Clinical trial NCT04489381
Conditions: Enterovirus Rhinovirus
Keywords: Enterovirus Rhinovirus
Sponsor: Romark Laboratories L.C.
Start date: 2020-08-19; Completion date: 2021-02-02
Enrollment: 214 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

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

Arms: arm 1: Two nitazoxanide 300 mg tablets orally twice daily for 5 days arm 2: Two placebo tablets orally twice daily for 5 days
Interventions: intervention 1: Nitazoxanide intervention 2: Placebo intervention 3: Vitamin Super B-Complex
Intervention descriptions: intervention 1: Two nitazoxanide 300 mg tablets administered orally twice daily with food for 5 days intervention 2: Two placebo tablets administered orally twice daily with food for 5 days intervention 3: Vitamin Super B-Complex administered orally twice daily to maintain the blind

Protocol documents:
Prot_SAP_000.pdf: 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
2 
C O N FI D E N TI A L  
 
 
I N V E S TI G A T O R’ S A G R E E M E N T  
C O N FI D E N TI A LI T Y  
T he i nf or mati o n i n t his pr ot oc ol is pr o vi de d t o y o u, as a n I n vesti gat or or c o ns ulta nt, f or re vie w b y 
y o u,  y o ur  staff,  a n d  a n  a p plica ble  i nstit uti o nal  re vie w  c o m mittee.  B y  acce pti n g  t his  d oc u me nt, 
y o u  a gree  t hat  i nf or mati o n  c o ntai ne d  herei n  will  be  c o nsi dere d  c o nfi de ntial  a n d  will  n ot  be 
discl ose d t o ot hers, wit h o ut writte n a ut h orit y fr o m T he R o mar k I nstit ute f or Me dical Researc h, 
e xce pt t o t he e xte nt necessar y t o o btai n: (a) I nstit uti o nal Re vie w B oar d a p pr o val a n d ( b) i nf or me d 
c o nse nt fr o m t h ose pers o ns t o w h o m t he i n vesti gati o nal me dici nal pr o d uct will be a d mi nistere d. 
A P P R O V A L O F  FI N A L P R O T O C O L  
M y  si g nat ure  bel o w  c o nstit utes  a gree me nt  wit h  t his  pr ot oc ol.  I  a m  pr o vi di n g  t he  necessar y 
ass ura nces t hat t his st u d y will  be c o n d ucte d b y me  a n d m y  staff acc or di n g t o all sti p ulati o ns of t he 
pr ot oc ol, i ncl u di n g all state me nts re gar di n g c o nfi de ntialit y, a n d i n c o m plete acc or da nce wit h all 
a p plica ble  re g ulati o ns  i ncl u di n g  c urre nt  G o o d  Cli nical  Practice  g ui deli nes  a n d  t he  et hical 
g ui deli nes  set  b y  t he  W orl d  Me dical  Asse m bl y  ( Declarati o n  of  Helsi n ki,  last  a me n d me nt  i n 
F ortaleza,  Brazil  Oct o ber  2 0 1 3).  F urt her m ore,  m y  si g nat ure  bel o w  i n dicates  t hat  s o urce 
d oc u me nts will be a vaila ble f or re vie w b y t he S p o ns or or t heir desi g nate d re prese ntati ve. 
 
Pri nci pal I n vesti gat or Si g nat ure:  
 
 
 
 
Pri nci pal I n vesti gat or 
Date  
 
Pri nt na me:  
 
 
Wit h  t he si g nat ure bel o w, t he S p o ns or a p pr o ves of t his pr ot oc ol. 
S p o ns or Si g nat ure: 
 
 
T he R o mar k I nstit ute f or Me dical Researc h   
Date 
Pri nt na me:  
 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
3 
C O N FI D E N TI A L  
 
 
T A B L E  O F  C O N T E N T S  
S T A T E M E N T O F C O M P LI A N C E  ................................................................................................. 1 
I N V E S TI G A T O R’ S A G R E E M E N T  ............................................................................................... 2 
T A B L E O F C O N T E N T S  ................................................................................................................ 3 
LI S T O F T A B L E S  ........................................................................................................................... 6 
LI S T O F FI G U R E S  ......................................................................................................................... 7 
1.  
P R O T O C O L S U M M A R Y  ........................................................................................... 8 
1. 1.  
S y n o psis  ........................................................................................................................ 8 
1. 2.  
Sc he d ule of Assess me nts  ............................................................................................ 1 1  
2.  
I N T R O D U C TI O N ...................................................................................................... 1 2  
2. 1.  
E nter o vir uses/ R hi n o vir uses  ......................................................................................... 1 2  
2. 2.  
Nitaz o xa ni de ( N T Z) ................................................................................................... 1 3  
2. 2. 1.  
N T Z  I n hi bits Viral Re plicati o n a n d C yt o ki ne Secreti o n  ............................................ 1 3  
2. 2. 2.  
P har mac o ki netics of N T Z  i n H u ma ns  ........................................................................ 1 4  
2. 2. 3.  
O ver vie w of Cli nical E x perie nce wit h  N T Z  ............................................................... 1 5  
2. 2. 4.  
Earl y Cli nical E x perie nce wit h  N T Z  i n Treat me nt of E V/ R V  ................................... 1 6  
2. 2. 5.  
St u d y R M 0 8- 3 0 0 5: N T Z i n t he Treat me nt of C ol ds D ue t o E V/ R V  .......................... 1 6  
2. 3.  
Rati o nale f or t he St u d y  ............................................................................................... 1 8  
3.  
S T U D Y O BJ E C TI V E S  .............................................................................................. 1 8  
4.  
S T U D Y D E SI G N  ....................................................................................................... 1 8  
4. 1.  
St u d y Desi g n O ver vie w  .............................................................................................. 1 8  
4. 2.  
Rati o nale f or I m p orta nt Iss ues i n t he St u d y Desi g n  ................................................... 1 9  
4. 2. 1.  
C h oice of N T Z D ose a n d D urati o n of Treat me nt  ....................................................... 1 9  
4. 2. 2.  
C h oice of C o ntr ol Gr o u p  ............................................................................................ 2 0  
4. 2. 3.  
C h oice of Patie nt P o p ulati o n  ...................................................................................... 2 0  
4. 2. 4.  
Use  of Vita mi n B C o m ple x S u p ple me nt  .................................................................... 2 1  
4. 2. 5.  
C h oice of Patie nt- Re p orte d O utc o me I nstr u me nt ....................................................... 2 2  
4. 2. 6.  
C h oice of Pri mar y E n d p oi nt  ....................................................................................... 2 2  
5.  
S T U D Y P O P U L A TI O N  ............................................................................................. 2 2  
5. 1.  
I ncl usi o n Criteria  ........................................................................................................ 2 2  
5. 2.  
E xcl usi o n Criteria  ....................................................................................................... 2 3  
5. 3.  
St u d y P o p ulati o n Di versit y  ......................................................................................... 2 4  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
4 
C O N FI D E N TI A L  
 
 
6.  
S T U D Y I N T E R V E N TI O N ........................................................................................ 2 4  
6. 1.  
St u d y I nter ve nti o n(s) A d mi nistrati o n  ......................................................................... 2 4  
6. 1. 1.  
St u d y I nter ve nti o n Descri pti o n  ................................................................................... 2 4  
6. 1. 2.  
D osi n g a n d A d mi nistrati o n  ......................................................................................... 2 5  
6. 2.  
Pre parati o n, Ha n dli n g, St ora ge a n d Acc o u nta bilit y  ................................................... 2 5  
6. 2. 1.  
Ac q uisiti o n a n d Acc o u nta bilit y  .................................................................................. 2 5  
6. 2. 2.  
Pac ka gi n g a n d La beli n g  .............................................................................................. 2 5  
6. 3.  
Ra n d o mizati o n a n d Bli n di n g  ...................................................................................... 2 6  
6. 4.  
St u d y I nter ve nti o n C o m plia nce  .................................................................................. 2 6  
6. 5.  
C o nc o mita nt T hera p y  ................................................................................................. 2 6  
7.  
S T U D Y I N T E R V E N TI O N DI S C O N TI N U A TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N  ................................................................................................ 2 7  
8.  
S T U D Y P R O C E D U R E S  ............................................................................................ 2 7  
8. 1.  
Visit Pr oce d ures  .......................................................................................................... 2 7  
8. 1. 1.  
I nf or me d C o nse nt  ....................................................................................................... 2 7  
8. 1. 2.  
Me dical Hist or y  .......................................................................................................... 2 8  
8. 1. 3.  
P h ysical E xa mi nati o n  ................................................................................................. 2 8  
8. 1. 4.  
B o d y Meas ure me nts a n d Resti n g Vital  Si g ns  ............................................................ 2 8  
8. 1. 5.  
Scree ni n g F L U -P R O  ................................................................................................... 2 9  
8. 1. 6.  
Ra n d o mizati o n a n d Dis pe nsi n g St u d y Me dicati o n  ..................................................... 2 9  
8. 1. 7.  
S u bject I nstr ucti o ns .................................................................................................... 2 9  
8. 1. 8.  
Da y  2- 5 S u bject C o ntact  ............................................................................................. 3 0  
8. 2.  
La b orat or y Assess me nts  ............................................................................................. 3 0  
8. 2. 1.  
Assess me nts i n t he Cli nic  ........................................................................................... 3 0  
8. 2. 2.  
Ce ntral La b orat or y Assess me nts  ................................................................................ 3 1  
8. 2. 3.  
P har mac o ki netics Assess me nts  .................................................................................. 3 1  
8. 2. 4.  
Pla n  f or M o nit ori n g Viral Resista nce  ......................................................................... 3 1  
8. 3.  
S u bject Diar y  .............................................................................................................. 3 1  
8. 3. 1.  
S u bject Diar y C o m pleti o n  .......................................................................................... 3 2  
8. 3. 2.  
S u bject Diar y C o m plia nce M o nit ori n g  ....................................................................... 3 2  
8. 4.  
A d verse E ve nts a n d Seri o us A d verse E ve nts  ............................................................. 3 2  
8. 4. 1.  
Defi niti o ns  .................................................................................................................. 3 2  
8. 4. 2.  
Rec or di n g a n d F oll o w U p  of A d verse E ve nts  ............................................................ 3 3  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
5 
C O N FI D E N TI A L  
 
 
8. 4. 3.  
Re p orti n g Re q uire me nt  ............................................................................................... 3 4  
8. 4. 4.  
Me dicati o n Err ors  ....................................................................................................... 3 4  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ....................................................................... 3 4  
9. 1.  
Sa m ple Size  Deter mi nati o n  ........................................................................................ 3 4  
9. 2.  
Efficac y Varia bles  ...................................................................................................... 3 4  
9. 3.  
Res p o nse Defi niti o ns  .................................................................................................. 3 5  
9. 3. 1.  
Res p o nse Defi niti o ns f or t he Pri mar y Efficac y A nal ysis  ........................................... 3 5  
9. 3. 2.  
Defi niti o ns f or C o m plicati o ns of C ol ds  ...................................................................... 3 6  
9. 4.  
Statistical  Met h o d ol o g y  .............................................................................................. 3 7  
9. 4. 1.  
Efficac y A nal yses  ....................................................................................................... 3 7  
9. 4. 2.  
P o p ulati o n P har mac o ki netics A nal ysis  ....................................................................... 3 9  
9. 4. 3.  
Safet y A nal yses  .......................................................................................................... 3 9  
1 0.  
O P E R A TI O N A L C O N SI D E R A TI O N S  ..................................................................... 3 9  
1 0. 1.  
Re g ulat or y, Et hical a n d St u d y O versi g ht C o nsi derati o ns  ........................................... 3 9  
1 0. 1. 1.  
Et hics  .......................................................................................................................... 3 9  
1 0. 1. 2.  
I n vesti gat or Res p o nsi bilities  ....................................................................................... 4 0  
1 0. 1. 3.  
Q ualit y Ass ura nce a n d Q ualit y C o ntr ol  ...................................................................... 4 0  
1 0. 1. 4.  
Safet y O versi g ht  ......................................................................................................... 4 0  
1 0. 1. 5.  
Data  Ha n dli n g a n d Rec or d Kee pi n g  ........................................................................... 4 0  
1 0. 1. 6.  
Cli nical M o nit ori n g  .................................................................................................... 4 1  
1 0. 1. 7.  
Pr ot oc ol De viati o ns  .................................................................................................... 4 1  
1 0. 1. 8.  
St u d y Disc o nti n uati o n a n d Cl os ure  ............................................................................ 4 1  
1 0. 1. 9.  
Data  a n d Re p ort Re q uire me nts  ................................................................................... 4 2  
1 0. 1. 1 0.  
C o nfi de ntialit y a n d Pri vac y  ........................................................................................ 4 2  
1 0. 1. 1 1.  
P u blicati o n a n d Data  S hari n g  ..................................................................................... 4 2  
1 0. 1. 1 2.  
Ke y  R oles a n d St u d y G o ver na nce  .............................................................................. 4 2  
1 1.  
R E F E R E N C E S  ........................................................................................................... 4 3  
A P P E N DI X 1.   P R O T O C O L R E VI SI O N HI S T O R Y  ................................................................. 4 6  
A P P E N DI X 2.   C O N T A C T I N F O R M A TI O N ............................................................................ 5 0  
A P P E N DI X 3.   LI S T O F E S S E N TI A L D O C U M E N T S F O R T H E SI T E  .................................. 5 1  
A P P E N DI X 4.   T O XI CI T Y G R A DI N G T A B L E S  ..................................................................... 5 3  
A P P E N DI X 5.  F L U - P R O D O M AI N/ S U B D O M AI N S T R U C T U R E  ........................................ 6 0  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
6 
C O N FI D E N TI A L  
 
 
LI S T  O F  T A B L E S  
Ta ble 1:   
Sc he d ule of Assess me nts  ............................................................................................ 1 1  
Ta ble 2:   
S u m mar y of Tiz o xa ni de a n d Tiz o xa ni de Gl uc ur o ni de P har mac o ki netics Para meters  
. .................................................................................................................................. 1 4  
Ta ble 3:  
S u m mar y of Tiz o xa ni de a n d Tiz o xa ni de Gl uc ur o ni de Tr o u g h Plas ma C o nce ntrati o ns 
( µ g/ m L) b y St u d y Da y  ................................................................................................ 1 5  
Ta ble 4:  
Pr o p orti o ns of S u bjects E x perie nci n g C o m plicati o ns a n d Br o nc hitis f or E V/ R V- 
I nfecte d S u bjects E nr olle d i n St u d y R M 0 8-3 0 0 5  ....................................................... 1 7  
Ta ble 5:   
St u d y Me dicati o n La bel  .............................................................................................. 2 5  
Ta ble 6:   
Pr ot oc ol Re visi o n Hist or y  .......................................................................................... 4 6  
Ta ble 7:   
St u d y C o ntact I nf or mati o n ......................................................................................... 5 0  
Ta ble 8:  
List  of Esse ntial D oc u me nts  ....................................................................................... 5 1  
Ta ble 9:   
Ta ble f or Cli nical A b n or malities: Vital  Si g ns  ............................................................ 5 3  
Ta ble 1 0:   Ta ble f or Cli nical A b n or malities: S yste mic ( Ge neral) ............................................... 5 4  
Ta ble 1 1:   Ta ble f or Cli nical A b n or malities: S yste mic Ill ness .................................................... 5 4  
Ta ble 1 2:   Ta ble f or La b orat or y A b n or malities: Ser u m  .............................................................. 5 5  
Ta ble 1 3:   Ta ble f or La b orat or y A b n or malities: He mat ol o g y  ..................................................... 5 8  
Ta ble 1 4:   Ta ble f or La b orat or y A b n or malities: Uri ne  ................................................................ 5 9  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
7 
C O N FI D E N TI A L  
 
 
LI S T  O F  FI G U R E S  
Fi g ure 1:  
Ti me t o S ustai ne d Res p o nse f or E V/ R V-I nfecte d S u bjects E nr olle d i n St u d y R M 0 8- 
3 0 0 5  ............................................................................................................................ 1 7  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
8 
C O N FI D E N TI A L  
 
 
1.  
P R O T O C O L  S U M M A R Y  
1. 1.  
S y n o psis  
Title  of  St u d y:  
A P hase 3, Ra n d o mize d, D o u ble -Bli n d, Place b o C o ntr olle d Trial t o 
E val uate  t he Efficac y  a n d Safet y  of  Nitaz o xa ni de  i n t he Treat me nt  of 
C ol ds D ue t o E nter ovir us/ R hi n ovir us I nfecti o n 
N a me  of  Test  Dr u g:  
Nitaz o xa ni de  3 0 0  m g  Ta blets  
N a me  of  Acti ve  I n gre die nt: 
Nitaz o xa ni de  
St u d y  S p o ns or:  
T he  R o mar k  I nstit ute f or Me dical  Researc h  
I N D N u m ber:  
1 4 0, 4 4 5  
S T U D Y  D E T AI L S  
A ntici p ate d  St u d y  Peri o d:  
J ul y 2 0 2 0  – Ma y  2 0 2 1  
Pr ot oc ol  & A me n d me nts:  
Ori gi nal  Pr ot oc ol:  J ul y 1 6,  2 0 2 0  
Versi o n  2. 0:  Dece m ber  2 3,  2 0 2 0  
I n vesti g at ors: 
M ulti ple  i n t he U S  
O B J E C TI V E S  
Pri mar y  O bjecti ve:    E val uate t he effect of N T Z i n re d uci n g t he ti me t o S ustai ne d Res p o nse c o m pare d 
t o place b o i n s u bjects wit h la b orat or y-c o nfir me d E V/ R V i nfecti o n  
Sec o n dar y  O bjecti ve:   E val uate t he pr o p orti o n of s u bjects re q uiri n g s yste mic a nti bi otics f or a n i nfecti o n 
sec o n dar y t o E V/ R V, i ncl u di n g p ne u m o nia, otitis me dia, br o nc hitis, si n usitis or 
p har y n gitis  
E x pl orat or y  O bjecti ves:  i. E val uate  t he  pr o p orti o n  of  s u bjects  p ositi ve  f or  E V/ R V  b y  P C R  at  eac h  of 
Da ys 4 a n d 1 0  
ii. E val uate  t he  pr o p orti o n  of  s u bjects  re q uiri n g  s yste mic  a nti bi otics  f or  eac h 
i nfecti o n sec o n dar y t o E V/ R V,  i ncl u di n g p ne u m o nia,  otitis  me dia,  br o nc hitis, 
si n usitis or p har y n gitis 
Safet y  O bjecti ve:  
Safet y  will  be  assesse d b y  a nal ysis of  a d verse e ve nts. 
M E T H O D O L O G Y  
St u d y  Desi g n:  
M ultice nter,  ra n d o mize d, d o u ble -bli n d  trial 
Tre at me nts:  
S u bjects  will  be  ra n d o mize d 1: 1  t o o ne  of  t he f oll o wi n g gr o u ps:  
Gr o u p  1 ( N T Z): 
T w o  N T Z  3 0 0  m g  ta blets b.i. d.  f or 5 da ys  
a d mi nistere d  orall y  wit h  f o o d. 
Gr o u p  2 ( Place b o): T w o  place b o  ta blets b.i. d.  f or 5 da ys  a d mi nistere d 
orall y  wit h  f o o d. 
St u d y  D ur ati o n:  
S u bjects  will  recei ve 2 ta blets b.i. d.  f or 5 da ys  ( 1 0 d oses).  T he  f oll o w u p 
peri o d will e xte n d t hr o u g h t he e n d of st u d y visit at st u d y Da y 2 8.  
S U B J E C T  P O P U L A TI O N  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
9 
C O N FI D E N TI A L  
 
 
N u m ber of S u bjects Pl a n ne d:  At least 3 5 0 u p t o 4 0 0 s u bjects wit h la b orat or y -c o nfir me d E V/ R V 
i nfecti o n. Data  f or s u bjects e nr olle d i n c o nc urre nt  st u d y R M 0 8 -3 0 0 8  ( C O VI D-1 9  treat me nt st u d y wit h  t he 
sa me selecti o n criteria a n d pr oce d ures) wit h la b orat or y c o nfir me d E V/ R V i nfecti o n at baseli ne will be 
all ocate d t o t his st u d y f or a nal ysis a n d will c o u nt t o war d t he 3 5 0 t o 4 0 0 re q uire d s u bjects.  
I ncl usi o n Criteri a:  
1.  Male  or  fe male at least 1 2  years  of  a ge 
2.  Prese nce of cli nical si g ns a n d/ or s y m pt o ms c o nsiste nt wit h w orse ni n g or sta ble E V/ R V i nfecti o n ( o ne 
of t he f oll o wi n g is re q uire d):  
a. Prese nce  of  at least t w o res pirat or y s y m pt o m d o mai ns  ( hea d, t hr oat, n ose,  c hest, c o u g h) wit h  a 
sc ore of ≥2 as deter mi ne d b y Scree ni n g F L U-P R O O R  
b.  Prese nce of at least o ne res pirat or y s y m pt o m d o mai n ( hea d, t hr oat, n ose, c hest, c o u g h) wit h a 
sc ore of ≥2 as deter mi ne d b y Scree ni n g F L U-P R O wit h p ulse rate ≥9 0 O R  
c. Prese nce of at least o ne res pirat or y s y m pt o m d o mai n ( hea d, t hr oat, n ose, c hest, c o u g h) wit h a 
sc ore of ≥2 as deter mi ne d b y Scree ni n g F L U-P R O wit h res pirat or y rate ≥1 6  
A N D  patie nt  re p orte d assess me nt  t hat s y m pt o ms are prese nt,  t he s y m pt o ms are n ot  c o nsiste nt wit h  t he 
s u bject’s us ual healt h, t he s y m pt o ms i nterfere wit h dail y acti vities, a n d t he s y m pt o ms ha ve w orse ne d 
or  re mai ne d  t he  sa me  relati ve  t o  t he  pre vi o us  da y,  as  c o nfir me d  b y  res p o nses  t o  q uesti o ns  i n  t he 
Scree ni n g F L U -P R O.  
3.  O nset  of  s y m pt o ms n o  m ore  t ha n 7 2  h o urs  bef ore  e nr oll me nt i n t he trial. O nset  of  s y m pt o ms is defi ne d 
as  t he  earlier  of  t he  first  ti me  at  w hic h  t he  s u bject  e x perie nce d  s u bjecti ve  fe ver  or  a n y  res pirat or y 
s y m pt o m ( hea dac he/ hea d c o n gesti o n, t hr oat s y m pt o ms, nasal s y m pt o ms, c hest s y m pt o ms, c o u g h).  
4.  Willi n g a n d a ble t o pr o vi de writte n i nf or me d c o nse nt (i ncl u di n g asse nt b y le gal g uar dia n if u n der 1 8 
years of a ge) a n d c o m pl y wit h t he re q uire me nts of t he pr ot oc ol, i ncl u di n g c o m pleti o n of t he s u bject 
diar y a n d all pr ot oc ol pr oce d ures.  
E xcl usi o n  Criteri a:  
1.  [Excl usi o n  criteri o n re m ove d i n pr ot oc ol  versi o n 2. 0.  See  Revisi o n  Hist ory  i n A p pe n dix 1. ] 
2.  S u bjects  w h o  e x perie nce d  a pre vi o us  e pis o de of  ac ute u p per  res pirat or y tract i nfecti o n, otitis,  br o nc hitis 
or si n usitis or recei ve d a nti bi otics f or t hese c o n diti o ns wit hi n t w o wee ks pri or t o a n d i ncl u di n g st u d y 
da y 1.  
3.  Se verel y  i m m u n o deficie nt pers o ns  i ncl u di n g: 
a. S u bjects wit h i m m u n ol o gic dis or ders or recei vi n g i m m u n os u p pressi ve t hera p y (e. g., f or or ga n or 
b o ne marr o w tra ns pla nts, i m m u n o m o d ulat or y t hera pies f or certai n a ut oi m m u ne diseases)  
b.  S u bjects  wit h  u ntreate d  HI V  i nfecti o n or  treate d HI V  i nfecti o n wit h   a C D 4  c o u nt bel o w  3 5 0 
cells/ m m 3 i n t he last si x m o nt hs 
c. S u bjects  acti vel y u n der g oi n g  s yste mic c he m ot hera p y  or  ra di ot hera p y treat me nt f or mali g na nc y  
d.  S u bjects  usi n g  ster oi ds as mai nte na nce  t hera p y f or a c hr o nic c o n diti o n 
4.  S u bjects  wit h  acti ve res pirat or y aller gies or  s u bjects e x pecte d t o re q uire a nti-aller g y me dicati o ns  d uri n g 
t he st u d y peri o d f or res pirat or y aller gies. 
5.  Fe males of c hil d beari n g p ote ntial w h o are eit her pre g na nt or se x uall y acti ve wit h o ut t he use of birt h 
c o ntr ol. Fe male  s u bjects of  c hil d-beari n g  p ote ntial  t hat are se x uall y acti ve m ust  ha ve  a ne gati ve  baseli ne 
pre g na nc y test a n d m ust a gree t o c o nti n ue a n acce pta ble met h o d of birt h c o ntr ol f or t he d urati o n of t he 
st u d y a n d f or 1 m o nt h  p ost -treat me nt.  A d o u ble  barrier  met 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 ycles pri or t o st u d y dr u g a d mi nistrati o n, a n I U D, or me dr o x y pr o gester o ne acetate  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
1 0  
C O N FI D E N TI A L  
 
