7 s y m pt o ms a bse nt or mil d a n d re m ai n e d s o f or at le ast 
2 1. 5 h o urs). T h e pri m ar y efficac y a n al ysis w as a c o m p aris o n of ti m es fr o m first d ose t o s y m pt o m alle viati o n 
f or s u bjects i n t h e N T Z a n d place b o tre at m e nt gr o u ps wit h la b orat or y-c o nfir m e d i nfl u e n z a at b aseli n e, d a y 2 
or d a y 3. T h e a n al ysis w as p erf or m e d usi n g a Pre ntic e Wilc o x o n test wit h a n al p h a of 0. 0 5.  
 
T w o h u n dre d si xt y -t hree ( 2 6 3) of t h e 3 2 4 s u bje cts e nr olle d i n t h e st u d y h a d la b orat or y-c o nfi r m e d i nfl u e n z a A 
or i nfl u e n za B i d e ntifie d i n a n as o p h ar y n g e al s w a b sa m ple c olle cte d at b aseli n e, d a y 2 or d a y 3.  3 8 % w ere 
i nfecte d wit h i nfl u e n za A s u bt y p e 2 0 0 9 H 1 N 1, 1 7 % wit h i nfl u e n z a A H 3 N 2, 4 3 % wit h i nfl u e n z a B , a n d 2 % 
w ere i nfecte d wit h t w o i nfl u e n z a vir uses .  
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
1 3  
 
I n  t h e  pri m ar y  a n al ysis,  ti m es  t o  alle viati o n  of  7  s y m pt o ms  w ere  n ot  statistic all y differe nt  f or  t h e  N T Z 
treat m e nt gr o u p c o m p are d t o t h e place b o. M e dia n ti m es fr o m first d ose t o alle viati o n of all s y m pt o ms w ere 
1 0 1 h o u rs [I Q R 6 8-1 5 3] f or t h e N T Z -tre ate d gr o u p c o m p are d t o 1 0 2. 5 ho u rs [I Q R 6 9-1 5 5] f or t h e pla c e b o 
gr o u p, p = 0. 6 1 3 2.  N e v ert h eless, t h e N T Z tre at m e nt gr o u p di d s h o w i m pr o v e m e nt i n ti m e t o alle viati o n of a 
c o m p osite  e n d p oi nt  m a d e  u p  of fe v er,  fe v eris h n ess  a n d  m y al gia  (a c ute  fe brile  ill n ess)  c o m p are d  t o  t h e 
place b o (n o mi n al  p = 0. 0 0 4 ),  a n d it s h o w e d m e dia n i m pr o v e m e nt of  4 2  h o urs  i n  ti m e  fr o m  first  d ose  u ntil 
s u bjects  w ere  a ble  t o  p erf or m  all  of  t h eir  n or m al  a cti vities  c o m p are d  t o  t h e  pla c e b o  ( N S). N o  si g nific a nt 
differe n ces (i.e.,  n o mi n al  p-v al u e  <  0. 0 5) i n  ti m e  t o  alle viati o n  of  t h e  res pirat or y  s y m pt o ms  w ere  o bser v e d 
b et w ee n gr o u ps.    
 
Ti m es  t o  alle viati o n  of t h e  7 s y m pt o ms,  es p e ciall y  t h e  res pirat or y  s y m pt o ms,  w ere  v er y  s h ort  d uri n g  t his 
p artic ular  seas o n.  I n t h e  s u bset s u bjects  i nfe cte d  wit h  i nfl u e n z a  A/ H 3 N 2,  t h e  d urati o n  of  s y m pt o ms  w as 
s o m e w h at  l o n g er,  a n d  i n  t his  s u bset, tre at m e nt  wit h  N T Z  w as  ass o ciate d  wit h  a  re d u cti o n  of  ti m e  t o 
alle viati o n of all s y m pt o ms ( differe n ce at m e dia n -2 3. 3 hrs [I Q R -2 1, -1 6] , N S). 
 
Treat m e nt wit h N T Z di d n ot i m p air t h e n or m al h u m oral a nti b o d y res p o nse t o i nfe cti o n.  N o resista n c e w as 
o bser v e d.  A d v erse e v e nts w ere si milar t o t h ose re p orte d b y s u bje cts re c ei vi n g pla c e b o, wit h t h e e x c e pti o n of 
a greater fre q u e n c y of mil d c hr o m at uria i n t h e 6 0 0 m g N T Z tre at m e nt  gr o u p ( 1 2. 9 %) c o m p are d t o t h e pla c e b o 
gr o u p ( 0 %).  N o n e of t h ese a d v erse e v e nts res ulte d i n i nterr u pti o n or disc o nti n u ati o n of t h era p y.  
 
D ata fr o m t h ese st u dies as w ell as hist oric al cli nic al trials of t h e a p pr o v e d n e ura mi ni d as e i n hi bit ors p oi nt t o 
t h e n ee d f or i m pr o v e d m et h o d ol o g y t o m e as ure tre at m e nt b e n efit f or st u dies of i nfl u e n z a a nti virals.  
 
1. 2. 7 
O v er vie w of Ot h er E x p erie n c e i n Cli nic 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 ee n m ar k ete d i n t h e U nite d States si n c e 2 0 0 3 a n d i n L ati n A m eric a si n c e 1 9 9 6.  It is esti m ate d t h at 
m ore  t h a n 2 5 0 milli o n  p atie nts  h a v e  b e e n  e x p ose d  t o  N T Z  p ost -m ar k eti n g  w orl d wi d e.    N o  dr u g -relate d 
seri o us a d v erse e v e nts h a v e b ee n re p orte d d uri n g p ost-m ar k eti n g e x p erie n c e wit h N T Z.  
 
P h ase 2 a n d 3 cli nical st u dies h a v e  b ee n c o n d u cte d i n a p pr o xi m atel y 5 , 60 0 s u bje cts t o e v al u ate t h e safet y a n d 
efficac y  of  N T Z  i n  treati n g  p arasitic,  b a cterial  a n d  viral  i nfe cti o ns.  D uri n g  t h es e  st u dies,  n o  dr u g -relate d 
seri o us a d v erse e v e nts h a v e b ee n o bser v e d.  T h e si d e effe cts h a v e b e e n us u all y of a mil d tra nsie nt n at ure, a n d 
less t h a n 1 % of s u bjects h a v e disc o nti n u e d t h era p y b e c a use of a n a d v erse e v e nt.  T h e m ost c o m m o n a d v erse 
e v e nts re p orte d i n cli nical trials i n cl u d e a b d o mi n al p ai n,  c hr o m at uria, diarr h e a, diz zi n ess, h e a d a c h e, n a use a 
a n d  v o miti n g  a n d  di d  n ot  differ  si g nific a ntl y  fr o m  t h ose  of  pla c e b o  e x c e pt  f or  c h r o m at uria  w hic h  w as 
re p orte d b y 4 t o 5 % of s u bjects a n d is attri b ute d t o uri n ar y e x creti o n of N T Z m eta b olites.  Cli nic al c h e mistr y 
a n d h e m at ol o g y o btai n e d b ef ore a n d after tre a t m e nt  h a v e  n ot  re v e ale d  a n y  a b n or m alities  attri b uta ble  t o  t h e 
test dr u g.1 5 
 
1. 3  
R ati o n ale f o r t h e St u d y  
 
T h ere  is  a n  i m p orta nt  n ee d  f or  n e w  tre at m e nts  of  i nfl u e n z a  t h at  m a y  offer  n o v el  m e c h a nis ms  of  a cti o n, 
i m pr o v e d  efficac y  a n d  safet y  pr ofiles  or  re d u c e d  ris ks  of  resista n c e.  T h ere  is  als o  a n  i m p orta nt  n e e d  f or 
i m pr o v e m e nt i n t h e m et h o d ol o g y use d t o e v al u ate t h e effe cti v e n ess of i nfl u e n z a a nti viral dr u gs.  N ota bl y, t h e 
p atie nt -re p orte d o utc o m es i nstr u m e nts use d f o r hist oric al cli nic al trials h a v e n ot b e e n v ali d ate d a c c or di n g t o 
c urre nt F D A sta n d ar ds. 
 
T his st u d y is a m ultice nter ra n d o mize d d o u ble -bli n d pla c e b o c o ntr olle d trial d esi g n e d t o e v al u ate effic a c y a n d 
safet y of N T Z 6 0 0 m g a d mi nistere d orall y t wic e d ail y f or fi v e d a ys c o m p are d t o a pla c e b o i n t h e tre at m e nt of 
u n c o m plicate d i nfl u e n za.   T h e st u d y will e m pl o y a n e w p atie nt -re p orte d o utc o m e q u esti o n n aire, F L U-P R O © , 
t h at  h as  b ee n  d e v el o p e d  a n d  v ali d ate d  a c c or di n g  t o  c urre nt  F D A  sta n d ar ds.  All s u bje cts will c o m plete t h e 
q u esti o n n aire d ail y f or 2 1 d a ys usi n g a n ele ctr o nic diar y f or a c c o u nta bilit y.  
 
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
1 4  
 
2  
S T U D Y O B J E C TI V E S  
 
T h e pri m ar y o bjecti v e of t his st u d y is t o e v al u ate t h e effe ct of 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 i nfl u e n z a c o m p are d t o t h at of a pla c e b o d ur i 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 t i m e t o ret ur n t o 
a bilit y t o p erf or m all n or m al acti vit ies. 
 
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 p r o p orti o n of 
s u bjects  e x p erie n ci n g  o n e  or  m ore  co m plic ati o ns  of  i nfl u e n z a  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,  w orse ni n g  of  pre-e xisti n g  h ealt h  c o n diti o ns ,  s yste mic  a nti bi otic  use  f or  i nfe cti o ns  sec o n d ar y  t o 
i nfl u e n za i nfecti o n, h os pitalizati o n d u e t o c o m plic ati o ns of i nfl u e n z a, a n d d e at h.  
 
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  res ol uti o n  of  fe brile  ill n ess, 
ti m e t o ret ur n t o us u al h ealt h, a n d c h a n g es i n viral titers fr o m b aseli n e t o e a c h of d a ys 2, 3 a n d 7. 
 
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 af et y of N T Z b y a n al ysis of a d v erse e v e nts  a n d e v al u ati o n 
of  t h e  effect  of  nitaz o x a ni d e  o n  i nfl u e n z a  a nti b o d y  res p o nse  a n d  e v al u ati o n  of  relati o ns hi ps  b et w e e n 
p h ar m ac o ki n etics a n d cli nical or  vir ol o gic res p o nses . 
 
 
3  
S T U D Y D E SI G N  
 
T h e  st u d y  will  b e  a  m ultice nt er,  ra n d o miz e d,  d o u ble -bli n d  trial  t o  e v al u ate  t h e  effic a c y  of  N T Z  c o m p are d  t o 
place b o  i n treati n g u n c o m plicate d i nfl u e n z a .  S u bje cts will b e sele cte d a c c or di n g t o t h e i n cl usi o n a n d e x cl usi o n 
criteria liste d b el o w.  T h e st u d y is d esi g n e d t o e nr oll at le ast  6 0 0  s u bje cts ( u p t o 7 0 0  m a xi m u m) wit h la b orat or y-
c o nfir m e d i nfl u e n za .  T otal e nr oll m e nt re q uire d t o a c hie v e t h is n u m b er is e x p e cte d t o b e a p pr o xi m atel y  8 0 0  t o 
1 2 0 0  s u bjects.  Pri or t o scree ni n g f or i n cl usi o n i n t h e st u d y, i nf or m e d c o nse nt will b e o btai n e d . 
 
I m m e diatel y  after  c o m pleti o n  of  i nf or m e d  c o nse nt,  scre e ni n g,  a n d  e nr oll m e nt  i n  t h e  st u d y,  t w o  b aseli n e 
n as o p h ar y n g eal  s w a bs  will  b e  c ollecte d  f or  viral  c ult ure  a n d  R T -P C R.    A  bl o o d  s a m ple  will  b e  c olle cte d  f or 
la b orat or y safet y tests a n d a nti-i nfl u e n za a nti b o dies, a n d a uri n e sa m ple will b e c olle cte d f or la b orat or y safet y 
tests.  S u bjects will recei v e i nstr u cti o n o n c o m pleti o n of t h eir ele ctr o nic diaries, c o n c o mita nt m e dic ati o ns a n d 
atte n di n g f oll o w -u p visits.  
 
T h e n s u bjects will b e ra n d o mize 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 ta blets b.i. d. f or 5 d a ys  
• 
Gr o u p 2 ( Place b o ):  Tw o place b o ta blets b.i. d. f or 5 d a ys  
 
T h e m e dicati o n will b e ta k e n t wice d ail y wit h f o o d  ( prefera bl y a hi g h-fat m e al, b ut at mi ni m u m a c ere al b ar).  
T h e  first  d ose  will  b e  ta k e n  wit h  f o o d  i n  t h e  p h ysicia n’s  offic e  u n d er  t h e  o bs er v ati o n  of  t h e Pri n ci p al 
I n v esti g at or or a m e m b er of t h e I n v esti g at or’s staff.  T h e se c o n d d ose will b e ta k e n b y t h e s u bje c t as cl ose as 
p ossi ble t o 1 2 h o urs after t h e first d ose.    
 
A n urse or ot h er st u d y p ers o n n el will visit e a c h  s u bje ct ( or t h e s u bje ct will ret ur n t o t h e cli nic) o n st u d y d a ys 2 
a n d 3 t o c ollect t w o n as o p h ar y n g eal s w a bs, t o re vie w p atie nt diaries, a n d t o re vie w s y m pt o ms a n d scre e n f or 
i nfl u e n za-relate d  c o m plicati o ns  i n cl u di n g si n usitis,  otitis,  br o n c hitis,  p n e u m o nia  a n d  c e ntral  n er v o us  s yste m 
disease.  S u bjects will b e referre d f or i m m e diate c are as n e e d e d b ase d o n t h e scre e ni n g.  A b l o o d sa m ple f or 
p h ar m ac o ki n etics will als o b e c ollecte d o n st u d y d a y 3.  T h e se d a y 2 a n d 3 visits will o c c ur at a p pr o xi m atel y 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
1 5  
 
t h e sa m e ti m e of d a y t h at t h e s u bject t o o k his/ h er first d ose of st u d y m e dic ati o n (r o u g hl y 2 4 a n d 4 8  h o urs p ost -
first  d ose).    O n  d a y  3, t h e  bl o o d  sa m ple  f or  p h ar m a c o ki n etics  will  b e  c olle cte d b ef ore  t h e  d os e.  T h e 
n as o p h ar y n g eal s w a bs will b e use d t o e v al u ate q u a ntitati v e c h a n g es i n viral s h e d di n g.  T h e bl o o d sa m ples will 
b e use d t o e v al u ate relati o ns hi ps b et w ee n p h ar m a c o ki n etics a n d vir ol o gic or cli nic al res p o nse.  St u d y sites or 
s u bjects  m a y  o pt  o ut  of  t h e d a y  2  a n d  d a y  3  visits  d u e  t o  site  staffi n g ,  p atie nt  a v aila bilit y or  ot h er  pra ctic al 
c o nsi d erati o ns  or  prefere n ce s;  n e v ert h eless, at  le ast  7 5 %  of  s u bje cts  e nr olle d  i n  t h e  trial  are  e x p e cte d  t o 
c o m plete t h e d a y 2 a n d d a y 3 visits a n d relate d pr o c e d ures (f o r viral ki n etics a n d p h ar m a c o ki n etics). 
 
A st u d y p h ysicia n, n urse or ot h er site p ers o n n el will m a k e d ail y tele p h o n e c alls t o s u bje cts f or t h e first fi v e d a ys 
of  d osi n g  t o  re vie w  s y m pt o ms  a n d  scre e n  f or  i nfl u e n z a -relate d  c o m plic ati o ns  i n cl u di n g  si n usitis,  otitis, 
br o n c hitis,  p n e u m o nia  a n d  ce ntral  n er v o us  s yste m  dise ase.    S u bje cts  will  b e  referre d  f or  i m m e diate  c are  as 
n ee d e d b ase d o n t h e scree ni n g. [ N ote: I n lie u of a tele p h o n e c all, t his i nf or m ati o n m a y b e o btai n e d d uri n g t h e 
d a y 2 or 3 office or h o m e visit s (see t h e pre c e di n g p ara gra p h).]  T h e st u d y sites a n d s u bje cts will b e bli n d e d 
fr o m vir ol o g y la b orat or y d ata u ntil after st u d y d a y 22 or, if e arlier, u ntil t h e s u bje ct is disc o nti n u e d fr o m t h e 
st u d y.  D uri n g t h e st u d y p eri o d, eac h s u bje ct will b e pres u m e d  t o h a v e i nfl u e n z a i nfe cti o n, a n d a n y w orse ni n g 
of s y m pt o ms or c o m plicati o ns will b e pres u m e d t o b e i nfl u e n z a -relate d. 
 
S u bjects will ret ur n t o t h e cli nic o n d a ys 7 a n d 2 2 f or p ost-tre at m e nt f oll o w-u p, i n cl u di n g t w o n as o p h ar y n g e al 
s w a bs,  dr u g  acc o u nta bility,  re p orti n g  of  a d v erse  e v e nts  a n d  c o m plic ati o ns  of  i nfl u e n z a.  Bl o o d  a n d  uri n e 
sa m ples f or la b orat or y safet y tests will b e c olle cte d at d a y 7, a n d a bl o o d sa m ple f or a nti -i nfl u e n z a a nti b o dies 
will b e c ollecte d o n d a y 2 2 .  A n urse or ot h er st u d y p ers o n n el will re vie w t h e ele ctr o nic p atie nt diar y e ntries 
d ail y (s y n c hr o nize d t o a w e b-b ase d d ata s yste m) t o e ns ure c o nte m p ora n e o us a n d c o m plete re c or di n g of diar y 
d ata.  S u bjects will m ai ntai n t h e electr o nic p atie nt  diar ies u ntil st u d y d a y 2 2 .  A n y visits t h at d o n ot o c c ur o n t h e 
prescri b e d d ate, or wit hi n 1 d a y of t h at d ate i n t h e c ase of t h e d a y 7 visit or wit hi n 3 d a ys after t h at d ate i n t h e 
case of t h e d a y 22 visit, will b e rec or d e d as pr ot o c ol d e viati o ns.  
 
A  ce ntral  la b orat or y  will  b e  use d  f or  la b orat or y  s afet y  tests,  a nti -i nfl u e n z a  a nti b o dies  a n d  vir ol o g y  testi n g.  
L a b orat or y  safet y  tests  will  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,  al b 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/ dire ct),  B U N,  cre ati 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 n  a n d  bl o o d).  Vir ol o g y  testi n g  will  i n cl u d e  R T -P C R  assa y  e Ple x ®  R es pirat 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 i d e ntif y i nfl u e n z a A ( n o n-s p e cific 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)  a n d H 3  s u bt y p es; i nfl u e n za B; res pirat or y s y n c ytial vir us A a n d B ( R S V); p arai nfl u e n z a 1, 2, 3 
a n d 4; h u m a n m eta p n e u m o vir us ( h M P V); a d e n o vir us  ( A-F) ; h u m a n r hi n o vir us/enter o vir us; 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; C hl a m y d o p hil a  p n e u m o ni a e ;  a n d M y c o pl as m a  p n e u m o ni a e  ( b aseli n e  a n d  d a y  7 
n as o p h ar y n g eal  s w a bs),  c ult ure  ( b aseli n e  a n d  d a y  7  n as o p h ar y n g e al  s w a bs),  a n d  q u a ntitati o n  of  i nfl u e n z a 
vir uses b y T CI D 5 0 ( b aseli n e an d  d a y s 2, 3 a n d 7 n as o p h ar y n g e al s w a bs).  F oll o w -u p sa m ples ( d a ys 2 , 3, 7 a n d  
2 2 )  c ollecte d  fr o m  s u bjects  w h o  d o  n ot  test  p ositi v e  f or  i nfl u e n z a  A  or  i nfl u e n z a  B  at  b aseli n e  will  n ot  b e 
a n al y ze d f or q u a ntitati v e i nfl u e n za viral titer.  
 
T his st u d y is e x p ec te d t o r u n fr o m D ece m b er 2 0 1 7 t hr o u g h A pril 2 0 1 9 . 
 
R ati o n ale f or i m p orta 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 oice of N T Z d ose 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 nic al trial ( 6 0 0 m g b.i. d. 
f or 5 d a ys) w as selecte d b ase d u p o n res ults of a P h ase 2 b/ 3  d ose -ra n g e fi n di n g cli nic al trial ( St u d y R M 0 8-
3 0 0 1) c o n d u cte d i n t h e U nite d States d uri n g t h e 2 0 1 0 -2 0 1 1 fl u se as o n.  I n t h at st u d y, tre at m e nt wit h 6 0 0 
m g N T Z b.i. d. f or 5 d a ys w as ass o ciate d wit h a statistic all y si g nific a nt  re d u cti o n i n ti m e fr o m first d ose t o 
alle viati o n of s y m pt o ms c o m p are d t o t h e pla c e b o.  A 3 0 0 m g N T Z d ose gr o u p als o e x p erie n c e d a re d u cti o n 
of  ti m e  t o  alle viati o n  of  s y m pt o ms  c o m p are d  t o  t h e  pla c e b o,  b ut  t h e  differe n c e  w as  n ot  statistic all y 
si g nifica nt.  T h e 6 0 0 m g N T Z d ose w as w ell t olerate d.  A d v ers e e v e nts re p orte d f or s u bje cts re c ei vi n g t h e 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
1 6  
 
6 0 0 m g d ose w ere si milar t o t h ose of s u bje cts re c ei vi n g t h e pla c e b o, wit h t h e e x c e pti o n of a hi g h er rate of 
diarr h ea ( 8. 1 % c o m p are d t o 3. 3 % f or t h e pla c e b o).  
 
•  
C h oic e  of  c o ntr ol  gr o u ps.   Acc or di n g  t o  F D A  G ui d a n c e,  a  pla c e b o -c o ntr olle d  rat h er  t h a n  n o n -i nferi orit y 
d esi g n  s h o ul d  b e  use d  f or  trials  e v al u ati n g  tre at m e nt  of  u n c o m plic ate d  i nfl u e n z a  b e c a use  t h e  ris ks  of 
recei vi n g  a  place b o  are  l o w,  a n d  t h e  effic a c y  of  a v aila ble  tre at m e nt  is  m o d est,  v aria ble  a n d  c a n n ot  b e 
pre dicte d w ell e n o u g h t o s u p p ort a n a d e q u ate i nferi orit y m ar gi n. 2 4  
 
•  
C h oice of p atie nt p o p ul ati o n.  T h e p o p ulati o n t o b e st u die d i n cl u d es a d ults a n d a d oles c e nts at le ast 1 2  y e ars 
of a g e wit h u n c o m plicate d i nfl u e n za.  T his is a p o p ulati o n si milar t o t h ose sele cte d f or st u dies R M 0 8 -3 0 0 1 , 
R M 0 8 -3 0 0 2 , a n d R M 0 8-3 0 0 3  of t h e N T Z 3 0 0 m g e xte n d e d rele ase ta blets . N o s afet y c o n c er ns h a v e b e e n 
i d e ntifie d fr o m t h ese cli nical trials.  
 
F or t h e  prese nt st u d y,  s o m e  s u bjects (e. g.,  s u bje cts  > 6 5  y e ars  of  a g e,  mil d  ast h m a,  sta g e  I  or  II  C O P D, 
dia b etes  m ellit us  if  n ot  p o orl y  c o ntr olle d ,  etc. – se e  I n cl usi o n/ E x cl usi o n  criteria  i n  S e cti o ns  4. 1  a n d  4. 2) 
w h o are at hi g h er ris k of i nfl u e n za c o m plic ati o ns a c c or di n g t o C D C criteria will b e  all o w e d t o p artici p ate 
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 are a ble t o c o m pl y wit h pr ot o c ol re q uire m e nts a n d d o n ot h a v e a 
pre -e xisti n g ill n ess or c o n diti o n t h at w o ul d pla c e t h e m at a n u nre as o n a bl y i n cre ase d ris k.  I n cl usi o n of t h ese 
p atie nts  i n t h e  st u d y  will  i m pr o v e  re cr uit m e nt  eff orts  a n d  will  pr o vi d e  i m p orta nt d ata  relate d  t o  t h e 
effecti v e n ess a n d safet y o f t h e N T Z 3 0 0 m g e xte n d e d rele ase ta blets i n t his p o p ulati o n.  N ota bl y, t h ere is 
li mite d e vi d e n ce  t o  s u p p ort  t h e  effecti v e n ess  of  e xisti n g  i nfl u e n z a  a nti virals  i n s u bje cts  at  hi g h er  ris k  of 
i nfl u e n za c o m plicati o ns. 
 
D ata fr o m p h ar m ac o ki n etics st u dies i n h e alt h y v ol u nte 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 dicate  t h at  t h e  p h ar m ac o ki n etics  of  t h e  m aj or  N T Z  m eta b olites,  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, 
f oll o wi n g oral a d mi nistrati o n of a N T Z 5 0 0 m g ta blet are si milar f or t h ese a g e gr o u ps. S afet y d ata is als o 
si milar f or t h ese a g e gr o u ps.  T h eref ore, t h e a d ult d ose is d e e m e d a p pr o priate f or p e diatric p atie nts d o w n t o 
1 2  y ears  of  a g e. Inf or m e d c o nse nt  will  b e re q uire d  f or s u bje ct p artici p ati o n  i n  t his  st u d y  (se e  Pr ot o c ol 
S ecti o n 1 5) .  A si g n e d asse nt  f or m will b e re q uire d f or a n y mi n ors e nr olle d  (≤ 1 8 y e ars of a g e or as lo c al 
re g ulati o ns  a p pl y) as  w ell  as  a  si g n e d  p are ntal/le g al  g u ar dia n  c o nse nt  b y  t h eir  p are nt/le g al  g u ar dia n 
all o wi n g f or t h e mi n or’s p artici p ati o n .   
 
A cc or di n g t o F D A G ui d a n ce,  a nti viral dr u g effic a c y i n c hil dre n c a n n ot b e e xtra p olate d fr o m d ata g e n erate d 
fr o m  trials  i n  a d ults  b eca use:  ( 1)  pri or  e x p os ure  a n d  i m m u nit y  t y pic all y  prese nt  i n  a d ults  m a y  affe ct 
i nfl u e n za ill n ess a n d res p o nse t o treat m e nt differe ntl y t h a n i n c hil dre n; a n d ( 2) viral s h e d di n g m a y differ i n 
p e diatric a n d a d ult a g e gr o u ps. 2 4 St u d y  of t h e effic a c y a n d safet y of t h e pr o d u ct i n c hil dre n is , t h eref ore, 
re q uire d i n  or d er  t o  h a v e  t h e  pr o d u ct  lic e nse d  f or  use  i n  p e diatric  p atie nts .  S e p arate  s u bset  a n al yse s  of 
safet y,  p h ar m ac o ki n etics  a n d  efficac y  d ata  f or  p e diatric  p atie nts  will  b e  p erf or m e d  t o  e v al u ate  t h e safet y 
a n d efficac y  of N T Z i n t his p o p ulati o n.  
 
•  
C h oice  of  P atie nt - Re p orte d  O utc o m e  I nstr u m e nt .  T his  cli nic al  trial  will  us e  a n e w,  re c e ntl y  rele ase d 
p atie nt -re p orte d  o utc o m e  q u esti o n n aire,  I n F L U e n z a  P atie nt-R e p orte d  O utc o m e  Q u esti o n n aire  ( F L U -
P R O © ).  
 
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 vic es t hr o u g h 
t h e  N ati o n al  C a n cer  I nstit ute  a n d  t h e  N ati o n al  I nstit utes  of  Aller g y  a n d  I nfe cti o us  Dise ases,  N ati o n al 
I nstit utes  of  H ealt h,  in  res p o nse  t o  t h e  n e e d  f or  i m pr o v e d  m etrics  t o  e v al u ate  tre at m e nt  effe ct  i n  c li nic al 
trials  of  dr u gs  f or  treat m e nt  of  i nfl u e n z a. It w as  d e v el o p e d  a n d  v ali d ate d  i n  a c c or d a n c e  wit h  F D A’s 
g ui d a n ce,  “ P atie nt -R e p orte d  O utc o m e  M e as ures:  Us e  i n  M e dic 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 Clai ms.” It h as als o b ee n v ali d ate d f or us e o n a n ele ctr o nic d e vic e as p art of a n ele ctr o nic diar y 
(“e Diar y ”) t h at ca n ti m e sta m p diar y e ntries t o e ns ure ti m el y re c or di n g, t h ere b y miti g ati n g ris ks of re c all 
bias.   W e will use a n electr o nic diar y f or t his cli nic al trial.  


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
1 7  
 
 
F L U -P R O is d esi g n e d t o c o m pre h e nsi v el y assess t h e prese n c e a n d se v erit y of i nfl u e n z a s y m pt o ms a cr oss 
b o d y  s yste ms.    T h e  q u esti o n n aire  h as  a d dresse d  iss u es  t h at  li mit  i nter pretati o n  of  hist oric al  i nfl u e n z a 
st u dies  b y  i n cl u di n g  e xte nsi v e  i n p ut  fr o m  i nfl u e n z a-i nfe cte d  p atie nts  t o  e ns ure  t hat  ( 1)  all  s y m pt o ms  of 
i nfl u e n za  are  assesse d  (c o nte nt  v ali dit y),  a n d  ( 2)  t h e  q u esti o ns  are  as k e d  i n  a  m a n n er  a n d  wit h  res p o nse 
o pti o ns  t h at  p atie nts  u n d ersta n d  (c o nte xt  v ali dit y)  a n d  t h at  disti n g uis h  b et w e e n  k n o w n  gr o u ps.    T h e 
res ulti n g  i nstr u m e nt  assesses  3 2  s y m pt o ms  of  i nfl u e n z a  a cr oss  si x  d o m ai ns  ( n ose,  t hr o at,  e y es, 
c h est/res pirat or y, g astr oi ntesti n al, b o d y/s yste mic).   E a c h q u esti o n pr o vi d es 5 res p o ns e o pti o ns i nste a d of 4 
use d i n tra diti o n al P R O i nstr u m e nts. 2 5, 2 6 
 
•  
C h oice  of  E n d p oi nts .  T h e  pri m ar y  ef fic 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 nse 
b ase d  u p o n  t h e  F L U -P R O ©  i nstr u m e nt.    T his is  dire cte d  t o  t h e  w a y  t h e  p atie nt “fe el s” as  m e as ure d  b y 
his/ h er  s y m pt o ms.   A  S y m pt o m R es p o nse  d efi niti o n will  b e d e v el o p e d  b ase d  u p o n  a  bli n d e d  re vi e w  of 
F L U -P R O s y m pt o m sc ores ( p o ole d f or all s u bje cts wit h o ut re g ar d t o tre at m e nt gr o u p assi g n m e nt s o as t o 
m ai ntai n  bli n di n g)  a n d  c orrelati o n  of  t h ose  sc ores  t o  t h e  ti m e  at  w hic h  s u bje cts  re p ort  t h at  t h e y  h a v e 
ret ur n e d t o t h eir us u al state of h ealt h (a “ yes” or “ n o ” q u esti o n i n c or p orate d i nt o t h e d ail y Q u esti o n n aire).   
T h e Ti m e t o S y m pt o m R es p o nse use 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 alc ulate d b as e d u p o n 
t his  res p o nse  d efi niti o n  a n d  pr o gra m m e d  pri or  t o  d ata b ase  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 ase d  a p pr o ac h  t o  d efi ni n g  res p o n d ers  e ns ures  t h at  t h e  s y m pt o m  res p o nse  d efi niti o n  is  v ali d  a n d 
m ea ni n gf ul  f or  t h e  s u bjects  p artici p ati n g  i n  e a c h  gi v e n  cli nic al  trial – a  p oi nt  t h at  m a y  b e  p artic ularl y 
i m p orta nt i n t h e case of a n ill n ess li k e i nfl u e n z a t h at is n ot u nif or m fr o m y e ar t o y e ar. 
 
T h e k e y  sec o n d ar y e n d p oi nt will b e Ti m e t o A bilit y t o P erf or m All N or m al A cti vities. T his e n d p oi nt will 
pr o vi d e i m p orta nt i nf or m ati o n wit h res p e ct t o t h e w a y a p atie nt “f u n cti o ns.”   E a c h of t h e pre vi o u s cli nic al 
trials of N T Z i n s u bjects wit h i nfl u e n z a h a v e i n dic ate d i m pr o v e m e nt i n t his e n d p oi nt w hile d ata c olle cti o n 
fr o m t h ose st u dies h as t y picall y n ot e xte n d e d o ut l o n g e n o u g h t o f ull y c h ara cteriz e t h e b e n efit. 
 
A n ot h er  sec o n d ar y e n d p oi nt will b e pr o p orti o ns of s u bje cts e x p erie n ci n g c o m plic ati o ns of i nfl u e n z a.  W e 
d o  n ot  e x p ect  t o  see  e n o u g h  c o m plic ati o ns  of  i nfl u e n z a  i n  t his  p o p ulati o n  t o  d e m o nstrate  differe n c es 
b et w ee n treat m e nt gr o u ps, a n d t h eref ore, t his e n d p oi nt is lesser i n pri orit y c o m p are d t o Ti m e t o A bilit y t o 
P erf or m All N or m al A cti vities.  All o t h er effic a c y e n d p oi nts will b e c o nsi d ere d e x pl orat or y. 
 
 
4  
P A TI E N T S E L E C TI O N  
 
T h e criteria f or i n cl usi o n a n d e x cl usi o n are d efi n e d b el o w:  
 
4. 1  
I n cl usi o n C riteri a 
 
1)  M ale a n d fe m ale s u bjects at least 1 2 y e ars  of a g e   
 
2)  Prese n ce  of  cli nical  si g ns  a n d/ or  s y m pt o ms  c o nsiste nt  wit h  a n  a c ute  ill n ess  c o m p ati ble  wit h  i nfl u e n z a 
i nfecti o n (eac h of t h e f oll o wi n g is re q uire d): 
a) oral te m p erat ure of ≥9 9. 4° F or ≥3 7. 4 ° C (o btai n e d i n offic e  or self -m e as ure d wit hi n 1 2 h o urs pri or t o 
scree ni n g – if  self-m eas ure d,  s u bje ct  m ust  als o  h a v e  ta k e n  a n  a nti p yretic  wit hi n  4  h o urs  pri or  t o 
scree ni n g), A N D  
b)  at least o n e of t h e f oll o wi n g res pirat or y s y m pt o ms ( c o u g h,  s ore t hr o at, n asal o bstr u cti o n), A N D  
c) at least o n e of t h e f oll o wi n g c o nstit uti o n a l s y m pt o ms (fati g u e, h e a d a c h e, m y al gia, fe v eris h n ess). 
 
3)  C o nfir m ati o n of i nfl u e n za A or B i nfe cti o n i n t h e l o c al c o m m u nit y b y o n e of t h e f oll o wi n g m e a ns: (a) t h e 
i nstit uti o n's l o cal la b orat or y, (b) t h e l o c al p u blic h e alt h s yste m , (c) t h e n ati o n al p u blic h e a lt h s yste m, or 
(d) a la b orat or y of a rec o g nize d n ati o n al or m ulti n ati o n al i nfl u e n z a s ur v eilla n c e sc h e m e  


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4)  O nset of ill n ess n o m ore t h a n 4 0 h o urs  b ef ore e nr oll m e nt i n t h e trial   
N ote:  Ti m e of o nset of ill n ess is d efi n e d as t h e e arlier of: 
a) t h e ti m e w h e n t h e te m p erat ure w as first m e as ure d as ele v ate d, O R  
b)  t h e  ti m e  w h e n  t h e  s u bject  e x p erie n c e d  t h e  prese n c e  of  at  le ast  o n e  res pirat or y  s y m pt o m  A N D  t h e 
prese n ce of at least o n e c o nstit uti o n al s y m pt o m . 
 
5)  Willi n g  a n d  a ble  t o  pr o vi d e  writte n  i nf or m e d  c o nse nt  (i n cl u di n g 
asse nt  b y  le g al  g u ar dia n  if  u n d er  1 8 
y ears of a g e) a n d c o m pl y wit h t h e re q uire m e nts of t h e pr ot o c ol, i n cl u di n g c o m pleti o n of t h e p atie nt diar y  
 
4. 2  
E x cl usi o n C riteri a  
 
1)  S e v erit y of ill n ess re q uiri n g or a ntici p ate d t o re q uire i n -h os pital c are  
 
2)  M o d er ate or se v ere  ast h m a  ( Gl o b al I nitiati v e f or Ast h m a ( GI N A) 2 0 1 7 classific ati o n) 
 
3)  C ystic fi br osis  
 
4)  Sta g e II, III  or  I V c hr o nic  o bstr u cti v e  p ul m o n ar y  dise ase  ( C O P D)  ( Gl o b al  I nitiati v e  f or  C hr o nic 
O bstr u cti v e P ul m o n ar y Disease ( G O L D) 2 0 1 7 classific ati o n)  
 
5)  N Y H A Class III o r I V c o n g esti v e h e art fail ure (at le ast m ar k e d li mitati o n of p h ysic al a cti vit y i n w hic h 
mi ni m al or di n ar y acti vit y res ults i n fati g u e, p al pitati o n, d ys p n e a, or a n gi n a p ai n)  
 
6)  C ar diac a rrh yt h mia  
 
7)  Im m u n o l o gic dis or d ers  or  recei vi n g  i m m u n os u p pressi v e  t h era p y   (e. g.,  f or  or g a n  or  b o n e  m arr o w 
tra ns pla nts, i m m u n o m o d ulat or y t h era pies f or c ertai n a ut oi m m u n e dise ases) 
 
8)  U ntreate d HI V i nfecti o n or treate d HI V i nfe 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  last  6 
m o nt hs  
 
9)  P ers o ns wit h sic kle cell a n e mia or ot h er h e m o gl o bi n o p at hies  
 
1 0)  P o orl y c o ntr olle d i ns uli n -d e p e n d e nt dia b etes m ellit us  ( H b A 1 C > 8. 0%)  
 
1 1)  R esi d e nts of a n y a g e of n ursi n g h o m es or ot h er l o n g -ter m c are i nstit uti o ns 
 
1 2)  C o n c urre nt i nfecti o n at t h e scree ni n g e x a mi n ati o n t h at re q uires  s yste mic a nti micr o bial t h era py 
 
1 3)  F e m ales of c hil d b eari n g p ote ntial w h o are eit h er pre g n a nt, bre ast -fe e di n g or are se x u all y a cti v e wit h o ut 
t h e use of birt h c o ntr ol.  F e m ale s u bje cts of c hil d -b e ari n g p ote ntial t h at are se x u all y a cti v e m ust h a v e a 
n e g ati v e b aseli n e pre g n a n c y test a n d m ust  a gre e t o c o nti n u e a n a c c e pta ble m et h o d of birt h c o ntr ol f or t h e 
d urati o n of t h e st u d y a n d f or 1 m o nt h p ost -tre at m e nt.  A d o u ble b arrier m et h o d, oral birt h c o ntr ol pills 
a d mi nistere d  f or  at  least  2  m o nt hl y  c y cles  pri or  t o  st u d y  dr u g  a d mi nistrati o n,  a n  I U D,  or 
m e dr o x y pr o g ester o n e acetate a d mi nistere d i ntra m usc ularl 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 nistrati o n are acce pta ble 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 ale s u bje cts 
are c o nsi d ere d of c hil d b eari n g p ote ntial u nles s t h e y are p ost m e n o p a usal (a bse n c e of m e nstr u al ble e di n g 
f or  1  y ear - or  6  m o nt hs  if  la b orat or y  c o nfir m ati o n  of  h or m o n al  stat us),  or  h a v e  h a d  a  h ystere ct o m y, 
bilateral t u b ular li g ati o n or bilateral o o p h or e ct o m y.  
 
