Clinical trial NCT04343248
Conditions: COVID-19 Viral Respiratory Illnesses
Keywords: COVID-19 Viral Respiratory Illnesses
Sponsor: Romark Laboratories L.C.
Start date: 2020-05-12; Completion date: 2021-02-01
Enrollment: 190 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Trial to evaluate the efficacy and safety of NTZ for post-exposure prophylaxis of COVID-19 and other VRIs in elderly LTCF residents.

Detailed description:
Multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of NTZ for post-exposure prophylaxis of COVID-19 and other VRIs in elderly LTCF residents.

Arms: arm 1: Two Nitazoxanide 300 mg tablets orally twice daily for 6 weeks arm 2: Two placebo tablets orally twice daily for 6 weeks
Interventions: intervention 1: Nitazoxanide intervention 2: Placebo intervention 3: Vitamin Super B-Complex
Intervention descriptions: intervention 1: Nitazoxanide 600 mg administered orally twice daily for six weeks intervention 2: Placebo administered orally twice daily for six weeks intervention 3: Vitamin Super B-Complex administered orally twice daily to maintain the blind

Protocol documents:
Prot_000.pdf: 
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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)  
 
P R O T O C O L N O. R M 0 8 -3 0 0 6  
 
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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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 


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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  


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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 


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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.  


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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 


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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.  


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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.  


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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 


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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: 




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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 


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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.  
 


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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  
 
 


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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.  
 
 






















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2 0 2 0  
 
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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.  








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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
S p eci al C o m m u nic ati o n
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C o p yri g ht 2 0 1 3 A m eri c a n M e di c al A s s o ci ati o n. All ri g ht s r e s er v e d.
D o w nl o a de d Fr o m: htt p://j a m a.j a m a net w or k.c o m/ b y a A meric a n Me dic al Ass oci ati o n User  o n 0 9/ 2 3/ 2 0 1 5

SAP_001.pdf: 




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Revision History 
 
Version 1.1 to 1.2 
1. Updated planned software from SAS to Python and related statistical packages 
(section 2.6). 
2. Updated document ownership from 
 to Romark Institute 
for Medical Research. 
 
Version 1.0 to 1.1 
1. Wording of futility analysis purpose in Section 2.4 clarified. 
2. Risk differences added to primary efficacy endpoint. 
3. Section 2.2.2 Sex, Age, and Race subgroup analyses for primary efficacy 
endpoint added. 
4. Sensitivity analyses added for missing values of primary efficacy variable. 
 
 


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Table of Contents 
Approval Page ............................................................................................................................ 2 
Revision History ....................................................................................................................... 33 
Abbreviations and acronyms .................................................................................................. 66 
1.0 Synopsis of Study Design Procedures ............................................................................ 77 
1.1 Design and Treatment ........................................................................................................ 77 
1.2 Study Procedures ............................................................................................................... 77 
1.3 Sample Size ..................................................................................................................... 1111 
2.0 Data Analysis Considerations ....................................................................................... 1212 
2.1 Types of Analyses .......................................................................................................... 1212 
2.2 Analysis Populations ..................................................................................................... 1212 
2.3 Missing Data Conventions ............................................................................................. 1313 
2.4 Interim Analyses ............................................................................................................. 1414 
2.5 Study Center Considerations in the Data Analysis ..................................................... 1515 
2.6 Documentation and Other Considerations .................................................................. 1515 
3.0 Analysis of Baseline Patient Characteristics ............................................................... 1515 
4.0 Analysis of Efficacy ........................................................................................................ 1616 
4.1 Efficacy Variables ........................................................................................................... 1616 
4.2 Efficacy Analysis ............................................................................................................ 1717 
5.0 Analysis of Safety ........................................................................................................... 1818 
5.1 Description of Safety Variables ..................................................................................... 1818 
5.2 Description of Safety Analyses ..................................................................................... 1818 
6.0 Other Relevant Data Analyses/Summaries .................................................................. 2020 
6.1 Patient Completion ......................................................................................................... 2020 
6.2 Prior and Concomitant Medications ............................................................................. 2020 
6.3 Death Report ................................................................................................................... 2020 


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7.0 References ...................................................................................................................... 2020 
8.0 List of Analysis Tables, Figures and Listings ............................................................. 2222 
 
 
 


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Abbreviations and acronyms 
AE 
Adverse Event 
ARI 
Acute Respiratory Illness 
ATC 
Anatomic Therapeutic Chemical 
CDER 
Center for Drug Evaluation and Research 
COVID-19 
Novel Corona Virus Infectious Disease, 2019 
CMH 
Cochran-Mantel-Haenszel Chi-square Test 
FDA 
US Food and Drug Administration 
IAP 
Interim Analysis Plan 
LTCF 
Long Term Care Facility 
NTZ 
Nitazoxanide 
RT-PCR 
Reverse Transcriptase-Polymerase Chain Reaction 
SARS-CoV-2 
Severe Acute Respiratory Syndrome-Corona Virus 2, the pathogen 
causing COVID-19 
TEAE 
Treatment Emergent Adverse Event 
VRI 
Viral Respiratory Illness 
WHO 
World Health Organization 
 
 
 


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1.0 Synopsis of Study Design Procedures 
 
1.1 Design and Treatment 
 
This is a multi-center, randomized, double-blind, placebo-controlled trial to assess the 
safety and efficacy of Nitazoxanide (NTZ) for post-exposure prophylaxis of COVID-19, 
the viral respiratory disease caused by the novel coronavirus SARS-CoV-2 and other viral 
respiratory illnesses (VRI) in residents of long-term care facilities (LTCF) aged 65 years 
and over.  
 