 
 
a d mi nistere d  i ntra m usc ularl y  f or  a  mi ni m u m  of  o ne  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  met h o ds  of  birt h  c o ntr ol  f or  i ncl usi o n  i nt o  t he  st u d y.  Fe male  s u bjects  are  c o nsi dere d  of 
c hil d beari n g p ote ntial u nless t he y are p ost me n o pa usal (a bse nce of me nstr ual blee di n g f or 1 year  - or 6 
m o nt hs  if  la b orat or y  c o nfir mati o n  of  h or m o nal  stat us),  or  ha ve  ha d  a  h ysterect o m y,  bilateral  t u b ular 
li gati o n or bilateral o o p h orect o m y. 
6.  S u bjects  resi di n g i n t he sa me h o use h ol d  wit h  a n ot her s u bject partici pati n g  i n t he st u d y. 
7.  Treat me nt  wit h  a n y i n vesti gati o nal dr u g  or  vacci ne  t hera p y wit hi n  3 0  da ys  pri or  t o scree ni n g a n d willi n g 
t o a v oi d t he m d uri n g t he c o urse of t he st u d y. 
8.  Recei pt  of  a n y d ose  of  N T Z  wit hi n  se ve n da ys  pri or  t o scree ni n g. 
9.  K n o w n  se nsiti vit y t o N T Z  or  a n y of  t he e xci pie nts  c o m prisi n g t he st u d y me dicati o n.  
1 0.  S u bjects  u na ble  t o s wall o w oral  ta blets or  ca ps ules. 
1 1.  S u bjects wit h k n o w n se vere heart, l u n g, ne ur ol o gical or ot her s yste mic disease t hat t he I n vesti gat or  
belie ves c o ul d precl u de safe partici pati o n.  
1 2.  S u bjects  li kel y or  e x pecte d t o re q uire h os pitalizati o n  u nrelate d  t o c ol d d uri n g  t he st u d y peri o d.  
1 3.  S u bjects w h o, i n t he j u d g me nt of t he I n vesti gat or, will be u nli kel y t o c o m pl y wit h t he re q uire me nts of 
t his pr ot oc ol i ncl u di n g c o m pleti o n of t he s u bject diar y. 
1 4.  S u bjects  ta ki n g me dicati o ns  c o nsi dere d  t o be  maj or  C Y P 2 C 8  s u bstrates. Refer  t o Ta ble  6 i n Secti o n 
6. 5 . 
1 5.  Pers o ns  wit h  a n y cli nical si g n or  s y m pt o ms s u g gesti ve of  se vere s yste mic ill ness wit h  C O VI D -1 9, 
i ncl u di n g t he f oll o wi n g: 
a. s h ort ness of  breat h  at rest, 
b.  resti n g p ulse  ≥1 2 5  beats  per  mi n ute,  
c. resti n g res pirat or y rate ≥3 0  breat hs  per  mi n ute,  or  
d.  S p O 2 ≤ 9 3 %  o n  r o o m air at sea le vel. 
1 6.  S u bjects k n o w n t o ha ve a dia g n ostic test p ositi ve f or S A R S- C o V- 2 or i nfl ue nza i nfecti o n 
wit hi n t he prece di n g t hree wee ks. 
A S S E S S M E N T S  
Effic ac y:  
• S u bjects  will  c o m plete a diar y  rec or di n g oral  te m perat ure t wice dail y  a n d t he F L U -P R O ©  patie nt 
re p orte d o utc o mes i nstr u me nt o nce dail y i n t he e ve ni n g f or 2 1 da ys f or efficac y e val uati o n. 
• S u bjects  will  be  c o ntacte d dail y  b y  site staff o n  st u d y da ys  2- 7 t o scree n f or pr o gressi o n  t o se vere 
ill ness or ot her c o m plicati o ns. 
Vir ol o g y:  Nas o p har y n geal  s wa b sa m ples will  be  c ollecte d o n  eac h of  st u d y Da ys  1,  4 a n d 1 0  f or a nal ysis 
of vir ol o g y e n d p oi nts.  
S afet y:  T he  safet y of  st u d y dr u g  a d mi nistrati o n  will  be  m o nit ore d  b y  assess me nt  of  a d verse e ve nts fr o m 
baseli ne t hr o u g h t he Da y 2 8 st u d y e xit, cli nical la b orat or y testi n g at baseli ne a n d o n Da y 1 0, p h ysical 
e xa mi nati o ns a n d vital si g ns assess me nts at scree ni n g, Da y 1 0 a n d Da y 2 2 a n d tele p h o ne m o nit ori n g/at 
h o me visits d uri n g Da y 2 t hr o u g h Da y 7 a n d Da y 2 8.  
P h ar m ac o ki netics:  O n  t he m or ni n g  of  Da y  4 pri or  t o d osi n g,  tr o u g h plas ma  sa m ples will  be  c ollecte d. 


 
Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
 
 
1. 2.  
Sc he d ule  of  Assess me nts  
T a ble 1:  
Sc he d ule  of Assess me nts  
 
 
 
Assess me nt  
Scree ni n g  
B aseli ne  
Tre at me nt  Peri o d  
Di ar y  Peri o d  
F oll o w -U p  Visits  
U nsc he d ule d  
 
D a y  1 
 
D a y  1 
 
D a y  2- 7 
 
D a y  1-2 1  
D a y 
4 ± 1  
D a y 
1 0 ± 3  
D a y 
2 2 + 3  
D a y 
2 8 + 3  
 
As  Nee de d  
Si g ne d  i nf or me d c o nse nt/asse nt 1 
X 
 
 
 
 
 
 
 
 
De m o gra p hics,  s m o ki n g & me dical  hist or y 2 
X 
 
 
 
 
 
 
 
 
Uri ne  pre g na nc y  test7 
X 
 
 
 
 
 
 
 
 
P h ysical  e xa mi nati o n 3 
X 
 
 
 
X 4 
X 4 
X 4 
 
X 4 
B o d y  wei g ht  a n d resti n g vital  si g ns5 
X 
 
 
 
X 
X 
X 
 
X 
C o m plete  Scree ni n g  F L U -P R O 6 
X 
 
 
 
 
 
 
 
 
E val uate  eli gi bilit y 7 
X 
 
 
 
 
 
 
 
 
C ollect  nas o p har y n geal  s wa bs8 
 
X 
 
 
X 
X 
 
 
 
C ollect  bl o o d  sa m ple f or la b safet y tests8 
 
X 
 
 
 
 
X 
 
X 
C ollect  bl o o d  sa m ple f or a nti b o d y tests8 
 
X 
 
 
 
 
X 
 
 
C ollect  bl o o d  sa m ple f or p har mac o ki netics 8 
 
 
 
 
X 
 
 
 
 
C ollect  uri ne  sa m ple f or r o uti ne uri nal ysis 8 
 
X 
 
 
 
 
X 
 
X 
Rec or d  c o nc o mita nt  me dicati o ns  
 
X 
 
 
X 
X 
X 
 
X 
Ra n d o mize  & dis pe nse  st u d y me dicati o n 9 
 
X 
 
 
 
 
 
 
 
First  d ose  a n d practice  diar y  i n-office 9, 1 0 
 
X 
 
 
 
 
 
 
 
Re vie w/rec or d  a d verse e ve nts 1 1 
 
X 
 
 
X 
X 
X 
 
X 
I nstr ucti o ns re: d osi n g,  c o nc o mita nt  me dicati o ns,  diar y 
c o m pleti o n, f oll o w -u p visits, a n d e mer ge nc y care 1 2 
 
X 
X 
 
X 
X 
X 
 
X 
C o ntact  s u bject t o scree n f or c o m plicati o ns 
 
 
X 1 3  
 
 
 
 
X 1 4  
 
C o m plete  diar y  (s u bject res p o nsi bilit y)1 0 
 
 
 
X 
 
 
 
 
 
Re vie w  s u bject diar y  e ntries (site res p o nsi bilit y)1 5 
 
 
 
X 
 
 
 
 
 
 
 
 
 
1 1  
C O N FI D E N TI A L  
1  See  Secti o n  8. 1. 1  
2  See  Secti o n  8. 1. 2  
3  See  Secti o n  8. 1. 3  
4  C o m plete d  as necessar y,  see Secti o n  8. 1. 3  
5  See  Secti o n  8. 1. 4  
6  See  Secti o n  8. 1. 5  
7  See  Secti o n  5. 0  
8  See  Secti o n  8. 2  
9  See  Secti o n  8. 1. 6  
1 0  See  Secti o n  8. 3. 1  
1 1  See  Secti o n  8. 4  
1 2  See  Secti o n  8. 1. 7  
1 3  See  Secti o n  8. 1. 8  
1 4  See  Secti o n  8. 1. 9  
1 5  See  Secti o n  8. 3. 2  
 
 
 
 
 
 
 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
1 2  
C O N FI D E N TI A L  
 
 
 
2.  
I N T R O D U C TI O N 
2. 1.  
E nter o vir uses/ R hi n o vir uses  
T here  are  m ore  t ha n  5 0 0  milli o n  n o n-i nfl ue nza  viral  res pirat or y  i nfecti o ns  or  “c o m m o n  c ol ds” 
eac h  year  i n  t he  U nite d  States,  wit h  a d ults  e x perie nci n g  as  ma n y  as  2- 6  ill nesses  per  year  a n d 
c hil dre n e x perie nci n g 6- 8 ( Fe n dric k et al. 2 0 0 3 , T ur ner 1 9 9 7 , W orrall 2 0 1 1 ). 
C ol ds ha ve bee n re p orte d t o acc o u nt f or as m uc h as 4 0 % of ti me l ost fr o m w or k i n t he e m pl o ye d 
p o p ulati o n a n d 3 0 % of sc h o ol a bse nces ( Kir k patric k 1 9 9 6 ). I n a st u d y c o n d ucte d fr o m N o ve m ber 
of 2 0 0 0 t o Fe br uar y of 2 0 0 1, t he t otal ec o n o mic i m pact of n o n-i nfl ue nza viral res pirat or y tract 
i nfecti o ns was nearl y $ 4 0 billi o n ( Fe n dric k et al. 2 0 0 3). A dj uste d f or i nflati o n ( Fe br uar y 2 0 0 1 t o 
Ja n uar y 2 0 1 8), t he ec o n o mic i m pact t o da y w o ul d e xcee d $ 5 6 billi o n (U S D O L B urea u of La b or 
Statistics 2 0 1 8 ). 
Fift y  ( 5 0)  t o  6 7 %  of  n o n-i nfl ue nza  viral  res pirat or y  tract  i nfecti o ns  are  ass ociate d  wit h  vir uses 
fr o m t he ge n us E nter o vir us ( E V), w hic h bel o n g t o t he Pic or na viri dae fa mil y (At ki ns o n et al. 2 0 1 6). 
Wit hi n t he E V ge n us, t here are prese ntl y fiftee n s pecies i ncl u di n g R hi n o vir us A, R hi n o vir us B, 
R hi n o vir us C a n d E nter o vir us A t hr o u g h L ( T he Pir bri g ht I nstit ute 2 0 1 8 ). T here are h u n dre ds of 
E V  ser ot y pes,  pre ve nti n g  t he  de vel o p me nt  of  a n  effecti ve  vacci ne  or  pr o d ucti o n  of  s ufficie nt 
i n di vi d ual i m m u nit y t o a v oi d m ulti ple i nfecti o ns a n n uall y (Jac o bs et al. 2 0 1 3). A lar ge maj orit y 
of res pirat or y tract i nfecti o ns ca use d b y vir uses fr o m t he E nter o vir us ge n us are d ue t o R hi n o vir us 
s pecies,  a n d  R T- P C R  assa ys  d o  n ot  disti n g uis h  bet wee n  t he  differe nt  s pecies  of  e nter o vir uses. 
T heref ore, i n t his d oc u me nt we will refer t o t hese vir uses as E nter o vir us/ R hi n o vir us ( E V/ R V). 
E V/ R V i nfecti o n has bee n descri be d as a “c yt o ki ne disease” beca use i nfecti o n is c haracterize d b y 
massi ve  u pre g ulati o n  of  I F N,  I L- 1,  I L- 6,  I L- 8,  T N F- α,  gra n ul oc yte  macr o p ha ge  c ol o n y- 
sti m ulati n g fact or a n d R A N T E S ( At ki ns o n et al. 2 0 1 6). C o m m o n s y m pt o ms i ncl u de r hi n orr hea, 
nasal  c o n gesti o n,  s ore  t hr oat,  c o u g h,  hea dac he,  fe ver,  a n d  malaise.  A  nat ural  hist or y  st u d y  of 
E V/ R V i nfecti o ns de m o nstrate d t hat patie nts were a ble t o self- dia g n ose a c ol d i n less t ha n a da y, 
wit h m ost patie nts self- dia g n osi n g less t ha n 8 h o urs fr o m s y m pt o m o nset ( Arr u da et al. 1 9 9 7 ). 
C ol ds d ue t o E V/ R V i nfecti o n are ge nerall y c o nsi dere d self-li miti n g a n d d o n ot ca use res pirat or y 
distress. Wit h a d va nces i n viral detecti o n met h o ds, h o we ver, c ol ds d ue t o E V/ R V i nfecti o n ha ve 
bee n  li n ke d  t o  e xacer bati o ns  of  C O P D,  ast h ma  de vel o p me nt,  se vere  br o nc hi olitis  i n  pe diatric 
patie nts, a n d fatal p ne u m o nia i n el derl y a n d i m m u n oc o m pr o mise d a d ults. T hese se vere o utc o mes 
are  i n  a d diti o n  t o  t he  mil der  c o m m o nl y  acce pte d  c o m plicati o ns  of  t he  c o m m o n  c ol d  i ncl u di n g 
sec o n dar y  otitis  me dia,  si n usitis,  p ne u m o nia,  a n d,  i n  pe diatric  patie nts,  cr o u p  a n d  br o nc hi olitis 
(Jac o bs et al. 2 0 1 3). 
Beca use t here are n o F D A -a p pr o ve d a nti viral dr u gs f or treat me nt of c ol ds d ue t o E Vs,  t he sta n dar d 
of  care  is  treat me nt  of  s y m pt o ms  wit h  o ver-t he-c o u nter  ( O T C)  s y m pt o m  relief  me dicati o n 
i ncl u di n g  a nti hista mi nes,  dec o n gesta nts,  a nal gesics,  a ntit ussi ves,  N S AI Ds,  a n d  c o m bi nati o ns 
t here of. M ost of t hese treat me nts ha ve n ot s h o w n clear be nefit (Alla n a n d Arr oll 2 0 1 4 ). A nti viral 
dr u gs t o miti gate t he i m pact of E V/ R V i nfecti o n are t heref ore nee de d. 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
1 3  
C O N FI D E N TI A L  
 
 
2. 2.  
Nit az o x a ni de  ( N T Z) 
N T Z is a t hiaz oli de a nti-i nfecti ve wit h i n vitr o acti vit y a gai nst parasites, a naer o bic bacteria, a n d 
vir uses ( A n ders o n a n d C urra n 2 0 0 7 ). 
A LI NI A ®  ( N T Z)  f or  Oral  S us pe nsi o n  ( patie nts  1  year  of  a ge  a n d  ol der)  a n d  A LI NI A  ( N T Z) 
Ta blets ( patie nts 1 2 years a n d ol der) are mar kete d i n t he U nite d States  f or t he treat me nt of diarr hea 
ca 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 .  A LI NI A  f or  Oral  S us pe nsi o n  a n d 
A LI NI A Ta blets ha ve n ot bee n s h o w n t o be s u peri or t o place b o f or t he treat me nt of diarr hea ca use d 
b y Cry pt os p ori di u m p arv u m i n HI V-i nfecte d or i m m u n o deficie nt patie nts (A LI NI A Prescri bi n g 
I nf or mati o n 2 0 1 9). 
2. 2. 1.  
N T Z I n hi bits Vir al Re plic ati o n a n d C yt o ki ne Secreti o n  
Tiz o xa ni de, t he acti ve circ ulati n g meta b olite of N T Z,  has bee n s h o w n t o p ossess a nti viral acti vit y 
i n cell c ult ure a gai nst a br oa d ra n ge of vir uses i ncl u di n g i nfl ue nza A a n d B vir uses, c or o na vir uses 
( S A R S- C o V- 2,  M E R S- C o V,  H C o V- 2 2 9 E,  H C o V- O C 4 3,  H C o V- N L 6 3,  ca ni ne  C o V  S-3 7 8,  
m uri ne c or o na vir us, m o use he patitis vir us strai n A 5 9 ( M H V- A 5 9)), parai nfl ue nza ( Se n dai) vir us, 
R S V A- 2, r ota vir us, n or o vir us, he patitis C vir us ge n ot y pes 1a a n d 1 b, Ja pa nese e nce p halitis vir us, 
de n g ue fe ver vir us- 2, yell o w fe ver vir us, he patitis B vir us, a n d h u ma n i m m u n o deficie nc y vir us 
( HI V) (R ossi g n ol 2 0 1 4, R ossi g n ol 2 0 1 6 , Wa n g et al. 2 0 2 0, Piace nti ni et al. 2 0 1 8, R o mar k data o n 
file). E x peri me nts i n He La R 1 9 cells ha ve s h o w n t hat N T Z i n hi bits re plicati o n of r hi n o vir us A 
ser ot y pes 2 a n d 1 6  ( R o mar k St u d y  Re p ort  R M 0 1 -0 4 3 4).  C o nce ntrati o ns  of  tiz o xa ni de re q uire d t o 
i n hi bit  re plicati o n  of  t hese  vir uses  b y  5 0 %  ( E C 5 0s)  were  ge nerall y  bet wee n  0. 2  a n d  3  µ M 
de pe n di n g u p o n t he test c o n diti o ns. 
T he  a nti-i nfl ue nza  acti vit y  of  nitaz o xa ni de  a n d  its  circ ulati n g  meta b olite,  tiz o xa ni de,  has  bee n 
i n vesti gate d i n h u ma n ( M o n oc ytic U 9 3 7, T-l y m p h oc ytic J ur kat, a n d Al ve olar t y pe II-li ke A 5 4 9) 
a n d  ca ni ne  ( M D C K)  cells  after  i nfecti o n  wit h  m ulti ple  differe nt  strai ns  of  i nfl ue nza  A  vir us 
i ncl u di n g oselta mi vir-resista nt a n d a ma nta di ne-resista nt strai ns (R ossi g n ol et al. 2 0 0 9 , As ht o n et 
al. 2 0 1 0 , Slee ma n  et al. 2 0 1 4 ). I n a st u d y of  t he s usce pti bilit y of  2 1 0  circ ulati n g seas o nal i nfl ue nza 
vir uses t o tiz o xa ni de de m o nstrate d me dia n E C 5 0 val ues ( ±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 nea ge) a n d B ( Ya ma gata li nea ge), res pecti vel y (Til ma nis et al. 2 0 1 7 ). 
La b orat or y st u dies t o e val uate t he p ote ntial f or resista nce of i nfl ue nza A vir us t o tiz o xa ni de ha ve 
bee n  u na ble  t o select f or resista nt vir us  ( R o mar k St u d y  Re p ort  R M 0 1 -0 4 1 7).  T hese  st u dies s u g gest 
a l o w p ote ntial f or resista nce. 
St u dies i n peri p heral bl o o d m o n o n uclear cells ha ve als o s h o w n tiz o xa ni de s u p presses secreti o n of 
pr o-i nfla m mat or y  c yt o ki nes  t hat  are  u pre g ulate d  b y  viral  res pirat or y  i nfecti o ns  ( V RIs). 
C o nce ntrati o ns re q uire d t o s u p press c yt o ki ne secreti o n b y 5 0 % f or I L- 2, I L- 4, I L- 5, I L- 6, I L- 8, 
I L- 1 0  a n d  T N F- α  ra n ge d  fr o m  2. 0  t o  9. 8  µ M  (R ossi g n ol  a n d  va n  Baale n  2 0 1 8 ,  R o mar k  St u d y 
Re p ort  9 2 6 4).  Nitaz o xa ni de  has  als o  bee n  s h o w n  t o  s u p press  I L- 6  pr o d ucti o n  i n  t hi o gl yc ollate 
br ot h-i njecte d mice ( H o n g et al. 2 0 1 2 ). 
O n g oi n g st u dies of t he mec ha nis m of acti o n of N T Z ha ve s h o w n N T Z a n d tiz o xa ni de m o d ulate 
mit oc h o n drial  f u ncti o n  b y  u nc o u pli n g  o xi dati ve  p h os p h or ylati o n.  St u dies  i n dicate  tiz o xa ni de 
decreases cell ular A T P i n a d ose- de pe n de nt ma n ner i n M D C K cells a n d i n M D C K cells i nfecte d 
wit h  i nfl ue nza vir uses.  Ma xi m u m i n hi biti o n of A T P  i n i nfl ue nza-i nfecte d or u ni nfecte d M D C K  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
1 4  
C O N FI D E N TI A L  
 