 


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1 4)  R ecei pt  of  a n y  d ose  of  N T Z, oselta mi vir ,  z a n a mi vir, p era mi vir, la ni n a mi vir, b al o x a vir,  a m a nta di n e  or 
ri m a nta di n e wit hi n 3 d a ys pri or t o scre e ni n g  
 
1 5)  Pri or treat m e nt wit h a n y i n v esti g ati o n al dr u g t h era p y wit hi n 3 0 d a ys  pri or t o scre e ni n g  
 
1 6)  S u bjects wit h acti v e res pirat or y aller gies or s u bje cts e x p e cte d t o re q uire a nti -aller g y m e dic ati o ns d uri n g 
t h e st u d y peri o d f or res pirat or y aller gies  
 
1 7)  K n o w n se nsiti vit y t o N T Z or a n y of t h e e x ci pie nts c o m prisi n g t h e N T Z ta blets  
 
1 8)  S u bjects u n a ble t o ta k e oral m e dicati o ns  
 
1 9)  Prese n ce of a n y pre -e xisti n g ill n ess or c o n diti o n t h at, i n t h e o pi ni o n of t h e I n v esti g at or, w o ul d pla c e t h e 
s u bject at a n u nreas o n a bl y i n crease d ris k t hr o u g h p artici p ati o n in t his st u d y  
 
2 0)  S u bjects 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 re q uire m e nts of 
t his pr ot o c ol 
 
 
5  
S T U D Y P R O C E D U R E S  
 
5. 1  
S cree ni n g E v al u ati o n ( d a y 1)  
 
B ef ore scree ni n g, s u bjects a n d t h eir p are nts/ g u ar dia n(s) will b e i nf or m e d o f t h e n at ure of st u d y, a n d writte n 
c o nse nt m ust b e o btai n e d pri or t o p artici p ati o n.  After gi v i n g i nf or m e d c o nse nt, t h e s u bje ct will b e assi g n e d a 
s u bject n u m b er, a n d t h e f oll o wi n g pr o ce d ures will b e c arrie d o ut: 
 
1)  C o m plete m e dical hist or y;  
 
2)  F ull p h ysical 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 vital si g ns ( bl o o d press ure, p ulse , res pirat or y rate 
a n d oral te m p erat ure  usi n g  sta n d ar d ele ctr o nic oral t h er m o m eter pr o vi d e d b y S p o ns or); 
 
3)  C ollect i o n of d e m o gra p hic i nf or m ati o n a n d s m o ki n g hist or y ; 
 
4)  Uri n e pre g n a n c y tes t f or all fe m ales of c hil d b e ari n g p ote ntial; 
 
5)  R ec or d i n g of s y m pt o ms a n d ti m e of o nset; a n d 
 
6)  E v al u ati o n  acc 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) criteria.  
 
W hile n ot re q uire d b y t his st u d y pr ot o c ol, l o c al i nfl u e n z a dia g n ostic testi n g m a y h a v e b e e n  c o n d u cte d pri or t o 
t h e scree ni n g visit i n acc or d a n ce wit h l o c al sta n d ar ds of c are.  R es ults of a n y s u c h l o c al i nfl u e n z a dia g n ostic 
tests will n ot  i m p act s u bject selecti o n.  S u bje cts will b e sele cte d s olel y o n t h e b asis of t h e eli gi bilit y criteria 
set  f orth i n t h e pr ot o c ol irres p ecti v e of t h e res ult of a n y l o c al i nfl u e n z a dia g n ostic test t h at m a y h a v e b e e n 
p erf or m e d.  
 
5. 2  
B aseli n e ( d a y 1, s a m e d a y as scree ni n g e v al u ati o n)  
 
At b aseli n e, t h e f oll o wi n g pr o ce d ures will b e c arrie d o ut:  
 
1)  C ollect i o n of t w o n as o p h ar y n geal 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 
Dia g n ostics) f or R T-P C R a n d c ult ure ; 


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2)  C ollecti o n of bl o o d sa m pl e f or a nti -i nfl u e n z a a nti b o dies; 
 
3)  C ollecti o n  of  bl o o d  sa m ple  f or  la b orat or y  s afet y  tests  i n cl u di n g  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 ceri 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 atase,  bilir u bi n  (t otal/ dire ct),  B U N, 
creati ni n e, s o di u m, p otassi u m, c hl ori d e;  
 
4)  C ollecti o n of a uri n e sa m ple f or r o uti n e uri n al ysis ( gl u c ose, pr otei n  a n d bl o o d);  
 
5)  R e vie w a n d rec or d i n g of a n y c o n c o mita nt m e dic ati o ns; 
 
6)  Pr o visi o n  of  a n  e lectr o nic  diar y  t o  s u bje ct  via  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 vic e,  a n d 
su bject  c o m pleti o n  of  b aseli n e ele ctr o nic diar 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  site 
p ers o n n el ;  
 
7)  R a n d o mizati o n a n d dis p e nsi n g of st u d y m e dic ati o n ( m e dic ati o n assi g n e d i n s e q u e ntial  or d er);  
 
8)  A d mi nistrati o n  of  t h e  f irst  d ose  of  st u d y  m e dic ati o n  wit h  f o o d  ( <  1  h o ur  after  f o od  i nta k e)  u n d er 
o bser 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 staff, a n d e ntr y i n diar y; a n d  
 
9)  I nstr u ct s u bject re g ar di n g: 
 
a. 
A d mi nistr ati o n of st u d y m e dic ati o n .  S u bje cts will b e i nstr u cte d t o ta k e t h e st u d y m e dic ati o n (t w o 
ta blets) t wice d ail y w it h f o o d ( < 1 h o ur after f o o d i nta k e).  T h e p atie nt s h o ul d ta k e his/ h er se c o n d 
d ose  as  cl ose  as  p ossi ble  t o  1 2  h o urs  after  t h e  first  d ose.    T h e n  h e/s h e  will  ta k e  t h e  st u d y 
m e dicati o n e v er y 1 2 h o urs  f or t h e re m ai ni n g 4 d a ys. 
 
b.  C o n c o mit a nt m e dic ati o ns .  S u bje cts will b e i nstr u cte d t h at t h e y m a y ta k e a c eta mi n o p h e n  f or fe v er 
if t h eir oral te m p erat ure  is ≥1 0 0. 4° F (3 8° C ).  N o ot h er s y m pt o m relief m e dic ati o n s h o ul d b e us e d.  
 
c. 
C o m pleti o n of p atie nt di ary .  S u bje cts will b e i nstr u cte d o n c o m pleti o n of  t h e ele ctr o nic  diar y.  
 
d.  Use  of  birt h  c o ntr ol .    F e m ale s u bje cts of  c hil d b e ari n g  p ote ntial,  if  se x u all y  a cti v e,  w ill  b e 
i nstr u cte d t o c o nti n u e a n ac c e pta ble m et h o d of birt h c o ntr ol f or t h e d urati o n of t h e st u d y a n d f or 1 
m o nt h p ost -treat m e nt.  A cc e pta ble m et h o ds of birt h c o ntr ol i n cl u d e a d o u ble b arrier m et h o d, oral 
birt h c o ntr ol pills, a n I U D, or m e dr o x y pr o g ester o n e  a c etate a d mi nistere d i ntra m usc ularl y.  
 
e. 
F oll o w -u p visits : P atie nts will b e i nstr u cte d t o ret ur n t o t h e cli nic f or f oll o w-u p o n d a y 7  a n d d a y 
2 2. 
 
f. 
S eeki n g e m er g e n cy c are or c o nt a cti n g t h e st u d y p h ysici a n or n urse : S u bje cts m ust b e i nf or m e d t o 
see k  e m er g e n cy  m e dical  care  or  c o nta ct  t h e  st u d y  p h ysicia n  or  n urse  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 liste 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 nite d States) 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 nite d States) 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 ble breat hi n g i n cl u di n g s h ort n ess of bre at h.   
•  
S e v ere h ea d ac h e, stiff n e c k, c o nf usi o n or e x c essi v e s o m n ole 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 xtre m el y hi g h fe v er > 1 0 4° F ( 4 0° C) .  


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•  
F e v er ( ≥1 0 0. 4° F or ≥3 8° C) lasts f or l o n g er t h a n 3 d a ys.   
•  
I n crease d diffic ult y breat hi n g.  
•  
W h eezi 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 aliz es t o o n e are 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 uses.   
•  
S y m pt o ms b ec o m e m ore se v ere or fre q u e n t.  
•  
F e v er ( ≥1 0 0. 4° F or ≥3 8° C) ret ur ns after b ei n g a bse nt f or 2 4 h o urs.  
•  
S y m pt o ms rec ur or a n y diffic ult y bre at hi n g f oll o wi n g 5 -1 0 d a ys res ol uti o n of i nfl u e n z a.  
•  
A n aller gic -li k e reacti o n o c c urs or is s us p e cte d 
•  
A b n or m al b e h a vi or  
 
1 0 ) R e vie w a n d rec or d a d v er se e v e nts.  
 
5. 3  
D a y 2 – D a y 2 2 
 
A st u d y p h ysicia n, n urse or ot h er site p ers o n n el  will re vie w e a c h s u bje ct ’s ele ctr o nic diar y  e ntries  d ail y  t o 
e ns ure c o m plia n ce wit h c ollecti o n of diar y d ata.   If a s u bje ct h as n ot c o m plete d his/ h er diar y or if err ors are 
s us p ecte d, t h e st u d y p ers o n n el will c o nta ct t h e s u bje ct t o i m ple m e nt a p pr o priate c orre cti v e a cti o ns.  
 
5. 4  
D a y 2 -5 T ele p h o n e M o nit o ri n g  
 
A st u d y p h ysicia n, n urse or ot h er site p ers o n n el will m a k e d ail y tele p h o n e c alls t o s u bje cts o n e a c h of d a ys 2, 
3,  4  a n d  5  of  d os i n g  t o  re vie w c o m plia n c e  wit h  st u d y  m e dic ati o n,  re vie w s y m pt o ms, scre e n  f or  i nfl u e n z a-
relate d  c o m plicati o ns  i n cl u di n g  si n usitis,  otitis,  br o n c hitis,  p n e u m o nia, c e ntral  n er v o us  s yste m  dise ase  a n d 
w orse ni n g  of  pre -e xisti n g  h ealt h  c o n diti o ns ,  a n d  re vie w a d v er se  e v e nts.  S u bje cts  will  b e  referre d  f or 
i m m e diate care as n ee d e d b ase d o n t h e scre e ni n g. All i nf or m ati o n g ai n e d fr o m tele 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 case re p ort f or ms f or ea c h s u bje ct.  [ N ote: I n lie u of a tele p h o n e c all, t his i nf or m ati o n m a y b e  
o btai n e d d uri n g t h e d a y 2 a n d 3 h o m e or offic e visits (se 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 ysicia n, n urse or ot h er st u d y p ers o n n el  will visit e a c h s u bje ct  at h o m e ( or at t h e cli nic or a n ot h er 
l o cati o n  as  a gree d  wit h  t h e s u bject)  o n  e a c h  of d a ys  2  a n d 3 t o (i) c olle ct  t w o  n as o p h ar y n g e al  s w a bs  f or 
d etecti n g ( R T-P C R) a n d q u a ntif yi n g ( T CI D5 0) i nfl u e n z a  vir us, a n d  (ii )  re vie w  s y m pt o ms  a n d  scre e n  f or 
i nfl u e n za-relate d  c o m plicati o ns  i n cl u di n g si n usitis,  otitis,  br o n c hitis,  p n e u m o nia, c e ntral  n er v o us  s yste m 
disease a n d w orse ni n g of pre -e xisti n g h e alt h c o n diti o ns as w ell as a d v erse e v e nts.  S u bje cts will b e referre d 
f or  i m m e diate  care  as  n ee d e d  b ase d  o n  t h e  scre e ni n g.  All  i nf or m ati o n  g ai n e d  fr o m  t h e se visit s will  b e 
i n cl u d e d i n t h e case re p ort f or ms f or ea c h s u bje ct.  I n a d diti o n, a bl o o d sa m ple f or p h ar m a c o ki n etics will b e 
c ollecte d  o n  d a y  3.    T h e d a y  2  a n d  d a y  3  visit s will  o c c ur at  a p pr o xi m atel y  t h e  sa m e  ti m e  of  d a y  t h at  t h e 
p atie nt t o o k his/ h er first d ose of st u d y m e dic ati o n  (a p pr o xi m atel y 2 4 a n d 4 8 h o urs after t h e first d ose) .  O n 
d a y 3, t h e bl o o d sa m ple f or p h ar m ac o ki n etics will b e c olle cte d b ef ore t h e first d ose  of t h at d a y . 
 
St u d y sites or s u bjects m a y o pt o ut of t h ese d a y 2 a n d d a y 3 visits d u e t o site staffi n g, p atie nt a v aila bilit y or 
ot h er  practical  c o nsi d erati o ns  or  prefere n c es;  n e v ert h eless  at  le ast  7 5 %  of  s u bje cts  e nr olle d  i n  t h e  trial  are 
e x p ecte d  t o  c o m plete  t h e  d a y  2  a n d  d a y  3  visits  a n d  relate d  pr o c e d ures  (f or  viral  ki n etics  a n d 
p h ar m ac o ki n etics).  
 
 
5. 6  
D a y 7 F oll o w -u p  ( +/- 1 d a y)  
 
S u bjec ts will ret ur n t o t h e cli nic o n d a y 7, a n d t h e f oll o wi n g pr o c e d ures will b e p erf or m e d:  
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
2 2  
 
1)  P h ysical e x a mi n ati o n.  Brief p h ysic al e x a mi n ati o n ( b o d y w ei g ht a n d vital si g ns wit h n ursi n g p h ysic al 
assess m e nt)  i n cl u di n g  s y m pt o m  dire cte d  p h ysicia n  p h ysic al  e x a mi n ati o n  as  re q uire d  b y  p atie nt 
s y m pt o ms. Vital  si g ns  will  i n cl u d e  bl o o d  press ure,  p ulse ,  res pirat or y  rate a n d  oral  te m p erat ure  ( use 
sta n d ar d electr o nic oral t h er m o m eter pr o vi d e d b y S p o ns or); 
 
2)  C ollect i 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 Dia g n ostics)  f or R T-
P C R a n d c ult ure ; 
 
3)  C ollect i o n  of bl o o d  sa m ple  f or  la b orat or y  safet y  tests  i n cl u di n g  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 ceri des,  al b 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/ dire ct),  B U N, 
creati ni n e, s o di u m, p otassi u m, c hl ori d e;  
 
4)  C ollect i o n of uri n e sa m ple f or r o uti n e uri n al ysis ( gl u c ose, pr otei n a n d bl o o d) ; 
 
5)  R e vie w of c o m plia n ce  wit h  st u d y  m e dic ati o n,  c olle ct io n  of  m e dic ati o n  b ottle  wit h  a n y  u n use d 
m e dicati o ns , a n d c o m pleti o n of t h e pill c o u nt l o g f or m; 
 
6)  R e vie w a n d rec or d i n g of c o n c o mita nt m e dic ati o ns; a n d  
 
7)  R e vie w a n d rec or d i n g of a d v erse e v e nts/si d e effe cts.  
 
5. 7  
D a y 2 2 F oll o w -u p  ( + 3 d a ys)  
 
S u bjects will ret ur n t o t h e cli nic o n d a y 2 2 , a n d t h e f oll o wi n g pr o c e d ures will b e p erf or m e d: 
 
1)  P h ysical e x a mi n ati o n. Brief p h ysic al e x a mi n ati o n ( b o d y w ei g ht a n d vital si g ns wit h n ursi n g p h ysic al 
assess m e nt)  i n cl u di n g  s y m pt o m  dire cte d  p h ysicia n  p h ysic al  e x a mi n ati o n  as  re q uire d  b y  p atie nt 
s y m pt o ms. Vital  si g ns  will  i n cl u d e  bl o o d  press ure ,  p ulse,  res pirat or y  rate a n d  oral  te m p erat ure  ( use 
sta n d ar d electr o nic oral t h er m o m eter pr o vi d e d b y S p o ns or); 
 
2)  C ollect i 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 Dia g n osti cs)  f or R T-
P C R a n d c ult ure (t o b e teste d f or prese n c e of vir us o nl y if t h e sa m ple c olle cte d at t h e pre c e di n g ti m e 
p oi nt h a d d etecta ble vir us);  
 
3)  C ollecti o n of bl o o d sa m ple f or a nti -i nfl u e n z a a nti b o dies; 
 
4)  R e vie w a n d rec or di n g of c o n c o mita nt m e dic ati o ns; a n d  
 
5)  R e vie w a n d rec or d i n g of a d v erse e v e nts/si d e effe cts.  N ote t h at 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 res ol uti o n or sta bilizati 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 nsc h e d ule d Visit  
 
S u bjects ret ur ni n g to t h e cli nic f or a n u nsc h e d ule d visit d u e t o w orse ni n g s y m pt o ms or a d v erse e v e nts will b e 
e v al u ate d at t h e discreti o n of t h e I n v esti g at or as is m e dic all y w arra nte d.  T ests a n d/ or pr o c e d ures p erf or m e d 
at t his visit m a y i n cl u d e, b ut are n ot li mite d t o t h e f oll o wi n g.  
 
1)  P h ysical e x a mi n ati o n. Brief  p h ysic al e x a mi n ati o n ( b o d y w ei g ht a n d vital si g ns wit h n ursi n g p h ysic al 
assess m e nt)  i n cl u di n g  s y m pt o m  dire cte d  p h ysicia n  p h ysic al  e x a mi n ati o n  as  re q uire d  b y  p atie nt 
s y m pt o ms. Vital  si g ns  will  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 er at ure ( use 
sta n d ar d electr o nic oral t h er m o m eter pr o vi d e d b y S p o ns or); 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
2 3  
 
 
2)  C ollect i 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 Dia g n ostics) f or R T-
P C R a n d c ult ure ; 
 
3)  C ollect i o n  of bl o o d  sa m ple  f or  la b orat or y  safet y  tests  i n cl u di n g  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 ceri 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 atase,  bilir u bi n  (t otal/ dire ct),  B U N, 
creati ni n e, s o di u m, p otassi u m, c hl ori d e;  
 
4)  C ollect i o n of uri n e sa m ple f or r o uti n e uri n al ysis ( gl u c ose, pr otei n  a n d bl o o d);  
 
5)  R e vie w of c o m plia n ce wit h st u d y m e dic ati o n;  
 
6)  R e vie w a n d rec or d i n g of c o n c o mita nt m e dic ati o ns; a n d  
 
7)  R e vie w a n d rec or d i n g of a d v erse e v e nts/si d e effe cts.  
     
5. 9  
St u d y Disc o nti n u ati o n  
 
R ules f or disc o nti n u ati o n of a p atie nt or f or dis c o nti n ui n g t h e st u d y are pr o vi d e d i n s e cti o n 1 1. 2 .  All s u bje cts 
disc o nti n u e d  fr o m  t h e  st u d y  b ef ore  d a y  7  will  b e  e v al u ate d  at  st u d y  disc o nti n u ati o n  usi n g  t h e  pr o c e d ures 
d escri b e d a b o v e f or d a y 7.  All s u bjects dis c o nti n u e d fr o m t h e st u d y after d a y 7 will b e e v al u ate d at st u d y 
disc o nti n u ati o n usi n g t h e pr o ce d ures d escri b e d a b o v e f or d a y 2 2 .  
 
5. 1 0  
Electr o nic S u bject  Di a r y  
 
Electr o nic s u bject  diaries will b e c o m plete d t wic e d ail y t hr o u g h d a y 2 1 .  T h e e le ctr o nic diaries will c a pt ure 
t h e f oll o wi n g i nf or m ati o n: 
 
1)  M e dicati o n i nta k e  (t wice d ail y at ti m e of m e dic ati o n i nta k e ). 
 
2)  O ral te m p erat ure (t wice d ail y at ti m e of m e dic ati o n i nta k e ).  U se sta n d ar d ele ctr o nic oral t h er m o m eter 
pr o vi d e d b y S p o ns or.  Oral te m p erat ure s h o ul d, prefera bl y, b e re c or d e d pri or t o a c eta mi n o p h e n  d osi n g 
or greater t h a n 4 h o urs after aceta mi n o p h e n  d ose.  
 
3)  Use  of  ot h er  m e dicati o ns  ta k e n  (i n cl u di n g a c eta mi n o p h e n ) b y  t h e  s u bje ct  n ot  pre vi o usl y  c a pt ure d  i n 
t h e s u bject’s m e dicati o n hist or y.  D o c u m e nt i n d etail i n cl u di n g d ose i n milli gra ms or ot h er a p plic a ble 
u nits , ti m e of i n g esti o n, a n d t h e re as o n f or use of t h e m e dic ati o n (at ti m e of m e dic ati o n i nta k e).  
 
4)  F L U -P R O Q u esti o n n aire ( o n ce d ail y b et w e e n 7 p m a n d 1 1 p m ) t o c h ara cteriz e s y m pt o ms of i nfl u e n z a.   
 
5)  A cti vit y assess m e nt usi n g a n 1 1 -p oi nt vis u al a n al o g sc ale ( 0 = u n a ble t o p erf or m n or m al a cti vit y, 1 0 = 
f ull y a ble t o p erf or m n or m al acti 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 erse e x p erie n ces  ( o n ce 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 Vir ol o g y T esti n g  a n d M o nit o ri n g R esist a n c e  
 
I n a n eff ort t o m o nit or p ote ntial resista n c e t o tiz o x a ni d e d uri n g st u d y R M 0 8-3 0 0 4 , t h e f oll o wi n g pr o c e d ures 
will b e p erf or m e d:  
 
1)  C ollecti o n of sa m ples : 
T w o n as o p h ar y n g eal s w a bs will b e c olle cte d fr o m e a c h p atie nt at B aseli n e ( d a y 1)  a n d  d a ys 2, 3,  7 a n d 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
2 4  
 
2 2. 
 
2)  T esti n g of bi ol o gical sa m ples  
a. 
E ac h B aseli n e sa m ple will b e s u bje cte d t o: ( 1) c ult ure t o d ete ct i nfl u e n z a A a n d B, ( 2) R T-P C R 
usi n g t h e e Ple x ®  R es pirat 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 ete ct  i nfl u e nz a  A 
( n o n-s p ecific 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; res pirat or y 
s y n c ytial  vir us A  a n d  B ( R S V);  p arai nfl u e n z a  1,  2,  3  a n d  4; h u m a n  m eta p n e u m o vir us  ( h M P V); 
a d e n o vir us  ( A-F) ; h u m a n r hi n o vir us/e nter o vir us;  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; 
C hl a m y d o p hil a p n e u m o ni a e ; 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 bject’s  B aseli n e  sa m ple  is  n e g ati v e  f or  i nfl u e n z a  b y R T -P C R,  his/ h er  d a y  2  a n d  d a y  3 
sa m ples  will  b e  s u bjecte d t o R T -P C R  usi n g  t h e e Ple x ®  R es pirat or y  P at h o g e n  P a n el t o  d ete ct 
res pirat or y p at h o g e ns. 
c. 
If t h e B aseli n e sa m ple or t h e d a y 2 or d a y 3  sa m ple is p ositi v e f or i nfl u e n z a A or i nfl u e n z a B, t h e 
B aseli n e sa m ple a n d eac h of t h e d a y 2 a n d 3  sa m ples will b e s u bje cte d t o T CI D 5 0 t o q u a ntif y  viral 
s h e d di n g. 
d.  D a y 7 sa m ples will b e  s u bje cte d  t o  c ult ure  a n d  R T-P C R usi n g  t h e e Ple x ®  R es pirat or y P at h o g e n 
P a n el .  All  sa m ples  p ositi v e  f or  i nfl u e n z a  A  or  i nfl u e n z a  B  will  als o  b e  s u bje cte d  t o  T CI D 5 0 t o 
q u a ntif y  viral s h e d di n g.  
e. 
D a y 2 2 sa m ples will b e s u bje cte d t o c ult ure a n d R T-P C R usi n g t h e  e Ple x ®  R es pirat or y P at h o g e n 
P a n el o nl y  if  t h e  sa m ple  c olle cte d  at  t h e  pre c e di n g  ti m e  p oi nt  ( d a y  7)  h a d  d ete cta ble  i nfl u e n z a 
vir us.    All  sa m ples  p ositi v e  f or  i nfl u e n z a  A  or  i nfl u e n z a  B  will  als o  b e  s u bje cte d  t o  T CI D 5 0 t o 
m eas ure viral s h e d di n g.  
 
3)  Dr u g s usce pti bilit y testi n g  
a. 
If a n y d a y 7 or d a y 2 2 sa m ple is p ositi v e f or i nfl u e n z a A or i nfl u e n z a B b y c ult ure, t h e vir us will 
b e is olate d a n d teste d f or s usc e pti bilit y t o tiz o x a ni d e ( T CI D 5 0).   
b.  T h e  B aseli n e  is olate  f or  s u bje cts  wit h  vir us  c ult ure d  at d a y  7  or 2 2  w ill  als o  b e  teste d  f or 
s usce pti bilit y t o tiz o x a ni d e, a n d t h e res ults will b e c o m p are d t o t h e res ults o bser v e d f or t h e d a y 7 
or 2 2 is olate. 
 
4)  N u cle oti d e se q u e n ci n g  
a. 
All d a y 7 or 2 2 sa m ples wit h re d u c e d s usc e pti bilit y (I C 5 0 > 2 x I C 5 0 at B aseli n e) or resista n c e (I C5 0 
≥1 0 x  I C 5 0 at  B aseli n e)  t o  tiz o x a ni d e  will  b e  s u bje cte d  t o  h e m a g gl uti ni n  a n d  n e ura mi ni d ase 
n u cle oti d e  se q u e n ci n g.    T h e  c orres p o n di n g  B aseli n e  sa m ple  will  als o  b e  s u bje cte d  t o 
h e m a g gl uti ni n  a n d  n e ura mi ni d ase  n u cle oti d e  se q u e n ci n g.    I nitial  g e n ot y pic  assess m e nts  of 
resista n ce t o tiz o x a ni d e will f o c us o n is olates dis pla yi n g t h e lar g est s hifts i n s usc e pti bilit y. 
b.  S e q u e n ci n g d ata f or d a y 7 or 2 2 is olates wit h re d u c e d s usc e pti bilit y or resista n c e t o tiz o x a ni d e will 
b e  c o m p are d  t o  se q u e n ce  d ata  f or  t h e  B aseli n e  sa m ple  t o  i d e ntif y  m utati o ns  t h at  m a y  c o nfer 
resista n ce. 
 
5)  St ora g e  of  sa m ples:  All  sa m ples  c olle cte d  d uri n g  t h e  st u d y  will  b e  st ore d  f or  at  le ast  2  y e ars  f or 
p ote ntial f ut ure testi n g.  
 
6)  Cli nical Vir ol o g y L a b orat or y:    
 
  
 
5. 1 2  
P re g n a n c y  
 
F ertilit y a n d re pr o d u cti o n st u dies i n a ni m als h a v e re v e ale d n o e vi d e n c e of i m p aire d fertilit y or h ar m t o t h e 
fet us d u e t o N T Z.  T h ere are, h o w e v er, n o a d e q u ate a n d w ell c o ntr olle d st u dies  of fertilit y or re pr o d u cti o n i n 
h u m a ns.  All p re g n a n cies i n cl u di n g t h ose of p art n ers of m ale s u bje cts i n cl u d e d i n t h e st u d y will b e re p orte d 
b y t h e i n v esti g ati o n al staff wit hi n 2 4 h o urs  of t h eir k n o wle d g e of t h e e v e nt usi n g a pre g n a n c y re p orti n g f or m. 


The Romark Institute for Medical Research 
6 
RANDOMIZATION 
Protocol RM0S-3004 Final v. 1.5 
Janua1y 3. 2019 
An independent third party 
will prepare a master randomization list and maintain the 
masking of the study. Randomization will be performed using permuted block randomization. Blocks of 
masked study medication will be assigned to each Investigator. Each Investigator will then assig n  treatment 
numbers to subjects who qualify for the study using centralized randomization procedures strntified by time 
since symptom onset for each subject (:S:24 hours, > 2 4 - 36 hours, and >36 hours). The treatment numbers will 
appear on the bottles containing the masked study medication. The randomization list will be masked to study 
participants including Sponsor, Investigators, study monitors, subjects and laboratory personnel. Unmasking 
for any individual patient will occur only if necessitated by emergency and knowledge of the medication being 
tak en will influence the medical management of the subject. Furthermore, if the event warrants submission of 
an IND Safety Report, then the subject will be unmasked for completion of the report. 
7 
DATA MANAGEMENT 
7.1 
Electr·onic Data Enh-y 
- - - i s
a source data collection solution that will allow the site staff to record subject data on 
 ch-iven 
source forms by using tablets provided by - - - - -
Its purpose is to 
eliminate the need for data transcription into a traditional electronic case  
to allow both real-
tin1e access to source data by authorized Sponsor personnel and real-time edit checks. 
111111111111111 is a mobile application for the capture of patient-repor1ed outcomes (PROs). Study 
 owed 
to use 
011 their own smartphones or a provisioned device 
provided by 
. in order to record PROs, concomitant medications and adverse events (in the 
form of an electronic subject dia r y) and to receive personalized study-specific reminders and education. 
- - - -
is the - -
web portal. It delivers real-time access to source data, and enables 
personn y 
review, clean and analyze study data. 
The site staff will u s e - - - - - a s
they meet with study subjects and perform study procedw-es. 
Computerized data cle e 
'used in addition to manual review including listings review, to 
check for discrepancies and to ensure consistency and completeness of the data. 
The responsible study monitor(s) will verify data, which can be performed remotely or at the clinical study 
site. The Investigator will ensw-e that the data recorded are accw-ate and complete. 
Queries emerging during data cleaning will be generated by data management or clinical research associates 
in - - - -
. The Investigator or his/her desig nee will answer the queries and update the sow-ce 
da  
Adverse events will be coded by data management using the latest version of the Medical Dictionaiy for 
Regulatory Activities (MedDRA); medications will be coded by data management using the latest version of 
the World Health Organization (WHO) DRUG dictionaiy. 
After the Last Subject Last Visit (LSL V) has taken place, the database will be cleaned as necessary. As soon 
as the database is considered clean, it will be locked. The locked database will be used in the final statistical 
25 
CONFIDENTIAL 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
2 6  
 
a n al ysis f or st u d y re p orti n g.  M eas ures will b e u n d erta k e n t o pr ote ct s u bje ct d ata h a n dle d d uri n g i ns p e cti o ns 
a g ai nst discl os ure t o u n a ut h orize d t hir d p arties.  S u bje ct c o nfi d e ntialit y will b e m ai ntai n e d at all ti m es.  
 
All  l isti n gs,  s u m m aries  a n d  a n al yses  will  b e  pr o d u c e d  usi n g  S A S  Statistic al  S oft w are  ( S A S  I nstit ute,  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 viati 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, re p orte d t o t h e i nstit uti o n al re vie w b o ar d (I R B) 
as  a p pr o pria te,  a n d  als o  re vie w e d  b y  t h e  assi g n e d  cli nic al  rese arc h  ass o ciate  ( C R A). D e viati o ns  will  b e 
re p orte d i n t h e electr o nic d ata ca pt ure s yste m. E a c h d e viati o n  will b e classifie 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 viati o n : 
A d e viati o n t h at h as a n i m p a ct o n s u bje ct s afet y, m a y s u bsta ntiall y alter ris ks 
t o s u bje cts, m a y h a v e a n effe ct o n t h e i nte grit y of t h e st u d y d ata, or m a y affe ct 
t h e s u bje ct’s willi n g n ess t o p artici p ate i n t h e st u d y  
Mi n or pr ot o c ol d e viati o n:  
All ot h er p r ot o c ol d e viati o ns. 
7. 3  
D at a Q u alit y Ass u r a n ce  
 
T h e acc urac y a n d relia bilit y of t h e st u d y d ata will b e ass ure d b y t h e s ele cti o n of q u alifie d I n v esti g at ors a n d 
a p pr o priate st u d y ce nter s, re vie w of pr ot o c ol pr o c e d ures wit h t h e I n v esti g at or a n d ass o ciate 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 dic  m o nit ori n g  visits  b y  t h e S p o ns or .  Writte n  i nstr u cti o ns  will  b e  pr o vi d e d  f or 
c ollecti o n, pre p arati o n, a n d s hi p m e nt of sa m ples.  
 
T h e  m o nit or  will  re vie w  t h e  s o urce  d ata  f or  a c c ura c y  a n d  c o m plete n ess,  a n d a n y  discre p a n c ies  will  b e 
res 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 priate.  
 
T h e S p o ns or will b e e ntitle d t o i ns p ect a n d a u dit t h e fa cilities us e d i n t h e cli nic al a n d la b orat 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 mize d c o pies of all t h e d ata files p e rtai ni n g t o t h e st u d y.  Si milar pr o ce d ures 
m a y  als o  b e  c o n d u cte d  b y  a g e nts  of  a n y  re g ulat 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 plia n c e 
pr o gra m or t o re vie w t h e res ults of t his st u d y i n s u p p ort of a re g ulat or y s u b missi o n.   T h e I n v esti g at or s h o ul d 
i mm e diatel 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 nta cte d b y a re g ulat 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 ecti o n. 
 
 
8  
S T A TI S TI C A L C O N SI D E R A TI O N S  
 
8. 1  
S a m ple Size C alc ul ati o n  
 
As d escri b e d i n secti o n 7. 3 b el o w, t h e S y m pt o m R es p o nse d efi niti o n f or t his st u d y will  b e d eri v e d fr o m  t h e 
s u bjects’ F L U -P R O  q u esti o n n aire  res p o nses.   T h e  F L U -P R O -d eri v e d  e n d p oi nt  is  e x p e cte d  t o  tra c k  v er y 
cl osel y  t o  ret ur n  t o  us u al  h ealt h  stat us  (a  d ail y  y es/ n o  q u esti o n  i n  t h e  F L U -P R O  q u esti o n n aire ).   P atie nt -
re p orte d o utc o m es f or ti m e t o ret ur n t o us u al h e alt h stat us h a v e  b e e n s h o w n t o tra c k v er y cl osel y wit h  ti m e t o 
a bilit y t o p erf or m 1 0 0 % of us u al acti vities. 2 7, 2 8 , 29  W e ass u m e , t h eref ore, t h at t h e c u m ulati v e  distri b uti o ns of 
ti m e  t o S y m pt o m  R es p o nse f or  t h e  pla c e b o tre at m e nt  gr o u p will cl osel y  refle ct  hist oric al  d ata (R o m ar k 
st u dies  R M 0 8-3 0 0 2  a n d  R M 0 8 -3 0 0 3 a n d  oselta mi vir  st u dies  W V 1 5 6 7 0  a n d  W V 1 5 6 7 1 ) f or  ti m e  fr o m  first 
d ose u ntil t h e s u bjects re p ort t h at t h e y are a ble t o p erf or m 1 0 0 % of us u al a cti vities .  B as e d u p o n d ata fr o m 
R o m ar k st u dies R M 0 8 -3 0 0 1, R M 0 8 -3 0 0 2 a n d R M 0 8 -3 0 0 3 , w e ass u m e t h at tre at m e nt wit h N T Z s h o ul d res ult 
i n re d u cti o n of at least 4 0 h o urs i n m e dia n ti m e t o s y m pt o m res p o nse wit h differe n c es b ei n g less at t h e first 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
2 7  
 
q u artile  a n d  greater  at  t h e  t hir d  q u artile .   B as e d  u p o n  t his  hist oric al  d ata,  t h e  f oll o wi n g  c ur v es h a v e  b e e n 
d e v el o p e d f or d eter mi ni n g sa m ple size . 
 
 
B ase d u p o n t h ese c ur v es, a  sa m ple size of 5 5 2  s u bje cts wit h la b orat or y -c o nfir m e d i nfl u e n z a (i.e. 2 7 6  f or e a c h 
of  t h e  2  gr o u ps)  will  pr o vi d e  9 0 %  p o w er  t o  d ete ct  a statistic all y  si g nific a nt  differe n c e  i n  t h e  s ur vi v al 
distri b uti o ns b et w ee n N T Z a n d place b o gr o u ps  ( 2-si d e d al p h a of 0. 0 5).  T his c alc ulati o n w as p erf or m e d f or 
t h e  G e h a n  ra n k  test  usi n g  S A S  P R O C  P O W E R  ( S A S  9. 4)  wit h  t h e  c ur v es  s h o w n  a b o v e  ( pr o p orti o n  n ot 
rec o v eri n g b y t h e e n d of eac h d a y w as use d as i n p ut) a n d c e ns ori n g at d a y 2 1 ( h o ur 5 0 4).  Ass u mi n g t h at 8 % 
of s u bjects will h a v e i n c o m plete d ata, w e arri v e at a sa m ple siz e of 6 0 0 s u bje cts i n t otal, 3 0 0 p er tre at m e nt 
gr o u p  t o yiel d at least a p pr o xi m atel y 5 5 0 wit h c o m plete d ata (all 6 0 0 s u bje cts will b e i n cl u d e d i n t h e pri m ar y 
a n al ysis wit h s u bjects wit h i n c o m plete d ata c e ns ore d as of t h eir last e ntr y) . 
 
B ase d u p o n t h ese calc ulati o ns, t h e st u d y will e nr oll at le ast 6 0 0  s u bje cts wit h la b orat or y-c o nfir m e d i nfl u e n z a 
u p  t o  a  m a xi m u m  of  7 0 0  s u bjects  wit h  la b orat or y-c o nfir m e d  i nfl u e n z a.    W e  esti m ate  t h at  t his  will  re q uire 
e nr oll m e nt of 8 0 0  t o 1, 2 0 0  s u bjects i n t otal ass u mi n g a fl u-p ositi v e rate b et w e e n 5 0 % a n d 7 5 %.  
 
