Phase 2a, Randomized, Doubleblind, Placebo-controlled Trial Evaluating the Antiviral Activity, Safety and Pharmacokinetics of Repeated Oral Doses of JNJ-64281802 Against Dengue-3 Infection in a Dengue Human Challenge Model in Healthy Adults
Phase: PHASE2
Conditions: Dengue
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

CI R 3 3 2  
 
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A P h ase 2 a, R a n d o mize d, D o u bl e -bli n d, Pl ace b o -c o ntr olle d Tri al t o 
E v al u ate t he A nti vir al Acti vit y, S afet y, a n d P h ar m ac o ki netics of 
Re pe ate d Or al D oses of J N J -6 4 2 8 1 8 0 2 A g ai nst De n g ue Ser ot y pe 3 
I nfecti o n i n a De n g ue H u m a n C h all e n ge M o del i n He alt h y A d ult 
P a rtici p a nts  
 
CI R  Pr ot oc ol  N u m ber  
3 3 2  
W C G Trac ki n g N u m ber   
2 0 2 1 3 5 5 7  
Ja nsse n Pr ot oc ol N u m ber 
6 4 2 8 1 8 0 2 D N G 2 0 0 2  
F D A  I N D N u m ber 
1 5 6 2 9 5  
 
 
I o nizi n g R a diati o n  
N o ne  
M ulti -i nstit uti o n 
Yes  
 
Pr oject  Ass ura n ce:  
F W A # 0 0 0 0 0 2 8 7 (J o h ns H o p ki ns Bl o o m ber g Sc h o ol of P u blic 
Healt h ) 
 
F W A # 0 0 0 0 0 7 2 7  (U ni versit y of Ver m o nt Me dical Ce nter ) 
F W A # 0 0 0 0 0 7 2 3 ( U ni versit y of Ver m o nt) 
 
 
 
Pr ot oc ol  Versi o n:  
v 8. 0  
Date:  
 
A u g ust 2 8 , 2 0 2 3  
 
 
 
S p o ns ore d b y:  
Office of Cli nical Researc h P olic y a n d Re g ulat or y O perati o ns ( O C R P R O)  
Di visi o n of Cli nical Researc h ( D C R)  
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseas es ( NI AI D)  
Nati o nal I nstit utes of Healt h ( NI H)  
 
T he i nf or mati o n c o ntai ne d herei n is t he pr o pert y of t he Nati o nal I nstit ute of Aller g y a n d 
I nfecti o us Dise ases, Nati o nal Instit utes of Healt h a n d ma y n ot be re pr o d uce d, p u blis he d,  or 
discl ose d t o ot hers wit h o ut t he writte n a ut h orizati o n of t he Nati o nal I nstit ute of Aller g y 
a n d I nfecti o us  Diseases.   

CI R 3 3 2  
 
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Te a m R oster  
Pri nci p al  I n vesti g at or: 
 
 
 
 
 
 
 
C o -in vesti g at or : 
 
 
 
 
 
 
 
 
 
 
Cli nic al  I n vesti g at ors: 
 
 
  
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
U n bli n de d I n vesti g at or:  
 
 
 
  
 
 
 
Scie ntific  I n vesti g at ors: 
 
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D

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O C R P R O  Re g ul at or y  Aff airs:  
 
 
 
 
 
 
 
  
 
 
 
 
S p o ns or  Me dic al  M o nit or:   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Cli nic al  St u d y Sites:  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
P P D
P P D
P P D
P P D

CI R 3 3 2  
 
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Rese arc h  L a b or at ories:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nic al  L a b or at ories:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P P D
P P D
P P D

CI R 3 3 2  
 
5  
 
 
T a ble of C o nte nts  
T A BL E O F C O N T E N T S  ................................................................................................................................................................... 5  
LI S T O F T A BL E S ............................................................................................................................................................................ 8  
1  
P R O T O C OL  P R E CI S  ............................................................................................................................................................ 1 3  
2  
I N T R O D U C TI O N ................................................................................................................................................................ 2 1  
 
B A C K G R O U N D - D E N G U E......................................................................................................................................................... 2 1  
 
B A C K G R O U N D - J NJ-6 4 2 8 1 8 0 2  .............................................................................................................................................. 2 2  
2. 2. 1  
N o n -Cli nic al St u di es  ...................................................................................................................................................... 2 2  
2. 2. 1. 1  
Pri m ary P h ar m ac ol o gy  ........................................................................................................................................................... 2 2  
2. 2. 1. 2  
S ec o n d ar y P h ar m ac ol o gy  ....................................................................................................................................................... 2 3  
2. 2. 1. 3  
S af ety P h ar m ac ol o gy  .............................................................................................................................................................. 2 3  
2. 2. 1. 4  
P h ar m ac o ki n etic a n d M et a b olic  Pr ofil e  ................................................................................................................................. 2 3  
2. 2. 1. 5  
T oxic ol o gy  .............................................................................................................................................................................. 2 5  
2. 2. 2  
Pr evi o us H u m a n Ex p eri e nc e wit h J NJ -6 4 2 8 1 8 0 2  .......................................................................................................... 2 6  
2. 2. 2. 1  
S af ety  ..................................................................................................................................................................................... 2 6  
2. 2. 2. 2  
H u m a n P h ar m ac o ki n etics  ....................................................................................................................................................... 2 6  
 
B A C K G R O U N D - D E N G U E H U M A N C H ALL E N G E M O D EL WI T H A R E C O M BI N A N T D E N V -3  S T R AI N .......................................................... 2 8  
2. 3. 1  
St u di es of D E N V -3 i n R h es us M o n k e ys  ......................................................................................................................... 2 8  
2. 3. 2  
M os q uit o Tr a ns missi bilit y of r D E N 3 Δ 3 0  ....................................................................................................................... 2 9  
2. 3. 3  
Cli nic al Ex p eri e nc e wit h r D E N 3 3 0  .............................................................................................................................. 2 9  
2. 3. 3. 1  
St u dy CI R 3 0 4  ......................................................................................................................................................................... 3 0  
2. 3. 3. 2  
St u dy CI R 3 0 9  ......................................................................................................................................................................... 3 0  
2. 3. 3. 3  
St u dy CI R 3 2 3  ......................................................................................................................................................................... 3 0  
2. 3. 3. 4  
S u m m ar y  ................................................................................................................................................................................ 3 1  
 
S T U D Y P R O D U C T S D E S C RI P TI O N S  .............................................................................................................................................. 3 2  
2. 4. 1  
J NJ-6 4 2 8 1 8 0 2  ............................................................................................................................................................... 3 2  
2. 4. 1. 1  
Cli nic al L ot Pr o d ucti o n  ............................................................................................................................................................ 3 2  
2. 4. 1. 2  
Fi n al C o nt ai n er of J NJ -6 4 2 8 1 8 0 2  ............................................................................................................................................ 3 2  
2. 4. 1. 3  
C o m p ositi o n of J NJ -6 4 2 8 1 8 0 2  ................................................................................................................................................ 3 2  
2. 4. 1. 4  
I nv esti g ati o n al Pr o d uct L a b el f or J NJ-6 4 2 8 1 8 0 2  .................................................................................................................... 3 3  
2. 4. 2  
r D E N 3 Δ 3 0, L ot D E N 3 # 1 1 4 A .......................................................................................................................................... 3 3  
2. 4. 2. 1  
S e e d L ot Pr o d ucti o n  ............................................................................................................................................................... 3 3  
2. 4. 2. 2  
Cli nic al L ot Pr o d ucti o n  ............................................................................................................................................................ 3 3  
2. 4. 2. 3  
Fi n al C o nt ai n er of r D E N 3 Δ 3 0, L ot D E N 3 # 1 1 4 A  ....................................................................................................................... 3 3  
2. 4. 2. 4  
C o m p ositi o n of r D E N 3 Δ 3 0, L ot D E N 3 # 1 1 4 A  ........................................................................................................................... 3 3  
2. 4. 2. 5  
I nv esti g ati o n al Pr o d uct L a b el f or r D E N 3 Δ 3 0, L ot D E N 3 # 1 1 4 A ............................................................................................... 3 4  
3  
O BJ E C TI V E S A N D E N D P OI N T S  ........................................................................................................................................... 3 4  
 
P RI M A R Y O BJ E C TI V E S  ............................................................................................................................................................. 3 4  
 
S E C O N D A R Y O BJ E C TI V E S  ......................................................................................................................................................... 3 4  
 
E X PL O R A T O R Y O BJ E C TI V ES  ...................................................................................................................................................... 3 4  
 
P RI M A R Y E N D P OI N T S  ............................................................................................................................................................. 3 5  
 
S E C O N D A R Y E N D P OI N TS  ......................................................................................................................................................... 3 5  
 
E X PL O R A T O R Y E N D P OI N TS  ....................................................................................................................................................... 3 5  
 
H Y P O T H ESI S  ......................................................................................................................................................................... 3 6  
4  
S T U D Y D E SI G N  .................................................................................................................................................................. 3 6  
 
O V E R ALL D E SI G N ................................................................................................................................................................... 3 6  
4. 1. 1  
St u dy D esi g n  ................................................................................................................................................................. 3 7  
4. 1. 1. 1  
I niti al E nr oll m e nt of S e nti n el C o h ort 1 ................................................................................................................................... 4 2  
4. 1. 1. 2  
E nr oll m e nt of R e m ai ni n g S u bj ects i n C o h ort 1  ....................................................................................................................... 4 2  
4. 1. 1. 3  
E nr oll m e nt of S u bj ects i n C o h ort 2 ......................................................................................................................................... 4 3  

CI R 3 3 2  
 
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4. 1. 2  
S a m pl e Siz e a n d Pl ac e b o R ati o  ..................................................................................................................................... 4 3  
4. 1. 3  
D ur ati o n of S u bj ect P artici p ati o n  ................................................................................................................................. 4 4  
4. 1. 4  
Esti m at e d D ur ati o n of t h e St u dy  .................................................................................................................................. 4 4  
4. 1. 5  
Tr e at m e nt Assi g n m e nt  ................................................................................................................................................. 4 4  
4. 1. 6  
Bli n di n g  ......................................................................................................................................................................... 4 4  
5  
S EL E C TI O N A N D E N R OLL M E N T O F  S U BJ E C T S  .................................................................................................................... 4 5  
 
IN CL U SI O N C RI T E RI A F O R R E C EI P T OF J NJ-6 4 2 8 1 8 0 2  T E S T A R TI CL E  ............................................................................................... 4 5  
5. 1. 1  
Lif estyl e C o nsi d er ati o ns f or J NJ -6 4 2 8 1 8 0 2  ................................................................................................................... 4 7  
 
E X CL USI O N C RI T E RI A F O R R E C EI P T OF J NJ-6 4 2 8 1 8 0 2  T E S T A R TI CL E  .............................................................................................. 4 8  
 
E X CL USI O N C RI T E RI A F O R R D E N 3 Δ 3 0  C H ALL E N G E  ...................................................................................................................... 5 1  
 
E A RL Y D I S C O N TI N U A TI O N O F S T U D Y D R U G  ................................................................................................................................. 5 1  
 
S U BJ E C T W I T H D R A W AL A N D T E R MI N A TI O N C RI T E RI A  ................................................................................................................... 5 1  
 
S P E CI AL S I TU A TI O NS :.............................................................................................................................................................. 5 2  
5. 6. 1  
C orr ect e d Q T ( Q Tc) Pr ol o n g ati o n  ................................................................................................................................. 5 2  
5. 6. 2  
Pr e g n a nc y  ..................................................................................................................................................................... 5 2  
5. 6. 3  
L ost t o F oll o w U p .......................................................................................................................................................... 5 2  
5. 6. 4  
I nc arc er ati o n ................................................................................................................................................................ 5 2  
5. 6. 5  
Miss e d d os e(s)  .............................................................................................................................................................. 5 2  
 
A C C E SS T O M E DI C AL R E C O R D S ................................................................................................................................................. 5 3  
6  
S T U D Y P R O D U C T  P R E P A R A TI O N  ....................................................................................................................................... 5 3  
 
J NJ-6 4 2 8 1 8 0 2  P R E -D O SI N G P R E P A R A TI O N  .............................................................................................................................. 5 3  
 
P R E -IN O C UL A TI O N P R E P A R A TI O N  ............................................................................................................................................. 5 3  
 
J NJ-6 4 2 8 1 8 0 2,  D E N V -3  A N D D IL U E N T S T O R A G E ..................................................................................................................... 5 4  
 
J NJ-6 4 2 8 1 8 0 2,  D E N V -3  A N D D IL U E N T A C C O U N T A BILI T Y  ........................................................................................................... 5 4  
 
S T O R A G E D I S P OSI TI O N O F U S E D/ UN U S E D S U P PLI E S  ..................................................................................................................... 5 4  
7  
S T U D Y  P R O C E D U R E S  ......................................................................................................................................................... 5 5  
 
R E C R UI T M E N T A N D G E N E R AL S C R E E NI N G  ................................................................................................................................... 5 5  
 
C O N S E N TI N G P R O C ES S ............................................................................................................................................................ 5 5  
 
S C R E E NI N G P R O C E D U R E S  ........................................................................................................................................................ 5 6  
 
D E T AIL E D S T U D Y P R O C E D U R ES  ................................................................................................................................................. 5 9  
 
S A F E T Y A S S E SS M E N TS............................................................................................................................................................. 6 0  
 
A N TI VI R AL A C TI VI T Y A SS ES S M E N T S ........................................................................................................................................... 6 0  
 
P H A R M A C O KI N E TI C A S S ES S M E N T S ............................................................................................................................................ 6 1  
7. 7. 1  
S a m pl e C oll ecti o n a n d H a n dli n g  ................................................................................................................................... 6 1  
7. 7. 2  
P h ar m ac o ki n etic A n alysis  ............................................................................................................................................. 6 2  
7. 7. 3  
P h ar m ac o ki n etic P ar a m et ers  ....................................................................................................................................... 6 2  
 
IM M U N E A S S E S S M E N TS .......................................................................................................................................................... 6 3  
7. 8. 1  
H u m or al I m m u n e R es p o ns e  ......................................................................................................................................... 6 4  
7. 8. 2  
C ell ul ar I m m u n e R es p o ns e  ........................................................................................................................................... 6 4  
 
B I O M A R K E R A S S ES S M E N T S ...................................................................................................................................................... 6 4  
 
V I R AL G E N O M E S E Q U E N CI N G .................................................................................................................................................. 6 4  
 
H U M A N L E U K O C Y T E A N TI G E N T Y PI N G A N D P H A R M A C O G E N O MI C E V AL U A TI O NS  ................................................................................ 6 5  
 
IN O C UL A TI O N WI T H R D E N 3 3 0  .............................................................................................................................................. 6 5  
 
S C H E D UL E D A D MI S SI O N T O T H E IN P A TI E N T U NI T  ......................................................................................................................... 6 5  
 
M E DI C A TI O N A D MI NI S T R A TI O N O F J NJ-6 4 2 8 1 8 0 2  .................................................................................................................... 6 6  
 
A N TI CI P A T E D IN P A TI E N T S T A Y A N D F OLL O W U P P R O C E D U R E S  ........................................................................................................ 6 8  
 
C O H O R T 1  S C H E D UL E O F P R O C E D U R E S  ...................................................................................................................................... 6 8  
 
C O H O R T 2  S C H E D UL E O F P R O C E D U R E S  ...................................................................................................................................... 8 1  
 
U N A N TI CI P A T E D A D MI SSI O N A N D D IS C H A R G E C RI T E RI A  ................................................................................................................ 9 2  
 
D E N G U E M E M O R Y E N H A N C E M E N T C A R D ( D M E C) ...................................................................................................................... 9 3  

CI R 3 3 2  
 
7  
 
 
C LI NI C AL L A B O R A T O R Y T E S TI N G ............................................................................................................................................... 9 3  
 
M E DI C AL H IS T O R Y A N D C O N C O MI T A N T M E DI C A TI O N S  ................................................................................................................. 9 5  
 
R E T E N TI O N O F S T U D Y S U BJ E C TS  ............................................................................................................................................... 9 7  
8  
A D V E R S E E V E N T  M O NI T O RI N G  ......................................................................................................................................... 9 7  
 
D E FI NI TI O N S ......................................................................................................................................................................... 9 7  
8. 1. 1  
A dv ers e E v e nt  ............................................................................................................................................................... 9 7  
8. 1. 2  
A dv ers e R e acti o n  .......................................................................................................................................................... 9 8  
8. 1. 3  
S us p ect e d A d v ers e R e acti o n ( S A R)  ............................................................................................................................... 9 8  
8. 1. 4  
Pr e g n a nc y  ..................................................................................................................................................................... 9 8  
8. 1. 5  
S eri o us A d v ers e E v e nt ( S A E)  ......................................................................................................................................... 9 9  
8. 1. 6  
U n ex p ect e d A d v ers e E v e nts .......................................................................................................................................... 9 9  
8. 1. 7  
S eri o us a n d U n ex p ect e d S us p ect e d A dv ers e R e acti o n ( S US A R)  ................................................................................... 9 9  
8. 1. 8  
U n a ntici p at e d Pr o bl e m ................................................................................................................................................. 9 9  
8. 1. 9  
U n a ntici p at e d Pr o bl e m t h at is n ot a n A dv ers e E v e nt ( U P n o n A E)  .............................................................................. 1 0 0  
8. 1. 1 0  
Pr ot oc ol D evi ati o n  .................................................................................................................................................. 1 0 0  
8. 1. 1 1  
S eri o us Pr ot oc ol D evi ati o n  ..................................................................................................................................... 1 0 0  
8. 1. 1 2  
N o n -c o m pli a nc e ..................................................................................................................................................... 1 0 0  
8. 1. 1 3  
Pr e -Existi n g C o n diti o ns, W ors e ni n g of Pr e -existi n g C o n diti o n  ............................................................................... 1 0 0  
 
A S S E SS M E N T O F A D V E R S E E V E N T S  .......................................................................................................................................... 1 0 0  
8. 2. 1  
I d e ntific ati o n of A d v ers e E v e nts ................................................................................................................................. 1 0 0  
8. 2. 2  
Pr ot oc ol -S p ecific A d v ers e E v e nt D efi niti o ns  ............................................................................................................... 1 0 1  
8. 2. 3  
D et er mi n ati o n of S ev erity ........................................................................................................................................... 1 0 2  
8. 2. 4  
R el ati o ns hi p wit h R ec ei pt of J NJ -6 4 2 8 1 8 0 2 T est Articl e or C h all e n g e  ........................................................................ 1 0 4  
8. 2. 5  
A dv ers e E v e nt Acti o n T a k e n  ....................................................................................................................................... 1 0 4  
8. 2. 6  
A dv ers e E v e nt O utc o m e  ............................................................................................................................................. 1 0 5  
8. 2. 7  
A dv ers e E v e nt S eri o us n ess  ......................................................................................................................................... 1 0 5  
 
A D V E R S E E V E N T R E P O R TI N G .................................................................................................................................................. 1 0 5  
8. 3. 1  
N o n -S eri o us A d v ers e E v e nts  ....................................................................................................................................... 1 0 5  
8. 3. 2  
S eri o us A d v ers e E v e nts  ............................................................................................................................................... 1 0 5  
8. 3. 3  
U n a ntici p at e d Pr o bl e ms  ............................................................................................................................................. 1 0 6  
 
S P O N S O R ’S R E P O R TI N G R E S P O N SI BILI TI ES  ................................................................................................................................ 1 0 6  
 
P A U SI N G R UL ES F O R T H E S T U D Y ............................................................................................................................................. 1 0 7  
8. 5. 1  
R e p orti n g a P a us e  ...................................................................................................................................................... 1 0 7  
8. 5. 2  
R es u m pti o n F oll o wi n g a P a us e  ................................................................................................................................... 1 0 7  
8. 5. 3  
Disc o nti n u ati o n of St u dy A g e nt  .................................................................................................................................. 1 0 7  
 
H AL TI N G R UL ES F O R T H E S T U D Y ............................................................................................................................................. 1 0 7  
8. 6. 1  
H alti n g r ul es f or J NJ -6 4 2 8 1 8 0 2  .................................................................................................................................. 1 0 7  
8. 6. 2  
H alti n g r ul es f or r D E N 3 3 0  ........................................................................................................................................ 1 0 8  
8. 6. 3  
R e p orti n g a St u dy H alt  ............................................................................................................................................... 1 0 8  
8. 6. 4  
R es u m pti o n of a H alt e d St u dy  .................................................................................................................................... 1 0 8  
 
S A F E T Y O V E R SI G H T  .............................................................................................................................................................. 1 0 9  
8. 7. 1  
S af ety R evi e w a n d C o m m u nic ati o ns Pl a n a n d Tr a nsf er of R e g ul at ory O bli g ati o ns  ................................................... 1 0 9  
8. 7. 2  
S p o ns or M e dic al M o nit or  ........................................................................................................................................... 1 0 9  
8. 7. 3  
NI AI D I ntr a m ur al D at a a n d S af ety M o nit ori n g B o ar d  ................................................................................................ 1 0 9  
9  
S T A TI S TI C AL C O N SI D E R A TI O N  .........................................................................................................................................1 0 9  
 
S A M PL E S I Z E D E T E R MI N A TI O N ............................................................................................................................................... 1 0 9  
 
A N TI VI R AL A C TI VI T Y A N AL Y S E S  ............................................................................................................................................... 1 1 1  
9. 2. 1  
Pri m ary E n d p oi nt  ........................................................................................................................................................ 1 1 2  
9. 2. 2  
S ec o n d ary E n d p oi nts  .................................................................................................................................................. 1 1 2  
 
S A F E T Y A N AL Y SI S  ................................................................................................................................................................. 1 1 3  
9. 3. 1  
A dv ers e E v e nts  ........................................................................................................................................................... 1 1 3  

CI R 3 3 2  
 
8  
 
9. 3. 2  
Cli nic al L a b or at ory T ests  ............................................................................................................................................ 1 1 3  
9. 3. 3  
Vit al Si g ns  ................................................................................................................................................................... 1 1 3  
9. 3. 4  
P h ysic al Ex a mi n ati o ns  ................................................................................................................................................ 1 1 3  
 
E L E C T R O C A R DI O G R A M A SS E SS M E N TS ...................................................................................................................................... 1 1 3  
 
P H A R M A C O KI N E TI C A N AL Y SI S  ................................................................................................................................................ 1 1 4  
 
IM M U N E A N AL YS E S  .............................................................................................................................................................. 1 1 4  
9. 6. 1  
H u m or al I m m u n e A n alys es  ......................................................................................................................................... 1 1 4  
9. 6. 2  
C ell ul ar I m m u n e A n alys es  .......................................................................................................................................... 1 1 5  
9. 6. 3  
Bi o m ark ers A n alys es  .................................................................................................................................................. 1 1 5  
9. 6. 4  
P h ar m ac o ki n etic/ P h ar m ac o dy n a mic A n alys es  .......................................................................................................... 1 1 5  
9. 6. 5  
Vir al G e n o m e S e q u e nc e A n alys es  ............................................................................................................................... 1 1 5  
9. 6. 6  
H u m a n L e u k oc yt e A nti g e n Ty pi n g a n d P h ar m ac o g e n o mic A n alys es  ......................................................................... 1 1 5  
9. 6. 7  
I g E I n d uc e d My el oi d C ell D e gr a d ati o n A n alysis.......................................................................................................... 1 1 6  
9. 6. 8  
I nt eri m A n alysis .......................................................................................................................................................... 1 1 6  
1 0  
D A T A C OLL E C TI O N A N D  M O NI T O RI N G  ............................................................................................................................1 1 7  
 
S O U R C E D O C U M E N T A TI O N A N D D A T A C OLL E C TI O N  .................................................................................................................... 1 1 7  
 
S T U D Y D O C U M E N T A TI O N  ...................................................................................................................................................... 1 1 8  
 
R E T E N TI O N O F S P E CI M E N S  .................................................................................................................................................... 1 1 8  
 
R E T E N TI O N O F R E C O R D S ....................................................................................................................................................... 1 1 8  
 
P R O T O C OL C O M PLI A N C E  ....................................................................................................................................................... 1 1 8  
 
C LI NI C AL IN V ES TI G A T O R ’S B R O C H U R E  ...................................................................................................................................... 1 1 9  
 
S T U D Y M O NI T O RI N G  ............................................................................................................................................................ 1 1 9  
1 1  
P R O T E C TI O N O F H U M A N  S U BJ E C T S  .................................................................................................................................1 2 0  
 
IN S TI T U TI O N AL R E VI E W B O A R D S ............................................................................................................................................. 1 2 0  
 
IN F O R M E D C O N S E N T  ............................................................................................................................................................ 1 2 0  
 
R I S K S ................................................................................................................................................................................ 1 2 0  
1 1. 3. 1  
J NJ-6 4 2 8 1 8 0 2  ......................................................................................................................................................... 1 2 0  
1 1. 3. 2  
C h all e n g e  ............................................................................................................................................................... 1 2 1  
1 1. 3. 3  
V e ni p u nct ur e  .......................................................................................................................................................... 1 2 1  
1 1. 3. 4  
P eri p h er al I ntr av e n o us (I V) C at h et er  ..................................................................................................................... 1 2 1  
1 1. 3. 5  
T o pic al A n est h etic Cr e a m ....................................................................................................................................... 1 2 1  
 
B E N E FI T S ........................................................................................................................................................................... 1 2 1  
 
C O M P E N S A TI O N  .................................................................................................................................................................. 1 2 1  
 
C O N FI D E N TI ALI T Y ................................................................................................................................................................. 1 2 2  
 
B I O H A Z A R D C O N T AI N M E N T  ................................................................................................................................................... 1 2 2  
1 2  
P U BLI C A TI O N  P OLI C Y  .......................................................................................................................................................1 2 2  
1 3  
S U P P O R TI N G D O C U M E N T A TI O N  .....................................................................................................................................1 2 3  
 
A P P E N DI X 1:  M O DI FI E D U S  F D A  T O XI CI T Y G R A DI N G T A BL E  ........................................................................................................ 1 2 3  
 
A P P E N DI X 2:  C O N T R A C E P TI V E A N D B A R RI E R G UI D A N C E  .............................................................................................................. 1 2 9  
R E F E R E N C E S  .............................................................................................................................................................................1 3 1  
 
L I S T O F T A BL E S  
T A BL E 1:  A B B R E VI A TI O N S  ......................................................................................................................................................................... 1 0  
T A BL E 2:  D O SI N G S C H E D UL E  ..................................................................................................................................................................... 1 4  
T A BL E 3:  S C H E D UL E O F P R O C E D U R ES –  C O H O R T 1  ........................................................................................................................................ 1 7  
T A BL E 4:  S C H E D UL E O F P R O C E D U R ES - C O H O R T 2  ......................................................................................................................................... 1 9  
T A BL E 5:  R E PLI C A TI O N A N D IM M U N O G E NI CI T Y O F D E N V -3  I N R H E S U S M O N K E Y S  .............................................................................................. 2 9  
T A BL E 6:  P R O T O C OL S R D E N 3 3 0  W A S A D MI NIS T E R E D  ................................................................................................................................. 2 9  

CI R 3 3 2  
 
9  
 
T A BL E 7:  C LI NI C AL R E S P O N S E T O RD E N 3 3 0  I N H E AL T H Y FL A VI VI R U S -N AÏ V E A D UL TS ( CI R 3 0 4, CI R 3 0 9,  A N D CI R 3 2 3)  ........................................... 3 1  
T A BL E 8:  S U M M A R Y O F V I R OL O GI C R E S P O N S E I N F L A VI VI R U S-N AI V E PL A C E B O R E CI PI E N T S C H ALL E N G E D WI T H R D E N 3 3 0  ......................................... 3 2  
T A BL E 9:  N E U T R ALI ZI N G A N TI B O D Y R E S P O N S E T O R D E N 3 3 0  ....................................................................................................................... 3 2  
T A BL E  1 0:  O V E R VI E W O F T H E C O H O R T S , G R O U P S , A N D N U M B E R O F P A R TI CI P A N T S  ............................................................................................ 3 8  
T A BL E 1 1:  S U M M A R Y O F S C H E D UL E O F IN T E RI M A N AL Y S ES A N D U N BLI N DI N G O F D A T A  ....................................................................................... 4 2  
T A BL E 1 2:  D E S C RI P TI O N O F S T U D Y D R U G  .................................................................................................................................................... 6 6  
T A BL E 1 3:  S OLI CI T E D A D V E R S E E V E N T S  ....................................................................................................................................................... 9 8  
T A BL E 1 4:  S E V E RI T Y D E FI NI TI O N S ............................................................................................................................................................ 1 0 2  
T A BL E 1 5:  L O C AL A N D S OLI CI T E D A D V E R S E E V E N T S  ..................................................................................................................................... 1 0 2  
T A BL E 1 6:  M E A N ( S T D) L O G 1 0  A U C D 1 -D 2 9  ( VL) (LO G 1 0  C O PI E S /M L/ 2 8  D A Y S ) I N IN F E C T E D P A R TI CI P A N T S P E R S T U D Y D R U G I N 1 0, 0 0 0  S I M UL A TI O NS
 ................................................................................................................................................................................................. 1 1 0  

CI R 3 3 2  
 
1 0  
 
 
T a ble 1 : A b bre vi ati o ns 
A 1 A G  
Al p h a -1 a ci d g l yc o p r ot ei n 
A B V  
alc o h ol b y v ol u m e  
A E  
a d v e rs e e v e nt  
A L T  
al a ni n e a mi n ot r a nsf e r ase  
A N C  
a bs ol ute n e ut r o p hil c o u nt  
A PI  
acti v e p h a r m a c e utic al i n gr e di e nt  
A S T  
as p art at e a mi n ot r a nsf e r as e  
A U C  
a r e a u n d e r t h e c u r v e  
A U C pl as m a  
ar e a u n d e r t h e J N J -6 4 2 8 1 8 0 2 pl as m a c o n c e nt r ati o n -ti m e c u r v e 
-H C G  
b et a h u m a n c h o ri o ni c g o n a d ot r o pi n  
B MI  
b o d y m ass i n d e x  
B U N  
bl o o d u r e a nit r o g e n  
C  
ca psi d  
C B C  
c o m pl et e bl o o d c o u nt  
C D C  
C e nt e rs f o r Dis e ase C o ntr ol a n d Pr e v e nti o n  
c D N A  
c o m pl e m e nt a r y de o x y ri b o n u cl ei c a ci d  
C F R  
C o d e of Fe d e r al R e g ul ati o ns  
C HI M  
C o nt r oll e d H u m a n I nf e cti o n M o d el  
CI R  
C e nt e r f o r I m m u ni z ati o n R ese a rc h  
C LI A  
Cli ni c al L a b o r at o r y I m p r o v e m e nt A m e n d m e nts  
C P K  
c r e ati n e p h os p h o ki n as e  
C R F  
c as e r e p o rt f o r m(s)  
C RI M S O N  
Cli ni c al R es e a r c h I nf o r m ati o n M a n a g e m e nt S yst e m of t h e NI AI D  
C R L  
C h a rl es Ri v e r L a b o r at o ri es  
C S O  
Cli ni c al S af et y Offi c e  
C V  
c o effi ci e nt of v a ri ati o n  
D D T  
D r u g D e v el o p m e nt T e a m  
D D U T  
D r u g D e v el o p m e nt U n bli n d e d T e a m  
D E N V  
d e n g u e vi r us (s e r ot y p es D E N 1, D E N 2, D E N 3, a n d D E N 4) 
D F  
d e n g u e f e v er  
D H C M  
de n g ue h u m a n c h alle n ge m o del  
D H F  
d e n g u e h e m o r r h a gic f e v e r  
D S M B  
D at a a n d S afet y M o nit o ri n g B o a r d  
D M E C  
D e n g u e M e m o r y E n h a n c e m e nt C a r d  
D N A  
d e o x y ri b o n u cl ei c a ci d  
D S S  
d e n g u e s h o c k s y n d r o m e 
E  
e n vel o p e p r ot ei n of d e n g u e vir us  
E C 5 0 
m e di a n 5 0 % eff e cti v e c o n c e nt r ati o n  
E C G  
el e ct r o c a r di o g r a m  
E U A  
E me r g e n c y Us e A ut h o ri z ati o n  
F D A  
F o o d a n d D r u g A d mi nistr ati o n  
G C P  
G o o d Cli ni c al Pr a cti c e  
H Bs A g  
h e p atitis B s u rf a c e a nti g e n  
H B V  
h e p atiti s B vi r us  
H C G  
h u m a n c h o ri o g o n a d ot r o pi n  
H C V  
h e p atitis C  vi r us  
HI D 5 0 
5 0 % h u m a n i nf e cti o us d os e  
HI V  
h u m a n i m m u n o d efi ci e n c y vi r us  
H L A  
h u m a n l e u k o c yt e a nti g e n  
 
 
H R T  
h o r m o n al r e pl a c e m e nt t h e r a p y  
I B 
i n v esti g at o r’s b r o c h u r e 
I C 5 0 
5 0 % i n hi bit o r y c o n c e nt r ati o n  
C CI

CI R 3 3 2  
 
1 1  
 
I C F 
i nf o r m e d c o ns e nt f o r m 
I C H 
I nt e r n ati o n al C o nf e r e n ce o n H a r m o ni sati o n  
I C M J E 
T he I nt e r n ati o n al C o m mitt e e of M e di c al J o u r n al E dit o rs  
I C S 
i nt r a c ell ul a r c yt o ki n e st ai ni n g 
I D S 
I n v esti g ati o n al D r u g S e r vi c e 
I g A,I g G,I g M,I g E 
i m m u n o gl o b uli ns A, G, M, E 
I N D 
i n v esti g ati o n al n e w d r u g 
I N R 
i nt e r n ati o n al n o r m ali z e d r ati o 
I R B 
I nstit uti o n al R e vi e w B o a r d 
I T T 
i nt e nt-t o-t r e at 
I V 
i nt r a v e n o us 
J H S P H  
J o h ns H o p ki ns Bl o o m b e r g S c h o ol of P u bli c H e alt h  
L D  
l o a di n g d os e 
LI D  
L a b o r at o r y of I nfe cti o us Dis e as es  
L L N  
l o we r li mit of n o r m al 
L L O Q  
l o we r li mit of q u a ntific ati o n 
M  
m e m b r a n e p r ot ei n of d e n g u e vi r us  
M D  
m a i nt e n a n c e d os e  
MI D
5 0 
5 0 % m os q uit o i nf e cti o us d os e  
NI AI D  
N ati o n al I nstit ute of All e r g y a n d I nf e cti o us Dise as es  
NI H  
N ati o n al I nstit utes of H e alt h  
N O A E L  
n o o bse r v e d a d v e rs e eff e ct l e vel  
N P  
n as o p h a r y n ge al  
N S  
n o n -str u ct u r al 
N S AI D  
n o n -ste r oi d al a nti-i nfl a m m at o r y dr u g 
O C R P R O  
Offi c e of Cli ni c al R es e a r c h P oli c y a n d R e g ul at o r y O p e r ati o ns  
P B M C  
p e ri p h e r al bl o o d m o n o n u cle ar c ell  
P F U  
pl a q u e -f o r mi n g u nits 
PI  
p ri n ci p al i n v esti g at o r  
P K  
p h a r m ac o ki n eti cs  
P O C B P  
p e rs o n of c hil d -b e a ri n g p ot e nti al  
P R N T  
pl a q u e r e d u cti o n n e ut r aliz ati o n tit e r  
P T/ P T T  
p r ot h r o m bi n ti m e/ p a rti al t h r o m b o pl asti n ti m e  
Q T c  
c o r r e cte d Q T i nt e r v al  
Q T c B  
Q T i nt er v al c o r re ct e d usi n g B a z ett ’s f o r m ul a 
Q T c F  
Q T i nt er v al  c o r re ct e d usi n g Fri d e ri ci a ’s f o r m ul a 
R E D C a p  
R es e ar c h El e ct r o ni c D at a C a pt u r e  
R N A  
ri b o n u cl ei c a ci d  
S A E  
se ri o us a d v e rs e e v e nt 
S A R  
s us pecte d a d verse re acti o n 
S C  
s u bc ut a ne o us 
S D  
st u d y d a y  
S L E V  
St. L o uis e n c e p h alitis vi r us  
S T D  
st a n d a r d d e vi ati o n 
S E  
st a n d a r d e r r o r 
S R C P  
S afet y Re vie w a n d C o m m u nic ati o n s Pl a n  
S D M  
site-directe d m ut a nts  
S U S A R  
se ri o us a n d u n e x p e ct e d s us p e ct e d a d ve rse r e acti o n 
tM a x  
the me di a n ti me t o m a xi m u m c o nce ntr ati o n  
T M a x  
m a xi m u m t e m p e r at u r e i n a 2 4 -h o u r p e ri o d  
T E A E  
t re at m e nt-e m e r g e nt a d v e rs e e v e nt  
U G T  
uri di ne di p h os p h ate -gl uc ur o n os yltr a nsfer ase  
U L N  
u p p e r li mit of n o r m al  
U P  
u n a nti ci p at e d p r o bl e m  
U S A  
U nit e d St at es of A m e ri c a  
U T R  
u nt r a nsl at e d r e gi o n  

CI R 3 3 2  
 
1 2  
 
V C D  
v ir ol o gi c all y-c o nfi r m e d d e n g u e  
V L  
vir al l o a d  
W B C  
w hit e bl o o d c o u nt  
W C G I R B  
W est e r n C o p e r ni c us G r o u p I nstit uti o n al R e vi e w B o a r d
 
W H O  
W o rl d H e alt h O r g a ni z ati o n  
W t 
wil d t y p e 

CI R 3 3 2  
 
1 3  
 
 
 
1  
Pr ot oc ol  Precis  
Pr ot oc ol  Title:  
A P hase 2a , 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 A nti viral Acti vit y, Safet y, a n d P har mac o ki netics  
of Re peate d Oral D o s es of J NJ-6 4 2 8 1 8 0 2  A gai nst  De n g ue 
Ser ot y pe 3  I nfecti o n i n a De n g ue H u ma n C h alle n ge M o del i n 
Healt h y A d ult Partici pa nts.  
Versi o n : 
v 7. 2  
Versi o n  D ate:  
A u g ust 2 8 , 2 0 2 3  
Versi o n Hist or y : 
v 1. 0 Marc h 3 1 , 2 02 1  
 
v 2. 0 J u ne 8, 2 0 2 1  
 
v 3. 0 A u g ust 1 2, 2 0 2 1  
 
v 4. 0 Dece m b er 2 2, 2 0 2 1  
 
v 5. 0 Ja n uar y 2 4, 2 0 2 2 
 
v 6. 0 A pril 1 3, 2 0 2 2  
 
v 7. 0 Fe br uar y 1 7, 2 0 2 3  
P h ase:  
P hase  2a  
Pri nci p al I n vesti g at or:   
 
 
 
 
 
 
 
S u bjects:  
Healt h y male a n d n o n -pre g na nt fe mal e s u bjects 1 8 t o 5 5  years of 
a ge, i ncl usi ve, wit h n o hist or y of pre vi o us D E N V or Zi ka vir us  
i nfecti o n. 
 
N u m ber of S u bjects:   
5 4  
St u d y  Desi g n:  
Place b o -c o ntr olle d, d o u ble -bli n d st u d y e val uati n g t he a bilit y of  
J NJ-6 4 2 8 1 8 0 2  t o pr otect a gai nst i nfecti o n wit h r D E N 3Δ 3 0 w he n  
J NJ-6 4 2 8 1 8 0 2 is a d mi nistere d be gi n ni n g fi ve d a ys pri or t o 
c halle n ge wit h r D E N 3 Δ 3 0 a n d c o nti n ue d t hr o u g h St u d y Da y 2 1  
f or C o h ort 1. F or C o h ort 2, J NJ-6 4 2 8 1 8 0 2 is a d mi nistere d  2  da ys 
pri or t o c halle n ge wit h r D E N 3 Δ 3 0 a n d c o nti n ue d t hr o u g h St u d y 
Da y 1 5 ( wee kl y  d ose re gi me n s) or St u d y Da y 2 1 ( dail y d ose 
re gi me n).  
P P D

CI R 3 3 2  
 
1 4  
 
T a ble 2 : D osi n g  Sc he d ule  
C O H O R T 1  
N U M B E R O F 
S U B J E C T S ( N)  
P R O D U C T  
D O S E  
D O SI N G 
D A Y S  
G R O U P 1  
1 0  
J NJ-6 4 2 8 1 8 0 2 C  
6 0 0 m g L D/ 2 0 0 m g M D  (hi g h d ose)  
-5 t o 2 1  
 
6  
Place b o  
Place b o  
-5 t o 2 1  
 
1 6  
r D E N 3Δ 3 0  
1 0 3 P F U  
1  
G R O U P 2  
6  
J NJ-6 4 2 8 1 8 0 2 C  
4 0 m g L D/ 1 0 m g M D  (l o w d ose) 
-5 t o 2 1  
 
6  
J NJ-6 4 2 8 1 8 0 2 C  
2 0 0 m g L D/ 5 0 m g M D ( me di u m d ose)  
-5 t o 2 1  
 
2  
Place b o  
Place b o  
-5 t o 2 1  
 
1 4  
r D E N 3Δ 3 0  
1 0 3 P F U  
1  
T O T A L S U B J E C T S C O H O R T 1: 3 0 A  
 
C O H O R T 2  
N U M B E R O F 
S U B J E C T S ( N)  
P R O D U C T  
D O S E  
D O SI N G D A Y S  
G R O U P 3  
6  
J NJ-6 4 2 8 1 8 0 2 D  
8 0 0 m g BI D L D  / 2 5 0 m g M D  
( dail y d osi n g) 
-2 t o 2 1 
2  
Place b o  
Place b o  
-2 t o 2 1 
8  
r D E N 3Δ 3 0  
1 0 3 P F U  
1  
G R O U P  4  
6  
J NJ-6 4 2 8 1 8 0 2 D  
4 5 0 m g BI D L D / 1 2 0 0 m g M D 
( wee kl y d osi n g) 
-2 t o 1, 8, 1 5  
2  
Place b o  
Place b o  
-2 t o 1, 8, 1 5  
8  
r D E N 3Δ 3 0  
1 0 3 P F U  
1  
G R O U P 5  
6  
J NJ-6 4 2 8 1 8 0 2 D  
2 5 0 m g BI D L D / 5 0 0 m g M D 
( wee kl y d osi n g)  
-2 t o 1, 8, 1 5  
2  
Place b o  
Place b o  
-2 t o 1, 8, 1 5  
8  
r D E N 3Δ 3 0  
1 0 3 P F U  
1  
S U B J E C T T O T A L C O H O R T 2: 2 4 B  
L D = l oa di n g d ose; M D = mai nte na n ce d ose; P F U = pla q ue -f or mi ng u nits ; BI D = 2 x per da y 
 
 
A.  I n or der t o acc o u nt f or a p ote ntial earl y disc o nti n uati o n , a ma xi m u m of 7 partici pa nts ca n be re place d i n 
case of disc o nti n uati o n bef ore last d ose of st u d y dr u g o n Da y 2 1.  
B.  I n or der t o acc o u nt f or a p ote ntial earl y disc o nti n uati o n, a ma xi m u m of 6 partici pa nts ca n be re place d i n 
case of disc o nti n uat i o n bef ore Da y  2 1   
C.  
 
D.  
 
 
I n vesti g ati o nal  Pr o d uct Descri pti o n s:  
 
J NJ-6 4 2 8 1 8 0 2 is a n o vel, p ote nt, pa n -ser ot y pic s m all-m olec ule i n hi bit or of  de n g ue vir us 
( D E N V) t ar geti n g D E N V n o nstr uct ural pr otei n ( N S) 4 B.  JNJ -6 4 2 8 1 8 0 2 is bei n g 
de vel o pe d f or t he pre v e nti o n a n d treat me nt of de n g ue i nfecti o n.  
 
 
T he “c h alle n ge” vir us, r D E N 3 Δ 3 0, is a li ve rec o m bi na nt D E N V-3 vir us a n d  will be 
a d mi nistere d s u bc uta ne o usl y at a d ose of 3 l o g 1 0 pla q ue -f or mi n g u nits (1 , 0 0 0 P F U ). 
S u m m ar y of pri m ar y st u d y o bjecti ves:  
•  T o assess t he a nti viral a cti vit y of J NJ -6 4 2 8 1 8 0 2 vers us place b o i n ter ms of re d ucti o n 
of D E N V -3 ri bo n ucleic aci d ( R N A ). 
C CI
C CI
C CI
C CI

CI R 3 3 2  
 
1 5  
 
S u m m ar y of sec o n d ar y st u d y o bjecti ves:   
•  T o assess t he safet y a n d t olera bilit y of J NJ -6 4 2 8 1 8 0 2.  
•  T o assess t he D E N V i nfecti o n -ass ociate d a d verse e ve nts (A E ). 
•  T o assess t he a nti viral acti vit y of J NJ -6 4 2 8 1 8 0 2 vers us place b o o n ot h er vir ol o gic 
e n d p oi nts.  
•  T o assess t he p h ar mac o ki netics ( P K ) of J NJ -6 4 2 8 1 8 0 2 f oll o wi n g re peate d oral d osi n g.  
•  T o e val uate t he rel ati o ns hi p bet wee n t he P K a n d t he a nti viral acti vit y of J NJ -6 4 2 8 1 8 0 2.  
•  T o assess t he a nti -D E N V -3 i m m u n o gl o b uli n M (I g M) a n d i m m u n o gl o buli n G ( I g G) 
a nti b o d y res p o nses.  
E x pl or at or y O bjecti ves:  
•  T o deter mi ne t he i nci de n ce of u nc o m plicate d de n g ue  i nfecti o n. 
•  T o e x pl ore t he a nti -D E N V -3 ne utralizi n g a nti b o d y res p o nse.  
•  T o e x pl ore t he a nti -D E N V -3 cell ular i m m u ne res p o nse.  
•  T o e x pl ore c h a n ges i n ser u m pr otei n le vels (i ncl u di n g c yt o ki nes).  
•  T o e x pl ore t he D E N V -3 N S 1 ser u m pr otei n le vels  (C o h ort 1 ; o pti o nal f or C o h ort 2 ). 
•  T o e x pl ore t he resista nce of D E N V -3 t o J NJ -6 4 2 8 1 8 0 2.  
•  T o e x pl ore t he relati o ns hi p bet wee n t he P K a n d t he safet y a n d t olera bilit y of 
J NJ-6 4 2 8 1 8 0 2.  
•  T o e x pl ore t he i m pact of h ost a n d vir al bas eli ne fact ors o n t he a nti viral acti vit y a n d 
safet y of J NJ-6 4 2 8 1 8 0 2.  
St u d y Desi g n:  
T he st u d y f oll o ws a n a d a pti ve 2 -sta ge desi g n c o nsisti n g of 2 c o h orts, eac h wit h u p t o 3 gr o u p s. 
T he 2  c o h orts will b e e nr olle d i n a sta g gere d ma n ner. As a s afet y meas ure, a se nti nel gr o u p of 
4  partici pa nts will be e nr olle d i n C o h ort 1 ( Gr o u p 1a) bef ore e nr olli n g t he re mai ni n g partici pa nts 
( Gr o u p 1 b a n d Gr o u p 2) i n t he c o h ort.  
After pr o vi di n g writte n i nf o r me d c o nse nt, s u bjects will u n der g o eli gi bilit y scree ni n g, i ncl u di n g 
me dical hist or y, p h ysical e xa mi nati o n, he mat ol o g y testi n g, li ver a n d re nal f u ncti o n testi n g, h u ma n 
i m m u n o deficie nc y vir us ( HI V) scree ni n g, he p atitis B a n d C scree ni n g, uri nal ysis, uri ne 
to xic ol o g y, electr o car di o gra m ( E C G ), a n d ser ol o g y scree ni n g f or pre vi o us D E N V a n d Zi ka vir us  
i nfecti o n.  
 
C o h ort 1: Ser u m/ uri ne pre g na nc y testi n g will be perf or m e d o n a p plica ble pers o ns of 
c hil d beari n g p ote ntial at m ulti ple  scree ni n g visits (if a p plica ble) a n d o n St u d y Da y -5  pri or t o 
a d mi nistrati o n of st u d y a ge nt. A n alc o h ol breat h test ma y  be a d mi nistere d (at PI/ pr o vi d er 
discreti o n)  u p o n pres e ntati o n t o t he u nit o n St u d y Da y -6. Partici pa nts  w h o are eli gi ble, will be 
a d mitte d t o t he i n patie nt u nit o n St u d y Da y -6  t hr o u g h St u d y Da y -4  d uri n g i nte nsi ve P K 
sa m pli n g. A d mi nistrati o n of J NJ-6 4 2 8 1 8 0 2 will be gi n o n St u d y Da y -5 a n d c o nti n ue t hr o u g h 
St u d y Da y 2 1. Recei pt of c halle n ge wit h r D E N 3 Δ 3 0 i n o c ulati o n will be sc he d ule d f or St u d y 
Da y 1.  

CI R 3 3 2  
 
1 6  
 
 
C o h ort 2: Ser ol o g y scree ni n g will als o be perf or me d f or 
West Nile vir us a n d St. L o uis 
e nce p h alitis vir us ( S L E V), i n a d diti o n t o D E N V a n d Zi ka. Ser u m/ uri ne pre g na nc y testi n g will 
be perf or me d o n a p plica ble pers o ns of c hil d beari n g p ote ntial at m ulti ple scree ni n g visits (if 
a p plica ble) a n d o n St u d y Da y -2 pri or t o a d mi nistrati o n of st u d y a ge nt. A n alc o h ol breat h test 
ma y be a d mi nistere d (at PI/ pr o vi der discreti o n) u p o n prese nt ati o n t o t he u nit o n St u d y Da y -3. 
Part ici pa nts w h o are eli gi ble will be a d mitte d t o t he i n patie nt u nit o n St u d y Da y -3 t hr o u g h 
St u d y Da y 1 d uri n g i nte nsi ve P K sa m pli n g. A d mi nistrati o n of J NJ -6 4 2 8 1 8 0 2 will be gi n o n 
St u d y Da y -2 a n d c o nti n u e t hr o u g h St u d y Da y 1 5 f or t he wee kl y d osi n g re gi me n s or  St u d y Da y 
2 1 f or dail y d osi n g re gi m en. Recei pt of c halle n ge wit h r D E N 3 Δ 3 0 i n oc ulati o n will be 
sc he d ule d f or St u d y D a y 1. 
 
T he C o h ort 2 re gi me ns are b ase d o n t he l o n g t 1/ 2 of t he c o m p o u n d a n d t he P K pr ofile o bs er ve d i n 
C o h ort 1, a n d t he feasi bilit y of wee kl y d ose re gi me n will be assesse d i n t he wee kl y d osi n g 
re gi me ns. 
 
S u bjects will be e val u ate d acc or di n g t o t he attac he d Sc he d ule of Pr oce d ures. D uri n g t he o ut patie nt 
a n d i n patie nt visits t hr o u g h St u d y Da y 2 2, t he s u bjects will be e val uate d b y a cli nicia n a n d  will 
ha ve bl o o d dra w n f or cli nical la b orat or y st u dies, vir ol o gic assa ys, a n d i m m u n ol o gic assa ys. 
S u bjects will meas ure t heir te m perat ures ( or ha v e t heir te m perat ures ta ke n  o nsite ) a n d rea di n gs 
will be rec or de d t wice a da y  fr o m St u d y Da y 1  t hr o u g h St u d y Day  2 9 (l o n ger as nee de d).   
 
C o h ort 1 : S u bjects will be see n at  t he cli nic f or t heir o nl y o ver ni g ht sta y fr o m St u d y Da y -6 
t o Da y -4. S u bjects will ta ke st u d y pr o d uct at h o m e o n Da y -3 a n d -2 a n d will be calle d t h ose 
da ys t o c o m plete a bri ef p h o ne visit. S u bjects will c o me f or i n pers o n cli nic visits f or d osi n g, 
bl o o d dra w a n d ot her st u d y acti vities o n St u d y Da y -1, Da y 1, a n d Da y 3. A p h o ne call will 
occ ur o n D a y 2 a n d D a y 4. I n -pers o n cli nic visits will occ ur o n : St u d y Da y 5, 7, 9, 1 1, 1 4 , 16 , 
1 8 , 2 1, 2 3, 2 5, a n d 2 9 . St u d y da y 2 1 will be a n ot h er P K sa m pli n g peri o d a n d t h us will be a 
f ull da y at t he cli nic wit h sc he d ule d bl o o d dra ws wit h n o o ver ni g ht sta y. Tele p h o ne calls will 
occ ur St u d y Da ys -3, -2, 2, 4, 6, 8, 1 0, 1 2,  1 3  1 5 , 17 , 19 , a n d 2 0  ( m ore ofte n as nee de d) as 
desi g nate d  i n Ta ble 3  a n d secti o n 7. 1 6 . F oll o w u p visits will occ ur o n St u d y Da ys 3 6, 4 3, 5 0, 
5 7, 6 3, 7 0 a n d s u bjects will c o m plete t heir fi nal st u d y visit o n St u d y Da y 8 5.  
 
C o h ort 2 : S u bjects will be see n at  t he cli nic f or t heir o nl y o ver ni g ht sta y fr o m St u d y Da y -3 t o 
Da y 1. S u bjects will c o me f or i n pers o n cli nic visits f or d osi n g, bl o o d dra w a n d ot h er st u d y 
acti vities o n St u d y Da y s 4 , 6, 8, 1 1, 1 3, 1 5, 1 8, 2 1, 2 5, a n d 2 9. St u d y Da y 1 5 ( wee kl y d osi n g 
re gi me ns) or D a y 2 1 ( dail y d osi n g re gi me n) will be a n ot her P K sa m pli n g peri o d a n d t h us will 
be a f ull da y at t he cli nic wit h sc he d ule d bl o o d dra ws wit h n o o ver ni g ht sta y.  F oll o w u p visits  
f or all partici pa nts will o cc ur o n St u d y Da ys 3 2, 3 6, 4 3, 5 7,  7 0 a n d s u bjects will c o m plete t heir 
fi nal st u d y visit o n St u d y Da y 8 5. If p artici pa nts h a ve a p ositi ve D E N V -3 q u alitati ve P C R res ult 
o n Da y 2 5 a n d/ or Da y 3 2,  a d diti o nal in -pers o n cli nic visits will  occ ur o n St u d y Da y 2 7 a n d/ or 
3 4  res pecti vel y, i n a d diti o n t o t he da ys liste d a b o v e. T he sc h e d ule of pr oce d ures is pr o vi de d i n 
Ta ble 4  a n d secti o n 7. 1 7 . 

CI R 3 3 2  
 
1 7  
 
T a ble 3 : Sc he d ule of Pr oce d ures –  C o h ort 1  
 
Scree n 5 
D osi n g St u d y D a ys (I n p atie nt visits  m ar ke d i n gr a y)  
 
F oll o w -u p St u d y D a ys 4 
Pr oce d ure  
-6 5 t o -6  
-6  
-5  -4  
-3  
-2  
-1  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  1 1  1 2  1 3  1 4  1 5  1 6  1 7  1 8  1 9  2 0  
2 1  
2 3  2 5  2 9  3 6  4 3  5 0  5 7  6 3  7 0  8 5  
I n-Pers o n Visit  
X  
X  
X  
X  
 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
P h o ne call Visit  
 
 
 
 
X  
X  
 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
X  
 
X  
 
X  
 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
I nf or me d C o nse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C O VI D -1 9 scree ni n g 
q uesti o ns  
X  
X  
X  
X  
 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
D M E C re vie w  
 
 
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
N P or mi d -t ur bi nate 
nasal s wa b  
 
[ X]1 0  
 
 
 
 
 
[ X]1 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[ X]1 0 
 
 
 
 
 
 
 
 
 
 
O ver ni g ht Sta y o n U nit  
 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
St u d y Dr u g  Ta ke n   
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
D E N V -3 I n oc ulati o n  
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical e xa m  
X 6  
 
X  
X  
 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 6  
Vital Si g ns  
X  
X  
X  
X  
 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o m plete Me dical 
Hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C ollecti o n of A Es  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o nc o mita nt T hera p y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
I g E1 2  
 
 
X  
 
 
 
 
X  
 
X *  
 
X *  
 
X *  
 
X *  
 
X *  
 
 
X *  
 
X *  
 
X *  
 
 
X *  
 
 
 
 
 
 
 
 
 
 
P K A nal ysis  
 
 
X 2  
X  
 
 
 
X  
 
 
 
 
 
X  
 
X  
 
X  
 
 
 
 
X  
 
 
 
 
X 1 3  
X  
X  
X  
 
 
 
X  
 
X  
X  
Q ua ntitati ve R T -P C R   
 
 
 
 
 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Q ualitati ve R T -P C R  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 3 
X  
X  
X  
X  
X  
X  
X  
Pla q ue Assa y  
 
 
 
 
 
 
[X ] [X ] 
 
[X ] 
 
[X ] 
 
[X ] 
 
[ X] 
 
[ X] 
 
 
[ X] 
 
[ X] 
 
[ X] 
 
 
[ X] [ X] [ X] [ X] [ X] [ X] [ X] [ X] [ X] [ X] [ X] 
N S 1 E LI S A  
 
 
 
 
 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
I g G & I g M E LI S A  
 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
 
 
X  
Ne utralizi n g A nti b o d y  
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
X  
 
 
X  
 
 
 
 
 
 
X  
Ser u m Pr otei n A nal ysis  
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
X  
 
 
 
X  
 
 
 
 
 
 
 
X  
 
 
 
 
X  
Viral Ge n o me 
Se q ue nci n g  
 
 
 
 
 
 
 
 
 
 
 
 
 
[X ] 
 
[X ] 
 
[X ] 
 
 
[X ] 
 
[X ] 
 
[X ] 
 
 
[ X] [X ] [X ] [X ] [ X] [ X] [ X] [ X] [ X] [ X] [ X] 
P B M C is olati o n  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
H ost R N A A nal ysis  
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
X  
 
 
 
X  
 
 
 
 
 
 
 
 
X  
 
 
 
X  
H L A Ge n ot y pi n g & 
P har mac o ge n o mics  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C M P  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
X  
 
 
 
C he mistr y Pa nel 9 
X  
 
X  
 
 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
C B C wit h differe ntial  
X  
 
X  
 
 
 
X  
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
X  
 
X  
 
 
 
X  
 
 
 
P T/ P T T  
X  
 
X  
 
 
 
X  
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
X  
 
X  
 
 
 
X  
 
 
 
HI V, H C V, H B V  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De n v/ Zi k v  scree ni n g 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre g na nc y Test 1  
X  
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
X  
 
 
 
 
 
 
X  
F S H Test 1 1 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CI R 3 3 2  
 
1 8  
 
 
Scree n 5 
D osi n g St u d y D a ys (I n p atie nt visits  m ar ke d i n gr a y)  
 
F oll o w -u p St u d y D a ys 4 
Pr oce d ure  
-6 5 t o -6  
-6  
-5  -4  
-3  
-2  
-1  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  1 1  1 2  1 3  1 4  1 5  1 6  1 7  1 8  1 9  2 0  
2 1  
2 3  2 5  2 9  3 6  4 3  5 0  5 7  6 3  7 0  8 5  
Uri nal ysis & Uri ne 
t o xic ol o g y Scree n 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol Breat h Test  
 
X 1 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 2 -lea d E C G8 
X  
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
X  
 
Aes = a d verse e ve nts; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; C B C = c o m plete bl o o d c o u nt; C M P = c o m pre he nsi ve meta b olic pa nel; E C G = electr ocar di o gra m; E LI S A = e nz y me -li n ke d 
i m m u n os or be nt assa y; F S H = f ollicle-sti m ulati n g h or m o ne; H B V = he patitis B vir us; H C V = he patitis C vir us; HI V = h u ma n i m m u n o deficie nc y vir us;  H L A = h u ma n le u k oc yte a nti ge n; N P = nas o p har y n geal; 
P B M C = peri p heral bl o o d m o n o n uclear cell; P K = p har mac o ki netics; P T/ P T T = pr ot hr o m bi n ti me/ partial t hr o m b o plasti n ti me ; R N A = ri b o n ucleic aci d; R T-P C R = re verse tra nscri pti o n p ol y merase c hai n reacti o n  
1.  
Ser u m or uri ne pre g na nc y testi n g o nl y perf or me d  f or pers o ns  of c hil d beari n g p ote ntial ..  
2.  
O n S D -5: 7 P K sa m ples will be c ollecte d d uri n g 1 6 -h o ur wi n d o w . 
3.  
Q ualitati ve R T -P C R will be perf or me d o n s a m ples c ollecte d o n D a ys 2 9, 3 6, 4 3, 5 0, 5 7, 6 3, 7 0, a n d 8 5.  If t he partici pa nt is D E N V-3 p ositi ve detecte d f or first ti me at Da y ≥2 9, q ualitati ve R T -P C R will be perf or me d 
t wice wee kl y ( prefer a bl y wit h 3 t o 4 d a ys i n bet wee n s a m ples) u ntil t he partici pa nt res ults are ne gati ve a n d u ntil res ol uti o n of D E N V i nfecti o n-ass ociate d Aes. Partici pa nts w h o are D E N V -3 p ositi ve o n Da y 8 5 
s h o ul d ret ur n f or a d diti o nal cli nical a n d vir ol o gic assess me nts u ntil t he partici pa nt res ults are ne gati ve a n d u ntil res ol uti o n of D E N V i nfecti o n -ass ociate d Aes. A d diti o nal testi n g usi n g differe nt n ucleic aci d base d 
met h o ds f or t he detecti o n a n d/ or q ua ntificati o n of D E N V -3 ma y be perf or me d.  
4.  
P h o ne calls t o c ollect ti me of d ose, ti me of last f o o d, A E’s, a n d c o nc o mita nt t hera p y o n S D -3, -2, 2, 4, 6, 8, 1 0, 1 2, 1 3, 1 5, 1 7, 1 9, a n d 2 0.  
5.  
Scree ni n g ma y occ ur o ver m ulti ple visits. Certai n pr oce d ures m ust be perf or me d wit hi n differe nt ti me fra me relati ve t o d osi n g, see Secti o n 7. 1 . Scree ni n g wi n d o w is Da y -6 5 t o Da y -6.  
6.  
A c o m plete p h ysical e xa m will be perf or me d at scree ni n g a n d o n Da y 8 5. At all ot her i n dicate d ti me p oi nts a f oc use d p h ysical e xa m will be perf or me d.  
7.  
[ X] Sa m ple will be c ollecte d, b ut test will o nl y be perf or me d if i n dicate d b y g ui deli nes i n t he pr ot oc ol.  
8.  
E C Gs are rec or de d pre -d ose  o n d osi n g d a ys . 
9.  
C he mistr y pa nel c o nsists of s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, calci u m, p h os p hate, al b u mi n, t otal p r otei n, t otal c h olester ol, creati ni ne, gl uc ose, A S T, A L T, G G T, H D L c h olester ol, L D L c h olester ol, 
tri gl yceri des, ma g nesi u m, calc ulate d creati ne cleara nce ( b y M D R D), li pase, a m ylase, t otal  bilir u bi n, al kali ne p h os p hatase, uric aci d 
1 0.  Nas o p har y n geal ( N P) or mi d -t ur bi nate s wa b t o test f or S A R S-C o V 2 –  t he vir us t hat ca uses C O VI D-1 9 –  will be c ollecte d fr o m all v ol u nteers re gar dless of vacci nati o n stat us base d o n g ui da nce fr o m fe deral, state, 
l ocal, a n d/ or i nstit uti o nal healt h officials * or at t he discreti o n of t he cli nicia n ( ma y be c ollecte d u p t o 7 2 h o urs i n a d va nce of state d c ollecti o n ti me).  
* T his g ui da nce ma y be i nf or me d b y t he l ocal C O VI D i nfecti o n rate, se verit y of i nfecti o ns, vacci nati o n rates, a n d ot her fact or s as t he C O VI D -1 9 pa n de mic c o nti n ues t o e v ol ve  a n d c ha n ge. N P or mi d -t ur bi nate s wa bs 
ma y be c ollecte d at ot her ti me -p oi nts if v ol u nteer has C O VI D -li ke s y m pt o ms.  
1 1.  F S H perf or me d o nl y i n fe males w h o ha ve st o p pe d me nstr uati n g f or > 1 2 c o nsec uti ve m o nt hs b ut < 2 4 m o nt hs. ( A n y o ne w h o has h a d a me n orr hea > 2 4  c o nsec uti ve m o nt hs is c o nsi dere d p ost me n o pa usal a n d d oes n ot 
re q uire F S H). 
1 2.  I n partici pa nts w h o de vel o p a ras h, a n a d diti o nal sa m ple will be c ollecte d at o nset of ras h a n d teste d. N ote d o n t his c hart wit h a n asteris k { X * } 
1 3.  O n St u d y Da y 2 1: 6 P K sa m ples will  be c ollecte d d uri n g a 1 2 -h o ur wi n d o w  
1 4.  Alc o h ol breat h test ma y be perf or me d at t he discreti o n of PI/ pr o vi der u p o n a d missi o n t o i n patie nt u nit  
 
 

CI R 3 3 2  
 
1 9  
 
T a ble 4 : Sc he d ule of Pr oce d ures - C o h ort 2  
 
Scree n 5 
I n p atie nt St a y 
Cli nic Visits  D uri n g D osi n g Wi n d o w(s)  
D = D ail y D osi n g Gr o u p; W = Wee kl y D osi n g Gr o u p s 
F oll o w -u p Cli nic Visits ( D a y 2 7 a n d 3 4 o nl y if 
i n dic ate d1 6) 
Pr oce d ure  
-6 2 t o -3  
-3  
-2  
-1  
1  
4  
6  
8  
1 1  
1 3  
1 5 D  
1 5 W  
1 8  
2 1 D  
2 1 W  
2 5  
2 7  
2 9  
3 2  
3 4  
3 6  
4 3  
5 7  
7 0  
8 5  
I n-Pers o n Visit  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
I nf or me d C o nse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C O VI D -1 9 scree ni n g q uesti o ns  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D M E C re vie w  
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
N P or mi d -t ur bi nate nasal s wa b 7, 
1 0  
 
[ X] 
 
 
 
 
 
 
 
 
 
 
 
[ X] 
[ X] 
 
 
 
 
 
 
 
 
 
 
O ver ni g ht Sta y o n U nit  
 
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
St u d y Dr u g Ta ke n at Cli nic ( Dail y 
D ose Re gi me n)  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
St u d y Dr u g Ta ke n at Cli nic 
( Wee kl y D ose Re gi me n) 
 
 
X  
X  
X  
 
 
X  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
D E N V -3 I n oc ulati o n  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical e xa m  
X 6 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
 
X  
 
 
 
 
X  
X  
X  
X 6 
Vital Si g ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o m plete Me dical Hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C ollecti o n of A Es  
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I g E 1 2 
 
 
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P K A nal ysis 2 
 
 
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Q ua ntitati ve R T -P C R   
 
 
 
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Q ualitati ve R T -P C R  
 
 
 
 
 
 
 
 
 
 
 
 
 
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Pla q ue Assa y 7 
 
 
 
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N S 1 E LI S A 4   
 
 
 
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I g G & I g M E LI S A  
 
 
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Ne utralizi n g A nti b o d y 1 4 
 
 
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Ser u m Pr otei n A nal ysis  
 
 
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Viral Ge n o me Se q ue nci n g 1 5 
 
 
 
 
 
 
 
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P B M C is olati o n  
 
 
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H ost R N A A nal ysis  
 
 
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H L A Ge n ot y pi n g & 
P har mac o ge n o mics  
 
 
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C M P  
 
 
 
 
 
 
 
 
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C he mistr y Pa nel 9 
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C B C wit h differe ntial  
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P T/ P T T  
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HI V, H C V, H B V  
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De n g ue/ Zi ka/ West Nile/ S L E V 
scree ni n g 
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Pre g na nc y Test 1  
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F S H Test 1 1 
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CI R 3 3 2  
 
2 0  
 
 
Scree n 5 
I n p atie nt St a y 
Cli nic Visits  D uri n g D osi n g Wi n d o w(s)  
D = D ail y D osi n g Gr o u p; W = Wee kl y D osi n g Gr o u p s 
F oll o w -u p Cli nic Visits ( D a y 2 7 a n d 3 4 o nl y if 
i n dic ate d1 6) 
Pr oce d ure  
-6 2 t o -3  
-3  
-2  
-1  
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Uri nal ysis & Uri ne t o xic ol o g y 
Scree n  
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Alc o h ol Breat h Test  
 
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1 2 -lea d E C G 8 
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A E s = a d verse e ve nts; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; C B C = c o m plete bl o o d c o u nt; C M P = c o m pre he nsi ve meta b olic pa nel ; E C G = electr ocar di o gra m; E LI S A = e nz y me -li n ke d 
i m m u n os or be nt assa y; F S H = f ollicle-sti m ulati n g h or m o ne; H B V = he patitis B vir us; H C V = he patitis C vir us; HI V = h u ma n i m m u n o deficie nc y vir us;  H L A = h u ma n le u k oc yte a nti ge n; N P = nas o p har y n geal; 
P B M C = peri p heral bl o o d m o n o n uclear cell; P K = p har mac o ki netics; P T/ P T T = pr ot hr o m bi n ti me/ partial t hr o m b o plasti n ti me ; R N A = ri b o n ucleic aci d; R T-P C R = re verse tra nscri pti o n p ol y merase c hai n reacti o n; 
A 1 A G = al p ha-1 aci d g l yc o pr otei n 
 
1.  
Ser u m or uri ne pre g na nc y testi n g o nl y perf or me d  f or pers o ns  of c hil d beari n g p ote ntial ..  
2.  
O n S D -2 : 7 P K sa m ples will be c ollecte d d uri n g 1 6 -h o ur wi n d o w : wit hi n t he 2 h o urs pri or t o d osi n g wit h J NJ -6 4 2 8 1 8 0 2 as well as 1, 2, 4, 8, 1 2  ( pri or t o sec o n d l oa di n g d ose), 1 6 h o urs after d osi n g.  
O n St u d y Da y 1 5 f or t he wee kl y d osi n g re gi me n a n d o n D a y 2 1 f or t he dail y d osi n g re gi me n: 6 P K sa m ples will be c ollecte d d uri n g a 1 2 -h o ur wi n d o w: wit hi n t he 2 h o urs pri or t o d osi n g wit h J N J-6 4 2 8 1 8 0 2 as well as 
1, 2, 4, 8, a n d 1 2  h o urs  after d osi n g. O n  D a y 2 1 f or t he wee kl y d osi n g re gi me n a n d D a y 1 5 f or t he dail y d osi n g  a n d all ot her st u d y da ys w here P K sa m ples are c ollecte d, a si n gle bl o o d c ollecti o n will occ ur pri or t o 
d osi n g wit h J NJ -6 4 2 8 1 8 0 2  (if a p plica ble). 
3.  
Q ualitati ve R T -P C R will be perf or me d o n sa m ples c ollecte d o n D a ys 2 5, 2 7 , 2 9, 3 2 , 3 4,  3 6, 4 3, 5 7, 7 0, a n d 8 5.  If a partici pa nt is D E N V-3 p ositi ve detecte d at Da y ≥2 5  ( or da y 2 3 if 2 5 is n ot a vaila ble), q ualitati ve 
R T -P C R f or t he set of partici pa nts e nr olle d i n t he sa me gr o u p a n d w h o were e nr olle d at t he sa me  da y  or later,  will be perf or me d  o n d a ys 2 7 a n d d a y 3 4  u ntil t he res ult partici pa nt res ults are ne gati ve a n d u nt il res ol uti o n 
of D E N V i nfecti o n -ass ociate d AE s. Partici pa nts w h o are D E N V-3 p ositi ve o n Da y 8 5 s h o ul d ret ur n f or a d diti o nal cli nical a n d vir ol o gic assess me nts u ntil t he partici pa nt res ults are ne gati ve a n d u ntil res ol uti o n of 
D E N V i nfecti o n -ass ociate d A E s. A d diti o nal testi n g usi n g differe nt n ucleic aci d base d met h o ds f or t he detecti o n a n d/ or q ua ntificati o n of D E N V -3 ma y be perf or me d.  
4.  
A nal ysis is o pti o nal, b ut sa m ples nee d t o be c ollecte d.  
5.  
Scree ni n g ma y occ ur o ver m ulti ple visits. Certai n pr oce d ures m ust be perf or me d wit hi n differe nt ti me fra me relati ve t o d osi n g, see Secti o n 7. 1 . Scree ni n g wi n d o w is Da y -6 2  t o Da y -2 . 
6.  
A c o m plete p h ysical e xa m will be perf or me d at scree ni n g a n d o n Da y 8 5. At all ot her i n dicate d ti me p oi nts a f oc use d p h ysical e xa m will be perf or me d.  
7.  
[ X] Sa m ple will be c ollecte d, b ut test will o nl y be perf or me d if i n dicate d b y g ui deli nes i n t he pr ot oc ol.  
8.  
E C Gs are rec or de d pre -d ose o n d osi n g d a ys . 
9.  
C he mistr y pa nel c o nsists of s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, calci u m, p h os p hate, al b u mi n, t otal p r otei n, t otal c h olester ol, creati ni ne, gl uc ose, A S T, A L T, G G T, H D L c h olester ol, L D L c h olester ol, 
tri gl yceri des, li pase, a m ylase, t otal  bilir u bi n, al kali ne p h os p hatase, uric aci d 
1 0.  Nas o p har y n geal ( N P) or mi d -t ur bi nate s wa b t o test f or S A R S-C o V -2  will be c oll ecte d fr o m all v ol u nteers re gar dless of vacci nati o n stat us base d o n g ui da nce fr o m fe deral, state, l ocal, a n d/ or i nstit uti o nal  healt h 
officials *  or at t he discreti o n of t he cli nicia n ( ma y be c ollecte d u p t o 7 2 h o urs i n a d va nce of state d c ollecti o n ti me).  
* T his g ui da nce ma y be i nf or me d b y t he l ocal C O VI D i nfecti o n rate, se verit y of i nfecti o ns, vacci nati o n rates, a n d ot her fact ors  as t he C O VI D -1 9 pa n de mic c o nti n ues t o e v ol ve a n d c ha n ge. N P or mi d -t ur bi nate s wa bs 
ma y be c ollecte d at ot her ti me -p oi nts if v ol u nte er has C O VI D -li ke s y m pt o ms.  
1 1.  F S H perf or me d o nl y i n fe males w h o ha ve st o p pe d me nstr uati n g f or > 1 2 c o nsec uti ve m o nt hs b ut < 2 4 m o nt hs. ( A n y o ne w h o has h a d a me n orr hea > 2 4 c o nsec uti ve m o nt hs is c o nsi dere d p ost me n o pa usal a n d d oes n ot 
re q uire F S H). 
1 2.  I n partici pa nts w h o de vel o p a ras h, a n a d diti o nal sa m ple will be c ollecte d at o nset of ras h a n d teste d. N ote d o n t his c hart wit h  a n asteris k { X * } 
1 3.  Alc o h ol breat h test ma y be perf or me d at t he discreti o n of PI/ pr o vi der u p o n a d missi o n t o i n patie nt u nit  
1 4.  D  -2 t o be ta ke n pre d ose. A nal ysis is o pti o nal , b ut sa m ples nee d t o be c ollecte d. 
1 5.  Se q ue nci n g c o n d ucte d o nl y if D E N V R N A p ositi ve . 
1 6.  I n-pers o n cli nic visits wit h sa m ple c ollecti o n will o nl y  occ ur o n St u d y Da y 2 7 a n d/ or 3 4 if t he D E N V -3 q ualitati ve P C R res ult s o n Da y 2 5 a n d/ or Da y 3 2, res pecti vel y, are p ositi ve.  
 