 
cells reac hes u p  t o 4 5 %  after 2 4  h o urs  of  e x p os ure  t o 1 0 0  µ M  tiz o xa ni de. I n t hese e x peri me nts,  a 
1 0 %  re d ucti o n  of  A T P  ac hie ve d  b y  a d di n g  less  t ha n  1 0  µ M  tiz o xa ni de  is  s ufficie nt  t o  i n hi bit 
i nfl ue nza vir us re plicati o n b y a p pr o xi matel y 9 0 %. T he decrease i n cell ular A T P d oes n ot affect 
cell via bilit y a n d is re versi ble after eli mi nati n g tiz o xa ni de fr o m t he c ult ure ( R ossi g n ol a n d va n 
Baale n  2 0 1 8 ).  St u dies  of  a  n u m ber  of  differe nt  vir uses  ha ve  s h o w n  viral  re plicati o n  is  A T P- 
de pe n de nt ( Braa k ma n et al. 1 9 9 2 , Braa k ma n et al. 1 9 9 1 , D o ms et al. 1 9 8 7 , C ha n g et al. 2 0 0 9 , 
Mirazi mi  a n d  S ve nss o n  2 0 0 0 ).  I n  t he  case  of  N T Z,  ke y  viral  pr otei ns  li ke  he ma g gl uti ni n 
(i nfl ue nza), F- pr otei n ( R S V a n d parai nfl ue nza), a n d N pr otei n (c or o na vir us) ha ve bee n i de ntifie d 
as p ote ntial e n d tar gets of t his mec ha nis m (R ossi g n ol et al. 2 0 0 9, Piace nti ni et al. 2 0 1 8, Ca o et al. 
2 0 1 5 ). I n a d diti o n, i n hi biti o n of  A T P  a n d its d o w nstrea m  effect o n  A M P -acti vate d pr otei n  ki nase 
acti vati o n has bee n s h o w n t o s u p press secreti o n of pr o-i nfla m mat or y c yt o ki nes ( Lee et al. 2 0 1 7 , 
Sa g et al. 2 0 0 8 , Wa n g et al. 2 0 0 3 ). 
T he acti vit y of N T Z  i n i n hi biti n g re plicati o n of a br oa d ra n ge of res pirat or y vir uses as well  as t he 
secreti o n  of  pr o-i nfla m mat or y  c yt o ki nes  u pre g ulate d  d uri n g  res pirat or y  vir us  i nfecti o n  has 
pr o m pte d cli nical de vel o p me nt of N T Z f or treat me nt or pr o p h yla xis of res pirat or y ill ness ca use d 
b y V RIs. 
2. 2. 2.  
P h ar m ac o ki netics of N T Z i n H u m a ns  
N T Z  is  n ot  detecta ble  i n  t he  plas ma  f oll o wi n g  oral  a d mi nistrati o n  of  t he  dr u g.  T he  mai n 
meta b olites of N T Z i n h u ma ns are tiz o xa ni de a n d tiz o xa ni de gl uc ur o ni de.  Tiz o xa ni de is hi g hl y 
b o u n d  t o  plas ma  pr otei ns  ( > 9 9 %).  T he  a bs or pti o n  of  N T Z  i n  i m me diate  release  ta blets  is 
si g nifica ntl y e n ha nce d ( C ma x a n d A U C of tiz o xa ni de a n d tiz o xa ni de gl uc ur o ni de i n plas ma are 
m ore  t ha n  d o u ble d)  w he n  it  is  a d mi nistere d  wit h  f o o d.  I n  faste d  h u ma n  v ol u nteers  recei vi n g  a 
si n gle 5 0 0 m g d ose of 1 4 C N T Z, a p pr o xi matel y o ne-t hir d of t he d ose was e xcrete d i n uri ne as 
tiz o xa ni de  a n d  tiz o xa ni de  gl uc ur o ni de,  a n d  t w o-t hir ds  was  e xcrete d  i n  feces  as  tiz o xa ni de.  N o 
ot her si g nifica nt meta b olites were detecte d ( N T- 3 0 0 C O VI D/ V RI-I n vesti gat ors Br oc h ure). 
T he  p har mac o ki netics  of  tiz o xa ni de  a n d  tiz o xa ni de  gl uc ur o ni de  d uri n g  re peate d  oral  d osi n g  of 
N T Z 3 0 0 m g e xte n de d release ta blets a d mi nistere d 6 0 0 m g t wice dail y wit h f o o d were e val uate d 
i n  healt h y  v ol u nteers.  T wel ve  ( 1 2)  s u bjects  recei ve d  t w o  N T Z  c o ntr olle d  release  ta blets  t wice 
dail y  wit h  f o o d f or 7 da ys.  T he  p har mac o ki netics  were  st u die d i n plas ma  u p  t o 1 2  h o urs  p ost -d ose 
after t he m or ni n g d ose o n Da y 1 a n d Da y 7, a n d bef ore t he m or ni n g d ose o n Da y 2 -6.  Base d o n 
mi xe d effect a nal ysis of varia nce, t he stea d y state tiz o xa ni de a n d tiz o xa ni de gl uc ur o ni de plas ma 
c o nce ntrati o ns was reac he d b y Da y 2, after o ne da y of treat me nt wit h N T Z at 6 0 0 m g b.i. d.  T he 
mai n p har mac o ki netics para meters of tiz o xa ni de a n d tiz o xa ni de gl uc ur o ni de are s u m marize d i n 
t he ta ble bel o w: 
T a ble  2:   S u m m ar y  of  Tiz o x a ni de  a n d  Tiz o x a ni de  Gl uc ur o ni de  P h ar m ac o ki netics 
P ar a meters  
 
P K  P ar a meter  ( u nit) 
Tiz o x a ni de  
Tiz o x a ni de  Gl uc ur o ni de  
 
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  
t ma 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)  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
1 5  
C O N FI D E N TI A L  
 
 
 
P K  P ar a meter  ( u nit) 
Tiz o x a ni de  
Tiz o x a ni de  Gl uc ur o ni de  
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 
t 1/ 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  
λz  ( 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  
Ca 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  
Val ues  are arit h metic mea n  ± S D,  e xce pt me dia n  (ra n ge) f or tma x  a n d tla g 
N = n u m ber of s u bjects wit h data; 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  
 
 
T a ble 3:  
S u m m ar y of Tiz o x a ni de a n d Tiz o x a ni de Gl uc ur o ni de Tr o u g h Pl as m a 
C o nce ntr ati o ns ( µ g/ m L) b y St u d y D a y 
 
A n al yte  
D a y  1 
D a y  2 
D a y  3 
D a y  4 
D a y  5 
D a y  6 
D a y  7 
Tiz o xa ni de  
0. 7 0 9  
( 1 3 9) 
1. 5 5  
( 1 0 0) 
2. 3 6  
( 1 0 1) 
3. 2 4  
( 1 0 0) 
3. 8 0  
( 1 4 6) 
3. 2 6  
( 1 1 9) 
3. 0 2  
( 9 9) 
Tiz o xa ni de 
Gl uc ur o ni de  
1. 3 9  
( 6 1) 
3. 6 8  
( 7 2) 
4. 3 8  
( 7 3) 
5. 3 5  
( 7 7) 
5. 8 3  
( 9 9) 
5. 9 4  
( 9 1) 
5. 6 5  
( 6 9) 
 
 
2. 2. 3.  
O ver vie w of Cli nic al E x perie nce wit h N T Z  
N T Z  has bee n mar kete d f or diarr heal disease ca use d b y Gi ar di a or Cry pt os p ori di u m i n t he U nite d 
States  si nce  2 0 0 3  a n d  i n  Lati n  A merica  si nce  1 9 9 6.  It  is  esti mate d  t hat  m ore  t ha n  3 5 0  milli o n 
patie nts  ha ve  bee n  e x p ose d t o N T Z  w orl d wi de.  N o  dr u g -relate d seri o us a d verse e ve nts ha ve  bee n 
re p orte d d uri n g p ost- mar keti n g e x perie nce wit h N T Z. 
O ver 7, 5 0 0 s u bjects ha ve bee n treate d wit h  N T Z  i n cli nical trials, i ncl u di n g 3, 1 4 7 s u bjects 1 2 years 
of  a ge  a n d  ol der  w h o  ha ve  bee n  e x p ose d  t o  t he  N T Z  3 0 0  m g  e xte n de d  release  ta blets  (as 
m o n ot hera p y,  n  =  2, 6 5 9,  or  i n  c o m bi nati o n  wit h  oselta mi vir,  n  =  4 8 8).  Of  t he  3, 1 4 7  s u bjects, 
2, 6 5 9 were gi ve n a d ose of 6 0 0 m g t wice dail y f or 5 da ys.  T he m ost c o m m o nl y (at least 2 % of 
treate d  s u bjects)  re p orte d  a d verse  e ve nts  ( A Es)  re gar dless  of  ca usalit y  assess me nt  were: 
c hr o mat uria  ( 1 0. 8 %),  diarr hea  ( 6. 3 %),  a b d o mi nal  pai n/a b d o mi nal  pai n  u p per/a b d o mi nal  pai n 
l o wer ( 2. 8 %), br o nc hitis ( 2. 8 %), na usea ( 2. 7 %), a n d hea dac he ( 2. 3 %). I n t he place b o-c o ntr olle d 
trials, t he rates of occ urre nce of A Es  di d n ot differ si g nifica ntl y fr o m t h ose of place b o e xce pt f or 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
1 6  
C O N FI D E N TI A L  
 
 
c hr o mat uria  ( 1 0. 8 %  c o m pare d  t o  0. 8 %  f or  place b o).  Less  t ha n  1 %  of  s u bjects  disc o nti n ue d 
t hera p y beca use of A Es ( N T- 3 0 0 I n vesti gat ors Br oc h ure- C O VI D/ V RI). 
2. 2. 4.  
E arl y Cli nic al E x perie nce wit h N T Z i n Tre at me nt of E V/ R V  
S u bjects wit h la b orat or y-c o nfir me d E V/ R V i nfecti o n were e nr olle d i n t w o p hase 3 ra n d o mize d 
place b o-c o ntr olle d cli nical trials of N T Z f or t he treat me nt of i nfl ue nza. S u bjects prese nte d t o t he 
cli nic wit h  oral te m perat ures ≥1 0 0. 4˚ F a n d at least o ne res pirat or y a n d o ne c o nstit uti o nal s y m pt o m. 
S u bjects  assesse d  se ve n  s y m pt o ms  as  a bse nt,  mil d,  m o derate  or  se vere  t wice  dail y  f or  at  least 
se ve n da ys (st u d y R M 0 8- 3 0 0 1) or at least 1 4 da ys (st u d y R M 0 8- 3 0 0 2) a n d u p t o 2 8 da ys. T he 
pri mar y e n d p oi nt f or b ot h st u dies was  Ti me  t o Alle viati o n of S y m pt o ms, defi ne d as all s y m pt o ms 
rate d  a bse nt  or  mil d  f or  at  least  2 1. 5  h o urs,  f or  s u bjects  wit h  la b orat or y-c o nfir me d  i nfl ue nza 
i nfecti o n. T his a nal ysis was re peate d f or s u bjects wit h la b orat or y-c o nfir me d E V/ R V i nfecti o n as 
e x pl orat or y a nal yses. 
St u d y R M 0 8- 3 0 0 1 was  a d ose-ra n gi n g st u d y c o m pari n g N T Z  6 0 0 m g  a n d N T Z  3 0 0 m g  t o place b o. 
Ei g ht y-ei g ht ( 8 8) s u bjects wit h E V/ R V as t he s ole i de ntifie d pat h o ge n were e nr olle d ( n = 2 9, 3 3 
a n d 2 6 i n t he N T Z 6 0 0 m g, N T Z 3 0 0 m g, a n d place b o gr o u ps, res pecti vel y). N o differe nces i n 
ti mes t o alle viati o n of s y m pt o ms were o bser ve d acr oss treat me nt gr o u ps [ Me dia n (I Q R): 1 0 5. 1 
( 6 0- 1 5 9) f or t he 6 0 0 m g  N T Z  gr o u p, 8 6. 7 ( 7 0- 1 1 9) f or t he 3 0 0 m g  N T Z  gr o u p, a n d 9 0. 8 ( 5 9- 1 3 4) 
f or t he place b o gr o u p]. 
St u d y R M 0 8- 3 0 0 2 was  a fact orial trial of N T Z  6 0 0 m g  a n d oselta mi vir ( O S T). T he st u d y e nr olle d 
2 2 8 s u bjects wit h  E V/ R V as t he s ole i nfecti o n at baseli ne ( n = 5 5, 5 1, 6 1 a n d 6 1 f or t he N T Z,  O S T, 
N T Z + O S T a n d place b o gr o u ps, res pecti vel y). S u bjects treate d wit h N T Z m o n ot hera p y ha d 3 1- 
h o ur treat me nt be nefit at t he me dia n c o m pare d t o place b o treate d s u bjects [ Me dia n (I Q R): 1 1 5. 6 
( 6 9- 2 1 0) f or t he N T Z  gr o u p, 1 4 6. 5 ( 9 2- 2 9 8) f or t he place b o gr o u p, p = 0. 0 3 9 0 f or t he Wilc o x o n test 
a n d p = 0. 0 1 2 8 f or t he L o g Ra n k test). 
T he  se ve n-s y m pt o m  scale  use d  i n  st u dies  R M 0 8- 3 0 0 1  a n d  R M 0 8- 3 0 0 2,  t h o u g h  use d  i n  nearl y 
e ver y hist orical st u d y of o ut patie nt a nti virals f or viral res pirat or y i nfecti o n, has n ot de m o nstrate d 
c o nte nt  vali dit y  n or  c o nte xt  vali dit y  a n d  lac ks  i nter nal  c o nsiste nc y  relia bilit y,  lea di n g  t o 
i nc o nsiste nt  res ults  acr oss  cli nical  trials,  i ncl u di n g  st u dies  of  a p pr o ve d  a nti virals  s uc h  as 
oselta mi vir. T he res ults of st u dies R M 0 8- 3 0 0 1 a n d R M 0 8- 3 0 0 2 f or me d t he h y p ot hesis t hat was 
t he basis of st u d y R M 0 8- 3 0 0 5: t hat treat me nt be nefit c o ul d be de m o nstrate d f or N T Z  c o m pare d t o 
place b o i n s u bjects wit h la b orat or y-c o nfir me d E V/ R V i nfecti o n wit h t he use of a n a p pr o priatel y 
de vel o pe d  a n d  vali date d  patie nt  re p orte d  o utc o mes  ( P R O)  i nstr u me nt  a n d  mea ni n gf ul  a nal ysis 
met h o d ol o g y.  
2. 2. 5.  
St u d y R M 0 8- 3 0 0 5: N T Z i n t he Tre at me nt of C ol ds D ue t o E V/ R V  
St u d y R M 0 8- 3 0 0 5 was a ra n d o mize d place b o-c o ntr olle d st u d y of N T Z i n t he treat me nt of c ol ds 
d ue t o E V/ R V. S u bjects c o m plete d a dail y diar y f or 2 1 da ys i ncl u di n g t he F L U- P R O i nstr u me nt, 
a  s y m pt o ms  q uesti o n naire  wit h  esta blis he d  c o nte nt  vali dit y,  c o nte xt  vali dit y,  relia bilit y  a n d 
res p o nsi ve ness  t o  c ha n ge.  Fi ve- h u n dre d  ei g ht y-f o ur  ( 5 8 4)  s u bjects  wit h  la b orat or y-c o nfir me d 
E V/ R V i nfecti o n were e nr olle d. T he met h o d ol o g y f or deri vi n g t he s y m pt o m res p o nse defi niti o n 
was i nte n de d t o c orrelate s y m pt o m rati n gs t o s u bject assess me nts of us ual healt h stat us (a yes/ n o 
gl o bal assess me nt q uesti o n i n F L U - P R O). Me dia n (I Q R) Ti mes  t o Ret ur n t o Us ual Healt h  were  
1 5 4. 1  ( 8 0- 3 2 0)  a n d  1 7 4. 9  ( 1 0 4- 3 4 5)  h o urs  f or  t he N T Z   a n d  place b o  gr o u ps, res pecti vel y 




Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
1 8  
C O N FI D E N TI A L  
 
 
Treat me nt  wit h  6 0 0  m g  N T Z  b.i. d.  f or  fi ve  da ys  was  well  t olerate d  b y  all  s u bjects.  T he  m ost 
fre q ue ntl y re p orte d T E A Es ( ≥2 % i n a n y treat me nt gr o u p) were c hr o mat uria ( n = 1 5 3 i n t he N T Z 
gr o u p a n d n = 1 0 i n t he place b o gr o u p, p < 0. 0 0 0 1,), diarr h oea ( n = 5 3 i n t he N T Z  gr o u p, n = 3 8 i n t he 
place b o  gr o u p,  N S),  a n d  na usea  ( n = 2 4  i n  t he  N T Z  gr o u p,  n = 1 9  i n  t he  place b o  gr o u p,  N S). 
Fre q ue nc y  a n d  se verit y  of  a d verse  e ve nts  were  si milar  acr oss  treat me nt  gr o u ps  e xce pt  f or 
c hr o mat uria, w hic h was mil d a n d m ore fre q ue nt i n t he N T Z gr o u p. 
2. 3.  
R ati o n ale  f or t he St u d y  
T here is a nee d f or a treat me nt f or c ol ds d ue t o E V/ R V i nfecti o n t hat c o ul d re d uce t he d urati o n of 
s y m pt o ms a n d p ote ntiall y  t he ris k of  c o m plicati o ns.  T his  st u d y will  e val uate t he safet y a n d efficac y 
of N T Z i n t he treat me nt of c ol ds d ue t o E V/ R V i nfecti o n. 
 
3.  
S T U D Y  O B J E C TI V E S  
Pri mar y O bjecti ve:  
T o  e val uate  t he  effect  of  N T Z  i n  re d uci n g  t he  ti me  t o  S ustai ne d 
Res p o nse  c o m pare d  t o  place b o  i n  s u bjects  wit h  la b orat or y-c o nfir me d 
E V/ R V i nfecti o n 
Sec o n dar y  O bjecti ve:   T o  e val uate t he pr o p orti o n  of  s u bjects re q uiri n g s yste mic a nti bi otics f or 
a n i nfecti o n sec o n dar y t o E V/ R V, i ncl u di n g p ne u m o nia, otitis me dia, 
br o nc hitis, si n usitis or p har y n gitis 
E x pl orat or y O bjecti ves:   i.  T o  e val uate t he pr o p orti o n of s u bjects p ositi ve f or E V/ R V b y P C R  
at eac h of Da ys 4 a n d 1 0  
ii. T o  e val uate t he pr o p orti o n of s u bjects re q uiri n g s yste mic a nti bi otics 
f or  a n y  a n d  eac h  i nfecti o n  sec o n dar y  t o  E V/ R V,  i ncl u di n g 
p ne u m o nia, otitis me dia, br o nc hitis, si n usitis or p har y n gitis 
Safet y O bjecti ve:     T o  e val uate safet y b y a nal ysis of a d verse e ve nts 
 
4.  
S T U D Y  D E SI G N  
4. 1.  
St u d y  Desi g n  O ver vie w  
T his  st u d y  is  a  m ultice nter,  ra n d o mize d,  d o u ble- bli n d,  place b o-c o ntr olle d  trial  desi g ne d  t o 
e val uate efficac y a n d safet y of N T Z  6 0 0 m g  a d mi nistere d orall y t wice dail y f or fi ve da ys c o m pare d 
t o a place b o f or t he treat me nt of c ol ds d ue t o E V/ R V i nfecti o n. 
S u bjects will  be stratifie d acc or di n g t o t he f oll o wi n g criteria: 
Se verit y of Ill ness: 
• Mil d  ill ness defi ne d  as baseli ne  assess me nts  of  ( 1) at 
least o ne res pirat or y d o mai n* wit h  a baseli ne sc ore 
≥2  a n d ( 2) resti n g p ulse < 9 0 beats per mi n ute a n d ( 3) 
resti n g res pirat or y rate < 2 0 breat hs per mi n ute. 
• 
M o derate ill ness defi ne d as baseli ne assess me nts of  
( 1) at least o ne res pirat or y d o mai n* wit h a baseli ne 
sc ore ≥2   a n d  eit her  ( 2)  resti n g  p ulse  ≥9 0  beats per  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
1 9  
C O N FI D E N TI A L  
 
 
 
 
 
 
 
 
Ti me  fr o m o nset of s y m pt o ms t o 
mi n ute or ( 3) resti n g res pirat or y rate ≥2 0 breat hs per 
mi n ute.  
* F or t his p ur p ose, res pirat or y d o mai ns s hall i ncl u de t he 
f oll o wi n g  5  F L U-P R O  d o mai ns/s u b d o mai ns:  c hest, 
c o u g h, n ose, t hr oat a n d hea d.  
ra n d o mizati o n: 
< 3 6 h o urs/ ≥3 6 h o urs  
Ris k of se vere ill ness ( per C D C):   
•  At   I ncrease d  Ris k:  S u bjects wit h   C O P D,  T y pe  2 
dia betes mellit us, o besit y ( B MI ≥3 0), c hr o nic ki d ne y 
disease, sic kle cell disease, seri o us heart c o n diti o ns 
(s uc h  as  heart  fail ure,  c or o nar y  arter y  disease,  or 
car di o m y o pat hies),  ast h ma  ( m o derate  or  se vere), 
cere br o vasc ular disease, c ystic fi br osis, h y perte nsi o n 
or  hi g h  bl o o d  press ure,  i m m u n oc o m pr o mise d  state 
( d ue  t o  i m m u ne  deficie ncies,  HI V,  use  of 
c ortic oster oi ds,  or  use  of  ot her  i m m u ne- wea ke ni n g 
me dicati o ns), ne ur ol o gic c o n diti o ns (e. g., de me ntia), 
li ver  disease,  p ul m o nar y  fi br osis,  past  or  prese nt 
hist or y  of  s m o ki n g,  t halasse mia,  or  t y pe  1  dia betes 
mellit us. S u bjects w h o are ≥6 5 years of a ge. 
• 
N ot  At  I ncrease d  Ris k:  S u bjects  wit h  n o ne  of  t he 
a b o ve c o n diti o ns 
Wit hi n strata, s u bjects will  be ra n d o mize d 1: 1 t o o ne of t he f oll o wi n g gr o u ps:  
• Gr o u p 1 ( N T Z):     T w o N T Z 3 0 0 m g ta blets b.i. d. f or 5 da ys  
• Gr o u p  2  ( Place b o):   T w o  place b o  ta blets  b.i. d.  f or  5  da ys 
T he st u d y is e x pecte d t o ta ke place fr o m J ul y 2 0 2 0 t hr o u g h Ma y  2 0 2 1. 
Data f or s u bjects e nr olle d i n c o nc urre nt st u d y R M 0 8- 3 0 0 8 ( C O VI D- 1 9 treat me nt st u d y wit h t he 
sa me  selecti o n  criteria  a n d  pr oce d ures)  wit h  la b orat or y  c o nfir me d  E V/ R V  i nfecti o n  at  baseli ne 
will  be all ocate d t o t his st u d y f or a nal ysis a n d will c o u nt t o war d t he 3 5 0 t o 4 0 0 re q uire d s u bjects. 
4. 2.  
R ati o n ale  f or I m p ort a nt Iss ues i n t he St u d y  Desi g n  
4. 2. 1.  
C h oice of N T Z D ose a n d D ur ati o n of Tre at me nt  
T he d ose of N T Z use d f or t his cli nical trial ( 6 0 0 m g b.i. d. f or 5 da ys) has bee n ass ociate d wit h 
re d ucti o ns  i n  d urati o ns  of  ill ness  i n  s u bjects  i nfecte d  wit h  i nfl ue nza,  E V/ R V,  a n d  c or o na vir us. 
D ose-ra n ge-fi n di n g st u d y R M 0 8- 3 0 0 1 i n s u bjects wit h i nfl ue nza i nfecti o n de m o nstrate d a d ose- 
de pe n de nt  efficac y  res p o nse  wit h  a  3 0 0  m g  b.i. d.  gr o u p  de m o nstrati n g  a  n o n-si g nifica nt 
i m pr o ve me nt o ver place b o. 
I n cli nical trials i n v ol vi n g 2, 6 5 9 s u bjects, a d verse e ve nts re p orte d b y s u bjects recei vi n g 6 0 0 m g 
N T Z b.i. d. f or 5 da ys were si milar t o t h ose of s u bjects recei vi n g t he place b o, wit h t he e xce pti o n 
of  a  hi g her  rate  of  c hr o mat uria  ( 1 0. 8 %  c o m pare d t o  0. 8 %  f or  t he  place b o).  St u dies  of N T Z  at 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
2 0  
C O N FI D E N TI A L  
 