8. 2  
Effic a c y V a ri a bles  
 
Pri m ar y Efficac y P ara m eter:  
Ti m e fr o m first d ose u ntil Sy m pt o m R es p o nse   
 
S ec o n d ar y Efficac y P ara m eters:  
i. 
Ti m e  fr o m  first  d os e  u ntil  s u bje cts  are  a ble  t o  p erf or m  1 0 0 %  of 
n or m al a cti vities (i.e., a sc ore of 1 0 o n t h e sc ale of 0 -1 0)  
 
ii. Pr o p orti o ns of s u bje cts e x p erie n ci n g o n e or m ore c o m plic ati o ns of 
i nfl u e n z a  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, 
w ors e ni n g of pre -e xisti n g h e alt h c o n diti o ns, s yste mic a nti bi otic use 
f or i nfe cti o ns se c o n d ar y t o i nfl u e n z a i nfe cti o n, h os pitaliz ati o n d u e 
t o i nfl u e n z a or c o m plic ati o ns of i nfl u e n z a a n d d e at h  
 
iii. Ti m e  t o  
S y m pt o m  
R es p o ns e 
e x cl u di n g  t h e  
F L U -P R O 
G astr oi ntesti n al a n d E y e d o m ai ns  
 
E x pl orat o r y Efficac y P ara m eters: 
i. 
Ti m e t o I n di vi d u al S y m pt o m R es p o nse 
ii. Ti m e t o F L U -P R O D o m ai n R es p o ns e  
iii. Ti m e t o R es ol uti o n of A c ute F e brile I ll n ess 
iv.  Ti m e t o R et ur n t o U s u al H e alt h  


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
2 8  
 
v.  C h a n g e i n i nfl u e n z a vir us titer ( T CI D 5 0) fr o m b aseli n e t o d a y 2 a n d 
fr o m b aseli n e t o d a y 3 
vi.  Pr o p orti o ns  of  s u bje cts wit h  vir us  d ete cte d  i n  n as o p h ar y n g e al 
s w a bs c olle cte d at e a c h of d a y s 2, 3 a n d 7  b y c ult ure a n d b y R T-
P C R  
 
8. 3  
R es p o nse D efi niti o ns  
 
S y m pt o m R es p o nse : 
T o b e d efi n e d b as e d u p o n a bli n d e d re vie w of s y m pt o m s c ores ( p o ole d 
f or  all  i nfl u e n z a-i nfe cte d  s u bje cts  wit h o ut  re g ar d  t o  tre at m e nt  gr o u p 
assi g n m e nt) t h at c orrelate t o t h e ti m e at w hic h s u bje cts re p ort t h at t h e y 
ret ur n  t o  us u al  h e alt h  (a  d ail y  gl o b al  assess m e nt  q u esti o n).  
M et h o d ol o g y  f or  t h e  c orrelati o n  will  b e  d efi n e d  i n  t h e  Statistic al 
A n al ysis  Pla n.   S y m pt o m  sc ores  m ust  b e  m ai ntai n e d  at  t h e  d efi n e d 
le v el  f or  at  le ast  2  d ail y  diar y  p eri o ds wit h o ut  a n y  s y m pt o m  relief 
m e dic ati o n d uri n g t h ose 2 d ail y diar y p eri o ds. 
 
Ti m e of S y m pt o m R es p o nse : 
T h e start of t h e first d ail y diar y  p eri o d i n w hic h S y m pt o m R es p o nse is 
ac hie v e d  a n d  is  m ai ntai n e d  f or  at  le ast 2  d ail y  diar y  p eri o ds  wit h o ut 
a n y s y m pt o m relief m e dic ati o n d u ri n g t h ose 2 d ail y diar y p eri o ds. 
 
Ti m e t o S y m pt o m R es p o nse : 
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 vities:  
S u bje ct  re p orts  a  sc ore  of  1 0  o n  t h e  0 -1 0  sc ale  f or  a bilit y  t o  p erf or m 
n or m al a cti vities, w hic h is m ai ntai n e d  f or at le ast 2 d ail y diar y p eri o ds 
wit h o ut s y m pt o m relief m e dic ati o n d uri n g t h ose 2 d ail y diar 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 vities:  
T h e ti m e  of  t h e  first  d ail y  diar y  e ntr y i n w hic h  t h e  s u bje ct  re p orts  a 
sc ore  of  1 0  o n  t h e  0-1 0  sc ale  f or  a bilit y  t o  p erf or m  n or m al  a cti vities, 
w hic h is m ai ntai n e d  f or at le ast 2 d ail y diar y p eri o ds wit h o ut s y m pt o m 
relief m e dic ati o n d uri n g t h ose 2 d ail y diar 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 vities:  
Ti m e ( h o urs)  fr o m  first  d ose 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 vities  
 
I n di vi d u al S y m pt o m R es p o nse: 
F or  e a c h  i n di vi d u al  s y m pt o m  ( n = 3 2),  a  sc ore  of ≤ t h e m a xi m u m 
res p o nse  v al u e  s p e cifie d  i n  t h e  S y m pt o m  R es p o nse  d efi niti o n 
m ai ntai n e d  f or  at  le ast 2  d ail y  diar y  p eri o ds  wit h o ut  s y m pt o m  relief 
m e dic ati o n  d uri n g t h ose 2 d ail y diar 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 nse:  
T h e  start  of  t h e  first d ail y  diar y  p eri o d  i n  w hic h  t h e  I n di vi d u al 
S y m pt o m  R es p o nse  is  a c hie v e d  a n d  is  m ai ntai n e d  f or  at  le ast 2  d ail y 
diar y  p eri o ds  wit h o ut s y m pt o m  relief  m e dic ati o n  d uri n g t h ose  2  d ail y 
diar 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 nse:  
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 nse 
 
F L U -P R O D o m ai n  R es p o nse : 
F or  e a c h  i n di vi d u al d o m ai n  ( n = 6 ), e a c h  ite m  sc ore d ≤ t h e m a xi m u m 
res p o nse  v al u e  s p e cifie d  i n  t h e  S y m pt o m  R es p o nse  d efi niti o n 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
2 9  
 
m ai ntai n e d  f or  at  le ast  2  d ail y  diar y  p eri o ds  wit h o ut  s y m pt o m  relief 
m e dic ati o n d uri n g t h ose 2 d ail y diar y p eri o ds  
 
Ti m e of F L U -P R O D o m ai n   
R es p o nse:  
F or  e a c h  d o m ai n ,  th e  start  of  t h e  first  d ail y  diar y  p eri o d  i n  w hic h  t h e 
F L U -P R O D o m ai n  R es p o ns e is a c hie v e d a n d is m ai ntai n e d  f or at le ast 
2 d ail y diar y p eri o ds wit h o ut s y m pt o m relief m e dic ati o n d uri n g t h ose 2 
d ail y diar 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 nse:  
Ti m e ( h o urs) fr o m first d ose 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 es ol uti o n of A c ute  
F e brile Ill n ess : 
O ral te m p erat ure is re c or d e d b y t h e p atie nt as < 1 0 0. 4° F ( < 3 8 ° C) a n d 
s y m pt o m  sc ores  f or e a c h  of   “b o d y  a c h es  or  p ai ns ” , “ c hills  or 
s hi v eri n g” , “ felt c ol d” , “ felt h ot” a n d “ s w e ati n g” are 0 or 1 a n d re m ai n 
s o t hr o u g h o ut 2 d ail y diar y p eri o ds wit h o ut s y m pt o m relief m e dic ati o n 
d uri n g t h ose 2 d ail y diar y p eri o ds  
 
Ti m e t o R es ol uti o n of   
A c ute F e brile Ill n ess : 
Ti m e ( h o urs) fr o m first d os e t o res oluti o n of a c ute f e brile ill n ess .  
 
R et ur n t o Us u al H ealt h : 
“ Y es”  res p o nse  t o  t h e  d ail y  F L U -P R O  gl o b al  assess m e nt  q u esti o n, 
“ H a v e y o u ret ur n e d t o y o ur us u al h e alt h t o d a y ? ” m ai ntai n e d  f or at le ast 
2 d ail y diar y p eri o ds wit h o ut s y m pt o m relief m e dic ati o n d uri n g t h ose 2 
d ail y d iar y p eri o ds 
 
Ti m e of R et ur n t o Us u al H ealt h:  
T h e ti m e of t h e first d ail y diar y e ntr y i n w hic h Us u al H e alt h is a c hie v e d 
a n d  is  m ai ntai n e d  f or  at  le ast 2  d ail y  diar y  p eri o ds  wit h o ut s y m pt o m 
relief m e dic ati o n d uri n g t h ose 2 d ail y diar y p eri o ds  
 
Ti m e t o R et ur n t o Us u al H ealt 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  
 
8. 4  
St atistic al M et h o d ol o g y  
 
T h e  statistical  m et h o d ol o g y  is  d escri b e d  briefl y  b el o w  a n d  will  b e  d es cri b e d  i n  d etail  i n  t h e S tatistic al 
A n al y sis P la n. 
 
8 . 4. 1 
Effic a c y A n al yses  
 
E fficac y a n al yse s will b e b ase d o n a p o p ulati o n c o nsisti n g of all s u bje cts t h at re c ei v e d at le ast o n e d ose of 
st u d y dr u g a n d h a d la b orat or y-d o c u m e nte d i nfl u e n z a i nfe cti o n  (i nfe cte d i nte nt-t o-tre at or I T TI p o p ulati o n).  
L a b orat or y -d o c u m e nte d  i nfl u e n za  i nfe cti o n  is  d efi n e d  b y  i d e ntific ati o n  of  i nfl u e n z a  vir us  i n 
n as o p h ar y n g eal secreti o ns b y R T -P C R or viral c ult ure at b aseli n e , d a y 2 or d a y 3 .   
 
T h ere will b e o n e pri m ar y efficac y a n al ys is: 
 
•  
Ti m e t o S y m pt o m R es p o nse  f or t h e N T Z tre at m e nt gr o u p will b e c o m p are d t o t h at of t h e pla c e b o 
treat m e nt  gr o u p  usi n g a  stratifie d  G e h a n -Wilc o x o n  test   (a  = 0. 0 5)  stratifie d  b y  ( 1)  ti m e  si n c e 
s y m pt o m  o nset  f or  eac h  s u bje ct  at  e nr oll m ent  ( ≥2 4  h o urs,  > 2 4 – 3 6  h o urs,  > 3 6  h o urs)  a n d  ( 2) 
w h et h er t h e s u bject recei v e d seas o n al i nfl u e n z a v a c ci n ati o n after A u g ust 1, 2 0 1 8 .  S u bje cts wit h o ut a 
S y m pt o m  R es p o nse  b ei n g  rec or d e d  will  b e  tre ate d  as  c e ns ore d  as  of  t h eir  last  diar y  wit h o ut  a 
d o c u m e nte d S y m pt o m R es p o nse.  


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 0  
 
 
If t h e pri m ar y a n al ysis is si g nifica nt at t h e 0. 0 5 le v el, a k e y se c o n d ar y effic a c y a n al ysis will b e f or m all y 
e v al u ate d at t h e 0. 0 5 le 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 vities  f or  t h e  t w o  tre at m e nt  gr o u ps  will  b e  c o m p are d 
usi n g a stratifie d  G e h a n -Wilc o x o n test  (a  = 0. 0 5)  stratifie d b y ( 1) ti m e si n c e s y m pt o m o nset f or e a c h 
s u bject at e nr oll m e nt (≥2 4 h o urs, > 2 4 – 3 6 h o urs, > 3 6 h o urs) a n d ( 2) w h et h er t h e s u bje ct re c ei v e d 
seas o n al  i nfl u e n za  v acci n ati o n  after  A u g ust  1,  2 0 1 8.  S u bje cts  wit h o ut  a n  A bilit y  t o  P erf or m  All 
N or m al A cti vities res p o nse b ei n g re c or d e d will b e tre ate d as c e ns ore d a s of t h eir last diar y wit h o ut a 
d o c u m e nte d A bilit y t o P erf or m All N or m al A cti vities res p o nse . 
 
If  b ot h  t h e  pri m ar y  a n al ysis  a n d  t h e  k e y  se c on d ar y  effic a c y  a n al ysis  are  si g nific a nt  at  t h e  0. 0 5  le v el, 
a n ot h er sec o n d ar y efficac y a n al ysis will b e f or m all y e v al u ate d at t h e 0. 0 5 le v el as f oll o ws:  
 
•  
Pr o p orti o ns of s u bjects e x p erie n ci n g o n e or m ore c o m plic ati o ns of i nfl u e n z a 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, w orse ni n g of pre -e xisti n g h e alt h c o n diti o ns, s yste mic a nti bi otic use 
f or i nfecti o ns sec o nd ar y t o i nfl u e n z a i nfe cti o n,  h os pitaliz ati o n d u e t o i nfl u e n z a or c o m plic ati o ns of 
i nfl u e n za a n d  d eat h  will  b e  c o m p are d  b et w e e n  t h e  tre at m e nt  gr o u ps  usi n g  a Fis h er’s  e x a ct  test   (a  
= 0. 0 5) . 
 
A t hir d  sec o n d ar y a n al ysis will b e p erf or m e d as f oll o ws: 
 
•  
T h e pri m ar y efficac y a n al ysis will b e re p e ate d usi n g o nl y ite ms fr o m t h e f o ur F L U -P R O d o m ai ns 
( B o d y/ S yste mic,  T hr o at,  C h est/ R es pirat or y  a n d  N ose) t h at  c orres p o n d  t o  t h e  se v e n  s y m pt o ms 
i n cl u d e d  i n  t h e  tra diti o n al  P R O  i nstr u m e nt  (fe v eris h n ess,  m y al gia,  h e a d a c h e,  fati g u e,  s ore  t hr o at, 
n asal  o bstr u cti o n  a n d  c o u g h).    F or  t his  se c o n d ar y  a n al ysis,  w e  will  d eri v e  t h e  S y m pt o m  R es p o nse 
d efi niti o n i n t h e sa m e m a n n er as f or d eri vi n g t h e S y m pt o m R es p o nse d efi niti o n use d i n t h e pri m ar y 
a n al ysis (after re m o vi n g t h e E y e a n d G astr oi ntesti n al s y m pt o ms).   
 
E x pl orat or y a n al yses will b e p erf or m e d as f oll o ws:  
 
•  
F or eac 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 v i d u al S y m pt o m R es p o nse f or t h e 
N T Z a n d place b o treat m e nt gr o u ps will b e c o m p are d usi n g t h e G e h a n -Wilc o x o n test.  
 
•  
F or  eac 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 nse  f or  t h e  N T Z  a n d 
place b o treat m e nt gr o u ps will b e c o m p are d usi n g t h e G e h a n -Wi lc o x o n test. 
 
•  
Ti m e  t o  R es ol uti o n  of  A c ute  F e brile  Ill n ess  f or  t h e  N T Z  a n d  pla c e b o  tre at m e nt  gr o u ps  will  b e 
c o m p are d usi n g t h e G e h a n -Wilc o x o n test.  
 
•  
Ti m e t o R et ur n t o Us u al H ealt h f or t h e N T Z a n d pla c e b o tre at m e nt gr o u ps will b e c o m p are d usi n g 
t h e G e h a n-Wil c o x o n test.  
 
•  
C h a n g es i n i nfl u e n za T CI D 5 0 viral titer s fr o m b aseli n e t o d a y 2 a n d fr o m b aseli n e t o d a y  3 f or t h e 
N T Z a n d place b o treat m e nt gr o u ps will b e c o m p are d usi n g a t -test. 
 
•  
F or s u bjects wit h  la b orat or y -c o nfir m e d  i nfl u e n z a,  t h e  pr o p orti o ns  of s u bje cts wit h  i nfl u e n z a  vir us 
d etecte d b y c ult ure i n n as o p h ar y n g e al s w a bs c olle cte d  at e a c h of d a y s 2, 3 a n d 7 will b e c o m p are d 
f or t h e t w o treat m e nt gr o u ps usi n g a Fis h er’s e x a ct test.    
 
S e nsiti vit y a n al yses f or t h e pri m ar y e n d p oi nt will i n cl u d e:  


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 1  
 
 
•  
R e p eat t h e pri m ar y efficac 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 nse of 2 1 d a ys f or s u bje cts 
t h at disc o nti n u e pri or t o d a y 2 1 wit h o ut a c hie vi n g S y m pt o m R es p o nse. 
 
•  
R e p eat t h e pri m ar y efficac y a n al ysis f or a “ p er pr ot o c ol” s u bs et.  
 
8. 4. 2  
I nfl u e n z a A nti b o d y Titer A n a l ysis 
 
F or s u bjects wit h la b orat or y -c o nfir m e d i nfl u e n z a at b aseli n e b y c ult ure or R T -P C R, c h a n g es i n i nfl u e n z a 
a nti b o d y titers fr o m b aseli n e t o d a y 2 2 will b e a n al y z e d b y c o m p aris o n of m e a ns as w ell as pr o p orti o ns of 
s u bjects  ser o pr otecte d ( d a y  22 a nti b o d y  titer ≥4 0) a n d  ser o c o n v erte d ( d a y  22 a nti b o d y  titer  > 4 x  b aseli n e 
titer) at d a y 2 2.   M ea ns will b e c o m p are d usi n g a t -test, a n d pr o p orti o ns will b e c o m p are d usi n g a Fis h er’s 
e x act test.  
 
8. 4. 3  
P o p ul ati o n P h a r m a c o ki n etics A n al ysis   
 
O n  d a y  3,  t h e  plas m a  sa m ples  will  b e  c olle cte d  b ef ore t h e  m or ni n g  d ose (at  t h e  tr o u g h).  T his  d ata  will 
all o w  f or  a n al ysis  of  relati o ns hi ps  b et w e e n tr o u g h plas m a  c o n c e ntrati o ns  a n d cli nic al  a n d vir ol o gic 
res p o nse. 
 
 
D a y  3  tr o u g h  plas m a  c o n ce ntrati o ns  of  tiz o x a ni d e  a n d  tiz o x a ni d e  g l u c ur o ni d e  will  b e  s u m m ariz e d 
d escri pti v el y  f or eac h  of  t h e  treat m e nt  gr o u ps.    E x pl orat or y  a n al yses  will  b e  c o n d u cte d  t o  e v al u ate 
relati o ns hi ps  b et w ee n  plas m a  c o n c e ntrati o ns  a n d  a g e,  ra 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 mita nt m e dicati o ns, c h a n g es i n viral titer o v er ti m e, ti m e fr o m first d ose t o S y m pt o m R es p o nse  a n d 
a d v erse e v e nts.  
 
8 . 4.4 
S afet y A n al yses  
 
All  ra n d o mize d s u bjects w h o  recei v e  t h e  st u d y  m e dic ati o n  will  b e  e v al u ate d  f or  dr u g  s afet y.  S afet y 
a n al yses will b e d o n e d escri pti v el y.  
 
 
9  
IN 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 nistr ati o n a n d D u r ati o n  
 
Gr o u p 1 ( N T Z):  
S u bjects  will  re c ei v e  t w o  N T Z  3 0 0  m g  ta blets b.i. d. wit h  f o o d  ( <  1  h o ur  after 
f o o d i nta k e) f or 5 d a ys. 
Gr o u p 2 ( Place b o ): 
S u bjects  will  re c ei v e  t w o  pla c e b o  ta blets  b.i. d.  w it h  f o o d  ( <  1  h o ur  after  f o o d 
i nta k e) f or 5 d a ys. 
 
T h e f o o d pri or t o dr u g i nta k e s h o ul d  prefera bl y  b e a hi g h -fat m e al, b ut at mi ni m u m a c ere 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 place b o ta blets w ere m a n ufa ct ure d f or R o m ar k L a b orat or ies, L. C. b y 
 
 i n t h e U nite d States.  T h e a cti v e f or m ulati o n f or t his st u d y is a y ell o w, fil m-c o ate d 
ta blet t h at c o ntai ns 3 0 0 m g N T Z pl us sta n d ar d e x ci pie nts.  T h e pla c e b o ta blet will h a v e t h e sa m e a p p e ara n c e 
a n d  i n acti v e i n gre die nts as t h e acti v e ta blet. 
 
9. 3  
P a c k a gi n g a n d L a b eli n g  
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 2  
 
N T Z or place b o ta blets will b e p ac k a g e d f or e a c h p atie nt i n a w hite H D P E b ottle, e a c h c o ntai ni n g 2 0 ta blets.  
T h e s u bjects will ta k e t w o ta blets at eac h d osi n g ti m e p oi nt.  T h e b ottles wi ll b e st ore d at r o o m te m p erat ure 
a n d will b ear a la b el wit h t h e f oll o wi n g i nf or m ati o n:  
2 0 Ta blets  
 
St u d y N  R M 0 8 -3 0 0 4 Treat m e nt N :  X X X X  
L ot:   
  
  
 
Pri nci p al I n vesti g at or:  
  
 
  
T a ke 2 T a blets b y M o ut h wit h F o o d  T wice D ail y  
C a uti o n: N e w Dr u g -Li mite d b y Fe deral  La w t o I n vesti gati o nal Use  
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 he R o m ar k I nstit ute f or M e dical Researc h  
 
 
9. 4  
D r u g A cc o u nt a bilit y  
 
M e dicati o n w ill b e dis p e nse d at b aseli n e.  M e dic ati o n c o m plia n c e will b e re vie w e d wit h e a c h s u bje ct d uri n g 
t h e D a y 2-5 T ele p h o n e M o nit ori n g.  At t h e d a y 7 visit, s u bje cts will b e as k e d t o ret ur n t h e b ottle i n w hic h t h e 
m e dicati o n w as dis p e nse d al o n g wit h a n y u n use d m e dic ati o n.  
 
T h e I n v esti g at or or  d esi g n ee is  re q uire d  t o  m ai ntai n  a d e q u ate  re 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 ates, q u a ntit y a n d use b y s u bje ct.  U n use d s u p plies m ust b e ret ur n e d t o t h e S p o ns or. 
 
9. 5  
S u bjec t C o m pli a n ce 
 
S u bject  c o m plia n ce wit h t h e p r 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 re c or d e d i n t h e E D C s yste m  at 
eac h visit.  
 
S u bjects will  b e  c o nsi d ere d  n o n -c o m plia nt  ( m aj or  pr ot o c ol  vi olati o n)  if  t h e y  h a v e  misse d  m ore  t h a n  t w o 
d oses of t h e st u d y m e dicati o n d uri n g t h e first t hre e  d a ys of t h e st u d y or if t h e y ta k e a n y pr o hi bite d/ disall o w e d 
m e dicati o n.   N o n -c o m plia n ce will n ot b e c a use f or disc o nti n u ati o n of s u bje ct p artici p ati o n i n t h e st u d y.  
 
9. 6  
Dis all o w e d M e dic ati o n  
 
T h e  f oll o wi n g  m e dicati o ns  will  n ot  b e  all o w e d  d uri n g  t h e  st u d y:  a n y  a nti viral  m e dic ati o n  f or  fl u  or  a n y 
prescri pti o n  or  n o n -prescri pti o n  m e dic ati o ns  classifie d  as  (i)  e x p e ct ora nts  a n d  c o u g h  pre p arati o ns,  (ii) 
a n al g esics  a n d  a nti p yretics  or  (iii)  a nti hista mi n es  ( A m eric a n  H os pital  F or m ular y  S er vic e  ( A H F S) 
classificati o n).  As a n e x ce pti o n t o t his r ule, s u bje cts will b e all o w e d t o us e a c eta mi n o p h e n  as n e c essar y f or 
fe v er if oral te m p erat ure  is ≥1 0 0. 4° F (3 8° C).  
 
M e dicati o ns f or pre -e xisti n g c o n diti o ns t h at are n ot e x cl u d e d (se e e x cl usi o n criteria) s h o ul d b e c o nti n u e d as 
presc ri b e d.  T h e use of s u c h m e dicati o n will b e re c or d e d i n t h e E D C s yste m . 
 
 
1 0  A D V E R S E E V E N T S  
 
T h e  ter m  “a d v erse  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 nte d  p h ysic al,  ps y c h ol o gic al  or 
b e h a vi oral  c h a n g e  e x p erie n ce d  b y  a  s u bje ct  d uri n g  t h e  c o urse  of  t h e  st u d y a n d  after  ta ki n g  t h e  first  d ose  of 
st u d y  m e dicati o n re g ar dless  of  its  se v erit y  or  relati 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 ecte d  w orse ni n g  of  pre-e xisti n g  c o n diti o ns,  cli nic all y  si g nific a nt  c h a n g es  i n  la b orat or y  v al u es, 
diseases  a n d  s y n dr o m es,  a n d  si g nifica nt  a n d  u n e x p e cte d  fail ures  of  p h ar m a c ol o gic al  a cti o n  of  ot h er 
m e dicati o ns.  S y m pt o ms of i nfl u e n za ( i.e., t h ose c a pt ure d i n t h e FL U -P R O Q u esti o n n aire ) a n d c o m plic ati o ns of 
i nfl u e n za  (e. g., p n e u m o nia,  otitis  m e dia ,  br o n c hitis,  si n usitis)  s h all  n ot  b e  re p orte d  as  a d v erse  e v e nts  u nless 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 3  
 
t h ere is a ca usal relati o ns hi p b et w ee n t h e st u d y m e dic ati o n a n d t h e e v e nt.  T h es e s y m pt o ms a n d c o m plic a ti o ns 
will b e a n al y ze d se p aratel y fr o m a d v erse e v e nts as t h e y are st u d y e n d p oi nts.  
 
B acterial p n e u m o nia, ac ute b acterial otitis m e dia a n d a c ute b a cterial si n usitis will b e re p orte d as c o m plic ati o ns 
of i nfl u e n za o nl y if t h e f oll o wi n g criteria are satisfie d : 
 
B acterial p n e u m o nia:  
1.  At least t w o of t h e f oll o wi n g s y m pt o ms: diffic ult y bre at hi n g, c o u g h, pr o d u cti o n of p ur ule nt s p ut u m, 
c h est p ai n  
2.  At least t w o of t h e f oll o wi n g vital si g n a b n or m alities: fe v er, h y p ote nsi o n, ta c h y c ar dia, ta c h y p n e a  
3.  At least o n e of t h e f o ll o wi n g fi n di n gs: h y p o x e mia, cli nic al e vi d e n c e of p ul m o n ar y c o ns oli d ati o n, 
ele v ate d w hite bl o o d cell c o u nt or le u k o p e nia  
4.  C h est ra di o gra p h fi n di n gs of n e w i nfiltrates i n a l o b ar or m ultil o b ar distri b uti o n.  
5.  Micr o bi ol o gic criteria: a p pr o priate s p ut u m s p e ci m e n  wit h fe w er t h a n 1 0 s q u a m o us e pit h elial c ells a n d 
m ore t h a n 2 5 p ol y m or p h o n u clear cells p er l o w p o w er fiel d  
 
A c ute b acterial o titis m e dia: 
1.  S y m pt o ms of ear p ai n or earac h e, e ar f ull n ess or d e cre ase d h e ari n g  
2.  O n e or m ore of t h e f oll o wi n g ot osc o pic fi n di n gs  p e rf or m e d b y a cli nicia n e x p erie n c e d i n ot osc o p y: 
•  B ul gi n g or f ull n ess of t h e t y m p a nic m e m bra n e (c o n v e xit y of t h e pla n e of t h e e ar dr u m), wit h l oss of 
a n at o mic la n d m ar ks o n vis u aliz ati o n,  
•  O p acificati o n of t h e t y m p a nic m e m bra n e re g ar dless of c ol or,  
•  Er yt h e m a o f t h e t y m p a nic m e m bra n e, or  
•  A b n or m al t y m p a nic m e m bra n e m o bilit y o n bi p h asic p n e u m atic ot os c o p y; a t y m p a nic m e m bra n e i n 
t h e n e utral p ositi o n or retracte d is n ot s ufficie nt e vi d e n c e of a c ute b a cterial  otitis m e dia  b e c a use 
t h ese fi n di n gs are n ot s p ecific e n ou g h t o disti n g uis h t h e dise ase fr o m otitis m e dia wit h eff usi o n  
 
B acterial si n usitis: 
1.  At least t w o of t h e f oll o wi n g s y m pt o ms:  
•  M a xillar y t o ot h p ai n ( u nilateral fi n di n gs c a n b e m ore s p e cific)  
•  F acial p ai n ( u nilateral fi n di n gs c a n b e m ore s p e cific)  
•  Fr o nt al h ea d ac h e  
•  P ur ule nt n asal disc h ar g e ( u nilateral fi n di n gs c a n b e m ore s p e cific)  
•  N e w o nset fet or oris ( b a d breat h)  
•  M or ni n g c o u g h  
•  N asal o bstr u cti o n  
2.  At least o n e of t h e f oll o wi n g si g ns:  
•  P ur ule nt secreti o ns fr o m si n us ostia o n e x a mi n ati o n  
•  A b n or m al si n us tra nsill u mi n ati o n  
•  P ai n o n p al p ati o n o v er si n uses  
•  F acial s w elli n g  
3.  R a di o gra p hic fi n di n gs c o nsiste nt wit h a c ute si n usitis   
 
A d v erse e v e nts will b e rec or d e d o n t h e a p pr o priate 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 se v erit y of e a c h 
a d v erse e v e nt will b e gra d e d o n a f o ur p oi nt sc ale: mil d, m o d erate, se v ere , or life t hre ate ni n g ( S e e A p p e n di x II).  
T h e d urati o n of t h e a d v erse e v e nt a n d relati o ns hi p t o t h e st u d y dr u g will als o b e re 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 res ol uti o n or sta b iliz ati o n e v e n b e y o n d t h e pla n n e d st u d y p eri o d. 
 
 
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 4  
 
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 re p orti n g of a d v ers e e v e nts:  
 
1)  S eri o us  A d v erse  E v e nt :  A n y  a d v erse  e x p erie n c e  o c c urri n g  at  a n y  d ose  t h at  is  fatal  or  life  t hre ate ni n g; 
re q uires i n-p at ie nt h os pitalizati o n or pr ol o n g ati o n of a n e xisti n g h os pitaliz ati o n; is a p ersiste nt si g nific a nt 
disa bilit y/i n ca p acit y; is a c o n g e nital a n o m al y or birt h d efe ct; or is a n i m p orta nt m e dic al e v e nt t h at m a y 
n ot  res ult  i n  d eat h,  b e  life -t hreate ni n g,  or  re q uire h os pitaliz ati o n  b ut,  b ase d  u p o n  a p pr o priate  m e dic al 
j u d g m e nt, m a y je o p ar dize t h e s u bje ct a n d m a y re q uire m e dic al or s ur gic al i nter v e nti o n t o pre v e nt o n e of 
t h e o utc o m es liste d a b o v e. 
 
2)  U n e x p ecte d  A d v erse E v e nt :  A n y  a d v erse  e x p erie n c e  t h at  is  n ot  i d e ntifie d  i n  n at ure,  se v erit y,  or 
fre q u e n c y i n t h e I n v esti g at or's Br o c h ure f or N T Z. 
 
3)  S e v erit y of a d v erse 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 xicit y Gra di n g S c ale T a bles 
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 pte d fr o m “ G ui d a n c e f or I n d ustr y: T o x icit y Gra di n g S c ale f or 
H ealt h y A d ult a n d A d olesce nt V ol u nte ers E nr olle d i n Pre v e nti v e V a c ci n e Cli nic al Trials ”, U S D e pt. of 
H H S,  F D A,  C D E R,  S e pte m b er  2 0 0 7  a n d  t h e  N ati o n al  I nstit utes  of  H e alt h,  N ati o n al  C a n c er  I nstit ute 
C o m m o n T er mi n ol o g y Criteria f or A d v erse E v e nts ( C T C A E) v ersi o n 5 . 0). 
 
4)  C a usalit y  (relati o ns hi p t o treat m e nt) will b e assesse d as f oll o ws: 
 
•  
D efi nitely  R el ate d:  T h e  a d v ers e  e v e nt  is  cle arl y  relate d  t o  t h e  i n v esti g ati o n al  a g e nt(s)  or  res e arc h 
i nter v e nti o n:  t h e  a d v erse  e v e nt  h as  a  te m p oral  relati o ns hi p  t o  t h e  a d mi nistrati o n  of  t h e 
i n v esti g ati o n al  a g e nt(s)  or  rese arc h  i nter v e nti o n,  f oll o ws  a  k n o w n  p atter n  of  res p o nse,  a n d  n o 
alter n ati v e ca use is prese nt.  
 
•  
Pr o b a bly R el ate d:  T h e a d v erse e v e nt is li k el y relate 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 erse e v e nt h as a te m p oral relati o ns hi p t o t h e a d mi nistrati o n of t h e i n v esti g ati o n al a g e nt(s) or 
researc h  i nter v e nti o n,  f oll o ws  a  k n o w n  or  s us p e cte d  p atter n  of  res p o nse,  b ut  a n  alter n ati v e  c a use 
m a y b e prese nt.  
 
•  
P ossi bly  R el ate d:  T h ere  is a  re as o n a ble  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 use d  b y  or  is 
li n k e d  i n  a  si g nifica nt  w a y  t o  t h e  rese arc h;  t h e  a d v erse  e v e nt  h as  a  te m p oral  relati o ns hi p  t o  t h e 
a d mi nistrati o n of t h e i n v esti g ati o n al a g e nt(s) or rese arc h i nter v e nti o n, f oll o ws a s us p e cte d p atter n of 
res p o nse, b ut a n alter n ati v e ca use is prese nt. 
 
•  
U nrel ate d ( or N ot R el ate d):  T h e a d v ers e e v e nt is cle arl y N O T relate d t o t h e i n v esti g ati o n al a g e nt(s) 
or  i nter v e nti o n:  t h e  a d v erse  e v e nt  h as  n o  te m p oral  relati o ns hi p  t o  t h e  a d mi nistrati o n  of  t h e 
i n v esti g ati o n al a g e nt(s) or rese arc h i nter v e nti o n, f oll o ws n o k n o w n or s us p e cte d p atter n of res p o nse, 
a n d a n alter n ati v e ca use is prese nt.  
 
U n d er d o u ble -bli n d treat 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 bje cts are ta ki n g t h e test dr u g.  
  
 
1 0. 2  
Cli nic al A d v erse E v e nts  
 
At  t h e  ti m e  of  eac h  ret ur n  visit,  t h e  s u bje ct  will  b e  q u esti o n e d  re g ar di n g  t h e  o c c urre n c e  a n d  n at ure  of  a n y 
a d v erse e v e nts.   All e v e nts m ust b e rec or d e d i n t h e s u bje cts' m e dic al re c or ds a n d i n t h e E D C s yste m .  A n y 
s u bject affecte d will be e x a mi n e d b y t h e I n v esti g at or as d e e m e d n e c essar y t o asc ertai n t h e c o urse of t h e e v e nt 
a n d a n y resi d u al effects.  
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 5  
 
All  m o d erate  a n d  se v ere  a d v erse  e v e nts  will  b e  re vie w e d  b y  t h e  Pri n ci p al  I n v esti g at or  w h o  will  d eter mi n e 
usi n g his/ h er b est cli nical j u d g m e n t w h et h er t h e y w arra nt t h e s u bje ct t o b e disc o nti n u e d fr o m t h e st u d y.  T h e 
S p o ns or will b e n otifie d i m m e diatel y if a s u bje ct is disc o nti n u e d fr o m t h e st u d y.   F or all a d v erse e v e nts t h at 
re q uire t h e s u bject t o b e disc o nti n u e d fr o m t h e st u d y, rele v a nt cli nical assess m e nts a n d la b orat or y tests will 
b e re p eate d as cli nicall y i n dicate d u ntil fi n al res ol uti o n or sta biliz ati o n of t h e e v e nt(s).  
 
All s u bjects will b e i nstr u cte d t o c o ntact t h e I n v esti g at or, I n v esti g at or's assista nts, or cli nic al p ers o n n el s h o ul d 
t h e s u bject h a v e a n y seri o us a d v erse e x p erie n c es.  S eri o us a d v erse e v e nts  ( S A Es), i n cl u di n g d e at h re g ar dless 
of t h e c a use, m ust b e re p orte d t o t h e S p o ns or i m m e diatel y ( wit hi n 2 4 h o urs of t h e i nitial re p ort).  
 
A seri o us e v e nt re q uiri n g i m m e diate n otific ati o n b y  tele p h o n e is a n e v e nt t h at: 
 
•  
res ults i n d eat h 
 
•  
is life t hreate ni n g  
 
•  
re q uires i n p atie nt h os pitalizati o n or pr ol o n g ati o n of a n e xisti n g h os pitaliz ati o n 
 
•  
is a p ersiste nt or si g nifica nt disa bilit y/i n c a p a cit y 
 
•  
is a c o n g e nital a n o m al y/ birt h d efect 
 
•  
a n i m p orta n t m e dical e v e nt t h at m a y n ot res ult i n d e at h, b e life-t hre ate ni n g, or re q uire h os pitaliz ati o n b ut, 
b ase d  u p o n  a p pr o priate  m e dical  j u d g m e nt,  m a y  je o p ar diz e  t h e  s u bje ct  a n d  m a y  re q uire  m e dic al  or 
s ur gical i nter v e nti o n t o pre v e nt o n e of t h e o utc o m es liste d a bo v e.  
 
A n o v er d ose is d efi n e d as a n y i nte nti o n al or u ni nte nti o n al c o ns u m pti o n of t h e dr u g b y a n y r o ute t h at e x c e e ds 
t h e  hi g h est  d ose  state d  i n  t h e  I n v esti g at or's  Br o c h ure  or  i n  a n  i n v esti g ati o n al  pr ot o c ol,  w hic h e v er  d ose  is 
lar g er.  O v er d oses  wit h o ut  a n  ass o ciate d a d v erse  e v e nt  s h o ul d  b e  re c or d e d,  b ut  n ot  re p orte d  as  a n  a d v erse 
e v e nt.  
 
1 0. 3  
R e p o rti n g R e q uire m e nt  
 
T h e  Pri n ci p al  I n v esti g at or  is  re q uire d  t o  n otif y  T h e  R o m ar k  I nstit ute  f or  M e dic al  R es e arc h  ( S p o ns or) 
i m m e diatel y  of  a n y  u n e x p ecte d,  fatal,  or  life-t hre ate ni n g  e x p erie n c e  a n d  all  u n us u al,  alar mi n g,  or  seri o us 
reacti o ns  t o  m e dicati o n  re g ar dless  of  a n y  o pi ni o ns  as  t o  t h e  c a use/effe ct  relati o ns hi p.  All S A E s will  als o  b e 
re p orte d t o t h e I R B.  A d v erse e v e nts s h o ul d b e re p orte d t o:  
 
T h e R o m ar k I nstit ute f or M e d ical R ese arc h  
M e dical Affairs  
  
 
 
 
1 0. 4  
M e dic ati o n M o dific ati o n/ Wit h d r a w al D u e t o a n A d v e rse E v e nt  
 
N o  d ose  a dj ust m e nt  is  p er mitte d  d uri n g  t h e  5 -d a y  tre at m e nt  p eri o d.    If  a  se v ere  a d v erse  re a cti o n  d e v el o ps 
d uri n g t h era p y, t h e st u d y m e dicati o n s h o ul d b e disc o nti n u e d, a n d t h e s u bje ct s h o ul d b e wit h dra w n fr o m t h e 
st u d y.  
 
 
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 6  
 
1 0. 5  
M e dic ati o n E rr o rs  
 
A  m e dicati o n e rr or  is  d efi n e d  as a n y  pre v e nta ble  e v e nt relate d t o  d osi n g  i nstr u cti o ns,  pr o d u ct  la b eli n g,  or 
p ac k a gi n g t h at ca uses or lea d s t o i n a p pr o priate m e dic ati o n use or s u bje ct h ar m w hile t h e m e dic ati o n is i n t h e 
c o ntr ol  of  t h e  i n v esti g ati v e  site  or  s u bje ct.  M e dic ati o n  err ors  w hic h  res ult  i n  a d v ers e  e v e nts  s h o u l d  b e 
rec or d e d a n d re p orte d as a d v erse e v e nts.  All ot h er m e dic ati o n err ors s h o ul d b e re p orte d t o t h e st u d y S p o ns or 
t hr o u g h t h e M e dical Affairs d e p art m e nt wit hi n 7 d a ys of i d e ntific ati o n b y t h e site.  
 
 
1 1  DI S C O N TI N U A TI O N  
 
1 1. 1  
St u d y Disc o nti n u ati o n:  
 
T h e st u d y m a y b e disc o nti n u e d u n d er t h e f oll o wi n g circ u msta n c es:  
 
1)  T h e S p o ns or reser v es t h e ri g ht t o dis c o nti n u e t h e st u d y at a n y ti m e.  
 
