A Multicenter, Double-Blind, Randomized, Parallel-Group, Active- and Placebo-Controlled Polysomnography Study to Evaluate the Efficacy, Safety, and Tolerability of JNJ-42847922 in Subjects With Insomnia Disorder
Phase: PHASE2
Conditions: Insomnia Disorders
Sponsor: Janssen Research & Development, LLC

1
Stat us: A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
J a nsse n Rese arc h & De vel o p me nt *
Cli nic al Pr ot oc ol
A M ultice nter, D o u ble - Bli n d, R a n d o mize d, P ar allel- Gr o u p, Acti ve- a n d Pl ace b o -
C o ntr olle d P ol ys o m n o gr a p h y St u d y t o E v al u ate t he Effic ac y, S afet y, a n d T oler a bilit y of 
J N J -4 2 8 4 7 9 2 2 i n S u bjects wit h I ns o m ni a Dis or der
Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 ; P h ase 2 b
J N J - 4 2 8 4 7 9 2 2 (selt ore x a nt/selecti ve ore xi n-2 rece pt or a nt a g o nist)
A m e n d me nt 3
*Ja nsse n Researc h & De vel o p me nt is a gl o bal or ga nizati o n t hat o perates t hr o u g h differe nt le gal e ntities i n
vari o us c o u ntries. T heref ore, t he le gal e ntit y acti n g as t he s p o ns or f or Ja nsse n Researc h & De vel o p me nt
st u dies ma y var y, s uc h as, b ut n ot li mite d t o Ja nsse n Bi otec h, Inc.; Ja nsse n Pr o d ucts, L P; Ja nsse n
Bi ol o gics, B V; Ja nsse n -Cila g I nter nati o nal N V; Ja nsse n, I nc; Ja nsse n Scie nces Irela n d U C ; or Ja nsse n
Researc h & De vel o p me nt, L L C. T he ter m “s p o ns or” is use d t hr o u g h o ut t he pr ot oc ol t o re prese nt t hese
vari o us le gal e ntitie s; t he s p o ns or is i de ntifie d o n t he C o ntact I nf or mati o n pa ge t hat acc o m pa nies t he
pr ot oc ol.
T his c o m p o u n d is bei n g i n vesti gate d i n P hase 2 cli nical st u dies. 
T his st u d y  will be c o n d ucte d u n der U S F o o d & Dr u g A d mi nistrati o n IN D re g ulati o ns 
( 2 1 C F R Part 3 1 2).
E u dr a C T N U M B E R: 2 0 1 7- 0 0 0 9 8 0- 3 3
St at us:
A p pr o ve d
D ate:
2 5 J ul y 2 0 1 8
Pre p are d b y:
Ja nsse n Researc h & De vel o p me nt, L L C
E D M S n u m ber:
E D M S -E RI - 1 3 6 8 2 4 2 1 9, 4. 0
G C P C o m pli a nce: T his st u d y will be c o n d ucte d i n c o m plia nce wit h G o o d Cli nical Practice, a n d a p plica ble re g ulat or y 
re q uire me nts. 
C o nfi de nti alit y St ate me nt
T he i nf or mati o n i n t his d oc u me nt c o ntai ns tra de secrets a n d c o m mercial i nf or mati o n t hat are pri vile ge d or c o nfi de ntial a n d 
ma y n ot be discl ose d u nless s uc h discl os ure is re q uire d b y a p plica ble la w or re g ulati o ns. I n a n y e ve nt, pers o ns t o w h o m t he 
i nf or mati o n is discl ose d m ust be i nf or me d t hat t he i nf or mati o n is pri vile ge d or c o nfide ntial a n d ma y n ot be f urt her discl ose d 
b y t he m. T hese restricti o ns o n discl os ure will a p pl y e q uall y t o all f ut ure i nf or mati o n s u p plie d t o y o u t hat is i n dicate d as 
pri vile ge d or c o nfi de ntial.
N C T 0 3 3 7 5 2 0 3

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
T A B L E O F C O N T E N T S
T A B L E O F C O N T E N T S ............................................................................................................................... 2
LI S T O F A T T A C H M E N T S ............................................................................................................................ 4
LI S T O F I N -T E X T T A B L E S A N D FI G U R E S ................................................................................................ 4
P R O T O C O L A M E N D M E N T S ....................................................................................................................... 5
S Y N O P SI S .................................................................................................................................................. 1 3
TI M E  AN D E V E N T S S C H E D U L E - P A R T 1 .............................................................................................. 2 2
TI M E  AN D E V E N T S S C H E D U L E - P A R T 2 ( F O R P H A R M A C O KI N E TI C A N D BI O M A R K E R 
S A M P LI N G, VI T A L  SI G NS, A N D E C G C O L L E C T E D O N NI G H T 2 A N D D A Y 3 ) ................................... 2 7
A B B R E VI A TI O N S ...................................................................................................................................... 2 8
D E FI NI TI O N S O F T E R M S .......................................................................................................................... 2 9
1.
I N T R O D U C TI O N................................................................................................................................ 3 0
1. 1.
B a c k gr o u n d .................................................................................................................................... 3 3
1. 1. 1.
N o n cli ni c al St u di e s ..................................................................................................................... 3 3
1. 1. 2.
Cli ni c al St u di e s ........................................................................................................................... 3 5
1. 2.
C o m p ar at or Dr u g ........................................................................................................................... 4 1
1. 3.
O v er all R ati o n al e f or t h e St u d y ...................................................................................................... 4 2
1. 4.
O v er all Ri s k a n d B e n efit A s s e s s m e nt ............................................................................................ 4 3
2.
O B J E C TI V E, E N D P OI N T S , AN D H Y P O T H E SI S ............................................................................. 4 4
2. 1.
O bj e cti v e s a n d E n d p oi nt s .............................................................................................................. 4 4
2. 2.
H y p ot h e si s ..................................................................................................................................... 4 7
3.
S T U D Y D E SI G N A N D R A T I O N AL E .................................................................................................4 7
3. 1.
O v er vi e w of St u d y D e si g n .............................................................................................................. 4 7
3. 2.
St u d y D e si g n R ati o n al e .................................................................................................................. 5 4
4.
S U B J E C T P O P U L A T I O N.................................................................................................................. 6 0
4. 1.
I n cl u si o n Crit eri a ............................................................................................................................ 6 0
4. 2.
E x cl u si o n Crit eri a ........................................................................................................................... 6 3
4. 3.
Pr o hi biti o n s a n d R e stri cti o n s ......................................................................................................... 6 7
5.
T R E A T M E N T A L L O C A TI O N A N D B LI N DI N G ................................................................................. 6 8
6.
D O S A G E A N D A D MI NI S T R A T I O N .................................................................................................. 6 9
7.
T R E A T M E N T C O M P LI A N C E ............................................................................................................ 7 0
8.
P R E S T U D Y A N D C O N C O MI T A N T T H E R A P Y ................................................................................ 7 0
9.
S T U D Y E V A L U A TI O N S .................................................................................................................... 7 2
9. 1.
St u d y Pr o c e d ur e s ........................................................................................................................... 7 2
9. 1. 1.
O v er vi e w ..................................................................................................................................... 7 2
9. 1. 2.
S cr e e ni n g P h a s e ........................................................................................................................ 7 2
9. 1. 3.
D o u bl e -Bli n d Tr e at m e nt P h a s e .................................................................................................. 7 5
9. 1. 4.
F oll o w -U p/ E n d -of -St u d y Vi sit ...................................................................................................... 7 6
9. 2.
Effi c a c y  E v al u ati o n s....................................................................................................................... 7 7
9. 2. 1.
P ol y s o m n o gr a p h y E v al u ati o n s ................................................................................................... 7 7
9. 2. 2.
P ati e nt S elf -r e p ort e d M e a s ur e s of Sl e e p.................................................................................... 7 7

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
9. 2. 2. 1.
S u bj e cti v e Sl e e p P ar a m et er s .................................................................................................. 7 7
9. 2. 2. 2.
P R O MI S -S D ( s h ort f or m 8 a) a n d P R O MI S -S RI ( s h ort f or m 8 a) ............................................. 7 8
9 . 2. 2. 3.
P ati e nt Gl o b al I m pr e s si o n of S e v erit y a n d I m pr o v e m e nt ........................................................ 7 8
9. 2. 3.
Cli ni ci a n -r e p ort e d M e a s ur e s of Sl e e p ........................................................................................ 7 9
9. 2. 3. 1.
Cli ni c al Gl o b al I m pr e s si o n of S e v erit y a n d I m pr o v e m e nt ........................................................ 7 9
9. 2. 3. 2.
I n s o m ni a S e v erit y I n d ex (I SI) .................................................................................................. 7 9
9. 3.
P h ar m a c o ki n eti c s ........................................................................................................................... 7 9
9. 3. 1.
E v al u ati o n s .................................................................................................................................8 0
9. 3. 2.
A n al yti c al Pr o c e d ur e s ................................................................................................................. 8 0
9. 3. 3.
P h ar m a c o ki n eti c P ar a m et er s ..................................................................................................... 8 0
9. 4.
Bi o m ar k er s ..................................................................................................................................... 8 1
9. 5.
P h ar m a c o g e n o mi c ( D N A) E v al u ati o n s .......................................................................................... 8 1
9. 6.
S af et y E v al u ati o n s ......................................................................................................................... 8 2
9. 7.
Ot h er E v al u ati o n s ........................................................................................................................... 8 7
9. 8.
S a m pl e C oll e cti o n a n d H a n dli n g .................................................................................................... 8 7
1 0.
S U B J E C T C O M P L E TI O N/ D I S C O N TI N U ATI O N O F S T U D Y T R E A T M E N T/ WI T H D R A W A L  
F R O M T H E S T U D Y ........................................................................................................................... 8 7
1 0. 1.
C o m pl eti o n ..................................................................................................................................... 8 7
1 0. 2.
Wi t h dr a w al fr o m t h e St u d y............................................................................................................. 8 7
1 0. 3.
Wi t h dr a w al Fr o m t h e U s e of R e s e ar c h S a m pl e s........................................................................... 8 8
1 1.
S T A T I S TI C AL M E T H O D S ................................................................................................................. 8 9
1 1. 1.
S u bj e ct I nf or m ati o n ........................................................................................................................ 8 9
1 1. 2.
S a m pl e Si z e D et er mi n ati o n ........................................................................................................... 8 9
1 1. 3.
Effi c a c y  A n al y s e s........................................................................................................................... 8 9
1 1. 4.
P h ar m a c o ki n eti c A n al y si s .............................................................................................................. 9 0
1 1. 5.
Bi o m ar k er A n al y si s ........................................................................................................................ 9 1
1 1. 6.
P h ar m a c o ki n eti c a n d P h ar m a c o d y n a mi c A n al y si s ........................................................................ 9 1
1 1. 7.
S af et y A n al y s e s ............................................................................................................................. 9 2
1 2.
A D V E R S E E V E N T R E P O R T I N G ...................................................................................................... 9 3
1 2. 1.
D efi niti o n s ...................................................................................................................................... 9 3
1 2. 1. 1.
A d v er s e E v e nt D efi niti o n s a n d Cl a s sifi c ati o n s ........................................................................... 9 3
1 2. 1. 2.
Attri b uti o n D efi niti o n s .................................................................................................................. 9 4
1 2. 1. 3.
S e v erit y Crit eri a .......................................................................................................................... 9 5
1 2. 2.
S p e ci al R e p orti n g Sit u ati o n s .......................................................................................................... 9 5
1 2. 3.
Pr o c e d ur e s ..................................................................................................................................... 9 6
1 2. 3. 1.
All A d v er s e E v e nt s ...................................................................................................................... 9 6
1 2. 3. 2.
S eri o u s A d v er s e E v e nt s ............................................................................................................. 9 7
1 2. 3. 3.
Pr e g n a n c y ................................................................................................................................... 9 8
1 2. 4.
C o nt a cti n g S p o n s or R e g ar di n g S af et y ........................................................................................... 9 8
1 3.
P R O D U C T Q U A LI T Y C O M P L A I N T H AN D LI N G .............................................................................. 9 8
1 3. 1.
Pr o c e d ur e s ..................................................................................................................................... 9 8
1 3. 2.
C o nt a cti n g S p o n s or R e g ar di n g Pr o d u ct Q u alit y ............................................................................ 9 9
1 4.
S T U D Y D R U G I N F O R M A T IO N ......................................................................................................... 9 9
1 4. 1.
P h y s i c al D e s cri pti o n of St u d y Dr u g( s) ........................................................................................... 9 9
1 4. 2.
P a c k a gi n g ...................................................................................................................................... 9 9
1 4. 3.
L a b eli n g .......................................................................................................................................... 9 9
1 4. 4.
Pr e p ar ati o n, H a n dli n g, a n d St or a g e ............................................................................................... 9 9
1 4. 5.
Dr u g A c c o u nt a bilit y ........................................................................................................................ 9 9
1 5.
S T U D Y -S P E CI FI C M A T E RI A L S ..................................................................................................... 1 0 0
1 6.
E T HI C A L A S P E C T S ....................................................................................................................... 1 0 1
1 6. 1.
St u d y- S p e cifi c D e si g n C o n si d er ati o n s ......................................................................................... 1 0 1
1 6. 2.
R e g ul at or y Et hi c s C o m pli a n c e ..................................................................................................... 1 0 3

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1 6. 2. 1.
I n v e sti g at or R e s p o n si biliti e s ..................................................................................................... 1 0 3
1 6. 2. 2.
I n d e p e n d e nt Et hi c s C o m mitt e e or I n stit uti o n al R e vi e w B o ar d ................................................. 1 0 3
1 6. 2. 3.
I nf or m e d C o n s e nt ..................................................................................................................... 1 0 5
1 6. 2. 4.
Pri v a c y of P er s o n al D at a .......................................................................................................... 1 0 6
1 6. 2. 5.
L o n g -T er m R et e nti o n of S a m pl e s f or A d diti o n al F ut ur e R e s e ar c h .......................................... 1 0 6
1 6. 2. 6.
C o u ntr y S el e cti o n ..................................................................................................................... 1 0 7
1 7.
A D M I NI S T R ATI V E R E Q UI R E M E N T S ............................................................................................ 1 0 7
1 7. 1.
Pr ot o c ol A m e n d m e nt s .................................................................................................................. 1 0 7
1 7. 2.
R e g ul at or y D o c u m e nt ati o n .......................................................................................................... 1 0 7
1 7. 2. 1.
R e g ul at or y A p pr o v al/ N otifi c ati o n .............................................................................................. 1 0 7
1 7. 2. 2.
R e q uir e d Pr e st u d y D o c u m e nt ati o n ........................................................................................... 1 0 7
1 7. 3.
S u bj e ct I d e ntifi c ati o n, E nr oll m e nt, a n d S cr e e ni n g L o g s .............................................................. 1 0 8
1 7. 4.
S o ur c e D o c u m e nt ati o n ................................................................................................................. 1 0 9
1 7. 5.
C a s e R e p o rt F or m C o m pl eti o n .................................................................................................... 1 0 9
1 7. 6.
D at a Q u alit y A s s ur a n c e/ Q u alit y C o ntr ol ...................................................................................... 1 1 0
1 7. 7.
R e c or d R et e nti o n ......................................................................................................................... 1 1 0
1 7. 8.
M o nit ori n g
.................................................................................................................................... 1 1 1
1 7. 9.
St u d y C o m pl eti o n/ T er mi n ati o n ..................................................................................................... 1 1 1
1 7. 9. 1.
St u d y C o m pl eti o n/ E n d of St u d y ................................................................................................ 1 1 1
1 7. 9. 2.
St u d y T er mi n ati o n ..................................................................................................................... 1 1 2
1 7. 1 0.
O n -Sit e A u dit s .............................................................................................................................. 1 1 2
1 7. 1 1.
U s e of I nf or m ati o n a n d P u bli c ati o n .............................................................................................. 1 1 2
R E F E R E N C E S .......................................................................................................................................... 1 1 4
I N V E S TI G AT O R A G R E E M E N T ............................................................................................................... 1 2 6
LI S T O F A T T A C H M E N T S
Att a c h m e nt 1:
L o w -F at Di et M e n u S u g g e sti o n s ( O pti o n al U s e) ...................................................... 1 1 9
Att a c h m e nt 2:
A v er a g e C aff ei n e C o nt e nt of V ari o u s B e v er a g e s .................................................... 1 2 1
Att a c h m e nt 3:
E x a m pl e s of C o n c o mit a nt Dr u g s t o b e A v oi d e d ( M o d er at e or Str o n g 
I n hi bit or/I n d u c er of C Y P 3 A 4 or C Y P 2 C 9 or D u al I n hi bit or/I n d u c er of C Y P 3 A 4 
a n d C Y P 2 C 9) ........................................................................................................... 1 2 2
Att a c h m e nt 4:
V ol u m e s of Bl o o d t o b e C oll e ct e d Fr o m E a c h S u bj e ct f or Cli ni c al L a b or at or y, 
P h ar m a c o ki n eti c, Bi o m ar k er, a n d P h ar m a c o g e n o mi c S a m pl e s ..............................1 2 3
Att a c h m e nt 5:
A nti ci p at e d E v e nt s .................................................................................................... 1 2 5
LI S T O F I N -T E X T T A B L E S A N D FI G U R E S
T A B L E S
T a bl e 1:
Li st of C o m pl et e d St u di e s ......................................................................................................... 3 6
T a bl e 2:
D o s e D e s cri pti o n ....................................................................................................................... 6 9
FI G U R E S
Fi g ur e 1:
O v er all St u d y D e si g n ................................................................................................................ 4 9
Fi g ur e 2:
S c h e m ati c O v er vi e w of t h e St u d y ............................................................................................. 5 3

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
P R O T O C O L A M E N D M E N T S
Pr ot oc ol Versi o n
Iss ue D ate
Ori gi nal Pr ot oc ol
2 9 Marc h 2 0 1 7
A me n d me nt 1
2 2 Ja n uar y 2 0 1 8
A me n d me nt 2
2 4 A pril 2 0 1 8
A me n d me nt 3
2 5 J ul y 2 0 1 8
A me n d me nts bel o w are liste d be gi n ni n g wit h t he m ost rece nt a me n d me nt.
A m e n d me nt 3 (2 5 J ul y 2 0 1 8)
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) of Directi ve 
2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
T he o ver all re as o n s f or t he a me n d me nt: T o re m o ve t he i nteri m a nal ysis fr o m t he pr ot oc ol . T o c ha n ge a 
sec o n dar y o bjecti ve t o a n e x pl orat or y o bjecti ve . T o c ha n ge a n e x pl orat or y c orrelati o n a nal ysis. T o clarif y t he 
i ncl usi o n criter ia re gar di n g t he f ollicle sti m ulati n g h or m o ne ( F S H) le vel t hres h ol d f or p ost me n o pa usal w o me n 
a n d t he ti me s pe nt i n be d as well as t he e xcl usi o n criteri o n f or t he t hres h ol d of E C G a b n or malities. T o a d d 
a b n or mal ( vi vi d) drea ms as a n a d verse e ve nt of s pecial i nterest. I n a d diti o n, ot her mi n or c ha n ges a n d 
clarificati o ns relate d t o st u d y pr oce d ures were ma de.
A p plica ble Secti o n(s)
Descri pti o n of C ha n ge(s)
R ati o n ale: T he i nteri m a nal ysis was re m o ve d as a n i m bala nce i n ge o gra p hical distri b uti o n a n d a ge (a d ults vs 
el derl y) has bee n o bser ve d a n d t here are n o re p orts of e mer ge nt safet y c o ncer ns.
S y n o psis ( O ver vie w of 
St u d y Desi g n; Statistical 
Met h o ds); A b bre viati o ns; 
Secti o n 3. 1 O ver vie w of 
St u d y Desi g n; Fi g ure 1; 
Secti o n 3. 2 St u d y Desi g n 
Rati o nale; Secti o n 5 
Treat me nt All oca ti o n a n d 
Bli n di n g; Secti o n 9. 1. 3 
D o u ble -bli n d Treat me nt 
P hase; Secti o n 1 1. 4 
P har m ac o ki netic A nal ysis 
Refere nce s t o i nteri m a nal ysis or i nteri m p o p ulati o n P K a n d e x p os ure res p o nse 
a nal ysis were r e mo ve d.
Secti o n 1 1. 3 I nteri m A nal ysis has bee n re m o ve d wit h n u m beri n g of s u bse q ue nt 
secti o ns ( 1 1. 4-1 1. 8) u p date d acc or di n gl y.
R ati o n ale: A c ha n ge i n t he sec o n dar y o bjecti ve t o assess t he effects o n c o g niti ve d o mai ns d uri n g t he st u d y was 
li mite d t o o bjecti ve assess me nts o nl y wit h s u bjecti ve assess me nts bei n g c o nsi dere d e x pl orat or y .
S y n o psis ( O bjecti ves, 
E n d p oi nts, a n d H y p ot hesis); 
Secti o n 2. 1 O bjecti ves a n d 
E n d p oi nts
T he sec o n dar y o bjecti ve of s u bjecti ve c o g niti ve assess me nts b y t he m o difie d 
P R O MI S -A p plie d C o g niti o n A bilities ( P R O MI S -A C A) was c ha n ge d t o a n 
e x pl orat or y o bjecti ve.
R ati o n ale: C ha n ge d n N A W/ hr t o n N A W w he n e x pl ori n g t he c orrelati o n w it h s-n N A W, s o t hat t he data t y pe f or 
b ot h meas ures i n t he c orrelati o n calc ulati o n is c o u nt data.
S y n o psis ( O bjecti ves, 
E n d p oi nts, a n d H y p ot hesis); 
Secti o n 2. 1 O bjecti ves a n d 
E n d p oi nts
C ha n ge d n u m ber of ni g htti me a w a ke ni n gs per h o ur ( n N A W/ hr) t o n u m ber of 
ni g htti me a wa ke ni n gs ( n N A W ).

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
R ati o n ale: A c ha n ge was ma de t o ali g n t he F S H le vel t hres h ol d f or i de ntificati o n of p ost me n o pa usal w o me n 
wit h t he ce ntral la b orat or y sta n dar d ra n ge. T he e n d b o u n dar y c o ncer ni n g ti me s pe nt i n be d wa s clarifie d t o refer 
t o getti n g o ut of be d rat her t ha n a wa ke ni n g.
Sect i o n 4. 1. I ncl usi o n 
Criteria

I ncl usi o n Criteri o n # 1: U p date d t o c ha n ge t he F S H le vel fr o m “ > 4 0 I U/ L or 
mI U/ m L” t o “ per ce ntral la b orat or y ra n ge”.

