A Randomized, Double-Blind, Placebo Controlled Trial to Evaluate the Efficacy and Safety of Nitazoxanide (NTZ) for Post-Exposure Prophylaxis of COVID-19 and Other Viral Respiratory Illnesses in Elderly Residents of Long-Term Care Facilities (LTCF)
Phase: PHASE3
Conditions: COVID-19, Viral Respiratory Illnesses
Sponsor: Romark Laboratories L.C.

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C O N FI D E N TI A L  
 
 
 
 
A R A N D O MI Z E D, D O U B L E -B LI N D, P L A C E B O C O N T R O L L E D T RI A L 
T O E V A L U A T E T H E E F FI C A C Y A N D S A F E T Y O F N I T A Z O X A NI D E 
( N T Z) F O R P O S T -E X P O S U R E P R O P H Y L A XI S O F C O VI D -1 9 A N D 
O T H E R VI R A L R E S PI R A T O R Y I L L N E S S E S I N E L D E R L Y R E SI D E N T S 
O F L O N G -T E R M C A R E F A CI LI TI E S ( L T C F)  
 
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St u dy S p o ns or:  
 
T he R o mar k I nstit ute f or Me dical Researc h  
 
 
 
 
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C O N FI D E N TI A L  
T A B L E O F C O N T E N T S  
P R O T O C O L N O. R M 0 8 -3 0 0 6  ........................................................................................................1  
I N V E S TI G A T O R’ S A G R E EM E N T  ...............................................................................................6  
S Y N O P SI S  ......................................................................................................................................7  
1.  
I N T R O D U C TI O N ......................................................................................................1 0  
1. 1.  
Viral Res pira t or y Ill nesses i n L o n g-Ter m Care Facilities  ..........................................1 0  
1. 1. 1.  
A nti virals St u die d f or C he m o pr o p h yla xis of Viral Res pirat or y Ill nesses  ..................1 0  
1. 2.  
Nitaz o xa ni de ( N T Z)  ....................................................................................................1 1  
1. 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 1  
1. 2. 2.  
P har mac o ki netics of N T Z i n H u ma ns  ........................................................................1 2  
1. 2. 3.  
Cli nical E x perie nce wit h Geriatric S u bjects ( ≥6 5 Years of A ge) E x p ose d t o 
N T Z 3 0 0 m g E xte n de d Release Ta blets i n Cli nical Trials  .........................................1 3  
1. 2. 4.  
O ver vie w of Ot her E x perie nce i n Cli nical Trials a n d P ost -mar keti n g 
S ur veilla nce  ................................................................................................................1 4  
1. 3.  
Rati o nale f or t he St u d y  ...............................................................................................1 5  
2.  
S T U D Y O BJ E C TI V E S  ..............................................................................................1 5  
3.  
S T U D Y D E SI G N  .......................................................................................................1 5  
4.  
S U BJ E C T S E L E C TI O N  .............................................................................................1 7  
4. 1.  
I ncl usi o n Criteria ........................................................................................................1 7  
4. 2.  
E xcl usi o n Criteria  .......................................................................................................1 8  
5.  
S T U D Y P R O C E D U R E S  ............................................................................................1 8  
5. 1.  
Scree ni n g E val uati o n ( Da y -9 0 t o Da y 1)  ....................................................................1 8  
5. 2.  
Baseli ne ( Da y 1, ma y be sa me da y as scree ni n g e val uati o n)  .....................................1 8  
5. 3.  
Dail y Da y 1 t hr o u g h Wee k 6  ......................................................................................2 0  
5. 4.  
S us pecte d A RI Visit  ...................................................................................................2 0  
5. 5.  
Wee k 1, Wee k 3, a n d Wee k 6 E val uati o ns ( ± 2 da ys)  ................................................2 1  
5. 6.  
Wee k 8 E val uati o n ( + 7 da ys)  .....................................................................................2 1  
5. 7.  
U nsc he d ule d Visit  .......................................................................................................2 2  
5. 8.  
St u d y Disc o nti n uati o n  ................................................................................................2 2  
5. 9.  
Pla n f or La b orat or y Safet y Tests  ................................................................................2 2  
5. 1 0.  
Pla n f or Vir ol o g y Testi n g a n d M o nit ori n g Resista nce  ...............................................2 2  
6.  
R A N D O MI Z A TI O N  ..................................................................................................2 3  
7.  
D A T A M A N A G E M E N T  ...........................................................................................2 3  

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C O N FI D E N TI A L  
7. 1.  
Electr o ni c Data E ntr y .................................................................................................2 3  
7. 2.  
Pr ot oc ol De viati o ns  ....................................................................................................2 4  
7. 3.  
Data Q ualit y Ass ura nce  ..............................................................................................2 4  
8.  
S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................2 5  
8. 1.  
Sa m ple Size Calc ulati o ns  ...........................................................................................2 5  
8. 2.  
Efficac y Varia bles  ......................................................................................................2 5  
8. 3.  
Res p o nse Defi niti o ns  ..................................................................................................2 6  
8. 4.  
Statistical Met h o d ol o g y  ..............................................................................................2 6  
8. 4. 1.  
Efficac y A nal yses  .......................................................................................................2 6  
8. 4. 2.  
P o p ulati o n P har mac o ki netics A nal ysis  .......................................................................2 7  
8. 4. 3.  
Safet y A nal yses  ..........................................................................................................2 7  
9.  
I N V E S TI G A TI O N A L P R O DU C T S  ..........................................................................2 7  
9. 1.  
Dr u g Re gi me ns, A d mi nistrati o n a n d D urati o n  ...........................................................2 7  
9. 2.  
I de ntit y of I n vesti gati o nal Pr o d ucts ............................................................................2 8  
9. 3.  
Pac ka gi n g a n d La beli n g  ..............................................................................................2 8  
9. 4.  
Dr u g Acc o u nta bilit y  ...................................................................................................2 9  
9. 5.  
S u b ject C o m plia nce ....................................................................................................2 9  
9. 6.  
Disall o we d Me dicati o n  ...............................................................................................2 9  
1 0.  
A D V E R S E E V E N T S  ..................................................................................................3 0  
1 0. 1.  
Defi niti o ns  ..................................................................................................................3 0  
1 0. 2.  
Cli nical A d verse E ve nts  .............................................................................................3 1  
1 0. 3.  
Re p orti n g Re q uire me nt  ...............................................................................................3 2  
1 0. 4.  
Me dicati o n M o dificati o n/ Wit h dra wal D ue t o a n A d verse E ve nt  ...............................3 2  
1 0. 5.  
Me dicati o n Err ors  .......................................................................................................3 2  
1 1.  
DI S C O N TI N U A TI O N  ...............................................................................................3 2  
1 1. 1.  
St u d y Disc o nti n uati o n  ................................................................................................3 2  
1 1. 2.  
S u bject Disc o nti n uati o n  ..............................................................................................3 3  
1 2.  
E L E C T R O NI C D A T A C O L L E C TI O N ( E D C) S Y S T E M  .........................................3 3  
1 3.  
R E T E N TI O N O F R E C O R D S  ....................................................................................3 3  
1 4.  
M O NI T O RI N G T H E S T U D Y  ...................................................................................3 4  
1 5.  
I N F O R M E D C O N S E N T ............................................................................................3 4  
1 6.  
E T HI C S  ......................................................................................................................3 5  
1 6. 1.  
St u d y -S pecific Desi g n C o nsi derati o ns  .......................................................................3 5  

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C O N FI D E N TI A L  
1 6. 2.  
I n vesti gat or Res p o nsi bilities .......................................................................................3 5  
1 6. 3.  
I nstit uti o nal Re vie w B oar d (I R B) ...............................................................................3 6  
1 6. 4.  
Pri vac y of Pers o nal Data  ............................................................................................3 7  
1 7.  
D A T A C O N FI D E N TI A LI T Y , DI S C L O S U R E O F D A T A, A N D 
P U B LI C A TI O N  ..........................................................................................................3 7  
1 8.  
D A T A A N D R E P O R T R E Q U I R E M E N T S ...............................................................3 8  
1 9.  
C O N T A C T I N F O R M A TI O N  ....................................................................................3 9  
2 0.  
LI S T O F R E F E R E N C E S  ............................................................................................4 0  
2 1.  
A P P E N DI C E S  ............................................................................................................4 3  
2 1. 1.  
A p pe n di x I: St u d y Sc he d ule  .......................................................................................4 4  
2 1. 2.  
A p pe n di x II: T o xicit y Gra di n g f or A d verse E ve nts  ...................................................4 5  
2 1. 3.  
A p pe n di x III: List of Esse ntial D oc u me nts f or t he I n vesti gati ve Site  ........................5 2  
2 1. 4.  
A p pe n di x I V: Pr ot oc ol Re visi o n Hist or y  ...................................................................5 4  
2 1. 5.  
A p pe n di x V: Declarati o n of Helsi n ki  .........................................................................5 9  
 

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C O N FI D E N TI A L  
LI S T O F T A B L E S  
Ta ble  1:  
List of A b bre viati o ns  ....................................................................................................9  
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 3  
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  ............................................................................................................1 3  
Ta ble  4:  
P o p ulati o n P har mac o ki netics, Tr o u g h Data, f or Geriatric S u bjects ≥6 5 Years 
of A ge fr o m P hase 2 b/ 3 a n d P hase 3 Cli nical Tr ials ..................................................1 4  
Ta ble  5:  
Cli nical S y m pt o ms Re q uire d f or S us pecte d A RI 1 (a da pte d fr o m Y u et al. 
2 0 2 0)  ...........................................................................................................................2 0  
Ta ble  6:  
St u d y Me dicati o n La bels  ............................................................................................2 8  
Ta ble  7:  
Maj or C Y P 2 C 8 S u bstrates  ..........................................................................................2 9  
Ta ble  8:  
C o ntact I nf or mati o n  ....................................................................................................3 9  
Ta ble  9:  
Sc he d ule of Assess me nts  ............................................................................................4 4  
Ta ble  1 0:  Ta ble f or Cli nical A b n or malities: Vital Si g ns  ............................................................4 5  
Ta ble  1 1:  Ta ble f or Cli nical A b n or malities: S yste mic ( Ge neral)  ...............................................4 6  
Ta ble  1 2:  Ta ble f or Cli nical A b n or malities: S yste mic Ill ness  ....................................................4 6  
Ta ble  1 3:  Ta ble f or La b orat or y A b n or malities: Ser u m  ..............................................................4 7  
Ta ble  1 4:  Ta ble f or La b orat or y A b n or malities: He mat ol o g y  .....................................................5 0  
Ta ble  1 5:  Ta ble f or La b orat or y A b n or malities: Uri ne  ................................................................5 1  
Ta ble  1 6:  List of Esse ntial D oc u me nts f or t he I n vesti gati ve Site  ...............................................5 2  
Ta ble  1 7:  Pr ot oc ol Re visi o n Hist or y  ...........................................................................................5 4  
 
 

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C O N FI D E N TI A L  
IN 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 wil l 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:  
 
 
 
 
 
 
 
 
 

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C O N FI D E N TI A L  
 
iii. T he pr o p orti o n of s u bjects ( wit h or wit h o ut s y m pt o ms) 
testi n g p ositi ve f or a nti b o dies t o S A R S -C o V -2 at  
eit her of  t he Wee k 6 or Wee k 8 visit s. 
E x pl or at o r y Effic ac y P ar a meter s: P r o p orti o n of s u bjects h os pitalize d d ue t o viral res pirat or y 
ill ness ( V RIs) or c o m plicati o ns t here of ; m ortalit y d ue t o 
V RIs  or c o m plicati o ns t here of; p r o p orti o n of s u bjects 
e x perie nci n g a c ute res pirat or y ill ness  ( A RI); pr o p orti o n of 
s u bjects h os pitalize d d ue t o A RI or c o m plicati o ns t here of, 
a n d m or talit y d ue t o A RI  or c o m plicati o ns t here of . 
S afet y P ar a meters:  
A d verse e ve nts  
Bi ol o gic al S a m ples:  
Bl o o d a n d uri ne sa m ples f or safet y will be c ollecte d f or all 
s u bjects at baseli ne, Wee k 3 , a n d Wee k 6 .  Bl o o d sa m ples 
f or p har mac o ki netics will be c ollecte d at t he Wee k 3  a n d 
Wee k 6  visits.   Bl o o d tests f or a nti-S A R S -C o V -2 a nti b o dies  
will be c ollecte d at Baseli ne, 
Wee k 6 a n d 
Wee k 8. 
Nas o p har y n geal s wa bs will be c ollecte d at baseli ne f or all 
s u bjects.  A d diti o nal nas o p har y n geal s wa bs 
will be 
c ollecte d b y t he I n vesti gat or at visits f or C O VI D -1 9/ V RI 
s y m pt o ms. 
St u d y Ce nters:  
M ultice nter , U S A  
Tri al D ur ati o n:  
A pril 2 0 2 0  –  Dece m ber  2 0 2 0  
 
 

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C O N FI D E N TI A L  
T a ble  1 : 
List of A b bre vi ati o ns  
A b bre vi ati o n  
Ter m  
A E  
A d verse E ve nt  
A L T  
Ala ni ne A mi n otra nsferase  
A RI  
Ac ute Res pirat or y Ill ness  
A S T  
As partate A mi n otra nsferase  
A T P  
A de n osi ne Tri p h os p hate  
b.i. d.  
T wice Dail y  
B U N  
Bl o o d Urea Nitr o ge n  
C M H  
C oc hra n -Ma ntel -Hae nszel  
C O P D  
C hr o nic O bstr ucti ve P ul m o nar y Disease  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  (ca use d b y S A R S-C o V -2)  
C R F  
Case Re p ort F or m  
E C 5 0  
5 0 % Effecti ve C o nce ntrati o n  
E D C  
Electr o nic Data C ollecti o n  
E V/ R V  
R hi n o vir us/ E nter o vir uses  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
G G T  
Ga m ma Gl uta m yl Tra nsferase  
H D L  
Hi g h De nsit y Li p o pr otei n  
HI V  
H u ma n I m m u n o deficie nc y Vir us  
h M P V  
H u ma n Meta p ne u m o vir us  
I C 5 0 
5 0 % I n hi bit or y C o nce ntrati o n  
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee  
I L 
I nterle u ki n 
I R B 
I nstit uti o nal Re vie w B oar d 
L D L  
L o w De nsit y Li p o pr otei n  
L T C F  
L o n g -Ter m Care Facilities  
M D C K  
Ma di n -Dar b y Ca ni ne Ki d ne y  
N T Z  
Nitaz o xa ni de  
R S V  
Res pirat or y S y nc ytial Vir us  
R T -P C R  
Re verse Tra nscri pti o n P ol y merase C hai n Reacti o n  
S A R S -C o V -2  
Se vere Ac ute Res pirat or y S y n dr o me C or o na vir us 2  
V RI  
Viral Res pirat or y Ill ness 