2)  A d v erse  e v e nt  listi n gs will  b e pr o d u c e d  f or  safet y  m o nit ori n g  at  le ast o n c e  e v er y  t w o  w e e ks  d uri n g 
recr uit m e nt.  Th e d ata will b e t este d t o d eter mi n e if t h ere are gre ater t h a n 5 % of t h e s u bje cts w h o h a v e 
h a d ≥ gra d e 3 a d v erse e v e nts c o nsi d ere d b y t h e I n v esti g at or t o b e p ossi bl y, pr o b a bl y or d efi nitel y relate d 
t o t h e st u d y dr u g ( d efi n e d b y t h e T o xicit y Gra di n g S c ale T a bles pr o vi d e d i n A p p e n di x II ). 
 
If  greater  t h a n  5 %  of  t h e  s u bjects  h a v e at  le ast  o n e gra d e  3  or  gra d e  4 a d v erse  e v e nt  c o nsi d ere d  t o  b e 
p ossi bl y, pr o b a bl y or d efi nitel y relate d t o t h e st u d y dr u g b y t h e st u d y M e dic al M o nit or, t h e n t h e st u d y 
m ust  b e  st o p p e d  a n d  t h e  I nstit uti o n al  R e vie w  B o ar ds,  a n d  F D A’s  Di visi o n  of  A nti viral  Dr u g  Pr o d u cts 
will b e n otifie d.  All safet y a n d acti vit y d ata will b e s u b mitte d t o t h e F D A i n a ti m el y m a n n er.   
 
1 1. 2  
S u bject Disc o nti n u ati o n:  
 
T reat m e nt will b e disc o nti n u e d f or i n di vi d u al s u bje cts f or t h e foll o wi n g re as o ns:  
 
1) 
A n aller gic -li k e reacti o n o cc urs or is s us p e cte d. 
 
2)  M e dical c o n diti o ns t h at m a y re q uire st u d y dis c o nti n u ati o n i n t h e I n v esti g at or’s j u d g m e nt. 
 
3)  S u bject d esire t o disc o nti n u e p artici p ati o n.  
 
I n t h e case of a n aller gic-li k e reacti on or ot h er m e dic al c o n diti o n re q uiri n g s u bje ct disc o nti n u ati o n, 
a p pr o priate treat m e nt will b e i nstit ute d b y t h e I n v esti g at or. 
 
 
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 yste m  will  b e  use d  f or  t his  st u d y  (
).  Pri or  t o  st u d y 
i nitiati o n, site staff a n d a ut h orize d R o m ar k p ers o n n el will b e trai n e d t o use t his s yste m.  
 
All electr o nic s o urce f or ms are t o b e c o m pletel y fille d o ut b y t h e e x a mi ni n g site staff a n d re vie 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). Ele ctr o nic diaries will b e c o m plete d b y t h e st u d y s u bje cts a n d re vie w e d b y st u d y 
p ers o n n el a n d a ut h orize d S p o ns or re prese ntati v es.  
 
 
 
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 7  
 
1 3  R E T E N TI O N O F R E C O R D S  
 
Esse ntial D o c u m e nts ( E Ds)  are d o c u m e nts t h at i n di vi d u all y a n d c olle 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  trial  a n d  q u alit y  of  t h e  d ata  pr o d u ce d.    T h e y  d e m o nstrate  t h e  c o m plia 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 sta n d ar ds a n d wit h all a p plic a ble re g ulat or y re q uire m e nts.  
I n c o m plia n ce 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 ntai n all e C R Fs a n d all E D C 
s o urce f or ms  a n d  s o urce d o c u m e nts  t h at  s u p p ort  t h e  d ata  c olle cte d  fr o m  e a c h  s u bje ct,  as  w ell  as  all  st u d y 
d o c u m e nts as s p ecifie d i n I C H/ G C P S ecti o n 8, Esse ntial D o c u m e nts f or t h e C o n d u ct of a Cli nic al Trial , a n d all 
st u d y d o c u m e nts as s p ecifie d b y t h e a p plic a ble re g ulat or y re q uire 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  Esse ntial  D o c u m e nt  f or  t h e  I n v esti g ati v e  Site.   Th e I n v esti g at or/i nstit uti o n  will  ta k e 
m eas ures t o pre v e nt acci d e ntal or pre m at ure d estr u cti o n of t h ese d o c u m e nts.  
Esse ntial d o c u m e nts liste d i n A p p e n di x III m ust b e retai n e d f or t h e d urati o n re q uire d b y a p plic a ble re g ulat or y 
a ut h orities  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 ese d o c u m e nts are n o l o n g er n e e d e d. 
If  it  b ec o m es  n ecessar y  f or  t h e S p o ns or or  t h e  a p pr o priate  re g ulat or y  a ut h orit y  t o  re vie w  a n y  d o c u m e ntati o n 
relati 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 re p orts.  
 
T h e S p o ns or is res p o nsi ble f or or g a nizi n g a n d m ai ntai ni ng t h e Trial M aster File w hic h is a cle ar d o c u m e ntati o n 
of t h e c o urse 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 cte d b y t h e S p o ns or a n d/ or a c o ntra ct res e arc h or g a niz ati o n ( C R O) a c c or di n g t o t h e 
S p o ns or’s sta n d ar d o p erati n g pr o ce d ures.  S ite  visits  will  b e  c o n d u cte d  b y  t h e  S p o ns or  at  re g ular  i nter v als  t o 
c o n d u ct i ns p ecti o ns.  
 
A n y  d ata tra nscri b e d i nt o t h e E D C s yste m  will b e 1 0 0 % s o urc e v erifie d.   
 
T h e I n v esti g at or will gra nt  re prese ntati v es of t h e S p o ns or's cli nic al o p erati o ns te a m a n d q u alit y te a m, as w ell as 
re g ulat or y  a g e n cies a n d  et hical  c o m mitte es  a c c ess to  i ns p e ct  fa cilities  a n d  re c or ds  (i n cl u di n g  s u bje ct  c h arts) 
rele v a nt t o t his st u d y a n d a grees t o assist t h e m o nit ors i n t h eir a cti vities, if re q u este d. 
 
Gi v e n t h e s h ort d urati o n of t his st u d y, t h e lar g e cli nic al e x p erie n c e wit h N T Z, a n d t h e p o p ulati o n b ei n g st u die d, 
t h e d ata fr o m t his st u d y will n ot b e m o nit ore d b y a n i n d e p e n d e nt d ata m o nit ori n g c o m mitte e.   
 
 
1 5  I N F O R M E D C O N S E N T 
 
E ac h s u bject m ust gi v e writte n c o nse nt a c c or di n g t o l o c al re q uire m e nts after t h e n at ure of t h e st u d y h as b e e n 
f ull y  e x plai n e d.  T h e i nf or m e d c o nse nt  f or m (I C F) m ust  b e  si g n e d  b ef ore  p erf or m a n c e  of  a n y  st u d y -relate d 
acti vit y.  T h e I C F m ust 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 re vie wi n g I R B.  It s h o ul d b e i n a c c or d a n c e 
wit h  pri n ci ples  t h at  ori gi n ate d  i n  t h e  D e clarati o n  of  H elsi n ki,  c urre nt  I C H  a n d  G C P  g ui d eli n es,  a p plic a ble 
re g ulat or y re q uire m e nts, a n d S p o ns or p olic y.  
 
B ef ore  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 o riz e d  m e m b er  of  t h e  i n v esti g ati o n al  staff  m ust 
e x plai n  t o  p ote ntial  s u bjects  t h e  ai ms,  m et h o ds,  re as o n a bl y  a ntici p ate d  b e n efits,  a n d  p ote ntial  h a z ar ds  of  t h e 
st u d y,  a n d  a n y  disc o mf ort  p artici p ati o n  i n  t h e  st u d y  m a y  e ntail.  S u bje cts  will  b e  i nf or m e d  t h at  t h eir 
p artici p ati o n is v ol u ntar y a n d t h at t h e y m a y wit h dra w c o nse nt t o p artici p ate 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 artici p ate will n ot affe ct t h e c are h e/s h e will re 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 n tai n a s u bject i d e ntific ati o n re gister f or t h e p ur p oses of l o n g-ter m f oll o w-u p if n e e d e d a n d 
t h at  t h eir  rec or ds  m a y  b e  accesse d  b y  h e alt h  a ut h orities  a n d  a ut h oriz e d S p o ns or staff  wit h o ut  vi olati n g  t h e 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 8  
 
c o nfi d e ntialit y of t h e s u bject, t o t h e e xte nt p er mitte d  b y t h e a p plic a ble la w(s) or re g ulati o ns.  B y si g ni n g t h e I C F 
t h e s u bject is a ut h orizi n g s u c h access, a n d a gre es t o all o w his or h er st u d y p h ysicia n t o re-c o nta ct t h e s u bje ct f or 
t h e p ur p ose of o btai ni n g c o nse nt f or a d diti o n al safet y e v al u ati o ns, if n e e d ed.  
 
T h e  s u bje ct  will  b e  gi v e n  s ufficie nt  ti m e  t o  re 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.  After  t his 
e x pla n ati o n a n d b ef ore e ntr y i nt o t h e st u d y, c o nse nt s h o ul d b e a p pr o priatel y re c or d e d b y m e a ns of t h e s u bje ct's 
p ers o n all y d ate d si g n at ure.  Af ter h a vi n g o btai n e d t h e c o nse 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 bje ct. 
 
If t h e s u bject is u n a ble t o rea d or write, a n i m p artial wit n ess s h o ul d b e prese nt f or t h e e ntire i nf or m e d c o nse nt 
pr o cess ( w hic h i n cl u d es rea di n g a n d e x plai ni n g all writte n i nf or m ati o n) a n d s h o ul d p ers o n all y d ate a n d si g n t h e 
I C F after t h e oral c o nse nt of t h e s u bject is o btai n e d, if p er mitte d b y l o c al la w. 
 
A sse nt fr o m a n y mi n or ( ≤ 1 8 y ears of a g e or as l o c al re g ulati o ns a p pl y) e nr olle d i nt o t h e st u d y will b e o btai n e d  
al o n g wit h  d o c u m e nte d c o nse nt fr o m t h eir p are nt/le g al g u ar dia n t o all o w t h e mi n or t o p artici p ate i n t h e st u d y .  
T h e asse nt a n d c o nse 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 relate d a cti vit y.   
 
Si g n e d I C Fs m ust re m ai n i n t h e s u bj ect's file(s) a n d b e a v aila ble f or v erific ati o n b y re prese ntati v es of R o m ar k, 
t h e I R B, a n d F D A/rele v a nt re g ulat or y a g e n cies at a n y ti m e.   
 
 
1 6  E T HI C S  
 
T h e  cli nical  trial  will  b e  p erf or m e d  i n  ac 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 dic al  Ass e m bl y 
( Declarati o n  of  H elsi n ki,  last  a m e n d m e nt  i n  F ortale z a , Bra zil,  O ct o b er  2 0 1 3 ).  Pri or  writte 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 nse nt  f or m  will  b e  o btai n e d  fr o m  t h e  a p pr o priate  l o c al  M e dic al  Et hics 
R e vie w B o ar d.  
 
1 6. 1  
St u d y -S p ecific D esi g n C o nsi d er ati o ns  
 
P ote ntial  s u bjects  will  b e  f ull y  i nf or m e d  of  t h e  ris ks  a n d  re q uire 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 bjects 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 affe ct t h eir d e cisi o n t o c o nti n u e p artici p ati o n.  T h e y will 
b e t ol d t h at t h eir c o nse nt t o p artici p ate i n t h e st u d y is v ol u ntar y a n d m a y b e wit h dra w n at a n y ti m e wit h n o 
reas 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 hic h t h e y w o ul d ot h er wise b e e ntitle d.  O nl y s u bje cts 
w h o are f ull y a ble t o u n d ersta n d t h e ris ks, b e n efits, a n d p ote n tial A Es of t h e st u d y, a n d pr o vi d e t h eir c o nse nt 
v ol u ntaril y will b e e nr olle d.  
 
1 6. 2  
I n v esti g at o r R es p o nsi bilities 
 
T h e I n v esti g at or is  res p o nsi ble  f or  e ns uri n g  t h at  t h e  cli nic 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 urre nt  I nter n ati o n al  C o nfere n c e  o n  H ar m o niz ati o n  (I C H)  g ui d eli n es  o n  G o o d  Cli nic al  Pra ctic e 
( G C P), a n d a p plica ble re g ulat or y a n d c o u ntr y-s p e cific re q uire m e nts. 
 
G o o d  Cli nical  Practice  is  a n  i nter n ati o n al  et hic al  a n d  s cie ntific  q u alit y  sta n d ar d  f or  d esi g ni n g,  c o n d u cti n g, 
rec or di n g,  a n d re p orti n g  st u dies  t h at  i n v ol v e  t h e  p artici p ati o n  of  h u m a n  s u bje cts.  C o m plia n c e  wit h  t his 
sta n d ar d  pr o vi d es  p u blic  ass ura n ce  t h at  t h e  ri g hts,  safet y,  a n d  w ell b ei n g  of  st u d y  s u bje cts  are  pr ote cte d, 
c o nsiste nt wit h t h e pri n ci ples t h at ori gi n ate d i n t h e D e cl arati o n of H elsi n ki, a n d t h at t h e cli nic al st u d y d ata are 
cre di ble.  
 
 
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
3 9  
 
1 6. 3  
I nstit uti o n al R e vie w B o a r d (I R B) 
 
B ef ore t h e start 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 ere re q uire d) will pr o vi d e t h e I R B wit h c urre nt 
a n d c o m plete c o pies 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 plica ble, 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 writte n m aterials t o b e pr o vi d e d t o t h e s u bje cts);  
•  
I n v esti g at or’s Br o c h ure ( or e q ui v ale 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 bject recr uiti n g m aterials;  
•  
i nfor m ati o n o n c o m p e nsati o n f or st u d y -relate d i nj uries or p a y m e nt t o s u bje cts f or p artici p ati o n i n t h e 
st u d y, if a p plica ble; 
•  
I n v esti g at or’s c urric ul u m vitae or e q ui v ale nt i nf or m ati o n ( u nless n ot re q uire d, as d o c u m e nte d b y I R B);  
•  
i nf or m ati o n re 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 affiliati o ns, ot h er p ote ntial c o nflicts 
of i nterest, a n d i n ce nti v es f or s u bje cts;  
•  
a n y ot h er d o c u m e nts t h at t h e I R B re 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 erta k e n o nl y after 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 plica ble  recr uiti n g  m aterials,  a n d  s u bje ct  c o m p e nsati o n  pr o gra ms,  a n d  t h e S p o ns or h as 
recei 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 letter m ust b e d ate d a n d m ust cle 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 ere  re q uire 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 ates t o t h e I R B f or t h eir re vie w a n d a p pr o v al, w h ere a p pr o priate:  
•  
pr ot o c ol a m e n d m e nts;  
•  
re visi o n(s) t o I C F a n d a n y ot h er writte n m aterials t o b e pr o vi d e d t o s u bje cts; 
•  
if a p plica ble, n e w or re vise d s u bje ct re cr uiti n g m aterials a p pr o v e d b y t h e S p o ns or ; 
•  
re visi o ns  t o  c o m p e nsati o n  f or  st u d y-relate d  i nj uries  or  p a y m e nt  t o  s u bje cts  f or  p artici p ati o n  i n  t h e 
st u d y, if a p plica ble; 
•  
I n v estig at or’s Br o c h ure a d d e n d a or n e w e diti o n(s);  
•  
s u m m aries of t h e stat us of t h e st u d y at i nter v als sti p ulate d i n g ui d eli n es of t h e I R B (at le ast a n n u all y);  
•  
re p orts of A Es t h at are seri o us, u nliste d, a n d ass o ciate 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 ersel y affe ct t h e safet y of t h e s u bje cts or t h e c o n d u ct of t h e st u d y; 
•  
d e viati 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 ate i m m e diate h a z ar ds t o t h e s u bje cts;  
•  
re p ort of d eat hs of s u bjects u n d er t h e I n v esti g at or’s c are;  
•  
n otificati o n if a n e w In v esti g at or is res p o nsi ble f or t h e st u d y at t h e site; 
•  
A n n u al  I N D  U p d ate  R e p ort,  S h ort  T er m  St u d y  S p e cific  S afet y  S u m m ar y  a n d  Li n e  Listi n gs,  w h ere 
a p plica ble;  
•  
a n y ot h er re q uire 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  are  p urel y  a d mi nistrati v e,  wit h  n o  c o nse q u e n c es  f or 
s u bjects,  d ata  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 plic a ble  i nf or m e d  c o nse nt  f or m a n d  asse nt  f or m 
re visi o ns  m ust  b e  s u b mitte d  pr o m ptl y  t o  t h e  I R B  f or  re vie w  a n d  a p pr o v al  b ef ore  i m ple m e ntati o n  of  t h e 
c h a n g e(s), e x ce pt w h e n n ecessar y t o eli mi n ate i m m e diate h a z ar d t o t h e st u d y s u bje cts.  If a d e viati 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 ple m e nte d  t o  eli mi n ate  a n  i m m e diate  h a z ar d  t o  st u d y  s u bje cts,  t h e n  t h e 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
4 0  
 
i m ple m e nte d d e viati o n or c h a n g e, t h e re as o ns f or it, a nd, if a p pr o priate, 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 mitte d t o t h e I R B as s o o n as p ossi ble. 
 
T h e re -a p pr o v al of t h e cli nical 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 nte 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 ere  re q uire d)  will  n ot if y  t h e  I R B  a b o ut  t h e  st u d y 
c o m pleti o n.  
 
1 6. 4  
P ri v a c y of P ers o n al D at a  
 
T h e c ollecti o n a n d pr o cessi n g of p ers o n al d ata fr o m s u bje cts e nr olle d i n t his st u d y will b e li mite d t o t h os e 
d ata t h at are n ecessar y t o i n v esti g ate t h e safet 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) use d i n 
t his st u d y. 
 
T h ese  d ata  m ust  b e  c ollecte d  a n d  pr o c ess e d  wit h  a d e q u ate  pre c a uti o ns  t o  e ns ure  c o nfi d e ntialit y  a n d 
c o m plia n ce  wit h  a p plica ble  d ata  pri v a c y  pr ote cti o n  la ws  a n d  re g ulati o ns.  A p pr o priate  te c h nic al  a n d 
or g a niz ati o n al m eas ures t o pr otect t h e p ers o n al d ata a g ai nst u n a ut h oriz e d discl os ures or a c c ess, a c ci d e ntal or 
u nla wf ul  d estr u cti o n,  or  acci d e ntal  l oss  or  alterati o n  m ust  b e  p ut  i n  pla c e.  S p o ns or  p ers o n n el  w h ose 
res p o nsi bilities re q uire access t o p ers o n al d ata agre e t o k e e p t h e i d e ntit y of st u d y s u bje cts c o nfi d e ntial.  
 
T h e i nf or m e d c o nse nt o btai n e d fr o m t h e s u bje ct i n cl u d es e x plicit c o ns e nt f or t h e pr o c essi n g of p ers o n al d ata 
a n d  f or  t h e I n v esti g at or t o  all o w  dire ct  a c c ess  t o  his  or  h er  ori gi n al  m e dic al  re c or ds  for  st u d y -relate d 
m o nit ori n g, a u dit, I R B re vie w, a n d re g ulat or y i ns p e cti o n.  T his c o ns e nt als o a d dress es t h e tra nsfer of t h e d ata 
t o ot h er e ntities a n d t o ot h er c o u ntries. 
 
 
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/ P U B LI C A TI O N  
 
D ata g e n erate d f or t h e  st u d y sh o ul d b e st ore d b y t h e I n v esti g at or i n a li mite d-a c c ess file are a a n d b e a c c essi ble 
o nl y  t o  re prese ntati v es  of  t h e  st u d y  site,  R o m ar k,  t h e  I R B,  a n d  F D A/rele v a nt  re g ulat or y  a g e n cies.    M e dic al 
i nf or m ati o n  res ulti n g  fr o m  a  s u bject’s  p artici p ati o n  i n  t his  st u dy  m a y  b e  gi v e n  t o  t h e  s u bje ct’s  p ers o n al 
p h ysicia n or t o t h e a p pr o priate m e dical p ers o n n el res p o nsi ble f or t h e s u bje ct’s w elfare.   
 
N o  i nf or m ati o n  t h at  ca n  b e  relate d  t o  a  s p e cific  i n di vi d u al  s u bje ct  m a y  b e  rele as e d  or  us e d  i n  a n y  fas hi o n 
wit h o ut t h e si g n e d writte n c o nse nt of t h at s u bje ct.  All re p orts a n d c o m m u nic ati o ns relati n g t o st u d y s u bje cts 
will i d e ntif y s u bjects o nl y b y i nitials a n d s u bje ct i d e ntific 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 plete 
s u bject  i d e ntificati o n  f or  p ur p oses  of  l o n g-ter 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  tre ate d  wit h 
strict a d h ere n ce t o pr ofessi o n al sta n d ar ds of c o nfi d e ntialit y. 
 
Site p ers o n n el will e nter d ata relati n g t o e a c h s u bje ct’s p artici p ati o n i n t h e st u d y i nt o t h e E D C s yste 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 yste m,  i d e ntific ati o n  n u m b ers  a n d  i nitials  will  b e  use d  t o  i d e ntif y  s u bje cts.  
S u bject n a m es will n ot b e use d i n t h e C R Fs.  M a n a g e m e nt of d ata fr o m t h e E D C s yste m  a n d t h e pr o d u cti o n of 
t h e cli nical st u d y re p ort will b e t h e res p o nsi bilit y of t h e S p o ns or.   A c c ess t o t h e d ata b as e will b e restricte d t o 
e m pl o y ees w h o h a v e b ee n trai n e d t o use t h e s yste m.   A c c ess t o t h e E D C s yste m  a n d st u d y re p ort will b e li mite d 
t o t h e I R B, F D A or ot h er re g ulat or y a g e n cies a n d t h e S p o ns or. 
 
Prese ntati o n a n d/ or p u blica ti o n of t h e res ults of t h e st u d y is e n c o ura g e d pr o vi d e d t h at T h e R o m ar k I nstit ute f or 
M e dical  R esearc h  is  n otifie d  i n  a d v a n ce  of  t h e  a ut h or's  i nte nt  a n d  is  gi v e n  t h e  o p p ort u nit y  t o  re vie w  t h e 
m a n uscri pt or a bstract 4 5 d a ys pri or t o its s u b missi o n f or prese ntati o n at a scie ntific m e eti n g or f or p u blic ati o n 
i n  a  scie ntific  j o ur n al.  T h e I n v esti g at ors will h a v e c o m plete a ut o n o m y re g ar di n g t h e c o nte nt a n d w or di n g of 
a n y  a bstracts,  prese ntati o ns,  a n d  scie ntific  p u blic 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.  
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
4 1  
 
 
1 8  D A T A/ R E P O R T R E Q UI R E M E N T S  
 
D ata re q uire d b y T h e R o m ar k I nstit ute f or M e dic al R es e arc h pri or t o a p pr o v al a n d i nitiati o n of t h e st u d y are as 
f oll o ws: 
 
1) 
C urric 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 nse nt a n d p atie nt 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.  
 
D ata a n d m aterials re q uire d b y T h e R o m ar k I nstit ute f or M e dic al R es e arc h b ef ore t h e st u d y c a n b e c o nsi d er e d 
c o m plete a n d ter mi n ate d are as f oll o ws:  
 
1)  Pre - a n d p ost -treat m e nt hist or y, p h ysic al e x a mi n ati o n a n d p atie nt e v al u ati o ns.  
 
2)  Pre - as w ell as i nteri m a n d p ost -tre at m e nt la b orat or y fi n di n gs a n d all s p e cial test res ults. 
 
3)  E D C f or ms  pr o p erl y c o m plete 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 dicati n g  dr u g  dis p e ns e d  a n d  ret ur n  of  t h e  u n us e d  s u p plies  t o  t h e  S p o ns or  or 
d estr u cti o n b y st u d y site.  
 
5)  Si g n e d I nf or m e d C o nse nt/ Asse nt fr o m e a c h s u bje ct.  
 
 
 


The Romark Institute for Medical Research 
19 CONTACT INFORMATION 
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Protocol RM0S-3004 Final v. 1.5 
42 
Janua1y 3, 2019 
CONFIDENTIAL 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
4 3  
 
2 0  R E F E R E N C E S  
 
1.  
W H O: W orl d H ealt h Or g a nizati o n. I nfl u e n z a ( S e as o n al) fa ct s h e et N o. 2 1 1; c. 2 0 1 5 [ u p d ate d 2 0 1 6 N o v; 
cite d  2 0 1 7  J ul  2 4;  visite d 2 0 1 7  J ul  2 4].  A v aila ble  at:  htt p:// w w w. w h o.i nt/ m e dia c e ntre/fa cts h e ets 
/fs 2 1 1/e n/ 
 
2.  
C D C.  Disease  b ur d e n  of  i nfl u e n z a.  [ u p d ate d  2 0 1 7  M a y  1 6;  cite d  2 0 1 7  J ul  2 6].  A v a ila ble 
at: htt ps:// w w w.c d c. g o v/ fl u/a b o ut/ dise ase/ b ur d e n ht m. 
 
3.  
W H O:  W orl d  H ealt h  Or g a nizat i o n.  W H O  o ut bre a k  c o m m u nic ati o n. W H O  H a n d b o o k  f or  J o ur n alists . 
U p d ate d D ece m b er 2 0 0 5. A v aila ble at: w w w. w h o.i nt/csr/ d o n/ H a n d b o o k _i nfl u e n z a _ p a n d e mic _ d e c 0 5.p df  
 
4. 
Wri g ht  P F,  N e u m a n n  G,  K a w a o k a  Y.  ( 2 0 0 7)  i n  Fiel d’s  Vir ol o g y,  5t h  E d.,  Li p pi n c ott,  Willia ms  a n d  
Wil ki ns, P hila d el p hia, p p. 1 6 9 1 -1 7 4 0 . 
 
5. 
P alese P, S h a w M. ( 2 0 0 7) i n  Fiel d’s Vir ol o g y, 5t h E d., Li p pi n c ott, Willia ms a n d Wil ki ns, P hila d el p hia, 
p p. 1 6 4 7 -1 6 8 9 . 
 
6. 
C o x NJ, S u b b ara o K. I nfl u e n za.  L a n c et  1 9 9 9; 3 5 4: 1 2 7 7 -1 2 8 2 . 
 
7. 
G u  J,  Xie  Z,  G a o  Z,  Li u  J,  K orte w e g  C,  Y e  J,  L a u  L T,  L u  J,  G a o  Z,  Z h a n g  B,  M c N utt  M A,  L u  M, 
A n d ers o n  V M,  G o n g  E,  Y u  A C,  Li p ki n  WI.   H 5 N 1  i nfe cti o n  of  t h e  res pirat or y  tra ct  a n d  b e y o n d:  a 
m olec ular p at h ol o g y st u d y.   L a n cet  2 0 0 7; 3 7 0: 1 1 3 7 -1 1 4 5 . 
 
8. 
H a y d e n F G, Fritz R, L o b o M C, Al v or d W,  Str o b er W, Stra us,  S E. L o c al a n d s yste mic c yt o ki n e res p o ns es 
d uri n g e x p eri m e ntal h u m a n i nfl u e n z a A vir us i nfe cti o n. R elati o n t o s y m pt o m f or m ati o n a n d h ost d efe nse.  
J Cli n I n vest  1 9 9 8; 1 0 1: 6 4 3 -6 4 9 . 
 
9. 
C h e u n g C Y, P o o n L L, L a u A S, L u k W, L a u Y L, S h ortri d g e K F,  G or d o n S, G u a n Y, P eiris J S.  I n d u cti o n 
of pr oi nfla m m at or y c yt o ki n es i n h u m a n m a cr o p h a g es b y i nfl u e n z a A ( H 5 N 1) vir uses: a m e c h a nis m f or 
t h e u n us u al se v erit y of h u m a n dise ase ?  L a n c et  2 0 0 2; 3 6 0: 1 8 3 1 – 1 8 3 7 . 
 
1 0 . 
B er n asc o ni  D,  A mici  C,  L a  Frazia  S,  Ia n ar o A,  S a nt or o  M G.  T h e  I k a p p a B  ki n as e  is  a  k e y  fa ct or  i n 
tri g g eri n g i nfl u e n za A vir us-i n d u ce d i nfla m m at or y c yt o ki n e pr o d u cti o n i n air w a y e pit h elial c ells.  J Bi ol 
C h e m   2 0 0 5; 2 8 0: 2 4 1 2 7 -2 4 1 3 4 . 
 
1 1 . 
G h e di n E, S e n g a m ala y N A, S h u m w a y M, Z a b ors k y J, F el d bl y u m T,  S u b b u V, S pir o DJ, Sitz J, K o o H, 
B ol ot o v P, D er n o v o y D, T at us o v a  T,  B a o  Y,  St  G e or g e  K,  T a yl or  J,  Li p m a n  DJ,  Fras er  C M,  T a u b e n -
b er g er J K, S alz b er g S L.  L ar g e -scale se q u e n ci n g of h u m a n i nfl u e n z a re v e als t h e d y n a mic n at ure of viral 
g e n o m e e v ol uti o n.  N at ure  2 0 0 5; 4 3 7: 1 1 6 2 – 1 1 6 6 . 
 
1 2. 
W e b b y RJ, W e bster R G. Are w e rea d y f or p a n d e mic i nfl u e n z a ?  S cie n c e  2 0 0 3; 3 0 2: 1 5 1 9 -1 5 2 2 . 
 
1 3 .  
H ori m ot o T, K a w a o k a Y.  I nfl u e n z a: less o ns fr o m p ast p a n d e mics, w ar ni n gs fr o m c urre nt i n ci d e nts.  N at 
R ev Micr o bi ol  2 0 0 5; 3: 5 9 1 -6 0 0.  
 
1 4. 
D a w o o d F S, J ulia n o A D, R ee d C, M eltz er MI, S h a y D K et al. Esti m ate d gl o b al m ortalit y ass o ciate d wit h 
t h e  first  1 2  m o nt hs  of  2 0 0 9  p a n d e mic  i nfl u e n z a  A  H 1 N 1  vir us  circ ulati o n:  a  m o d eli n g  st u d y. L a n c et 
I nfect Dis 2 0 1 2; 1 2: 6 8 7 -9 5.  
 
1 5. 
A n d ers o n V R, C urra n M P. N T Z : A re vie w of its use i n t h e tre at m e nt of g astr oi ntesti n al i nfe cti o ns. Dr u gs  
2 0 0 7; 6 7: 1 9 4 7 -1 9 6 7.  
 
1 6. 
Ali nia ( nitaz o x a ni d e ) prescri 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 pri  2 0 1 7. 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
4 4  
 
 
1 7. 
R ossi g n ol J F, L a Frazia S, C hia p p a L, Ci u c ci A, S a nt or o M G. T hia z ol i d es, a n e w class of a nti-i nfl u e n z a 
m olec ules  tar g eti n g  viral  h e m a g gl uti ni n  at  t h e  p ost -tra nslati o n al  le v el. J  Bi ol  C h e m  2 0 0 9;  2 8 4: 2 9 7 9 8 -
2 9 8 0 8.  
 
1 8 .  
As ht o n L V, C alla n R L, R a o S, L a n d olt G A. I n vitr o s usc e pti bilit y of c a ni n e i nfl u e n z a A ( H 3 N 8) vir us t o 
nit az o x a ni d e a n d tiz o x a ni d e. V et M e d I nt  2 0 1 0; 2 0 1 0: 8 9 1 0 1 0.  
 
1 9 .  
Slee m a n K, Mis hi n V P, G u o Z, G arte n RJ, B alis h A, Fr y A M, Villa n u e v a J, Ste v e ns J, G u b are v a L V. 
A nti viral s usce pti bilit y of v aria nt i nfl u e n z a A( H 3 N 2) v vir us es is olate d i n t h e U nite d States fr o m  2 0 1 1 t o 
2 0 1 3. A nti micr o b A g e nts C h e m ot h er  2 0 1 4; 5 8: 2 0 4 5 -5 1.  
 
2 0.  
Til m a nis  D,  v a n  B aale n  C,  O h  D Y,  R ossi g n ol  J -F,  H urt  A C.    T h e  s usc e pti bilit y  of  circ ulati n g  h u m a n 
i nfl u e n za  vir uses  t o  tiz o x a ni d e,  t h e  a cti v e  m eta b olite  of  nita z o x a ni d e. A ntivir  R es  2 0 1 7; 
d o i: 1 0. 1 0 1 6/j.a nti viral. 2 0 1 7. 1 0. 0 0 2. 
 
2 1.  
B elar d o G, C e n ciarelli O, L a Frazia S, R ossi g n ol J F, S a nt or o M G. S y n er gistic effe ct of nita z o x a ni d e wit h 
n e ura mi ni d ase  i n hi bit ors  a g ai nst  i nfl u e n z a  A  vir uses  i n  vitr o. A nti micr o b  A g e nts  C h e m ot h er  2 0 1 5; 
5 9: 1 0 6 1 -9.  
 
2 2. 
R ossi g n ol J F. Nitaz o x a ni d e: A first -i n-class br o a d -s p e ctr u m a nti viral a g e nt. A ntivir al R es  2 0 1 4; 1 1 0: 9 4 -
1 0 3.  
 
2 3. 
H affiz ula  J,  H art m a n  A,  H o p p ers  M,  R es nic k  H,  S a m u drala  S,  Gi n n o c hi o  C,  B ar di n  M,  R ossi g n ol  J F. 
Effect  of  nitaz o x a ni d e  i n  a d ults  a n d  a d oles c e nts  wit h  a c ute  u n c o m plic ate d  i nfl u e n z a:  a  d o u ble -bli n d, 
ra n d o mize d, place b o c o ntr olle d, p h ase 2 b/ 3 trial. L a n c et I nfe ct Dis  2 0 1 4; 1 4: 6 0 9 -1 8.  
 
2 4. 
U. S. F o o d a n d Dr u g A d mi nistrati o n. G ui d a n c e f or I n d ustr y, I nfl u e n z a: D e v el o pi n g Dr u gs f or Treat m e nt 
a n d/ or  Pr o p h yla xis.  A v aila ble at:  
w w w f d a. g o v/ d o w nl o a ds/ dr u gs/ g ui d a n c e c o m plia n c ere g ulat or yi nf or m ati o n/ g ui d a n c es/ u c m 0 9 1 2 1 9  
 
2 5.  
P o w ers J H, et al. D e v el o p m e nt of t h e Fl u -P R O: a p atie nt -re p orte d o utc o m e ( P R O) i nstr u m e nt t o e v al u ate 
s y m pt o ms of i nfl u e n za. B M C I nfect D is 2 0 1 5; 1 6: 1.  
 
2 6.  
P o w ers J H, et al. R elia bilit y, v ali dit y, a n d res p o nsi v e n ess of i nfl u e n z a p atie nt -re p orte d o utc o m e ( F L U-
P R O ® ) sc ores i n i nfl u e n za-p ositi v e p atie nts. V al u e i n H e alt h . A v aila ble o nli n e a h e a d of pri nt 2 1 A u g ust 
2 0 1 7 at htt p:// w w w.scie n ce dir ect.c o m/scie n c e/article/ pii/ S 1 0 9 8 3 0 1 5 1 7 3 0 2 1 4 0/.  
 
2 7. 
Os b or n e  R.,  H a wt h or n e  G,  P a p a nic ola o u  M,  W e g m u eller  Y.    M e as ure m e nt  of  ra pi d  c h a n g es  i n  h e alt h 
o utc o m es i n p e o ple wit h i nfl u e n za s y m pt o ms. J O utc o m es R es  2 0 0 0; 4: 1 5 -3 0.  
 
2 8. 
Cli nical  St u d y  R e p ort  W -1 4 4 1 0 2,  Pr ot o c ol  W V 1 5 6 7 0.    R o c h e.  A v aila ble  at:  htt ps: w w w.i n d ustr y d o c u 
m e ntsli brar y. u csf.e d u/ dr u g/ d o cs/ #i d =s q p m 0 2 1 7.  
 
2 9. 
Cli nical  St u d y  R e p ort  W -1 4 4 1 0 3,  Pr ot o c ol  W V 1 5 6 7 1.    R o c h e.    A v aila ble  at:  htt ps: w w w.i n d ustr y d o c u 
m e ntsli brar y. u csf.e d u/ dr u g/ d o cs/ #i d =t q p m 0 2 1 7.  
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
4 5  
 
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 ule  
 
A p p e n di x II:  
T o xicit y Gra di n g f or A d ult A d v ers e E v e nts  
 
A p p e n di x I II:  
List of Esse ntial D o c u m e nts f or t h e I n v esti g ati v e Site  
 
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 eclarati o n of H elsi n ki  
 
 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
4 6  
 
2 1. 1  
A p p e n di x I .    St u d y S c h e d ule  
 
 
S cree ni n g  
( D a y 1) 
B aseli 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 nsc 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 
X 3 
X 
Bl o o d sa m ple f or p h ar m ac o ki n etics  
 
 
 
 
 
 
X 4 
Bl o o d sa m ple f or a nti -i nfl u e n za 
a nti b o dies  
 
 
X  
 
  
 
 
 
X  
 
Bl o o d sa m ple f or la b orat or y safet y 
tests5 
 
 
X  
 
 
 
 
 
 
X 
X 
Uri n e sa m ple f or r o uti n e uri n al ysis 5 
 
 
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 ple te 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 ucti o ns re: d osi n g, c o nc o mita nt 
m e dicati o ns, patie nt 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 p atie nt diar y  e ntries  
 
 
 
 
X 6 
 
 
X 6 
S cree n f or i nfl u e n za-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 ner 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 7 
 
1 D a y 7 a n d 2 2 p h ysical e xa m is a brief p h ysical e xa m ( vital si g ns a n d n ursi n g p h ysical assess m e nt) i ncl u di n g s y m pt o m directe d p h ysicia n 
p h ysical e xa mi nati o n as re q uire d b y patie nt s y m pt o ms.  Vita l si g ns i ncl u de bl o o d press ure, p ulse, res pirat or y rate a n d oral te m perat ure.  
2 N as o p har y n geal s w a bs o n da ys 2 a n d 3  will be c ollecte d at t he patie nt’s h o me ( or cli nic or a n ot her l ocati o n as a gree d wit h t he patie nt).  
3 N as o p har y n geal s w a bs c ollecte d o n da y 2 2 will o nl y be teste d f or t he prese nce of vir us if t he sa m ple fr o m da y 7  ha d detecta ble vir us.  
4 Bl o o d sa m ple  c ollecte d pre -d ose o n da y 3.  
5 La b orat or y safet y tests i ncl u de he m o gl o bi n, he m at 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 ns a n d bl o o d).  
6 All s u bjects  will m ai ntai n a n electr o nic diar y u ntil da y 2 2 ( + 3 ).  Site staff will c o ntact s u bjects as nee de 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 . 
7 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 be perf or m e d at u nsc he d ule d visit if a p plica ble.  
 