I ncl usi o n Criteri o n # 9: Clarifie d te xt c o ncer ni n g ti me s pe nt i n be d wit h g o i n g
t o be d bet wee n 8 P M a n d 1 A M a n d t y picall y a wa ke n getti n g o ut of be d
bet w ee n 5 A M a n d 9 A M .
R ati o n ale: A c ha n ge was ma de t o i ncrease t he t hres h ol d of E C G a b n or malities f or e xcl usi o n after re vie wi n g 
a d diti o nal cli nical data t o re d uce e xcl usi o ns, partic ula rl y f or t he el derl y.
Secti o n 4. 2. E xcl usi o n 
Criteria
E xcl usi o n Criteri o n # 4: U p date d t o i ncrease t he P R i nter val fr o m > 2 0 0 msec t o 
> 2 1 0 msec.
R ati o n ale: A clarificati o n c o ncer ni n g retesti n g of scree ni n g val ues as well as retests at a later ti me p oi nt wa s 
ma de t o i m pr o ve s u bject e nr oll me nt i n t he st u d y. T he c ollecti o n of bl o o d sa m ples f or la b orat or y tests wa s 
clarifie d t o be u n der fasti n g c o n diti o ns , e xce pt at scree ni n g, t o e ns ure c o nsiste nc y of data c ollecti o n. T he 
la b orat or y sa m pli n g ti me o n Da y 1 5 was c ha n ge d t o c oi nci de wit h bi o mar ker a n d P K sa m ple ti mes t o si m plif y 
site pr oce d ures.
Secti o n 4. S u bject 
P o p ulati o n ; Secti o n 9. 1. 2. 
Scree ni n g P hase
Ti m e a n d E ve nts Sc he d ule –
Part 1; 
Secti o n 9. 6. Safet y 
E val uati o ns
Clarificati o n t hat e xce pti o nal a n d li mite d retesti n g of a b n or mal , b ut n ot cli nicall y 
si g nifica nt, scree ni n g val ues is li mite d t o la b orat or y val ues, vital si g ns, or E C G 
val ues. Als o, s u bjects w h o fail i nitial scree ni n g (e xce pt f or P S G, C S D -M, I SI, or 
D S M -5 criteria f or i ns o m n ia dis or der), b ut ma y be eli gi ble f or st u d y partici pati o n 
i n t he f ut ure, ma y be rescree ne d f or p ote ntial f ut ure e nr oll me nt as s u bjects wit h 
ne w s u bject n u m bers. C o nsiste nc y of P S G a n d C S D -M te xt rele va nt t o retesti n g 
ma de w here a p plica ble.
Clarifie d t hat bl o o d sa m ples f or la b orat or y tests s h o ul d be c ollecte d u n der fasti n g 
c o n diti o ns, e xce pt at scree ni n g, (Ti m e a n d E ve nts Sc he d ule , f o ot n ote h h; 
Secti o n 9. 6 ) a n d t hat cli nical la b orat or y tests s h o ul d be c ollecte d at 8 hr 1 5 mi n o n 
D a y 1 5 , n ot at 1 2 hr ( Ti me a n d E ve nts Sc he d ule-Part 1) .
R ati o n ale: T o clarif y t hat pre d ose assess me nts s h o ul d be relate d t o st u d y dr u g a d mi nistrati o n f or greater 
c o nsiste nc y acr oss sites .
Ti m e a n d E ve nts Sc he d ule –
Part 1 
(f o ot n ote d)
T o clarif y t hat pre d ose assess me nts s h o ul d occ ur 9 0 mi n utes pri or t o st u d y dr u g 
a d mi nistrati o n a n d n ot be relate d t o li g hts o ut or be dti me.
R ati o n ale: T o clarif y t hat re d ucti o n of  caffei ne i nta ke as a c o nc o mita nt t hera p y was per mitte d.
Secti o n 8. Prest u d y a n d 
C o nc o mita nt T hera p y
Caffei ne use ma y be re d uce d o ver 5 da ys after si g ni n g of I C F t o 5 0 0 m g/ da y.
R ati o n ale: A b n or mal Drea ms is cate g orize d as a n a d verse dr u g reacti o n a n d s o c o nsi dere d as a n a d verse e ve nt 
( A E) of s pecial i nterest . T heref ore, wor di n g re gar di n g t he re p orti n g of t his has bee n i ncl u de d.
Secti o n 3. 2. St u d y Desi g n 
Rati o nale ( A Es of S pecial 
I nterest); Secti o n 9. 6. Safet y 
E val uati o ns ( A d verse e ve nts 
of S pecial I nterest)
A d diti o n of “ A b n or mal ( Vi vi d) Drea ms” a s a n a d verse e ve nt of s pecial i nterest.
R ati o n ale: Clarificati o n t hat e xce pti o ns t o ni g htti me P K sa m pli n g ma y be all o we d f or sites i n all c o u ntries t o 
i mpr o ve site partici pati o n i n t he st u d y .

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
S y n o psis ( P har mac o ki netic 
E val uati o ns); Ti m e a n d 
E ve nts Sc he d ule – Part 1
(f o ot n ote y); Secti o n 3. 1. 
O ver vie w of St u d y Desi g n; 
Secti o n 9. 3. 1. E val uati o ns
U p date d te xt relate d t o e xce pti o ns t o t he o ver ni g ht P K sa m pli n g o n Ni g ht 1 4.
R ati o n ale: R e mo val of re d u n da nt i nf or mati o n.
Secti o n 3. 2. St u d y Desi g n 
Rati o nale
Re m o val of re d u n da nt i nf or mati o n c o ncer ni n g z ol pi de m use f or i ns o m nia 
dis or der .
R ati o n ale: T he st u d y dr u g pac ka gi n g d oes n ot c o ntai n a tear -off la bel.
Secti o n 5. Treat me nt 
All ocati o n a n d Bli n di n g
Refere nce t o a tear -off la bel was re m o ve d.
R ati o n ale: Mi n or gra m matical/t y p o gra p hical c ha n ges f oll o wi n g t he pre parati o n of A me n d me nt 2 ha ve bee n 
c orrecte d.
Ti m e a n d E ve nts Sc he d ule –
Part 1

Ti m e p oi nt 0 was m o ve d t o Da y 1 fr o m Da y 2 ( M or ni n g)

E C G at t he 8 hr 3 0 mi n ti me p oi nt o n Da y 1 4 ( M or ni n g) was a d de d
A m e n d me nt 2 (2 4 A pril 2 0 1 8)
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) of Directi ve 
2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
T he o ver all re as o n f or t he a me n d me nt: T o a d d res ults of t he male a n d fe male rat fertilit y st u dies. T o e xcl u de 
f urt her e nr oll me nt of w o me n of c hil d beari n g p ote ntial ( W O C B P). I n a d diti o n, ot her mi n or c ha n ges a n d 
clarificati o ns relate d t o st u d y pr oce d ures were ma de.
A p plica ble Secti o n(s)
Descri p ti o n of C ha n ge(s)
R ati o n ale: T o u p date n o ncli nical data.
Secti o n 1. 1. 1 . N o ncli nical 
St u dies ( T o xic ol o g y); 
Refere nces ( 9 2 -9 6 )

A d de d res ults fr o m t he male a n d fe male rat fertilit y st u dies a n d rele va nt 
i nf or mati o n fr o m t he literat ure.

N e w  literat ure refere nces a d de d.
R ati o n ale: T he fe male rat fertilit y st u d y s u g geste d t hat J NJ-4 2 8 4 7 9 2 2 re d uce d fe male fertilit y rates at all d oses 
st u die d. Si nce it is n ot k n o w n w hat t he rele va nce of t hese fi n di n gs are t o a w o m a n’s a bilit y t o bec o me pre g na nt 
after ta ki n g J NJ -4 2 8 4 7 9 2 2, n o ne w W O C B P w ill be i ncl u de d i n t his st u d y u ntil m ore is lear ne d a b o ut t he effect 
of J NJ-4 2 8 4 7 9 2 2 o n fe male re pr o d ucti o n.
S y n o psis ( S u bject 
P o p ulati o n); 
Secti o n 3. 2. St u d y Desi g n 
Rati o nale; 
Secti o n 4. 1. I ncl usi o n 
Criteria

I ncl usi o n Criteri o n # 1: Re vise d te xt t o i n dicate t hat t he st u d y p o p ulati o n will 
i ncl u de me n a n d wo m e n “of n o n -c hil d be ari n g p ote nti al ( W O N C B P) ” . A d de d 
a defi niti o n of W O N C B P.

Clarifie d i n ot her rele va nt secti o ns t hat t he st u d y p o p ulati o n will i ncl u de me n 
a n d wo m e n “o f n o n-c hil d be ari n g p ote nti al ( W O N C B P)”.

W here t he t otal n u m ber of ra n d o mize d s u bjects is gi ve n, t he p o p ulati o n w as 
si m pl y descri be d as “s u bjects ” ( beca use t he t otal ra n d o mize d p o p ulati o n will 
i ncl u de s o me W O C B P e nr olle d bef ore A me n d me nt 2).

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Secti o n 1. 4. O verall Ris k 
a n d Be nefit Assess me nt; 
Secti o n 3. 2. St u d y Desi g n 
Rati o nale; 
Secti o n 1 6. 1. St u d y -S pecific 
Desi g n C o nsi derati o ns
A d de d a d diti o nal te xt t o e x plai n t hat n o ne w W O C B P w ill be e nr olle d base d o n 
t he res ults of t he fe male rat fertilit y st u d y.
Secti o n 4. 1. I ncl usi o n 
Criteria
I ncl usi o n Criteria # 1 0 a n d # 1 1 ha ve bee n delete d (t hese criteria are n o l o n ger 
re q uire d n o w t hat t he fe male p o pulati o n is restricte d t o W O N C B P. Rele va nt 
i nf or mati o n o n W O N C B P fr o m Criteri o n # 1 0 has bee n m o ve d t o Criteri o n # 1).
Secti o n 4. 2. E xcl usi o n 
Criteria
E xcl usi o n Criteri o n # 2 2: Ma de t he f oll o wi n g re visi o n:
Is pre g na nt, or breastfee di n g , or pl a n ni n g t o bec o me pre g n a nt w h ile
e nr olle d i n t his st u d y or wit hi n 1 m o nt h after t he last d ose of st u d y dr u g.
S y n o psis ( Safet y 
E val uati o ns); 
Ti m e a n d E ve nts Sc he d ule
( Part 1); 
Secti o n 3. 2. St u d y Desi g n 
Rati o nale ( Safet y 
E val uati o ns); 
Secti o n 9. 1. 2. Scree ni n g; 
Secti o n 9. 6 . Safet y 
E val uati o ns ( Cli nical 
La b orat or y Tests) ; 
Attac h me nt 4
T he sc he d ule d ser u m a n d uri ne pre g na nc y tests were re m o ve d fr o m t he Ti me a n d 
E ve nts sc he d ule a n d f o ot n ote s ‘ n’ a n d ‘ o’ were u p date d as f oll o w s:
n.
W o m e n of c hil d beari n g p ote ntial o nl y. “Ser u m or uri ne pre g n a ncy tests m ay 
be perf or me d, as deter mi ne d necess ary by t he i nve sti g at or, t o est a blis h t he 
a bse nce of pre g n a ncy at a ny ti me d uri n g t he s u bject’s p artici p ati o n i n t he 
st u dy. A F S H test m ay als o be perf or me d at i nvesti g at or j u d g me nt t o assist i n 
deter mi ni n g if a w o m a n is of n o n -c hil d be ari n g p ote nti al. ”
o
Me nstr ual c ycle trac ki n g was u p date d t o bei n g li mite d t o pre me n o pa usal 
w o me n (als o Secti o ns 3. 2 a n d 9. 1. 2) .
W or di n g o n pre g na nc y testi n g t hr o u g h o ut t he pr ot oc ol w as u p date d t o clarif y t hat 
pre g na nc y or F S H tests ca n be perf or me d if deter mi ne d necessar y b y t he 
i n vesti gat or.
R ati o n ale: Mi n or c ha n ges/clarificati o ns were ma de t o t he ti mi n g a n d c o n d uct of st u d y pr oce d ures t o all o w  
fle xi bilit y t o i n vesti gat ors a n d clarif y ti mi n g of pr ot oc ol pr oce d ures.
Ti m e a n d E ve nts Sc he d ule
( Part 1)

T h e w i n d o w f or t he 8 hr 3 0 mi n ti me p oi nt o n Da y s 2 a n d 1 4 a n d t he 8 hr 
1 5 m i n ti me p oi nt o n Da y 1 5 was wi de ne d fr o m ± 1 5 mi n utes t o ± 3 0 mi n utes .

T o ali g n C S D- M wit h ot her e P R O assess me nts, t he C S D -M ti m e p oi nts were 
m o ve d t o t he 8 h r 3 0 mi n ti me p oi nt o n Da ys 2 a n d 1 4 a n d t o t he 8 hr 1 5 mi n 
ti me p oi nt o n Da y 1 5. T he pre vi o us ti me p oi nts f or C D S -M assess me nts ( 9 hr 
1 5 m i n o n Da ys 2 a n d 1 4 a n d 9 hr o n Da y 1 5) were delete d.

T he f o ot n ote f or K S S assess me nts i n t he Ti me a n d E ve nts Sc he d ule was 
c ha n ge d fr o m ‘s’ t o ‘t’. 

K S S was delete d fr o m f o ot n ote ‘ m’ a n d ‘s’.

T h e w or di n g i n f o ot n ote ‘ m’ a n d ‘s’ pertai ni n g t o t he or der of st u d y 
assess me nts was re vise d t o i n dicate t hat t he pr o p ose d or der is a 
rec o m me n d ati o n , n ot a re q uire me nt. 
Ti m e a n d E ve nts Sc he d ule 
( Part 2; f o ot n ote c); 
Secti o n 9. 6 . Safet y 
E val uati o ns 
( Electr ocar di o gra m [ E C G])
T h e w or di n g pertai ni n g t o t he or der of st u d y assess me nts was re vise d t o i n dicate 
t hat t he pr o p ose d or der ( E C G(s), vital si g ns, bl o o d dra w) is a rec o m me n d ati o n , 
n ot a re q uire me nt.
Secti o n 9. 6 . Safet y 
E val uati o n s ( Vital si g ns); 
Secti o n 1 1. 8. Safet y 
A nal yses
A xillar y te m perat ure was a d de d t o vital si g ns.
Secti o n 9. 1. 3. D o u ble -Bli n d 
Tr eat me nt P hase
T h e w or di n g pertai ni n g t o tra ns p ortati o n h o m e o n Da y 1 5 was re vise d t o all o w 
i n vesti gat ors t o use t heir j u d g me nt c o ncer ni n g tra ns p ortati o n if t here are c o ncer ns 
a b o ut resi d ual effects.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
R ati o n ale: A dj ust me nts were ma de t o i ncl usi o n/e x cl usi o n criteria.
Secti o n 4. 1. I ncl usi o n 
Criteria

I ncl usi o n Criteri o n # 1 3: T he te xt was u p date d as s h o w n bel o w:
“ D uri n g t he st u d y a n d f or a mi ni m u m of 1 s per mat o ge nesis c ycle ( defi ne d as 
a p pr o xi matel y 3 m o nt hs) after recei vi n g t he last d ose of st u d y dr u g , i n 
a d diti o n t o t he hi g hl y effecti ve met h o d of c o ntrace pti o n , a ma n”
Secti o n 4. 2 . E xcl usi o n 
Criteria

E xcl usi o n Criteri o n # 1: U p date d t o e xcl u de s u bjects wit h narc ole ps y.

E xcl usi o n Criteri o n # 2 4: U p date d t o e xcl u de s u bjects w h o are v ul nera ble 
“d ue t o i nv ol u nt ary dete nti o n (s uc h as f or le g al re as o ns) ”
R ati o n ale: T o clarif y t hat c o nc o mita nt t hera pies d o n ot nee d t o be rec or de d f or s u bjects w h o fail scree ni n g u nless 
t here is a n a d verse e ve nt. 
Secti o n 8. Prest u d y a n d 
C o nc o mita nt T hera p y
A d de d t he f oll o wi n g te xt: “ F or s u bjects w h o f ail scree ni n g, c o nc o mit a nt 
t her a pies d o n ot nee d t o be rec or de d u nless t here is a n a dverse eve nt. ”
R ati o n ale: W or di n g re gar di n g t he re p orti n g pr ocess f or a d verse e ve nts of s pecial i nterest was u p date d.
Secti o n 9. 6. Safet y 
E val uati o ns ( Ad verse e ve nts 
of S pecial I nterest)
T he f oll o w i n g se nte nce was u p date d as s h o w n bel o w:

W he n re p orte d, t he i n vesti gat or will be re q uire d t o c o m plete a detaile d 
s u m mar y of t he e ve nt a n d its cli nical c o urse utilizi n g t he C R F pa ge “ A E of 
s peci al i nterest n arr ative f or m ” as s o o n as i nf or mati o n o n t he o utc o me 
(rec o vere d, res ol vi n g, or o n g oi n g) is a vaila ble. “I n a d diti o n, t he A E s h o ul d 
be m arke d as a n A E of s peci al i nterest i n t he C R F. ”   
R ati o n ale: W or di n g re gar di n g t he tra ns missi o n of seri o us a d verse e ve nts t o t he s p o ns or was u p date d t o re m o ve 
refere nce t o t he Safet y Re p ort F or m, as it is n ot rele va nt f or t his st u d y.
Secti o n 1 2. 3. 2. Seri o us 
A d verse E ve nts
T he f oll o w i n g se nte nce was u p date d as s h o w n bel o w:

I nf or mati o n re gar di n g S A Es will be tra ns mitte d t o t he s p o ns or usi n g t he 
Seri o us A d verse E ve nt F or m a n d Safet y Re p ort F or m, w hic h must be 
c o m plete d a n d re vie we d “si g ne d ” b y a p h ysicia n fr o m t he st u d y site, a n d 
tra ns mitte d t o t he s p o ns or wit hi n 2 4 h o urs. T he i nitial a n d f oll o w-u p re p orts 
of a seri o us a d verse e ve nt s h o ul d be “ m a de ” tra ns mitte d electr o nicall y or b y  
facsi mile (fa x).
R ati o n ale: Mi n or err ors w ere n ote d
T hr o u g h o ut t he pr ot oc ol
Mi n or gra m matical, f or matti n g, or s pelli n g c ha n ges were ma de a n d 
i nc o nsiste ncies were c orrecte d.
A m e n d me nt 1 (2 2 Ja n uar y 2 0 1 8 )
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) of Directi ve 
2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
T he o ver all re as o n f or t he a me n d me nt: T he o verall reas o n f or t he a m e n d me nt is t o u p date e xcl usi o n criteria, 
base d o n H ealt h A ut h orit y re q uest t o e ns ure breastfee di n g w o me n are e xcl u de d fr o m t he st u d y a n d t o pr o vi de 
m o re detail o n certai n cli nical c o n diti o ns t hat are c o ntra-i n dicate d f or z ol pi de m use (acc or di n g t o S m P C/ PI)
A p plica ble Secti o n(s)  
Descri pti o n of C ha n ge(s)
R ati o n ale: Base d o n Healt h A ut h orit y fee d bac k, t he s p o ns or has u p date d t he e xcl usi o n criteria t o e ns ure 
s u bject’s safet y b y a d di n g t he f oll o wi n g:
-
A d diti o nal c o ntrai n dicati o ns f or z ol pi de m use (acc or di n g t o t he S m P C/ PI) 
-
Lac k of res p o nse t o pre vi o us z ol pi de m ( or J NJ -4 2 8 4 7 9 2 2) treat me nt
-
W o m e n w h o are pre g na nt, or breastfee di n g or pla n ni n g t o bec o me pre g na nt

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Secti o n 4. 2 ( E xcl usi o n 
Criteri o n 1)
E xa m ples of s pecific c o ntrai n dicati o ns (fr o m t he z ol pi de m S m P C/ PI) w ere a d de d 
t o clarif y t he e xcl usi o n criteri o n f or s u bjects wit h a hist or y or c urre ntl y cli nicall y 
si g nifica nt p ul m o nar y dist ur ba nce b y t he a d diti o n of “(e g, ac ute or se vere 
res pirat or y failure)”; ne ur ol o gic dist ur ba nce b y t he a d diti o n of “(e g, m yast he nia 
gra vis),”; a n d t he a d diti o n of “ narc ole ps y, narr o w a n gle gla uc o ma”.
Secti o n 4. 2 ( E xcl usi o n 
Criteri o n 1 9)  
A d de d “lac k of res p o nse” t o t he e xcl usi o n criteri o n.
Secti o n 4. 2 ( E xcl usi o n 
Criteri o n 2 2)
A d de d a ne w e xcl usi o n criteri o n: “Is pre g na nt, or breastfee di n g, or pla n ni n g t o 
bec o me pre g na nt w hile e nr olle d i n t his st u d y or w it hi n 1 m o nt h after t he last d ose 
of st u d y dr u g”
R ati o n ale: T o e ns ure s u bject’s safet y, clarificati o ns ha ve bee n ma de t o Pr o hi biti o n a n d Restricti o n wit h re gar d t o 
c o m bi nati o n of alc o h ol a n d h y p n otics wit h a referral t o t he S m P C/ PI f or z ol pi de m. 
Secti o n 4. 3 ( Pr o hi biti o ns 
a n d Restricti o ns)
A d de d t he f oll o wi n g t o Pr o hi biti o n a n d Restricti o ns # 2 : “A d diti o nall y, s u bjects 
will be re mi n de d a b o ut t he ne gati ve c o nse q ue nces of c o m bi ni n g h y p n otics a n d 
alc o h ol (refer t o S m P C/ PI f or z ol pi de m). ”
R ati o n ale : Clarificati o ns ha ve bee n a d de d t o gra d uall y ta per off c hr o nic be nz o diaze pi ne use
Secti o n 8 ( Prest u d y a n d 
C o nc o mita nt Me dicati o ns)
A d diti o n of t he f oll o wi n g te xt: “ T he i n vesti gat or s h o ul d c o nsi der if 5 da ys is 
s ufficie nt f or t he disc o nti n uati o n of t he h y p n otic/se dati n g me dicati o ns s uc h as f or 
c hr o nic be nz o diaze pi ne use w here a pr ol o n ge d ta per ma y be m ore a p pr o priate.” 
R ati o n ale: Cla rificati o ns ha ve bee n ma de t o Ti me a n d E ve nt sc he d ule, m ore detail t o secti o ns bel o w
Ti m e a n d E ve nt Sc he d ule
Part 1 ; Secti o n 3. 1
( O ver vie w of St u d y 
Desi g n) , Secti o n 9. 1. 2
( Scree ni n g P hase), Secti o n 
9. 1. 3 ( D o u ble -bli n d 
Treat me nt P hase); Secti o n 
9. 3. 1 ( E val uati o ns
- U p date d (re) -a d missi o n ti me fra mes o n da ys of P S G m o nit ori n g
- Wi de ne d t he wi n d o w all o wa nce f or pre d ose assess me nts o n P S G ni g hts
- Clarifie d t hat if t he Da y  13 visit is dela ye d t he n st u d y assess me nts wi ll 
be dela ye d wit h t he sa me wi n d o w ( ma xi m u m 2 da ys) s o t hat 
res pecti ve ti me t o d osi n g a n d last d ose is preser ve d
- A d de d all o wa nce f or s u bjects t o lea ve t he st u d y site o n Da y 1 bet wee n 
t he a d missi o n a n d pre d ose assess me nts
- A d de d a d diti o nal i nstr ucti o ns f or m o nit ori n g f or c o mplia nce t o st u d y 
pr o hi biti o ns/restricti o ns 
a n d 
alc o h ol 
a n d/ or 
dr u g 
use 
u p o n 
re-a d missi o n of s u bjects o n P S G da ys
- Eli mi nati o n of res pirat or y rate m o nit ori n g, w hic h ha d bee n me nti o ne d 
o nl y i n t he f o ot n ote 
- Clarificati o n o n trai ni n g sessi o ns f or b o d y s wa y d uri n g scree ni n g i n 
parallel wit h C o g niti ve Batter y trai ni n g sessi o ns
- U p date d te xt relate d t o e xce pti o ns t o t he o ver ni g ht P K sa m pli n g o n 
Ni g ht 1 4 f or Ja pa nese sites a n d a d de d a wi n d o w  all o wa nce f or Da y 
1 5 P K a n d bi o mar ker sa m pli n g f or Ja pa nese sites
- Delete d Da y 2 trac ki n g of me nstr ual c ycle
- C ha n ge d D N A sa m pli n g t o occ ur at a d missi o n o n Da y 1, rat her t ha n 
wit hi n 1 5 mi n utes of d osi n g
Ti m e a n d E ve nt Sc he d ule 
f o ot n otes 
C ha n ges t o f o ot n otes are s h o w n i n q u otati o n mar ks a n d stri ke o ut:
b.
All s u bjects will re p ort t o t he st u d y site o n Da y  1 3 wit hi n “a p pr o xi matel y” 4 
h o urs bef ore be dti me “ wit h s ufficie nt ti me t o c o mplete all assess me nts a n d P S G 
pre p pri or t o be dti me” .
d.
Pre d ose assess me nts are t o be perf or me d 4 5 “ wit hi n 9 0” mi n utes 
( ± 1 5 
mi n utes) pri or t o li g hts o ut o n P S G ni g hts or pri or to be dti me o n n o n- P S G ni g hts. 
“ T hese s h o ul d be perf or me d as cl ose t o be dti me as p ossi ble, b ut ta ki n g i nt o 
acc o u nt t hat P S G pre parati o ns nee d t o occ ur after c o g niti ve a n d b o d y  swa y 
assess me nts.”