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1.  
I N T R O D U C TI O N 
1. 1.  Vir al Res pir at or y Ill nesses i n L o n g-Ter m C are F a cilities  
Res pirat or y tract i nfecti o ns res ult i n a p pr o xi matel y 4  milli o n deat hs gl o ball y  eac h year .  T he 
el derl y p o p ulati o n is at dis pr o p orti o nate ris k d ue t o a ge -relate d c haracteristics s uc h as frailt y 
a n d i m m u n ose nesce nce.  M ore o ver, t his p o p ulati o n e x perie nces m ore se vere ill nesses, a 
lar ger n u m ber of h os pitalizati ons a n d greater m ortalit y rates.  T he el derl y p o p ulati o n is 
gr o wi n g ra pi dl y a n d will d o u ble b y 2 0 5 0.  L T C Fs are a n i m p orta nt s u bset of t he el derl y 
p o p ulati o n, i n de vel o pe d c o u ntries a p pr o xi matel y 5 % li v e i n t hese facilities.  L T C F  resi de nts 
are at ele vate d ris k of ac q uiri n g res pirat or y tract i nfecti o ns d ue t o ele vate d i nfecti o n rates, 
w hic h ma y be a m plifie d  i n part d ue t o cl ose li vi n g c o n diti o ns  (C hil ds et al. 2 0 1 9 , Mc Geer et 
al. 2 0 0 0 ).   
A n arra y of viral res pirat or y pat h o ge ns occ ur i n t his p o p ulati o n, i ncl u di n g c or o na vir uses, 
R S V, r hi n o vir uses a n d h M P V , wit h i nfecti o ns occ urri n g i n as ma n y as 4 1 % of L T C F 
resi de nts s ur ve ye d (False y et al.  2 0 0 8 , C hec o vic h et al. 2 0 2 0 ).  R hi n o vir uses ha ve be e n 
ass ociate d wit h as m uc h as 5 9 % of L T C F o ut brea ks a n d ma y res ult i n se vere disease  (L o n gti n 
et al . 2 0 1 0).  R S V a n d h M P V  are wi del y re p orte d t o circ ulate d uri n g a n i nfl ue nza seas o n, 
wit h R S V i nfecti o ns occ urri n g at 4 ti mes t he rate of t he ge n eral p o p ulati o n i n t he el derl y 
(Ursic et al. 2 0 1 6, T h o m ps o n et al. 2 0 0 3 ).  O ut brea ks of seas o nal strai ns of c or o na vir us ha ve 
bee n re p orte d, wit h t he p ote ntial t o ca use se vere res pirat or y ill ness  (Ha n d et al. 2 0 1 8 ).  
F urt her m ore, o ut brea ks of S A R S -C o V -2  i n L T C Fs ha ve bee n ass ociate d wit h wi des prea d 
i nfecti o n a m o n gst resi de nts a n d hi g h m ortalit y rates (Mc Mic hael et al. 2 0 2 0, Ki m ball et al. 
2 0 2 0 ).     
I nfl ue nza is t he o nl y res pirat or y vir us f or w hic h a vacci ne e xists.  M ore o ver, vacci ne efficac y  
is varia ble, wit h di mi nis he d vacci ne res p o nses i n t he el derl y  (G o o d wi n et al. 2 0 0 6 ).  As m uc h 
as 9 0 % of t h ose resi di n g i n L T C Fs are vacci nate d f or i nfl ue nza, yet at least half of t hese 
facilities re p ort o ut brea ks e ver y year (Mc Geer et al. 2 0 0 0 ).  T he Ce nters f or Disease C o ntr ol 
a n d Pre ve nti o n rec o m me n ds c he m opr o p h yla xis f or all L T C F  resi de nts i n facilities 
e x perie nci n g a n i nfl ue nza o ut brea k re gar dless of vacci nati o n stat us  (Ce nters f or Disease 
C o ntr ol a n d Pre ve nti o n 2 0 1 9 ).  H o we ver, t hese rec o m me n dati o ns are li mite d t o i nfl ue nza 
si nce t here are n o a vaila ble a ge nts f or t he c he m o pr o p h yla xis of ot her res pirat or y vir uses. 
C o nsi deri n g t he lac k of vacci ne a n d c he m o pr o p h yla xis a vaila bilit y  f or m ost pat h o ge ns, 
i nefficac y of i nfl ue nza vacci nati o n, e n ha nce d rate of s prea d i n t his setti n g a n d e mer ge nce of 
n o vel viral res pirat or y pat h o ge ns a n o vel br oa d -s pectr u m c he m o pr o p h yla xis strate g y is of 
para m o u nt i m p orta nce i n t his p o p ulati o n.  
1. 1. 1.  
A nti vir als St u die d f or C he m o pr o p h yl a xis of  Vir al Res pir at or y Ill nesses 
T he o nl y dr u g a p pr o ve d f or c he m opr o p h yla xis  i n t his p o p ulati o n, f or a n y res pirat or y 
vir us , is oselta mi vir w hic h is o nl y f or i nfl ue nza A a n d B i nfecti o ns.  Oselta mi vir was 
st u die d i n a seas o nal (c o m m u nit y o ut brea k) i n el derl y patie nts resi di n g i n a n ursi n g h o me.  
T he maj orit y of s u bjects were vacci nate d ( > 8 0 %), 4 3 % of s u bjects ha d car diac dis or ders 
a n d 1 4 % ha d c hr o nic air wa y o bstr ucti ve dis or ders.  I n t his st u d y, s u bjects were gi ve n 
oselta mi vir 7 5 m g o nce dail y f or 6 wee ks  or matc hi n g place b o .  Oselta mi vir treat me nt 
res ulte d i n a 9 2 % re d ucti o n i n t he i nci de nce of la b orat or y-c o nfir me d cli nical i nfl ue nza 

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 1 1  of 5 9  
C O N FI D E N TI A L  
c o m pare d t o place b o ( place b o 1 2/ 2 7 2 ( 4. 4 %), oselta mi vir 1/ 2 7 6 ( 0. 4 %); p = 0. 0 0 2)  
(T A MI F L U ®  Prescri bi n g I nf or mati o n 2 0 1 9 , Peters et al. 2 0 0 1).   
T here are n o dr u gs a p pr o ve d f or t he treat me nt or pr o p h yla xis of viral res pirat or y 
i nfecti o ns ca use d b y ot her c o m m o n res pirat or y pat h o ge ns li ke c or o na vir us, R S V, 
r hi n o vir us, h M P V, a n d parai nfl ue nza.  
1. 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 with 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  P rescri bi n g Inf or mati o n 2 0 1 9 ). 
1. 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 , 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 u s, 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 ).  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 C5 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 ( T il 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 cell s 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 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  

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 1 2  of 5 9  
C O N FI D E N TI A L  
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 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 b it 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 v e 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 , 
Mi razi 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 tr eat me nt or pr o p h yla xis of 
res pirat or y ill ness ca use d b y V RIs . 
1. 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 ( Cma 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 4C N T Z, a p pr o xi matel y o ne -t hir d of t he 
d ose was e xcre te 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 nif ica nt meta b olites were detecte d (N T Z 
3 0 0 m g Ta blets 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 h e 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 

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 1 3  of 5 9  
C O N FI D E N TI A L  
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  
tma x  ( h) 
6. 0 0 ( 4. 0 0-9. 0 0)  
5. 0 0 ( 3. 0 0 -8. 0 0)  
6. 0 0 ( 5. 0 0 -1 1. 0 0)  
5. 5 0 ( 0. 0 0 -7. 0 2)  
tla g ( h) 
0. 0 0 ( 0. 0 0 -2. 0 0)  
0. 0 0 ( 0. 0 0 -0. 0 0)  
0. 5 0 ( 0. 0 0 -2. 0 0)  
0. 0 0 ( 0. 0 0 -0. 0 0)  
A U C 0 -t ( µ g. h/ m L) 
2 6. 9  ± 1 6. 1  
5 2. 5 ± 3 3. 7  
2 9. 5  ± 1 2. 1  
7 5. 0 ± 3 7. 8  
A U C 0 - Τ  ( µ g. h/ m L) 
2 8. 6  ± 1 6. 3 a 
4 8. 3 ± 3 1. 9 b 
3 0. 5  ± 1 2. 2 c 
7 5. 2 ± 3 7. 9  
C  Τ  ( µ g/ m L) 
0. 7 0 9 ± 0. 9 8 7  
1. 7 2 ± 2. 0 4  
1. 3 9 ± 0. 8 4 6  
3. 8 9 ± 2. 8 8  
A U C 0 -∞ ( µ g. h/ m L) 
2 7. 8 ± 1 7. 8 b 
5 2. 3 ± 3 5. 6 b 
3 5. 3 ± 1 6. 5 d 
6 2. 1 ± 2 4. 2 e 
t1/ 2 ( h) 
1. 6 6 ± 0. 4 0 8 b 
2. 1 9 ± 0. 4 8 5 b 
2. 7 0 ± 0. 8 4 8 c 
4. 9 9 ± 5. 2 0  
λ z ( 1/ h) 
0. 4 4 1 ± 0. 1 0 6 b 
0. 3 3 1 ±  0. 0 7 3 3 b 
0. 2 8 2 ± 0. 0 9 0 2 c 
0. 2 0 1 ± 0. 0 8 1 3  
C a v g ( µ g/ m L) 
N A  
4. 0 2 ± 2. 6 6 b 
N A  
6. 2 7 ± 3. 1 6  
C mi n  ( µ g/ m L) 
N A  
1. 5 0 ± 1. 8 3  
N A  
3. 6 3 ± 3. 0 0  
P T F ( %)  
N A  
1 9 3 ± 3 9. 1 b 
N A  
1 0 1 ± 4 0. 7  
S wi n g ( %)  
N A  
1 0 3 9 ± 6 5 6  
N A  
2 6 8 ± 1 9 4  
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 t la 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  
P K P ar a meter ( u nit)  
Tr o u g h C o nce ntr ati o ns ( µ g/ m L  
Me a n ( C V %)  
D ose Gr o u p  
Nitaz o xa ni de  
D a y  
 
1 ( a)  
2  
3  
4  
5  
6  
7 ( b)  
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  
( 9 9. 7) 
3. 8 0  
( 1 4 6) 
3. 2 6  
( 1 1 9) 
3. 0 2  
( 9 8. 6) 
Tiz o xa ni de 
Gl uc ur o ni de  
1. 3 9  
( 6 1. 0) 
3. 6 8  
( 7 2. 3) 
4. 3 8  
( 7 2. 8) 
5. 3 5  
( 7 7. 2) 
5. 8 3  
( 9 8. 8) 
5. 9 4  
( 9 1. 2) 
5. 6 5  
( 6 8. 7) 
1. 2. 3.  
Cli nic al E x perie nce wit h Geri atric S u bjects ( ≥6 5 Ye ars of A ge) E x p ose d t o N T Z  
3 0 0 m g E xte n de d Rele ase T a blets i n Cli nic al Tri als  
Of t he 3, 1 4 7 s u bjects e x p ose d t o N T Z 3 0 0 m g e xte n de d release ta blets i n cli nical trials, 
8 9 were el derl y a d ults a ge d 6 5 years a n d ol der.  F o urtee n ( 1 4) of t hese s u bjects recei ve d 
a si n gle 6 0 0 m g d ose i n a p har mac o ki netic st u d y, w hile 7 5 s u bjects were e nr ol le d i n 
P hase 3 cli nical trials f or t he treat me nt of i nfl ue nza a n d c o m m o n c ol d d ue t o 
e nter o vir us/r hi n o vir us.  I n t he P hase 3 trials, all were treate d wit h nitaz o xa ni de 6 0 0 m g 
t wice dail y f or 5 da ys, t w o of w hic h recei ve d nitaz o xa ni de i n c o m bi nati o n wit h 
os elta mi vir.  

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 1 4  of 5 9  
C O N FI D E N TI A L  
O verall, t he t y pe a n d se verit y of A Es re p orte d i n t his p o p ulati o n were si milar t o t he t otal 
p o p ulati o n a n d t he k n o w n a d verse e ve nt pr ofile f or t he dr u g.  I n t he p har mac o ki netic 
st u d y o nl y t w o a d verse e ve nts were re p orte d i n t w o s u bjects ( hea dac he a n d diarr hea), 
b ot h were mil d i n nat ure a n d n ot c o nsi dere d t o be relate d t o nitaz o xa ni de.  I n P hase 2 b/ 3 
a n d P hase 3 cli nical trials, t w o s u bjects e x perie nce d seri o us a d verse e ve nts u nrelate d t o 
st u d y me dicati o n, b ut rat her relate d t o a pre-e xisti n g his t or y of a c o nc urre nt c o n diti o n.  
O ne of t he s u bjects e x perie nce d a n e xacer bati o n of c o n gesti ve heart fail ure was 
h os pitalize d a n d s u bse q ue ntl y rec o vere d.  T he ot her s u bject ha d a hist or y of se vere bac k 
a n d nec k pai n a n d was h os pitalize d f or m usc ul os keletal  pai n.  T his s u bject als o 
rec o vere d.  T he ot her a d verse e ve nts e x perie nce d b y geriatric s u bjects were mil d t o 
m o derate i n nat ure.  T he m ost c o m m o nl y re p orte d A Es (at least 2 %) f or geriatric s u bjects 
recei vi n g nitaz o xa ni de i n P hase 3 st u dies ( n = 7 5) re gar dless of ca usalit y assess me nt 
were: diarr hea ( 9. 3 %), c hr o mat uria ( 6. 7 %), na usea ( 2. 7 %), a n d hea dac he ( 2. 7 %).  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 t he place b o.   
P o p ulati o n p har mac o ki netic data f or tiz o xa ni de a n d tiz o xa n i de gl uc ur o ni de tr o u g hs 
( pri or t o ne xt d ose) fr o m geriatric s u bjects recei vi n g nitaz o xa ni de 6 0 0 m g t wice dail y f or 
5 da ys is a vaila ble f or 5 0 s u bjects e nr olle d P hase 2 b/ 3 a n d P hase 3 cli nical trials.  A 
c o m paris o n of t his data t o t he a d ult p o p ulati o n ( 1 8 t o 6 4 years of a ge) fr o m t hese st u dies 
is prese nte d i n t he f oll o wi n g ta ble ( N T Z 3 0 0 m g Ta blets I n vesti gat ors Br oc h ure). 
T a ble  4 : 
P o p ul ati o n P h ar m ac o ki netics, Tr o u g h D at a, f or Geri atric S u bjects ≥6 5 Ye ars 
of A ge fr o m P h ase 2 b/ 3 a n d P h ase 3 Cli nic al Tri al s 
Met a b olite  
Tr o u g h D at a  
S u bjects ≥6 5 ye ars  
Tr o u g h D at a  
S u bjects 1 8 t o 6 4 ye ars  
Tiz o xa ni de  
0. 8 6 μ g/ m L ( n = 5 0)  
0. 8 1 μ g/ m L ( n = 1 3 0 5)  
Tiz o xa ni de gl uc ur o ni de  
3. 0 8 μ g/ m L ( n = 5 0)  
2. 3 4 μ g/ m L ( n = 1 3 1 4)  
1. 2. 4.  
O ver vie w of Ot her E x perie nce i n Cli nic al Tri als a n d P ost -m ar keti n g S ur veill a nce  
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 pati e 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 8 6  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 m i 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 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 Z 3 0 0 m g Ta blets I n vesti gat ors Br oc h ure ). 