CI R 3 3 2  
 
2 1  
 
2  
I ntr o d ucti o n 
 
B ac k gr o u n d - De n g ue  
De n g ue is ca use d b y a n y of t he 4 a nti ge nicall y disti nct de n g ue vir us ( D E N V ) ser ot y pes ( D E N V-
1, -2, -3, a n d -4), w hi c h bel o n g t o t he ge n us Fl avi vir us  i n t he fa mil y of t he Fl aviviri d ae . T he D E N Vs 
are h u ma n pat h o ge ns w hic h are tra ns mitte d t hr o u g h t he bite of a n i nfecte d fe male m os q uit o of t he 
ge n us Ae des , m ai nl y of t he s pecies Ae des a e gy pti  a n d t o a lesser e xt e nt Ae des  al b o pict us  [1 ]. De n g ue 
is e n de mic i n m ore t ha n 1 2 5 c o u ntries, a n d has als o a gai n bec o me e n de mic i n t he U nite d States of 
A merica ( U S A) a n d its territ ories  [2 ]. A b o ut half of t he gl o bal p o p ulati o n is c urre ntl y at ris k of 
bec o mi n g i nfecte d wit h D E N V  [3 , 4 ]. Acc or di n g t o t he W orl d Healt h Or ga nizati o n ( W H O), d e n g ue is 
a m o n g t he t o p 1 0 t hreats t o gl o bal healt h i n 2 0 1 9  [5 ].  
T he act ual n u m bers of d e n g ue cas es are u n d er re p orte d a n d ma n y cas es are misclassifie d as ot her 
fe brile ill nesses s uc h as malaria. It is esti mate d t hat t here are 3 9 0 milli o n D E N V i nfecti o ns gl o ball y 
per year, of w hic h 9 6  milli o n ma nifest cli nicall y ( wit h a n y se v erit y of t he disease)  [3 ]. O n a v era g e, 
eac h y ear a b o ut 5 0 0, 0 0 0  de n g ue cases re q uire h os pitalizati o n d ue t o se vere a n d life -t hreate ni n g disease 
a n d u p t o 2 5, 0 0 0  patie nts die d ue t o de n g ue.  
D uri n g a pri mar y D E N V i nfecti o n, a p pr o xi matel y  7 5 % of t he i n di vi d uals re mai n as y m pt o matic  [6 ]. 
T h ose w h o  s h o w cli nic al s y m pt o ms mai nl y de vel o p a n ac ute, s elf-li miti n g fe brile ill ness. T he first 
cli nical s y m pt o ms oc c ur 3 t o 8  da ys after a bite b y a D E N V -i nfect e d a n d vir e mic m os q uit o. Res ol uti o n 
of i nfecti o n us uall y occ urs wit hi n 4  t o 7 da ys d ue t o a r o b ust i n nate a n d a da pti ve i m m u ne res p o nse  [7 ]. 
A s maller perce nta g e of D E N V i nf ecti o ns res ult i n se vere de n g u e o utc o mes s uc h as de n g u e 
he m orr ha gic fe v er  ( D H F) a n d de n g u e s h oc k s y n dr o me  ( D S S). Sec o n dar y D E N V i nf ecti o ns or 
i nfecti o ns wit h partic ularl y vir ule nt viral str ai ns are t h o u g ht t o be ass oci ate d wit h a n i n crease d ris k f or 
se vere d e n g ue [8 ].  
D uri n g classical d e n g ue fe ver  ( D F), a n a br u pt o nset of fe v er is acc o m pa nie d b y a wi de ra n ge of 
p ote ntial s y m pt o ms, ie, m yal gia, art hral gia, h ea d ac he, a n d ras h; wit h retr o -or bital pai n a n d l o wer b ac k 
pai n bei n g pr ot ot y pical s y m pt o ms. Als o v o miti n g, na usea, a n d a n ore xi a are c o m m o n  [9 ]. D uri n g t his 
fe brile p has e, t h ose t hat will pr o gress t o se vere or re mai n n o n se vere ca n n ot be disti n g uis he d. T he 
critical p hase is c haract erize d b y a n i ncrease d pr o pe ns it y f or ca pillar y lea ka ge a n d he m orr ha g e, 
t y picall y ma nifeste d b y scattere d petec hi ae, he mat uria, a n d gastr oi ntesti nal he m orr ha ge [7 , 1 0 ]. 
Wit h o ut earl y dia g n osis a n d pr o per ma na ge m e nt, s o me patie nts e x perie nce s h oc k fr o m plas ma lea ka g e 
or less c o m m o nl y bl o o d l oss, w hic h ca n res ult i n a s u d de n deteri orati o n of t h e pa tie nt’s c o n diti o n [1 0 ].  
C urre ntl y, t here is n o d e n g ue -s pecifi c treat me nt a vaila ble a n d t h us, cli nical treat me nt is pri nci pall y 
s u p p orti ve i n nat ure.  
I n Dece m ber 2 0 1 5, t he first vacci ne a gai nst D E N V was lice nse d i n Me xic o. T he c hi meric yell o w fe ver 
–  D E N V tetra vale nt de n g ue vacci ne ( C Y D -T D V; De n g va xia ® ) is a li ve atte n uate d vacci ne de vel o p e d 
b y Sa n ofi Paste ur. B y N o ve m ber 2 0 1 6, t he vacci ne ha d b ee n a p pr o ve d f or us e i n 1 8  c o u ntries i ncl u di n g 
Brazil, M e xic o, El Sal va d or, C osta Rica, a n d t he P hili p pi nes. I n late 2 0 1 7, t he vacci ne was wit h dra w n 
a gai n fr o m t he P hili p pia n mar ket be ca use of safet y c o ncer ns, w hic h le d t o r e v ocati o n of t he vacci ne’s 
lice ns ure i n t he P hili p pi nes i n Fe br uar y 2 0 1 9. I n Ma y 2 0 1 9, the vacci ne was a p pr o ve d i n t he U S A f or 
t he pre ve nti o n of de n g ue disease ca us e d b y all D E N V ser ot y p es ( D E N V-1, -2, -3, a n d -4) i n 
i n di vi d uals, 9 t hr o u g h 1 6 years of a g e, w h o ha ve l a b orat or y c o nfir me d pre vi o us de n g ue i nfecti o n a n d 
w h o li ve i n e n de mic areas. T he wi des prea d use of t he vacci n e, h o we v er, is n ot f oresee n per t h e W H O 
w or ki n g gr o u p f or i m m u nizati o n, as a n u m ber of fact ors nee d f urt her c o nsi derati o n  [1 1 ]. T he Strate gic 

CI R 3 3 2  
 
2 2  
 
A d vis or y Gr o u p of E x perts rec o m me n de d c o u ntri es t o c o nsi der t he i ntr o d ucti o n of De n g va xia ®  o nl y 
i n ge o gra p hic setti n gs ( n ati o nal or s u b nati o nal) wit h hi g h de n g ue e n de micit y. 
D uri n g rece nt years, dr u gs de vel o pe d f or pr o p h ylactic use are sl o wl y getti n g m ore atte nti o n as p ote ntial 
alter nati ves t o pre ve nt d e n g ue  [1 2 ]. Pr o p h yla xis c o ul d be be neficial f or tra velers t o de n g uee n de mi c 
re gi o ns (e g, ai d w or kers, t o urists, b usi ness a n d militar y tra velers, a n d e x patriates), as well as f or 
v ul nera ble p o p ulati o ns li vi n g i n e n de mic re gi o ns. B y pre ve nti n g vire mia a n d/ or b y re d uci n g viral l oa d, 
D E N V i nfecti o n -ass ociat e d m or bi dit y a n d m ortalit y c o ul d be re d uce d re m ar ka bl y or e v e n pre v e nte d  
[1 2 ]. I n a d diti o n, a n effic aci o us a n d safe pr o p h ylactic a nti -D E N V  c o m p o u n d c o ul d p ote ntiall y als o be 
use d as a t hera pe utic a ge nt.  
J NJ-6 4 2 8 1 8 0 2 is a n o v el a nti -D E N V s mall m olec ule tar g eti n g D E N V N S 4 B. It has s h o w n p ote nt 
a nti viral acti vit y acr oss all 4 D E N V s er ot y pes i n n o ncli nical st u dies  [1 3 ]. A P hase 1 first -i n-h u ma n 
st u d y 6 4 2 8 1 8 0 2 D N G 1 0 0 has bee n perf or m e d. A s u m mar y of t he res ults is pr o vi de d i n secti o n 2. 2 .  
T his is a P hase 2a st u d y utilizi n g a de n g ue h u ma n c halle n ge m o del ( D H C M) i n w hic h healt h y a d ult 
partici pa nts are i n o c ulate d wit h a rec o m bi na nt D E N V -3 str ai n, r D E N 3 3 0 , 5 da ys after i nitiati o n of 
dail y d osi n g wi t h J NJ-6 4 2 8 1 8 0 2 or place b o (ie, a d mi nistere d as pre -e x p os ure pr o p h yla xis). T he ai m 
of t he st u d y is t o assess t h e a nti viral acti vit y of J NJ -6 4 2 8 1 8 0 2 i n a pr o p h ylactic setti n g, a n d t o e xa mi n e 
t he safet y, t olera bilit y, p har mac o ki netics ( P K), a n d t he relati o nshi p bet w ee n t he P K a n d t he a nti viral 
acti vit y of re peate d oral d oses of J NJ -6 4 2 8 1 8 0 2, c o m pare d wit h place b o. T his st u d y is i nte n de d t o 
i nf or m t he pr o p h ylactic de vel o p me nt pr o gra m f or J NJ-6 4 2 8 1 8 0 2, i ncl u di n g cli nical st u dies t o assess 
t he effic ac y of J NJ-6 4 2 8 1 8 0 2 t o pre ve nt D E N V i nfecti o n.  
 
B ac k gr o u n d  - J N J -6 4 2 8 1 8 0 2  
2. 2. 1  N o n -Cli nic al  St u dies  
 
2. 2. 1. 1  Pri m ary P h ar m ac ol o gy  
J NJ-6 4 2 8 1 8 0 2 is a n o vel a nti -D E N V s mall -m olec ule tar geti n g D E N V N S 4 B.  
 
J NJ-6 4 2 8 1 8 0 2 s h o we d p ote nt i n vitr o a nti viral acti vit y a gai nst D E N V irres pecti ve of ser ot y p es a n d 
ge n ot y pes. T he me dia n 5 0 % effecti ve c o n ce ntr ati o n ( E C 5 0) was 0. 0 5 n M wit h a selecti vit y i n de x of 
4 8, 0 0 0 a gai nst D E N V -2/ 1 6 6 8 1/e G F P i n Ver o cells. I n t h e pres e nce of 5 0 % h u ma n ser u m, t he a nti vir al 
acti vit y of J NJ -6 4 2 8 1 8 0 2 a gai ns t D E N V-2/ 1 6 6 8 1/e G F P decreas e d 2 8 -f ol d. J NJ-6 4 2 8 1 8 0 2 s h o we d 
o verall p ote nt a nti viral acti vit y a gai nst all 4 D E N V ser ot y pes (la b -a da pte d strai ns a n d cli nical is olates) 
wit h s u b -na n o m olar or l o w na n o m olar me dia n E C 5 0 val ues a gai nst m ost strai ns a n d has a hi g h  
s pecificit y t o war ds D E N V. 
 
T he i n vitr o resista nce pr ofile a n d t he m olec ular tar get of J NJ -6 4 2 8 1 8 0 2 was c h aracterize d usi n g i n 
vitr o selecti o n e x peri me nts i n Ver o cells i nfecte d wit h t he D E N V -2/ Re ga strai n or t he 
 
a n d S D Ms a nal yses. Se ve ral m utati o ns wit hi n t he N S 4 B pr otei n were o bser ve d. T h e acti vit y of 
J NJ-6 4 2 8 1 8 0 2 a gai nst m uta nt D E N V -2/ 1 6 6 8 1 i n t he tra nsie nt re plic o n assa y was re d uce d 1 1 - t o 4 9 0-
f ol d c o m pare d t o wil d t y pe ( W T; E C 5 0 = 0. 3 n M) w he n t h e teste d D E N V-2/ 1 6 6 8 1 har b ore d t he si n gle 
m utati o n 
, V 9 1 A, L 9 4 F, 
, T 1 0 8I, 
 or F 2 3 7 Y i n t he N S 4 B pr otei n, or t he 
d o u ble m utati o ns 
 i n t he N S 4 B pr otei n. 
 
T he e mer g e nce of m utati o ns wit hi n t h e N S 4 B pr otei n a n d t he re d uce d acti vit y of J NJ -
6 4 2 8 1 8 0 2 c o nferre d b y t hese N S 4 B m utati o ns, s u g gest N S 4 B as bei n g t he tar get of J NJ -6 4 2 8 1 8 0 2.  
C CI
C CI
C CI
C CI
C CI
C CI
C CI

CI R 3 3 2  
 
2 3  
 
 
I n D E N V-2 i n oc ulate d mice treate d wit h J N J-6 4 2 8 1 8 0 2, d ose -de pe n d e nt viral ri b o n ucleic aci d 
( R N A) re d ucti o ns i n ser u m 
 c o m pare d wit h ve hicle treate d mice 
were o bser ve d a n d w ere ass ociate d wit h a si g nifica nt effect o n s ur vi v al. I n a n o n -h u ma n pri mate 
m o del, n o  viral R N A was detecte d at t he hi g hest d oses of J NJ -6 4 2 8 1 8 0 2 ( 
 3 m g/ k g/ d ose) 
a gai nst D E N V-2/ 1 6 6 8 1 a n d at t he d ose of 6 m g/ k g a gai nst D E N V -1/ 4 5 A Z 5 gi ve n pr o p h ylacticall y, 
i n dicati n g t hat J NJ-6 4 2 8 1 8 0 2 is hi g hl y effecti ve i n pre ve nti n g i nf ecti o n after  D E N V c h alle n ge i n t his 
r hes us m o n ke y m o del. 
 
2. 2. 1. 2  Sec o n d ary P h ar m ac ol o gy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. 2. 1. 3  S afety P h ar m ac ol o gy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. 2. 1. 4  P h ar m ac o ki netic a n d Met a b olic Pr ofile  
 
 
 
 
 
 
 
C CI
C CI
C
CI
C CI
C CI

CI R 3 3 2  
 
2 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

CI R 3 3 2  
 
2 5  
 
. 
 
2. 2. 1. 5  T o xic ol o gy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI

CI R 3 3 2  
 
2 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. 2. 2  Pre vi o us H u m a n E x perie nce  wit h J N J -6 4 2 8 1 8 0 2  
T he P hase 1 first-i n-h u ma n st u d y 6 4 2 8 1 8 0 2 D N G 1 0 0 1 has e val uate d t he safet y, t olera bilit y, a n d P K of 
i ncreasi n g si n gle a n d m ulti ple oral d oses of J NJ-6 4 2 8 1 8 0 2 i n a t otal of 1 2 2 healt h y a d ult partici pa nts 
(ie, 3 9 partici pa nts i n t h e si n gle asce n di n g d ose part, 4 7 participa nts i n t he m ulti ple asce n di n g d ose 
part, a n d 3 6 partici pa nts i n t he oral bi oa vaila bilit y part).  
2. 2. 2. 1  S afety  
J NJ-6 4 2 8 1 8 0 2 was ge nerall y safe a n d well t olerate d. N o safet y c o ncer ns were i de ntifie d at si n gle  d oses 
u p t o 1, 2 0 0 m g a n d at m ulti ple d oses u p t o 5 6 0 m g o nce dail y f or 1 0 da ys or 4 0 0 m g o nce  dail y f or 
3 1  da ys. T w o Gra d e 2 e v e nts of ras h occ urre d i n t he m ulti ple asce n di n g d ose part t hat  were c o nsi dere d 
ver y li kel y r elate d t o J NJ -6 4 2 8 1 8 0 2 b y t he i n vesti gat or. O ne Gra d e 2 ras h  occ urre d i n a partici pa nt  i n 
t he 1 0-da y 5 6 0 m g J NJ -6 4 2 8 1 8 0 2 gr o u p o n t he last da y of d osi n g  ( Da y 1 0), a n d res ol v e d after 3 5 da ys. 
T he ot her Gra de 2 ras h occ urre d i n a partici pa nt i n t he 3 1 -da y  4 0 0 m g J NJ -6 4 2 8 1 8 0 2 gr o u p o n d osi n g 
Da y 1 3, a n d res ol ve d after 4 7 da ys. T his partici pa nt  c o m plete d t he 3 1 -da y d osi n g peri o d as pla n ne d.  
 
 
  
 
2. 2. 2. 2  H u m a n P h ar m ac o ki netics  
6 4 2 8 1 8 0 2 D N G 1 0 0 1 ( D N G 1 0 0 1)   
F oll o wi n g si n gle -d ose a d mi nistrati o n wit h J NJ-6 4 2 8 1 8 0 2  ( 5 0-1, 2 0 0 m g), f or m ulate d as oral s ol uti o n, 
t he e x p os ure i ncrease d d ose pr o p orti o nall y fr o m 5 0 t o 1 5 0 m g a n d less t ha n d ose pr o p orti o nall y fr o m 
C CI
C CI

CI R 3 3 2  
 
2 7  
 
2 4 0 t o 1, 2 0 0 m g, w hile f oll o wi n g m ulti ple d osi n g t he e x p os ure of J NJ -6 4 2 8 1 8 0 2 i ncreas e d cl oser t o 
d ose pr o p orti o nall y o ver t he i n vesti gate d d ose ra n ge ( 5 0 t o 5 6 0 m g) c o m pare d wit h si n gle d osi n g.  
T he me dia n ti me t o ma xi m u m c o nce ntrati o n (t ma x ) ra n ge d fr o m 7 t o 1 0 h o urs, a n d t he ter mi nal 
eli mi nati o n half -life w as 6. 3 t o 9. 2 da ys f oll o wi n g si n gle a n d m ulti ple d osi n g. T he acc u m ulati o n fact or 
varie d fr o m 4. 3 t o 7. 3 f oll o wi n g 1 0 da ys of dail y d osi n g a n d was 1 4. 6 f oll o wi n g 3 1 da ys of dail y 
d osi n g. T he  i nter-s u bject varia bilit y i n e x p os ure, e x presse d as perce nta ge c o efficie nt of variati o n  ( C V), 
was 8. 6 % t o 5 8 %.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 4 2 8 1 8 0 2 D N G 1 0 0 4 ( D N G 1 0 0 4) 
 
 
 
 
 
 
 
 
 
 
6 4 2 8 1 8 0 2 D N G 1 0 0 5  ( D N G 1 0 0 5)  
 
 
 
 
 
  
C CI
C CI
C CI

CI R 3 3 2  
 
2 8  
 
6 4 2 8 1 8 0 2 D N G 1 0 0 6  ( D N G 1 0 0 6)  
 
 
 
  
 
 
 
 
 
 
 
 
  
F or t he m ost c o m pre he n si ve n o ncli nical a n d cli nical i nf or mati o n re gar di n g J NJ-6 4 2 8 1 8 0 2 , refer t o t he 
latest versi o n of t he I n v esti gat or's Br oc h ure (I B). 
 
B ac k gr o u n d - De n g ue H u m a n C h alle n ge M o del wit h a Rec o m bi n a nt  D E N V -3  Str ai n  
T he D E N V -3 D H C M t o be use d i n st u d y 6 4 2 8 1 8 0 2 D N G 2 0 0 2 (f urt her referre d t o as D N G 2 0 0 2) uses 
rD E N 3 3 0  w hic h was d eri ve d fr o m D E N V -3 Sle ma n/ 7 8. D uri n g t he i nitial o ut brea k of t he pare nt 
strai n, D E N V-3 Sle ma n/ 7 8 i n Ja va, t he ill ness o bser ve d was far m or e mil d t ha n pre vi o us D E N V -3 
i nfecti o ns a n d i n dee d less se vere c o m pare d wit h a n ot her D E N V -3 strai n, Ba nt ul, w hic h was circ ulati n g 
at t he sa me ti me. T he maj orit y of t h ose i nfect e d ha d o nl y fe ver a n d n o n -s pecific c o nstit uti o nal 
s y m pt o ms, wit h ver y fe w se vere cases a n d n o deat hs ass ociate d wit h i nfecti o n wit h D E N V -3 
Sle ma n/ 7 8.  E pi de mi ol o gic i n vesti gati o ns of t he D E N V -3 Sle ma n o ut brea k le d i n vesti gat ors t o 
c o ncl u de t hat t his was a nat urall y atte n u ate d vir us a n d w o ul d be a g o o d ca n di date f or vacci n e 
de vel o p me nt  [1 4 ]. rD E N 3 3 0 was ori gi nall y de vel o pe d b y t he Nati o nal I nstit utes of Healt h ( NI H) as 
a li ve atte n u ate d vacci n e f or t he pre ve nti o n of ill ness d ue t o D E N V -3. It was m o difie d  b y a 
3 1 -n ucle oti de deleti o n i n t he 3´ u ntra nslate d re gi o n  ( U T R) of t he p are nt strai n of D E N V -3 Sle ma n/ 7 8 
a n d was t heref ore desi g n ate d r D E N 3 3 0  [1 5 ]. H o we ver, i n precli nical st u dies of r D E N 33 0 i n n o n -
h u ma n pri mates, r D E N 3 3 0 
was  n ot atte n uate d c o m pare d 
wit h its 
wil d -t y pe pare nt vir us 
(secti o n 2. 3. 1 ). F or t his reas o n, it was a ba n d o ne d as a ca n di date vacci ne a n d re p ur p ose d as a vir us t o 
be use d i n de n g ue c o ntr olle d h u ma n i nfecti o n st u dies. I n first e v al uati o n of r D E N 3 3 0  i n h u ma ns, t he 
vir e mia a n d react o g e nicit y data, partic ularl y t he ras h, i n dicate d t he vir us was m ore s uita ble as a 
c halle n ge vir us  (secti o n 2. 3. 3 ). T he vir us has bee n e val uate d or utilize d as a c halle n ge vir us i n t hree 
h u ma n cli nical trials ( Ta ble 6 ). 
2. 3. 1  St u dies of D E N V -3 i n R hes us M o n ke ys  
T he re plicati o n ( vire mia), i m m u n o ge nicit y, a n d pr otecti ve efficac y of D E N V -3 were st u die d i n  r hes us 
m o n ke ys. M o n ke ys i n oc ulate d wit h t he wt D E N V -3 Sle ma n/ 7 8 were vire mi c f or 2. 5 da ys,  wit h a mea n 
pea k titer of 2. 0 l o g 1 0 P F U/ m L. A si g nifica nt differe nce was n ot f o u n d i n t h e mea n pea k titer of vire mia 
or t he d urati o n of vire mi a i n d uce d b y wt D E N V -3 Sle ma n/ 7 8, t he rec o m bi na nt pare nt vir us r D E N 3, 
a n d r D E N 3 3 0 ( T a ble 5 ) i n dicati n g t hat r D E N 33 0 was n ot atte n uate d c o m pare d t o t he wil dt y pe a n d 
rec o m bi na nt pare nt vir us es D E N V-3 Sle ma n/ 7 8.  
 
C CI

CI R 3 3 2  
 
2 9  
 
T a ble 5 : Re plic ati o n a n d I m m u n o ge nicit y of D E N V-3 i n R hes us M o n ke ys  
 
D ose 
(l o g1 0 
P F U / m L) 
% wit h 
V ire mi a 
Me a n N o. 
of V ire mic 
D a ys per 
M o n ke y  
Me a n P e a k  
V ir us T iter 
(l o g1 0 P F U/ m L 
± S E)  
Ge o metric 
M e a n S er u m -
N e utr alizi n g 
A nti b o d y T iter 
D E N V -3 Sle me n/ 7 8  
5  
7 5  
2. 5  
2. 0 ± 0. 4  
3 2 5  
r D E N 3 
5  
1 0 0  
2. 3  
1. 4 ± 0. 2  
3 6 3  
r D E N 33 0  
5  
1 0 0  
2. 0  
1. 5 ± 0. 2  
2 6 5  
 
2. 3. 2  M os q uit o Tr a ns missi bilit y of r D E N 3 Δ 3 0  
T he pare nt vir us of t he r D E N 3 Δ 3 0  c halle n g e vir us,  D E N V -3  Sle ma n/ 7 8, is p o orl y tra ns mitte d t o 
m os q uit oes . In g esti o n of 4. 1 l o g 1 0  P F U of wt D E N V -3  Sle ma n/ 7 8 b y A. a e gy pti  m os q uit oes i nfect e d 
t he mi d g ut of o nl y 4 of 2 8 ( 1 4 %) of  m os q uit oes teste d a n d disse mi nate d fr o m t he mi d g ut i n o nl y 2 of 
2 8 ( 7 %) m os q uit oes. T he D E N 3 Δ 3 0 vir us  de m o nstrate d si milar i nfecti vit y c o m pare d t o t he pare nt 
strai n, D E N V-3 Sle ma n/ 7 8  i n m os q uit oes [1 5 ]. T he re q uire d d ose of wt D E N V -3 Sle ma n/ 7 8 e xcee ds 
5 l o g 1 0  P F U/ m L i n bl o o d t o all o w f or tra ns missi o n t o A. ae gy pti  m os q uit oes, t he nat ural vect or of 
de n g ue vir us. As descri be d bel o w  (secti o n 2. 3. 3 ), t he mea n pea k titer ac hie ve d b y r D E N 33 0 i n 
i nfecte d v ol u nteers is < 2 l o g1 0 P F U/ m L, se veral l o g 1 0 bel o w t hat re q uire d f or tra ns missi o n. F or t h ese 
reas o ns, r D E N 33 0 d o es n ot p ose a ris k f or tra ns missi o n a n d all cli nical trials ha ve bee n c o n d u cte d as 
o ut patie nt st u dies t hr o u g h o ut t he year. F or m ore details o n t he n o ncli nical a n d cli nical i nf or mati o n 
re gar di n g r D E N 33 0, refer t o t he r D E N 3 3 0 I n vesti gat or's Br oc h ure (I B).   
2. 3. 3  Cli nic al E x perie nce wit h r D E N 3 3 0  
T he D E N V -3 c h alle n ge vir us r D E N 3 3 0 has bee n st u die d i n 3 se parate cli nical trials  (Ta ble 6 ). T h e 
use of t he differe nt d oses is e x plai ne d bel o w.  All 3 st u dies were a p pr o ve d f or a n d c o n d u cte d as 
o ut p atie nt st u dies  wit h o ut se as o n al restricti o ns . M ore t ha n 8 0 s u bjects ha ve bee n  i n oc ul ate d wit h 
r D E N 33 0 ( 4 0 of w h o m were fla vi vir us -naï ve) a n d tra ns missi o n of t h e vir us t o a t hir d p art y h as n ot 
occ urre d. See secti o n 2. 3. 2  f or a m ore detaile d dis c ussi o n of t he p o or tra ns missi bilit y o f t his vir us. 
 
T a ble 6 : Pr ot oc ols r D E N 33 0  w as a d mi nistere d  
CI R pr ot oc ol 
n u m ber  
Cli nic altri als. g o v  
n u m ber  
I N D n u m ber D ose a d mi nistere d  
(l o g1 0 P F U)  
3 0 4  
N C T 0 2 6 8 4 3 8 3  
1 6 7 6 5  
3  
3 0 9  
N C T 0 2 8 7 3 2 6 0  
1 5 7 5 3  
4  
3 2 3  
N C T 0 3 4 1 6 0 3 6  
1 5 7 5 3  
3  
  
T he cli nical res p o nse t o r D E N 3 3 0 i n fl a vi vir us -naï ve a d ults c o m pare d wit h place b o is pres e nte d i n 
Ta ble 7 . V ol u nteers i n CI R 3 0 9 a n d 3 2 3 ser ve d as t heir o w n c o ntr ols (t he y recei ve d place b o at d ose 1 
a n d were c halle n g e d 6 m o nt hs later wit h r D E N 3 3 0). I n CI R 3 0 4, r D E N 3 3 0 was gi ve n t o 1 0 
v ol u nteers a n d pla ce b o was gi ve n t o 4 v ol u nteers. F or t his a nal ysis, t he cli nical res p o ns e of all 
v ol u nteers w h o recei v e d r D E N 3 3 0 as a c h alle n g e vir us is c o m bi ne d f or st atistical p o wer. Fe ver was 
o bser ve d i n o nl y  2 v ol u nteers ( 5. 0 %). T he fe ver laste d less t ha n 2 4 h o u rs i n b ot h v ol u nteers. T he 
i nci de nce of ras h, n e utr o pe nia, t hr o m b o c yt o pe nia, 
m yal gia, a n d retr o-or bital pai n o cc urre d i n 
si g nifica ntl y hi g her i n  v ol u nteers w h o  recei ve d r D E N 33 0 c o m pare d t o place b o ( m ulti ple 
c o m paris o ns c orrecti o n n ot perf or me d).  T he res ul ts of eac h i n di vi d ual st u d y are des cri be d b el o w. 

CI R 3 3 2  
 
3 0  
 
2. 3. 3. 1  St u dy CI R 3 0 4  
I n st u d y CI R 3 0 4, 1 4 healt h y fla vi vir us-naï ve a d ults were e nr olle d a n d ra n d o ml y assi g ne d t o recei ve 
eit her r D E N 3 Δ 3 0 or pla ce b o. Te n partici pa nts recei ve d 3 l o g 1 0 P F U of r D E N 3 Δ 3 0 a n d 4  recei v e d 
place b o. 
All 1 0 r D E N 3 Δ 3 0 reci pie nts ha d d etecta ble vir e mia 
wit h a 
mea n pea k titer of 
1. 7 7  l o g1 0 P F U/ m L, a mea n da y of o ns et of vir e mia at Da y 4. 6, a mea n da y of pea k vir e mia at Da y  5. 3, 
a n d a me a n d urati o n of vire mia of 3. 4 d a ys ( Ta bl e 8 ). Fe ver was n ot e x perie nce d b y a n y partici pa nt  
h o we ver, 8/ 1 0 r D E N 3 Δ 3 0 reci pie nts de v el o pe d a mac ul o pa p ular ras h of w hic h 5 were gra de d as 
m o dera te (ie, Gra de 2, defi ne d i n t he pr ot oc ol as s y m pt o matic ras h [ pr urit us/ pai n] t hat d oes n ot 
i nterfere wit h f u ncti o n) i n i nte nsit y. T he mea n da y of o nset of t he ras h was st u d y Da y 7. 1 a n d t h e mea n 
d urati o n of ras h was 2 1 da ys. F oll o wi n g a si n gle d ose of r D E N 3 3 0, 1 0/ 1 0 ( 1 0 0 %) of partici pa nts 
ser oc o n verte d t o D E N V-3 wit h a reci pr ocal ge o m etric mea n pea k D E N V -3 ne utralizi n g a nti b o d y titer 
of 3 9 5. 7 ( Ta ble 9 ).  
2. 3. 3. 2  St u dy CI R 3 0 9  
I n st u d y CI R 3 0 9, t he pr otecti ve efficac y of a li ve atte n uate d tetra vale nt de n g ue vacci ne T V 0 0 5 a gai nst 
c halle n ge wit h 1 0 4 P F U of r D E N 3 3 0 6 m o nt hs f oll o wi n g vacci nati o n was e v al uate d i n h ealt h y 
fla vi vir us-naï ve a d ults. Beca use t he mea n pe a k titer of vir us f oll o wi n g c halle n ge wit h r D N E 3 3 0 was 
l o wer t ha n t hat ac hie v e d wit h a n ot her c h alle n ge vir us, r D E N 23 0 gi ve n at t he sa me d ose [1 6 ], a 1 0-
f ol d hi g her c halle n g e d ose ( 4 l o g1 0 P F U) w as c h ose n i n a n atte m pt t o i ncrease t he p ea k titer of vir us 
ac hie ve d after c halle n ge wit h r D E N 3 3 0. A place b o gr o u p was als o i ncl u de d. Bel o w, a s u m mar y of 
t he data fr o m partici pa nts w h o were c halle n ge d wit h r D E N 33 0 after ha vi n g recei ve d place b o ( N = 2 0) 
is prese nte d.  
Ac ute d e n g ue ill ness wit h fe ver w as n ot o bs er ve d i n a n y D E N 3 Δ 3 0  reci pie nt. All place b o reci pie nts 
w h o were c halle n g e d wit h r D E N 3 3 0 d e vel o pe d ras h. T he mea n da y of o nset of t he ras h was st u d y 
Da y 7. 2 a n d t he mea n d urati o n of ras h was 1 0. 4 da ys. Se ve ntee n o ut of 2 0  ( 8 5 %) p artici pa nts 
de vel o pe d i nfecti o us vire mia ( detect a ble b y tiss ue c ult ure). T h e mea n pea k titer of r D E N 3 3 0 
rec o vere d p ost-c halle n ge was 1. 0 7 l o g 1 0 P F U/ m L  (Ta ble 8 ). T he mea n da y of o nset of vire mia was at 
st u d y Da y 4. 6 a n d t he m ea n da y of p ea k vir e mia was at st u d y Da y 5. 5 . T h e mea n d urati o n of vir e mia 
was 2 da ys. F oll o wi n g a si n gle d ose of r D E N 3 Δ 3 0, 1 7 / 2 0 (8 5 %) partici pa nts ser oc o n verte d t o D E N V-
3 wit h a reci pr ocal ge o metric mea n pea k D E N V -3 ne utralizi n g a nti b o d y titer of  3 3 3. 8 (Ta ble 9 ). A 
d ose of 4 l o g 1 0 P F U of r D E N 3 3 0 i nfecte d o nl y 8 5 % of fla vi vir us -n aï ve v ol u nteers.  
2. 3. 3. 3  St u dy CI R 3 2 3  
I n st u d y CI R 3 2 3, t he pr otecti ve efficac y of a li ve atte n uate d tetra vale nt de n g ue vacci ne T V 0 0 3 a gai nst 
c halle n ge wit h r D E N 3 3 0 or r D E N 2 ∆3 0 (ie, a rec o m bi na nt D E N V -2 c halle n ge str ai n) 2 8 da ys 
f oll o wi n g vacci nati o n was e val uate d i n healt h y fla vi vir us-naï ve a d ults. A place b o gr o u p was als o 
i ncl u de d. Bel o w, a s u m mar y of t he data fr o m partici pa nts w h o were c hall e n ge d wit h 3 l o g 1 0 P F U of 
r D E N 33 0 after ha vi n g r ecei ve d pl ace b o v acci n e ( N = 1 0) is prese nte d.  
r D E N 33 0 w as rec o vere d fr o m all 1 0 place b o reci pie nts w h o were c halle n ge d wit h r D E N 3 3 0. T h e 
mea n pea k titer of r D E N 3 3 0 rec o v ere d p ost -c halle n ge was 1. 3 8 l o g 1 0 P F U/ m L. T he mea n da y of 
o nset of vire mia was at Da y 5 p ost -c halle n ge, t he mea n da y of pea k vire mia was at Da y  5. 5 
p ost -c halle n ge, a n d t he mea n d urati o n of vire mia was 3. 1 da ys ( Ta ble 8 ). Ni ne o ut of 1 0 place b o 
reci pie nts c h alle n ge d wit h r D E N 33 0 d e vel o pe d a ras h. T h e mea n da y of o nset of ras h was st u d y Da y 
8. 3 a n d t he mea n d urati o n of t he ras h was 1 2 da ys. T he ras h was gra de d as m o derate i n 7 of t he 9 
place b o reci pie nts w h o d e vel o pe d ras h f oll o wi n g c halle n ge. F oll o wi n g a si n gle d ose of r D E N 3 ∆3 0, 

CI R 3 3 2  
 
3 1  
 
1 0/ 1 0 ( 1 0 0 %) of partici pa nts ser oc o n verte d t o D E N V -3 wit h a reci pr ocal ge o metric mea n pea k D E N V -
3 ne utralizi n g a nti b o d y titer of 3 8 8. 9  ( me dia n = 6 1 8. 6), Ta ble 9 . 
 
2. 3. 3. 4  S u m m ary  
r D E N 3 Δ 3 0, w he n a d mi nistere d at a d ose of 3 l o g 1 0  P F U t o fla vi vir us -naï ve partici p a nts, i n d uces 
vire mia i n 1 0 0 % of i n oc ulate d partici pa nts, b ut is ass ociate d wit h o nl y mil d cli nical si g ns a n d 
s y m pt o ms. T he c halle n g e vir us d oes n ot ca use D F  b ut i n d uces ras h i n 8 0 t o 1 0 0 % of t he p artici pa nts, 
a n d als o i n d uc es ot her cli nical si g ns a n d s y m pt o ms c o nsiste nt wit h de n g ue s uc h as h ea d ac he, 
retr o-or bital pai n, a n d m yal gia.  A hi g her d ose of t he D E N V -3 c halle n ge vir us ( 4 l o g 1 0 P F U of 
r D E N 33 0 ) was use d i n t his st u d y t o atte m pt t o i m pr o ve t he pea k titer p ost-c halle n ge.  I nt eresti n gl y, 
w he n gi ve n 3 l o g 1 0 P F U of r D E N 3 3 0 i n st u d y CI R 3 0 4  a n d CI R 3 2 3 , all 2 0 partici pa nts ( 1 0 0 %) ha d 
r D E N 33 0 rec o v ere d fr o m t he bl o o d , ha d  a hi g her mea n pea k titer of r D E N 3 3 0 , a n d ser oc o n verte d 
t o D E N V-3 , as c o m pare d t o st u d y CI R 3 0 9 i n w hic h t he hi g her d ose of r D E N 3 3 0 was a ble t o i nfect 
o nl y 8 5 % of t he 2 0 fla vi vir us -naï ve s u bjects . Base d o n t he vire mia a n d i nfecti vit y data fr o m t hese 
st u dies, f ut ure c halle n ge st u dies wit h r D E N 33 0 will use a d ose of 3 l o g 1 0 P F U as t he d ose of 4 l o g 1 0 
P F U di d n ot res ult i n a hi g her pea k viral l o a d  a n d res ulte d i n fe wer s u bjects ser oc o n verti n g t o D E N V -
3 . 
T a ble 7 : Cli nic al res p o nse t o r D E N 33 0 i n he alt h y fl a vi vir us -n aï ve a d ults ( CI R 3 0 4, CI R 3 0 9, 
a n d CI R 3 2 3)  
A d verse e v e nt  
r D E N 33 0  
( n =4 0 ) 
C o ntr ol 1 
( n =4 0 ) 
p v al ue ( 1 -si de d)2 
I njecti o n site: 
 
 
 
 
Er yt he m a  
2 2. 5 %  
0. 0 %  
0. 0 0 1 2  
 
Pai n  
0. 0 %  
0. 0 %  
n/a  
 
Te n der ness  
3 0. 0 %  
0. 0 %  
0. 0 0 4 1  
 
I n d ur ati o n 
1 5. 0 %  
7 .5 %  
0. 0 1 2 8  
S yste mic : 
 
 
 
 
Fe ver  
5. 0 %  
0. 0 %  
0. 2 4 6 8  
 
Hea dac he  
6 5. 0 %  
4 7. 5 %  
0. 0 8 8 0  
 
R as h  
9 2. 5. 0 %  
2. 5 %  
< 0. 0 0 0 1  
 
Ne utr o pe ni a 3 
2 2. 5 %  
2. 5 %  
0. 0 0 7 2  
 
Ele vate d A L T  
0. 0 %  
0. 0 %  
n/a  
 
M yal gia  
3 5. 0 %  
1 7. 5 %  
0. 6 0 3 1  
 
Art hral gia  
1 2. 5 %  
2. 5 %  
0. 1 0 0 4  
 
Retr o -or bit al P ai n  
4 5. 0 %  
1 2. 5 %  
0. 0 0 1 3  
 
F ati g ue  
4 5. 0 %  
2 5. 0 %  
0. 0 5 0 0  
 
Pr ol o n ge d P T  
2. 5 %  
7. 5 %  
0. 9 4 2 2  
 
Pr ol o n ge d P T T  
5 . 0 % 
0. 0 %  
0. 2 4 6 8  
 
T hr o m b oc yt o pe ni a 4 
1 2. 5 %  
0. 0 %  
0. 0 2 7 4  
1.  S u bjects were t heir o w n c o ntr ols i n CI R 3 0 9 a n d 3 2 3. F o ur place b o c o ntr ols were e nr olle d i n CI R 3 0 4.  
2.  Pr o ba bilit y is greater f or r D E N 3 3 0 t ha n f or place b o  
3.  Ne utr o pe nia was d efi ne d as a n A N C ≤ 1, 0 0 0/ m m 3. 
4.  All cases b ut 1 were mil d i n i nte nsit y. T he ot her case was m o derate ( ≥7 5, 0 0 0 - < 1 0 0, 0 0 0/ m m 3)  
5.  B ol de d val ues i n dicate d si g nifica nt p val ue wit h o ut m ulti ple c o m paris o n’s c orrecti o n   
6.  n/a = n o n -a p plica ble  
 

CI R 3 3 2  
 
3 2  
 
T a ble 8 : S u m m ar y of Vir ol o gic Res p o nse i n Fl a vi vir us-n ai ve pl ace b o reci pie nts c h alle n ge d 
wit h r D E N 3 3 0  
St u d y  
N o. Vire mic 
P artici p a nts 
( %) 
D ose 
(l o g1 0  P F U)  
Me a n D a y of 
O nset 
of  Vire mi a  
Me a n D a y 
of Pe a k 
Vire mi a  
Me a n Pe a k Titer 
(l o g1 0  P F U/ m L)  
Me a n D ur ati o n 
of Vire mi a 
( d a ys) 
CI R 3 0 4 ( n = 1 0)  
1 0 ( 1 0 0 %)  
3  
4. 6  
5. 3  
1. 7 7  
3. 4  
CI R 3 0 9 ( n = 2 0)  
1 7 ( 8 5 %)  
4  
4. 6  
5. 5  
1. 0 7  
2. 0  
CI R 3 2 3 ( n = 1 0)  
1 0 ( 1 0 0 %)  
3  
5. 0  
5. 5  
1. 3 8  
3. 1  
 
T a ble 9 : Ne utr alizi n g A nti b o d y R es p o nse t o r D E N 3 3 0  
 
D ose  
Ge o metric me a n pe a k 
ne utr alizi n g a nti b o d y titer, 
reci pr oc al ( me di a n)  
% ser oc o n versi o n  
CI R 3 0 4 ( n = 1 0)  
3 l o g 1 0 P F U  
3 9 5. 7 ( 3 0 6. 5)  
1 0 0  
CI R 3 0 9 ( n = 2 0 ) 
4 l o g 1 0 P F U  
3 3 3. 8 ( 6 4 0)  
8 5  
CI R 3 2 3 ( n = 1 0)  
3 l o g 1 0 P F U  
3 8 8. 9 ( 6 1 8. 6)  
1 0 0  
 
 
St u d y Pr o d uct s Descri pti o ns  
J NJ-6 4 2 8 1 8 0 2 is a n o vel, p ote nt, pa n -ser ot y pic s mall-m olec ule i n hi bit or of de n g ue vir us ( D E N V) 
tar geti n g D E N V n o nstr uct ural pr otei n ( N S) 4 B. J NJ-6 4 2 8 1 8 0 2 is bei n g de vel o pe d f or t he pre ve nti o n 
a n d treat me nt of d e n g ue i nfecti o n.  
T h e li ve rec o m bi na nt vir us strai n r D E N 3 3 0 h a s bee n i de ntifie d as  D E N V s uita ble f or use i n d e n g u e  
c o ntr olle d h u ma n i nf ecti o n m o dels . T his i n vesti gati o nal D E N V-3 is  base d o n a c o m ple me ntar y 
de o x yri b o n ucleic aci d ( c D N A)-d eri ve d D E N V -3 (strai n Sle me n/ 7 8) i n w hi c h t he 3´ U T R of D E N V -3  
c o ntai ns a 3 0 -n ucle oti de deleti o n ( n ucle oti des 1 7 3 – 1 4 3) t hat is h o m ol o g o us t o t he Δ 3 0  deleti o n i n t he 
3´ U T R of r D E N 4 3 0 ( na me d 3 0 f or c o nsiste nc y) [1 5 ]. 
 
2. 4. 1  J N J -6 4 2 8 1 8 0 2  
2. 4. 1. 1  Cli nic al L ot Pr o d ucti o n  
T his  i nf or mati o n will be a vaila ble f or refere nce i n t he p har mac y m a n ual.  
 
2. 4. 1. 2   Fi n al C o nt ai ner of J N J -6 4 2 8 1 8 0 2  
T his i nf or mati o n will be a vaila ble f or refere nce i n t he p har mac y m a n ual.  
 
2. 4. 1. 3  C o m p ositi o n of J N J -6 4 2 8 1 8 0 2  
F or C o h ort 1, t he dr u g pr o d uct is s u p plie d as 
 
 F or t h e q ualitati ve c o m p ositi o n  of 
t he 
, please refer t o t he latest versi o n of t h e I n v esti gat or's Br oc h ure (I B) f or 
J NJ-6 4 2 8 1 8 0 2  
 
F or C o h ort 2, t he dr u g pr o d uct is s u p plie d as 
 
 F or th e 
C CI
C CI
C CI

CI R 3 3 2  
 
3 3  
 
q ualitati v e c o m p ositi o n of t he 
 refer t o t h e latest v ersi o n of t he I n vesti gat or's 
Br oc h ure (I B) f or J NJ -6 4 2 8 1 8 0 2  
 
2. 4. 1. 4  I nvesti g ati o n al Pr o d uct L a bel f or J N J-6 4 2 8 1 8 0 2  
T he i n vesti gati o n al pr o d uct la bel f or J NJ-6 4 2 8 1 8 0 2  will be pr o vi de d i n t he  p har mac y m a n ual.  
 
2. 4. 2  r D E N 3 Δ 3 0, L ot D E N 3 # 1 1 4 A  
2. 4. 2. 1  See d L ot Pr o d ucti o n  
A plas mi d was c o nstr uct e d t o e nc o de t he e ntire g e n o me of D E N V -3 Sle ma n/ 7 8. T he c D N A of t he 3´ 
U T R of t he D E N V -3 Sl e ma n/ 7 8 was t he n m o difie d t o i ntr o d uce a 3 1 -n u cle oti de deleti o n t hat was 
h o m ol o g o us t o t h e D E N 4 Δ 3 0 deleti o n. Ge n o me -le n gt h, ca p pe d R N A tra nscri pts were s y nt hesize d 
fr o m t he plas mi d p 3 Δ 3 0 a n d p urifie d. Vir us was rec o v ere d i n q u alifie d Ver o cells tra nsfecte d wit h 
p urifie d R N A tra nscri pts usi n g D O T A P li p os o mal tra nsfecti o n rea ge nt. T he vir us rec o vere d was 
desi g nate d r D E N 3 Δ 3 0 a n d was s u bse q ue ntl y ter mi nall y dil ute d t hree ti mes, a n d fi nall y passa ge d a n 
a d diti o nal t w o ti mes i n Ver o cells t o ge n erate t h e s ee d vir us.  
 
2. 4. 2. 2  Cli nic al L ot Pr o d ucti o n  
T he r D E N 3 Δ 3 0 see d vir us was tra nsferre d fr o m
 
 t o t he  
 
 as t he see d vir us f or pr o d ucti o n of t he 
vacci ne p o ol. T h e vir us was a m plifie d b y a si n gle passa ge i n Ver o cells i n ser u m -free me di u m t o 
pr o d uce t he Fi nal Dr u g Pr o d uct, r D E N 3 Δ 3 0 (l ot D E N 3 # 1 1 4 A). T h e Fi nal Dr u g Pr o d uct was 
ma n ufact ur e d o n J ul y 2 3, 2 0 1 4.  
 
2. 4. 2. 3  Fi n al C o nt ai ner of r D E N 3 Δ 3 0, L ot D E N 3 # 1 1 4 A  
T he Fi nal Dr u g Pr o d uct was dis pe nse d as 0. 6 -m L ali q u ots of a p pr o xi matel y 6. 1 l o g 1 0 P F U/ m L  li ve 
rec o m bi na nt de n g ue vir us t y pe 3 r D E N 3 Δ 3 0 Ver o-gr o w n vir us vacci n e i nt o 1. 8 -m L sterile cr y o vials 
a n d st ore d at -8 0° C ± 1 5° C. T he titer of t he r D E N 3 Δ 3 0 (l ot D E N 3 # 1 1 4 A) Fi nal Dr u g Pr o d uct, as 
deter mi ne d o n A u g ust 1 2, 2 0 1 4, was a p pr o xi matel y 6. 1 l o g 1 0 P F U/ m L.  
 
2. 4. 2. 4  C o m p ositi o n of r D E N 3 Δ 3 0, L ot D E N 3 # 1 1 4 A  
T he Fi n al Dr u g Pr o d uct c o m p ositi o n is a c o nce ntrati o n of li ve rec o m bi na nt r D E N 3 Δ 3 0  Ver o -gr o w n 
vir us vacci ne (l ot D E N 3 # 1 1 4 A) i n Lei b o vitz L -1 5 me di u m c o ntai ni n g 1 X s ucr ose, p h os p hate b uffer, 
gl uta mate  (S P G ). 
 
T he p ote nc y of r D E N 3 Δ 3 0 ( L ot D E N 3 # 1 1 4 A) is 6. 1 l o g 1 0 P F U/ m L P F U/ m L.  
 
C CI
P P D
P P D

CI R 3 3 2  
 
3 4  
 
2. 4. 2. 5  I nvesti g ati o n al Pr o d uct L a bel f or r D E N 3 Δ 3 0, L ot D E N 3 # 1 1 4 A 
 
Fi g ure 1 : L a bel f or r D E N 3 Δ 3 0, L ot D E N 3 # 1 1 4 A ( E nl ar ge d S a m ple) 
 
 
 
 
 
 
 
 
 
 
 
 
 
N O T E: Si nce ma n ufact ure of t he Fi nal Dr u g Pr o d uct, e val uati o n of li ve atte n uate d D E N V  vacci nes 
( de vel o pe d at LI D/ NI AI D/ NI H) i n b ot h l a b orat or y a n d cli nical sit uati o ns i n dicates  t hat t hes e vir uses 
are sta ble a n d p ote nt w h e n st ore d at a te m perat ur e of -8 0° C ± 1 5° C.  T heref ore, -8 0° C ± 1 5° C is t he 
rec o m me n de d st ora ge c o n diti o n f or t he Fi nal Dr u g Pr o d uct. 
 
3  
O bjecti ves  a n d E n d p oi nts  
 
Pri m ar y O bjecti ves  
1.  T o assess t he a nti viral a cti vit y of J NJ -6 4 2 8 1 8 0 2 vers us place b o i n ter ms of re d ucti o n of 
D E N V -3 R N A.  
 
Sec o n d ar y O bjecti ves  
1.  T o assess t he safet y a n d t olera bilit y of J NJ -6 4 2 8 1 8 0 2.  
2.  T o assess t he D E N V i nfecti o n -ass ociate d A Es.  
3.  T o assess t he a nti viral a cti vit y of J NJ -6 4 2 8 1 8 0 2 vers us place b o o n ot her vir ol o gic e n d p oi nts.  
4.  T o assess t he P K of J NJ -6 4 2 8 1 8 0 2 f oll o wi n g re peate d oral d osi n g.  
5.  T o e val uate t he relati o ns hi p bet wee n t he P K a n d t he a nti viral acti vit y of J NJ-6 4 2 8 1 8 0 2.  
6.  T o assess t he a nti -D E N V -3 I g M a n d I g G a nti b o d y res p o nses.  
 
 
E x pl or at or y O bjecti ves  
1.  T o deter mi ne t he rate of u nc o m plicate d de n g u e  i nfecti o n. 
2.  T o e x pl ore t he a nti -D E N V -3 ne utralizi n g a nti b o d y res p o nse.  
3.  T o e x pl ore t he a nti -D E N V -3 cell ular i m m u ne res p o nse. 
4.  T o e x pl ore c h a n ges i n ser u m pr otei n le vels (i ncl u di n g c yt o ki nes).  
5.  T o e x pl ore t he D E N V -3 N S 1 ser u m pr otei n le vels  ( C o h ort 1; o pti o nal f or C o h ort 2). 
6.  T o e x pl ore t he resista nce of D E N V -3 t o J NJ -6 4 2 8 1 8 0 2.  
7.  T o e x pl ore t he relati o ns hi p bet wee n t h e P K a n d t h e safet y a n d t olera bilit y of J NJ -6 4 2 8 1 8 0 2.  
LI V E R E C O M BI N A N T D E N G U E VI R U S T Y P E 3  
r D E N 33 0 V E R O -G R O W N VI R U S V A C CI N E  
 
C A U TI O N: N E W D R U G LI MI T E D  
B Y F E D E R A L ( U S A) L A W T O  
I N V E S TI G A TI O N A L U S E 
 
St ore at -7 5 ± 1 5° C  
C harles Ri ver La b orat ori es, Mal ver n, P A  
 

CI R 3 3 2  
 
3 5  
 
8.  T o e x pl ore t he i m pa ct of h ost a n d viral baseli ne fact ors o n t he a nti viral acti vit y a n d safet y of 
J NJ-6 4 2 8 1 8 0 2.  
 
 
Pri m ar y E n d p oi nts  
1.  Area u n d er t he D E N V -3 R N A v iral l oa d (V L ) c o n ce ntrati o n -ti me c ur ves fr o m i m me diatel y 
bef ore i n o c ulati o n ( baseli ne o n Da y 1) u ntil Da y 2 9 ( A U C D 1 -D 2 9  [ V L]). 
 
 
Sec o n d ar y E n d p oi nts  
1.  Safet y a n d t olera bilit y as meas ure d b y rec or di n g of A Es, p h ysical e xa mi nati o ns, vital si g ns, 
E C Gs, a n d cli nical la b orat or y assess me nts.  
2.  Occ urre nce a n d s e v erit y of D E N V i nfecti o n  ass ociate d A Es.  
3.  Vir ol o gic e n d p oi nts deri ve d fr o m q ua ntitati ve D E N V -3 R N A, i ncl u di n g:  
•  area u n der t he l o g 1 0-tra nsf or me d D E N V-3 R N A V L c o nce ntrati o n -ti m e c ur ves fr o m 
i m me diatel y bef ore i n oc ulati o n ( baseli ne o n Da y 1) u ntil Da y 2 9 ( A U C D 1 -D 2 9  [l o g1 0 V L])  
•  pea k of det ecta ble D E N V -3 R N A  
•  d urati o n of dete cta ble D E N V -3 R N A  
•  ti me t o first o nset of dete cta ble D E N V-3 R N A  
•  
prese nce of det ecta ble D E N V -3 R N A  
4.  Vir ol o gic e n d p oi nts deri ve d fr o m q ua ntitati ve peri p heral D E N V -3 i nfecti o us viral titer (f urt h er 
referre d t o as i nfecti o us vire mia), i ncl u di n g: 
•  area u n der t he i nf ecti o us vire mia c ur ves fr o m i m me diatel y bef ore i n oc ulati o n ( baseli ne o n 
Da y 1) u ntil Da y  2 9  
•  area u n d er t he l o g 1 0-tra nsf or me d vire mia c ur ves 
•  pea k of det ecta ble vir e mia le vel  
•  d urati o n of dete cta ble vir e mia  
•  ti me t o first o nset of dete cta ble vire mia 
•  prese nce of det ecta ble vire mia  
5.  P K ( plas ma c o nce ntrati o ns or e x p os ure p ara m eters) of J NJ -6 4 2 8 1 8 0 2.  
6.  Occ urre nce a n d ma g nit u de of a nti -D E N V -3 t otal I g M a n d I g G a nti b o d y titers.  
7.  Ti me t o fi rst o nset of a nti-D E N V -3 t otal I g M a n d I g G a nti b o d y titers.  
 
 
E x pl or at or y E n d p oi nts  
1.  Prese nce of dete cta ble D E N V -3 R N A o n at least 1  ti me p oi nt d uri n g t he st u d y wit h or 
wit h o ut D E N V i nfecti o n -ass ociate d A Es.  
2.  Occ urre nce a n d ma g nit u de of a nti -D E N V -3 ne utralizi n g a nti b o d y res p o nse  ( o pti o nal a nal ysis 
f or C o h ort 2). 
3.  Occ urre nce a n d ma g nit u de of a nti -D E N V -3 cell ular i m m u ne res p o nse.  

CI R 3 3 2  
 
3 6  
 
4.  Ma g nit u de of ser u m pr ot ei ns (i ncl u di n g c yt o ki nes).  
5.  Occ urre nce a n d ma g nit u de  of D E N V -3 N S 1 ser u m pr otei n le vels  ( o pti o nal f or C o h ort 2). 
6.   C ha n ges i n t he viral ge n o me se q ue nce ( wit h a f oc us o n N S 4 B) bet wee n vir us use d f or 
i n oc ulati o n a n d vir us prese nt d uri n g i nfecti o n i n partici pa nts wit h detecta bl e D E N V-3 R N A 
after i n oc ul ati o n.  
7.  H u ma n le u k oc yte a nti ge n ( H L A) ge n ot y pi n g a n d p har mac o g e n o mic a nal ys es.  
8.  Bi o mar ker a nal ysis via tr a nscri pti o nal pr ofili n g of h ost R N A.  
 
 
H y p ot hesis  
T he pri mar y h y p ot hesis of  t his st u d y is t hat t he hi g hest d ose of J NJ-6 4 2 8 1 8 0 2 is s u peri or t o place b o 
wit h res pect t o its a nti viral acti vit y i n healt h y a d ult partici pa nts i n oc ulate d wit h r D E N 33 0,  as 
meas ure d  b y D E N V -3 R N A V L A U C fr o m i m me diatel y bef ore i n oc ulati o n (baseli ne o n Da y 1 ) u ntil 
Da y 2 9  (A U C D 1 -D 2 9 [ V L]). 
4  
St u d y Desi g n  
 
O ver all Desi g n  
T his st u d y is a m ulti ce nter, ra n d o mize d, pl ace b o -c o ntr olle d, d o u ble-bli n d , i nter ve nti o nal P has e 2a, 
st u d y i n n or mal healt h y a d ult s u bjects 1 8 –  5 5  years of a ge, i ncl usi ve, recr uite d fr o m t he metr o p olita n 
Balti m ore/ Was hi n gt o n, D C area  & B urli n gt o n/ Ver m o nt . T he st u d y f oll o ws a n a da pti ve 2 -sta ge desi g n 
c o nsisti n g  of 2 c o h orts, eac h wit h u p t o 3 gr o u p s. T he 2 c o h orts will be e nr olle d i n a sta g gere d ma n ner. 
As a safet y meas ur e, a se nti nel gr o u p of 4  partici pa nts will be e nr olle d i n C o h ort 1 ( Gr o u p 1 a) b ef ore 
e nr olli n g t he re mai ni n g p artici pa nts ( Gr o u p 1 b a n d Gr o u p 2) i n t he c o h ort.  
T he p ur p os e of t his st u d y is t o e val u ate t he cli nical a n d vir ol o gic res p o nse t o re peat e d d oses of 
i n vesti gati o n pr o d uct J NJ-6 4 2 8 1 8 0 2 w he n a d mi nistere d orall y i n h ealt h y, D E N V a n d ZI K V -naï ve, 
n o n -pre g na nt, a d ult v ol u nteers w h o are s u bse q ue ntl y i n oc ulate d wit h r D E N 33 0, a rec o m bi na nt 
D E N V -3 strai n,  t o e x pl or e t he a nti viral acti vit y of re peate d oral d oses of J NJ-6 4 2 8 1 8 0 2 vers us place b o.  
T he safet y, t olera bilit y, P K, a n d t he relati o ns hi p bet wee n t he P K a n d a nti viral acti vit y of J NJ -6 4 2 8 1 8 0 2 
will als o be e v al uate d.  Pl ace b o reci pie nts are i ncl u de d i n t he st u d y as a c o ntr ol t o better a ssess st u d y 
a ge nt ass ociate d v ers us n o n -st u d y a ge nt ass ociat e d A Es  a n d t o act as i nf ecti vit y c o ntr ols f oll o wi n g 
a d mi nistrati o n of r D E N 3 3 0 .  
After pr o vi di n g writte n i nf or me d c o nse nt, s u bjects will u n der g o eli gi bilit y scree ni n g, i ncl u di n g 
me dical hist or y, p h ysical e xa mi nati o n, he mat ol o g y testi n g, li ver a n d re n al f u ncti o n testi n g, h u ma n 
i m m u n o deficie nc y vir us ( HI V) scree ni n g, he p atitis B a n d C scree ni n g, uri nal ysis, uri ne t o xic ol o g y 
scree ni n g, E C G scree ni n g, alc o h ol breat h test scree ni n g ( per PI/ pr ovi d er  discreti o n) , C O VI D -1 9 
testi n g (if deter mi ne d necessar y b y t he cli nicia n or per g ui deli nes ), a n d ser ol o g y scree ni n g f or pre vi o us  
i nfecti o n of D E N V a n d ZI K V  ( Co h ort 1)  a n d D E N V , ZI K V, West Nile  vir us, a n d S L E V ( Co h ort 2) . 
A t w o -ste p a p pr oac h t o s cree nin g ma y be use d, as descri be d i n secti o n 7. 3 .  
 
Ser u m  or uri ne  pre g n a nc y testi n g will be perf or m e d o n a p plica ble  pers o ns of c hil d beari n g p ote ntial . 
All scree ni n g tests m ust be perf or me d wit hi n 6 0 da ys of i nitiati o n of J NJ -6 4 2 8 1 8 0 2 st u d y a g e nt at 
St u d y Da y -5  ( Co h ort 1)  or St u d y Da y -2 ( C o h ort 2) . HI V s cree ni n g m ust be perf or me d wit hi n 2 wee ks 
of J NJ-6 4 2 8 1 8 0 2 st u d y a ge nt a d mi nistrati o n . Pre g na nc y scree ni n g will occ ur at a p plica ble scree ni n g 
visit(s) , be re peat e d o n t he first d a y of J NJ -6 4 2 8 1 8 0 2 a d mi nistrati o n  pri or t o a d mi nistrati o n , a n d o n 

CI R 3 3 2  
 
3 7  
 
t he da y of i n oc ulati o n wit h r D E N 33 0 pri or t o i n oc ulati o n wit h r D E N 33 0 . All cli nicall y si g nifica nt 
a b n or malities will be re vie we d wit h s u bjects a n d referral f or f oll o w -u p care will be pr o vi de d. S u bjects 
will be deter mi ne d t o be eli gi ble base d o n t he i ncl usi o n a n d e xcl usi o n criteria f o u n d i n secti o n 5  of t his 
pr ot oc ol. F or s u bjects w h o are eli gi ble, t h e St u d y Da y -5  ( Co h ort 1)  or St u d y Da y -2  ( Co h ort 2)  visit 
will be sc he d ule d f or i nitiati o n of J NJ-6 4 2 8 1 8 0 2 .  
 
F or C o h ort 1 : S u bjects will prese nt t o t he i n patie nt u nit o n St u d y Da y -6 . A fter eli gi bilit y criteria ha v e 
bee n re vie we d a n d c o nfir me d, s u bjects will b e a d mitte d d uri n g t h is peri o d of i nte nsi ve P K sa m pli n g. 
D osi n g  wit h J NJ -6 4 2 8 1 8 0 2 or place b o  will be gi n  o n St u d y Da y -5 . Disc har ge will occ ur o n St u d y 
Da y  -4.  D osi n g wit h J NJ -6 4 2 8 1 8 0 2 will be o bser ve d i n -cli nic o n Da ys -5, -4, -1, 1, 3, 5, 7, 9 , 1 1, 14 , 
1 6 , 18 , a n d 2 1. S u bjects will ha ve p h o ne c o ntact o n Da ys -3, -2, 2, 4, 6, 8, 1 0, 1 2, 1 3 , 15 , 1 7 , 1 9, a n d 
2 0 t o rec or d ti me of d ose, ti me of last f o o d i nta ke , a n d re vie w A Es a n d c o nc o mita nt t hera p y . Dail y 
d osi n g wit h J NJ -6 4 2 8 1 8 0 2 or place b o will occ ur fr o m St u d y  Da y -5  t hr o u g h St u d y Da y 2 1. O n St u d y 
Da y 2 1  s u bjects will prese nt t o t he u nit f or a sec o n d i nte nsi ve P K sa m pli n g peri o d  f or a f ull da y. O n 
St u d y Da y 1, all s u bjects will be c halle n ge d wit h r D E N 33 0 .  
 
F or C o h ort 2 : S u bjects will prese nt t o t he i n patie nt u nit o n St u d y Da y -3. After eli gi bilit y criter ia ha v e 
bee n re vie we d a n d c o nfir me d, s u bjects will b e a d mitte d d uri n g t h is peri o d of i nte nsi ve P K sa m pli n g. 
D osi n g wit h J NJ -6 4 2 8 1 8 0 2 or place b o will be gi n o n St u d y Da y -2. Disc har ge will occ ur o n St u d y 
Da y  1. D osi n g wit h J NJ -6 4 2 8 1 8 0 2 will be o bs er ve d i n -cli nic o n Da ys -2, -1, 1, 4, 6, 8, 1 1, 1 3, 1 5, 1 8, 
a n d 2 1 f or t he dail y d osi n g re gi me n a n d o n Da ys -2, -1, 1, 8 a n d 1 5 f or t he wee kl y d osi n g re gi me n s. 
I n t he dail y d osi n g re gi me n wit h J NJ -6 4 2 8 1 8 0 2 or place b o , t wice dail y d osi n g will occ ur fr o m St u d y 
Da y  -2 to St u d y Da y -1, a n d dail y d osi n g fr o m St u d y Da y 1  to  St u d y Da y 2 1. In t he wee kl y d osi n g 
re gi me ns, t wice dail y d osi n g will occ ur fr o m St u d y Da y  -2 t o St u d y Da y -1, a n d wee kl y d osi n g w hic h 
will occ ur o n S t u d y Da y 1, S t u d y Da y 8, a n d St u d y Da y 1 5. O n St u d y Da y 2 1  f or t he dail y re gi me n, 
a n d o n S t u d y D a y 1 5 f or t he wee kl y re gi me n s, s u bjects will prese nt t o t he u nit f or a sec o n d i nte nsi ve 
P K sa m pli n g peri o d f or a f ull da y. O n St u d y Da y 1, all s u bjects will be c halle n ge d wit h r D E N 33 0 . 
 
D uri n g t he i n patie nt visits o n St u d y Da y -6 t o -4  ( C o h ort 1) a n d St u d y Da y -3 t o 1 ( C o h ort 2) , t h e 
s u bjects will be e val uat e d b y a cli nicia n a n d will ha ve bl o o d dra w n f or cli nical la b orat or y st u dies, 
vir ol o gic assa ys, a n d i m m u n ol o gic assa ys. D uri n g t he o ut p atie nt visits s u bjects will ret ur n t o t h e cli nic  
f or e v al uati o n a n d f or bl o o d dra w as s pecifie d i n t he Sc he d ule of Pr oce d ures . St u d y Da y 8 5  will be 
t heir fi nal visit. S u bjects will ha ve t heir te m perat ure meas ure d i n clinic or meas ure t heir te m perat ur es 
at h o me t wice dail y fr o m St u d y Da y 1  t hr o u g h St u d y Da y 2 9. 
 