 Participants will be randomized (1:1) within LTCF (i.e., within strata) to one of 
• Group I (NTZ)—Two 300 mg NTZ tablets orally b.i.d. (twice daily) for six weeks; 
• Group II (Placebo)—Two placebo tablets b.i.d. (twice daily) for six weeks. 
 
All participants will receive a B-complex vitamin (
 
) twice daily to mask potential chromaturia that may be 
associated with NTZ. 
 
1.2 Study Procedures 
 
Screening 
Patients will be screened from Study Day -90 to Study Day 1. After giving informed 
consent, the subject will be assigned a subject number and complete the following 
procedures:  
1. Complete medical history. 
2. Physical examination including body weight and vital signs (blood pressure, 
pulse, respiratory rate and body temperature). 
3. Collection of demographic information and smoking history. 
4. Evaluation according to eligibility (inclusion and exclusion) criteria. 
The information collected during the screening period must be current through the time 
of randomization. 
Baseline 
At Baseline (Study Day 1, which may be the same day as the screening evaluation) the 
subject will be randomized to Group I or Group II and complete the following 
procedures: 
1. Collection of two nasopharyngeal swabs (one from each nostril) using nylon 
flocked dry swabs for RT-PCR. 
2. Collection of blood sample for laboratory safety tests and anti-SARS-CoV-2 
antibodies. 


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3. Collection of a urine sample for routine urinalysis (appearance, glucose, protein 
and blood). 
4. Review and recording of any concomitant medications. 
5. Completion of baseline electronic symptom diary entries. 
6. Randomization and dispensing of study medication (medication assigned in 
sequential order). Subjects will be considered enrolled in the study upon the 
randomized assignment to a treatment group. 
7. Administration of the first dose of study medication with food (< 1 hour after food 
intake) and a B complex vitamin (
 
) under observation of Investigator or a member of 
Investigator’s staff, and entry in the medication administration record. 
8. The subject will be instructed regarding the administration of study medication, 
completion of the electronic subject diary, use of birth control, follow-up visits at 
weeks 1, 3, 6, 8, and on seeking emergency medical care or contacting the 
study physician or nurse under specific conditions. 
CONTACT STUDY PHYSICIAN, IF:  
• Trouble breathing including shortness of breath 
• Severe headache, stiff neck, confusion, or excessive somnolence 
• If fever (≥99°F or ≥37.2°C) returns after being absent for 24 hours 
• Increased difficulty breathing 
• Wheezing develops 
• New pain develops or pain localizes to one area, such as an ear, the 
throat, the chest, or the sinuses 
• Symptoms become more severe or frequent 
• Symptoms recur or any difficulty breathing following 5-10 days resolution 
of illness 
• An allergic-like reaction occurs or is suspected 
• Abnormal behavior 
Study Weeks 1 through 6 (Daily) 
A caregiver will record the time of each study medication intake.  Once daily, the caregiver 
will (i) inquire regarding the health of the subject, (ii) record any concomitant medications, 
and (iii) ask the subject once daily, “do you feel like you have symptoms of a cold or flu?”  
If the subject responds “yes”, the caregiver will have the subject complete a FLU-PRO© 
diary to evaluate the subject’s symptoms.   


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If the subject reports (i) at least one of the Lower Respiratory Symptoms presented in 
Text Table 1 below or (ii) at least one symptom from each of the Upper Respiratory 
Symptoms and Systemic Symptoms categories presented in Text Table 1 below, the 
subject will then contact the study physician to complete a “Suspected ARI Visit” with the 
procedures provided below.  
 
Table 1: Clinical Illness Required for Diagnosis of ARI1 (adapted from Yu et al. 
2020) 
Upper Respiratory Symptoms 
Lower Respiratory Symptoms 
Systemic Symptoms 
• Nasal congestion/rhinorrhea 
(runny or dripping nose, 
congested or stuffy nose, 
head congestion, sinus 
pressure) 2 
• Sore throat (sore or painful 
throat) 2 
• Cough (coughing, chest 
congestion, chest tightness, dry 
or hacking cough, wet or loose 
cough) 2 
• Dyspnea (shortness of breath) 2 
• Sputum (coughing up sputum or 
phlegm) 2 
• Wheezing 
• Myalgias or arthralgias (body 
aches or pains) 2 
• Fatigue (weak or tired, 
sleeping more than usual) 2 
• Headache 
• Decreased appetite (lack of 
appetite, did not feel like 
eating) 2 
• Feverishness (felt hot, chills or 
shivering, felt cold, sweating) 2 
1 Suspected ARI requires self-reporting of any Lower Respiratory Symptom, or at least one Upper 
Respiratory Symptom together with one Systemic Symptom. 
2 Lay language used in the FLU-PRO© questionnaire is presented in parentheses. 
Suspected ARI Visit 
Subjects reporting any lower respiratory symptom or at least one upper respiratory 
symptom and one systemic symptom are considered to have a suspected acute 
respiratory illness (ARI) and will complete the following procedures at an unscheduled 
Suspected ARI Visit. 
1. Physical examination as warranted by the Investigator for any change from 
baseline. 
2. Body weight and collection of vital signs to include blood pressure, pulse, 
respiratory rate and body temperature. 
3. Collect two nasopharyngeal swabs using nylon flocked dry swabs for RT-PCR at 
the Suspected ARI Visit.  
4. Collect two nasopharyngeal swabs 24 to 36 hours later, and then again 4 to 5 
days later. 