 
hi g her d oses ha ve s h o w n d ose- de pe n de nt i ncreases i n t he fre q ue nc y of re p orte d diarr hea a n d ot her 
gastr oi ntesti nal si de effects, t heref ore n o hi g her d ose is pla n ne d f or t his st u d y. 
4. 2. 2.  
C h oice of C o ntr ol Gr o u p  
A place b o c o ntr ol is a p pr o priate f or t he st u d y d ue t o lac k of a n y a p pr o ve d acti ve c o ntr ol. 
4. 2. 3.  
C h oice of P atie nt P o p ul ati o n  
T he p o p ulati o n t o be st u die d i ncl u des a d ults a n d a d olesce nts wit h c ol ds c o nsiste nt wit h E V/ R V 
i nfecti o n. Beca use t here are n o a p pr o ve d a nti virals f or t he treat me nt of E V/ R V, s u bjects will n ot 
be pre ve nte d fr o m bei n g prescri be d resc ue me dicati o n f or c o m plicati o ns if warra nte d. T heref ore, 
partici pati o n i n t he st u d y will n ot p ose u nreas o na ble ris k t o a n y eli gi ble s u bject. Disc ussi o n of 
s pecific eli gi bilit y criteria is prese nte d bel o w. 
4. 2. 3. 1.  
C h oice of Si g ns a n d S y m pt o ms Re q uire d  f or I ncl usi o n 
Data fr o m st u dies R M 0 8- 3 0 0 4 a n d R M 0 8- 3 0 0 5 i n dicate t hat, i n s u bjects i nfecte d wit h i nfl ue nza, 
E V/ R V  or seas o nal c or o na vir us, s u bjects wit h  l o w s y m pt o m sc ores f or t he hea d, t hr oat, n ose, c hest 
a n d c o u g h s y m pt o m d o mai ns i n t he a bse nce of ele vate d p ulse or res pirat or y rate, ill ness ma y be 
e x pecte d  t o  res ol ve  q uic kl y.  T hese  s u bjects  ha ve  less  o p p ort u nit y  t o  be nefit  fr o m  a nti viral 
treat me nt. F urt her, s u bjects w h o i n dicate t hat s y m pt o ms are alrea d y i m pr o vi n g are als o u nli kel y 
t o  be nefit  fr o m  treat me nt.  T heref ore,  s u bjects  will  be  re q uire d  t o  ha ve  a  sc ore  ≥2  f or  t w o 
res pirat or y s y m pt o m d o mai ns ( hea d, t hr oat, n ose, c hest, or c o u g h) or a sc ore ≥2  f or o ne res pirat or y 
s y m pt o m d o mai n i n t he prese nce of ele vate d vital si g ns ( p ulse ≥9 0 beats per mi n ute or res pirat or y 
rate ≥1 6 breat hs per mi n ute). S u bjects will  be e xcl u de d if t he y re p ort ha vi n g n o s y m pt o ms ( gl o bal 
assess me nt),  bei n g  at  t heir  us ual  healt h,  t hat  t heir  s y m pt o ms  d o  n ot  i nterfere  wit h  t heir  us ual 
acti vities, or t hat t heir s y m pt o ms ha ve i m pr o ve d si nce yester da y. S u bjects prese nti n g wit h si g ns 
or s y m pt o ms c o nsiste nt wit h se vere C O VI D- 1 9 (resti n g s h ort ness of breat h, resti n g p ulse ≥1 2 5, 
resti n g res pirat or y rate ≥3 0) will als o be e xcl u de d fr o m t he st u d y. 
4. 2. 3. 2.  
I ncl usi o n of S u bjects At  Le ast 1 2 Ye ars of A ge ( N o U p per  A ge Li mit)  
T he p o p ulati o n t o be st u die d i ncl u des a d ults a n d a d olesce nts at least 1 2 years of a ge wit h c ol ds 
c o nsiste nt wit h  E V/ R V i nfecti o n. T his is a p o p ulati o n si milar t o t h ose selecte d f or st u dies R M 0 8- 
3 0 0 1,  R M 0 8- 3 0 0 2,  R M 0 8- 3 0 0 3,  R M 0 8- 3 0 0 4  a n d  R M 0 8- 3 0 0 5  of  t he N T Z   3 0 0 m g  e xte n de d 
release ta blets i n m ore t ha n 5, 0 0 0 s u bjects wit h  c ol ds or i nfl ue nza-li ke ill ness. N o  safet y c o ncer ns 
ha ve  bee n  i de ntifie d  fr o m  t hese  cli nical  trials.  Data  fr o m  p har mac o ki netics  st u dies  i n  healt h y 
v ol u nteers 1 2 t o 1 7 years of a ge or 1 8 t o 6 5 years of a ge i n dicate t hat t he p har mac o ki netics of t he 
maj or N T Z  meta b olites, tiz o xa ni de a n d tiz o xa ni de gl uc ur o ni de, 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 hese a ge gr o u ps. Safet y data is als o si milar f or t hese a ge gr o u ps. 
T heref ore, t he a d ult d ose is dee me d a p pr o priate f or pe diatric patie nts d o w n t o 1 2 years of a ge. 
I nf or me d  c o nse nt  will  be  re q uire d  f or  s u bject  partici pati o n  i n  t his  st u d y  (see  Secti o n 8. 1. 1 ).  A 
si g ne d  asse nt  f or m  will  be  re q uire d  f or  a n y  mi n ors  e nr olle d  ( ≤  1 8  years  of  a ge  or  as  l ocal 
re g ulati o ns a p pl y) as well  as si g ne d pare ntal/le gal g uar dia n c o nse nt b y t heir pare nt/le gal g uar dia n 
all o wi n g f or t he mi n or’s partici pati o n. 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
2 1  
C O N FI D E N TI A L  
 
 
4. 2. 3. 3.  
I ncl usi o n of S u bjects wit h U n derl yi n g C o n diti o ns  
F or t he prese nt st u d y, s o me s u bjects (e. g., s u bjects > 6 5 years of a ge, u n derl yi n g ast h ma or C O P D, 
dia betes mellit us, u n derl yi n g car di o vasc ular disease, etc. – see I ncl usi o n/ E xcl usi o n criteria) w h o 
are at hi g her ris k of c o m plicati o ns or e xacer bati o ns of u n derl yi n g c o n diti o ns will be all o we d t o 
partici pate  if,  i n  t he  j u d g me nt  of  t he  i n vesti gat or,  t he y  are  a ble  t o  c o m pl y  wit h  pr ot oc ol 
re q uire me nts a n d are n ot e x pecte d t o re q uire h os pitalizati o n. T here is n o a p pr o ve d a nti viral f or 
c ol ds d ue t o E V/ R V, a n d s u bjects will n ot be pre ve nte d fr o m bei n g prescri be d resc ue me dicati o n 
f or  c o m plicati o ns.  T heref ore,  partici pati o n  i n  t he  st u d y  will  n ot  p ose  u nreas o na ble  ris k  t o  a n y 
eli gi ble s u bject. 
T he p har mac o ki netics of t he pr o p ose d d ose of N T Z ha ve bee n st u die d i n s u bjects wit h re nal a n d 
he patic i m pair me nt a n d n o d ose a dj ust me nt is rec o m me n de d i n t hese p o p ulati o ns. A t h or o u g h Q Tc 
st u d y of N T Z at d oses of 6 7 5 m g a n d 2 7 0 0 m g f o u n d n o pr ol o n gati o n of t he Q Tc i nter val. 
C Y P 4 5 0 i n hi biti o n assa ys i n dicate t hat tiz o xa ni de i n hi bits C Y P 2 C 8 wit h  a n I C 5 0 of 4. 3 µ M, b ut a 
mec ha nistic  static  m o del  use d  f or  p ote ntial  dr u g- dr u g  i nteracti o ns  i n dicate d  t hat  a  cli nical 
i nteracti o n ste m mi n g fr o m C Y P 2 C 8 i n hi biti o n b y tiz o xa ni de is u nli kel y. 
W hile tiz o xa ni de is m ore t ha n 9 9. 9 % b o u n d t o plas ma pr otei ns, a n i n viv o dr u g- dr u g i nteracti o n 
st u d y f o u n d n o i nteracti o n bet wee n N T Z a n d warfari n. Tiz o xa ni de i n hi bits t he B C R P tra ns p orter 
a n d  t heref ore  ma y  affect  t he  p har mac o ki netics  of  B C R P  s u bstrates,  s uc h  as  r os u vastati n.  C o- 
a d mi nistrati o n  of  N T Z  a n d  r os u vastati n  f or  se ve n  da ys  le d  t o  a  4 0 %  i ncrease  i n  t he  C m a x  of 
r os u vastati n  a n d  8 0 %  a n d  7 0 %  i ncreases  of  r os u vastati n  A U C0-t a n d  A U C 0- ∞,  res pecti vel y. 
H o we ver, t he s h ort d urati o n of treat me nt i n t his st u d y is n ot a ntici pate d t o ca use a d verse effects 
relate d t o c o-a d mi nistrati o n of N T Z a n d r os u vastati n. 
F or m ore detaile d i nf or mati o n, refer t o t he N T - 3 0 0 I n vesti gat or’s Br oc h ure-C O VI D/ V RI.  
4. 2. 3. 4.  
E xcl usi o n of S u bjects wit h Si g nific a nt I m m u n o deficie nc y 
I n di vi d uals  wit h  si g nifica nt  i m m u n o deficie nc y,  s uc h  as  patie nts  u n der g oi n g  c he m ot hera p y, 
tra ns pla nt reci pie nts recei vi n g i m m u n os u p pressi ve t hera p y, a n d HI V patie nts wit h ver y l o w C D 4 
c o u nts  are  m ore  s usce pti ble  t o  l o n ger  d urati o ns  of  ill ness  a n d  m ore  li kel y  t o  e x perie nce 
c o m plicati o ns d ue t o viral res pirat or y i nfecti o ns. T his is a n i m p orta nt p o p ulati o n i n w hic h t o st u d y 
a nti viral dr u gs f or t he treat me nt of viral res pirat or y i nfecti o ns. N o net heless, t hese s u bjects will  be 
e xcl u de d fr o m t he prese nt st u d y d ue t o ( 1) t he li keli h o o d of l o n ger viral s he d di n g necessitati n g 
l o n ger  c o urses  or  hi g her  d oses  of  treat me nt  t ha n  w hat  is  pr o p ose d  i n  t his  st u d y,  a n d  ( 2)  t he 
li keli h o o d  t hat  s y m pt o ms  of  ill ness  ma y  prese nt  differe ntl y  i n  i m m u n oc o m pr o mise d  pers o ns 
c o m pare d t o i m m u n oc o m pete nt pers o ns d ue t o re d uce d a bilit y t o pr o d uce t he i m m u ne res p o nse 
t hat res ults i n s y m pt o ms (va n der Vries et al. 2 0 1 3 , St. J u de C hil dre n’s Researc h H os pital ). 
4. 2. 4.  
Use  of Vit a mi n B C o m ple x S u p ple me nt  
All  s u bjects  will  recei ve  a  vita mi n  B  c o m ple x  s u p ple me nt  (
,  
 
) o ne ta blet t wice a da y wit h st u d y me dicati o n. T his d ose 
f oll o ws t he ma n ufact urer’s la bele d d osi n g. T he p ur p ose of t he s u p ple me nt is t o hel p mas k a n y 
c hr o mat uria attri b ute d t o N T Z  a n d ai d i n mai ntai ni n g st u d y bli n di n g. T he s u p ple me nt will  s u p pl y 
eac h s u bject wit h t he f oll o wi n g Perce nt Dail y Val ues base d o n a 2, 0 0 0 cal orie diet: vita mi n B 1 
1, 3 3 3 %, vita mi n B 2 8 2 4 %, vita mi n B 3 2 4 0 %, vita mi n B 5 3 6 0 %, vita mi n B 6 1 0 0 0 %, vita mi n B 7  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
2 2  
C O N FI D E N TI A L  
 
 
1 0 0 %, vita mi n B 1 2 1 5, 0 0 0 %, f olate 1 0 0 %, a n d vita mi n C 2 6 7 %. C o nsi deri n g t his s u p ple me nt will 
pr o vi de well  be y o n d t he nee de d dail y all o wa nce of t hese water -s ol u ble vita mi ns, e xcess a m o u nts 
are e x pecte d t o be e xcrete d i n t he uri ne a n d pr o vi de disc ol orati o n. 
4. 2. 5.  
C h oice of P atie nt- Re p orte d O utc o me I nstr u me nt 
T his cli nical trial will  use t he I n F L Ue nza Patie nt- Re p orte d O utc o me Q uesti o n naire ( F L U-P R O).  
F L U - P R O was  de vel o pe d wit h  t he s u p p ort of t he U. S. De part me nt of Healt h  a n d H u ma n Ser vices 
t hr o u g h  t he  Nati o nal  Ca ncer  I nstit ute  a n d  t he  Nati o nal  I nstit utes  of  Aller g y  a n d  I nfecti o us 
Diseases, Nati o nal I nstit utes of Healt h, i n res p o nse t o t he nee d f or i m pr o ve d metrics t o e val uate 
treat me nt effect i n cli nical trials of dr u gs f or t he treat me nt of i nfl ue nza a n d ot her res pirat or y tract 
viral  diseases.  It  was  de vel o pe d  a n d  vali date d  i n  acc or da nce  wit h  F D A’s  g ui da nce,  “ Patie nt- 
Re p orte d O utc o me Meas ures: Use  i n Me dical Pr o d uct De vel o p me nt t o S u p p ort La beli n g Clai ms.” 
It has als o bee n vali date d f or use o n a n electr o nic de vice as part of a n electr o nic diar y (“e Diar y”) 
t hat ca n ti me sta m p diar y e ntries t o e ns ure ti mel y rec or di n g, t here b y miti gati n g ris ks of recall bias. 
We will use a n electr o nic diar y f or t his cli nical trial.  F L U -P R O was se paratel y vali date d f or use 
i n a p o p ulati o n wit h n o n-i nfl ue nza li ke ill ness a n d als o has rece ntl y bee n use d i n vacci ne st u dies 
wit h  ol der a d ults f or t he pre ve nti o n of R S V (P o wers et al. 2 0 1 8, Y u  et al. 2 0 2 0). Data  fr o m R o mar k 
st u dies R M 0 8- 3 0 0 4 a n d R M 0 8- 3 0 0 5 als o i n dicates vali dit y a n d a bilit y t o detect c ha n ge i n patie nts 
i nfecte d wit h E nter ovir us/ R hi n ovir us or seas o nal c or o na vir us. 
4. 2. 6.  
C h oice of Pri m ar y E n d p oi nt  
T he  pri mar y  e n d p oi nt  was  de vel o pe d  usi n g  data  c ollecte d  fr o m  1, 4 6 7  s u bjects  i nfecte d  wit h 
i nfl ue nza, E nter ovir us/ R hi n ovir us or seas o nal c or o na vir uses d uri n g R o mar k st u dies R M 0 8- 3 0 0 4 
a n d  R M 0 8- 3 0 0 5.  T he  e n d p oi nt  defi nes  a  le vel  of  s y m pt o m  i m pr o ve me nt  t hat  c o nstit utes  a 
mea ni n gf ul wit hi n- patie nt c ha n ge i n healt h stat us. T he deter mi nati o n of mea ni n gf ul ness was  base d 
o n  e m piric  e vi de nce  deri ve d  fr o m  t he  use  of  a nc h or  q uesti o ns.  T he  e n d p oi nt  re q uires  ( 1)  oral 
te m perat ure < 1 0 0. 4 º F, ( 2) re d ucti o n of t otal s y m pt o m se verit y sc ore fr o m t he pre vi o us da y, ( 3) 
t he  patie nt  t o  pr o vi de  c o nfir mati o n  t hat  s y m pt o ms  are  at  least  s o me w hat  better,  a n d  ( 4)  n o 
s y m pt o m  d o mai n  i ncrease  e xce pt  bel o w  bac k gr o u n d  le vels  f or  t he  re mai n der  of  t he  st u d y 
(s ustai ne d res p o nse). T hese bac k gr o u n d le vels were deri ve d base d o n s y m pt o m sc ores re p orte d b y 
patie nts at t he ti me t he y als o re p orte d bei n g at us ual healt h. 
 
5.  
S T U D Y  P O P U L A TI O N  
5. 1.  
I ncl usi o n Criteri a  
1.  Male  or fe male o ut patie nts at least 1 2 years of a ge 
2.  Prese nce of cli nical si g ns a n d/ or s y m pt o ms c o nsiste nt wit h  w orse ni n g or sta ble c ol d d ue t o 
E V/ R V i nfecti o n ( o ne of t he f oll o wi n g is re q uire d): 
a. Prese nce of at least t w o res pirat or y s y m pt o m d o mai ns ( hea d, t hr oat, n ose, c hest, c o u g h) 
wit h a sc ore of ≥2 as deter mi ne d b y Scree ni n g F L U- P R O O R  
b.  Prese nce of at least o ne res pirat or y s y m pt o m d o mai n ( hea d, t hr oat, n ose, c hest, c o u g h) 
wit h a sc ore of ≥2 as deter mi ne d b y Scree ni n g F L U- P R O wit h p ulse rate ≥9 0 O R  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
2 3  
C O N FI D E N TI A L  
 
 
c. Prese nce of at least o ne res pirat or y s y m pt o m d o mai n ( hea d, t hr oat, n ose, c hest, c o u g h) 
wit h a sc ore of ≥2 as deter mi ne d b y Scree ni n g F L U- P R O wit h res pirat or y rate ≥1 6 
A N D  patie nt re p orte d assess me nt t hat s y m pt o ms are prese nt, t he s y m pt o ms are n ot c o nsiste nt 
wit h  t he s u bject’s us ual healt h, t he s y m pt o ms i nterfere wit h  dail y acti vities, a n d t he s y m pt o ms 
ha ve w orse ne d or re mai ne d t he sa me relati ve t o t he pre vi o us da y, as c o nfir me d b y res p o nses 
t o q uesti o ns i n t he Scree ni n g F L U- P R O. 
3.  O nset of s y m pt o ms n o m ore t ha n 7 2 h o urs bef ore e nr oll me nt i n t he trial. O nset of s y m pt o ms 
is defi ne d as t he earlier of t he first ti me at w hic h t he s u bject e x perie nce d s u bjecti ve fe ver or 
a n y res pirat or y s y m pt o m ( hea d, t hr oat, n ose, c hest, or c o u g h s y m pt o ms). 
4.  Willi n g a n d a ble t o pr o vi de writte n i nf or me d c o nse nt (i ncl u di n g asse nt b y le gal g uar dia n if 
u n der 1 8 years of a ge) a n d c o m pl y wit h t he re q uire me nts of t he pr ot oc ol, i ncl u di n g 
c o m pleti o n of t he s u bject diar y a n d all pr ot oc ol pr oce d ures. 
5. 2.  
E xcl usi o n  Criteri a  
1.  [Criteri o n re m ove d i n pr ot oc ol versi o n 2. 0 See Revisi o n Hist ory i n A p pe n dix 1. ] 
2.  S u bjects w h o e x perie nce d a pre vi o us e pis o de of ac ute u p per res pirat or y tract i nfecti o n, otitis, 
br o nc hitis or si n usitis or recei ve d a nti bi otics f or t hese c o n diti o ns wit hi n t w o wee ks pri or t o 
a n d i ncl u di n g st u d y da y 1. 
3.  Se verel y i m m u n o deficie nt pers o ns i ncl u di n g: 
a. S u bjects wit h i m m u n ol o gic dis or ders or recei vi n g i m m u n os u p pressi ve t hera p y (e. g., f or 
or ga n or b o ne marr o w tra ns pla nts, i m m u n o m o d ulat or y t hera pies f or certai n a ut oi m m u ne 
diseases)  
b.  S u bjects wit h u ntreate d HI V i nfecti o n or treate d HI V i nfecti o n wit h a C D 4 c o u nt bel o w 
3 5 0 cells/ m m 3 i n t he last si x m o nt hs 
c. S u bjects  acti vel y  u n der g oi n g  s yste mic  c he m ot hera p y  or  ra di ot hera p y  treat me nt  f or 
mali g na nc y  
d.  S u bjects usi n g ster oi ds as mai nte na nce t hera p y f or c hr o nic c o n diti o ns 
4.  S u bjects  wit h  acti ve  res pirat or y  aller gies  or  s u bjects  e x pecte d  t o  re q uire  a nti-aller g y 
me dicati o ns d uri n g t he st u d y peri o d f or res pirat or y aller gies. 
5.  Fe males  of c hil d beari n g p ote ntial w h o are eit her pre g na nt or se x uall y acti ve wit h o ut t he use of 
birt h c o ntr ol.  Fe male s u bjects of c hil d -beari n g p ote ntial t hat are se x uall y acti ve m ust ha ve a 
ne gati ve  baseli ne  pre g na nc y  test  a n d  m ust  a gree  t o  c o nti n ue  a n  acce pta ble  met h o d  of  birt h 
c o ntr ol f or t he d urati o n  of  t he st u d y a n d f or 1 m o nt h  p ost -treat me nt.  A d o u ble  barrier  met 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 ycles  pri or  t o  st u d y  dr u g 
a d mi nistrati o n, a n I U D, or me dr o x y pr o gester o ne acetate a d mi nistere d i ntra m usc ularl y f or a 
mi ni m u m  of  o ne  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  met h o ds  of  birt h 
c o ntr ol f or i ncl usi o n i nt o t he st u d y.  Fe male s u bjects are c o nsi dere d of c hil d beari n g p ote ntial 
u nless  t he y  are  p ost me n o pa usal  (a bse nce  of  me nstr ual  blee di n g  f or  1  year -  or  6  m o nt hs  if 
la b orat or y  c o nfir mati o n  of  h or m o nal  stat us),  or  ha ve  ha d  a  h ysterect o m y,  bilateral  t u b ular 
li gati o n or bilateral o o p h orect o m y. 
6.  S u bjects resi di n g i n t he sa me h o use h ol d wit h  a n ot her s u bject partici pati n g i n t he st u d y. 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
2 4  
C O N FI D E N TI A L  
 
 
7.  Treat me nt wit h a n y i n vesti gati o nal dr u g or vacci ne t hera p y wit hi n 3 0 da ys pri or t o scree ni n g 
a n d willi n g t o a v oi d t he m d uri n g t he c o urse of t he st u d y. 
8.  Recei pt of a n y d ose of N T Z  wit hi n se ve n da ys pri or t o scree ni n g. 
9.  K n o w n se nsiti vit y t o N T Z or a n y of t he e xci pie nts c o m prisi n g t he st u d y me dicati o ns  
1 0.  S u bjects u na ble t o s wall o w oral ta blets or ca ps ules. 
1 1.  S u bjects wit h   k n o w n  se vere  heart,  l u n g,  ne ur ol o gical  or  ot her  s yste mic  disease  t hat  t he 
I n vesti gat or belie ves c o ul d precl u de safe partici pati o n. 
1 2.  S u bjects li kel y or e x pecte d t o re q uire h os pitalizati o n u nrelate d t o c ol d d uri n g t he st u d y peri o d.  
1 3.  S u bjects  w h o, i n  t he  j u d g me nt  of  t he  I n vesti gat or, will   be  u nli kel y t o  c o m pl y wit h   t he 
re q uire me nts of t his pr ot oc ol i ncl u di n g c o m pleti o n of t he s u bject diar y. 
1 4.  S u bjects ta ki n g me dicati o ns c o nsi dere d t o be maj or C Y P 2 C 8 s u bstrates. Refer t o Ta ble 6 i n 
Secti o n 6. 5 . 
1 5.  Pers o ns wit h  a n y cli nical si g n or s y m pt o ms s u g gesti ve of se vere s yste mic ill ness wit h  C O VI D- 
1 9, i ncl u di n g t he f oll o wi n g: 
a. s h ort ness of breat h at rest, 
b.  resti n g p ulse ≥1 2 5 beats per mi n ute,  
c. resti n g res pirat or y rate ≥3 0 breat hs per mi n ute, or  
d.  S p O 2 ≤ 9 3 % o n r o o m air at sea le vel. 
1 6.  S u bjects  k n o w n t o  ha ve  a  dia g n ostic test  p ositi ve  f or  S A R S- C o V- 2  or  i nfl ue nza  i nfecti o n 
wit hi n t he prece di n g t hree wee ks. 
5. 3.  
St u d y  P o p ul ati o n  Di versit y  
T he  S p o ns or  will  select  cli nical  sites  t o  s u p p ort  recr uit me nt  of  a  di verse  a n d  re prese ntati ve 
p o p ulati o n, i ncl u di n g ol der i n di vi d uals a n d racial a n d et h nic mi n orities. 
 