4. 1. 1  St u d y Desi g n  
T he st u d y f oll o ws a n a da pti ve 2 -sta ge desi g n c o nsisti n g of 2 c o h orts, eac h wit h u p t o 3 gr o u ps 
(Ta ble  1 0 ). T h e 2 c o h orts will be e nr olle d i n a sta g gere d ma n ner. As a s afet y meas ure, a s e nti nel gr o u p 
of 4  p artici pa nts will b e e nr olle d i n C o h ort 1 ( Gr o u p 1a) bef ore e nr olli n g t he re mai ni n g p artici p a nts 
(Gr o u p 1 b a n d Gr o u p 2) i n t he c o h ort. Base d o n t he res ults fr o m C o h ort 1, t he s p o ns or ( O C R P R O) 
t o get her wit h t he Dr u g De vel o p me nt Tea m ( D D T) a n d D S M B ma y deci de t o ter mi nate t he st u d y after 
C o h ort 1.  
 
. I n 
C o h ort 1, a l oa di n g d ose ( L D) p eri o d of 5 d a ys will be f oll o we d b y a mai nte na nce d ose ( M D) peri o d 
of 2 1 da ys, re s ulti n g i n a t otal d osi n g peri o d of 2 6 da ys. D oses will be ta ke n o nce dail y i n b ot h t he L D 
a n d M D peri o ds. T he L D will be 3  ( hi g h d os e re gi me n) or 4 (me di u m a n d l o w d ose re gi me n ) ti mes t he 
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CI R 3 3 2  
 
3 8  
 
M D. T he f oll o wi n g d oses will be a d mi nistere d i n C o h ort 1: hi g h d ose  (6 0 0 -m g L D f or t he L D p eri o d 
a n d 2 0 0-m g M D f or t he M D peri o d ), m e di u m d ose ( 2 0 0 -m g L D f or t he L D peri o d a n d 5 0 -m g M D f or 
t he M D peri o d), l o w d ose ( 4 0-m g d osi n g L D f or t he L D peri o d a n d 1 0 -m g M D f or t he M D peri o d ). 
N ote t hat t he st u d y will n ot i ncl u de a “ Da y 0”. 
 
 
I n C o h ort 2, a l oa di n g d ose ( L D) p eri o d of 2 d a ys will be f oll o we d b y a mai nte na nce d os e ( M D) t h at 
will be a d mi nistere d o n o ne of t w o sc he d ul es : dail y f or a peri o d of 2 1 d a ys ( gr o u p 3) or wee kl y f or a 
peri o d of 1 5 da ys ( gr o u ps 4 a n d 5). D oses will be t a ke n t wice dail y d uri n g t he l oa di n g d ose peri o d a n d 
o nce dail y d uri n g t he mai nte na nce d os e peri o d f or gr o u p 3,  a n d o nce wee kl y f or gr o u ps  4, a n d 5.   
T he f oll o wi n g d oses will be a d mi nistere d i n C o h ort 2:  
•  Gr o u p 3: 8 0 0  m g t wic e dail y f or L D peri o d  (t otal of 4 d oses o v er 2 da ys / dail y t otal of 1, 6 0 0 m g 
per da y f or 2 da ys ) a n d 2 5 0  m g dail y f or M D peri o d ( 2 1 da ys). 
•  Gr o u p 4: 4 5 0  m g t wi ce d ail y f or L D peri o d (t otal of 4 d oses o v er 2 da ys / d ail y t otal of 9 0 0 m g 
per da y f or 2 da ys ) a n d 1 2 0 0  m g wee kl y f or M D peri o d (t otal of 3 d oses a d mi nistere d o ver 
1 5  da ys) . 
•  Gr o u p 5: 2 5 0  m g t wic e d ail y f or L D peri o d (t otal of 4 d oses o v er 2 d a ys / d ail y t otal of 5 0 0  m g 
per da y f or 2 da ys ) a n d 5 0 0 m g wee kl y f or M D peri o d (t otal of 3 d oses a d mi nistere d o ver 
1 5  da ys) . 
T a ble  1 0 : O ver vie w of t he C o h orts, Gr o u ps, a n d N u m ber of P artici p a nts  
C o h ort  
Gr o u p  
 
C o h ort 1 a 
Gr o u p 1 a (hi g h  d ose  se nti nel gr o u p):  
J NJ-6 4 2 8 1 8 0 2 ( hi g h  d ose) ( 6 0 0 -m g L D/ 2 0 0 -m g M D) vers us 
place b o  
N = 4  
 
Se nti nel Gr o u p:  
 
 
2  hi g h  +  
 
 
2  place b o   
Gr o u p 1 b  (re mai ni n g hi g h d ose ) 
J NJ-6 4 2 8 1 8 0 2 ( hi g h  d ose) ( 6 0 0 -m g L D/ 2 0 0 -m g M D) vers us place b o  
N = 1 2  
 
 
8  hi g h  +  
 
 
4  place b o   
Gr o u p 2  (l o w/ me di u m d ose):  
J NJ-6 4 2 8 1 8 0 2 ( l o w d ose) ( 4 0 -m g L D/ 1 0 -m g M D) A N D   
J NJ-6 4 2 8 1 8 0 2 ( me di u m d ose) ( 2 0 0 -m g L D/ 5 0 -m g M D) vers us 
place b o  
N = 1 4  
 
 
6  l o w +   
6 me di u m  +  
2  place b o  
 
 
S u bt ot al N: 3 0 b  
C o h ort 2 c 
Gr o u p 3: J NJ -6 4 2 8 1 8 0 2  ( 8 0 0-m g  BI D  L D/ 2 5 0 -m g Q D M D)  vers us 
place b o  
8 ( 6 acti ve + 2 place b o)  
 
Gr o u p 4: J NJ -6 4 2 8 1 8 0 2 ( 4 5 0 m g BI D L D/ 1 2 0 0 m g Q 7 D  M D ) vers us 
place b o  
8 ( 6 acti ve + 2 place b o)  
 
Gr o u p 5: J NJ -6 4 2 8 1 8 0 2 ( 2 5 0 -m g BI D L D/ 5 0 0 -m g Q 7 D M D ) vers us 
place b o  
8 ( 6 acti ve + 2 place b o)  
 
 
S u bt ot al N: 2 4 d  
 
 
T ot al N: 5 4  
L D = l oa di n g d ose; M D = mai nte na n ce d ose; N = n u m ber of partici pa nts ; BI D = 2 x dail y; Q D = dail y; Q 7 D = wee kl y  
 
 
. 
a 
A se nti nel gr o u p of 4  partici pa nts will be e nr olle d bef ore t he re mai ni n g 2 6  partici pa nts i n t he c o h ort. S u bjects i n 
Gr o u p  1 will be ra n d o mize d bet wee n Hi g h d ose a n d place b o. S u bjects i n Gr o u p 2 will be ra n d o mize d bet wee n 
L o w d ose, Me di u m d ose,  a n d place b o.  
C CI
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CI R 3 3 2  
 
3 9  
 
b I n or der t o acc o u nt f or a p ote ntial earl y disc o nti n uati o n, a ma xi m u m of 7 partici pa nts ca n be re place d i n case of 
disc o nti n uati o n bef ore last d ose of st u d y dr u g o n Da y 2 1.  
c 
T he  3 d osi n g re gi me ns selecte d f or e val uati o n i n C o h ort 2 were selecte d base d o n i nteri m a nal ysis data fr o m 
C o h ort  1.   
d I n or der t o acc o u nt f or a p ote ntial earl y disc o nti n uati o n, a ma xi m u m of 6 partici pa n ts ca n be re place d i n case of 
disc o nti n uati o n bef ore Da y 2 1.  
 
 
T he ai m of C o h ort 1 is t o assess 
 t he s u p eri or a nti viral acti vit y of t he hi g h est 
d ose of J NJ-6 4 2 8 1 8 0 2 v ers us place b o a n d t o c ollect data f or t h e c haract erizati o n of a relati o ns hi p 
bet wee n t he P K a n d a nti viral acti vit y of J NJ -6 4 2 8 1 8 0 2 base d o n D E N V -3 R N A. I n C o h ort 2, t he ai m 
is t o f urt her c haract erize t he relati o ns hi p bet wee n t he P K a n d a nti viral acti vit y. 
T here are 3 se q ue ntial p h ases t o t he st u d y : scree ni n g, d osi n g (i ncl u di n g i n oc ulati o n wit h r D E N 33 0), 
a n d f oll o w-u p. Partici pa nts e nr olle d i n C o h ort 1 will atte n d scree ni n g visits bet wee n Da y -6 5 a n d 
Da y  -6 , i ncl usi ve. F or t hese partici pa nts, re peate d dail y oral d osi n g wit h J NJ -6 4 2 8 1 8 0 2 or place b o will 
be i nitiate d o n Da y -5, a s u bc uta ne o us (S C ) i njecti o n wit h r D E N 33 0 will ta ke place o n Da y  1, a n d 
d osi n g wit h J NJ -6 4 2 8 1 8 0 2 or place b o will e n d o n Da y  2 1 (ie, a t otal d osi n g d urati o n of 2 6 da ys). 
D osi n g wit h J NJ -6 4 2 8 1 8 0 2 will be i nitiate d 5 da ys bef ore  i n oc ulati o n wit h r D E N 3 3 0  t o ac hie ve near-
t o-stea d y-state J NJ-6 4 2 8 1 8 0 2 plas ma c o nce ntrati o ns b y t he ti me of i n oc ulati o n. All partici pa nts will 
be f oll o we d u p u ntil a p pr o xi matel y 6 4  da ys after l ast d ose of st u d y dr u g (ie, St u d y Da y 8 5).  
Partici pa nts e nr olle d i n C o h ort 2 will atte n d scree ni n g visits bet wee n Da y -6 5 a n d Da y  -3, i ncl usi v e. 
F or t hes e partici pa nts, re peate d oral d osi n g wit h J NJ -6 4 2 8 1 8 0 2 or place b o will be i nitiate d o n Da y -2, 
a s u bc uta ne o us ( S C) i njecti o n wit h r D E N 3 3 0 will ta ke place o n Da y  1, a n d d osi n g wit h J NJ -
6 4 2 8 1 8 0 2 or place b o will e n d o n Da y  2 1 (ie, a t otal d osi n g d urati o n of 2 3  da ys ) f or t he dail y d osi n g 
gr o u p  a n d o n Da y 1 5 (ie, a t otal d osi n g d urati o n of 1 7 da ys) f or t he wee kl y d osi n g gr o u ps. T wice dail y 
d osi n g wit h J NJ -6 4 2 8 1 8 0 2 will be i nitiate d 2 da ys bef ore i n oc ul ati o n wit h r D E N 3 3 0 t o ac hie ve near -
t o-stea d y-state J NJ-6 4 2 8 1 8 0 2 plas ma c o nce ntrati o ns b y t he ti me of i n oc ulati o n. All partici pa nts will 
be f oll o we d u ntil a p pr o xi matel y 6 4  da ys after  last d ose of st u d y dr u g f or d ail y d osi n g a n d 7 0 da ys aft er 
last d ose of st u d y dr u g f or wee kl y d osi n g (ie, St u d y Da y 8 5).  
Partici pa nts will visit t he st u d y site at scree ni n g  visits  a n d at re g ular ti me p oi nts d uri n g t he  d osi n g a n d  
f oll o w-u p p hase, as i n dicate d i n secti o n 7 . D osi n g wit h J NJ-6 4 2 8 1 8 0 2 or place b o, a n d t he S C i njecti o n 
wit h r D E N 3 3 0  will occ ur i n t he i n p atie nt a n d/ or o ut patie nt cli nical trial u nit u n der t he s u per visi o n of 
t he st u d y-site pers o n nel. Partici pa nts will be ke pt u n der o bser vati o n f or at least 3 0  mi n utes i n t he 
cli nical trial u nit after  i nitial d osi n g a n d/ or i n oc ulati o n t o e ns ure t heir safet y, a n d a n y reacti o ns d uri n g 
t his peri o d will be d o c u me nte d. T his o bser vati o n peri o d will n ot b e re q uir e d aft er Da y 1 . Partici pa nts 
will sta y i n -h o use  at t he cli nical trial u nit  d uri n g t he i nte nsi ve P K sa m pli n g peri o d fr o m t h e m or ni n g 
of D a y -6  ( Co h ort 1)  or St u d y Da y -3  ( Co h ort 2)  u ntil at least 2 4 h o urs p ost first d ose (ie, t he m or ni n g 
of Da y  -4  [C o h ort 1 ] or Da y 1  [C o h ort 2 ]). 
Partici pa nts will be n otifie d t o i nf or m t he site of a n y A E (s). Partici pa nts will als o be pr o vi de d wit h a 
wallet car d t o carr y wit h t he m d uri n g t he st u d y t hat pr o vi des 2 4 -h o ur c o ntact i nf or mati o n f or t he st u d y 
tea m. A D H C M me dical state me nt t o i ncl u de i n t he partici pa nt’s me di cal file will be pr o vi de d t o t he 
partici pa nts or maile d t o t heir pri mar y care p h ysicia n.  
If a partici pa nt m eets criteria f or a d missi o n t o t he i n patie nt u nit (as liste d i n secti o n 7. 1 8 ), h e or s h e 
ma y be a d mitte d at t he i n vesti gat or's discreti o n f or cl oser o bser vati o n.  
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CI R 3 3 2  
 
4 0  
 
Ke y assess me nts will i ncl u de t he deter mi nati o n of t he a nti viral acti vit y of J NJ -6 4 2 8 1 8 0 2 vers us 
place b o ( m eas ure d b y D E N V-3 R N A a n d vire mi a) , t he safet y a n d t olera bilit y of J NJ-6 4 2 8 1 8 0 2, t he 
P K of J NJ -6 4 2 8 1 8 0 2, a n d t he a nti -D E N V -3 h u m oral i m m u ne res p o nse. Safet y a n d t olera bilit y will be 
assesse d t hr o u g h A E re p orti n g , p h ysical e x a mi nati o ns, vital si g ns , E C Gs, an d cli nical la b orat or y t ests. 
F urt her m ore, t he effect of J NJ-6 4 2 8 1 8 0 2 o n t he cli nical c o urse of D E N V i nfecti o n will be e val uate d 
base d o n t he i n vesti gat or’s assess me nt of D E N V i nfecti o n -ass o ciate d A Es a n d a n y D E N V i nfecti o n -
ass ociate d ill ness e x perie nce d b y t he partici pa nts. I n a d diti o n, t he st u d y will i ncl u de t he c ollecti o n of 
bl o o d sa m ples f or viral g e n o me se q u e nci n g, H L A ge n ot y pi n g a n d p har mac o ge n o mic ( D N A) researc h, 
cell ular i m m u ne res p o ns e a nal ysis, a n d e x pl orat or y bi o mar ker a n al yses (i ncl u di n g ser u m p r otei n 
meas ure me nts a n d tra nscri pti o nal pr ofili n g of h ost R N A). F or m ore details o n all st u d y assess me nts 
a n d pr oce d ures, r efer t o secti o n  7 .  
F or p a rtici pa nts w h o disc o nti n ue st u d y dr u g pre mat urel y f or a n y reas o n ot her t ha n wit h dra wal of 
c o nse nt bef ore t he e n d of t he d osi n g p h ase, a n earl y d osi n g wit h dra wal visit s h o ul d be sc h e d ule d as 
s o o n as p ossi ble after decisi o n f or disc o nti n uati o n. At t he earl y d osi n g wit h dra wal visit, assess me nts 
of t he Da y 2 1  (C o h ort 1 + C o h ort 2 dail y d osi n g)/ Da y 1 5 ( C o h ort 2 wee kl y d osi n g)  visit will be 
perf or me d  o n a n o ut patie nt basis,  wit h o nl y t h e i nitial P K sa m ple b ei n g c ollecte d a n d wit h t he 
e xce pti o n of d osi n g acti vit y . T he partici pa nts will t he n e nter t he 6 4 or 7 0 -da y f oll o w -u p p has e  
(de pe n di n g o n  d ail y or w ee kl y d osi n g re gi me n) , wit h visits f or Da y 2 2-8 5  ( dail y d osi n g) or Da y 1 6-8 5 
( wee kl y d osi n g) as i n dicate d  i n Ta ble 3 : Sc he d ule of Pr oce d ures –  C o h ort 1  
Scree n 5 
D osi n g St u d y D a ys (I n p atie nt visits  m ar ke d i n gr a y)  
 
F oll o w -u p St u d y D a ys
ure  
-6 5 t o -6  
-6  
-5  -4  
-3  
-2  
-1  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  1 1  1 2  1 3  1 4  1 5  1 6  1 7  1 8  1 9  2 0  
2 1  
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l ysis  
 
 
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n o me 
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CI R 3 3 2  
 
4 1  
 
Scree n 5 
D osi n g St u d y D a ys (I n p atie nt visits  m ar ke d i n gr a y)  
 
F oll o w -u p St u d y D a ys
ure  
-6 5 t o -6  
-6  
-5  -4  
-3  
-2  
-1  
1  
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n ot y pi n g & 
c o ge n o mics  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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r y Pa nel 9 
X  
 
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h differe ntial  
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C V, H B V  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
k v  scree ni n g 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c y Test 1  
X  
 
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st 1 1 
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is & Uri ne 
o g y Scree n 
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Breat h Test  
 
X 1 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 E C G8 
X  
 
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Aes = a d verse e ve nts; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; C B C = c o m plete bl o o d c o u nt; C M P = c o m pre he nsi ve meta b olic 
pa nel; E C G = electr ocar di o gra m; E LI S A = e nz y me -li n ke d i m m u n os or be nt assa y; F S H = f ollicle-sti m ulati n g h or m o ne; H B V = he patitis B vir us; H C V = 
he patitis C vir us; HI V = h u ma n i m m u n o deficie nc y vir us;  H L A = h u ma n le u k oc yte a nti ge n; N P = nas o p har y n geal; P B M C = peri p heral bl o o d m o n o n uclear 
cell; P K = p har mac o ki netics; P T/ P T T = pr ot hr o m bi n ti me/ partial t hr o m b o plasti n ti me ; R N A = ri b o n ucleic aci d; R T-P C R = re verse tra nscri pti o n p ol y merase 
c hai n reacti o n  
1 5.  Ser u m or uri ne pre g na nc y testi n g o nl y perf or me d  f or pers o ns  of c hil d beari n g p ote ntial ..  
1 6.  O n S D -5: 7 P K sa m ples will be c ollecte d d uri n g 1 6 -h o ur wi n d o w . 
1 7.  Q ualitati ve R T -P C R will be perf or me d o n s a m ples c ollecte d o n D a ys 2 9, 3 6, 4 3, 5 0, 5 7, 6 3, 7 0, a n d 8 5.  If t he partici pa nt is D E N V-3 p ositi ve detecte d f or 
first ti me at Da y ≥2 9, q ualitati ve R T-P C R will be perf or me d t wice wee kl y ( prefer a bl y wit h 3 t o 4 d a ys i n bet wee n s a m ples) u ntil t he partici pa nt res ults are 
ne gati ve a n d u ntil res ol uti o n of D E N V i nfecti o n -ass ociate d Aes. Partici pa nts w h o are D E N V -3 p ositi ve o n Da y 8 5 s h o ul d ret ur n f or a d diti o nal cli nical a n d 
vir ol o gic assess me nts u ntil t he partici pa nt res ults are ne gati ve a n d u ntil res ol uti o n of D E N V i nfecti o n -ass ociate d Aes. A d diti o nal testi n g usi n g differe nt 
n ucleic aci d base d met h o ds f or t he detecti o n a n d/ or q ua ntificati o n of D E N V -3 ma y be perf or me d.  
1 8.  P h o ne calls t o c ollect ti me of d ose, ti me of last f o o d, A E’s, a n d c o nc o mita nt t hera p y o n S D -3, -2, 2, 4, 6, 8, 1 0, 1 2, 1 3, 1 5, 1 7, 1 9, a n d 2 0.  
1 9.  Scree ni n g ma y occ ur o ver m ulti ple visits. Certai n pr oce d ures m ust be perf or me d wit hi n differe nt ti me fra me relati ve t o d osi n g, see Secti o n 7. 1 . Scree ni n g 
wi n d o w is Da y -6 5 t o Da y -6.  
2 0.  A c o m plete p h ysical e xa m will be perf or me d at scree ni n g a n d o n Da y 8 5. At all ot her i n dicate d ti me p oi nts a f oc use d p h ysical e xa m will be perf or me d.  
2 1.  [ X] Sa m ple will be c ollecte d, b ut test will o nl y be perf or me d if i n dicate d b y g ui deli nes i n t he pr ot oc ol.  
2 2.  E C Gs are rec or de d pre -d ose  o n d osi n g d a ys . 
2 3.  C he mistr y pa nel c o nsists of s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, calci u m, p h os p hate, al b u mi n, t otal p r otei n, t otal c h olester ol, creati ni ne, gl uc ose, 
A S T, A L T, G G T, H D L c h olester ol, L D L c h olester ol, tri gl yceri des, ma g nesi u m, calc ulate d creati ne cleara nce ( b y M D R D), li pase, a m ylase, t otal  bilir u bi n, 
al kali ne p h os p hatase, uric aci d  
2 4.  Nas o p har y n geal ( N P) or mi d -t ur bi nate s wa b t o test f or S A R S-C o V 2 –  t he vir us t hat ca uses C O VI D-1 9 –  will be c ollecte d fr o m all v ol u nteers re gar dless of 
vacci nati o n stat us base d o n g ui da nce fr o m fe deral, state, l ocal, a n d/ or i nstit uti o nal healt h officials *  or at t he discreti o n of t he cli nicia n ( ma y be c ollecte d u p 
t o 7 2 h o urs i n a d va nce of state d c ollecti o n ti me). 
* T his g ui da nce ma y be i nf or me d b y t he l ocal C O VI D i nfecti o n rate, se verit y of i nfecti o ns, vacci nati o n rates, a n d ot her fact or s as t he C O VI D -1 9 pa n de mic 
c o nti n ues t o e v ol ve  a n d c ha n ge. N P or mi d -t ur bi nate s wa bs ma y be c ollecte d at ot her ti me-p oi nts if v ol u nteer has C O VI D -li ke s y m pt o ms.  
2 5.  F S H perf or me d o nl y i n fe males w h o ha ve st o p pe d me nstr uati n g f or > 1 2 c o nsec uti ve m o nt hs b ut < 2 4 m o nt hs. ( A n y o ne w h o has ha d a me n orr hea > 2 4 
c o nsec uti ve m o nt hs is c o nsi dere d p ost me n o pa usal a n d d oes n ot re q uire F S H).  
2 6.  I n partici pa nts w h o de vel o p a ras h, a n a d diti o nal sa m ple will be c ollecte d at o nset of ras h a n d teste d. N ote d o n t his c hart wit h a n asteris k { X * } 
2 7.  O n St u d y Da y 2 1: 6 P K sa m ples will  be c ollecte d d uri n g a 1 2 -h o ur wi n d o w  
2 8.  Alc o h ol breat h test ma y be perf or me d at t he discreti o n of PI/ pr o vi der u p o n a d missi o n t o i n patie nt u nit  
 
 

CI R 3 3 2  
 
4 2  
 
 ( C o h ort 1) a n d Ta ble 4  ( C o h ort 2). 
A D D T  as well as t he NI AI D I ntra m ur al Dat a a n d Safet y M o nit ori n g B oar d ( D S M B ) a n d Dr u g 
De vel o p me nt U n bli n de d Tea m  (D D U T ) will be c o m missi o ne d f or t his st u d y.  
T he D D T is t he J a nsse n c ore st u d y te a m i n c har g e of t he d e vel o p me nt of t he Ja nsse n i n vesti gati o nal 
pr o d uct J NJ -6 4 2 8 1 8 0 2 a n d i ncl u des, b ut is n ot li mite d t o, t he C o m p o u n d De vel o p me nt Tea m Lea d er, 
t he Me dical L ea d, t h e P K  Lea d, t he Bi ostatisticia n, a n d t he Vir ol o gist. T he pri mar y res p o nsi bilities of 
t his tea m are t o re vie w t he bli n de d safet y data re p ort ge nerate d b y t he D S M B fr o m  t he se nti nel gr o u p 
i n or der t o deter mi ne if t he safet y a n d t olera bilit y of t he d osi n g wit h J NJ-6 4 2 8 1 8 0 2/ place b o a n d 
i n oc ulati o n wit h r D E N 3Δ 3 0 were s h o w n t o b e acce pta ble t o all o w d osi n g of t he re mai n der v ol u nteers  
of C o h ort 1; t o re vie w t he u n bli n de d p har mac o ki netic a n d vir ol o gic data at t he i nteri m a nal ysis after 
C o h ort 1 G r o u p 1 reac h e d Da y 2 9 
 t o re vie w t h e 
u n bli n de d p har mac o ki netic a n d vir ol o gic data at t he i nteri m  a n al ysis after C o h ort 1 ( Gr ou ps 1 a, 1 b, 
a n d G r o u p 2) c o m plet e D a y 8 5 i n or der t o deter mi ne t he d osi n g stre n gt h a n d peri o dicit y of J NJ-
6 4 2 8 1 8 0 2 f or C o h ort 2 of t he st u d y ; t o re vie w all a vaila ble safet y data if o ne of t he st u d y p a usi n g r ules 
ha ve bee n met, i n or der t o deter mi ne t he n e xt ste ps. T he D D T will s u b mit t he writte n D D T s u m mar y 
re p orts wit h rec o m me n dati o ns t o t he D S M B.  
T he NI AI D I ntr a m ural D S M B i ncl u des i n de pe n de nt  e x perts t hat d o n ot ha ve direct i n v ol ve me nt i n t he 
c o n d uct of t he st u d y a n d ha ve n o si g nifica nt c o nflicts of i nterests as d efi n e d b y NI AI D p olic y. T h e 
NI AI D I ntra m ural D S M B is c o nstit ute d t o re vie w t he safet y data of I ntra m ural NI AI D cli nical st u dies 
t hat re q uire D S M B o versi g ht, a n d c o nsists of e x perts i n i nfecti o us diseases, bi ostatistics, a n d cli nical 
trials. T he Pri nci pal I n v esti gat or ( PI)/ desi g nee will pr o vi de t he D S M B e xec uti ve secretar y wit h 
bli n di n g c o des i n a seale d e n vel o pe i n case t he D S M B re q uir es t his i nf or mati o n t o ma ke its 
rec o m me n dati o ns. T he D S M B will re vie w t he st u d y pri or t o i nitiati o n a n d t wice a year t hereafter a n d 
will be i n v ol ve d i n t he u n bli n de d e val uati o n of t h e data of t he first 4  p artici pa nts i n C o h ort 1 a n d i n 
t he i nteri m a nal ysis of all partici pa nts i n C o h ort 1 (secti o n 9. 6. 8 ). T he 
D S M B 
will 
ma ke 
rec o m me n dati o ns re gar di n g c o nti n uati o n or disc o nti n uati o n of t he st u d y at t hese ti mes. T h ese re vie ws 
ma y or ma y n ot i ncl u de u n bli n de d data. T he B oar d ma y c o n ve ne a d diti o nal re vie ws as necessar y. Pri or 
t o eac h re vie w, a s u m mar y of c u m ulati ve safet y data w ill be s u b mitte d i n a f or mat acce pta ble t o t he 
B oar d t o get her wit h t he D D T a n d/ or D D U T re p orts if a vaila ble. T he B oar d will re vie w t he st u d y data 
t o e val uate t he safet y, efficac y, st u d y pr o gress a n d c o n d uct of t he st u d y. Re p orts of S A Es a n d deat hs 
will be s u b mitte d b y t he PI t o t he B o ar d at t h e sa me ti me t he y are re p orte d t o t he s p o ns or a n d I R B. All 
U na ntici pate d Pr o ble ms ( U Ps) will be s u b mitte d t o t he D S M B at t h e sa m e ti me t he y are s u b mitte d t o 
t he I R B or I N D s p o ns or. I N D Safet y Re p orts will be s u b mitte d t o t he D S M B b y t he i n vesti gat or after 
t heir recei pt. T he PI will n otif y t he D S M B of a n y cases of i nte nti o nal or u ni nte nti o nal u n bli n di n g as 
s o o n as p ossi ble. T he PI will n otif y t he B oar d w he n s pecific pa usi n g r ules are met (secti o n 8. 5 ) a n d 
o btai n a rec o m me n d ati o n c o ncer ni n g c o nti n uati o n, m o dificati o n, or ter mi nati o n of t he st u d y. T he PI 
will s u b mit t he writte n D S M B s u m mar y re p orts wit h rec o m me n dati o ns t o t he I R B(s).  
T he D D U T will c o nsist of Ja nsse n pers o n nel, na m el y a cli nicia n wit h e x pertise i n i nfecti o us diseases, 
a vir ol o gist, a me dical safet y officer, a  p har m ac o metricia n, a n d a statisticia n, n o ne of w h o m will be 
part of t he D D T. If, i n t he j u d g me nt of t he i n vesti gat or a n d/ or t he S p o ns or ( O C R P R O) me dical 
m o nit or, a si g nifica nt or u ne x pecte d s afet y e ve nt occ urs, t h e D S M B will deci de if a re vie w of 
u n bli n de d safet y data will be nee de d. T he D S M B will f or m ulate rec o m me n de d decisi o ns/acti o ns t o 
t he D D U T wit h res pect t o a n y c ha nges t o c o n d uct t hat is dee me d necessar y base d o n t he e mer gi n g 
safet y a n d t olera bilit y data. T his ma y i ncl u de t he pa use or cl os ur e of treat me nt ar ms. T he fi nal decisi o n 
will be ta ke n i n c olla b orati o n bet wee n t he D S M B a n d t he D D U T. T he D D U T will als o b e i n v o l ve d i n 
C CI

CI R 3 3 2  
 
4 3  
 
t he first i nteri m a nal ysis after Gr o u p 1a a n d Gr o u p 1 b ( hi g h d ose) a n d i n t he sec o n d i nteri m a nal ysis 
of all partici p a nts i n C o h ort 1 d uri n g w hic h t he D S M B, st u d y tea m, D D T a n d D D U T will be u n bli n de d 
(secti o n 9. 6. 8 ). T he D D U T will als o be i n v ol ve d i n t he u n bli n de d first i nteri m a nal ysis after Gr o u p 1a 
a n d Gr o u p 1 b ( hi g h d ose) c o m plete d Da y 2 9 a n d i n t he u n bli n de d sec o n d i nteri m a nal ysis w he n all 
partici pa nts i n C o h ort 1 c o m plete d t he Da y 8 5  ( 
 

CI R 3 3 2  
 
4 4  
 
Ta ble 1 1 : S u m mar y of S c he d ule of Interi m A nal yses a n d U n bli n di n g of D ata 
). 
T he i n de pe n de nt i nter nal p har mac o metricia n of Ja nsse n ma y recei ve u n bli n de d treat me nt assi g n me nts 
pri or t o c o m pleti o n of St u d y Da y 8 5 of C o h ort 1, Gr o u p 2 wit h a de q uate fire walls s o t h e D D T will 
re mai n bli n de d. T his earlier u n bli n di n g of t he p h ar mac o metricia n ca n be d o ne i n or der t o all o w t he 
pre parati o n of t he P K/ P D m o del nee d e d t o assess t he o bjecti ve of t he P K/ P D relati o ns hi p after t he 
sec o n d i nteri m a nal ysis.  
 
 

CI R 3 3 2  
 
4 5  
 
T a ble 1 1 : S u m m ar y of S c he d ule of Interi m A n al yses a n d U n bli n di n g of D at a  
 
Bli n de d or u n bli n de d  
Re vie we d b y  
Ti meli ne  
Se nti nel Re vie w C o h ort 
1, Gr o u p 1a ( n = 4) 
U n bli n de d  
D S M B o nl y  
After se nti nel gr o u p (G r o u p 
1a) c o m pletes D 2 1   
 
I nteri m A nal ysis  # 1: 
C o h ort 1, Gr o u p 1 b 
( n = 1 2) 
C o h ort 1 Gr o u p 1  
U n bli n de d  
D S M B , D D U T1, D D T  
After Gr o u p 1a a n d 1 b 
c o m pletes D2 9  
S t u d y T ea m 
After Gr o u p 1a a n d 1 b 
c o m pletes D 8 5 
I nteri m A nal ysis # 2: 
C o h ort 1, Gr o u p 2 
( n = 1 4) 
U n bli n de d  
D S M B , D D U T 2, D D T, 
a n d S t u d y T ea m 
After G r o u p 2 c o m pletes 
D 8 5  
1.  T he D D U T ma y re q uest o ne or m ore s u bjects’ treat me nt assi g n me nt pri or t o st u d y da y 2 9  f or re vie w of a safet y 
iss ue o nl y. 
2.  T he D D U T ma y re q uest o ne or m ore s u bjects’ treat me nt assi g n me nt pri or t o st u d y da y 8 5 f or re vie w of a safet y 
iss ue o nl y. 
 
4. 1. 1. 1  I niti al E nr oll me nt of Se nti nel C o h ort  1  
T he first 4  partici pa nts i n C o h ort 1 ( Gr o u p 1a) will recei ve t he first d ose of st u d y dr u g  or place b o  at 
least 2 1  da ys bef ore t he re mai ni n g 2 6  parti ci pa nts i n t he c o h ort. T hese 4  partici pa nts will first be 
ra n d o mize d i n a 1 :1  rati o t o t he hi g h -d ose gr o u p or place b o  ( Gr o u p 1a).  
4. 1. 1. 2  E nr oll me nt of Re m ai ni n g  S u bjects i n C o h ort 1   
T he re mai ni n g 1 2  p artici pa nts i n Gr o u p 1 b  will be ra n d o mize d i n a 2 : 1 rati o t o t he hi g h -d os e gr o u p or 
place b o . Partici pa nts i n Gr o u p 2 will  be ra n d o mize d i n a 3 :3 :1  rati o t o t he l o w d ose of J NJ-6 4 2 8 1 8 0 2, 
me di u m d ose of J NJ -6 4 2 8 1 8 0 2, or place b o ( T a ble  1 0 ). T he L D will be 3 ti mes ( hi g h d ose re gi me n) or 
4 ti mes (me di u m a n d l o w d ose re gi me n ) t h e M D. 
 
 
 
T he f oll o wi n g L D/ M D re gi me ns will be selecte d f or t he 2 gr o u ps i n C o h ort  1:  
•  Hi g h -d ose re gi me n; 6 0 0 -m g L D ( Da ys -5 t o -1)/ 2 0 0 -m g M D ( Da ys 1 t o 2 1).  
•  Me di u m -d ose re gi me n; 2 0 0 -m g L D ( Da ys -5 t o -1)/ 5 0 -m g M D ( Da ys 1 t o 2 1).  
•  L o w -d ose re gi me n; 4 0 -m g L D ( Da ys -5 t o -1)/ 1 0 -m g M D ( Da ys 1 t o 2 1).  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
  
 
  
  
  
  
  
  
  
 
 
 
 
 
 
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C CI
C CI
C CI

CI R 3 3 2  
 
4 6  
 
 A first i nteri m a nal ysis will be perf or me d w he n all partici pa nts fr o m Gr o u p 1a a n d Gr o u p 1 b h a v e 
c o m plete d t he Da y 2 9 visit or disc o nti n ue d earlier  
. E nr oll me nt will n ot be 
st o p pe d d uri n g t his i nteri m a nal ysis. T his i nteri m a n al ys is will i ncl u de P K a nal ysis, D E N V R N A  
a nal ysis, a n d s afet y a nal ysis. A sec o n d i nteri m a nal ysis will be perf or m e d w he n all partici pa nts fr o m 
Gr o u p  1  a n d Gr o u p  2  ha ve c o m plete d t he Da y 8 5 visit or disc o nti n ue d earlier . T his a nal ysis  will be 
d o ne t o select t h e d ose re gi me ns f or C o h ort 2 . 
4. 1. 1. 3  E nr oll me nt of S u bjects i n C o h ort 2  
Base d o n t he i nteri m a n al ysis res ults of C o h ort 1, t hree s e parate d osi n g re gi me ns were s electe d f or 
C o h ort 2 ( Ta ble  1 0 ).  
Wit hi n C o h ort 2, ra n d o mizati o n will be bala nce d o ver t he differe nt gr o u ps b y usi n g ra n d o ml y 
per m ute d bl oc ks. Ra n d o mizati o n wit hi n bl oc ks will be 1: 1: 1: 1 wit h 1 p artici pa nt assi g ne d t o eac h of 
t he 3 J NJ-6 4 2 8 1 8 0 2 d ose re gi me ns a n d t he last partici pa nt of eac h bl oc k assi g ne d t o 1 of t he 3 
c orres p o n di n g pla ce b o re gi me ns. T he 3 place b o re gi me ns will be e q uall y b ala nce d  o v er t he differe nt 
bl oc ks . T he d osi n g d urati o n will n ot e xcee d t he ma xi m u m d osi n g d urati o n ( 3 1 da ys) of s t u d y 
6 4 2 8 1 8 0 2 D N G 1 0 0 1.  Sel ecte d d ose re gi me ns a n d rati o nales are bel o w:  
•  Gr o u p 3: 8 0 0  m g t wic e dail y f or L D peri o d (t otal of 4 d oses o v er 2 da ys / dail y t otal of 1, 6 0 0  m g 
per da y f or 2 d a ys) a n d 2 5 0  m g dail y f or M D p eri o d ( 2 1 da ys). T he rati o nale bei n g t o m a xi mize 
J NJ-6 4 2 8 1 8 0 2 a nti viral a cti vit y f or dail y d osi n g wit hi n N O A E L safet y li mits .  
•  Gr o u p 4: 4 5 0  m g t wic e d ail y f or L D peri o d (t otal of 4 d oses o v er 2 d a ys / d ail y t otal of 9 0 0  m g 
per da y f or 2 da ys) a n d 1 2 0 0  m g wee kl y f or M D peri o d (t otal of 3 d oses a d mi nistere d o ver 
1 5  da ys , ie, Da y  1, 8 , a n d 1 5). T he rati o nale bei n g t o ma xi mize J NJ -6 4 2 8 1 8 0 2 a nti viral acti vit y 
f or wee kl y d osi n g wit hi n N O A E L safet y li mits.   
•  Gr o u p 5: 2 5 0  m g t wic e d ail y f or L D peri o d (t otal of 4 d oses o v er 2 d a ys / d ail y t otal of  5 0 0  m g 
per da y f or 2 da ys) a n d 5 0 0  m g wee kl y f or M D peri o d (t otal of 3 d oses a d mi nistere d o ver 
1 5  da ys , ie, Da y  1, 8, a n d 1 5 ). T he rati o nale bei n g t o f urt her c haract erize t he P K/ P D 
relati o ns hi p of J NJ-6 4 2 8 1 8 0 2.  
 
 
 
 
   
4. 1. 2  S a m ple  Size a n d Pl ace b o R ati o  
T he  tar g et sa m ple siz e is 5 4  male a n d fe m ale a d ult partici pa nts, 1 8 t o 5 5  years of a g e,  w h o  recei v e 
r D E N 3 Δ 3 0 o n Da y 1 a n d c o m plete t he J NJ-6 4 2 8 1 8 0 2 d osi n g peri o d . T he t otal sa m ple size f or t he 
st u d y will be a ma xi m u m of 6 7  i n di vi d uals o ver t he 2 c o h orts, i ncl u di n g a ma xi m u m of 7 partici pa nts 
i n C o h ort 1 a n d 6 partici pa nts i n C o h ort 2  w h o ca n be re place d  i n case of disc o nti n uati o n bef ore Da y 
2 1.  A n y s u bject w h o  d o es n ot recei ve st u d y a ge nt d ue t o i neli gi bilit y o r wit h dra wal  of c o nse nt pri or t o 
a d mi nistrati o n of J NJ -6 4 2 8 1 8 0 2 will n ot  be c o nsi dere d e nr olle d a n d t heref ore will n ot  be f oll o we d.  
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CI R 3 3 2  
 
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4. 1. 3  D ur a ti o n of S u bject P a rtici p ati o n  
S u bjects will be f oll o we d f or a p pr o xi matel y 9 0 da ys. S u bjects will be scree ne d u p t o 6 0  da ys pri or t o 
i nitiati o n of JN J-6 4 2 8 1 8 0 2  o n St u d y Da y -5  ( Co h ort 1)  or St u d y Da y -2 ( C o h ort 2) . T he t otal d urati o n 
of st u d y partici pati o n (i n cl u di n g scree ni n g) will be a p pr o xi matel y 9 1 t o 1 5 0 da ys.  
4. 1. 4  Esti m ate d  D ur ati o n of t he St u d y  
T he e ntire d urati o n of t he st u d y is a p pr o xi matel y 9 9  wee ks . Scree ni n g pr oce d ures s h o ul d be c o m plete d 
wit hi n 6 0  da ys pri or t o i nitiati o n of t he test art icle J NJ-6 4 2 8 1 8 0 2 . T he st u d y will last f or a p pr o xi matel y 
9 0 da ys  fr o m t he ti me t he last s u bject i nitiates J NJ-6 4 2 8 1 8 0 2 . 
4. 1. 5  Tre at me nt Assi g n me nt  
S u bjects will be ra n d o ml y assi g ne d t o recei ve J NJ-6 4 2 8 1 8 0 2  or place b o. Treat me nt  assi g n me nt will 
be deter mi ne d usi n g a ra n d o m n u m ber ge nerat or t o pre pare t he se q ue nce i n w hic h s u bjects are assi g ne d 
t o recei ve J NJ-6 4 2 8 1 8 0 2  or pla ce b o , a n d all s u bjects 
will recei ve D E N V -3 challe n g e . T h e 
ra n d o mizati o n will be bal a nce d b y usi n g ra n d o ml y per m ute d bl oc ks a n d will be stratifie d b y ce nter. If 
a gr o u p is recr uite d o ver differe nt ce nters , eac h ce nter s h o ul d recr uit c o m plete bl oc ks  (T a ble  1 0 ). A 
master l o g of treat me nt assi g n me nts will be  mai ntai ne d i n a se parate rec or d fr o m ot her st u d y  
R ec or ds, i n a l oc ke d r o o m wit h li mite d access. A seale d e n vel o p e c o ntai ni n g a c o p y of t he treat me nt 
assi g n me nt will als o be ke pt b y t he D S M B  exec uti ve secretar y . 
 
S u bjects will n ot be i nf or me d of t h eir tr eat me nt assi g n me nt u nless re q uest e d  i n writi n g. If a s u bject 
re q uests t o be i nf or me d of t heir treat me nt assi g n me nt, t he y ma y be n otifie d of t his after t he last s u bject 
i n t heir Gr o u p ( C o h ort 1, Gr o u p 1 or Gr o u p 2) or C o h ort  2  c o m plet es St u d y Da y 8 5 a n d t he dat aset  f or 
t hat gr o u p/ c o h ort is clea n e d a n d cl ose d , as n otif yi n g t he m earl y ma y u n bli n d st u d y staff.  
 
4. 1. 6  Bli n di n g  
T his st u d y will be c o n d ucte d as a d o u ble -bli n d st u d y t o a v oi d biase d assess me nt of A Es.  Differe nt 
 stre n gt hs will be use d f or t he differe nt d ose le vels t hat will be a d mi nistere d 
(Ta ble  1 0 )/differe nt ( dail y -wee kl y) re gi me n ( C o h ort  2) . As 
 
t he d ose l e vels/re gi me ns are differe nt i n a p p eara nce, bli n di n g acr oss t h e gr o u ps ca n n ot be ac hie ve d. 
H o we ver, t he d os e sele cti o n i n C o h ort 1 will per mit t he bli n d t o be mai nt ai n e d bet w ee n t h e 2 l o w est 
d ose gr o u ps. T o e na bl e bli n di n g wit hi n gr o u ps, matc hi n g place b o  
 f or eac h d os e le vel /r e gi me n 
will be pr o vi de d.  T h e st u d y will be u n bli n de d acc or di n g t o tr eat me nt c o h ort a n d gr o u p  t o e na bl e a 
better u n dersta n di n g of t h e safet y pr ofile of t he dr u g . C o h ort 1, Gr o u p 1 will be u n bli n de d f or t he D D T 
after partici pa nts i n Gr o u p 1 c o m plet e St u d y Da y 2 9  a n d t he data bas e h as bee n clea ne d a n d cl ose d.  
T he  St u d y Tea m will be u n bli n de d after partici p a nts i n Gr o u p 1 c o m plete St u d y Da y 8 5. C o h ort 1, 
Gr o u p 2 will be u n bli n de d after p artici pa nts i n Gr o u p 2 c o m plet e St u d y Da y 8 5 a n d t he data base h a s 
bee n clea n e d a n d cl ose d. C o h ort 2 will be u n bli n de d after partici pa nts i n C o h ort 2 c o m plete St u d y Da y 
8 5 a n d t he data b ase ha s b ee n cle a ne d a n d cl ose d. 
T he s u bject, i n vesti gat or, a n d cli nical staff will n ot k n o w w hic h treat me nt gr o u p t he s u bject has  bee n 
assi g ne d  u ntil t he s pecifi e d ti me p oi nt . I n a d diti o n, ot her p ers o n nel assi g ne d t o m o nit or t he st u d y will 
n ot k n o w t he  treat me nt assi g n me nt of t he s u bject. T he p har m acist will be u n bli n de d as t he st u d y dr u g 
will be pr o vi de d i n H D P E b ottles. T o all o w selecti o n of sa m ples, t he bi oa nal ytical la b orat or y will 
recei v e ra n d o mizati o n lists per tr eat me nt. U n bli n di n g of t he ra n d o mizati o n c o de will be perf or me d at 
t he bi oa nal ytical la b orat or y o nl y a n d will be s u bjecte d t o a pr oce d ure t hat will e ns ure t hat c o des will 
n ot be re veale d t o a n y o n e i n v ol ve d i n t he c o n d uct of t he st u d y . N o o ne o utsi de of t he la b will  ha ve 
access t o t his i nf or mati o n u ntil t he st u d y is u n bli n de d  as descri be d a b o ve . Ra n d o mizati o n c o des will 
be discl ose d f ull y o nl y if t he st u d y ti me p oi nts descri be d ha ve b ee n m et a n d t h e cli nical dat a base relat e d 
C CI
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CI R 3 3 2  
 
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t o t he e nr oll me nt gr o u p is clea ne d a n d cl ose d. H o we ver, t he ra n d o mizati o n c o des a n d t he tr a nslati o n 
of ra n d o mizati o n c o des  i nt o st u d y dr u g gr o u ps will be discl ose d f or t he i nteri m a nal yses as d escri b e d 
i n secti o n 9. 6. 8 . C o des will o nl y be discl ose d f or s u bje cts i ncl u de d i n t he a nal yses. A n d  if it bec o m es 
necessar y t o u n bli n d a s pecific s u bject’s assi g n me nt f or e mer ge nc y me dical  ma na ge me nt, t he  PI will 
c o ntact t he I n v esti gati o nal Dr u g Ser vice researc h p har mac y u n bli n de d st u d y staff a n d o btai n t h e 
treat me nt assi g n me nt of t he s u bject i n q uesti o n. O nl y t hat s pecific s u bject’s treat me nt assi g n me nt will 
be u n bli n de d . T he D S M B will recei ve t he treat m e nt assi g n me nt, if t he B oar d felt it necessar y. Ja nsse n 
w o ul d n ot recei ve t h e u n bli n de d treat me nt assi g n me nt i n t his case.  
5  
Selecti o n a n d E nr oll me nt of  S u bjects  
Scree ni n g f or eli gi ble partici pa nts will be perf or me d d uri n g scree ni n g visits bet wee n Da y -6 5  
( Co h ort  1)  or Da y -6 2  ( Co h ort 2)  a n d Da y -6  ( Co h ort 1)  or Da y -3  ( Co h ort 2) . I n case t he first scree ni n g 
visit is pla n ne d t o ta ke pl ace wit hi n 1 4 da ys bef ore first d os e of st u d y dr u g, a d diti o nal scree ni n g visits 
ma y n ot be  a p plica ble, a n d all scree ni n g assess me nts ma y  be perf or me d d uri n g o ne si n gle sc ree ni n g 
visit. If t here are m ulti ple scree ni n g visits, s o me assess me nts ma y be re p eat e d. A n i ncl usi o n/e xcl usi o n 
criteria c hec k is perf or m e d at scree ni n g  a n d b ef ore a d mi nistrati o n of t he first d ose of st u d y dr u g o n 
St u d y Da y  -5  ( Co h ort 1)  or St u d y Da y -2  ( Co h ort 2) . A d diti o nall y, partici pa nts  will be e val uate d  pri or 
t o c halle n ge a d mi nistrati o n o n St u d y Da y 1  t o e ns ure t hat t he y d o n ot meet a n y criteria w hic h w o ul d 
e xcl u de t he m fr o m r D E N 3 Δ 3 0 c halle n ge . 
N ote: T he scree ni n g p eri o d bet wee n t he first s cree ni n g visit a n d t he first d ose of st u d y dr u g m a y be 
pr ol o n ge d be y o n d 6 0 d a ys f or a p artici pa nt f oll o wi n g a case -b y -case e val uati o n a n d disc ussi o n wit h 
t he D D T .  
T he i ncl usi o n a n d e x cl usi o n criteria f or recei pt of J NJ-6 4 2 8 1 8 0 2 test article  a n d f or recei pt of 
r D E N 3 Δ 3 0 c halle n g e are descri be d bel o w. If t here is a q u esti o n a b o ut t hese criteri a, t he i n vesti gat or 
m ust c o ns ult wit h t he dr u g de vel o p me nt tea m a n d res ol ve a n y iss ues b ef ore e nr olli n g a p artici pa nt i n 
t he st u d y. Wai vers are n ot all o we d.  
F or a disc ussi o n of t he st atistical c o nsi derati o ns of partici pa nt selecti o n, refer t o secti o n  9. 1 , Sa m pl e 
Size Deter mi nati o n.  
 
I ncl usi o n Criteri a  f or R ecei pt of J N J -6 4 2 8 1 8 0 2  Test Articl e  
Eac h p ote ntial partici p a nt m ust satisf y all of t he f oll o wi n g criteria t o recei v e t he J NJ-6 4 2 8 1 8 0 2 test 
article: 
 
1.  Male or fe m ale.  
2.  1 8 t o 5 5  years of a ge, i ncl usi ve, at ti me of scree ni n g.  
3.  Healt h y o n t he basis of p h ysical e xa mi nati o n, me dical hist or y, a n d vital si g ns perf or me d at 
scree ni n g. If t h ere are a b n or malities, t he partici pa nt ma y be i ncl u d e d o nl y if t he i n vesti gat or 
j u d ges t he a b n or malities t o be n ot cli nicall y rele va nt. T his deter mi nati o n m ust be rec or de d i n 
t he partici pa nt's s o urce d oc u me nts.  
4.  Healt h y o n t he basis of cli nical la b orat or y tests perf or me d at scree ni n g. A b n or malities i n 
la b orat or y tests will be gra de d acc or di n g t o t he m o difie d U S F D A To xicit y Gra di n g Scale 
(secti o n 1 3. 1 ). Partici pa nts wit h la b orat or y a b n or malities of Gra de 1, e xce pt A S T/ A L T tests, 
ma y be i ncl u de d o nl y if t he i n vesti gat or j u d ges t he a b n or malities or de viati o ns fr o m n or mal t o 

CI R 3 3 2  
 
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be n ot c li nicall y rele va nt. Assess me nt of re n al t o xicit y will be ma de usi n g t he creati ni ne val ue 
a n d n ot t he e G F R i n t he t o xicit y ta ble.  
5.  M ust pass t he c o m pre h e nsi o n 
assess me nt i n dicati n g t hat t he partici pa nt u n dersta n ds t he 
p ur p ose, pr oce d ures, a n d p ote ntial ris ks  a n d be nefits of t he st u d y, after rea di n g t he i nf or me d 
c o nse nt a n d after t he i n v esti gat or or desi g nee h as pr o vi de d detaile d i nf or mati o n o n t he st u d y 
a n d a ns were d t he p ote nti al partici pa nt’s q uesti o ns.  
6.  M ust ha ve a b o d y mass i n de x ( B MI , wei g ht i n k g di vi de d b y t he s q uare of hei g ht i n meters) 
bet wee n 1 8. 0 a n d 3 5 . 0 k g/ m2, e xtre mes i ncl u de d. 
7.  M ust ha ve a n or m al 1 2 -l ea d E C G at s cree ni n g ( m ac hi ne rea d a n d/ or ass esse d b y i n vesti gat or 
or car di ol o gist), i ncl u di n g n or mal si n us r h yt h m ( heart rate b et wee n 4 5 a n d 1 0 0  beats per mi n ute 
[ b p m], e xtre m es i ncl u de d), Q Tc F [1 7 ] ≤4 5 0 ms f or male partici pa nts a n d ≤4 7 0 ms f or fe mal e 
partici pa nts, Q R S i nter val < 1 1 0 ms, a n d P R i nter val ≤2 2 0 ms. If t h e res ults of t he E C G are 
o utsi d e t he n or mal ra n ges, t he partici pa nt m a y be i ncl u de d o nl y if t he i n v esti gat or j u d ges t he 
de viati o ns fr o m n or mal t o be n ot cli nicall y rele va nt. T his deter mi nati o n m ust be rec or de d i n 
t he partici pa nt's s o urce d oc u me nts a n d i nitiale d a n d date d b y t he i n vesti gat or. 
8.  M ust ha ve a bl o o d press ure (after t he partici pa nt is s u pi ne f or ≥5 mi n utes) bet wee n 9 0 a n d 
1 4 0  m m H g s yst olic, e xtre mes i ncl u de d, a n d ≤9 0 m m H g diast olic at scree ni n g. T w o re p eat 
meas ure me nts are all o we d i n t he a bse nce of a n y ot her c o ncer ni n g healt h sc ree ni n g iss ues. 
9.  M ust c o m plete t he i nf or me d c o nse nt pr ocess i n de pe n de ntl y a n d wit h o ut assista nce a n d si g n a n 
i nf or me d c o nse nt f or m (I C F) i n dicati n g t hat he or s he u n dersta n ds t he p ur p ose of, a n d 
pr oce d ures re q uir e d f or, t he st u d y a n d is willi n g t o partici pa te i n t he st u d y.  
1 0.  All  pers o ns  of c hil d beari n g p ote ntial m ust ha ve a ne gati ve hi g hl y se nsiti ve ser u m ( β -h u ma n 
c h ori o nic g o na d otr o pi n) pre g na nc y t est at scree ni n g . 
1 1.  A v ol u nteer m ust be (as defi ne d i n  secti o n 1 3. 2 , A p pe n di x  2 : C o ntrace pti ve a n d Barrier 
G ui da nce ) 
a. 
N ot of c hil d beari n g p ote ntial , or  
b.  Of c hil d beari n g p ote n tial a n d practici n g a hi g hl y effecti ve, prefera bl y user i n de pe n de nt 
met h o d of c o ntrace pti o n a n d a grees t o re mai n o n a hi g hl y effecti ve met h o d w hile recei vi n g 
st u d y dr u g a n d u ntil 9 0 da ys after t h e last d ose - t h e e n d of rele va nt s yste mi c e x p os ure. 
c. 
N ote : T he i nteracti o n bet wee n J NJ -6 4 2 8 1 8 0 2 a n d h or m o ne -base d c o ntrace pti ves has n ot 
bee n assesse d. T he effi cac y of h or m o ne -base d c o ntrace pti ves ma y b e decreas e d w he n 
c o-a d mi nistere d wit h J NJ -6 4 2 8 1 8 0 2 a n d t heref ore a pers o n of c hil d beari n g p ote ntial  usi n g 
h or m o ne -base d c o ntr ace pti ves 
m ust use a n a d diti o nal, barrier -base d c o ntrace pti ve 
met h o d . 
1 2.  A pers o n of c hil d beari n g p ote ntial  m ust a gree n ot t o d o nate e g gs ( o va, o oc yt es) f or t he p ur p os es 
of assiste d re pr o d ucti o n d uri n g t he st u d y a n d f or 9 0 da ys after t h e last d ose of st u d y dr u g.  
1 3.  D uri n g t he st u d y a n d f or 9 0 da ys after t he last d ose of st u d y dr u g, pers o ns w h o are ha vi n g 
se x ual rel ati o ns hi ps i n w hic h t heir part ner m a y b ec o me pre g na nt m ust wear a c o n d o m w he n 
e n ga gi n g i n a n y acti vit y t hat all o ws f or passa ge of e jac ulate t o a n ot her p ers o n. Pers o ns w h o are 

CI R 3 3 2  
 
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ha vi n g se x ual relati o ns hi ps i n w hic h t h eir part ner ma y bec o m e pre g na nt  s h o ul d als o be a d vise d 
of t he be n efit f or t heir p art ner t o use a hi g hl y effecti ve met h o d of c o ntr ace pti o n as c o n d o ms 
ma y brea k or lea k.  
1 4.  A s per m-pr o d uci n g  partici pa nt m ust a gree n ot t o d o nate s per m f or t he p ur p ose of re pr o d ucti o n 
d uri n g t he st u d y a n d f or 9 0 da ys after t h e last d ose of st u d y dr u g.  
1 5.  M ust be willi n g a n d a ble t o a d here t o t he st u d y re q uire me nts a n d lifest yle restricti o ns s pecifie d 
in t he pr ot oc ol.  See secti o n 5. 1. 1 , bel o w f or det ails o n lifest yle c o nsi derati o ns.  
1 6.  A vaila ble f or t h e d urati o n of t he st u d y, w hic h is a p pr o xi matel y 8 5 da ys  aft er c halle n g e. 
N ote:  Retesti n g of a b n or mal val ues t h at ma y lea d t o e x cl usi o n will be all o we d per PI’s discreti o n . 
Retesti n g t o re place l ost sa m ples or br o ke n t u bes is per mitte d. Retesti n g will be perf or me d d uri n g a n 
u nsc he d ule d visit wit hi n t he scree ni n g p hase ( wit hi n 6 0  or 1 4 da ys bef ore first d ose of st u d y dr u g, as 
a p pr o priate). Partici pa nts wit h a n or mal or n o n-cli nicall y si g nifica nt val ue (<  Gra de 1 , e xce pt f or 
A L T/ A S T ) at retest ma y be i ncl u de d.   
5. 1. 1  Lifest yle C o nsi der ati o ns f or J N J -6 4 2 8 1 8 0 2  
P ote ntial partici pa nts m ust be willi n g a n d a ble t o a d here t o t he f oll o wi n g lifest yle restricti o ns d uri n g 
t he st u d y t o be eli gi ble f or partici pati o n: 
1.  Refer t o secti o n 7. 2 1 , C o nc o mita nt T hera p y f or details re g ar di n g pr o hi bite d a n d restrict e d 
t hera p y d uri n g t he st u d y. 
2.  A gree t o f oll o w all re q uire me nts t hat m ust be met d uri n g t he st u d y as n ote d i n t he I n cl usi o n 
a n d E xcl usi o n Criteria.  
3.  U n us ual stre n u o us e xer cise ma y affect st u d y -s pecifie d assess me nts a n d safet y la b orat or y 
res ults; f or t his reas o n, u n us ual stre n u o us e xercis e (as ass esse d b y t he i n v esti gat or) s h o ul d be 
a v oi de d fr o m ≥4 d a ys bef ore first d ose of st u d y dr u g ( Da y -9) u ntil 3 0 da ys after last d os e o f 
st u d y dr u g ( Da y 5 1). 
4.  M ust n ot d o nate bl o o d or bl o o d pr o d ucts d uri n g t h e st u d y or wit hi n 6 m o nt hs after l ast d ose of 
st u d y dr u g. 
5.  M ust n ot partici pate i n a n ot her i n vesti gati o nal st u d y  wit h t he e xce pti o n of a C O VI D 1 9 vacci n e 
st u d y d uri n g t he st u d y or wit hi n 9 0 da ys after last d ose of st u d y dr u g.  
6.  M ust n ot tra vel t o a n y d e n g ue -e n d e mic re gi o n (as defi ne d b y t he U nite d States Ce nters f or 
Disease C o ntr ol a n d Pre v e nti o n  [ C D C] [1 8 ]).  
7.  M ust li mit t he use of f o o d or dri n ks/ be vera ges c o ntai ni n g alc o h ol t o t he a bs ol ute mi ni m u m 
fr o m 1 da y ( Co h ort 1)  or 4 8 h o urs  ( Co h ort 2)  bef ore first d ose of st u d y dr u g ( Da y -6  f or 
C o h ort  1 a n d Da y -4  f or C o h ort 2) u ntil Da y 8 5 .  
a. It is reco m me n de d t o n ot use alc o h ol fr o m scree ni n g u ntil t he St u d y Da y 2 5 f oll o w -u p 
visit.  

CI R 3 3 2  
 
5 1  
 
b.  H o we ver, i f a n y alc o h ol is c o ns u me d , u p t o 2 sta n dar d dri n k c o ns u m pti o ns dail y will 
be all o we d. A sta n d ar d dri n k is defi ne d as a 3 5 0 m L glass of 5 % alc o h ol -b y -v ol u me 
( A B V) beer, a 1 5 0  m L glass of 1 2 % A B V wi n e, or a 4 5 m L glass of 4 0 % A B V 
( 8 0 pr o of) s pirit.  
8.  M ust refrai n fr o m c o ns u m pti o n of gra pefr uit or gra pefr uit j uice fr o m 7 d a ys bef ore first d ose 
of st u d y dr u g  (Da y -1 2  [C o h ort 1 ] a n d Da y -9  [C o h ort 2 ]) u ntil Da y 8 5 .  
9.  M ust refrai n fr o m all use of e ner g y dri n ks a n d a v oi d e xcessi ve use of caffei ne fr o m 4 8  h o urs 
bef ore first d ose of st u d y dr u g  ( m or ni n g of Da y -7  f or C o h ort 1 a n d Da y -4 f or C o h ort 2 ) u ntil 
Da y 8 5 . 
a. H o we ver, l i mite d use of caffei nate d m et h yl xa nt hi nes (e g, c offee, tea, c ola, a n d 
c h oc olate) is all o we d ( ≤5 0 0 m g/ da y, as c o ntai ne d i n 5 c u ps of tea or c offee or 8 ca ns of 
c ola).  
1 0.  Ma y n ot use dr u gs of a b use (i ncl u di n g a m p heta mi ne, bar bit urate, c o cai n e, met ha d o ne, a n d 
o piates) u ntil 3 wee ks after t he last d ose of st u d y dr u g.  
1 1.  S h o ul d n ot c o ns u me a n y f o o d c o ntai ni n g p o p p y see ds or c o dei ne -c o nt ai ni n g f or m ulati o n 
starti n g 7 2 h o urs bef ore t he scree ni n g visits a n d bef ore a n y visit d uri n g t he f oll o w -u p p hase (t o 
a v oi d a false -p ositi ve uri ne dr u g test).  
1 2.  C o h ort 1: S h o ul d f oll o w t h e restricti o ns o n f o o d a n d water i nta ke a n d t he i nstr ucti o ns f or t he 
ti mi n g of t he sta n dar dize d meals pr o vi de d d uri n g i nte nsi ve P K sa m pli n g (refer t o T a ble 3 ). 
C o h ort 2: T he st u d y i nter ve nti o n is t o be ta ke n i n fe d c o n diti o ns, ie, wit hi n 3 0 mi n utes after t he 
start of t he partici pa nt’s re g ular meal or s nac k , as a p plica ble. D uri n g o nsite visits u p t o D a y 2 1 
a sta n dar dize d meal will be pr o vi de d a ma x i m u m of 3 0  mi n ut es pri or t o d osi n g. T he ti me of 
t he meal will be rec or de d i n t he e C R F. 
 
E xcl usi o n Criteri a  f or Recei pt of J N J -6 4 2 8 1 8 0 2 Test Articl e  
A n y p ote ntial partici pa nt w h o meets a n y of t h e f oll o wi n g criteria will be e xcl u de d fr o m partici pati n g 
i n t he st u d y: 
1.  Hist or y of li ver or re nal i m pair me nt ( creati ni ne n or mal ra n g es ; si g nifica nt car di ac, v asc ular, 
p ul m o nar y, gastr oi ntesti nal (s uc h as si g nifica nt di arr hea, gastri c stasis, or c o nsti pati o n t hat i n 
t he i n vesti gat or’s o pi ni o n c o ul d i nfl ue n ce dr u g a bs or pti o n or bi oa vaila bilit y  [e g, c o nsti pati o n 
lasti n g > 2 da ys]), e n d ocri ne, ne ur ol o gic, h e mat ol o gic, r he u mat ol o gic, n e o plastic, a ut oi m m u ne, 
or meta b olic dist ur ba nces.  
2.  K n o w n aller gies, h y pers e nsiti vit y, or i nt olera nce t o J NJ -6 4 2 8 1 8 0 2 or its e xci pie nts (refer t o t he 
I B f or J NJ-6 4 2 8 1 8 0 2), or a na p h yla xis or a n gi oe de ma f oll o wi n g J NJ -6 4 2 8 1 8 0 2 a d mi nistrati o n.  
3.  Hist or y of a se vere aller gic reacti o n or a na p h yla xis.  
 
4.  Ta ke n a n y disall o we d t hera pies as n ote d i n secti o n 7. 2 1 , C o nc o mita nt T hera p y bef ore first d ose 
of st u d y dr u g.  

CI R 3 3 2  
 
5 2  
 
5.  Recei ve d a n i n vesti gati o nal i nter ve nti o n (i ncl u di n g i n vesti gati o nal vacci nes) or use d a n 
i n vasi ve i n vesti gati o nal me dical de vice wit hi n 6 m o nt hs bef ore first d ose of st u d y dr u g, or is 
c urre ntl y e nr olle d i n a n i n vesti gati o nal st u d y, or is pla n ni n g t o be e nr olle d i n a n i n vesti gati o nal 
st u d y wit hi n 9 0 da ys after last d ose of st u d y dr u g. Wit h t he e xce pti o n of 
partici pati o n i n 
C O VI D -1 9 vacci ne tr ials a n d/ or recei pt of C O VI D-1 9 vacci ne s lice ns e d or u n der E mer ge n c y 
Use A ut h ori zati o n  (E U A ) w hic h ca n b e recei v e d at a n y ti me . 
6.  Pers o ns of c hil d beari n g p ote ntial o nl y: Pre g na nt as deter mi ne d b y a p ositi ve -h u ma n c h ori o nic 
g o na d otr o pi n test, breastfee di n g, or pla n ni n g t o b ec o me pre g na nt d uri n g t he st u d y or wit hi n 
9 0  da ys after l ast d ose of st u d y dr u g.  
7.  Pla ns t o i m pre g nate a n d hel p c o ncei ve a c hil d d uri n g t he st u d y or wit hi n 9 0 da ys after last d ose 
of st u d y dr u g.  
8.  A n y c o n diti o n f or w hic h, i n t he o pi ni o n of t he i n vesti gat or, partici pati o n w o ul d n ot be i n t he 
best i nterest of t he partici pa nt (e g, c o m pr o mise t he well -bei n g) or t hat c o ul d pre v e nt, li mit, or 
c o nf o u n d t he pr ot oc ol -s p ecifie d ass ess me nts. 
9.  Bl o o d  test c o nfir mi n g c urre nt i nfecti o n wit h h u ma n i m m u n o deficie nc y vir us t y pe 1 or 2 ( HI V-
1 or HI V -2), he patitis B vir us ( H B V), or he p atitis C vir us ( H C V) . 
1 0.   C o h ort 1: B l o o d test c o nfir mi n g past or c urre nt i nfecti o n wit h or vacci nati o n f or a n y of t he 
f oll o wi n g fla vi vir uses: D E N V or  Zi ka vir us ( ZI K V ). 
C o h ort 2:  B l o o d test c o nfir mi n g past or c urre nt i nf ecti o n wit h a n y of t he f oll o wi n g fla vi vir uses: 
D E N V , Zi ka vir us ( ZI K V ), West Nile vir us, or S L E vir us  or hist or y of vacci nati o n (lice nse d 
or e x peri me nt al) f or d e n g ue, Zi ka v ir us, or Ja p a n ese E nce p halitis vir us (J EV ).  
N ote: Bl o o d la b orat or y testi n g will assess t he prese nce of a nti b o dies at scree ni n g.  
1 1.  Rece nt (i n t h e past 4 wee ks) tra vel t o a n y d e n g ue -e n de mic re gi o n (as defi ne d b y t he U S C D C ) 
or ha vi n g defi nite pla ns t o tra vel t o a de n g u e  e n de mic re gi o n  d uri n g t h e st u d y . P ote ntial 
partici pa nts ma y be eli gi ble f or e nr oll me nt ≥4 wee ks after t h eir ret ur n fr o m a de n g ue -e n de mic 
re gi o n. 
1 2.  Recei ve d  or pl a ns t o recei ve:  
d.  Lice nse d li ve atte n uat e d vacci nes - wit hi n 2 8 d a ys bef ore first d ose of st u d y dr u g u ntil 
2 8  da ys after l ast d ose of st u d y dr u g . 
e. 
Ot her lice nse d ( n ot li ve) vacci nes - wit hi n 1 4 da ys bef ore first d ose of st u d y dr u g u ntil 
1 4  da ys after l ast d ose of st u d y dr u g.  
f. 
C O VI D -1 9  vacci nes , eit her lice nse d or u n der E U A , are all o we d at a n y ti me d uri n g t he 
st u d y h o we ver e v er y eff ort will be ma de t o a v oi d t he a b o v e wi n d o ws of ti me of 
a d mi nistrati o n.  
N ote: V acci nati o ns a g ai nst D E N V a n d Zi ka vir us are n ot all o we d u ntil 9 0 da ys aft er last d os e 
of st u d y dr u g.  