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5. The subject will complete a FLU-PRO© symptom diary daily until he/she 
responds “yes” to the FLU-PRO© question, “Have you returned to your usual 
health?” for 3 consecutive days or until the Week 6 Visit, whichever occurs first.  
The daily FLU-PRO© diary will be completed between 4:00 pm and 8:00 pm.  A 
caregiver may assist the subject with completing the diary if necessary. 
6. Review and recording of concomitant medications. 
7. Review and recording of adverse events/side effects. 
8. Laboratory investigations for safety may be performed as warranted based upon 
the Investigator’s judgment.   
9. Subjects testing positive for a respiratory virus by RT-PCR may receive standard 
of care as clinically warranted by the Investigator.   
Regardless of symptoms or laboratory data, the subject will continue treatment until 
the 6-week treatment period has ended.   
Week 1, Week 3 and Week 6 Evaluations (+ 2 days) 
Study personnel (physician, nurse, or other study personnel) will visit each subject at 
Week 3 and Week 6 and performing the following procedures: 
1. Physical examination as warranted by the Investigator for any change from 
baseline. 
2. Body weight and collection of vital signs to include blood pressure, pulse, 
respiratory rate and body temperature. 
3. Collection of blood sample for laboratory safety tests, pharmacokinetics (pre-
dose) and anti-SARs-CoV-2 antibodies (antibody testing at Week 6 visit only). 
4. Collection of urine sample for routine urinalysis. 
5. Review of compliance with study medication, collection of medication bottle with 
any unused medications (Week 6 visit only), and completion of the pill count log 
form. 
6. Review and recording of concomitant medications. 
7. Review and recording of adverse events/side effects and complications. Note 
that all adverse events and complications must be followed until their resolution 
or stabilization even beyond the 8-week study period. 
Week 8 Evaluation (+ 7 days) 
Study personnel (physician, nurse, or other study personnel) will visit each subject at 
Week 3 and Week 6 and performing the following procedures: 
1. Physical examination as warranted by the Investigator for any change from 
baseline. 
2. Collection of blood sample for anti-SARs-CoV-2 antibodies. 


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3. Review and recording of concomitant medications. 
4. Review and recording of adverse events/side effects and complications. Note 
that all adverse events and complications must be followed until their resolution 
or stabilization even beyond the 8-week study period. 
5. Document any infections diagnosed during the follow-up period. 
Other Unscheduled Visits 
Subjects requiring an unscheduled visit due to worsening symptoms or adverse events 
will be evaluated at the discretion of the Investigator as is medically warranted.  Tests 
and/ or procedures performed at this visit may include, but are not limited to, the following: 
1. Physical examination as warranted by the Investigator for any change from 
baseline. 
2. Body weight and collection of vital signs to include blood pressure, pulse, 
respiratory rate and body temperature. 
3. Collection of two nasopharyngeal swabs using nylon flocked dry swabs for RT-
PCR. 
4. Collection of blood sample for laboratory safety tests. 
5. Collection of urine sample for routine urinalysis. 
6. Review of compliance with study medication. 
7. Review and recording of concomitant medications. 
8. Review and recording of adverse events/side effects. 
1.3 Sample Size 
Recent reports of COVID-19 in long-term care facilities in the United States have 
suggested a high rate of transmission of the SARS-CoV-2 virus, but infection control 
procedures may significantly decrease transmission (McMichael et al. 2020, Kimball et 
al. 2020). A recent study of 264 elderly volunteers (≥65 years of age) reported 1.6 
respiratory tract infections (not laboratory-confirmed) per person-year indicating 
approximately a 20% probability of respiratory tract infection over a given 6-week period 
(Mannick et. al, 2018).  Infection control procedures in place during the period covered by 
this clinical trial are also expected to reduce the transmission of other respiratory viruses. 
For purposes of calculating sample size, we assume that the proportion of subjects 
experiencing COVID-19 over a 6-week period is 5%, the proportion of subjects 
experiencing any VRI is 10%, and that effective prophylaxis will reduce the rate of COVID-
19 and other VRIs by 80%.   
A Cochran-Mantel-Haenszel (CMH) chi-square test stratifying by 20 LTCFs will have 
87.1% statistical power to detect the difference between 5% and 1% rates of occurrence 
of COVID-19 across all strata at a two-sided alpha of 0.047 with a total sample size of 
800, allocated equally to strata (LTCFs) and treatment groups within strata.  The statistical 


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power remains >87% when the number of LTCFs is 5, 10, 16 or 20.  The CMH chi-square 
test has 91% power to detect the difference between 10% and 2% rates of occurrence of 
VRIs over all strata at a two-sided alpha of 0.001 with 800 subjects allocated equally to 
20 LTCFs. Both tests are insensitive to stratum size. Varying the number of subjects per 
stratum (LTCF) between a minimum of 8 to a maximum of 80 while holding both the effect 
size and total sample constant results in changes in the third significant figure of the test’s 
power. 
A sample size of 800 subjects (400 per treatment group) was selected.  
 