6.  
S T U D Y  I N T E R V E N TI O N 
6. 1.  
St u d y  I nter ve nti o n(s) A d mi nistr ati o n  
6. 1. 1.  
St u d y I nter ve nti o n Descri pti o n  
N T Z  3 0 0 m g  e xte n de d release ta blets f or use i n t his st u d y are yell o w, r o u n d, c o n ve x, fil m-c oate d, 
bi-la yer  ta blets  f or  oral  a d mi nistrati o n.  Eac h  ta blet  c o ntai ns  3 0 0  m g  of  N T Z  a n d  t he  i nacti ve 
i n gre die nts. 
Place b o ta blets will  ha ve t he sa me a p peara nce a n d i nacti ve i n gre die nts as t he acti ve N T Z  3 0 0 m g 
e xte n de d release ta blet. 
T he vita mi n B c o m ple x s u p ple me nt is 
 ma n ufact ure d b y 
 
. T he s u p ple me nt will s u p pl y eac h s u bject wit h t he f oll o wi n g Perce nt 
Dail y  Val ues base d o n a 2, 0 0 0-cal orie diet: vita mi n B 1 1, 3 3 3 %, vita mi n B 2 8 2 4 %, vita mi n B 3  




Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
2 6  
C O N FI D E N TI A L  
 
 
6. 3.  
R a n d o miz ati o n  a n d  Bli n di n g  
S u bjects will  be ra n d o mize d 1: 1 t o recei ve eit her N T Z  + vita mi n B c o m ple x or place b o + vita mi n 
B c o m ple x. A n  i n de pe n de nt t hir d part y  will  pre pare  a master  ra n d o mizati o n list a n d mai ntai n  t he 
mas ki n g  of  t he  st u d y.  S u bjects  w h o  q ualif y  f or  t he  st u d y  will  be  assi g ne d  t o  treat me nt  usi n g 
ce ntralize d  ra n d o mizati o n  pr oce d ures.  T he  treat me nt  n u m bers  will  a p pear  o n  t he  b ottles 
c o ntai ni n g  t he  mas ke d  st u d y  me dicati o n.  T he  ra n d o mizati o n  list  will  be  mas ke d  t o  st u d y 
partici pa nts i ncl u di n g S p o ns or, I n vesti gat ors, st u d y m o nit ors, statisticia ns, s u bjects a n d la b orat or y 
pers o n nel.  U n mas ki n g  pr oce d ures  will  be  detaile d  i n  t he  Me dical  M o nit ori n g  Pla n  a n d 
I n vesti gat ors will be pr o vi de d i nstr ucti o ns f or u n mas ki n g. 
6. 4.  
St u d y  I nter ve nti o n C o m pli a nce  
S u bject c o m plia nce wit h  st u d y me dicati o n will  be c hec ke d b y site staff dail y d uri n g t he treat me nt 
peri o d. S u bjects will ret ur n t he treat me nt kit wit h a n y u n use d me dicati o n t o t he cli nic at t he Da y 
1 0 visit. S u bjects will  be c o nsi dere d n o n-c o m plia nt ( maj or pr ot oc ol de viati o n) if t he y ha ve misse d 
m ore t ha n t w o d oses of t he i n vesti gati o nal me dicati o n d uri n g t he first t hree da ys of t he st u d y. N o n- 
c o m plia nce will n ot be ca use f or disc o nti n uati o n of s u bject partici pati o n i n t he st u d y. 
6. 5.  
C o nc o mit a nt  T her a p y  
T he f oll o wi n g me dicati o ns will  n ot be all o we d d uri n g t he st u d y: t o pical or s yste mic dec o n gesta nts, 
nasal  c ortic oster oi ds,  a n d  a n y  prescri pti o n  or  n o n- prescri pti o n  me dicati o ns  classifie d  as  (i) 
e x pect ora nts  a n d  c o u g h  pre parati o ns,  (ii)  a nal gesics  a n d  a nti p yretics,  (iii)  a nti hista mi nes 
( A merica n  H os pital  F or m ular y  Ser vice  ( A H F S)  classificati o n)  or  (i v)  me dicati o ns  c o nsi dere d 
maj or  C Y P 2 C 8  s u bstrates  (see Ta ble  6 bel o w).  As  a n  e xce pti o n  t o  t his  r ule,  s u bjects  will  be 
all o we d t o use aceta mi n o p he n a n d/ or de xtr o met h or p ha n as necessar y f or disa bli n g s y m pt o ms. 
T a ble 6:     M aj or C Y P 2 C 8 S u bstr ates  
 
Ge neric  N a me  
Br a n d  N a me(s)  
T her a pe utic  Use  a n d/ or  Dr u g  Cl ass  
A m o di a q ui ne  
B A S O Q UI N,  C A M O Q UI N, 
F L A V O Q UI N  
A nti malarial  
D a pr o d ust at  ( G S K 1 2 7 8 8 6 3) 
* 
A ntia ne mic,  pr ol yl  h y dr o x ylase 
i n hi bit or 
D as a b u vir  ( A B T-3 3 3)  
E X VI E R A  
A nti viral,  N S B 5  i n hi bit or 
E nz al ut a mi de  
X T A N DI  
A ntica ncer,  a ntia n dr o ge n 
M o ntel u k ast  
SI N G U L AI R  
A ntiast h matic,  L T R A  
Pi o glit az o ne  
A C T O S  
A nti dia betic,  P P A R -γ a g o nist 
Re p a gli ni de  
N O V O N O R M,  P R A N DI N  
A nti dia betic,  me gliti ni de  a nal o g 
S o urce:  Bac k ma n  et al. 2 0 1 6  
* C urre ntl y  liste d as i n vesti gati o nal o nl y  a n d n ot  yet  gra nte d  a tra de na me  b y  t he ma n ufact urer  
S u bjects  are  als o  pr o hi bite d  fr o m  ta ki n g  h y dr o x yc hl or o q ui ne,  c hl or o q ui ne,  re m desi vir, 
azit hr o m yci n  or l o pi na vir/rit o na vir d uri n g t he st u d y e xce pt as sta n dar d- of-care resc ue me dicati o n.  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
2 7  
C O N FI D E N TI A L  
 
 
Me dicati o ns f or pre-e xisti n g c o n diti o ns t hat are n ot e xcl u de d (see e xcl usi o n criteria) s h o ul d be 
c o nti n ue d  as  prescri be d.  Sta n dar d- of-care  resc ue  me dicati o n  is  per mitte d  f or  c o m plicati o ns  of 
C O VI D- 1 9 ill ness. T he use of s uc h me dicati o n will be rec or de d i n t he E D C s yste m. 
 
7.  
S T U D Y  I N T E R V E N TI O N DI S C O N TI N U A TI O N  A N D 
P A R TI CI P A N T DI S C O N TI N U A TI O N  
Treat me nt will  be disc o nti n ue d f or i n di vi d ual s u bjects f or t he f oll o wi n g reas o ns: 
1.  A n  aller gic reacti o n occ urs or is s us pecte d. 
2.  Me dical  c o n diti o ns  t hat ma y   re q uire  i n vesti gati o nal  me dicati o n  disc o nti n uati o n i n  t he 
I n vesti gat or’s j u d g me nt. 
3.  S u bject desire t o disc o nti n ue partici pati o n.  
I n t he case of a n aller gic reacti o n or ot her me dical c o n diti o n re q uiri n g s u bject disc o nti n uati o n, 
a p pr o priate treat me nt will be i nstit ute d b y t he I n vesti gat or. 
S u bjects will  be e nc o ura ge d t o c o m plete all pr ot oc ol-s pecifie d f oll o w- u p visits e ve n if st u d y dr u g 
is wit h dra w n. 
 
8.  
S T U D Y  P R O C E D U R E S  
8. 1.  
Visit  Pr oce d ures  
St u d y  pr oce d ures t o  be  c o m plete d at eac h  visit  are  i n dicate d i n  t he Sc he d ule  of  Assess me nts . 
Descri pti o ns of selecte d pr oce d ures are o utli ne d i n t he f oll o wi n g secti o ns. 
8. 1. 1.  
I nf or me d C o nse nt  
Eac h  s u bject m ust gi ve writte n c o nse nt acc or di n g t o l ocal re q uire me nts after t he nat ure of t he st u d y 
has  bee n  f ull y e x plai ne d.  T he  i nf or me d c o nse nt f or m (I C F) m ust  be  si g ne d bef ore  perf or ma nce  of 
a n y st u d y -relate d acti vit y. T he i nf or me d c o nse nt f or m will be a p pr o ve d b y b ot h t he S p o ns or a n d 
b y  t he re vie wi n g I R B. T he y  will  be  i n acc or da nce  wit h  pri nci ples  t hat ori gi nate d  i n t he Declarati o n 
of Helsi n ki, c urre nt I C H a n d G C P g ui deli nes, a p plica ble re g ulat or y re q uire me nts, a n d S p o ns or 
p olic y. T he I C F ma y be si g ne d usi n g wet i n k or di gital si g nat ure. 
Bef ore e nr oll me nt i n t he st u d y, t he I n vesti gat or or a n a ut h orize d me m ber of t he i n vesti gati o nal 
staff  m ust  e x plai n  t o  p ote ntial  s u bjects  t he  ai ms,  met h o ds,  reas o na bl y  a ntici pate d  be nefits,  a n d 
p ote ntial hazar ds of t he st u d y, a n d a n y disc o mf ort partici pati o n i n t he st u d y ma y e ntail.  S u bjects 
will  be  i nf or me d  t hat  t heir  partici pati o n  is  v ol u ntar y  a n d  t hat  t he y  ma y  wit h dra w  c o nse nt  t o 
partici pate at a n y ti me.  T he y will be i nf or me d t hat c h o osi n g n ot t o partici pate will n ot affect t he 
care  he/s he  will  recei ve.  Fi nall y,  t he y  will  be  t ol d  t hat  t he  I n vesti gat or  will  mai ntai n  a  s u bject 
i de ntificati o n re gister f or t he p ur p oses of l o n g-ter m f oll o w- u p if nee de d a n d t hat t heir rec or ds ma y 
be accesse d  b y healt h a ut h orities a n d a ut h orize d S p o ns or staff wit h o ut vi olati n g t he c o nfi de ntialit y 
of  t he s u bject, t o t he e xte nt per mitte d  b y  t he a p plica ble  la w(s) or  re g ulati o ns. B y  si g ni n g t he I C F 
t he s u bject is a ut h orizi n g s uc h access, a n d a grees t o all o w his or her st u d y p h ysicia n t o re-c o ntact 
t he s u bject f or t he p ur p ose of o btai ni n g c o nse nt f or a d diti o nal safet y e val uati o ns, if nee de d. O nl y  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
2 8  
C O N FI D E N TI A L  
 
 
s u bjects w h o are f ull y a ble t o u n dersta n d t he ris ks, be nefits, a n d p ote ntial A Es of t he st u d y, a n d 
pr o vi de t heir c o nse nt v ol u ntaril y will be e nr olle d. 
T he  s u bject  will  be  gi ve n  s ufficie nt  ti me  t o  rea d  t he  I C F  a n d  t he  o p p ort u nit y  t o  as k  q uesti o ns. 
After t his e x pla nati o n a n d bef ore e ntr y i nt o t he st u d y, c o nse nt s h o ul d be a p pr o priatel y rec or de d 
b y  mea ns  of  t he s u bject's pers o nall y  date d  si g nat ure. After  ha vi n g  o btai ne d  t he c o nse nt, a c o p y of 
t he I C F m ust be gi ve n t o t he s u bject. 
If  t he  s u bject  is  u na ble  t o  rea d  or  write,  a n  i m partial  wit ness  s h o ul d  be  prese nt  f or  t he  e ntire 
i nf or me d  c o nse nt  pr ocess  ( w hic h  i ncl u des  rea di n g  a n d  e x plai ni n g  all  writte n  i nf or mati o n)  a n d 
s h o ul d pers o nall y date a n d si g n t he I C F after t he oral c o nse nt of t he s u bject is o btai ne d, if per mitte d 
b y l ocal la w. 
Asse nt fr o m a n y mi n or ( ≤ 1 8 years of a ge or as l ocal re g ulati o ns a p pl y) e nr olle d i nt o t he st u d y will 
be o btai ne d al o n g wit h  d oc u me nte d c o nse nt fr o m t heir pare nt/le gal g uar dia n t o all o w t he mi n or t o 
partici pate  i n t he st u d y. T he  asse nt a n d c o nse nt f or ms m ust  be  si g ne d pri or  t o t he perf or ma nce  of 
a n y st u d y relate d acti vit y. 
Si g ne d I C Fs m ust re mai n i n t he s u bject's file(s) a n d be a vaila ble f or verificati o n b y re prese ntati ves 
of R o mar k, t he I R B, a n d F D A/rele va nt re g ulat or y a ge ncies at a n y ti me. 
8. 1. 2.  
Me dic al Hist or y  
All  rele va nt me dical hist or y s h o ul d be e ntere d i n t he E D C  s yste m at t he Scree ni n g visit. Rele va nt 
me dical hist or y i ncl u des: 
1.  A n y disease, c o n diti o n or s ur ger y acti ve at t he ti me of t he Scree ni n g visit;  
2.  A n y disease, c o n diti o n or s ur ger y e n di n g wit hi n t w o m o nt hs of t he Scree ni n g visit; or  
3.  A n y ot her disease, c o n diti o n or s ur ger y rele va nt t o t he s u bject’s i nfecti o n or cli nical 
ma na ge me nt.  
8. 1. 3.  
P h ysic al E x a mi n ati o n  
P h ysical e xa mi nati o ns will  i ncl u de assess me nt of eac h b o d y s yste m i ncl u di n g s ki n, hea d (e ye, ear 
a n d  n ose),  nec k,  m o ut h/t hr oat,  l y m p h  n o des,  car di o vasc ular,  res pirat or y,  gastr oi ntesti nal, 
ne ur ol o gical, a n d m usc ul os keletal s yste ms as well as ge neral a p peara nce f or a b n or malities. 
T he  I n vesti gat or  will  c o m plete  a  f ull  p h ysical  e xa mi nati o n  at  t he  Scree ni n g  visit.  P h ysical 
e xa mi nati o ns  s h o ul d  occ ur  at  f oll o w- u p  a n d  u nsc he d ule d  visits  as  re q uire d  b y  s y m pt o ms  or 
a d verse c ha n ges fr o m baseli ne. 
8. 1. 4.  
B o d y Me as ure me nts a n d Resti n g Vit al Si g ns  
B o d y meas ure me nts a n d resti n g vital si g ns will  i ncl u de assess me nt of t he f oll o wi n g: 
1.  Hei g ht ( Scree ni n g visit o nl y)  
2.  Wei g ht  
3.  Oral te m perat ure 
4.  Bl o o d press ure  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
2 9  
C O N FI D E N TI A L  
 
 
5.  P ulse rate 
6.  Res pirat or y rate 
7.  O x y ge n sat urati o n 
8. 1. 5.  
Scree ni n g  F L U-P R O  
T he F L U - P R O q uesti o n naire will  be a d mi nistere d d uri n g t he Scree ni n g visit t o c o nfir m s y m pt o ms 
re q uire d f or eli gi bilit y. 
8. 1. 6.  
R a n d o miz ati o n a n d Dis pe nsi n g  St u d y Me dic ati o n  
Ra n d o mizati o n  a n d  st u d y  me dicati o n  kit  assi g n me nt  will  be  acc o m plis he d  usi n g  a n  I nteracti ve 
Ra n d o mizati o n T o ol (I R T) feat ure i n t he E D C s yste m after all scree ni n g pr oce d ures ha ve bee n 
c o m plete d a n d t he s u bject has bee n deter mi ne d t o be eli gi ble f or t he st u d y. Site staff will wit ness 
t he  s u bject  ta ke  t he  first  d ose  of  st u d y  me dicati o n  i n  t he  cli nic  as  s o o n  as  p ossi ble  f oll o wi n g 
ra n d o mizati o n a n d rec or d t he date a n d ti me of me dicati o n i nta ke i n t he E D C s yste m. 
8. 1. 7.  
S u bject I nstr ucti o ns 
At  eac h s u bject c o ntact, site staff will  i nstr uct t he s u bject re gar di n g: 
1.  A d mi nistr ati o n of st u dy me dic ati o n. S u bjects will  be i nstr ucte d t o ta ke t he st u d y me dicati o n 
(t w o  ta blets)  t wice  dail y  wit h  t he  m or ni n g  a n d  e ve ni n g  meals,  a p pr o xi matel y  e ver y  1 2 
h o urs ( < 1 h o ur after f o o d i nta ke, prefera bl y a hi g h-fat meal  b ut at a mi ni m u m a cereal bar) 
a n d a B c o m ple x vita mi n 
 
). 
2.  C o m pleti o n of s u bject di ary. S u bjects will be re mi n de d t o c o m plete t he electr o nic diar y 
a n d a n y q uesti o ns will be a ns were d. 
3.  Use of birt h c o ntr ol.  Fe male s u bjects of c hil d beari n g p ote ntial, if se x uall y acti ve, will be 
i nstr ucte d t o c o nti n ue a n acce pta ble met h o d of birt h c o ntr ol f or t he d urati o n of t he st u d y 
a n d  f or  1  m o nt h  p ost-treat me nt.  Acce pta ble  met h o ds  of  birt h  c o ntr ol  i ncl u de  a  d o u ble 
barrier  met h o d,  oral  birt h  c o ntr ol  pills,  a n  I U D,  or  me dr o x y pr o gester o ne  acetate 
a d mi nistere d i ntra m usc ularl y. 
4.  F oll o w- u p visits. S u bjects will  be re mi n de d of t he st u d y sc he d ule a n d of t he ne xt sc he d ule d 
visit.  
5.  Seeki n g  e mer ge ncy  c are  or  c o nt acti n g  t he  st u dy  p hysici a n  or  n urse .  S u bjects  m ust  be 
i nf or me d t o see k e mer ge nc y me dical care or c o ntact t he st u d y p h ysicia n or n urse if t he y 
de vel o p a n y of t he f oll o wi n g s y m pt o ms liste d bel o w at a n y p oi nt d uri n g t he st u d y. 
C O N T A C T S T U D Y  P H Y SI CI A N I F Y O U  H A V E:  
• 
Tr o u ble breat hi n g i ncl u di n g s h ort ness of breat h  
• 
Se vere hea dac he, stiff nec k, c o nf usi o n or e xcessi ve s o m n ole nce 
• 
If fe ver ( ≥9 9° F or ≥3 7. 2° C) ret ur ns after bei n g a bse nt f or 2 4 h o urs  
• 
I ncrease d diffic ult y breat hi n g  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
3 0  
C O N FI D E N TI A L  
 
 
• 
W heezi n g de vel o ps  
• 
Ne w pai n de vel o ps or pai n l ocalizes t o o ne area, s uc h as a n ear, t he t hr oat, t he c hest, 
or t he si n uses 
• 
S y m pt o ms bec o me m ore se vere or fre q ue nt 
• 
S y m pt o ms rec ur or a n y diffic ult y breat hi n g f oll o wi n g 5- 1 0 da ys res ol uti o n of ill ness 
• 
A n  aller gic-li ke reacti o n occ urs or is s us pecte d 
• 
A b n or mal be ha vi or  
8. 1. 8.  
D a y 2- 7 S u bject C o nt act  
Site  staff will  c o ntact eac h s u bject b y tele p h o ne o n st u d y Da ys 2- 7 t o verif y:  
1.  Di d  t he s u bject ta ke all e x pecte d d oses of st u d y me dicati o n?  
2.  Di d  t he s u bject c o m plete all e x pecte d electr o nic diaries?  
3.  D oes t he s u bject ha ve w orse ni n g s y m pt o ms or a d verse e ve nts t hat warra nt a n 
u nsc he d ule d visit? 
4.  D oes t he s u bject ha ve s h ort ness of breat h at rest? If yes, i nstr uct t he s u bject t o c o me t o 
t he cli nic f or a n u nsc he d ule d visit t o scree n f or pr o gressi o n of ill ness or refer t o h os pit al 
as w arr a nte d. If t he s u bject is referre d t o t he h os pit al or e mer ge ncy de p art me nt, t he 
I nvesti g at or will atte m pt t o o bt ai n h os pit al rec or ds i n dic ati n g S p O2 or P a O 2/ Fi O2 fr o m 
t he s u bject f or t he p ur p oses of defi ni n g pr o gressi o n t o severe C O VI D- 1 9 ill ness. T he 
S p O 2 or P a O 2/ Fi O2 o bt ai ne d fr o m h os pit al rec or ds will be e ntere d o n a n U nsc he d ule d 
Visit e C R F. 
If t he s u bject has misse d  me dicati o n or electr o nic diaries, t he site staff will  re-trai n t he s u bject o n 
t he i m p orta nce of me dicati o n a n d diar y c o m plia nce. 
T his c o ntact ma y  occ ur at t he Da y  4 or u nsc he d ule d visit i n lie u of tele p h o ne c o ntact. 
8. 1. 9.  
D a y 2 8 S u bject C o nt act  
Site staff will c o ntact eac h s u bject b y tele p h o ne o n st u d y Da y 2 8 t o deter mi ne if t he s u bject has 
e x perie nce d  a n y  ne w  a d verse  e ve nts,  de vel o pe d  se vere  C O VI D- 1 9  ill ness,  or  re q uire d 
h os pitalizati o n f or a n y reas o n. 
If warra nte d, t he Da y  2 8 s u bject c o ntact ma y  als o occ ur i n- pers o n at t he cli nic or a n ot her 
l ocati o n as a gree d u p o n b y t he site a n d s u bject. 
8. 2.  
L a b or at or y  Assess me nts  
8. 2. 1.  
Assess me nts i n t he Cli nic  
A uri ne pre g na nc y test will be perf or me d i n t he cli nic o nl y f or w o me n of c hil d beari n g p ote ntial 
( p ost- me narc he, pre- me n o pa use, n ot s ur gicall y sterile) at t he Scree ni n g visit. 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
3 1  
C O N FI D E N TI A L  
 
