Clinical trial NCT05048875
Conditions: Dengue
Keywords: Dengue Serotype 3 Healthy Participants
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2022-02-03; Completion date: 2024-09-10
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The investigational study drug, JNJ-64281802, is being developed for the prevention and treatment of dengue infection. This study is hypothesizing that the highest dose of the investigational study drug is superior to receiving a placebo with respect to its antiviral activity in healthy adult participants inoculated with Dengue Serotype 3.

Detailed description:
This study is a multicenter, randomized, placebo-controlled, double-blind, interventional Phase 2a, study in normal healthy adult subjects 18 - 55 years of age, inclusive, recruited from the metropolitan Baltimore/Washington, DC area \& Burlington/Vermont. The study follows an adaptive 2-stage design consisting of 2 cohorts, each with up to 3 groups. The 2 cohorts will be enrolled in a staggered manner. As a safety measure, a sentinel group of 4 participants will be enrolled in Cohort 1 (Group 1a) before enrolling the remaining participants (Group 1b and Group 2) in the cohort.

The purpose of this study is to evaluate the clinical and virologic response to repeated doses of investigation product JNJ-64281802 when administered orally in healthy, DENV and ZIKV-naïve, non-pregnant, adult volunteers who are subsequently inoculated with rDEN3delta30, a recombinant DENV-3 strain, to explore the antiviral activity of repeated oral doses of JNJ-64281802 versus placebo. The safety, tolerability, PK, and the relationship between the PK and antiviral activity of JNJ-64281802 will also be evaluated. Placebo recipients are included in the study as a control to better assess study agent associated versus non-study agent associated AEs and to act as infectivity controls following administration of rDEN3delta30.

After providing written informed consent, subjects will undergo eligibility screening, including medical history, physical examination, hematology testing, liver and renal function testing, human immunodeficiency virus (HIV) screening, hepatitis B and C screening, urinalysis, urine toxicology screening, ECG screening, alcohol breath test screening (per PI/provider discretion), COVID-19 testing (if determined necessary by the clinician or per guidelines), and serology screening for previous infection of DENV and ZIKV (Cohort 1) and DENV, ZIKV, West Nile virus, and SLEV (Cohort 2).

Serum or urine pregnancy testing will be performed on applicable persons of childbearing potential. All screening tests must be performed within 60 days of initiation of JNJ-64281802 study agent at Study Day -5 (Cohort 1) or Study Day -2 (Cohort 2). HIV screening must be performed within 2 weeks of JNJ-64281802 study agent administration. Pregnancy screening will occur at applicable screening visit(s), be repeated on the first day of JNJ-64281802 administration prior to administration, and on the day of inoculation with rDEN3delta30 prior to inoculation with rDEN3delta30. All clinically significant abnormalities will be reviewed with subjects and referral for follow-up care will be provided. Subjects will be determined to be eligible based on the inclusion and exclusion criteria for this protocol. For subjects who are eligible, the Study Day -5 (Cohort 1) or Study Day -2 (Cohort 2) visit will be scheduled for initiation of JNJ-64281802.

For Cohort 1: Subjects will present to the inpatient unit on Study Day -6. After eligibility criteria have been reviewed and confirmed, subjects will be admitted during this period of intensive PK sampling. Dosing with JNJ-64281802 or placebo will begin on Study Day -5. Discharge will occur on Study Day -4. Dosing with JNJ-64281802 will be observed in-clinic on Days -5, -4, -1, 1, 3, 5, 7, 9, 11, 14, 16, 18, and 21. Subjects will have phone contact on Days -3, -2, 2, 4, 6, 8, 10, 12, 13, 15, 17, 19, and 20 to record time of dose, time of last food intake, and review AEs and concomitant therapy. Daily dosing with JNJ-64281802 or placebo will occur from Study Day -5 through Study Day 21. On Study Day 21 subjects will present to the unit for a second intensive PK sampling period for a full day. On Study Day 1, all subjects will be challenged with rDEN3delta30.