2.0 Data Analysis Considerations 
 
2.1 Types of Analyses 
 
Data analyses will consist of analyzing patient characteristics, safety, and efficacy data. 
 
2.2 Analysis Populations 
 
2.2.1 Population Definitions 
 
Subjects will be considered enrolled in the study upon completion of the baseline 
procedures. The following analysis populations will be used in the study. 
 
• Safety Population – the safety population includes all patients who are enrolled 
in the study and that have received at least one dose of the assigned treatment 
arm (NTZ or placebo) 
• Intention to Treat Population (ITT) – the ITT population includes all patients in 
the safety population who did not have a laboratory detected respiratory virus 
infection at the baseline visit. 
 
The safety population will be used for all safety analyses. The ITT population will be the 
primary population for all efficacy analyses.  
 
Data listings displaying the patients excluded from each population will be created.  These 
listings will be relative to all patients enrolled in the study.  
 
2.2.2 Subgroup Definitions 
 
Safety analyses will be grouped by treatment received. The primary efficacy analysis will 
be grouped by sex (male/female), age (65 to 79 years, 80 years and over), and race 
(white/non-white). 
 


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2.3 Missing Data Conventions 
 
Date variables with missing items will be imputed as shown in Text Table 2 below.  
 
Table 2. Imputation rules for missing dates. 
Data 
Handling Convention 
Adverse event onset 
date 
If onset date is completely missing, impute with the date of first dose. 
 
If year is missing, impute with the year of enrollment. 
 
If only year or if year and day are present: 
• If year = year of first dose, then set month and day to the date of the first 
dose. 
• If year < year of first dose, then set month and day to December 31. 
• If year > year of first dose, then set month and day to January 1. 
 
If month and year are present, but day is missing: 
• If year = year of first dose and 
o If month = month of first dose, then set day to day of first dose. 
o If month < month of first dose, then set day to the last day of the month. 
o If month > month of first dose, then set day to the first day of the month. 
• If year < year of first dose, then set day to the last day of the month. 
• If year > year of first dose, then set day to the first day of the month. 
• For all other cases, set onset date to the date of first dose. 
Adverse event end date 
If the end date is partially or completely missing, set to the last date the 
subject was known to be in the study. 
Concomitant medications 
start date 
If start date is completely missing, it will not be imputed. 
 
If only year or if year and day are present, set the month and day to 
January 1. 
 
If year and month are present and day is missing, set day to the first day of 
the month. 
Concomitant medications 
end date 
If end date is missing, frequency is “1X” and the medication is not listed as 
“ONGOING”, then end date should be set to equal the start date. 
 
If end date is completely missing, it will not be imputed. 
 
If only year or if year and day are present, set the month and day to 
December 31. 
 
If year and month are present and day is missing, set day to the last day of 
the month. 
 
While every effort will be made to compile the data in accordance with intent-to-treat, it is 
likely that some subjects will have missing endpoints.  Sensitivity analyses will be 
performed to assess the influence missing primary endpoints may have on the study’s 
conclusions. The first analysis will be a best-case analysis, assigning infected status to 
all missing COVID-19 disease and VRI status in the placebo arm and non-infected status 
to these variables in the NTZ arm. The second sensitivity analysis will be a worst-case 


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analysis. This analysis will assign infected status for COVID-19 disease and VRI to 
missing values in the NTZ arm and non-infected status to the missing values in the 
placebo arm. Finally, a tipping point analysis will use multiple imputation methods to 
determine the allocation of infected and non-infected status to missing values in the NTZ 
arm which changes the study conclusions. 
 
2.4 Interim Analyses 
  
A first review for safety will be conducted by the Independent Data Monitoring Committee 
(IDMC) when 20% of the planned number of subjects have completed three weeks of 
treatment. This review will examine the available data for safety signals contained in the 
AE, vital sign, and clinical laboratory data. 
An unblinded analysis may be performed under circumstances defined in the IDMC 
charter, which relate to the rate of COVID-19 illnesses and the rate of occurrence of 
diarrhea as an adverse event.  
If conditions required for unblinding are satisfied, futility will be assessed using a 
conditional power approach assessing the efficacy of NTZ for the COVID-19 endpoint. 
The IDMC will recommend stopping for futility if the conditional power of the study at that 
stage is less than 30%. The conditional power will be calculated according to Chow and 
Chang (2007): 
Conditional Power = 1 −Φ 23𝑧!"#!
$
−𝑧!"%"
$
−δ
𝜎7𝑛$9. 
In the above, za refers to the a-th quantile of the Standard Normal distribution, a2 is the 
planned final significance level of the study, p1 > a2 is the p-value at the first interim 
analysis, d is the observed study effect size (i.e., the difference in observed rates in the 
two groups), s is the observed standard error of the difference in rates at the interim, and 
n2 is the number of subjects remaining to be enrolled in the study. 
A second review for safety and futility will be conducted by the IDMC when 50% of the 
planned number of subjects have completed 6 weeks of treatment. An unblinded analysis 
will be conducted under circumstances defined in the IDMC charter, which relate to the 
rate of COVID-19 illnesses, the rate of occurrence of diarrhea as an adverse event and 
other safety considerations. Futility will be concluded if the CMH test statistic for 
comparing the treatment groups on the COVID-19 endpoint is less than 0.179 (i.e., a p-
value greater than 0.3278). This bound was set using O’Brien-Fleming bounds for futility 
with overall a = 0.049. 
An interim analysis of effectiveness will be performed when there are at least 25 
laboratory-confirmed COVID-19 cases observed among the study participants. If the 
assumptions made in the power calculations are correct (COVID-19 rate is 0.05 in the 
placebo group and 0.01 in the NTZ group) we expect to observe only 24 events during 
the entire study. If this milestone is reached early, it indicates that the assumptions were 