 
8. 2. 2.  
Ce ntr al L a b or at or y Assess me nts  
A ce ntral la b orat or y will be use d f or safet y a n d dia g n ostic vir ol o g y testi n g. A la b orat or y ma n ual 
will be pr o vi de d t o eac h cli nical site wit h sa m ple c ollecti o n a n d ha n dli n g details. 
8. 2. 2. 1.  
L a b or at or y S afet y Assess me nts  
Bl o o d tests f or safet y m o nit ori n g will  i ncl u de he m o gl o bi n, he mat ocrit, c o m plete bl o o d c o u nt (t otal 
a n d differe ntial), platelet c o u nt, ra n d o m bl o o d s u gar, t otal c h olester ol, H D L, L D L, tri gl yceri des, 
al b u mi n, A S T,  A L T,  G G T,  al kali ne p h os p hatase, bilir u bi n (t otal/ direct), B U N, creati ni ne, s o di u m, 
p otassi u m, c hl ori de. 
R o uti ne uri nal ysis will  i ncl u de a p peara nce, gl uc ose, pr otei n, a n d bl o o d.  
8. 2. 2. 2.  
Di a g n ostic Vir ol o g y Testi n g  
Dia g n ostic vir ol o g y testi n g will  be perf or me d usi n g nas o p har y n geal s wa b sa m ples c ollecte d at t he 
Baseli ne, Da y 4 a n d Da y 1 0. T he nas o p har y n geal sa m ple f or vir ol o g y testi n g will be c ollecte d 
usi n g  a  si n gle  nas o p har y n geal  s wa b  i nserte d  i nt o  b ot h  n ostrils  i n  acc or da nce  wit h  pr oce d ures 
detaile d i n t he st u d y-s pecific la b orat or y ma n ual. 
T he e Ple x ®  Res pirat or y Pat h o ge n Pa nel ( Ge n Mar k, Carls ba d, C A) will  be use d t o detect i nfl ue nza 
A ( n o n-s pecific as t o s u bt y pe); i nfl ue nza A H 1, H 1 N 1 ( 2 0 0 9), H 3 s u bt y pes; i nfl ue nza B; R S V A 
a n d B; parai nfl ue nza 1, 2, 3 a n d 4; h M P V; a de n o vir us; h u ma n E V/ R V; c or o na vir us N L 6 3, H K U 1, 
2 2 9 E a n d O C 4 3; C hla m y d o p hila p ne u m o niae; a n d M yc o plas ma p ne u m o niae. 
T he A pti ma ®  S A R S- C o V- 2 Assa y ( H ol o gic, I nc, Sa n Die g o, C A) will be use d t o detect S A R S- 
C o V -2.  
All  Baseli ne nas o p har y n geal s wa bs will  be teste d b y b ot h P C R assa ys. 
P ost- baseli ne sa m ples ( Da ys 4 a n d 1 0) will  o nl y be teste d b y t he e Ple x Res pirat or y Pat h o ge n Pa nel 
( R P P) a n d will  o nl y be teste d if t he sa m ple fr o m t he prece di n g ti me p oi nt was  p ositi ve f or E V/ R V. 
F or e xa m ple, a s u bject w h o is p ositi ve f or E V/ R V at Baseli ne will ha ve t he Da y 4 sa m ple teste d 
b y t he e Ple x R P P. If t he s u bject’s Da y 4 sa m ple is ne gati ve f or E V/ R V, t he Da y 1 0 sa m ple will 
n ot be teste d. 
8. 2. 3.  
P h ar m ac o ki netics Assess me nts  
Bl o o d sa m ples f or p har mac o ki netics a nal ysis will  be se nt t o t he ce ntral la b orat or y b y t he site a n d 
s hi p pe d  t o  a  referral  la b orat or y  f or  a nal ysis.  Sa m ple  c ollecti o n  a n d  ha n dli n g  details  will  be 
i ncl u de d i n t he ce ntral la b orat or y ma n ual. 
8. 2. 4.  
Pl a n f or M o nit ori n g Vir al Resist a nce  
If a n y Da y  1 0 nas o p har y n geal s wa b sa m ple is p ositi ve f or E V/ R V b y t he e Ple x R P P, t he Baseli ne 
a n d Da y  1 0 nas o p har y n geal s wa b sa m ples f or t he s u bject will  be teste d f or p ost-treat me nt re d uce d 
s usce pti bilit y t o tiz o xa ni de. 
8. 3.  
S u bject  Di ar y  
T he s u bject diar y will  be use d t o ge nerate pri mar y efficac y data. T heref ore, diar y c o m plia nce is of 
critical i m p orta nce. 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
3 2  
C O N FI D E N TI A L  
 
 
8. 3. 1.  
S u bject Di ar y C o m pleti o n  
S u bjects will  c o m plete a diar y i ncl u di n g: 
• Oral te m perat ure ta ke n usi n g t he st u d y t her m o meter t wice dail y ( m or ni n g a n d e ve ni n g), 
a n d 
• T he F L U - P R O©  s y m pt o ms q uesti o n naire dail y i n t he e ve ni n g. 
T he diar y will  be c o m plete d usi n g t he s u bject’s s mart p h o ne or pr o visi o ne d de vice.  
Site staff will e ns ure s u bject access a n d a bilit y t o c o m plete t he diar y d uri n g t he Baseli ne visit b y 
ha vi n g t he s u bject c o m plete a practice diar y i n t he office. S u bjects will c o m plete t he first p ost- 
Scree ni n g diar y at h o me o n t he e ve ni n g of st u d y Da y 1. 
S u bjects will  recei ve electr o nic re mi n ders t o c o m plete t he diar y dail y t o e ns ure c o m plia nce. 
8. 3. 2.  
S u bject Di ar y C o m pli a nce M o nit ori n g  
It is t he res p o nsi bilit y of t he cli nical site t o e ns ure t hat s u bjects are c o m pleti n g t he diar y as directe d. 
E- mail n otificati o ns will be se nt t o t he site dail y wit h a list of s u bjects w h o misse d t he pre vi o us 
da y’s diar y i n or der t o direct f oll o w- u p c o ntact wit h t he s u bject t o re-trai n o n t he i m p orta nce of 
t he diar y. Site staff ma y als o vie w a diar y c o m pleti o n re p ort at a n y ti me wit hi n t he E D C s yste m. 
8. 4.  
A d verse  E ve nts  a n d  Seri o us  A d verse  E ve nts  
8. 4. 1.  
Defi niti o ns  
T he f oll o wi n g defi niti o ns will  a p pl y t o t he re p orti n g of a d verse e ve nts: 
1.  A d verse E ve nt: A n y u n wa nte d p h ysical, ps yc h ol o gical or be ha vi oral c ha n ge e x perie nce d 
b y  a  s u bject  d uri n g  t he  c o urse  of  t he  st u d y  a n d  after  ta ki n g  t he  first  d ose  of  st u d y 
me dicati o n re gar dless of its se verit y or relati o n t o t he st u d y.  A d verse e ve nts ma y i ncl u de 
s y m pt o ms, si g ns, u ne x pecte d w orse ni n g of pre-e xisti n g c o n diti o ns, cli nicall y si g nifica nt 
c ha n ges  i n  la b orat or y  val ues,  diseases  a n d  s y n dr o mes,  a n d  si g nifica nt  a n d  u ne x pecte d 
fail ures  of  p har mac ol o gical  acti o n  of  ot her  me dicati o ns.  S y m pt o ms  of  viral  res pirat or y 
i nfecti o ns  ( V RIs)  (c o u g h,  s ore,  t hr oat,  nasal  o bstr ucti o n,  fati g ue,  hea dac he,  m yal gia,  or 
fe veris h ness) will n ot be re p orte d as a d verse e ve nts. 
2.  Seri o us A d verse E ve nt: A n y a d verse e x perie nce occ urri n g at a n y d ose t hat is fatal or life 
t hreate ni n g;  re q uires  i n- patie nt  h os pitalizati o n  or  pr ol o n gati o n  of  a n  e xisti n g 
h os pitalizati o n; is a persiste nt si g nifica nt disa bilit y/i nca pacit y; is a c o n ge nital a n o mal y or 
birt h  defect;  or  is  a n  i m p orta nt  me dical  e ve nt  t hat  ma y  n ot  res ult  i n  deat h,  be  life- 
t hreate ni n g, or re q uire h os pitalizati o n b ut, base d u p o n a p pr o priate me dical j u d g me nt, ma y 
je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of 
t he o utc o mes liste d a b o ve. 
3.  U ne x pecte d  A d verse  E ve nt:  A n y  a d verse  e x perie nce  t hat  is  n ot  i de ntifie d  i n  nat ure, 
se verit y, or fre q ue nc y i n t he I n vesti gat or's Br oc h ure f or N T Z. 
4.  Se verit y of a d verse e ve nts will be assesse d as mil d, m o derate, se vere or p ote ntiall y life- 
t hreate ni n g  b y  t he  I n vesti gat or  usi n g  t he  T o xicit y  Gra di n g  Scale  Ta bles  pr o vi de d  i n 
A p pe n di x 4 ( deri ve d a n d a da pte d fr o m “ G ui da nce f or I n d ustr y: T o xicit y Gra di n g Scale  f or 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
3 3  
C O N FI D E N TI A L  
 
 
Healt h y A d ult a n d A d olesce nt V ol u nteers E nr olle d i n Pre ve nti ve Vacci ne Cli nical Trials”, 
U S De pt. of H H S, F D A, C D E R, Se pte m ber 2 0 0 7 a n d t he Nati o nal I nstit utes of Healt h, 
Nati o nal  Ca ncer  I nstit ute  C o m m o n  Ter mi n ol o g y  Criteria  f or  A d verse  E ve nts  ( C T C A E) 
versi o n 5. 0). 
5.  Ca usalit y (relati o ns hi p t o treat me nt) will  be assesse d  as f oll o ws: 
• 
Defi nitely Rel ate d : T he a d verse e ve nt is clearl y relate d t o t he i n vesti gati o nal a ge nt(s) 
or  researc h  i nter ve nti o n:  t he  a d verse  e ve nt  has  a  te m p oral  relati o ns hi p  t o  t he 
a d mi nistrati o n  of  t he  i n vesti gati o nal  a ge nt(s)  or  researc h  i nter ve nti o n,  f oll o ws  a 
k n o w n patter n of res p o nse, a n d n o alter nati ve ca use is prese nt. 
• 
Pr o b a bly Rel ate d : T he a d verse e ve nt is li kel y relate d t o t he i n vesti gati o nal a ge nt(s) or 
i nter ve nti o n: t he a d verse e ve nt has a te m p oral relati o ns hi p t o t he a d mi nistrati o n of t he 
i n vesti gati o nal a ge nt(s) or researc h i nter ve nti o n, f oll o ws a k n o w n or s us pecte d patter n 
of res p o nse, b ut a n alter nati ve ca use ma y be prese nt. 
• 
P ossi bly  Rel ate d :  T here  is  a  reas o na ble  p ossi bilit y  t hat  t he  e ve nt  ma y  ha ve  bee n 
ca use d b y or is li n ke d i n a si g nifica nt wa y t o t he researc h; t he a d verse e ve nt has a 
te m p oral relati o ns hi p t o t he a d mi nistrati o n of t he i n vesti gati o nal a ge nt(s) or researc h 
i nter ve nti o n,  f oll o ws  a  s us pecte d  patter n  of  res p o nse,  b ut  a n  alter nati ve  ca use  is 
prese nt.  
• 
U nrel ate d  ( or  N ot  Rel ate d) :  T he  a d verse  e ve nt  is  clearl y  N O T  relate d  t o  t he 
i n vesti gati o nal a ge nt(s) or i nter ve nti o n: t he a d verse e ve nt has n o te m p oral relati o ns hi p 
t o t he a d mi nistrati o n of t he i n vesti gati o nal a ge nt(s) or researc h i nter ve nti o n, f oll o ws 
n o k n o w n or s us pecte d patter n of res p o nse, a n d a n alter nati ve ca use is prese nt. 
U n der d o u ble- bli n d treat me nt c o n diti o ns, it s h o ul d be ass u me d t hat all s u bjects are ta ki n g 
t he test dr u g. 
8. 4. 2.  
Rec or di n g a n d F oll o w U p  of A d verse E ve nts  
At  t he ti me of eac h visit, t he s u bject will  be q uesti o ne d re gar di n g t he occ urre nce a n d nat ure of a n y 
a d verse e ve nts a n d all e ve nts will be rec or de d i n t he s u bject’s me dical rec or ds a n d i n t he E D C 
s yste m. A n y s u bject affecte d will  be e xa mi ne d b y t he I n vesti gat or as dee me d necessar y t o ascertai n 
t he c o urse of t he e ve nt a n d a n y resi d ual effects. All a d verse e ve nts m ust be f oll o we d u ntil t heir 
res ol uti o n or sta bilizati o n e ve n be y o n d t he pla n ne d st u d y peri o d. 
All m o derate a n d se vere a d verse e ve nts will be re vie we d b y t he Pri nci pal I n vesti gat or w h o will 
deter mi ne usi n g his/ her best cli nical j u d g me nt w het her t he y warra nt t he s u bject t o be disc o nti n ue d 
fr o m t he st u d y.  T he S p o ns or will be n otifie d i m me diatel y if a s u bject is disc o nti n ue d fr o m t he 
st u d y. F or all a d verse e ve nts t hat re q uire t he s u bject t o be disc o nti n ue d fr o m t he st u d y, rele va nt 
cli nical  assess me nts  a n d  la b orat or y  tests  will  be  re peate d  as  cli nicall y  i n dicate d  u ntil  fi nal 
res ol uti o n or sta bilizati o n of t he e ve nt(s). 
All  s u bjects  will  be  i nstr ucte d  t o  c o ntact  t he  I n vesti gat or,  I n vesti gat or's  assista nts,  or  cli nical 
pers o n nel s h o ul d t he s u bject ha ve a n y seri o us a d verse e x perie nces. 
A n o ver d ose is defi ne d as a n y i nte nti o nal or u ni nte nti o nal c o ns u m pti o n of t he dr u g b y a n y r o ute 
t hat e xcee ds t he hi g hest d ose state d i n t he I n vesti gat or's Br oc h ure or i n a n i n vesti gati o nal pr ot oc ol,  




Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
3 5  
C O N FI D E N TI A L  
 
 
Sec o n dar y Efficac y Para meter:   
Pr o p orti o ns of s u bjects re q uiri n g s yste mic a nti bi otics f or a n 
i nfecti o n sec o n dar y t o E V/ R V, i ncl u di n g p ne u m o nia, otitis 
me dia, br o nc hitis, si n usitis or p har y n gitis 
E x pl orat or y Efficac y Para meters: 
i.  Pr o p orti o n of s u bjects p ositi ve f or E V/ R V b y P C R at 
Da ys 4 a n d 1 0. 
ii. T o  e val uate t he pr o p orti o n of s u bjects re q uiri n g s yste mic 
a nti bi otics f or a n y a n d eac h i nfecti o n sec o n dar y t o 
E V/ R V, i ncl u di n g p ne u m o nia, otitis me dia, br o nc hitis, 
si n usitis or p har y n gitis 
9. 3.  
Res p o nse  Defi niti o ns  
9. 3. 1.  
Res p o nse Defi niti o ns f or t he Pri m ar y Effic ac y A n al ysis  
S ustai ne d Res p o nse: 
A  decrease  i n  t otal  F L U- P R O  sc ore  fr o m  t he 
pre vi o us  diar y  wit h  patie nt  assess me nt  t hat 
s y m pt o ms  are  at  least  “s o me w hat  better  t ha n 
yester da y”,  n o  oral  te m perat ure  ≥1 0 0. 4° F  i n  t he 
pri or 2 4 h o urs, a n d n o f ut ure i ncrease i n a n y of t he 
F L U - P R O  d o mai ns  e xce pt  wit hi n  t he  f oll o wi n g 
le vels: 
 
 
F L U -P R O  D o m ai n * 
B ac k gr o u n d  Le vel  
B o d y/ S yste mic  
0. 5 6  
T hr oat  
0. 6 7  
E yes  
0. 6 7  
Gastr oi ntesti nal  
2. 0 0  
Hea d  
2. 0 0  
N ose  
Sc ore  at ti me of  res p o nse or 
0. 7 5, w hic he ver is greater  
C hest  
Sc ore  at ti me of  res p o nse or 
0. 0 0, w hic he ver is greater  
C o u g h  
Sc ore  at ti me of  res p o nse or 
1. 7 5, w hic he ver is greater  
* A dia gra m of t he F L U- P R O d o mai n/s u b d o mai n 
str uct ure is attac he d as A p pe n di x 5. 
 
Ti me  of S ustai ne d Res p o nse:  
T he ti me of t he first diar y at w hic h all S ustai ne d  
Res p o nse criteria are met.  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
3 6  
C O N FI D E N TI A L  
 
 
Ti me  t o S ustai ne d Res p o nse:  
T he ti me  ( h o urs)  fr o m  t he  first  d ose  of st u d y 
me dicati o n a n d t he Ti me  of S ustai ne d Res p o nse.  
9. 3. 2.  
Defi niti o ns f or C o m plic ati o ns of C ol ds  
C o m plicati o ns of c ol ds are i nfecti o ns sec o n dar y t o c ol ds re q uiri n g s yste mic a nti bi otics, i ncl u di n g 
p ne u m o nia, otitis me dia, br o nc hitis, si n usitis a n d p har y n gitis. Dia g n ostic criteria f or t hese 
i nfecti o ns are as f oll o ws: 
Bacterial P ne u m o nia (criteria fr o m F D A  G ui da nce f or I n d ustr y, C o m m u nity- Ac q uire d B acteri al 
P ne u m o ni a: Devel o pi n g Dr u gs f or Tre at me nt ): 
1.  At  least t w o of t he f oll o wi n g s y m pt o ms: diffic ult y breat hi n g, c o u g h, pr o d ucti o n of 
p ur ule nt s p ut u m, c hest pai n, a n d 
2.  At  least t w o of t he f oll o wi n g vital si g n a b n or malities: fe ver, h y p ote nsi o n, tac h ycar dia, 
tac h y p nea, a n d 
3.  At  least o n of t he f oll o wi n g fi n di n gs: h y p o xe mia, cli nical e vi de nce of p ul m o nar y 
c o ns oli dati o n, ele vate d w hite bl o o d cell c o u nt or le u k o pe nia, a n d 
4.  If perf or me d, c hest ra di o gra p h fi n di n gs of ne w i nfiltrates i n a l o bar or m ultil o bar 
distri b uti o n, a n d 
5.  If perf or me d, micr o bi ol o gic criteria: a p pr o priate s p ut u m s peci me n wit h fe wer t ha n 1 0 
s q ua m o us e pit helial cells a n d m ore t ha n 2 5 p ol y m or p h o n uclear cells per l o w p o wer fiel d. 
 
Ac ute Bacterial Otitis  Me dia (criteria fr o m F D A  G ui da nce f or I n d ustr y, Ac ute B acteri al Otitis  
Me di a: Devel o pi n g Dr u gs f or Tre at me nt ): 
1.  S y m pt o ms of ear pai n or ear ac he, ear f ull ness or decrease d heari n g, a n d 
2.  O ne or m ore of t he f oll o wi n g ot osc o pic fi n di n gs perf or me d b y a cli nicia n e x perie nce d i n 
ot osc o p y:  
a. B ul gi n g or f ull ness of t he t y m pa nic me m bra ne (c o n ve xit y of t he pla ne of t he 
ear dr u m), wit h l oss of a nat o mic la n d mar ks o n vis ualizati o n, 
b.  O pacificati o n of t he t y m pa nic me m bra ne re gar dless of c ol or, 
c. Er yt he ma of t he t y m pa nic me m bra ne, or  
d.  If perf or me d, a b n or mal t y m pa nic me m bra ne m o bilit y o n bi p hasic p ne u matic 
ot osc o p y (a t y m pa nic me m bra ne i n t he ne utral p ositi o n or retracte d is n ot s ufficie nt 
e vi de nce of ac ute bacterial otitis me dia beca use t hese fi n di n gs are n ot s pecific e n o u g h 
t o disti n g uis h t he disease fr o m otitis me dia wit h eff usi o n) 
Ac ute Bacterial Si n usitis (criteria deri ve d fr o m F D A  G ui da nce f or I n d ustr y, Ac ute B acteri al 
Si n usitis: Devel o pi n g Dr u gs f or Tre at me nt ): 
1.  At  least t w o of t he f oll o wi n g s y m pt o ms: 
• Ma xillar y t o ot h pai n ( u nilateral fi n di n gs ca n be m ore s pecific) 
• Facial  pai n ( u nilateral fi n di n gs ca n be m ore s pecific) 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
3 7  
C O N FI D E N TI A L  
 
 
• Fr o ntal hea dac he  
• P ur ule nt nasal disc har ge ( u nilateral fi n di n gs ca n be m ore s pecific) 
• Ne w  o nset fet or oris ( ba d breat h)  
• M or ni n g c o u g h 
• Nasal  o bstr ucti o n  
2.  At  least o ne of t he 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 xa mi nati o n 
• A b n or mal si n us tra nsill u mi nati o n 
• Pai n  o n pal pati o n o ver si n uses 
• Facial  s welli n g 
3.  If perf or me d, ra di o gra p hic fi n di n gs c o nsiste nt wit h  ac ute si n usitis 
Ac ute Stre pt oc occal P har y n gitis (criteria deri ve d fr o m I D S A, Cli nic al Pr actice G ui deli ne f or t he 
Di a g n osis a n d M a n a ge me nt of Gr o u p A Stre pt oc occ al P h ary n gitis ): 
1.  S ore t hr oat c o nsiste nt wit h  ac ute stre pt oc occal p har y n gitis a n d 
2.  T hr oat s wa b sa m ple p ositi ve f or gr o u p A stre pt oc occ us b y ra pi d a nti ge n detecti o n test 
( R A D T) a n d/ or c ult ure. 
Ac ute Bacterial Br o nc hitis (criteria deri ve d fr o m F D A G ui da nce f or I n d ustr y, Ac ute B acteri al 
Ex acer b ati o ns of C hr o nic Br o nc hitis i n P atie nts wit h C hr o nic O bstr uctive P ul m o n ary Dise ase 
a n d K n uts o n a n d Bra u n 2 0 0 2 ): 
1.  Ne w  or i ncrease d c o u g h, d ys p nea or c hest ti g ht ness 
2.  Ne w  or i ncrease d s p ut u m pr o d ucti o n  
3.  Prese nce of tac h y p nea, w heezi n g, r o nc hi, crac kles or pr ol o n ge d e x pirati o n 
4.  Hist or y a n d p h ysical e xa mi nati o n r ules o ut ot her ca uses of c o u g h 
5.  N o  e vi de nce of p ul m o nar y c o ns oli dati o n  
9. 4.  
St atistic al  Met h o d ol o g y  
T he statistical met h o d ol o g y is descri be d briefl y bel o w a n d will  be descri be d i n detail i n t he 
Statistical A nal ysis Pla n. 
9. 4. 1.  
Effic ac y A n al yses  
Efficac y a nal yses will  be base d o n a p o p ulati o n c o nsisti n g of all s u bjects ra n d o mize d w h o recei ve 
at least o ne d ose of st u d y me dicati o n a n d are p ositi ve f or E V/ R V b y P C R at Baseli ne. F or ti me- 
t o-e ve nt  a nal yses,  a  test  of  si g nifica nce  (as  descri be d  i n  t he  f oll o wi n g)  will  be  perf or me d  wit h 
descri pti ve statistics pr o vi de d, i ncl u di n g t he use of Ka pla n- Meier fi g ures. 
T here will  be o ne pri mar y efficac y a nal ysis: 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
3 8  
C O N FI D E N TI A L  
 