CI R 3 3 2  
 
5 3  
 
1 3.  E m pl o yee of t he i n vesti gat or or st u d y site wit h direct i n v ol ve me nt i n t he pr o p ose d st u d y or 
ot her st u dies u n d er t h e directi o n of t hat i n vesti gat or or st u d y site, as well as fa mil y me m b ers 
of t he e m pl o yees or t h e i n vesti gat or.  
1 4.  A n y cli nicall y rel e va nt s ki n disease (as assess e d b y t he i n vesti gat or) i n t he past 6 m o nt hs , s uc h 
as acti ve der matitis, acti ve ecze ma, dr u g ras h, ps oriasis, , a n d urticaria.  
1 5.  Ha vi n g  d o nate d or l ost > 1 u nit of bl o o d ( 5 0 0 m L) wit hi n 3 0  da ys or > 1 u nit of plas ma ( 2 5 0  m L) 
wit hi n 7 da ys bef ore first d ose of st u d y dr u g  or ha vi n g t he i nte nti o n t o d o nate bl o o d or bl o o d 
pr o d ucts d uri n g t he st u d y a n d wit hi n 6 m o nt hs after last d ose of st u d y dr u g .  
1 6.  Recei pt of bl o o d pr o d ucts wit hi n t he past 6 m o nt hs  of i nitiati o n of st u d y dr u g , i ncl u di n g 
tra nsf usi o ns or i m m u n o gl o b uli n, or a ntici pate d recei pt of a n y bl o o d pr o d ucts or 
i m m u n o gl o b uli n d uri n g t he 2 8 da ys f oll o wi n g c halle n ge. 
1 7.  K n o w n  or s us pecte d c o n ge nital or ac q uire d i m m u n o deficie nc y  or u se of i m m u n os u p pressi ve 
c ortic oster oi ds (e xcl u di n g t o pical a n d n asal) or i m m u n os u p pressi ve dr u gs  wit hi n 2 8  da ys 
bef ore first d ose of st u d y dr u g  u ntil  2 8 da ys f oll o wi n g t he last d ose of st u d y dr u g.  
1.  A n i m m u n os u p pressi ve d ose of c ortic oster oi ds is defi ne d as ≥1 0 m g pre d nis o ne 
e q ui vale nt per d a y f or ≥1 4 da ys.  
1 8.  Use of a n y  str o n g c yt oc hr o me P 4 5 0 ( C Y P) 3 A 4  i n hi bit ors (e g, clarit hr o m yci n, itrac o naz ole), 
C Y P 3 A 4 i n d ucers (e g, p he n yt oi n, rifa m pi n), or s u bstrates f or C Y P 3 A 4 wit h a narr o w 
t hera pe utic ra n g e (e g, alf e nta nil, c ycl os p ori n ), U G T 1 A 9 i n hi bit ors or i n d u cers (e g, pr o be neci d, 
rifa m pi n, mefe na mic aci d), C Y P 2 C 8 (e g, re p a gli ni de), C Y P 2 C 9 (e g, warfari n, t ol b uta mi de) , 
B C R P (e g p ra vastati n, f olic aci d), or C Y P 2 C 1 9 (e g, S -me p he n yt oi n, o me praz ole) wit hi n 
1 4  da ys bef ore first d ose of st u d y dr u g. Certai n ot her me dicati o ns are all o we d i ncl u di n g 
metf or mi n, le v ot h yr o xi n e, H 1 a n d H 2 rece pt or a nt a g o nists, wea k C Y P 3 A 4 i n hi bit ors, selecti ve 
ser ot o ni n re u pta ke i n hi bit ors, selecti ve n ore pi n e p hri ne re u pt a ke i n hi bit ors, tric yclic a nti -
de pressa nts, a n xi ol ytics, a n d be nz o diaze pi nes . 
1 9.  A n y si g nifica nt alc o h ol or dr u g a b use i n t he past 1 2 m o nt hs t hat has ca use d m e dical, 
occ u pati o nal, or fa mil y pr o ble ms, as i n dicate d b y partici pa nt hist or y, or p ositi ve test res ult(s) 
f or  dr u gs of a b use (i ncl u di n g a m p heta mi ne, bar bit urate, b e nz o diaze pi ne, c o cai ne, met h a d o ne, 
a n d o piates) at scree ni n g.  
2 0.  Be ha vi oral, c o g niti ve, or ps yc hiatric disease t hat, i n t he o pi ni o n of t he i n vesti gat or, affects t he 
s u bject’s a bilit y t o u n dersta n d a n d c o o perate wit h t he re q uire m e nts of t he st u d y pr ot oc ol.  
2 1.  Se vere ast h ma (e me r ge n c y r o o m visit or h os pitalizati o n wit hi n t he last 6 m o nt hs). 
2 2.  As ple nia . 
2 3.  Ref usal t o all o w s peci me n st ora ge f or f ut ure researc h.  
 
2 4.  Hist or y of ris k fact ors f or T orsa des d e P oi ntes (e g, heart fail ure, h y p o kale mia, fa mil y hist or y 
of L o n g Q T S y n dr o me ). 
 

CI R 3 3 2  
 
5 4  
 
N O T E:  T he i n vesti gat or s h o ul d e ns ure t hat all st u d y e nr oll me nt criteria h a ve bee n met at scree ni n g. 
All a vaila ble cli nic al la b orat or y res ults a n d a n y ot her assess me nts p erf or me d i n bet wee n t he scree ni n g 
visits a n d first d ose of st u d y dr u g s h o ul d be ta ke n i nt o c o nsi derati o n bef ore e nr oll me nt. If a partici pa nt's 
cli nical stat us c ha n ges (i ncl u di n g a n y a vaila ble la b orat or y res ults or recei pt of a d diti o nal me dical 
rec or ds) after scree ni n g b ut bef ore first d ose of st u d y dr u g s uc h t hat he or s he n o l o n ger meets all 
eli gi bilit y criteria, t he n t h e partici p a nt s h o ul d n ot b e ra n d o mize d a n d s h o ul d n ot e nter t h e d osi n g p h as e.   
 
E xcl usi o n Criteri a f or r D E N 3 Δ 3 0  C h alle n ge  
Partici pa nts meeti n g a n y of t he f oll o wi n g criteri a at t he pla n ne d ti me of i n oc ulati o n wit h r D E N 3 Δ 3 0 
C hal le n ge will n ot be eli gi ble f or t he i n oc ulati o n a n d will be wit h dra w n fr o m t he st u d y  or c ha n ge d t o 
off treat me nt a n d f oll o we d f or safet y, base d o n t he i n vesti gat or’s discreti o n : 
1.  B o d y te m perat ure ≥3 8. 0° C  ( 1 0 0. 4° F), c o nfir me d b y re peat meas ure m e nts at least 1 0 mi n utes 
after t he first meas ur e me nt . 
 
2.  Ac ute ill ness . 
 
3.  A n y ot her cli nical or l a b orat or y fi n di n g t hat w o ul d e xcl u de t he p artici pa nt fr o m i n oc ulati o n 
(i ncl u di n g, b ut li mite d t o, a p ositi ve uri ne/ser u m pre g na nc y t est), as ass esse d b y t he 
i n vesti gat or.  
 
E arl y Disc o nti n u ati o n of St u d y Dr u g  
F or partici pa nts w h o disc o nti n ue st u d y dr u g pre mat urel y f or reas o ns ot her t ha n wit h dra wal of c o nse nt, 
a n earl y disc o nti n uati o n of st u d y dr u g  visit s h o ul d be s c he d ule d as s o o n as p ossi ble after d ecisi o n f or 
disc o nti n uati o n. D uri n g t he earl y disc o nti n uati o n of st u d y dr u g , assess me nts of t he Da y 1 5 ( C o h ort 2 
o nl y)/ 2 1 visit s h o ul d be perf or me d  wit h o nl y t he i nitial P K sa m ple t o be dra w n a n d wit h t he e xce pti o n 
of  d osi n g acti vit y . T he partici pa nts will t he n e nter t he 6 4 -da y f oll o w -u p p h ase.  
 
S u bject  Wit h dr a w al a n d Ter mi n ati o n Criteri a  
A s u bject will n ot be c o nsi dere d t o ha v e c o m plete d t he trial if a n y of t he f oll o wi n g a p pl y. H o we ver, 
a n y s u bject w h o has recei ve d J NJ-6 4 2 8 1 8 0 2 , rD E N 3 3 0,  o r place b o , will be e nc o ura ge d t o re mai n i n 
t he st u d y at t he discreti o n of t he i n vesti gat or a n d f oll o w t he g ui deli nes i n secti o n 5. 4  or at t he dis creti o n 
of t he i n vesti gat or . U p t o  7 partici pa nts i n C o h ort  1 a n d 6 partici pa nts i n C o h ort 2  ma y  be re place d if 
su bjects  are wit h dr a w n  pri or t o St u d y D a y 2 1.  
1. Rese arc h ter mi n ate d b y S p o ns or , D D T,  or I n vesti g at or  –  a p plies if t he e ntire st u d y is 
ter mi nate d b y t he s p o ns or, D D T,  or i n vesti gat or f or a n y reas o n.  
2. Wit h dr a w al of c o nse nt  –  a p plies t o a s u bject w h o wit h dra ws c o ns e nt t o partici pate i n t he 
st u d y f or a n y reas o n. 
3. N o nc o m pli a nt wit h pr ot oc ol  –  a p plies t o a  s u bject w h o d oes n ot or is n ot a ble t o c o m pl y 
wit h pr ot oc ol -s pecific visits or e val uati o ns o n a c o nsiste nt basis s uc h t hat a de q uate f oll o w -u p 
is n ot p ossi ble, a n d t he s u bject’s safet y a n d i nte grit y of t he st u d y data w o ul d be c o m pr o mise d 
b y c o nti n ui n g i n t he trial.  
4. Wit h dr a w n b y PI  –  ma y occ ur if t he i n vesti gat or belie ves t hat it is i n t he best i nterest of t he 
s u bject t o be wit h dra w n fr o m t he st u d y. 

CI R 3 3 2  
 
5 5  
 
5. Ot her  –  is a cate g or y use d w he n pre vi o us cate g ories d o n ot a p pl y a n d re q uires a n 
e x pla nati o n.  
 
S peci al  Sit u ati o ns : 
5. 6. 1  C orrecte d Q T ( Q Tc ) P r ol o n g ati o n  
If a cli nicall y si g nifica nt fi n di n g is i de ntifie d (i ncl u di n g, b ut n ot li mite d t o c ha n ges fr o m bas eli ne i n 
Q Tc F) after e nr oll me nt, t he i n vesti gat or or q u alifie d desi g nee will deter mi ne if t he partici pa nt ca n 
c o nti n ue i n t he st u d y a n d if a n y c ha n ge i n partici pa nt ma na ge me nt is nee de d. T his will be d oc u me nte d 
a p pr o priatel y i n t h e s o ur ce d oc u m e ntati o n.  A n y n e w cli nicall y rele va nt fi n di n g s h o ul d be re p orte d as 
a n A E. A partici p a nt w h o meets eit her of t he f oll o wi n g cri teri o n base d o n t he E C G rea di n gs will be 
wit h dra w n fr o m st u d y i nter ve nti o n  b ut will c o nti n ue t o be f oll o w e d fo r safet y.  
•  Q Tc > 5 0 0 msec  
•  C ha n ge fr o m bas eli ne of Q Tc > 6 0 ms ec  
5. 6. 2  Pre g n a nc y  
A n y s u bject w h o bec o mes pre g na nt d uri n g t he st u d y peri o d  will be e nc o ura ge d t o re mai n i n t he st u d y 
f or peri o dic safet y e v al uati o ns a n d will be f oll o we d u ntil c o m pleti o n of her pre g na nc y  a n d o ne 
a d diti o nal visit as nee de d t o o btai n pr e g na nc y o utc o me i nf or mati o n . T h e s u bject will be as ke d t o si g n 
a rel ease of m e dical i nf or mat i o n f or m s o t hat rec or ds ca n b e o btai n e d fr o m her o bstetrici a n re gar di n g 
t he o utc o me of t he pre g n a nc y.  
5. 6. 3  L ost t o F oll o w  U p  
A s u bject w h o is n ot reac ha ble b y t ele p h o ne or ot h er mea ns of c o m m u nicati o n a n d t heref ore n ot a ble 
t o be l oc ate d is c o nsi dere d l ost t o f oll o w -u p. A s u bject ma y be c o nsi dere d l ost t o f oll o w -u p a n d 
wit h dra w n fr o m t he st u d y o nce 3  d oc u me nte d  atte m pts ha ve bee n ma de t o c o ntact t he s u bject, f oll o we d 
b y n o nres p o nse t o a certifie d letter t o t he last k n o w n a d dress re q uesti n g t h at t he s u bject c o ntact t he 
cli nical site. 
5. 6. 4  I nc arcer ati o n 
I n t he e ve nt a s u bject bec o mes i ncarcerate d d uri n g t he st u d y, he or s he will be ta ke n off tr eat me nt f or 
t he d urati o n of his/ her i ncarcerati o n. He/s he ma y be ter mi nate d fr o m t he st u d y if t h e peri o d of 
i ncarcerati o n will pre v e nt t he s u bject fr o m ma ki n g t he sc he d ule d visits. 
5. 6. 5  Misse d d ose(s)  
•  Partici pa nts  t hat miss 1  d ose d uri n g t he L oa di n g D ose Peri o d ( Da y -5 t o Da y -1  f or C o h ort 1, 
a n d D a y -2 t o D a y -1 f or C o h ort 2 ) will nee d t o st o p t he st u d y tr eat me nt a nd be re place d. T he 
ne w partici pa nt will be assi g ne d t o t he sa me treat me nt as t he wit h dra w n s u bject t hat t he y 
re place. 
•  Partici pa nts , wit h t he e xce pti o n of wee kl y d osi n g i n C o h ort 2, t hat miss 2  c o nsec uti ve d oses 
d uri n g t he Mai nte na nce Peri o d ( Da y 1 t o Da y 2 1) will nee d t o st o p t he st u d y treat me nt a n d be 
re place d. T he ne w partici pa nt will be assi g ne d t o t he sa me treat me nt as t he wit h dra w n s u bject 
t hat t he y re place.  
•  F or p artici pa nts, wit h t h e e x c e pti o n of wee kl y d osi n g i n C o h ort 2,  t hat miss 2  d oses i n o ne 
wee k d uri n g t he Mai nte n a nce Peri o d ( Da y 1 t o Da y 2 1) , t he site nee ds t o c o ntact t he Ja nsse n 
Cli nical Researc h Ma na g er a n d t he s p o ns or i m me diatel y a n d t he Ja nsse n st u d y tea m will deci de 
o n a case -b y -case b asis w het her t he s u bject nee ds t o be re place d or ca n c o nti n ue.  
•  Partici pa nts recei vi n g w ee kl y d osi n g i n C o h ort 2 t hat miss a d ose d uri n g t he Mai nte n a nce 
Peri o d ( Da y 1 t o D a y 1 5) will nee d t o st o p t he st u d y treat me nt a n d be re place d. T he ne w 
partic i pa nt will be assi g n e d t o t he sa me treat me nt as t he wit h dra w n s u bject t hat t he y re place. 
 

CI R 3 3 2  
 
5 6  
 
F or i nf or m ati o n o n t he d osi n g wi n d o ws, please refer t o t he p har mac y ma n ual.  
 
Access t o Me dic al R ec o r ds  
T he me dical hist or y of a s u bject will be  o btai ne d fr o m t he s u bje ct a n d will be d oc u me nte d. Me dical 
rec or ds fr o m a n o utsi de i nstit uti o n ma y be re q uest e d t o verif y met h o d of c o ntrace pti o n a n d ma y als o 
be re q ueste d t o clarif y t h e s u bject’s me dical hist or y or clarificati o n of A Es  as nee de d. M e dical rec or ds 
fr o m a n o utsi de i nstit uti o n will n ot be re q ueste d wit h o ut t he me dical release f or m si g ne d b y t he s u bject. 
6  
St u d y Pr o d uct  Pre p ar ati o n  
 
J N J -6 4 2 8 1 8 0 2  Pre -d osi n g Pre p ar ati o n  
J NJ-6 4 2 8 1 8 0 2 is bei n g de vel o pe d b y Gl o bal P u blic Healt h, a d i visi o n of Ja nsse n P har mace utica N V., 
re pres e nte d b y Ja nsse n P har mace utica N V i n B el gi u m  a n d b y Ja nsse n Researc h a n d De vel o p m e nt, 
L L C  i n t he U nite d States. 
All J NJ-6 4 2 8 1 8 0 2
 m ust be st ore d at c o ntr olle d te m perat ures  as i n dicate d o n t he 
pr o d uct -s pecific la b eli n g. A n y te m perat ure e xc ursi o n m ust be re p orte d t o t he dr u g de vel o p me nt tea m 
wit hi n o ne b usi ness da y  of k n o wle d ge of t he e xc ursi o n. After e x p os ure t o a te m perat ure e xc ursi o n, t he 
will n ot be use d u ntil writte n a p pr o val ha s bee n gi ve n b y t he dr u g de vel o p me nt tea m. 
O n St u d y Da y -1  ( C o h ort 1) or St u d y Da y 1 ( C o h ort 2) , st u d y site p ers o n nel will i nstr uct partici p a nts 
of gr o u p 3 ( partici pa nts assi g ne d t o dail y d osi n g) o n h o w t o st ore st u d y dr u g f or at  h o me use.  
Refer t o t he p har mac y ma n ual/st u d y  -site i n vesti gati o nal pr o d uct a n d pr oce d ures ma n ual f or a d diti o nal 
g ui da nce o n J NJ-6 4 2 8 1 8 0 2  ha n dli n g a n d st ora ge.  
 
Pre -I n oc ul ati o n Pre p ar ati o n  
M o n o vale nt c halle n g e vir us f or t his pr ot oc ol will be st or e d at a NI AI D -c o ntracte d re p osit or y  u ntil  
re q ueste d b y t he cli nical site. Vials of fr oze n test a ge nt f or a d mi nistrati o n will be f or m all y re q u este d 
f or tra nsf er t o t he cli nical site b y t he PI/ desi g nee after I nstit uti o nal Re vie w B oar d (I R B) a p pr o val f or 
t he st u d y has b ee n gra nt e d a n d t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) has  b ee n i n recei pt of t he 
pr ot oc ol f or at least 3 0 da ys wit h o ut iss ui n g a cli nical h ol d. T he test a ge nt  ma y be tra nsferre d t o t he 
st u d y site pri or t o I R B a p pr o val a n d F D A re vie w o nl y f or t he p ur p ose  of deter mi ni n g t he titer of t he 
test a ge nt. 
 
After tra nsfer t o t he cli nical site, m o n o vale nt vir us will be st ore d i n a l oc ke d freezer at  -8 0° C ± 1 5° C 
u ntil ti me of use. Eac h vir us is s u p plie d as a c o nce ntrate t hat m ust be dil ute d wit h  Plas ma L yte A  
I nje cti o n p H 7. 4. t o t he pr o per d ose pri or t o a d mi nistrati o n . Plas ma L yte is a sterile, n o n p yr o ge nic 
is ot o nic i ntra ve n o us s ol uti o n f or i njecti o n. 
 
After t he t est a ge nt has b ee n pre pare d at t he cli nical site, a n ali q u ot of t ha we d, u n dil ute d (if  a v aila ble), 
a n d dil ute d test a g e nt will be titrate d. A d diti o nall y, t he test a ge nt m a y be titrate d  peri o dicall y t o e ns ure 
p ote nc y. T he I n vesti gati o nal Dr u g Ser vice  (I D S) p har m ac y  will be res p o nsi ble f or pre pari n g t h e 
c halle n ge. T he r D E N 3 3 0 c halle n ge will be pre pare d as  site-of -i njectio n f or m ulati o ns. Pri or t o 
i n oc ulati o n, t he PI/ desi g n ee will s u p pl y a prescri pti o n re q uest f or m t o t he I D S f or test a ge nt pre parati o n 
t hat will i ncl u de t he pr ot oc ol n u m ber, date of i n oc ulati o n, d ose, r o ute of a d mi nistrati o n, test a ge nt 
na me, test a g e nt l ot n u m ber,  test a ge nt titer (c o nce ntrati o n), i n vesti gati o nal ne w dr u g (I N D) n u m ber, 
a n d n u m ber of d os es t o  be a d mi nistere d.  
 
C CI
C CI

CI R 3 3 2  
 
5 7  
 
A d mi xt ure r D E N 3 3 0 ( 3. 3 l o g 1 0  P F U/ m L)  will be pre pare d acc or di n g t o t he site’s sta n dar d o perati n g 
pr oce d ures.  I D S staff will pre pare t he c orrect d os e of r D E N 33 0 f or eac h s u bject i n a bi osafet y h o o d 
usi n g ase ptic tec h ni q u e. Test a ge nts will be dil ute d wit h Plas ma L yte A, p H 7. 4  i ntra ve n o us s ol uti o n, 
U S P. T he dil ute d c halle n ge will be dra w n u p t o a  v ol u me of 0. 5 m L i n a  1 -m L s yri n ge a n d la bele d 
acc or di n g t o sta n dar d o perati n g pr oce d ures.  T he la bel e d s yri n ges will be tr a ns p orte d at r o o m 
te m perat ur e or o n wet ice t o t he cli nic f or a d mi nistrati o n. Test a ge nt m ust be use d wit hi n 6 h o urs of 
bei n g re m o ve d fr o m t he freezer or  refri gerat or.  
 
 
J N J -6 4 2 8 1 8 0 2 , D E N V-3 a n d Dil ue nt St or a ge  
J NJ-6 4 2 8 1 8 0 2  a n d place b o  
 will be st ore d refri gerat e d i n I n v esti gati o nal Dr u g 
Ser vices (I D S)  or at t he cli nic site w here t he a g e nt will be a d mi nistere d . J NJ-6 4 2 8 1 8 0 2 a n d place b o 
 will be st ore d a m bie nt i n I n vesti gati o nal Dr u g Ser vices (I D S) or at t he cli nic site 
w here t he a ge nt will be a d mi nistere d.  
 
T he r D E N 3 3 0 c halle n g e vir us  s h o ul d re mai n fr oze n at -8 0° C  ±  1 5° C u ntil j ust pri or t o use. Test 
a ge nts s h o ul d ne ver be  refr oze n f or re use i n test article pre parati o n. Plas maL yte will be st ore d per t he 
ma n ufact ur er’s  rec o m me n dati o n. C halle n ge vir us a n d dil ue nt c o m p o ne nts s h o ul d be o pe ne d fr o m ne w  
c o ntai ners f or eac h use. N o c o m p o ne nt s h o ul d be re use d f or f ut ure c ha lle n ge pre parati o n s. 
 
T he  c halle n g e vir us ca n n ot  be use d u ntil it is verifie d b y t he s p o ns or as acce pt a ble f or us e.  If t he 
s p o ns or dee ms t he c halle n ge vir us u n acce pta ble f or use, it will be q u ara nti ne d u ntil f urt her  dir ecti o ns 
fr o m t he s p o ns or are recei ve d. If a c h alle n ge vir us  is dee me d u nacce pta ble f or use, it will be dis p ose d 
of per t he s p o ns or’s i nstr ucti o n a n d a ne w s hi p me nt will be re q ueste d.  
 
If the J NJ-6 4 2 8 1 8 0 2 test article is dee me d u nacce pta ble f or use, it will be q uara nti ne d as per t he 
p har mac y m a n u al u ntil f urt her  directi o ns fr o m t he D D T  are recei v e d. If t he J NJ-6 4 2 8 1 8 0 2 test article  
is dee me d u nacce pta bl e f or use, it will be dis p ose d of per t he D D T’s  i nstr ucti o n a n d a ne w s hi p me nt 
will be re q ueste d.  
 
J N J -6 4 2 8 1 8 0 2 , D E N V-3 a n d Dil ue nt Acc o u nt a bilit y  
T he u n bli n de d dis pe nser pers o n nel will mai ntai n a n acc urate i n ve nt or y a n d acc o u nta bilit y rec or d  of 
eac h st u d y a ge nt f or t his st u d y. Partiall y use d vials of s t u d y a ge nt or dil ue nt  c o m p o ne nts will  n ot b e 
refr o ze n or re use d f or f ut ure i n oc ulati o ns. 
 
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all J NJ-6 4 2 8 1 8 0 2  recei ve d at t he st u d y site is 
i n ve nt orie d a n d acc o u nte d f or t hr o u g h o ut t he st u d y. T he J NJ-6 4 2 8 1 8 0 2  a d mi nistere d t o t he partici pa nt 
m ust be d oc u me nte d o n t he dr u g acc o u nta bilit y f or m.  
 
St or a ge  Dis p ositi o n of Use d/ U n use d S u p plies  
After t he u n bli n de d dis pe nser pers o n n el ha ve dil ute d t he c halle n g e vir us  a n d dra w n u p t he s yri n ges  f or 
a d mi nistrati o n, t he y wil l re m o ve t he la bel fr o m t he test a ge nt vial(s) a n d place o n t he test a g e nt 
pre parati o n f or m. I n t his ma n ner, m o nit ori n g pers o n nel will be a ble t o verif y t he  acc o u nta bilit y of all 
test a ge nt vials us e d f or t he st u d y. I n a d diti o n, t he n u m ber of test a g e nt vials use d will be acc o u nte d 
f or i n t he st u d y-s pecifi c dr u g acc o u nt a bilit y l o g. 
 
A n ali q u ot of u n dil ute d (if a vaila ble) a n d dil ute d r D E N 33 0 will be titrate d b y la b orat or y  p ers o n nel 
after t he c halle n g e vir us  has bee n pre pare d a n d d eli vere d t o t he cli nical staff. T his is d o ne t o  c o nfir m 
t he p ote nc y of t he test a g e nt a d mi nistere d t o t he s u bjects. 
C CI
C CI

CI R 3 3 2  
 
5 8  
 
 
At least 1 ali q u ot (if a vaila ble) of dil ute d r D E N 33 0 will als o be fr oze n a n d st ore d at -8 0° C ±  1 5° C at 
t he cli nical site f or f ut ure re-titrati o n if nee de d. After t he s yri n ges ha ve bee n dis pe nse d a n d ali q u ots 
re m o ve d f or titrati o n, a n y re mai ni n g test a ge nt will be destr o ye d b y t he la b orat or y pers o n nel per 
sta n dar d o perati n g pr oce d ures. A n y u n use d dil ue nt fr o m o pe ne d vi als/ b ottles will als o be destr o ye d.  
 
All J NJ-6 4 2 8 1 8 0 2  will be st ore d a n d dis p ose d of acc or di n g t o t he p har mac y ma n ual/st u d y -site 
i n vesti gati o nal pr o d uct a n d pr oce d ures ma n ual. St u d y-site pers o n nel m ust n ot c o m bi ne c o nte nts of t he 
J NJ-6 4 2 8 1 8 0 2  c o ntai ners.  
JNJ -6 4 2 8 1 8 0 2  m ust be h a n dle d i n strict acc or da n ce wit h t he pr ot oc ol a n d t h e c o ntai ner la bel, a n d m ust 
be st ore d at t he st u d y site i n a li mite d -access area or i n a l oc ke d ca bi net u n der a p pr o priat e 
e n vir o n me ntal c o n diti o ns.  U n use d J NJ-6 4 2 8 1 8 0 2  m ust be a vaila ble f or verificati o n b y t he s p o ns or’s 
st u d y-site 
m o nit or d uri n g o n-site 
m o nit ori n g visits. T he  ret ur n of u n use d st u d y dr u g  will be 
d oc u me nte d o n t he dr u g ret ur n f or m. W he n t he st u d y site is a ut h orize d t o destr o y pr o d uct  a n d J NJ-
6 4 2 8 1 8 0 2  s u p plies are destr o ye d o n site, t his m ust als o be d oc u me nte d o n t h e dr u g ret ur n f or m.  
J NJ-6 4 2 8 1 8 0 2  s h o ul d be a d mi nistere d u n der t he s u per visi o n of t he i n vesti gat or or a q ualifie d me m ber 
of t he st u d y -site pers o n nel. J NJ-6 4 2 8 1 8 0 2  will be a d mi nistere d o nl y t o par tici pa nts i n t he st u d y. J NJ-
6 4 2 8 1 8 0 2  ma y n ot be rel a bele d or reassi g ne d f or use b y ot her p artici pa nts.  T he i n vesti gat or a grees t o 
n ot st ore J NJ-6 4 2 8 1 8 0 2  at a n y site ot her t ha n t he st u d y site a gree d u p o n wit h t he D D T  a n d t o 
a d mi nister t he st u d y dr u g o nl y at  t he st u d y site. F urt h er g ui da nce a n d i nf or mati o n f or t he fi n al 
dis p ositi o n of u n use d J NJ-6 4 2 8 1 8 0 2  are pr o vi de d i n t he  p har mac y ma n ual/st u d y  site- i n vesti gati o nal 
pr o d uct a n d pr o ce d ures ma n ual.  
7  
St u d y  Pr oce d ures  
T he f oll o wi n g se cti o ns pr o vi de a detaile d lis ti n g of t he pr oce d ures a n d st u dies t o be p erf or me d i n t his 
pr ot oc ol at desi g nate d ti me p oi nts.  
 
Recr uit me nt  a n d Ge ner al Scree ni n g  
S u bjects ma y be recr uite d fr o m a variet y of s o urces i ncl u di n g, b ut n ot li mite d t o, s u bjects pre vi o usl y 
e nr olle d i n trials at t he cli nical sites, t he use of a ce nter -wi de I R B -a p pr o ve d scree ni n g pr ot oc ol, 
electr o nic me dical rec or d recr uit me nt messa g es, a n d/ or usi n g st u d y -s pecific I R B -a p pr o ve d pri nt, 
electr o nic a n d/ or ot her m e dia a d vertisi n g.  
 
After a n i nitial p h o ne s cree n ( usi n g a n I R B -a p pr o ve d P h o ne Scree n/I nitial C o ntact f or m) b y cli nic staff 
f oc use d o n pr o vi di n g bac k gr o u n d i nf or mati o n of t he trial a n d a re vie w of basic i n cl usi o n a n d e xcl usi o n 
criteria, a scree ni n g visit ma y be sc h e d ule d.  Sc h e d uli n g ma y occ ur ma n uall y ( via  p h o ne /te xt wit h 
staff), or via a HI P A A -c o m plia nt electr o ni c self -sc he d uli n g t o ol pr o vi de d b y J o h ns H o p ki ns 
U ni versit y .  
 
C o nse nti n g  Pr ocess  
D uri n g t he scr ee ni n g pr ocess, w hic h ma y re q uir e m ore t ha n 1 visit, t he s u bject will u n der g o a r o b ust 
i nf or me d c o nse nt pr ocess. At t he first scree ni n g visit, t he s u bjects ma y be pr o vi de d wit h a rea d-o nl y 
c o p y of t he i nf or me d c o nse nt f or m t o ta ke h o me wit h t he m. A d diti o na l materials ma y  i ncl u de a fact 
s heet relate d t o de n g ue disease a n d  fre q ue ntl y as ke d st u d y q uesti o ns ma y be pr o vi de d. We e nc o ura g e 

CI R 3 3 2  
 
5 9  
 
o ur s u bjects t o rea d t he c o nse nt f or m at h o me pri or t o c o mi n g t o t h eir fi nal s cree ni n g visit. At t his visit, 
t he s u bject will rea d t he c o nse nt f or m, be e nc o ura ge d t o as k q uesti o ns, a n d t he n c o m plete a 
c o m pre he nsi o n ass ess me nt. T h e c o m pre h e nsi o n assess me nt is desi g ne d t o test t he s u bject’s k n o wle d g e 
of t he m ost perti ne nt a n d i m p orta nt details a b o ut t he st u d y. T he s u bject m ust be a ble t o c o m plete t he 
i nf or me d c o nse nt pr ocess a n d c o m pre he nsi o n ass ess me nt  i n de pe n de ntl y a n d wit h o ut assista nce. Site 
s pecific c o nse nti n g d oc u me nts will be use d. S t u d y staff will re vie w a n d disc uss t he a ns wers fr o m t he 
assess me nt t o i de ntif y t h ose areas of t h e i nf or m e d c o nse nt f or m t hat nee d f urt her re vie w wit h t h e 
s u bject. T his r o b ust pr oce d ure will hel p e ns ure t hat t he s u bject has s uffi cie nt u n dersta n di n g of t he 
st u d y bef ore t he c o nse nt f or m is si g ne d. T he s u bject ma y eit her si g n t h e c o nse nt f or m d uri n g t he 
scree ni n g visit or ret ur n after f urt her c o nsi d erati o n. T he s u bject will be e nc o ura ge d t o as k q uesti o n s t o 
fa mil y, frie n ds, or a n y o n e else at h o m e if desir e d. T he s u bject will als o be pr o vi de d wit h a si g ne d c o p y 
of t he i nf or me d c o ns e nt. All st u d y -relate d pr oce d ures will occ ur o nl y aft er t he i nf or me d c o nse nt is 
si g ne d. 
 
Scree ni n g  Pr oce d ures  
Scree ni n g f or eli gi ble p artici pa nts will be perf or me d d uri n g o ne or m or e  scree ni n g visit bet wee n 
Da y  -6 5 a n d Da y  -6  f or C o h ort 1 , or Da y -6 2 a n d  Da y -3  f or C o h ort 2 . I n case t he first scree ni n g visit 
is pla n ne d t o ta ke pl ace wit hi n 1 4 da ys bef ore first d ose of st u d y dr u g, t h e sec o n d scree ni n g visit m a y 
n ot be  a p plica ble, a n d all scree ni n g assess me nts ma y  be perf or me d d uri n g o ne si n gle scree ni n g visit. 
If t here are t w o or m ore scree ni n g visits s o me of t h e ass ess me nts ma y be re peate d. A brief 
i ncl usi o n/e xcl usi o n criteria c heck is perf or me d at scree ni n g  a n d bef ore t he first d ose of st u d y dr u g o n 
Da y -5  ( Co h ort 1)  or Da y -2  ( Co h ort 2) . A n a b bre viate d e x cl usi o n criteri a c hec k will be perf or me d  
bef ore t h e c halle n g e o n St u d y Da y 1  per secti o n 5. 3  a b o ve. 
N ote: T he scree ni n g peri o d bet wee n t he first scree ni n g visit a n d t he first a d mi nistrati o n of st u d y dr u g 
ma y be pr ol o n ge d be y o n d 6 0 da ys f or a partici p a nt f oll o wi n g a case -b y -cas e e val uati o n a n d disc ussi o n 
wit h t he Ja nsse n D D T .  
S u bjects will u n der g o t he f oll o wi n g scree ni n g pr oce d ures b et wee n S t u d y Da y -6 5  a n d -6  f or C o h ort 1 , 
or  St u d y Da y -6 2 a n d D a y -3  f or C o h ort 2 :   
1.  E x plai n t he st u d y a n d I nf or me d C o nse nt pr ocess t o t he s u bject.  
2.  E ns ure t hat t he s u bj ect h as s uccessf ull y c o m plete d t he i nf or me d c o nse nt c o m pre he nsi o n 
assess me nt, has si g ne d t he i nf or me d c o ns e nt, a n d recei ve d a c o p y of t he si g ne d i nf or me d 
c o nse nt. T he c o m pre h e nsi o n assess me nt m ust be c o m p lete d i n de pe n de ntl y a n d wit h o ut 
assista nce.  
3.  O btai n de m o gra p hics . 
4.  C O VI D -1 9  scree ni n g q u esti o ns if re q uire d per facilit y a n d/ or l ocal g ui deli nes . 
5.  N as o p har y n geal ( N P) or mi d-t ur bi nate s wa b ma y be c ollecte d t o test f or S A R S-C o V 2 –  
t he vir us t hat ca us es C O VI D -1 9  will o nl y be c ollecte d bas e d o n g ui da nce fr o m fe d eral, 
state, l ocal, a n d/ or i nstit uti o nal healt h officials * or at t he discreti o n of t he cli nicia n.  
* T his g ui da nce ma y be i nf or me d b y t he l ocal C O VI D i n fecti o n rate, s e verit y of i nfecti o ns, 
vacci nati o n rates, a n d ot her fact ors as t he C O VI D -1 9 pa n de mic c o nti n ues t o e v ol ve a n d 
c ha n ge.  

CI R 3 3 2  
 
6 0  
 
6.  E ns ure t hat HI V pre -t est c o u nseli n g a n d HI V testi n g ha ve  bee n p erf or me d a n d 
d oc u me nte d ( wit hi n 1 4 d a ys of d osi n g ). 
7.  Elicit a  c o m plete me dical hist or y, i ncl u di n g me nstr ual a n d c o ntrace pti ve hist or y, hist or y 
of s ur gical sterilizati o n  f or all s u bjects.  
8.  Re vie w i ncl usi o n/e xcl usi o n criteria .  
9.  O btai n  hei g ht, b o d y wei g ht a n d B MI.  
1 0.  O btai n 1 2 lea d E C G, i deall y i n a s u pi ne p ositi o n after greater a n d or e q u al t o fi ve mi n utes 
rest i n a s u pi ne p ositi o n. E C Gs are rec o m me n de d t o be perf or me d bef ore vital si g ns a n d 
bl o o d dra w.  
1 1.  Perf or m a c o m plete p h ysical e xa mi nati o n  w hi c h i ncl u des a re vie w o f t he f oll o wi n g 
s yste ms: hea d/ nec k/t h yr oi d, e yes/ears/ n ose/t hr oat ; res pirat or y; car di o v asc ular; l y m ph 
n o des; a b d o me n; s ki n m usc ul os keletal ; a n d ne ur ol o gical. Breast, a n orect al, a n d ge nital 
e xa mi nati o ns will be perf or me d w he n me dicall y i n dicate d.  
1 2.   O btai n vital si g ns i ncl u di n g ( s yst olic a n d diast olic bl o o d press ure  a n d p ulse , b ot h o btai ne d 
i deall y w he n s u pi ne f or greater t ha n or e q u al t o 5 mi n utes rest); o btai n b o d y te m perat ur e i n 
a bse nce of a nti p yretic m e dicati o ns .  
1 3.  O btai n a p pr o xi matel y 1 5  m L of bl o o d f or t he f oll o wi n g la b orat or y scree ni n g tests:  
• 
C o h ort 1: pre vi o us fla vi vir us i nfecti o n  of D E N V or ZI K V   
• 
C o h ort 2: pre vi o us fla vi vir us i nfecti o n  of D E N V, ZI K V, West Nile vir us, a n d 
S L E V  
• 
H B V  
• 
H C V  
1 4.  O btai n ~ 1 5 .7  m L of bl o o d  f or t he f oll o wi n g la b orat or y scree ni n g tests:  
• 
C o m plete bl o o d c o u nt ( C B C) wit h differe ntial  
• 
C he mistr y pa nel  
i. S o di u m  
ii. P otassi u m  
iii. C hl ori de  
i v. Bicar b o nate  
v.  Bl o o d urea nitr o ge n ( B U N)  
vi.  Creati ni ne  
vii.  Gl uc ose  
viii.  Calci u m  
i x. P h os p hate  
x.  Al b u mi n  
xi.  T otal pr otei n  
xii.  T otal c h olester ol  

CI R 3 3 2  
 
6 1  
 
xiii.  A s partate a mi n otra nsferase ( AS T ) 
xi v.  A la ni ne a mi n otra nsferas e (A L T ) 
x v.  Ga m ma -gl uta m yltra nsferase ( G G T)   
x vi.  T otal bilir u bi n  
x vii.  Al kali ne p h os p hatase  
x viii.  Uric aci d  
xi x.  Hi g h -de nsit y li p o pr otei n ( H D L) c h olester ol  
x x.  L o w -de nsit y li p o pr otei n ( L D L) c h ol ester ol  
x xi.  Tri gl yceri des  
x xii.  M a g nesi u m  (C o h ort 1  o nl y )  
x xiii.  Li pase  
x xi v.  A m ylase  
• 
P r ot hr o m bi n ti me/ partial t hr o m b o plasti n ti me ( P T/ P T T) 
* A d diti o nal ser u m pre g na nc y tests ma y b e perf or me d, as deter mi ne d necessar y b y t he 
i n vesti gat or or re q uire d b y l ocal re g ul ati o n, t o esta blis h t he a bse nce of pre g na nc y at a n y ti me 
d uri n g t he st u d y.  
1 5.  O btai n uri ne s a m ple f or uri ne di pstic k testi n g ( gl u c ose, bilir u bi n, ket o nes, s pecific gra vit y, 
bl o o d, p H, pr otei n, ur o bili n o ge n, nitrite, le u k oc yte esterase ), if p ositi ve pr otei n will be 
deter mi ne d q ua ntiti vel y a n d t he se di me nt will be e xa mi ne d micr osc o picall y.  
1 6.  O btai n ser u m f or beta h u ma n c h ori o nic g o na d otr o pi n ( -H C G ) testi n g i n pers o ns of 
c hil d beari n g p ote ntial . Ser u m pre g na n c y will be perf or me d at i nitial scree n ( Da y -6 5 
t o -6  [C o h ort 1 ] or Da y -6 2  t o -3 [C o h ort 2 ]) a n d re peate d at su bse q u e nt  scree ni n g (if 
a p plica ble).   
1 7.  O btai n 3. 5  m L of bl o o d f or f ollicle-sti m ulati n g h or m o ne (F S H ) testi n g f or all partici pa nts 
wit h fe male re pr o d ucti ve or ga ns  w h o ha ve st o p p e d me nstr uati n g bet wee n 1 2 -2 4 m o nt hs 
c o nsec uti vel y b ut d o n ot ha ve d oc u me ntati o n , or if d oc u me ntati o n is u n o btai na ble, of 
o varia n  fail ure b y me dical rec or ds.  
1 8.  Ma y o btai n me dical release f or m t o c o nfir m met h o d of birt h c o ntr ol or d oc u me ntati o n of 
o varia n fail ure  (f or a p pli ca ble s u bjects). 
1 9.  C o u nsel pers o ns of c hil d beari n g p ote ntial  t o a v oi d bec o mi n g pre g na nt d uri n g t he st u d y. 
2 0.  Assess f or C o nc o mita nt T hera p y.  
• 
I n cas e pla n n e d first d os e of st u d y dr u g c oi nci d es wit h i nfl ue nza seas o n (t y picall y 
fr o m t he be gi n ni n g of Oct o ber u ntil Marc h/ A pril), vacci nati o n wit h a n i nfl ue nza 
vacci ne ≥3 3 d a ys bef ore c halle n ge ( Da y  -3 3) is str o n gl y e nc o ura g e d t h o u g h n ot a n 
eli gi bilit y criteri o n.  
• 
V acci n ati o n wit h a C O VI D -1 9  v acci ne ≥3 3 da ys bef ore c halle n g e ( Da y  -3 3) is 
str o n gl y e nc o ura g e d t h o u g h n ot a n eli gi bilit y criteri o n. 
2 1.  Ma y o btai n alc o h ol breat h test at t he discreti o n of PI/ pr o vi der.  

CI R 3 3 2  
 
6 2  
 
2 2.  O btai n a p pr o xi matel y 5  m L of bl o o d f or HI V -1 a n d HI V -2 testi n g ( will be perf or me d 
wit hi n 1 4 da ys of i nitiati o n of J NJ -6 4 2 8 1 8 0 2). Alter nati vel y, a ra pi d HI V t est ma y be us e d 
if a Cli nical La b orat or y I m pr o ve me nt A me n d me nts ( CLI A) wai ver has bee n gra nte d t o t he 
site. 
2 3.  O btai n uri ne t o xic ol o g y scree n i n g f or ‘ dr u gs of a b use’ i ncl u di n g b ut n ot li mite d t o testi n g 
f or a m p heta mi ne, b ar bit urate, be n z o diaze pi ne, c o cai ne, met ha d o ne, a n d o pi ates.   
 
 
Det aile d St u d y Pr oce d ures  
T he st u d y pr oce d ures t o be perf or me d at eac h visit are liste d bel o w. A d diti o nal tests ma y be  d o ne at 
t he discreti o n of t h e PI/ pr o vi der t o e val uate c o n c o mita nt ill ness or f urt her e val uate a n A E  e x p erie n ce d 
b y a s u bject.  
At eac h visit, v ol u nteers will be as ke d w het her or n ot t he y ha ve e x perie nce d a n y C O VI D -1 9 s y m pt o ms 
( per facilit y a n d/ or l ocal scree ni n g g ui deli nes) or if t he y ha ve ha d a n e x p os ure t o s o me o ne wit h 
C O VI D -1 9 pri or t o c o mi n g i nt o t he cli nic  ( per facilit y a n d/ or l ocal scree ni n g g ui deli nes). If t he 
v ol u nteer re p orts s y m pt o ms c o nsiste nt wit h C O VI D -1 9 a n d t he y are alrea d y e nr olle d i n t he st u d y, a n 
N P or mi d -t ur bi nate s wa b will be c ollecte d a n d teste d f or C O VI D-1 9 o n site or at t he res pecti ve l ocal 
la b orat or y. If t his is u na v aila ble, t he v ol u nteer will be referre d for l ocal testi n g. T he v ol u nteer will n ot 
c o me i nt o t he cli nic u ntil t he res ult is c o nfir me d t o be ne gati ve ( ~ 4 5 mi n utes) or per c urre nt facilit y 
g ui deli nes f or C O VI D -1 9 scree ni n g pr oce d ures. S h o ul d a v ol u nteer test p ositi ve f or S A R S -C o V -2 at 
a n y p oi nt d uri n g t he st u d y, t he v ol u nteer will be as ke d t o q uara nti ne acc or di n g t o c urre nt C D C 
g ui deli nes. We will re vie w c urre nt C D C g ui deli nes wit h t he v ol u nteer. We will defer all i n -pers o n 
visits u ntil after t he v ol u nteer has c o m plete d t heir q uara nti ne or if a C O VI D -1 9 p ositi ve researc h s pace 
is a vaila ble t he y will be br o u g ht t o t hat l ocati o n. 
 
P h ot o gra p hs ma y be ta ke n of t he i njecti o n site. I n  a d diti o n, p h ot o gra p hs ma y be ta ke n of ot her areas 
of t he s ki n bef ore a n d/ or after i n oc ul ati o n t o  rec or d t he c haract eristics of a n y ras h t hat ma y de v el o p. 
T o mai ntai n partici pa nt c o nfi de ntialit y, p ossi ble i de ntifiers, s uc h as t att o os,  je welr y, a n d cl ot hi n g will 
n ot be i ncl u de d i n t he p h ot o gra p hs  w he ne ver p ossi ble . All eff orts will be ta ke n t o n ot i de ntif y t he 
s u bject. At a n y p oi nt d uri n g t he st u d y partici pa nts  ma y ref use t o ha ve t heir p h ot o gra p h ta ke n, t his will 
n ot affect t heir e nr oll me nt stat us or c o m pe nsati o n .  
 
T he  t otal v ol u me of bl o o d t o be dra w n o ver t he 8-we e k p ost -i n oc ulati o n peri o d is a p pr o xi matel y 
5 0 0  m L, a little less t ha n d o nati n g a u nit of bl o o d. T his a m o u nt is wit hi n NI H g ui deli nes ( Me di cal 
A d mi nistrati ve P olic y 9 5 -9) f or a d ult bl o o d d o nati o n a n d s h o ul d n ot c o m pr o mise t he healt h of  st u d y 
s u bjects. T he t otal a m o u nt of bl o o d dra w n o ver t he d urati o n of t he st u d y is a p pr o xi matel y 6 8 0  m L  f or 
C o h ort 1 a n d 6 1 0 m L f or C o h ort 2 . A t o pical a nest hetic crea m ma y be us e d d uri n g bl o o d dra w at t he 
p hle b ot o mist’s discreti o n t o ease t he disc o mf ort of t he pr oce d ure.  
 
F or  st u d y visits wit h o verla p pi n g wi n d o ws f or t he visit, s u bjects will be sc he d ule d s o t hat t w o st u d y 
visits f or a n i n di vi d ual d o N O T occ ur o n t he sa m e da y.  
Ta ble  3 : Sc he d ule of Pr oce d ures –  C o h ort 1  
Scree n 5 
D osi n g St u d y D a ys (I n p atie nt visits  m ar ke d i n gr a y)  
 
F oll o w -u p St u d y D a ys
ure  
-6 5 t o -6  
-6  
-5  -4  
-3  
-2  
-1  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  1 1  1 2  1 3  1 4  1 5  1 6  1 7  1 8  1 9  2 0  
2 1  
2 3  2 5  2 9  3 6  4 3  5 0  5 7  
n Visit  
X  
X  
X  
X  
 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
all Visit  
 
 
 
 
X  
X  
 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
X  
 
X  
 
X  
 
X  
X  
 
 
 
 
 
 
 
 

CI R 3 3 2  
 
6 3  
Scree n 5 
D osi n g St u d y D a ys (I n p atie nt visits  m ar ke d i n gr a y)  
F oll o w -u p St u d y D a ys
ure  
-6 5 t o -6  
-6
-5
-4
-3
-2
-1
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  1 1  1 2  1 3  1 4  1 5  1 6  1 7  1 8  1 9  2 0  
2 1  
2 3  2 5  2 9  3 6  4 3  5 0  5 7  
e d C o nse nt  
X  
-1 9 scree ni n g 
ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
e vie w  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
i d -t ur bi nate 
wa b  
[ X]1 0  
[ X]1 0  
[ X]1 0
ht Sta y o n U nit  
X  
X  
r u g  Ta ke n   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
3 I n oc ulati o n  
X  
 e xa m  
X 6  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
e Me dical 
 
X  
o n of A Es  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
ita nt T hera p y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X *  
X *  
X *  
X *  
X *  
X *  
X *  
X *  
X *  
l ysis  
X 2  
X  
X  
X  
X  
X  
X  
X 1 3  
X  
X  
X  
X  
ti ve R T -P C R   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
ve R T -P C R  
X 3 
X  
X  
X  
X  
Assa y 
[X ] [X ] 
[X ] 
[X ] 
[X ] 
[ X] 
[ X] 
[ X] 
[ X] 
[ X] 
[ X] [ X] [ X] [ X] [ X] [ X] [ X] [ X] [
I S A  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
g M E LI S A  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
zi n g A nti b o d y  
X  
X  
X  
X  
X  
Pr otei n A nal ysis  
X  
X  
X  
X  
X  
X  
n o me 
i n g  
[X ] 
[X ] 
[X ] 
[X ] 
[X ] 
[X ] 
[ X] [X ] [X ] [X ] [ X] [ X] [ X] [ X] [
s olati o n  
X  
X  
X  
X  
A A nal ysis  
X  
X  
X  
X  
X  
X  
n ot y pi n g & 
c o ge n o mics  
X  
X  
X  
X  
X  
r y Pa nel 9 
X  
X  
X  
X  
X  
h differe ntial  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
C V, H B V  
X  
k v  scree ni n g 
X  
c y Test 1  
X  
X  
X  
X  
X  
st 1 1 
X  
is & Uri ne 
o g y Scree n 
X  
Breat h Test  
X 1 4  
 E C G8 
X  
X  
X  
X  
Aes = a d verse e ve nts; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; C B C = c o m plete bl o o d c o u nt; C M P = c o m pre he nsi ve meta b olic 
pa nel; E C G = electr ocar di o gra m; E LI S A = e nz y me -li n ke d i m m u n os or be nt assa y; F S H = f ollicle-sti m ulati n g h or m o ne; H B V = he patitis B vir us; H C V = 
he patitis C vir us; HI V = h u ma n i m m u n o deficie nc y vir us;  H L A = h u ma n le u k oc yte a nti ge n; N P = nas o p har y n geal; P B M C = peri p heral bl o o d m o n o n uclear 
cell; P K = p har mac o ki netics; P T/ P T T = pr ot hr o m bi n ti me/ partial t hr o m b o plasti n ti me ; R N A = ri b o n ucleic aci d; R T-P C R = re verse tra nscri pti o n p ol y merase 
c hai n reacti o n  
2 9.
Ser u m or uri ne pre g na nc y testi n g o nl y perf or me d  f or pers o ns  of c hil d beari n g p ote ntial ..
3 0.
O n S D -5: 7 P K sa m ples will be c ollecte d d uri n g 1 6 -h o ur wi n d o w . 
3 1.
Q ualitati ve R T -P C R will be perf or me d o n s a m ples c ollecte d o n D a ys 2 9, 3 6, 4 3, 5 0, 5 7, 6 3, 7 0, a n d 8 5.  If t he partici pa nt is D E N V-3 p ositi ve detecte d f or 
first ti me at Da y ≥2 9, q ualitati ve R T-P C R will be perf or me d t wice wee kl y ( prefer a bl y wit h 3 t o 4 d a ys i n bet wee n s a m ples) u ntil t he partici pa nt res ults are 
ne gati ve a n d u ntil res ol uti o n of D E N V i nfecti o n -ass ociate d Aes. Partici pa nts w h o are D E N V -3 p ositi ve o n Da y 8 5 s h o ul d ret ur n f or a d diti o nal cli nical a n d 
vir ol o gic assess me nts u ntil t he partici pa nt res ults are ne gati ve a n d u ntil res ol uti o n of D E N V i nfecti o n -ass ociate d Aes. A d diti o nal testi n g usi n g differe nt 
n ucleic aci d base d met h o ds f or t he detecti o n a n d/ or q ua ntificati o n of D E N V -3 ma y be perf or me d.
3 2.
P h o ne calls t o c ollect ti me of d ose, ti me of last f o o d, A E’s, a n d c o nc o mita nt t hera p y o n S D -3, -2, 2, 4, 6, 8, 1 0, 1 2, 1 3, 1 5, 1 7, 1 9, a n d 2 0.
3 3.
Scree ni n g ma y occ ur o ver m ulti ple visits. Certai n pr oce d ures m ust be perf or me d wit hi n differe nt ti me fra me relati ve t o d osi n g, see Secti o n 7. 1 . Scree ni n g 
wi n d o w is Da y -6 5 t o Da y -6.  
3 4.
A c o m plete p h ysical e xa m will be perf or me d at scree ni n g a n d o n Da y 8 5. At all ot her i n dicate d ti me p oi nts a f oc use d p h ysical e xa m will be perf or me d.
3 5.
[ X] Sa m ple will be c ollecte d, b ut test will o nl y be perf or me d if i n dicate d b y g ui deli nes i n t he pr ot oc ol.

CI R 3 3 2  
 
6 4  
 
3 6.  E C Gs are rec or de d pre -d ose  o n d osi n g d a ys . 
3 7.  C he mistr y pa nel c o nsists of s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, calci u m, p h os p hate, al b u mi n, t otal p r otei n, t otal c h olester ol, creati ni ne, gl uc ose, 
A S T, A L T, G G T, H D L c h olester ol, L D L c h olester ol, tri gl yceri des, ma g nesi u m, calc ulate d creati ne cleara nce ( b y M D R D), li pase, a m ylase, t otal  bilir u bi n, 
al kali ne p h os p hatase, uric aci d  
3 8.  Nas o p har y n geal ( N P) or mi d -t ur bi nate s wa b t o test f or S A R S-C o V 2 –  t he vir us t hat ca uses C O VI D-1 9 –  will be c ollecte d fr o m all v ol u nteers re gar dless of 
vacci nati o n stat us base d o n g ui da nce fr o m fe deral, state, l ocal, a n d/ or i nstit uti o nal healt h officials *  or at t he discreti o n of t he cli nicia n ( ma y be c ollecte d u p 
t o 7 2 h o urs i n a d va nce of state d c ollecti o n ti me). 
* T his g ui da nce ma y be i nf or me d b y t he l ocal C O VI D i nfecti o n rate, se verit y of i nfecti o ns, vacci nati o n rates, a n d ot her fact or s as t he C O VI D -1 9 pa n de mic 
c o nti n ues t o e v ol ve  a n d c ha n ge. N P or mi d -t ur bi nate s wa bs ma y be c ollecte d at ot her ti me-p oi nts if v ol u nteer has C O VI D -li ke s y m pt o ms.  
3 9.  F S H perf or me d o nl y i n fe males w h o ha ve st o p pe d me nstr uati n g f or > 1 2 c o nsec uti ve m o nt hs b ut < 2 4 m o nt hs. ( A n y o ne w h o has ha d a me n orr hea > 2 4 
c o nsec uti ve m o nt hs is c o nsi dere d p ost me n o pa usal a n d d oes n ot re q uire F S H).  
4 0.  I n partici pa nts w h o de vel o p a ras h, a n a d diti o nal sa m ple will be c ollecte d at o nset of ras h a n d teste d. N ote d o n t his c hart wit h a n asteris k { X * } 
4 1.  O n St u d y Da y 2 1: 6 P K sa m ples will  be c ollecte d d uri n g a 1 2 -h o ur wi n d o w  
4 2.  Alc o h ol breat h test ma y be perf or me d at t he discreti o n of PI/ pr o vi der u p o n a d missi o n t o i n patie nt u nit  
 
 

CI R 3 3 2  
 
6 5  
 
Ta ble 3  s u m marizes t he fre q ue nc y a n d ti mi n g of a nti viral acti vit y, P K, bi o mar ker, p h ar mac o ge n o mic, 
a n d safet y meas ure m e nts a p plica ble t o t his st u d y. Ta ble 4  pr o vi des t his i nf or mati o n f or C o h ort 2. 
A d diti o nal ser u m or uri ne pre g na n c y tests ma y be perf or me d, as det er mi ne d necessar y b y t he 
i n vesti gat or or re q uire d b y l ocal re g ulati o n, t o esta blis h t he a bse nce of pre g na nc y at a n y ti me d uri n g 
t he st u d y 
A d diti o nal N P or mi d -t ur bi nate s wa bs m a y be c ollecte d, as d eter mi ne d n ecessar y b y t he C O VI D -1 9 
scree ni n g q uesti o n naire t hr o u g h o ut t he c o urse of t he st u d y  a n d l ocal/facilit y scree ni n g g ui deli nes , t o 
esta blis h t he a bse nce of i nfecti o n wit h S A R S -C o V 2.  
 
S afet y Assess me nts  
Safet y a n d t olera bilit y will be e val uate d t hr o u g h o ut t he st u d y fr o m si g ni n g of t he I C F u ntil t he last 
st u d y-relate d acti vit y, or u ntil t he partici pa nt has b ee n d ee me d l ost t o f oll o w -u p aft er d e m o nstrati o n of 
d ue dili ge nce of f oll o w -u p eff orts.  
D E N V i nfecti o n -ass ociat e d A Es  will be meas ure d usi n g t he f oll o wi n g para meters: ti me t o res ol uti o n 
a n d se v erit y of t he D E N V i nfecti o n-ass ociate d A Es . T hese are d efi ne d as s yste mic reacti o ns a n d will 
be rec or de d as s olicite d A Es b y t he i n vesti gat or i n t he electr o nic case re p ort f or ms ( e C R Fs) (see T a ble 
1 3  f or c o m plete list). D E N V i nfecti o n -ass ociate d A Es will be m o nit ore d at eac h visit b y t he 
i n vesti gat or or desi g ne e as s olicite d A Es t o assess w het her i n patie nt a d missi o n criteria are m et (secti o n 
7. 1 8 ). B o d y te m perat ure will be rec or de d t wice dail y b y st u d y staff a n d/or b y t he partici pa nts fr o m 
Da y  1 u p t o a n d i ncl u di n g Da y 2 9 usi n g t he pr o vi de d t her m o meter a n d de n g ue me m or y e n ha nce me nt  
card. I n case of fe v er o n Da y 2 9, partici pa nts will be i nstr ucte d t o rec or d t h eir b o d y te m perat ure dail y 
u ntil res ol uti o n. Partici pa nts w h o re p ort D E N V i nfecti o n -ass o ciate d A Es o n or after Da y 2 9, will be 
i nstr ucte d t o ret ur n t o t he st u d y site f or a cli nical e val uati o n, safet y la b orat or y assess me nts, a n d 
q ualitati ve 
R T -P C R testi n g. I n case t he o bser ve d 
D E N V i nfecti o n -ass ociate d 
A Es, cli nical 
assess me nts, or de n g ue -s pecific la b orat or y para meters (ie, platelet c o u nt, w hite bl o o d cell c o u nt, 
pr ot hr o m bi n ti me, a n d  he mat ocrit) are >  Gra d e 2 i n se verit y, wit h or wit h o ut detecta ble D E N V -3 R N A, 
t he partici pa nt will be f oll o we d-u p o n a n o ut patie nt basis b y dail y tele p h o ne calls c o n d ucte d b y t h e 
st u d y-site pers o n nel u ntil res ol uti o n of t he D E N V i nfecti o n ass o ciate d - A Es.  De n g u e -s pecific 
la b orat or y para meters will be e val uate d u ntil d oc u me nte d res ol uti o n. 
T he st u d y will i ncl u de t he f oll o wi n g e val uati o ns of safet y a n d t olera bilit y acc or di n g t o t he ti me p oi nts 
pr o vi de d i n secti o n 7. 4 : 
•  
A E s 
•  
Cli nical la b orat or y tests  
•  
Vital si g ns  
•  
P h ysical e xa mi nati o n  
A n y cli nicall y rele v a nt c ha n ges occ urri n g d uri n g t he st u d y m ust be rec or de d i n t he A d verse E ve nt 
secti o n of t he case re p ort f or ms ( C R F ). 
 
A nti vir al Acti vit y Assess m e nts  
At ti me p oi nts s pecifie d i n  Ta ble 3  (C o h ort 1) a n d Ta ble 4  (C o h ort 2 ), bl o o d sa m ples will be o btai ne d 
f or meas ur e me nt of le v els of:  

CI R 3 3 2  
 
6 6  
 
•  
D E N V -3 R N A  
•  
V ire mia (ie, i nf ecti o us D E N V-3)  
•  
D E N V -3 N S 1 pr otei n  (re q uire d f or C o h ort 1 ; a nal ysis o pti o nal f or C o h ort 2 ) 
D E N V -3 R N A ser u m le vels will be assesse d usi n g a vali date d q ua ntitati ve D E N V -3 R T -P C R assa y . 
Q ualitati ve R T -P C R will als o be perf or me d . If t he partici pa nt is D E N V-3 p ositi ve  detecte d at D ay  ≥2 9  
i n C o h ort 1 , q u alit ative R T-P C R will be perf or me d t wice wee kly u ntil t he p artici p a nt res ults are 
ne g ative a n d u ntil res ol uti o n of D E N V i nfecti o n -ass oci ate d A Es.   
F or C o h ort 2, if a p artici p a nt is p ositive f or t he o n  D ay ≥2 5  ( or d ay 23  if d ay 2 5 n ot av ail a ble),  
a d diti o n al visit s o n D ay 2 7 a n d D ay 3 4 s h o ul d occ ur , me a ni n g 2 -3 d ays s a m pli n g  is re q uire d.  
Partici pa nts w h o are D E N V -3 p ositi ve b y  q ualitati ve R T -P C R  o n Da y 8 5 s h o ul d ret ur n f or a d diti o nal 
cli nical a n d vir ol o gic assess me nts u ntil t he partici pa nt res ults are ne g ati ve a n d u ntil res ol uti o n of 
D E N V i nfecti o n ass ociat e d A Es. A d diti o nal testi n g usi n g differe nt n uclei c aci d -bas e d met h o ds f or t he 
detecti o n a n d/ or q ua ntifi cati o n of D E N V -3 ma y be perf or me d. D E N V -3 vire mia will be deter mi ne d 
usi n g an  assa y f or i nfecti o us vir us q ua ntificati o n s uc h as a pl a q ue ass ay. I n a d diti o n, a nti viral acti vit y 
ma y 
be e x p l ore d b y assessi n g 
N S 1 pr otei n usi n g a n e nz y me-li n ke d i m m u n os or be nt assa y 
( E LI S A)-b ase d ass a y a n d/ or a n 
N S 1 test, 
w hic h are d esi g ne d f or p oi nt -of -care use (e g, 
i m m u n oc hr o mat o gra p h y-base d met h o ds). Det ails of t he ass ays use d will be pr ovi de d i n t he l a b or at o ry 
m a n u al . 
T he c ha n g es i n D E N V -3 V L will n ot be re p orte d as A Es or S A Es.  
Sa m ples ma y be use d b y t he s p o ns or f or a d diti o nal assess me nts a nal yzi n g t he ser ol o gic a n d vir ol o gi c 
c haracteristics of t he D E N V -3 i nf ecti o n a n d t he a nti viral acti vit y of t he st u d y dr u g, i ncl u di n g vir al 
ge n ot y pic a n d p he n ot y pi c assess me nts.  
 
P h ar m a c o ki netic Assess m e nts  
7. 7. 1  S a m ple C ollecti o n a n d H a n dli n g  
Ve n o us bl o o d sa m ples will be ta ke n f or meas ure me nt of plas ma c o nce ntrati o ns of J NJ -6 4 2 8 1 8 0 2 at 
t he ti me p oi nts i n dicate d i n Ta ble 3  (C o h ort 1) a n d Ta ble 4  ( C o h ort 2). A d diti o nal P K sa m pli n g ma y 
be perf or me d o n t he n o n -i nte nsi ve P K da ys (e g, i n t he e ve nt of a n o ver d ose) o n ot her ti me p oi nts, i n 
c o ns ultati o n wit h t he Ja nsse n dr u g de vel o p me nt tea m. T he  e xact dates a n d ti mes of bl o o d sa m pli n g 
m ust be rec or de d i n t he C R F or la b orat or y re q uisiti o n f or m.  
C o h ort 1: O n St u d y D a y -5 a n d Da y 2 1 , P K s a m ples will be c ollecte d wit hi n t he 2 h o urs pri or t o 
d osi n g wit h J NJ-6 4 2 8 1 8 0 2 as well as 1, 2, 4, 8, 1 2 , 1 6  (at st u d y da y -5 o nl y)  a n d 2 4  h o urs  (at st u d y 
da y -5 o nl y)  aft er d osi n g . O n all ot her st u d y da ys w here P K sa m ples are c ollect e d, a si n gle bl o o d 
c ollecti o n will occ ur pri or t o d osi n g wit h J NJ-6 4 2 8 1 8 0 2 . 
C o h ort 2  D ail y D osi n g : O n St u d y Da y -2 a n d Da y 2 1, P K sa m ples will be c ollecte d wit hi n t he 2 h o urs 
pri or t o d osi n g wit h J NJ-6 4 2 8 1 8 0 2 as well as 1, 2, 4, 8, a n d 1 2 h o urs after d osi n g. O n St u d y Da y -2, 
P K sa m ples will als o be c ollecte d 1 6 a n d 2 4  h o urs after d osi n g. O n all ot her st u d y da ys w here P K 
sa m ples are c ollecte d, a si n gle bl o o d c ollecti o n will occ ur pri or t o d osi n g wit h J NJ-6 4 2 8 1 8 0 2  (if 
a p plica ble).  

CI R 3 3 2  
 
6 7  
 
C o h ort 2 Wee kl y D osi n g:  O n St u d y Da y -2 a n d D a y 1 5, P K sa m ples will be c ollecte d wit hi n t he 
2  h o urs pri or t o d osi n g wit h J NJ-6 4 2 8 1 8 0 2 as well as 1, 2, 4, 8, a n d 1 2 h o urs after d osi n g. O n St u d y 
Da y -2, P K sa m ples will als o be c ollecte d 1 6 a n d 2 4  h o urs after d osi n g. O n all ot her st u d y da ys w here 
P K sa m ples are c ollecte d, a si n gle bl o o d c ollecti o n will occ ur pri or t o d osi n g wit h J NJ-6 4 2 8 1 8 0 2  (if 
a p plica ble).  
T he f oll o wi n g nee d t o be rec or de d i n t he C R F:  
C o h ort 1:  
•  Date a n d ti me of d osi n g wit h st u d y dr u g o n t he da y of t he P K bl o o d sa m pli n g.  
•  W het her st u d y dr u g was ta ke n wit h f o o d o n t he da y of P K bl o o d sa m pli n g.  
•  Date a n d ti me of last me al bef ore d osi n g wit h st u d y dr u g  o n t he da y of P K bl o o d sa m pli n g. 
•  Date a n d ti me of  t he first meal after d osi n g wit h st u d y dr u g o n Da y -5 a n d 2 1 .  
•  Date a n d ti me of last w at er i nta ke bef ore d osi n g wit h st u d y dr u g o n Da y  -5 a n d Da y 2 1.  
C o h ort 2 : 
•  Date a n d ti me  of  P K  bl o o d sa m pli n g 
•  Date a n d ti me of d osi n g wit h st u d y dr u g  
•  W het her st u d y  dr u g was ta ke n wit h f o o d  
•  Date a n d ti me of last me al bef ore d osi n g wit h st u d y dr u g  
7. 7. 2  P h ar m ac o ki netic A n al ysis  
Plas ma sa m ples will be a nal yze d t o deter mi ne c o nce ntrati o ns of J NJ -6 4 2 8 1 8 0 2 usi n g a vali date d, 
s pecific, a n d s e nsiti ve li q ui d c hr o mat o gra p h y-ta n de m mass s pectr o metr y ( L C -M S/ M S) met h o d u n der 
t he s u per visi o n of t he D D T’s  Bi oa nal ytical La b orat or y De p art me nt of Bi o a nal ysis.  
P har mac o ki netic sa m ples fr o m partici pa nts assi g ne d t o place b o (e xce pt f or sa m ples ta ke n pre -d ose o n 
Da y -5  [C o h ort 1 ] or Da y -2  [C o h o rt 2 ]) will n ot be a n al yze d u nl ess u ne x p ecte d res ults s h o ul d occ ur. 
All plas ma P K sa m ples fr o m partici pa nts recei vi n g J NJ -6 4 2 8 1 8 0 2 will be a nal yze d f or J NJ -6 4 2 8 1 8 0 2 
c o nce ntr ati o ns.  
T o all o w selecti o n of s a m ples, t he bi oa nal ytical la b orat or y will recei ve ra n d o mizati o n lists per 
treat me nt. U n bli n di n g of t he ra n d o mizati o n c o de will be perf or me d at t he bi oa nal ytical la b orat or y o nl y 
a n d will be s u bjecte d t o a pr oce d ure t hat will e ns ure t hat c o des will n ot be re veale d t o a n y o ne i n v ol ve d 
i n t he c o n d uct of t he st u dy.  N o o ne o utsi de of t he la b will ha ve access t o t his i nf or mati o n  u ntil t he 
st u d y is f ull y u n bli n de d. 
At t he D D T’s  discreti o n, plas ma sa m ples ma y be a nal yze d f or circ ulati n g m eta b olites usi n g a q u alifie d 
researc h met h o d. I n a d diti o n, plas ma P K sa m ples ma y be st ore d f or f ut ure e x pl orat or y a nal ysis of 
pr otei n bi n di n g, bi o mar kers, a n d t he met a b olite pr ofile.  
7. 7. 3  P h ar m ac o ki ne tic P ar a meters  
Base d o n t he i n di vi d ual plas ma c o nce ntrati o n -ti me data, usi n g t he act ual sa m pli n g ti mes (secti o n 9. 5 ), 
at least t he f oll o wi n g P K para meters will be der i v e d f or J NJ-6 4 2 8 1 8 0 2 :  

CI R 3 3 2  
 
6 8  
 
C o h ort 1:  
•  O n Da y -5: C ma x , tma x , A U Cτ a n d Ca v g. 
•  O n Da ys -4 t o Da y 2 0: C tr o u g h ( o n da ys w he n bl o o d sa m pli n g f or P K is c o n d ucte d). 
•  O n Da y 2 1: C tr o u g h, Cmi n , Cma x , tma x , A U Cτ, Ca v g, a n d FI. 
C o h ort 2  D ail y Re gi m e n : 
•  O n Da y -2: C ma x , tma x , A U Cτ a n d C a v g. 
•  O n Da ys -1 t o Da y 2 0: C tr o u g h ( o n da ys w he n bl o o d sa m pli n g f or P K is c o n d ucte d: -1, 1, 4, 8, 
1 1, 1 5, 1 8 ). 
•  O n Da y 2 1: C tr o u g h, Cmi n , Cma x , tma x , A U Cτ, Ca v g, a n d FI. 
C o h ort 2  Wee kl y Re gi me n : 
•  O n Da y -2: C ma x , tma x , A U Cτ a n d C a v g. 
•  O n Da ys -1 t o Da y 1 1 : Ctr o u g h ( o n da ys w he n bl o o d sa m pli n g f or P K is c o n d ucte d: -1, 1, 4, 8, 
1 1 ). 
•  O n Da y 1 5: C tr o u g h, Cmi n , Cma x , tma x , A U Cτ, Ca v g, a n d FI. 
F or t he P K para meters, d efi niti o ns a n d met h o ds of calc ulati o n are:  
•  
C ma x : ma xi m u m o bser ve d a nal yte c o n ce ntrati o n;  
•  
C mi n : mi ni m u m o bser ve d a nal yte c o n ce ntrati o n; 
•  
C tr o u g h: o bser ve d a nal yte c o nce ntr ati o n j ust bef ore t he be gi n ni n g or at t he e n d of a d osi n g 
i nter val; 
•  
C a v g: a vera ge a nal yte c o n ce ntrati o n o ver t he d osi n g i nter val (τ) calc ulat e d as A U Cτ/τ; 
•  
tma x : t he act ual sa m pli n g ti me t o reac h t he ma xi m u m o bser ve d a n al yte c o nce ntrati o n; 
•  
FI: perce nta g e fl uct uati o n ( variati o n) bet w ee n ma xi m u m a n d mi ni m u m a nal yte c o nce ntrati o n 
at stea d y-state, calc ulat e d as 1 0 0 x ([ C ma x  - C mi n ] / Ca v g); 
•  
A U C τ: area u n der t he pl as ma c o n ce ntrati o n -ti me c ur ve d uri n g t he d osi n g i nter val (t h o urs); 
calc ulate d b y li ne ar -li near tra pez oi dal s u m mati o n. 
Act ual sa m pli n g ti mes will be c hec ke d f or maj or a berrati o ns. I n case a maj or a berrati o n occ urs f or a n 
act ual sa m pli n g ti me of > 2 0. 0 0 % d e viati o n fr o m t h e sc he d ule d ti me, t his plas ma c o nce ntr ati o n will be 
e xcl u de d fr o m descri pti v e statistics i n t he plas ma c o nce ntr ati o n ta ble.  
 