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conservative and merit review given the high rate of mortality observed from COVID-19 
illness in this population.  This review will be conducted by the IDMC in accordance with 
its charter and will encompass both a safety and efficacy determination. In the event that 
the timing of the interim analysis of effectiveness is near that of the second review for 
safety and futility, analyses of safety, futility and effectiveness may be performed 
simultaneously.  
O’Brien-Fleming bounds are used to set the Type I error rates for the third interim and 
final analyses. The interim efficacy review will be performed with a = 0.0052 (overall), 
allocated 0.005 to the COVID-19 endpoint and 0.0002 to the VRI endpoint. The final data 
analysis (if the efficacy hypotheses are not rejected at the interim review) will be 
performed with a = 0.048, allocated 0.047 to the COVID-19 endpoint and 0.001 to the 
VRI endpoint. Power at the interim analysis is 31% for the COVID-19 endpoint. If the 
interim review for efficacy does not occur (i.e., the event count of 25 is not reached or 
reached too late in the study for the interim review to be useful), the alpha levels for the 
final analysis will be 0.049 for the COVID-19 endpoint and 0.001 for the VRI endpoint. 
2.5 Study Center Considerations in the Data Analysis 
 
A study center is defined as a treatment administration site (i.e., LTCF) or group of 
treatment administration sites under the control and supervision of the same Principal 
Investigator (PI).  There will be no selective pooling of study centers – all sites will be 
pooled. The study is planned to be conducted at multiple sites. 
 
2.6 Documentation and Other Considerations 
 
The data analyses will be conducted using Python and supported statistical packages. 
 
3.0 Analysis of Baseline Patient Characteristics 
 
Baseline and demographic characteristics of the safety population will be summarized. 
Continuous variables (age, baseline height, baseline weight) will be summarized via 
mean, standard deviation, minimum, median, maximum, and number of non-missing 
responses. Categorical variables (gender, race, and ethnicity) will be summarized via 
counts and percentages.   
 
A detailed listing of baseline data for each patient in the safety population will also be 
provided as shown in Appendix B. 
 


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4.0 Analysis of Efficacy 
 
4.1 Efficacy Variables 
 
The efficacy variables are categorical in nature: the presence or absence of ARI, VRI, or 
COVID-19 and sequelae during the study period or COVID-19 and sequelae (i.e., 
hospitalization and death) during the study period. 
 
Symptomatic COVID-19 is defined as an ARI after start of treatment and before the end 
of the 6-week treatment period associated with detection of SARS-CoV-2 by RT-PCR 
assay of nasopharyngeal swab.  
Symptomatic VRI is defined as an ARI after start of treatment and before the end of the 
6-week treatment period associated with detection of any respiratory virus by RT-PCR 
assay of nasopharyngeal swab.  
ARI is defined as " 0.5 increase from baseline in mean symptom score in the 
chest/respiratory domain of the FLU-PRO© instrument; or an increase of at least 0.5 in 
the mean symptom score of at least two of the following FLU-PRO© domains: 
body/systemic, nose, throat. 
 
Primary Efficacy Variables 
There are two primary efficacy variables:  
1. The presence or absence of symptomatic COVID-19 disease identified after the 
start of treatment and before the end of the 6-week treatment period. 
2. The presence or absence of symptomatic VRI (including COVID-19) identified after 
the start of treatment and before the end of the 6-week treatment period. 
 
Secondary Efficacy Variables 
The secondary efficacy variables are: 
 
1. Hospitalization due to COVID-19 or complications thereof. 
2. Mortality due to COVID-19 or complications thereof. 
3. The presence or absence of anti-SARS-CoV-2 antibodies at either of the Week 6 
or Week 8 visits. 
 
Exploratory Efficacy Variables 
The exploratory efficacy variables are: 
 
1. Hospitalization due to VRI or complications thereof 
2. Mortality due to VRI or complications thereof 
3. Presence or absence of an ARI 
4. Hospitalization due to ARI or complications thereof 


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5. Mortality due to ARI or complications thereof. 
 