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1. 3.  R ati o n ale f or t he St u d y  
T here is a n i m p orta nt nee d f or t hera pies t o pre ve nt V RIs, es peciall y i n at-ris k p o p ulati o ns 
li ke t h ose i n li vi n g i n L T C Fs.  V RIs  i n L T C Fs are a critical healt h c o ncer n d ue t o t he 
b ur ge o ni n g patie nt p o p ulati o n , i ncrease d m or bi dit y a n d m ortalit y i n el derl y a d ults a n d t he 
lac k of a vaila ble treat me nts f or a br oa d arra y of vir uses.  O selta mi vir is a vaila ble f or 
treatme nt a n d c he m o pr o p h yla xis, yet it is li mite d t o o nl y i nfl ue nza i nfecti o ns w hile data 
i n dicates m ulti ple ot her n o n -i nfl ue nza vir uses are a si g nifica nt ca use of V RI i n t his 
p o p ulati o n.      
N T Z’s  br oa d -s pectr u m of acti vit y a gai nst res pirat or y vir uses  ma kes it a g o o d ca n di dat e f or 
c he m opr o p h yla xis as it has de m o nstrate d acti vit y a gai nst t he c o m m o n pat h o ge ns ass ociate d 
wit h V RI .  I m p orta ntl y, pre vi o us st u dies ha ve de m o nstrate d N T Z has a fa v ora ble safet y 
pr ofile a n d l o w ris k f or  de vel o pi n g viral  resista nce. 
T his st u d y will be c o n d ucte d d uri n g a ti me w he n C O VI D -1 9  (ca use d b y S A R S -C o V -2 ) is 
circ ulati n g p osi n g si g nifica nt ris k t o el derl y patie nts wit h u n derl yi n g healt h c o n diti o ns.   
T here is a n i m p orta nt nee d f or a n oral 
me dicati o n t hat c o ul d be a d mi nistere d as 
c he m opr o p h yla xis of C O VI D -1 9 i n patie nts i n L T C Fs.  
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 6 wee ks 
c o m pare d t o a place b o f or p ost -e x p os ure pr o p h yl a xis of C O VI D -1 9 a n d ot her V RIs i n el derl y 
L T C F resi de nts . 
2.  
S T U D Y O B J E C TI V E S  
T he pri mar y o bjecti ve s of t his st u d y are t o e val uate t he effect of N T Z a d mi nistere d orall y 
6 0 0 m g t wice dail y f or 6 wee ks  i n pre ve nti n g s y m pt o matic la b orat or y-c o nfir me d C O VI D -
1 9 a n d ot her V RIs  i n el derl y L T C F resi de nts c o m pare d t o t hat of a place b o.  
Sec o n dar y o bjecti ves are t o e val uate t he effect o n (i) h os pitalizati o n d ue t o C O VI D -1 9 or 
c o m plicati o ns t here of, (ii) m ortalit y d ue t o C O VI D -1 9 or c o m plicati o ns t here of , a n d (iii) t he 
pr o p orti o n of s u bjects ( wit h or wit h o ut s y m pt o ms) testi n g p ositi ve f or a nti b o dies t o S A R S -
C o V -2 at eit her of t he Wee k 6 or Wee k 8 visit s. 
E x pl orat or y o bjecti ves i ncl u de  (i) h os pitalizati o n d ue t o V RI or c o m plicati o ns t here of, (ii) 
m ortalit y d ue t o V RI  or c o m plicati o ns t here of , (iii) pr o p orti o ns of s u bjects e x perie nci n g 
ac ute res pirat or y ill ness ( A RI), ( i v) h os pitalizati o n d ue t o A RI or c o m plicati o ns t here of , a n d 
( v) m ortalit y d ue t o A RI or c o m plicati o ns t here of.       
Ot her i m p orta nt o bjecti ves i ncl u de  e val uati o n of t he safet y of N T Z b y a nal ysis of a d verse 
e ve nts a n d e val uati o n of relati o ns hi ps bet wee n p har mac o ki netics a n d cli nical or vir ol o gic 
res p o nses. 
3.  
S T U D Y D E SI G N  
T he st u d y will be a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d trial t o 
e val uate t he efficac y a n d safet y of N T Z f or p ost -e x p os ure pr o p h yla xis of C O VI D -1 9 a n d 
ot her V RIs i n el derl y L T C F resi de nts.  

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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 pl e 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 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.       
 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 
me trics 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.”    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 ). 
 C h oice of A RI Defi niti o n .  T he pri mar y e n d p oi nt of t his trial re q uires a deter mi nati o n t hat 
a n A RI has occ urre d.  We ha ve defi ne d A RI as “ ≥0. 5 i ncrease fr o m baseli ne i n mea n 
s y m pt o m sc ore f or t he c hest/res pirat or y F L U-P R O d o mai n or ≥0. 5 i ncrease fr o m baseli ne 
i n 
mea n s y m pt o m sc ore f or at least t w o of t he f oll o wi n g F L U -P R O ©  d o mai ns : 
b o d y/s yste mic, n ose, t hr oat .”  I n arri vi n g at t his defi niti o n, we re vie we d p u blis he d mea n 
F L U -P R O ©  s y m pt o m sc ore data o ver t he c o urse of R S V ill ness (Y u et al.  2 0 2 0 ) as well 
as data fr o m rece ntl y c o m plete d cli nical trials i n a p pr o xi matel y 3, 0 0 0 s u bjects wit h c ol ds 
a n d i nfl ue nza ( R o mar k, data o n file).  T he A RI defi niti o n re q uires a n i ncrease i n 
s y m pt o m sc ores fr o m baseli ne, alt h o u g h t he ma g nit u de of t he re q uire d i ncrease ( ≥0. 5) i n 
mea n d o mai n sc ores is l o w, a n d we are re q uiri n g t hat t he i ncrease i n mea n sc ore be 
ac hie ve d f or o nl y o ne or t w o of t he f o ur d o mai ns.   
4.  
S U B J E C T S E L E C TI O N  
T he criteria f or i ncl usi o n a n d e xcl usi o n are defi ne d bel o w:  
4. 1.  I ncl usi o n Criteri a 
1.  Male  a n d fe male resi de nts of L T C Fs at least 5 5  years of a ge . 
2.  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 a n d c o m pl y wit h t he re q uire me nts of 
t he pr ot oc ol. 
3.  At least o ne s y m pt o matic la b orat or y -c o nfir me d C O VI D -1 9  ill ness i de ntifie d a m o n g 
resi de nts or staff of t he L T C F wit hi n 1 0  da ys pri or t o ra n d o mizati o n. 

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4. 2.  E xcl usi o n Criteri a  
1.  Alz hei mer’s disease, de me ntia, or ot her me ntal i nca pacit y w hic h precl u des c o m pre he nsi o n 
of t he st u d y re q uire me nts or s y m pt o m diar y .    
2.  S u bjects e x pecte d t o re q uire h os pitalizati o n wit hi n t he 8 -wee k treat me nt a n d f oll o w-u p 
peri o d.  
3.  S u bjects wit h a hist or y  of C O VI D -1 9  or k n o w n t o ha ve de vel o pe d a nti -S A R S -C o V -2 
a nti b o dies . 
4.  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 or a nti viral t hera p y 
f or i nfl ue nza 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. 
5.  Recei pt of a n y d ose of N T Z wit hi n 7 da ys pri or t o scree ni n g.  
6.  T reat me nt wit h a n y i n vesti gati o nal dr u g or vacci ne wit hi n 3 0 da ys pri or t o scree ni n g  or 
u n 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 . 
7.  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.  
8.  S u bjects u na ble t o s wall o w oral ta blets or ca ps ules.  
9.  S u bj ects 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  7  . 
1 0.  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. 
5.  
S T U D Y P R O C E D U R E S  
All st u d y visits are t o occ ur i n t he s u bject’s h o me facilit y.  
5. 1.  Scree ni n g E v al u ati o n ( D a y -9 0 t o Da y 1)  
Bef ore scree ni n g, s u bjects will be i nf or me d of t he nat ure of st u d y, a n d writte n c o nse nt m ust 
be o btai ne d pri or t o partici pati o n.  After gi vi n g i nf or me d c o nse nt, t he s u bject will be assi g ne d 
a s u bject n u m ber, a n d t he f oll o wi n g pr oce d ures will be carrie d o ut:  
1.  C o m plete me dical hist or y.  
2.  P h ysical e xa mi nati o n i ncl u di n g b o d y wei g ht a n d vital si g ns ( bl o o d press ure, p ulse, 
res pirat or y rate a n d b o d y te m perat ure). 
3.  C ollecti o n of de m o gra p hic i nf or mati o n a n d s m o ki n g hist or y.  
4.  E val uati o n acc or di n g t o eli gi bilit y (i ncl usi o n a n d e xcl usi o n) criteria . 
T he  i nf or mati o n c ollecte d d uri n g t he scree ni n g peri o d m ust be c urre nt t hr o u g h t he ti me of 
ra n d o mizati o n. 
5. 2.  B aseli ne ( D a y 1, m a y be s a me d a y as scree ni n g e v al u ati o n) 
At baseli ne, t he f oll o wi n g pr oce d ures will be carrie d o ut:  

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5. 3.  D ail y D a y 1  t hr o u g h Wee k 6  
A care gi ver will rec or d t he ti me of eac h st u d y me dicati o n i nta ke .  O nce dail y, t he care gi ver  
will (i) i n q uire re gar di n g t he healt h of t he s u bject, (ii) rec or d a n y c o nc o mita nt me dicati o ns, 
a n d (iii) as k t he s u bject o nce dail y, “ d o y o u feel li ke y o u ha ve s y m pt o ms of a c ol d or fl u?”  
If t he s u bject res p o n ds “ yes” , t he care gi ver will ha ve t he s u bject c o m plete a F L U -P R O ©  diar y 
t o e val uate t he s u bject’s s y m pt o ms.  If t he s u bject re p orts (i) at least o ne  of t he  L o wer 
R es pirat or y S y m pt o m s prese nte d i n Ta ble  5  bel o w or  (ii) at least o ne s y m pt o m fr o m eac h of 
t he U p per Res pirat or y S y m pt o ms a n d S yste mic S y m pt o ms cate g ories prese nte d i n Ta ble  5  
bel o w , the care gi ver will t he n c o ntact t he st u d y p h ysicia n or n urse t o c o m plete a “ S us pecte d 
A RI Visit” wi t h t he pr oce d ures pr o vi de d bel o w. 
 T a ble  5 : 
Cli nic al S y m pt o ms  Re q uire d f or S us pecte d A RI 1 ( a d a pte d fr o m Y u et al. 
2 0 2 0 ) 
U p per Res pir at or y S y m pt o ms  L o wer Res pir at or y S y m pt o ms  
S yste mic S y m pt o ms  
 Nasal c o n gesti o n/r hi n orr hea 
(r u n n y or dri p pi n g n ose, 
c o n geste d or st uff y n ose, hea d 
c o n gesti o n, si n us press ure)  2 
 S ore t hr oat (s ore or pai nf ul 
t hr oat) 2 
 C o u g h (c o u g hi n g, c hest 
c o n gesti o n, c hest ti g ht ness, dr y 
or hac ki n g c o u g h, wet or l o ose 
c o u g h)  2 
 D ys p nea (s h or t ness of breat h) 2 
 S p ut u m (c o u g hi n g u p s p ut u m 
or p hle g m)  2 
 W heezi n g  
 M y al gias or art hral gias ( b o d y 
ac hes or pai ns)  2 
 Fati g ue ( wea k or tire d, 
slee pi n g m or e t ha n us ual)  2 
 Hea dac he  
 Decrease d a p petite (lac k of 
a p petite, di d n ot feel li ke 
eati n g)  2 
 Fe veris h ness (felt h ot, c hills or 
s hi veri n g, felt c ol d, s weati n g)  2 
1 S us pecte d A RI re q uires self -re p orti n g of a n y L o wer Res pirat or y S y m pt o m, or at least o ne U p per 
Res pirat or y S y m pt o m t o get her wit h o ne S yste mic S y m pt o m . 
2  La y la n g ua ge use d i n t he F L U -P R O ©  q uesti o n naire is prese nte d i n pare nt heses.  
5. 4.  S us pecte d A RI  Visit  
S u bjects re q uiri n g S us pecte d A RI Visit will be e val uate d as f oll o ws:  
1.  P h ysical e xa mi nati o n as warra nte d b y t he I n vesti gat or f or a n y c ha n ge fr o m baseli ne . 
2.  B o d y wei g ht a n d c ollecti o n of vital si g ns t o i ncl u de bl o o d press ure, p ulse, res pirat or y rate 
a n d b o d y te m perat ure . 
3.  C ollecti o n of t w o nas o p har y n geal s wa bs usi n g n yl o n fl oc ke d dr y s wa bs f or R T -P C R.  
4.  C ollect t w o nas o p har y n geal s wa bs 2 4 t o 3 6 h o urs later a n d t he n a gai n 4 t o 5 da ys later.  
5.  T he s u bj ect will c o m plete a F L U -P R O ©  s y m pt o m diar y dail y u ntil he/s he res p o n ds “ yes” 
t o t he F L U-P R O ©  q uesti o n, “ Ha ve y o u ret ur ne d t o y o ur us ual healt h?” f or 3 c o nsec uti ve 
da ys or u ntil t he Wee k 8 Visit, w hic he ver occ urs first.  T he dail y F L U -P R O ©  diar y will be 

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c o mplete d bet wee n 4: 0 0 p m a n d 8: 0 0 p m.  A care gi ver ma y assist t he s u bject wit h 
c o m pleti n g t he diar y if nee de d.   
6.  Re vie w a n d rec or di n g of c o nc o mita nt me dicati o ns. 
7.  Re vie w a n d rec or di n g of a d verse e ve nts/si de effects.  
8.  La b orat or y i n vesti gati o ns f or safet y ma y be perf or me d as warra nte d base d u p o n t he 
I n vesti gat or’s j u d g me nt.   
9.  If a s u bject tests p ositi ve f or a res pirat or y vir us b y R T-P C R, t hat s u bject ma y recei ve 
sta n dar d of care as cli nicall y warra nte d b y t he I n vesti gat or.   
Re gar dless of s y m pt o ms or la b orat or y data, t he s u bject will c o nti n ue treat me nt u ntil t he 6 -
wee k treat me nt peri o d has e n de d.   
5. 5.  Wee k 1, Wee k 3 , a n d Wee k 6  E v al u ati o ns  (± 2  d a y s) 
A st u d y p h ysicia n, n urse or ot her st u d y pers o n nel will visit eac h s u bject at Wee k 1, Wee k 3 , 
a n d Wee k 6 , a n d t he f oll o wi n g pr oce d ures will be perf or me d: 
1.  P h ysical e xa mi nati o n as warra nte d b y t he I n vesti gat or f or a n y c ha n ge fr o m baseli ne.    
2.  B o d y wei g ht a n d c ollecti o n of vital si g ns t o i ncl u de bl o o d press ure, p ulse, res pirat or y rate 
an d b o d y te m perat ure. 
3.  Wee k 3 a n d 
Wee k 6 o nl y, c ollecti o n of bl o o d sa m ple f or la b orat or y safet y tests , 
p har mac o ki netics ( pre -d ose)  a n d a nti-S A Rs -C o V -2 a nti b o dies  (a nti b o d y testi n g at Wee k 6 
visit o nl y) . 
4.  Wee k 3 a n d Wee k 6 o nl y, c ollecti o n of uri ne sa m ple f or r o uti ne uri nal ysis. 
5.  Re vie w of c o m plia nce wit h st u d y me dicati o n, c ollecti o n of me dicati o n b ottle wit h a n y 
u n use d me dicati o ns  ( Wee k 6 visit o nl y) , a n d c o m pleti o n of t he pill c o u nt l o g f or m. 
6.  Re vie w a n d rec or di n g of c o nc o mita nt me dicati o ns.  
7.  Re vie w a n d rec or di n g of a d verse e ve nts/si de effects a n d c o m plicati o ns.  N ote t hat all 
a d verse e ve nts a n d c o m plicati o ns 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 8 -wee k  st u d y peri o d. 
5. 6.  Wee k 8  E v al u ati o n  (+ 7  d a y s) 
A st u d y p h ysicia n, n urse o r ot her st u d y pers o n nel will visit eac h s u bject at Wee k 8 a n d t he 
f oll o wi n g pr oce d ures will be perf or me d: 
1.  P h ysical e xa mi nati o n as warra nte d b y t he I n vesti gat or f or a n y c ha n ge fr o m baseli ne.   
2.  C ollecti o n of bl o o d sa m ple f or a nti-S A Rs -C o V -2 a nti b o dies.  
3.  Re vie w a n d rec or d c o nc o mita nt me dicati o ns.  
4.  Re vie w a n d rec or d a d verse e ve nts/si de effects a n d c o m plicati o ns.  N ote t hat all a d verse 
e ve nts a n d c o m plicati o ns 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 8 -wee k st u d y peri o d.  
5.  D oc u me nt a n y i nfecti o ns dia g n ose d d uri n g t he f oll o w -u p peri o d.  