I m m u ne Assess m e nts 
Bl o o d sa m ples f or t he ass ess me nt of h u m or al a n d cell ular i m m u ne res p o ns es will be c ollecte d fr o m all 
partici pa nts acc or di n g t o t he ti me p oi nts i n dicate d  i n Ta ble 3  (C o h ort 1) a n d Ta ble 4  ( C o h ort 2). 
Sa m ples c ollecte d f or i m m u n o ge nicit y a nal yses m a y a d diti o nall y be use d t o e val uate safet y or efficac y 
as pects t hat a d dress c o n cer ns arisi n g d uri n g or after t he st u d y peri o d. Ge netic a nal yses will n ot b e 
perf or me d o n t h ese sa m ples. Partici pa nt c o nfi de ntialit y will be mai ntai ne d.  

CI R 3 3 2  
 
6 9  
 
7. 8. 1  H u m or al I m m u ne Res p o nse  
Bl o o d sa m ples will be o btai ne d f or t he assess me nt of ser u m a nti b o d y res p o nses. A nti -D E N V -3 I g G 
a n d I g M a nti b o dies will be meas ure d usi n g E LI S A. T he prese n ce  of ne utralizi n g a nti b o dies a g ai nst 
D E N V ma y be d eter mi ne d usi n g a pla q ue re d ucti o n ne utralizati o n assa y  or fl o w c yt o metr y -bas e d ass a y 
usi n g sta n dar d la b orat or y pr ot oc ols. T he P R N T 5 0 is defi ne d as t he hi g hest dil uti o n of a nti b o d y t hat 
re d uces t h e nu m ber of f oci or pla q ues b y 5 0 %, c o m pare d t o t he pla q ue titer of t he vir us al o ne.  A nal ysis 
will be o pti o nal f or C o h ort 2.  
Ser u m sa m ples f or i n vi v o researc h (t o i n vesti gate p ote ntial J NJ -6 4 2 8 1 8 0 2 -s pecific I g E i n d uce d 
m yel oi d cell de gra n ulati o n) will be a na l yze d i n partici pa nts w h o de vel o p ras h d uri n g t he st u d y. 
Sa m ples will be c ollecte d  fr o m all partici pa nts pre d ose at Da y -5  f or C o h ort 1 , Da y -2  f or C o h ort 2 , 
a n d prec h alle n ge at D a y  1  f or b ot h c o h orts. I n partici pa nts w h o de vel o p ras h, t he sa m ple will be 
re peat e d w he n t he ras h is o bser ve d . 
7. 8. 2  Cell ul ar I m m u ne Res p o nse  
Peri p heral bl o o d m o n o n uclear cell ( P B M C) sa m ples ma y be a nal y ze d t o assess D E N V -3 -s pecific T 
a n d B cell i m m u ne res p o nses usi n g assa ys s uc h as e nz y me -li n ke d i m m u n os p ot assa y ( E LI S p ot) a n d/ or 
i ntracell ular c yt o ki ne stai ni n g (I C S) after sti m ulati o n wit h D E N V -3 -s pecifi c a nti ge ns. E LI S p ot detects 
T cells t hat secrete i nterfer o n g a m ma (I F N -γ) or B cells t hat secret e I g G a n d/ or I g M , w hereas I C S 
deter mi nes t he fre q u e nc y of C D 4 + a n d C D 8 + T cells secreti n g c yt o ki nes s uc h as I F N -γ, i nterle u ki n 
(I L)-2 a n d t u m or necr osis fact or ( T N F) -α.  
A d diti o nal e x peri me nts ma y be perf or m e d t o f urt her p he n ot y picall y a n d f u ncti o nall y c haracterize 
P B M Cs b y met h o ds s uc h as fl o w c yt o metr y, mass c yt o metr y ( C y T O F) , or si n gle cell tra nscri pt o mics 
t o e val uate i n nate a n d a da pti ve i m m u ne res p o nses. Left o ver P B M C sa m ples ma y be use d at t he 
s p o ns or's discreti o n f or a d diti o nal e x pl orat or y res earc h rel ate d t o D E N V i nfecti o n or J NJ-6 4 2 8 1 8 0 2  
(safet y/a nti viral a cti vit y).  
 
Bi o m ar ker Assess m e nts  
Bl o o d sa m pli n g f or bi o mar ker a nal yses will be perf or me d at t he ti me p oi nts i n dicate d i n Ta bl e 3  f or 
C o h ort 1 a n d Ta ble 4  f or C o h ort 2. 
Sa m ples f or h ost R N A mi g ht be use d f or tra nscri pti o nal pr ofili n g (e g, usi n g micr oarra y tec h n ol o g y). 
Ser u m sa m ples f or pr otei n a nal yses mi g ht be a nal yze d usi n g assa ys s uc h as E LI S A or L u mi ne x. 
Pr osta gla n di ns a n d le u k otrie nes ma y be meas ure d usi n g a n E LI S A.  
E xa m ples of a nal ytes t hat c o ul d be i n vesti gate d b y messe n ger R N A assess me nt a n d/ or pr otei n 
meas ure me nts i ncl u de, b ut are n ot l i mite d t o, i nterfer o n-sti m ulate d ge ne (I S G)-1 5, I L -2, I L -6, I L -8, 
I L-1 0, I L -1 2, I L -1 5, I L -1 8, T N F -α, I F N -γ, a n d c he m o ki ne ( C -X -C m otif) li ga n d 1 0 ( C X C L 1 0, als o 
referre d t o as i nterfer o n-i n d uci ble pr otei n-1 0).  
Sa m ples ca n o nl y be use d f or researc h relate d t o J NJ-6 4 2 8 1 8 0 2  or D E N V i nfecti o n or ma y be use d t o 
de vel o p tests/assa ys rel ate d t o J NJ-6 4 2 8 1 8 0 2  or D E N V i nfecti o n.   
 Vir al Ge n o me Se q ue nci n g  
Bl o o d sa m pli n g f or viral ge n o me se q ue nci n g a n al ysis will be perf or me d at t he ti me p oi nts i n dicate d i n 
Ta ble 3  f or C o h ort 1 a n d Ta ble 4  f or C o h ort 2. V iral ge n o me se q ue nci n g ma y be perf or me d if D E N V 
R N A -3 is p ositi ve c o nsi deri n g t he li mits of t he se q ue nci n g assa y.  

CI R 3 3 2  
 
7 0  
 
Se q ue nci n g of t he D E N V -3 ge n o me will be perf or me d t o m o nit or D E N V -3 vari a nts . Viral ge n o me 
se q ue nci n g a n al ysis will be perf or me d b y se q ue n ci n g t he N S 3 a n d N S 4 B ge ne s a n d ot her re gi o ns of 
t he D E N V-3 ge n o me (if warra nte d) t o c haracterize e mer gi n g D E N V -3 varia nts ass ociate d wit h 
resista nce t o J NJ-6 4 2 8 1 8 0 2 c o m pare d wit h t he se q ue nce of t he r D E N 33 0  strai n use d f or i n oc ulati o n. 
Partici pa nts w h o recei ve d J NJ -6 4 2 8 1 8 0 2 or place b o will be a nal yze d.  
Sa m ples ma y be use d b y t he s p o ns or f or a d diti o nal assess me nts a nal yzi n g t he ser ol o gic a n d vir ol o gi c 
c haracteristics of D E N V -3 i nf ecti o n a n d a nti viral acti vit y a n d safet y of J NJ -6 4 2 8 1 8 0 2, i ncl u di n g viral 
ge n ot y pic a n d p he n ot y pi c assess me nts.   
 H u m a n L e uk oc yte A nti ge n T y pi n g a n d P h ar m ac o ge n o mic E v al u ati o ns  
A bl o o d sa m ple f or H L A ge n ot y pi n g a n d f or p har mac o ge n o mic researc h will be c olle cte d at bas eli ne 
(ie, bef ore first d ose of st u d y dr u g), t o deter mi ne t he H L A t y pe of eac h partici pa nt a n d t o all o w t he 
i de ntificati o n of ge netic fact ors t hat ma y i nfl ue n ce t he P K, a nti viral acti vit y, or safet y/t olera bilit y of 
J NJ-6 4 2 8 1 8 0 2. H L A ge n ot y pi n g a n d p har mac o ge n o mic ( D N A) researc h 
ma y hel p t o e x plai n 
i nteri n di vi d ual varia bilit y i n cli nical o utc o mes a n d i de ntif y p o p ulati o n s u b gr o u ps t hat res p o n d 
differe ntl y t o a dr u g. Parti ci pati o n i n t he H L A t y pi n g a n d t he p h ar mac o ge n o mic researc h is ma n dat or y.  
T hes e a n al yses ma y b e c o n d ucte d u n der t he s u per visi o n of t he s p o ns or or D D T a n d ma y be re p orte d 
se parat el y fr o m t he mai n st u d y re p ort. If necessar y, t he sa m ple ma y be c ollecte d at a later ti me p oi nt 
wit h o ut c o nstit uti n g a pr ot oc ol de viati o n.  
 In oc ul ati o n  wit h r D E N 3 3 0  
T he D E N V -3  i n vesti gati o nal c halle n g e materi al is r D E N 3 Δ 3 0 ( L ot D E N 3 # 1 1 4 A) c o m p ose d of a 
c o nce ntr ati o n of li ve, rec o m bi na nt r D E N 3 Δ 3 0 Ver o Gr o w n Vir us Vacci ne, i n L -1 5 me di u m c o ntai ni n g 
1 X S P G. T he p ote nc y of r D E N 3 Δ 3 0 ( L ot  D E N 3  # 1 1 4 A) is 6. 1 l o g 1 0 P F U/ m L. S u bjects will recei v e 
r D E N 33 0 o n St u d y Da y 1.  T he li ve r D E N 3 3 0 vir uses will be ke pt fr oze n at -8 0° C ±  1 5° C u ntil j ust 
bef ore use, at w hic h ti me t he y will be t ha we d, dil ute d, a n d dra w n u p f or  a d mi nistrati o n. r D E N 3 Δ 3 0 is 
dil ute d wit h Plas ma -l yte A, p H 7. 4 i ntra v e n o us s ol uti o n, U S P t o t he fi nal c o nce ntrati o n of 3 l o g 1 0 
P F U/ 0. 5 m L i n a 1 -m L s yri n ge f or S C  i njecti o n. r D E N 33 0  will b e ke pt o n wet ice  fr o m t he ti me it is 
t ha we d or re m o ve d fr o m t he refri g erat or u ntil dil ute d wit h Plas ma -l yte i nt o its fi nal f or m ulati o n. It will 
t he n be d eli vere d at r o o m te m perat ur e or o n wet ice t o cli nical staff f or a d mi nistrati o n. A v ol u me of 
0. 5 m L of r D E N 3 3 0 will be deli vere d b y S C  i njecti o n i n t he delt oi d re gi o n of t he u p per ar m wit h a 
nee dle of a p pr o priate g a u ge a n d le n gt h after wi pi n g t he i njecti o n site wit h alc o h ol.  O n Da y 1, 
partici pa nts will be i n oc ulate d wit h r D E N 33 0  3 0 t o 6 0 mi n utes after a d mi nistrati o n of st u d y dr u g.  
 Sc he d ule d A d miss io n t o t he I n p atie nt U nit  
C o h ort 1: S u bje cts will be a d mitte d t o t he i n patie nt u nit o n St u d y Da y -6  t hr o u g h t he st u d y visit o n 
St u d y Da y -4 d ue t o t he i nte nsi ve P K sa m pli n g d uri n g t hese ti me p oi nts . O n t he da y of a d missi o n t o 
t he i n patie nt u nit o n St u d y Da y -6 , m ore s u bjects ma y be i n vite d t o t he cli nic t ha n  will be e nr olle d. 
T hese s u bjects will be alter nates a n d will be ra n d o mize d a n d recei ve J NJ-6 4 2 8 1 8 0 2 or place b o  o nl y if 
ot her s u bjects are n ot a v aila ble t o recei ve st u d y pr o d uct or are f o u n d t o b e i neli gi ble o n t he da y of t est 
article a d mi nistrati o n ( St u d y  Da y -5) . T h ose s u bj ects w h o are alter nates will be i nf or me d t hat t he y are 
alter nates w h e n t he y are i n vite d t o t he cli nic.  
 
C o h ort 2: S u bje cts will be a d mitte d t o t he i n patie nt u nit o n St u d y Da y -3 t hr o u g h t he st u d y visit o n 
St u d y Da y 1 d u e t o t he i nte nsi v e P K sa m pli n g d uri n g t hese ti me p oi nts. O n t he da y of a d missi o n t o t he 
i n patie nt u nit o n St u d y Da y -3 , m ore s u bjects ma y be i n vite d t o t he cli nic t ha n will be e nr olle d. T hese 

CI R 3 3 2  
 
7 1  
 
s u bjects will be alter nates a n d will be ra n d o mize d a n d recei ve J NJ -6 4 2 8 1 8 0 2 or pl ace b o o nl y if ot h er 
s u bjects are n ot a v aila ble t o recei ve st u d y pr o d uct or are f o u n d t o be i neli gi ble o n t he da y of test article 
a d mi nistrati o n ( St u d y Da y -2) . T h ose s u bjects w h o are alter nat es will be i nf or me d t hat t he y are 
alter nates w h e n t he y are i n vite d t o t he cli nic.  
 Me dic ati o n A d mi nistr ati o n of J N J -6 4 2 8 1 8 0 2  
Partici pa nts will recei ve st u d y dr u g (ie, J NJ -6 4 2 8 1 8 0 2 or place b o) as d escri be d i n Ta bl e 1 2 .  
 
 
 
. D osi n g  
re gi me ns f or C o h ort 2 were sel ecte d base d o n t he s afet y, efficac y, a n d P K fi n di n gs of C o h ort 1 a n d o n 
t he relati o ns hi p bet wee n t he P K a n d t he a nti viral acti vit y o btai ne d fr o m t h e C o h ort 1 i nteri m res ults 
a nal ysis.   
T a ble 1 2 : Descri pti o n of St u d y Dr u g  
St u d y  Dr u g  
J NJ-6 4 2 8 1 8 0 2  
Place b o  
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
 
 
 
  
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matc hi n g place b o f or eac h d ose le vel  
D os a ge le vel(s)  
C o h ort 1 : 
•  
Gr o u p 1: 6 0 0 m g ( L D)/ 2 0 0 m g ( M D) 
o nce dail y  
•  
Gr o u p 2:  4 0  m g  ( L D)/ 1 0 m g ( M D) o nce 
dail y or 2 0 0  m g  ( L D)/ 5 0 m g ( M D) o nce 
dail y  
 
C o h ort 2 :  
•  
Gr o u p 3 : 8 0 0 m g ( L D) t wice dail y / 
2 5 0 m g ( M D) o nce dail y  
•  
Gr o u p 4 : 4 5 0 m g ( L D) t wice dail y / 
1 2 0 0 m g ( M D) wee kl y  
•  
Gr o u p 5 : 2 5 0 m g ( L D) t wice dail y / 
5 0 0 m g ( M D) wee kl y  
 
 
C o h ort 1 : matc hi n g place b o o nce dail y.  
 
 
 
 
 
 
C o h ort  2 :  
•  
M atc hi n g place b o t wice dail y (l oa di n g d ose 
peri o d)  f or all re gi me ns.  
•  
Matc hi n g place b o o nce dail y ( mai nte na n ce 
d ose 
peri o d 
G r o u p 
3 ) 
or 
wee kl y 
( mai nte na nce d ose peri o d G r o u ps 4,  5  ) 
 
C CI
C CI
C CI
C CI
C
C
I
C CI

CI R 3 3 2  
 
7 2  
 
St u d y  Dr u g  
J NJ-6 4 2 8 1 8 0 2  
Place b o  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
R o ute of 
a d mi nistr ati o n  
Oral  
Oral  
D osi n g d ur ati o n  
C o h ort 1 : 2 6 da ys (fr o m Da y -5 t o Da y 2 1); L D peri o d of 5 da ys ( Da ys -5 t o -1) f oll o we d b y a 
M D peri o d of 2 1 da ys ( Da ys 1 t o 2 1).  
 
C o h ort 2 :  
•  
D ail y d osi n g: 2 3 da ys (fr o m Da y -2 t o Da y 2 1); L D peri o d of 2 da ys ( Da ys -2 t o -1) f oll o we d 
b y a M D peri o d of 2 1 da ys ( Da ys  1 t o 2 1).  
•  
Wee kl y d osi n g : L D peri o d of 2 da ys ( Da ys -2 t o -1) f oll o we d b y a M D  o n  Da y  1, Da y 8 , a n d 
Da y 1 5 (peri o d  of 3 wee ks ) 
 
L oc ati o n  
All st u d y dr u g i nta ke will ta ke place at t he st u d y site , at t he i n patie nt u nit i n case of i n patie nt 
a d missi o n , or self a d mi nistrati o n at h o me 
Ti m e of D osi n g  
I n t he m or ni n g ( 6 A M t o 1 2 P M), eac h da y. C o h ort 2: L oa di n g d oses will b e gi ve n t wice dail y  
(a p pr o xi matel y 1 2 h o urs a part). 
Use  
E x peri me ntal  
Place b o  
I M P or NI M P 
I M P 
I M P 
S o urci n g  
Pr o vi de d ce ntrall y b y t he D D T . 
Pr o vi de d ce ntrall y b y t he D D T . 
C CI
C CI
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CI R 3 3 2  
 
7 3  
 
St u d y  Dr u g  
J NJ-6 4 2 8 1 8 0 2  
Place b o  
F o o d/f asti n g 
re q uire m e nt  
C o h ort 1:  O n Da ys -5 a n d 2 1, partici pa nts s h o ul d ha ve faste d f or at least 1 0 h o urs bef ore st u d y 
dr u g i nta ke a n d ha v e l u nc h a p pr o xi matel y 4 h o urs after st u d y dr u g i nta ke. T h us, brea kfast is n ot 
all o we d o n t hese da ys. O n t he ot her d osi n g da ys, partici pa nts s h o ul d ha ve  faste d f or at least 
8  h o urs bef ore st u d y dr u g i nta ke a n d ha ve brea kfast at least 1 h o ur after st u d y dr u g i nta ke.  
O n Da y -5 a n d Da y 2 1, i nta ke of water is n ot all o we d fr o m 2 h o urs bef ore u ntil 2  h o urs after 
st u d y dr u g i nta ke, e x ce pt f or t he water use d f or st u d y dr u g i nta ke. 
C o h ort 2:  T he st u d y i nter ve nti o n is t o be ta ke n i n fe d c o n diti o ns, ie, wit hi n 3 0 mi n utes after t he 
start of t he partici pa nt’s re g ular meal , as a p plica ble. St u d y dr u g i nta ke ca n  be f oll o we d b y t he 
i nta ke of a p pr o xi matel y 2 4 0 m L ( 8 o u nces) of n o ncar b o nate d water. T he ta blets s h o ul d be 
s wall o we d i ntact. 
P ac k a gi n g a n d 
l a beli n g 
St u d y dr u g will be pr o vi de d i n c hil d -resista nt H D P E b ottles (ie, n ot pac ka ge d f or i n di vi d ual 
partici pa nt n u m bers). Eac h c o ntai ner will c o ntai n i nf or mati o n a n d be la bele d as re q uire d per 
c o u ntr y re g ulat or y re q uire me nts. La bels m ust re mai n affi xe d t o t he c o ntai ner.  
A = acti ve; H D P E = hi g h -de nsit y p ol yet h yle ne; 
; I M P = i n vesti gati o nal 
me dici nal pr o d uct; L D = l oa di n g d ose; M D = mai nte na nce d ose; NI M P = n o ni n vesti gati o nal me dici nal pr o d uct; 
P  =  place b o.  
 
 A ntici p ate d I n p atie nt St a y a n d F oll o w U p Pr oce d ures  
D uri n g t he  a ntici pate d  i n patie nt sta y, t he s u bject will ha ve vital si g ns ( bl o o d press ure, heart rate, a n d 
oral te m perat ur e) ta ke n t wice a da y. A f oc use d p h ysical e xa mi nati o n will be perf or m e d eac h da y w hile 
i n patie nt (e xcl u di n g C o h ort 1 Da y -6  a n d C o h ort 2 Da y -3 ) a n d at desi g nate d o ut patie nt visits. A 
f oc use d p h ysical e xa m m a y  i ncl u de, b ut is n ot li mite d t o, bl o o d press ure, h eart rate, t e m perat ure, s ki n 
e xa mi nati o n  a n d or o p har y n x  e x a mi nati o n . A d diti o nal p h ysical e xa m c o m p o ne nts 
or p h ysical 
e xa mi nati o ns o n a d diti o nal st u d y da ys  ma y be d o ne if cli nicall y i n dicate d at t he pr o vi der’s discreti o n.  
 
Ta ble 3  s u m marizes t he fre q ue n c y a n d ti mi n g of a nti viral acti vit y, P K, i m m u ne, bi o m ar ker, H L A 
ge n ot y pi n g a n d p har m ac o ge n o mic, a n d safet y m eas ure m e nts a p plica ble t o t his st u d y  f or C o h ort 1.  
Ta ble 4  pr o vi des t his i nf or mati o n f or C o h ort 2. A d diti o nall y, detaile d i nf or mati o n f or st u d y visits is 
pr o vi de d i n secti o n 7. 1 6  f or C o h ort 1 a n d secti o n 7. 1 7  f or C o h ort 2. 
If m ulti ple assess me nts are sc he d ul e d at t he s a me ti me p oi nt, it is rec o m me n de d t o a d here t o f oll o wi n g 
or der of assess me nts: 1 2 -lea d E C G(s), vital si g ns, bl o o d draw. Bl o o d c ollecti o ns f or P K a n d a nti viral 
acti vit y assess me nts s h o ul d be ke pt as cl ose t o t he s pecifie d ti me as p ossi ble. Ot her meas ure me nts ma y 
be d o ne earlier t ha n t he s pecifie d ti me p oi nts if nee de d. Act ual dates a n d ti mes of assess me nts m ust be 
rec or ded i n t he s o urce d o c u me ntati o n a n d C R F.  
A d diti o nal ser u m or uri ne pre g na n c y tests ma y be perf or me d, as det er mi ne d necessar y b y t he 
i n vesti gat or or re q uire d b y l ocal re g ulati o n, t o esta blis h t he a bse nce of pre g na nc y at a n y ti me d uri n g 
t he st u d y. 
 C o h ort 1  Sc he d ule of Pr oce d ures  
T he st u d y sc he d ule is als o o utli ne d i n Ta ble 3 . 
 
C o h ort 1 St u d y D a y -6 ( A d missi o n t o In p atie nt U nit)  
Partici pa nts will sta y i n -h o use d uri n g t he i nte nsi ve P K sa m pli n g peri o d fr o m Da y -6 u ntil at 
least 2 4 h o urs p ost first d ose (ie, t he m or ni n g of Da y -4).  
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
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CI R 3 3 2  
 
7 4  
 
2.  A N P or mi d -t ur bi nate s wa b t o test f or C O VI D-1 9 ma y be c ollecte d  if det er mi ne d 
necessar y b y t he cli nicia n or per g ui deli nes, (t h e s wa b ma y be o btai n e d u p t o 7 2 h o urs i n 
a d va nce of st u d y visit).  
3.  A d mit t o i n patie nt u nit.  
4.  Verif y t hat i nf or m e d c o nse nt was o btai ne d a n d t hat t he c o nse nt f or m was si g ne d b y b ot h 
t he s u bject a nd st u d y staff.  
5.  Rec or d vital si g ns ( s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
6.  Re vie w pre g n a nc y pre ve nti o n wit h t he s u bject.  
7.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
8.  Re vie w a n d d oc u me nt A Es.   
9.  Re vie w i ncl usi o n a n d e x cl usi o n criteria.  
 
C o h ort 1 St u d y D a y -5 ( Be gi n J N J -6 4 2 8 1 8 0 2 Test Article A d mi nistr ati o n)  
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes). 
2.  Verif y t hat all a p plica ble eli gi bilit y criteria ha ve b ee n met.  
3.  St o p water i nta k e t w o h o urs pri or t o a d mi nistrati o n of st u d y dr u g. I nt ake of w ater is n ot 
all o we d fr o m 2 h o urs bef ore u ntil 2 h o urs after st u dy dr u g i nt ake, exce pt f or t he w ater 
use d f or st u dy dr u g i nt ake. Rec or d last water i nta ke, a n d w he n water i nt a ke is restarte d 
f oll o wi n g st u d y dr u g a d mi nistrati o n.  
4.  Rec or d last f o o d i nta ke. L ast f o o d i nt ake s h o ul d be 1 0 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n, a n d first f o o d i nt ake s h o ul d b e at le ast 4 h o urs aft er st u dy dr u g 
a d mi nistr ati o n.  
5.  Perf or m 1 2 -L ea d E C G pri or t o d osi n g, s h o ul d be perf or me d i n s u pi ne p ositi o n, after ≥5 
mi n utes rest i n s u pi ne p ositi o n.  
6.  Rec or d vital si g ns ( s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y  te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n). Vital 
si g ns will be assesse d pre-d ose a n d 8 h o urs p ost -d ose.  
7.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
8.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
9.  Re vie w a n d d oc u me nt A Es.  
1 0.  F or a p plica ble p ers o ns of c hil d beari n g p ote ntial, perf or m -H C G testi n g. E ns ure t he test 
is ne gati ve bef ore pr ocee di n g wit h st u d y dr u g a d mi nistrati o n. A p ositi ve test will e xcl u de 
t he s u bject fr o m t he st u d y see secti o n 5. 2 . 
1 1.  Pri or t o st u d y dr u g a d mi nistrati o n, o btai n a p pr o xi matel y ~ 1 5. 7 m L of bl o o d f or P T/ P T T, 
C B C wit h differe ntial , a n d c he mistr y p a nel. T hese l a b or at o ry st u dies are dr a w n as 
b aseli ne v al ues a n d will n ot  deter mi ne eli gi bility.   
1 2.  Bl o o d sa m ple c ollecti o n f or P K a nal ysis. O btai n ~ 3 m L of bl o o d f or pre -d ose P K a nal ysis 
wit hi n t he 2 h o urs pri or t o d osi n g wit h st u d y dr u g. A n a d diti o nal ~ 3 m L of bl o o d will be 
c ollecte d f or P K a nal ysis at t he f oll o wi n g ti me p oi nts p ost a d mi nistrati o n wit h st u d y dr u g: 
+ 1 h o ur, + 2 h o urs, + 4 h o urs, + 8 h o urs, + 1 2 h o urs, a n d + 1 6 h o urs.  
1 3.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 5 m L of bl o o d f or I g G & I g M E LI S A, I g E 
a nal ysis, a n d ser u m pr otei n a nal ysis.  
1 4.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 0 m L of bl o o d f or cell ular i m m u nit y ( P B M C) 
a nal ysis a n d H L A g e n ot y pi n g a n d p har mac o g e n o mics.  
1 5.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 2. 5 m L of bl o o d f or h ost R N A assess me nts.  
1 6.  A d mi ni ster l oa di n g d ose of t he st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o.  

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1 7.  O bser ve f or at l east 3 0 mi n utes after st u d y dr u g a d mi nistrati o n a n d e val uate f or i m me diate 
h y perse nsiti vit y.  
1 8.  Res u me water i nta k e a p pr o xi matel y 2 h o urs after st u d y dr u g i nta ke.  
1 9.  A d here t o sta n d ar d l u nc h, after n o o n s n ac k a n d di n ner dietar y restricti o ns. R ec or d start a n d 
st o p ti mes of all f o o d i nta ke. St a n d ar d l u nc h will st art a p pr oxi m ately 4 h o urs p ost d ose 
(ri g ht after P K s a m pli n g at + 4 h p ost d ose h as bee n perf or me d). St a n d ar d after n o o n s n ack 
will s t art a p pr oxi m ately 7 h o urs p ost d ose. St a n d ar d di n ner will st art a p pr oxi m ately 1 0 
h o urs p ost d ose. All start a n d st o p ti mes of i nta ke of f o o d s h o ul d be rec or de d o n St u d y 
Da y -5.   
2 0.  Pr o vi de e d ucati o n b y st u d y staff o n t he si g ns a n d s y m pt o ms of p ote ntial A Es, a n d h o w a n d 
w he n t o c o ntact st u d y staff.  
2 1.  Distri b ute wallet car d wit h i n vesti gat or c o ntact i nf or mati o n a n d p ost -st u d y D H C M 
me dical state me nt.  
 
C o h ort 1 St u d y D a y -4 ( Disc h ar ge fr o m I n p atie nt U nit ) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Rec or d last f o o d i nta ke. L ast f o o d i nt ake s h o ul d be st a n d ar d di n ner o n St u dy D ay -5, 
p artici p a nt s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g a d mi nistr ati o n.  
3.  Rec or d vita l si g ns (s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
5.  Re v ie w a n d d oc u me nt c o nc o mita nt t hera p y. 
6.  Re vie w a n d d oc u me nt A Es.  
7.  C ollect ~ 3 m L of bl o o d f or P K a n al ysis. T his bl o o d c ollecti o n s h o ul d occ ur pri or t o 
a d mi nistrati o n of st u d y dr u g o n St u d y Da y -4, a n d a p pr o xi mat el y 2 4 h o urs f oll o wi n g 
a d mi nistrati o n of st u d y a d m i nistrati o n o n St u d y Da y -5.  
8.  A d mi nister l oa di n g d ose of t he st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o.  
9.  O bser ve f or at l east 3 0 mi n utes after st u d y dr u g a d mi nistrati o n a n d e val uate f or i m me diate 
h y perse nsiti vit y.  
1 0.  Res u me n or mal f o o d i nta ke at least 1 h o ur f oll o wi n g  st u d y dr u g i nta ke o n St u d y Da y -4 
a n d a p pr o xi matel y 2 4 h o urs after st u d y dr u g i nta k e o n Da y -5.  
 
C o h ort 1 St u d y D a y -3 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
2.  Re vie w a n d d oc u me nt A Es.  
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
4.  Rec or d ti me s u bject self -a d mi nistere d l oa di n g d ose of t he st u d y dr u g, J NJ-
6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y -2 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke,  s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
2.  Re vie w a n d d oc u me nt A Es.  
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
4.  Rec or d ti me s u bject self -a d mi nistere d l oa di n g d ose of t he st u d y dr u g, J NJ-
6 4 2 8 1 8 0 2/ place b o.  

CI R 3 3 2  
 
7 6  
 
 
C o h ort 1 St u d y D a y -1 ( o n -site visit)  
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
3.  Rec or d vital si g ns ( s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
5.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
6.  Re vie w a n d d oc u me nt A Es.  
7.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0. 0 m L of bl o o d f or D E N V -3 viral l oa d 
deter mi nati o n ( q ua ntitati ve P C R, pla q ue assa y, & N S 1 ). 
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 5. 7 m L of bl o o d f or P T/ P T T, C B C wit h 
differe ntial , a n d c he mistr y pa nel. 
9.  A d mi nister l oa di n g d ose of t he st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o.  
1 0.  O bser ve f or at l east 3 0 mi n utes after st u d y dr u g a d mi nistrati o n a n d e val uate f or i m me diate 
h y perse nsiti vit y.  
1 1.  S u bject s h o ul d wait t o res u me n or mal f o o d i nta ke f or at least 1 h o ur f oll o wi n g st u d y dr u g 
a d mi nistrati o n.  
 
C o h ort 1 St u d y D a y 1 ( O ut p atie nt c h alle n ge wit h D E N V -3)  
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  A N P or mi d -t ur bi nate s wa b t o test f or C O VI D-1 9 m a y be c ollecte d if deter mi ne d 
necessar y b y t he cli nicia n or per g ui d eli nes, (t he s wa b ma y be o btai ne d u p t o 7 2 h o urs i n 
a d va nce of st u d y visit).  
3.  F or a p plica ble p ers o ns of c hil d beari n g p ote ntial, perf or m -H C G testi n g. E ns ure t he test 
is ne gati ve b ef ore pr ocee di n g; a p ositi ve test will e xcl u de t he s u bject fr o m t he st u d y as per 
pr ot oc ol, secti o n 5. 3 .  
4.  Re vie w pre g n a nc y pre ve nti o n wit h t he s u bject.  
5.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
6.  Verif y t hat all a p plica ble eli gi bilit y criteria f or c h alle n ge wit h D E N V -3 ha ve bee n met, see 
secti o n 5 . 
7.  Perf or m 1 2 -L ea d E C G, s h o ul d be perf or me d i n su pi ne p ositi o n, after ≥5 mi n utes rest i n 
s u pi ne p ositi o n. 
8.  Rec or d pre d os e vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rate s u pi ne 
after ≥5 mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic m e dicati o n).  
9.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute 
c o m plai nts.   
1 0.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
1 1.  Re vie w a n d d oc u me nt A Es.  
1 2.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 m L of bl o o d f or P K a nal ysis.  
1 3.  Pri or t o st u d y dr u g a d mi nistra ti o n, c ollect ~ 1 0 m L of bl o o d f or D E N V-3 viral l o a d 
deter mi nati o n ( q ua ntitati ve P C R, pla q ue assa y, N S 1) a n d h u m or al i m m u nit y  (I g G, I g M, 
ne utralizi n g a nti b o d y), a n d I g E t esti n g.  
1 4.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o . St u dy dr ug i nt ake 
s h o ul d t ake pl ace 3 0 t o 6 0 mi n utes bef ore D E N V-3 i n oc ul ati o n.  

CI R 3 3 2  
 
7 7  
 
1 5.  A d mi nister a si n gle S C i njecti o n wit h a rec o m bi n a nt D E N V -3 strai n.  
1 6.  E val uati o n of t he i njecti o n site.  
1 7.  O bser ve f or at le ast 3 0 -mi n utes after d osi n g/c halle n ge a n d e val uat e f or i m me diat e 
h y perse nsiti vit y.  
1 8.  Rec or d te m perat ure a n d a n y l ocal react o ge ni cit y at least 3 0 mi n utes p ost c halle n ge.  
1 9.  Distri b ute De n g ue Me m or y E n ha nce me nt Car d ( D M E C) t o s u bjects  
2 0.  Pr o vi de e d ucati o n b y st u d y staff descri bi n g t he pr o per use of t he t h er m o m eter, t he si g ns 
a n d s y m pt o ms of p ote ntial A Es, a n d h o w a n d w he n t o c o ntact st u d y staff.  
2 1.  S u bject s h o ul d wait t o res u me n or mal f o o d i nta ke f or at least 1 h o ur f oll o wi n g st u d y dr u g 
a d mi nistrati o n.  
 
C o h ort 1 St u d y D a y 2 ( p h o ne visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject self -a d mi nistere d d ose of t he st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y 3 ( o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
3.  Rec or d vital si g ns ( s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Re vie w D M E C.  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts. 
6.  Re vie w a n d d oc u me nt A Es.  
7.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0. 0 m L of bl o o d f or D E N V -3 viral l oa d 
deter mi nati o n ( q ua ntitati ve P C R, pla q ue assa y, & N S 1) a n d ser u m pr otei n a nal ysis. 
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 2. 5 m L f or h ost R N A assess me nts.  
1 0.  Perf or m e va l u ati o n of t he i njecti o n site.  
1 1.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o.  
1 2.  S u bject s h o ul d wait t o res u me n or mal f o o d i nta ke f or at least 1 h o ur f oll o wi n g st u d y dr u g 
a d mi nistrati o n.  
 
C o h ort 1 St u d y D a y 4 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject s elf -a d mi nistere d 
mai nte na nce d ose of t he st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o.  
 

CI R 3 3 2  
 
7 8  
 
C o h ort 1 St u d y D a y 5 ( o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n.  
3.  Rec or d vital si g ns ( S yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne aft er 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Re vie w D M E C.  
5.  Perf o r m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute 
c o m plai nts.  
6.  Re vie w a n d d oc u me nt A Es.  
7.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
8.  Perf or m e val u ati o n of t he i njecti o n site.  
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 5. 0 m L of bl o o d  f or D E N V-3 viral l oa d 
deter mi nati o n ( q ua ntitati ve P C R, pla q ue assa y, & N S 1 ). 
1 0.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 5. 7 m L of bl o o d f or P T/ P T T, C B C wit h 
differe ntial , a n d c he mistr y pa nel. 
1 1.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o.  
1 2.  S u bject s h o ul d wait t o res u me n or mal f o o d i nta ke f or at least 1 h o ur f oll o wi n g st u d y dr u g 
a d mi nistrati o n.  
 
C o h ort 1 St u d y D a y 6 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d m i nistr ati o n. 
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject s elf -a d mi nistere d 
mai nte na nce d ose of t he st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y 7 ( o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f asted f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n.  
3.  Rec or d vital si g ns ( S yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne aft er 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Re vie w D M E C.  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
6.  Re vie w a n d d oc u me nt A Es.  
7.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
8.  Perf or m e val u ati o n of t he i njecti o n site.  
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 m L of bl o o d f or P K a nal ysis  
1 0.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l o a d 
deter mi nati o n ( q ua ntitati ve P C R, pla q ue assa y, & N S 1 ), a n d viral ge n o me s e q ue nci n g. 
1 1.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o.  
1 2.  S u bject s h o ul d wait t o res u me n or mal f o o d i nta ke f or at least 1 h o ur f oll o wi n g st u d y dr u g 
a d mi nistrati o n.  
 

CI R 3 3 2  
 
7 9  
 
C o h ort 1 St u d y D a y 8 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n.  
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject s elf -a d mi nistere d 
mai nte na nce d ose of t he st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y 9 ( o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n.  
3.  Rec or d vital si g ns ( s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n ut es rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Re vie w D M E C.  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
6.  Re vie w a n d d oc u me nt A Es.  
7.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 m L of bl o o d f or P K a nal ysis  
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l o a d 
deter mi nati o n ( q ua ntitati ve P C R, pla q ue ass a y, & N S 1 ), ser u m pr otei ns a n d viral ge n o m e 
se q ue nci n g. 
1 0.  Pri or t o  st u d y dr u g a d mi nistrati o n, c ollect ~ 3 0 m L of bl o o d f or cell ular i m m u nit y ( P B M C) 
a nal ysis.  
1 1.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 2. 5 m L of bl o o d f or h ost R N A assess me nts.  
1 2.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o.  
1 3.  S u bject s h o ul d wait t o res u me n or mal f o o d i nta ke f or at least 1 h o ur f oll o wi n g st u d y dr u g 
a d mi nistrati o n.  
 
C o h ort 1 St u d y D a y 1 0 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n.  
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject s elf -a d mi nistere d 
mai nte na nce d ose of t he st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y 1 1 ( o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n.  
3.  Rec or d vital si g ns ( s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Re vie w D M E C.  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  

CI R 3 3 2  
 
8 0  
 
c o m plai nts.  
6.  Re vie w a n d d oc u me nt A Es.  
7.  Re vie w a n d d oc u me nt c o nc o mit a nt t hera p y.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 m L of bl o o d f or P K a nal ysis.  
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l o a d 
deter mi nati o n ( q ua ntitati ve P C R, pla q ue assa y, N S 1 ), h u m oral i m m u nit y (I g G, I g M, & 
n e utralizi n g a nti b o d y), a n d viral ge n o me se q u e nci n g.  
1 0.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0. 7 m L of bl o o d f or P T/ P T T, C B C wit h 
differe ntial , a n d C M P. 
1 1.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o.  
1 2.  S u bject s h o ul d wait t o res u me n or mal f o o d i nta ke f or at least 1 h o ur f oll o wi n g st u d y dr u g 
a d mi nistrati o n . 
 
C o h ort 1 St u d y D a y 1 2 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s ho ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n.  
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject s elf -a d mi nistere d 
mai nte na nce d ose of t he st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y 1 3 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n.  
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject s e lf-a d mi nistere d 
mai nte na nce d ose of t he st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y 1 4 ( o n site visit)  
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
3.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Re vie w D M E C.  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
6.  Re vie w a n d d oc u me nt A Es.  
7.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l oa d 
deter mi nati o n ( q ua ntitati ve P C R, pla q ue assa y, N S 1 ), h u m oral i m m u nit y (I g G & I g M), 
ser u m pr otei ns a n d viral ge n o me se q ue n ci n g. 
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 2. 5 m L of bl o o d f or h ost R N A assess me nts.  
1 0.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o.  

CI R 3 3 2  
 
8 1  
 
1 1.  S u bje ct s h o ul d wait t o res u me n or mal f o o d i nta ke f or at least 1 h o ur f oll o wi n g st u d y dr u g 
a d mi nistrati o n.  
 
C o h ort 1 St u d y D a y 1 5 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
2.  R e vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject s elf -a d mi nistere d 
mai nte na nce d ose of t he st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y 1 6 ( o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per fa cilit y scree ni n g g ui deli nes).  
2.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
3.  Rec or d vital si g ns ( s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Re vie w D M E C.  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
6.  Re vie w a n d d oc u me nt A Es.  
7.  Re vie w a n d d oc u me nt c o nc o mita ntt hera p y.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 m L of bl o o d f or P K a nal ysis.  
9.   Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 0 m L of bl o o d f or cell ular i m m u nit y ( P B M C)  
1 0.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l o a d 
deter mi nati o n ( q ua ntitati ve P C R, pla q ue assa y, N S 1), h u m oral i m m u nit y (I g G & I g M), 
a n d viral ge n o me s e q ue n ci n g.  
1 1.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o.  
1 2.  S u b ject s h o ul d wait t o res u me n or mal f o o d i nta ke f or at least 1 h o ur f oll o wi n g st u d y dr u g 
a d mi nistrati o n.  
 
C o h ort 1 St u d y D a y 1 7 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject s elf -a d mi nistere d 
mai nte na nce d ose of t he st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y 1 8 ( o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
3.  Rec or d vital si g ns ( s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Re vie w D M E C.  

CI R 3 3 2  
 
8 2  
 
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
6.  Re vie w a n d d oc u me nt A Es.  
7.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l o a d 
deter mi nati o n ( q ua ntitati ve P C R, pla q ue assa y, N S 1 ), h u m oral i m m u nit y (I g G, I g M, & 
ne utralizi n g a nti b o d y) , ser u m pr otei n a nal ysis a n d viral ge n o me se q u e nci n g. 
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 2. 5 m L of bl o o d f or h ost R N A assess me nts.  
1 0.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0. 7 m L of bl o o d f or P T/ P T T, C B C wit h 
differe ntial , a n d C M P.  
1 1.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o.  
1 2.  S u bject s h o ul d wait t o res u me n or mal f o o d i nta ke f or at least 1 h o ur f oll o wi n g st u d y dr u g 
a d mi nistrati o n . 
 
C o h ort 1 St u d y D a y 1 9 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr ug 
a d mi nistr ati o n . 
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject s elf -a d mi nistere d 
mai nte na nce d ose of t he st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y 2 0 ( p h o ne c o nt act visit)  
1.  Rec or d last f o o d i nta ke, s u bject s h o ul d h ave f aste d f or at le ast 8 h o urs pri or t o st u dy dr u g 
a d mi nistr ati o n . 
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d ti me s u bject s elf -a d mi nistere d 
mai nte na nce d ose of t he st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o.  
 
C o h ort 1 St u d y D a y 2 1 (e ntire d a y cli nic visit)  
1.  Scree ni n g q ue sti o ns f or C O VI D-1 9 ( per facilit y scree ni n g g ui deli nes).  
2.   A N P or mi d -t ur bi nate s wa b t o test f or C O VI D-1 9 ma y be c ollecte d if deter mi ne d 
necessar y b y t he cli nicia n or per g ui d eli nes, (t he s wa b ma y be o btai ne d u p t o 7 2 h o urs i n 
a d va nce of st u d y visit).  
3.  St o p water i nta k e t w o h o urs pri or t o a d mi nistrati o n of st u d y dr u g. I nt ake of w ater is n ot 
all o we d fr o m 2 h o urs bef ore u ntil 2 h o urs after st u dy dr u g i nt ake, exce pt f or t he w ater 
use d f or st u dy dr u g i nt ake. Rec or ds last water i nt a ke, a n d w he n water i nta ke is r estarte d 
f oll o wi n g st u d y dr u g a d mi nistrati o n.  
4.  Rec or d last f o o d i nta ke. L ast f o o d i nt ake  s h o ul d be 1 0 h o urs pri or  t o st u dy dr u g 
a d mi nistr ati o n, a n d first f o o d i nt ake s h o ul d b e at le ast 4 h o urs aft er st u dy dr u g 
a d mi nistr ati o n.   
5.  Re vie w D M E C.  
6.  Perf or m 1 2 L ea d E C G , s h o ul d be perf or me d i n s u pi ne p ositi o n, after ≥5 mi n utes rest i n 
s u pi ne p ositi o n. 

CI R 3 3 2  
 
8 3  
 
7.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne after ≥ 
5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me d icati o n). O n Da y 
2 1, vital si g ns will be assesse d pre -d ose a n d 8 h o urs p ost -d ose. W he n s c he d ule d f or t he 
s a me ti me p oi nt, vit al si g ns s h o ul d be assesse d bef ore bl o o d dra w. 
8.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.   
9.  Re vie w a n d d oc u me nt A Es.  
1 0.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
1 1.  Bl o o d sa m ple c ollecti o n f or P K a nal ysis. O btai n ~ 3 m L of bl o o d f or pre -d ose P K a nal ysis 
wit hi n t he 2 h o urs pri or t o d osi n g wit h st u d y dr u g. A n a d diti o nal ~ 3 m L of bl o o d will be 
c ollecte d f or P K a nal ysis at t he f oll o wi n g ti me p oi nts p ost a d mi nistrati o n wit h st u d y dr u g: 
+ 1 h o ur, + 2 h o urs, + 4 h o urs, + 8 h o urs, a n d + 1 2 h o urs.  
1 2.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l o a d 
deter mi nati o n ( q ua ntitati ve P C R, p la q ue assa y, N S 1), h u m oral i m m u nit y (I g G, I g M, & 
ne utralizi n g a nti b o d y) a n d viral ge n o me se q u e nci n g.  
1 3.  F or a p plica ble pers o ns of c hil d beari n g p ote ntial, p erf or m −H C G testi n g  
1 4.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o.  
1 5.  Res u me water  i nta k e a p pr o xi matel y 2 h o urs after st u d y dr u g i nta ke.  
1 6.  A d here t o sta n d ar d l u nc h, after n o o n s n ac k a n d di n ner dietar y restricti o ns. R ec or d start a n d 
st o p ti mes of all f o o d i nta ke. St a n d ar d l u nc h will st art a p pr oxi m ately 4 h o urs p ost d ose 
(ri g ht after P K s a mpli n g at + 4 h p ost d ose h as bee n perf or me d). St a n d ar d after n o o n s n ack 
will st art a p pr oxi m ately 7 h o urs p ost d ose. St a n d ar d di n ner will st art a p pr oxi m ately 1 0 
h o urs p ost d ose. All start a n d st o p ti mes of i nta ke of f o o d s h o ul d be rec or de d o n St u d y 
Da y 2 1.   
 
C o h ort 1 St u d y D a y 2 3 ( + 1/ -1 d a ys, o n site visit)  
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d vital si g ns ( S yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne aft er 
≥ 5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
6.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
7.  C ollect ~ 2 0 m L of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve P C R, pla q ue 
assa y, N S 1), h u m oral i m m u nit y (I g G & I g M), a n d viral ge n o me se q u e nci n g.  
8.  C ollect ~ 3 m L bl o o d f or P K a nal ysis  
9.  C ollect ~ 1 5. 7 m L of bl o o d f or P T/ P T T, C B C wit h differe ntial , a n d c he mistr y pa nel . 
 
C o h ort 1 St u d y D a y 2 5 ( + 1/ -1 d a ys, o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes). 
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
6.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  

CI R 3 3 2  
 
8 4  
 
7.  C ollect ~ 3 m L of bl o o d f or P K a nal ysis.  
8.  C ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve P C R, pla q ue 
assa y N S 1), h u m oral i m m u nit y (I g G & I g M), a n d viral ge n o me se q u e nci n g. 
 
C o h ort 1 St u d y D a y 2 9 ( + 1/ -1 d a ys, o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Re vie w D M E C.  
3.  Re vie w a n d d oc u me nt A Es.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
5.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne after ≥ 
5  mi n utes re st, a n d b o d y te m perat ur e i n t he a bse n ce of a nti p yretic me dicati o n).  
6.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
7.  F or a p plica ble pers o ns of c hil d beari n g p ote ntial, p erf or m -H C G testi n g.  
8.  Re vie w pre g n a nc y pre ve nt i o n wit h t he s u bject. 
9.  C ollect ~ 3 0 m L of bl o o d f or P B M Cs  
1 0.  C ollect ~ 1 5 m L of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve P C R, pla q ue 
assa y, N S 1) , q ualitati ve P C R, h u m oral i m m u nit y (I g G, I g M, & ne utralizi n g a nti b o d y), a n d 
viral ge n o me se q u e nci n g. 
1 1.  C ollect ~ 3 m L of bl o o d f or P K a nal ysis.  
1 2.  C ollect ~ 1 0. 7 m L of bl o o d f or P T/ P T T, C B C wit h differe ntial , a n d C M P. 
 
C o h ort 1 St u d y D a y 3 6 ( + 2/ -2 d a ys, o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Re vie w a n d d oc u me nt A Es.  
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
4.  Rec or d vital si g ns ( s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
5.  Perf or m i nteri m hist or y  a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute 
c o m plai nts.  
6.  C ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve P C R, pla q ue 
assa y, N S 1) , q ualitati ve P C R, h u m oral i m m u nit y (I g G & I g M), a n d viral ge n o m e 
se q ue nci n g. 
 
C o h ort 1 St u d y D a y 4 3 ( + 2/ -2 d a ys, o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Re vie w a n d d oc u me nt A Es  
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
4.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne after ≥ 
5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse n ce of a nti p yretic me dicati o n).  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute 
c o m plai nts.  
6.  C ollect 1 0 m L of bl o o d f or D E N V -3 viral l oa d d eter mi nati o n ( q ua ntitati v e P C R, pla q ue 
assa y, N S 1) , q ualitati ve P C R, h u m oral i m m u nit y (I g G & I g M), ser u m pr otei ns a n d viral 
ge n o me se q ue n ci n g.  
 
C o h ort 1 St u d y D a y 5 0 ( + 2/ -2 d a ys, o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  

CI R 3 3 2  
 
8 5  
 
2.  Re vie w a n d d oc u me nt A Es.  
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
4.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne after ≥ 
5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse n ce of a nti p yretic me dicati o n).  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute 
c o m plai nts.  
6.  C ollect ~ 1 0. 0 m L of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve P C R, pla q ue 
assa y, & N S 1 ), q ualitati ve P C R, a n d viral ge n o me se q ue nci n g. 
7.  C ollect ~ 2. 5 m L of bl o o d f or h ost R N A assess me nts.  
 
C o h ort 1 St u d y D a y 5 7 ( + 2/ -2 d a ys, o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Re vie w a n d d oc u me nt A Es.  
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
4.  Re vie w pre g n a nc y pre ve nti o n wit h t he s u bject.  
5.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne after ≥ 
5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse n ce of a nti p yretic me dicati o n).  
6.  Pe rf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute 
c o m plai nts.  
7.  C ollect ~ 3 m L of bl o o d f or P K a nal ysis.  
8.  C ollect ~ 2 0 m L of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve P C R, pla q ue 
assa y, N S 1) , q ualitati ve P C R,  h u m oral i m m u nit y (I g G & I g M), a n d viral ge n o m e 
se q ue nci n g. 
9.  C ollect ~ 1 0. 7 m L of bl o o d f or P T/ P T T, C B C wit h differe ntial , a n d C M P.  
 
C o h ort 1 St u d y D a y 6 3 ( + 2/ -2 d a ys, o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Re vie w a n d d oc u me nt A Es.  
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
4.  Rec or d vital si g ns ( s yst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
5.  Perf or m i nteri m hist or y a n d  f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute 
c o m plai nts.  
6.  C ollect ~ 2 0 m L of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve P C R, pla q ue 
assa y, & N S 1), q ualitati ve P C R a n d viral ge n o me se q ue nci n g.  
 
C o h ort 1 St u d y D a y 7 0 ( + 2/ -2 d a ys, o n -site visit) 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y scree ni n g g ui deli nes).  
2.  Re vie w a n d d oc u me nt A Es.  
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
4.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne after ≥ 
5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse n ce of a nti p yretic me dicati o n).  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute 
c o m plai nts.  
6.  C ollect ~ 3 m L of bl o o d f or P K a nal ysis.  
7.  C ollect ~ 2 0 m L of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve P C R, pla q ue 
assa y, N S 1), q ualitati ve P C R, h u m oral i m m u nit y (I g G, I g M, & ne utralizi n g a nti b o d y),  
ser u m pr otei ns a n d viral ge n o me se q ue n ci n g. 

CI R 3 3 2  
 
8 6  
 
 
C o h ort 1 St u d y D a y 8 5 ( + 3/ -3 d a ys, E n d of St u d y)  
1.  Scree ni n g q uesti o ns f or C O VI D -1 9 ( per facilit y screeni n g g ui deli nes) .  
2.  Re vie w a n d d oc u me nt A Es.  
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
4.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne after ≥ 
5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse n ce of a nti p yretic me dicati o n).  
5.  Perf or m 1 2 -L ea d E C G, s h o ul d be perf or me d i n s u pi ne p ositi o n, after ≥5 mi n utes rest i n 
s u pi ne p ositi o n. 
6.  Perf or m i nteri m hist or y, c o nce ntr ati n g o n a n y ac ute c o m plai nts,  a n d c o m plete p h ysical 
e xa m.  
7.  O btai n wei g ht.  
8.  Perf or m c o m plete p h ysical e xa mi na ti o n. 
9.  F or a p plica ble pers o ns of c hil d beari n g p ote ntial, p erf or m -H C G testi n g.  
1 0.  R e vie w pre g na n c y pre v e nti o n wit h t he s u bject.  
1 1.  C ollect ~ 3 m L of bl o o d f or P K a nal ysis.  
1 2.  C ollect ~ 2 0 m L of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve P C R, pla q ue 
assa y, N S 1), q ualitati ve P C R, h u m oral i m m u nit y (I g G, I g M, & ne utralizi n g a nti b o d y), 
ser u m pr otei ns a n d viral ge n o me se q ue n ci n g. 
1 3.  C ollect ~ 3 0 m L of bl o o d f or cell ular i m m u nit y ( P B M C).  
1 4.  C ollect ~ 2. 5 m L of bl o o d f or h ost R N A assess me nts.  
 
 C o h ort 2  Sc he d ule of P r oce d ures  
T he st u d y sc he d ule f or C o h ort 2 is als o o utli ne d i n Ta ble 4 . Partici pa nts i n t he wee kl y d osi n g gr o u p 
ha ve t he sa me n u m b er of visits after disc har ge fr o m t he i n patie nt u nit, h o we ver, t he y o nl y r ecei ve 
st u d y dr u g o n Da ys 8 a n d 1 5. Visit acti vities t hat occ ur “ pri or t o st u d y dr u g a d mi nistrati o n”  f or t he 
dail y d ose gr o u ps  als o a p pl y t o t he wee kl y d ose gr o u p, e ve n w he n n o d os e is gi ve n .   
 
C o h ort 2 St u d y D a y -3 (A d missi o n t o I n p atie nt U nit ) 
Partici pa nts will sta y i n -h o use d uri n g t he i nte nsi ve P K sa m pli n g peri o d fr o m Da y -3  u ntil at 
least 2 4 h o urs p ost first d ose (ie, t he m or ni n g of Da y 1 ). 
1.  Scree ni n g q uesti o ns f or C O VI D -1 9  ( per facilit y scree ni n g g ui deli nes) .  
2.  A N P or mi d -t ur bi nate s wa b t o test f or C O VI D-1 9  ma y be c ollecte d if det er mi ne d 
necessar y b y t he cli nicia n or per g ui deli nes , (t h e s wa b ma y be o btai n e d u p t o 7 2 h o urs i n 
a d va nce of st u d y visit).  
3.  Alc o h ol breat h test ( PI discreti o n) . 
4.  A d mit t o i npatie nt u nit . 
5.  Verif y t hat i nf or m e d c o nse nt was o btai ne d a n d t hat t he c o nse nt f or m was si g ne d b y b ot h  
t he s u bject a n d st u d y staff. 
6.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
7.  Re vie w pre g n a nc y pre ve nti o n wit h t he s u bject.  
8.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
9.  Re vie w a n d d oc u m e nt A E s.  
1 0.  Re vie w i ncl usi o n a n d e x cl usi o n criteria.  
 
C o h ort 2 St u d y D a y -2  (Be gi n J N J -6 4 2 8 1 8 0 2  Test Article A d mi nistr ati o n ) 
1.  Verif y t hat all a p plica ble eli gi bilit y criteria ha ve b ee n met.  

CI R 3 3 2  
 
8 7  
 
2.  Rec or d last f o o d i nta ke.  
S ta n dar d meal wit hi n 3 0 mi n utes  pri or t o dr u g i nta ke . Rec or d w het her st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o, was a d mi nistere d wit h f o o d a n d wit hi n 3 0 mi n utes pri or t o dr u g i nta ke.  
3.  Perf or m 1 2 -L ea d E C G  pri or t o d osi n g , s h o ul d be perf or me d i n s u pi ne p ositi o n, after ≥5 
mi n utes rest i n s u pi ne p osi ti o n. 
4.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n). Vital 
si g ns will be assesse d pre-d ose a n d 8 h o urs p ost -d ose.  
5.  Perf or m i nteri m  hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
6.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
7.  Re vie w a n d d oc u me nt A E s. 
8.  F or a p plica ble p ers o ns of c hil d beari n g p ote ntial , perf or m -H C G testi n g. E ns ure t he test 
is ne gati ve bef ore pr ocee di n g  wit h st u d y dr u g a d mi nistrati o n.  A  p ositi ve test will e xcl u de 
t he s u bject fr o m t he st u d y, see secti o n 5. 2 . 
9.  Pri or t o st u d y dr u g a d mi nistrati o n, o btai n a p pr o xi matel y ~ 1 5 .7  m L of bl o o d f or P T/ P T T, 
C B C  wit h differe ntial , a n d c he mistr y p a nel . T hese l a b or at ory st u dies are dr a w n as 
b aseli ne v al ues a n d will n ot  deter mi ne eli gi bility.   
1 0.  Bl o o d sa m ple c ollecti o n f or P K  a nal ysis . O btai n ~ 3  m L of bl o o d f or pre -d ose P K a nal ysis 
wit hi n t he 2 h o urs pri or t o d osi n g wit h st u d y dr u g. A n a d diti o nal ~ 3  m L of bl o o d will be 
c ollecte d f or P K a n al ysis at t he f oll o w i n g ti me p oi nts p ost  a d mi nistrati o n of t he  st u d y dr u g: 
+ 1 h o ur, + 2 h o urs, + 4 h o urs, + 8 h o urs, + 1 2 h o urs, a n d + 1 6 h o urs.  Rec or d ti me of bl o o d 
sa m ples. N ote t he sec o n d d ose of st u d y dr u g s h o ul d be a d mi nistere d after t he 1 2 h o ur P K 
dra w per Ta ble 4 f o ot n ote.  
1 1.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 5 m L of bl o o d  f or D E N V I g G & I g M E LI S A , 
I g E a nal ysis, ne utralizi n g a nti b o dies,  a n d ser u m pr otei n a nal ysis.  
1 2.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 0  m L of b l o o d f or cell ular i m m u nit y ( P B M C) 
a nal ysis  a n d H L A g e n ot y pi n g a n d p har mac o g e n o mics .  
1 3.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 2. 5 m L of b l o o d f or h ost R N A assess me nts. 
1 4.  Pri o r t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3  m L f o r A 1 A G assess me nt. 
1 5.  A d mi nister l oa di n g d ose of t he st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o.  Rec or d ti me of 
a d mi nistrati o n.   
1 6.  O bser ve f or at l east 3 0 mi n utes after st u d y dr u g a d mi nistrati o n  a n d e val uate f or i m me diate  
h y perse nsiti vit y.  
1 7.  A d mi nister sec o n d l oa di n g d ose of st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o a p pr o xi matel y 1 2 
h o urs after i nitial d ose. Sec o n d d ose s h o ul d be gi ve n A F T E R t he  1 2 h o ur P K dra w p er 
Ta ble 4 f o ot n ote. Sta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta k e. Rec or d ti me of 
meal a n d ti me of st u d y dr u g a d mi nistrati o n. O bser ve f or at least 3 0 mi n utes after st u d y 
dr u g a d mi nistrati o n a n d e val uate f or i m me diate h y perse nsiti v it y.  
1 8.  A d here t o sta n d ar d l u nc h, after n o o n s n ac k , a n d di n ner dietar y restricti o ns.  
St a n d ar d me al is t ake n wit hi n 3 0  mi n pri or t o dr u g i nt ake . 
 
C o h ort 2 St u d y D a y -1 (I n p atie nt)  
1.  Rec or d last f o o d i nta ke . 
S ta n dar d meal wit hi n 3 0 mi n utes  pri or t o dr u g i nta ke . Rec or d w het her st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2 / place b o, was a d mi nistere d wit h f o o d a n d wit hi n 3 0 mi n utes pri or t o dr u g i nta ke. 
2.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  

CI R 3 3 2  
 
8 8  
 
3.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute  
c o m plai nts.  
4.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
5.  Re vie w a n d d oc u me nt A E s. 
6.  Pri or t o st u d y dr u g a d mi nistrati o n,  collect ~ 1 0  m L of bl o o d  f or D E N V-3 viral l o a d 
deter mi nati o n  (q ua ntitati ve P C R , pla q ue assa y , a n d N S 1 ). 
7.  C ollect ~ 3  m L of bl o o d f or P K a n al ysis. T his bl o o d c ollecti o n s h o ul d occ ur pri or t o 
a d mi nistrati o n of st u d y dr u g o n St u d y Da y -1, a n d a p pr o xi mat el y 2 4 h o urs f oll o wi n g 
a d mi nistrati o n of st u d y a d mi nistrati o n o n St u d y Da y -2. Rec or d ti me of bl o o d sa m ple.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 5 . 7 m L of bl o o d f or P T/ P T T, C B C wit h 
differe ntial , a n d c he mistr y pa nel. 
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3  m L f or A 1 A G assess me nt  
1 0.  A d mi nister l oa di n g d ose of t he st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o.  Rec or d ti me of 
a d mi nistrati o n.  
1 1.  O bser ve f or at l east 3 0 mi n utes after st u d y dr u g a d mi nistrati o n  a n d e val uate f or i m me diate  
h y perse nsiti vit y.  
1 2.  A d mi nister sec o n d l oa di n g d ose of st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o a p pr o xi matel y 1 2 
h o urs aft er i nitial d ose. Sta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta ke. Rec or d ti me 
of meal a n d ti me of st u d y dr u g a d mi nistrati o n. O bser ve f or at least 3 0 mi n utes after st u d y 
dr u g a d mi nistrati o n a n d e val uate f o r i m me diate h y perse nsiti vit y.  
 
C o h ort 2 St u d y D a y 1  (C h alle n ge  wit h D E N V -3 , D isc h ar ge fr o m I n p atie nt U nit) 
1.  F or a p plica ble p ers o ns of c hil d beari n g p ote ntial , perf or m -H C G testi n g. E ns ure t he test 
is ne gati ve b ef ore pr ocee di n g; a p ositi ve test will e xcl u de t he s u bject fr o m t he st u d y as per 
pr ot oc ol, secti o n  5. 3 .  
2.  Re vie w pre g n a nc y pre ve nti o n wit h t he s u bject. 
3.  S ta n dar d meal wit hi n 3 0 mi n utes  pri or t o dr u g i nta ke . Rec or d w het her st u d y dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o, was a d mi nistere d wit h f o o d a n d wit hi n 3 0 mi n utes pri or t o dr u g i nta ke.  
4.  Verif y t hat all a p plica ble eli gi bilit y criteria f or c h alle n ge wit h D E N V -3  ha ve bee n met , see 
secti o n 5 . 
5.  Perf or m 1 2 -L ea d E C G  pri or t o d osi n g , s h o ul d be perf or me d i n s u pi ne p ositi o n, after ≥5 
mi n utes rest i n s u pi ne p ositi o n.  
6.  Rec or d  pre d os e  vital si g ns ( syst olic a n d diast olic bl o o d press ure a n d p u lse/ heart rate s u pi ne 
after ≥5 mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic m e dicati o n).  
7.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute  
c o m plai nts.   
8.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
9.  Re vie w a n d d oc u me nt A E s. 
1 0.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3  m L of bl o o d f or P K  a nal ysis . Rec or d ti me of 
bl o o d sa m ple.   
1 1.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0  m L of bl o o d  f or D E N V-3 viral l o a d 
deter mi nati o n (q ua ntitati ve P C R , pla q ue assa y , a n d N S 1 ) a n d h u m oral i m m u nit y  (I g G a n d  
I g M; ne utralizi n g a nti b o d y ), a n d I g E testi n g.  
1 2.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3  m L f or A 1 A G assess me nt  
1 3.  A d mi nister  mai nte na nce d ose of  t he st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o . St u dy dr u g i nt ake 
s h o ul d t ake pl ace 3 0 t o 6 0 mi n utes bef ore D E N V-3 i n oc ul ati o n.  Rec or d ti me  of 
a d mi nistrati o n.  
1 4.  A d mi nister a si n gle S C  i njecti o n wit h a rec o m bi n a nt D E N V -3 strai n.  

CI R 3 3 2  
 
8 9  
 
1 5.  E val uati o n of t he i njecti o n site.  
1 6.  O bser ve f or at le ast 3 0  mi n ute s after d osi n g/c halle n ge  a n d e v al uate f or i m me diate 
h y perse nsiti vit y . 
1 7.  Rec or d te m perat ure a n d a n y l ocal react o ge ni cit y  at least 3 0 mi n utes  p ost c halle n ge.  
1 8.  Pr o vi de e d ucati o n b y st u d y staff descri bi n g t he pr o per use of t he t h er m o m eter, t he si g ns 
a n d s y m pt o ms of p ote ntial A Es, a n d h o w a n d w he n t o c o ntact st u d y staff.  E d ucati o n b y 
st u d y staff will als o i ncl u de pr o per st u d y dr u g st ora ge at h o me ( Gr o u p 3).  
1 9.  Distri b ute wallet car d wit h i n ves ti gat or c o ntact i nf or mati o n a n d p ost-st u d y D H C M 
me dical state me nt.  
2 0.  Distri b ute De n g ue Me m or y E n ha nce me nt Car d ( D M E C) t o s u bjects . 
 
C o h ort 2 St u d y D a y 4 ( o n-site visit)  
1.  D ail y d osi n g o nl y : S ta n dar d meal wit hi n 3 0 mi n utes  pri or t o dr u g i nta ke . Rec or d w het her 
st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o, was a d mi nistere d wit h f o o d a n d wit hi n 3 0  mi n utes 
pri or t o dr u g i nta k e o n St u d y Da ys 2 a n d 3. Rec or d ti me of meal o n St u d y Da y 4.  
2.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
3.  Re vie w D M E C.  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute  
c o m plai nts.  
5.  R e vie w a n d d oc u me nt A E s.  
6.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
7.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 m L of bl o o d f or P K a nal ysis. Rec or d ti me of 
bl o o d sa m ple.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c olle ct ~ 1 0  m L of bl o o d f or D E N V -3 viral l o a d 
d eter mi nati o n  (q ua ntitati ve P C R, pla q ue assa y , a n d N S 1)  a n d ser u m pr otei n a nal ysis . 
9.  Pri or t o st u d y dr u g a d mi nistrati o n , c ollect ~ 2. 5 m L f or h ost R N A assess me nts.  
1 0.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3  m L f or A 1 A G assess me nt  
1 1.  Perf or m e val u ati o n of t he i njecti o n site.  
1 2.  D ail y 
d osi n g 
o nl y: 
A d mi nister 
mai nte na nce 
d ose 
of 
t h e st u d y 
dr u g, J NJ-
6 4 2 8 1 8 0 2/ place b o  wit hi n 3 0 mi n utes of meal . Rec or d ti me of a d mi nistrati o n.   
 
C o h ort 2 St u d y D a y 6 ( o n-site visit) 
1.  D ail y d osi n g o nl y : S ta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta ke. Rec or d w het her 
st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o, was a d mi nistere d wit h f o o d a n d wit hi n 3 0  mi n utes 
pri or t o dr u g i nta ke  o n St u d y Da y 5  (at h o me). Rec or d ti me of meal o n St u d y Da y 6. 
2.  Rec or d vital si g ns (S yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne aft er 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
3.  Re vie w D M E C.   
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
5.  Re vie w  a n d d oc u me nt A E s.  
6.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
7.  Perf or m e val u ati o n of t he i njecti o n site.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 5  m L of bl o o d f or D E N V -3 viral l o a d 
deter mi nati o n  (q ua ntitati ve P C R , pla q ue assa y , a n d N S 1 ). 
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 5 . 7 m L of  bl o o d f or P T/ P T T, C B C  wit h 
differe ntial , a n d c he mistr y pa nel . 

CI R 3 3 2  
 
9 0  
 
1 0.  D ail y 
d osi n g 
o nl y: 
A d mi nister  mai nte na nce 
d ose 
of  t h e st u d y 
dr u g, J NJ-
6 4 2 8 1 8 0 2/ place b o  wit hi n 3 0 mi n utes of meal . Rec or d ti me of a d mi nistrati o n.   
 
C o h ort 2 St u d y D a y 8  ( o n-site visit) 
1.  D ail y d osi n g o nl y:  S ta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta ke. Rec or d w het her 
st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o, was a d mi nistere d wit h f o o d a n d wit hi n 3 0 mi n utes 
pri or t o dr u g i nta ke  o n St u d y Da y 7. Rec or d ti me of meal o n St u d y Da y 8 . 
2.  Wee kl y d osi n g o nl y:  Sta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta ke. Rec or d ti me 
of meal o n St u d y Da y 8.  
3.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press u re a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Re vie w D M E C.  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
6.  Re vie w  a n d d oc u me nt A E s.  
7.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 m L of bl o o d f or P K a nal ysis . Rec or d ti me of 
bl o o d sa m ple.  
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0  m L of bl o o d  f or D E N V-3 viral l o a d 
deter mi n ati o n (q ua ntitati ve P C R , pla q ue assa y , a n d N S 1 ), ser u m pr otei ns a n d viral ge n o me 
se q ue nci n g. 
1 0.  Pri or t o st u d y dr u g a d mi nistrati o n , c ollect ~ 3 0 m L of bl o o d f or cell ular i m m u nit y ( P B M C) 
a nal ysis.  
1 1.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 2. 5 m L of bl o o d f or h ost R N A assess me nts.  
1 2.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3  m L f or A 1 A G assess me nt  
1 3.  D ail y d osi n g A N D Wee kl y d osi n g:  A d mi nister mai nte na nce d ose of t h e st u d y dr u g, J NJ-
6 4 2 8 1 8 0 2/ place b o  wit hi n 3 0 mi n utes of meal . Rec or d ti me of a d mi nistrati o n.   
 