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
f.  If nee de d, t he Da y 1 3 st u d y site visit c o ul d be dela ye d f or a ma xi m u m of 2 da ys 
(ie, u p t o Da y 1 5) t o all o w for a s ufficie nt wi n d o w of ti me f or t he s u bject t o ret ur n 
t o t he st u d y site. I n cases w he n t he Da y 1 3 visit is dela ye d, s u bjects s h o ul d 
c o nti n ue t o ta ke st u d y dr u g “a n d all sc he d ule d st u d y assess me nts sc he dule d 
after war ds will be dela ye d wit h t he sa me wi n d o w  (ma xi m u m 2 d a y s) s o t hat 
res pecti ve ti me t o d osi n g a n d last d ose is preser ve d”.
j.
If s u bject lea ves t he st u d y site bet w ee n “scree ni n g P S G assess me nt”, a n d/ or 
Ni g hts 1 a n d 2 a n d/ or bet wee n Ni g hts 1 3 a n d 1 4 “ or after m or ni n g assess me nts o n 
D a y  1”, s u bjects s h o ul d be teste d f or alc o h ol“/ dr u g” use w he n t he y ret ur n t o t he 
st u d y site..
m.
W he n sc he d ule d pr oce d ures c oi nci de, t he y s h o ul d ta ke place i n t he f oll o wi n g 
or der: E C G - > vital si g ns ( bl o o d press ure, heart rate res pirat or y rate -> c o g niti ve 
test batter y-> b o d y s wa y -> K S S -> bl o o d dra ws f or P K.
r.
T w o c o g niti ve test batter y “a n d b o d y s wa y” trai ni n g sessi o ns d uri n g Part 2 of 
t he scree ni n g p hase.
y.   T o be c ollecte d fr o m all s u bjects. “ N ote: At st u d y sites i n Ja pa n, a n e xce pti o n 
t o t he o ver ni g ht P K sa m ples o n Ni g ht 1 4 ma y be ma de after disc ussi o n wit h t he 
s p o ns or’s me dical m o nit or. T he reas o n f or t he e xce pti o n m ust be d oc u me nte d i n 
t he s o urce d oc u me nts. If p ossi ble, t he 8- h o ur 1 5 -mi n ute P K c ollecti o n sh o ul d b e 
o btai ne d e ve n if perf or me d u p t o 1 2 h o urs after d osi n g. T he c orrect ti me of t he 
c ollecti o n s h o ul d be n ote d.”
z.  T o be c ollecte d fr o m all s u bjects. “N ote: At st u d y sites i n Ja pa n, if t he D a y 1 5 
m o r ni n g bi o mar ker sa m ple ca n n ot be o btai ne d at t he re q ueste d ti me p oi nt , it ca n be 
o btai ne d u p t o 1 2 h o urs p ost -d ose if nee de d wit h t he c orrect ti me d oc u me nte d .”
g g. “O n Da y 1, a d missi o n assess me nts s uc h as fasti n g la bs s h o ul d be c o m plete d 
a n d t he n a s u bject ma y lea ve t he st u d y ce nter a n d ret ur n at least 3- 4 h o urs pri or t o 
be dti me t o c o m plete pre d ose a n d P S G assess me nts. ”
R ati o n ale: U p date d n o ncli nical t o xic ol o g y data a n d relate d st u d y c o n d uct
Secti o n 1. 1. 1 ( T o xic ol o g y), 
Secti o n 3. 2 ( St u d y Desi g n 
Rati o nale) , Refere nces
A d de d t o xic ol o g y res ults fr o m a 6 -m o nt h rat a n d 9 -m o nt h d o g st u d y t hat relate t o 
p ossi ble C N S effects i n h u ma ns
Secti o n 9. 6 ( Safet y 
E val uati o ns ; A d verse 
E ve nts)
A d de d t he f oll o wi n g: “ As wit h a n y C N S -acti ve me dicati o n, i n vesti gat ors s h o ul d 
m o nit or caref ull y a n d d oc u me nt a n y C N S -relate d a d verse e ve nt i ncl u di n g tre m or, 
ata xia, a b n or mal se nsati o n, c o nf usi o n, or p ossi bilit y of seiz ure.”
R ati o n ale: Clarificati o n of st u d y c o n d uct t hat will n ot affect safet y 
Title Pa ge , hea ders, etc
A d de d t he ge neric na me f or J NJ -4 2 8 4 7 9 2 2, ie selt ore xa nt, i n se veral l ocati o ns i n 
a d diti o n t o t he pre vi o us descri pt or of selecti ve ore xi n-2 rece pt or a nta g o nist .
Secti o n 6. (D osa ge a n d 
A d m i nistrati o n)
A d de d t hat t he st u d y dr u g will be ta ke n wit h “a p pr o xi matel y” 1 0 0 m L of water
Secti o n 9. 1. 3 ( D o u ble -
Bli n d Treat me nt P hase)
Ma de t he f oll o wi n g deleti o n (s h o w n i n stri ke -o ut te xt): St u d y pr oce d ures d uri n g 
t he d o u ble-bli n d treat me nt p hase t o assess safet y, t olera bilit y, efficac y, 
c o m plia nce, a n d ot her e val uati o ns (e g, P K a n d bi o mar kers) will occ ur as per t he 
T i me a n d E ve nts Sc he d ule - Part 1 a n d T i me a n d E ve nts Sc he d ule - Part 2 . 
S u bjects will re p ort t o t he st u d y site i n t he m or ni n g o n Da ys 1 a n d Da y 1 3 i n a 
faste d state

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Secti o n 9. 4. ( Bi o mar kers);
A d de d t he f oll o wi n g te xt: “If a s u bject d oes n ot f oll o w  a l o w-fat diet, t his is n ot 
c o nsi dere d a pr ot oc ol de viati o n a n d s h o ul d be n ote d o n t he bi o mar ker re q uest 
f or m”.
Attac h me nt 1
Clarifie d l o w -fat diet restricti o ns: T o mi ni mize i nterfere nce ca use d b y li pi d 
c o nte nt i n bl o o d s peci me ns c ollecte d f or bi o mar ker e val uati o n, s u bjects s h o ul d 
f oll o w a l o w-fat diet “f or t he meal” f or at least 8 h o urs pri or t o bl o o d c ollecti o n. 
“ A l o w-fat diet d oes n ot nee d t o be f oll o we d if t he s u bject has bee n fasti n g f or at 
least 8 h o urs pri or t o t he bl o o d dra w.”
Secti o n 9. 6 (Safet y
E val uati o ns )
Delete d t he f oll o wi n g se nte nce: “ Vital si g ns s h o ul d be meas ure d i n n o n -fasti n g 
c o n diti o ns w he ne ver p ossi ble.”
R ati o n ale: A d diti o nal i nstr ucti o ns f or assess me nt of s u bjects pri or t o disc har ge o n Da y 2/ Da y 3
Secti o n 9. 1. 3 ( D o u ble -
bli n d Treat me nt P hase)
Ma de re vise d t o t he f oll o wi n g state me nt: 
O n Da y 1, s u bjects w ill be a d mitte d t o t he st u d y site bet wee n 8: 0 0 A M a n d n o o n 
a n d will re mai n i n t he st u d y site u ntil n o o n “assess me nts are c o m plete d i n t he 
m o r ni n g” of Da y 2 ( 1 o ver ni g ht)”.
O n Da y 2 ( or Da y 3 i n s u bjects u n der g oi n g o ver ni g ht P K sa m pli n g), s u bjects 
s h o ul d be acc o m pa nie d h o me or use prearra n ge d tra ns p ortati o n “ nee d t o be alert, 
a wa ke, a n d wit h n o resi d ual effects of t he me dicati o ns (s uc h as effects o n bala nce) 
bef ore t he y ca n be rel ease d fr o m t he st u d y ce nter. If t here are a n y c o ncer ns a b o ut 
resi d ual effects t he s u bject s h o ul d be acc o m pa nie d h o me or use prearra n ge d 
tra ns p ortati o n”
R ati o n ale: Clarificati o n relate d t o use of prest u d y a nti de pressa nt a n d ot her C N S me dicati o ns.
Secti o n 8 ( Prest u d y a n d 
C o nc o mita nt T hera p y) 
Clarifie d t hat s u bjects s h o ul d n ot use a nti de pressa nt me dicati o ns, B Z Ds, 
bar bit uates, etc, fr o m at least 5 da ys “after si g ni n g t he I C F” bef ore scree ni n g u ntil 
t he f oll o w-u p visit.
R ati o n ale: Mi n or err ors w ere n ote d
T hr o u g h o ut t he pr ot oc ol
Mi n or gra m matical, f or matti n g, or s pelli n g c ha n ges were ma de a n d 
i nc o nsiste ncies were c orrecte d.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
S Y N O P SI S
A 
M ultice nter, 
D o u ble -Bli n d, 
R a n d o mize d, 
P ar allel -Gr o u p, 
Acti ve - a n d Pl ace b o -C o ntr olle d 
P ol ys o m n o gr a p h y St u d y t o E v al u ate t he Effic ac y, S afet y, a n d T oler a bilit y of  JN J -4 2 8 4 7 9 2 2 i n 
S u bjects wit h I ns o m ni a Dis or der
J NJ- 4 2 8 4 7 9 2 2 is a s h ort-acti n g, p ote nt a n d selecti ve a nta g o nist of t he h u ma n ore xi n - 2 rece pt or ( O X 2 R) 
t hat is bei n g de vel o pe d f or t he treat me nt of i ns o m nia a n d maj or de pressi ve dis or der ( M D D). Acti vati o n of 
ore xi n ne ur o ns c o ntri b utes t o t he mai nte na nce of wa kef ul ness; t heref ore, t he bl oc ka de of ore xi n rece pt ors, 
i n partic ular O X 2 R, is a n o vel p har mac ol o gic a p pr oac h f or t he treat me nt of i ns o m nia.
Si n gle a n d m ulti ple d ose st u dies i n rats at vari o us d ose le vels de m o nstrate d t hat J NJ- 4 2 8 4 7 9 2 2 re d uce d 
late nc y t o n o n- ra pi d e ye m o ve me nt ( N R E M) slee p, i ncrease d N R E M slee p d urati o n, a n d di d n ot i m pact 
ra pi d e ye m o ve me nt (R E M ) slee p.
B y da m pe ni n g t he s yste m res p o nsi ble f or h y perar o usal, as o p p ose d t o e n ha nci n g t he se dati ve effects of 
t he i n here nt ga m ma -a mi n o b ut yric aci d ( G A B A)-er gic s yste m, J NJ- 4 2 8 4 7 9 2 2 is e x pecte d t o de m o nstrate 
efficac y i n i n d uci n g a n d mai ntai ni n g slee p, wit h o ut t he si de effects ass ociate d wit h ot her classes of 
se dati ve h y p n otics, s uc h as m usc ular at o nia res ulti n g i n bala nce iss ues, c o g niti ve deficits a n d a nter o gra de 
a m nesia, a n d de pe n de nce a n d t olera nce. T hese si de effects are partic ularl y tr o u bli n g t o t he el derl y gi ve n 
t he i ncreasi n g pre vale nce of n oct uria (t he i nterr u pti o n of slee p o ne or m ore ti mes at ni g ht t o v oi d) wit h 
a gi n g, res ulti n g i n ni g htti me a wa ke ni n g re q uiri n g a de q uate ps yc h o m ot or c o or di nati o n a n d c o g niti ve 
ca pacit y t o arise fr o m be d a n d safel y na vi gate t o t he ba t hr o o m d uri n g t he ni g ht wit h o ut i nci de nt.
T o date, J NJ -4 2 8 4 7 9 2 2 has s h o w n g o o d t olera bilit y a n d safet y i n a d ult a n d el derl y s u bjects. T he m a xi mal 
dail y d ose le vels a d mi nistere d i n si n gle- a n d m ulti ple -d ose st u dies are 8 0 m g a n d 6 0 m g, res pecti vel y. 
Preli mi nar y safet y res ults fr o m St u d y 4 2 8 4 7 9 2 2 E DI 1 0 1 4 i n el derl y healt h y s u bject c o h orts s h o w t hat 
si n gle e ve ni n g d osi n g of J NJ-4 2 8 4 7 9 2 2 1 0 m g a n d 2 0 m g d oses are well t olerate d.
T he ai m of t his st u d y is t o i n vesti gate t he effects of 3 d oses of J NJ-4 2 8 4 7 9 2 2 ( 5, 1 0, a n d 2 0 m g), 
c o m pare d t o place b o, o n slee p o nset a n d mai nte na nce a n d t o f urt her d oc u me nt t he safet y a n d t olera bilit y 
of J NJ- 4 2 8 4 7 9 2 2 u p o n m ulti ple ( 1 4 da ys) d ose a d mi nistrati o n i n s u bjects wit h i ns o m nia dis or der. I n 
a d diti o n, effects of J NJ- 4 2 8 4 7 9 2 2 o n slee p para meters ( o bjecti ve a n d s u bjecti ve), resi d ual effects, a n d 
c o g niti o n will be c o m pare d t o t h ose effects of z ol pi de m t o i n vesti gate p ote ntial differe nces bet wee n t he 
c o m p o u n ds. T he res ults of t his st u d y will be use d t o i nf or m t he P hase 3 de vel o p me nt pla n.
O B J E C TI V E S , E N D P OI N T S, A N D H Y P O T H E SI S
O bjecti ves
E n d p oi nts
Pri m ar y

T o assess t he d ose -res p o nse of 3 d oses of 
J NJ-4 2 8 4 7 9 2 2 ( 5, 1 0, a n d 2 0 m g) c o m pare d t o 
place b o o n a n o bjecti ve meas ure of slee p o nset 
i n s u bjects wit h i ns o m nia dis or der.

C ha n ge fr o m baseli ne i n late nc y t o persiste nt 
slee p ( L P S) as meas ure d b y p ol ys o m n o gra p h y 
(P S G ) o n Ni g ht 1
Ke y Sec o n d ar y

T o assess t he d ose -res p o nse of 3 d oses of 
J NJ- 42 8 4 7 9 2 2 ( 5, 1 0, a n d 2 0 m g) c o m pare d t o 
place b o 
o n 
a n 
o bj ecti ve 
meas ure 
of 
mai nte na nce 
o f slee p 
i n s u bjects 
wit h 
i ns o m nia dis or der.

C ha n ge fr o m baseli ne i n 
wa ke after slee p 
o nset (W A S O ) o ver t he first 6 h o urs as 
meas ure d b y P S G o n Ni g ht 1

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
O bjecti ves
E n d p oi nts
Sec o n d ar y
Effic acy

T o 
assess 
t he effect 
of 
J NJ-4 2 8 4 7 9 2 2 
c o m pare d 
wit h 
place b o 
i n 
i m pr o vi n g 
a d diti o nal o bjecti ve slee p para meters
C ha n ge fr o m baseli ne i n P S G para meters 
i ncl u di n g:

L P S o n Ni g ht 1 3

W A S O o ver t he first 6 h o urs o n Ni g ht 1 3

T otal slee p ti me ( T S T ) ( o ver 6 a n d 8 h o urs) o n 
Ni g hts 1 a n d 1 3 

Slee p effic ie nc y (S E ) o n Ni g hts 1 a n d 1 3

ot her 
sec o n dar y 
P S G 
slee p 
para meters 
( detailed i n Secti o n 9. 2. 1 ) o n Ni g hts 1 a n d 1 3

T o 
assess 
t he effect 
of 
J NJ-4 2 8 4 7 9 2 2 
c o m pare d 
wit h 
z ol pi de m 
i n 
i m pr o vi n g 
o bjecti ve slee p para meters
C ha n ge fr o m baseli ne i n P S G para meters o n 
Ni g hts 1 a n d 1 3 i ncl u di n g:

L P S

W A S O o ver t he first 6 h o urs

T S T ( o ver 6 a n d 8 h o urs) 

S E 

ot her 
sec o n dar y 
P S G 
slee p 
para met ers 
( detaile d i n Secti o n 9. 2. 1)

T o 
assess 
t he effect 
of 
J NJ-4 2 8 4 7 9 2 2 
c o m pare d wit h 
z ol pi de m a n d place b o o n 
self-re p orte d meas ures of slee p
Patie nt- re p orte d meas ures i ncl u di n g:

C ha n ge 
fr o m baseli ne i n s u bjecti ve slee p 
para meters as meas ure d 
b y t he C o nse ns us 
Slee p 
Diar y
–
M or ni n g 
A d mi nistrati o n 
( C S D-M), i n t he m or ni n g o n Da ys 2 a n d 1 4

C ha n ge fr o m baseli ne i n slee p dist ur ba nce a n d 
i m pair me nt as meas ure d 
b y t he Nati o nal 
I nstit utes o f Healt h Patie nt Re p orte d O utc o me 
Meas ure me nt I nf or mati o n S yste m ( P R O MI S) 
s h ort 
f or m 
8a 
f or 
Slee p 
Dist ur ba nce 
( P R O MI S-S D) a n d P R O MI S s h ort f or m 8a f or 
Slee p Relate d I m pair me nt ( P R O MI S-S RI ) o n 
Da ys 8 a n d 1 4

C ha n ge fr o m baseli ne i n s u bject's assess me nt 
of i ns o m nia se verit y usi n g t he Patie nt Gl o bal 
I m pressi o n
–
Se verit y ( P GI-S) scale a n d 
s u bject's 
assess me nt 
of 
i m pr o ve me nt i n 
i ns o m nia usi n g t he Patie nt Gl o bal I m pressi o n
– I m pr o ve me nt ( P GI-I) scale o n Da y 1 4.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
O bjecti ves
E n d p oi nts

T o 
assess 
t he effect 
of 
J NJ-4 2 8 4 7 9 2 2 
c o m pare d wit h 
z ol pi de m a n d place b o i n 
i m pr o vi n g:
–
Res p o nse 
a n d re missi o n of i ns o m nia 
s y m pt o ms

Pr o p orti o n of res p o n ders, defi ne d as a ≥5 0 % 
re d ucti o n fr o m baseli ne i n t otal sc ore o n t he 
I ns o m nia Se verit y I n de x (I SI) o n Da y 1 4

Pr o p orti o n 
of s u bjects wit h 
re missi o n of 
i ns o m nia s y m pt o ms, defi ne d as a t otal sc ore 
≤1 0 o n t he I SI o n Da y 1 4
–
Cli nical 
se verit y a n d i m pr o ve me nt of 
i ns o m nia s y m pt o ms

C ha n ge fr o m baseli ne i n cli nicia n's assess me nt 
of i ns o m nia se verit y usi n g t he Cli nical Gl o bal 
I m pressi o n
–
Se verit y 
( C GI-S) 
a n d 
i m pr o ve me nt i n i ns o m nia usi n g t he Cli nical 
Gl o bal I m pressi o n – I m pr o ve me nt ( C GI-I) on 
Da y 1 4
S afety

T o 
assess t he safet y a n d t olera bilit y of 
J NJ- 4 2 8 4 7 9 2 2 c o m pare d wit h z ol pi de m a n d 
place b o i n s u bjects wit h i ns o m nia dis or der
Safet y assess me nts i ncl u di n g:

A d verse e ve nts ( A Es) 

Pr o p orti o n of all seri o us A Es
(S A Es ) a n d 
e ve nts 
of 
s pecial 
i nterest 
(e. g., 
falls, 
paras o m nias)

Vital 
si g ns, 
p h ysical 
e xa mi nati o ns , 
electr ocar di o gra m 
(E C G ), 
a n d 
la b orat or y 
para meters

C ol u m bia 
S uici de 
Se verit y 
Rati n g 
Scale 
( C-S S R S)