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5. 7.  U nsc he d ule d Visit  
S u bjects re q uiri n g a n u nsc he d ule d visit d ue t o w orse ni n g s y m pt o ms or a d verse e ve nts will 
be e val uate d at t he discreti o n of t he I n vesti gat or as is me dicall y warra nte d.  Tests a n d/ or 
pr oce d ures perf or me d at t his visit ma y i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
1.  P h ysi cal e xa mi nati o n as warra nte d b y t he I n vesti gat or f or a n y c ha n ge fr o m baseli ne . 
2.  B o d y wei g ht a n d c ollecti o n of vital si g ns t o i ncl u de bl o o d press ure, p ulse, res pirat or y rate 
a n d b o d y te m perat ure . 
3.  C ollecti o n of t w o nas o p har y n geal s wa bs usi n g n yl o n fl oc ke d dr y  s wa bs f or R T-P C R.  
4.  C ollecti o n of bl o o d sa m ple f or la b orat or y safet y tests.  
5.  C ollecti o n of uri ne sa m ple f or r o uti ne uri nal ysis.  
6.  Re vie w of c o m plia nce wit h st u d y me dicati o n.  
7.  Re vie w a n d rec or di n g of c o nc o mita nt me dicati o ns. 
8.  Re vie w a n d rec or di n g of a d verse e ve nt s/si de effects. 
5. 8.  St u d y Disc o nti n u ati o n  
R ules f or disc o nti n uati o n of a s u bject or f or disc o nti n ui n g t he st u d y are pr o vi de d i n S ecti o n 
1 1. 2 .  All s u bjects disc o nti n ue d fr o m t he st u d y bef ore Wee k 6  will be e val uate d at st u d y 
disc o nti n uati o n usi n g t he pr oce d ures descri be d a b o ve f or t he Wee k 6  e val uati o n .  T h ose 
disc o nti n ue d after Wee k 6 will be e val uate d as warra nte d b y t he I n vesti gat or.   
5. 9.  Pl a n f or L a b or at or y S afet y Tests  
A ce ntral la b orat or y will be use d f or la b orat or y safet y t esti n g.  Bl o o d tests will i ncl u de 
he m o gl o bi n, he mat ocrit, c o m plete bl o o d c o u nt (t otal a n d differe ntial), platelet c o u nt, ra n d o m 
bl o o d s u gar, t otal c h olester ol, H D L, L D L, tri gl yceri des, al b u mi n, A S T, A L T, G G T, al kali ne 
p h os p hatase, bilir u bi n (t otal/ direct),  B U N, creati ni ne, s o di u m, p otassi u m, c hl ori de.  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.  
5. 1 0.  Pl a n f or Vir ol o g y Testi n g a n d M o nit ori n g Resist a nce  
Bl o o d sa m ples c ollecte d at Baseli ne, Wee k 6 a n d Wee k 8 will be teste d f or a nti -S A R S -C o V -
2 a nti b o dies at a ce ntral la b orat or y usi n g a vali date d assa y ( w he n s uc h bec o me a vaila ble ).  
Vir ol o g y testi n g of nas o p har y n geal s wa b sa m ples will be c o n d ucte d as descri be d bel o w . 
1.  C ollecti o n of sa m ples:  
T w o nas o p har y n geal s wa bs will be c ollecte d fr o m eac h s u bject at Baseli ne ( Da y 1) , at 
eac h S us pecte d A RI Visit, 2 4 t o 3 6 h o urs after eac h S us pecte d A RI  V isit, 4 t o 5 da ys 
after eac h S us pecte d A RI Visit a n d as warra nte d b y t he I n vesti gat or . 
2.  Testi n g of bi ol o gical sa m ples:  
Eac h nas o p har y n geal s wa b  sa m ple will be s u bjecte d t o R T-P C R usi n g 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) 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 

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 2 3  of 5 9  
C O N FI D E N TI A L  
a n d B; parai nfl ue nza 1, 2, 3 a n d 4; h M PV; 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 hl a my d o p hil a p ne u m o ni ae ; a n d Myc o pl as m a 
p ne u m o ni ae .  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 test f or S A R S -C o V -2 .  
3.  Dr u g s usce pti bilit y testi n g:  
If a n y S u s pecte d A RI Visit  nas o p har y n geal s wa b sa m ple is p ositi ve f or a V RI, t he vir us 
will be is olate d (if p ossi ble) a n d teste d f or s usce pti bilit y t o tiz o xa ni de.   
4.  St ora ge of sa m ples:  All sa m ples c ollecte d d uri n g t he st u d y will be st ore d f or at least 2 
years f or p ote ntial f ut ure testi n g.  
5.  Cli nical vir ol o g y la b orat or y f or dia g n ostic testi n g:   
  
 
 
6.  Cli nical vir ol o g y la b orat or y f or dr u g  s usce pti bilit y testi n g: 
 
 
 
6.  
R A N D O MI Z A TI O N  
S u bjects will be ra n d o mize d 1: 1 b y strat u m  t o recei ve eit her N T Z or place b o.  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 nstructi o ns f or u n mas ki n g.  
7.  
D A T A M A N A G E M E N T  
7. 1.  Electr o nic D at a E ntr y  
Data will be tra nscri be d fr o m s o urce d oc u me nts i nt o a n electr o nic data ca pt ure ( E D C) 
s yste m. 
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 st u d y -s pecific 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 data 
ma na ge me nt or cli nical researc h ass ociates.   T he I n vesti gat or or his/ her desi g nee will a ns wer 
t he q ueries a n d u p date t he s o urce data, if nee de d.  

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 2 4  of 5 9  
C O N FI D E N TI A L  
A d verse e ve nts a n d c o m or bi d c o n diti o ns will be c o de d b y data ma na ge me nt usi n g t he latest 
versi o n of t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) .  Me dicati o ns will 
be c o de d b y dat a 
ma na ge me nt usi n g t he 
W orl d Healt h Or ga nizati o n ( W H O) Dr u g 
D icti o nar y. 
After t he l ast su bject last v isit has ta ke n place, t he data base will be clea ne d as necessar y.  As 
s o o n as t he data base is c o nsi dere d clea n, it will be l oc ke d.  T he l oc ke d data base will  be use d 
i n t he fi nal statistical a nal ysis f or st u d y re p orti n g.  Meas ures will be u n derta ke n t o pr otect 
s u bject data ha n dle d d uri n g i ns pecti o ns a gai nst discl os ure t o u na ut h orize d t hir d parties.  
S u bject c o nfi de ntialit y will be mai ntai ne d at all ti mes.  
7. 2.  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 gne d cli nical researc h 
ass ociate .  De viati o ns will be re p orte d i n t he cli nical trial m a 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 o t oc ol de viati o ns. 
7. 3.  D at a Q u alit y  Ass ur a nce  
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 .  
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 sa m ples.  
T he 
m o nit or 
will re vie w t he s o urce data f or acc urac y a n d c o m plet e ness, a n d a n y 
discre pa ncies will be res ol ve d wit h t he I n vesti gat or or desi g nee, as a p pr o priate.  
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 h e 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.  

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 2 5  of 5 9  
C O N FI D E N TI A L  
8.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
8. 1.  S a m ple Size C alc ul ati o ns  
Rece nt re p orts of C O VI D -1 9 i n l o n g -ter m care facilities i n t he U nite d States ha ve s u g geste d 
a hi g h rate of tra ns missi o n of t he S A R S -C o V -2 vir us, b ut i nfecti o n c o ntr ol pr oce d ures ma y 
si g nifica ntl y decrease tra ns missi o n (Mc Mic hael et al. 2 0 2 0, Ki m ball et al. 2 0 2 0 ). A rece nt 
st u d y of 2 6 4 el derl y v ol u nteers ( ≥6 5 years of a ge) re p orte d 1. 6 res pirat or y tract i nfecti o ns 
( n ot la b orat or y-c o nfir me d) per pers o n -year i n dicati n g a p pr o xi matel y a 2 0 % pr o ba bilit y of 
res pirat or y tract i nfecti o n o ver a gi ve n 6-wee k peri o d ( Ma n nic k et. al, 2 0 1 8 ).  I nfecti o n 
c o ntr ol pr oce d ures i n place d u ri n g t he peri o d c o vere d b y t his cli nical trial are als o e x pecte d 
t o re d uce t he tra ns missi o n of ot her res pirat or y vir uses. 
F or p ur p oses of calc ulati n g o ur sa m ple size, we ass u me t hat t he pr o p orti o n of s u bjects 
e x perie nci n g C O VI D -1 9 o ver a 6 -wee k peri o d is 5 % , t he pr o p orti o n of s u bjects e x perie nci n g 
a n y V RI is 1 0 % , a n d t hat effecti ve pr o p h yla xis will re d uce t he rate of C O VI D-1 9 a n d ot her 
V RIs b y 8 0 % .  I nfl ue nza pr o p h yla xis st u dies of oselta mi vir ha ve res ulte d i n a p pr o xi matel y 
8 0 % re d ucti o n of i nfl ue nza ill nes s a m o n g resi de nts of l o n g-ter m care facilities (see Ta mifl u®  
prescri bi n g i nf or mati o n).  
A C oc hra n -Ma ntel -Hae nszel ( C M H) c hi -s q uare test stratif yi n g b y 2 0 L T C Fs will ha ve 
9 2. 8 % statistical p o wer t o detect t he differe nce bet wee n 5 % a n d 1 % rates of occ urre nce of 
C O VI D -1 9 o ver all strata at a n al p ha of 0. 0 4 9 wit h a t otal sa m ple size of 8 0 0, all ocate d 
e q uall y t o strata ( L T C Fs) a n d treat me nt gr o u ps wit hi n strata.  T he statistical p o wer re mai ns 
> 9 2 % w he n t he n u m ber of L T C Fs is 5, 1 0, 1 6 or 2 0.   T he C M H c hi -s q uare test has 9 3. 9 % 
p o wer t o detect t he differe nce bet wee n 1 0 % a n d 2 % rates of occ urre nce of V RIs o ver all 
strata at a n al p ha of 0. 0 0 1 wit h 8 0 0 s u bjects all ocate d e q uall y t o 2 0 L T C Fs.   A dj usti n g t he 
strat u m size t o ass u me u ne q ual all ocati o n w hile h ol di n g t he effect size a n d t otal sa m ple size 
c o nsta nt res ults i n ne gli gi ble c ha n ges (i.e., c ha n ges i n t he t hir d si g nifica nt fi g ure) i n t he st u d y 
p o wer.  
A sa m ple size of 8 0 0 s u bjects ( 4 0 0 per treat me nt gr o u p) was selecte d.    
8. 2.  Effic ac y V ari a bles  
Pri mar y Efficac y Para meter s: 
i. T he pr o p orti o n of s u bjects 
wit h s y m pt o matic 
la b orat or y-c o nfir me d  C O VI D -1 9 i de ntifie d after 
start of treat me nt a n d bef ore t he e n d of t he 6 -wee k 
treat me nt peri o d 
 
ii. T he pr o p orti o n of s u bjects 
wit h s y m pt o matic 
la b orat or y-c o nfir me d  V RI i de ntifie d after start of 
treat me nt a n d bef ore t he e n d of t he 6 -wee k 
treat me nt peri o d 
Sec o n dar y Efficac y Para meters:  
i. T he pr o p orti o n of s u bjects h os pitalize d d ue t o 
C O VI D -1 9 or c o m plicati o ns t here of  
 
ii. M ortalit y d ue t o C O VI D -1 9 or c o m plicati o ns 
t here of 

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 2 6  of 5 9  
C O N FI D E N TI A L  
 
iii. T he pr o p or ti o n of s u bjects ( wit h or 
wit h o ut 
s y m pt o ms) testi n g p ositi ve f or a nti b o dies t o 
S A R S -C o V -2 at  eit her of t he Wee k 6 or Wee k 8 
visit s 
E x pl orat or y Efficac y Para meter s: 
H os pitalizati o n d ue t o V RI or c o m plicati o ns t here of, 
m ortalit y d ue t o 
V RI or c o m plicati o ns t here of, 
pr o p orti o ns of s u bjects e x perie nci n g ac ute res pirat or y 
ill ness ( A RI), h os pitalizati o n 
d ue t o 
A RI 
or 
c o m plicati o ns t here of, a n d m ortalit y d ue t o A RI or 
c o m plicati o ns t here of .  
8. 3.  Res p o nse Defi niti o ns  
A RI:  
≥0. 5 i ncrease fr o m baseli ne i n 
mea n s y m pt o m sc ore f or t he 
c hest/res pirat or y F L U -P R O d o mai n or ≥0. 5 i ncrease fr o m baseli ne 
i n mea n s y m pt o m sc ore f or at least t w o of t he f oll o wi n g F L U -
P R O ©  d o mai ns : b o d y/s yste mic, n ose, t hr oat . 
C O VI D -1 9:  
A RI after start of tr eat me nt a n d bef ore t he e n d of  t he 6 -wee k 
treat me nt peri o d ass ociate d wit h detecti o n of S A R S -C o V -2 b y R T -
P C R assa y of nas o p har y n geal s wa b.  
V RI : 
A RI after start of treat me nt a n d bef ore t he e n d of  t he 6 -wee k 
treat me nt peri o d ass ociate d wit h detecti o n of a n y res pirat or y vir us 
b y  R T -P C R assa y of nas o p har y n geal s wa b .   
8. 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.  
8. 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 
wit h o ut a la b orat or y -detecte d viral res pirat or y i nfecti o n at t he baseli ne visit (i nte nti o n -
t o-treat or I T T p o p ulati o n).      
T here will be t w o pri mar y efficac y a nal yses:  
 T he pr o p orti o n of s u bjects e x perie nci n g  C O VI D -1 9  i n 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 t w o-si de d C oc hra n-
Ma ntel -Hae nszel  ( C M H) c hi-s q uare test ( α = 0. 04 9 ).  
 T he pr o p orti o n of s u bjects e x perie nci n g  V RI i n t he N T Z tr eat 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 t w o-si de d C M H  c hi-s q uare 
test ( α = 0. 00 1 ). 
Sec o n da r y a nal yses will be perf or me d as f oll o ws: 