C o h ort 2 St u d y D a y 1 1  ( o n-site visit) 
1.  D ail y d osi n g o nl y: Sta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta ke. Rec or d w het her 
st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o, was a d mi nistere d wit h f o o d a n d wit hi n 3 0 mi n utes 
pri or t o dr u g i nta ke o n St u d y Da ys 9 a n d 1 0. Rec or d ti me of meal o n St u d y Da y 1 1 . 
2.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
3.  Re vie w D M E C.  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute  
c o m plai nts.  
5.  R e vie w a n d d oc u me nt A E s.  
6.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
7.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 m L of bl o o d f or P K a n al ysis.  Rec or d ti me 
of bl o o d sa m ple.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0  m L  of bl o o d f or D E N V -3 viral l o a d 
deter mi nati o n  (q ua ntitati ve P C R , pla q ue assa y , a n d N S 1 ), h u m oral i m m u nit y  (I g G a n d  
I g M), a n d viral g e n o me s e q ue nci n g . 
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 . 7 m L of  bl o o d f or P T/ P T T, C B C  wit h 
differe ntial , a n d C M P . 
1 0.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3  m L f or A 1 A G assess me nt  

CI R 3 3 2  
 
9 1  
 
1 1.  D ail y 
d osi n g 
o nl y: 
A d mi nister 
mai nte na nce 
d ose 
of 
t h e st u d y 
dr u g, J NJ-
6 4 2 8 1 8 0 2/ place b o  wit hi n 3 0 mi n utes of meal . Rec or d ti me of a d mi nistrati o n.  
 
C o h ort 2 St u d y D a y 1 3 (o n site  visit)  
1.  D ail y d osi n g o nl y:  Sta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta ke. Rec or d  
w het her st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o, was a d mi nistere d wit h f o o d a n d wit hi n 3 0 
mi n utes pri or t o dr u g i nta ke  o n St u d y Da y 1 2. Rec or d ti me of m eal o n St u d y Da y 1 3 . 
2.  Rec or d vital si g ns ( syst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne after 
≥5  mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
3.  Re vie w D M E C.  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y  ac ute 
c o m plai nts.  
5.  Re vie w a n d d oc u me nt A E s.  
6.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
7.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l oa d 
deter mi nati o n ( q ua ntitati ve P C R , pla q ue assa y , N S 1), h u m oral i m m u nit y (I g G & I g M), 
ser u m pr otei ns a n d viral ge n o me se q ue n ci n g.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 2. 5 m L of bl o o d f or h ost R N A assess me nts.  
9.  D ail y 
d osi n g 
o nl y: 
A d mi nister 
mai nte na nce 
d ose 
of t h e st u d y 
dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o  wit hi n 3 0 mi n utes of meal. Rec or d ti me of a d mi nistrati o n.  
 
 
C o h ort 2 St u d y D a y 1 5: See bel o w pr oce d ures de pe n di n g o n D ail y or Wee kl y D osi n g  
D ail y D osi n g ( O n -site Visit)  
1.  Sta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta ke . Rec or d w h et her st u d y dr u g, 
J NJ-6 4 2 8 1 8 0 2/ place b o, was a d mi nistere d wit h f o o d a n d wit hi n 3 0 mi n utes pri or t o 
dr u g i nta ke  o n St u d y Da y 1 4 . Rec or d ti me of meal o n St u d y D a y 1 5.  
2.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne 
after ≥5 mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic m e dicati o n).  
3.  Re vie w D M E C.  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute 
c o m plai nts.  
5.  Re vie w a n d d oc u me nt A Es.  
6.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
7.  Bl o o d s a m ple c ollecti o n pri or t o st u d y dr u g a d mi nistr ati o n:  
a. C ollect ~ 3 m L of bl o o d f or P K a nal ysis. Rec or d ti me of bl o o d sa m ple .  
b.  C ollect ~ 3 0  m L  of bl o o d f or cell ular i m m u nit y ( P B M C)  
c. C ollect ~ 1 0  m L  of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve 
P C R, pla q ue assa y, N S 1), h u m oral i m m u nit y (I g G & I g M), a n d viral 
ge n o me se q ue n ci n g.  
8.  A d mi nister mai nte na nce d ose of t he st u d y dr u g , J NJ-6 4 2 8 1 8 0 2/ place b o. R ec or d ti me 
of a d mi nistrati o n.   
 
Wee kl y  D o si n g ( O n-site Visit; E ntire D a y)  
1.  Sta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta ke. Rec or d ti me of meal o n St u d y 
Da y 1 5.  
2.  Rec or d vital si g ns (s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rate s u pi ne after 
> 5 mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n.  

CI R 3 3 2  
 
9 2  
 
3.  Perf or m 1 2 Lea d E C G  pri or t o d osi n g , s h o ul d be perf or me d i n s u pi ne p ositi o n, after ≥5 
mi n utes rest i n s u pi ne p ositi o n.  
4.  Re vie w D M E C .  
5.  Perf or m i nteri n hist or y a n d f oc use d p h ysi cal e xa m, c o nce ntrati n g o n a n y ac ute 
c o m plai nts.  
6.  Re vie w a n d d oc u me nt A Es.  
7.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
8.  Bl o o d  sa m ple c ollecti o n pri or t o st u d y dr u g a d m i nistrati o n:  
a.   O btai n ~ 3  m L of bl o o d f or pre -d ose P K a nal ysis wit hi n t he 2 h o urs pri or t o 
d osi n g wit h st u d y dr u g. Rec or d ti me of bl o o d sa m ple.  
b.  C ollect ~ 3 0  m L  of bl o o d f or cell ular i m m u nit y ( P B M C)  
c. C ollect ~ 1 0  m L  of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve 
P C R, pla q ue assa y, N S 1), h u m oral i m m u nit y (I g G & I g M), a n d viral 
ge n o me se q ue n ci n g.  
d.  C ollect ~ 3  m L  f or A 1 AG  assess me nt  
9.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o. Rec or d ti me 
of a d mi nistrati o n.   
1 0.  Bl o o d sa m ple c ollecti o n after st u d y dr u g a d mi nistrati o n:  
a. C ollect ~ 3  m L  of bl o o d f or P K a nal ysis at + 1 h o ur after st u d y dr u g 
a d mi nistrati o n. Rec or d sa m ple c ollecti o n ti me.  
b.  C ollect ~ 3  m L  of bl o o d f or P K a nal ysis at + 2 h o urs after s t u d y dr u g 
a d mi nistrati o n. Rec or d sa m ple c ollecti o n ti me.  
c. C ollect ~ 3  m L  of bl o o d f or P K a nal ysis at + 4 h o urs after st u d y dr u g 
a d mi nistrati o n. Rec or d sa m ple c ollecti o n ti me.  
d.  C ollect ~ 3  m L  of bl o o d f or P K a nal ysis at + 8 h o urs after st u d y dr u g 
a d mi nistrati o n. Rec or d sa m ple c ollecti o n ti me.  
e. C ollect ~ 3  m L  of bl o o d f or P K a nal ysis at + 1 2 h o ur after st u d y dr u g 
a d mi nistrati o n. Rec or d sa m ple c ollecti o n ti me.  
 
C o h ort 2 St u d y D a y 1 8  (o n -site visit)  
1.  D ail y d osi n g o nl y : S ta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta ke. R ec or d w het her 
st u d y dr u g, J NJ-6 4 2 8 1 8 0 2/ place b o, was a d mi nistere d wit h f o o d a n d wit hi n 3 0 mi n utes 
pri or t o dr u g i nta ke  o n St u d y Da ys 1 6 a n d 1 7 (at h o me). Rec or d ti me of meal o n St u d y da y 
1 8 . 
2.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure  a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
3.  Re vie w D M E C.  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e x a m  (if i n dicate d), c o n ce ntrati n g o n a n y 
ac ute  
c o m plai nts.  
5.  Re vie w  a n d d oc u me nt A E s. 
6.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.   
7.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3 m L of bl o o d f or P K a nal ysis. Rec or d ti me 
of bl o o d sa m ple.  
8.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 m L of bl o o d f or D E N V -3 viral l o a d 
deter mi nati o n ( q ua ntitati ve P C R , pla q ue assa y, N S 1 ), h u m oral i m m u nit y ( I g G, I g M), 
ser u m pr otei n a nal ysis a n d viral ge n o me se q u e nci n g.  
9.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 2. 5 m L of bl o o d f or h ost R N A assess me nts.  

CI R 3 3 2  
 
9 3  
 
1 0.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 1 0 . 7 m L of bl o o d f or P T/ P T T, C B C wit h 
differe ntial , a n d C M P.  
1 1.  Pri or t o st u d y dr u g a d mi nistrati o n, c ollect ~ 3  m L f or A 1 A G assess me nt  
1 2.  D ail y 
d osi n g 
o nl y: 
A d mi nister 
mai nte na nce 
d ose 
of t h e st u d y 
dr u g, J NJ -
6 4 2 8 1 8 0 2/ place b o. Rec or d ti me  of a d mi nistrati o n.  
 
C o h ort 2 St u d y D a y 2 1: See bel o w pr oce d ures de pe n di n g o n D ail y or Wee kl y D osi n g  
 
D a y 2 1: Wee kl y D osi n g ( O n -site Visit)  
1.  Rec or d vital si g ns ( s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rat e s u pi ne 
after ≥5 mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic m e dicati o n).  
2.  Re vie w D M E C.  
3.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o nce ntrati n g o n a n y ac ute 
c o m plai nts.  
4.  Re vie w a n d d oc u me nt A Es.  
5.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
6.  Bl o o d s a m ple c ollecti o n : 
a. C ollect ~ 3 m L of bl o o d f or P K a nal ysis. Rec or d ti me of bl o o d sa m ple.  
b.  C ollect ~ 3 0  m L  of bl o o d f or cell ular i m m u nit y ( P B M C)  
c. C ollect ~ 1 0  m L  of bl o o d f or D E N V -3 viral l oa d d eter mi nati o n ( q ua ntitati ve 
P C R, pla q ue assa y, N S 1), h u m oral i m m u nit y (I g G & I g M), a n d viral ge n o me 
se q ue nci n g.  
7.  F or a p plica ble pers o ns of c hil d beari n g p ote ntial, p erf or m β -H C G testi n g  
 
D a y 2 1: D ail y D osi n g ( O n -site Visit; E ntire D a y)  
1.  Sta n dar d meal wit hi n 3 0 mi n utes pri or t o dr u g i nta ke. Rec or d ti me of meal o n St u d y 
Da y 2 1. Rec or d w het her st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o, was a d mi nistere d wit h 
f o o d a n d wit hi n 3 0 mi n utes pri or t o dr u g i nta ke o n S t u d y Da ys 1 9 a n d 2 0 (at h o me). 
2.  Rec or d vital si g ns (s yst olic a n d diast olic bl o o d press ure a n d p ulse/ heart rate s u pi ne after 
> 5 mi n utes rest, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n.  
3.  Perf or m 1 2 Lea d E C G pri or t o d osi n g, s h o ul d be perf or me d i n s u pi ne p ositi o n, after ≥5 
mi n utes rest i n s u pi ne p ositi o n.  
4.  Re vie w D M E C  
5.  Perf or m i nteri n hist or y a n d f oc use d p h ysi cal e xa m, c o nce ntrati n g o n a n y ac ute 
c o m plai nts.  
6.  Re vie w a n d d oc u me nt A Es.  
7.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y.  
8.  Bl o o d  sa m ple c ollecti o n pri or t o st u d y dr u g a d mi nistrati o n:  
a.  O btai n ~ 3  m L of bl o o d f or pre -d ose P K a nal ysis wit hi n t he 2 h o urs pri or t o 
d osi n g wit h st u d y dr u g. Rec or d ti me of bl o o d sa m ple.  
b.  C ollect ~ 3 0  m L  of bl o o d f or cell ular i m m u nit y ( P B M C)  
c. C ollect ~ 1 0  m L  of bl o o d f or D E N V -3 viral l oa d deter mi nati o n ( q ua ntitati ve 
P C R, pla q ue assa y, N S 1), h u m oral i m m u nit y (I g G & I g M), a n d viral 
ge n o me se q ue n ci n g.  
d.  C ollect ~ 3  m L  f or A 1 AG  assess me nt  
9.  A d mi nister mai nte na nce d ose of t he st u d y dr u g, J NJ -6 4 2 8 1 8 0 2/ place b o. Rec or d ti me 
of a d mi nistrati o n.   
1 0.  Bl o o d sa m ple c ollecti o n after st u d y dr u g a d mi nistrati o n:  

CI R 3 3 2  
 
9 4  
 
a. C ollect ~ 3  m L  of bl o o d f or P K a nal ysis at + 1 h o ur after st u d y dr u g 
a d mi nistrati o n. Rec or d sa m ple c ollecti o n ti me.  
b.  C ollect ~ 3  m L  of bl o o d f or P K a nal ysis at + 2 h o urs after st u d y dr u g 
a d mi nistrati o n. Rec or d sa m ple c ollecti o n ti me.  
c. C ollect ~ 3  m L  of bl o o d f or P K a nal ysi s at + 4 h o urs after st u d y dr u g 
a d mi nistrati o n. Rec or d sa m ple c ollecti o n ti me.  
d.  Reassess vital si g ns at + 8 h o urs p ost st u d y dr u g a d mi nistrati o n. C ollect 
~ 3  m L  of bl o o d f or P K a nal ysis at + 8 h o urs after st u d y dr u g a d mi nistrati o n. 
Rec or d sa m ple c ollecti o n ti me . 
e. C ollect ~ 3  m L  of bl o o d f or P K a nal ysis at + 1 2 h o ur after st u d y dr u g 
a d mi nistrati o n. Rec or d sa m ple c ollecti o n ti me.  
1 1.  F or a p plica ble pers o ns of c hil d beari n g p ote ntial, p erf or m β -H C G testi n g  
 
C o h ort 2 St u d y D a y 2 5 ( + 1/ -1 d a ys , o n -site visit) 
1.  Re vie w D M E C.  
2.  Re vie w a n d d oc u me nt A E s. 
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
4.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e x a m  (if i n dicate d), c o n ce ntrati n g o n a n y 
ac ute c o m plai nts.  
6.  C ollect ~ 3  m L of bl o o d f or P K  a nal ysis.  Rec or d ti me of bl o o d sa m ple.  
7.  C ollect ~ 1 0  m L o f bl o o d f or D E N V-3 vir al l oa d deter mi nati o n  (q ua ntitati ve P C R , 
q ualitati ve P C R, pla q ue assa y , N S 1 ), a n d viral ge n o me se q ue nci n g .  
8.  C ollect ~ 3  m L f or A 1 A G assess me nt  
 
C o h ort 2 St u d y D a y 2 7  (+ 1/ -1 d a ys, o n -site visit) –  Visit t o be c o n d ucte d o nl y if D E N V -3 vir al 
l o a d p ositi ve o n D a y 2 5  i n at le ast 1 p artici p a nt of t he gr o u p recr uite d o n t he s a me d a y or 
l ater. 
1.  Re vie w D M E C.  
2.  Re vie w a n d d oc u me nt A E s. 
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
4.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ul se/ h eart rate s u pi ne after 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute  
c o m plai nts.  
6.  C ollect ~ 1 0 m L of bl o o d  f or D E N V-3  vir al l oa d deter mi nati o n  ( q ua ntitati ve P C R, 
q ualitati ve P C R, pla q ue assa y , N S 1) , a n d viral ge n o me se q ue nci n g. 
 
C o h ort 2 St u d y D a y 2 9 ( + 1/ -1 d a ys , o n -site visit) 
1.  Re vie w D M E C.  
2.  Re vie w a n d d oc u me nt A E s. 
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
4.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥ 5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ys ical e x a m (if i n dicate d), c o n ce ntrati n g o n a n y 
ac ute c o m plai nts.  
6.  F or a p plica ble pers o ns of c hil d beari n g p ote ntial , p erf or m -H C G testi n g.  

CI R 3 3 2  
 
9 5  
 
7.  Re vie w pre g n a nc y pre ve nti o n wit h t he s u bject.  
8.  C ollect ~ 3 0 m L of bl o o d f or P B M Cs  
9.  C ollect ~ 1 5  m L of bl o o d f or D E N V -3 viral l oa d deter mi nati o n  (q ua ntitati ve P C R, pla q ue 
assa y, N S 1), q u alitati ve P C R, h u m oral i m m u nit y (I g G a n d I g M), a n d viral ge n o m e 
se q ue nci n g. 
1 0.  C ollect ~ 3  m L of bl o o d f or P K a nal ysis.  Rec or d ti me of bl o o d sa m ple.  
1 1.  C ollect ~ 1 0 . 7 m L of bl o o d f or P T/ P T T, C B C  wit h differe ntial , a n d C M P. 
1 2.  C ollect ~ 3  m L f or A 1 A G assess me nt . 
 
C o h ort 2 St u d y D a y 3 2  (+ 1/ -1 d a ys, o n -site visit)  
1.  Re vie w D M E C.  
2.  Re vie w a n d d oc u me nt A E s. 
3.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
4.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e x a m  (if i n dicate d), c o n ce ntrati n g o n a n y 
ac ute c o m plai nts . 
6.  C ollect ~ 1 0 m L of bl o o d  f or D E N V-3  vir al l oa d deter mi nati o n  ( q ua ntitati ve P C R, 
q ualitati ve P C R, pla q ue assa y , N S 1) , h u m oral i m m u nit y (I g G a n d I g M),  a n d  viral ge n o me 
se q ue nci n g. 
 
C o h ort 2 St u d y D a y 3 4  (+ 1/ -1 d a ys, o n -site visit) –  Visit t o be c o n d ucte d o nl y if D E N V -3 vir al 
l o a d p ositi ve o n D a y 3 2   i n at le ast 1 p artici p a nt of t he g r o u p recr uite d o n t he s a me d a y or 
l ater.  
1.  Re vie w a n d d oc u me nt A Es.  
2.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
3.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e x a m  (if i n dicate d), c o n ce ntrati n g o n a n y 
ac ute c o m plai nts.  
5.  C ollect ~ 1 0 m L of bl o o d  f or D E N V-3  vir al l oa d deter mi nati o n  ( q ua ntitati ve P C R, 
q ualitati ve P C R, pla q ue assa y , N S 1) , h u m oral i m m u nit y (I g G a n d I g M), a n d  viral ge n o me 
se q ue nci n g. 
 
C o h ort 2 St u d y D a y 3 6 ( + 2/ -2 d a ys, o n -site visit) 
1.  Re vie w a n d d oc u me nt A E s. 
2.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
3.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥5  mi n utes res t, a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysi cal e x a m  (if i n dicate d), c o n ce ntrati n g o n a n y 
ac ute c o m plai nts.  
5.  C ollect ~ 1 0  m L of bl o o d  f or D E N V-3  viral l oa d deter mi nati o n  (q ua ntitati ve P C R, pla q ue 
assa y, N S 1 ), q ualitati ve P C R, a n d viral ge n o me se q ue nci n g . 
 
C o h ort 2 St u d y D a y 4 3  ( +3 /-3  d a ys, o n -site visit) 
1.  Re vie w a n d d oc u me nt A E s 
2.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 

CI R 3 3 2  
 
9 6  
 
3.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥ 5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute 
c o m plai nts.  
5.  C ollect 1 0 m L of bl o o d  f or D E N V-3 viral l oa d d eter mi nati o n  (q ua ntitati v e P C R, pla q ue 
assa y, N S 1 ), q ua litati ve P C R, h u m oral i m m u nit y  (I g G & I g M a n d ne utrali zi n g a nti b o d y ), 
ser u m pr otei ns a n d viral ge n o me se q ue n ci n g . 
6.  C ollect ~ 3 m L of bl o o d f or P K a nal ysis. Rec or d ti me of bl o o d sa m ple.  
7.  C ollect ~ 3  m L f or A 1 A G assess me nt . 
 
C o h ort 2 St u d y D a y 5 7 ( +2/ -2 d a ys, o n -site visit) 
1.  Re vie w a n d d oc u me nt A E s. 
2.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
3.  Re vie w pre g n a nc y pre ve nti o n wit h t he s u bject.  
4.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥ 5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
5.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute 
c o m plai nts.  
6.  C ollect ~ 3  m L of bl o o d f or P K a nal ysis . Rec or d ti me of bl o o d sa m ple.  
7.  C ollect ~ 2 0  m L of bl o o d  f or D E NV -3 viral l oa d deter mi nati o n  (q ua ntitati ve P C R, pla q ue 
assa y, N S 1 ), q ualitati ve P C R,  a n d viral ge n o me se q ue nci n g . 
8.  C ollect ~ 1 0 . 7 m L of bl o o d f or P T/ P T T, C B C  wit h differe ntial , a n d C M P.  
9.  C ollect ~ 3  m L f or A 1 A G assess me nt . 
 
C o h ort 2 St u d y D a y 7 0  ( +2/ -2 d a ys, o n -site visit) 
1.  Re vie w a n d d oc u me nt A E s. 
2.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
3.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥ 5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Perf or m i nteri m hist or y a n d f oc use d p h ysical e xa m, c o n ce ntrati n g o n a n y ac ute 
c o m plai nts.  
5.  C ollect ~ 2 0  m L of bl o o d  f or D E N V-3 viral l oa d deter mi nati o n  (q ua ntitati ve P C R, pla q ue 
assa y, N S 1 ), q ualitati ve P C R, h u m oral i m m u nit y  (I g G, I g M), ser u m pr ot ei ns a n d vir al 
ge n o me se q ue n ci n g . 
6.  C ollect ~ 3  m L f or A 1 A G assess me nt . 
 
C o h ort 2 St u d y D a y 8 5 ( + 3/ -3 d a ys, E n d of St u d y)  
1.  Re vie w a n d d oc u me nt A E s. 
2.  Re vie w a n d d oc u me nt c o nc o mita nt t hera p y. 
3.  Rec or d vital si g ns ( syst olic a n d di ast olic bl o o d press ure a n d p ulse/ h eart rate s u pi ne after 
≥ 5  mi n utes rest , a n d b o d y te m perat ur e i n t he a bse nce of a nti p yretic me dicati o n).  
4.  Perf or m 1 2 -L ea d E C G, sh o ul d be perf or me d i n s u pi ne p ositi o n, after ≥5 mi n utes rest i n 
s u pi ne p ositi on . 
5.  Perf or m i nteri m hist or y , c o nce ntr ati n g o n a n y ac ute c o m plai nts. 
6.  O btai n wei g ht . 
7.  Perf or m c o m plete  p h ysical e xa mi nati o n . 
8.  F or a p plica ble pers o ns of c hil d beari n g p ote ntial , p erf or m -H C G testi n g . 
9.  R e vie w pre g n a nc y pre ve nti o n wit h t he s u bject. 

CI R 3 3 2  
 
9 7  
 
1 0.  C ollect ~ 3  m L of bl o o d f or P K a nal ysis.  Rec or d ti me of bl o o d sa m ple.  
1 1.  C ollect ~ 2 0  m L of bl o o d f or  D E N V -3 viral l oa d deter mi nati o n  (q ua ntitati ve P C R, pla q ue 
assa y, N S 1), q ualitati ve P C R, h u m oral i m m u nit y  (I g G, I g M, & ne utralizi n g a nti b o d y ), 
ser u m pr otei ns a n d viral ge n o me se q ue n ci n g.  
1 2.  C ollect ~ 3 0  m L of bl o o d  f or cell ular i m m u nit y ( P B M C). 
1 3.  C ollect ~ 2. 5  m L of bl o o d  f or h ost R N A assess me nts. 
1 4.  C ollect ~ 3  m L f or A 1 A G assess me nt . 
 
 U n a ntici p ate d A d missi o n a n d Disc h ar ge Criteri a  
If a p artici pa nt has a fe ver, t he y will be i nstr ucte d t o rec h ec k t heir te m perat ur e i n o ne h o ur p er pr ot oc ol. 
If fe v er persists, t he n partici pa nts will be as ke d t o ta ke aceta mi n o p he n, a n a nti p yretic. If t he partici pa nt 
re mai ns fe brile at o ne h o ur f oll o wi n g me dicati o n, t he y will be as ke d t o c o me t o t he cli nic f or 
e val uati o n. Cli nical e val u ati o n will c o nsist of assess me nt b y a cli nicia n, p h ysical e xa m, a n d l a b orat or y 
e val uati o n (c o m plete bl o o d c o u nt, ala ni ne a mi n otra nsferase [ A L T], i n ter nati o nal n or malize d rati o 
[IN R]/ partial t hr o m b o pl asti n ti me [ P T T]). If t he partici pa nt d oes n ot meet criteria f or a d missi o n as 
bel o w, t he n t he partici pa nt will be all o we d t o g o h o me a n d ret ur n t o t he cli nic t he ne xt d a y f or cli nici a n 
e val uati o n. If t he p artici pa nt d oes meet criteria f or a d missi o n as bel o w, t he n the i n patie nt sta y ma y 
ra n ge fr o m 3-9 da ys ( or l o n ger) d e pe n di n g o n cli nical s y m pt o ms.  D osi n g wit h J NJ-6 4 2 8 1 8 0 2/ place b o  
will c o nti n ue u nless s pecific pa usi n g criteri a are met.  
A d missi o n t o t he i n patie nt u nit or h os pital will u lti matel y be base d o n t he i n vesti gat or’s discreti o n 
w het her it is a p pr o pri ate f or t he partici pa nt t o be m o nit ore d i n t he i n patie nt u nit vers us se nt t o t he 
e mer ge n c y de p art me nt f or e val uati o n a n d treat me nt. Bel o w are g e neral g ui deli nes f or a d missi o n t o t he 
i n patie nt u nit or h os pital b ut t he decisi o n ulti matel y will be u p t o t h e i n vesti gat or’s discreti o n.  If t h e 
v ol u nteer is n ot ill e n o u g h t o warra nt a d missi o n t he i n patie nt u nit or h os pital b ut d oes n ot feel well 
e n o u g h t o c o me t o t he cli nic f or f oll o w -u p e va l uati o n, a tele-healt h visit will be d o ne.  
Criteria f or i n patie nt or h os pital a d missi o n w o ul d i ncl u de:  
B o d y te m perat ure > 3 8. 0° C ( 1 0 0. 4 ° F) f or > 1 2 h o urs wit h a n y o ne of t he f oll o wi n g:  
•  
O ne Gra d e 3 val ue f or a bs ol ute ne utr o p hil c o u nt ( A N C)  per t he m o difie d U S F D A To xicit y 
Gra di n g Scale  (A p pe n di x 1 : M o difie d U S F D A T o xicit y Gra di n g Ta ble ); O R 
•  
O ne Gra de 3 val ue or t w o Gra de 2 v al ues f or plat elets, A L T, or I N R/ P T T per t he m o di fie d 
U S F D A T o xicit y Gra di n g Scale ( A p pe n di x 1 : M o difie d U S F D A T o xicit y Gra di n g Ta ble ); 
O R  
•  
Cli nical e vi de nce of de h y drati o n wit h i na bilit y t o t olerate oral fl ui ds; O R 
•  
Cli nicia n discreti o n.  
T he u nit will be staffe d 2 4 h o urs a da y f or t he d urati o n of t he i n patie nt sta y. A cli nicia n will e val uate 
all s u bjects at least t wice per d a y f or t he d urati o n of t he i n p atie nt sta y a n d will be a v aila ble 2 4 h o urs a 
da y f or t he d urati o n of t he i n patie nt sta y s h o ul d he/s he b e nee de d. D uri n g t he i n patie nt sta y, t h e 
sc he d ule d acti vities fr o m t he Sc he dule of Pr oce d ures  (Ta bl e 3  [ C o h ort 1] a n d Ta ble 4  [C o h ort 2] ) will 
be  c o nti n ued  if a d mitte d t o t he i n patie nt u nit a n d if t he partici pa nt c o nti n ues t o c o nse nt. If a partici p a nt 
is a d mitte d t o t he h os pital the Sc he d ule of Pr oce d ures will be p a use d . D uri n g t he i n patie nt u nit sta y, 
the fre q ue n c y of vital si g ns m o nit ori n g will i ncrease t o at least 3 ti mes a da y a n d a d diti o nal cli nical 
la b orat or y st u dies ma y b e perf or me d t o f oll o w-u p o n a n y cli nical la b orat or y a b n or malities t hat m a y 

CI R 3 3 2  
 
9 8  
 
ha ve de vel o pe d d uri n g t he i n patie nt sta y. A d diti o nal dia g n ostic st u dies ma y be perf or me d s h o ul d t he 
s u bject’s cli nical c o n diti o n warra nt (e. g., c hest x-ra y [C X R ], ultras o u n d, a n d E C G). S h o ul d a s u bject 
lea ve t h e i n patie nt u nit earl y e v er y eff ort will b e ma de t o f oll o w-u p  wit h t he s u bject dail y t o m o nit or 
f or si g ns/s y m pt o ms of ill ness.  
T he partici pa nts will be disc har ge d fr o m t he i n patie nt u nit w he n t he y meet A L L  of t he f oll o wi n g 
disc har ge criteria:  
•  
Afe brile f or 4 8 h o urs.  
•  
A n y ot her c o nti n ui n g A Es ( p ossi bl y, pr o ba bl y, or relate d) are  Gra d e 2.  
•  
Relia ble cli nical f oll o w -u p ca n be ass ure d.  
All partici pa nts disc har ge d fr o m t he i n patie nt u nit or h os pital will fall bac k t o t he defa ult sc he d ule of 
dail y visits t o t he o ut patie nt c li nical trial u nit u ntil last d osi n g da y, if c o nti n ui n g o n treat me nt, a n d 
t hereafter at t he s p ecifie d ti me p oi nts d uri n g t he f oll o w-u p p hase . 
 De n g ue Me m or y E n h a nce me nt  C ar d  ( D M E C) 
O n St u d y Da y 1 , su bjects will be pr o vi de d a de n g ue me m or y e n ha nce m e nt car d w hic h is use d as  a 
me m or y ai d  t o hel p v ol u nteers re p ort te m perat ur e t o staff w he n t he y ret ur n at t he f oll o w-u p visits.  
T he y will be gi ve n t he car d o n t heir Da y 1  visit  a n d will be as ke d t o rec or d t heir te m perat ure t wi ce 
dail y t hr o u g h a n d i ncl u di n g D a y 2 9 (o n -site te m perat ur e rea di n gs ma y b e use d f or t he te m p erat ure 
rec or di n gs if v ol u nteer alrea d y has a site visit a n d will ha ve t heir te m perat ures ta ke n o n site). Staff will 
re vie w t he D M E C at eac h st u d y visit t hr o u g h St u d y Da y  2 9 a n d rec or d t he te m perat ure o n a s e parate 
s o urce d oc u m e nt.  
 
T he D M E C  will n ot be c ollecte d b y t he st u d y staff as s u bject’s rec or di n gs will n ot be c o nsi dere d 
re q uire d d ata. 
 
Staff will i nstr uct s u bjects h o w t o use t he t her m o meters, t o ta ke t heir te m perat ur es at a p pr o xi mat el y 
t he sa me ti mes eac h d a y, a n d t o ta ke a d diti o nal te m perat ures if t he y feel t he y ha ve ele vat e d 
te m perat ur es. S u bjects will be as ke d t o wait at least 1 5 mi n utes after eati n g, dri n ki n g, a n d s m o ki n g 
bef ore ta ki n g t heir t e m perat ures. T h e y will be as ke d t o c o nfir m a n ele vate d t e m perat ur e ( ≥1 0 0. 4° F) b y 
reta ki n g t he te m perat ur e after a 2 0-mi n ute i nter val a n d at 1 h o ur. 
Ele vate d t e m perat ures n ot 
d oc u me nte d t o last at  least 1 h o ur will n ot be c o nsi dere d a n A E or i ncl u de d i n t he a nal ysis. 
 
F oll o wi n g Da y 2 9, t e m perat ur e will o nl y be rec or de d ( o utsi de of r o uti ne rec or di n gs at st u d y visits) if 
t he v ol u nteer feels fe v eris h.  
 
 Cli nic al L a b or at or y Testi n g  
Usi n g sta n dar d tec h n i q ues, Q uest Dia g n ostics, or ot her C LI A certifie d la b orat ories will perf or m t he 
f oll o wi n g tests: 
1.  C B C wit h differe ntial  
2.  C he mistr y pa nel  
• S o di u m  
• P otassi u m  

CI R 3 3 2  
 
9 9  
 
• C hl ori de  
• Bicar b o nate  
• Bl o o d urea nitr o ge n ( B U N)  
• Creati ni ne  
• Gl uc ose  
• Calci u m  
• P h os p hate  
• Al b u mi n  
• T otal pr otei n  
• T otal c h olester ol  
• A S T  
• A L T  
• Ga m ma -gl uta m yltra nsf erase ( G G T)   
• T otal bilir u bi n  
• Al kali ne p h os p hatase  
• Uric aci d  
• Hi g h -de nsit y li p o pr otei n ( H D L) c h olester ol  
• L o w -de nsit y li p o pr otei n ( L D L) c h ol ester ol 
• Tri gl yceri des  
• Ma g nesi u m  (C o h ort 1 o nl y ) 
• Calc ulate creati ni ne cle ara nce ( b y M D R D f or m ula)  
• Li pase  
• A m ylase  
2.  A 1 A G  ( C o h ort 2 o nl y) 
3.  P T/ P T T  
4.  HI V assa y (scree ni n g a nti b o d y assa y wit h c o nfir m ati o n f or p ositi ve a nti b o d y assa ys)  
5.  He patitis B scree ni n g b y testi n g f or He patitis B S urface A nti ge n ( H Bs A g ) 
6.  He patitis C scree ni n g b y testi n g f or He patitis C a nti b o d y. If p ositi ve, test is c o nfir me d b y 
testi n g f or He patitis C R N A. If He patitis C a nti b o d y is p ositi ve b ut R N A is ne gati ve, t he 
v ol u nteer is assesse d as h a vi n g a past i nfecti o n t hat has bee n cleare d. I n t his case, t he s u bject 
is eli gi ble f or t he st u d y. 
7.  Uri nal ysis (i n t he e ve nt of a n a b n or m al uri ne di pstic k test)  
8.  Ser u m -H C G, if re q uir e d  
9.  Uri ne t o xic ol o g y scree n  

CI R 3 3 2  
 
1 0 0  
 
I n a d diti o n, cli nic staff m a y  perf or m a n Alc o h ol Breat h Test  at t he dis creti o n of PI/ pr o vi d er usi n g a 
c o m merciall y a v aila ble kit.  
Uri ne a n d s er u m -H C G testi n g will be perf or me d at t he cli nical tri al site usi n g a n F D A -a p pr o ve d 
pre g na nc y test kit. Uri ne di pstic k testi n g will be perf or me d at t he cli nical trial site usi n g a n F D A -
a p pr o ve d pr o d uct. I n t he e ve nt of a reacti ve -H C G  test, a ser u m sa m ple will be se nt t o t he a p pr o priate 
la b f or c o nfir mati o n. HI V testi n g ma y be p erf or me d at t he cli nical trial site usi n g a n F D A -a p pr o ve d 
ra pi d test kit or se nt t o t he cli nical la b orat or y. I n t he e ve nt of a reacti ve ra pi d HI V test, a ser u m sa m ple 
will be se nt t o t he a p pr o priate la b f or c o nfir mati o n. Deter mi nati o n of D E N V  vir us titer b y R T -P C R 
a n d vir us c ult ure, pla q u e re d u cti o n ne utr alizati o n a nti b o d y assa ys,  a nti viral acti vit y assess m e nts, 
p har mac o ki netic c o nce n trati o ns, h u m oral i m m u ne resp o nse, bi o mar ker assess me nts, viral ge n o m e 
se q ue nci n g, H L A ge n ot y pi n g a n d p har mac o ge n o mic e val uati o ns a n d cell ular i m m u ne st u dies will be 
d o ne  eit her at t he cli nical trial site la b orat or y  or at t he D D T’s i n dicate d site la b orat ory.  
 M e dic al Hist or y a n d C o nc o mit a nt Me dic ati o ns  
Partici pa nts  m ust ha ve disc o nti n ue d all me dicati o n, i ncl u di n g o ver -t he-c o u nter pr o d ucts, her bal 
me dicati o n, or dietar y s u p ple me nts s uc h as pr o d ucts c o ntai ni n g Hy peri c u m perf or at u m  ( St. J o h n’s 
w ort)  at le ast 7  da ys ( St u d y Da y -1 2  or l o n ger, base d o n half -life) bef ore first d ose of st u d y dr u g, 
e xce pt f or vita mi ns, paraceta m ol/acet a mi n o p he n, a ntic oa g ula nt me dicati o n, as piri n, or n o n -ster oi dal 
a nti-i nfla m mat or y dr u gs (N S AI Ds ), h or m o ne re place me nt t hera p y i n p ost me n o pa usal fe mal e 
partici pa nts , a n d ot her s elect me dicati o ns wit h restricti o ns liste d bel o w . C o ntrace pti ve me dicati o ns 
s h o ul d be c o nti n ue d a n d f oll o w t he re q uire m e nts as liste d i n t he i ncl usi o n/e xcl usi o n criteria.  
T he f oll o wi n g  me dicati o n s ot her t ha n t he st u d y dr u g are all o we d d uri n g (a part of) t he st u d y: 
•  Vita mi ns  
•  A ceta mi n o p he n  [ T Y L E N O L] a n d i b u pr ofe n [ A D VI L or M O T RI N ] ma y b e use d u p t o  3 d a ys 
bef ore first d ose of st u d y dr u g (C o h ort 1 Da y  -8  a n d C o h ort 2  Da y -5 ). After t hat, t he 
i n vesti gat or ma y per mit t he use of aceta mi n o p he n /i b u pr ofe n fr o m 3 da ys b ef ore first d ose of 
st u d y dr u g u ntil t he last P K sa m ple has bee n ta ke n  ( St u d y Da y 8 5) at ≤2 0 0 0  m g per da y , a n d 
≤5  gra ms per wee k  f or aceta mi n o p he n a n d u p t o 1 2 0 0  m g  per da y  a n d < 5 g ra ms per wee k  f or 
I b u pr ofe n. I n case aceta mi n o p he n /i b u pr ofe n is use d, t he date a n d ti me of d osi n g, t he i n dicati o n, 
t he d ose, a n d t he d osi n g re gi me n m ust be rec or de d i n t he C o nc o mita nt T hera p y Secti o n of t he 
C R F.  If p ossi ble, partici pa nts s h o ul d a v oi d ta ki n g aceta mi n o p he n /i b u pr ofe n wit hi n 6 h o urs 
bef ore m eas uri n g b o d y te m perat ure.  
•  Occasi o nal use of as piri n or N S AI Ds  [e xc e pt f or i b u pr ofe n; see g ui da nce a b o ve] is all o we d at 
t he discreti o n of t he i n vesti gat or a n d o n a  cas e-b y -case disc ussi o n wit h J a nsse n. As piri n ca n 
i nterfere wit h t he a bilit y of t he bl o o d t o cl ot. It is n ot a ntici pate d t hat a n y partici pa nts will ha ve 
se vere D E N V  i nfecti o n wit h blee di n g pr o ble ms, h o we ver, it is still rec o m me n de d t o a v oi d t hese 
dr u g s. T he i n vesti gat or ma y rec o m me n d aceta mi n o p he n or a n e q ui vale nt , w hic h ca n be use d 
safel y f or fe v ers a n d b o d y ac hes. I n case a ntic o a g ula nt me dicati o n  as piri n, or N S AI Ds are us e d, 
t he date a n d ti me of dosi n g, t he i n dicati o n, t he d ose, a n d t he d osi n g re gi me n m ust be rec or de d 
i n t he C o nc o mita nt T hera p y Secti o n of t he C R F.  

CI R 3 3 2  
 
1 0 1  
 
•  Sta ble h or m o ne re pla ce me nt t hera p y (ie, sa me d ose a n d n ot starti n g or st o p pi n g h or m o ne 
re place me nt t hera p y f or 2 wee ks b ef ore  first d os e of st u d y dr u g  u ntil t he e n d of t he st u d y)  i n 
p ost me n o pa usal fe male partici pa nts is all o we d. It s h o ul d be n ote d t hat J NJ-6 4 2 8 1 8 0 2  ma y 
affect t he effecti ve ness of h or m o ne re place me nt t hera p y a ge nts w he n c o a d mi nistere d.  T he use 
of h or m o ne re place me nt t hera p y m ust  be rec or de d i n t he C o nc o mita nt T hera p y Secti o n of t he 
C R F. A p plica ble pr oce d ures a n d treat me nt g ui d a nce bas e d o n pac ka g e i nserts s h o ul d be 
res pect e d. 
•  Certai n ot her m e dicati o ns are all o we d i n cl u di n g metf or mi n , le v ot h yr o xi n e, H 1 a n d H 2 rece pt or 
a nta g o nists , wea k C Y P 3 A 4 i n hi bit ors, , selecti ve ser ot o ni n re u pta ke in hi bit ors, selecti ve 
n ore pi ne p hri ne 
re u pt a k e 
in hi biti ors, 
tric ylclic 
anti -de pressa nts, 
a n xi ol o ytics, 
a n d 
b e nz o diaze pi nes   
Ot her c o me dicati o n is all o we d i n t he f oll o wi n g cases:  
•  
I n case of c uta ne o us reacti o n/ras h a n d/ or a n aller gic reacti o n, t he use of cetirizi ne, 
le v ocetirizi ne, t o pic al c ortic oster oi ds, or a nti pr uritic a ge nts i n t he rec o m me n de d d ose sc he m e 
is per mitte d. 
•  
I n case of se vere na us ea, t he use of a nti-e m etics, e xce pt d o m p eri d o ne, is per mitte d.  
I n case a n y of t h ese me dicati o ns are us e d, t he d ose a n d d osi n g re gi me n m ust be rec or de d i n t he 
C o nc o mita nt T hera p y Secti o n of t he C R F.  
P artici pa nts m ust n ot recei ve  i n vesti gati o nal vacci nes fr o m 6 m o nt hs bef ore first d ose of st u d y dr u g 
u ntil 9 0 da ys after last d ose of st u d y dr u g,  lice ns e d li ve atte n uate d v acci n es fr o m 2 8 da ys bef ore first 
d ose of st u d y dr u g u ntil 2 8 da ys after last d ose of st u d y dr u g, or ot her lice ns e d ( n ot li ve) vacci nes fr o m 
1 4  da ys bef ore first d ose of st u d y dr u g u ntil 1 4 da ys after last d ose of st u d y dr u g.  C O VI D -1 9  lice ns e d 
or E U A vacci nes are all o we d t o be recei ve d at a n y p oi nt d uri n g t he st u d y.  V acci nati o ns  a g ai nst D E N V 
a n d ZI K V  are n ot all o we d u ntil 9 0 d a ys after last d ose of st u d y dr u g.  I n case t he p artici pa nt is 
vacci nat e d, t he d ose m ust be rec or de d i n t he C o nc o mita nt T hera p y Secti o n of t he C R F. 
Partici pa nts m ust n ot use a n y  i m m u n os u p pressi ve c ortic oster oi ds (e xcl u di n g t o pical a n d nasal) or 
i m m u n os u p pressi ve dr u gs fr o m 2 8 da ys b ef ore first d ose of st u d y dr u g  u ntil 2 8  da ys after last d ose of 
st u d y dr u g . A n  i m m u n os u p pressi ve d ose of c ortic oster oi ds is defi ne d as ≥1 0 m g pre d nis o ne e q ui vale nt 
per da y f or ≥1 4 da ys. I n case i m m u n os u ppressi v e c ortic oster oi ds or i m m u n os u p pressi ve dr u gs  are 
use d, t he date a n d ti me of d osi n g, t he i n dicati o n, t he d ose, a n d t he d osi n g re gi me n m ust be rec or de d i n 
t he C o nc o mita nt T hera p y Secti o n of t he C R F. 
Partici pa nts m ust n ot use a n y  str o n g C Y P 3 A 4 i n hi bit o rs (e g, clarit hr o m yci n, itrac o naz ole) [ wea k 
C Y P 3 A 4 i n hi bit ors are all o we d ], C Y P 3 A 4 i n d ucers (e g, p he n yt oi n, rifa m pi n), or s u bstrates f or 
C Y P 3 A 4 wit h a narr o w t hera pe utic ra n g e (e g, alfe nta nil, c ycl os p ori n ), U G T 1 A 9 i n hi bit ors or i n d ucers 
(e g, pr o be neci d, rifa m pi n, mefe na mic aci d), C Y P 2 C 8 (e g, re pa gli ni de), C Y P 2 C 9 (e g, warfari n, 
t ol b uta mi de), B C R P (e g , Pra vastati n a n d f olic aci d),  or C Y P 2 C 1 9 (e g,  S -me p he n yt oi n, o me praz ol e) 
fr o m 1 4 da ys bef ore first d ose of st u d y dr u g u ntil 2 8  da ys  after last d ose of st u d y dr u g. I n cas e a n y of 
t hese i n hi bit ors or s u bstrates are use d, t he dat e a n d ti me of d osi n g, t he i n dicati o n, t he d ose, a n d t he 
d osi n g re gi me n m ust be rec or de d i n t he C o n c o mita nt T hera p y Secti o n of t he C R F.  

CI R 3 3 2  
 
1 0 2  
 
If me dical c o n diti o ns n ot relate d t o t he st u d y arise af ter i n oc ul ati o n a n d dict ate t he use of m e dicati o ns, 
partici pa nts are e nc o ura g e d t o o btai n a p pr o priate care, c o m pl y wit h t he c o urse of t hera p y as prescri b e d 
b y t heir p h ysicia n, a n d i nf or m t he i n vesti gat or as s o o n as p ossi ble . T he  D D T m ust be n otifie d i n 
a d va nce ( or as s o o n as p ossi ble t hereafter) of a n y i nsta nces i n w hic h pr o hi bite d t hera pies are 
a d mi nistere d. F or a n y c o nc o mita nt t hera p y gi ve n as a tr eat me nt f or a n e w c o n diti o n or a w orse ni n g of 
a n e xisti n g  c o n diti o n  (relati ve t o t he mo me nt of si g ne d I C F) , t he c o n diti o n m ust be d oc u me nte d i n t he 
A d verse E v e nt Secti o n of t he C R F.   
C o nc o mita nt t hera pies m ust be rec or de d i n t he C R F t hr o u g h o ut t he st u d y fr o m t he scree ni n g visit 
perf or me d b et wee n Da ys -1 2  a n d -6 u ntil t he last st u d y -relate d acti vit y, or u ntil t he partici pa nt has 
bee n dee me d l ost t o f oll o w -u p aft er d e m o nstrati o n of d ue dili ge nce of f oll o w -u p eff orts . If a v ol u nteer 
is scree n e d b ut n ot s u bse q ue ntl y e nr olle d, c o n c o mita nt t hera p y will n ot be f oll o we d fr o m t he ti me t he 
partici pa nt  is d ee me d i neli gi ble or e nr oll me nt is c o m plete wit h o ut t he s u bject recei vi n g t he t est article.  
 Rete nti o n of St u d y S u bjects  
We will e m pl o y se v eral strate gies ai me d at retai ni n g s u bjects t hr o u g h st u d y c o m pleti o n. D uri n g 
scree ni n g, w e will o btai n detaile d pri mar y l o cat or i nf or mati o n, as well as sec o n dar y c o nt act 
i nf or mati o n. S u bjects will als o pr o vi de i nf or m ati o n f or pe o pl e w h o ma y be c o ntacte d if pri mar y a n d 
sec o n dar y mea ns of c o nt act fail. L ocat or i nf or mati o n will be re vie we d wit h s u bjects at eac h visit ( i.e., 
a d dresses, p h o n e n u m bers, e mail a d dresses). I n a d diti o n, birt h da y car ds/ h oli da y car ds ma y b e maile d 
t o c hec k a d dress es, a n d re mi n ders ma y b e se nt usi n g vari o us met h o ds (i n cl u di n g b ut n ot li mite d t o 
p h o ne, e mail, te xt mess a gi n g, electr o nic me dia, a n d p ostal m ail). All d ata will be mai ntai ne d a n d 
u p date d i n a pass w or d pr otecte d l ocat or d ata bas e.  
8  
A d verse E ve nt  M o nit ori n g  
 
Defi niti o ns  
8. 1. 1  A d verse E ve nt  
A n y u nt o war d or u nfa v ora ble me dical occ urre nce i n a h u ma n s u bject, i ncl u di n g a n y a b n or mal si g n 
(e. g. a b n or mal p h ysical e xa m or la b orat or y fi n di n g), s y m pt o m, or diseas e, te m p orall y ass ociate d wit h 
t he s u bject’s partici p ati o n i n t he researc h, w het her or n ot c o nsi dere d relat e d t o t he researc h. 
All A Es will be e val uate d f or se verit y, acti o n ta ke n, seri o us ness, o utc o m e a n d relati o ns hi p t o 
eit her/ b ot h test articles as descri be d i n secti o n 8  i n t his pr ot oc ol. 
If a dia g n osis is cli nicall y e vi de nt ( or s u bse q ue ntl y deter mi ne d), t he dia g n osis rat her t ha n t he i n di vi d ual 
si g ns a n d s y m pt o ms or la b a b n or malities will be rec or de d as t he A E. A Es will be c ollecte d f or t he 
d urati o n of t he st u d y  be gi n ni n g st u d y s pecific c o nse nti n g a n d a n y test article -rel ate d A Es i de ntifie d 
t hr o u g h o ut t he st u d y peri o d will be f oll o we d u ntil res ol uti o n.  If a s u bject c o nse nts b ut is n ot 
s u bse q ue ntl y e nr olle d, A Es f or t hat s u bject will n ot be f oll o we d fr o m t he ti me t he s u bject is dee me d 
i neli gible f or e nr oll me nt  or e nr oll me nt is c o m plete wit h o ut t he s u bject recei vi n g t he test article.  
A Es are cate g oriz e d as s olicite d A Es a n d ot her A Es. S olicite d A Es i ncl u de l ocal react o g e nicit y,  
s yste mic react o ge nicit y, a n d la b orat or y e ve nts. S olicite d A Es are t h ose e ve nts t hat t he cli nicia n is 
s pecificall y e val uati n g are liste d i n T a ble 1 3 . All A Es are e val uate d usi n g t he A d verse E v e nt Gra di n g 
Ta ble i n 1 3. 1 , A p pe n di x 1.  

CI R 3 3 2  
 
1 0 3  
 
All a b n or mal la b orat or y fi n di n gs will be re vie we d o n a r o uti ne basis  b y t he PI t o i de ntif y p ote nti al 
safet y si g nals. A n a b n or mal la b n ot i ncl u de d o n t he t o xicit y ta ble s h o ul d be assesse d i n a si milar 
fas hi o n t o t he criteri a a b o ve. 
8. 1. 2  A d verse R e acti o n  
A n a d vers e reacti o n is a n A E t hat is ca use d b y a n i n vesti gati o nal a ge nt ( dr u g or bi ol o gic).  
8. 1. 3  S us pecte d A d verse Re a cti o n ( S A R)  
A n A E  f or w hic h t here is a reas o na bl e p ossi bilit y t hat t he i n vesti gati o nal a ge nt ca use d t he A E . 
“ Reas o na ble p ossi bilit y” mea ns t hat t here is e vi de nce t o s u g gest a ca us al relati o ns hi p bet wee n t he test 
article a n d t he A E . A s us pecte d a d v erse reacti o n ( S A R) i m plies a lesser de gree of certai nt y a b o ut 
ca usalit y t ha n a d verse reacti o n t hat i m plie d a hi g h de gree of certai nt y.  
 
T a ble 1 3 : S olicite d A d verse E ve nts 
S yste mic Re act o ge nicit y  
 
L oc al Re act o ge nicit y  
 -Fe v er  
 
 -I njecti o n site pai n 
 -Hea d ac he  
 
 -I njecti o n site er yt h e ma 
 -Retr o -or bital pai n ( R O P)  
 
 -I njecti o n site te n der ness 
 -Na usea  
 
 -I njecti o n site i n d urati o n 
 -Fati g ue  
 
 -I njecti o n site pr uritis 
 -M yal gia  
 
 
 -Art hral gia  
 
 
 -Dr u g  Ras h  
 -Ras h  Mac ul o -Pa p ular  
 
 
 -L oss of A p petite  
 
 
 -V o miti n g  
 
 
 -Diarr h ea  
 
 
 -A b d o mi nal Pai n  
 
 
 
8. 1. 4  Pre g n a nc y  
Pre g na nc y itself is n ot a n A E. H o we v er, c o m plicati o ns of pre g na n cies are A Es a n d ma y be s eri o us 
a d verse e ve nts ( S A Es). E ve nts t hat meet S A E criteria d uri n g pre g n a nc y, deli ver y, or i n t he ne o n ate 
(e. g., c o n ge nital a n o mal y/ birt h defect) are re p ortable t o t he Cli nical Safet y Office ( C S O) per t he 
s p o ns or’s re p orti n g g ui deli nes. Perti ne nt o bstetrical i nf or mati o n f or all pre g na ncies will be re p orte d t o 
t he C S O via t he R E D Ca p re p orti n g s yste m wit hi n 1 b usi ness da y fr o m site a ware n ess of t he pre g na nc y 
o n t he Pre g na nc y N otificati o n a n d O utc o me F or m. 
Pre g na nc y o utc o m e data (e. g., deli ver y o utc o me, s p o nta ne o us or el ecti ve ter mi nati o n of t he pre g na n c y) 
will be re p orte d t o t he C S O wit hi n 3 b usi ness da ys of t he site’s a ware ness o n a pr ot oc ol -s p ecifie d f or m. 
If a v ol u nteer bec o mes pre g na nt, s h e will n ot b e i ncl u de d i n t he per pr ot oc ol a nal ysis b ut will be 
i ncl u de d i n t he i nte nt-t o-treat (I T T) a n al ysis  
•  T he pre g n a nc y will be re p orte d t o t he D S M B a n d/ or I R B (if a p plica ble).  
•  T he pre g n a nc y will be re p orte d t o Ja nsse n D r u g De vel o p me nt Tea m.  

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8. 1. 5  Seri o us A d verse E ve nt ( S A E)  
A n S A E is a n A E t hat is deter mi ne d t o be “seri o us” w het her c o nsi dere d relate d t o t he i n vesti gati o nal 
a ge nt or n ot. S A Es will be c ollecte d f or t he d urati o n of t he trial. A n S A E res ults i n 1 or m ore of t h e 
foll o wi n g o utc o mes:  
•  Deat h d uri n g t he p eri o d of pr ot oc ol -defi ne d s ur veilla nce  (e nr oll me nt t hr o u g h st u d y disc har ge). 
•  Life t hreate ni n g e ve nt, d efi ne d as a n e v e nt t hat pl aces a s u bject at i m me diate ris k of d eat h at 
t he ti me of t he e ve nt a n d d oes n ot refer t o a n e ve nt t hat h y p ot heticall y mi g ht ha ve ca use d d eat h 
were it m ore s e vere.  
•  I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, defi ne d as at least a n 
o ver ni g ht sta y i n t he h os pital or e mer ge nc y war d f or tr eat me nt t hat w o ul d ha ve bee n 
i na ppr o priate if a d mi nistere d i n t he o ut patie nt setti n g.  
•  C o n ge nital a n o mal y or birt h defect.  
•  Persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
•  Ot her me dicall y i m p orta nt e ve nt * . 
* Me dical a n d scie ntif ic j u d g me nt s h o ul d be e xercise d i n d eci di n g w het her e x p e dite d re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life 
t hreate ni n g or res ult i n deat h or res ult i n h os pitalizati o n b ut ma y je o par dize t he s u bject or ma y re q uire 
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. T hese will als o us uall y be c o nsi dere d seri o us. 
Eac h A E will be cl assifie d b y t he i n vesti gat or/ desi g nee as “seri o us ” or “ n o n -seri o us.” A S A E nee ds t o 
meet o nl y 1 or m ore of t h e a b o ve criteria t o be c o nsi dere d seri o us.  
8. 1. 6  U ne x pecte d A d ve rse E v e nts  
A n A E  is c o nsi dere d u ne x pecte d if it is n ot liste d i n t he I B or Pac k a ge I ns ert (f or mar k ete d pr o d ucts) 
or is n ot liste d at t he s pecificit y or se verit y t hat has bee n o bser ve d. “ E x pecte d” d oes n ot mea n t hat t he 
e ve nt is e x p ecte d wit h p har mac ol o gicall y si milar dr u gs, t h e u n derl yi n g disease(s) or c o nc o mita nt 
me dicati o n s. It is t he res p o nsi bilit y of t he I N D S p o ns or t o ma ke t his deter mi nati o n. 
8. 1. 7  Seri o us a n d U ne x pecte d S us pecte d A d verse Re acti o n ( S U S A R)  
A S U S A R is a S us pecte d A d verse Reacti o n t hat is b ot h Seri o us a n d U ne x p ecte d.  
8. 1. 8  U n a ntici p ate d Pr o ble m  
A n U na ntici pate d Pr o ble m  ( U P) is a n y e ve nt, i nci de nt, e x perie n ce, or o utc o me t hat is: 
1.  u ne x pecte d i n ter ms of n at ure, se v erit y, or fre q ue nc y i n relati o n t o  
a. t he researc h ris ks t hat are descri be d i n t he I R B-a p pr o ve d res earc h pr ot oc ol 
a n d i nf or me d c o ns e nt d oc u me nt; I B or ot h er st u d y d oc u me nts; a n d  
b.  t he c haracteristics of t he s u bject p o p ulati o n bei n g st u die d; a n d 
2.  p ossi bl y, pr o ba bl y,  or defi nitel y relate d t o partici p ati o n i n t he researc h; a n d  
3.  places s u bjects or ot hers at a greater ris k of har m (i ncl u di n g p h ysical, ps yc h ol o gical, 
ec o n o mic, or s ocial h ar m) t ha n was pre vi o usl y k n o w n or rec o g nize d. ( A n A E wit h a seri o us 
o utc o me will be c o nsi dere d i ncrease d ris k).  

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8. 1. 9  U n a ntici p ate d Pr o ble m t h at is n ot a n A d verse E ve nt ( U P n o n A E)  
A n u na ntici pate d pr o ble m t hat d oes n ot fit t he defi niti o n of a n A E , b ut w hic h ma y, i n t he o pi ni o n of 
t he i n vesti gat or, i n v ol ve ris k t o t he s u bject, affect ot hers i n t he researc h st u d y, or si g nifica ntl y i m pact 
t he i nte grit y of res earc h data. S uc h e v e nts w o ul d be c o nsi dere d a n o n-seri o us U P. F or e x a m ple, we 
will re p ort occ urre n ces of breac hes of c o nfi de ntialit y, acci de ntal destr u cti o n of st u d y rec or ds, or 
u nacc o u nte d -f or st u d y dr u g. 
8. 1. 1 0  Pr ot oc ol D e vi ati o n  
A pr ot oc ol de viati o n is a n y c ha n ge, di ver ge n ce, or de part ure fr o m t he st u d y desi g n or pr oce d ures i n 
a n I R B -a p pr o ve d res earc h pr ot oc ol t hat has a maj or i m pact o n t he s u bject’s ri g hts, safet y, or well -
bei n g a n d/ or t he c o m plete ness, acc urac y,  or relia bilit y of t he st u d y d ata. Pr ot oc ol d e viati o ns are 
desi g nate d as seri o us or n o n -seri o us a n d f urt her c haract erize d as:  
1.  T h ose t hat occ ur beca use a me m ber of t h e res earc h tea m de viates fr o m t he pr ot oc ol  
2.  T h ose t hat are i d e ntifie d bef ore t h e y occ ur b ut ca n n ot be pre ve nte d  
3.  T h ose t hat are dis c o vere d after t he y o cc ur  
8. 1. 1 1  Seri o us Pr ot oc ol De vi ati o n  
A seri o us pr ot oc ol de vi ati o n is a n y c ha n ge, di ver ge nce, or de p art ure fr o m t he st u d y desi g n or 
pr oce d ures i n a n I R B -a p pr o ve d researc h pr ot oc ol t hat has a maj or i m pact o n t he s u bject’s ri g hts, safet y, 
or well -bei n g a n d/ or t h e c o m plete ness, acc urac y,  or relia bilit y of t he st u d y data.  
8. 1. 1 2  N o n -c om pli a nce  
T he fail ure t o c o m pl y wit h a p plica ble NI H H u ma n Researc h Pr ot ecti o n Pr o gra m ( H R P P) p olicies, 
I R B re q uire me nts, or re g ulat or y re q uire m e nts f or t he pr otecti o n of h u ma n s u bjects. N o n-c o m plia nce 
is f urt her c h aracteriz e d as: 
1.  Seri o us: N o n -c o m plia nce t ha t 
a. 
I n creases ris ks, or ca uses har m, t o s u bjects 
b.  
Decreases p ote ntial b e nefits t o s u bjects  
c. 
C o m pr o mises t he i nte grit y of t he NI H -H R P P  
d.  
I n v ali dates t he st u d y data 
2.  
C o nti n ui n g: N o n -c o m plia nce t hat is rec urri n g  
3.  
Mi n or: N o n -c o m plia nce t hat, is neit her seri o us n or c o nti n ui n g  
8. 1. 1 3  Pre -E xisti n g C o n diti o ns, W orse ni n g of Pre -e xisti n g C o n diti o n  
Sta ble c hr o nic c o n diti o ns w hic h are prese nt pri or t o st u d y s pecific c o nse nti n g a n d d o n ot w orse n are 
n ot c o nsi dere d A Es a n d will be acc o u nt e d f or i n t he s u bject’s me dical hist or y. E xacer bati o n or 
w orse ni n g of pre -e xisti n g c o n diti o ns are defi n e d as A Es a n d are e v al uat e d usi n g t he sa me criteria 
descri be d i n secti o n 8. 2  i n t his pr ot oc ol. 
 
Assess m e nt  of A d verse E ve nts  
8. 2. 1  I de ntific ati o n of A d vers e E ve nts 
All A Es occ urri n g fr o m t he ti me t he s u bject si g ns st u d y specific co ns e nt  t hr o u g h t he e n d of t he st u d y 
will be d oc u me nte d, rec or de d, a n d re p orte d.  If t he s u bject si g ns t he c o nse nt b ut is n ot s u bse q ue ntl y 
e nr olle d, A Es will n o l o n ger be c ollecte d fr o m t he ti me t he s u bject is dee me d i neli gi ble f or e nr oll me nt  
or e nr oll me nt is c o m plete wit h o ut t he s u bject rec ei vi n g test article . T he  I n v esti gat or will assess all A Es 

CI R 3 3 2  
 
1 0 6  
 
wit h res pect t o Seri o us ness, Se verit y, a n d  Ca usalit y  acc or di n g t o t he f oll o wi n g g ui deli nes.  A n 
assess me nt of safet y will i ncl u de cli nical o bser vati o ns a n d m o nit ori n g of he mat ol o gical,  bl o o d 
c he mistr y, a n d i m m u n ol o gic para meters. Safet y will be e v al uate d b y m o nit ori n g t he  s u bjects f or l o cal 
a n d s yste mic a d vers e reacti o ns d uri n g t he c o urse of t he trial.  
 
C o h ort 1: S u bjects will be  cl osel y m o nit ore d f or 3 0 mi n utes f oll o wi n g  a d mi nistrati o n of st u d y 
a ge nt(s) at i n pers o n visits u ntil Da y 3 of d osi n g . S u bjects will be see n  i n t he cli nic nearl y e v er y 
ot her da y  bet wee n  St u d y Da ys -6  a n d 2 9 . A n o ver ni g ht a d missi o n  t o t he i n patie nt u nit will occ ur 
o n St u d y Da ys -6 t o -4  f or a peri o d of i nte nsi ve P K sa m pli n g. A d diti o nall y, s u bjects will ret ur n t o 
t he cli nic o n St u d y Da ys 3 6, 4 3, 5 0, 5 7, 6 3, 7 0 a n d 8 5  at a mi ni m u m, a n d ma y be as ke d t o ret ur n 
m ore ofte n if warra nte d.  Tele p h o ne visits will occ ur o n St u d y Da ys  -3, -2, 2, 4, 6, 8, 1 0, 1 2,  1 3,  1 5, 
1 7 , 19 , a n d 2 0  t o gat her rele va nt st u d y i nf or mati o n  a n d assess f or A Es .  
 
C o h ort 2:  S u bjects will be cl osel y m o nit ore d f or 3 0 mi n utes f oll o wi n g a d mi nistrati o n of st u d y 
a ge nt(s) at i n pers o n visits u ntil Da y 1 of d osi n g. S u bjects will be see n i n t he cli nic e ver y 2 -3 da ys 
bet wee n disc har ge fr o m t he i n patie nt u nit a n d St u d y Da y 2 1 . A n o ver ni g ht a d missi o n t o t he 
i n patie nt u nit will occ ur o n St u d y Da ys -3 t o 1 f or a peri o d of i nte nsi ve P K sa m pli n g. A d diti o nall y, 
s u bjects will ret ur n t o t he cli nic e ver y 3 -4 da ys b et wee n St u d y Da y 2 5  a n d St u d y Da y 3 6; a n d e v er y 
1  t o 2  wee ks t hereafter u ntil St u d y Da y 8 5 . If a p artici pa nt tests p ositi ve f or D E N V-3 R N A o n St u d y 
D a y 25  (or St u d y D a y 2 1 if 2 5 is n ot a vaila ble), a d diti o nal visit o n D a y 2 7 a n d D a y 3 4 s h o ul d o cc ur 
mea ni n g 2 -3 da ys sa m pli n g is re q uire d . O ut patie nt st u d y visits will occ ur o n St u d y Da ys 4, 6, 8, 1 1, 
1 3, 1 5, 1 8, 2 1, 2 5, 2 9, 3 2, 3 6, 4 3, 5 7, 7 0, a n d 8 5 at a mi ni m u m , a n d partici pa nts ma y be as ke d t o 
ret ur n m ore ofte n if warra nte d.   
 
St u d y  staff will re vie w s u bjects’ re p orte d te m perat ures a n d/ or cli nical te m p erat ur es fr o m St u d y Da y 1 
t hr o u g h St u d y Da y 2 9  t o assess f or A Es. At eac h visit t hr o u g h S t u d y D a y 2 9 , s u bjects will be q u erie d 
a b o ut p ossi ble  st u d y dr u g/c halle n ge-relate d A Es (s olicite d A Es) a n d will ha ve a f oc use d p h ysical e x a m 
perf or me d  e xcl u di n g C o h ort 1 Da y -6  a n d C o h ort 2 Da y -3 . A st u d y cli nicia n will be a vaila ble t o 
s u bjects b y tele p h o ne or pa ger 2 4 h o urs a da y d uri n g t he  st u d y e val uati o n peri o d. 
 
All A Es will be rec or de d  (e. g., i n t he st u d y-s pecifie d case re p ort f or m [ C R F]/researc h data base) 
t hr o u g h t he d urati o n of t he st u d y, u nless as state d a b o ve t he s u bject si g ns c o nse nt b ut is n ot 
s u bse q ue ntl y e nr olle d.  
 
All S A Es will be assesse d a p pr o priatel y as A Es a n d re p orte d f oll o wi n g S A E re p orti n g g ui deli nes  
o utli ne d i n secti o n 8. 3. 2  of t his pr ot oc ol.  
 
8. 2. 2  P r ot oc ol -S pecifi c A d verse E ve nt Defi niti o ns  
Fe ver:  Te m perat ure ≥ 1 0 0. 4° F lasti n g at least 1 h o ur . 
Dr u g  R as h:  Dr u g i n d uce d e xa nt he m; a c uta ne o us reacti o n t o a dr u g  t y picall y c haracterize d b y 
hi ves, a n d/ or blisters, a n d/ or er yt he ma, c o nsiste nt wit h dr u g ras h. 
R as h  M ac ul o -P a p ul ar : Areas of mac ular or mac ul o -pa p ular ras h o ver t he tr u n k a n d / or e xtr e mities 
a n d ma y i ncl u de t he face/ nec k area as well , si milar t o de n g ue li ke ras h s ee n i n pre vi o us de n g ue 
c halle n ge st u dies . 
He a d ac he:  A pai n l ocat e d i n t he hea d, o v er t h e e y es, at t he te m ples, or at t h e base of t h e s k ull.  
R O P:  Bilateral pai n sit uate d be hi n d t he or bits of t he e ye . 
N a use a:  Disc o mf ort i n t he st o mac h wit h a n ur g e t o v o mit . 
F ati g ue:  E xcessi ve tire d ness f oll o wi n g mi ni mal e xerti o n . 

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M y al gi a:  Pai n i n t he m uscles t hat is f o u n d i n > 2 m uscle gr o u ps . 
Art hr al gi a:  Pai n t hat is f o u n d i n > 2 j oi nts.  
L oss of A p petite:  D ecrease d desire t o eat, u ni nte nti o nal wei g ht l oss a n d n ot feeli n g h u n gr y . 
V o miti n g:  A dis or der c haract erize d b y t he refle xi ve act of e jecti n g t he c o nte nts of t he st o mac h 
t hr o u g h t he m o ut h.  
Di arr he a:  A dis or d er c haract erize d b y a n i ncrease i n fre q ue nc y a n d/ or l o ose or water y b o wel 
m o ve me nts.  
A b d o mi n al p ai n: A dis or der c haracteri ze d b y a se nsati o n of mar k e d disc o mf ort i n t he a b d o mi nal 
re gi o n, lasti n g at least se veral mi n utes.  
 
8. 2. 3  Deter mi n ati o n of Se verit y  
T he i n vesti gat or/ desi g ne e will assess all A E se verit y usi n g t he f oll o wi n g classificati o ns.  
 
T a ble 1 4 : Se verit y Defi niti o ns  
Se verit y  
Defi ne d  
Gra de 1 ( Mil d)  
E ve nt t hat is easil y t olerate d, ma y re q uir e 1 d ose of me dicati o n/treat me nt 
Gra de 2 ( M o derate)  
E ve nt t hat i nterferes wit h dail y acti vit y or re q uir es m ore t ha n 1 d ose of 
me dicati o n/treat me nt  
Gra de 3 ( Se vere)  
E ve nt t hat pre ve nts dail y acti vit y a n d re q uir es me dical i nter ve nti o n 
Gra de  4  ( Life-
t hreate ni n g) 
A n A E  t hat is dee me d b y t he st u d y cli nicia n, t he me dical m o nit or, or a n 
o utsi de cli nicia n cari n g f or t he s u bject t o be a life -t hreate ni n g e v e nt 
Gra de 5 ( Deat h)  
A n y A E  t hat res ults i n t he deat h of t he s u bj ect 
 
S olicite d A E se verit y gr a di n g classificati o ns are liste d i n  Ta ble 1 5 . All ot her A Es will be gra de d i n 
se verit y usi n g t he A d v erse E ve nt Gra di n g T a ble in  A p pe n di x 1 : M o difie d U S F D A T o xicit y 
Gra di n g Ta ble . 
 