 
• 
Ti me t o S ustai ne d Res p o nse f or t he N T Z treat me nt gr o u p will be c o m pare d t o t hat of t he 
place b o  treat me nt  gr o u p  usi n g  a  stratifie d  Ge ha n- Wilc o x o n  test  ( α = 0. 0 5)  w here 
stratificati o n  will  f oll o w  t hat  use d  f or  ra n d o mizati o n.  S u bjects  wit h o ut  a  S ustai ne d 
Res p o nse rec or de d will be treate d as ce ns ore d as of t he last diar y wit h o ut a d oc u me nte d 
S ustai ne d Res p o nse. 
If t he pri mar y a nal ysis is si g nifica nt at t he 0. 0 5 le vel, t he ke y sec o n dar y efficac y a nal ysis will be 
f or mall y e val uate d at t he 0. 0 5 le vel as f oll o ws: 
• 
Pr o p orti o ns of s u bjects re q uiri n g s yste mic a nti bi otics f or a n i nfecti o n sec o n dar y t o E V/ R V, 
i ncl u di n g p ne u m o nia, otitis me dia, br o nc hitis, si n usitis or p har y n gitis, will be c o m pare d 
bet wee n t he treat me nt gr o u ps usi n g a C oc hra n- Ma ntel- Hae nszel ( C M H) test stratifie d b y 
t he  ra n d o mizati o n  strata.  N ote  t hat  t he  st u d y  is  n ot  p o were d  t o  detect  statisticall y 
si g nifica nt differe nces f or t his a nal ysis. 
E x pl orat or y a nal yses will  be perf or me d as f oll o ws: 
• 
Pr o p orti o ns of s u bjects p ositi ve f or E V/ R V b y P C R at st u d y Da y 4 a n d Da y 1 0 will be 
c o m pare d  bet wee n  t he  treat me nt  gr o u ps  usi n g  a  C oc hra n- Ma ntel- Hae nszel  ( C M H)  test 
stratifie d b y t he ra n d o mizati o n strata. 
• 
Pr o p orti o ns of s u bjects re q uiri n g s yste mic a nti bi otics f or eac h of p ne u m o nia, otitis me dia, 
br o nc hitis, si n usitis or p har y n gitis, will  be c o m pare d bet wee n t he treat me nt gr o u ps usi n g a 
C oc hra n- Ma ntel- Hae nszel ( C M H) test stratifie d b y t he ra n d o mizati o n strata. 
T his trial is bei n g c o n d ucte d d uri n g t he C O VI D- 1 9 pa n de mic a n d is li kel y t o e nr oll si g nifica nt 
n u m bers of s u bjects wit h C O VI D- 1 9. Pri or t o data base l oc k a n d u n bli n di n g, a p o ole d a nal ysis of 
t he  bli n de d  s u bject  data  will  be  c o m plete d  t o  c o u nt  t he  n u m ber  of  s u bjects  wit h  la b orat or y- 
c o nfir me d S A R S- C o V- 2 i nfecti o n. 
I n  t he  e ve nt  t hat  ≥3 5 0  s u bjects  wit h  la b orat or y-c o nfir me d  S A R S- C o V- 2  i nfecti o n  ha ve  bee n 
e nr olle d,  it  is  e x pecte d  t hat  t his  will  pr o vi de  ≥9 0 %  p o wer  t o  detect  a  statisticall y  si g nifica nt 
differe nce i n t he Ti me  t o S ustai ne d Res p o nse s ur vi val distri b uti o ns bet wee n t he N T Z  a n d place b o 
treat me nt gr o u ps [t w o-si de d al p ha = 0. 0 5, calc ulati o ns perf or me d f or t he Ge ha 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)  base d  u p o n  data  fr o m  R o mar k  trials  R M 0 8- 3 0 0 4  a n d  R M 0 8- 3 0 0 5 
ass u mi n g e q ual all ocati o n of s u bjects acr oss treat me nt ar ms]. I n t his case, s u bjects wit h  la b orat or y- 
c o nfir me d S A R S- C o V- 2 will be a nal yze d u n der a se parate Statistical A nal ysis Pla n t hat will be 
si g ne d a n d place d o n file pri or t o data base l oc k. T he Statistical  A nal ysis Pla n  will  s pecif y Ti me  t o 
S ustai ne d Res p o nse (as descri be d a b o ve) as t he pri mar y efficac y e n d p oi nt t o be a nal yze d at t he 
0. 0 5 le vel a n d a c o m paris o n of pr o p orti o ns e x perie nci n g pr o gressi o n t o se vere C O VI D- 1 9 ill ness 
( defi ne d  as  s h ort ness  of  breat h  at  rest  a n d  S p O2≤9 3 %  o n  r o o m  air)  usi n g  a  C oc hra n- Mae ntel- 
Hae nszel ( C M H) test stratifie d b y t he ra n d o mizati o n strata as t he ke y sec o n dar y a nal ysis. Da y 4 
a n d  Da y  1 0  nas o p har y n geal  s wa bs  will  be  a nal yze d  f or  t he  prese nce  of  S A R S- C o V- 2  f or  all 
s u bjects p ositi ve f or S A R S- C o V- 2 at Baseli ne a n d Da y  2 2 nas o p har y n geal s wa bs will  be a nal yze d 
if t he Da y 1 0 sa m ple is p ositi ve f or S A R S- C o V- 2 [a nal ysis usi n g A pti ma®  S A R S- C o V- 2 Assa y 
( H ol o gic, I nc, Sa n Die g o, C A) as descri be d i n Secti o n 8. 2. 2. 2 ]. Pr o p orti o ns of s u bjects p ositi ve 
f or S A R S- C o V- 2 at Da y 4 a n d Da y 1 0 will be c o m pare d acr oss treat me nt gr o u ps usi n g a C M H 
test  stratifie d b y  t he  ra n d o mizati o n  strata  as  a n  e x pl orat or y  a nal ysis.  Ser ol o g y  sa m ples  will  be 
a nal yze d f or q ua ntitati ve I g G a n d I g M a nti b o dies a n d descri pti ve statistics of t he res ults will  be  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
3 9  
C O N FI D E N TI A L  
 
 
prese nte d  b y  treat me nt  gr o u p.  Safet y  a n d  p har mac o ki netics  will  be  a nal yze d  as  descri be d  i n 
secti o ns 9. 4. 2 a n d 9. 4. 3 bel o w. 
9. 4. 2.  
P o p ul ati o n P h ar m ac o ki netics A n al ysis  
O n  Da y  4,  plas ma  sa m ples  will  be  c ollecte d  bef ore  t he  m or ni n g  d ose  (at  t he  tr o u g h)  f or 
deter mi nati o n of dr u g c o nce ntrati o n.  T hese data will all o w f or a nal ysis of relati o ns hi ps bet wee n 
tr o u g h plas ma c o nce ntrati o ns a n d cli nical a n d vir ol o gic res p o nse. 
Tr o u g h  plas ma  c o nce ntrati o ns  of  tiz o xa ni de  a n d  tiz o xa ni de  gl uc ur o ni de  will  be  s u m marize d 
descri pti vel y  f or  N T Z-treate d  s u bjects.  E x pl orat or y  a nal yses  will  be  c o n d ucte d  t o  e val uate  t he 
relati o ns hi ps bet wee n plas ma c o nce ntrati o ns a n d a ge, race, ge n der, b o d y wei g ht, b o d y mass  i n de x, 
V RI a n d a d verse e ve nts. 
9. 4. 3.  
S afet y A n al yses  
All ra n d o mize d s u bjects w h o recei ve at least o ne d ose of st u d y me dicati o n will be e val uate d f or 
dr u g safet y. Safet y a nal yses will be d o ne descri pti vel y. 
 
1 0.  
O P E R A TI O N A L  C O N SI D E R A TI O N S  
1 0. 1.  
Re g ul at or y,  Et hic al  a n d  St u d y  O versi g ht  C o nsi der ati o ns  
1 0. 1. 1.  
Et hics  
T he cli nical trial will be perf or me d i n acc or da nce wit h t he g ui deli nes set b y t he W orl d Me dical 
Asse m bl y ( Declarati o n of Helsi n ki, last a me n d me nt i n F ortaleza, Brazil, Oct o ber 2 0 1 3). 
I nf or me d c o nse nt will  be o btai ne d fr o m eac h s u bject as descri be d i n Secti o n 8. 1. 1 . 
Pri or writte n a p pr o val of t he st u d y pr ot oc ol a n d of t he i nf or me d c o nse nt f or m will  be o btai ne d b y 
t he S p o ns or fr o m t he a p pr o priate ce ntral or l ocal I R B. 
Pri or t o st u d y i nitiati o n, t he I n vesti gat or will  pr o vi de t he I R B wit h  re q uire d d oc u me nts f or re vie w 
a n d a p pr o val. See  A p pe n di x 3 : List  of Esse ntial D oc u me nts f or desi g nati o n of d oc u me nts t hat ma y 
be re q uire d b y t he I R B pri or t o st u d y i nitiati o n or d uri n g t he c o urse of st u d y c o n d uct. N o  site will 
scree n s u bjects u ntil t he I R B has gi ve n f ull a p pr o val of re q uire d d oc u me nts a n d t he data a p pr o val 
letter i de ntif yi n g t he I R B a n d t he d oc u me nts a p pr o ve d is deli vere d t o t he st u d y S p o ns or. 
F or  all  pr ot oc ol  a me n d me nts  (e xcl u di n g  t he  o nes  t hat  are  p urel y  a d mi nistrati ve,  wit h  n o 
c o nse q ue nces f or s u bjects, data or st u d y c o n d uct), t he a me n d me nt a n d a p plica ble i nf or me d c o nse nt 
f or m a n d asse nt f or m re visi o ns m ust be s u b mitte d pr o m ptl y t o t he I R B f or re vie w a n d a p pr o val 
bef ore i m ple me ntati o n of t he c ha n ge(s), e xce pt w he n necessar y t o eli mi nate i m me diate hazar d t o 
t he st u d y s u bjects. If a de viati o n  fr o m, or  a c ha n ge t o t he pr ot oc ol  was  i m ple me nte d t o eli mi nate 
a n i m me diate hazar d t o st u d y s u bjects, t he n t he i m ple me nte d de viati o n or c ha n ge, t he reas o ns f or 
it, a n d, if a p pr o priate, t he pr ot oc ol a me n d me nt s h o ul d be s u b mitte d t o t he I R B as s o o n as p ossi ble.  
T he re-a p pr o val of t he cli nical st u d y b y t he I R B s h o ul d be d oc u me nte d i n writi n g.  
At  t he e n d of t he st u d y, t he I n vesti gat or ( or S p o ns or w here re q uire d) will  n otif y t he I R B a b o ut t he 
st u d y c o m pleti o n. 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
4 0  
C O N FI D E N TI A L  
 
 
1 0. 1. 2.  
I n vesti g at or Res p o nsi bilities  
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat t he cli nical st u d y is perf or me d i n acc or da nce wit h 
t he  pr ot oc ol,  c urre nt  I nter nati o nal  C o nfere nce  o n  Har m o nizati o n  (I C H)  g ui deli nes  o n  G o o d 
Cli nical Practice ( G C P), a n d a p plica ble re g ulat or y a n d c o u ntr y s pecific re q uire me nts. 
G o o d  Cli nical  Practice  is  a n  i nter nati o nal  et hical  a n d  scie ntific  q ualit y  sta n dar d  f or  desi g ni n g, 
c o n d ucti n g,  rec or di n g,  a n d  re p orti n g  st u dies  t hat  i n v ol ve  t he  partici pati o n  of  h u ma n  s u bjects. 
C o m plia nce wit h t his sta n dar d pr o vi des p u blic ass ura nce t hat t he ri g hts, safet y, a n d well bei n g of 
st u d y s u bjects are pr otecte d, c o nsiste nt wit h t he pri nci ples t hat ori gi nate d i n t he Declarati o n of 
Helsi n ki, a n d t hat t he cli nical st u d y data are cre di ble. 
1 0. 1. 3.  
Q u alit y Ass ur a nce a n d Q u alit y C o ntr ol  
T he  acc urac y  a n d  relia bilit y  of  t he  st u d y  data  will  be  ass ure d  b y  t he  selecti o n  of  q ualifie d 
I n vesti gat ors a n d a p pr o priate st u d y ce nters, re vie w of pr ot oc ol pr oce d ures wit h t he I n vesti gat or 
a n d ass ociate d pers o n nel pri or t o t he st u d y, a n d b y peri o dic m o nit ori n g visits b y t he S p o ns or or 
S p o ns or’s re prese ntati ves (see Secti o n 1 0. 1. 6 ). Writte n i nstr ucti o ns will  be pr o vi de d f or c ollecti o n, 
pre parati o n a n d s hi p me nt of bi ol o gical sa m ples. 
T he S p o ns or will be e ntitle d t o i ns pect a n d a u dit t he facilities use d i n t he cli nical a n d la b orat or y 
parts of t he st u d y, as well  as t o ma ke a n o n y mize d c o pies of all t he data files pertai ni n g t o t he st u d y. 
Si milar pr oce d ures ma y als o be c o n d ucte d b y a ge nts of a n y re g ulat or y b o d y, eit her as part of a 
nati o nal G C P c o m plia nce pr o gra m or t o re vie w t he 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 he I n vesti gat or s h o ul d i m me diatel y n otif y t he S p o ns or if t he y ha ve bee n c o ntacte d 
b y a re g ulat or y a ge nc y c o ncer ni n g a n u pc o mi n g i ns pecti o n. 
Q ualit y  o versi g ht  of  st u d y  ma na ge me nt  will  be  acc o m plis he d  acc or di n g  t o  t he  st u d y-s pecific 
I nte grate d Q ualit y a n d Ris k Ma na ge me nt Pla n. 
1 0. 1. 4.  
S afet y O versi g ht  
T he S p o ns or a n d Me dical M o nit or will  be res p o nsi ble f or safet y o versi g ht of t he st u d y. Pr oce d ures 
f or safet y o versi g ht are descri be d i n t he st u d y-s pecific Me dical M o nit ori n g Pla n. 
1 0. 1. 5.  
D at a H a n dli n g a n d Rec or d Kee pi n g  
1 0. 1. 5. 1.  D at a C ollecti o n a n d M a n a ge me nt Res p o nsi bilities  
S p o ns or  Data  ma na ge me nt  will  be  res p o nsi ble  f or  o versi g ht  of  data  c ollecti o n,  clea ni n g  a n d 
l oc ki n g acc or di n g t o t he st u d y-s pecific Data Ma na ge me nt Pla n. 
Data will be c ollecte d o n site-s pecific s o urce data f or ms a n d tra nscri be d i nt o a n electr o nic data 
ca pt ure ( E D C) s yste m b y site staff. T he res p o nsi ble st u d y m o nit or(s) will  verif y data acc or di n g t o 
t he Cli nical M o nit ori n g Pla n, eit her re m otel y or at t he cli nical st u d y site. T he I n vesti gat or will 
e ns ure t hat t he data rec or de d are acc urate a n d c o m plete. 
Q ueries e mer gi n g d uri n g data clea ni n g will be ge nerate d wit hi n t he E D C s yste m b y m o nit ors or 
data ma na ge me nt pers o n nel. T he I n vesti gat or a n d/ or desi g nee will  a ns wer t he q ueries a n d u p date 
t he s o urce data, as nee de d. 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
4 1  
C O N FI D E N TI A L  
 
 
1 0. 1. 5. 2.  St u d y Rec or ds Rete nti o n  
T he I n vesti gat or/i nstit uti o n will  mai ntai n all C R Fs, E D C  s o urce f or ms, a n d s o urce d oc u me nts t hat 
s u p p ort  t he  data  c ollecte d  fr o m  eac h  s u bject,  as  well  as  all  st u d y  d oc u me nts  as  s pecifie d  i n 
I C H/ G C P  Secti o n  8,  a n d  all  st u d y  d oc u me nts  as  s pecifie d  b y  t he  a p plica ble  re g ulat or y 
re q uire me nts f or t he d urati o n re q uire d b y a p plica ble re g ulat or y a ut h orities or u ntil t he S p o ns or 
i nf or ms t he I n vesti gat or/i nstit uti o n t hat t hese d oc u me nts are n o l o n ger nee de d. 
If  it  bec o mes  necessar y  f or  t he  S p o ns or  or  t he  a p pr o priate  re g ulat or y  a ut h orit y  t o  re vie w  a n y 
d oc u me ntati o n relati n g t o t his st u d y, t he I n vesti gat or m ust per mit access t o s uc h re p orts. 
T he  S p o ns or  will  be  res p o nsi ble  f or  mai ntai ni n g  t he  Trial  Master  File  w hic h  is  a  clear 
d oc u me ntati o n of t he c o urse of t he st u d y. 
1 0. 1. 6.  
Cli nic al M o nit ori n g  
Cli nical  m o nit ori n g  will  be  c o n d ucte d  b y  t he  S p o ns or  a n d/ or  a  c o ntract  researc h  or ga nizati o n 
( C R O) acc or di n g t o t he st u d y-s pecific Cli nical M o nit ori n g Pla n. 
T he I n vesti gat or will gra nt re prese ntati ves of t he S p o ns or's cli nical o perati o ns tea m a n d q ualit y 
tea m, as well  as re g ulat or y a ge ncies a n d et hical c o m mittees access t o i ns pect facilities a n d rec or ds 
(i ncl u di n g s u bject c harts) rele va nt t o t his st u d y a n d a grees t o assist t he m o nit ors i n t heir acti vities, 
if re q ueste d. 
1 0. 1. 7.  
Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns will be d oc u me nte d b y t he I n vesti gat or, re p orte d t o t he i nstit uti o nal re vie w 
b oar d  (I R B)  as  a p pr o priate,  a n d  als o  re vie we d  b y  t he  assi g ne d  cli nical  researc h  ass ociate. 
De viati o ns  will  be  re p orte d  i n  t he  cli nical  trial  ma na ge me nt  s yste m  or  a p plica ble  E D C.  Eac h 
de viati o n will be classifie d as maj or or mi n or acc or di n g t o t he f oll o wi n g defi niti o ns: 
Maj or pr ot oc ol de viati o n:    A de viati o n t hat has a n i m pact o n s u bject safet y, ma y  s u bsta ntiall y 
alter  ris ks  t o  s u bjects,  ma y  ha ve  a n  effect  o n  t he  i nte grit y  of  t he 
st u d y data, or ma y affect t he s u bject’s willi n g ness t o partici pate i n 
t he st u d y 
Mi n or pr ot oc ol de viati o n:    All ot her pr ot oc ol de viati o ns.  
1 0. 1. 8.  
St u d y Disc o nti n u ati o n a n d Cl os ure  
T he st u d y ma y be disc o nti n ue d u n der t he f oll o wi n g circ u msta nces:  
1.  T he S p o ns or reser ves t he ri g ht t o disc o nti n ue t he st u d y at a n y ti me. 
2.  A d verse e ve nt listi n gs will  be pr o d uce d f or safet y m o nit ori n g at least o nce e ver y t w o wee ks 
d uri n g recr uit me nt.  T he data will be teste d t o deter mi ne if t here are greater t ha n 2 0 % of 
t he s u bjects w h o ha ve ha d ≥ Gra de 3 a d verse e ve nts c o nsi dere d b y t he I n vesti gat or t o be 
p ossi bl y, pr o ba bl y or defi nitel y relate d t o t he st u d y dr u g ( defi ne d b y t he T o xicit y Gra di n g 
Scale Ta bles pr o vi de d i n A p pe n di x 4 ). 
If greater t ha n 2 0 % of t he s u bjects ha ve at least o ne Gra de 3 or Gra de 4 a d verse e ve nt 
c o nsi dere d  t o  be  p ossi bl y,  pr o ba bl y  or  defi nitel y  relate d  t o  t he  st u d y  dr u g  b y  t he  st u d y 
Me dical M o nit or, t he n t he st u d y m ust be st o p pe d a n d t he I nstit uti o nal Re vie w B oar ds, a n d 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
4 2  
C O N FI D E N TI A L  
 
 
F D A’s Di visi o n of A nti viral Dr u g Pr o d ucts will be n otifie d.  All safet y a n d efficac y data 
will be s u b mitte d t o t he F D A i n a ti mel y ma n ner. 
1 0. 1. 9.  
D at a a n d Re p ort Re q uire me nts  
See A p pe n di x  3 :  List  of  Esse ntial  D oc u me nts  f or  desi g nati o n  of  d oc u me nts  re q uire d  fr o m  t he 
I n vesti gat or b y t he S p o ns or pri or t o a p pr o val a n d i nitiati o n of t he st u d y a n d bef ore t he st u d y ca n 
be c o nsi dere d c o m plete a n d ter mi nate d. 
1 0. 1. 1 0.  
C o nfi de nti alit y a n d Pri v ac y  
T he c ollecti o n a n d pr ocessi n g of pers o nal data fr o m s u bjects e nr olle d i n t his st u d y will  be li mite d 
t o t h ose data t hat are necessar y t o i n vesti gate t he safet y, q ualit y, a n d utilit y of t he i n vesti gati o nal 
st u d y dr u g(s) use d i n t his st u d y. 
T hese data will  be c ollecte d a n d pr ocesse d wit h  a de q uate preca uti o ns t o e ns ure c o nfi de ntialit y a n d 
c o m plia nce wit h a p plica ble data pri vac y pr otecti o n la ws a n d re g ulati o ns. A p pr o priate tec h nical 
a n d  or ga nizati o nal  meas ures  t o  pr otect  t he  pers o nal  data  a gai nst  u na ut h orize d  discl os ures  or 
access,  acci de ntal  or  u nla wf ul  destr ucti o n,  or  acci de ntal  l oss  or  alterati o n  will  be  p ut  i n  place. 
S p o ns or pers o n nel w h ose res p o nsi bilities re q uire access t o pers o nal data a gree t o kee p t he i de ntit y 
of st u d y s u bjects c o nfi de ntial. 
T he i nf or me d c o nse nt o btai ne d fr o m t he s u bject i ncl u des e x plicit c o nse nt f or t he pr ocessi n g of 
pers o nal data a n d f or t he I n vesti gat or t o all o w direct access t o his or her ori gi nal me dical rec or ds 
f or  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 pecti o n.  T his  c o nse nt  als o 
a d dresses  t he  tra nsfer  of  t he  data  t o  ot her  e ntities  a n d  t o  ot her  c o u ntries.  All  re p orts  a n d 
c o m m u nicati o ns relati n g t o t he st u d y s u bjects will i de ntif y s u bjects o nl y b y i nitials a n d s u bject 
i de ntificati o n n u m ber. 
Data ge nerate d f or t he st u d y will be st ore d b y t he I n vesti gat or i n a li mite d-access file area a n d be 
accessi ble o nl y t o re prese ntati ves of t he st u d y site, R o mar k, t he I R B, a n d F D A/rele va nt re g ulat or y 
a ge ncies.  Me dical  i nf or mati o n res ulti n g fr o m a s u bject’s partici pati o n  i n t his st u d y ma y  be  gi ve n 
t o  t he  s u bject’s  pers o nal  p h ysicia n  or  t o  t he  a p pr o priate  me dical  pers o n nel  res p o nsi ble  f or  t he 
s u bject’s welfare. 
1 0. 1. 1 1.  
P u blic ati o n a n d D at a S h ari n g  
Prese ntati o n a n d/ or p u blicati o n of t he res ults of t he st u d y is e nc o ura ge d pr o vi de d t hat T he R o mar k 
I nstit ute  f or  Me dical  Researc h  is  n otifie d  i n  a d va nce  of  t he  a ut h or's  i nte nt  a n d  is  gi ve n  t he 
o p p ort u nit y t o re vie w t he ma n uscri pt or a bstract 4 5 da ys pri or t o its s u b missi o n f or prese ntati o n at 
a scie ntific meeti n g  or  f or p u blicati o n  i n a scie ntific j o ur nal. T he  I n vesti gat ors will  ha ve  c o m plete 
a ut o n o m y  re gar di n g  t he  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 blicati o ns arisi n g fr o m t his st u d y, i ncl u di n g t he decisi o n of w het her or n ot t o p u blis h. 
1 0. 1. 1 2.  
Ke y  R oles a n d St u d y G o ver n a nce  
See  A p pe n di x 2 f or a list of ke y pers o n nel a n d c o ntact i nf or mati o n. 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
4 3  
C O N FI D E N TI A L  
 