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 2 8  of 5 9  
C O N FI D E N TI A L  
T he f o o d pri or t o dr u g i nta ke s h o ul d prefera bl y be a hi g h -fat meal, b ut at mi ni m u m a cereal 
bar.  
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 
( ma n ufact urer’s la bele d d osi n g) t o hel p mas k a n y p ote ntial 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.     
9. 2.  I de ntit y of I n vesti g ati o n al Pr o d ucts 
T he act i ve f or m ulati o n f or t his st u d y is a yell o w, fil m-c oate d ta blet t hat c o ntai ns 3 0 0 m g 
N T Z pl us sta n dar d e xci pie nts.  T he place b o ta blet 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 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 2 4 0 %, vita mi n B 5 3 6 0 %, vita m i n B 6 1 0 0 0 %, vita mi n B 7 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 %.  
9. 3.  P ac k a gi n g a n d L a beli n g  
N T Z or place b o ta blets will be pac ka ge d i n w hite 3 0 cc H D P E b ottle s, eac h c o ntai ni n g 2 0  
ta blets.  Eac h s u bject will recei ve a b o xe d kit c o ntai ni n g 1 8 0 ta blets (9 b ottles).  T he s u bjects 
will ta ke t w o ta blets wit h f o o d at eac h d osi n g ti me p oi nt.  T he kits  will be st ore d at r o o m 
te m perat ure a n d will bear la bels wit h t he f oll o wi n g i nf or mati o n:  
T a ble  6 : 
St u d y Me dic a ti o n L a bels 
E xter n al B o x L a bel  
Pri nci p al I n vesti g at or:  
9 B ottles ( 2 0 Ta blets Eac h)  
1 8 0 Ta blets  T otal  
St u d y N° R M 0 8 -3 0 0 6  
Treat me nt N°: X X X X  
L ot:  
 
 
T a ke 2 T a blets b y M o ut h wit h F o o d  T wice D ail y  
Ca uti o n: Ne w Dr u g -Li mite d b y Fe deral La w t o I n vesti gati o nal Use  
S T O R E A T R O O M T E M P E R A T U R E • D O N O T U S E B E Y O N D E N D O F S T U D Y  
K E E P O U T O F R E A C H O F C HI L D R E N  
St u d y S p o ns or: T he R o mar k I nstit ute f or Me dical Researc h  
 
 
I n di vi d u al B ottle L a bel 

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 2 9  of 5 9  
C O N FI D E N TI A L  
2 0 Ta blets  
St u d y N° R M 0 8 -3 0 0 6  
Treat me nt N°: X X X X   
L ot:  
 
 
T a ke 2 T a blets b y M o ut h wit h F o o d  T wice D ail y  
Ca uti o n: Ne w Dr u g -Li mite d b y Fe deral La w t o I n vesti gati o nal Use  
S T O R E A T R O O M T E M P E R A T U R E • D O N O T U S E B E Y O N D E N D O F S T U D Y  
K E E P O U T O F R E A C H O F C HI L D R E N  
St u d y S p o ns or: T he R o mar k I nstit ute f or Me dical Researc h 
 
9. 4.  Dr u g Acc o u nt a bilit y  
Me dicati o n will be dis pe nse d at baseli ne.  Me dicati o n c o m plia nce will be re vie we d wit h eac h 
s u bject at eac h sc he d ule d a n d u nsc he d ule d visit , s u bjects will be as ke d t o ret ur n t he b ottle s 
i n w hic h t he me dicati o n was dis pe nse d al o n g wit h an y u n use d me dicati o n.  
T he I n vesti gat or or desi g nee is re q uire d t o mai ntai n a de q uate rec or ds of t he dis p ositi o n of 
all st u d y dr u g, i ncl u di n g dates, q ua ntit y a n d use b y s u bject.  U n use d s u p plies m ust be 
ret ur ne d t o t he S p o ns or. 
9. 5.  S u bject C o m pli a nce  
S u bject c o m plia nce wit h t he pr ot oc ol will be c hec ke d b y t he I n vesti gat or a n d rec or de d i n t he 
E D C s yste m at eac h visit.  
S u bjects will be c o nsi dere d n o n -c o m plia nt if t he y ha ve misse d m ore t ha n 2 0 % of t he d oses 
of t he st u d y me dicati o n  ( maj or pr ot oc ol vi olati o n).  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.  
9. 6.  Dis all o we d Me dic ati o n  
D uri n g t he acti ve treat me nt c o urse of t he st u d y, c o nc o mita nt use of me dicati o ns c o nsi dere d 
maj or C Y P 2 C 8 s u bstrates are pr o hi bite d, see bel o w.  
T a ble  7 : 
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 y et gra nte d a tra de na me b y t he ma n ufact urer.  

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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, N T Z (e xce pt as 
t he bli n de d i n vesti gati o nal me dicati o n) or a n y ot her i n vesti gati o nal me dicati o n or vacci ne 
d uri n g t he st u d y.   Si nce tiz o xa ni de is hi g hl y pr otei n -b o u n d a n d ma y c o m pete wit h plas ma 
pr otei n bi n di n g sites, c o-a d mi nistrati o n of N T Z  a n d warfari n s h o ul d be a v oi de d if reas o na bl y 
p ossi ble .  If c o-a d mi nistrati o n of N T Z  a n d warfari n ca n n ot be a v oi de d, t he i n vesti gat or m ust 
m o nit or pr ot hr o m bi n ti me a n d i nter nati o nal n or malize d rati o ( P T/I N R) i n s u bjects ta ki n g 
warfari n  as cli nicall y warra nte d . 
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. T he use of s u c h me dicati o n will be rec or de d i n t he E D C s yste m.  
1 0.  A D V E R S E E V E N T S  
T he ter m “a d verse e ve nt” is defi ne d f or p ur p oses of t his st u d y as 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 t a 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 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, 
fe veris h ness) a n d c o m plicati o ns of V RIs  will n ot be re p orte d as a d verse e ve nts.  
A d verse e ve nts will be rec or de d o n t he a p pr o priate E D C f or ms t hr o u g h o ut t he st u d y, a n d t he 
se verit y of eac h a d verse e ve nt will be gra de d o n a f o ur-p oi nt scale: mil d, m o derate, se vere, 
or life -t hreate ni n g (See A p pe n di x II ).  T he d urati o n of t he a d verse e ve nt a n d relati o ns hi p t o 
t he st u d y dr u g will als o be rec or de d.  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. 
1 0. 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 ver se e ve nts: 
1.  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.  
2.  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. 
3.  Se verit y of a d verse e ve nts  will be assesse d b y t he I n vesti gat or usi n g t he T o xicit y 
Gra d i n g Scale Ta bles pr o vi de d i n A p pe n di x II  ( 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 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 h e 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). 

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4.  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 n t 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. 
1 0. 2.  Cli nic al A d verse E ve nts  
At t he ti me of eac h ret ur n 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.  All e ve nts m ust be rec or de d i n t he s u bjects' 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 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 nt act 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 per ie nces.  Seri o us a d verse e ve nts, 
i ncl u di n g deat h re gar dless of t he ca use, m ust be re p orte d t o t he S p o ns or i m me diatel y ( wit hi n 
2 4 h o urs o f t he i nitial re p ort). 
A seri o us e ve nt re q uiri n g i m me diate n otificati o n  b y tele p h o ne is a n e ve nt t hat:  
 res ults i n deat h 
 is life t hreate ni n g  

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 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 or sig nifica nt di sa bilit y/i nca pacit y 
 is a c o n ge nital a n o mal y/ birt h defect 
 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 n e of t he o utc o mes 
liste d a b o ve. 
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, w hic he ver d ose is lar ger.  O ver d oses wit h o ut a n ass ociate d a d verse 
e ve nt s h o ul d be rec or de d, b ut n ot re p orte d as a n a d verse e ve nt.  
1 0. 3.  Re p orti n g Re q uire me nt  
T he Pri nci pal I n vesti gat or is re q uire d t o n otif y T he R o mar k I nstit ute f or Me dical Researc h 
( S p o ns or) i m me diatel y of a n y u ne x pecte d, fatal, or life-t hreate ni n g e x perie nce a n d all 
u n us ual, alar mi n g, or seri o us reacti o ns t o me dicati o n re gar dless of a n y o pi ni o ns as t o t he 
ca use/effect relati o ns hi p.  All seri o us a d verse e ve nts will als o be r e p orte d t o t he I R B.  
A d vers e e ve nts s h o ul d be re p orte d t o:  
T he R o mar k I nstit ute f or Me dical Researc h  
Me dical Affairs  
  
  
 
 
1 0. 4.  Me dic ati o n M o dific ati o n/ Wit h dr a w al D ue t o a n A d verse E ve nt  
If a se vere a d verse reacti o n de vel o ps d uri n g t hera p y, t he st u d y me dicati o n s h o ul d be 
disc o nti n ue d, a n d t he s u bject s h o ul d be wit h dra w n fr o m t he st u d y.  
1 0. 5.  Me dic ati o n Err ors  
A me dicati o n err or is defi ne d as a n y pre ve nta ble e ve nt relate d t o d osi n g i nstr ucti o ns, pr o d uct 
la beli n g, or pac ka gi n g t hat ca uses or lea ds t o i na p pr o priate me dicati o n use or s u bject har m 
w hile t he me dicati o n is i n t he c o ntr ol of t he i n vesti gati ve site or s u bject.  Me dicati o n err ors 
w hic h res ult i n a d verse  e ve nts s h o ul d be rec or de d a n d re p orte d as a d verse e ve nts.  All ot her 
me dicati o n err ors s h o ul d be re p orte d t o t he st u d y S p o ns or t hr o u g h t he Me dical Affairs 
de part me nt wit hi n 7 da ys of i de ntificati o n b y t he site.  
1 1.  DI S C O N TI N U A TI O N  
1 1. 1.  St u d y Disc o nti n u ati o n  
T 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: 

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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 wil l 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 vide d i n A p pe n di x II ). 
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 ns tit uti o nal Re vie w B oar ds, 
a n d F D A’s Di visi o n of A nti -I nfecti ves will be n otifie d.  All safet y a n d acti vit 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 1. 2.  S u bject Disc o nti n u ati 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 st u d y 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.  
1 2.  E L E C T R O NI C D A T A C O L L E C TI O N ( E D C) S Y S T E M  
A n E D C s y ste m will be use d f or t his st u d y.  Pri or t o st u d y i nitiati o n, site staff a n d a ut h orize d 
R o mar k pers o n nel  will be trai ne d t o use t his s yste m.  
All s o urce f or ms are t o be fille d o ut c o m pletel y b y t he e xa mi ni n g site staff a n d re vie we d a n d 
si g ne d off o n b y t he I n vesti gat or(s).   
1 3.  R E T E N TI O N O F R E C O R D S  
Esse ntial D oc u me nts are d oc u me nts t hat i n di vi d uall y a n d c ollect i vel y per mit e val uati o n of 
t he c o n d uct of a trial a n d q ualit y of t he data pr o d uce d.  T he y de m o nstrate t he c o m plia nce of 
t he I n vesti gat or, S p o ns or, a n d m o nit or wit h t he G C P sta n dar ds a n d wit h all a p plica ble 
re g ulat or y re q uire me nts. 
I n c o m plia nce wit h t he I CH/ G C P g ui deli nes, t he I n vesti gat or/i nstit uti o n will mai ntai n all 
C R Fs a n d all 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, Esse ntial 
D oc u me nts f or  t he C o n d uct of a Cli nical Trial, 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 nt(s).  A list of t hese d oc u me nts is f o u n d i n A p pe n di x III : 
List of Esse ntial D oc u me nt f or t he I n vesti gati ve Site .  T he I n vesti gat or/i nstit uti o n wi ll ta ke 
meas ures t o pre ve nt acci de ntal or pre mat ure destr ucti o n of t hese d oc u me nts.  

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Esse ntial d oc u me nts liste d i n A p pe n di x III  m ust be retai ne d 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 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 is res p o nsi ble f or or ga nizi n g a n d 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 4.  M O NI T O RI N G T H E S T U D Y  
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  
acc or di n g t o sta n dar d o perati n g pr oce d ures.  Site visits will be c o n d ucte d b y t he S p o ns or or 
t heir re prese ntati ves at re g ular i nter vals t o c o n d uct i ns pecti o ns.  
A f ull descri pti o n of t he m o nit ori n g pr oce d ures f or t his st u d y will be detaile d i n t he 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 hica l 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. 
A n I n de pe n de nt  Data M o nit ori n g C o m mittee  (I D M C) will be or ga nize d f or t his st u d y.  A 
f ull descri pti o n of t he I D M C pr oce d ures f or t his st u d y will be detaile d i n t he Me dical 
M o nit ori n g ( Safet y) Pla n  a n d I D M C C harter .  T he I D M C will cl osel y m o nit or t he i nci de nce 
of diarr hea as it c o ul d p ote ntiall y be a ve hicle f or t he s prea d of S A R S -C o V -2.  E nr oll me nt 
will be pa use d w hile t he I D M C c o n d ucts its first i nteri m a nal ysis  of safet y a n d f utilit y.  T he 
I D M C ma y als o c o n d uct a nal yses of safet y, f utilit y a n d effecti ve ness if t he n u m ber of 
C O VI D -1 9 ill nesses is hi g her t ha n a ntici pate d.       
1 5.  I N F O R M E D C O N S E N T  
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 for 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. 
Bef ore e n r 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 

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a ut h orize d S p o ns or staff wit h o ut vi olati n g t he c o nf i 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 co nse nt f or a d diti o nal safet y e val uati o ns, if nee de 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 hich 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. 
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 verif icati 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.   
1 6.  E T HI C S  
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 Fortaleza, Brazil, Oct o ber 
2 0 1 3 ).  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 fr o m t he a p pr o priate l ocal Me dical Et hics Re vie w B oar d.  
1 6. 1.  St u d y -S pecific Desi g n C o nsi der ati o ns  
P ote ntial s u bjects will be f ull y i nf or me d of t he ris ks a n d re q uire me nts of t he st u d y a n d d uri n g 
t he st u d y s u bjects will be gi ve n a n y ne w i nf or mati o n t hat ma y affect t heir decisi o n t o 
c o nti n ue partici pati o n.  T he y will be t ol d t hat t heir c o nse nt t o partici pate i n t he st u d y is 
v ol u ntar y a n d ma y be wit h dra w n at a n y ti me wit h n o reas o n gi ve n a n d wit h o ut pe nalt y or 
l oss of be nefits t o w hic h t he y w o ul d ot her wise be e ntitle d.  O nl y 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.  
1 6. 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 Cl i 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.  