The Romark Institute for Medical Research 
Protocol RM0S-3004 Final v. 1.5 
21.2 
Appendix II. Toxicity Grading for Adve1·se Events 
Janua1y 3. 2019 
[Deri ved and adapted from "Guidance for hidustry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials", US Dept. of HHS, FDA, CDER, 
September 2007] 
Tables fo1· Clinical Abnormalities 
Vital Signs* 
Mild 
Moderate 
(Gnde 1) 
(Grade 2) 
Fever 
(°C) . .  
38.0- 38.4 
38.5-38.9 
(OF) . .  
100.4-101.l 
101.2-102.0 
Tachycardia - beats per 
101-115
116 - 130 
minute 
Bradycardia - beats per 
5 0 - 5 4  
4 5 - 4 9  
minute*** 
Hypertension (systolic)-
141 - 150 
151 -155 
mmHg 
Hypertension (diastolic)-
9 1 - 9 5  
9 6 - 100 
lll1l1 Hg 
Hy p otension (systolic) -
8 5 - 8 9  
8 0 - 8 4  
mm Hg 
Respiratory Rate - breaths 
17-20 
21-25 
per minute 
•
Subject should be at rest for all vital sig n  measurements .
** Oral temperature; no recent hot or cold beverages or smoking . 
Seve1·e 
Potentially Life 
(Grade 3) 
Threatening 
(Grade 4) 
39.0-40 
> 4 0
102.l - 104 
> 104 
>130
ER visit or 
hospitalization for 
an·hythmia 
<45 
ER visit or 
hospitalization for 
an·hythmia 
> 155 
ER v-isitor 
hospitalization for 
malig n a nt 
hy p e1tension 
> 100 
ER visit or 
hospitalization for 
malig n a nt 
hy p e1tension 
<80 
ER visit or 
hospitalization for 
hy p otensive shock 
> 25 
Intubation 
. . .  When resting heart rate is between 60 - l 00 beats per minute. Use clinical judg m ent when characterizing bradycardia 
among some healthy subject populations, for example, conditioned athletes. 
47 
CONFIDENTIAL 


The Romark Institute for Medical Research 
Protocol RM0S-3004 Final v. 1.5 
Appendix II. 
Toxicity Grading Scale Tables fo1· Clinical Abnormalities (continued) 
Systemic (General) 
 1ild 
Moderate 
Severe 
(Grade 1) 
(Grade 2) 
(Grade 3) 
Nausea/vomiting 
No interference 
Some interference 
Prevents daily 
,vith activity or 1 - 2 
with acti1rity or> 2 
activity. requires 
episodes/24 hours 
episodes/24 hours 
outpatient IV 
hydration 
Diarrhea 
2 - 3 loose stools or 
4 - 5 stools or 
6 or more watery 
< 400 gms/24 hours 
400 - 800 gms/24 
stools or 
hours 
> 800gms/24 hours 
or re.quires 
outpatient IV
hydration 
Headache 
No interference with 
Repeated use of non-
Significant: any 
activity 
narcotic pain 
use of narcotic 
reliever > 24 how·s or 
pain reliever or 
some interference 
prevents daily 
with activity 
activity 
Fatig ue 
No interference with 
Some interference 
Significant: 
activity 
with activity 
prevents daily 
activity 
Myalgia 
No interference with 
Some interference 
Significant: 
activity 
with activity 
prevents daily 
activ;ty 
Systemic Illness 
Mild 
Moderate 
Severe 
(Grade 1) 
(Grade 2) 
(Grade 3) 
Illness or clinical adverse 
No interference with 
Some interference 
Prevents daily 
event (as defined 
activ;ty 
with activ;ty not 
activ;ty and 
according to applicable 
requiring medical 
requires medical 
regulations) 
intervention 
intervention 
48 
Janua1y 3, 2019 
Potentially Life 
Threatening 
(Grade 4) 
ER visitor 
hospitalization for 
hy p otensive shock 
ER visitor 
hospitalization 
ER visitor 
hospitalization 
ER visitor 
hospitalization 
ER visit or 
hospitalization 
Potentially Life 
Threatenini: 
(Grade 4) 
ER visit or 
hospitalization 
CONFIDENTIAL 


The Romark Institute for Medical Research 
Protocol RM0S-3004 Final v. 1.5 
Appendix II. 
Toxicity Grading Scale Tables fo1· Labo1·ato1-y Abnormalities 
Janua1y 3, 2019 
The laboratory values provided in the tables below serve as guidelines and are de pendent upon institutional normal parameters. 
Serum* 
Mild 
Model'8te 
Severe 
Potentially Life 
(Grade 1) 
(G1·ade 2) 
(Grade 3) 
Threatening 
(Grade 4)** 
Sodium - Hyponatremia mEq/L 
132-134
130-131
125 -129 
< 125 
Sodium - Hypematremia mEq/L 
144-145
146 - 147 
148 - 150 
> 150 
Potassium - Hyperkalemia mEq/L 
5.1 - 5.2 
5.3- 5.4 
5.5- 5.6 
> 5.6 
Potassium - Hy p okalemia rnEq/L 
3.5-3.6
3.3-3.4
3 . 1 - 3.2 
< 3.1 
Chloride -rnEq/L*0
Asymptomatic or 
Moderate; 
Severe or 
Life-threatening 
mild symptoms; 
mininial, local or 
medically 
consequences: 
clinical or 
noninvasive 
significant but not 
urgent 
dia211ostic 
intervention 
immediately life 
intervention 
obs 1vations only; 
indicated; limiting 
threatening; 
indicated 
intervention not 
age-appropriate 
hospitalization or 
indicated 
instmrnental ADL 
prolongation of 
existing 
hospitalization 
indicated; 
disabling; lintiting 
self care ADL 
Glucose - Hypoglycemi a mg/dL 
6 5 - 6 9  
55-64 
4 5 - 5 4  
<45 
Glucose -Hyperglycemia 
Insulin 
Fasting - mg/dL 
100-110
111-125
>125
requirements or 
Random - mg/dL 
110- 125 
126-200
>200
hy p erosmolar 
coma 
Blood Urea Nitrogen 
2 3 - 2 6  
27-31 
>31
Requires dialysis 
BUNmg/dL 
Creatinine - mg/dL 
1.5 -1.7 
1.8- 2.0 
2.1- 2.5 
> 2.5 or requires 
dialvsis
Calcilllll - hy p oca lcemia mg/dL 
8.0-8.4 
7.5- 7.9 
7.0- 7.4 
<7.0
Calcilllll - hy p ercalcemia mg/dL 
10.5 - 11.0 
11.1-11.5 
11.6- 12.0 
> 12.0 
MagnesiUlll - hy p omagnesemia mg/dL 
1.3 - 1.5 
1.1- 1.2 
0 . 9 - 1.0 
<0.9
Phosphorous - hy p ophosphatemi a 
2.3 -2.5 
2.0-2.2 
1.6- 1.9 
< 1.6 
mg/dL 
CPK-mg/dL 
1.25 -1.5 X 
1.6-3.0xULN 
3.1-10 x ULN 
>lOxULN
ULN**** 
Albumin - Hy p oalbumi nemia g/dL 
2.8-3.1 
2.5-2.7 
<2.5 
-
Total Protein- Hypoproteinem.ia g/dL 
5.5-6.0 
5.0-5.4 
< 5.0 
--
The laboratory values provided in the tables serve as guidelines and are de p endent upon institutional nonnal 
parameters. Institutional nom1al reference ranges should be provided to demonstrate that they are appropriate. 
The clinical sig n s  or symptoms associated with laboratory abnonnalitics might result in characterization of the 
laboratory abno1malities as Potentially Life Threatening (Grade 4). For example. a low sodium value that falls within a 
grade 3 para.meter (125-129 m E /
L) should be recorded as a grade 4 hy p onatremia event if the subject had a new seiwre
associated with the low sodium value. 
Derived from the National Institutes of Health. National Cancer Institute Common Tenni..nology Criteria for Adverse 
Events (CTCAE) Version 5.0. ADL- Activities of Daily Living refer to preparing meals, shopping for groceries or 
clothes. using the telephone, managing money, etc. selfcare ADL refer to bathing, dressing and tmdressing. feeding 
self, using the toilet, taking medications, and not bedridden. 
''ULN" is the upper limit of the nonnal range. 
49 
CONFIDENTIAL 


The Romark Institute for Medical Research 
Protocol RM0S-3004 Final v. 1.5 
Appendix II. 
Toxicity Grading Scale Tables fo1· Labo1·ato1-y Abnormalities (continued) 
Serum* 
Mild 
Mode1·ate 
Severe 
(Grade 1) 
(Grade 2) 
(Grade 3) 
Alkaline phosphate -
1.1 - 2.0 x ULN 
2.1- 3.0 x ULN 
3 . 1 - l 0 x U L N  
increase by factor 
Liver Function Tests -ALT, AST 
1.1 -2.5 x ULN 
2.6- 5.0 x ULN 
5 . 1 - l 0 x U L N  
increase by factor 
Liver Function Tests - GOT*** 
>ULN-2.5x
>2.5 - 5.0 x ULN 
>5.0-20.0 X 
increase by factor 
ULN
ULN 
Bilirubin - when accompanied by any 
1.1 - 1.25 x ULN 
1.26 - 1.5 x ULN 
1.51 -1.75 X 
increase in Liver Function Test 
ULN 
increase bv factor 
Bilimbin - when Liver Function Test is 
1.1 - 1.5 X ULN 
1.6- 2.0 x ULN 
2.0- 3.0 x ULN 
nonnal· increase by factor 
Cholesterol••• 
ULN-300 mg/dL 
>300 - 400 mg/dL 
>400 - 500 mg/dL 
Triglycerides- mg/dL••• 
150 mg/dL- 300 
>300 mg/dL- 500 
>500mg/dL-
me/dL 
me/dL 
1000 me/dL 
HDL-mg/dL*** 
Asymptomatic or 
Moderate; 
Severe or 
mild symptoms: 
minimal, local or 
medically 
clinical or 
nomnvas1ve 
significant but not 
diaguostic 
intervention 
immediately life 
observations only; 
indicated; limiting 
threatening; 
intervention not 
age-appropriate 
hospitalization or 
indicated 
instnunental ADL 
prolongation of 
existing 
hospitalization 
indicated: 
disabling; lintiting 
self care ADL 
LDL-mg!dL••• 
Asymptomatic or 
Moderate; 
Severe or 
mild symptoms; 
minimal, local or 
medically 
clinical or 
norunvas1vc 
significant but not 
diaguostic 
intervention 
immediately life 
obse1vations only; 
indicated; limiting 
threatening: 
intervention not 
age-appropriate 
hospitalization or 
indicated 
instnunental ADL 
prolongation of 
existing 
hospitalization 
indicated; 
disabling; lintiting 
self care ADL 
Janua1y 3, 2019 
Potentially Life 
Threatening 
(Grade 4)** 
>lOxULN
> l0xULN
>20.0xULN
> 1.75 xULN
> 3.0x ULN
>500mg/dL
>lO00mg/dL
Life-threatening 
co11sequences: 
urgent 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
The laboratory values provided in the tables serve as guidelines and arc de p endent upon institutional nonnal 
parameters. Institutional nomial reference ranges should be provided to demonstrate that they are appropriate. 
•••• 
The clinical sig n s  or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnonnalities as Potentially Life 11:ireatening (Grade 4). For example. a low sodirnn value that falls within a 
grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hy p onatremia event if the subject had a new seizure 
associated with the low sodillll1 value. 
Derived from the National Institutes of Health. National Cancer Institute Common Tenninology Criteria for Adverse 
Events (CTCAE) Version 5.0. ADL- Activities of Daily Living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. selfcare ADL refer to bathing, dressing and undressing. feeding 
self, using the toilet, taking medications, and not bedridden. 
"ULN" is the upper limit of the noruial range . 
50 
CONFIDENTIAL 


The Romark Institute for Medical Research 
Protocol RM0S-3004 Final v. 1.5 
Appendix II. 
Toxicity Grnding Scale Tables for Laboratory Abnormalities (continued) 
Hematology * 
 1ild 
Moderate 
Severe 
(Grade 1) 
(Grade 2) 
(Grade 3) 
Hemoglobin (Female) -
11.0- 12.0 
9.5- 10.9 
8.0-9.4 
gm/dL 
Hemoglobin (Female) 
AJ.1y decrease - 1.5 
1.6-2.0 
2.1- 5.0 
chan2e from baseline value 
-2111/dL 
Hemoglobin (Male) -
12.5 - 13.5 
10.5 - 12.4 
8.5- 10.4 
gm/dL 
Hemoglobin (Male) 
AJ.1y decrease - 1.5 
1.6-2.0 
2.1- 5.0 
change from baseline value 
-gm/dL
Hematocrit - % . .
Asymptomatic or 
Moderate; minimal. 
Severe or medically 
mild symptoms; 
local or noninvasive 
significant but not 
clinical or diagnostic 
intervention 
inimediately life 
observations only; 
indicated; limiting 
threatening; 
intervention not 
age-appropriate 
hospitalization or 
indicated 
instrumental ADL 
prolongation of 
existing 
hospitalization 
indicated; disabling; 
limiting self care 
ADL 
WBC Increase - cell/mnl 
I 0,800 - 15,000 
15,001 - 20,000 
20,001- 25, 000 
WBC Decrease - cell/mm' 
2,500 - 3,500 
1,500- 2,499 
1,000- 1,499 
Lymphocytes Decrease -
750-1,000
500-749
250-499
cell/llllll3 
Neutrophils Decrease -
1,500 - 2,000 
1,000- 1.499 
500-999
cell/ =
3 
Eosinophils - c e l l ! = '  
650-1500
1501 - 5000 
> 5000 
Platelets Decreased -
c e l l / =3 
125.000- 140,000 
100,000- 124,000 
25,000 - 99,000 
PT - increase by factor 
1.0- 1.10 x ULN• . .  
1.11 - 1.20 x ULN 
1.21 - 1.25 x ULN 
(prothrombin time) 
PTT - increase by factor 
1.0-1.2 x ULN 
1.21 -1.4 x ULN 
1.41 - 1.5 x ULN 
(partial thromboplastin 
time) 
Fibrinogen increase -
400-500
501 -600 
> 600 
ml!'.ldL 
Fibrinogen decrease -
150-200
125 - 149 
100-124
mg/dL 
Janua1y 3. 2019 
Potentially Life 
Threatening (Grade 
4) 
<8.0 
>5.0
< 8.5 
>5.0
Life-threatening 
consequences; urgent 
inte1-vention 
indicated 
>25,000 
< 1,000 
<250
< 500 
Hy p creosinophilic 
<25,000 
> 1.25 ULN
> l.5xULN
-
< 100 or associated 
with gross bleeding 
or disseminated 
intravascular 
coagulation (DIC) 
TI1e laboratory values provided in the tables serve as guideliues and are dependent upon institutional normal parameters. 
Institutional normal refereuce rauges should be provided to demonstrate that they are appropriate. 
** 
Derived from the National Institutes of Health, National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0. ADL- Activities of Daily Living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. selfcare ADL refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bed.ridden. 
''ULN" is the upper limit of the nonnal rauge. 
51 
CONFIDENTIAL 


The Romark Institute for Medical Research 
Protocol RM0S-3004 Final v. 1.5 
Appendix II. 
Toxicity Grading Scale Tables fo1· Labo1·ato1-y Abnormalities (continued) 
Urine* 
Mild 
Moderate 
Severe 
(Grade 1) 
(Grade 2) 
(Grade 3) 
Protein 
Trace 
I+ 
2+ 
Glucose 
Trace 
I+ 
2+ 
Blood (microscopic)-
I - IO 
11-50 
> 50 and/or gross
red blood cells per high 
blood 
power field (rbc/hpf) 
Janua1y 3, 2019 
Potentially Life 
Threatening 
(Grade 4) 
Hospitalization or 
dialysis 
Hospitalization for 
hy p erglycemia 
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion 
*
The laboratory values provided in the tables serve as guidelines and arc dependent upon institutional nonnal parameters. 
Institutional nonnal reference ranges should be provided to demonstrate that they arc appropriate. 
52 
CONFIDENTIAL 


The Romark Institute for Medical Research 
Protocol RM0S-3004 Final v. 1.5 
Janua1y 3, 2019 
21.3 
Appendix III. List of Essential DocU1Dents for the Investigative Site 
1. 
2. 
3. 
4. 
5. 
6. 
7. 
8. 
9. 
10. 
11. 
12. 
13. 
14. 
15. 
16. 
Study No: RM0S-3004 
Title of Document 
Investigator's Brochme and Updates 
Signed protocol (all versions) and amendments, if any, and sample EDC fonns 
Information given to trial subject 
• Informed consent form (all versions), Any other written information, Advertisement for 
subject recruitment @j!Se  including all al? licable translations 
Financial agreement between the Investigator/institution and the Sponsor for the trial 
Signed agreement between involved parties 
• Financial Disclosure of Investigator/institution and Sponsor 
• Confidential Disclosm·e A eement of Investigator/institution and S onsor 
Dated, documented approval/favorable opinion ofIRB of the following: 
• Protocol and any amendments 
• Informed consent form and any revisions 
• Any other written info1mation to be provided to the subjects 
• Advertisement for subject recmitment (if t1Sed) 
• Subject compensation (if any) 
• Any other documents given approval 
• Continuing review of the trial 
Institutional Review Board composition 
Regulatory notice of Principal Investigator and sub-Investigators, FDA Fonn 1572 
Cuniculum vitae and/or other relevai1t documents evidencing qualifications of Investigator and 
sub-Investigators 
Normal values/ranges and updates for medical/laboratory/technical procedm·es and/or tests 
included in the protocol 
Medical/laboratory technical procedures/tests and updates: 
• certification or 
• accreditation or 
• established quality control and/or external quality assessment or 
• other validation (where required) 
Shipping records for investigational product(s) and trial-related materials 
Certificate(s) of Analysis of investigational product(s) shipped 
Unblinding procedure to docmnent how, in case of an emergency, identity of blinded 
investigational roduct can be revealed without breaking the blind for the remaining subjects 
Site initiation monitoring report 
Relevant communications other than site visits: 
• Letters/ emails 
• Meeting notes 
• Notes of tele hone calls 
Si 
ed infonned consent forms 
Sow·ce docwnents 
Sig}!ed, dated, and com leted EDC forms to include doctunentation ofEDC form cotTections 
Notification by origi!iating Investigator to S onsor of serious adverse events and related rep011s 
Notification by Investigator, where a licable, to IRB of llllex ected serious adverse dmg 
53 
CONFIDENTIAL 


T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3 , 2 01 9  
 
 
C O N FI D E N TI A L  
 
 
5 4  
 
 
 
reacti o ns a n d of ot h er safet y i nf or m ati o n 
2 2. 
N otificati o n b y S p o ns or t o I n v esti g at or of sa fet y i nf or m ati o n 
2 3. 
Interi m or a n n u al re p orts t o I R B  a n d a ut h orit y/ies (if a p plic a ble)  
2 4. 
S u bject S cree ni n g l o g  
2 5. 
S u bject i d e ntificati o n c o d e list  t o p er mit i d e ntific ati o n of all s u bje cts e nr olle d i n t h e trial i n c ase 
f oll o w-u p is re q uire d  
2 6. 
S u bject e nr oll m e nt l o g  
2 7. 
In v esti g ati o n al pr o d u ct acc o u nta bilit y  re c or ds (re c ei pt, st ora g e, dis p e nsi n g, s hi p m e nt, ret ur n or 
d estr u cti o n ) 
2 8. 
S i g n at ure s h eet t o d o c u m e nt si g n at ures a n d i nitials of all p ers o ns a ut h oriz e d t o m a k e e ntries a n d/ or 
c orrecti o ns o n e C R Fs  
2 9. 
R ec or d of retai n e d b o d y fl ui ds/tiss u e sa m ples (if a n y)  
3 0 . 
Fi n al re p ort b y I n v esti g at or/i nstit uti o n t o I R B  
3 1.  
A u dit C ertificate (if a v aila ble)  


The Romark Institute for Medical Research 
21.4 
Appendix IV. Protocol Revision History 
Summary of Changes 
Initial Version 
Protocol version 1. 1 d ated December 14, 2017 
Pre-Enrollment l/i date 
Protocol RM08-3004 Final v. 1.5 
Purpose: 
Update the protocol to remove urine tests for ketones and pH that were inadvertently included in the previous version 
Effective Date: 
December 28, 2017 
January 3, 2019 
Change 1: 
Page 15, Section 3, Sh1dy Design and page 20, Section 5.2, Baseline and page 22, Section 5.6, Day 7 Follow-up and page 23, Section 5.8, 
Unscheduled Visit and page 46, Section 21.1, Appendix I: Study Schedule 
Action: 
Amendment 1 
Pm ose: 
Effective Date: 
Change 1: 
Change 2: 
Action: 
Amendment2 
Pmpose: 
Effective Date: 
Change l: 
Change 2: 
Deleted "ketones, H '  from the list of w-inal sis t.ests 
A revised rotocol version 1.2 dated December 28, 201 7 was 0enerated 
Page 17, Section 4.1, "Inclusion Criteria" 
Changed oral temperature criteria from "a) oral le111perat11re of?.99.4 °F or ?.37.4 °C obtained in office, AND" to "a) oral temperah1re of?.99.4 °F 
or ?.37.4 •c (obtained in office or self-measured within 12 hours prior to screening - if self-measured, subject 111ust also have taken an antipyrelic
within 4 hours rior to screenin ), AND" 
Page 42, Section 19, "CONTACT INFORMATION" 
Changed medical monitor name and e-mail address from 
"to 
A revised protocol version 1.3 dated Febrruuy 6, 2018 was generated 
Administrative update to the protocol to (1) updated the expected trial dw-ation, (2) update the exclusion criteria for influenza season-specific 
vaccination dates, and (3) update the exclusion criteria to exclude use ofbaloxavir 
Jw1e 15, 2018 
Page 5, Protocol Synopsis, Trial Duration and Page 15, Section 3, Study Design 
Changed trial dw-ation from "December 2017- October 2018" to "December 2017-April 2019" 
Page 19, Section 4.2, Exclusion Criteria 
Changed exclusion criteri on #14 from "Vaccination for seasonal influenza on or after August 1, 2017" to "Vaccination for seasonal influenza on 
or after (i) August 1, 2017 in the case o f  subjects enrolled during the 2017/2018flu season in the Northern He111isphere, (ii) Februa,y 1, 2018 in 
the case o f  subjects enrolled during the 2018flu season in the Southern Hemisphere, or (iii) August 1, 2018 in the case o f  subjects enrolled 
durin the 2018/2019 
11 season in the Northern Hemis here." 
55 
CONFIDENTIAL 


The Romark Institute for Medical Research 
Protocol RM08-3004 Final v. 1.5 
January 3, 2019 
Summa1-y of Changes 
Change 3: 
Page 19, Section 4.2, Exclusion Criteria 
Changed exclusion criterion # 15 from "Receipt of any dose o f  NTZ, oseltamivir, zanamivir, peramivir, laninamivir, amantadine or rimantadine 
within 3 days prior to screening." to "Receipt of any dose of N1Z, oseltamivil; zanamivil; peramivir, laninamivir, baloxavir, amantadine or 
rimantadine within 3 da y s  prior to screening. " 
Action: 
A revised protocol version 1.4 dated June 15, 2018 was generated 
Amendment3 
Pmpose: 
Update the protocol (1) to remove the exclusion criterion for influenza vaccination in order to have the studied population more accurately reflect 
the population affected by influenza and to ensure robust patient enrolhnent, (2) to clarify endpoint response definitions in accordance with the 
way patient dia r y  questions are phrased, and (3) to make additional administrative updates. 
Change 1: 
Page 19, Section 4.2, Exclusion Criteria 
Deleted exclusion criterion 4, "Vaccination for seasonal influenza on or after {i) August 1, 2017 in the case o f  subjects enrolled during the 
2017/2018flu season in the Northern Hemisphere, {ii) Febmmy 1, 2018 in the case o f  subjects enrolled dwing the 2018flu season in the 
Southern Hemisphere, or (iii) Au ust 1, 2018 in the case of subjects enrolled durinf( the 2018/2019/lu season in the Northern Hemisphere." 
Change 2: 
Page 25, Section 7.1, Electronic Data Enhy 
Updated "Adverse e vents will be coded by data management using the Medical Dictionmy for Reg11lat01y Activities {MedDRA) version 15.1; 
medications will be coded by data management using the World Health Organization {WHO) DRUG dictiona1y. "to "Adverse e vents will be 
coded by data management using the latest version of the Medical Dictionmy for Regulato,y Activities {MedDRA); medications will be coded by 
data management using the latest version o f  the World Health Organi::.ation {WHO) DRUG dicfionm)I." 
Change 3: 
Page 28, Section 8.3, Response Definitions 
Updated the definition of Tin1e of Ability to Pe1fo1m All Nom1al Activities from "Die start of the first daily dimy period in which the subject 
reports a score o f  10 on the 0-10 scale for ability to pe1fo1111 normal activities, which is maintained for at least 2 daily dia1y periods without 
symptom relief medication dwing those 2 daily dia1y periods" to 'The time o f  the first daily dia1y entry in which the subject reports a score of 10 
on the 0-10 scale for ability to pe1fo1111 nonnal activities, which is maintained for at least 2 daily dia,y pe1iods without s ymp tom relief medication 
durinf( those 2 dailv diarv periods". 
Change 4: 
Page 29, Section 8.3, Response Definitions 
Updated the definition of Time of Return to Usual Health from "The sta11 of the first daily dimy pe1iod in which Usual Health is achiered and is 
maintained for at least 2 dai y dia,y pe1iods without symptom relief medication during those 2 daily dia,y pe1iods" to "The time of the first daily 
dia1y en fly in which Usual Health is achiet·ed and is maintained for at least 2 daily dia1y periods without symptom relief medication dwing those 
2 daily dia,y periods". 
Change 5: 
Page 29, Section 8.4.1, Efficacy Analyses 
Updated stratification specification for the primary and key secondary efficacy analyses from "where sh·atification will follow that used for 
randomization" to "sh·atified by (1) time since s ymptom onset for each subject at enrollment (?.24 hours, > 24 - 36 hours, > 36 hours) and (2) 
whether the subject received seasonal influenza vaccination after August 1, 2018." 
56 
CONFIDENTIAL 


The Romark Institute for Medical Research 
Protocol RM0S-3004 Final v. 1.5 
January 3, 2019 
Summa1-y of Changes 
Change 6: 
Page 32, Section 10, Adverse Events 
Updated "Symptoms of influenza (cough, sore throat, nasal obsh1.1ction, fatigue, headache, myalgia, f e verishness) and complications of influenza 
(pneumonia, ofitis media, bronchitis, sinusitis) shall not be reported as adverse e vents unless there is a causal relationship between the study 
medication and the e vent." to "Symptoms of influenza (i.e., those caph1red in the FLU-PRO Questionnaire) and complications of influenza (e.g., 
pneumonia, otitis media, bronchitis, sinusitis) shall not be reported as adverse events unless there is a causal relationship between the sh.1dy 
medication and the e vent. " 
Change 7: 
Page 37, Section 15, Informed Consent 
Deleted "Electronic infonned consent systems and services will be used for this study 
). Prior to initiation, site 
staff and auth01ized Romark personnel will be trained lo use the system." and updated t e su sequent section text to update references to eICFs 
to ICFs a er. 
Change 8: 
Page 42, Section 19, Contact Infonnation 
Change 9: 
Change 10: 
Action: 
Updated Sponsor Project Management name and mobile phone number from 
"Name: 
Page 50, Appendix II, Toxicity Grading Scale Tables for Laborato1y Abno1111alities 
Updated grading categories for Cholesterol abnormalities from: 
Mild (Grade 1): 201-210 mg/dL 
Moderate (Grade 2): 211-225 mgldL 
S evere (Grade 3): >226 mg/dL 
to 
Mild (Grade 1): ULN - 300 mgldL 
Moderate (Grade 2): > 300-400 mgldL 
S evere (Grade 3): >400-500 mgldL 
Potentially Life-threatening: >500 mgldL 
and updated CTCAE version from 4.0 to 5.0 in table footnote. 
Pages 53-54, Appendix ill, List of Essential Documents for the Investigative Site 
Updated per "ICH E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(Rl) Guidance for Indus try" 
A revised protocol version 1.5 dated January 3, 2019 was generated 
57 
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T h e R o m ar k I nstit ute f or M e dical R esearc h  
Pr ot o c ol R M 0 8 -3 0 0 4 Fi n al v. 1. 5 
Ja n u ar y 3, 2 0 1 9 
 
 
C O N FI D E N TI A L  
 
 
5 8  
 
2 1. 5  
A p p e n di x V.  D ecl a r ati o n of H elsi n ki  
 


Clinical Review & Education 
Special Communication 
World Medical Association Declaration of Helsinld 
Ethical Principles for Medical Research 
Involving Human Subjects 
World Medical Association 
Adopted by the 18th WMA General Assembly, Helsinki, Finland. June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan. October 1975 
35th WMA General Assembly. Venice, Italy. October 1983 
41st WMA General Assembly. Hong Kong. September 1989 
48th WMA General Assembly. Somerset West. Republic of South Africa. October 1996 
52nd WMA General Assembly. Edinburgh. Scotland. October 2000 
53rd WMA General Assembly. Washington. DC. USA. October 2002 (Note of Clarification added) 
55th WMA General Assembly. Tokyo. Japan. October 2004 (Note of Clarification added) 
59th WMA General Assembly. Seoul. Republic of Korea. October 2008 
64th WMA General Assembly. Fortaleza. Brazil. October 2013 
Preamble 
1. The World Medical Association (WMA) has developed the Dec-
laration of Helsinki as a statement of ethical principles for medi-
cal research involving human subjects, including research on 
identifiable human material and data.
The Declaration is intended to be read as a whole and each of
its constituent paragraphs should be applied with consider-
ation of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA. the Declaration is ad-
dressed primarily to physicians. The WMA encourages others
who are involved in medical research involving human subjects 
to adopt these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with
the words, "The health of my patient will be my first consider-
ation," and the International Code of Medical Ethics declares that,
"A physician shall act in the patient's best interest when provid-
ing medical care.· 
4. It is the duty of the physician to promote and safeguard the
health, well-being and rights of patients. including those who are 
involved in medical research. The physician's knowledge and con-
science are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must in-
clude studies involving human subjects. 
6. The primary purpose of medical research involving human sub-
jects is to understand the causes, development and effects of
diseases and improve preventive, diagnostic and therapeutic in-
terventions (methods, procedures and treatments). Even the
Jama.com 
best proven interventions must be evaluated continually through 
research for their safety, effectiveness. efficiency, accessibility 
and quality. 
7. Medical research is subject to ethical standards that promote and 
ensure respect for alt human subjects and protect their health
and rights. 
8. While the primary purpose of medical research is to generate new
knowledge, this goal can never take precedence over the rights 
and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research 
to protect the life, health, dignity, integrity, right to self-
determination. privacy, and confidentiality of personal informa·
tion of research subjects. The responsibility for the protection
of research subjects must always rest with the physician or other
health care professionals and never with the research subjects, 
even though they have given consent. 
10. Physicians must consider the ethical. legal and regulatory norms 
and standards for research involving human subjects in their own
countries as well as applicable international norms and stan-
dards. No national or international ethical. legal or regulatory re-
quirement should reduce or eliminate any of the protections for
research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that mini-
mises possible harm to the environment.
12. Medical research involving human subjects must be conducted
only by individuals with the appropriate ethics and scientifJC edu-
cation, training and qualifications. Research on patients or
healthy volunteers requires the supervision of a competent and
appropriately qualified physician or other health care profes-
sional. 
JAMA November 27. 2013 Volume 310. Number 20 
2191 
Copyright 2013 American Medical Association. AU rights reserved. 
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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 ps t h at ar e u n d err e pr es e nt e d i n  m e dic al r es e arc h s h o ul d
b e pr o vi d e d a p pr o pri at e acc ess t o p artici p ati o n i n r es e arc h.
1 4. P h ysici a ns  w h o c o m bi n e  m e di c al r es e ar c h  wit h  m e dic al c ar e
s h o ul d i n v ol v e t h eir p ati e nts i n r es e arc h o nl y t o t h e e xt e nt t h at
t his is j ustifi e d b y its p ot e nti al pr e v e nti v e, di a g n ostic or t h er a-
p e utic v al u e a n d if t h e p h ysici a n h as g o o d r e as o n t o b eli e v e t h at
p artici p ati o n i n t h e r es e arc h st u d y  will n ot a d v ers el y aff ect t h e
h e alt h of t h e p ati e nts  w h o s er v e as r es e arc h s u bj ects.
1 5. A p pr o pri at e c o m p e ns ati o n a n d tr e at m e nt f or s u bj ects  w h o ar e
h ar m e d as a r es ult of p arti ci p ati n g i n r es e ar c h  m ust b e e n-
s ur e d.
Ris ks, B ur d e ns a n d B e n efits
1 6. I n  m e dic al pr actic e a n d i n  m e dic al r es e arc h,  m ost i nt er v e nti o ns
i n v ol v e ris ks a n d b ur d e ns.
M e dic al r es e arc h i n v ol vi n g h u m a n s u bj ects  m a y o nl y b e c o n-
d uct e d if t h e i m p ort a nc e of t h e o bj ecti v e o ut w ei g hs t h e ris ks a n d
b ur d e ns t o t h e r es e arc h s u bj ects.
1 7. All  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 b e pr e-
c e d e d b y c ar ef ul ass ess m e nt of pr e dict a bl e ris ks a n d b ur d e ns
t o t h e i n di vi d u als a n d gr o u ps i n v ol v e d i n t h e r es e arc h i n c o m-
p aris o n  wit h f or es e e a bl e b e n efits t o t h e m a n d t o ot h er i n di vi d u-
als or gr o u ps aff ect e d b y t h e c o n diti o n u n d er i n v esti g ati o n.
M e as ur es t o  mi ni mis e t h e ris ks  m ust b e i m pl e m e nt e d. T h e ris ks
m ust b e c o nti n u o usl y  m o nit or e d, ass ess e d a n d d oc u m e nt e d b y
t h e r es e arc h er.
1 8. P h ysici a ns  m a y n ot b e i n v ol v e d i n a r es e arc h st u d y i n v ol vi n g h u-
m a n s u bj ects u nl ess t h e y ar e c o nfi d e nt t h at t h e ris ks h a v e b e e n
a d e q u at el y ass ess e d a n d c a n b e s atisf act oril y  m a n a g e d.
W h e n t h e ris ks 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 efits or
w h e n t h er e is c o ncl usi v e pr o of of d efi niti v e o utc o m es, p h ysi-
ci a ns  m ust ass ess  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 ps a n d I n di vi d u als
1 9. S o m e gr o u ps a n d i n di vi d u als ar e p artic ul arl y v ul n er a bl e a n d  m a y
h a v e a n i ncr 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 nc urri n g a d-
diti o n al h ar m.
All v ul n er a bl e gr o u ps a n d i n di vi d u als s h o ul d r e c ei v e s p e cifi-
c all y c o nsi d er e d pr ot ecti o n.
2 0.  M e dic al r es e arc h  wit h a v ul n er a bl e gr o u p is o nl y j ustifi e d if t h e
r es e arc h is r es p o nsi v e t o t h e h e alt h n e e ds or pri oriti es of t his
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 his 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 actic es or i nt er v e nti o ns t h at r es ult
fr o m t h e r es e arc h.
Sci e ntific R e q uir e m e nts a n d R es e arc h Pr ot oc ols
21.  M e dic al r es e arc h i n v ol vi n g h u m a n s u bj ects  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 es, b e b as e d o n a t h or o u g h
k n o wl e d g e of t h e sci e ntific lit er at ur e, ot h er r el e v a nt s o urc es 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, as 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 als us e d f or r es e arc h
m ust b e r es p ect e d.
2 2. T h e d esi g n a n d p erf or m a nc e of e ac h r es e arc h st u d y i n v ol vi n g
h u m a n s u bj ects  m ust b e cl e arl y d escri b e d a n d j ustifi e d i n a r e-
s e arc h pr ot oc ol.
T h e pr ot oc ol s h o ul d c o nt ai n a st at e m e nt of t h e et hic al c o nsi d-
er ati o ns i n v ol v e d a n d s h o ul d i n dic at e h o w t h e pri nci pl es i n t his
D ecl ar ati o n h a v e b e e n a d dr ess e d. T h e pr ot oc ol s h o ul d i ncl 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 ns ors, i nstit uti o n al affili a-
ti o ns, p ot e nti al c o nflicts of i nt er est, i nc e nti v es f or s u bj ects a n d
i nf or m ati o n r e g ar di n g pr o visi o ns f or tr e ati n g a n d/ or c o m p e n-
s ati n g s u bj ects  w h o ar e h ar m e d as a c o ns e q u e nc e of p artici p a-
ti o n i n t h e r es e arc h st u d y.
I n cli nic al tri als, t h e pr ot oc ol  m ust als o d escri b e a p pr o pri at e ar-
r a n g e m e nts f or p ost-tri al pr o visi o ns.
R es e arc h Et hics C o m mitt e es
2 3. T h e r es e arc h pr ot oc ol  m ust b e s u b mitt e d f or c o nsi d erati o n, c o m-
m e nt, g ui d a nc e a n d a p pr o v al t o t h e c o nc er n e d r es e arc h et hics
c o m mitt e e b ef or e t h e st u d y b e gi ns. T his c o m mitt e e  m ust b e
tr a ns p ar e nt i n its f u ncti o ni n g,  m ust b e i n d e p e n d e nt of t h e r e-
s e arc h er, t h e s p o ns or a n d a n y ot h er u n d u e i nfl u e nc e a n d  m ust
b e d ul y q u alifi e d. It  m ust t a k e i nt o c o nsi d er ati o n t h e l a ws a n d
r e g ul ati o ns of t h e c o u ntr y or c o u ntri es i n  w hic h t h e r es e arc h is
t o b e p erf or m e d as  w ell as a p plic a bl e i nt er n ati o n al n or ms a n d
st a n d ar ds b ut t h es e  m ust n ot b e all o w e d t o r e d uc e or eli mi n at e
a n y of t h e pr ot ecti o ns f or r es e arc h s u bj ects s et f ort h i n t his D ec-
l ar ati o n.
T h e c o m mitt e e  m ust 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 es. T h e r es e arc h er  m ust 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, es p eci all y i nf or m ati o n a b o ut a n y s eri o us a d v ers e
e v e nts. N o a m e n d m e nt t o t h e pr ot oc ol  m a y b e  m a d e  wit h o ut
c o nsi 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 es e arc h ers  m ust 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 gs a n d c o n-
cl usi o ns.
Pri v ac y a n d C o nfi d e nti alit y
2 4. E v er y pr ec a uti o n  m ust b e t a k e n t o pr ot ect t h e pri v ac y of r e-
s e arc h s u bj ects a n d t h e c o nfi d e nti alit y of t h eir p ers o n al i nf or-
m ati o n.
I nf or m e d C o ns e nt
2 5. P artici p ati o n b y i n di vi d u als c a p a bl e of gi vi n g i nf or m e d c o ns e nt
as s u bj ects i n  m e dic al r es e arc h  m ust b e v ol u nt ar y. Alt h o u g h it
Cli nic al R e vi e w & E d uc ati o n
S p eci al C o m m u nic ati o n
W orl d  M e dic al Ass oci ati o n D ecl ar ati o n of H elsi 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 ns ult f a mil y  m e m b ers or c o m m u nit y
l e a d ers, 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 ns e nt  m a y
b e e nr oll e d i n a r es e arc h st u d y u nl ess h e or s h e fr e el y a gr e es.
2 6. I n  m e dic al r es e arc h i n v ol vi n g h u m a n s u bj ects c a p a bl e of gi vi n g
i nf or m e d c o ns e nt, e ac h p ot e nti al s u bj ect  m ust b e a d e q u at el y
i nf or m e d of t h e ai ms,  m et h o ds, s o urc es of f u n di n g, a n y p os-
si bl e c o nfli cts of i nt er est, i nstit uti o n al affili ati o ns of t h e r e-
s e arc h er, t h e a ntici 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 disc o mf ort it  m a y e nt ail, p ost-st u d y pr o visi o ns a n d a n y
ot h er r el e v a nt as p ects of t h e st u d y. T h e p ot e nti al s u bj ect  m ust
b e i nf or m e d of t h e ri g ht t o r ef us e t o p artici p at e i n t h e st u d y or
t o  wit h dr a w c o ns e nt t o p artici p at e at a n y ti m e  wit h o ut r e pri-
s al. S p eci al att e nti o n s h o ul d b e gi v e n t o t h e s p ecific i nf or m a-
ti o n n e e ds of i n di vi d u al p ot e nti al s u bj ects as  w ell as t o t h e  m et h-
o ds us e d t o d eli v er t h e i nf or m ati o n.
Aft er e ns uri n g t h at t h e p ot e nti al s u bj ect h as u n d erst o o d t h e i n-
f or m ati o n, t h e p h ysici 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 ust t h e n s e e k t h e p ot e nti al s u bj ect’s fr e el y- gi v e n i n-
f or m e d c o ns e nt, pr ef er a bl y i n  writi n g. If t h e c o ns e nt c a n n ot b e
e x pr ess e d i n  writi n g, t h e n o n- writt e n c o ns e nt  m ust b e f or m all y
d oc u m e nt e d a n d  wit n ess e d.
All  m e dic al r es e arc h s u bj ects 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 utc o m e a n d r es ults of t h e st u d y.
27.  W h e n s e e ki n g i nf or m e d c o ns e nt f or p artici p ati o n i n a r es e arc h
st u d y t h e p h ysici a n  m ust b e p artic ul arl y c a uti o us if t h e p ot e n-
ti al s u bj ect is i n a d e p e n d e nt r el ati o ns hi p  wit h t h e p h ysici a n or
m a y c o ns e nt u n d er d ur ess. I n s uc h sit u ati o ns 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
is c o m pl et el y i n d e p e n d e nt of t his r el ati o ns hi p.
2 8. F or a p ot e nti al r es e arc h s u bj ect  w h o is i nc 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 ysici 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 ncl u d e d i n a r es e arc h st u d y t h at h as n o li k eli h o o d of b e n efit
f or t h e m u nl ess it is 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 es e nt e d b y t h e p ot e nti al s u bj ect, t h e r es e arc h c a n n ot i n-
st e a d b e p erf or m e d  wit h p ers o ns c a p a bl e of pr o vi di n g i n-
f or m e d c o ns e nt, a n d t h e r es e arc h e nt ails o nl y  mi ni m al ris 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 es e arc h s u bj ect  w h o is d e e m e d i nc a p a bl e of
gi vi n g i nf or m e d c o ns e nt is a bl e t o gi v e ass e nt t o d ecisi o ns a b o ut
p artici p ati o n i n r es e arc h, t h e p h ysici a n  m ust s e e k t h at ass e nt i n
a d diti o n t o t h e c o ns e nt of t h e l e g all y a ut h oris e d r e pr es e nt a-
ti v e. T h e p ot e nti al s u bj ect’s diss e nt s h o ul d b e r es p ect e d.
3 0. R es e arc h i n v ol vi n g s u bj ects  w h o ar e p h ysic all y or  m e nt all y i n-
c a p a bl e of gi vi n g c o ns e nt, f or e x a m pl e, u nc o nsci o us p ati e nts,
m a y b e d o n e o nl y if t h e p h ysic 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 ec ess ar y c h aract eristic of t h e
r es e arc h gr o u p. I n s uc h circ u mst a nc es t h e p h ysici 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. If
n o s uc h r e pr es e nt ati v e is a v ail a bl e a n d if t h e r es e arc 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 oc e e d  wit h o ut i nf or m e d c o ns e nt pr o-
vi d e d t h at t h e s p ecific r e as o ns f or i n v ol vi n g s u bj ects  wit h a c o n-
diti o n t h at r e n d ers t h e m u n a bl e t o gi v e i nf or m e d c o ns e nt h a v e
b e e n st at e d i n t h e r es e arc h pr ot oc ol a n d t h e st u d y h as b e e n a p-
pr o v e d b y a r es e arc h et hics c o m mitt e e. C o ns e nt t o r e m ai n i n t h e
r es e arc h  m ust b e o bt ai n e d as s o o n as p ossi bl e fr o m t h e s u bj ect
or a l e g all y a ut h oris e d r e pr es e nt ati v e.
31. T h e p h ysici a n  m ust f ull y i nf or m t h e p ati e nt  w hic h as p ects of t h eir
c ar e ar e r el at e d t o t h e r es e arc h. T h e r ef us al of a p ati e nt t o p ar-
tici p at e i n a st u d y or t h e p ati e nt’s d ecisi o n t o  wit h dr a w fr o m t h e
st u d y  m ust n e v er a d v ers el y aff ect t h e p ati e nt- p h ysici a n r el a-
ti o ns hi p.
3 2. F or  m e dic al r es e arc h usi n g i d e ntifi a bl e h u m a n  m at eri al or d at a,
s uc h as r es e arc 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 ks or
si mil ar r e p osit ori es, p h ysici a ns  m ust s e e k i nf or m e d c o ns e nt f or
its c oll ecti o n, st or a g e a n d/ or r e us e. T h er e  m a y b e e xc e pti o n al
sit u ati o ns  w h er e c o ns e nt  w o ul d b e i m p ossi 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 es e ar c h. I n s u c h sit u ati o ns t h e r e-
s e arc h  m a y b e d o n e o nl y aft er c o nsi d er ati o n a n d a p pr o v al of a
r es e arc h et hics c o m mitt e e.
Us e of Pl ac e b o
3 3. T h e b e n efits, ris ks, b ur d e ns a n d eff ecti v e n ess of a n e w i nt er-
v e nti o n  m ust b e t est e d a g ai nst t h os e of t h e b est pr o v e n i nt er-
v e nti o n(s), e xc e pt i n t h e f oll o wi n g circ u mst a nc es:
W h er e n o pr o v e n i nt er v e nti o n e xists, t h e us e of pl ac e b o, or n o
i nt er v e nti o n, is acc e pt a bl e; or
W h er e f or c o m p elli n g a n d sci e ntific all y s o u n d  m et h o d ol o gic al
r e as o ns t h e us e of a n y i nt er v e nti o n l ess eff ecti v e t h a n t h e b est
pr o v e n o n e, t h e us e of pl ac e b o, or n o i nt er v e nti o n is n ec ess ar y
t o d et er mi n e t h e effic ac 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 ec ei v e a n y i nt er v e nti o n l ess eff ecti v e t h a n
t h e b est pr o v e n o n e, pl ac e b o, or n o i nt er v e nti o n  will n ot b e s u b-
j ect t o a d diti o n al ris ks of s eri o us or irr e v ersi bl e h ar m as a r es ult
of n ot r ec ei vi n g t h e b est pr o v e n i nt er v e nti o n.
E xtr e m e c ar e  m ust b e t a k e n t o a v oi d a b us e of t his o pti o n.
P ost-Tri al Pr o visi o ns
3 4. I n a d va nc e of a cli nic al tri al, s p o ns ors, r es e arc h ers a n d h ost c o u n-
tr y g o v er n m e nts s h o ul d  m a k e pr o visi o ns f or p ost-tri al acc ess f or
all p artici p a nts  w h o still n e e d a n i nt er v e nti o n i d e ntifi e d as b e n-
efici al i n t h e tri al. T his i nf or m ati o n  m ust als o b e discl os e d t o p ar-
tici p a nts d uri n g t h e i nf or m e d c o ns e nt pr oc ess.
R es e arc h R e gistr ati o n a n d P u blic ati o n a n d Diss e mi n ati o n
of R es ults
3 5. Ev er y r es e arc h st u d y i n v ol vi n g h u m a n s u bj ects  m ust b e r e gis-
t er e d i n a p u blicl y acc essi bl e d at a b as e b ef or e r ecr uit m e nt of t h e
first s u bj ect.
W orl d  M e dic al Ass oci ati o n D ecl ar ati o n of H elsi n ki
S p eci al C o m m u nic ati o n
Cli nic al R e vi e w & E d uc 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 es e arc h ers, a ut h ors, s p o ns ors, e dit ors a n d p u blis h ers all h a v e
et hic al o bli g ati o ns  wit h r e g ar d t o t h e p u blic ati o n a n d diss e mi-
n ati o n of t h e r es ults of r es e arc h. R es e arc h ers h a v e a d ut y t o  m a k e
p u blicl y a v ail a bl e t h e r es ults of t h eir r es e arc h o n h u m a n s u b-
j ects a n d ar e acc o u nt a bl e f or t h e c o m pl et e n ess a n d acc ur ac y of
t h eir r e p orts. All p arti es s h o ul d a d h er e t o acc e pt e d g ui d eli n es
f or et hic al r e p orti n g. N e g ati v e a n d i nc o ncl usi v e as  w ell as p osi-
ti v e r es ults  m ust b e p u blis h e d or ot h er wis e  m a d e p u blicl y a v ail-
a bl e. S o urc es of f u n di n g, i nstit uti o n al affili ati o ns a n d c o nflicts
of i nt er est  m ust b e d ecl ar e d i n t h e p u blic ati o n. R e p orts of r e-
s e arc h n ot i n acc or d a nc e  wit h t h e pri nci pl es of t his D ecl ar ati o n
s h o ul d n ot b e acc e pt e d f or p u blic ati o n.
U n pr o v e n I nt er v e nti o ns i n Cli nic al Pr actic e
37. 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 ns d o n ot e xist or ot h er k n o w n i nt er v e nti o ns h a v e b e e n
i n eff ecti v e, t h e p h ysici a n, aft er s e e ki n g e x p ert a d vic e,  wit h i n-
f or m e d c o ns e nt fr o m t h e p ati e nt or a l e g all y a ut h oris e d r e pr e-
s e nt ati v e,  m a y us 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 ysi-
ci a n's j u d g e m e nt it off ers h o p e of s a vi n g lif e, r e- est a blis hi n g
h e alt h or all e vi ati n g s uff eri n g. T his i nt er v e nti o n s h o ul d s u bs e-
q u e ntl y b e  m a d e t h e o bj ect of r es e arc h, d esi g n e d t o e v al u at e
its s af et y a n d effic ac y. I n all c as es, n e w i nf or m ati o n  m ust 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 blicl 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 es p o n di n g A ut h or: W orl d  M e dic al
Ass oci 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 nc e;  w m a @ w m a. n et.
P u blis h e d  O nli n e: Oct 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.
Dis cl ai m er: © 2 01 3  W orl d  M e dic al Ass oci ati o n, I nc.
All Ri g hts R es er v e d. All i nt ell ect u al pr o p ert y ri g hts
i n t h e D ecl ar ati o n of H elsi n ki ar e v est e d i n t h e
W orl d  M e dic al Ass oci ati o n. T h e  W M A h as gr a nt e d
J A M A e xcl usi v e ri g hts t o p u blis h t h e
E n glis h-l a n g u a g e v ersi o n of t h e D ecl ar ati o n
t hr o u g h D ec 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 dc ast is a v ail a bl e at
w w w.j a m a.c o m.
Cli nic al R e vi e w & E d uc ati o n
S p eci al C o m m u nic ati o n
W orl d  M e dic al Ass oci ati o n D ecl ar ati o n of H elsi 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