4.2 Efficacy Analysis 
 
4.2.1 Primary Efficacy Variables 
The study has two primary efficacy endpoints: reduction in symptomatic COVID-19 
disease and reduction in all VRI. The study-wise a level is set at 0.05, allocated with 
0.049 to the COVID-19 endpoint and 0.001 to the all VRI endpoint.  See Section 2.4 for 
details on how the study- wise a level will be allocated to the interim and final analyses.  
For each endpoint, the following hypotheses will be tested 
H&: 𝑝! = 𝑝$
H!: 𝑝! ≠𝑝$, 
here, p1 represents the probability of symptomatic disease (either COVID-19 or VRI) in 
the NTZ treatment group and p2 represents the probability of symptomatic disease in the 
placebo group. 
 
The proportion of subjects experiencing symptomatic COVID-19 disease in the NTZ 
treatment group will be compared to the similar proportion in the placebo group using a 
two-sided CMH test with continuity correction at a=0.047. The test will be stratified by 
LTCF. The contingency tables will be provided with rates relative to the treatment 
margins. A 95% confidence interval for the odds ratio of symptomatic COVID-19 infection 
in the NTZ group relative to the placebo group will be provided. The risk difference for the 
treatment groups and a 95% confidence interval for the difference will be provided.  
 
The proportion of subjects experiencing symptomatic VRI infections in the NTZ treatment 
group will be compared to the similar proportion in the placebo group using a two-sided 
CMH test, stratified by LTCF with continuity correction at a=0.001. The contingency 
tables will be provided with rates relative to the treatment margins. A 95% confidence 
interval for the odds ratio of symptomatic VRI in the NTZ group relative to the placebo 
group will be provided. The risk difference for the treatment groups and a 95% confidence 
interval for the difference will be provided. 
 
CMH analyses of symptomatic COVID-19 disease and symptomatic VRI will be repeated 
with subjects divided by sex (female or male), age (65- to 79 years or 80 years and over), 
and race (white or non-white). Estimates and confidence intervals for the odds ratio and 
relative risk differences will be provided. 
 
Best-case and worst-case sensitivity analyses will be performed as outlined in Section 
2.3 above. In addition, a tipping point analysis will be performed, imputing various levels 
of COVID-19 and VRI infection rates to missing values in the NTZ arm to determine the 
infection rate at which the study conclusions change. 
 
4.2.2 Secondary Efficacy Variables 
The proportion of subjects in the NTZ and placebo groups experiencing hospitalization 
due to COVID-19 or its complications will be analyzed using a CMH test stratified by LTCF 


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with appropriate continuity correction at an unadjusted a=0.05. The contingency tables 
will be provided with rates relative to the treatment margins. 
 
The mortality rate due to COVID-19 or complications in the two treatment groups will be 
compared using a CMH test stratified by LTCF with continuity correction at unadjusted 
a=0.05. Contingency tables with rates computed relative to the treatment margins will be 
provided. 
 
The proportion of subjects in the treatment groups testing positive for SARS-CoV-2 
antibodies at either Week 6 or Week 8 will be compared using a CMH test stratified by 
LTCF. The contingency tables will be provided with rates computed relative to the 
treatment margins. 
 
4.2.3 Exploratory Efficacy Variables 
Hospitalization due to VRI or complication thereof, mortality due to VRI or complications 
thereof, Presence of an ARI, hospitalization due to ARI or complications thereof, and 
mortality due to ARI or complications thereof will each be summarized in a three-way 
contingency table (Stratum*Treatment*Variable) with counts and percentages relative to 
the table row (i.e., treatment) margins. A CMH test stratifying by LTCF will be provided 
for each variable. 
 
5.0 Analysis of Safety  
 
5.1 Description of Safety Variables 
 
The safety analysis variables are defined as follows: 
 
• Adverse Events (AEs) 
• Clinical Laboratory Values (Hematology, Blood Chemistry, and Urinalysis) 
• Physical Exam 
• Vital Signs 
 
The following describes the safety analyses to be performed for the study.  All safety 
analyses will be performed on the safety population.  
  
5.2 Description of Safety Analyses 
 
Adverse Events  
Adverse events will be graded by the investigator according to the “Guidance for Industry: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Trials” (FDA/CDER, 2007) as adapted in the Study Protocol. The 
investigator will also assess causality (relationship to treatment) as Definitely related, 
Probably related, Possibly related, and Unrelated. AEs will be coded using the Medical 
Dictionary for Regulatory Activities version 23.0 or higher (MedDRA®). Treatment-


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emergent AEs (TEAEs), defined as any AE that occurs after a patient receives the first 
dose of the assigned study treatment, will be summarized by the number and proportion 
of patients reporting at least one occurrence of the AE.  Frequencies and rates of each 
TEAE will be summarized by MedDRA preferred term within system organ class (SOC), 
by severity grade, and relation to treatment for each treatment group.  The rate calculation 
will be based on the number of patients in the safety population for the relevant treatment 
group. 
 
Treatment emergent serious adverse events (TESAEs) will be summarized and displayed 
by frequency and rate by MedDRA preferred term within SOC. 
 
A by-patient AE data listing of all adverse events including verbatim term, coded term, 
grade, and relation to treatment will be provided.   
Laboratory Tests  
Clinical laboratory tests will be performed at the times prescribed in the protocol. The 
following clinical laboratory tests will be performed:   
 
Hematology:  
Hemoglobin, hematocrit, complete white blood count (total and differential), 
platelet count, random blood glucose, total cholesterol, HDL, LDL, and 
triglycerides. 
Clinical Chemistry: 
AST, ALT, GGT, alkaline phosphatase, bilirubin (total and direct), BUN, creatinine, 
sodium, potassium, and chloride. 
Urinalysis:  
Appearance, glucose, protein, and blood. 
 