For Cohort 2: Subjects will present to the inpatient unit on Study Day -3. After eligibility criteria have been reviewed and confirmed, subjects will be admitted during this period of intensive PK sampling. Dosing with JNJ-64281802 or placebo will begin on Study Day -2. Discharge will occur on Study Day 1. Dosing with JNJ-64281802 will be observed in-clinic on Days -2, -1, 1, 4, 6, 8, 11, 13, 15, 18, and 21 for the daily dosing regimen and on Days -2, -1, 1, 8 and 15 for the weekly dosing regimens. In the daily dosing regimen with JNJ-64281802 or placebo, twice daily dosing will occur from Study Day -2 to Study Day -1, and daily dosing from Study Day 1 to Study Day 21. In the weekly dosing regimens, twice daily dosing will occur from Study Day -2 to Study Day -1, and weekly dosing which will occur on Study Day 1, Study Day 8, and Study Day 15. On Study Day 21 for the daily regimen, and on Study Day 15 for the weekly regimens, subjects will present to the unit for a second intensive PK sampling period for a full day. On Study Day 1, all subjects will be challenged with rDEN3delta30.

During the inpatient visits on Study Day -6 to -4 (Cohort 1) and Study Day -3 to 1 (Cohort 2), the subjects will be evaluated by a clinician and will have blood drawn for clinical laboratory studies, virologic assays, and immunologic assays. During the outpatient visits subjects will return to the clinic for evaluation and for blood draw as specified in the Schedule of Procedures. Study Day 85 will be the final visit for Cohort 1. Study Day 85 will be the final visit for Cohort 2\*. Subjects will have their temperature measured in clinic or measure their temperatures at home twice daily from Study Day 1 through Study Day 29.

Arms: arm 1: Sentinel high-dose. Four participants will be enrolled in Group 1a before enrolling the remaining participants to Group 1b (12 participants total in Group 1, all same dosing regimen). Note group 1a and group 1b are combined into one arm, because the dosing regimen is the same and they were not separated during final statistical analysis. arm 2: Group 2 includes Medium and low dose, 14 participants total. Enrolled after completion of Group 1a. arm 3: Group 2 includes Medium and low dose, 14 participants total. Enrolled after completion of Group 1a. arm 4: Matching placebo. Note Group 1 placebo and group 2 placebo are combined per sponsor data analysis.
Interventions: intervention 1: Cohort 1 - Group 1 JNJ High Dose intervention 2: Cohort 1 - Group 2 JNJ Medium Dose intervention 3: Cohort 1 - Group 2 JNJ Low Dose intervention 4: Cohort 1 - Group 1/2 Placebo
Intervention descriptions: intervention 1: High dose: 600-mg loading dose for 5 days/200-mg maintenance dose for 21 days intervention 2: Medium dose: 200-mg loading dose for 5 days/50-mg maintenance dose for 21 days intervention 3: Low dose: 40-mg loading dose for 5 days/10-mg maintenance dose for 21 days intervention 4: Matching placebo. Note Group 1 placebo and group 2 placebo are combined per sponsor data analysis.

Protocol documents:
Prot_SAP_000.pdf: 
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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 
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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.   


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B A C K G R O U N D - J NJ-6 4 2 8 1 8 0 2  .............................................................................................................................................. 2 2  
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N o n -Cli nic al St u di es  ...................................................................................................................................................... 2 2  
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Pri m ary P h ar m ac ol o gy  ........................................................................................................................................................... 2 2  
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S ec o n d ar y P h ar m ac ol o gy  ....................................................................................................................................................... 2 3  
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S af ety P h ar m ac ol o gy  .............................................................................................................................................................. 2 3  
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P h ar m ac o ki n etic a n d M et a b olic  Pr ofil e  ................................................................................................................................. 2 3  
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T oxic ol o gy  .............................................................................................................................................................................. 2 5  
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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  
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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  
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St u di es of D E N V -3 i n R h es us M o n k e ys  ......................................................................................................................... 2 8  
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M os q uit o Tr a ns missi bilit y of r D E N 3 Δ 3 0  ....................................................................................................................... 2 9  
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Cli nic al Ex p eri e nc e wit h r D E N 3 3 0  .............................................................................................................................. 2 9  
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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  
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J NJ-6 4 2 8 1 8 0 2  ............................................................................................................................................................... 3 2  
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Fi n al C o nt ai n er of J NJ -6 4 2 8 1 8 0 2  ............................................................................................................................................ 3 2  
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C o m p ositi o n of J NJ -6 4 2 8 1 8 0 2  ................................................................................................................................................ 3 2  
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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  
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r D E N 3 Δ 3 0, L ot D E N 3 # 1 1 4 A .......................................................................................................................................... 3 3  
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S e e d L ot Pr o d ucti o n  ............................................................................................................................................................... 3 3  
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Cli nic al L ot Pr o d ucti o n  ............................................................................................................................................................ 3 3  
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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  
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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  
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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  
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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  
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S T U D Y D E SI G N  .................................................................................................................................................................. 3 6  
 