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1 6. 3.  I nstit uti o n al Re vie w B o ar d (I R B) 
Bef ore t he start 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 pr o vi de t he 
I R B wit h c urre nt a n d c o m plete c o pies of t he f oll o wi n g d oc u me nts: 
 Fi nal pr ot oc ol a n d, if a p plica ble, a me n d me nts  
 S p o ns or -a p pr o ve d I C F (a n d a n y ot her writte n materials t o be pr o vi de d t o t he s u bjects)  
 I n vesti gat or’s Br oc h ure ( or e q ui vale nt i nf or mati o n) a n d a d de n da 
 S p o ns or -a p pr o ve d s u bject recr uiti n g materials  
 I nf or mati o n o n c o m pe nsati o n f or st u d y-relate d i nj uries or pa y me nt t o s u bjects f or 
partici pati o n i n t he st u d y, if a p plica ble  
 I n vesti gat or’s c urric ul u m vitae or e q ui vale nt i nf or mati o n ( u nless n ot re q uire d, as 
d oc u me nte d b y I R B)  
 I nf or mati o n re gar di n g f u n di n g, na me of t he S p o ns or, i nstit uti o nal affiliati o ns, ot her 
p ot e ntial c o nflicts of i nterest, a n d i nce nti ves f or s u bjects  
 A n y ot her d oc u me nts t hat t he I R B re q uests t o f ulfill its o bli gati o n  
T his st u d y will be u n derta ke n o nl y after t he I R B has gi ve n f ull a p pr o val of t he fi nal pr ot oc ol, 
a me n d me nts (if a n y), t he I C F, a p pl ica ble recr uiti n g materials, a n d s u bject c o m pe nsati o n 
pr o gra ms, a n d t he S p o ns or has recei ve d a c o p y of t his a p pr o val.  T his a p pr o val letter m ust 
be date d a n d m ust clearl y i de ntif y t he I R B a n d t he d oc u me nts bei n g a p pr o ve d.  
D uri n g 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 se n d t he f oll o wi n g 
d oc u me nts a n d u p dates t o t he I R B f or t heir re vie w a n d a p pr o val, w here a p pr o priate:  
 Pr ot oc ol a me n d me nts  
 Re visi o n(s) t o I C F a n d a n y ot her writte n materials t o be pr o vi de d t o s u bjects  
 If a p plica ble, ne w or re vise d s u bject recr uiti n g materials a p pr o ve d b y t he S p o ns or 
 Re visi o ns t o c o m pe nsati o n f or st u d y -relate d i nj uries or pa y me nt t o s u bjects f or 
partici pati o n i n t he st u d y, if a p plica ble  
 I n vesti gat or’s Br oc h ure a d de n da or ne w e diti o n(s) 
 S u m maries of t he stat u s of t he st u d y at i nter vals sti p ulate d i n g ui deli nes of t he I R B (at 
least a n n uall y) 
 Re p orts of A Es t hat are seri o us, u nliste d, a n d ass ociate d wit h t he i n vesti gati o nal dr u g  
 Ne w i nf or mati o n t hat ma y a d versel y affect t he safet y of t he s u bjects or t he c o n d uct of 
t he st u d y 
 De viati o ns fr o m or c ha n ges t o t he pr ot oc ol t o eli mi nate i m me diate hazar ds t o t he s u bjects  
 Re p ort of deat hs of s u bjects u n der t he I n vesti gat or’s care  
 N otificati o n if a ne w I n vesti gat or is res p o nsi ble f or t he st u d y at t he site  

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 A n n ual I N D U p date Re p ort, S h ort Ter m St u d y S pecific Safet y S u m mar y a n d Li ne 
Listi n gs, w here a p plica ble  
 A n y ot her re q uire me nts of t he I R B  
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 a s 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.  
1 6. 4.  Pri v ac y of Pers o n al D at a  
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 
m ust be c ol lecte 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 m ust 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.  
1 7.  D A T A C O N FI D E N TI A LI T Y , DI S C L O S U R E O F D A T A, A N D P U B LI C A TI O N  
Data ge nerate d f or t he st u d y s h o ul d 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 pria te me dical pers o n nel res p o nsi ble f or t he s u bject’s welfare.   
N o i nf or mati o n t hat ca n be relate d t o a s pecific i n di vi d ual s u bject ma y be release d or use d i n 
a n y fas hi o n 
wit h o ut t he si g ne d 
writte n c o nse nt of t hat s u bject.  
All re p orts a n d 
c o m m u nicati o ns rel ati n g t o 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.  T he I n vesti gat or will kee p c o m plete s u bject i de ntificati o n f or 

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p ur p oses of l o n g -ter m f oll o w-u p, if nee de d.  T his i nf or mati o n will be treate d wit h strict 
a d here nce t o pr ofessi o nal sta n dar ds of c o nfi de ntialit y.  
Site pers o n nel will e nter data relati n g t o eac h s u bject’s partici pati o n i n t he st u d y i nt o t he 
E D C s yste m pr o vi de d b y t he S p o ns or.  I n t he E D C s yste m, i de ntificati o n n u m bers a n d i nitials 
will be use d t o i de ntif y s u bjects.  S u bject na mes will n ot be use d i n t he C R Fs.  Ma na ge me nt 
of data fr o m t he E D C s yste m a n d t he pr o d ucti o n of t he cli nical st u d y re p ort will be t he 
res p o nsi bilit y of t he S p o ns or.  Access t o t he data base will be restricte d t o e m pl o yees w h o 
ha ve bee n trai ne d t o use t he s yste m.  Access t o t he E D C s yste m a n d st u d y re p ort will be 
li mite d t o t he I R B, F D A or ot her re g ulat or y a ge ncies a n d t he S p o ns or. 
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 na l.  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 8.  D A T A A N D R E P O R T R E Q U I R E M E N T S 
Dat a re q uire d b y T he R o mar k I nstit ute f or Me dical Researc h pri or t o a p pr o val a n d i nitiati o n 
of t he st u d y are as f oll o ws:  
1.  C urric ul u m vitae of t he Pri nci pal I n vesti gat or a n d all C o -I n vesti gat ors.  
2.  C o p y of t he I R B -a p pr o ve d I nf or me d C o nse nt a n d s u bject i nf or mati o n f or ms.  
3.  C o p y of t he I R B a p pr o val f or t he c o n d uct of t he st u d y.  
Data a n d materials re q uire d b y T he R o mar k I nstit ute f or Me dical Researc h 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 are as f oll o ws:  
1.  Pre - a n d p ost -treat me nt hist or y, p h ysical e xa mi nati o n a n d s u bject e val uati o ns.  
2.  Pre - as well as i nteri m a n d p ost -treat me nt la b orat or y fi n di n gs a n d all s pecial test res ults. 
3.  E D C f or ms pr o perl y c o m plete d a n d si g ne d b y t he Pri nci pal I n vesti gat or.  
4.  Dr u g I n ve nt or y L o gs i n dicati n g dr u g dis pe nse d a n d re t ur n of t he u n use d s u p plies t o t he 
S p o ns or or destr ucti o n b y st u d y site.  
5.  Si g ne d I nf or me d C o nse nt/ Asse nt fr o m eac h s u bject.  

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2 0.  LI S T O F R E F E R E N C E S  
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.  
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. 
As ht o n L V, Calla n R L, Ra o S, La n d olt G A. I n vitr o s u sce 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.  
B raa 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 ollec ti 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.  
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n.  Atla nta, G A.  I nteri m G ui da nce f or I nfl ue nza O ut brea k 
Ma na ge me nt i n L o n g -Ter m Care a n d P ost -Ac ute Care Facilities  [I nter net]. [ u p date d 1 8 N o v 2 0 1 9 ; 
cite d 1 2 Mar 2 0 2 0] . A vaila ble fr o m: htt ps:// w w w.c dc. g o v/fl u/ pr ofessi o nals/i nfecti o nc o ntr ol/ltc -
facilit y-g ui da nce. ht m    
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.  
C hec o vic h 
M M, Ba rl o w S, S h ult P. E val uati o n of vir uses ass ociate d w it h ac ute res pirat or y 
infe cti o ns i n lo n g -ter m care facilities usi n g a n o vel m et h o d: Wisc o nsi n, 2 0 1 6 -2 0 1 9. J A m Me d Dir 
Ass oc  2 0 2 0; 2 1: 2 9 -3 3.  
C hil ds  A, Z ull o A R, J o yce N R, Mc C o ne g h y K W, va n Aalst R, et al. T he b ur de n of res pirat or y 
i nfecti o ns a m o n g ol der a d ults i n l o n g-ter m care: a s yste matic re vie w. B M C Geri atrics  2 0 1 9; 
1 9: 2 1 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.  
False y A R, Dallal G E, F or mica M A, A n d oli na G G, Ha mer D H, Le ka L L, Me y da ni S N. L o n g -
ter m care facilities: A c or n uc o pia of viral pat h o ge ns. J A m Geri atr S oc 2 0 0 8; 5 6: 1 2 8 1 -8 5.  
G o o d wi n K , Vi b o u d C, Si m o nse n L. A nti b o d y res p o nse t o i nfl ue nza vacci nati o n i n t he el derl y: A 
q ua ntitati ve re vie w. V acci ne  2 0 0 6; 2 4: 1 1 5 9 -6 9.  
Ha n d J, R ose E B, Sali nas A, L u X, Sa kt hi vel S K, Sc h nei der E, Wats o n J T . Se vere res pirat or y 
ill ness o ut brea k ass ociate d wit h h u ma n c or o na vir us N L 6 3 i n a l o n g -ter m care facilit y. E mer g 
I nfect Dis 2 0 1 8 ; 2 4: 1 9 6 4-6 6 . 
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.  

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 4 1  of 5 9  
C O N FI D E N TI A L  
Ki m ball A, Hatfiel d K M, Ar o ns M, Ja mes A, Ta yl or J, et a l. As y m pt o matic a n d pres y m pt o matic 
S A R S -C o V -2 i nfecti o ns i n resi de nts of a l o n g -ter m care s kille d n ursi n g facilit y— Ki n g C o u nt y, 
Was hi n gt o n, Marc h 2 0 2 0 . M M W R M or b M ort al Wkly Re p  2 0 2 0;  6 9: 3 7 7 -3 8 1 . 
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.  
L o n gti n J, Marc ha n d -A usti n A, Wi nter A -L, Patel S, Es ha g hi A, et al. R hi n o vir us o ut brea ks i n  
lo n g -ter m care facilities, O ntari o, Ca na da. E mer g I nfect Dis 2 0 1 0; 1 6: 1 4 6 3 -6 5 . 
Ma n nic k J B, M orris M, H oc ke y H -U, R o ma G, Bei bel M, et. al.  T O R C 1i n hi biti o n e n ha nces 
i m m u ne f u ncti o n a n d re d uces i nfecti o ns i n t he el derl y. Sci Tr a nsl Me d  2 0 1 8; 1 0:eaa q 1 5 6 4.  
M c Mic hael T M, Clar k S, P o g osja ns S, Ka y M, Le wis J, et al. C O VI D -1 9 i n a l o n g -ter m care 
facilit y— Ki n g C o u nt y, Was hi n gt o n, Fe br uar y 2 7 – Marc h 9, 2 0 2 0.  M M W R M or b M ort al Wkly Re p  
2 0 2 0;  6 9: 3 3 9 -3 4 2.  
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.  
Mc Geer A, Sitar D S, Ta m bl y n S E, K ol be F, Orr P, A o ki F Y . Use of a nti viral pr o p h yla xis i n 
i nfl ue nza o ut brea ks i n l o n g ter m care facilities. C a n J I nfect Dis 2 0 0 0; 1 1: 1 8 7 -9 2 . 
M o nt o A S, Br ya n E R, O h mit  S. R hi n o vir us i nfecti o ns i n Tec u mse h, Mic hi ga n: Fre q ue nc y of 
ill ness a n d n u m ber of ser ot y pes. J I nfect Dis  1 9 8 7; 1 5 6: 4 3 -4 9.  
Peters P H Jr, Gra ve nstei n S, N or w o o d P, De B oc k V, Va n C o uter A, et al. L o n g-ter m use of 
oselta mi vir f or t he pr o p h yla xis of i nfl ue nza i n a vacci nate d f rail ol der p o p ulati o n. J A m Geri atr 
S oc  2 0 0 1; 4 9: 1 0 2 5 -3 1 . 
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.  
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, 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.  
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.  

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 4 2  of 5 9  
C O N FI D E N TI A L  
Sa g D, Car li 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.  
T A MI F L U ( o selta mi vir) prescri bi n g i nf or mati o n. Ge ne ntec h, I nc., S o ut h Sa n Fra ncisc o, C A, 
A u g ust 2 0 1 9.  
T h o m ps o n W W, S ha y D K, Wei ntra u b E, Bra m mer L, C o x N A n ders o n LJ, F u k u da K.  M ortalit y 
ass ociate d wit h i nfl ue nza a n d res pirat or y s y nc ytial vir us i n t he U nite d States. J A M A 2 0 0 3; 
2 8 9 : 1 7 9-8 6.  
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.  
Ursic T, Mi ksic  N G, L usa L, Strle F, Petr o vec M . Viral res pirat or y i nfecti o ns i n a n ursi n g h o me: 
a si x-m o nt h pr os pecti v e st u d y. B M C I nfect Dis  2 0 1 6; 1 6: 6 3 7 . 
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 k i 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 fu ncti o n. J Bi ol 
C he m  2 0 0 3; 2 7 8: 2 7 0 1 6 -2 3.  
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 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 4 3  of 5 9  
C O N FI D E N TI A L  
2 1.  A P P E N DI C E S  
A p p e n di x I: 
St u d y Sc he d ule  
A p pe n di x II:  
T o xicit y Gra di n g f or A d verse E ve nts  
A p pe n di x III:  List of Esse ntial D oc u me nts f or t he I n vesti gati ve Site  
A p pe n di x I V:  Pr ot oc ol Re visi o n Hist or y  
A p pe n di x V:  
Declarati o n of Helsi n ki  
 
 

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4. 0  
 
A u g ust 2 8 , 2 0 2 0 
 
Pa ge 4 4  of 5 9  
C O N FI D E N TI A L  
2 1. 1.  A p pe n di x I: St u d y Sc he d ule  
T a ble  9 : 
Sc he d ule of Assess me nts  
 
Scree ni n g 
( D a y-9 0 t o 
D a y 1)  
B aseli ne 
( D a y 1) 
D a y 1 -
Wee k 6  
Wee ks 
1, 3, 6  
Wee k 
8  
S us pecte d 
A RI  
Visit  
U nsc he d - 
ule d Visit  
Si g ne d i nf or me d c o nse nt  
X  
 
 
 
 
 
 
C o m plete me dical hist or y  
X  
 
 
 
 
 
 
P h ysical e xa mi nati o n  
X  
 
 
X 1 
X  
X 1 
X  
B o d y wei g ht/ vital si g ns 2  
X  
 
 
X  
 
X  
X  
De m o gra p hics/s m o ki n g hist or y  
X  
 
 
 
 
 
 
Rec or d b o d y  te m perat ure 
X  
 
 
X  
 
X  
X  
E val uate acc or di n g t o 
i ncl usi o n/e xcl usi o n criteria 
X  
 
 
 
 
 
 
C ollect nas o p har y n geal s wa bs  
 
X  
 
 
 
X 3 
X  
Bl o o d sa m ple f or p har mac o ki netics 4  
 
 
 
X  
 
 
 
Bl o o d sa m ple f or la b orat or y safet y tests 5 
 
X  
 
X  
 
 
X  
Bl o o d sa m ple f or a nti b o d y testi n g  
 
X  
 
X 7 
X  
 
 
Uri ne sa m ple f or r o uti ne uri nal ysis 5 
 
X  
 
X  
 
 
X  
Rec or d c o nc o mita nt me dicati o ns  
 
X  
X  
X  
X  
X  
X  
Ra n d o mizati o n/ dis pe nse st u d y 
me dicati o n  
 
X  
 
 
 
 
 
C o m plete s y m pt o m diar y  
 
X  
X 6  
 
 
X  
 
First d ose, t he n st u d y me dicati o n t wice 
dail y f or 6 wee ks  
 
X  
X  
 
 
 
 
I nstr ucti o ns re: d osi n g, c o nc o mita nt 
me dicati o ns, f oll o w -u p visits a n d 
see ki n g e mer ge nc y care 
 
X  
 
X  
 
 
X  
Re vie w/rec or d a d verse  e ve nts 
 
X  
 
X  
X  
X  
X  
I n q uire re gar di n g c ol d/fl u s y m pt o ms a n d 
refer f or S us pecte d A RI visit if yes  
 
 
X  
 
 
 
 
Re vie w c o m plia nce wit h st u d y 
me dicati o n, c ollect c o ntai ner wit h 
u n use d me dicati o n, c o m plete pill c o u nt 
l o g f or m 
 
 
 
X  
 
 
 
D oc u me nt a n y i nfecti o ns dia g n ose d 
d uri n g f oll o w -u p peri o d  
 
 
 
 
X  
 
 
1  P h ysical e xa mi nati o n as warra nte d b y t he I n vesti gat or f or a n y c ha n ge fr o m Baseli ne.  
2    B o d y wei g ht a n d c ollecti o n of vital si g ns t o i ncl u de bl o o d press ure, p ulse, res pirat or y rate a n d b o d y te m p erat ure.  
3 Nas o p har y n geal s wa bs are t o be c oll ecte d at a S us pecte d A RI Visit a n d re peat s wa bs c ollect e d 2 4  t o 3 6 h o urs  a n d 4  t o 5 da ys  later.  
4  Wee k 3 a n d 6 visit o nl y, b l o o d sa m pl e t o be c ollecte d pre -d ose.  
5  Wee k 3 a n d 6 visit o nl y, a b orat or y s afet y tests i ncl u de  he m o gl o bi n, he mat ocrit, c o m plete bl o o d c o u nt (t otal a n d differe ntial), platelet c o u nt, 
ra n d o m bl o o d s u gar, t otal c h olester ol, H D L, L D L, tri gl yceri des, al b u mi n, A S T, A L T, G G T, al kali ne p h os p hatase, bilir u bi n (t otal/ direct), B U N, 
creati ni ne, s o di u m, p otassi u m, c hl ori de a n d r o uti ne uri nal ysis ( a p peara nce, gl uc ose, pr otei ns a n d bl o o d).  
6  If t he s u bject meets t he criteri a f or a S us pecte d A RI, t h e n he/s he will be as ke d t o c o m plete a s y m pt o m diar y, a n d t he n c o nti n ue dail y wit h t he 
s y m pt o m diar y bet wee n 4 p m a n d 8  p m eac h da y u ntil t he s u bject ret ur ns t o us ual healt h f or 3 c o nsec uti ve da ys  or u ntil t he Wee k 6 Visit, 
w hic he ver c o mes first .  A care gi ver ma y assist t he s u bject wit h t he diar y e ntr y if nee de d. 
7  Wee k 6 o nl y.  
 