Clinical laboratory results and the change from baseline (CFB, baseline defined as the 
value at the baseline visit) will be summarized for the safety population with summary 
statistics (mean, standard deviation, n, minimum, median, maximum) by time point for 
each treatment group. Clinical laboratory results will be classified as “Normal”, or 
“Abnormal”; “Abnormal” results will be further classified by the PI as “Clinically significant” 
(CS) or “Not clinically significant” (NCS). Clinical laboratory results will be summarized by 
a shift table from baseline with categories “Normal”, “Abnormal (NCS)”, and “Abnormal 
(CS)”. Urinalysis appearance results will appear only in the shift table. 
 
All clinically significant abnormal laboratory findings will be reported as AEs. All AEs 
recorded will be listed. 
 
Physical Exam  
Physical exams will be performed as outlined in the protocol. All clinically significant 
abnormal PE findings will be recorded as AEs.  All physical exam data will be listed as 
shown in Appendix B. 
 


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Vital Signs  
Vitals signs will include weight, heart rate, respiratory rate, blood pressure (diastolic and 
systolic), and temperature.  Vital signs will be taken as outlined in the protocol. The 
baseline visit vital signs will be used for baseline for changes at the Week 3 and Week 6 
follow-up visits. If repeat vital signs are taken at a given time point, then the last 
measurement will be used for the analysis tables.   
 
Vital signs will be summarized for the safety population with summary statistics (mean, 
standard deviation, n, minimum, median, maximum) by time point and study arm. All vital 
signs will be listed. 
 
6.0 Other Relevant Data Analyses/Summaries 
 
6.1 Patient Completion  
 
A table will be constructed with counts and percentages of subject completion status 
showing counts for each withdrawal reason.  Tabulations will be performed overall for the 
safety population.  
 
A data listing of all patients’ completion status with withdrawal reasons will also be 
constructed. 
 
6.2 Prior and Concomitant Medications 
 
All prior/concomitant medications taken by or administered to a patient will be collected 
from the 30 days prior to treatment through the completion of the follow-up visit. 
Medications will be coded using the most recent version of the WHO Drug Dictionary. A 
summary of frequencies for ATC Levels I and IV will be provided, as will a data listing of 
concomitant medications will be provided.   
 
6.3 Death Report 
 
The number and percentage of deaths from all causes will be computed by treatment 
group for the safety population.  All death report data will be listed. 
 
6.4 Additional Baseline Data 
 
Medical history will be presented in a data listing for the safety population. History events 
will be coded using the current version of MedDRA. 
 
7.0 References 
Chow, SC and Chang, M Adaptive Design Methods in Clinical Trials. 2007. Chapman and 
Hall, Boca Raton, FL. 


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FDA/CDER Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. US Department of 
Health and Human Services. September 2007. (Retrieved 28April2020 from 
https://www.fda.gov/media/73679/download). 
Kimball A, Hatfield KM, Arons M, James A, Taylor J, et al. Asymptomatic and 
presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled nursing 
facility—King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep 2020; 
69:377-381. 
Mannick JB, Morris M, Hockey H-U, Roma G, Beibel M, et. al.  TORC1 inhibition 
enhances immune function and reduces infections in the elderly. Sci Transl Med 2018; 
10:eaaq1564. 
McMichael TM, Clark S, Pogosjans S, Kay M, Lewis J, et al. COVID-19 in a long-term 
care facility—King County, Washington, February 27–March 9, 2020. MMWR Morb Mortal 
Wkly Rep 2020; 69:339-342. 
Yu J, Powers JH, Vallo D, Falloon J. Evaluation of efficacy endpoints for a phase IIb study 
of a respiratory syncytial virus vaccine in older adults using patient-reported outcomes 
with laboratory confirmation. Value Health 2020; 23:227-35. 
 
 
 
 


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8.0 List of Analysis Tables, Figures and Listings 
 