Resi d ual effects as meas ure d b y :
–
T he 
prese nce of ne xt da y s u bjecti ve 
resi d ual effects as meas ure d 
b y 
t he 
Kar oli ns ka 
Slee pi ness Scale ( K S S) o n 
Da ys 2 a n d 1 4 
– 
P ost ural sta bilit y ( b o d y s wa y) as meas ure d 
wit h a n ata xia meter o n Da ys 2 a n d 1 4 i n 
t he m or ni n g a n d o n Da y 1 5 at 4 -h o urs p ost 
Ni g ht 
1 4 d ose ( mi d dle of t he ni g ht 
a wa ke ni n g)

T o 
o bjecti vel y assess
t he effect of J NJ-
4 2 8 4 7 9 2 2 
c o m pare d 
wit h 
z ol pi de m 
a n d 
place b o o n c o g niti ve d o mai ns as meas ure d i n 
t he m or ni n g after d osi n g as well as d uri n g 
mi d dle of t he ni g ht a wa ke ni n g

C ha n ge i n c o g niti o n c o m pare d t o pre -d ose 
assess me nt o n o bjecti ve c o g niti ve assess me nt 
as meas ure d 
b y a c o m p uterize d batter y of 
c o g niti ve tests i n t he m or ni n g o n Da ys 2 a n d 
1 4 

C o g niti ve perf or ma nce o n Da y 1 5 at 4- h o urs 
p ost Ni g ht 
1 4 d ose ( mi d dle of t he ni g ht 
a wa ke ni n g) as meas ure d b y a c o m p uterize d 
batter y of c o g niti ve tests

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
O bjecti ves
E n d p oi nts

T o e val uate p ote ntial wit h dra wal effects after 
c o nti n u o us ni g htl y d osi n g wit h J NJ -4 2 8 4 7 9 2 2, 
z ol pi de m, or place b o

C ha n ge i n s u bjecti ve slee p para meters fr o m 
Da y 1 4 as c o m pare d t o Da y 1 7 as meas ure d b y 
t he C S D- M

C ha n ge i n P h ysicia n Wit h dra wal 
C hec klist 
( P W C) fr o m Da y 1 4 t o Da y 1 7

T he 
Be nz o diaze pi ne 
Wit h dra wal 
S y m pt o m 
Q uesti o n naire ( B W S Q) f or self-assess me nt of 
wit h dra wal s y m pt o ms o n Da y 1 7
P h ar m ac o ki netic O bjecti ves

T o assess t he e x p os ure of J NJ- 4 2 8 4 7 9 2 2 a n d acti ve meta b olites M 1 2 a n d M 1 6, i n s u bjects wit h 
i ns o m nia, a n d t o e x pl ore t he effects of c o variates o n s uc h e x p os ure

T o c haracterize t he e x p os ure-res p o nse relati o ns hi p of J NJ- 4 2 8 4 7 9 2 2 wit h res pect t o meas ures of 
efficac y a n d/ or safet y

F or efficac y: L P S a n d W A S O 
o ver t he first 6 h o urs b y P S G o n Ni g ht 1 vs meas ures of 
J NJ-4 2 8 4 7 9 2 2 e x p os ure

F or safet y: C o g niti ve perf or ma nce o n Da y 1 5 at 4 h o urs p ost Ni g ht 1 4 d ose ( mi d dle of t he ni g ht 
a wa ke ni n g) vs meas ures of J NJ - 4 2 8 4 7 92 2 e x p os ure
E x pl or at or y O bjecti ves

T o e x pl ore t he effect of J NJ -4 2 8 4 7 9 2 2, c o m pare d wit h z ol pi de m a n d place b o , o n c o g niti ve d o mai ns ,
as meas ure d b y t he c ha n ge fr o m baseli ne i n s u bjecti ve assess me nt of c o g niti ve effects of treat me nt 
o n Da ys 8 a n d 1 3, usi n g the m o difie d P R O MI S -A p plie d C o g niti o n A bilities ( P R O MI S -A C A) .

T o e x pl ore patie nt -re p orte d le vel of satisfacti o n wit h t he use of J NJ-4 2 8 4 7 9 2 2 c o m pare d t o z ol pi de m 
i n s u bjects wit h i ns o m nia dis or der usi n g t he A b bre viate d Treat me nt Satisfacti o n Q uesti o n naire f or 
Me dicati o n ( T S Q M -9) o n Da y 1 4

T o deter mi ne t he c orrelati o n bet wee n t he f oll o wi n g slee p para meters o btai ne d b y P S G rec or di n gs o n 
Ni g hts 
1 a n d 1 3 ( o bjecti ve) a n d C S D -M 
(s u bjecti ve o n t he f oll o wi n g m or ni n g): 
L P S a n d 
self-re p orte d slee p o nset late nc y (s S O L); T S T a n d s u bjecti ve T S T (s T S T); W A S O a n d s u bjecti ve 
W A S O (s W A S O); n u m ber of ni g htti me a wa ke ni n gs ( n N A W) a n d s u bjecti ve n u m ber of ni g htti me 
a wa ke ni n gs (s-n N A W); a n d S E a n d s u bjecti ve q ualit y of slee p (s Q U A L) i n s u bjects wit h i ns o m nia 
dis or der