T a ble 1 5 : L oc al a n d S olicite d A d verse E ve nts  
L oc al Re act o ge nicit y  
Gr a de  
Se verit y  
I njecti o n Site Te n der ness  
I njecti o n Site Pr uritis  
I njecti o n Site Pai n 
 
1  
2  
 
3  
E ve nt t hat is easil y t olerate d, ma y re q uire 1 d ose of me dicati o n  
E ve nt t hat i nterferes wit h dail y acti vit y or re q uires > 1 d ose of 
me dicati o n  
E ve nt t hat pre ve nts dail y acti vit y  
4  
Life -t hreat e ni n g 
I njecti o n Site I n d urati o n 
I njecti o n Site Er yt he ma 
1  
2  
3  
> 0 - 2 0 m m  
> 2 0 - 5 0 m m  
> 5 0 m m  
4  
Life t hreate ni n g  
S yste mic Re act o ge nicit y  
Gr a de  
Se verit y  
Fe ver ( oral)  
1  
2  
3  
1 0 0. 4° F –  1 0 1. 4° F  
1 0 1. 5° F –  1 0 2. 4° F  
≥1 0 2. 5° F  
4  
Life -t hreat e ni n g 
Ras h  Mac ul o -Pa p ular  
1  
Ras h is prese nt b ut as y m pt o matic  a n d  ma y re q uire o ne d ose of 
me dicati o n.  
2  
Ras h is s y m pt o matic ( pr urit us/ pai n) , a n d / or re q uires m ore t ha n o ne 
d ose  of me dicati o n b ut  d oes n ot i nterfere wit h f u ncti o n.  
3  
Ras h is s y m pt o matic a n d i nterferes wit h f u ncti o n  
4  
Life -t hreat e ni n g 

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Dr u g Ras h  
1  
Ras h is prese nt b ut as y m pt o matic a n d 
ma y re q uire o ne d ose of 
me dicati o n.  
2  
Ras h is s y m pt o matic ( pr urit us/ pai n), a n d/ or re q uires m ore t ha n o ne 
d ose of me dicati o n b ut d oes n ot i nterfere wit h f u ncti o n.  
3  
Ras h is s y m pt o matic a n d i nterferes wit h f u ncti o n  
4  
Life -t hreat e ni n g 
Hea dac he  
Retr o -or bital pai n  
Na usea  
Fati g ue  
M yal gia  
Art hral gia  
A b d o mi nal Pai n  
 
1  
E ve nt 
t hat 
is 
easil y 
t olerate d, 
ma y 
re q uire 
1 
d ose 
of 
me dicati o n/treat me nt  
2  
E ve nt t hat i nterferes wit h dail y acti vit y or re q uires m ore t h a n 1 d ose of 
me dicati o n/treat me nt  
3  
E ve nt t hat pre ve nts dail y acti vit y  
4  
Life -t hreat e ni n g 
L oss of A p petite  
 
1  
L oss of a p petite wit h o ut alterati o n i n eati n g ha bits  
2  
Oral i nta ke altere d wit h o ut si g nifica nt wei g ht l oss or mal n utriti o n; oral 
n utriti o nal s u p ple me nts i n dicate d  
3  
Ass ociate d wit h si g nifica nt wei g ht l oss or mal n utriti o n (e. g. i na de q uate 
oral cal oric i nta ke a n d/ or fl ui d i nta ke); t u be fee di n g or T P N i n dicate d  
4  
Life t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d  
V o miti n g  
1  
I nter ve nti o n n ot i n dicate d 
2  
O ut patie nt I V h y drati o n; me dical i nter ve nti o n i n dicate d  
3  
T u be fee di n g, T P N or h os pitalizati o n i n dicate d  
4  
E R visit or h os pitalizati o n f or h y p ote nsi ve s h oc k  
Diarr hea  
1  
I ncrease of < 4 st o ols per da y o ver baseli n e 
2  
I ncrease of 4-6 st o ols per da y o ver baseli n e 
3  
I ncrease of 7 or m ore st o ols per da y o ver baseli n e; h os pitalizati o n 
i n dicate d; li miti n g self care A D L 
4  
E R visit or h os pitalizati o n  
De n g ue -s pecific l a b or at or y 
p ar a meters  
Gr a de  
Se verit y  
He m o gl o bi n ( W o me n)  
1  
2  
3  
9. 5 – 1 0. 7 g m/ d L  
8. 0 – 9. 4 g m/ d L  
< 7. 9 g m/ d L  
4  
Life -t hreate ni n g 
He m o gl o bi n ( Me n)  
1  
2  
3  
1 1 – 1 2. 5 g m/ d L  
9. 0 – 1 0. 9 g m/ d L  
< 8. 9 g m/ d L  
4  
Life -t hreate ni n g 
Ne utr o pe nia  
( Re d uce d A N C) 
1  
2  
3  
7 5 0 – 9 9 9/ m m 3 
5 0 0 – 7 4 9/ m m 3 
< 5 0 0 m m 3 
4  
Life -t hreate ni n g 
Le u k oc yt osis  
(I ncrease d W B Cs) 
1  
2  
3  
1 1, 5 0 0 – 1 3, 0 0 0/ m m 3 
1 3, 0 0 1 – 1 5, 0 0 0/ m m 3 
≥ 1 5, 0 0 0 or < 1, 0 0 0/ m m 3 
4  
Life -t hreate ni n g 
T hr o m b oc yt o pe nia  
( Decrease d Platelets) 
1  
2  
3  
≥ 1 0 0, 0 0 0 – 1 2 0, 0 0 0/ m m 3 
≥ 7 5, 0 0 0 – 9 9, 9 9 9/ m m 3 
< 7 4, 9 9 9/ m m 3 
 
4  
Life -t hreat e ni n g 
P T  
1  
2  
3  
> 1. 0 – 1. 2 5 x U L N  
> 1. 2 5 – 1. 5 x U L N  
> 1. 5 x U L N  
 
4  
Life -t hreat e ni n g 
P T T  
1  
2  
> 1. 0 – 1. 6 6 x U L N  
> 1. 6 6 – 2. 3 3 x U L N  

CI R 3 3 2  
 
1 0 9  
 
3  
> 2. 3 3 x U L N  
 
4  
Life -t hreat e ni n g 
A L T  
1  
2  
3  
> 1. 2 5 – 2. 5 x  U L N  
> 2. 5 – 5. 0 x  U L N  
> 5. 0 x U L N  
4  
Life -t hreate ni n g 
 
8. 2. 4  Rel ati o ns hi p wit h Recei pt of J N J -6 4 2 8 1 8 0 2  Test Articl e or C h alle n ge  
T he cli nical i n vesti gat or will assess all A Es f or t heir relati o ns hi p t o t he JN J-6 4 2 8 1 8 0 2 test article  or 
c halle n ge usi n g t he f oll o wi n g classificati o ns:   
 
Defi nitel y relate d:   
Clear -c ut te m p or al ass oci ati o n, wit h n o ot he r p ossi ble ca use 
 
Pr o ba bl y relate d:   
Reas o na ble te m p or al ass ociati o n, a n d a p ote ntial alter nati ve  
 
eti ol o g y is n ot a p pare nt  
 
P ossi bl y relate d:   
Less clear te m p oral ass o ciati o n; ot her eti ol o gies als o p ossi ble  
 
U nli kel y relate d:   
Te m p oral ass ociati o n bet wee n t h e A E a n d t he J NJ-6 4 2 8 1 8 0 2 test 
article /c halle n g e, or t he nat ure of t he e v e nt is s uc h t hat t he J NJ-
6 4 2 8 1 8 0 2 test article/ c h alle n ge is n ot  li kel y t o ha ve ha d a n y 
reas o na bl e ass ociati o n wit h t he o bser ve d ill ness/e ve nt (ca us e a nd 
effect relati o ns hi p i m pr o ba ble b ut n ot  i m p ossi ble) 
 
U nrelate d:   
T he 
A E is c o m pletel y i n de pe n de nt of J NJ-6 4 2 8 1 8 0 2 test 
article/c halle n g e a d mi nistrati o n, a n d/ or e vi de nce e xists t hat t he 
e ve nt is defi nitel y  relat e d t o a n ot her eti ol o g y 
 
T he de gree of certai n t y wit h w hic h a n A E ca n b e attri b ute d t o st u d y a ge nt a d mi nistrati o n will be 
deter mi ne d b y h o w well t he e ve nt c a n be u n d erst o o d i n ter ms of o ne or m ore of t he f oll o wi n g:  
•  A reacti o n of a si milar n at ure ha vi n g pre vi o usl y bee n o bser ve d wit h t his t y pe of J NJ-6 4 2 8 1 8 0 2 
test article or c h alle n ge, a n d/ or f or m ulati o n or nat urall y occ urri n g de n g ue ill ness  
•  T he e ve nt h a vi n g ofte n bee n re p orte d i n t h e literat ure f or si milar t y pes of test articles or  
c halle n ge pr o d u cts  
 
All l ocal i njecti o n -site reacti o ns will be c o nsi dere d ca us all y relat e d t o i n oc ulati o n. Ca usalit y  
assess me nt is base d o n i nf or mati o n a vaila ble at t he ti me of t he A E assess me nt. T he i n vesti gat or  ma y 
re vise t he ca usalit y assess me nt as a d diti o nal i nf or mati o n bec o mes a vaila bl e. 
8. 2. 5  A d verse E ve nt Acti o n T a ke n  
T he i n vesti gat or/ desi g ne e will assess t he acti o n ta ke n b y t he s u bject or t he st u d y staff i n relati o n  
t o t he A E, usi n g t he f oll o wi n g classificati o ns: 
Acti o n  
1 = N o ne  
2 = Re me dial t hera p y ( m ore t ha n 1 d ose of me dicati o n re q uire d)  
3 = Disc o nti n ue d st u d y  
4 = H os pitalizati o n  
5 = Ot her  

CI R 3 3 2  
 
1 1 0  
 
 
8. 2. 6  A d verse E ve nt O utc o me  
T he i n vesti gat or/ desi g ne e will assess t he o utc o me of t he A E, eit her at res ol uti o n or t he e n d of t he  
stu d y peri o d, usi n g t he f oll o wi n g classificati o ns:  
O utc o me  
1 = Res ol ve d  
2 = C o nti n ui n g  
3 = C o nti n ui n g C hr o nic C o n diti o n  
4 = U n k n o w n, Off -St u d y bef ore c o ul d c o nfir m res ol uti o n of A E  
5 = Deat h  
6 = U n k n o w n  
8. 2. 7  A d verse E ve nt Seri o us ness  
T he i n vesti gat or/ desi g ne e will cate g ori ze all A Es as eit her s eri o us or n o n -seri o us usi n g t he criteri a 
defi ne d i n secti o n 8. 2. 3  of t his pr ot oc ol.  
 
A n y e ve nts d efi ne d as s eri o us will als o b e re p orte d f oll o wi n g S A E re p orti n g g ui deli nes o utli ne d i n 
secti o n 8. 3. 2  of t his pr ot oc ol.  
 
 
A d verse E ve nt Re p orti n g  
8. 3. 1  N o n -Seri o us A d verse E ve nts  
N o n -seri o us A Es will be f oll o we d t o res ol uti o n or u ntil t he st u d y e n ds a n d will be re p orte d t o  t he 
s p o ns or a n d D D T as re q u este d, t o t he I R B acc or di n g t o I R B p olicies, t o t he D S M B as re q uire d, a n d t o  
t he F D A at least a n n uall y i n t he a n n ual re p ort. If a v ol u nteer si g ns c o nse nt b ut is n ot s u bse q ue ntl y 
e nr olle d t he A E will n ot be f oll o we d t o res ol uti o n or re p orte d.  
 
A Es meeti n g t he pa usi n g criteria o utli ne d i n secti o n 8. 5  of t his pr ot oc ol will be re p orte d  t o t he s p o ns or 
a n d D D T f oll o wi n g t he S A E re p orti n g g ui deli nes. A E data will be s u b mitte d t o t he I N D S p o ns or a n d 
D D T  w he n re q ueste d f or peri o dic safet y assess m e nts, re vie w of I N D a n n ual re p orts, re vie w  of I N D 
safet y re p orts, a n d pre parati o n of fi nal st u d y re p orts. 
8. 3. 2  Seri o us A d verse E ve nts  
Office of Cli nic al Res e a rc h P olic y a n d Re g ul at or y O per ati o ns Cli nic al S afet y Office  
( O C R P R O) a n d J a nsse n Dr u g De vel o p me nt Te a m ( D D T)  
All S A Es (re gar dl ess of relati o ns hi p a n d w het her or n ot t he y are als o U Ps) m ust be re p orte d 
acc or di n g t o t he s p o ns or’s re p orti n g pla n b y usi n g t he R E D Ca p s yste m. Deat hs a n d i m me diatel y life 
t hreate ni n g S A Es m ust be re p ort e d t o t he C S O a n d t he Ja nsse n D D T  wit hi n 1 b usi ness da y after t he 
site bec o mes a w are of t h e e ve nt. All ot her S A Es will be re p orte d wit hi n 3 w or ki n g da ys of 
n otificati o n of t he S A E occ urre nce t o:  
•  R E D Ca p we bsite: htt ps://cri ms o nre d ca p. cc. ni h. g o v/r e dca p/i n d e x. p h p  
•  O C R P R O C S O P h o ne: 3 0 1 -8 4 6 -5 3 0 1, Fa x: 3 0 1 -8 4 6 -6 2 2 4, E -mail: rc hs psafet y @ mail. ni h. g o v 
•  Ja nsse n Dr u g De vel o p me nt Tea m E mail : II S-BI O -VI R O -G C O @its.j nj.c o m  
  
S A Es t hat ha ve n ot res ol ve d b y t he e n d of t he f oll o w -u p peri o d are f oll o w e d u ntil fi nal o utc o me is 
k n o w n. If it is n ot p ossi ble t o o btai n a fi nal o utc o me f or a n S A E (e. g., t he s u bject is l ost t o  f oll o w-
u p), t he reas o n a fi nal o ut c o me c o ul d n ot be o btai n e d will be rec or de d b y t h e i n vesti gat o r o n t he A E 
C R F a n d acc or di n g t o t he s p o ns or’s re p orti n g g ui deli nes.  

CI R 3 3 2  
 
1 1 1  
 
 
S A Es t hat occ ur after t he st u d y f oll o w -u p peri o d ( St u d y Da y 8 5 ) t hat are re p orte d t o a n d are assess e 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 st u d y dr u g m u st be re p orte d t o 
t he C S O. 
 
S A Es t hat occ ur after t he s u bject si g ns c o nse nt b ut pri or t o e nr oll me nt , will n ot be f oll o we d u ntil 
res ol uti o n a n d will n ot be re p orte d.  
 
D at a a n d S afet y M o nit o ri n g B o ar d  
All S A Es m ust be re p ort e d b y tele p h o ne (f oll o we d b y writte n re p ort), e mail, or fa x wit hi n 1 w or ki n g 
da y of n otificati o n of t he S A E occ urre nce t o:  
•  
T he D S M B e x ec uti ve s ecretar y –  P h o ne: 3 0 1 -8 4 6 -5 3 0 1, Fa x: 3 0 1 -8 4 6 -6 2 2 4, E mail:  
niai d ds m bia @ mail. ni h. g o v  
 
J o h ns H o p ki ns U ni versit y Bi os afet y C o m mittee  
All S A Es m ust be re p ort e d b y tele p h o ne (f oll o we d b y writte n re p ort), e mail, or fa x wit hi n 1  w or ki n g 
da y of n otificati o n of t he S A E occ urre nce t o:  
•  T he J H U I nstit uti o nal Bi osafet y C o m mittee: P h o ne: 4 1 0 -9 5 5 -5 9 1 8, Fa x 4 1 0 -9 5 5 -5 9 2 9  
 
I nstit uti o n al Re vie w B o ar d Re p orti n g  
All S A Es will be re p orte d t o Wester n C o per nic us Gr o u p I nstit uti o nal Re vie w B oar d  (W C G I R B) a n d 
J H S P H I R B as per g ui d eli nes  bel o w:  
 
•  W C G I R B G ui deli nes:  
o  W C G I R B  P h o ne:  8 5 5 -8 1 8 -2 2 8 9  
o  w w w. W C GI R B.c o m  f or u p date d re p orti n g g ui deli nes 
•  J H S P H I R B G ui deli nes: 
o  J H S P H I R B P h o ne: 1-8 8 8 -2 6 2 -3 2 4 2, Fa x: 4 1 0 -5 0 2 -0 5 8 4  
o  htt ps:// w w w.j hs p h.e d u/ offices -a n d -ser vi ces/i nstit uti o nal-re vie w-b o ar d/i n de x. ht ml  f or 
u p date d re p orti n g g ui deli nes  
8. 3. 3  U n a ntici p ate d Pr o ble ms  
U na ntici pate d Pr o ble ms t hat are als o A E s m ust be re p orte d t o t he C S O a n d se nt b y usi n g t he 
R E D Ca p s yste m n o later t ha n 7 cale n d ar da ys of site a ware ness of t h e e ve nt. U Ps t hat are n ot A Es 
are n ot r e p orte d t o t he S p o ns or C S O.   
 
Re p ort U Ps  t hat are als o A E s t o t he C S O acc or di n g t o t he s p o ns or’s re p orti n g g ui deli nes  or a l ocal 
I R B U P  f or m. 
 
U Ps t hat occ ur after t he s u bject si g ns c o nse nt t he s u bject b ut d oes n ot s u bse q ue ntl y get e nr olle d will 
n ot be f oll o we d t o c o m pleti o n a n d will n ot be re p orte d.  
 
S p o ns or’s Re p orti n g  Res p o nsi bilities  
S U S A Rs, as defi ne d i n 2 1 C o de of Fe deral Re g ulati o ns ( C F R) 3 1 2. 3 2 a n d deter mi ne d b y t he  I N D 
s p o ns or, m ust be re p orte d t o t he F D A a n d all partici pati n g i n vesti gat ors as I N D Safet y  Re p orts.  

CI R 3 3 2  
 
1 1 2  
 
T he s p o ns or will als o s u b mit a brief re p ort of t he pr o gress of t he i n vesti gati o n t o t he F D A o n a n a n n ual 
basis, as defi ne d i n 2 1 C F R 3 1 2. 3 3. S  
A Es t hat are als o u na ntici pate d pr o ble ms will be s u m marize d b y t he I N D s p o ns or a n d distri b ute d  t o 
i n vesti gat ors. 
 
P a usi n g R ules f or t he St u d y  
T he pa usi n g criteri a f or b ot h J NJ-6 4 2 8 1 8 0 2 a n d r D E N 3 3 0 are liste d bel o w. T he pa usi n g criteria f or 
i n di vi d ual s u bjects i n t his st u d y i ncl u de a n y o ne or m ore of t he f oll o wi n g: 
•  A s u bject e x perie n ces a n S A E t hat is u ne x pecte d ( per t he i n vesti gat or’s br oc h ure or pr o d uct 
la bel) a n d p ossi bl y, pr o b a bl y, or defi nitel y rel ate d t o a st u d y a ge nt; 
•  A s u bject e x perie nces t w o gra de 3 or greater A Es t hat are u ne x pecte d ( per t he i n vesti gat or’s 
br oc h ure or pr o d uct la b el) a n d p ossi bl y, pr o ba bl y, or defi nitel y relat e d t o a st u d y a ge nt.  
T he pri nci p al i n vesti gat or/st u d y c hair(s) or t he C S O ma y als o pa use d osi n g/st u d y i nter ve nti o ns f or o n e 
or m ore s u bjects f or a n y safet y iss ue. T he st u d y safet y o versi g ht b o dies (e. g., D S M B, S M C, a n d/ or 
I S M) ma y rec o m me n d a pa use t o t he C S O. 
8. 5. 1  Re p orti n g a P a use  
If a pa usi n g criteri o n is met, a descri pti o n  of t he A E (s) or safet y iss ue m ust be re p orte d b y t he pri nci pal 
i n vesti gat or wit hi n 1 b usi ness da y t o t he C S O a n d t he IR B acc or di n g t o t heir re q uire me nts. T h e 
pri nci pal i n vesti gat or will als o n otif y t he D S M B. I n a d diti o n, if a p plica ble t he C S O or d esi g nee will 
n otif y all ot her site i n vesti gat ors b y e mail or t hr o u g h t he s pecifie d p at h wa y.  
8. 5. 2  Res u m pti o n F oll o wi n g a P a use  
T he C S O, i n c olla b orati o n wit h t he pri nci pal i n vesti gat or , D S M B , a n d t he Ja nsse n Dr u g 
D e vel o p me nt T ea m (a n d/ or D D U T if a p plica ble) will deter mi ne if st u d y acti vities, i ncl u di n g b ot h 
J NJ-6 4 2 8 1 8 0 2 a n d r D E N 3 3 0 a d mi nistrati o n, ma y be res u me d a n d a n y a d diti o nal m o di ficati o ns or 
re q uire me nts t hat ma y ap pl y, f or t he affect e d s u bject(s), or w het her t h e e ve nts t hat tri g gere d t he 
pa use re q uir e e x p a nsi o n t o a st u d y halt (see bel o w).  
 
T he C S O or s p o ns or desi g nee will n otif y t he pri nci pal i n vesti gat or of t he decisi o n. T he pr i nci pal 
i n vesti gat or will n otif y ot her i n vesti gat ors a n d t he I R B of t he d ecisi o n acc or di n g t o t he I R B’s 
pr ocess.  
8. 5. 3  Disc o nti n u ati o n of St u d y A ge nt  
A s u bject w h o d oes n ot res u me st u d y a ge nt/i nter ve nti o n/treat me nt will c o nti n ue t o be f oll o we d f or 
pr ot oc ol -s pecifi e d safet y assess me nts or as cli nicall y i n dicate d, w hic he v er is m ore c o nser vati ve. 
 
H alti n g  R ules f or t he St u d y  
T he halti n g criteria f or b ot h J NJ-6 4 2 8 1 8 0 2 a n d r D E N 3 3 0 are liste d bel o w. If d uri n g t he st u d y, d osi n g 
wit h J NJ -6 4 2 8 1 8 0 2 or r D E N 3 3 0 is c o nsi dere d t o raise si g nifica nt s afet y c o ncer ns (i.e., w he n a 
s pecific set of halti n g  criteria ha ve bee n m et), f urt her d osi n g of partici p a nts will be halt e d pe n di n g a 
re vie w of all a vaila ble d ata b y t he st u d y s p o ns or ( O C RP R O) , t he NI AI D I ntra m ural D S M B, t he site 
a n d t he J a nsse n Dr u g D e vel o p me nt T ea m  (a n d/ or D D U T  if a p plica ble) to assess w het her t he h alt  ca n 
be lifte d or n ot, or w het h er ot her ste ps are n ee de d.  
8. 6. 1  H alti n g r ules f or J N J -6 4 2 8 1 8 0 2  
Bel o w is a list of e ve nts t hat will lea d t o a halt  i n f urt her d osi n g wit h st u d y dr u g a n d a n e mer g e nc y 
D S M B meeti n g calle d f or t he B oar d t o c o nsi der w het her t o lift t he st u d y halt . U nless i n dicate d 
ot her wise, t he list is o nl y a p plica ble f or c o n cer ne d A Es t hat are c o nsi dere d relate d t o st u d y dr u g b y t h e 
i n vesti gat or. If safet y c o ncer ns i n Co h ort 1 w o ul d o nl y raise at t he hi g hest d ose, f urt her d osi n g of 

CI R 3 3 2  
 
1 1 3  
 
partici pa nts at t h e hi g hest d ose will be halte d  w hile ra n d o mizati o n a n d d osi n g at t he l o w er d os e le vels 
ma y c o nti n ue. T h e ra n d o mizati o n rati o t o J NJ -6 4 2 8 1 8 0 2 vers us place b o will be ke pt at t he  2: 2: 1 rati o.  
•  
≥2 partici pa nts i n a c o h ort ha ve ≥ Gra de 3 ras h e ve nts, re g ar dless of st u d y dr u g relate d n ess; 
O R  
•  
≥2 partici pa nts i n a c o h ort ha ve ≥1 J NJ -6 4 2 8 1 8 0 2 -relate d S A E; O R  
•  
≥6 partici pa nts i n a c o h ort ha ve ≥ Gra de 3 J NJ-6 4 2 8 1 8 0 2 -relate d A Es  i n d e pe n de nt of wit hi n 
or n ot wit hi n t he sa me s yste m or ga n class; O R  
•  
≥6 partici pa nts i n a c o h ort ha ve ≥ Gra de 2, J NJ -6 4 2 8 1 8 0 2  relate d la b orat or y a b n or malities 
t hat are c o nsi d ere d cli nicall y rele va nt b y t he i n vesti gat or.  
8. 6. 2  H alti n g  r ules f or r D E N 3 3 0  
As r D E N 3 3 0 is a c hall e n ge vir us a n d is e x pect e d t o ha ve greater react o ge nicit y t ha n a vacci ne or 
t hera pe utic, differe nt halti n g  criteria will be use d f oll o wi n g a d mi nistrati o n of t his vir us.  F oll o wi n g 
a d mi nistrati o n of r D E N 3 3 0, t he f oll o wi n g criteri a will be use d t o defi ne u nacce pta ble react o ge ni cit y 
of t he c halle n g e vir us.  
1.  
O ne or m ore s u bjects i n a c o h ort e x peri e nce a n S A E (as d efi ne d i n secti o n 8. 1. 5  of t his 
pr ot oc ol) t hat is deter mi ne d t o be p ossi bl y, pr o ba bl y, or defi nitel y relate d t o r D E N 3 3 0 (as 
defi ne d i n secti o n 8. 2. 4  of t his pr ot oc ol);  
2.  
O ne  or m ore s u bjects i n a c o h ort e x p erie nce a na p h yla xis t hat is p ossi bl y, pr o ba bl y, or 
defi nitel y relate d r D E N 33 0;  
3.  
T hree or m ore s u bjects i n a c o h ort e x p erie n ce t he sa me Gra d e 3 l a b orat or y a b n or malit y t hat 
is p ossi bl y, pr o ba bl y, or defi nitel y relate d t o r D E N 33 0;  
4.  
T hree or m ore s u bjects i n a c o h ort e x p erie n ce a n A N C < 5 0 0/ m m 3 f or a n y d urati o n1; or 
5.  
T hree or m ore s u bjects i n a c o h ort e x perie nce a de n g ue -li ke ill ness f oll o wi n g r D E N 33 0 
a d mi nistrati o n, defi ne d as a n i nfecti o n 2 ass ociate d wit h fe ver a n d t w o of t he f oll o wi n g 
s y m pt o ms: 
a. 
Gra de 3 or greater h ea dac he lasti n g ≥ 4 8 h o urs  
b.  
Gra de 3 or greater g e neralize d m yal gia lasti n g ≥ 4 8 h o urs   
1 T hese halti n g  r ules res ulte d fr o m pre vi o us disc ussi o ns bet wee n NI AI D a n d t he F D A o n P hase 1 cli nical trials of si mil ar 
i n vesti gati o nal li ve atte n uate d D E N V vacci nes (refere nce I N Ds 8 4 6 3, 1 3 7 3 0, a n d 1 3 8 8 6) a n d de n g ue c o ntr olle d h u ma n 
i nfecti o n m o del vir uses (refere n ce I N Ds 1 5 7 5 3  a n d 1 6 7 6 5 ). 
2I nfecti o n is defi ne d as rec o ver y of de n g ue vir us b y c ult ure or P C R fr o m t he bl o o d of a v ol u nteer  
8. 6. 3  Re p orti n g a St u d y  H alt  
If a halti n g  r ule is i de ntifie d b y t he St u d y PI/ Pr ot oc ol C hair a n d/ or t he C S O, a descri pti o n of t he A E (s) 
or safet y iss ue will be re p orte d b y t he PI  or d esi g nee wit hi n 1 b usi ness d a y of s p o ns or a ware ness t o 
t he ot her Site I n vesti gat ors. T he St u d y PI/ Pr ot oc ol C hair will n otif y t he D S M B  a n d t he Ja nsse n Dr u g 
D e vel o p me nt T ea m. T he Site I n vesti gat ors will n otif y t heir l ocal I R Bs. Safet y data re p orts a n d c han ges 
i n st u d y stat us will be s u b mitte d t o t he a p plica ble I R B pr o m ptl y, i n acc or da nce wit h i nstit uti o nal 
p olic y. T his c o nstit utes a mi ni m u m criteri o n, a n d t he decisi o n t o halt t he trial ma y be ma de o n t he basis 
of a n y ot her criteri a t hat, i n t he j u d g me nt of  t he i n v esti gat ors, F D A, I R B, D S M B, D D T  (a n d/ or D D U T 
if a p plica ble) or S p o ns or,  i n dicate a p ote ntiall y seri o us safet y c o ncer n. 
8. 6. 4  R es u m pti o n of a H alte d St u d y  
T he C S O, t he NI AI D I ntra m ural D S M B, a n d t he Ja nsse n Dr u g D e vel o p me nt T ea m  (a n d/ or D D U T if 
a p plica ble) will  assess w het her t he halt  ca n b e lifte d or n ot, or w het her ot her ste ps are nee de d. T h e 

CI R 3 3 2  
 
1 1 4  
 
C S O or desi g nee will n otif y t he site i n vesti gat ors of t he decisi o n  t o res u me t he st u d y. T he site 
i n vesti gat ors will n otif y t heir l ocal I R B(s) of t h e d ecisi o n. 
 
S afet y  O versi g ht  
8. 7. 1  S afet y Re vie w a n d C o m m u nic ati o ns Pl a n a n d Tr a nsfer of Re g ul at or y O bli g ati o ns  
A Safet y Re vie w a n d C o m m u nicati o n s Pla n ( S R C P) has bee n de vel o pe d f or t he pr ot oc ol. T he S R C P 
is a n i nter nal c o m m u nicati o ns d oc u me nt bet wee n the PI a n d t he I N D S p o ns or C S O, w hic h deli neat es 
t he safet y o versi g ht res p o nsi bilities of t he PI, t he C S O, a n d ot her sta ke h ol ders. T he S R C P als o i ncl u des 
t he o verall pla n f or c o n d ucti n g peri o dic safet y s ur veilla nce ass ess me nts. 
 
T he I N D S p o ns or a n d t he PI w ill si g n a f or mal Safet y Re vie w a n d C o m m u nicati o n Pla n ( S R C P)  w hic h 
d oc u me nts t hat t he PI h as acce pt e d t he res p o nsi bilit y f or peri o dic safet y s ur veilla nce assess me nts as 
o utli ne d i n 2 1 C F R 3 1 2. 3 2( b).  
8. 7. 2  S p o ns or Me dic al M o nit or  
A Me dical M o nit or  re prese nti n g the I N D S p o ns or  ( O C R P R O), will be a p p oi nte d f or o v ersi g ht of s afet y 
i n t his cli nical st u d y. T he S p o ns or 
Me dical 
M o nit or will be res p o nsi ble f or perf or mi n g safet y 
assess me nts as o utli ne d i n a Safet y Re vie w a n d C o m m u nicati o ns Pla n ( S R C P ) as defi ne d i n 
secti o n 8. 7. 1  
8. 7. 3  NI AI D I ntr a m ur al D at a a n d S afet y M o nit ori n g B o ar d  
T he NI AI D i ntra m ur al D S M B i ncl u des i n de pe n de nt e x perts t hat d o n ot ha v e direct i n v ol ve me nt  i n t h e 
c o n d uct of t he st u d y a n d ha ve n o si g nifica nt c o nflicts of i nterests as d efi n e d b y NI AI D  p olic y. T h e 
NI AI D i ntra m ur al D S M B is c o nstit ute d t o re vie w t he safet y data of NI AI D  i ntra m ural cli nical st u dies 
t hat re q uire D S M B o versi g ht, a n d c o nsists of e x perts i n i nfecti o us  diseases, bi ostatistics, a n d cli nical 
trials. T he PI’s d esi g nee will pr o vi de t he D S M B e xec uti ve s ecretar y wit h bli n di n g c o des i n a seale d 
e n vel o pe i n case t he D S M B re q uires t his i nf or mati o n t o  ma ke its rec o m me n dati o ns. T he D S M B will 
re vie w t he st u d y pri or t o i nitiati o n a n d t wice a year t hereafter. T he b oar d ma y c o n ve ne a d diti o nal 
re vie ws as necessar y. Pri or t o eac h re vie w, t he PI will s u b mit a s u m mar y of c u m ulati ve safet y data i n 
a f or mat acce pta ble ( b y u n bli n de d c o h ort if  re q u este d) t o t he b oar d. T he b oar d will re vie w t he st u d y 
data t o e val uate t he safet y, efficac y,  st u d y pr o gress a n d c o n d uct of t he st u d y. Re p orts of S A Es will be 
s u b mitte d b y t he PI t o t he b oar d at t he sa me ti me t he y are re p ort e d t o t he s p o ns or a n d I R B. All 
u na ntici pa te d pr o ble ms will be s u b mitte d t o t he D S M B at t he sa me ti me t he y are s u b mitte d t o t he I R B 
or I N D s p o ns or. I N D  Safet y Re p orts will be s u b mitte d t o t he D S M B b y t he i n vesti gat or after t heir 
recei pt. T he PI will n otif y t he D S M B of a n y cases of i nte nti o nal or u ni nte nti o nal u n bli n di n g as s o o n 
as p ossi ble. T he  PI will n otif y t he b oar d at t he ti me halti n g criteri a are met, a n d o btai n a 
rec o m me n dati o n c o n cer ni n g c o nti n uati o n, m o dificati o n, or ter mi nati o n of t he st u d y. T he PI will s u b mit 
t he writte n D S M B s u m mar y re p o rts wit h rec o m m e n dati o ns t o t he I R B(s). 
9  
St atistic al C o nsi der ati o n  
Statistical a nal ysis will be d o ne b y t he s p o ns or or Ja nsse n pers o n nel. A ge neral d escri pti o n of t he 
statistical met h o ds t o be use d t o a nal yze t he a nti viral acti vit y a n d safet y data is o utli n e d bel o w. S pecific 
details will be pr o vi de d i n t he Statistical A nal ysis Pla n  ( S A P). 
 
S a m ple  Size Deter mi n ati o n  
C o h ort 1 is i nte n de d t o assess 
of t he s u peri or a nti viral acti vit y of t he hi g hest d ose 
of J NJ-6 4 2 8 1 8 0 2  w he n c o m pare d t o place b o a n d t o c ollect data f or t he c haracterizati o n of a 
relati o ns hi p bet wee n t h e P K a n d a nti viral acti vit y of J NJ-6 4 2 8 1 8 0 2 base d o n D E N V -3 R N A.  
C CI

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A hi g her n u m ber of partici pa nts will be ra n d o mize d t o t he hi g hest d ose gr o u p t o get a better esti mate 
o n t he effect o n D E N V -3 R N A at t he hi g hest feasi ble d ose.  
Base d o n t he c urre ntl y a vaila ble data, t he i nfecti o n rate u n der pl ace b o is ass u me d t o be 9 0 % a n d t he 
mea n l o g 1 0 A U C D 1 -D 2 9 ( V L) of t h ose partici pa nts 
w h o are i nfecte d is ass u me d t o be 
5. 5  l o g1 0 c o pies/ m L/ 2 8 da ys wit h a n S T D of 0. 7 0 l o g 1 0 c o pies/ m L/ 2 8 da ys.  
T hese data were use d t o si m ulate 1 0, 0 0 0 trials, eac h wit h 6 partic i pa nts o n place b o a n d 1 0  p artici pa nts 
o n hi g h d ose, or a t otal of 1 6  partici pa nts. Data were si m ulate d usi n g a Ber n o ulli distri b uti o n f or t he 
i nfecti o n rate. F or t h ose partici pa nts w h o were i nfecte d, t he c orres p o n di n g l o g1 0 A U C D 1 -D 2 9 ( V L) 
was si m ulate d usi n g a n or mal distri b uti o n. U n der t he h y p ot hesis t hat acti ve st u d y dr u g is s u peri or t o 
place b o at t he hi g h est d ose, t he me a n of t he n or mal distri b uti o n f or partici pa nts o n acti ve st u d y dr u g 
was re d uce d wit h 3 0 % f or t he hi g h d ose,  w hile t he sa me S D was use d o v er t he differe nt gr o u ps. T o b e 
a ble t o dra w v ali d c o n cl usi o ns o n t he a nti viral acti vit y of J NJ -6 4 2 8 1 8 0 2, at least 6 5 % of t he i n oc ulat e d 
place b o p artici pa nts s h o ul d test p ositi ve f or D E N V -3. Wit h t he ass u me d i nfecti o n rat e of 9 0 %, t he 
pr o ba bilit y of m o del fail ure (i.e., < 6 5 % of i n oc ulat e d place b o partici p a nts i nfecte d) is < 2 %. T he res ults 
o ver t he 1 0, 0 0 0 si m ulate d trials are s h o w n i n Ta bl e 1 6 . 
T a ble 1 6 : Me a n ( S T D) L o g 1 0 A U C D 1 -D 2 9 ( V L) ( L o g 1 0 C o pies/ m L/ 2 8 D a ys) i n I nfecte d 
P artici p a nts per St u d y Dr u g i n 1 0, 0 0 0 Si m ul ati o ns  
 
Pl ace b o  
J N J -6 4 2 8 1 8 0 2  
 
 
Hi g h  
Mea n  
5. 5 0  
4. 0 5  
S T D  
0. 6 6  
0. 5 3  
N ote: Ta ble prese nts t he 
mea ns of t he 1 0, 0 0 0 
mea ns a n d sta n dar d de viati o ns. Si m ulate d val ues bel o w 
3. 1  l o g1 0  c o pies/ m L/ 2 8 da ys were c o nsi dere d as n o ni nfecte d partici pa nts. T he me dia n i nfecti o n rate was 7 8 % i n t he 
hi g h d ose gr o u p a n d 1 0 0 % place b o d ose gr o u p.  
A t o bit a nal ysis was d o n e i n eac h of t he si m ulate d trials f or w hic h at least 6 5 % of i n o c ulate d place b o 
partici pa nts were i nfecte d, wit h t he l o g 1 0 A U C D 1 -D 2 9 ( V L) as de pe n d e nt varia ble a n d tr eat me nt as a 
fi xe d c o vari ate. I n t his a nal ysis of varia nce m o d el f or left-ce ns ore d dat a, a n or ma ll y distri b ute d err or 
ter m was use d. Val ues are left ce ns ore d at t he val ue 3.1  l o g1 0 c o pies/ m L/ 2 8 da ys, wit h 4 0 c o pies/ m L 
t he ass u me d li mit of dete cti o n. 
 
 
 
 T he n u m ber of partici pa nts i n 
C o h ort 1 is c o nsi dere d s ufficie nt f or t he i nitial c h aract erizati o n of a relati o ns hi p bet wee n t he P K a n d 
a nti viral acti vit y of J NJ -6 4 2 8 1 8 0 2. I n or der  t o acc o u nt f or a p ote ntial earl y disc o nti n uati o n of a 
ma xi m u m of 7  partici pa nts ca n be re pl ace d i n case of disc o nti n uati o n bef ore last d ose of st u d y dr u g 
o n Da y 2 1.  
Base d o n t he i nteri m a nal ysis res ults of C o h ort 1, u p t o 3 d osi n g re gi me ns ( d ose, d osi n g d urati o n, a n d 
d osi n g fre q ue nc y) ca n b e selecte d f or e val uati o n i n C o h ort 2 ( secti o n 9. 5 ). C o h ort 2 is i nte n de d t o 
f urt her c haract erize t he a nti viral acti vit y of J NJ-6 4 2 8 1 8 0 2 a n d t he relati o ns hi p bet wee n t he P K a n d t he 
a nti viral acti vit y base d o n D E N V -3 R N A. Wit hi n C o h ort 2, a n a d diti o nal 2 4 partici pa nts ca n be 
ra n d o mize d i n a n e q uall y bala nce d rati o ( 1: 1: 1 i n case of 3 gr o u ps) t o t he select e d J NJ-6 4 2 8 1 8 0 2 
d osi n g re gi me ns a n d matc hi n g place b o s. . I n or der t o acc o u nt f or a p ote ntial earl y disc o nti n uati o n rate 
of u p t o 2 5 %, a ma xi m u m of 6 partici pa nts ca n b e re place d i n case of disc o nti n uati o n bef ore Da y 2 1  . 
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T he selecti o n of t he mi d a n d l o w d ose i n a d diti o n t o t he hi g h d ose is t o s u p p ort t he o bjec ti ve t o 
c haracteri ze t he relati o ns hi p bet wee n t he e x p os ure of J NJ -6 4 2 8 1 8 0 2 a n d t he a nti viral acti vit y of J NJ -
6 4 2 8 1 8 0 2. T o t his e n d, a p o p ulati o n m o deli n g a p pr oac h will be use d, b as e d o n a viral ki netic m o d el 
pre vi o usl y de vel o pe d t o descri be t h e vire mia -ti me pr ofile d uri n g a pri mar y De n g ue i nfecti o n [1 9 ]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T he t otal sa m ple size f or t he st u d y will be a ma xi m u m of 6 7 partici pa nts o ver t he 2 c o h orts, i e,  
4  partici pa nts f or t h e 
Hi g h -d ose Se nti nel 
Gr o u p ( Gr o u p 1a), 1 2 p artici pa nts f or 
Gr o u p 1 b,  
1 4  partici pa nts f or Gr o u p 2, 7 p ossi ble re place me nts f or C o h ort 1, 2 4 partici pa nts f or C o h ort 2,  a n d 
6  p ossi ble re place m e nts f or C o h ort 2.  
 
A nti vir al  Acti vit y  A n al yse s 
All partici pa nts w h o are ra n d o mize d, w h o are i n oc ulate d wit h t he rec o m bi na nt D E N V -3, a n d w h o 
recei v e at le ast 1 d ose of st u d y dr u g will c o nstit ute t he I T T p o p ulati o n. All partici pa nts w h o are 
i ncl u de d i n t he I T T p o p ulati o n wit h o ut pr ot oc ol deviati o ns t hat affect t he a nti viral acti vit y assess me nt 
will c o nstit ute t he per -pr ot oc ol ( P P) p o p ulati o n. T he P P p o p ulati o n will be use d f or all a nti viral acti vit y  
a nal yses t o test t he pr o p h ylactic effect u n d er o pti mal c o n diti o ns. Treat me nt  assi g n me nt f or t his 
p o p ulati o n will be defi ne d b y act ual tr eat me nt recei ve d.  As se nsiti vit y a n al ysis, t he I T T p o p ulati o n 
will als o be use d i n a n e x pl orat or y a nal ysis. N ote t hat s u bse q ue nt c o nfir mat or y trials i n t he fiel d will 
use t he I T T p o p ulati o n f or a nal ysis t o assess t he acti vit y of t he dr u g i n ter ms of real-w orl d feasi bilit y.  
Treat me nt  assi g n me nt f or t his p o p ulati o n will be defi ne d as treat me nt pla n ne d b y ra n d o mizati o n.  
T he a nti viral acti vit y a nal yses will o nl y be vali d i n case at least 6 5 % of t h e i n oc ulate d partici pa nts i n 
t he place b o gr o u p test p ositi ve f or D E N V-3 (ie, ha ve detecta ble D E N V -3 R N A), ot her wise n o a nti vir al 
acti vit y c o ncl usi o ns ca n be dra w n fr o m t his st u d y.   
C
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9. 2. 1  Pri m ar y E n d p oi nt  
T he pri mar y a n al ysis will be base d o n a  t o bit A N O V A a n al ysis wit h l o g1 0 A U C D 1 -D 2 9  ( V L) as 
de pe n de nt vari a ble a n d treat me nt as a fi xe d c o variate. As f or t he deter mi nati o n of t he sa m ple size 
(secti o n 9. 1 ), a n or mall y distri b ute d err or ter m will be  use d. Val ues will be left ce ns ore d at t he val ue 
2. 7 0 l o g 1 0 c o pies/ m L/ 2 8 da ys, wit h 3 6 c o pies/ m L t he ass u me d li mit of detecti o n a n d val ues < L O D 
i m p ute d wit h 1 8 c o pies/ m L 
 
 
 
 
 
 
.  
Descri pti ve statistics o n t he area u n d er t he ti me D E N V -3 R N A c ur ves will be cal c ulate d f or eac h gr o u p 
se parat el y. 
9. 2. 2  Sec o n d ar y E n d p oi nts  
T he pri mar y a n al ysis will be re peate d wit h A U C D 1 -D 2 9 (l o g1 0V L) as de pe n de nt varia ble.  Val ues will b e 
left ce ns ore d at t he val u e 3 5. 2 8 l o g1 0 c o pies/ m L/ 2 8 da ys, wit h 3 6 c o pies/ m L t he ass u me d li mit of 
detecti o n a n d val u es < L O D i m p ute d wit h 1 8  c o pies/ m L 
Descri pti ve statistics a n d mea n (a n d sta n d ar d err or  ( S E)) gra p hs will be s h o w n of t he l o g1 0 D E N V -3 
R N A act ual val ues a n d c ha n ges fr o m b aseli ne o ver ti me.  
T he pr o p orti o n of partici pa nts wit hi n t he D E N V -3 R N A cate g ories ( ≥ l o wer li mit of  q ua ntificati o n 
[ L L O Q], < L L O Q tar get detect e d a n d <  L L O Q t ar get n ot detect e d) will be s h o w n i n a fre q u e nc y 
ta b ulati o n per a nal ysis ti me p oi nt.  
Ti me t o first o nset of d etecta ble D E N V -3 R N A will be a n al yze d usi n g Ka pla n -M eier esti mates 
a nal ysis. A s u m mar y t a ble i ncl u di n g n u m ber of partici pa nts i ncl u de d i n t he a nal ysis, n u m ber of 
partici pa nts ce ns ore d, 2 5 t h a n d 7 5 t h perce ntiles a n d me dia n ti me -t o e v e nt, wit h 9 5 % c o nfi de n ce 
i nter vals bas e d o n l o g-l o g tra nsf or mati o n met h o d, will be prese nt e d. T he data will be prese nte d 
gra p hicall y usi n g t he Ka pla n -Meier esti mate of t h e s ur vi val f u ncti o n b y treat me nt.  
T he pea k D E N V -3 R N A a n d t he d urati o n of detecta ble D E N V -3 R N A will be a nal yse d usi n g 
descri pti ve statistics.  
Si milar a nal yses will be perf or me d f or t he D E N V -3 vire m ia. 
Fre q u e nc y t a b ulati o ns a n d descri pti ve statistics will be use d t o s u m mari ze t he occ urre n ce a n d d urati o n 
of D E N V i nfecti o n -ass ociate d A Es.  
Descri pti ve statistics will als o be use d t o descri be t he I g M a n d I g G a nti b o d y res p o nse. T he pr o p orti o n 
of partici pa nts wit h a nti b o d y p ositi vit y, a n d t he titer a n d ti mi n g of t he a nti b o d y res p o nse will be 
deter mi ne d.  D escri pti ve statistics will i ncl u de sa m ple size, mea n, sta n d ar d de viati o n, C V , ge o metric 
mea n, me dia n, mi ni m u m, a n d ma xi m u m.  
C CI
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Descri pti ve statistics will be pr o vi de d per C o h ort a n d d ose re gi me n.  Place b o data will be p o ole d b y  
C o h ort, o ver t he differe nt re gi me ns.  
 
S afet y A n al ysis  
All safet y a nal yses will b e ma de o n t h e Safet y p o p ulati o n. All partici pa nts e nr olle d i nt o t he st u d y w h o 
recei v e at least 1  d ose of st u d y dr u g  will be i ncl u de d i n t he safet y p o p ulati o n. Partici pa nts i n t his 
p o p ulati o n will be defi ne d b y t he st u d y dr u g recei ve d, n ot b y ra n d o mizati o n assi g n me nt.  
Safet y data will be prese nte d descri pti vel y  b y C o h ort . N o statistical testi n g of safet y data is pla n ne d.  
Baseli ne will be defi ne d as t he last o bser vati o n bef ore first d ose of st u d y dr u g f or all safet y a nal yses.  
9. 3. 1  A d verse E ve nts  
T he ver bati m ter ms use d i n t he C R F b y t he i n vesti gat or t o i de ntif y A Es will be c o d e d usi n g t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). A n y A E occ urri n g at or after first d os e of st u d y dr u g 
t hr o u g h t he da y of l ast d ose pl us 2 0 da ys is c o nsi dere d t o be tr eat me nt e mer ge nt. All re p orte d  A Es will 
be i ncl u de d i n t h e a n al ysis. F or eac h A E, t he perce nt a ge of partic i pa nts w h o e x perie nce at l east 
1  occ urre nce of t he gi ve n e ve nt will be s u m marize d b y st u d y dr u g gr o u p.  
S u m maries, listi n gs, datasets, or partici p a nt narrati ves ma y be pr o vi de d, as a p pr o pri ate, f or t h os e 
partici pa nts w h o die, w h o disc o nti n ue st u d y dr u g d ue t o a n A E, or w h o e x perie nce a n A E of at least 
Gra de 3, or a n S A E.  
T he m o difie d U S F D A T o xicit y Gra di n g T a ble i n A p pe n di x 1 : M o difi e d U S F D A T o xicit y Gra di n g 
Ta ble  will b e use d f or A E re p orti n g i n t his st u d y.  
9. 3. 2  Cli nic al L a b or at or y Tests  
La b orat or y d ata will be s u m marize d b y t y pe of la b orat or y test. Refere nce ra n ges a n d mar ke dl y 
a b n or mal res ults (s pecifi e d i n t he S A P) will be use d i n t he s u m mar y of la b orat or y data. Descri pti v e 
statistics will be calc ulate d f or eac h la b orat or y a n al yte at baseli ne a n d f or o bser ve d val ues a n d c ha n g es 
fr o m baseli ne at eac h sc he d ule d ti me p oi nt. C ha n ges fr o m bas eli ne res ults will be prese nte d i n pre- 
vers us p ost -i nter ve nti o n cr oss-ta b ulati o ns ( wit h cl asses f or b el o w, wit hi n, a n d a b o ve n or mal ra n g es). 
Fre q u e nc y ta b ulati o ns of t he a b n or malities will be ma de. A listi n g of partici pa nts wit h a n y la b orat or y 
res ults o utsi de t he refere nce ra n ges will be pr o vi de d. A listi n g of partici pa nts wit h a n y mar ke dl y 
a b n or mal la b orat or y res ults ( Gra de 3 or Gra d e 4) will als o be pr o vi de d.  
9. 3. 3  Vit al Si g ns  
Vital si g ns i ncl u di n g b o d y te m perat ure, p uls e/ heart rate a n d bl o o d press ure (s yst olic a n d diast olic) 
(s u pi ne) will be s u m mari ze d o ver ti me, gra p hicall y a n d/ or usi n g descri pti v e statistics. T he perce nta ge 
of partici pa nts wit h val u es be y o n d cli nicall y i m p orta nt li mits  (see A p pe n di x 1 : M o difie d U S F D A 
T o xicit y Gra di n g Ta ble ) will be s u m marize d.  
9. 3. 4  P h ysic al E x a mi n ati o ns  
P h ysical e xa mi nati o n fi n di n gs will be s u m marize d at eac h sc h e d ule d ti me p oi nt. Fre q ue n c y ta b ulati o ns 
of t he a b n or malities will be ma de.  
 
Electr oc a r di o gr a m Assess m e nts  
T he effects o n car di o vasc ular vari a bles (safet y E C Gs) will be e val uate d b y mea ns of descri pti ve 
statistics a n d fre q ue nc y ta b ulati o ns. T hese ta bles will i ncl u de o bser ve d val ues a n d c ha n g es fr o m 
baseli ne val ues t o all o w detecti o n of cli nical l y rele va nt c ha n ges i n i n di vi d uals. T he E C G varia bles t hat 

CI R 3 3 2  
 
1 1 9  
 
will be a nal yz e d are h eart rate, P R i nter val, Q R S i nter val, Q T i nter val, a n d c orrect e d Q T ( Q Tc) i nter val 
usi n g t he f oll o wi n g c orrecti o n met h o ds: Q T c orrecte d acc or di n g t o Bazett's f or m ula ( Q Tc B), Q T 
c orrecte d acc or di n g t o Fri dericia's f or m ula ( Q Tc F). Descri pti ve statistics of Q Tc i nter vals a n d c ha n ges 
fr o m bas eli ne will be s u m marize d at eac h s c he d ule d ti me p oi nt. T he perce nta ge of partici pa nts wit h 
Q Tc i nter val > 4 5 0 millisec o n ds, > 4 8 0 millisec o n ds, or > 5 0 0 millisec o n ds will be s u m marize d, as will 
t he perce nta ge of p artici pa nts wit h Q Tc i nter val i ncreas es fr o m baseli ne > 3 0 millisec o n ds t o ≤ 6 0 
millisec o n ds, or > 6 0 millisec o n ds. T he perce nta ge of s u bjects wit h a b n or malities a n d treat me nt -
e mer ge nt a b n or malities will be ta b ulate d.  
 
P h ar m ac o ki netic A n al ysi s 
All partici pa nts w h o recei ve d at least 1 d ose of st u d y dr u g a n d w h o ha ve at least 1 P K para meter v al ue 
will be i ncl u de d i n t he P K a nal ysis. All partici pa nts w h o recei v e d at least 1 d ose of st u d y dr u g a n d  
w h o ha ve at least 1 plas ma c o nce ntrati o n data val ue after d osi n g will be i ncl u de d i n t he descri pti ve 
statistics. 
Descri pti ve statistics will be calc ulate d f or t he plas ma c o nce ntr ati o ns of J NJ -6 4 2 8 1 8 0 2 a n d f or t he 
deri ve d P K para meters, as a p plica ble. Stat istics will i ncl u de sa m ple size ( n), mea n, ST D, C V, 
ge o metric mea n, m e dia n, mi ni m u m, a n d ma xi m u m.  
F or eac h partici pa nt, plas ma c o nce ntrati o n -ti me d ata will be gra p hicall y prese nte d. Si milarl y, gra p hs 
of t he me a n plas ma c o n ce ntrati o n -ti me pr ofiles a n d o verla y gra p hs wit h c o m bi ne d i n di vi d ual plas ma 
c o nce ntr ati o n -ti me pr ofiles will be pr o d uce d. P har mac o ki netic p ara met ers will be s u bjecte d t o a n 
e x pl orat or y gra p hical a n al ysis i ncl u di n g vari o us tra nsf or mati o ns t o o btai n a ge neral o v er vie w.  
C o h ort 1: Pre d ose plas ma c o nce ntr ati o ns ( C tr o u g h) o n Da ys -4, 1, 7, 9, 1 1, 1 6  a n d 2 1 will be 
c o m pare d gra p hic all y t o assess t he ac hi e ve me nt of stea d y -state c o nce ntrati o ns of J NJ-6 4 2 8 1 8 0 2.  
C o h ort 2 D ail y  D osi n g: Pre d ose plas ma c o nce ntr ati o ns ( C tr o u g h) o n Da ys -1, 1, 4, 8, 1 1, 1 5, 1 8 , a n d 
2 1  will be c o m pare d gra p hicall y t o assess t he ac hie ve me nt of stea d y -stat e c o nce ntr ati o ns of J NJ-
6 4 2 8 1 8 0 2 . 
C o h ort 2 Wee kl y D osi n g: Pre d ose plas ma c o nce ntrati o ns ( C tr o u g h) o n Da ys -1, 1, 8, a n d 1 5 will  be 
c o m pare d gra p hic all y t o assess t he ac hi e v e me nt of stea d y -state c o nce ntrati o ns of J NJ-6 4 2 8 1 8 0 2 . 
S pecial atte nti o n will be pai d t o t he plas ma c o nce ntrati o ns a n d P K para meters of t h ose p artici pa nts 
w h o die d, w h o ha v e disc o nti n ue d t he st u d y d ue t o a n A E, or w h o e x p erie n ce d a n A E of at least Gra de  3, 
or a n S A E.  
 
I m m u ne A n al yses  
9. 6. 1  H u m or al I m m u ne A n al yses  
Ser oc o n versi o n will be defi ne d as a ≥ 4 -f ol d i ncreas e i n de n g u e a nti b o d y titer (I g M, I g G, or 
ne utralizi n g  A b ) at a n y ti me-p oi nt p ost -D E N V -3 c halle n ge c o m pare d wit h baseli ne.  
Descri pti ve statistics will be  use d t o des cri be t he ne utralizi n g a nti b o d y res p o nse. T he pr o p orti o n of 
partici pa nts wit h a nti b o d y p ositi vit y, i ncl u di n g ne utralizi n g a nti b o dies a n d t he titer a n d ti mi n g of t he 
a nti b o d y res p o nse will be deter mi ne d.   
Descri pti ve st atistics will i ncl u de s a m p le size, mea n, ST D, C V, ge o metric mea n, me dia n, mi ni m u m, 
a n d ma xi m u m.   

CI R 3 3 2  
 
1 2 0  
 
9. 6. 2  Cell ul ar I m m u ne A n al yses  
Descri pti ve statistics will be use d t o descri be t he ma g nit u de of t he I F N -γ T cell res p o nse or t he C D 4 + 
a n d C D 8 + T cell res p o nses (e x pressi n g at least 1 c yt o ki ne s uc h as I L -2, T N F -α or I F N -γ s pecific t o 
a n y a nti ge n) or B cell res p o nse as defi ne d b y E LI S p ot a n d/ or I C S, res pecti vel y. C ha n ges fr o m baseli ne 
(if prese nt) will als o be ta b ulate d f or P B M Cs d uri n g t he d osi n g a n d f oll o w-u p p hase. T he pr o p orti o n 
of p artici pa nts wit h p ositi ve res p o nses base d o n t he ma g nit u de of t he I F N -γ T cell res p o nse or t he 
C D 4 + or C D 8 + T cell res p o nses or B cells t hat secrete I g G a n d/ or I g M, as d efi ne d b y E LI S p ot a n d/ or 
I C S, res p ecti vel y, will be deter mi ne d. 
Descri pti ve st atistics will i ncl u de s a m ple size, mea n, S T D, C V, ge o metric mea n, me dia n, mi ni m u m, 
a n d ma xi m u m.   
9. 6. 3  Bi o m ar kers A n al yses  
Statistical a p pr oac h es t o e x pl ore c orrelati o ns bet w ee n cli nical o utc o me a n d bl o o d bi o mar kers v ar y a n d 
de pe n d o n t he differe nt data t y pes of t he a p plie d tec h n ol o g y platf or ms, as well as o n t he e xte nt of 
o bser ve d differe nces bet wee n p artici pa nts. A nal yses will be c o n d ucte d at t he s p o ns or’s discreti o n, will 
al wa ys be u n d er t he s p o ns or's s u per visi o n, a n d res ults will be prese nte d i n t he cli nical st u d y  re p ort or 
a se parate re p ort.  
9. 6. 4  P h ar m ac o ki netic/ P h ar m ac o d y n a mic A n al yses  
T he relati o ns hi p bet wee n t he P K a n d a nti viral acti vit y of J NJ -6 4 2 8 1 8 0 2 will be e x pl ore d gra p hicall y 
a n d a nal yz e d usi n g statistical met h o ds, as data all o w. A s na ps h ot date f or P K a n d P D sa m ples t o b e 
a nal yze d will be d efi ne d , if re q uir e d. Sa m ples c ollecte d bef ore t his date will be i ncl u de d i n t h e P K/ P D 
a nal yses. Sa m ples c ollect e d after t he s n a ps h ot date will be a nal yze d at a later date a n d m a y be i ncl u d e d 
i n a P K/ P D re-a nal ysis w he n t he y bec o me a v aila ble after t he s u bjects i n C o h ort 1 ha ve c o m plete d or 
disc o nti n ue d  t he st u d y a n d t he data ha ve b ee n cl ea ne d. M ore details will be pr o vi de d i n a se parate 
a nal ysis pla n  a n d t he res ults will be prese nte d i n a se parate re p ort . 
U n bli n de d P K/ P D a nal y ses will be perf or me d b y i n de pe n de nt i nter nal p har mac o metricia ns of Ja nss e n  
usi n g data a vaila bl e at a pre -d efi ne d s n a ps h ot date, wit h a de q uat e fire walls s o t he D D T a n d st u d y 
s p o ns or will re mai n bli n de d. At t he ti me of t he sec o n d i nteri m a nal ysis, t he D S M B a n d D D U T  will 
re vie w res ults of t he P K/ P D a nal yses a n d t he d osi n g re gi me n selecte d b y t he D D T. 
If c o n d uct e d, a nal ysis r es ults of t he relati o ns hi p bet wee n t he P K a n d s electe d safet y e n d p oi nts will be 
prese nte d i n a s e parate re p ort.  
9. 6. 5  Vir al Ge n o me Se q ue nce A n a l yses 
T he res ults of D E N V -3 viral ge n o me s e q ue nci n g will be e val uat e d b y t he s p o ns or vir ol o gist. Rele va nt 
c ha n ges i n t he D E N V -3 viral ge n o me will be ta b ulate d a n d descri be d f or partici pa nts wit h detecta ble 
D E N V -3 R N A d uri n g t he st u d y peri o d.  
A d diti o nal e x pl orat or y c haract erizati o n of t he D E N V -3 viral ge n o me s e q u e nce a n d p he n ot y p e ma y be 
perf or me d a n d re p orte d s e parat el y.  
9. 6. 6  H u m a n Le u k oc yte A nti ge n  T y pi n g a n d P h ar m ac o ge n o mic A n al yses  
T he statistical a p pr oac h f or a nal ysi n g t he e x pl orat or y h ost D N A  researc h ma y de pe n d o n t he o bjecti ve 
of t he a nal yses ( a nti viral acti vit y , safet y, a n d P K) a n d p ossi bl y rele va nt ge nes at t he ti me of a nal ysis. 
A nal yses will be c o n d u ct e d at t he s p o ns or’s discreti o n, will al wa ys be u n der t he s p o ns or's s u per visi o n, 
a n d res u lts will be prese nte d i n t he cli nical st u d y re p ort or a se p arate re p ort. 

CI R 3 3 2  
 
1 2 1  
 
D N A sa m ples will be a nal yze d f or H L A ge n ot y pi n g a n d p har m ac o ge n o mic a nal yses. A d diti o n al 
a nal yses ma y be c o n d uct e d if it is h y p ot hesize d t hat t his ma y hel p res ol ve iss ues wit h t he cli nical data.  
D N A sa m ples m a y be us e d f or res earc h relate d t o J NJ -6 4 2 8 1 8 0 2 a n d c o me dicati o ns, if a p plica bl e, or 
de n g ue. T he y ma y als o b e use d t o de vel o p tests/assa ys relate d t o J NJ -6 4 2 8 1 8 0 2 a n d c o me dicati o ns i n 
t he pr ot oc ol, if a p plica bl e, a n d de n g ue. P har mac o ge n o mic researc h ma y c o nsist of t he a nal ysis of o ne 
or m ore ca n di date ge nes or of t he a nal ysis of ge netic mar kers t hr o u g h o ut t h e ge n o me (as a p pr o pri ate) 
i n relati o n t o J NJ-6 4 2 8 1 8 0 2 a n d c o me dicati o ns, if a p plica ble, or d e n g ue cli nical e n d p oi nts.  
9. 6. 7  I g E In d uc e d M yel oi d C ell D e gr a d ati o n  A n al ysis  
Ser u m sa m ples f or i n vi v o researc h (t o i n vesti gate p ote ntial J NJ -6 4 2 8 1 8 0 2 -s pecific I g E i n d uce d 
m yel oi d cell de gra n ulati o n) will be a nal y ze d i n partici pa nts w h o d e vel o p ras h d uri n g t he st u d y. 
Sa m ples will be c ollecte d  fro m all partici pa nts pre d ose at Da y  -5  ( C o h ort 1), Da y -2 ( C o h ort 2),  a n d 
prec halle n g e at Da y  1. I n partici pa nts w h o de vel o p ras h, t he sa m ple will be re peate d w h e n t he ras h is 
o bser ve d . 
9. 6. 8  I nteri m A n al ysis  
T w o i nteri m a nal yses are pla n ne d d uri n g t he e xec uti o n  of t he trial. T he B oar d will  re vie w t he i nteri m 
a nal yses a n d d eci de w h et her t he criteri o n of f utilit y ha d bee n met.  
Interi m a nal ysis  # 1  is pla n ne d as s o o n as t he last partici pa nt i n Gr o u p 1 b c o m plet es St u d y Da y 2 9  or  
disc o nti n ue d earlier ) a n d data e ntr y is c o m plet e. T his a nal ysis will be 
 
 c o nsi dere d as t he pri mar y a n al ysis. T he data f or Gr o u ps 1a a n d 1b  of C o h ort 1  will 
be u n bli n de d o nl y f or s u bjects i ncl u de d i n t his i nteri m a nal ysis  a n d o nl y f or me m bers of t he D S M B, 
t he D D U T a n d t h e  D D T  (see  
 
C CI

CI R 3 3 2  
 
1 2 2  
 
Ta ble 1 1 : S u m mar y of S c he d ule of Interi m A nal yses a n d U n bli n di n g of D ata 
). U n bli n di n g will occ ur after all t he s u bjects i n Gr o u ps 1 a a n d 1b  ha ve c o m plete d Da y 2 9 or 
di sc o nti n ue d earlier a n d t he data ha v e bee n clea ne d. E nr ol me nt ca n c o nti n ue d uri n g t his i nteri m 
a nal ysis e xec uti o n.  If t he D S M B re q uests i n di vi d ual u n bli n de d data pri or t o t he i nteri m a nal yses, it 
will be pr o vi de d t o t he m  T he res ults of t his i nteri m a nal ysis will be s hare d wit h t he st u d y s p o ns or, t he 
NI AI D I ntra m ur al D S M B, t he Ja nsse n Dr u g De v el o p me nt U n bli n de d Tea m  ( D D U T), a n d t he J a nsse n 
Dr u g De v el o p me nt Tea m  ( D D T). T h e st u d y tea m will re mai n bli n de d f or t his a nal ysis. T h e D S M B 
will re vie w t he i nteri m a nal ysis  a n d ma ke rec o m me n dati o ns t o c o nti n ue or t o st o p t he e nr ol me nt of 
Gr o u p 2 , C o h ort 1. 
 
 
 
. 
T he Ja nsse n D D T a n d D D U T will als o re vie w t he i nteri m a nal ysis a n d ma ke rec o m me n dati o ns t o 
pr ocee d or n ot t o pr ocee d t o Gr o u p 2, C o h ort 1. T he fi nal decisi o n t o c o nti n ue or st o p t he st u d y will be 
ta ke n i n c olla b orati o n wit h t he s p o ns or ( O C R P R O), D D T, D D U T an d D S M B . T he trial ma y be st o p p e d 
f or f utilit y base d o n t he res ults of t his a nal ysis. T he st u d y tea m ca n get access t o t he u n bli n de d res ults 
of t his a nal ysis w he n all s u bjects i n C o h ort 1, G r o u p 1 ( Gr o u ps 1a, 1 b) h a v e c o m plete d St u d y Da y 8 5. 
Interi m a nal ys is # 2 is pla n ne d as s o o n as t he last p artici pa nt i n C o h ort 1 c o m pletes t he trial ( St u d y Da y 
8 5) . As f or t he first i nteri m a nal ysis, data e ntr y s h o ul d be c o m plete, a n d data s h o ul d be f ull y clea ne d 
bef ore t h e c o de is br o ke n. T his i nteri m a nal ysis will be used t o e val uate t h e relati o ns hi p bet wee n t h e 
P K a n d a nti viral acti vit y of J NJ 6 4 2 8 1 8 0 2 , t o d et er mi ne w het her a d diti o nal d osi n g re gi me ns will be 
e val uate d i n C o h ort  2, a n d (if a p plica ble) t o deci d e o n t he d ose, d osi n g d urati o ns, a n d d osi n g fre q ue n c y 
f or C o h ort 2 . T he pri mar y a nal ysis will be re peat e d as a se nsiti vit y a nal ysis. T he st u d y s p o ns or will 
c o ns ult wit h t he NI AI D I ntr a m ural D S M B, a n d t he Ja nsse n Dr u g De v el o p me nt Tea m  w h o a n al yzes 
a n d defi ne s t he d osi n g re gi me n(s) f or C o h ort 2. T he D S M B will re vie w t he i nteri m a nal ysis a n d ma ke 
rec o m me n dati o ns t o pr ocee d or n ot t o pr ocee d wit h e nr ol me nt of C o h ort 2. T he Ja nsse n D D T a n d 
D D U T will als o re vie w t he i nteri m a nal ysis a n d ma ke rec o m me n dati o ns t o c o nti n ue or t o st o p t he 
e nr ol me nt of C o h ort  2 . 
F or eac h of t he i nteri m a nal yses, a g gre gat e dat a o n D E N V  i nf ecti o n-ass o ciate d A Es (ras h i ncl u d e d), 
data o n pri mar y a n d sec o n dar y e n d p oi nts, a n d P K data will be a vaila ble f or re vie w, as a p pr o pri ate, b y 
t he st u d y s po ns or, t he NI AI D I ntra m ur al D S M B, a n d t he Ja nsse n Dr u g D e vel o p me nt T ea m t o assess 
w het her t he st u d y n ee ds t o c o nti n ue. A n e x pe dite d safet y re p ort will b e pre p are d if t he a n al ysis 
i n dicates t hat t hese D E N V i nfecti o n-ass oci ate d A Es occ ur m ore fre q ue ntl y i n J NJ -6 4 2 8 1 8 0 2 reci pie nts 
t ha n i n place b o reci pie nts, s u g gesti n g t hat t here ma y be a reas o na bl e p ossi bilit y of dr u g ca usalit y. T he 
NI AI D I ntr a m ural D S M B me m bers, st u d y t ea m me m bers, NI H statisticia n, t he me m b ers of t he Ja nsse n 
D D T  will be u n bli n de d  after all s u bjects i n C o h ort 1 , Gr o u p 1 ( Gr o u ps 1a, 1 b) ha v e c o m plet e d St u d y 
Da y 8 5 . After e nr ol me nt of C o h ort 1, Gr o u p 2, t he NI AI D I ntra m ur al D S M B me m bers, st u d y tea m 
me m bers, NI H statisticia n, t he me m bers of t he Ja nsse n D D T will be u n bli n de d after all s u bjects i n  
C o h ort 1, Gr o u p 2 h a ve c o m plete d St u d y Da y 8 5  a n d t h e dat a base has bee n clea ne d a n d cl ose d . T he 
S A P will descri be t he pla n ne d i nteri m a nal yses i n greater detail.  
Re vie ws of safet y data at ti mes ot her t ha n t he ti mes of i nteri m a nal yses will be d o ne b y t he D S M B 
wit h n o u n bli n di n g of st u d y tea m me m bers or J a nsse n.  
1 0  D at a C ollecti o n  a n d  M o nit ori n g  
C CI

CI R 3 3 2  
 
1 2 3  
 
 S o urce D oc u me nt ati o n  a n d D at a C ollecti o n  
C o m plete s o urce d oc u me ntati o n (la b orat or y test re p orts, h os pital or me dical rec or ds, pr o gress n otes, 
o bser vati o ns, et c.) is re q uire d f or e v er y st u d y s u bject f or t he d urati o n of t he st u d y. T he s u bject’s st u d y 
rec or d m ust rec or d his/ her partici pati o n i n t he cli nical trial a n d, after u n bli n di n g, t he ra n d o mizati o n 
i n oc ulati o n recei v e d ( wit h d oses a n d fre q u e ncy) or ot her c o nc o mita nt me dicati o ns or i nter ve nti o ns 
a d mi nistere d, as well as a n y a d vers e reacti o ns e x perie nce d d uri n g t he trial.  
 