 
1 1.  
R E F E R E N C E S  
A LI NI A ( nitaz o xa ni de) prescri bi n g i nf or mati o n. R o mar k, L. C., Ta m pa, F L,  J u ne 2 0 1 9.  
Alla n  G M,  Arr oll B. Pre ve nti o n a n d treat me nt of t he c o m m o n c ol d: ma ki n g se nse of t he 
e vi de nce. C M AJ 2 0 1 4 Fe b 1 8; 1 8 6( 3): 1 9 0- 1 9 9. 
A n ders o n V R, C urra n M P.  N T Z:  A re vie w of its use i n t he treat me nt of gastr oi ntesti nal 
i nfecti o ns. Dr u gs 2 0 0 7; 6 7: 1 9 4 7- 6 7. 
Arr u da E,  Pit kara nta A,  Wite k  TJ,  D o yle C, Ha y de n F G.  Fre q ue nc y a n d Nat ural Hist or y of 
R hi n o vir us I nfecti o ns i n A d ults d uri n g A ut u m n. J Cli n Micr o bi o N o v 1 9 9 7; 2 8 6 4- 2 8 6 8. 
As ht o n L V, Calla n R L, Ra o S, La n d olt G A. I n vitr o s usce pti bilit y of ca ni ne i nfl ue nza A ( H 3 N 8) 
vir us t o nitaz o xa ni de a n d tiz o xa ni de. Vet Me d I nt 2 0 1 0; 2 0 1 0: 8 9 1 0 1 0. 
Bac k ma n J T, Fil p p ula A M,  Nie mi  M,  Ne u v o ne n PJ.  R ole of c yt oc hr o me P 4 5 0 2 C 8 i n dr u g 
meta b olis m a n d i nteracti o ns. P h ar m ac ol Rev 2 0 1 6; 6 8: 1 6 8- 2 4 1. 
At ki ns o n S K,  Sa d ofs k y L R, M orice A H.  H o w d oes r hi n o vir us ca use t he c o m m o n c ol d c o u g h? 
B MJ O pe n Res pir at ory Rese arc h 2 0 1 6; 3:e 0 0 0 1 1 8.  
Braa k ma n I, Hele ni us J, Hele ni us A.  R ole of A T P  a n d dis ul p hi de b o n ds d uri n g pr otei n f ol di n g 
i n t he e n d o plas mic retic ul u m. N at ure 1 9 9 2; 3 5 6: 2 6 0- 6 2. 
Braa k ma n I, H o o ver- Litt y  H,  Wa g ner K R, Hele ni us A.  F ol di n g of i nfl ue nza he ma g gl uti ni n i n 
t he e n d o plas mic retic ul u m. J Cell Bi ol 1 9 9 1; 1 1 4: 4 0 1- 1 1. 
Ca o J, F orrest J C, Z ha n g X.  A scree n of t he NI H c ollecti o n s mall m olec ule li brar y i de ntifies 
p ote ntial c or o na vir us. A ntivir al Res 2 0 1 5; 1 1 4: 1- 1 0. 
C ha n g C W, Li  H C, Hs u  C F, C ha n g C Y, L o  S Y.  I ncrease d A T P  ge nerati o n i n t he h ost cell is 
re q uire d f or efficie nt vacci nia vir us pr o d ucti o n. J Bi o me d Sci 2 0 0 9; 1 6: 8 0. 
D o ms R W, Keller  D S,  Hele ni us A,  Balc h W E.  R ole of a de n osi ne tri p h os p hate i n re g ulati n g t he 
asse m bl y a n d tra ns p ort of vesic ular st o matitis vir us G pr otei n tri mers. J Cell Bi ol 1 9 8 7; 
1 0 5: 1 9 5 7 -6 9.  
Fe n dric k A M, M o nt o A S, Ni g hte n gale B, Sa mes M. T he ec o n o mic b ur de n of n o n-i nfl ue nza- 
relate d viral res pirat or y i nfecti o n i n t he U nite d States.  Arc h  I nter n Me d 2 0 0 3; 1 6 3( 4): 4 8 7- 9 4.  
Ha da d G M, A b del Sala m R A, E mara S. Vali date d a n d o pti mize d hi g h- perf or ma nce li q ui d 
c hr o mat o gra p hic deter mi nati o n of tiz o xa ni de, t he mai n  acti ve meta b olite of nitaz o xa ni de i n 
h u ma n uri ne, plas ma a n d breast mil k. J C hr o m at o gr Sci . 2 0 1 2; 5 0: 5 0 9- 1 5. 
H o n g S K, Ki m HJ, S o n g C S, C h oi I S, Lee J B, Par k S Y. Nitaz o xa ni de s u p presses I L- 6 
pr o d ucti o n i n L P S -sti m ulate d m o use macr o p ha ges a n d T G -i njecte d mice.  I nt I m m u n o p h ar m ac ol 
2 0 1 2; 1 3: 2 3- 2 7. 
Jac o bs S E,  La ms o n D M,  St.  Ge or ge K,  Wals h  TJ.  H u ma n R hi n o vir uses. Cli n Micr o b Rev  2 0 1 3; 
2 6( 1): 1 3 5 -1 5 2.  


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
4 4  
C O N FI D E N TI A L  
 
 
Kir k patric k G L.  T he C o m m o n C ol d. Pri m ary C are: Cli nics i n Office  Pr actice 1 9 9 6; 2 3( 4): 6 5 7- 
6 7 5.  
Lee  J H, Z ha n g Y,  Z ha o Z,  Ye  X,  Z ha n g X,  Wa n g H,  Ye  J. I ntracellel ular A T P  i n bala nce of pr o- 
i nfla m mat or y a n d a nti-i nfla m mat or y c yt o ki nes i n a di p ose tiss ue wit h a n d wit h o ut tiss ue 
e x pa nsi o n. I nt J O bes 2 0 1 7; 4 1: 6 4 5- 5 1. 
Mirazi mi A,  S ve nss o n L.  A T P  is re q uire d f or c orrect f ol di n g a n d dis ulfi de b o n d f or mati o n 
r ota vir us V P 7. J Vir ol 2 0 0 0; 7 4: 8 0 4 8- 5 2. 
Piace nti ni S, La Frazia S, Ricci o A, Pe derse n J Z, T o pai A, et al. Nitaz o xa ni de i n hi bits 
para m y x o vir us re plicati o n b y tar geti n g t he F usi o n pr otei n f ol di n g: r ole of gl yc o pr otei n-s pecific 
t hi ol o xi d ore d uctase E R p 5 7. Sci Re p 2 0 1 8; 8: 1 0 4 2 5. 
Pil or ge L,  C hartier M,  Meritet J-F,  et al. R hi n o vir uses as a n U n prece de nte d Ca use of I nfl ue nza- 
Li ke Ill ness i n Pre g na nc y D uri n g t he 2 0 0 9- 2 0 1 0 I nfl ue nza Pa n de mic. J Me d Vir ol 2 0 1 3; 
8 5( 8): 1 4 7 3 -7.  
P o wers J H, Bacci E D, Lei d y N K, P o o n J L, Stri n ger S, et al. Perf or ma nce of t he i n F L Ue nza 
patie nt-re p orte d o utc o me ( F L U- P R O) diar y i n patie nts wit h  i nfl ue nza-li ke ill ness (I LI). P L o S 
O N E 2 0 1 8 1 3( 3): d 0 1 9 4 1 8 0. 
R ossi g n ol J F, La  Frazia S,  C hia p pa L,  Ci ucci A,  Sa nt or o M G.  T hiaz oli des, a ne w class of a nti- 
i nfl ue nza m olec ules tar geti n g viral he ma g gl uti ni n at t he p ost-tra nslati o nal le vel. J Bi ol C he m 
2 0 0 9; 2 8 4: 2 9 7 9 8- 8 0 8. 
R ossi g n ol J F, va n Baale n C. Br oa d-s pectr u m a nti viral nitaz o xa ni de i n hi bits A T P- de pe n de nt 
re plicati o n of res pirat or y vir uses a n d pr oi nfla m mat or y c yt o ki nes [ A bstract]. Prese nte d at t he 2 n d 
I nter nati o nal Meeti n g o n Res pirat or y Pat h o ge ns. Si n ga p ore, Marc h 7- 9, 2 0 1 8. 
R ossi g n ol J F. Nitaz o xa ni de, a ne w dr u g ca n di date f or t he treat me nt of Mi d dle East  res pirat or y 
s y n dr o me c or o na vir us. J I nfect P u blic He alt h 2 0 1 6; 9: 2 2 7- 3 0. 
R ossi g n ol J F. Nitaz o xa ni de: A first-i n-class br oa d-s pectr u m a nti viral a ge nt. A ntivir al Res  2 0 1 4; 
1 1 0: 9 4 -1 0 3.  
Sa g  D,  Carli n g D,  St o ut R D, S uttles J. A M P -acti vate d pr otei n ki nase pr o m otes macr o p ha ge 
p olarizati o n t o a n a nti-i nfla m mat or y f u ncti o nal p he n ot y pe. J I m m u n ol 2 0 0 8; 1 8 1: 8 6 3 3- 4 1. 
Slee ma n K, Mis hi n V P, G u o Z, Garte n RJ, Balis h A, et al. A nti viral s usce pti bilit y of varia nt 
i nfl ue nza A( H 3 N 2) v vir uses is olate d i n t he U nite d States  fr o m 2 0 1 1 t o 2 0 1 3. A nti micr o b A ge nts 
C he m ot her 2 0 1 4; 5 8: 2 0 4 5- 5 1. 
St.  J u de C hil dre n’s Researc h H os pital. I nfecti o ns i n I m m u n oc o m pr o mise d Patie nts.  Accesse d 
2 2 J u n 2 0 2 0.  A vaila ble at: htt ps:// w w w.stj u de. or g/treat me nt/ patie nt-res o urces/care gi ver- 
res o urces/i nfecti o n-ti ps/i nfecti o ns-i m m u n oc o m pr o mise d-patie nts. ht ml  
T he Pir bri g ht I nstit ute, U K.  ( 2 0 1 8). E nter o vir us. Retrie ve d fr o m: 
htt p:// w w w. pic or na viri dae.c o m/e nter o vir us/ e nter o vir us. ht m 


Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
4 5  
C O N FI D E N TI A L  
 
 
Til ma nis D, va n Baale n C, O h D Y, R ossi g n ol J- F, H urt A C. T he s usce pti bilit y of circ ulati n g 
h u ma n i nfl ue nza vir uses t o tiz o xa ni de, t he acti ve meta b olite of nitaz o xa ni de. A ntivir Res  2 0 1 7; 
1 4 7: 1 4 2 -4 8.  
T ur ner R B. E pi de mi ol o g y, Pat h o ge nesis, a n d Treat me nt of t he C o m m o n C ol d. A n n als of 
Aller gy, Ast h m a & I m m u n ol o gy 1 9 9 7; 7 8( 6): 5 3 1- 5 4 0. 
U nite d States  De part me nt of La b or – B urea u of La b or Statistics.  C PI I nflati o n Calc ulat or.  
A vaila ble at: htt ps:// w w w. bls. g o v/ data/i nflati o n _calc ulat or. ht m  
va n der Vries E,  Stittelaar  KJ,  va n A mer o n ge n G,  et al. Pr ol o n ge d i nfl ue nza vir us s he d di n g a n d 
e mer ge nce of a nti viral resista nce i n i m m u n oc o m pr o mise d patie nts a n d ferrets. P L o S P at h o g . 
2 0 1 3; 9( 5):e 1 0 0 3 3 4 3.  
Wa n g M,  Ca o R, Z ha n g L,  Ya n g X,  Li u  J, et al. Re m desi vir a n d c hl or o q ui ne effecti vel y i n hi bit 
t he rece ntl y e mer ge d n o vel c or o na vir us ( 2 0 1 9- n C o V) i n vitr o. Cell Res 2 0 2 0; 3 0: 2 6 9- 7 1. 
Wa n g W,  Ya n g X,  de Sila nes I L, Carli n g D,  G or os pe M.  I ncrease d A M P: A T P  Rati o a n d A M P - 
acti vate d pr otei n ki nase acti vit y d uri n g cell ular se nesce nce li n ke d t o re d uce d H u R f u ncti o n. J 
Bi ol C he m 2 0 0 3; 2 7 8: 2 7 0 1 6- 2 3. 
W orrall G.  C o m m o n c ol d. C a n F a m P hysici a n 2 0 1 1; 5 7( 1 1): 1 2 8 9- 1 2 9 0.  
Y u  J, P o wers J H, Vall o  D,  Fall o o n J. E val uati o n of efficac y e n d p oi nts f or a p hase II b st u d y of a 
res pirat or y s y nc ytial vir us vacci ne i n ol der a d ults usi n g patie nt-re p orte d o utc o mes wit h 
la b orat or y c o nfir mati o n. V al ue He alt h 2 0 2 0; 2 3: 2 2 7- 3 5. 




Pr ot oc ol R M 0 8- 3 0 0 9  FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
4 7  
C O N FI D E N TI A L  
 
 
S u m m ar y  of  C h a n ges  
 
• 
A d de d  e xcl usi o n criteria 1 6,  “S u bjects  k n o w n t o h ave  a di a g n ostic  test p ositive  f or S A R S -C o V - 2 or  i nfl ue nz a 
i nfecti o n wit hi n t he prece di n g t hree weeks.” 
C ha n ge  3:  
Secti o n  1. 1  Sy n o psis , Secti o n  1. 2  Sc he d ule  of  Assess me nts , Secti o n  8 St u dy  Pr oce d ures , A p pe n di x  5 F L U -P R O  
D o m ai n/ S u b -d o m ai n Str uct ure  
U p date d  st u d y pr oce d ures  t o i ncl u de: 
• 
Da y  6 a n d 7 tele p h o ne calls f or s u bject m o nit ori n g  
• 
Da y  2 8  ( ± 3 da ys)  tele p h o ne c o ntact f or e n d-of -st u d y safet y f oll o w-u p  
• 
Baseli ne  a n d Da y  2 2  c ollecti o n of  bl o o d  sa m ples f or ser ol o g y testi n g 
• 
S u bjects  will  c o m plete practice  diar y  i n t he cli nic at t he Baseli ne  visit  
• 
S u bjects  will  rec or d oral  te m perat ure t wice dail y  i n t he s u bject diar y  
• 
S u bject  diar y  will  i ncl u de assess me nt  of  l oss of  taste a n d l oss of  s mell 
C ha n ge  4:  
Secti o n  1. 1  Sy n o psis , Secti o n  4. 1  St u dy  Desi g n  Overvie w  
S pecifie d  t hat data  f or s u bjects e nr olle d i n c o nc urre nt  st u d y R M 0 8 -3 0 0 8  ( C O VI D-1 9  treat me nt st u d y wit h  t he sa me 
selecti o n criteria a n d pr oce d ures) wit h la b orat or y c o nfir me d E V/ R V i nfecti o n at baseli ne will be all ocate d t o t his 
st u d y f or a nal ysis a n d will c o u nt t o war d t he 3 5 0 t o 4 0 0 re q uire d s u bjects. 
C ha n ge  5:  
Secti o n  4. 1  St u dy  Desi g n  Overvie w  
U p date d  t he ra n d o mizati o n stratificati o n fr o m: 
Severity  of  Ill ness: 
• 
≤1  res pir at ory d o m ai n *  wit h  sc ore ≥2  at  b aseli ne  
• 
2 res pir at ory d o m ai n *  wit h  sc ores ≥2  at  b aseli ne  
• 
≥3  res pir at ory d o m ai ns *  wit h  sc ores ≥2  at  b aseli ne  
* F or  t his p ur p ose,  res pir at ory d o m ai ns  s h all i ncl u de t he f oll o wi n g 5 F L U -P R O 
d o m ai ns/s u b d o m ai ns: c hest, c o u g h, n ose, t hr o at a n d he a d.  
U n derlyi n g  Ast h m a,  C O P D  or  
Di a betes:  
S u bjects  wit h  or  wit h o ut  active  ast h m a,  C O P D  or  di a betes  
S m oki n g  Hist ory:  
P ast  s m oker, c urre nt s m oker, or  never  s m oke d 
 
T o:  


Pr ot oc ol R M 0 8- 3 0 0 9  FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
4 8  
C O N FI D E N TI A L  
 
 
S u m m ar y  of  C h a n ges  
 
Severity  of  Ill ness: 
• 
Mil d  ill ness defi ne d  as  b aseli ne  assess me nts  of  ( 1) at  le ast o ne  res pir at ory 
d o m ai n *  wit h  a b aseli ne  sc ore ≥2  a n d  ( 2) resti n g p ulse  < 9 0  be ats  per  mi n ute 
a n d ( 3) resti n g res pir at ory r ate < 2 0 bre at hs per mi n ute.  
• 
M o der ate ill ness defi ne d as b aseli ne assess me nts of ( 1) at le ast o ne 
res pir at ory d o m ai n *  wit h  a b aseli ne  sc ore ≥2  a n d  eit her ( 2) resti n g p ulse  
≥9 0  be ats  per  mi n ute  or  ( 3) resti n g res pir at ory r ate ≥2 0  bre at hs  per  mi n ute.  
* F or  t his p ur p ose,  res pir at ory d o m ai ns  s h all i ncl u de t he f oll o wi n g 5 F L U -P R O 
d o m ai ns/s u b d o m ai ns: c hest, c o u g h, n ose, t hr o at a n d he a d.  
Ti me  fr o m o nset  of  sy m pt o ms t o 
r a n d o miz ati o n: 
< 3 6  h o urs/ ≥3 6 h o urs  
Risk  of  severe ill ness ( per C D C):   
• 
At  I ncre ase d Risk:  S u bjects  wit h  C O P D,  Ty pe  2 di a betes  mellit us,  o besity  
( B MI ≥3 0), c hr o nic ki d ney dise ase, sickle cell dise ase, seri o us he art 
c o n diti o ns (s uc h as he art f ail ure, c or o n ary artery dise ase, or 
c ar di o my o p at hies), ast h m a ( m o der ate or severe), cere br ov asc ul ar dise ase, 
cystic fi br osis, hy perte nsi o n or hi g h bl o o d press ure, i m m u n oc o m pr o mise d 
st ate ( d ue t o i m m u ne deficie ncies,  HI V,  use  of  c ortic oster oi ds,  or  use  of  ot her 
i m m u ne-we ake ni n g me dic ati o ns), ne ur ol o gic c o n diti o ns (e. g., de me nti a), 
liver dise ase, p ul m o n ary fi br osis, p ast or prese nt hist ory of s m oki n g, 
t h al asse mi a, or ty pe 1 di a betes mellit us. S u bjects w h o are ≥6 5 ye ars of a ge. 
• 
N ot  At  I ncre ase d Risk:  S u bjects  wit h  n o ne  of  t he a b ove  c o n diti o ns 
C ha n ge  6:  
Secti o n  9. 4. 1  Effic acy  A n alyses  
A d de d:  
T his  tri al is bei n g  c o n d ucte d  d uri n g  t he C O VI D -1 9  p a n de mic  a n d  is likely t o e nr oll si g nific a nt n u m bers  of  s u bjects 
wit h C O VI D -1 9. Pri or t o d at a b ase l ock a n d u n bli n di n g, a p o ole d a n alysis of t he bli n de d s u bject d at a will be 
c o m plete d t o c o u nt t he n u m ber of s u bjects wit h l a b or at ory -c o nfir me d S A R S -C o V -2 i nfecti o n.  
I n t he eve nt t h at ≥3 5 0 s u bjects wit h l a b or at ory-c o nfir me d S A R S -C o V -2 i nfecti o n h ave bee n e nr olle d, it is ex pecte d 
t h at t his will pr ovi de ≥9 0 % p o wer t o detect a st atistic ally si g nific a nt differe nce i n t he Ti me t o S ust ai ne d Res p o nse 
s urviv al distri b uti o ns  bet wee n  t he N T Z  a n d  pl ace b o  tre at me nt gr o u ps  [t w o-si de d al p h a = 0. 0 5,  c alc ul ati o ns  perf or me d 
f or t he Ge h a n r a nk test usi n g S A S P R O C P O W E R ( S A S 9. 4) b ase d u p o n d at a fr o m R o m ark tri als R M 0 8-3 0 0 4 a n d 
R M 0 8 -3 0 0 5 ass u mi n g e q u al all oc ati o n of s u bjects acr oss tre at me n t ar ms]. I n t his c ase, s u bjects wit h l a b or at ory- 
c o nfir me d S A R S -C o V -2 will be a n alyze d u n der a se p ar ate St atistic al A n alysis Pl a n t h at will be si g ne d a n d pl ace d o n 
file pri or  t o d at a b ase  l ock. T he  St atistic al  A n alysis  Pl a n  will  s pecify Ti me  t o S ust ai ne d  Res p o nse  ( as descri be d  a b ove)  


Pr ot oc ol R M 0 8- 3 0 0 9  FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
4 9  
C O N FI D E N TI A L  
 
 
S u m m ar y  of  C h a n ges  
 
as t he pri m ary effic acy e n d p oi nt t o be a n alyze d at t he 0. 0 5 level a n d a c o m p aris o n of pr o p orti o ns ex perie nci n g 
pr o gressi o n  t o severe C O VI D -1 9  ill ness ( defi ne d as  s h ort ness of  bre at h  at  rest a n d  S p O 2 ≤9 3 %  o n  r o o m air)  usi n g  a 
C oc hr a n -M ae ntel -H ae nszel ( C M H) test str atifie d by t he r a n d o miz ati o n str at a as t he key sec o n d ary a n alysis. D ay 4 
a n d D ay 1 0 n as o p h ary n ge al s w a bs will be a n alyze d f or t he prese nce of S A R S -C o V -2 f or all s u bjects p ositive f or 
S A R S -C o V -2 at B aseli ne a n d D ay 2 2 n as o p h ary n ge al s w a bs will be a n a lyze d if t he D ay 1 0 s a m ple is p ositive f or 
S A R S -C o V -2 [ a n alysis usi n g A pti m a ® S A R S -C o V -2 Ass ay ( H ol o gic, I nc, S a n Die g o, C A) as descri be d i n Secti o n 
8. 2. 2. 2]. Pr o p orti o ns of s u bjects p ositive f or S A R S -C o V -2 at D ay 4 a n d D ay 1 0 will be c o m p are d acr oss tre at me nt 
gr o u ps  usi n g  a C M H  test str atifie d by  t he r a n d o miz ati o n str at a as  a n  ex pl or at ory  a n alysis.  Ser ol o gy  s a m ples will  be 
a n alyze d f or q u a ntit ative I g G a n d I g M a nti b o dies a n d descri ptive st atistics of t he res ults will be prese nte d by 
tre at me nt gr o u p. S afety a n d p h ar m ac oki netics will be a n alyze d as descri be d i n secti o ns 9. 4. 2 a n d 9. 4. 3 bel o w. 
C ha n ge  7:  
A p pe n di x  2 C o nt act  I nf or m ati o n 
U p date d  c o ntact i nf or mati o n f or S p o ns or  Pr oject  Ma na ge me nt  a n d Ce ntral  La b orat or y  






















Pr ot oc ol R M 0 8- 3 0 0 9 FI N A L v 2. 0  
Dece m ber 2 3, 2 0 2 0  
6 0  
C O N FI D E N TI A L  
 
 
A P P E N DI X  5.  F L U -P R O  D O M AI N/ S U B D O M AI N  S T R U C T U R E