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T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 of 4 3  
C O N FI D E N TI A L  
1.  R E VI SI O N HI S T O R Y  
V e rsi o n  
D ate  
R e visi o n 
A ut h o r  
C o m m e nts  
1. 0  
0 4J A N 2 0 1 8  
 
Ori gi n al S A P  
1. 1  
1 1 D E C 2 0 1 8  
 
U p d ate stratific ati o n fa ct ors a n d res p o nse d efi niti o ns f or “ Ti m e 
of R et ur n t o A bilit y t o P erf or m N or m al A cti vities” a n d “ Ti m e 
of R et ur n t o Us u al H e alt h ” i n a c c or d a n c e wit h pr ot o c ol v 1. 5  
1. 2  
T B D  
 
U p d ate t o:  
1.  Clarif y  h a n dli n g of missi n g c o n c o mita nt m e dic ati o ns e n d 
d ates a n d ti m es of d osi n g ( S e cti o n 8. 4);  
2.  A d d pr ot o c ol d e viati o n c ate g or y “ G C P ” ( S e cti o n s 9. 1. 2 , 
9. 2);  
3.  R e m o v e s u bje ct i nitials a n d uri n e pre g n a n c y test res ult 
fr o m D e m o gra phic D ata listi n g ( S e cti o n 9. 1. 2);  
4.  Clarif y d efi niti o n  of “ti m e fr o m s y m pt o m o nset” t o m e a n 
t h e ti m e i n h o urs b et w e e n t h e ti m e of first d ose of st u d y 
m e dic ati o n a n d t h e p atie nt -re p orte d ti m e of s y m pt o m o nset 
( S e cti o ns 9. 1. 4, 1 0. 2, 1 0. 2. 2, 1 0. 4. 1, 1 0. 4. 3, 1 0.5. 1  - 
1 0. 5. 4 ); 
5.  Clarif y s o urc e of ti m e of first d ose d ata ( S e cti o ns 1 0. 2 , 
1 0. 4. 1 , 1 0. 4. 3, 1 0. 5. 1 - 1 0. 5. 4);  
6.  U p d ate c u m ulati v e distri b uti o n p ara m eters f or sele cti o n of 
m a xi m u m s y m pt o m res p o nse criteria fr o m 7 5 % -9 0 % t o 
9 0 % -9 5 %  ( S e cti o n 1 0. 2. 1); 
7.  U p d ate pr o c e d u re f or sele cti o n of m a xi m u m s y m pt o m 
res p o nse criteria w h ere t h e n u m b er of d ail y diar y re c or ds t o 
b e e v al u ate d e x c e e ds t h e c a p a cit y of t h e I T s yste m  ( S e cti o n 
1 0. 2. 1) ; 
8.  Clarif y m a xi m u m s y m pt o m res p o nse criteria i n cl u di n g 
i m pr o v e m e nt of e x a m ple c ase ( S e cti o n 10. 2. 1) ; 
9.  Clarif y i m p a ct of s y m pt o m relief m e dic ati o n use o n Ti m e 
t o F L U-P R O D o m ai n R es p o nse  a n d R es ol uti o n of A c ute 
F e brile Ill n ess  a n al yse s ( S e cti o ns 1 0. 5. 2 , 1 0. 5. 3); 
1 0.  S p e cifie d t h at  t h e pri m ar y a n d se c o n d ar y effic a c y a n al yses 
will b e a n al y z e d i n a hierarc h ic al fas hi o n ( S e cti o n 1 0. 4); 
a n d  
1 1.  Clarifie d d eri v ati o n of a n al ysis v aria bles f or a n al ysis of 
Pr o p orti o ns of S u bje cts wit h D ete cta ble Vir us at D a ys 2, 3 
a n d 7 ( S e cti o n 1 0. 5. 6) . 
 
 
 
 




T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 4 of 4 3  
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 dic al 
R es e arc 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:  
P a g 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:  
Nita z o x a ni d e  3 0 0 m g T a blets  
N a m e of A cti v e I n g r e die nt:  
Nita z o x a ni d e  
Title Of St u d y:  
A P h ase III R a n d o miz e 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 Nita z o x a ni d e i n t h e Tre at m e nt of U n c o m pl ic ate d I nfl u e n z a 
I n v esti g at o rs:   
Multic e nter  
St u die d p e ri o d:  
D e c e m b er 2 0 1 7 – A pril 2 0 1 9  
P h as e of d e v el o p m e nt:  III 
O bje cti v es:  
T h e pri m ar y o bje cti v e of t his st u d y is t o e v al u ate t h e effe ct i v e n ess of n ita 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. w it h f o o 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 i nfl u e n z a c o m p are d t o 
t h at  of  a  pla c e 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 s e c o n d ar y effic a c y o bje cti 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 i m e  t o 
ret ur n t o a bilit y t o p erf or m all n or m al a cti vit ies. 
Ot h er s e c o n d ar y effic a c y o bje cti v es i n cl u d e e v al u ati n g t h e effe ct of N T Z c o m p are d t o pla c e b o o n:  
a)  t h e  pr o p orti o n  of  s u bje cts  e x p erie n ci n g  o n e  or  m ore  co m plic ati o ns  of  i nf l u e n z a  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,  w orse ni n g  of  pre -e xisti n g  h e alt h  c o n diti o ns, 
s yste mic  a nti bi otic  use  f or  i nfe cti o ns  se c o n d ar y  t o  i nfl u e n z a  i nfe cti o n,  h os pitaliz ati o n  d u e  t o 
c o m plic ati o ns of i nfl u e n z a, a n d d e at h ; a n d 
b)  t h e d ur ati o n of  s y m pt o ms of i nfl u e n z a 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 o ur F L U-P R O 
d o m ai ns  ( B o d y/ S yste mic,  T hr o at,  C h est/ R es pirat or y  a n d  N ose)  t h at  c orres p o n d  t o  t h e  s e v e n 
s y m pt o ms i n cl u d e d i n t h e tra diti o n al p atie nt -re p orte d o utc o m es i nstr u m e nt (fe v eris h n ess, m y al gia, 
h e a d a c h e, fati g u e, s ore t hr o at, n asal o bstr u cti o n a n d c o u g h) . 
Ot h er i m p orta nt o bje cti v es i n cl u d e e v al u ati o n of t h e safet y of N T Z b y a n al ysis of a d v erse e v e nts  a n d 
effe ct o n i nfl u e n z a a nti b o d y titers . 
N u m b e r of S u bje ct s:  
A s a m ple siz e of  at le ast 6 0 0  ( u p t o a m a xi m u m of 7 0 0) s u bje cts wit h la b orat or y -c o nfir m e d i nfl u e n z a is 
pla n n e d f or t h e st u d y. T his is esti m ate d t o re q uire a p pr o xi m atel y 8 0 0 t o 1 2 0 0 s u bje cts i n t otal. 
St u d y D esi g n:  
M ultic e nter ra n d o miz e d d o u ble -bli n d pla c e b o c o ntr olle d tr ial f or e v al u ati o n of effic a c y a n d safet y of 
N T Z  i n t h e tre at m e nt of u n c o m plic ate d i nfl u e n z a  
P o p ul ati o n:  
M ales a n d f e m ales ≥1 2  y e ars of a g e wit h u n c o m plic ate d  i nfl u e n z a 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 5 of 4 3  
C O N FI D E N TI A L  
St u d y D os e a n d 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 ail y ( b.i. d.) wit h f o o d f or 5 d a ys. 
Gr o u p 2 ( Pla c e b o):  
T w o pla c e b o ta blets orall y b.i. d. wit h f o o d f or 5 d a ys.   


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 6 of 4 3  
C O N FI D E N TI A L  
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  ...............................................................................................................................3  
3.  T E C H NI C A L S U M M A R Y R E P O R T  ....................................................................................................4  
5.  LI S T O F A B B R E VI A TI O N S  .................................................................................................................8  
6.  I N T R O D U C TI ON ...................................................................................................................................9  
7.  S T U D Y D E S C RI P TI O N  .........................................................................................................................9  
7. 1  
St u d y O bje cti v es  ............................................................................................................................9  
7. 2  
St u d y D esi g n  ...............................................................................................................................1 0  
7. 3  
S a m ple Siz e J ustific ati o n  .............................................................................................................1 1  
7. 4  
D ata C olle cti o n  ............................................................................................................................1 2  
8.  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 2  
8. 1  
A n al ysis P o p ulati o ns  ...................................................................................................................1 2  
8. 2  
D ata Prese ntati o n C o n v e nti o ns  ....................................................................................................1 3  
8. 3  
H a n dli n g of U nsc h e d ule d Assess m e nts  .......................................................................................1 3  
8. 4  
H a n dli n g of Missi n g D ata  ...........................................................................................................1 3  
9.  G E N E R A L C H A R A C T E RI S TI C S  .......................................................................................................1 5  
9. 1  
G e n eral C h ara cteristics T a bles a n d Fi g ures  ................................................................................1 5  
9. 1. 1  
D is p ositi o n of S u bje cts ................................................................................................... 1 5  
9. 1. 2  
Pr ot o c ol D e viati o ns  ........................................................................................................ 1 5  
9. 1. 3  
D e m o gra p hics  ................................................................................................................. 1 5  
9. 1. 4  
Dise ase C h ara cteristics  ................................................................................................... 1 5  
9. 1. 5  
Pri or a n d C o n c o mita nt M e dic ati o n  ................................................................................ 1 6  
9. 1. 6  
M e dic al Hist or y a n d C o n c o mita nt Dis e as es  ................................................................... 1 6  
9. 1. 7  
Tre at m e nt E x p os ure  ........................................................................................................ 1 6  
9. 2  
G e n eral C h ara cteristics Listi n gs  ..................................................................................................1 6  
1 0.  E F FI C A C Y  ............................................................................................................................................1 7  
1 0. 1  G e n eral  1 7  
1 0. 2  Pri m ar y Effic a c y A n al ysis: Ti m e t o S y m pt o m R es p o nse  ...........................................................1 8  
1 0. 2. 1  D eri v ati o n of t h e S y m pt o m R es p o nse D efi niti o n  .......................................................... 1 9 
1 0 . 2. 2 A n al ysis of t h e Pri m ar y Effic a c y P ara m eter  .................................................................. 2 1  
1 0. 3  S e nsiti vit y A n al yses of t h e Pri m ar y Effic a c y A n al ysis  ...............................................................2 1  
1 0. 3. 1  S e nsiti vit y A n al ysis Ass u mi n g Ti m e of S y m pt o m R es p o nse of 2 1 D a ys f or Disc o nti n u e d 
S u bje cts  .......................................................................................................................... 2 1  
1 0. 3. 2  S e nsiti vit y A n al ysis f or a “ P er Pr ot o c ol” S u bset  ........................................................... 2 1  
1 0. 4  S e c o n d ar y Effic a c y A n al yses  ......................................................................................................2 2  
1 0. 4. 1  Ti m e t o A bilit y t o P erf or m All N or m al A cti vities  ......................................................... 2 2  
1 0. 4. 2  Pr o p orti o n of S u bje cts E x p erie n ci n g C o m plic ati o ns of I nfl u e n z a  ................................. 2 3  
1 0. 4. 3  Ti m e  t o  M o difie d  S y m pt o m  R es p o nse  E x cl u di n g  F L U -P R O  G astr oi ntesti n al  a n d  E y e 
D o m ai ns  .......................................................................................................................... 2 3  
1 0. 5  E x pl orat or y Effic a c y A n al yses  ....................................................................................................2 5  
1 0. 5. 1  Ti m e t o I n di vi d u al S y m pt o m R es p o nse  ......................................................................... 2 5  
1 0. 5. 2  Ti m e t o F L U -P R O D o m ai n R es p o nse  ............................................................................ 2 7  
1 0. 5. 3  Ti m e t o R es ol uti o n of A c ute F e brile  Ill n ess ................................................................... 2 8  
1 0. 5. 4  Ti m e t o R et ur n t o Us u al H e alt h  ...................................................................................... 3 0  
1 0. 5. 5  C h a n g e i n I nfl u e n z a Vir us Titer ( T CI D 5 0) fr o m B aseli n e t o D a y 2 a n d fr o m B aseli n e t o 
D a y 3  .............................................................................................................................. 3 1  
1 0. 5. 6  Pr o p orti o ns of S u bje cts wit h D ete cta ble Vir us at D a ys 2, 3 a n d 7  ................................. 3 1  
1 0. 6  Ot h er E x pl orat or y A n al yses  ........................................................................................................3 2  


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 7 of 4 3  
C O N FI D E N TI A L  
1 0. 6. 1  A n al ysis of I nfl u e n z a A nti b o d y Titers  ........................................................................... 3 2  
1 0. 6. 2  P o p ulati o n P h ar m a c o ki n etics A n al ysis  .......................................................................... 3 3  
1 0. 7  Effic a c y Listi n gs  ..........................................................................................................................3 3  
1 1.  S A F E T Y  ................................................................................................................................................3 5  
1 1. 1  S afet y T a bles a n d Fi g ures  ...........................................................................................................3 5  
1 1. 1. 1 S u m m ar y of All Tre at m e nt E m er g e nt A d v e rse E v e nts ( T E A Es) .................................... 3 5  
1 1. 1. 2 S u m m aries of T E A Es b y S O C a n d Preferre d T er m  ......................................................... 3 5  
1 1. 1. 3 L a b orat or y R es ults a n d C h a n g es fr o m B aseli n e  .............................................................. 3 5  
1 1. 1. 4 S u m m aries of Vital Si g ns R es ul ts a n d C h a n g es fr o m B aseli n e ....................................... 3 6  
1 1. 1. 5 S u m m aries of P h ysic al E x a mi n ati o n R es ults a n d C h a n g es fr o m B aseli n e  ...................... 3 6  
1 1. 2  S afet y Listi n gs  .............................................................................................................................3 6  
1 2.  R E F E R E N C E S  ......................................................................................................................................3 8  
A p p e n di x I: S c h e d ule of Assess m e nts  .........................................................................................................3 9  
A p p e n di x II: D ata Dis pla ys  .........................................................................................................................4 0  
 
 
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 8 of 4 3  
C O N FI D E N TI A L  
5. 
LI S T O F A B B R E VI A TI O N S  
 
A E  
A d v erse e v e nt  
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.  
T wic e d ail y  
B U N  
Bl o o d ure a nitr o g e n  
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  
F D A  
U. S. F o o d a n d Dr u g A d mi nistrati o n  
G G T  
G a m m a -gl uta m yl tra 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  
L D L  
L o w d e nsit y li p o pr otei n  
L L N  
L o w er li mit of n or m al  
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 v erse tra nscri ptase p ol y m erase c h ai n re a cti o n  
S A E  
S eri o us a d v erse e v e nt  
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 CI D 5 0 
Tiss u e c ult ure 5 0 % i nfe cti v e d ose  
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  
U L N  
U p p er li mit of n or m al  
 
 
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 9 of 4 3  
C O N FI D E N TI A L  
6.  I N T R O D U C TI O N  
 
T h e p ur p os e of t his statistic al a n al ysis pla n ( S A P) is t o d escri b e t h e pla n n e d a n al yses a n d d ata dis pla ys t o 
b e i n c l u d e d i n t h e Cli nic al St u d y R e p ort ( C S R) f or Pr ot o c ol R M 0 8-3 0 0 4.  
 
All d e cisi o ns re g ar di n g fi n al a n al ysis as d efi n e d i n t his S A P will b e m a d e pri or t o u n bli n di n g of t h e st u d y 
d ata. F urt h er i nf or m ati o n c a n b e f o u n d i n t h e pr ot o c ol.  
 
T h e S A P  is b ase d o n: 
 
•  
Pr ot o c ol R M 0 8 -3 0 0 4, Fi n al  V ersi o n 1. 5 , D e c e m b er 1 2 , 2 0 18 
•  
I nter n ati o n al C o nfere n c e o n H ar m o nisati o n G ui d eli n es E 4 a n d E 9; a n d 
•  
Dis c ussi o ns wit h t h e U. S. F o o d a n d Dr u g A d mi nistrati o n ( F D A).  
 
T h e p ur p os e of t his d o c u m e nt is t o d escri b e a n al ysis p o p ulati o ns a n d t o d etail m et h o d ol o g y f or d eri vi n g 
v aria bles, h a n dli n g missi n g d ata, a n d a n al y zi n g effic a c y a n d safet y d ata.  
 
T h e S A P m a y b e re vise d or a m e n d e d t o refle ct t h e re q uire m e nts of pr ot o c ol a m e n d m e nts or re g ulat or y 
re q u ests, b ut m ust b e fi n aliz e d, a p pr o v e d a n d pla c e d o n file b ef ore t h e d ata b as e is l o c k e d. D e viati o ns fr o m 
t h e S A P will b e n ote d i n t h e C S R. 
 
 
7. 
S T U D Y D E S C RI P TI O N  
 
7 . 1 
St u d y O bje cti v es  
 
T h e pri m ar y o bje cti v e of t his 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 or all y 
6 0 0 m g b.i. d. wit h f o o 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 i nfl u e n z a c o m p are d t o 
t h at of a pla c e b o. 
 
A k e y se c o n d ar y effic a c y o bje cti 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 i m e t o 
ret ur n t o a bilit y t o p erf or m all n o r m al a cti vities. 
 
Ot h er s e c o n d ar y effic a c y o bje cti v es i n cl u d e e v al u ati n g t h e effe ct of N T Z c o m p are d t o pla c e b o o n:  
a)  t h e  pr o p orti o n  of  s u bje cts  e x p erie n ci n g  o n e  or  m ore  co m plic ati o ns  of  i nfl u e n z a  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,  w or se ni n g  of  pre-e xisti n g  h e alt h  c o n diti o ns, 
s yste mic a nti bi otic use f or i nfe cti o ns se c o n d ar y t o i nfl u e n z a i nfe cti o n, h os pitaliz ati o n d u e t o 
c o m plic ati o ns of i nfl u e n z a, a n d d e at h ; a n d 
b)  t h e d urati o n of  s y m pt o ms of i nfl u e n z a 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 o ur F L U-
P R O  d o m ai ns  ( B o d y/ S yste mic,  T hr o at,  C h est/ R es pirat or y  a n d  N ose)  t h at  c orres p o n d  t o  t h e 
se v e n  s y m pt o ms  i n cl u d e d  i n  t h e  tra diti o n al p atie nt -re p orte d  o utc o m es i nstr u m e nt 
(fe v eris h n ess, m y al gia, h e a d a c h e, fati g u e, s ore t hr o at, n asal o bstr u cti o n a n d c o u g h) . 
 
E x pl orat or y effic a c y o bje cti 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  e a c 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 
res ol uti o n of fe brile ill n ess, ti m e t o ret ur n t o us u al h e alt h, a n d c h a n g es i n viral titers fr o m b aseli n e t o 
e a c h of d a ys 2, 3 a n d 7.  
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 1 0  of 4 3  
C O N FI D E N TI A L  
Ot h er i m p orta nt o bje cti v es i n cl u d e e v al u ati o n of t h e safet y of N T Z b y a n al ysis of a d v erse e v e nts  a n d 
e v al u ati o n  of  t h e  effe ct  of  nita z o x a ni d e  o n  i nfl u e n z a  a nti b o d y  res p o nse  a n d  e v al u ati o n  of 
relati o ns hi ps b et w e e n p h ar m a c o ki n etics a n d cli nic al or vir ol o gic res p o nses. 
 
7 . 2 
St u d y D esi g n  
 
T h e  st u d y  will  b e  a  m ultic e nter,  ra n d o miz e d,  d o u ble -bli n d  trial  t o  e v al u ate  t h e  effic a c y  of  N T Z 
c o m p are d t o pla c e b o  i n tre ati n g u n c o m plic ate d i nfl u e n z a .  S u bje cts will b e s ele cte d a c c or di n g t o t h e 
i n cl usi o n a n d e x cl usi o n criteria liste d i n t h e pr ot o c ol.  T h e st u d y is d esi g n e d t o e nr oll at le ast 6 0 0  
s u bje cts ( u p t o 7 0 0  m a xi m u m) wit h la b orat or y -c o nfir m e d i nfl u e n z a.  T otal e nr oll m e nt re q uire d t o 
a c hie v e t hi s n u m b er is e x p e cte d t o b e a p pr o xi m atel y 8 0 0  t o 1 2 0 0  s u bje cts.  Pri or t o scre e ni n g f or 
i n cl usi o n i n t h e st u d y, i nf or m e d c o nse nt will b e o btai n e d. 
 
I m m e diatel y  after  c o m pleti o n  of  i nf or m e d  c o nse nt,  scre e ni n g,  a n d  e nr oll m e nt  i n  t h e  st u d y,  t w o 
b as eli n e n as o p h ar y n g e al s w a bs will b e c olle cte d f or viral c ult ure a n d R T -P C R.  A bl o o d sa m ple will 
b e  c olle cte d  f or  la b orat or y  safet y  tests  a n d  a nti -i nfl u e n z a  a nti b o dies,  a n d  a  uri n e  sa m ple  will  b e 
c olle cte d f or la b orat or y safet y tests.  S u bje cts will re c e i v e i nstr u cti o n o n c o m pleti n g  t h eir ele ctr o nic 
diaries, re c or di n g c o n c o mita nt m e dic ati o ns a n d atte n di n g f oll o w -u p visits.  
 
T h e n s u bje cts will b e ra n d o miz 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 ta blets b.i. d. f or 5 d a ys  
• Gr o u p 2 ( Pla c e b o):  
T w o pla c e b o ta blets b.i. d. f or 5 d a ys  
 
T h e m e dic ati o n will b e ta k e n i n t h e m or ni n g a n d e v e ni n g wit h f o o d .  T h e first d ose will b e ta k e n wit h 
f o o d i n t h e p h ysicia n’s offic e u n d er t h e o bser v ati o n of t h e Pri n ci p al I n v esti g at or or a m e m b er of t h e 
I n v esti gat or’s staff.  T h e se c o n d d ose will b e ta k e n b y t h e p atie nt as cl ose as p ossi ble t o 1 2 h o urs 
after t h e first d ose.  
 
A 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 bje ct  ( or t h e s u bje ct will ret ur n t o t h e cli nic) o n 
st u d y  d a ys  2  a n d 3 t o  c olle ct  t w o  n aso p h ar y n g e al  s w a bs,  t o  re vie w  p atie nt  diaries,  a n d  t o  re vie w 
s y m pt o ms  a n d  scre e n  f or  i nfl u e n z a-relate d  c o m plic ati o ns  i n cl u di n g  si n usitis,  otitis,  br o n c hitis, 
p n e u m o nia  a n d  c e ntral  n er v o us  s yste m  dise ase.    S u bje cts  will  b e  referre d  f or  i m m e diate  c are  as 
n e e d e d b ase d o n t h e scre e ni n g.  A b l o o d sa m ple f or p h ar m a c o ki n etics will als o b e c olle cte d o n st u d y 
d a y 3.  T h ese  d a y 2 a n d 3 visits will o c c ur at a p pr o xi m atel y t h e sa m e ti m e of d a y t h at t h e s u bje ct t o o k 
his/ h er first d ose of st u d y m e dic ati o n (r o u g hl y 2 4 a n d 4 8 h o urs p ost -first d ose).  O n d a y 3, t h e bl o o d 
s a m ple f or p h ar m a c o ki n etics will b e c olle cte d b ef ore t h e d ose.  T h e n as o p h ar y n g e al s w a bs will b e 
us e d t o e v al u ate q u a ntitati v e c h a n g es i n viral s h e d di n g.  T h e bl o o d sa m ples will b e use d t o e v al u ate 
relati o ns hips b et w e e n p h ar m a c o ki n etics a n d vir ol o gic or cli nic al res p o nse.  St u d y sites or s u bje cts 
m a y o pt o ut of t h e d a y 2 a n d d a y 3 visits d u e t o site staffi n g, p atie nt a v aila bilit y or ot h er pra ctic al 
c o nsi d erati o ns or prefere n c es; n e v ert h eless, at le ast 7 5 % of s u bje cts e nr olle d i n t h e trial are e x p e cte d 
t o  c o m plete  t h e  d a y  2  a n d  d a y  3  visits  a n d  relate d  pr o c e d ures  (f or  viral  ki n etics  a n d 
p h ar m a c o ki n etics).  
 
A st u d y p h ysicia n, n urse or ot h er site p ers o n n el will m a k e d ail y tele p h o n e c alls t o s u bje cts f or t h e 
first fi v e d a ys of d osi n g t o re vie w s y m pt o ms a n d scre e n f or i nfl u e n z a-relate d c o m plic ati o ns i n cl u di n g 
si n usitis, otitis, br o n c hitis, p n e u m o nia a n d c e ntral n er v o us s yste m dise ase.  S u bje cts will b e referre d 
f or  i m m e diate  c are  as  n e e d e d  b ase d  o n  t h e  scre e ni n g.  [ N ote:  I n  lie u  of  a  tele p h o n e  c all,  t his 
i nf or m ati o n  m a y  b e  o btai n e d  d uri n g  t h e  d a y  2  or  3 offic e  or  h o m e  visits  (se e t h e  pre c e di n g 
p ara gra p h ).]  T h e st u d y sites a n d s u bje cts will b e bli n d e d fr o m vir ol o g y la b orat or y d ata u ntil after 
st u d y d a y 22 or, if e arlier , u ntil t h e s u bje ct is dis c o nti n u e d fr o m t h e st u d y.  D uri n g t h e st u d y p eri o d, 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 1 1  of 4 3  
C O N FI D E N TI A L  
e a c h  s u bje ct  will  b e  pres u m e d  t o  h a v e  i nfl u e n z a  i nfe cti o n,  a n d  a n y  w orse ni n g  of  s y m pt o ms  or 
c o m plic ati o ns will b e pres u m e d t o b e i nfl u e n z a -relate d. 
 
S u bje cts  will  ret ur n  t o  t h e  c li nic  o n  d a ys  7  a n d  22 f or  p ost-tre at m e nt  f oll o w-u p,  i n cl u di n g  t w o 
n as o p h ar y n g e al  s w a bs,  dr u g  a c c o u nta bilit y,  re p orti n g  of  a d v erse  e v e nts  a n d  c o m plic ati o ns  of 
i nfl u e n z a.  Bl o o d a n d uri n e sa m ples f or la b orat or y safet y tests will b e c olle cte d at d a y 7, a n d a bl o o d 
s a m ple f or a nti-i nfl u e n z a a nti b o dies will b e c olle cte d o n d a y 22 .  A n urs e or ot h er st u d y p ers o n n el 
will re vie w t h e ele ctr o nic p atie nt diar y e ntries d ail y (s y n c hr o niz e d t o a w e b -b ase d d ata s yste m) t o 
e ns ure c o nte m p ora n e o us a n d c o m plete re c or di n g of diar y d ata.  S u bje cts will m ai ntai n t h e ele ctr o nic 
p atie nt  diar ies u ntil st u d y d a y 2 2 .  A n y visits t h at d o n ot o c c ur o n t h e pres cri b e d d ate, or wit hi n 1 d a y 
of t h at d ate i n t h e c ase of t h e d a y 7 visit or wit hi n 3 d a ys  after  i n t h e c ase of t h e d a y 22 visit  will b e 
re c or d e d as pr ot o c ol d e viati o ns. 
 
A c e ntral la b orat or y will b e use d f or la b orat or y safet y tests, a nti -i nfl u e n z a a nti b o dies a n d vir ol o g y 
testi n g.  L a b orat or y safet y tests will 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 nt ial), 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, al b 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/ dire ct), B U N, cre ati 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 n  a n d bl o o d).  Vir ol o g y testi n g will i n cl u d e R T -P C R 
ass a y  t o  i d e ntif y i nfl u e n z a  A  ( n o n-s p e cific  as  t o  s u bt y p e);  i nfl u e n z a  A  H 1,  H 3  a n d  H 1 N 1  ( 2 0 0 9) 
s u bt y p es; i nfl u e n z a B; res pirat or y s y n c ytial vir us A a n d B ( R S V); p arai nfl u e n z a 1, 2, 3 a n d 4; h u m a n 
m eta p n e u m o vir us  ( h M P V) ;  a d e n o vir us;  h u m a n  r hi n o vir us/e nter o vir us;  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 aseli n e a n d d a y 7 n as o p h ar y n g e al s w a bs), c ult ure ( b aseli n e a n d d a y 7 
n as o p h ar y n g e al s w a bs), a n d q u a ntitati o n of i nfl u e n z a vir uses b y T CI D 5 0 ( b aseli n e a n d  d a y s 2, 3 a n d 
7 n as o p h ar y n g e al s w a bs).  F oll o w -u p sa m ples ( d a ys 2 , 3 a n d 7) c olle cte d fr o m s u bje cts w h o d o n ot 
test p ositi v e f or i nfl u e n z a A or i nfl u e n z a B at b aseli n e will n ot b e a n al y z e d f or q u a ntitati v e i nfl u e n z a 
viral titer.  
 