 

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4 . 0 
 
 
 
A u g ust 2 8 , 
2 0 2 0  
 
Pa ge 5 5  of 5 9  
C O N FI D E N TI A L  
S u m m ar y of  C h a n ges  
C ha n ge 8  
Secti o n 4. 1: Re vise d I ncl usi o n Criteria # 3 t o “ At least o ne s y m pt o matic la b orat or y -c o nfir me d C O VI D -1 9 ill ness i de ntifie d 
a m o n g resi de nts or staff of t he L T C F wit hi n 1 0 da ys pri or t o ra n d o mizati o n.”  
C ha n ge 9  
Secti o n 4. 2:  
 
Re vise d E xcl usi o n Criteria # 2 t o “ S u bjects e x pecte d t o re q uire h os pitalizati o n wit hi n t he 8 -wee k treat me nt a n d 
f oll o w-u p peri o d.”  
 
A d de d E xcl usi o n Criteria # 3, “ S u bjects wit h a hist or y of C O VI D -1 9 or k n o w n t o ha ve de vel o pe d a nti -S A R S -C o V -2 
a nti b o dies.”  Ot her E xcl usi o n Criteria were m o ve d d o w n o ne n u m ber acc or di n gl y.  
C ha n ge 1 0  
Secti o n 5. 1:  
 
Re vise d t h e Scree ni n g E val uati o n wi n d o w fr o m Da y -3 0 t o Da y -9 0.  
 
Re m o ve d o n ite m # 4 , “ …re peat at Baseli ne if scree ni n g is n ot perf or me d t he sa me da y as Baseli ne.”  
 
A d de d, “ T he i nf or mati o n c ollecte d d uri n g t he scree ni n g peri o d m ust be c urre nt t hr o u g h t he ti me of ra n d o mizati o n.”  
C ha n ge 1 1  
Secti o n 5. 2:  
 
Ite m # 1, re m o ve d “( C o pa n Dia g n ostics)”. 
 
Ite m # 2, a d de d “ …a n d a nti-S A Rs -C o V -2 a nti b o dies.”  
 
Ite m 8 b, a d de d “ …a n d Wee k 8.” 
C ha n ge 1 2  
Secti o n 5. 3:  
 
Re place d, “If t he s u bject re p orts at least o ne s y m pt o m fr o m a n y 2 of t he 3 s y m pt o m cate g ories prese nte d i n Ta ble 5 
bel o w, t he care gi ver will t he n c o ntact t he st u d y p h ysicia n or n urse, …” wit h “If t he s u bject re p orts (i) at least o ne of 
t he L o wer Res pirat or y S y m pt o ms prese nte d i n Ta ble 5 bel o w or (ii) at least o ne s y m pt o m fr o m eac h of t he U p per 
Res pirat or y S y m pt o ms a n d S yste mic S y m pt o ms cate g ories prese nte d i n Ta ble 5 bel o w, t he care gi ver will t he n 
c o ntact t he st u d y p h ysicia n or n urse t o c o m plete a “ S us pecte d A RI Visit” wit h t he pr oce d ures pr o vi de d bel o w.”  
 
Re m o ve d, t he rest of t he p ara gra p h a n d t he ne xt para gra p h bef ore Ta ble 5.  T his i nf or mati o n was a d de d t o secti o n 
5. 4.     
C ha n ge 1 3  
Ta ble 5: Re vise d f o ot n ote 1 t o rea d, “ S us pecte d A RI re q uires self -re p orti n g of a n y L o wer Res pirat or y S y m pt o m, or at least 
o ne U p per Res pirat or y S y m pt o m t o get her wit h o ne S yste mic S y m pt o m.”  
C ha n ge 1 4  
A d de d, “ Secti o n 5. 4 S us pecte d A RI Visit” a n d c o nte nts t herei n.  
C ha n ge 1 5  
Secti o n 5. 5 (f or merl y 5. 4):  
 
Ite m # 3, a d de d “ …a n d a nti-S A Rs -C o V -2 a nti b o dies (a nti b o d y testi n g at Wee k 6 visit o nl y).”  
 
Ite m # 7, re vise d t o “ … 8-wee k st u d y peri o d.”  
C ha n ge 1 6  
A d de d, “ Secti o n 5. 6 Wee k 8 E val uati o n ( + 7 da ys)” a n d c o nte nts t herei n.  

Pr ot oc ol R M 0 8 -3 0 0 6  L T C F v 4 . 0 
 
A u g ust 2 8 , 2 0 2 0 
 
 
Pa ge 5 9  of 5 9  
C O N FI D E N TI A L  
2 1. 5.  
A p pe n di x V: Decl ar ati o n of Helsi n ki  
 

C o p yri g ht 2 0 1 3 A m eri c a n M e di c al A s s o ci ati o n. All ri g ht s r e s er v e d.
1 3. Gr o u ps t h at ar e u n d err e pr es e nt e d i n  m e dic al r es e arc h s h o ul d
b e pr o vi d e d a p pr o pri at e acc ess t o p artici p ati o n i n r es e arc h.
1 4. P h ysici a ns  w h o c o m bi n e  m e di c al r es e ar c h  wit h  m e dic al c ar e
s h o ul d i n v ol v e t h eir p ati e nts i n r es e arc h o nl y t o t h e e xt e nt t h at
t his is j ustifi e d b y its p ot e nti al pr e v e nti v e, di a g n ostic or t h er a-
p e utic v al u e a n d if t h e p h ysici a n h as g o o d r e as o n t o b eli e v e t h at
p artici p ati o n i n t h e r es e arc h st u d y  will n ot a d v ers el y aff ect t h e
h e alt h of t h e p ati e nts  w h o s er v e as r es e arc h s u bj ects.
1 5. A p pr o pri at e c o m p e ns ati o n a n d tr e at m e nt f or s u bj ects  w h o ar e
h ar m e d as a r es ult of p arti ci p ati n g i n r es e ar c h  m ust b e e n-
s ur e d.
Ris ks, B ur d e ns a n d B e n efits
1 6. I n  m e dic al pr actic e a n d i n  m e dic al r es e arc h,  m ost i nt er v e nti o ns
i n v ol v e ris ks a n d b ur d e ns.
M e dic al r es e arc h i n v ol vi n g h u m a n s u bj ects  m a y o nl y b e c o n-
d uct e d if t h e i m p ort a nc e of t h e o bj ecti v e o ut w ei g hs t h e ris ks a n d
b ur d e ns t o t h e r es e arc h s u bj ects.
1 7. All  m e di c al r es e ar c h i n v ol vi n g h u m a n s u bj e cts  m ust b e pr e-
c e d e d b y c ar ef ul ass ess m e nt of pr e dict a bl e ris ks a n d b ur d e ns
t o t h e i n di vi d u als a n d gr o u ps i n v ol v e d i n t h e r es e arc h i n c o m-
p aris o n  wit h f or es e e a bl e b e n efits t o t h e m a n d t o ot h er i n di vi d u-
als or gr o u ps aff ect e d b y t h e c o n diti o n u n d er i n v esti g ati o n.
M e as ur es t o  mi ni mis e t h e ris ks  m ust b e i m pl e m e nt e d. T h e ris ks
m ust b e c o nti n u o usl y  m o nit or e d, ass ess e d a n d d oc u m e nt e d b y
t h e r es e arc h er.
1 8. P h ysici a ns  m a y n ot b e i n v ol v e d i n a r es e arc h st u d y i n v ol vi n g h u-
m a n s u bj ects u nl ess t h e y ar e c o nfi d e nt t h at t h e ris ks h a v e b e e n
a d e q u at el y ass ess e d a n d c a n b e s atisf act oril y  m a n a g e d.
W h e n t h e ris ks ar e f o u n d t o o ut w ei g h t h e p ot e nti al b e n efits or
w h e n t h er e is c o ncl usi v e pr o of of d efi niti v e o utc o m es, p h ysi-
ci a ns  m ust ass ess  w h et h er t o c o nti n u e,  m o dif y or i m m e di at el y
st o p t h e st u d y.
V ul n er a bl e Gr o u ps a n d I n di vi d u als
1 9. S o m e gr o u ps a n d i n di vi d u als ar e p artic ul arl y v ul n er a bl e a n d  m a y
h a v e a n i ncr e as e d li k eli h o o d of b ei n g  wr o n g e d or of i nc urri n g a d-
diti o n al h ar m.
All v ul n er a bl e gr o u ps a n d i n di vi d u als s h o ul d r e c ei v e s p e cifi-
c all y c o nsi d er e d pr ot ecti o n.
2 0.  M e dic al r es e arc h  wit h a v ul n er a bl e gr o u p is o nl y j ustifi e d if t h e
r es e arc h is r es p o nsi v e t o t h e h e alt h n e e ds or pri oriti es of t his
gr o u p a n d t h e r e s e ar c h c a n n ot b e c arri e d o ut i n a n o n-
v ul n er a bl e gr o u p. I n a d diti o n, t his gr o u p s h o ul d st a n d t o b e n-
efit fr o m t h e k n o wl e d g e, pr actic es or i nt er v e nti o ns t h at r es ult
fr o m t h e r es e arc h.
Sci e ntific R e q uir e m e nts a n d R es e arc h Pr ot oc ols
21.  M e dic al r es e arc h i n v ol vi n g h u m a n s u bj ects  m ust c o nf or m t o g e n-
er all y a c c e pt e d s ci e ntifi c pri n ci pl es, b e b as e d o n a t h or o u g h
k n o wl e d g e of t h e sci e ntific lit er at ur e, ot h er r el e v a nt s o urc es of
i nf or m ati o n, a n d a d e q u at e l a b or at or y a n d, as a p pr o pri at e, a ni-
m al e x p eri m e nt ati o n. T h e  w elf ar e of a ni m als us e d f or r es e arc h
m ust b e r es p ect e d.
2 2. T h e d esi g n a n d p erf or m a nc e of e ac h r es e arc h st u d y i n v ol vi n g
h u m a n s u bj ects  m ust b e cl e arl y d escri b e d a n d j ustifi e d i n a r e-
s e arc h pr ot oc ol.
T h e pr ot oc ol s h o ul d c o nt ai n a st at e m e nt of t h e et hic al c o nsi d-
er ati o ns i n v ol v e d a n d s h o ul d i n dic at e h o w t h e pri nci pl es i n t his
D ecl ar ati o n h a v e b e e n a d dr ess e d. T h e pr ot oc ol s h o ul d i ncl u d e
i nf or m ati o n r e g ar di n g f u n di n g, s p o ns ors, i nstit uti o n al affili a-
ti o ns, p ot e nti al c o nflicts of i nt er est, i nc e nti v es f or s u bj ects a n d
i nf or m ati o n r e g ar di n g pr o visi o ns f or tr e ati n g a n d/ or c o m p e n-
s ati n g s u bj ects  w h o ar e h ar m e d as a c o ns e q u e nc e of p artici p a-
ti o n i n t h e r es e arc h st u d y.
I n cli nic al tri als, t h e pr ot oc ol  m ust als o d escri b e a p pr o pri at e ar-
r a n g e m e nts f or p ost-tri al pr o visi o ns.
R es e arc h Et hics C o m mitt e es
2 3. T h e r es e arc h pr ot oc ol  m ust b e s u b mitt e d f or c o nsi d erati o n, c o m-
m e nt, g ui d a nc e a n d a p pr o v al t o t h e c o nc er n e d r es e arc h et hics
c o m mitt e e b ef or e t h e st u d y b e gi ns. T his c o m mitt e e  m ust b e
tr a ns p ar e nt i n its f u ncti o ni n g,  m ust b e i n d e p e n d e nt of t h e r e-
s e arc h er, t h e s p o ns or a n d a n y ot h er u n d u e i nfl u e nc e a n d  m ust
b e d ul y q u alifi e d. It  m ust t a k e i nt o c o nsi d er ati o n t h e l a ws a n d
r e g ul ati o ns of t h e c o u ntr y or c o u ntri es i n  w hic h t h e r es e arc h is
t o b e p erf or m e d as  w ell as a p plic a bl e i nt er n ati o n al n or ms a n d
st a n d ar ds b ut t h es e  m ust n ot b e all o w e d t o r e d uc e or eli mi n at e
a n y of t h e pr ot ecti o ns f or r es e arc h s u bj ects s et f ort h i n t his D ec-
l ar ati o n.
T h e c o m mitt e e  m ust h a v e t h e ri g ht t o  m o nit or o n g oi n g st u d-
i es. T h e r es e arc h er  m ust pr o vi d e  m o nit ori n g i nf or m ati o n t o t h e
c o m mitt e e, es p eci all y i nf or m ati o n a b o ut a n y s eri o us a d v ers e
e v e nts. N o a m e n d m e nt t o t h e pr ot oc ol  m a y b e  m a d e  wit h o ut
c o nsi d er ati o n a n d a p pr o v al b y t h e c o m mitt e e. Aft er t h e e n d of
t h e st u d y, t h e r es e arc h ers  m ust s u b mit a fi n al r e p ort t o t h e c o m-
mitt e e c o nt ai ni n g a s u m m ar y of t h e st u d y’s fi n di n gs a n d c o n-
cl usi o ns.
Pri v ac y a n d C o nfi d e nti alit y
2 4. E v er y pr ec a uti o n  m ust b e t a k e n t o pr ot ect t h e pri v ac y of r e-
s e arc h s u bj ects a n d t h e c o nfi d e nti alit y of t h eir p ers o n al i nf or-
m ati o n.
I nf or m e d C o ns e nt
2 5. P artici p ati o n b y i n di vi d u als c a p a bl e of gi vi n g i nf or m e d c o ns e nt
as s u bj ects i n  m e dic al r es e arc h  m ust b e v ol u nt ar y. Alt h o u g h it
Cli nic al R e vi e w & E d uc ati o n
S p eci al C o m m u nic ati o n
W orl d  M e dic al Ass oci ati o n D ecl ar ati o n of H elsi n ki
21 9 2 
J A M A
N o v e m b er 2 7, 2 01 3 V ol u m e 31 0, N u m b er 2 0
j a m a.c o m
C o p yri g ht 2 0 1 3 A m eri c a n M e di c al A s s o ci ati o n. All ri g ht s r e s er v e d.
D o w nl o a de d Fr o m: htt p://j a m a.j a m a net w or k.c o m/ b y a A meric a n Me dic al Ass oci ati o n User  o n 0 9/ 2 3/ 2 0 1 5