Table No. 
Table Title 
14.1.1.1 
Subject Disposition Summary by Treatment and Overall (All Subjects) 
14.1.2.1 
Summary of Major Protocol Deviations (Safety Population) 
14.1.2.2 
Summary of Minor Protocol Deviations (Safety Population) 
14.1.3.1 
Summary of Demographic Categorical Variables by Treatment and Stratum (Safety 
Population) 
14.1.3.2 
Summary of Demographic Quantitative Variables by Treatment and Stratum (Safety 
Population) 
14.1.4 
Summary of Treatment Compliance (Safety Population) 
14.2.1.1 
Cochran-Mantel-Haenszel Test Results: Symptomatic COVID-19 Subject Status (ITT 
Population) 
14.2.1.2 
Cochran-Mantel-Haenszel Test Results: Symptomatic VRI Subject Status (ITT 
Population) 
14.2.1.3 
Cochran-Mantel-Haenszel Test Results: Symptomatic COVID-19 Subject Status with 
Best-Case and Worst-Case Analysis of Missing Data (ITT Population) 
14.2.1.4 
Cochran-Mantel-Haenszel Test Results: Symptomatic VRI Subject Status with Best-
Case and Worst-Case Analysis of Missing Data (ITT Population) 
14.2.1.5 
Cochran-Mantel-Haenszel Test Results: Symptomatic COVID-19 Subject Status with 
Tipping Point Analysis of Missing Data (ITT Population) 
14.2.1.6 
Cochran-Mantel-Haenszel Test Results: Symptomatic VRI Subject Status with Best- 
Tipping Point Analysis of Missing Data (ITT Population) 
14.2.1.7 
Cochran-Mantel-Haenszel Test Results by Sex: Symptomatic COVID-19 Subject Status 
(ITT Population) 
14.2.1.8 
Cochran-Mantel-Haenszel Test Results by Sex: Symptomatic VRI Subject Status (ITT 
Population) 
14.2.1.9 
Cochran-Mantel-Haenszel Test Results by Age Group: Symptomatic COVID-19 Subject 
Status (ITT Population) 
14.2.1.10 
Cochran-Mantel-Haenszel Test Results by Age Group: Symptomatic VRI Subject Status 
(ITT Population) 
14.2.1.11 
Cochran-Mantel-Haenszel Test Results by Race: Symptomatic COVID-19 Subject 
Status (ITT Population) 
14.2.1.12 
Cochran-Mantel-Haenszel Test Results by Race: Symptomatic VRI Subject Status (ITT 
Population) 
14.2.2.1 
Cochran-Mantel-Haenszel Test Results: COVID-19 Related Hospitalization Status (ITT 
Population) 


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Table No. 
Table Title 
14.2.2.2 
Cochran-Mantel-Haenszel Test Results: COVID-19 Related Mortality Subject Status 
(ITT Population) 
14.2.2.3 
Cochran-Mantel-Haenszel Test Results: COVID-19 Antibody Test Subject Status (ITT 
Population) 
14.2.3.1 
Cochran-Mantel-Haenszel Test Results: VRI Related Hospitalization Subject Status 
(ITT Population) 
14.2.3.2 
Cochran-Mantel-Haenszel Test Results: VRI Related Mortality Subject Status (ITT 
Population) 
14.2.3.3 
Cochran-Mantel-Haenszel Test Results: ARI Subject Status (ITT Population) 
14.2.3.4 
Cochran-Mantel-Haenszel Test Results: ARI Related Hospitalization Subject Status 
(ITT Population) 
14.2.3.5 
Cochran-Mantel-Haenszel Test Results: ARI Related Mortality Subject Status (ITT 
Population) 
14.3.1.1 
Treatment Emergent Adverse Events Summary: Total AE, Toxicity Grade, Relationship 
to Treatment, Serious AEs by Treatment (Safety Population) 
14.3.1.2 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term, and 
Treatment (Safety Population) 
14.3.1.3 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term, 
Treatment, and Toxicity Grade (Safety Population) 
14.3.1.4 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term, 
Treatment, and Relationship to Treatment (Safety Population) 
14.3.1.5 
Treatment Emergent Serious Adverse Events by System Organ Class, Preferred Term, 
and Treatment (Safety Population) 
14.3.2.1 
Clinical Laboratory Summary Statistics: Hematology (Safety Population) 
14.3.2.2 
Clinical Laboratory Shift Tables: Hematology (Safety Population) 
14.3.3.1 
Clinical Laboratory Summary Statistics: Clinical Chemistry (Safety Population) 
14.3.3.2 
Clinical Laboratory Shift Tables: Clinical Chemistry (Safety Population) 
14.3.4.1 
Clinical Laboratory Summary Statistics: Urinalysis (Safety Population) 
14.3.4.2 
Clinical Laboratory Shift Tables: Urinalysis (Safety Population) 
14.3.5 
Vital Signs Summary Statistics (Safety Population) 
14.3.6 
Prior and Concomitant Medications (Safety Population) 
 
 


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Listing No. 
 
 
Data Listing Title 
16.2.1 
Subject Disposition and Off-Treatment Listing (All records) 
16.2.2 
Protocol Deviations Listing (Safety Population) 
16.2.3 
Patients Excluded from the Efficacy Analysis (Safety Population) 
16.2.4.1 
Subject Demographics Listing (Safety Population) 
16.2.4.2 
Medical History Listing (Safety Population) 
16.2.4.3 
Concomitant Medications Listing (Safety Population) 
16.2.5.1 
Treatment Compliance Listing (Safety Population) 
16.2.5.2 
Drug Concentration Data Listing (Safety Population) 
16.2.6.1 
Subject Primary Efficacy Variables Listing: COVID-19 Status, VRI Status (Safety 
Population) 
16.2.6.2 
Subject Secondary Efficacy Variables Listing: ARI Status, Hospitalization Status, 
Mortality (Safety Population) 
16.2.6.3 
SARS-CoV-2 Antibody Status (Safety Population) 
16.2.7.1 
Adverse Events Listing (Safety Population) 
16.2.7.2 
Subject Deaths Listing (Safety Population) 
16.2.8.1 
Hematology Listing (Safety Population) 
16.2.8.2 
Clinical Chemistry Listing (Safety Population) 
16.2.8.3 
Urinalysis Listing (Safety Population) 
16.2.9.1 
Physical Examination Listing (Safety Population) 
16.2.9.2 
Vital Signs Listing (Safety Population)