T his st u d y is e x p e cte d t o r u n fr o m D e c e m b er 2 0 1 7 t hr o u g h A pril 2 0 1 9 . 
 
7 . 3 
S a m ple Siz e J ustific ati o n  
 
T h e  S y m pt o m  R es p o nse  d efi niti o n  f or  t his  st u d y  will  b e  d eri v e d  fr o m  t h e  s u bje cts’  F L U -P R O 
q u esti o n n aire r es p o nses as d escri b e d i n se cti o n 1 0. 2. 1 b el o w.  T h e F L U -P R O -d eri v e d e n d p oi nt is 
e x p e cte d t o tra c k v er y cl osel y t o ret ur n t o us u al h e alt h stat us (a d ail y y es/ n o q u esti o n i n t h e F L U -
P R O q u esti o n n aire).   P atie nt -re p orte d o utc o m es f or ti m e t o ret ur n t o us u al he alt h stat us h a v e b e e n 
s h o w n t o tra c k v er y cl osel y wit h ti m e t o a bilit y t o p erf or m 1 0 0 % of us u al a cti vities. 1, 2, 3 W e ass u m e , 
t h eref ore, t h at t h e c u m ulati v e  distri b uti o ns of ti m e t o sy m pt o m res p o nse f or t h e pla c e b o tre at m e nt 
gr o u p will  cl osel y  refle ct hist o ric al d ata  ( R o m ar k  st u dies  R M 0 8 -3 0 0 2  a n d  R M 0 8 -3 0 0 3  a n d 
os elta mi vir st u dies W V 1 5 6 7 0 a n d W V 1 5 6 7 1) f or ti m e fr o m first d ose u ntil t h e s u bje cts re p ort t h at 
t h e y are a ble t o p erf or m 1 0 0 % of us u al a cti vities.  B ase d u p o n d ata fr o m R o m ar k st u dies R M 0 8 -
3 0 0 1, R M 0 8 -3 0 0 2 a n d R M 0 8 -3 0 0 3, w e ass u m e t h at tre at m e nt wit h N T Z s h o ul d res ult i n re d u cti o n 
of at le ast 4 0 h o urs i n m e dia n ti m e t o s y m pt o m res p o nse wit h differe n c es b ei n g less at t h e first q u artile 
a n d  gre ater  at  t h e  t hir d  q u artile.    B ase d  u p o n  t his  hist oric al  d ata, t h e  f oll o wi n g  c ur v es  h a v e  b e e n 
d e v el o p e d f or d eter mi ni n g sa m ple siz e.  
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 1 2  of 4 3  
C O N FI D E N TI A L  
 
 
B as e d u p o n t h ese c ur v es, a  sa m ple siz e of 5 5 2  s u bje cts wit h la b orat or y -c o nfir m e d i nfl u e n z a (i.e. 2 7 6  
f or e a c h of t h e 2 gr o u ps) will pr o vi d e 9 0 % p o w er t o d ete ct a statistic all y si g nific a nt differe n c e i n t h e 
s ur vi v al distri b uti o ns b et w e e n N T Z a n d pla c e b o gr o u ps ( 2-si d e d al p h a of 0. 0 5).  T his c alc ulati o n w as 
p erf or m e d f or t h e G e h a n ra n k test usi n g S A S P R O C P O W E R ( S A S 9. 4) wit h t h e c ur v es s h o w n a b o v e 
( pr o p orti o n n ot re c o v eri n g b y t h e e n d of e a c h d a y w as use d as i n p ut) a n d c e ns ori n g at d a y 2 1 ( h o ur 
5 0 4).  Ass u mi n g t h at 8 % of s u bje cts will h a v e i n c o m plete d ata, w e arri v e at a sa m ple siz e of 6 0 0 
s u bje cts i n t otal, 3 0 0 p er tre at m e nt gr o u p. 
 
B as e d u p o n t h ese c alc ulati o ns, t h e st u d y will e nr oll at le ast 6 0 0  s u bje cts wit h la b orat or y-c o nfir m e d 
i nfl u e n z a u p t o a m a xi m u m of 7 0 0  s u bje cts wit h la b orat or y-c o nfir m e d i nfl u e n z a.  W e esti m ate t h at 
t his will re q uire e nr oll m e nt of 8 0 0  t o 1, 2 0 0  s u bje cts i n t otal ass u mi n g a fl u-p ositi v e rate b et w e e n 5 0 % 
a n d 7 5 %. 
 
7. 4  
D ata C olle cti o n  
 
D ata will b e c olle cte d usi n g a n ele ctr o nic d ata c a pt ure ( E D C) s yste m a n d ele ctr o nic s u bje ct diaries 
pr o vi d e d b y Cli nic al I n k, I n c.  
 
M e dic al hist or y a n d a d v ers e e v e nts will b e c o d e d usi n g t h e latest v ersi o n of M e d D R A. Pri or a n d 
c o n c o mita nt m e dic ati o ns will b e c o d e d usi n g  t h e latest v ersi o n of W H O Dr u g. 
 
 
8.  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  
 
8. 1  
A n al ysis P o p ulati o ns  
 
T hre e p o p ulati o ns will b e d esi g n ate d f or t h e p ur p ose of t h ese a n al yses:  
 
T a ble 1. D efi niti o n of A n al ysis P o p ul ati o ns  
A n al ysis P o p ul ati o n  
D efi niti o n  
All Tre ate d  
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  
C o nfir m e d I nfl u e n z a  
T h e  s u bs et  of  t h e  All  Tre ate d  p o p ulati o n  w h o  are  p ositi v e  f or 
i nfl u e n z a b y R T-P C R  or c ult ure 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  C o nfir m e d  I nfl u e n z a  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  


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 1 3  of 4 3  
C O N FI D E N TI A L  
 
8. 2 
D ata Prese ntati o n C o n v e nti o ns  
 
T h e f oll o wi n g c o n v e nti o ns a re a p plie d t o all d ata prese ntati o ns a n d s u m m aries. 
 
T a ble 2 . D at a P r es e nt ati o n C o n v e 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, 
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. 00 0 0 1, prese nt as < 0 . 00 0 0 1  
If r o u n d e d res ult is 1. 0 0 00 0 , pres e nt as > 0. 9 9 99 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  
D ata prese nte d b y visit  
S u m m ariz e b y n o mi n al st u d y visit  
R a n d o miz ati o n gr o u ps  
Prese nt  as “ N T Z ” a n d “ Pla c e b o ” i n t h at or d er  
 
T h e e x p e cte d la y o ut of e a c h ta ble, listi n g a n d fi g ure will b e a p pr o v e d se p aratel y fr o m t h e S A P. Mi n or 
c h a n g es t o titles or n u m b eri n g will n ot n e c essitate a re visi o n of t h e S A P n or will t h e y b e c o nsi d ere d 
d e viati o ns fr o m t h e pla n n e d a n al yses.  
 
8 . 3 
H a n dli n g of U nsc h e d ule d Assess m e nts  
 
R es ults of u nsc h e d ule d assess m e nts will b e i n cl u d e d i n listi n gs, b ut will n ot b e use d i n d escri pti v e 
statistics. 
 
8. 4  
H a n dli n g of Missi n g D ata  
 
Missi n g d ata will b e h a n dle d as f oll o ws:  
 
 
 
 
 
 
 
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 1 4  of 4 3  
C O N FI D E N TI A L  
 
T a ble 3. H a n dli n g of M issi 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 
o  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. 
o  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.  
o  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 n u 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.  
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  missi n g,  fre q u e n c y  is  “ 1 X ”  a n d  t h e  m e dic ati o n  is  n ot 
liste d as “ O N G OI N G ”, t h e n e n d d ate s h o ul d b e s et t o e qu al t h e start 
d ate.  
 
If t h e criteria a b o v e are n ot m et, t h e f oll o wi n g i m p utati o n r ules a p pl y: 
•  
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 d a 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.  
 
If t h ere is n o F L U-P R O Q u esti o n n aire c o m plete d o n t h at d ate, t h e ti m e 
will b e i m p ute d as 1 2: 0 0 p. m.  
 
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 1 5  of 4 3  
C O N FI D E N TI A L  
9.  G E N E R A L C H A R A C T E RI S TI C S  
 
9. 1  
G e n eral C h ara cteristics T a bles a n d Fi g ures  
 
All ta bles will prese nt d ata f or t h e o v erall st u d y a n d b y tre at m e nt gr o u p.  
 
9. 1. 1  
Dis p ositi o n of S u bje cts  
 
T h e  dis p ositi o n  ta bles  will  s u m m ariz e  t h e  c o u nt  a n d  p erc e nta g e  of  s u bje cts  w h o  c o m plete d or 
dis c o nti n u e d  fr o m  t h e  st u d y  a n d  t h e  m e a n  ( S D),  m e dia n  (I Q R),  a n d  mi ni m u m  a n d  m a xi m u m 
n u m b er of d a ys i n t h e st u d y.  
 
A n al ysis P o p ulati o n(s):  All Tre ate d  
C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
N u m b er  of  d a ys  i n  st u d y  =  d ate  of  st u d y  c o m pleti o n/e arl y 
ter mi n ati o n – d ate of ra n d o miz ati o n + 1  
 
9. 1. 2  
Pr ot o c ol D e viati o ns  
 
T h e d e viati o ns ta bles will s u m m ariz e t h e c o u nt a n d p erc e nta g e of s u bje c ts wit h pr ot o c ol d e viati o ns 
b y d e viati o n classific ati o n ( m aj or , mi n or , or G C P) a n d t h e c o m m o n  d e viati o n ter m.  
 
A n al ysis P o p ulati o n(s):  All Tre ate d  
C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
N o n e  
 
9. 1. 3  
D e m o gra p hics  
 
T h e d e m o gra p hics ta bles will s u m m ariz e se x, a g e at scre e ni n g ( y e ars), ra c e, h ei g ht (c m), w ei g ht 
( k g), B MI ( k g/ m2), s m o ki n g stat us a n d v a c ci n ati o n stat us  as c olle cte d at scre e ni n g/ b aseli n e  usi n g 
d es cri pti v e statistics.  
 
A n al ysis P o p ulati o n(s):  All Tre ate d  
C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
•  A g e i n y e ars at scre e ni n g = d ate of scre e ni n g – d ate of birt h  
•  B MI = w ei g ht i n k g / ( h ei g ht i n c m / 1 0 0) 2 
 
9. 1. 4  
Dis e ase C h ara cteristics  
 
T h e dise ase c h ara cteristics ta bles will s u m m ariz e oral te m p erat ure i n -offic e (° F), oral te m p erat ure 
(° F), ti m e fr o m o nset of s y m pt o ms  t o t h e ti m e of first d ose ( h o urs), vir us i nfe cti o n(s), res pirat or y 
s y m pt o ms,  a n d  c o nstit uti o n al  s y m pt o ms  as  c olle cte d  at  scre e ni n g/ b aseli n e  usi n g  d escri pti v e 
statistics. 
 
A n al ysis P o p ulati o n(s):  All Tre ate d  
C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
Oral  te m p erat ure  =  m a xi m u m  of  oral  te m p erat ure  re c or d e d  i n  t h e 
cli nic at scre e ni n g/ b aseli n e a n d self -re p ort b y t h e s u bje ct 
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 1 6  of 4 3  
C O N FI D E N TI A L  
9. 1. 5  
Pri or a n d C o n c o mita nt M e dic ati o n  
 
T h e pri or a n d c o n c o mita nt m e dic ati o n ta bles will s u m m ariz e t h e n u m b er a n d p erc e nta g e of s u bje cts 
re c ei vi n g e a c h m e dic ati o n b y L e v el 4 A n at o mic al T h era p e utic C h e mic al ( A T C) classific ati o n a n d 
sta n d ar diz e d m e dic al n a m e. 
 
A n al ysis P o p ulati o n(s):  All Tre ate d  
C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
•  Pri or m e dic ati o n classific ati o n = m e dic ati o ns wit h st o p d ates pri or 
t o scre e ni n g d ate 
•  C o n c o mita nt  m e dic ati o n  classific ati o n  =  m e dic ati o ns  wit h 
a d mi nistrati o n  o c c urri n g  o n  or  after  t h e  d ate  of  t h e  first 
a d mi nistrati o n of st u d y dr u g u ntil t h e e n d of t h e st u d y  
 
9. 1. 6  
M e dic al Hist or y  a n d C o n c o mita nt Dise ases  
 
T h e m e dic al hist or y  a n d c o n c o mita nt dise ases  ta bles will s u m m ariz e t h e n u m b er a n d p erc e nta g e of 
s u bje cts re p orti n g e a c h m e dic al hist or y  e v e nts  b y s yste m or g a n class . 
 
A n al ysis P o p ulati o n(s):  All Tre ate d  
C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
•  M e dic al  hist or y  classific ati o n  =  e v e nts  wit h  st o p  d ates  pri or  t o 
scre e ni n g d ate 
•  C o n c o mita nt dise ase classific ati o n = e v e nts wit h st o p d ates o n or 
after t h e d ate of t h e first a d mi nistrati o n of st u d y dr u g u ntil t h e e n d 
of t h e st u d y  
 
9. 1. 7  
Tre at m e nt E x p os ure  
 
T h e tre at m e nt e x p os ure ta bles will s u m m ariz e t h e t otal n u m b er of d a ys o n t h era p y a n d n u m b er of 
ta blets ta k e n usi n g d escri pti v e statistics. 
 
A n al ysis 
P o p ulati o n(s):  
All Tre ate d  
C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
N u m b er of ta blets ta k e n = n u m b er of d o ses re p orte d t o h a v e b e e n ta k e n 
o n t h e diar y * 2  
 
9. 2  
G e n eral C h ara cteristics Listi n gs  
 
G e n eral  c h ara cteristics  listi n gs will i n cl u d e d ata s p e cifie d i n T a ble 4 f or all s u bje cts prese nte d b y 
s u bje ct n u m b er a n d tre at m e nt gr o u p. 
 
T a ble 4 . D at a P r es e nte d i n Ge n e r 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  
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  
Tre at m e nt st o p p e d ( Y/ N)  
S u bje ct disc o nti n u e d ( Y/ N)  


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 1 7  of 4 3  
C O N FI D E N TI A L  
Listi n g  
D at a P r ese nte d  
Classific ati o n ( M aj or/ Mi n or / G C P) 
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  
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 e r 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  
V a c ci n ati o n stat us ( Y/ N)  
B as eli n e Dise ase C h ara cteristics  
Oral te m p erat ure i n offic e (° F)  
Hi g h est oral te m p erat ure (° F)  
Ti m e fr o m o nset of s y m pt o ms 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)  
R es pirat or y s y m pt o ms  
C o nstit uti o n al s y m pt o ms  
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 o rte 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 ns e 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 bjects w h o are n ot i n cl u d e d i n t h e C o nfir m e d I nfl u e n za p o p ulati o n d u e t o n e g ati v e R T -P C R a n d c ult ure assa ys will n ot 
b e c o nsi d ere d e x cl u d e d fr o m efficac y a n al ysis  
 
 
1 0.   EF FI C A C Y  
 
1 0. 1  G e n eral  
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 1 8  of 4 3  
C O N FI D E N TI A L  
U nl ess ot h er wise s p e cifie d, all statistic al tests will use t w o -si d e d tests at t h e α = 0. 0 5 le v el.   
 
T h e f oll o wi n g d efi niti o ns will a p pl y t o m ulti ple effic a c y a n al yses:  
 
D ail y Diar y P eri o d  
E a c h d ail y diar y p eri o d will b e gi n 2 4 h o urs pri or t o t h e ti m e of 
diar y assess m e nt  a n d e n d at t h e ti m e of diar y assess m e nt . 
 
S y m pt o m R elief M e dic ati o n  
A n y m e dic ati o n ta k e n f or a s y m pt o m of i nfl u e n z a as i n dic ate d b y 
t h e s u bje ct d uri n g t h e st u d y p eri o d.  
 
1 0. 2  Pri m ar y Effic a c y A n al ysis: Ti m e t o S y m pt o m R es p o nse  
 
T h e pri m ar y effic a c y a n al ysis will b e t h e c o m p aris o n of t h e ti m e fr o m first  d ose of st u d y m e dic ati o n 
t o s y m pt o m res p o nse b et w e e n tre at m e nt gr o u ps usi n g K a pla n-M eier s ur vi v al c ur v es a n d t h e G e h a n -
Wilc o x o n test  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 dic ati o n ( 0 -
2 4, > 2 4 -≤3 6, or > 3 6 h o urs fr o m o nset), a n d ( 2) v a c ci n ati o n stat us ( Y/ N).  
 
D efi niti o ns:  
 
S y m pt o m R es p o nse  
T h e set of criteria t o b e d efi n e d b ase d u p o n a bli n d e d re vi e w of 
s y m pt o m  sc ores  ( p o ole d  f or  all  i nfl u e n z a-i nfe cte d  s u bje cts 
wit h o ut re g ar d t o tre at m e nt gr o u p assi g n m e nt) t h at c orrelate t o t h e 
ti m e  at  w hic h  s u bje cts  re p ort  t h at  t h e y  ret ur n  t o  us u al  h e alt h  (a 
d ail y gl o b al assess m e nt q u esti o n) .  M et h o d ol o g y t o b e us e d f or 
t h e d eri v ati o n of t h e S y m pt o m R es p o nse d efi niti o n is d escri b e d i n 
s e cti o n 1 0. 2. 1 b el o w.  S y m pt o m sc ores m ust b e m ai ntai n e d at t h e 
d efi n e d  le v el  f or  at  le ast  2  d ail y  diar y  p eri o ds  wit h o ut  a n y 
s y m pt o m relief m e dic ati o n d uri n g or b et w e e n t h ose 2 d ail y d iar y 
p eri o ds.  
 
Ti m e of S y m pt o m R es p o nse  
T h e  start  of  t h e  first  d ail y  diar y  p eri o d  i n  w hic h  S y m pt o m 
R es p o nse is a c hie v e d a n d is m ai ntai n e d f or at le ast t w o d ail y diar y 
p eri o ds wit h o ut a n y s y m pt o m relief m e dic ati o n d uri n g or b et w e e n 
t h ose t w o d ail y diar y p eri o ds. 
 
Ti m e t o S y m pt o m R es p o nse  
Ti m e ( h o urs) fr o m t h e first d ose of st u d y m e dic ati o n t o t h e Ti m e 
of S y m pt o m R es p o nse.  
 
V aria bles Use d f or t h e A n al ysis  
T h e pri m ar y effic a c y a n al ysis will re q uire t h e f oll o wi n g v aria bles:  
 
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.  


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 1 9  of 4 3  
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  
 
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  fro 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 0. 2. 1  D eri v ati o n of t h e S y m pt o m R es p o nse D efi niti o n  
 
T h e S y m pt o m R es p o nse d efi niti o n will b e d eri v e d b ase d u p o n a n al ysis of bli n d e d d ail 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 h e d ail y F L U-P R O q u esti o n, “ H a v e y o u ret ur n e d t o y o ur us u al 
h e alt h t o d a y ? ”  f or s u bje cts wit h la b orat or y-c o nfir m e d i nfl u e n z a.  
 
T h e S y m pt o m R es p o nse d efi niti o n will c o nsist of a m a xi m u m res p o nse criteri o n ( 0, ≤1, ≤2, ≤3 or 
≤4) f or e a c h of t h e 3 2 F L U -P R O ite ms.  
 
T h e o bje cti v e of t his pr o c e d ure is t o i d e ntif y t h e S y m pt o m R es p o nse d efi niti o n t h at mi ni miz es t h e 
diar y -le v el misclassific ati o n rate b et w e e n S y m pt o m R es p o nse a n d Us u al H e alt h stat us as re p orte d 
b y t h e i nfl u e n z a-p ositi v e s u bje cts  e nr olle d i n t his st u d y.   
 
Pr o c e d ure:  
1.  E v al u ate  w h et h er  e a c h  d ail y  diar y  re c or d  h as  a c hie v e d  ret ur n  t o  us u al  h e alt h  (re q uiri n g  2 
c o nse c uti v e d ail y diar y assess m e nts wit h “ y es” res p o nse t o t h e “ us u al h e alt h ” q u esti o n i n F L U -
P R O  wit h o ut use of s y m pt o m relief m e dic ati o n d uri n g or b et w e e n t h ose d ail y diar y p eri o ds ). 
T his ste p will cre ate a “ R et ur n e d ” v aria ble wit h p ossi ble v al u es of “ Y ” f or e a c h d ail y diar y 
re c or d t h at c o nstit utes ret ur n t o us u al h e alt h a n d “ N ” f or e a c h d ail y diar y re c or d t h at d o es n ot. 
 
2.  D eter mi n e  t h e  set  of  p ossi ble  S y m p t o m  R es p o nse  d efi niti o ns  t o  b e  e v al u ate d b y  sele cti n g 
p ote ntial m a xi m u m res p o nse criteria t h at are li k el y t o c orrelate w ell wit h ret ur n t o us u al h e alt h.  
 
a. E x a mi n e t h e c u m ulati v e distri b uti o n of or di n al s y m pt o m assess m e nt res p o nses f or t h e t w o 
c o nse c uti v e diar y re c or ds at w hic h s u bje cts ret ur n t o Us u al H e alt h.  
 
b.  M a xi m u m  res p o ns e  criteria  will  b e sele cte d  f or  c o nsi d erati o n  as  p art  of  t h e  S y m pt o m 
R es p o n se d efi niti o n if t h e y are i n cl u d e d i n t h e ≥9 0 % - ≤9 5 % c u m ulati v e distri b uti o n of 
s y m pt o m assess m e nts at t h e ti m e of ret ur n t o us u al h e alt h. If a m a xi m u m res p o nse criteri o n 
i n cl u d es t h e 9 5t h p erc e ntile a n d e x c e e ds t h e 9 5 % c u m ulati v e distri b uti o n, t h e criter i o n will 
still b e sele cte d f or c o nsi d erati 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: 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 0  of 4 3  
C O N FI D E N TI A L  
 
 
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 e a c h p ossi ble S y m pt o m R es p o nse d efi niti o n, e v al u ate w h et h er e a c h d ail y diar y  re c or d h as 
a c hie v e d S y m pt o m R es p o nse (t w o c o nse c uti v e diar y e ntries wit h all s y m pt o ms assesse d ≤ t h e 
m a xi m u m res p o nse v al u es wit h n o s y m pt o m relief m e dic ati o n i nta k e d uri n g  or b et w e e n  t h ose 
t w o d ail y diar y p eri o ds). T his ste p will cre ate a “ R es p o n d e d ” v aria ble wit h p ossi ble v al u es of 
“ Y ” f or e a c h d ail y diar y re c or d t h at h as a c hie v e d S y m pt o m R es p o nse a n d “ N ” f or e a c h d ail y 
diar y re c or d t h at h as n ot a c hie v e d S y m pt o m R es p o nse.  T his ste p will b e p erf or m e d o n a d ata  
st ora g e/ V M i nfrastr u ct ure t h at c a n s u p p ort e val u ati o n of 4. 2 billi o n d ail y diar y re c or ds wit h 
differe nt p ossi ble S y m pt o m R es p o nse d efi niti o ns. If t h e n u m b er of diar y re c or d e v al u ati o ns 
re q uire d ( n u m b er of p ossi ble S y m pt o m R es p o nse d efi niti o ns m ulti plie d b y n u m b er of d ail y 
diar y re c or ds t o b e e v al u ate d) e x c e e ds 4. 2 billi o n, g o b a c k t o ste p 2 b a b o v e, a n d i n cre ase t h e 
≥9 0 %  c u m ulati v e  distri b uti o n  t hres h ol d  b y  0. 1 %  i n cre m e nts  u ntil  t h e  n u m b er  of  p ossi ble 
m a xi m u m res p o nse criteria is re d u c e d t o a n u m b er t h at will res ult i n e v al u ati o n of ≤4. 2 billi o n 
d ail y diar y re c or ds.  
 
4.  F or e a c h p ossi ble S y m pt o m R es p o nse d efi niti o n, d eter mi n e t h e d efi niti o n’s misclassific ati o n 
rate b y c o m p ari n g t h e “ R es p o n d e d ” a n d “ R et ur n e d ” v aria bles f or e a c h d ail y diar y re c or d. T h e 
p erc e nta g e of d ail y diar y re c or ds wit h mis m atc h e d “ R es p o n d e d ” a n d “ R et ur n e d ” v al u es (e. g., 
“ Y ” a n d “ N ”) will c o nstit ute t h at S y m pt o m R es p o nse d efi niti o n’s misclassific ati o n rate.  
 
5.  T h e S y m pt o m R es p o nse d efi niti o n ret ur ni n g t h e l o w est misclassific ati o n rate will b e sele cte d 
as t h e S y m pt o m R es p o nse d efi niti o n f or t h e st u d y a n d will b e use d t o c alc ulate t h e pri m ar y 
effic a c y p ara m eter (ti m e t o S y m pt o m R es p o nse) f or e a c h s u bje ct.  
 
6.  If  t w o  or  m ore  S y m pt o m  R es p o nse  d efi niti o ns  pr o d u c e  t h e  l o w est  misclassific ati o n  rate  (a 
“tie ”), t h e S y m pt o m R es p o nse d efi niti o n wit h t h e l o w er s u m of sc ores will b e sele cte d. I n t h e 
e v e nt t h at t h e s u m of sc ores are als o e q u al, t h e S y m pt o m R es p o nse d efi niti o n wit h t h e s m allest 
a bs ol ute differe n c e b et w e e n t h e pr o p orti o n of false p ositi v es (“ R es p o n d e d ” b ut n ot “ R et ur n e d ”) 
a n d false n e g ati v es (“ R et ur n e d ” b ut n ot “ R es p o n d e d ”) will b e sele cte d.  If t h ere is still a tie, 
t h e d efi niti o n wit h t h e l o w est s u m of m a xi m u m res p o nse v al u es f or t h e B o d y/ S yste mic d o m ai n 
will b e sele cte d, a n d if t h at is still a tie, t h e d efi niti o n wit h t h e l o w est s u m of m a xi m u m res p o nse 
v al u es f or t h e E y e d o m ai n will b e sele cte d, a n d s o o n f or t h e G astr oi ntesti n al, T hr o at, N ose a n d 
C h est/ R es pirat or y d o m ai ns.  If t h ere is still a tie, list t h e ite ms u n d er t h e B o d y/ S yste mic, E y e, 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 1  of 4 3  
C O N FI D E N TI A L  
G astr oi ntesti n al,  T hr o at , N ose  a n d  C h est/ R es pirat or y  d o m ai ns  i n  al p h a b etic al  or d er  a n d 
c o m p are t h e m a xi m u m res p o nse v al u es u ntil a d efi niti o n wit h t h e l o w est ite m sc ore c a n b e 
sele cte d. 
 
T h e  S y m pt o m  R es p o nse  D efi niti o n  sele cte d  i n  t his  ste p  will  b e  a p plie d  f or  a n y  s u bse q u e nt 
a n al ysis t h at c alls f or t h e p ri m ar y effic a c y a n al ysis t o b e re p e ate d u nless ot h er wise s p e cifie d. 
 
1 0. 2. 2  A n al ysis of t h e Pri m ar y Effic a c y P ara m eter  
 
T h e pri m ar y effic a c y p ara m eter, ti m e t o S y m pt o m R es p o nse, will b e d eri v e d as f oll o ws:  
 
E v e nt:  
Ti m e of S y m pt o m R es p o nse – ti m e of t h e first d ose 
C e ns ore d:  Ti m e of last s y m pt o m assess m e nt – ti m e of t h e first d ose 
 
If S y m pt o m R es p o nse is a c hie v e d at t h e ti m e of t h e first s y m pt o m assess m e nt diar y re c or d, t h e 
s u bje ct will b e e x cl u d e d fr o m t h e a n al ysis. 
 
If Sy m pt o m R es p o nse  is n ot a c hie v e d prior t o a s u bje ct’s  last a v aila ble diar y assess m e nt, b ut t h e  
criteria are m et at t h e last a v aila ble diar y assess m e nt wit h n o e vi d e n c e of s y m pt o m relief m e dic ati o n 
i nta k e d uri n g t h at diar y p eri o d, ti m e of S y m pt o m R es p o nse will b e c o nsi d ere d t o h a v e o c c urre d a t 
t h e start of t h e last d ail y diar y p eri o d. 
 
Ti m e t o S y m pt o m R es p o nse f or t h e N T Z tre at m e nt gr o u p will b e c o m p are d t o t h at of t h e pla c e b o 
tre at m e nt gr o u p usi n g a G e h a n-Wilc o x o n test stratifie d f or ( 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 dic ati o n ( 0-2 4, > 2 4 -≤3 6, or > 3 6 h o urs fr o m o nset) , a n d ( 2) v a c ci n ati o n stat us 
( Y/ N). T h e c o m p aris o n will b e gra p hic all y d e picte d usi n g K a pla n -M eier c ur v es.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
E v e nt:  
Ti m e of s y m pt o m res p o nse – ti m e of t h e first d ose 
C e ns ore d:  Ti m e of last s y m pt o m assess m e nt – ti m e of t h e first d ose 
 
1 0. 3  S e nsiti vit y A n al yses of t h e Pri m ar y Effic a c y A n al ysis  
 
1 0. 3. 1  S e nsiti vit y A n al ysis Ass u mi n g Ti m e of S y m pt o m R es p o nse of 2 1 D a ys f or Disc o nti n u e d S u bje cts  
 
R e p e at t h e pri m ar y effic a c y a n al ysis ass u mi n g a ti m e of S y m pt o m R es p o nse of 2 1 d a ys ( 5 0 4 h o urs 
fr o m first d ose of st u d y m e dic ati o n) f or s u bje cts w h o disc o nti n u e d t h e st u d y pri or t o a c hie vi n g 
S y m pt o m R es p o nse.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
S e e S e cti o n 1 0. 2: Pri m ar y Effic a c y A n al ysis.  
 
1 0. 3. 2  S e nsiti vit y A n al ysis f or a “ P er Pr ot o c ol” S u bset  
 
R e p e at t h e pri m ar y effic a c y a n al ysis f or t h e P er Pr ot o c ol p o p ulati o n.  
 
A n al ysis P o p ulati o n(s):  P er Pr ot o c ol  
D eri v e d V aria bles:  
S e e S e cti o n 1 0. 2: Pri m ar y Effic a c y A n al ysis.   
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 2  of 4 3  
C O N FI D E N TI A L  
1 0. 4  S e c o n d ar y Effic a c y A n al yses  
 
If  t h e  pri m ar y  a n al ysis  is  si g nific a nt  at  t h e  0. 0 5  le v el,  t h e  se c o n d ar y  effic a c y  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 will b e f or m all y e v al u ate d at t h e 0. 0 5 le v el.  If t h e pri m ar y 
a n al ysis  a n d  t h e  se c o n d ar y  effic a c y  a n al ysis  of  Ti m e  t o  R et ur n  t o  N or m al  A cti vities  are  b ot h 
si g nific a nt at t h e 0. 0 5 le v el, t h e se c o n d ar y effic a c y a n al ysis of Pr o p orti o ns of S u bje cts E x p erie n ci n g 
C o m plic ati o ns of I nfl u e n z a will b e f or m all y e v al u ate d at t h e 0. 0 5 le v el.  If a n y of t h ese a n al yses is 
n ot si g nific a nt at t h e 0. 0 5 le v el, t h e s u bse q u e nt a n al yses or a n al ysis will b e p erf or m e d as e x pl orat or y.  
 
1 0. 4. 1  Ti m e t o A bilit y t o P erf or m All N or m al A cti vities  
 
D efi niti o ns:  
 
A bilit y t o P erf or m All  
N or m al A cti vities  
S u bje ct  r e p orts  a  sc ore  of  1 0  o n  t h e  0 -1 0  sc ale  f or  a bilit y  t o 
p erf or m n or m al a cti vities a n d m ai ntai ns t h e sc ore f or at le ast t w o 
c o nse c uti v e  d ail y  diar y  p eri o ds  wit h o ut  s y m pt o m  relief 
m e dic ati o n d uri n g or b et w e e n t h ose t w o d ail y diar 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 vities  
T h e ti m e  of  t h e  first  diar y  e ntr y i n  w hic h  t h e  s u bje ct  a c hie v es 
A bilit y t o P erf or m All N or m al A cti vities  
 
Ti m e t o A bilit y t o P erf or m  
All N or m al A cti vities  
Ti m e ( h o urs) fr o m first d ose 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 vities  
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire t h e f oll o wi n g v aria bles:  
 
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 bj e 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 s c 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 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.  
 
A n al ysis  
T h e  effic a c y  p ara m eter,  Ti m e  t o  A bilit y  t o  P erf or m  All  N or m al  A cti vities,  will  b e  d eri v e d  as 
f oll o ws: 
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 3  of 4 3  
C O N FI D E N TI A L  
E v e nt:  
Ti m e of A bilit y t o P erf or m All N or m al A cti vities – ti m e of t h e first d ose 
C e ns ore d:  Ti m e of last a bilit y assess m e nt – ti m e of t h e first d ose 
 
If A bilit y to P erf or m All N or m al A cti vities is a c hie v e d at t h e ti m e of t h e first a bilit y  assess m e nt 
diar y re c or d, t h e s u bje ct will b e e x cl u d e d fr o m t h e a n al ysis.  
 
If t h e s u bje ct d o es n ot a c hie v e A bilit y t o P erf or m All N or m al A cti vities pri or t o t h e  s u bje ct’s last 
a v ai la ble diar y assess m e nt, b ut  re c or ds a “ 1 0 ” f or a bilit y t o p erf or m all n or m al a cti vities at t h e last 
a v aila ble diar y assess m e nt wit h n o e vi d e n c e of s y m pt o m relief m e dic ati o n i nta k e d uri n g t h at diar y 
p eri o d, ti m e of A bilit y t o P erf or m All N or m al A cti vities w ill b e c o nsi d ere d t o h a v e o c c urre d at t h e 
ti m e of t h e last a v aila ble diar y assess m e nt. 
 
Ti m e t o A bilit y t o P erf or m All N or m al A cti vities f or t h e N T Z tre at m e nt gr o u p will b e c o m p are d 
t o t h at of t h e pla c e b o tre at m e nt gr o u p usi n g a G e h a n-Wilc o x o n test stratif ie d f or ( 1) ti m e fr o m 
o ns et of ill n ess t o ti m e of first d ose of st u d y m e dic ati o n ( 0 -2 4, > 2 4 -≤3 6, or > 3 6 h o urs fr o m o nset), , 
a n d ( 2) v a c ci n ati o n stat us  ( Y/ N). T h e c o m p aris o n will b e gra p hic all y d e picte d usi n g K a pla n -M eier 
c ur v es.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
E v e nt:  
Ti m e of A bilit y t o P erf or m All N or m al A cti vities – ti m e 
of t h e first d ose  
C e ns ore d:  Ti m e of last a bilit y  assess m e nt – ti m e of t h e first d ose 
 
1 0. 4. 2  Pr o p orti o n of S u bje cts E x p erie n ci n g C o m plic ati o ns of I nfl u e n z a  
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire t h e f oll o wi n g v aria bles:  
 
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 i nfl u e n z a  
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 of i nfl u e n z a if t h e e v e nt m e ets 
pr ot o c ol -s p e cifie d criteria 
 
A n al ysis  
P r o p orti o ns  of  s u bje cts  e x p erie n ci n g  o n e  or  m ore  c o m plic ati o ns  of  i nfl u e n z a  will  b e  c o m p are d 
b et w e e n t h e tre at m e nt gr o u ps usi n g a Fis h er’s e x a ct test.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
N o n e  
 
1 0. 4. 3  Ti m e t o M o difie d S y m pt o m R e s p o nse E x cl u di n g F L U-P R O G astr oi ntesti n al a n d E y e D o m ai ns  
 
T his  a n al ysis  will  re p e at  t h e  m et h o d ol o g y  f or  d eri vi n g  a n d  a n al y zi n g  t h e  Ti m e  t o  S y m pt o m 
R es p o nse,  b ut  will  e x cl u d e  fr o m  c o nsi d erati o n  t h ose  F L U -P R O  ite ms  i n  t h e  E y e  a n d  
G astr oi ntesti n al d o m ai ns. E x cl u d e d ite ms will b e: te ar y or w ater y e y es, s ore or p ai nf ul e y es, e y es 
s e nsiti v e  t o  li g ht,  felt  n a use o us  (fe eli n g  li k e  y o u  w a nte d  t o  t hr o w-u p),  st o m a c h  a c h e,  v o mit 
(fre q u e n c y), a n d diarr h e a (fre q u e n c y). 
 
D efi niti o ns:  
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 4  of 4 3  
C O N FI D E N TI A L  
M o difie d S y m pt o m R es p o ns e  
T h e set of criteria t o b e d efi n e d b ase d u p o n a bli n d e d re vie w of 
s y m pt o m sc ores fr o m o nl y  t h e N ose, T hr o at, C h est/ R es pirat or y, 
a n d  B o d y/ S yste mic  d o m ai ns  ( p o ole d  f or  all  i nfl u e n z a-i nfe cte d 
s u bje cts  wit h o ut  re g ar d  t o  tre at m e nt  gr o u p  assi g n m e nt)  t h at 
c orrelate t o t h e ti m e at w hic h s u bje cts re p ort t h at t h e y ret ur n t o 
us u al h e alt h (a d ail y gl o b al assess m e nt q u esti o n) .  M et h o d ol o g y 
t o b e use d f or t h e d eri v ati o n of t h e M o difie d S y m pt o m R es p o nse 
d efi niti o n is d escri b e d i n d etail b el o w.  S y m pt o m sc ores m ust b e 
m ai ntai n e d at t h e d efi n e d le v el f or at le ast 2 d ail y diar y p eri o ds  
wit h o ut a n y s y m pt o m relief m e dic ati o n d uri n g or b et w e e n t h ose 2 
d ail y diar y p eri o ds.  
 
Ti m e of M o difie d S y m pt o m  
R es p o nse  
T h e  start  of  t h e  first  d ail y  diar y  p eri o d  i n  w hic h  M o difie d 
S y m pt o m R es p o nse is a c hi e v e d a n d is m ai ntai n e d f or at le ast t w o 
d ail y diar y p eri o ds wit h o ut a n y s y m pt o m relief m e dic ati o n d uri n g 
or b et w e e n t h ose t w o d ail y diar y p eri o ds.  
 
Ti m e t o M o difie d S y m pt o m  
R es p o nse  
Ti m e ( h o urs) fr o m t h e first d ose of st u d y m e dic ati o n t o t h e Ti m e 
of M o dif ie d S y m pt o m R es p o nse. 
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire t h e f oll o wi n g v aria bles:  
 
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 cor 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  e x c e pt t h ose 
b el o n gi n g t o t h e E y e a n d 
G astr oi ntesti n al d o m ai ns  
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 2 5  
s y m pt oms will b e c o d e d t o n u m eric al v al u es 0 -
4.  T h e  n u m eric al  v al u es  re prese nt  or di n al 
res p o nses  a n d  t h eref ore  c a n n ot  b e  s u m m e d, 
a v era g e d, or tre ate d as c o nti n u o us d ata.  
 
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.  