T o e x pl ore dia g n ostic bi o mar kers a n d e val uate c ha n ge i n bi o mar kers relate d t o i m m u ne s yste m (e g, 
hi g h -se nsiti vit y C- reacti ve pr otei n [ hs C R P]), gr o wt h fact ors (e g, brai n -deri ve d ne ur otr o p hic fact or 
[ B D N F]), k y n ure ni ne meta b olites (e g, q ui n oli nic aci d), a n d - h y p ot hala mic – pit uitar y – a dre nal (H P A )
a xis mar kers (e g, c ortis ol) t hat ma y be relate d t o cli nical res p o nse (i ncl u di n g P S G), n o n -res p o nse, or 
safet y para meters of J NJ-4 2 8 4 7 9 2 2 vers us place b o.
H y p ot hesis
T he pri mar y h y p ot hesis of t his st u d y is: i n s u bjects wit h i ns o m nia dis or der, J NJ- 4 2 8 4 7 9 2 2 will res ult i n 
si g nifica ntl y s h orte ne d L P S val ues vers us place b o, as meas ure d b y P S G o n Ni g ht 1, a n d e x hi bit a 
d ose -res p o nse relati o ns hi p.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 7
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
O V E R VI E W O F S T U D Y D E SI G N
T his is a m ultice nter (U nite d States [U S ], E ur o pea n U ni o n [ E U ], a n d Ja pa n), ra n d o mize d, d o u ble -bli n d, 
parallel -gr o u p, acti ve- a n d place b o -c o ntr olle d d ose fi n di n g st u d y t o assess t he efficac y a n d safet y of 
J NJ- 4 2 8 4 7 9 2 2 i n b ot h a d ult ( 1 8 t o 6 4 years, i ncl usi ve) a n d el derl y ( 6 5 t o 8 5 ye ars, i ncl usi ve) s u bjects 
wi t h i ns o m nia dis or der. I n a d diti o n, effects of J NJ- 4 2 8 4 7 9 2 2 o n slee p para meters ( o bjecti ve a n d 
s u bjecti ve) a n d c o g niti o n will be c o m pare d t o t h ose effects of z ol pi de m, t o i n vesti gate p ote ntial 
differe nces bet wee n t he c o m p o u n ds. A t otal of 3 6 0 s u bjects, a ge d 1 8 t o 8 5 years i ncl usi ve, wit h i ns o m nia 
dis or der will be ra n d o mize d. T he pla n is t o ra n d o mize a p pr o xi matel y e q ual pr o p orti o ns of a d ult a n d 
el derl y s u bjects a n d t heref ore t he n u m ber ra n d o mize d i n eit her a ge gr o u p s h o ul d n ot e xcee d 
a p pr o xi matel y 6 0% of t he pla n ne d t otal sa m ple size.
S u bjects will be ra n d o mize d i n a 1: 1: 1: 1: 1 rati o t o recei ve 1 of 5 treat me nts: place b o:J NJ -4 2 8 4 7 9 2 2 
5 m g:J NJ -4 2 8 4 7 9 2 2 1 0 m g: J NJ- 4 2 8 4 7 9 2 2 2 0 m g: z ol pi de m.
F or all s u bjects, t his st u d y will c o nsist of a n eli gi bilit y scree ni n g p hase, a d o u ble -bli n d treat me nt p hase, 
a n d a f oll o w-u p visit.
T he d urati o n of partici pati o n i n t he st u d y f or a n i n di vi d ual s u bject (i ncl u di n g scree ni n g a n d f oll o w- u p 
visit) will be u p t o 6 1 da ys.
S U B J E C T P O P U L A TI O N
Me n a n d w o me n of n o n -c hil d beari n g p ote nti al (W O N C B P ), a ge d bet wee n 1 8 t o 8 5 years (i ncl usi ve), wit h
a Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders, 5t h e diti o n ( D S M-5) dia g n osis of i ns o m nia 
dis or der a n d a n I SI t otal sc ore ≥1 5, w h o are ot her wise healt h y or prese nt wit h sta ble, well -c o ntr olle d, 
c hr o nic c o n diti o ns, will be i ncl u de d i n t his st u d y. I n a d diti o n, s u bjects will ha ve a n s S O L ≥4 5 mi n utes 
a n d a n s W A S O ≥6 0 mi n utes (assesse d usi n g t he C S D -M) o n at least 3 ni g hts o ver a n y 7- da y peri o d 
d uri n g Part 1 of scree ni n g ( Da y - 3 5 t o Da y -1 5). F o r s u bjects ta ki n g h y p n otic dr u gs at t he ti me of si g ni n g 
t he i nf or me d c o nse nt f or m (I C F), t hese h y p n otic dr u gs s h o ul d be disc o nti n ue d wit hi n 5 da ys after si g ni n g 
t he I C F. C o m pleti o n of t he I SI a n d C S D -M m ust start at least 5 da ys after t he last d ose of all h y p n otic 
dr u g s.
D uri n g Part 2 of scree ni n g, a n o bj ecti ve assess me nt of i ns o m nia b y P S G rec or di n g a n d e val uati o n o ver 
2 ni g hts will be perf or me d. T he 2 ni g hts of scree ni n g P S G ac q uisiti o ns will be c o n d ucte d c o nsec uti vel y. 
T hese assess me nts s h o ul d be c o m plete d bet wee n Da y - 1 4 a n d Da y - 5 (ie, 5 da ys bef ore Da y 1) t o all o w 
f or a nal ysis of t he P S G data a n d esta blis h eli gi bilit y f or ra n d o mizati o n. T he first ni g ht’s P S G data will be 
use d t o e xcl u de a n y s u bject wit h peri o dic li m b m o ve me nts
( P L M)/restless le g s y n dro me ( R L S), slee p 
a p nea, or paras o m nias. T he first a n d sec o n d ni g hts’ P S G rec or di n gs will be use d t o assess o bjecti ve slee p 
e ntr y criteria f or i ns o m nia. S u bjects are re q uire d t o meet t he f oll o wi n g o bjecti ve slee p i ncl usi o n criteria: a 
2- ni g ht mea n L P S of ≥2 5 mi n utes wit h neit her ni g ht < 2 0 mi n utes, a 2- ni g ht me a n W A S O ≥3 0 mi n utes, 
a n d a 2 -ni g ht mea n T S T ≤6. 5 h o urs wit h neit her ni g ht > 7 h o urs.
D O S A G E A N D A D MI NI S T R A TI O N
J NJ- 4 2 8 4 7 9 2 2 is s u p plie d f or t his st u d y as ca ps ules ( o ver-e nca ps ulate d ta blets) of 2. 5-, 1 0-, a n d 2 0- m g. 
T he J NJ-4 2 8 4 7 9 2 2 5 m g d ose will c o nsist of t w o 2. 5 m g ca ps ules. All ot her J NJ- 4 2 8 4 7 9 2 2 d oses will 
c o nsist of 1 acti ve a n d 1 place b o ca ps ule eac h. Z ol pi de m will be s u p plie d as a ca ps ule ( o ver -e nca ps ulate d 
ta blet), c o ntai ni n g 5 -m g z ol pi de m. T h e 5- m g
d ose of z ol pi de m will c o nsist of 1 acti ve a n d 1 place b o 
ca ps ule; t he 1 0 m g d ose of z ol pi de m will c o nsist of t w o 5 m g ca ps ules. Place b o will be s u p plie d as 
matc hi n g ca ps ules a n d, f or s u bjects ra n d o mize d t o place b o, t he d ose will c o nsist of 2 place b o ca ps ules.
O n Da ys 1 t hr o u g h 1 4 of t he d o u ble -bli n d treat me nt p hase, s u bjects will recei ve J NJ-4 2 8 4 7 9 2 2, z ol pi de m,
or place b o o nce dail y, at n or mal be dti me o n n o n -P S G ni g hts or 1 5 mi n utes pri or t o li g hts o ut o n ni g hts of 
P S G rec or di n g.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
E F FI C A C Y E V A L U A TI O N S
O ver ni g ht P S G will be perf or me d o n Ni g ht 1 a n d Ni g ht 1 3 of t he d o u ble -bli n d treat me nt p hase. T he P S G 
e val uati o ns i ncl u de: L P S, W A S O, T S T, S E, h o url y W A S O, wa ke d uri n g t otal slee p peri o d, wa ke after 
fi nal a wa ke ni n g, R E M d urati o n, R E M late nc y , t otal ti me s pe nt i n slee p sta ges N 1, N 2 a n d N 3, n u m ber of 
ni g htti me a wa ke ni n gs (n N A W ) o ver 6 h o urs, n N A W/ hr, ti me t o first a wa ke ni n g after slee p, pr o p orti o n of 
s u bjects wit h slee p-o nset R E M, n u m ber of slee p c ycles, a m o u nt of dee p (sl o w-wa ve) slee p, a n d slee p 
electr oe nce p hal o gra p h ( E E G) p o wer s pectr u m/slee p e p oc h. S u bjecti ve slee p para meters (s S O L, s T S T, 
s W A S O, s-n N A W, s Q U A L, a n d s u bjecti ve refres he d feeli n g o n wa ki n g [s F R E S H]) will be assesse d 
usi n g t he C S D -M o n eac h m or ni n g t hr o u g h o ut t he scree ni n g p hase , d o u ble -bli n d p hase , a n d f oll o w-u p 
p hase . Da yti me e x perie nce of slee p-relate d i m pair me nts will be assesse d per t he P R O MI S -S RI. Effects 
o n slee p dist ur ba nce will be assesse d via t he P R O MI S -S D. Cli nical a n d s u bjecti ve assess me nt of 
i ns o m nia se verit y a n d i m pr o ve me nt will be perf or me d usi n g t he I SI, C GI-S, P GI - S, C GI-I, a n d P GI-I.
P H A R M A C O KI N E TI C E V A L U A TI O N S
A p har mac o ki netic (P K ) sa m ple will be c ollecte d fr o m all s u bjects 1 5 m i n utes after t he last d ose of st u d y 
dr u g o n Ni g ht 1 4 a n d o n Da y 1 5 at 4 h o urs a n d at 8 h o urs 1 5 mi n utes p ost Ni g ht 1 4 e ve ni n g d ose as 
i n dicate d i n t he Ti m e a n d E ve nts Sc he d ule – Part 1. I n a d diti o n, P K sa m ples will be c ollecte d o n 
Ni g ht 2/ Da y 3 fr o m, at mi ni m u m, 4 0 n o n- el derl y a d ult s u bjects a n d 4 0 el derl y su bj ects, at t he st u d y sites 
wit h i nte nsi ve P K sa m pli n g ca pa bilities.
N ote: A n
e xce pti o n t o t he o ver ni g ht P K sa m ples o n Ni g ht 1 4 ma y be ma de after disc ussi o n wit h t he 
s p o ns or’s me dical m o nit or. T he reas o n f or t he e xce pti o n m ust be d oc u me nte d i n t he s o urce doc u me nts. If 
p ossi ble, t he 8- h o ur 1 5- mi n ute P K c ollecti o n s h o ul d be o btai ne d e ve n if perf or me d u p t o 1 2 h o urs after 
d osi n g. T he c orrect ti me of t he c ollecti o n s h o ul d be n ote d.
BI O M A R K E R E V A L U A TI O N S
Bl o o d sa m ples f or bi o mar ker e val uati o n will be c ollecte d p er t he T i me a n d E ve nts Sc he d ule - Part 1 a n d 
T i me a n d E ve nts Sc he d ule - Part 2 .
Bi o mar ker a nal yses will i ncl u de ( b ut are n ot li mite d t o) mar kers relate d t o i m m u ne s yste m acti vit y 
( hs C R P, i nterle u ki n-6), gr o wt h fact ors ( B D N F), k y n ure ni ne meta b olites, 
a n d H P A a xis acti vati o n 
(c ortis ol).
P H A R M A C O G E N O MI C ( D N A) E V A L U A TI O N S
Bl o o d sa m ples f or ge netic researc h will be c ollecte d fr o m s u bjects w h o c o nse nt se paratel y t o t his 
c o m p o ne nt of t he st u d y ( w here l ocal re g ulati o ns per mit). S u bject partici pati o n i n p har mac o ge n o mic 
researc h is o pti o nal.
S A F E T Y E V A L U A TI O N S
T he safet y a n d t olera bilit y of t he st u d y dr u g will be e val uate d t hr o u g h o ut t he st u d y. Safet y e val uati o ns 
will i ncl u de c ollecti o n of A Es, A Es of s pecial i nterest, c o nc o mita nt me dicati o ns, p h ysical e xa mi nati o n, 
b o d y wei g ht, vital si g ns, 1 2 -lea d E C G, uri ne dr u g testi n g, a n d cli nical la b orat or y tests.
I n a d diti o n, resi d ual se dati o n will be teste d s u bjecti vel y via t he K S S. P ote ntial c o g niti ve/ ps yc h o m ot or 
effects will be meas ure d s u bjecti vel y b y t he s u bject via P R O MI S -A C A a n d o bjecti vel y b y a c o m p uterize d 
c o g niti ve test batter y. P ost ural sta bilit y will be e val uate d o bjecti vel y t hr o u g h assess me nt of b o d y s wa y. 
P ote ntial wit h dra wal effects will be assesse d b y t he cli nicia n usi n g t he P W C a n d re p orte d b y s u bjects 
usi n g t he B W S Q. E mer ge nce of s uici dal i deati o n wil l be assesse d usi n g t he C-S S R S.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
E X P L O R A T O R Y E V A L U A TI O N S
E x pl orat or y assess me nts will be d o ne usi n g t he T S Q M - 9 t o e x pl ore t he le vel of satisfacti o n wit h t he use 
of J NJ -4 2 8 4 7 9 2 2 vers us z ol pi de m.
S T A TI S TI C A L M E T H O D S
Sa m ple Size Deter mi nati o n
T he t otal sa m ple size is calc ulate d o n t he basis of t he M ulti ple 
C o m paris o n Pr oce d ure -M o deli n g 
( M C P- M o d) test a p plie d t o war ds t he place b o a n d t he J NJ-4 2 8 4 7 9 2 2 d ose gr o u ps at t he fi nal a nal ysis. T he 
ca n di date m o del set c o nsi dere d f or t he deter mi nati o n of t he sa m ple size c o nsists of t he f o ur m o del 
pr ofiles: “li near”, “e ma x”, “si g E ma x”, a n d “e x p o ne ntial”. Gi ve n t he a vaila ble data wit h J NJ -4 2 8 4 7 9 2 2 i n 
t he 
tar get 
p o p ulati o n 
(i ns o m nia 
dis o r der) 
fr o m 
t he 
P r o of- of-C o nce pt 
( P o C) 
st ud y 
( St u d y 4 2 8 4 7 9 2 2I S M 2 0 0 2), a treat me nt differe nce of 2 0 mi n utes bet wee n J NJ-4 2 8 4 7 9 2 2 a n d place b o f or 
L P S was ass u me d wit h a sta n dar d de viati o n of 4 5 mi n utes. A t otal of 3 6 0 ra n d o mize d s u bjects will 
pr o vi de a n a vera ge wei g hte d 
p o wer of a p pr o xi matel y 8 5 % ( de pe n di n g o n t he u n derl yi n g tr ue 
d ose -res p o nse pr ofile), assu mi n g a 1 -si de d si g nifica nce le vel of 0. 0 5 a n d a 1 2 % o verall dr o p o ut rate i n t he 
d o u ble -bli n d p hase .
Efficac y A nal ys es
Efficac y a nal yses will be base d o n t he f ull a nal ysis set ( F A S) w hic h c o nsists of all s u bjects w h o were 
ra n d o ml y assi g ne d t o st u d y dr u g a nd recei ve d at least 1 d ose of st u d y dr u g.
Pri m ar y esti m a n d
T he pri mar y esti ma n d, t he mai n cli nical q ua ntit y of i nterest t o be esti mate d i n t he st u d y, is defi ne d b y t he 
f oll o wi n g 3 c o m p o ne nts:
P o p ul ati o n: a d ult a n d el derl y s u bjects wit h i ns o m nia dis or der
E n d p oi nt: c ha n ge fr o m baseli ne i n L P S as meas ure d b y P S G o n Ni g ht 1
Me as ure of I nter ve nti o n:
t he effect of t he i nitiall y ra n d o mize d treat me nt o n t he e n d p oi nt.
T he pri mar y efficac y e n d p oi nt, c ha n ge fr o m baseli ne i n L P S as meas ure d b y P S G o n Ni g ht 1, will be
a nal yze d usi n g a n a nal ysis of c o varia nce ( A N C O V A) m o del, wit h fact ors f or re gi o n ( U S/ E U a n d J apa n), 
treat me nt ( place b o a n d J NJ- 4 2 8 4 7 9 2 2 d ose gr o u ps), a n d a ge gr o u p (a d ult a n d el derl y) a n d baseli ne L P S 
as a c o nti n u o us c o variate. T he treat me nt effects will be esti mate d usi n g least s q uares mea ns. T he fi nal 
a nal ysis will use t he ge neralize d M C P -M o d a p pr oac h (a h y bri d met h o d ol o g y t hat c o m bi nes m ulti ple 
c o m paris o n pr oce d ures wit h m o deli n g tec h ni q ues), w hic h will be a p plie d t o war ds esti mates o btai ne d 
fr o m t he A N C O V A m o del t o esta blis h a d ose -res p o nse si g nal a n d t o deter mi ne d ose(s) t o be use d i n t he 
P hase 3 st u dies. T he ca n di date m o del set will i ncl u de f o ur m o del pr ofiles: “li near”, “e ma x”, “si g E ma x”, 
a n d “e x p o ne ntial”. M C P -M o d has bee n q ualifie d b y t he E ur o pea n M e dici nes A ge nc y.
T he ke y sec o n dar y e n d p oi nt (c ha n ge fr o m baseli ne i n W A S O o ver t he first 6 h o urs after i nitial slee p 
o nset as meas ure d b y P S G o n Ni g ht 1) will be a nal yze d usi n g t he sa me a p pr oac h as descri be d a b o ve f or 
t he pri mar y e n d p oi nt, i ncl u di n g usi n g t he ge neralize d M C P- M o d a p pr oac h.
F or t he pri mar y a n d ke y sec o n dar y e n d p oi nts (c ha n ge fr o m baseli ne i n L P S a n d W A S O o n Ni g ht 1), a 
sec o n dar y a nal ysis wit h a ge i ncl u de d as a c o nti n u o us c o variate i n t he m o del will als o be carrie d o ut. 
A d diti o nal c o variates m a y als o be i ncl u de d as se nsiti vit y a nal yses.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
2 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Z ol pi de m is i ncl u de d i n t he st u d y i n or der t o i n vesti gate p ote ntial differe nces bet wee n z ol pi de m a n d 
J NJ- 4 2 8 4 7 9 2 2. Z ol pi de m will n ot be i ncl u de d i n t he pri mar y A N C O V A m o del a n d t he ge neralize d 
M C P -M o d a nal ysis; h o we ver, a n a d diti o nal a nal ysis of c ha n ge fr o m baseli ne i n L P S a n d W A S O 
o n 
Ni g ht 1 will be perf or me d usi n g A N C O V A, i ncl u di n g z ol pi de m, t o c o m pare z ol pi de m wit h eac h 
J NJ-4 2 8 4 7 9 2 2 d ose a n d place b o usi n g t w o -si de d 9 5 % c o nfi de nce i nter vals f or t he differe nce b et wee n t he 
gr o u ps .
S u b gr o u p a nal yses b y a ge gr o u p (a d ult vs. el derl y) will be perf or me d o n t he pri mar y, ke y sec o n dar y, a n d 
sec o n dar y efficac y e n d p oi nts.
T he a nal yses f or t he ot her efficac y e n d p oi nts will be descri be d i n t he Statistical A nal ysis Pla n ( S A P ). F or 
all sec o n dar y efficac y e n d p oi nts, n o m ulti plicit y a dj ust me nt will be a p plie d a n d n o mi nal p- val ues will be 
prese nte d.
P har mac o ki netic A nal ysis
Plas ma c o nce ntrati o ns f or J NJ- 4 2 8 4 7 9 2 2, M 1 2, 
a n d M 1 6 
(as a p plica ble) will 
be a nal yze d a n d 
s u m marize d b y d ose , da y a n d ti me p oi nt, usi n g descri pti ve statistics. A p o p ulati o n base d P K a nal ysis 
usi n g P K data fr o m a selecti o n of P hase 1 a n d P hase 2 st u dies will be perf or me d at t he c o m pleti o n of t he 
st u d y. P ost -h oc Ba yesia n esti mates of P K para meters f or J NJ- 4 2 8 4 7 9 2 2 (a n d, if necessar y, f or acti ve
meta b olites M 1 2 a n d M 1 6) fr o m t he p o p ulati o n P K a nal ysis ma y be use d f or e x pl orat or y e x p os ure -
res p o nse a nal yses.
P o p ulati o n P K a nal ysis of plas ma c o nce ntrati o n -ti me data of J NJ- 4 2 8 4 7 9 2 2 will be perf or me d usi n g 
n o nli near mi xe d -effects m o deli n g. Data ma y be c o m bi ne d wit h t h ose of ot her selecte d st u dies t o s u p p ort a 
rele va nt str uct ural m o del. A vaila ble baseli ne s u bject c haracteristics ( de m o gra p hics, la b orat or y varia bles, 
ge n ot y pes, race, etc.) will be i ncl u de d i n t he m o del as necessar y. P ost -h oc Ba yesia n i n di vi d ual esti mates 
of P K para meters will 
be ge nerate d fr o m t he p o p ulati o n P K a nal ysis f or p ote ntial use i n 
e x p os ure-res p o nse a nal ysis. A s na ps h ot date f or P K sa m ples t o be a nal yze d will be defi ne d, if re q uire d. 
Sa m ples c ollecte d bef ore t his date will be a nal yze d f or J NJ -4 2 8 4 7 9 2 2, M 1 2, a n d M 1 6 (as a p plica ble) a n d 
i ncl u de d i n t he p o p ulati o n P K a nal ysis. Sa m ples c ollecte d after t he s na ps h ot date will be a nal yze d at a 
later date, a n d ma y be i ncl u de d i n a p o p ulati o n P K re-a nal ysis w he n t he y bec o me a vaila ble after data base 
l oc k. Details f or t he p o p ulati o n P K a n d e x p os ure -res p o nse a nal ysis will be descri be d i n a sta n dal o ne 
a nal ysis pla n a n d t he res ults of t he p o p ulati o n P K a n d e x p os ure-res p o nse a nal ysis will be prese nte d i n a 
se parate re p ort.
Data will be liste d f or all s u bjects wit h a vaila ble plas ma c o nce ntrati o ns per treat me nt gr o u p. S u bjects will 
be e xcl u de d fr o m t he P K a nal ysis if t heir data d o n ot all o w f or acc urate assess me nt of t he P K (e g, 
i nc o m plete a d mi nistrati o n of t he st u d y dr u g; missi n g 
i nf or mati o n of d osi n g a n d sa m pli n g ti mes; 
c o nce ntrati o n data n ot s ufficie nt f or P K para meter calc ulati o n).
All c o nce ntrati o ns bel o w t he l o west q ua ntifia ble c o nce ntrati o n or missi n g data will be la bele d as s uc h i n 
t he c o nce ntrati o n data base. A ll s u bjects a n d sa m ples e xcl u de d fr o m t he a nal ysis will be clearl y 
d oc u me nte d i n t he st u d y re p ort.
F or J NJ- 4 2 8 4 7 9 2 2 d ose gr o u p s, descri pti ve statistics will be calc ulate d f or all i n di vi d ual deri ve d P K 
para meters i ncl u di n g e x p os ure i nf or mati o n of J NJ - 4 2 8 4 7 92 2 a n d, if nee de d, M 1 2, a n d M 1 6.
Bi o mar ker A nal ysis
Bi o mar kers will be ta b ulate d b y treat me nt a n d s u m mar y statistics will be calc ulate d. P ost d ose c ha n ges i n 
bi o mar kers will be s u m marize d b y treat me nt gr o u p. Ass ociati o ns bet wee n baseli ne bi o mar ker le vels a nd 
cli nical e n d p oi nts ma y be e x pl ore d. D ue t o li mite d sa m pli n g, t he a nal yses will be e x pl orat or y.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
2 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
E x pl orat or y a nal yses ma y be perf or me d f or a d diti o nal bl o o d base d bi o mar kers, if a p plica ble.
Res ults ma y be prese nte d i n a se parate re p ort. 
Pla n ne d bi o mar ker a nal yses ma y be deferre d if e mer gi n g st u d y data s h o w n o li keli h o o d of pr o vi di n g 
usef ul scie ntific i nf or mati o n. All bi o mar ker data o btai ne d fr o m t his st u d y ma y als o be i ncl u de d i n a n 
o n g oi n g cr oss -st u d y a nal ysis t o i n vesti gate t he relati o ns hi p bet wee n cli ni cal dia g n oses, p he n ot y pes, a n d 
bi o mar kers.
P har mac o ki netic a n d P har mac o d y na mic A nal ysis
T he relati o ns hi p bet wee n t he e x p os ure of J NJ-4 2 8 4 7 9 2 2 a n d its acti ve meta b olites M 1 2 a n d M 1 6 (as 
nee de d) a n d cli nicall y rele va nt safet y a n d/ or efficac y meas ures ma y be e val uate d gra p hicall y. F or safet y, 
c ha n ge fr o m place b o i n c o m p uterize d batter y of c o g niti ve tests vs 4- h o ur plas ma c o nce ntrati o n o n 
Ni g ht 1 4 ma y be e x pl ore d. F or efficac y, c ha n ge i n L P S vs plas ma c o nce ntrati o n at rele va nt ti me p oi nts 
ma y als o be e x pl ore d. If nee de d, f urt her mat he matical m o deli n g t o c haracterize t he relati o ns hi p ma y be 
perf or me d.
Safet y A nal ysis
Safet y a nal yses will be base d o n t he safet y a nal ysis set, w hic h c o nsists of all s u bjects w h o are ra n d o ml y 
assi g ne d t o st u d y dr u g a n d recei ve at leas t 1 d ose of st u d y dr u g. T he safet y a nal ysis set is t he sa me as t he 
F A S.
A d verse e ve nts will be c o de d usi n g t he c urre nt versi o n of Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A). All treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) (ie, A Es wit h o nset d uri n g t he treat me nt 
p hase or t hat are a c o nse q ue nce of a pre -e xisti n g c o n diti o n t hat has w orse ne d si nce baseli ne) will be 
i ncl u de d i n t he a nal ysis. Seri o us a d verse e ve nts will be s u m marize d se paratel y b y treat me nt gr o u p. 
A d verse e ve nts of s pecial i nterest are cata ple x y, slee p paral ysis, c o m ple x slee p-relate d be ha vi ors 
( paras o m nias), a n d falls. S u m maries of s u bjects wit h A Es of s pecial i nterest ma y be prese nte d se paratel y.
La b orat or y data will be s u m marize d b y t y pe of la b orat or y test. Descri pti ve statistics will be calc ulate d f or 
eac h la b orat or y a nal yte at baseli ne a n d f or o bser ve d val ues a n d c ha n ges fr o m baseli ne at eac h sc he d ule d 
ti me p oi nt.
Descri pti ve statistics of vital si g n val ues f or o bser ve d val ues a n d c ha n ges fr o m baseli ne will be 
s u m marize d at eac h sc hed ule d ti me p oi nt b y treat me nt. T he perce nta ge of s u bjects wit h val ues be y o n d 
cli nicall y i m p orta nt li mits will be s u m marize d.
S u bjects wit h a b n or mal fi n di n gs i n p h ysical e xa mi nati o n a n d E C Gs will be liste d. Res ults fr o m t he 
C- S S R S, P R O MI S -A C A, c o g niti ve test batter y, K S S, a n d b o d y s wa y will be ta b ulate d at eac h sc he d ule d 
ti me p oi nt b y treat me nt.
Res ults fr o m t he P W C a n d t he B W S Q will be ta b ulate d b y treat me nt.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
2 6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
k.
T o be c o m plete d b y s u bjects ≥6 5 years of a ge.
l.
See T i me a n d E ve nts Sc he d ule - Part 2 . Sa m ples s h o ul d be c ollecte d u n der l o w fat diet c o n diti o ns (see Attac h me nt 1 ); n o c o ns u m pti o n of alc o h olic be vera ges f or at least 1 2 h o urs 
pri or t o sa m pli n g; stre n u o us e xercise s h o ul d be a v oi de d f or 2 4 h o urs pri or t o t he sa m pli n g.
m.
W he n sc he d ule d pr oce d ures c oi nci de, it is rec o m me n de d t hat t hese ta ke place i n t he f oll o wi n g or der: E C G -> vital si g ns ( bl o o d press ure, heart rate) -> c o g niti ve test batter y-> b o d y 
s wa y-> bl o o d dra ws f or P K .
n.
Ser u m or uri ne pre g na nc y tests ma y be perf or me d, as deter mi ne d necessar y b y t he i n vesti gat or, 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 s u bject’s partici pa ti o n i n 
t he st u d y. A F S H test ma y als o be perf or me d at i n vesti gat or j u d g me nt t o assist i n deter mi ni n g if a w o ma n is of n o n-c hil d beari n g p ote ntial.
o.
Date of last me nstr ual peri o d a n d a vera ge le n gt h of me nstr ual c ycle ( da ys) will be c ollecte d fr o m pre me n o pa usal w o me n still ha vi n g me ns es.
p.
Rec or de d o n Da y 8.
q.
O n t he ni g ht of f orce d a wa ke ni n g ( Ni g ht 1 4), n o P S G ac q uisiti o n will occ ur; t he e ve nt of f orce d a wa ke ni n g is se parate fr o m t he P S G c ollecti o n.
r.
T w o c o g niti ve test batter y a n d b o d y s wa y trai ni n g sessi o ns d uri n g Part 2 of t he scree ni n g p hase.
s.
T he pr oce d ures are rec o m me n de d t o be perf or me d i n t he f oll o wi n g or der: c o g niti ve test batter y - > b o d y s wa y.
t.
Wit hi n 1 h o ur after t he e n d of eac h scree ni n g P S G.
u.
T he P W C s h o ul d be a d mi nistere d o nl y b y t he cli nicia n o ver t he tele p h o ne.
v.
A tele p h o ne c o ntact will c ollect t he f oll o wi n g assess me nts: P W C, A E c ollecti o n, a n d c o nc o mita nt me dicati o n. T he B W S Q is a self-a d mi nistere d test, a n d n ot d o ne via tele p h o ne 
c o ntact. S u bjects will c o m plete t his test wit hi n t he first h o ur of a wa ke ni n g.
w.
Fr o m Da ys 1 t o 1 4. O nce dail y, 1 5 mi n utes pri or t o li g hts o ut o n ni g hts w he n P S G is rec or de d at t he st u d y site ( Ni g hts 1 a n d 1 3) a n d at n or mal be dti me w he n s u bjects will 
self-a d mi nister t he d ose of st u d y dr u g at h o me or o n n o n -P S G ni g hts at t he st u d y site ( Ni g hts 2 t o 1 2, Ni g ht 1 4).
x.
T he e xact date a n d ti me of t he last d ose of st u d y dr u g bef ore t he P K  sa m ple c ollecti o n will be rec or de d. T he e xact ti me of t he last meal i nta ke pri or t o d osi n g bef ore P K  sa m pli n g 
will als o be rec or de d.
y.
T o be c ollecte d fr o m all s u bjects. N ote: A n e xce pti o n t o t he o ver ni g ht P K sa m ples o n Ni g ht 1 4 ma y be ma de after disc ussi o n wit h t he s p o ns or’s me dical m o nit or. T he reas o n f or t he 
e xce pti o n m ust be d oc u me nte d i n t he s o urce d oc u me nts. If p ossi ble, t he 8 -h o ur 1 5 -mi n ute P K c ollecti o n s h o ul d be o btai ne d e ve n if perf or me d u p t o 1 2 h o urs after d osi n g. T he 
c orrect ti me of t he c ollecti o n s h o ul d be n ote d.
z.
T o be c ol lecte d fr o m all s u bjects. N ote: At st u d y sites i n Ja pa n, if t he Da y 1 5 m or ni n g bi o mar ker s a mple ca n n ot be o btai ne d at t he re queste d ti me p oi nt, it ca n be o btai ne d u p t o 1 2 
h o urs p ost -d ose if nee de d wit h t he c orrect ti me d oc u me nte d .
aa.
T he p har mac o ge n o mic sa m pl e s h o ul d be c ollecte d at t he s pecifie d ti me p oi nt, h o we ver if necessar y it ma y be c ollecte d at a later ti me p oi nt wit h o ut c o n stit uti n g a pr ot oc ol de viati o n. 
P har mac o ge n o mic bl o o d sa m ple will be c ollecte d o nl y fr o m s u bjects w h o ha ve c o nse nte d t o pr o vi de o pt i o nal D N A sa m ple f or p har mac o ge n o mic researc h ( w here l ocal re g ulati o ns 
per mit).
b b.
T he 2 ni g hts of scree ni n g P S G ac q uisiti o ns will be c o n d ucte d c o nsec uti vel y. T hese assess me nts s h o ul d be c o m plete d bet wee n Da y -1 4 a n d a p pr o xi matel y Da y -5 t o all o w f or 
a nal ysis of t he P S G data a n d esta blis h eli gi bilit y f or ra n d o mizati o n.
cc.
O ver ni g ht P S G rec or di n gs will start 1 5 mi n utes after d ose a d mi nistrati o n a n d c o nti n ue f or 8 h o urs.
d d.
S u bjects will rec or d t heir s u bjecti ve assess me nt of slee p (s S O L, s T S T, s W A S O, s-n N A W, s Q U A L, s FR E S H) wit hi n 1 h o ur after t he e n d of P S G o n ni g hts w he n P S G rec or di n g is 
perf or me d, or wit hi n 1 h o ur after a wa ke ni n g w he n at h o me/st u d y site usi n g t he C S D-M t hr o u g h o ut t he st u d y (ie, t he C S D-M s h o ul d be c o m plete d dail y fr o m start of scree ni n g 
t hr o u g h t he foll o w -u p visit). F or s u bjects usi n g h y p n otic dr u gs at t he ti me of si g ni n g t he I C F, a d mi nistrati o n of t he C S D-M s h o ul d start at least 5 d a y s after t heir last d ose of all 
h y p n otic dr u g s.
ee.
F or s u bjects usi n g h y p n otic dr u gs at t he ti me of si g ni n g t he I C F, a d mi nistrati o n of t he I SI s h o ul d occ ur at least 5 da ys afte r t heir last d ose of all h y p n otic dr u g s.
ff.
Yell o w s ha di n g i n t his ta ble re prese nts pr oce d ures t o be perf or me d w hile s u bjects are reside nt at t he st u d y site (ie, fr o m Da y 1 t hr o u g h n o o n of Da y 2 f or t h ose s u bjects n ot 
partici pati n g i n i nte nsi ve o ver ni g ht P K sa m pli n g [ or t hr o u g h n o o n of Da y 3 f or t h ose s u bjects partici pati n g i n i nte nsi ve o ver ni g ht P K sa m pli n g], a n d fr o m Da y 1 3 t hr o u g h n o o n of  
Da y 1 5).
g g.
O n Da y 1, a d missi o n assess me nts s uc h as fasti n g la bs s h o ul d b e c o m plete d a n d t he n a s u bject ma y lea ve t he st u d y ce nter a n d ret ur n at least 3- 4 h o urs pri or t o be dti me t o c o m plete 
pre d ose a n d P S G assess me nts.
h h.
P ostscree ni n g bl o o d sa m ples f or clinical la b orat or y a nal ysis s h o ul d be o btai ne d u n der fasti n g c o n diti o ns.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
2 8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
A B B R E VI A TI O N S
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A N C O V A
a nal ysis of c o varia nce
A S T
as partate a mi n otra nsferase
A U C
area u n der t he c o nce ntrati o n -ti me c ur ve
B D N F
brai n -deri ve d ne ur otr o p hic fact or
B W S Q
Be nz o diaze pi ne Wit h dra w al S y m pt o m Q uesti o n naire
B Z D
be nz o diaze pi ne
C GI -I
Cli nical Gl o bal I m pressi o n – I m pr o ve me nt
C GI - S
Cli nical Gl o bal I m pressi o n – Se verit y
C R F
case re p ort f or m(s)
C S D - M
C o nse ns us Slee p Diar y – M or ni n g A d mi nistrati o n
C- S S R S
C ol u m bia S uici de Se verit y Rati n g Scale
C Y P
c yt oc hr o me P 4 5 0
D N A
de o x yri b o n ucleic aci d
D O R A
d ual ore xi n ( ore xi n -1 a n d ore xi n -2) rece pt or a nta g o nist
D S M - 5
Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders ( 5 t h e diti o n)
E C G
electr ocar di o gra m
e D C
electr o nic data ca pt ure
E E G
electr oe nce p hal o gra p h
E U
E ur o pea n U ni o n
F A S
f ull a nal ysis set
F D A
F o o d a n d Dr u g A d mi nistrati o n
G A B A
ga m ma -a mi n o b ut yric aci d
G C P
G o o d Cli nical Practice
G L P
G o o d La b orat or y Practice
H b A 1c
he m o gl o bi n A 1c
H P A
h y p ot hala mic – pit uitar y – a dre nal
hs C R P
hi g h -se nsiti vit y C-reacti ve pr otei n
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I R B
I nstit uti o nal Re vie w B oar d
I SI
I ns o m nia Se verit y I n de x
I W R S
i nteracti ve we b res p o nse s yste m
K S S
Kar oli ns ka Slee pi ness Scale
L P S
late nc y t o persiste nt slee p
M C P -M o d
M ulti ple C o m paris o n Pr oce d ure -M o deli n g
M D D
maj or de pressi ve dis or der
n N A W
n u m ber of ni g htti me a wa ke ni n gs
n N A W/ hr
n u m ber of ni g htti me a wa ke ni n gs per h o ur
N O A E L
n o o bser ve d a d verse effect le vel
N R E M 
n o n- ra pi d e ye m o ve me nt
O X 2 R
ore xi n -2 rece pt or
P D
p har mac o d y na mic (s)
P GI -I
Patie nt Gl o bal I m pressi o n – I m pr o ve me nt
P GI - S
Patie nt Gl o bal I m pressi o n – Se verit y
PI
prescri bi n g i nf or mati o n
P K
p har mac o ki netic (s)
P L M
peri o dic le g m o ve me nt
P o C
Pr o of -of -C o nce pt
P Q C
Pr o d uct Q ualit y C o m plai nt
P R O MI S
Patie nt Re p orte d O utc o me Meas ure me nt I nf or mati o n S yste m
P R O MI S -A C A
Patie nt Re p orte d O utc o me Meas ure me nt I nf or mati o n S yste m – A p plie d C o g niti o n — A bilities
P R O MI S -S D
Patie nt Re p orte d O utc o me Meas ure me nt I nf or mati o n S yste m – Slee p Dist ur ba nce
P R O MI S -S RI
Patie nt Re p orte d O utc o me Meas ure me nt I nf or mati o n S yste m – Slee p Relate d I m pair me nt

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
2 9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
P S G
p ol ys o m n o gra p h y
P W C
P h y sicia n Wit h dra wal C hec klist
R E M
Ra pi d E ye M o ve me nt 
R L S
restless le g s yn dr o me
s-n N A W
s u bjecti ve n u m ber of ni g htti me a wa ke ni n gs
S A E
seri o us a d verse e ve nt
S A P
S tatistical A nal ysis P la n
S E
slee p effici e nc y
s F R E S H
s u bjecti ve refres he d feeli n g o n wa ki n g
S m P C
S u m mar y of Pr o d uct C haracteristics
s Q U A L
s u bjecti ve q ualit y of slee p
s S O L
self-re p orte d slee p o nset late nc y
s T S T
s u bjecti ve t otal slee p ti me
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
s W A S O
s u bjecti ve wa ke after slee p o nset
T E A E
treat me nt-e mer ge nt a d verse e ve nt
T S H
t h yr oi d-sti m ulati n g h or m o ne
T S Q M - 9
A b bre viate d Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n
T S T
t otal slee p ti me
U L N
u p per li mit of n or mal
U S
U nite d States
W A S O
wa ke after slee p o nset
W O C B P
w o me n of c hil d beari n g p ote ntial
W O N C B P
w o me n of n o n- c hil d beari n g p ote ntial
D E FI NI TI O N S O F T E R M S
A U C
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve
A U C ∞
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o i nfi nite ti me
A U C 0 -1 2 h
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m zer o t o 1 2 h o urs
C ma x
ma xi m u m dr u g c o nce ntrati o n
tma x
ti me t o ma xi m u m dr u g c o nce ntrati o n