O V E R ALL D E SI G N ................................................................................................................................................................... 3 6  
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St u dy D esi g n  ................................................................................................................................................................. 3 7  
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I niti al E nr oll m e nt of S e nti n el C o h ort 1 ................................................................................................................................... 4 2  
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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  
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E nr oll m e nt of S u bj ects i n C o h ort 2 ......................................................................................................................................... 4 3  


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S a m pl e Siz e a n d Pl ac e b o R ati o  ..................................................................................................................................... 4 3  
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D ur ati o n of S u bj ect P artici p ati o n  ................................................................................................................................. 4 4  
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Esti m at e d D ur ati o n of t h e St u dy  .................................................................................................................................. 4 4  
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Tr e at m e nt Assi g n m e nt  ................................................................................................................................................. 4 4  
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Bli n di n g  ......................................................................................................................................................................... 4 4  
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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  
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C orr ect e d Q T ( Q Tc) Pr ol o n g ati o n  ................................................................................................................................. 5 2  
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Pr e g n a nc y  ..................................................................................................................................................................... 5 2  
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L ost t o F oll o w U p .......................................................................................................................................................... 5 2  
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I nc arc er ati o n ................................................................................................................................................................ 5 2  
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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  
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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  
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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  
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S a m pl e C oll ecti o n a n d H a n dli n g  ................................................................................................................................... 6 1  
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P h ar m ac o ki n etic A n alysis  ............................................................................................................................................. 6 2  
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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  
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H u m or al I m m u n e R es p o ns e  ......................................................................................................................................... 6 4  
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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  


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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  
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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  
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A dv ers e E v e nt  ............................................................................................................................................................... 9 7  
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A dv ers e R e acti o n  .......................................................................................................................................................... 9 8  
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S us p ect e d A d v ers e R e acti o n ( S A R)  ............................................................................................................................... 9 8  
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Pr e g n a nc y  ..................................................................................................................................................................... 9 8  
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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  
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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  
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I d e ntific ati o n of A d v ers e E v e nts ................................................................................................................................. 1 0 0  
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Pr ot oc ol -S p ecific A d v ers e E v e nt D efi niti o ns  ............................................................................................................... 1 0 1  
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D et er mi n ati o n of S ev erity ........................................................................................................................................... 1 0 2  
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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  
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A dv ers e E v e nt Acti o n T a k e n  ....................................................................................................................................... 1 0 4  
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A dv ers e E v e nt O utc o m e  ............................................................................................................................................. 1 0 5  
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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  
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N o n -S eri o us A d v ers e E v e nts  ....................................................................................................................................... 1 0 5  
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S eri o us A d v ers e E v e nts  ............................................................................................................................................... 1 0 5  
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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  
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R e p orti n g a P a us e  ...................................................................................................................................................... 1 0 7  
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R es u m pti o n F oll o wi n g a P a us e  ................................................................................................................................... 1 0 7  
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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  
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H alti n g r ul es f or J NJ -6 4 2 8 1 8 0 2  .................................................................................................................................. 1 0 7  
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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  
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  
I g E 1 2 
 
 
X  
 
X  
X *  
X *  
X *  
X *  
X *  
X *  
X *  
X *  
X *  
X *  
 
 
 
 
 
 
 
 
 
 
P K A nal ysis 2 
 
 
X 2 
X  
X  
X  
 
X  
X  
 
X 2 
X 2 
X  
X 2 
X 2 
X  
 
X  
 
 
 
X  
X  
 
X  
A 1 A G  
 
 
X  
X  
X  
X  
 
X  
X  
 
 
X  
X  
X  
 
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  
X  
Q ualitati ve R T -P C R  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
X 3 
X  
X  
X  
X  
X  
X  
X  
X  
X  
Pla q ue Assa y 7 
 
 
 
[ X] 
[ 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 4   
 
 
 
X  
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 1 4 
 
 
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 1 5 
 
 
 
 
 
 
 
[ X] 
[ 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  
X  
 
 
X  
 
 
 