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 5  of 4 3  
C O N FI D E N TI A L  
 
D eri v ati o n of t h e M o difie d S y m pt o m R es p o nse D efi niti o n  
 
D eri v ati o n  of  t h e  M o difie d  S y m pt o m  R es p o nse  d efi niti o n  will  b e  a c c o m plis h e d  usi n g  t h e 
pr o c e d ure  i n  se cti o n  1 0. 2. 1  a p plie d  t o  o nl y  t h e  2 5  F L U -P R O  ite ms  i n  t h e  N ose,  T hr o at, 
C h est/ R es pirat or y, a n d B o d y/ S yste mic D o m ai ns . 
 
A n al ysis  
T h e effic a c y p ara m eter, ti m e t o M o difie d S y m pt o m R es p o nse, will b e d eri v e d as f oll o ws:  
 
E v e nt:  
Ti m e of M o difie d S y m pt o m R es p o nse – ti m e of t h e first d ose 
C e ns ore d:  Ti m e of last s y m pt o m assess m e nt – ti m e of t h e first d ose 
 
If  M o difie d  S y m pt o m  R es p o nse  is  a c hie v e d  at  t h e  ti m e  of  t h e  first  s y m pt o m  assess m e nt  diar y 
re c or d, t h e s u bje ct will b e e x cl u d e d fr o m t h e a n al ysis.  
 
If  t h e  M o difie d  S y m pt o m  R es p o nse is  n ot  a c hie v e d  pri or  t o a  s u bje ct’s  last  diar y a v aila ble  
ass ess m e nt,  b ut  t h e  criteria  are  m et  at  t h e  last  a v aila ble  diar y  assess m e nt  wit h  n o  e vi d e n c e  of 
s y m pt o m relief m e dic ati o n i nta k e d uri n g t h at diar y p eri o d, Ti m e of M o difie d S y m pt o m R es p o nse 
will b e c o nsi d ere d t o h a v e o c c urre d at t h e start of t h e last d ail y diar y p eri o d.  
 
Ti m e t o M o difie d S y m pt o m R es p o nse f or t h e N T Z tre at m e nt gr o u p will b e c o m p are d t o t h at of t h e 
pla c e b o tre at m e nt gr o u p usi n g a G e h a n -Wilc o x o n test stratifie d f or ( 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 dic ati o n  ( 0-2 4,  > 2 4 -≤3 6,  or  > 3 6  h o urs  fr o m  o nset) ,  a n d  ( 2) 
v a c ci n ati o n stat us  ( Y/ N) . T h e c o m p aris o n will b e gra p hic all y d e picte d usi n g K a pla n-M eier c ur v es.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I n fl u e n z a 
D eri v e d V aria bles:  
E v e nt:  
Ti m e of M o difie d S y m pt o m R es p o nse – ti m e of t h e first 
d ose  
C e ns ore d:  Ti m e of last s y m pt o m assess m e nt – ti m e of t h e first d ose 
 
1 0. 5  E x pl orat or y Effic a c y A n al yses  
 
1 0. 5. 1  Ti m e t o I n di vi d u al S y m pt o m R es p o nse  
 
D efi niti o ns : 
 
I n di vi d u al S y m pt o m R es p o nse F or e a c h i n di vi d u al s y m pt o m ( n = 3 2), a sc ore of ≤ t h e m a xi m u m 
res p o nse  v al u e s p e cifie d  b y  t h e  S y m pt o m  R es p o nse  d efi niti o n 
m ai ntai n e d f or at le ast t w o c o nse c uti v e d ail y diar y p eri o ds wit h o ut 
s y m pt o m  relief  m e dic ati o n  d uri n g  or  b et w e e n  t h ose  d ail y  diar 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 nse  
T h e  start  of  t h e  first  d ail y  diar y  p eri o d  i n  w hic h I n di vi d u al 
S y m pt o m R es p o nse is a c hie v e d a n d is m ai ntai n e d f or at le ast t w o 
d ail y diar y p eri o ds wit h o ut a n y s y m pt o m relief m e dic ati o n d uri n g 
or b et w e e n t h ose t w o d ail y diar y p eri o ds.  
 
Ti m e t o I n di vi d ual S y m pt o m  


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 6  of 4 3  
C O N FI D E N TI A L  
R es p o nse  
Ti m e ( h o urs) fr o m t h e first d ose of st u d y m e dic ati o n t o t h e Ti m e 
of I n di vi d u al S y m pt o m R es p o nse.  
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire t h e f oll o wi n g v aria bles:  
 
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 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 o f 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  fl u 
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 n al ysis  
T h e effic a c y p ara m eter, ti m e t o I n di vi d u al S y m pt o m R es p o nse, will b e d eri v e d as f oll o ws:  
 
E v e nt:  
Ti m e of I n di vi d u al S y m pt o m R es p o nse – ti m e of t h e first d ose 
C e ns ore d:  Ti m e of last s y m pt o m assess m e nt – ti m e of t h e first d ose 
 
If  I n di vi d u al  S y m pt o m  R es p o nse  is  a c hie v e d  at  t h e  ti m e  of  t h e  first  s y m pt o m  assess m e nt  diar y 
re c or d, t h e s u bje ct will b e e x cl u d e d fr o m t h e a n al ysis. 
 
If  t h e  I n di vi d u al  S y m pt o m  R es p o nse is  n ot  a c hie v e d  pri or  t o a  su bje ct’s  last a v aila ble  diar y 
ass ess m e nt,  b ut  t h e  criteria  are  m et  at  t h e  last a v aila ble diar y  assess m e nt  wit h  n o  e vi d e n c e  of 
s y m pt o m relief m e dic ati o n i nta k e d uri n g t h at diar y p eri o d, Ti m e of I n di vi d u al S y m pt o m R es p o nse 
will b e c o nsi d ere d t o h a v e o c c urre d  at t h e start of t h e last d ail y diar y p eri o d.  
 
Ti m e t o I n di vi d u al S y m pt o m R es p o nse f or t h e N T Z tre at m e nt gr o u p will b e c o m p are d t o t h at of 
t h e pla c e b o tre at m e nt gr o u p usi n g a G e h a n-Wilc o x o n test stratifie d f or ( 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 dic ati o n  ( 0-2 4,  > 2 4 -≤3 6,  or  > 3 6  h o urs  fr o m  o nset), ,  a n d  ( 2) 
v a c ci n ati o n stat us ( Y/ N). T h e c o m p aris o n will b e gra p hic all y d e picte d usi n g K a pla n-M eier c ur v es.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a  


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 7  of 4 3  
C O N FI D E N TI A L  
D eri v e d V aria bles:  
E v e nt:  
Ti m e of I n di vi d u al Sy m pt o m R es p o nse – ti m e of t h e first 
d ose  
C e ns ore d:  Ti m e of last s y m pt o m assess m e nt – ti m e of t h e first d ose 
 
1 0. 5. 2  Ti m e t o F L U -P R O D o m ai n R es p o nse  
 
D efi niti o ns:  
 
F L U -P R O D o m ai n R es p o nse  
F or e a c h F L U -P R O d o m ai n ( n = 6), e a c h ite m/s y m pt o m sc ore d ≤ 
t h e m a xi m u m res p o nse v al u e s p e cifie d b y t h e S y m pt o m R es p o nse 
d efi niti o n a n d m ai ntai n e d f or at le ast t w o c o nse c uti v e d ail y diar y 
p eri o ds  wit h o ut  s y m pt o m  relief  m e dic ati o n  d uri n g  or  b et w e e n 
t h ose d ail y diar y p eri o ds 
 
Ti m e of F L U -P R O D o m ai n  
R es p o nse  
T h e  start  of  t h e  first  d ail y  diar y  p eri o d  i n  w hic h  F L U -P R O 
D o m ai n R es p o nse is a c hie v e d a n d is m ai ntai n e d f or at le ast t w o 
d ail y diar y p eri o ds wit h o ut a n y s y m pt o m relief m e dic ati o n d uri n g 
or b et w e e n t h ose t w o d ail y diar 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 nse  
Ti m e ( h o urs) fr o m t h e first d ose of st u d y m e dic ati o n t o t h e Ti m e 
of F L U -P R O D o m ai n R es p o nse.  
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire t h e f oll o wi n g v aria bles:  
 
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.  
 
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 ass i 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.  
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 8  of 4 3  
C O N FI D E N TI A L  
A n al ysis  
T h e effic a c y p ara m eter, T i m e t o F L U -P R O D o m ai n R es p o nse, will b e d eri v e d as f oll o ws:  
 
E v e nt:  
Ti m e of F L U -P R O D o m ai n R es p o nse – ti m e of t h e first d ose 
C e ns ore d:  Ti m e of last s y m pt o m assess m e nt – ti m e of t h e first d ose 
 
If F L U -P R O  D o m ai n R es p o nse  is  a c hie v e d  at  t h e  ti m e  of  t h e  first  s y m pt o m  assess m e nt  diar y 
re c or d, t h e s u bje ct will b e e x cl u d e d fr o m t h e a n al ysis. 
 
If  t h e F L U -P R O  D o m ai n R es p o nse  is  n ot  a c hie v e d  pri or  t o a  s u bje ct’s  last a v aila ble  diar y 
ass ess m e nt,  b ut  t h e  criteria  are  m et  at  t h e  last a v aila ble diar y  assess m e nt  wit h  n o  e vi d e n c e  of 
s y m pt o m relief m e dic ati o n i nta k e d uri n g t h at diar y p eri o d, Ti m e of F L U -P R O D o m ai n R es p o nse 
will b e c o nsi d ere d t o h a v e o c c urre d at t h e start of t h e last d ail y diar y p eri o d.  
 
Ti m e t o F L U -P R O D o m ai n R es p o nse f or t h e N T Z tre at m e nt gr o u p will b e c o m p are d t o t h at of t h e 
pla c e b o tre at m e nt gr o u p usi n g a G e h a n -Wilc o x o n test stratifie d f or ( 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 dic ati o n  ( 0-2 4,  > 2 4 -≤3 6,  or  > 3 6  h o urs  fr o m  o nset) ,  a n d  ( 2) 
v a c ci n ati o n stat us  ( Y/ N). T h e c o m p aris o n will b e gra p hic all y d e picte d usi n g K a pla n-M eier c ur v es.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
E v e nt:  
Ti m e of F L U -P R O D o m ai n R es p o nse – ti m e of t h e first 
d ose  
C e ns ore d:  Ti m e of last s y m pt o m assess m e nt – ti m e of t h e first d ose 
 
1 0. 5. 3  Ti m e t o R es ol uti o n of A c ute F e brile Ill n ess  
 
D efi niti o ns:  
 
R es ol uti o n of A c ute F e brile  
Ill n ess 
S y m pt o m  sc ores  f or  e a c h of  “ b o d y  a c h es  or  p ai ns”,  “ c hills  or 
s hi v eri n g ”, “felt c ol d ”, “felt h ot” a n d “s w e ati n g ” are 0 or 1 a n d 
re m ai n s o f or t w o c o nse c uti v e d ail y diar y p eri o ds wit h n o re c or d 
of  oral  te m p erat ure ≥1 0 0. 4° F  ( < 3 8° C)  or  s y m pt o m  relief 
m e dic ati o n use f or t h ese s y m pt o ms d uri n g or b et w e e n t h ose t w o 
d ail y diar y p eri o ds.  
 
Ti m e of R es ol uti o n of A c ute  
F e brile Ill n ess  
T h e  start  of  t h e  first  d ail y  diar y  p eri o d  i n  w hic h  R es ol uti o n  of 
A c ute F e brile Ill n ess is a c hie v e d a n d is m ai ntai n e d f or at le ast t w o 
d ail y diar y p eri o ds wit h o u t a n y s y m pt o m relief m e dic ati o n d uri n g 
or b et w e e n t h ose t w o d ail y diar y p eri o ds.  
 
Ti m e t o R es ol uti o n of A c ute  
F e brile Ill n ess  
Ti m e ( h o urs) fr o m t h e first d ose of st u d y m e dic ati o n t o t h e Ti m e 
of R es ol uti o n of A c ute F e brile Ill n ess.  
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire t h e f oll o wi n g v aria bles:  
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 2 9  of 4 3  
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  
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 a n d 
te m p erat ure assess m e nt 
re c or d 
S u bje ct diar y  
 
Oral te m p erat ure 
assess m e nt f or e a c h 
te m p erat ure assess m e nt 
re c or d 
S u bje ct diar y  
Oral  te m p erat ure  will  b e  re c or d e d  t wic e  d ail y 
d uri n g  t h e  tre at m e nt  p eri o d .  T his  d ata  is 
re c or d e d  
c o nte m p ora n e o usl y  
wit h 
m e as ure m e nt  i n c o ntrast t o s y m pt o m diar y d ata, 
w hic h  is  i nte n d e d  t o  c h ara cteriz e  m a xi m u m 
s y m pt o m i nte nsit y or fre q u e n c y o v er a 2 4-h o ur 
re c all p eri o d. 
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 nsi t 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 fi v e 
rele v a nt 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  diaries  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 edic 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 s y m pt o ms c a pt ure d  i n  t h e  F L U -P R O 
q u esti o n n aire.  
 
A n al ysis  
T h e effic a c y p ara m eter, Ti m e t o R es ol uti o n of A c ute F e brile Ill n ess , will b e d eri v e d as f oll o ws: 
 
E v e nt:  
Ti m e of R es ol uti o n of A c ute F e brile Ill n ess – ti m e of t h e first d ose 
C e ns ore d:  Ti m e of last s y m pt o m assess m e nt – ti m e of t h e first d ose 
 
If t h ere is a te m p erat ure assess m e nt b et w e e n diar y assess m e nts t h at is n ot < 1 0 0. 4° F ( < 3 8° C), t h e 
e arliest a s u bje ct m a y a c hie v e R es ol uti o n of A c ute F e brile Ill n ess is t h e start of t h e n e xt d ail y diar y 
p eri o d.  
 
If t h e R es ol ut i o n of A c ute F e brile Ill n ess is n ot a c hie v e d pri or t o a s u bje ct’s  last a v aila ble  diar y 
ass ess m e nt,  b ut  t h e  criteria  are  m et  at  t h e  last  a v aila ble  diar y  assess m e nt  wit h  n o  e vi d e n c e  of 
s y m pt o m relief m e dic ati o n i nta k e d uri n g t h at diar y p eri o d, Ti m e of R es ol u ti o n of A c ute F e brile 
Ill n ess will b e c o nsi d ere d t o h a v e o c c urre d at t h e start of t h e last d ail y diar y p eri o d.  
 
Ti m e t o R es ol uti o n of A c ute F e brile Ill n ess f or t h e N T Z tre at m e nt gr o u p will b e c o m p are d t o t h at 
of t h e pla c e b o tre at m e nt gr o u p usi n g a G e h a n -Wi lc o x o n test stratifie d f or ( 1) ti m e fr o m o nset of 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 3 0  of 4 3  
C O N FI D E N TI A L  
ill n ess t o ti m e of first d ose of st u d y m e dic ati o n ( 0-2 4, > 2 4 -≤3 6, or > 3 6 h o urs fr o m o nset),  a n d ( 2) 
v a c ci n ati o n stat us  ( Y/ N). T h e c o m p aris o n will b e gra p hic all y d e picte d usi n g K a pla n-M eier c ur v es.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
E v e nt:  
Ti m e of R es ol uti o n of A c ute F e brile Ill n ess – ti m e of t h e 
first d ose 
C e ns ore d:  Ti m e of last s y m pt o m assess m e nt – ti m e of t h e first d ose 
 
1 0. 5. 4  Ti m e t o R et ur n t o Us u al H e alt h  
 
D efi niti o ns:  
 
R et ur n t o Us u al H e alt h  
“ Y es”  res p o nse  t o t h e  d ail y  F L U-P R O  gl o b al  assess m e nt 
q u esti o n,  “ H a v e  y o u  ret ur n e d  t o  y o ur  us u al  h e alt h  t o d a y ? ” 
m ai ntai n e d f or at le ast t w o c o nse c uti v e d ail y diar y p eri o ds wit h o ut 
s y m pt o m  relief  m e dic ati o n  d uri n g  or  b et w e e n  t h ose  t w o  d ail y 
diar y p eri o ds  
 
Ti m e of R et ur n t o U s u al H e alt h T h e ti m e  of  t h e  first  diar y  e ntr y i n  w hic h  t h e  s u bje ct  a c hie v es 
R et ur n t o Us u al H e alt h  
 
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 ose t o t h e Ti m e of R et ur n t o Us u al H e alt h  
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire  t h e f oll o wi n g v aria bles: 
 
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 c o mita nt 
m e dic ati o ns pri or t o u n bli n di n g.  
 
A n al ysis  
T h e effic a c y p ara m eter, Ti m e t o R et ur n t o Us u al H e alt h , will b e d eri v ed as f oll o ws:  
 
E v e nt:  
Ti m e of R et ur n t o Us u al H e alt h – ti m e of t h e first d ose 
C e ns ore d:  Ti m e of last a bilit y assess m e nt – ti m e of t h e first d ose 
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 3 1  of 4 3  
C O N FI D E N TI A L  
If R et ur n t o Us u al H e alt h is a c hie v e d at t h e ti m e of t h e first s y m pt o m assess m e nt diar y re c or d, t h e 
s u bje ct will b e e x cl u d e d fr o m t h e a n al ysis.  
 
If t h e s u bje ct d o es n ot a c hie v e R et ur n t o Us u al H e alt h pri or t o t h e  s u bje ct’s last a v aila ble  diar y 
ass ess m e nt, b ut  re c or ds a “Y es ” f or t h e ret ur n t o us u al h e alt h gl o b al assess m e nt q u esti o n at t h e last 
a v aila ble diar y as sess m e nt wit h n o e vi d e n c e of s y m pt o m relief m e dic ati o n i nta k e d uri n g t h at diar y 
p eri o d, ti m e of R et ur n t o Us u al H e alt h will b e c o nsi d ere d t o h a v e o c c urre d at t h e ti m e of t h e last 
a v aila ble diar y assess m e nt . 
 
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 tre atm e nt gr o u p will b e c o m p are d t o t h at of t h e pla c e b o 
tre at m e nt gr o u p usi n g a G e h a n-Wilc o x o n test stratifie d f or ( 1) o nset of ill n ess t o ti m e of first d ose 
of st u d y m e dic ati o n ( 0 -2 4, > 2 4 -≤3 6, or > 3 6 h o urs fr o m o nset), a n d ( 2) w h et h er t h e v a c ci n ati o n 
stat us ( Y/ N). T h e c o m p aris o n will b e gra p hic all y d e picte d usi n g K a pla n-M eier c ur v es.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
E v e nt:  
Ti m e of A bilit y t o P erf or m All N or m al A cti vities – ti m e 
of t h e first d ose  
C e ns ore d:  Ti m e of last a bilit y  assess m e nt – ti m e of t h e first d ose 
 
1 0. 5. 5  C h a n g e i n I nfl u e n z a Vir us Titer ( T CI D 5 0) fr o m B aseli n e t o D a y 2 a n d fr o m B aseli n e t o D a y 3 
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire t h e f oll o wi n g v aria bles:  
 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
T CI D 5 0 vir us titer  
L a b orat or y 
d ata  
T CI D 5 0 v al u es will b e re p orte d as “ 1 0 ^ -3. 2 ”, f or 
e x a m ple.  F or  a n al ysis  p ur p oses,  t h e  v al u es 
s h o ul d  b e  n e g ati v e  l o g-tra nsf or m e d.  F or  t h e 
e x a m ple  a b o v e,  t h e  a n al ysis  v al u e  w o ul d  b e 
“ 3. 2 ”.  
 
A n al ysis  
M e a n c h a n g es i n i nfl u e n z a viral titers fr o m b as eli n e t o d a y 2 a n d fr o m b as eli n e t o d a y 3 f or t h e 
N T Z a n d t h e pla c e b o tre at m e nt gr o u ps will b e c o m p are d usi n g a t -test. 
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a  
D eri v e d V aria bles:  
M e a n c h a n g e i n i nfl u e n z a viral titer fr o m b as eli n e t o d a y 2:  
m e a n of ( d a y 2 T CI D 5 0 v al u e – b aseli n e T CI D 5 0 v al u e) f or e a c h 
s u bje ct wit hi n t h e tre at m e nt gr o u ps 
M e a n c h a n g e i n i nfl u e n z a viral titer fr o m b aseli n e t o d a y 3:  
m e a n of ( d a y 3 T CI D 5 0 v al u e – b aseli n e T CI D 5 0 v al u e) f or e a c h 
s u bje ct wit hi n t h e tre at m e nt gr o u ps 
 
1 0. 5. 6  Pr o p orti o ns of S u bje cts wit h D ete cta ble Vir us at D a ys 2, 3 a n d 7  
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire t h e f oll o wi n g v aria bles:  
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 3 2  of 4 3  
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  
T CI D 5 0 vir us titer  
L a b orat or y 
d ata  
T CI D 5 0 v al u es will b e re p orte d as “ 1 0 ^ -3. 2 ”, f or 
e x a m ple. F or a n al ysis p ur p oses, a n y n u m eric al 
res ult will b e tre ate d as “ p ositi v e ”. A res ult of 
“ N o  Vir us  Is olate d ”  will  b e  tre ate d  as 
“ n e g ati v e ”.  
 
A n al ysis  
T h e pr o p orti o n of s u bje ct s  wit h  a  p ositi v e  res ult  b y T CI D 5 0 at  e a c h  of  d a ys  2,  3,  a n d  7  will  b e 
c o m p are d  a cr oss tre at m e nt gr o u ps  usi n g a Fis h er’s e x a ct test.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nf l u e n z a 
D eri v e d V aria bles:  
Pr o p orti o n of s u bje cts wit h d ete cta ble vir us at d a y 2:  
N u m b er of s u bje cts wit h “ p ositi v e ” res ult b y T CI D 5 0 at d a y 2 
di vi d e d  b y  t h e  t otal  n u m b er  of c o nfir m e d  i nfl u e n z a  s u bje cts 
wit h a d a y 2 T CI D 5 0 res ult f or e a c h tre at m e nt gr o u p  
P r o p orti o n of s u bje cts wit h d ete cta ble vir us at d a y 3: 
N u m b er of s u bje cts wit h “ p ositi v e ” res ult b y T CI D 5 0 at d a y 3 
di vi d e d  b y  t h e  t otal  n u m b er  of c o nfir m e d  i nfl u e n z a  s u bje cts 
wit h a d a y 3 T CI D 5 0 res ult f or e a c h tre at m e nt gr o u p 
Pr o p orti o n of s u bje cts wit h d ete cta ble vir us at d a y 7:  
N u m b er of s u bje cts wit h “ p ositi v e ” res ult b y T CI D 5 0 at d a y 7 
di vi d e d b y t h e t otal n u m b er of c o nfir m e d i nfl u e n z a s u bje cts f or 
e a c h tre at m e nt gr o u p  (s u bje cts wit h n o T CI D5 0 res ult at d a y 7 
will b e ass u m e d t o h a v e a res ult of “ n e g ati v e ” b e c a use d a y 7 
sa m ples w ere n ot teste d b y T CI D 5 0 if tra diti o n al viral c ult ure 
w as n e g ati v e f or t h e sa m ple)  
 
1 0. 6  Ot h er E x pl orat or y A n al yses  
 
1 0. 6. 1  A n al ysis of I nfl u e n z a A nti b o d y Titers  
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire t h e f ol l o wi n g v aria bles: 
 
V a ri a ble  
S o u r c e  
F o r m at/ N otes  
I nfl u e n z a a nti b o d y titer 
v al u es  
L a b orat or y 
d ata  
I nfl u e n z a a nti b o d y titer v al u es will b e re p orte d 
as “ 1/ 2 0 ”, f or e x a m ple. T h e d e n o mi n at or of t h e 
fra cti o n will b e use d f or a n al ysis p ur p oses.  
 
A n al ysis  
C h a n g e s  i n  i nfl u e n z a  a nti b o d y  titers  will  b e  a n al y z e d  b y  c o m p aris o n  of  m e a ns  as w ell  as 
pr o p orti o ns  of  s u bje cts  ser o pr ote cte d  ( d a y  2 2  a nti b o d y  titer ≥4 0)  a n d  ser o c o n v erte d  ( d a y  2 2 
a nti b o d y titer > 4 x b aseli n e titer) at d a y 2 2. M e a ns will b e c o m p are d  a cr oss tre at m e nt gr o u ps  usi n g 
a t -test a n d pr o p orti o ns will b e c o m p are d a cr oss tre at m e n t gr o u ps usi n g a Fis h er’s e x a ct test.  
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a  


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 3 3  of 4 3  
C O N FI D E N TI A L  
D eri v e d V aria bles:  
M e a n c h a n g e i n i nfl u e n z a a nti b o d y titers fr o m b as eli n e t o d a y 2 2 : 
M e a n of ( d a y 2 2 i nfl u e n z a a nti b o d y titer – b aseli n e i nfl u e n z a 
a nti b o d y titer) f or e a c h s u bje ct a cr oss tre at m e nt gr o u ps 
Pr o p orti o n of s u bje cts ser o pr ote cte d at d a y 2 2: 
N u m b er of s u bje cts wit h d a y 2 2 a nti b o d y titer ≥4 0  di vi d e d b y 
t h e  t otal  n u m b er  of  i nfl u e n z a-p ositi v e  s u bje cts  wit h  b ot h 
b aseli n e a n d d a y 2 2 d ata  f or e a c h tre at m e nt gr o u p 
Pr o p orti o n of s u bje cts ser o c o n v erte d at d a y 2 2: 
N u m b er of s u bje cts wit h d a y 2 2 a nti b o d y titer 4 x t h e b aseli n e 
titer di vi d e d b y t h e t otal n u m b er of i nfl u e n z a -p ositi v e s u bje cts  
wit h b ot h b aseli n e a n d d a y 2 2 d ata  f or e a c h tre at m e nt gr o u p 
 
 
1 0. 6. 2  P o p ulati o n P h ar m a c o ki n etics A n al ysis  
 
V aria bles Use d f or t h e A n al ysis  
T h e a n al ysis will re q uire t h e f oll o wi n g v aria bles:  
 
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 
us e  
C R F  
 
A d v erse e v e nts  
C R F  
 
 
A n al ysis  
Plas m a c o n c e ntrati o ns of T a n d T G will b e s u m m ariz e d d escri p ti v el y f or b ot h tre at m e nt gr o u ps. 
E x pl orat or y a n al yses will b e c o n d u cte d t o e v al u ate relati o ns hi ps b et w e e n plas m a c o n c e ntrati o ns 
a n d a g e, ra 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 mita nt m e dic ati o ns ( y es/ n o), c h a n g es 
i n viral titer o v er ti m e, Ti m e to S y m pt o m R es p o nse, a n d a d v erse e v e nts ( y es/ n o). F or c o nti n u o us 
fa ct ors,  t h e  relati o ns hi p  wit h  plas m a  c o n c e ntrati o ns  will  b e  assesse d  b y  S p e ar m a n’s  c orrelati o n 
a n al ysis a n d P e ars o n’s c orrelati o n a n al ysis. F or c ate g oric al fa ct ors, plas m a c o n c e ntrati o ns will  b e 
c o m p are d a m o n g gr o u ps usi n g t h e Kr us k al -W allis test.  
 
 
A n al ysis P o p ulati o n(s):  C o nfir m e d I nfl u e n z a , N T Z-tre ate d o nl y 
D eri v e d V aria bles:  
•  C o n c o mita nt  m e dic ati o ns  use:  if  a n y  c o n c o mita nt  m e dic ati o n  is 
use d, t h e n “ y es”, ot h er wise “ n o ”  
•  A d v erse  e v e nts:  if  a n y  a d v erse  e v e nt  is  re p orte d,  t h e n  “ y es”, 
ot h er wise “ n o ”  
•  C h a n g es i n viral titer o v er ti m e: se e se cti o n 1 0. 5. 5  
•  Ti m e t o S y m pt o m R es p o nse: se e se cti o n 1 0. 2  
 
 
1 0. 7  Effic a c y Listi n gs  
 
Effic a c y listi n gs will i n cl u d e d ata s p e cifie d i n T a ble 5 f or all s u bje cts prese nte d b y s u bje ct n u m b er 
a n d tre at m e nt gr o u p.  


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 3 4  of 4 3  
C O N FI D E N TI A L  
 
T a ble 5 . D at a P r es e nte d i n Effic a c 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)  
C o m plic ati o ns of I nfl u e n z a  
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 u tc 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 M o difie d 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 M o difie d 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 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 at e/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 es ol uti o n of A c ute F e brile Ill n e ss 
D ate/ti m e of first d ose  
D ate/ti m e of R es ol uti o n of A c ute F e brile Ill n ess  
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  
Tra diti o n al C ult ure res ult  
T CI D 5 0 res ult 
I nfl u e n z a A nti b o d y Titer D ata 
St u d y d a y  
I nfl u e n z a t y p e 
A nti b o d y titer  
 
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 3 5  of 4 3  
C O N FI D E N TI A L  
1 1.   SA F E T Y  
 
1 1. 1  S afet y T a bles a n d Fi g ures  
 
U nless ot h er wise s p e cifie d, a ll safet y ta bles will b e b ase d o n t h e All Tre ate d p o p ulati o n a n d  prese nt 
d ata  b y tre at m e nt gr o u p.  
 
A d v ers e e v e nts s u m m ar y ta bles will use t h e f oll o wi n g al g orit h ms f or c o u nti n g s u bje ct e v e nts:  
 
•  
Preferre d  ter m:  E a c h  s u bje ct  will  b e  c o u nte d  o n c e  wit hi n  e a c h  u ni q u e  preferre d  ter m  at  t h e 
m a xi m u m  gra d e.  
•  
S yste m or g a n class: E a c h s u bje ct is c o u nte d o nl y o n c e at t h e m a xi m u m gra d e at e a c h s yste m 
or g a n class le v el.  
•  
A n y e v e nt: E a c h s u bje ct wit h a n e v e nt is c o u nte d o nl y o n c e at t h e m a xi m u m gra d e.  
 
1 1. 1. 1 S u m m ar y of All Tre at m e nt E m er g e nt A d v erse E v e nts  ( T E A Es) 
 
T h e s u m m ar y of all T E A Es will s u m m ariz e t h e f oll o wi n g:  
 
•  
T h e t otal n u m b er of T E A Es;  
•  
T h e n u m b er a n d p erc e nta g e of s u bje cts wit h at le ast o n e T E A E;  
•  
T h e n u m b er a n d p erc e nta g e of s u bje cts wit h at le ast o n e S A E;  
•  
T h e n u m b er a n d p erc e nta g e of s u bje cts wit h a T E A E b y t h e m a xi m u m se v erit y gra d e; a n d  
•  
T h e n u m b er a n d p erc e nta g e of s u bje cts wit h a T E A E b y t h e cl osest relati o ns hi p t o t h e st u d y dr u g.  
 
1 1. 1. 2 S u m m aries  of T E A Es b y S O C a n d Preferre d T er m  
 
T h e n u m b er a n d p erc e nt of s u bje cts wit h T E A Es will b e s u m m ari z e d b y S O C a n d preferre d ter m 
wit h t h e f oll o wi n g v ariati o ns  i n prese ntati o n: 
 
•  
N u m b er a n d p erc e nt of s u bje cts wit h T E A Es will b e s u m m ariz e d b y S O C a n d preferre d ter m ; 
•  
N u m b er a n d p erc e nt of s u bje cts wit h T E A Es will b e s u m m ariz e d b y S O C, preferre d ter m a n d 
s ev erit y ; 
•  
N u m b er a n d p erc e nt of s u bje cts wit h gra d e ≥3 T E A Es b y S O C a n d preferre d ter m ; 
•  
N u m b er a n d p erc e nt of s u bje cts 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 
m e dic ati o n;  
•  
N u m b er a n d p erc e nt of s u bje cts wit h u n e x p e cte d T E A Es b y S O C a n d preferre d t er m;  
•  
N u m b er a n d p erc e nt of s u bje cts wit h S A Es b y S O C a n d preferre d ter m; a n d  
•  
N u m b er a n d p erc e nt of T E A Es le a di n g t o st u d y wit h dra w al b y S O C a n d preferre d ter m.  
 
1 1. 1. 3 L a b orat or y  R es ults  a n d C h a n g es  fr o m B aseli n e 
 
N u m eric al  h e m at ol o g y a n d ser u m bi o c h e mistr y v al u es will b e c o n v erte d t o SI u nits a n d classifie d as 
N or m al, Gra d e 1, Gra d e 2, Gra d e 3 or Gra d e 4 a c c or di n g t o refere n c e ra n g es  i n dic ate d i n t h e pr ot o c ol 
t o xicit y  gra di n g  sc ale  ta bles  (se e  A p p e n di x  II). Uri n al ysis  res ults  will  b e  classifie d  as  N or m al  o r 
A b n or m al b ase d o n refere n c e ra n g es pr o vi d e d b y t h e c e ntral la b orat or y.  
 
H e m at ol o g y,  ser u m bi o c h e mistr y, a n d uri n al ysis la b orat or y res ults a n d c h a n g e fr o m B aseli n e  will b e 
s u m m ariz e d usi n g d escri pti v e statistics f or e a c h visit.  
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 3 6  of 4 3  
C O N FI D E N TI A L  
S hift ta bles will dis pla y  s hifts fr o m  B aseli n e  i n  la b orat or y  res ults classific ati o n  ( Gra d e 1/ 2/ 3/ 4  or 
N or m al/ A b n or m al)  b y st u d y d a y.  
 
1 1. 1. 4 S u m m aries of Vital Si g ns  R es ults a n d C h a n g es fr o m B aseli n e  
 
Vital si g ns d ata will b e classifie d as N or m al, Gra d e 1, Gra d e 2, Gra d e 3 or Gra d e 4  b ase d o n t h e 
refere n c e ra n g es i n dic ate d i n t h e pr ot o c ol t o xicit y gra di n g sc ale ta bles (se e A p p e n di x II). 
 
Vital si g ns res ults a n d c h a n g e fr o m B aseli n e will b e s u m m ariz e d usi n g d escri pti v e statistics f or e a c h 
visit.  
 
S hift ta bles will dis pla y s hifts fr o m B aseli n e i n vital si g ns classific ati o n ( Gra d e 1/ 2/ 3/ 4 ) b y st u d y d a y.  
 
1 1. 1. 5 S u m m aries of P h ysic al E x a mi n ati o n R es ults a n d C h a n g es fr o m B aseli n e  
 
T h e n u m b er a n d p erc e nt of s u bje cts wit h a b n or m al p h ysic al e x a mi n ati o n fi n di n gs will b e s u m m ariz e d 
b y b o d y s yste m f or e a c h visit.  
 
A s hift ta ble will dis pla y c h a n g es i n p h ysic al e x a mi n ati o n classific ati o n ( N or m al/ A b n or m al) at e a c h 
visit b y b o d y s yste m.  
 
1 1. 2  S afet y Listi n gs   
 
S afet y listi n gs will i n cl u d e d ata s p e cifie d i n T a ble 6 f or all s u bje cts prese nte d b y s ubje ct n u m b er a n d 
tre at m e nt gr o u p. 
 
T a ble 6 . D at a P r es e 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)  
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)  


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 3 7  of 4 3  
C O N FI D E N TI A L  
Listi n g  
D at a P r ese nte d  
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  
 
 
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n  Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 01 9  
 
P a g e 3 8  of 4 3  
C O N FI D E N TI A L  
1 2.  R E F E R E N C E S  
1 .  Os b or n e R, H a wt h or n e G, P a p a nic ola o u M , W e g m u eller Y. M e as ure m e nt of ra pi d c h a n g es i n h e alt h 
o utc o m es i n p e o ple wit h i nfl u e n z a s y m pt o ms. J O utc o m es R es  2 0 0 0; 4: 1 5 -3 0.  
2. 
Cli nic al  
St u d y  
R e p ort  
W -1 4 4 1 0 2,  
Pr ot o c ol  
W V 1 5 6 7 0.  
R o c h e.  
A v aila ble  
at: 
htt ps:// w w w.i n d ustr y d o c u m e ntsli brar y. u csf.e d u/ dr u g/ d o cs/ #i d =s q p m 0 2 1 7.  
3. 
Cli nic al  
St u d y  
R e p ort  
W -1 4 4 1 0 3,  
Pr ot o c ol  
W V 1 5 6 7 1.  
R o c h e.  
A v aila ble  
at: 
htt ps:// w w w.i n d ustr y d o c u m e ntsli brar y. u csf.e d u/ dr u g/ d o cs/ #i d =t q p m 0 2 1 7.  
 


T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al A n al ysis Pla n Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0 , 2 0 1 9 
 
P a g e 3 9  of 4 3  
C O N FI D E N TI A L  
A p p e n di x I: S c h e d ule of Assess m e nts  
 
 
S cree ni n g  
( D a y 1) 
B aseli 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 nsc he 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 xcl 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 
X 3 
X 
Bl o o d sa m ple f or p h ar m ac o ki n etics  
 
 
 
 
 
 
X 4 
Bl o o d  
sa m ple 
f or  
a nti-i nfl u e n za 
a nti b o dies  
 
 
X  
 
  
 
 
X  
 
Bl o o d sa m ple f or la b orat or y safet y tests 5 
 
 
X  
 
 
 
 
 
X 
X 
Uri n e sa m ple f or r o uti n e uri n al ysis 5 
 
 
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 ucti o ns  re:  d osi n g,  c o nc o mita nt 
m e dicati o ns, patie nt 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 p atie nt diar y  e ntries  
 
 
 
 
X 6 
 
 
X 6 
S cree n  
f or 
i nfl u e n za-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 ner  
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 7 
 
1 D a y 7 a n d 2 2  p h ysical e xa m is a brief p h ysical e xa m ( vital si g ns a n d n ursi n g p h ysical assess m e nt) i ncl u di n g s y m pt o m directe d p h ysicia n p h y sical 
e xa mi nati o n as re q uire d b y patie nt s y m pt o ms.  Vital si g ns i ncl u de bl o o d press ure, p ulse, res pirat or y rate a n d or al te m perat ure.  
2 N as o p har y n geal s w a bs o n da ys 2 a n d 3  will be c ollecte d at t he patie nt’s h o me ( or cli nic or a n ot her l ocati o n as a gree d wit h t he patie nt).  
3 N as o p har y n geal s w a bs c ollecte d o n da y  2 2  will o nl y be teste d f or t he prese nce of vir us if t he sa m p le fr o m da y 7  ha d detecta ble vir us.  
4 Bl o o d sa m ple  c ollecte d pre -d ose o n da y 3.  
5 La b orat or y safet y tests i ncl u de he m o gl o bi n, he m at 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 ns a n d bl o o d).  
6 All s u bjects will m ai ntai n a n electr o nic diar y u ntil da y 2 2 ( + 3).  Site st aff will c o ntact s u bjects as nee de 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 . 
7 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 be perf or m e d at u nsc he d ule d visit if a p plica ble.  
 
 
 








T h e R o m ar k I nstit ute f or M e dic al R ese arc h   
 
Statistic al  A n al ysis Pla n Fi n al  v 1. 2 
Pr ot o c ol R M 0 8 -3 0 0 4  
 
J ul y 2 0, 2 0 1 9 
 
P a g e 4 3  of 4 3  
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. 1 0  
Listi n g of I nfl u e n z a A nti b o d y Titer D ata  
Listi n g  
C o nfir m e d I nfl u e n z a  
1 6. 2. 7  
Listi n g of A d v erse E v e nts  
Listi n g  
All Tre ate d  
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  
All Tre ate d  
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  
All Tre ate d  
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  
All Tre ate d  
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  
All Tre ate d  
1 6. 2. 9. 1  
Li sti n g of Vital Si g ns D ata 
Listi n g  
All Tre ate d  
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  
All Tre ate d