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
3 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1.
I N T R O D U C TI O N
J NJ- 4 2 8 4 7 9 2 2 (selt ore xa nt) is a s h ort-acti n g, p ote nt a n d selecti ve a nta g o nist of t he h u ma n 
ore xi n - 2 rece pt or ( O X 2 R) t hat is bei n g de vel o pe d f or t he treat me nt of i ns o m nia a n d maj or 
de pre ssi ve dis or der ( M D D). Acti vati o n of ore xi n ne ur o ns c o ntri b utes t o t he mai nte na nce of 
wa kef ul ness; t heref ore, t he bl oc ka de of ore xi n rece pt ors, i n partic ular O X 2 R, is a n o vel 
p har mac ol o gic a p pr oac h f or t he treat me nt of i ns o m nia. Alt h o u g h i nc o nsiste ncies e xist i n t he 
scie ntific literat ure, t here is gr o wi n g e vi de nce t o s u g gest t hat selecti ve O X 2 R a nta g o nists ma y 
c o nfer certai n be nefits o ver d ual ore xi n ( ore xi n- 1 a n d ore xi n -2) rece pt or a nta g o nists ( D O R As), 
i ncl u di n g greater preser vati o n of p h y si ol o gic slee p architect ure a n d re d uce d lia bility f or 
cata ple x y. 7 ,1 0 ,1 6 ,1 7 ,1 8 ,5 1 ,7 0 Beca use
t he distri b uti o n of ore xi n ne ur o ns is m ore
discrete t ha n t he 
relati vely gl o bal distri b uti o n of t he ga m ma -a mi n o b ut yric aci d ( G A B A)-er gic s yste m i n t he brai n, 
it was h y p ot hesize d t hat t he ore xi n -tar gete d t hera pe utics w o ul d re d uce or eli mi nate u n desira ble 
h y p n otic a d verse effects, as " off-tar get" effects w o ul d be mi ni mize d. 7 4 ,7 9 J NJ- 4 2 8 4 7 9 2 2 ma y  be 
prefera ble f or treati n g patie nts wit h i ns o m nia dis or der w he n c o m pare d wit h t he be nz o diaze pi nes 
( B Z D) a n d n o n-B Z D G A B A m o d ulat ors s uc h as z ol pi de m, zale pl o n, z o picl o ne, a n d esz o picl o ne, 
t o get her k n o w n as t he “ Z-dr u gs”. J NJ-4 2 8 4 7 9 2 2 is e x pecte d t o de m o nstrate efficac y in i n d uci n g 
a n d mai ntai ni n g 
slee p, wit h o ut t he si de effects ass ociate d wit h ot her classes of se dati ve 
h y p n otics, s uc h as
m usc ular 
at o nia (res ulti n g i n bala nce iss ues), c o g niti ve deficits a n d 
a nter o gra de a m nesia, a n d de pe n de nce a n d t olera nce.
I ns o m nia as a s ym pt o m affects u p t o 5 0 % of t he ge neral p o p ulati o n , w hile i ns o m nia wit h 
si g nifica nt d a y ti me c o nse q ue nces is esti mate d t o affect 7 % t o 1 3 % of t he p o p ulati o n a n d is 
rec o g nize d as a maj or p u blic healt h iss ue.4 3 I n a po p ulati o n -base d st u d y acr oss E ur o pe, it was 
re p orte d t hat u p t o 3 7 % of i n di vi d uals re p orte d i ns o m nia s ym pt o ms wit h at least mil d d a y ti me 
i m pact.5 9 Alt h o u g h a lac k of u nif or mit y  in c lassif yi n g ins o m nia has c o ntri b ute d t o differe nces i n 
re p orti n g rates,1 9 it is wi del y a gree d t hat i ns o m nia is a pre vale nt c o m plai nt i n cli nical practice, 
w het her prese nti n g al o ne or as a c o m or bi dit y wit h a n ot her me dical or ps yc hiatric dis or der. Data 
fr o m l o n git u di nal st u dies s u g gest t hat, f or ma n y i n di vi d uals, i ns o m nia bec o mes a c hr o nic iss ue, 
affecti n g e ner g y, c o g niti ve f u ncti o ni n g, m o o d, a n d ge neral healt h; a p pr o xi matel y 7 0 % of pers o ns 
wit h i ns o m nia will c o nti n ue t o re p ort i ns o m nia a ye ar later, a n d a p pr o xi matel y 50 % re p ort 
i ns o m nia u p t o 3 ye ars later.5 2 ,5 4 ,5 5 St u dies c o nsiste ntl y sh o w a n i ncreasi n g pre vale nce of 
i ns o m nia wit h a ge, a n d a hi g her pre vale nce i n w o me n vers us me n. 3 8 ,4 0 ,4 1 ,4 2 ,5 6 ,6 0 T he Nati o nal 
Slee p F o u n dati o n "Slee p i n A merica P oll " base d o n 1, 0 0 0 i nter vie ws of w or ki n g A merica ns 
( mi ni m u m 3 0 h o urs/ wee k) , c o n d ucte d i n 2 0 0 7, i n dicate d t hat 4 4 % of t he res p o n de nts re p orte d
less t ha n 7 h o urs of slee p o n w or k da y s. O verall, 6 5 % of t hese res p o n de nts re p orte d slee p 
pr o ble ms f or a fe w ni g hts a wee k, w hereas 4 2 % s uffere d fr o m i ns o m nia e ver y ni g ht i n t he past 
m o nt h . As a direct c o nse que nce of i ns o m nia, d a y ti me slee pi ness was re p orte d t o i nterfere wit h a 
t hir d of res p o n de nts’ dail y  acti vities i ncl u di n g w or k, dri vi n g, a n d s ocial acti vities. 5 7
A gi n g is ass ociate d wit h a gra d ual decli ne i n slee p q ualit y, mar ke d b y  more fra g me nte d slee p 
wit h 
s h orter peri o ds of sl o w wa ve 
slee p, i ncreasi n g slee p late nc y, a n d re d uce d slee p 
efficie nc y.4 ,5 0
I ns o m nia is partic ularl y  co m m o n a m o n g ol der pers o ns, wit h 
t he re p orte d 
pre vale nce ra n gi n g fr o m 2 1 % t o m ore t ha n 4 0 % acr oss st u dies.1 3 ,3 6 I n cli nical practice, t here are 
se veral slee p c o m plai nts c haracteristic of i ns o m nia –
diffic ult y i nitiati n g slee p, diffic ult y 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
3 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
of a p pr o xi matel y 10 h o urs , i n c o ntrast t o J NJ-4 2 8 4 7 9 2 2 wit h a half -life of 2 t o 3 h o urs. T he 
s h orter P K pr ofile of J NJ - 4 2 8 4 7 9 2 2 is e x pecte d t o res ult i n a m ore fa v ora ble a d verse e ve nt (A E )
pr ofile c o m pare d t o s u v ore xa nt ( Secti o n 1. 1. 2 , Cli nical St u dies). N o selecti ve ore xi n a nta g o nists
are c urre ntl y a p pr o ve d f or t he treat me nt of i ns o m nia.
T he ore xi n ne ur o pe pti des ( ore xi n -A a n d ore xi n -B, als o k n o w n as h y p ocreti n -1 a n d h y p ocreti n -2) 
are pr o d uce d b y  a cl uster of ne ur o ns wit hi n t he lateral p osteri or h y p ot hala m us 1 6 a n d pr oject 
wi del y  thr o u g h o ut t he brai n . T he ore xi ns pla y  a maj or r ole i n t he re g ulati o n of slee p-wa ke 
states.2 8 Acti vati o n of ore xi n ne ur o ns c o ntri b utes t o t he mai nte na nce o f wa kef ul ness . L oss of 
h y p ot hala mic ore xi n ne ur o ns i n h u ma ns res ults i n narc ole ps y, a c o n diti o n c haracterize d b y  
e xcessi ve slee pi ness, h y p na g o gic hall uci nati o ns, a n d cata ple x y .8 6 Ore xi ns me diate t heir effect b y  
sti m ulati n g 2 cl osel y relate d G pr otei n -c o u ple d rece pt ors, ore xi n - 1 rece pt or a n d O X 2 R , l ocate d 
i n wa ke -acti ve m o n oa mi ner gic a n d c h oli ner gic s yste ms.6 3 ,7 2 It has bee n de m o nstrate d t hat t he 
ar o usal effect
of ore xi n -A 
de pe n d s
o n hista mi ner gic 
acti vati o n via t he O X 2 R 
i n t he 
t u ber o ma m millar y n ucle us .2 1 ,3 4
A P hase 2a Pr o of - of-C o nce pt ( P o C) st u d y (St u d y 4 2 8 4 7 9 2 2I S M 2 0 0 2) t o e val uate t he efficac y, 
safety, a n d t olera bilit y of t he 4 0- m g
d ose of J NJ-4 2 8 4 7 9 2 2, a d mi nistere d o ver 5 da y s vers us 
place b o ( 2-w a y  cr oss o ver desi g n) i n s u bjects wit h i ns o m nia wit h o ut ps y c hiatric c o m or bi dities 
s h o we d a statistically si g nifica nt a n d cli nicall y mea ni n gf ul effect o n slee p efficie nc y (S E ), L P S, 
a n d T S T , a n d a m o dest effect o n W A S O
c o m pare d t o place b o . T he effects of J NJ- 4 2 8 4 7 9 2 2 o n 
si m ulate d car dri vi n g were 
i n vesti gate d i n a s mall 3 -wa y  cr oss o ver e x pl orat or y st u d y 
( St u d y 4 2 8 4 7 9 2 2 E DI 1 0 1 1 ) i n h ealt h y a d ult s u bjects wit h o ut i ns o m nia. C o m pare d t o 1 0 -m g 
z ol pi de m, a d mi nistrati o n of 4 0- m g J NJ-4 2 8 4 7 9 2 2 le d t o a m ore tra nsie nt a n d lesser de gree of 
i m pair me nt i n o bjecti ve a n d s u bjecti ve dri vi n g perf or ma nce t hat lar gel y nor malize d at 6 h o urs 
after d ose a d mi nistrati o n. ( Refer t o Secti o n 1. 1. 2 , Cli nical St u dies f or a d diti o nal details).
T o date, J NJ- 4 2 8 4 7 9 2 2 has bee n s h o w n t o be well t olerate d i n a d ult a n d el derl y su bjects. T he 
ma xi mal dail y d ose le vels a d mi nistere d i n si n gle- a n d m ulti ple d ose st u dies are 8 0- m g  an d 
6 0- m g, 
res pecti vely.  
Preli mi nar y 
safet y 
res ults 
fr o m 
a n 
o n g oi n g 
st u d y 
(St u d y 4 2 8 4 7 9 2 2 E DI 1 0 1 4 ) i n el derl y healt h y s u bject c o h orts s h o w t hat si n gle e ve ni n g d osi n g of 
J NJ-4 2 8 4 7 9 2 2 1 0 m g a n d 2 0 m g d oses are well t olerate d.
F or t he m ost c o m pre he nsi ve n o ncli nical a n d cli nical i nf or mati o n re gar di n g J NJ- 4 2 8 4 7 9 2 2, refer 
t o t he latest versi o n of t he I n vesti gat or's Br oc h ure f or J NJ-4 2 8 4 7 9 2 2 .3 5
C CI

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
3 3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
T he ter m "s p o ns or" use d t hr o u g h o ut t his d oc u me nt refers t o t he e ntities liste d i n t he C o ntact 
I nf or mati o n pa ge(s), w hic h will be pr o vi de d as a se parate d oc u me nt.
1. 1.
B a c k gr o u n d
1. 1. 1.
N o n cli ni c al St u di e s
N o ncli nical P har mac ol o g y
Safet y  P har mac ol o g y
P har mac o ki netics a n d Pr o d uct Meta b olis m i n A ni mals
C CI
C CI
C CI

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
3 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
T o xic ol o g y
C CI
C CI

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
3 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1. 1. 2.
Cli ni c al St u di e s
T o date, cli nical c o n d uct has bee n c o m plete d i n 1 1 P hase 1 cli nical st u dies a n d 1 P hase 2 st u d y
wit h oral s us pe nsi o n a n d s oli d d osa ge f or m ulati o ns of J NJ- 4 2 8 4 7 9 2 2. A t otal of 2 3 9 healt h y 
C CI

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
3 6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
male a n d fe male s u bjects, 6 8 male a n d fe male s u bjects wit h M D D , a n d 2 8 male a n d fe male 
s u bjects wit h
i ns o m nia partici pate d i n t hese st u dies, of w h o m 2 7 1 s u bjects recei ve d at least 
1 d ose 
of 
J NJ-4 2 8 4 7 9 2 2 
(Ta ble 1 ). I n a d diti o n, 
a n 
o pe n -la bel si n gle 
d os e 
st u d y
( St u d y 4 2 8 4 7 9 2 2 E DI 1 0 1 4) i n healt h y  ad ult a n d el derl y su bjects t o assess t he effects of a ge a n d 
se x o n t he P K of J NJ-4 2 8 4 7 9 2 2 is o n g oi n g.
T a ble 1:
List of C o m plete d St u dies
St u d y N u m ber
Brief O bjecti ve
F or m ul ati o n/ 
J N J -4 2 8 4 7 9 2 2 D ose 
( D ose ti mi n g)
P o p ul ati o n
T ot al N o. of 
S u bjects 
( E nr olle d/ 
C o m plete d/
D ose d wit h 
J N J -4 2 8 4 7 9 2 2)
P h ase 1
4 2 8 4 7 9 2 2 E DI 1 0 0 1
Safet y, t olera bilit y, a n d 
p har mac o ki netics ( P K ).
Oral S us pe nsi o n/ 1 0, 2 0, 
4 0, a n d 8 0 m g ( mor ni n g, 
faste d), 2 0 m g ( m or ni n g, 
fe d), a n d 20 m g (e ve ni n g, 
at least 4 h o urs after 
di n ner) , si n gle d ose
Healt h y male s u bjects
5 7/ 5 7/ 3 8
4 2 8 4 7 9 2 2 E DI 1 0 0 2
Effect of J NJ -4 2 8 4 7 9 2 2 o n 
p ol ys o m n o gra p h y ( P S G) 
meas ures a n d de pressi ve 
s y m pt o ms.
Oral s us pe nsi o n/ 1 0, 2 0 or 
4 0 m g ( be dti me, 4 t o 
5 h o urs after di n ner) , 
si n gle d ose
S u bjects wit h M D D 
wit h i ns o m nia w h o are 
sta bl y treate d wit h 
a nti de pressa nts
2 0/ 1 8/ 2 0
4 2 8 4 7 9 2 2 E DI 1 0 0 3
Safet y, t olera bilit y, P K, a n d 
p har mac o d y na mics ( P D)
Oral s us pe nsi o n/ 5, 1 0, 2 0, 
4 0, a n d 6 0 m g ( m or ni n g, 
1 h o ur after t he start of a 
li g ht brea kfast), multi -
asce n di n g d ose f or 1 0 da ys
Healt h y s u bjects
4 0/ 3 9/ 3 0
4 2 8 4 7 9 2 2 E DI 1 0 0 4
Bi oa vaila bilit y, f o o d effect, 
safet y a n d t olera bilit y.
Oral s us pe nsi o n vs 
ta blet/ 2 0 m g ( m or ni n g, 
faste d), si n gle d ose
Healt h y male s u bjects
1 8/ 1 7/ 1 8
4 2 8 4 7 9 2 2 E DI 1 0 0 5
Effect of itrac o naz ole o n 
P K, safet y a n d t olera bilit y 
of J NJ-4 2 8 4 7 9 2 2.
S us pe nsi o n/ 5 m g 
( m or ni n g, faste d), si n gle 
d ose
Healt h y male s u bjects
1 6/ 1 6/ 1 6
4 2 8 4 7 9 2 2 E DI 1 0 0 6 
Effect of ra be praz ole o n P K, 
safet y a n d t olera bilit y of 
J NJ-4 2 8 4 7 9 2 2.
Ta bl et/ 2 0 m g ( m or ni n g, 
faste d), si n gle d ose
Healt h y male s u bjects
1 6/ 1 6/ 1 6
4 2 8 4 7 9 2 2 E DI 1 0 0 9
Effect of rifa m pi n o n P K, 
safet y a n d t olera bilit y of 
J NJ-4 2 8 4 7 9 2 2.
Ta blet/ 4 0 m g ( m or ni n g, 
faste d), si n gle d ose
Healt h y s u bjects
1 4/ 1 4/ 1 4
4 2 8 4 7 9 2 2 E DI 1 0 1 0
Effect of J NJ -4 2 8 4 7 9 2 2 o n 
P K, safet y, a n d t olera bilit y 
of mi daz ola m a n d warfari n; 
a n d P D of warfari n.
Ta blet/ 2 0 m g ( m or ni n g, 
faste d), u p t o 9 da ys
Healt h y s u bjects
1 8/ 1 7/ 1 7
4 2 8 4 7 9 2 2 E DI 1 0 1 1
D urati o n of effects of 
J NJ-4 2 8 4 7 9 2 2, z ol pi de m, 
a n d place b o o n si m ul ate d 
car dri vi n g a n d c o g niti ve 
perf or ma nce.
Ta blet/ 4 0 m g ( be dti me, 
4 h o urs after a sta n dar d 
di n ner) , si n gle d ose
Healt h y s u bjects
3 6/ 3 5/ 3 5
4 2 8 4 7 9 2 2I S M 1 0 0 2
Safet y, t olera bilit y a n d P K 
of J NJ -4 2 8 4 7 9 2 2 i n healt h y 
Ja pa nese su bjects .
Ta blet/ 5, 2 0 or 4 0 m g 
( m orni n g, faste d), si n gle 
asce n di n g d ose
Healt h y Ja pa nese male 
s u bjects
2 4/ 2 4/ 1 8
4 2 8 4 7 9 2 2 M D D 1 0 0 1
Safet y, efficac y a n d 
bi o mar ker st u d y wit h 
J NJ-4 2 8 4 7 9 2 2.
Ta blet/ 2 0 m g ( be dti me, 
3 t o 5 h o urs after di n ner) , 
u p t o 2 8 da ys
S u bjects wit h Maj or 
De pressi ve Dis or der
4 8/ 4 7/ 2 2
P h ase 2
4 2 8 4 7 9 2 2I S M 2 0 0 2
Efficac y, safet y a n d 
t olera bilit y of 
J NJ-4 2 8 4 7 9 2 2.
Ta blet/ 4 0 m g ( be dti me,
3 t o 5 h o urs after di n ner) 
f or 5 da ys
S u bjects wit h i ns o m nia 
dis or der wit h o ut 
ps yc hiatric c o m or bi dit y
2 8/ 2 7/ 2 7

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
3 7
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
P har mac o ki netics ( P K)
C CI

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
3 8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
P har mac o d y na mics ( P D)
C CI
C CI

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
3 9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
C CI

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
4 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Safet y  a n d T olera bilit y
C CI
C CI

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
4 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1. 2.
C o m p ar at or Dr u g
C CI
C CI

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
4 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1. 3.
O v er all R ati o n al e f or t h e St u d y
I ns o m nia as a s ym pt o m affects u p t o 5 0 % of t he ge neral p o p ulati o n, w hile i ns o mnia wit h 
si g nifica nt d a y ti me c o nse q ue nces is esti mate d t o affect 7 % t o 1 3 % of t he p o p ulati o n a n d is 
rec o g nize d as a maj or p u blic healt h iss ue.4 3 Alt h o u g h a lac k of u nif or mit y  in classif yi n g 
i ns o m nia has c o ntri b ute d t o differe nces i n re p orti n g rates,1 9 it is wi del y agree d t hat i ns o m nia is a 
pre vale nt c o m plai nt i n cli nical practice, w het her prese nti n g al o ne or as a c o m or bi dit y wit h 
a n ot her me dical or ps y c hiatric dis or der. Data fr o m l o n git u di nal st u dies s u g gest t hat, f or ma n y 
i n di vi d uals, i ns o m nia bec o mes a c hr o nic iss ue, affecti n g e ner g y, c o g niti ve f u ncti o ni n g, m o o d, 
a n d ge neral healt h; a p pr o xi matel y 70 % of pers o ns wit h i ns o m nia will c o nti n ue t o re p ort 
i ns o m nia a ye ar later, a n d a p pr o xi matel y 50 % re p ort i ns o m nia u p t o 3 ye ars later.5 2 ,5 4 ,5 5 St u dies 
c o nsiste ntl y sh o w a n i ncreasi n g pre vale nce of i ns o m nia wit h a ge, a n d a hi g her pre vale nce i n 
w o me n vers us me n. 3 8 ,4 0 ,4 1 ,4 2 ,5 6 ,6 0
J NJ- 4 2 8 4 7 9 2 2 is a p ote nt a n d selecti ve a nta g o nist of t he h u ma n O X 2 R t hat is bei n g de vel o pe d 
f or t he treat me nt o f i ns o m nia a n d M D D. I n rats, J NJ- 4 2 8 4 7 9 2 2 q uic kl y  an d re versi bl y bi n ds t o 
O X 2 R i n t he brai n after oral a d mi nistrati o n a n d re d uces slee p late nc y an d i ncreases t otal slee p 
d urati o n w hile ha vi n g mi ni mal, n o n- si g nifica nt effects o n R E M slee p. 
T o date, t he st u dies c o n d ucte d i n s u p p ort of t he de vel o p me nt pr o gra m ha ve f oc use d o n detecti o n 
of a s o m n ole nce si g nal a n d o n safet y a n d t olera bilit y in healt h y  su bjects a n d i n s u bjects wit h 
M D D a n d/ or i ns o m nia. I n hu ma n s u bjects, J NJ- 4 2 8 4 7 9 2 2 i n d uce d d ose -relate d s o m n ole nce i n 
healt h y  su bjects after m or ni n g a d mi nistrati o n. W he n a d mi nistere d at be dti me i n a 1- h o ur p hase 
a d va nce m o del i n s u bjects wit h M D D wit h c o m or bi d i ns o m nia, si n gle d oses of 1 0 t o 4 0 m g  
decrease d L P S a n d i ncrease d T S T. I n the P o C m ulti ple d ose st u d y in a d ult s u bjects wit h 
i ns o m nia dis or der wit h o ut ps y c hiatric c o m or bi dit y (St u d y  42 8 4 7 9 2 2I S M 2 0 0 2), all s u bjects 
recei ve d 4 0 m g at be dti me f or 5 d a y s. O verall, o bjecti ve ( per P S G) a n d s u bjecti ve slee p 
para meters were b ot h i m pr o ve d b y treat me nt with J N J-4 2 8 4 7 9 2 2 a n d c orrelate d well. T he res ults 
s h o we d a m ore pr o n o u nce d effect o n S E, L P S, a n d T S T wit h a m o dest effect o n W A S O, 
c o nsiste nt wit h t he res ults see n i n St u d y 4 2 8 4 7 9 2 2 E DI 1 0 0 2 f or t he 2 0- m g d ose. T hese data ha ve 
c o nsiste ntl y sh o w n a s o m n ole nce-i n d uci n g effect of J NJ- 4 2 8 4 7 9 2 2, c o nsiste nt wit h a h y p n otic 
pr ofile.
T o date, J NJ- 4 2 8 4 7 9 2 2 has bee n s h o w n t o be well t olerate d i n a d ult a n d el derl y su bjects. T he 
ma xi mal dail y d ose le vels a d mi nistere d i n si n gle- a n d m ulti ple -d ose st u dies are 8 0 m g  an d 
6 0 m g, res pecti vely. Preli mi nar y  safet y res ults fr o m St u d y  42 8 4 7 9 2 2 E DI 1 0 1 4 i n el derl y healt h y 
s u bject c o h orts s h o w t hat si n gle e ve ni n g d osi n g of J NJ- 4 2 8 4 7 9 2 2 1 0 m g a n d 2 0 m g  doses are 
well t olerate d.
As t he ne xt ste p i n t he de vel o p me nt of J NJ-4 2 8 4 7 9 2 2, t his st u d y will f oc us o n deter mi ni n g t he 
cli nicall y effecti ve d ose ra n ge a n d st u d yi n g safet y a n d t olera bilit y of a ra n ge of d oses.
I n this st u d y, t he d ose -res p o nse pr ofile will be c haracterize d i n a d ult a n d el derl y s u bjects wit h 
i ns o m nia dis or der. A d diti o nall y , J NJ- 4 2 8 4 7 9 2 2 will be e val uate d f or safety a n d t olera bilit y 
acr oss a ra n ge of d oses. T he ai m of t his st u d y is t o i n vesti gate t he effects of 3 d oses of 
J NJ- 4 2 8 4 7 9 2 2 ( 5, 1 0, a n d 2 0 m g ), c o m pare d t o place b o, o n slee p o nset a n d mai nte na nce a n d t o