Data fr o m s o urce d oc u m e ntati o n f or s u bjects e nr olle d i n t he st u d y will be e ntere d i nt o t he Cli nical 
Researc h I nf or mati o n M a n a ge me nt S yste m of t he NI AI D ( C RI M S O N) Data S yste m. T he data e ntr y 
is t o be c o m plete d o n a n o n g oi n g basis d uri n g t he st u d y. Data e ntr y i nt o C RI M S O N will be perf or me d 
b y a ut h orize d i n di vi d uals a n d eac h i n di vi d ual e nt eri n g data i nt o C RI M S O N will ha ve a u ni q ue  user 
I D a n d pass w or d. C orrecti o ns t o t he data s yste m s hall be trac k e d electr o nicall y ( pass w or d pr ot ecte d) 
wit h ti me, date, i n di vi d ual ma ki n g t he c orrecti o n, a n d w hat was c ha n g e d.  
 
C orrecti o ns t o t he s o urce d oc u me nt m ust be ma de b y stri ki n g t hr o u g h t he i n c orrect e ntr y wit h a si n gle 
li ne (ta ki n g care n ot t o o bliterate or re n d er t he ori gi nal e ntr y ille gi ble) a n d e nteri n g t he c orrect 
i nf or mati o n a djace nt t o t he i nc orrect e ntr y. C orrecti o ns m ust be i nitiale d a n d date d b y t he pers o n 
ma ki n g t he c orrecti o n w he ne v er p ossi ble. S o urce d oc u me ntati o n s h o ul d s u p p ort t he data c ollecte d i n 
C RI M S O N  a n d  m ust be si g ne d a n d date d b y t he p ers o n rec or di n g a n d/ or re vie wi n g t he data.  
 
T he i n vesti gat or is res p o nsi ble f or t h e acc urac y, c o m plete ness a n d ti meli ness of t h e dat a re p or te d t o 
t he S p o ns or i n t he C RI M S O N Data S yste m. All d ata e ntere d i nt o C RI M S O N s h o ul d be re vie we d b y 
t he i n vesti gat or/ desi g nee a n d si g ne d as re q uire d wit h writte n or electr o nic si g nat ure, as a p pr o priate. 
Data re p orte d i n C RI M S O N s h o ul d be c o nsiste nt wit h s o u rce d o c u me nts or t he discre pa n cies s h o ul d 
be e x plai ne d. S o urce d o c u me ntati o n will be ma de a vaila ble f or re vi e w or a u dit b y t he S p o ns or or 
desi g nee a n d a n y a p plica ble Fe d eral a ut h orities . 
 St u d y D oc u me nt ati o n   
St u d y -relate d d oc u m e ntati o n will be c o m plete d as re q uire d b y t he I R Bs, t h e S p o ns or, a n d re g ulat or y 
a ut h orities. C o nti n ui n g re vie w d oc u me ntati o n will be s u b mitte d b y t he i n vesti gat or t o t he I R Bs b y t he 
a n ni versar y date of i nitial re vie w as s p ecifie d b y eac h I R B. A n a n n u al re p ort will be s u b mitte d b y t h e 
S p o ns or t o t he F D A acc or di n g t o re g ulati o ns. T hese re p orts will pr o vi de a brief des cri pti o n of t he 
pr o gress of t he i n vesti gati o n as o utli ne d i n t he C o de of Fe d eral Re g ulati o ns ( C F R), Title 2 1, Part 
3 1 2. 3 3 ( 2 1 C F R 3 1 2. 3 3), a n d will i ncl u de a n y re visi o ns of t he pr ot oc ol if n ot pre vi o usl y s u b mitte d. 
 
T he PI will mai ntai n a de q uate rec or ds t o acc o u nt f or t he dis p ositi o n of t he i n vesti gati o nal pr o d uct, 
i ncl u di n g dates of recei pt a n d q ua ntit y, c urre nt i n ve nt or y, a n d dis pe nsati o n t o s u bjects. If t he st u d y is 
ter mi nate d, s us pe n d e d, or c o m plete d, all u n use d c halle n ge vir us  will be dis p ose d of p er s p o ns or’s 
i nstr ucti o ns a n d u n use d J NJ-6 4 2 8 1 8 0 2 st u d y pr o d uct will be dis p ose d of per D D T i nstr ucti o ns . 
 Rete nti o n  of S peci m e ns  
All s peci me ns c ollect e d as part of t his trial wi ll be st ore d i n defi nitel y for f ut ure researc h as p art of o ur 
a p pr o ve d bi osa m ple re p osit or y f or vacci ne researc h. T hese sa m ples ma y b e use d  b y t he s p o ns or, t he 
site, t he Ja nsse n dr u g de vel o p me nt tea m or its part ners t o lear n m ore a b o ut fla vi vir us i nfecti o n a n d 
ot her diseases , or t o u n dersta n d J NJ-6 4 2 8 1 8 0 2 or de vel o p test s relate d t o J NJ-6 4 2 8 1 8 0 2 . T hese 
sa m ples will n ot be s ol d or use d t o ma ke c o m mercial pr o d ucts. All sa m ples st ore d i n t he re p osit or y 
will be la bele d wit h t he st u d y s u bject  I D n u m bers, w hic h, by t he msel v es, ca n n ot i d e ntif y st u d y 
s u bjects, b ut are li n ka ble t o ot her researc h data bases (e. g., fr o m q uesti o n n aires, cli nical assess me nts, 
l o g b o o ks, etc.) ge nerate d b y t he mai n st u d y. T he re p osit or y data bas e will c o ntai n o nl y t he st u d y s u bject 

CI R 3 3 2  
 
1 2 4  
 
I D n u m bers. A  master l o g li n ki n g t he st u d y s u bject I D n u m bers t o t he na mes of t he s u bjects will be 
mai ntai ne d  i n a p ass w or d-pr otecte d data base s yst e m wit h li mite d access t o a ut h orize d res earc h tea m  
me m bers.  
 
Partic ipa nts ma y wit h dra w t heir c o nse nt f or t heir s a m ples t o be st ore d f or f ut ure researc h.  
 Rete nti o n  of Rec or ds  
T he PI is res p o nsi ble f or retai ni n g all esse ntial d oc u me nts liste d i n t he I nter nati o nal C o nfere nce  o n 
Har m o nisati o n (I C H) G o o d Cli nical Practice ( G C P) g ui deli nes. Trial -relate d d oc u m e nts will be  
mai ntai ne d b y t he i n vesti gat or i n a s ec ure st ora g e facilit y f or a peri o d of 2 years after fi nal  mar keti n g 
a p pr o val or if 2 years ha ve ela pse d si nce t h e f or mal dis c o nti n uati o n of  t he pr o d uct’s cli nical 
de vel o p me nt. T hese rec or ds are als o t o be mai ntai ne d i n c o m plia nce wit h  I R B, state, a n d fe deral 
me dical rec or ds’ rete nti o n re q uire me nts, w hic he v er is l o n gest. T he  s p o ns or is re q uire d t o i nf or m t he 
i n vesti gat or as t o w he n s uc h d oc u me nts nee d n o l o n ger be retai ne d. St ora ge of all trial-relat e d 
d oc u me nts will be  s uc h t hat c o nfi d e ntialit y will be strictl y mai ntai ne d t o t h e e xte nt pr o vi de d b y fe deral, 
state, a n d l ocal la ws.  
 
It is t he PI’s res p o nsi bilit y t o retai n c o pies of s o urce d oc u me nts u ntil recei pt of writte n n otificati o n t o 
t he c o ntrar y fr o m NI AI D O C R P R O. St u d y d oc u me nts s h o ul d n ot be d estr o ye d wit h o ut pri or writte n 
a gree m e nt bet wee n NI AI D O C R P R O a n d t he PI. S h o ul d t he PI wis h t o  assi g n t he st u d y rec or ds t o 
a n ot her p art y a n d/ or m o ve t o a n ot her l ocati o n, t he PI m ust pr o vi de  writte n n otificati o n of s uc h i nte nt  
t o NI AI D O C R P R O, wit h t he na me of t he pers o n w h o will acce pt res p o nsi bilit y f or t he tra nsferre d 
rec or ds a n d/ or t he ne w l ocati o n. NI AI D m ust be n otifie d i n writi n g, a n d writte n per missi o n m ust be 
recei v e d b y t he site pri or t o destr ucti o n or rel ocati o n of researc h rec or ds.  
 Pr ot oc ol  C o m pli a nce  
T he PI will c o n d uct t h e trial i n c o m plia nce wit h t h e pr ot oc ol a gree d t o b y t h e s p o ns or. T he  i n v esti gat or 
will n ot i m ple me nt a n y de viati o n fr o m, or c ha n g es t o, t he pr ot oc ol wit h o ut  a gree me nt, pri or re vie w,  
a n d d oc u me nte d a p pr o val b y t he s p o ns or , t he D D T  a n d t he I R B t hat gra nte d  ori gi nal a p pr o val f or t he 
st u d y. T he D S M B will b e ma de a w are of all pr ot oc ol re visi o ns ( ot h er  t h a n a d mi nistrati ve) a n d will 
re vie w a n y c ha n g es t o t he pr ot oc ol t hat i n v ol ve D S M B o versi g ht or i n v ol ve c ha n ges t o t he st u d y’s 
data a n d safet y m o nit ori n g pla n.  H o we ver, t he i n vesti gat or ma y i m ple me nt a de viati o n fr o m, or c h a n g e 
i n, t he pr ot oc ol t o eli mi n ate a n i m me diat e hazar d(s) t o s u bjects wit h o ut pri or I R B or s p o ns or a p pr o val, 
or w he n t he  c h a n ge(s) i n v ol ves o nl y l o gistical or a d mi nistrati ve as p ects of t he trial (i.e., c ha n ge of 
tele p h o ne n u m ber[s]). I n t he e ve nt of a me dical e m er ge nc y, t he PI will perf or m a n y me di cal pr oce d ures  
t hat are dee me d me dic all y a p pr o priate. 
 
As s o o n as p ossi ble, t h e i m ple me nte d de viati o n or c ha n g e, t he reas o ns f or it, a n d, if a p pr o priate,  t h e 
pr o p ose d pr ot oc ol a me n d me nt(s) s h o ul d be s u b mitte d t o t he S p o ns or, D D T, I R B, D S M B, a n d t he 
re g ulat or y a ut h orities. 
 Cli nic al  I n vesti g at or’s Br oc h ure 
I n v esti gat ors will recei ve t he c urre nt versi o ns of t h e Cli nical I Bs f or J NJ-6 4 2 8 1 8 0 2  test article a n d f or 
r D E N 3 Δ 3 0, w hi c h c o m pre he nsi vel y des cri be all t he a vaila ble precli nical e x perie nce wit h t he 
e x peri me ntal J NJ-6 4 2 8 1 8 0 2 test article a n d c h alle n ge vir us. If rele va nt  ne w i nf or mati o n b ec o m es 
a vaila ble d uri n g t he c o urse of t he tri al, t he i n vesti gat ors will recei ve a  re vis e d br oc h ure or a n 
a me n d me nt t o t he c ur re nt versi o n. 

CI R 3 3 2  
 
1 2 5  
 
 St u d y M o nit ori n g  
As per I C H -G C P 5. 1 8 a n d F D A 2 1 C F R 3 1 2. 5 0, cli nical pr ot oc ols are re q uire d t o be a de q u atel y  
m o nit ore d b y t he s p o ns or. T his st u d y m o nit ori n g will be c o n d ucte d acc or di n g t o t he “ NI AI D  
I ntr a m ural Cli nical M o nit ori n g G ui deli nes.” T he s p o ns or will m o nit or all as pects of t he st u d y,  wit h 
res pect t o c urre nt G C P, f or c o m plia nce wit h a p pli ca ble g o ver n me nt re g ul ati o ns. Pri or t o t he start of 
t he st u d y, t he i n vesti gat or will be i nf or me d of t he fre q ue nc y of m o nit ori n g visits a n d will be gi v e n 
reas o na bl e n otificati o n pri or t o eac h visit. T he o bjecti ves of a m o nit ori n g visit will be t o verif y t he 
pr o m pt a n d acc urat e rec or di n g of all m o nit ore d d ata p oi nts, a n d pr o m pt re p orti n g of  S A Es; t o c hec k 
t he a vaila bilit y of si g ne d i nf or me d c o ns e nt f or ms a n d d oc u me ntati o n of t he  i nf or me d c o nse nt pr o cess 
f or eac h m o nit ore d s u bj ect; t o c o m pare C RI M S O N re p orts a n d li ne listi n gs wit h s o urce data f or 
c o m plete ness a n d acc urac y; a n d t o hel p e ns ure i n vesti gat ors are i n  c o m plia nce wit h t he pr ot oc ol. T he 
m o nit ors wi ll als o i ns pect t he cli nic al site re g ulat or y files t o e ns ure t hat re g ulat or y re q uir e me nts 
( Offic e f or H u ma n Res earc h Pr otecti o ns, F D A) a n d a p plica ble g ui deli nes (I C H G C P) are bei n g 
f oll o we d. D uri n g t he m o nit ori n g visit, t he i n vesti gat or (a n d/ or desi g ne e) a n d ot her st u d y pers o n nel 
s h o ul d be a vaila ble t o disc uss t he st u d y. St u d y d oc u me nts m ust be a vaila ble f or re vie w t hr o u g h o ut t h e 
c o urse of t he st u d y. T he s p o ns or  will retai n ori gi nal c o pies of F or m F D A 1 5 7 2 a n d c o pies of ot her 
st u d y d oc u me nts as dee me d necess ar y.  
 
T he i n vesti gat or (a n d/ or desi g nee) will ma ke st u d y d oc u me nts (e. g., c o nse nt f or ms, C RI M S O N,  a n d 
perti ne nt h os pital or cli nical rec or ds) rea dil y a vaila ble f or i ns pecti o n b y t he l ocal I R B, t he  F D A, t h e 
site m o nit ors, a n d NI AI D staff f or c o nfir mati o n of t he st u d y data. 
 
A s pecific pr ot oc ol m o nit ori n g pla n will be disc usse d wit h t he PI a n d st u d y staff pri or t o  e nr oll me nt. 
T he pla n will o utli ne t he fre q ue nc y of m o nit ori n g visits base d o n s uc h fact ors as  st u d y e nr oll me nt, dat a 
c ollecti o n stat us, a n d r e g ulat or y o bli gati o ns.  
1 1  Pr otecti o n  of H u m a n  S u bjects  
 I nstit uti o n al Re vie w B o ar ds  
T he PI will be res p o nsi ble f or o bt ai ni n g I R B a p pr o val f or t he st u d y. Bef ore t he start of t he st u d y,  t he 
a p pr o priate d o c u me nts (i ncl u di n g, b ut n ot li mite d t o, t he pr ot oc ol, I B, I nf or me d C o nse nt F or m, 
i nf or mati o n s heets, a n d a d vertise me nts) will be s u b mitte d t o t he I R B f or a p pr o val. A c o p y of t h e st u d y 
a p pr o val (i ncl u di n g a p pr o val of t he i nf or me d c o nse nt f or m) is  t o be mai ntai ne d i n t he i n v esti gat or 
st u d y d oc u me nt bi n der a n d a c o py will be s u p plie d t o t he  s p o ns or. D uri n g t he st u d y, t he i n vesti gat or 
is res p o nsi ble f or pr o vi di n g t he I R B wit h all d oc u me nts s u bject t o re vi e w (e. g., pr ot oc ol a me n d me nts, 
i nf or me d c o nse nt f or m u p dates, a d vertise me nts, a n d a n y writte n i nf or mati o n t hat ma y be pr o vi de d t o 
t he s u bject). A n n ual re p orts o n t he pr o gress of t he st u d y will be ma de t o t h e I R B b y t he i n vesti gat or i n 
acc or da nce wit h I R B g ui deli nes a n d g o ver n m e nt r e g ulati o ns.   
 I nf or me d C o nse nt  
I n o btai ni n g a n d d oc u me nti n g i nf or me d c o ns e nt, t he i n vesti gat or a n d st u d y staff m ust c o m pl y  wit h  t h e 
a p plica ble re g ulat or y re q uire me nts, G C P g ui deli nes, a n d et hical pri nci ples. T he writte n  i nf or me d 
c o nse nt f or m m ust be a p pr o ve d b y t he I R B pri or t o its use. T he s u bject ma y wit h dra w  c o nse nt at a n y 
ti me d uri n g t he c o urse of t he trial. A c o p y of t he i nf or me d c o nse nt d oc u me nt will  be gi ve n t o t he 
s u bject f or his or her rec or ds. T he ri g hts a n d welfare of t he s u bjects will be  pr otecte d b y e m p hasizi n g 
t o t he m t hat t he q u alit y of t heir me dical care will n ot be a d v ersel y affecte d if t he y d ecli ne t o p artici pate 
i n t his st u d y.  

CI R 3 3 2  
 
1 2 6  
 
 Ris ks  
Ris ks t o t he s u bjects are ass ociate d wit h ve ni p u n ct ure, t o pical a n est hetic crea m, a n d st u d y  a ge nt(s). 
T hese ris ks are o utli ne d b el o w. Fe mal e s u bjects will be ca uti o ne d of t he u n k n o w n ris k of st u d y a ge nts 
t o t he fet us a n d will be a d vise d t o use effecti ve birt h c o ntr ol met h o ds f or t he d urati o n of t he st u d y . 
1 1. 3. 1  J N J -6 4 2 8 1 8 0 2  
J NJ-6 4 2 8 1 8 0 2  has b ee n teste d caref ull y a n d e xte nsi vel y i n la b orat or y a ni mals ( rats a n d d o gs) 
acc or di n g t o r e g ulat or y g ui deli nes  a n d it is c o nsi dere d ge n erall y safe a n d well t olerate d i n a ni mals .  
 
I n cli nical st u dies, d uri n g st u d y 6 4 2 8 1 8 0 2 D N G 1 0 0 1, w he n t este d f or t he first ti me i n h ealt h y 
partici pa nts, J NJ -6 4 2 8 1 8 0 2 was g e nerall y safe a n d well t olerate d.  T w o Gra de 2 ( mil d t o m o derate) 
e ve nts of ras h occ urre d i n t he m ulti ple asce n di n g d ose part t hat were c o nsi dere d ver y li kel y rel ate d t o 
J NJ-6 4 2 8 1 8 0 2 b y t he i n vesti gat or. O ne Gra de 2 ( mil d t o m o derate) ras h occ urre d i n a s u bject i n t he 
1 0  da y 5 6 0 m g J NJ -6 4 2 8 1 8 0 2 gr o u p, o n t he last da y of d osi n g ( Da y 1 0), a n d res ol ve d after 3 5 da ys. 
T he ot her Gra de 2 ( mil d t o m o derate) ras h  occ urre d i n a s u bject i n t he 3 1 -da y 4 0 0 m g J NJ -6 4 2 8 1 8 0 2 
gr o u p, o n d osi n g Da y 1 3, a n d res ol ve d after 4 7 da ys. T his s u bject c o m plete d t he 3 1 -da y treat me nt 
peri o d as pla n ne d. Base d o n t h is li mite d a m o u nt of data fr o m FI H st u d y 6 4 2 8 1 8 0 2 D N G 1 0 0 1, ras h is 
c o nsi dere d a p ote ntial ris k. Caref ul cli nical m o nit ori n g of ras h e v e nts will be perf or me d i n all pla n ne d 
cli nical st u dies f or J NJ -6 4 2 8 1 8 0 2.  
 
I n fe male partici pa nt s of c hil d beari n g p ote ntial , t he effects of J NJ -6 4 2 8 1 8 0 2 o n a n u n b or n c hil d or 
i nfa nt are n ot pr o perl y k n o w n . Preca uti o ns will be ta ke n t o pre v e nt pre g n a nc y i n fe mal e s u bjects as 
o utli ne d i n secti o n 5. 1  a b o ve.  
 
I n male partici pa nts, t he effect of J NJ -6 4 2 8 1 8 0 2 o n a n u n b or n c hil d or i nfa nt are u n k n o w n. Ta ki n g t he  
me dici nal pr o d uct d uri n g t he st u d y c o ul d lea d t o a n u n k n o w n ris k f or a n e m br y o or  fet us a n d t he effect 
of J NJ -6 4 2 8 1 8 0 2 o n s per m is u n k n o w n . F or t his reas o n, barrier c o ntrace pti o n is re q uire d as o utli ne d 
i n secti o n 5. 1  a b o ve.  
 
S u bjects ma y be as ke d t o defer r o uti ne i m m u nizati o ns (s uc h as i nfl ue nza) u ntil f or 2 8 da ys pri or t o 
first d ose of st u d y dr u g a n d f or 2 8 d a ys f oll o wi n g last d ose of st u d y dr u g  f or lice nse d li ve atte n uate d 
vacci nes. S u bjects ma y be as ke d t o defer r o uti ne i m m u nizati o ns (s uc h as i nfl ue nza) u ntil f or 1 4 da ys 
pri or t o first d ose of st u d y dr u g a n d f or 1 4 d a ys f oll o wi n g last d ose of st u d y dr u g f or ot her lice ns e d 
( n ot li ve) vacci nes. T he e xce pti o n t o t his is C O VI D -1 9 vacci nes lice nse d or u n der E U A. T his ma y 
i ncreas e t he ris k t hat t he s u bject will be i nfecte d wit h a n i nfl ue nza vir us d uri n g t his peri o d. As wit h 
a n y i n vesti gati o nal st u d y a ge nt, t here is a t he oretical p ossi bilit y of ris ks a b o ut w hic h we ha ve n o 
prese nt k n o wle d ge. S u bjects will be i nf or me d of a n y s uc h ris ks s h o ul d f urt her i nf or mati o n bec o m e 
a vaila ble.  
1 1. 3. 2  C h alle n ge  
P ossi ble l ocal c h alle n ge reacti o ns i ncl u d e p ai n, s welli n g, or er yt h e ma f or 2 t o 3 d a ys, 
l y m p ha de n o pat h y, or pr urit us at t he i njecti o n site. S yste mic reacti o ns s uc h as mac ular p a p ular ras h a n d 
tra nsie nt ne utr o pe nia h a ve bee n o bser ve d i n s o me s u bjects i nfecte d wit h ot her rec o m bi na nt de n g ue 
vacci ne ca n di dates. Ot her p ote ntial s yste mic reacti o ns t hat ma y occ ur i ncl u de s y m pt o ms of de n g ue 
s uc h as fe ver, hea d ac he, p h ot o p h o bia, e ye pai n, ras h, ge neralize d myal gias, art hral gias, ele vate d A L T, 
ne utr o pe nia, el e vate d P T T, or decrease d pl atelet c o u nt. I m me diate h y p erse nsiti vit y reacti o ns i ncl u di n g 
urticaria, a na p h yla xis, or ot her I g E -m e diate d res p o nses are p ossi ble , as wit h a n y pr o d uct. S u bjects w h o 
recei v e o nl y r D E N 33 0 ma y be at i ncreas e d ris k of m ore se vere dis ease if t he y bec o m e i nfecte d wit h 
a n ot her wt D E N V ser ot y pe i n t he f ut ure.  

CI R 3 3 2  
 
1 2 7  
 
1 1. 3. 3  Ve ni p u nct ure  
T he t otal a m o u nt of bl o o d t o be dra w n t hr o u g h o ut t he 8 5 -da y  d urati o n of t he st u d y is  a p pr o xi matel y 
6 7 8  m L f or C o h ort 1 a n d 6 1 0  m L  f or C o h ort 2. 
 
Ris ks occasi o nall y ass o ciate d wit h v e ni p u nct ure i ncl u de e xcessi ve blee di n g, pai n, br uisi n g, or  
he mat o ma at t he site of ve ni p u nct ure, li g ht hea d e d ness, a n d s y nc o pe (rarel y). I nfecti o n ma y occ ur  
rarel y 
1 1. 3. 4  Peri p her al I nt r a ve n o us (I V)  C at heter  
Ris ks ass ociate d wit h peri p heral I V cat heter place me nt i ncl u de  e xcessi ve blee di n g, pai n, br u isi n g, or 
he mat o m a at t he site of I V place me nt . Li g ht hea de d ness or s y n c o pe (rarel y).  Air e m b olis m, 
e xtra vas c ular dr u g a d mi nistrati o n, a n d  i ntraarteri al i njecti o n are rare.  I nfecti o n or i nfla m mati o n ma y 
occ ur.  
1 1. 3. 5  T o pic al A nest hetic Cre a m  
Ris ks occasi o nall y ass o ciate d wit h t he use of t o pical a nest hetic crea m i ncl u de te m p orar y s ki n  
disc ol orati o n, s ki n irritati o n, ras h, hi ves, a n d rarel y, dizzi ness or dr o wsi n ess.  
 Be nefits   
S u bjects will n ot recei ve a n y direct be nefit fr o m partici pati o n i n t his st u d y. T he y will recei ve a  p h ysical 
e xa mi nati o n a n d la b orat or y scree ni n g f or HI V i nfecti o n, he patitis B i nfecti o n, a n d  he p atitis C 
i nfecti o n. T he y may p ote ntiall y de vel o p a nti b o dies a gai nst o ne or m ore d e n g ue  vir uses.  It is h o p e d t hat 
i nf or mati o n gai ne d i n t his st u d y will c o ntri b ute t o t he de vel o p me nt of a s afe a n d effecti ve tr eat me nt of 
de n g ue  i nfecti o n. 
 C o m pe ns ati o n   
C o h ort 1: S u bjects will be c o m pe nsate d u p t o $ 1 0 0 f or scree ni n g, u p t o $ 2 0 0  f or i n oc ulati o n da y  
( Da y 1) , u p t o $ 3 0 0 f or eac h  i n patie nt/f ull da y  ( Da y -6  a n d Da y -5 ) a n d u p t o $ 2 5 0 f or eac h f ull da y 
( Da y 2 1), u p t o $ 5 0 f or at h o me d osi n g wit h p h o ne call ( Da y -3, -2, 2, 4, 6, 8, 1 0, 1 2, 1 3 , 15 , 17 , 1 9, 
2 0), a n d u p t o $ 1 0 0 f or eac h c o m plete d sc he d ule d d osi n g or f oll o w -u p visit . T he y will als o recei ve u p 
t o $ 7 5 f or ret ur ni n g a c o m plete d te m perat ure / d osi n g l o g. T he y will als o recei ve u p t o a $ 3 0 0 b o n us 
if all st u d y visits are c o m plete d o n ti me. S u bjects will be c o m pe nsate d f or t he scree ni n g o nl y if t he y 
are e nr olle d i n t he st u d y. S u bjects will o nl y be c o m pe nsate d f or t h e visits t hat t he y  c o m plete. Alter n ates 
w h o c o me t o t he cli nic o n St u d y Da y -6 a n d are i n patie nt o ver ni g ht b ut w h o are n ot d ose d wit h st u d y 
dr u g  d ue  t o f ulfill me nt of e nr oll me nt f or t hat d a y will be c o m pe nsate d u p t o $2 0 0. S u bjects e nr olle d 
i n t he st u d y will recei ve a ma xi m u m t otal c o m pe nsati o n of u p t o $ 4, 1 7 5 . 
 
C o h ort 2: S u bjects will b e c o m pe ns ate d u p t o $ 2 0 0 f or scree ni n g if e nr olle d, u p t o $ 2 5 0 f or i n o c ulati o n 
da y ( Da y 1), u p t o $ 3 0 0 f or eac h i n patie nt  ni g ht ( Da y -3, -2, -1 ), a n d u p t o $ 2 5 0 f or eac h f ull da y ( Da y 
1 5 f or wee kl y d o si n g, a n d Da y 2 1 f or d ail y d osi n g), a n d u p t o $ 1 2 5 f or eac h c o m plete d sc he d ul e d 
d osi n g or f oll o w -u p visit  ( 1 7 t otal). T he y will als o recei ve u p t o $ 7 5 f or ret ur ni n g a c o m plete d 
te m perat ur e / d osi n g l o g. T he y will als o recei v e u p t o a $ 3 0 0 b o n us if all st u dy visits are c o m plete d o n 
ti me. S u bjects will be c o m pe nsate d f or t he scree ni n g o nl y if t he y are e nr olle d i n t he st u d y. S u bjects 
will o nl y be c o m p e nsate d f or t h e visits t hat t he y c o m plete. Alter nat es w h o c o me t o t he cli nic o n St u d y 
Da y -3 a n d are i n patie nt o ver ni g ht b ut w h o are n ot d ose d wit h st u d y dr u g d ue t o f ulfill me nt of 
e nr oll me nt f or t hat da y will be c o m pe nsate d u p t o $ 2 0 0. S u bjects e nr olle d i n t he st u d y will recei ve a 
ma xi m u m t otal c o m pe nsati o n of u p t o $ 3 8 5 0  f or sta n dar d f oll o w u p sc h e d ule c o nsisti n g of 1 5 d osi n g 
or f oll o w u p visits ( $ 4 1 0 0 if Da y 2 7 a n d Da y 3 4 are i n dicate d base d o n la b res ults)  

CI R 3 3 2  
 
1 2 8  
 
 C o nfi de nti alit y  
All st u d y -relate d i nf or mati o n will be st ore d sec urel y at t he st u d y site. All s u bject i nf or mati o n will  b e 
st ore d i n l oc ke d file ca bi nets i n areas wit h access li mite d t o st u d y staff. All la b orat or y  s peci me ns, 
re p orts, st u d y data c ollecti o n, a n d pr ocess a n d a d mi nistrati ve f or ms will be i de ntifie d b y c o de d n u m ber 
o nl y t o mai ntai n s u bject c o nfi de ntialit y. C o m p uter e ntr y will be d o ne us i n g a st u d y I D n u m ber f or eac h 
s u bject a n d all l ocal d ata bases will be sec ure d wit h pass w or d-pr otecte d  access s yste ms. F or ms, lists, 
l o g b o o ks, a p p oi nt me nts b o o ks, a n d a n y ot her listi n gs t hat li n k s u bject st u d y I D n u m bers t o ot her 
i de ntif yi n g i nf or mati o n will be st ore d i n a se parate, l oc ke d file i n a n area wit h li mite d access. A 
s u bject’s st u d y i nf or mati o n will n ot be release d wit h o ut t he writte n per missi o n of t he s u bject, e xce pt 
as necess ar y f or m o nit ori n g b y t he S p o ns or a n d/ or its  c o ntract ors a n d t he F D A.  
 Bi o h az ar d  C o nt ai n me nt  
As t he tra ns missi o n of HI V a n d ot her bl o o d -b or ne pat h o ge ns ca n o cc ur t hr o u g h c o ntact wit h  
c o nta mi nate d nee dles, bl o o d, a n d bl o o d pr o d ucts, a p pr o priate bl o o d a n d secreti o n preca uti o ns  will be 
e m pl o ye d b y all pers o n nel d uri n g t he dra wi n g of bl o o d a n d s hi p pi n g a n d ha n dli n g of all  s peci me ns f or 
t his st u d y, as c urre ntl y rec o m me n de d b y t he C D C  a n d t he NI H.  
 
All i nfecti o us s peci me ns will be tr a ns p orte d usi n g pac ka gi n g ma n date d i n t he C o d e of Fe deral  
Re g ulati o ns, 4 2 C F R Part 7 2. Please als o re fer t o i n di vi d ual carri er g ui deli nes (e. g., Fe deral E x press, 
Air b or ne E x press) f or s pecific i nstr ucti o ns.  
1 2  P u blic ati o n  P olic y  
T he I nter n ati o nal C o m mittee of Me dical J o ur nal E dit ors (I C MJ E) me m b er j o ur nals ha ve a d o pte d  a 
trials’ re gistrati o n p olic y as a c o n diti o n f or p u blicati o n. T his p olic y re q uir es t hat all cli nical trials be 
re gistere d pri or t o e nr oll me nt of a n y s u bject i n a p u blic trials re gistr y, s uc h as Cli nical Trials. g o v, w hi c h 
is s p o ns ore d b y t he Nati o nal Li brar y of M e dici ne. T he I C MJ E defi nes a cli ni cal trial as a n y researc h 
pr oject t hat pr os pecti vel y assi g ns h u ma n s u bjects t o i nter ve nti o n  or c o m paris o n gr o u ps t o st u d y t he 
ca use-a n d-effect relati o ns hi p bet wee n a me dical i nter ve nti o n  a n d a healt h o utc o me. St u dies desi g ne d 
f or ot her p ur p oses, s uc h as t o st u d y p har mac o ki netics or maj or t o xicit y, w o ul d be e xe m pt fr o m t his 
p olic y.  
 
 
 

CI R 3 3 2  
 
1 2 9  
 
1 3  S u p p orti n g D oc u me nt ati o n  
 A p pe n di x 1 : M o difie d U S F D A T o xicit y Gr a di n g T a ble  
 
Ge ner al Se v erit y 
Gr a di n g 1 
Gr a de I –  Mil d  
Gr a de II –  M o der ate  
Gr a de III - 
Se vere  
Gr a de I V  
L ocal React o ge nicit y  
 
 
 
 
Pai n  
D oes n ot i nterfere 
wit h acti vit y  
Re peate d use of n o n -
narc otic pai n relie ver 
> 2 4 h o urs or 
i nterferes wit h acti vit y 
A n y use of 
narc otic pai n 
relie ver or 
pre ve nts dail y 
acti vit y  
E mer ge n c y r o o m visit 
or h os pitalizati o n  
Te n der ness  
Mil d disc o mf ort t o 
t o uc h 
Disc o mf ort wit h 
m o ve me nt  
Si g nifica nt 
disc o mf ort at rest  
E mer ge n c y r o o m visit 
or h os pitalizati o n  
I njecti o n Site Pr urit us 
Pr urit us t hat is easil y 
t olerate d 
Pr urit us t hat i nterferes 
wit h dail y acti vit y  
Pr urit us t hat 
pre ve n ts dail y 
acti vit y  
E mer ge n c y r o o m visit 
or h os pitalizati o n  
Er y t he ma/ Re d ness 
2. 5 - 5  cm  
5. 1 –  1 0 c m  
> 1 0 c m  
Necr osis or e xf oliati ve 
der matitis  
I n d urati o n/s welli n g 
2. 5 - 5  cm  a n d d oes 
n ot i nterfere wit h 
acti vit y  
5. 1 –  1 0 c m  or 
i nterferes wit h acti vit y 
> 1 0 c m  or 
pre ve nts dail y 
acti vit y  
Necr osis  
S yste mic React o ge nicit y  
Gra d e I –  Mil d  
Gra de II –  M o derate  
Gra de III - Se vere  
Gra de I V - p ote ntiall y 
life-t hreate ni n g u nless 
ot her wise n ote d  
Fe ver ( Oral)  
1 0 0. 4° F –  1 0 1. 4° F  
1 0 1. 5° F –  1 0 2. 4° F  
≥1 0 2. 5°  - 1 0 4° F   
> 1 0 4° F  
Hea dac he  
N o i nterfere n ce wit h 
acti vit y  
Re peate d use of n o n -
narc otic pai n relie ver 
> 2 4 h o urs or s o me 
i nterfere nce wit h 
acti vit y  
A n y use of 
narc otic pai n 
relie ver or 
pre ve nts dail y 
acti vit y  
E R visit or 
h os pitalizati o n  
Retr o -Or bital Pai n 
( R O P) 
N o i nterfere n ce wit h 
acti vit y  
R O P t hat i nterferes 
wit h dail y acti vit y or 
re q uires > 1 d ose of 
me dicati o n  
R O P t hat pre ve nts 
dail y acti vit y  
E R visit or 
h os pitalizati o n  
Na usea  
N o i nterfere n ce wit h 
acti vit y or 1 –  2 
e pis o des i n 2 4 h o urs  
Interferes wit h dail y 
acti vit y  or re s ults i n 
> 2 e pis o des/ 2 4 h o urs  
P re ve nts dail y 
acti vit y , re q uires 
o ut patie nt 
h y drati o n  
E R visit or 
h os pitalizati o n  
Fati g ue  
N o i nterfere n ce wit h 
acti vit y  
Fati g ue t hat i nterferes 
wit h dail y acti vit y or 
re q uires > 1 d ose of 
me dicati o n  
Fati g ue t hat 
pre ve nts dail y 
acti vit y  
E R visit or 
h os pitalizati o n  
M y al gia  
N o i nterfere n ce wit h 
acti vit y  
M y al gia t hat i nterferes 
wit h dail y acti vit y or 
re q uires > 1 d ose of 
me dicati o n  
M y al gia t hat 
pre ve nts dail y 
acti vit y 
E R visit or 
h os pitalizati o n  
Art hral gia  
N o i nterfere n ce wit h 
acti vit y  
Art hral gia t hat 
i nterferes wit h dail y 
acti vit y or re q uires > 1 
d ose of me dicati o n  
Art hral gia t hat 
pre ve nts dail y 
acti vit y  
E R visit or 
h os pitalizati o n  
Ras h Mac ul o -Pa p ular  
Ras h is prese nt b ut 
as y m pt o matic , ma y 
re q uire 1 d ose of 
me dicati o n/treat me nt  
Ras h is s y m pt o matic 
( pr urit us/ pai n), 
i nterferes wit h dail y 
acti vities or re q uires > 
1 d ose of me dicati o n  
Ras h is 
s y m pt o matic a n d 
i nterferes wit h 
f u ncti o n 
E R visit or 
h os pitalizati o n  

CI R 3 3 2  
 
1 3 0  
 
Ge ner al Se v erit y 
Gr a di n g 1 
Gr a de I –  Mil d  
Gr a de II –  M o der ate  
Gr a de III - 
Se vere  
Gr a de I V  
Dr u g Ras h  ( hi ves, 
blisters, er yt he ma, 
c o nsiste nt wit h dr u g 
ras h) 
Ras h is prese nt b ut 
as y m pt o matic , ma y 
re q uire 1 d ose of 
me dicati o n/treat me nt  
Ras h is s y m pt o matic 
( pr urit us/ pai n), 
i nterferes wit h dail y 
acti vities or re q uires > 
1 d ose of me dicati o n  
Ras h is 
s y m pt o matic a n d 
i nterferes wit h 
f u ncti o n 
E R visit or 
h os pitalizati o n  
A b d o mi nal Pai n  
A b d o mi nal p ai n t hat is 
prese nt b ut easil y 
t olerate d, ma y re q uire 
1 d ose of 
me dicati o n/treat me nt  
A b d o mi nal pai n  t hat 
i nterferes wit h dail y 
acti vit y or  re q uires > 1 
d ose of me dicati o n  
A b d o mi nal p ai n 
t hat pre ve nts dail y 
acti vit y 
E R visit or 
h os pitalizati o n  
L oss of A p petite  
L oss of a p petite 
wit h o ut alterati o n i n 
eati n g ha bits 
Oral i nta ke altere d 
wit h o ut si g nifica nt 
wei g ht l oss or 
mal n utriti o n; oral 
n utriti o nal s u p ple me nts 
i n dicate d 
Ass ociate d wit h 
si g nifica nt wei g ht 
l oss or mal n utriti o n 
(e. g. i na de q uate 
oral cal oric i nta ke 
a n d/ or fl ui d i nta ke); 
t u be fee di n g or 
T P N i n dicate d  
E R visit or 
h os pitalizati o n  
V o miti n g  
I nter ve nti o n n ot 
i n dicate d 
O ut patie nt I V 
h y drati o n; me dical 
i nter ve nti o n i n dicate d 
T u be fee di n g, T P N 
or h os pitalizati o n 
i n dicate d 
E R visit or 
h os pitalizati o n  
Diarr hea  
2 –  3 l o ose st o ols or < 
4 0 0 g ms/ 2 4 h o urs  
4 –  5 st o ols or 4 0 0 –  
8 0 0 g ms/ 2 4 h o urs  
6  or m ore water y 
st o ols or > 
8 0 0 g ms/ 2 4 h o urs or 
re q uires o ut patie nt 
I V h y drati o n 
E R visit or 
h os pitalizati o n  
S olicite d La b A Es  
Gra d e I –  Mil d  
Gra de II –  M o derate  
Gra de III - Se vere  
Gra de I V - p ote ntiall y 
life-t hreate ni n g u nless 
ot her wise n ote d  
He m o gl o bi n (fe male)  
9. 5 - 1 0. 7 g m/ d L  
8. 0 - 9. 4 g m/ d L  
< 7. 9 g m/ d L  
E R visit or 
h os pitalizati o n  
He m o gl o bi n ( male)  
1 1. 0 - 1 2. 5 g m/ d L  
9. 0 –  1 0. 9 g m/ d L  
< 8. 9 g m/ d L  
E R visit or 
h os pitalizati o n  
Ne utr o pe nia ( Re d uce d 
A N C) 2 
≥7 5 0 -9 9 9/ m m 3  
≥5 0 0 -7 4 9/ m m 3  
< 5 0 0/ m m 3  
E R visit or 
h os pitalizati o n  
Le u k oc yt osis (I ncrease d 
W B Cs)  
1 1, 5 0 0 - 1 3, 0 0 0/ m m 3  
1 3, 0 0 1 - 1 5, 0 0 0/ m m 3  
> 1 5, 0 0 0  
E R visit or 
h os pitalizati o n  
T hr o m b oc yt o pe nia 
( Re d uce d Platelets) 
1 0 0, 0 0 0 –  
1 2 0, 0 0 0/ m m 3  
7 5, 0 0 0 - 9 9, 9 9 9/ m m 3  
< 7 4, 9 9 9/ m m 3  
E R visit or 
h os pitalizati o n  
P T  
> 1. 0 - 1. 2 5 x u p per 
li mit of n or mal 
( U L N) 
> 1. 2 5 - 1. 5 x U L N  
> 1. 5 x U L N  
E R visit or 
h os pitalizati o n  
P T T  
> 1. 0 - 1. 6 6 x U L N  
> 1. 6 6 - 2. 3 3 x U L N  
> 2. 3 3 x U L N  
E R visit or 
h os pitalizati o n  
A L T  ( Ala ni ne 
A mi n otra nsferase)  
> 1. 2 5 - 2. 5 x U L N  
> 2. 5 - 5. 0 x U L N  
> 5. 0  - < 1 0 x U L N  
> 1 0 x U L N  
Ot her La b orat or y Val u es  
Gra d e I –  Mil d  
Gra de II –  M o derate  
Gra de III - Se vere  
Gra de I V - p ote ntiall y 
life-t hreate ni n g u nless 
ot her wise n ote d  
Al b u mi n, L o w  
3. 0 t o < L L N g/ d L  
≥2. 0 t o < 3. 0 g/ d L  
< 2. 0 g/ d L  
N A  
Creati ni ne  
1. 5 - 1. 7 m g/ d L  
> 1. 7 –  2. 0 m g/ d L  
> 2. 0  - 2. 5 m g/ d L  
> 2. 5 or re q uires 
dial ysis  
Fi bri n o ge n  decrease –  
m g/ d L  
1 5 0  - 2 0 0 m g   
1 2 5 - 1 4 9  
 1 0 0 - 1 2 4  
< 1 0 0 m g/ d L, or 
ass ociate d wit h gr oss 
blee di n g, or ass ociate d 

CI R 3 3 2  
 
1 3 1  
 
Ge ner al Se v erit y 
Gr a di n g 1 
Gr a de I –  Mil d  
Gr a de II –  M o der ate  
Gr a de III - 
Se vere  
Gr a de I V  
wit h disse mi nate d 
c oa g ulati o n  
Fi bri n o ge n  i ncrease 
m g/ d L  
4 0 0 - 5 0 0  
5 0 1 - 6 0 0  
> 6 0 0  
-- 
Creati ne p h os p h o ki nase 
( C P K) 
≥1. 5  x U L N - 2  x 
U L N  
> 2  x U L N - 4  x U L N  
> 4 - 1 0  x U L N  
> 1 0 x U L N  
S o di u m: H y p o natre mia  
1 3 0 –  1 3 4 m E q/ L  
1 2 3 –  1 2 9 m E q/ L  
< 1 2 2 m E q/ L  
E R visit or 
h os pitalizati o n  
S o di u m: H y per natre mia  
1 4 5 –  1 5 0 m E q/ L  
1 5 1 –  1 5 7 m E q/ L  
> 1 5 8 m E q/ L  
E R visit or 
h os pitalizati o n  
P otassi u m: H y p o kale mia  
3. 1 –  3. 2 m E q/ L  
2. 9 –  3. 0 m E q/ L  
< 2. 8 m E q/ L  
E R visit or 
h os pitalizati o n  
P otassi u m: 
H y per kale mia  
5. 2 –  5. 5 m E q/ L  
5. 6 –  6. 0 m E q/ L  
> 6. 1 m E q/ L  
E R visit or 
h os pitalizati o n  
P h os p hate: 
H y p o p h os p hate mia  
2. 0 –  2. 2 m g/ d L  
1. 5 –  1. 9 m g/ d L  
< 1. 4 m g/ d L  
E R visit or 
h os pitalizati o n  
Calci u m ( C orrecte d f or 
Al b u mi n): 
H y p ocalce mia  
1. 9 5 –  2. 0 4 m m ol/ L  
1. 7 5 –  1. 9 4 m m ol/ L  
< 1. 7 4 m m ol/ L  
E R visit or 
h os pitalizati o n  
Calci u m ( C orrecte d f or 
Al b u mi n): 
H y percalce mia  
2. 5 1 –  2. 8 8 m m ol/ L  
2. 8 9 –  3. 1 3 m m ol/ L  
> 3. 1 4 m m ol/ L  
E R visit or 
h os pitalizati o n  
Ma g nesi u m: 
H y p o ma g nese mia  
0. 6 0 –  0. 7 4 m m ol/ L  
0. 4 5 –  0. 5 9 m m ol/ L  
< 0. 4 4 m m ol/ L  
E R visit or 
h os pitalizati o n  
T otal Bilir u bi n 
( h y per bilir u bi ne mia) 
> 1. 1  t o < 1. 6  x U L N  
> 1. 6  t o < 2. 6  x U L N  
2. 6  t o < 5. 0 x U L N  
≥5. 0 x U L N  
Gl uc ose: H y p o gl yce mia  
( N o nfasti n g, N o Pri or 
Dia b etes)  
5 5 –  6 9 m g/ d L  
4 0 –  5 4 m g/ d L  
< 3 9 m g/ d L  
E R visit or 
h os pitalizati o n  
Gl uc ose: H y per gl yce mia  
( N o nfasti n g, N o Pri or 
Dia b etes)  
1 1 6 –  1 6 0 m g/ d L  
1 6 1 –  2 5 0 m g/ d L  
> 2 5 1 m g/ d L  
I ns uli n re q uire me nts or 
h y per os m olar c o ma  
Bicar b o nate, L o w  
1 6. 0 t o < L L N 
( m E q/ L; m m ol/ L) 
1 1. 0 t o < 1 6. 0 ( m E q/ L; 
m m ol/ L)  
8. 0 t o < 1 1. 0 
( m E q/ L; m m ol/ L) 
< 8. 0 ( m E q/ L; m m ol/ L)  
C h olester ol, Fasti n g, 
Hi g h  
2 0 0 t o < 2 4 0 ( m g/ d L)  
2 4 0 t o < 3 0 0 ( m g/ d L) 
≥3 0 0 ( m g/ d L)  
N A  
L D L, Fasti n g, Hi g h  
1 3 0 t o < 1 6 0 ( m g/ d L)  
1 6 0 t o < 1 9 0 ( m g/ d L)  
≥1 9 0 ( m g/ d L)  
N A  
Tri gl yceri des  
—  
4 0 0 –  7 5 0 m g/ d L  
> 7 5 1 m g/ d L  
 
Li ver Tra nsa mi nase 
( L F Ts) 
G G T  
A S T  
Al k P h os  
 
> 1. 2 5 –  2. 5 x U L N  
> 1. 2 5 –  2. 5 x U L N  
> 1. 2 5 –  2. 5 x U L N  
 
> 2. 5 –  5. 0 x U L N  
> 2. 5 –  5. 0 x U L N  
> 2. 5 –  5. 0 x U L N  
 
> 5. 0 - 1 0 x U L N  
> 5. 0 - 1 0 x U L N  
> 5. 0 - 1 0 x U L N  
 
 
> 1 0 x U L N  
> 1 0 x U L N  
> 1 0 x U L N  
Pa ncreatic A m ylase  
Li pase  
> 1. 0 –  1. 5 x U L N  
> 1. 0 –  1. 5 x U L N  
> 1. 5 –  2. 0 x U L N  
> 1. 5 –  2. 0 x U L N  
> 2. 0  - 5 x U L N  
> 2. 0  - 5 x U L N  
> 5 x U L N  
> 5 x U L N  
Uric Aci d, Hi g h ( m g/ d L)  
7. 5 t o < 1 0. 0 m g/ d L  
1 0. 0 t o < 1 2. 0 m g/ d L  
1 2. 0 t o < 1 5. 0 
m g/ d L  
≥1 5. 0 m g/ d L  
Ot her Car di o vasc ular  
Gra d e I –  Mil d  
Gra de II –  M o derate  
Gra de III - Se vere  
Gra de I V - p ote ntiall y 
life-t hreate ni n g u nless 
ot her wise n ote d  

CI R 3 3 2  
 
1 3 2  
 
Ge ner al Se v erit y 
Gr a di n g 1 
Gr a de I –  Mil d  
Gr a de II –  M o der ate  
Gr a de III - 
Se vere  
Gr a de I V  
Car diac Arr h yt h mia  
As y m pt o matic; 
tra nsie nt 
d ysr h yt h mia, n o 
t hera p y re q uire d 
Rec urre nt/ persiste nt 
d ysr h yt h mia; 
s y m pt o matic t hera p y 
re q uire d 
u nsta ble 
d ysr h yt h mia, 
h os pitalizati o n a n d 
t hera p y re q uire d 
E R visit or 
h os pitalizati o n f or 
arr h yt h mia 
Pr ol o n ge d Q Tc I nter val 
(as per Bazett’s f or m ula) 
0. 4 5 t o 0. 4 7 sec o n ds  
> 0. 4 7 t o 0. 5 0 sec o n ds  
> 0. 5 0 sec o n ds O R 
≥ 0. 0 6 sec o n ds 
a b o ve baseli ne  
Life -t hreate ni n g 
c o nse q ue n ces (e. g. 
T orsa de de p oi ntes, or 
ot her ass ociate d 
seri o us ve ntric ular 
d ysr h yt h mia)  
Tac h ycar dia  –  beats per 
mi n ute  
1 0 1  —  1 1 5   
1 1 6 —  1 3 0  
> 1 3 0  
E R visit or 
h os pitalizati o n f or 
arr h yt h mia  
Bra d ycar dia  –  beats per 
mi n ute 3 
5 0  —  5 4   
4 5  —  4 9   
< 4 5  
E R visit or 
h os pitalizati o n f or 
arr h yt h mia  
H y perte nsi o n  
Tra nsie nt, i ncrease 
> 2 0 m m H g diast olic 
B P; n o t hera p y 
re q uire d 
Rec urre nt; c hr o nic 
i ncrease > 2 0 m m H g 
diast olic B P; t hera p y 
re q. 
ac ute t hera p y 
re q uire d o ut patie nt 
or h os pitalizati o n 
p ossi ble  
E R visit or 
h os pitalizati o n f or 
mali g na nt h y perte nsi o n  
H y p ote nsi o n  
Tra nsie nt ort h ostatic 
h y p ote nsi o n wit h 
heart rate i ncrease d 
b y 2 0 beats/ mi n or 
decrease d b y < 1 0 m m 
H g s yst olic B P, n o 
t hera p y re q uire d 
S y m pt o ms or B P 
decrease d b y < 2 0 m m 
H g s yst olic, 
c orrecta ble wit h oral 
fl ui d t hera p y 
Mea n arterial 
press ure < 6 0 m m 
H g, I V fl ui ds 
re q uire d, or 
h os pitalizati o n  
E R visit or 
h os pitalizati o n f or 
h y p ote nsi ve s h oc k  
Pericar ditis  
N o i nterfere n ce wit h 
acti vit y  
S o me i nterfere nce 
wit h acti vit y n ot 
re q uiri n g me dical 
i nter ve nti o n 
Pre ve nts dail y 
acti vit y a n d 
re q uires me dical 
i nter ve nti o n 
E R or visit or 
h os pitalizati o n  
He m orr ha ge, Bl o o d L oss  
Mi ni mal bl o o d l oss, 
as y m pt o matic, n o 
t hera p y re q uire d 
S y m pt o matic bl o o d 
l oss a n d n o tra nsf usi o n 
re q uire d 
S y m pt o matic 
A N D tra nsf usi o n 
of 1 -2 u nits of 
bl o o d or pac ke d 
re d cells 
Massi ve bl o o d l oss or 
> 2 u nits tra nsf use d  
Ot her Gastr oi ntesti nal  
Gra d e I –  Mil d  
Gra de II –  M o derate  
Gra de III - Se vere  
Gra de I V - p ote ntiall y 
life-t hreate ni n g u nless 
ot her wise n ote d  
Oral 
Disc o mf ort/ D ys p ha gia  
Diffic ult y s wall o wi n g 
b ut a ble t o eat a n d 
dri n k  
U na ble t o s wall o w 
s oli ds 
U na ble t o dri n k 
fl ui ds; I V fl ui ds 
re q uire d 
E R or visit or 
h os pitalizati o n  
C o nsti pati o n  
C o nsti pati o n less 
t ha n 72  h o urs a n d 
re q uires me dicati o n 
f or relief 
M o derate a b d o mi nal 
pai n 7 2  h o urs wit h 
i m pacti o n, re q uiri n g 
t hera p y 
Re q uiri n g 
disi m pacti o n or 
h os pital treat me nt  
E R or visit or 
h os pitalizati o n  
Ot her Res pirat or y  
Gra d e I –  Mil d  
Gra de II –  M o derate  
Gra de III - Se vere  
Gra de I V - p ote ntiall y 
life-t hreate ni n g u nless 
ot her wise n ote d  
Br o nc h os pas m Ac ute  
Tra nsie nt; n o 
t hera p y; F E V 1 or 
pea k fl o w re d uce d t o 
7 0 - < 8 0 %  
T hera p y re q uire d; 
n or malizes wit h 
br o nc h o dilat or; F E V 1 
or pea k fl o w 5 0 - 6 9 %  
N o n or malizati o n 
wit h 
br o nc h o dilat or; 
F E V 1 or pea k fl o w 
2 5 –  4 9 %, 
retracti o ns 
E R or visit or 
h os pitalizati o n  

CI R 3 3 2  
 
1 3 3  
 
Ge ner al Se v erit y 
Gr a di n g 1 
Gr a de I –  Mil d  
Gr a de II –  M o der ate  
Gr a de III - 
Se vere  
Gr a de I V  
D ys p nea  
D ys p nea o n e xerti o n  
D ys p nea wit h n or mal 
acti vit y  
D ys p nea at rest  
E R or visit or 
h os pitalizati o n  
Ot her Ne ur ol o gic  
Gra d e I –  Mil d  
Gra de II –  M o derate  
Gra de III - Se vere  
Gra de I V - p ote ntiall y 
life-t hreate ni n g u nless 
ot her wise n ote d  
N uc h al Ri gi dit y  
--  
-- 
Prese nce of 
N uc hal ri gi dit y  
E R or visit or 
h os pitalizati o n  
Ne ur o ps yc h ol o gical  
 
Mil d c o nf usi o n or 
c o g niti ve i m pair me nt  
M o derate c o nf usi o n or 
c o g niti ve i m pair me nt  
Se vere c o nf usi o n 
or c o g niti ve 
i m pair me nt 
E R or visit or 
h os pitalizati o n  
Ne ur ocere b ellar  
Sli g ht i nc o or di nati o n 
or 
d ys dia d oc h o ki nesia  
I nte nti o n tre m or, 
d ys metria, sl urre d 
s peec h, or n ysta g m us 
Ata xia re q uiri n g 
assis ta nce t o wal k 
or ar m 
i nc o or di nati o n 
i nterferi n g wit h 
A D Ls  
E R or visit or 
h os pitalizati o n  
Ne ur o m ot or  
Mil d wea k ness i n 
m uscle of feet, b ut 
a ble t o wal k; a n d/ or 
mil d i ncrease i n 
refle xes 
M o derate wea k ness i n 
feet or le gs, e. g. 
u na ble t o perf or m 
dee p k nee be n d, mil d 
wea k ness i n ha n ds, 
l oss of pre vi o usl y 
prese nt refle x or 
de vel o p me nt of 
h y perrefle xia.  
Mar ke d distal 
wea k ness  
E R or visit or 
h os pitalizati o n  
Ne ur ose ns or y  
Mil d i m pair me nt 
( decrease d se nsati o n 
i n f ocal area or 
s y m metrical 
distri b uti o n)  
 
M o derate s y m metrical 
i m pair me nt, mil d 
i m pair me nt t hat is n ot 
s y m metrical 
 
Se vere i m pair me nt 
( decrease d or l oss 
of se nsati o n t o 
k nees or wrists) or 
l oss of se nsati o n of 
at least m o derate 
de gree i n m ulti ple 
areas or f u ncti o ns  
E R or visit or 
h os pitalizati o n  
Parest hesia  
( B ur ni n g, Ti n gli n g, etc.) 
Mil d disc o mf ort; n o 
t hera p y re q uire d 
M o derate disc o mf ort; 
n o n -narc otic a nal gesia 
re q uire d 
Se vere disc o mf ort; 
or narc otic 
a nal gesia re q uire d 
wit h s y m pt o matic 
i m pr o ve me nt 
E R or visit or 
h os pitalizati o n  
Ot her Der mat ol o gic  
Gra d e I –  Mil d  
Gra de II –  M o derate  
Gra de III - Se vere  
Gra de I V - p ote ntiall y 
life-t hreate ni n g u nless 
ot her wise n ote d  
Der matitis  
Ras h is prese nt b ut 
as y m pt o matic  
Ras h is s y m pt o matic 
( pr urit us/ pai n) b ut 
d oes n ot i nterfere wit h 
f u ncti o n 
Ras h is 
s y m pt o matic a n d 
i nterferes wit h 
f u ncti o n 
E R or visit or 
h os pitalizati o n  
Ot her Uri nal ysis  
Gra d e I –  Mil d  
Gra de II –  M o derate  
Gra de III –  Se vere  
Gra de I V - p ote ntiall y 
life-t hreate ni n g u nless 
ot her wise n ote d  
Pr otei n uria: Ra n d o m 
Uri ne  
1 +  
2 + - 3 +  
4 +  
E R or visit or 
h os pitalizati o n  
Pr otei n uria: 2 4 H o ur 
Uri ne  
2 0 0 m g –  1 g l oss/ da y 
or < 0. 3 % or < 3 g/ L  
> 1 –  2 g l oss/ da y or 
0. 3 % - 1. 0 % or 3 –  1 0 
g/ L  
> 2 g l oss/ da y or 
> 1. 0 % or > 1 0 g/ L  
E R or visit or 
h os pitalizati o n  
He m at uria (I n t he 
A bse n ce of 
Micr osc o pic o nl y,  
6 -1 0 r bc/ h pf  
> 1 0 r bc/ h pf  
Gr oss, wit h or 
wit h o ut cl ots;  
E R or visit or 
h os pitalizati o n  

CI R 3 3 2  
 
1 3 4  
 
1. 
Gra d e 5 will be assi g ne d t o a n y A E  t hat res ults i n deat h 
2. T hese val ues f or ne utr o pe nia are val ues t hat ha ve bee n use d i n de n g ue c o ntr olle d h u ma n i nfecti o n m o del st u dies 
a n d de n g ue li ve atte n uate d vacci ne st u dies  
3. W h e n resti n g heart rate is  b etw ee n 6 0 –  1 0 0  b eats p er m in u te. Use clin ical ju d ge m e nt w he n c h aracterizi n g 
br ad y card ia am o n g  so m e heal th y s u bject  p o p u latio n s, fo r e xam p le, co n d itio ne d at h letes. 
 
 
 
Ge ner al Se v erit y 
Gr a di n g 1 
Gr a de I –  Mil d  
Gr a de II –  M o der ate  
Gr a de III - 
Se vere  
Gr a de I V  
Cer vic o -va gi nal 
Blee di n g)  
or R B C casts  
Ot her Miscella n e o us  
Gra d e I –  Mil d  
Gra de II –  M o derate  
Gra de III - Se vere  
Gra de I V - p ote ntiall y 
life-t hreate ni n g u nless 
ot her wise n ote d  
Malaise  
Malaise t hat is easil y 
t olerate d 
Malaise t hat i nterferes 
wit h dail y acti vit y  
Malaise t hat 
pre ve nts dail y 
acti vit y  
E R or visit or 
h os pitalizati o n  

CI R 3 3 2  
 
1 3 5  
 
 A p pe n di x  2 : C o ntr ace pti ve a n d B arrier G ui d a nce 
Partici pa nts m ust f oll o w c o ntrace pti ve meas ures as o utli ne d i n secti o n 5. 1 , I n cl usi o n Criteria.  
Defi niti o ns  
Pers o ns  of C hil d be ari n g P ote nti al ( P O C B P)  
A pers o n  is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile (see bel o w).  
Fe m ale  N ot of C hil d be ari n g P ote nti al  
•  
pre me n arc h al  
 
A pre me narc h al state is o ne i n w hic h me narc he h as n ot yet occ urre d.  
•  
p ost me n o p a us al  
 
A p ost me n o pa usal stat e is defi ne d as n o m e nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me di cal 
ca use. A hi g h F S H le v el ( > 4 0 I U/ L or mI U/ m L) i n t he p ost me n o pa usal ra n ge ma y be us e d t o 
c o nfir m a p ost me n o pa us al state i n pers o ns  n ot usi n g h or m o nal c o ntrace pti o n or h or m o na l 
re place me nt t hera p y ( H R T), h o we ver i n t he a bs e nce of 1 2 m o nt hs of a me n orr hea, a si n gle 
F S H meas ur e me nt is i ns ufficie nt.  A p ers o n is c o nsi dere d p ost me n o pa usal defi niti vel y wit h 
>  2 4 m o nt hs of c o ns ec uti ve a me n orr hea a n d a F S H le vel is n ot re q uire d t o c o nfi r m. If t here 
is a q uesti o n a b o ut me n o pa usal stat us i n pers o ns  o n H R T, t he p ers o n  will be re q uire d t o us e 
o ne of t he n o n -estr o ge n -c o ntai ni n g h or m o nal hi g hl y effecti ve c o ntrace pti ve met h o ds if the y  
wis h t o c o nti n ue H R T d uri n g t he st u d y  
•  
per m a ne ntl y sterile (f or t he p ur p ose of t his st u d y) 
 
Per ma ne nt sterilizati o n met h o ds i ncl u de h ysterect o m y, bilateral sal pi n gect o m y, a n d bilateral 
o o p h orect o m y, a n d s h o ul d ha ve bee n perf or me d ≥3 m o nt hs bef ore first d os e of st u d y dr u g.  
N ote: If t he c hil d beari n g p ote ntial c ha n ges aft er start of t he st u d y (e g, a pre me narc h al pers o n  
e x perie n ces me narc he) or t he ris k of pre g na nc y c ha n ges (e g, a P O C B P w h o is n ot heter ose x uall y acti ve 
bec o mes acti ve), a P O C B P  m ust be gi n a hi g h l y effecti ve met h o d of c o ntrace pti o n, as d escri be d 
t hr o u g h o ut t he i ncl usi o n criteria. 
If re pr o d ucti ve stat us is q uesti o na ble, a d diti o nal e val uati o n s h o ul d be c o nsi dere d. 
C o ntrace pti ve ( birt h c o ntr ol) use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal re g u lati o ns 
re gar di n g t he acce pta ble met h o ds of c o ntrace pti o n f or partici pa nts  i n cli nical st u dies. 
T y pical use fail ure rat es ma y differ fr o m t h ose w he n use d c o nsiste ntl y a n d c orrectl y.   
E x a m ples of C o ntr ace pti ves  
E X A M P L E S O F C O N T R A C E P TI V E S a A L L O W E D D U RI N G T H E  S T U D Y I N C L U D E:  
U S E R I N D E P E N D E N T  
Hi g hl y Effecti ve Met h o ds T h at Are User I n de pe n de nt F ail ure r ate of < 1 % per ye ar w he n use d 
c o nsiste ntly a n d c orrectly.  
•  I ntra uteri ne De vice ( H or m o nal or C o p per) 
•  I m pla nta ble pr o gest o ge n-o nl y h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n b 
•  Bilateral t u bal occl usi o n  
•  Vasect o mize d part ner  

CI R 3 3 2  
 
1 3 6  
 
( V asect o mize d p art ner is a hi g hly effective c o ntr ace ptive met h o d pr ovi de d t h at t he p art ner is t he s ole sex u al 
p art ner of t he pers o n  of c hil d be ari n g p ote nti al a n d t he a bse nce of s per m h as bee n c o nfir me d. If n ot, 
a d diti o n al hi g hly effective met h o d (s) of c o nt r ace pti o n s h o ul d be use d. S per m at o ge nesis cycle is 
a p pr oxi m ately 7 4 d ays.)  
U S E R D E P E N D E N T  
Hi g hl y Effecti ve Met h o ds T h at Are User De pe n de nt  F ail ure r ate of < 1 % per ye ar w he n use d 
c o nsiste ntly a n d c orrectly.  
•  C o m bi ne d (estr o ge n - a n d pr o gest o ge n -c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n b 
− oral  
− i ntra v a gi nal 
− tra ns der mal 
− i njecta ble 
•  Pr o gest o ge n -o nl y h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n b 
− oral  
− i njecta ble 
•  Se x ual a bsti ne n ce  
( Sex u al a bsti ne n ce is c o nsi dere d a hi g hly effective met h o d o nly if defi ne d as refr ai ni n g fr o m heter osex u al 
i nterc o urse d uri n g t he e ntire peri o d of risk ass oci ate d wit h t he st u dy dr u g . T he reli a bility of sex u al 
a bsti ne n ce nee ds t o be ev al u ate d i n rel ati o n t o t he d ur ati o n of t he st u dy a n d t he preferre d a n d us u al lifestyle 
of t he p artici p a nt.)  
N O T A L L O W E D A S S O L E M E T H O D O F C O N T R A C E P TI O N D U RI N G T H E S T U D Y ( n ot 
c o nsi dere d t o be hi g hl y effecti ve)  
•  Pr o gest o ge n -o nl y oral h or m o nal c o ntrace pti o n w here i n hi biti o n of o v ulati o n is n ot t he pri mar y m o de of 
acti o n  
•  Male or fe male c o n d o m wit h or wit h o ut s per mici de
c 
•  Ca p, dia p hra g m, or s p o n ge wit h s per mici de  
•  A c o m bi nati o n of male c o n d o m wit h eit her ca p, dia p hra g m, or s p o n ge wit h s per mici de ( d o u ble -barrier 
met h o ds) c 
•  Peri o dic a bsti ne n ce (cale n dar, s y m pt ot her mal, p ost -o v ulati o n met h o ds)  
•  Wit h dra wal (c oit us -i nterr u pt us) 
•  S per mici des al o ne  
•  Lactati o nal a me n orr hea met h o d ( L A M)  
a) T y pical use fail ure rates ma y differ fr o m t h ose w he n use d c o nsiste ntl y a n d c orrectl y . Use s h o ul d be 
c o nsiste nt wit h l ocal re g ulati o ns re gar di n g t he use of c o ntrace pti ve met h o ds f or partici pa nts i n 
cli nical st u dies. 
b)  H or m o nal c o ntrace pti o n ma y be s usce pti ble t o i nteracti o n wit h t he st u d y dr u g , w hic h ma y re d uce 
t he efficac y of t he c o ntrace pti ve met h o d. I n a d diti o n, c o nsi der if t he h or m o nal c o ntrace pti o n ma y 
i nteract wit h t he st u d y dr u g . 
c) Male c o n d o m a n d fe male c o n d o m s h o ul d n ot be use d t o get her ( d ue t o ris k of fail ure wit h fricti o n).  
 
 

CI R 3 3 2  
 
1 3 7  
 
R E F E R E N C E S  
 
1. Carri n gt o n L B, Si m m o ns C P. H u ma n t o m os q uit o tra ns missi o n of de n g ue vir uses. Fr o nt 
I m m u n ol 2 0 1 4 ; 5: 2 9 0. 
2. Ce nters f or Disease C o ntr ol a n d Pre ve nti o n . De n g ue e pi de mi ol o g y. A vaila ble at: 
htt ps:// w w w.c dc. g o v/ de n g ue/e pi de mi ol o g y/i n de x. ht ml Acces se d Ja n u ar y 1 4 2 0 2 0. 
3. B hatt S, Get hi n g P W, Bra d y OJ, et al. T he gl o b al distri b uti o n a n d b ur de n of de n g ue. Nat ure 
2 0 1 3 ; 4 9 6: 5 0 4-7.  
4. W orl d Healt h Or ga niz ati o n. Te n t hreats t o gl o b al healt h i n 2 0 1 9. A vaila ble at: . 
htt ps:// w w w. w h o.i nt/e mer ge ncies/te n -t hreats-t o-gl o bal -healt h -i n-2 0 1 9. Accesse d Ja n uar y 1 4 
2 0 2 0.  
5. Pa y ne A M. Oral i m m u nizati o n a gai nst p oli o m yelitis. B ull W orl d Healt h Or ga n 1 9 6 0 ; 2 3: 6 9 5-
7 0 3.  
6. Cla p ha m H, C u m mi n gs D, J o ha nss o n M. I m m u ne stat us alters t he pr o b a bilit y of a p pare nt 
ill ness d ue t o de n g ue vir us i nfecti o n: E vi de nce fr o m a p o ole d a nal ysis acr oss m ulti ple c o h ort a n d 
cl uster st u dies. . P L o S Ne gl Tr o p D is 2 0 1 7 ; 1 1:e 0 0 0 5 9 2 6. 
7. W hite h or n J, Si m m o ns C P. T he pat h o ge nesis of de n g ue. Vacci ne 2 0 1 1 ; 2 9: 7 2 2 1-8.  
8. M urra y N, Q u a m M, Wil der -S mit h A. E pi de mi ol o g y of de n g ue: past, prese nt a n d f ut ure 
pr os pects. Cli n E pi de mi ol 2 0 1 3 ; 5: 2 9 9 0 3 0 9. 
9. W orl d H ealt h O r ga niz ati o n. De n g ue G ui deli nes f or dia g n osis, treat me nt, pre ve nti o n, a n d 
c o ntr ol. Ge ne v a: W orl d Healt h Or ga ni z ati o n, 2 0 0 9 . 
1 0. G u bler DJ. De n g u e a n d de n g ue he m orr ha gic fe ver. Cli n Micr o bi ol Re v 1 9 9 8 ; 1 1: 4 8 0-9 6.  
1 1. W orl d Healt h Or ga ni zati o n . De n g ue a n d se vere de n g ue. A vaila ble at: 
htt p:// w w w. w h o.i nt/ me diace ntr e/facts heets/fs 1 1 7/ e n/. Accesse d Ja n u ar y 1 4 2 0 2 0.  
1 2. W hite h or n J, Yac o u b S, A n ders K L, et al. De n g ue t hera p e utics, c he m o pr o p h yla xis, a n d allie d 
t o ols: state of t he art a n d f ut ure directi o ns. P L o S Ne gl Tr o p Dis 2 0 1 4 ; 8:e 3 0 2 5. 
1 3. Xie X, Z o u J, Wa n g Q Y, S hi P Y. Tar geti n g de n g ue vir us N S 4 B pr otei n f or dr u g disc o ver y. 
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