C o p yri g ht 2 0 1 3 A m eri c a n M e di c al A s s o ci ati o n. All ri g ht s r e s er v e d.
m a y b e a p pr o pri at e t o c o ns ult f a mil y  m e m b ers or c o m m u nit y
l e a d ers, n o i n di vi d u al c a p a bl e of gi vi n g i nf or m e d c o ns e nt  m a y
b e e nr oll e d i n a r es e arc h st u d y u nl ess h e or s h e fr e el y a gr e es.
2 6. I n  m e dic al r es e arc h i n v ol vi n g h u m a n s u bj ects c a p a bl e of gi vi n g
i nf or m e d c o ns e nt, e ac h p ot e nti al s u bj ect  m ust b e a d e q u at el y
i nf or m e d of t h e ai ms,  m et h o ds, s o urc es of f u n di n g, a n y p os-
si bl e c o nfli cts of i nt er est, i nstit uti o n al affili ati o ns of t h e r e-
s e arc h er, t h e a ntici p at e d b e n efits a n d p ot e nti al ris ks of t h e st u d y
a n d t h e disc o mf ort it  m a y e nt ail, p ost-st u d y pr o visi o ns a n d a n y
ot h er r el e v a nt as p ects of t h e st u d y. T h e p ot e nti al s u bj ect  m ust
b e i nf or m e d of t h e ri g ht t o r ef us e t o p artici p at e i n t h e st u d y or
t o  wit h dr a w c o ns e nt t o p artici p at e at a n y ti m e  wit h o ut r e pri-
s al. S p eci al att e nti o n s h o ul d b e gi v e n t o t h e s p ecific i nf or m a-
ti o n n e e ds of i n di vi d u al p ot e nti al s u bj ects as  w ell as t o t h e  m et h-
o ds us e d t o d eli v er t h e i nf or m ati o n.
Aft er e ns uri n g t h at t h e p ot e nti al s u bj ect h as u n d erst o o d t h e i n-
f or m ati o n, t h e p h ysici a n or a n ot h er a p pr o pri at el y q u alifi e d i n-
di vi d u al  m ust t h e n s e e k t h e p ot e nti al s u bj ect’s fr e el y- gi v e n i n-
f or m e d c o ns e nt, pr ef er a bl y i n  writi n g. If t h e c o ns e nt c a n n ot b e
e x pr ess e d i n  writi n g, t h e n o n- writt e n c o ns e nt  m ust b e f or m all y
d oc u m e nt e d a n d  wit n ess e d.
All  m e dic al r es e arc h s u bj ects s h o ul d b e gi v e n t h e o pti o n of b ei n g
i nf or m e d a b o ut t h e g e n er al o utc o m e a n d r es ults of t h e st u d y.
27.  W h e n s e e ki n g i nf or m e d c o ns e nt f or p artici p ati o n i n a r es e arc h
st u d y t h e p h ysici a n  m ust b e p artic ul arl y c a uti o us if t h e p ot e n-
ti al s u bj ect is i n a d e p e n d e nt r el ati o ns hi p  wit h t h e p h ysici a n or
m a y c o ns e nt u n d er d ur ess. I n s uc h sit u ati o ns t h e i nf or m e d c o n-
s e nt  m ust b e s o u g ht b y a n a p pr o pri at el y q u alifi e d i n di vi d u al  w h o
is c o m pl et el y i n d e p e n d e nt of t his r el ati o ns hi p.
2 8. F or a p ot e nti al r es e arc h s u bj ect  w h o is i nc a p a bl e of gi vi n g i n-
f or m e d c o ns e nt, t h e p h ysici a n  m ust s e e k i nf or m e d c o ns e nt fr o m
t h e l e g all y a ut h oris e d r e pr es e nt ati v e. T h es e i n di vi d u als  m ust n ot
b e i ncl u d e d i n a r es e arc h st u d y t h at h as n o li k eli h o o d of b e n efit
f or t h e m u nl ess it is i nt e n d e d t o pr o m ot e t h e h e alt h of t h e gr o u p
r e pr es e nt e d b y t h e p ot e nti al s u bj ect, t h e r es e arc h c a n n ot i n-
st e a d b e p erf or m e d  wit h p ers o ns c a p a bl e of pr o vi di n g i n-
f or m e d c o ns e nt, a n d t h e r es e arc h e nt ails o nl y  mi ni m al ris k a n d
mi ni m al b ur d e n.
2 9.  W h e n a p ot e nti al r es e arc h s u bj ect  w h o is d e e m e d i nc a p a bl e of
gi vi n g i nf or m e d c o ns e nt is a bl e t o gi v e ass e nt t o d ecisi o ns a b o ut
p artici p ati o n i n r es e arc h, t h e p h ysici a n  m ust s e e k t h at ass e nt i n
a d diti o n t o t h e c o ns e nt of t h e l e g all y a ut h oris e d r e pr es e nt a-
ti v e. T h e p ot e nti al s u bj ect’s diss e nt s h o ul d b e r es p ect e d.
3 0. R es e arc h i n v ol vi n g s u bj ects  w h o ar e p h ysic all y or  m e nt all y i n-
c a p a bl e of gi vi n g c o ns e nt, f or e x a m pl e, u nc o nsci o us p ati e nts,
m a y b e d o n e o nl y if t h e p h ysic al or  m e nt al c o n diti o n t h at pr e-
v e nts gi vi n g i nf or m e d c o ns e nt is a n ec ess ar y c h aract eristic of t h e
r es e arc h gr o u p. I n s uc h circ u mst a nc es t h e p h ysici a n  m ust s e e k
i nf or m e d c o ns e nt fr o m t h e l e g all y a ut h oris e d r e pr es e nt ati v e. If
n o s uc h r e pr es e nt ati v e is a v ail a bl e a n d if t h e r es e arc h c a n n ot b e
d el a y e d, t h e st u d y  m a y pr oc e e d  wit h o ut i nf or m e d c o ns e nt pr o-
vi d e d t h at t h e s p ecific r e as o ns f or i n v ol vi n g s u bj ects  wit h a c o n-
diti o n t h at r e n d ers t h e m u n a bl e t o gi v e i nf or m e d c o ns e nt h a v e
b e e n st at e d i n t h e r es e arc h pr ot oc ol a n d t h e st u d y h as b e e n a p-
pr o v e d b y a r es e arc h et hics c o m mitt e e. C o ns e nt t o r e m ai n i n t h e
r es e arc h  m ust b e o bt ai n e d as s o o n as p ossi bl e fr o m t h e s u bj ect
or a l e g all y a ut h oris e d r e pr es e nt ati v e.
31. T h e p h ysici a n  m ust f ull y i nf or m t h e p ati e nt  w hic h as p ects of t h eir
c ar e ar e r el at e d t o t h e r es e arc h. T h e r ef us al of a p ati e nt t o p ar-
tici p at e i n a st u d y or t h e p ati e nt’s d ecisi o n t o  wit h dr a w fr o m t h e
st u d y  m ust n e v er a d v ers el y aff ect t h e p ati e nt- p h ysici a n r el a-
ti o ns hi p.
3 2. F or  m e dic al r es e arc h usi n g i d e ntifi a bl e h u m a n  m at eri al or d at a,
s uc h as r es e arc h o n  m at eri al or d at a c o nt ai n e d i n bi o b a n ks or
si mil ar r e p osit ori es, p h ysici a ns  m ust s e e k i nf or m e d c o ns e nt f or
its c oll ecti o n, st or a g e a n d/ or r e us e. T h er e  m a y b e e xc e pti o n al
sit u ati o ns  w h er e c o ns e nt  w o ul d b e i m p ossi bl e or i m pr a cti-
c a bl e t o o bt ai n f or s u c h r es e ar c h. I n s u c h sit u ati o ns t h e r e-
s e arc h  m a y b e d o n e o nl y aft er c o nsi d er ati o n a n d a p pr o v al of a
r es e arc h et hics c o m mitt e e.
Us e of Pl ac e b o
3 3. T h e b e n efits, ris ks, b ur d e ns a n d eff ecti v e n ess of a n e w i nt er-
v e nti o n  m ust b e t est e d a g ai nst t h os e of t h e b est pr o v e n i nt er-
v e nti o n(s), e xc e pt i n t h e f oll o wi n g circ u mst a nc es:
W h er e n o pr o v e n i nt er v e nti o n e xists, t h e us e of pl ac e b o, or n o
i nt er v e nti o n, is acc e pt a bl e; or
W h er e f or c o m p elli n g a n d sci e ntific all y s o u n d  m et h o d ol o gic al
r e as o ns t h e us e of a n y i nt er v e nti o n l ess eff ecti v e t h a n t h e b est
pr o v e n o n e, t h e us e of pl ac e b o, or n o i nt er v e nti o n is n ec ess ar y
t o d et er mi n e t h e effic ac y or s af et y of a n i nt er v e nti o n
a n d t h e p ati e nts  w h o r ec ei v e a n y i nt er v e nti o n l ess eff ecti v e t h a n
t h e b est pr o v e n o n e, pl ac e b o, or n o i nt er v e nti o n  will n ot b e s u b-
j ect t o a d diti o n al ris ks of s eri o us or irr e v ersi bl e h ar m as a r es ult
of n ot r ec ei vi n g t h e b est pr o v e n i nt er v e nti o n.
E xtr e m e c ar e  m ust b e t a k e n t o a v oi d a b us e of t his o pti o n.
P ost-Tri al Pr o visi o ns
3 4. I n a d va nc e of a cli nic al tri al, s p o ns ors, r es e arc h ers a n d h ost c o u n-
tr y g o v er n m e nts s h o ul d  m a k e pr o visi o ns f or p ost-tri al acc ess f or
all p artici p a nts  w h o still n e e d a n i nt er v e nti o n i d e ntifi e d as b e n-
efici al i n t h e tri al. T his i nf or m ati o n  m ust als o b e discl os e d t o p ar-
tici p a nts d uri n g t h e i nf or m e d c o ns e nt pr oc ess.
R es e arc h R e gistr ati o n a n d P u blic ati o n a n d Diss e mi n ati o n
of R es ults
3 5. Ev er y r es e arc h st u d y i n v ol vi n g h u m a n s u bj ects  m ust b e r e gis-
t er e d i n a p u blicl y acc essi bl e d at a b as e b ef or e r ecr uit m e nt of t h e
first s u bj ect.
W orl d  M e dic al Ass oci ati o n D ecl ar ati o n of H elsi n ki
S p eci al C o m m u nic ati o n
Cli nic al R e vi e w & E d uc ati o n
j a m a.c o m
J A M A
N o v e m b er 2 7, 2 01 3 V ol u m e 31 0, N u m b er 2 0
21 9 3
C o p yri g ht 2 0 1 3 A m eri c a n M e di c al A s s o ci ati o n. All ri g ht s r e s er v e d.
D o w nl o a de d Fr o m: htt p://j a m a.j a m a net w or k.c o m/ b y a A meric a n Me dic al Ass oci ati o n User  o n 0 9/ 2 3/ 2 0 1 5

C o p yri g ht 2 0 1 3 A m eri c a n M e di c al A s s o ci ati o n. All ri g ht s r e s er v e d.
3 6. R es e arc h ers, a ut h ors, s p o ns ors, e dit ors a n d p u blis h ers all h a v e
et hic al o bli g ati o ns  wit h r e g ar d t o t h e p u blic ati o n a n d diss e mi-
n ati o n of t h e r es ults of r es e arc h. R es e arc h ers h a v e a d ut y t o  m a k e
p u blicl y a v ail a bl e t h e r es ults of t h eir r es e arc h o n h u m a n s u b-
j ects a n d ar e acc o u nt a bl e f or t h e c o m pl et e n ess a n d acc ur ac y of
t h eir r e p orts. All p arti es s h o ul d a d h er e t o acc e pt e d g ui d eli n es
f or et hic al r e p orti n g. N e g ati v e a n d i nc o ncl usi v e as  w ell as p osi-
ti v e r es ults  m ust b e p u blis h e d or ot h er wis e  m a d e p u blicl y a v ail-
a bl e. S o urc es of f u n di n g, i nstit uti o n al affili ati o ns a n d c o nflicts
of i nt er est  m ust b e d ecl ar e d i n t h e p u blic ati o n. R e p orts of r e-
s e arc h n ot i n acc or d a nc e  wit h t h e pri nci pl es of t his D ecl ar ati o n
s h o ul d n ot b e acc e pt e d f or p u blic ati o n.
U n pr o v e n I nt er v e nti o ns i n Cli nic al Pr actic e
37. I n t h e tr e at m e nt of a n i n di vi d u al p ati e nt,  w h er e pr o v e n i nt er-
v e nti o ns d o n ot e xist or ot h er k n o w n i nt er v e nti o ns h a v e b e e n
i n eff ecti v e, t h e p h ysici a n, aft er s e e ki n g e x p ert a d vic e,  wit h i n-
f or m e d c o ns e nt fr o m t h e p ati e nt or a l e g all y a ut h oris e d r e pr e-
s e nt ati v e,  m a y us e a n u n pr o v e n i nt er v e nti o n if i n t h e p h ysi-
ci a n's j u d g e m e nt it off ers h o p e of s a vi n g lif e, r e- est a blis hi n g
h e alt h or all e vi ati n g s uff eri n g. T his i nt er v e nti o n s h o ul d s u bs e-
q u e ntl y b e  m a d e t h e o bj ect of r es e arc h, d esi g n e d t o e v al u at e
its s af et y a n d effic ac y. I n all c as es, n e w i nf or m ati o n  m ust b e r e-
c or d e d a n d,  w h er e a p pr o pri at e,  m a d e p u blicl y a v ail a bl e.
A R TI C L E I N F O R M A TI O N
C orr es p o n di n g A ut h or: W orl d  M e dic al
Ass oci ati o n, 1 3, c h. d u L e v a nt, CI B - B âti m e nt A,
01 21 0 F er n e y- V olt air e, Fr a nc e;  w m a @ w m a. n et.
P u blis h e d  O nli n e: Oct o b er 1 9, 2 01 3.
d oi:1 0.1 0 01/j a m a. 2 01 3. 2 81 0 5 3.
Dis cl ai m er: © 2 01 3  W orl d  M e dic al Ass oci ati o n, I nc.
All Ri g hts R es er v e d. All i nt ell ect u al pr o p ert y ri g hts
i n t h e D ecl ar ati o n of H elsi n ki ar e v est e d i n t h e
W orl d  M e dic al Ass oci ati o n. T h e  W M A h as gr a nt e d
J A M A e xcl usi v e ri g hts t o p u blis h t h e
E n glis h-l a n g u a g e v ersi o n of t h e D ecl ar ati o n
t hr o u g h D ec e m b er 31, 2 01 3.
O nli n e- O nl y C o nt e nt: A u di o p o dc ast is a v ail a bl e at
w w w.j a m a.c o m.
Cli nic al R e vi e w & E d uc ati o n
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