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
4 3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
f urt her d oc u me nt t he safet y an d t olera bilit y of J NJ- 4 2 8 4 7 9 2 2 u p o n m ulti ple ( 1 4 d a y s) d ose 
a d mi nistrati o n i n s u bjects wit h i ns o m nia dis or der. 
I n a dditi o n, effects of J NJ- 4 2 8 4 7 9 2 2 o n slee p para meters ( o bjecti ve a n d s u bjecti ve), resi d ual 
effects, a n d c o g niti o n will be c o m pare d t o t h ose effects of z ol pi de m, t o i n vesti gate p ote ntial
differe nces bet wee n t he c o m p o u n ds .
T he res ults of t his st u d y  will be use d t o i nf or m t he P hase 3 de vel o p me nt pla n.
1. 4.
O v er all Ri s k a n d B e n efit A s s e s s m e nt
As f urt her descri be d i n Secti o n 1 , I ntr o d ucti o n, a n d t he rati o nale f or t his st u d y (Secti o n 1. 3 , 
O verall Rati o nale f or t he St u d y ), i ns o m nia is a c o m m o n s ym pt o m wit h si g nifica nt d a y ti me 
c o nse q ue nces a n d is rec o g nize d as a maj or p u blic healt h iss ue. F or ma n y i n di vi d uals, i ns o m nia 
bec o mes a c hr o nic iss ue, affecti n g e ner g y , c o g niti ve f u ncti o n, m o o d, a n d ge neral healt h. 
T he c urre ntl y availa ble data (see Secti o n 1. 1. 2 , Cli nical St u dies, a n d t he J NJ- 4 2 8 4 7 9 2 2 
I n vesti gat or’s Br oc h ure 3 5) s u p p ort t his cli nical st u d y that i n vesti gates t he efficac y an d safet y of 
J NJ-4 2 8 4 7 9 2 2 i n a d ult a n d el derl y s u bjects wit h i ns o m nia.
Base d o n t he res ults of i nitial P hase 1 a n d P hase 2a P S G stu dies, i m pr o ve me nts i n i ns o m nia 
s ym pt o ms ha ve bee n o bser ve d f oll o wi n g si n gle e ve ni n g d oses of J NJ-4 2 8 4 7 9 2 2 ( 1 0, 2 0, a n d 
4 0 m g) i n s u bjects wit h M D D a n d i ns o m nia, a n d after m ulti ple e ve ni n g d oses of J NJ- 4 2 8 4 7 9 2 2
( 4 0 m g f or 5 d a y s) i n s u bjects wit h i ns o m nia wit h o ut ps y c hiatric c o m or bi dit y. T he effect of 
J NJ-4 2 8 4 7 9 2 2 o n i ns o m nia s y m pt o ms was cli nicall y  relev a nt as earl y as Da y  1 of e x p os ure, wit h 
s u bjects s h o wi n g a n d i m pr o ve me nt i n b ot h o bjecti ve a n d s u bjecti ve slee p para meters i n t he 
m ulti ple -d ose st u d y . 
A d d iti o nall y, t he safety a n d t olera bilit y data s o far acc u m ulate d f or J NJ- 4 2 8 4 7 9 2 2 i n healt h y 
s u bjects, s u bjects wit h i ns o m nia dis or der, a n d s u bjects wit h M D D a n d i ns o m nia were ge nerall y  
acce pta ble base d o n a t h or o u g h re vie w of t he safet y  i nf or mati o n fr o m c o mplete d cli nical st u dies. 
N o deat h or S A Es were re p orte d after s u bjects recei ve d J NJ-4 2 8 4 7 9 2 2. T he m ost c o m m o nl y 
re p orte d T E A Es were s o m n ole nce, hea dac he, a n d dizzi ness wit h m ost T E A Es bei n g mil d or 
m o derate i n i nte nsit y. A d verse dr u g reacti o ns attri b ute d t o J NJ-4 2 8 4 7 9 2 2 were slee p paral ys is,
s o m n ole nce, a n d a b n or mal drea ms. Fe w s u bjects re p orte d t hese e ve nts at d oses pla n ne d f or t his 
C CI

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
4 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
st u d y an d all were self-li mite d a n d mil d or m o derate i n i nte nsit y. Base d o n t he s h ort half -life of 
J NJ- 4 2 8 4 7 9 2 2, n o acc u m ulati o n of st u d y dr u g is e x pecte d. ( Refer t o Secti o n 1. 1. 2 , Cli nical 
St u dies, a n d t he J NJ -4 2 8 4 7 9 2 2 I n vesti gat or’s Br oc h ure 3 5 f or a d diti o nal details). 
T o e ns ure safe use of t he st u d y dr u g, besi des r o uti ne safet y m o nit ori n g a n d s u bject ma na ge me nt, 
t his pr ot oc ol als o i ncl u des s pecific ris k miti gati o n strate gies as f oll o ws: n o f urt her e nr oll me nt of 
w o me n of c hil d beari n g p ote ntial ( W O C B P) , si nce a fe male rat fertilit y st u d y s u g geste d t hat 
J NJ- 4 2 8 4 7 9 2 2 re d uce d fe male rat fertilit y rates at all d oses st u die d; restricti o ns o n dri vi n g, 
o perati n g mac hi ner y , or e n ga gi n g i n hazar d o us acti vit y whe n s u bjects ha ve ha d less t ha n 6 h o urs 
slee p t he ni g ht bef ore ( Secti o n 4. 3 , Pro hi biti o n a n d Restricti o ns); o ver ni g ht i n -h o use o bser vati o n 
of s u bjects at st u d y sites after t he first d ose a d mi nistrati o n of st u d y dr u g (see T i me a n d E ve nts 
Sc he d ule - Part 1 ); pa y i n g s pecial atte nti o n t o cli nicall y si g nifica nt A Es t hat are k n o w n t o ha ve 
bee n 
re p orte d wit h
dr u gs 
of 
t he sa me p har mac ol o gical 
class ( Secti o n 9. 6 , Safet y 
E val uati o ns/ A d verse E ve nts of S pecial I nterest); a n d re d uci n g s uici dalit y ris k i n here nt i n t he 
u n derl y i n g de pressi o n b y  excl u di n g hi g h ris k s u bjects ( Secti o n 4. 2 , E xcl usi o n Criteria) a n d 
perf or mi n g C -S S R S at e ver y  site visit ( Secti o n 9. 6 , Safet y E val uati o ns/ C-S S R S). 
T he i nf or mati o n o btai ne d t o date re gar di n g J NJ- 4 2 8 4 7 9 2 2 s u g gests t hat t he p ote ntial be nefits t o 
patie nts wit h i ns o m nia i n f ulfilli n g a n u n met me dical nee d o ut wei g h t he i de ntifie d (ie, a d verse 
dr u g reacti o ns) a n d p ote ntial ris ks (see A d verse E ve nts of S pecial I nterest i n Secti o n 9. 6 , Safet y 
E val uati o ns) at t he d oses selecte d f or f urt her i n vesti gati o n.
2.
O B J E C TI V E , E N D P OI N T S, A N D H Y P O T H E SI S
2. 1.
O bj e cti v e s a n d E n d p oi nt s
O bjecti ves
E n d p oi nts
Pri m ar y

T o assess t he d ose -res p o nse of 3 d oses of 
J NJ-4 2 8 4 7 9 2 2 ( 5, 1 0, a n d 2 0 m g) c o m pare d t o 
place b o o n a n o bjecti ve meas ure of slee p o nset 
i n s u bjects wit h i ns o m nia dis or der.

C ha n ge fr o m baseli ne i n L P S as meas ure d b y 
P S G o n Ni g ht 1
Ke y Sec o n d ar y

T o assess t he d ose -res p o nse of
3 d oses of 
J NJ- 42 8 4 7 9 2 2 ( 5, 1 0, a n d 2 0 m g) c o m pare d t o 
place b o 
o n 
a n 
o bj ecti ve 
meas ure 
of 
mai nte na nce 
of 
slee p 
i n s u bjects 
wit h 
i ns o m nia dis or der.

C ha n ge fr o m baseli ne i n W A S O o ver t he first 
6 h o urs as meas ure d b y P S G o n Ni g ht 1
Sec o n d ar y
Effic acy

T o 
assess 
t he effect 
of 
J NJ-4 2 8 4 7 9 2 2 
c o m pare d 
wit h 
place b o 
i n 
i m pr o vi n g 
a d diti o nal o bjecti ve slee p para meters
C ha n ge fr o m baseli ne i n P S G para meters 
i ncl u di n g:

L P S o n Ni g ht 1 3

W A S O o ver t he first 6 h o urs o n Ni g ht 1 3

T S T ( o ver 6 a n d 8 h o urs) o n Ni g hts 1 a n d 1 3 

S E o n Ni g hts 1 a n d 1 3

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
4 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
O bjecti ves
E n d p oi nts

ot her 
sec o n dar y 
P S G 
slee p 
para meters 
( detaile d i n Secti o n 9. 2. 1 ) o n Ni g hts 1 a n d 1 3

T o 
assess 
t he effect 
of 
J NJ-4 2 8 4 7 9 2 2 
c o m pare d 
wit h 
z ol pi de m 
i n 
i m pr o vi n g 
o bjecti ve slee p para meters
C ha n ge fr o m baseli ne i n P S G para meters o n 
Ni g hts 1 a n d 1 3 i ncl u di n g:

L P S

W A S O o ver t he first 6 h o urs

T S T ( o ver 6 a n d 8 h o urs) 

S E 

ot her 
sec o n dar y 
P S G 
slee p 
para meters 
( detaile d i n Secti o n 9. 2. 1 )

T o 
assess 
t he effect of 
J NJ-4 2 8 4 7 9 2 2 
c o m pare d wit h 
z ol pi de m a n d place b o o n 
self-re p orte d meas ures of slee p
Patie nt- re p orte d meas ures i ncl u di n g:

C ha n ge 
fr o m baseli ne i n s u bjecti ve slee p 
para meters as meas ure d 
b y t he C o nse ns us 
Slee p 
Diar y
–
M or ni n g 
A d mi nistrati o n 
( C S D-M) ,1 1 i n t he m or ni n g o n Da ys 2 a n d 1 4

C ha n ge fr o m baseli ne i n slee p dist ur ba nce a n d 
i m pair me nt as meas ure d 
b y t he Nati o nal 
I nstit utes of Healt h Patie nt Re p orte d O utc o me 
Meas ure me nt I nf or mati o n S yste m ( P R O MI S) 
s h ort 
f or m 
8a 
f or 
Slee p 
Dist ur ba nce 
( P R O MI S-S D) a n d P R O MI S s h ort f or m 8a f or 
Slee p Relate d I m pair me nt ( P R O MI S-S RI ) o n 
Da ys 8 a n d 1 4

C ha n ge fr o m baseli ne i n s u bject's assess me nt 
of i ns o m nia se verit y usi n g t he Patie nt Gl o bal 
I m pressi o n
–
Se verit y ( P GI-S) scale a n d 
s u bject's 
assess me nt 
of 
i m pr o ve me nt i n 
i ns o m nia usi n g t he Patie nt Gl o bal I m pressi o n
– I m pr o ve me nt ( P GI -I) scale o n Da y 1 4.

T o 
assess 
t he effect 
of 
J NJ-4 2 8 4 7 9 2 2 
c o m pare d wit h 
z ol pi de m a n d pla ce b o i n 
i m pr o vi n g:
–
Res p o nse 
a n d re missi o n of i ns o m nia 
s y m pt o ms

Pr o p orti o n of res p o n ders, defi ne d as a ≥5 0 % 
re d ucti o n fr o m baseli ne i n t otal sc ore o n t he 
I ns o m nia Se verit y I n de x (I SI) o n Da y 1 4

Pr o p orti o n 
of s u bjects wit h 
re missi o n of 
i ns o m nia s y m pt o ms, def i ne d as a t otal sc ore 
≤1 0 o n t he I SI o n Da y 1 4
–
Cli nical 
se verit y a n d i m pr o ve me nt of 
i ns o m nia s y m pt o ms

C ha n ge fr o m baseli ne i n cli nicia n's assess me nt 
of i ns o m nia se verit y usi n g t he Cli nical Gl o bal 
I m pressi o n
–
Se verit y 
( C GI-S) 
a n d 
i m pr o ve me nt i n i ns o m nia u si n g t he Cli nical 
Gl o bal I m pressi o n – I m pr o ve me nt ( C GI-I) o n 
Da y 1 4

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
4 6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
O bjecti ves
E n d p oi nts
S afety

T o 
assess t he safet y a n d t olera bilit y of 
J NJ- 4 2 8 4 7 9 2 2 c o m pare d wit h z ol pi de m a n d 
place b o i n s u bjects wit h i ns o m nia dis or der
Safet y assess me nts i ncl u di n g:

A d verse e ve nts ( A Es) 

Pr o p orti o n of all S A Es a nd e ve nts of s pecial 
i nterest (eg, falls, paras o m nias)

Vital si g ns, p h ysical e xa mi nati o ns, E C G, a n d 
la b orat or y para meters

C- S S R S

Resi d ual effects as meas ure d b y:
–
T he prese nce of ne xt da y s u bjecti ve 
resi d ual effects as meas ure d 
b y t he 
Kar oli ns ka 
Slee pi ness Scale ( K S S) o n 
Da ys 2 a n d 1 4 
–
P ost ural 
sta bilit y 
( b o d y 
s wa y) 
as 
meas ure d wit h a n ata xia meter o n Da ys 2 
a n d 1 4 i n t he m or ni n g a n d o n Da y 1 5 at 
4- h o urs p ost Ni g ht 1 4 d ose ( mi d dle of t he 
ni g ht a wa ke ni n g)

T o 
o bjecti vel y assess
t he effect of J NJ-
4 2 8 4 7 9 2 2 
c o m pare d 
wit h 
z ol pi de m 
a n d 
place b o o n c o g niti ve d o mai ns as meas ure d
i n
t he m or ni n g after d osi n g as well as d uri n g 
mi d dle of t he ni g ht a wa ke ni n g

C ha n ge i n c o g niti o n c o m pare d t o pre -d ose 
assess me nt o n o bjecti ve c o g niti ve assess me nt 
as me as ure d b y a c o m p uterize d batter y of 
c o g niti ve tests i n t he m or ni n g o n Da ys 2 a n d 
1 4 

C o g niti ve perf or ma nce o n Da y
1 5 at 4- h o urs 
p ost Ni g ht 
1 4 d ose ( mi d dle of t he ni g ht 
a wa ke ni n g) as meas ure d b y a c o m p uteri ze d 
batter y of c o g niti ve tests 

T o e val uate p ote nt ial wit h dra wal effects after 
c o nti n u o us ni g htl y d osi n g wit h J NJ-4 2 8 4 7 9 2 2, 
z ol pi de m, or place b o

C ha n ge i n su bjecti ve slee p para meters fr o m 
Da y 1 4 as c o m pare d t o Da y 1 7 as meas ure d b y 
t he C S D- M

C ha n ge i n P h ysicia n Wit h dra wal 
C hec klist 
( P W C) fr o m Da y 1 4 t o Da y 1 7

T he 
Be nz o diaze pi ne 
Wit h dra wal 
S y m pt o m 
Q uesti o n naire ( B W S Q) f or self-assess me nt of 
wit h dra wal s y m pt o ms o n Da y 1 7
P h ar m ac o ki netic O bjecti ves

T o assess t he e x p os ure of J NJ- 4 2 8 4 7 9 2 2 a n d acti ve meta b olites M 1 2 a n d M 1 6, i n s u bjects 
wit h i ns o m nia, a n d t o e x pl ore t he effects of c o variates o n s uc h e x p os ure

T o c haracterize t he e x p os ure -res p o nse relati o ns hi p of J NJ-4 2 8 4 7 9 2 2 wit h 
res pect t o 
meas ures of efficac y  a n d/ or safety

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
4 7
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8

F or efficac y: L P S a n d W A S O o ver t he first 6 h o urs b y  PS G o n Ni g ht 1 vs meas ures of 
J NJ-4 2 8 4 7 9 2 2 e x p os ure

F or safety:  Co g niti ve perf or ma nce o n Da y  15 at 4 h o urs p ost Ni g ht 1 4 d ose ( mi d dle of 
t he ni g ht a wa ke ni n g) vs meas ures of J NJ-4 2 8 4 7 9 2 2 e x p os ure
E x pl or at or y O bjecti ves

T o e x pl ore t he effect of J NJ- 4 2 8 4 7 9 2 2, c o m pare d wit h z ol pi de m a n d place b o, o n c o g niti ve 
d o mai ns, as meas ure d b y  the c ha n ge fr o m baseli ne i n s u bjecti ve assess me nt of c o g niti ve 
effects of treat me nt o n D a y s 8 a n d 1 3, usi n g t he m o difie d P R O MI S- A p plie d C o g niti o n 
A bilities ( P R O MI S- A C A).

T o e x pl ore patie nt -re p orte d le vel of satisfacti o n wit h t he use of J NJ- 4 2 8 4 7 9 2 2 c o m pare d t o 
z ol pi de m i n s u bjects wit h i ns o m nia dis or der usi n g t he A b bre viate d Treat me nt Satisfacti o n 
Q uesti o n naire f or Me dicati o n ( T S Q M- 9) o n Da y  1 4

T o deter mi ne t he c orrelati o n bet wee n t he f oll o wi n g slee p para meters o btai ne d b y  PS G 
rec or di n gs o n Ni g hts 1 a n d 1 3 ( o bjecti ve) a n d C S D -M 
(s u bjecti ve o n t he f oll o wi n g 
m or ni n g): L P S a n d self-re p orte d slee p o nset late nc y (s S O L); T S T a n d s u bjecti ve T S T 
(s T S T); W A S O a n d s u bjecti ve W A S O (s W A S O); n u m ber of ni g htti me a wa ke ni n gs (n N A W )
a n d s u bjecti ve n u m ber of ni g htti me a wa ke ni n gs (s- n N A W ); a n d S E a n d s u bjecti ve q uality of 
slee p (s Q U A L) i n s u bjects wit h i ns o m nia dis or der

T o e x pl ore dia g n ostic bi o mar kers a n d e val uate c ha n ge i n bi o mar kers relate d t o i m m u ne 
s yste m (e g, hi g h -se nsiti vit y C-reacti ve pr otei n [ hs C R P]), gr o wt h fact ors (e g, brai n -deri ve d 
ne ur otr o p hic fact or [ B D N F]), k y n ure ni ne meta b olites (e g, q ui n oli nic aci d), a n d H P A
a xis 
mar kers (e g, c ortis ol) t hat ma y be relate d t o cli nical res p o nse (i ncl u di n g P S G), n o n-res p o nse, 
or safet y para meters of J NJ -4 2 8 4 7 9 2 2 vers us place b o.
Refer t o Secti o n 9 , St u d y E val uati o ns f or e val uati o ns relate d t o e n d p oi nts.
2. 2.
H y p ot h e si s
T he pri mar y  hy p ot hesis of t his st u d y is: i n s u bjects wit h i ns o m nia dis or der, J NJ- 4 2 8 4 7 9 2 2 will 
res ult i n si g nifica ntly s h orte ne d L P S val ues vers us place b o, as meas ure d b y P S G o n Ni g ht 1 , a n d 
e x hi bit a d ose-res p o nse relati o ns hi p.
3.
S T U D Y D E SI G N A N D R A T I O N AL E
3. 1.
O v er vi e w  of St u d y  D e si g n
T his is a m ultice nter ( U S, E U, a n d Ja pa n), ra n d o mize d, d o u ble -bli n d, parallel- gr o u p, acti ve- a n d 
place b o -c o ntr olle d d ose fi n di n g st u d y to assess t he efficac y an d safet y of J NJ- 4 2 8 4 7 9 2 2 i n b ot h 
a d ult ( 1 8 t o 6 4 ye ars, i ncl usi ve) a n d el derl y (6 5 t o 8 5 ye ars, i ncl usi ve) s u bjects wit h i ns o m nia 
dis or der. I n a d diti o n, effects of J NJ-4 2 8 4 7 9 2 2 o n slee p para meters ( o bjecti ve a n d s u bjecti ve) a n d 
c o g niti o n will be c o m pare d t o t h ose effects of z olpi de m, t o i n vesti gate p ote ntial differe nces 
bet wee n t he c o m po u n ds . A t otal of 3 6 0 s u bjects, a ge d 1 8 t o 8 5 ye ars i ncl usi ve, wit h i ns o m nia 
dis or der will be ra n d o mize d. T he pla n is t o ra n d o mize a p pr o xi matel y eq ual pr o p orti o ns of a d ult
a n d el derl y s u bjects a n d t heref ore t he n u m ber ra n d o mize d i n eit her a ge gr o u p s h o ul d n ot e x cee d 
a p pr o xi matel y 6 0 % of t he pla n ne d t otal sa m ple size.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
4 8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
T he efficac y, d ose - a n d e x p os ure -res p o nse relati o ns hi p, safety, a n d t olera bilit y of 3 d oses of 
J NJ- 4 2 8 4 7 9 2 2 ( 5, 1 0, a n d 2 0 m g ) c o m pare d t o place b o a n d z ol pi de m w he n a d mi nistere d ni g htl y 
o ver 1 4 da y s (at n or mal be dti me o n n o n-P S G ni g hts or 1 5 mi n utes pri or t o li g hts o ut o n ni g hts of 
P S G rec or di n g) will be assesse d. S u bjects will be ra n d o mize d i n a 1: 1: 1: 1: 1 rati o t o recei ve 1 of 
5 treat me nts: place b o:J NJ- 4 2 8 4 7 9 2 2 5 m g:J NJ -4 2 8 4 7 9 2 2 1 0 m g: J NJ- 4 2 8 4 7 9 2 2 2 0 m g:z ol pi de m .
F or all s u bjects, t his st u d y will c o nsist of a n eli gi bilit y scree ni n g p hase, a d o u ble -bli n d treat me nt 
p hase, a n d a f oll o w -u p visit.
A dia gra m of t he o verall st u d y  desi g n is pr o vi de d bel o w i n Fi g ure 1 .