 
 
 
X  
H ost R N A A nal ysis  
 
 
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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C B C wit h differe ntial  
X  
 
X  
X  
 
 
X  
 
X  
 
 
 
X  
 
 
 
 
X  
 
 
 
 
X  
 
 
P T/ P T T  
X  
 
X  
X  
 
 
X  
 
X  
 
 
 
X  
 
 
 
 
X  
 
 
 
 
X  
 
 
HI V, H C V, H B V  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De n g ue/ Zi ka/ West Nile/ S L E V 
scree ni n g 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre g na nc y Test 1  
X  
 
X  
 
X  
 
 
 
 
 
 
 
 
X  
X  
 
 
X  
 
 
 
 
 
 
X  
F S H Test 1 1 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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  
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  
Uri nal ysis & Uri ne t o xic ol o g y 
Scree n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol Breat h Test  
 
X 1 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 2 -lea d E C G 8 
X  
 
X  
 
X  
 
 
 
 
 
X  
X  
 
X  
X  
 
 
 
 
 
 
 
 
 
X  
 
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 
C CI


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
C CI


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.  
C CI


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  
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  
 
 
 
 
 
 
 
 
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  
 


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  
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 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  
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).  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
  
 
  
  
  
  
  
  
  
 
 
 
 
 
 
C CI
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.  
C CI
C CI


CI R 3 3 2  
 
4 7  
 
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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C CI


CI R 3 3 2  
 
4 8  
 
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  
 
4 9  
 
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  
 
5 0  
 
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
C CI


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).  
C CI


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.  


CI R 3 3 2  
 
7 5  
 
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.  


CI R 3 3 2  
 
1 0 4  
 
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 


CI R 3 3 2  
 
1 0 8  
 
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


CI R 3 3 2  
 
1 1 5  
 
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  . 
C CI


CI R 3 3 2  
 
1 1 6  
 
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
CI


CI R 3 3 2  
 
1 1 7  
 
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
C CI


CI R 3 3 2  
 
1 1 8  
 
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. 
A nti viral Res 2 0 1 5 ; 1 1 8: 3 9-4 5.  
1 4. G u bler DJ, S u har y o n o W, L u bis I, Era m S, G u nars o S. E pi de mic de n g ue 3 i n ce ntral J a va, 
ass ociate d wit h l o w vire mia i n ma n. A m J Tr o p Me d H y g 1 9 8 1 ; 3 0: 1 0 9 4-9.  
1 5. Bla ne y J E, Jr., Ha ns o n C T, Firest o ne C Y, Ha nle y K A, M ur p h y B R, W hite hea d S S. 
Ge neticall y m o difie d, li v e atte n uate d d e n g ue vir us t y pe 3 vacci n e ca n di d ates. A m J Tr o p Me d 
H y g 2 0 0 4 ; 7 1: 8 1 1-2 1.  


CI R 3 3 2  
 
1 3 8  
 
1 6. Kir k patric k B D, W hite hea d S S, P ierce K K, et al. T he li ve atte n uat e d de n g ue vacci ne T V 0 0 3 
elicits c o m plete pr otecti o n a gai nst de n g ue i n a h u ma n c halle n ge m o d el. Sci Tra nsl Me d 2 0 1 6 ; 
8: 3 3 0ra 3 6.  
1 7. Fri deri cia L S. T he d urati o n of syst ole i n t he el ectr ocar di o gra m of n or m al su bjects a n d 
p atie nts wit h h eart d iseas e. . Acta Me di ca Sca n di n a vica 1 9 2 0 ; 5 7: 4 6 9-8 6.  
1 8. Ce nters f or Disease C o ntr ol a n d Pre ve nti o n . Areas wit h ris k of d e n g u e. 2 0 1 9. A vaila ble at: 
htt ps:// w w w.c dc. g o v/ de n g ue/areas wit hris k/i n de x. ht ml. Accesse d Ja n u ar y 1 4 2 0 2 0.  
1 9. Cla p ha m H E, Tric o u V, Va n Vi n h C ha u N, Si m m o ns C P, Fer g us o n N M. Wit hi n -h ost viral 
d y na mics of de n g ue s er ot y pe 1 i nfecti o n. J R S oc I nterface 2 0 1 4 ; 1 1: 2 0 1 4 0 0 9 4.