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
5 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Scree ni n g
After pr o vi di n g writte n i nf or me d c o nse nt a n d wit hi n 3 5 da y s pri or t o ra n d o mizati o n ( Da y 1), 
s u bjects e x perie nci n g i ns o m nia dis or der will be scree ne d t o e val uate t heir eli gi bilit y for st u d y 
part ici pati o n. T he scree ni n g e xa mi nati o n c o nsists of 2 parts.
Part 1 of Scree ni n g : T he first part of t he eli gi bilit y scree ni n g will be c o m plete d bet wee n Da y  -3 5 
a n d D a y  - 1 5. D uri n g t he first 5 da y s of scree ni n g, all h y p n otic a n d se dati n g me dicati o ns nee d t o 
be ta pere d a n d st o p pe d (see Secti o n 8 , Prest u d y  an d C o nc o mita nt T hera p y). Part 1 of scree ni n g
will c o nsist of a ge neral healt h assess me nt a n d a n assess me nt of s u bjecti ve i ns o m nia. I n ad diti o n 
t o meeti n g scree ni n g criteria o n meas ures of ge neral healt h, i n or der t o b e eli gi ble f or Part 2 of 
t he scree ni n g p hase , s u bjects m ust meet t he f oll o wi n g slee p criteria:

Dia g n osis of i ns o m nia dis or der acc or di n g t o t he Dia g n ostic a n d Statistical Ma n ual of Me ntal 
Dis or ders, 5t h e diti o n, ( D S M - 5)

I SI ≥1 5 5 ,5 3
N ote: F or s u bjects ta ki n g h y p n otic dr u gs at t he ti me of si g ni n g t he i nf or me d c o nse nt, 
a d mi nistrati o n of t he ISI  m ust occ ur at least 5 da ys after t he last d ose of all h y p n otic dr u g s.

s S O L ≥4 5 mi n utes a n d s W A S O ≥6 0 mi n utes o n at least 3 ni g hts o ver a n y 7-d a y  peri o d 
usi n g t he C S D -M. ( A s u bject’s slee p patter ns m ust be ca pt ure d f or a mi ni m u m of 7 da y s 
usi n g t he C S D -M d uri n g Part 1 of scree ni n g, pri or t o scree ni n g P S G assess me nts. Data 
c ollecte d o n be dti me ha bits d uri n g scree ni n g wit h t he C S D -M will be use d t o deter mi ne 
me dia n ha bit ual be dti me f or P S G a c q uisiti o n at t he st u d y site.)
N ote: F or s u bjects ta ki n g h y p n otic dr u gs at t he ti me of si g ni n g t he i nf or me d c o nse nt, 
a d mi nistrati o n of t he C S D -M m ust start at least 5 d a y s after t he last d ose of all h y p n otic 
dr u g s.
S u bjects w h o ha ve met all i ncl usi o n a n d e xcl usi o n criteria i n t his first part of scree ni n g will t he n 
u n der g o Part 2 of t he scree ni n g p hase.
Part 2 of Scree ni n g : Part 2 of t he scree ni n g p hase will c o nsist of a n o bjecti ve assess me nt of 
i ns o m nia b y  PS G rec or di n g a n d e val uati o n o ver 2 ni g hts. T he 2 ni g hts of scree ni n g P S G 
ac q uisiti o ns will be c o n d ucte d c o nsec uti vel y. T hese assess me nts s h o ul d be c o m plete d bet wee n 
D a y  -1 4 a n d a p pr o xi matel y D a y  - 5 (ie, 5 d a y s bef ore Da y 1) t o all o w f or a nal ys is of t he P S G 
data a n d esta blis h eli gi bilit y for ra n d o mizati o n. T he first ni g ht’s P S G data will be use d t o 
e xcl u de a n y su bject wit h P L M / R LS, slee p a p nea, or paras o m nias. T he first a n d sec o n d ni g hts’ 
P S G rec or di n gs will be use d t o assess o bjecti ve slee p e ntr y criteria f or i ns o m nia. S u bjects are 
re q uire d t o meet t he f oll o wi n g o bjecti ve slee p i ncl usi o n criteria, as meas ure d b y P S G:

2- ni g ht mea n L P S of ≥2 5 mi n utes, wit h neit her ni g ht < 2 0 mi n utes,

2- ni g ht mea n W A S O ≥3 0 mi n utes, a n d

2 - ni g ht mea n T S T ≤6. 5 h o urs, wit h neit her ni g ht > 7 h o urs.
B ot h parts of scree ni n g m ust be c o m plete d bef ore ra n d o mizati o n o n Da y  1.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
5 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
T w o trai ni n g sessi o ns f or t he c o g niti ve test batter y a n d b o d y s wa y assess me nts will be perf or me d 
d uri n g Part 2 of t he scree ni n g p hase t o fa miliarize t he s u bject wit h t he test pr oce d ures a n d t o 
re d uce lear ni n g effects d uri n g t he st u dy.
D o u ble -bli n d Tre at me nt P h ase
T he d o u ble -bli n d treat me nt p hase will c o nsist of 1 4 da y s of d osi n g wit h st u d y dr u g, f oll o we d b y  
n o n- d os i n g da ys ( Da ys 1 5 a n d 1 6) t o assess wit h dra wal effects o n Da y 1 7. 
S u bjects will be a d mitte d t o t he st u d y site bet wee n 8: 0 0 A M a n d n o o n o n Da y 1 of t he 
d o u ble -bli n d treat me nt p hase a n d will re mai n at t he st u d y site u ntil a p pr o xi matel y n o o n of Da y 2 
( 1 o ver ni g ht). A t least 4 0 n o n- el derl y a d ult s u bjects a n d 4 0 el derl y su bjects will re mai n at t he 
st u d y sites wit h P K sa m pli n g e x perie nce f or a n a d diti o nal ni g ht ( Ni g ht 2) f or c ollecti o n of P K, 
bi o mar ker sa m ples, a n d ot her pr oce d ures (see T i me a n d E ve nts Sc he d ule - Part 2 ). F or t h ose 
s u bjects partici pati n g i n i nte nsi ve o ver ni g ht P K sa m pli n g o n Ni g ht 2, st u d y dr u g will be 
a d mi nistere d at t he st u d y site o n Ni g ht 2 a n d t he y will be disc har ge d fr o m t he st u d y site at
ar o u n d n o o n of Da y  3 ( 2 o ver ni g hts).
O n Da y  1, u p o n c o m pleti o n of all st u d y relate d m or ni n g pr oce d ures t he s u bject ma y  lea ve a n d 
ret ur n i n ti me f or t he pre -P S G assess me nts, h o we ver t he prefere nce is f or t he s u bjects t o sta y on 
site t o m o nit or caffei ne i nta ke, na p pi n g, etc. I n cases w he n s u bjects are n ot sta yi n g at t he site 
d uri n g d a y ti me i n bet wee n st u d y relate d pr oce d ures, we as k f or a d diti o nal m o nit ori n g t o e ns ure 
c o m plia nce t o pr o hi biti o ns/restricti o ns a n d t o perf or m a d diti o nal dr u g/alc o h ol tests u p o n re-
a d missi o n. Als o, caffei ne i nta ke, na p pi n g stat us a n d me dicati o n i nta ke s h o ul d be c hec ke d .
S u bject s s h o ul d ret ur n i n ti me f or all pre d ose assess me nts t o be c o m plete d. 
All s u bjects will ret ur n t o t he st u d y  site o n Da y 1 3 wit hi n a p pr o xi matel y 4 h o urs pri or t o be dti me 
f or a n a d diti o nal o ver ni g ht P S G rec or di n g o ver 8 h o urs a n d will re mai n i n t he st u d y site u ntil 
n o o n of Da y  1 5 ( 2 o ver ni g hts). Meals, as a p pr o priate, m a y  be pr o vi de d at t he st u d y site. S u bjects 
will be pr o hi bite d fr o m na p pi n g o n D a y  14 w hile at t he st u d y site pri or t o d osi n g of st u d y dr u g. 
O n Ni g ht 1 4, fiftee n mi n utes after ta ki n g t he last d ose of t he st u d y dr u g , a P K sa m ple will be 
c ollecte d fr o m all s u bjects. O n Ni g ht 1 4 ( Da y  1 5), 4 h o urs after t he e ve ni n g d osi n g, s u bjects will 
be a wa ke ne d ( mi d dle of -t he-ni g ht a wa ke ni n g) a n d as ke d t o i m me diately p erf or m a c o g niti ve test 
batter y , a p ost ural sta bilit y (b o d y s wa y) assess me nt , a n d c o m plete a K S S assess me nt . I n 
a d diti o n, a P K sa m ple will be c ollecte d fr o m all s u bjects at t his ti me p oi nt , after t he c o g niti ve 
testi n g, a n d bef ore ret ur ni n g t o slee p. N o P S G will be c ollecte d o n Ni g ht 1 4. O n t he m or ni n g of 
D a y 1 5, a P K sa m ple a n d a bi o mar ker sa m ple will be c ollecte d at 8 h o ur s 1 5 mi n utes p ost Ni g ht 
1 4 e ve ni n g d ose a n d s u bjects will be e val uate d f or cli nical a n d safet y  assess me nts, a n d t hereafter 
will be disc har ge d at ar o u n d n o o n. St u d y  dr u g will be a d mi nistere d i n a d o u ble -bli n d ma n ner f or 
1 4 c o nsec uti ve ni g hts, at 1 5 mi n utes pri or t o li g hts o ut o n ni g hts w he n P S G is rec or de d at t he 
st u d y site (ie, Ni g hts 1 a n d 1 3) or at n or mal be dti me o n n o n- P S G ni g hts (ie, Ni g hts 2 t o 1 2 a n d 
1 4). A tele p h o ne c o ntact will occ ur o n Da y  17 t o e val uate safet y (A Es) a n d t he p ote ntial 
wit h dra wal effects ( P W C a n d B W S Q).
N ote: A n e xce pti o n t o t he o ver ni g ht P K sa m ples o n Ni g ht 1 4 ma y  b e ma de after disc ussi o n wit h 
t he s p o ns or’s me dical m o nit or. T he reas o n f or t he e xce pti o n m ust be d oc u me nte d i n t he s o urce 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
5 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
d oc u me nts. If p ossi ble, t he 8- h o ur 1 5 -mi n ute P K c olle cti o n s h o ul d be o btai ne d e ve n if perf or me d 
u p t o 1 2 h o urs after d osi n g. T he c orrect ti me of t he c ollecti o n s h o ul d be n ote d.
T he D a y  15 m or ni n g P K a n d bi o mar ker sa m pli n g s h o ul d be c ollecte d i n all s u bjects b ut ma y  be 
c ollecte d u p t o 1 2 h o urs after d osi n g if t he sa m ple ca n n ot be o btai ne d b y 8 h o urs a n d 1 5 mi n utes 
of d osi n g. T he act ual ti me of c ollecti o n s h o ul d be n ote d o n t he re q uisiti o n f or m a n d s h o ul d be as 
cl ose t o 8 h o urs a n d 1 5 mi n utes as p ossi ble . T he reas o n f or t he e xce pti o n m ust be d oc u me nte d i n 
t he so urce d oc u me nts.
If nee de d, t he D a y  13 st u d y site visit c o ul d be dela y e d f or a ma xi m u m of 2 da y s (ie, u p t o 
D a y 1 5) t o all o w f or a s ufficie nt wi n d o w of ti me f or t he s u bject t o ret ur n t o t he st u d y site. I n 
cases w he n t he D a y 1 3 visit is dela y e d, s u bjects sh o ul d c o nti n ue t o ta ke st u d y dr u g a n d all 
sc he d ule d st u d y assess me nts sc he d ule d after war ds will be dela y e d wit h t he sa me wi n d o w 
( ma xi m u m 2 da ys) s o t hat res pecti ve ti me t o d osi n g a n d last d ose is preser ve d.
T hr o u g h o ut t he d o u ble -bli n d treat me nt p hase, s u bjects will 
rec or d t heir dail y s u bjecti ve 
assess me nt of slee p wit hi n t he first h o ur of a wa ke ni n g usi n g t he C S D -M.
F oll o w -u p/ E n d of St u d y Visit
S u bjects will ret ur n t o t he st u d y site f or t he F oll o w - u p/ E n d of St u d y V isit wit hi n 7 t o 1 0 da y s 
( Da ys 2 1 -2 4) after t he last d ose of st u d y dr u g (ie, Da y  14 ). At t he f oll o w-u p visit, safety 
assess me nts/ pr oce d ures will be c o m plete d as per t he T i me a n d E ve nts Sc he d ule - Part 1 . If a 
s u bject pre mat urel y  wit h dra ws fr o m t he st u d y, t he E n d of St u d y  Visit assess me nts s h o ul d be 
perf or me d as s o o n as p ossi ble.
T he d urati o n of partici pati o n i n t he st u d y for a n i n di vi d ual s u bject (i ncl u di n g scree ni n g a n d 
f oll o w-u p visit) will b e u p t o 6 1 da y s. 
A dia gra m of t he st u d y desi g n is pr o vi de d bel o w i n Fi g ure 2 .

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
5 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
3. 2.
St u d y D e si g n R ati o n al e
St u d y P o p ul ati o n
T he st u d y po p ulati o n will i ncl u de a d ult a n d el derl y me n a n d W O N C B P
(a ge d 1 8 t o 8 5 ye ars, 
i ncl usi ve) w h o meet D S M - 5 dia g n ostic criteria f or i ns o m nia dis or der wit h a n I SI t otal sc ore 
≥1 5 w h o are ot her wise me dicall y  sta ble. I n a d diti o n, s u bjects will ha ve a n s S O L ≥4 5 mi n utes 
a n d a n s W A S O ≥6 0 mi n utes o n at least 3 ni g hts o ver a n y 7- d a y  perio d usi n g t he C S D -M
d uri n g 
Part 1 of scree ni n g. O bjecti ve i ns o m nia criteria i ncl u de a 2 -ni g ht mea n L P S of ≥2 5 mi n utes wit h 
neit her ni g ht < 2 0 mi n utes, a 2- ni g ht mea n W A S O 
≥3 0 mi n utes, a n d a 2- ni g ht mea n T S T 
≤6. 5 h o urs, wit h neit her ni g ht > 7 h o urs d uri n g Part 2 of scree ni n g. T he o bjecti ve i ns o m nia 
criteria selecte d f or t his st u d y ha ve bee n m o difie d fr o m t h ose use d i n St u d y  42 8 4 7 9 2 2I S M 2 0 0 2 
( P hase 2a) i n or der t o ali g n t he criteria m ore cl osel y wit h t h ose pre vi o usl y  use d i n s u v ore xa nt 
cli nical st u dies: t he 2-ni g ht mea n L P S was re vise d fr o m ≥3 0 mi n utes t o ≥2 5 mi n utes, t he W A S O 
was re vise d fr o m > 3 0 mi n utes t o ≥3 0 mi n utes, a n d t he 2- ni g ht T S T of ≤6 h o urs o n b ot h ni g hts 
was re vise d t o a 2 -ni g ht mea n ≤6. 5 h o urs, wit h neit her ni g ht > 7 h o urs d uri n g Part 2 of scree ni n g.
I n t his st u d y, a p o p ulati o n s h o w n t o ha ve b ot h s u bjecti ve a n d o bjecti ve (as meas ure d b y  PS G) 
slee p dist ur ba nce will be selecte d, as t hese i n di vi d uals ma y  be nefit m ost fr o m treat me nt wit h 
J NJ-4 2 8 4 7 9 2 2 or z ol pi de m.
T here are n o u nif or m or u ni versall y  acce pted i ncl usi o n criteria f or cli nical st u dies i n i ns o m nia 
base d o n P S G para meters. A rece nt a nal ys is of t he se nsiti vit y an d s pecificit y of P S G criteria t o 
defi ne i ns o m nia s h o we d t hat b y  usi n g P S G criteria, s uc h as t h ose s pecifie d i n t his pr ot oc ol, 
> 5 0 % of i ns o m nia patie nts will be e xcl u de d fr o m partici pati n g. 2 0 I n t heir re vie w of t he literat ure, 
Lic hstei n a n d c ollea g ues ( 2 0 0 3)4 4
c o ncl u de d t hat s u bjecti ve criteria ( L P S a n d W A S O 
> 3 0 mi n utes occ urri n g 3 ni g hts a wee k f or at least 6 m o nt hs) relia bl y characterize d i ns o m nia. 
I ncl usi o n of s u bjects base d o n o bjecti ve P S G criteria is e x pecte d t o i ncrease t he a bilit y to 
q ua ntitate dr u g effects i n a li mite d s u bject sa m ple. Re q uiri n g s u bjects t o meet D S M -5 criteria f or 
i ns o m nia dis or der f urt her m ore i ntr o d uces fre q ue nc y (at least 3 ni g hts per wee k) a n d d urati o n 
( prese nt f or at least 3 m o nt hs) 
criteria t hat, i n a d diti o n t o t he necessar y  su bjecti ve slee p 
pr o ble ms, ha ve bee n s h o w n t o res ult i n a relia ble c haracterizati o n of i ns o m nia.
J NJ- 4 2 8 4 7 9 2 2 has bee n e val uate d f or e m br yo- fetal gr o wt h a n d de vel o p me nt i n G L P st u dies i n 
rats a n d rab bits. I n t he pre g na nt S pra g ue -Da wle y rats t here were n o effects o n fetal gr o wt h a n d 
de vel o p me nt at a n y d ose. Si milarl y , i n t he pre g na nt Ne w Zeala n d W hite ra b bits J NJ-4 2 8 4 7 9 2 2 
di d n ot i n d uce a n y unt o war d effects o n fetal gr o wt h a n d de vel o p me nt at a n y dose teste d. 
H o we ver, a fe male rat fertilit y st u d y s u g geste d a re d ucti o n i n fe male fertilit y. Si nce it is n ot 
k n o w n w hat t he rele va nce of t hese fi n di n gs are t o a w o ma n’s a bilit y to bec o me pre g na nt after 
ta ki n g J NJ- 4 2 8 4 7 9 2 2, n o ne w W O C B P will be i ncl u de d i n t his st u d y until m ore is lear ne d a b o ut 
t he effect of J NJ-4 2 8 4 7 9 2 2 o n fe male re pr o d ucti o n. 
Bli n di n g, C o ntr ol, Tre at me nt Gr o u ps
A place b o c o ntr ol will be use d t o esta blis h t he fre q ue nc y an d ma g nit u de of c ha n ges i n cli nical 
e n d p oi nts t hat ma y  occ ur i n t he a bse nce of acti ve treat me nt. I n a d diti o n t o place b o c o ntr ol, a n 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
5 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
acti ve c o ntr ol, z ol pi de m, will be use d i n or der t o i n vesti gate p ote ntial differe nces bet wee n 
J NJ- 4 2 8 4 7 9 2 2 a n d z ol pi de m. Ra n d o mizati o n will be use d t o mi ni mize bias i n t he assi g n me nt of 
s u bjects t o treat me nt gr o u ps, t o i ncrease t he li keli h o o d t hat k n o w n a n d u n k n o w n s u bject 
attri b utes (e g, de m o gra p hic a n d baseli ne c haracteristics) are e ve nl y bala nce d acr oss treat me nt 
gr o u ps, a n d t o e n ha nce t he vali dit y  of statistical c o m paris o ns acr oss treat me nt gr o u p s. Bli n de d 
treat me nt will be use d t o re d uce p ote ntial bias d uri n g data c ollecti o n a n d e val uati o n of cli nical 
e n d p oi nts.
Z ol pi de m has bee n selecte d as a c o m parat or beca use it is t he m ost c o m m o nl y prescri be d slee p 
me dicati o n i n t he E U , U S, a n d Ja pa n, a n d is a n effecti ve n o n- B Z D h y p n otic i n t he ma na ge me nt 
of s h ort -ter m i ns o m nia. 
D N A a n d Bi o m ar ker C ollecti o n
It is rec o g nize d t hat ge netic variati o n ca n be a n i m p orta nt c o ntri b ut or y fact or t o i nteri n di vi d ual 
differe nces i n dr u g distri b uti o n a n d res p o nse a n d ca n als o ser ve as a mar ker f or disease 
s usce pti bilit y an d pr o g n osis. P har mac o ge n o mic researc h m a y  hel p t o e x plai n i nteri n di vi d ual 
varia bilit y  in cli nical o utc o mes a n d m a y  hel p t o i de ntif y po 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. T he g oal of t he p har mac o ge n o mic c o m p o ne nt is t o c ollect de o x yri b o n ucleic 
aci d ( D N A ) t o all o w t he i de ntificati o n of ge netic fact ors t hat ma y i nfl ue nce t he P K , P D , efficac y, 
safety, or t olera bilit y of J NJ- 4 2 8 4 7 9 2 2 a n d t o i de ntif y ge netic fact ors ass ociate d wit h i ns o m nia 
d is or der.
E vi de nce has de m o nstrate d i nteracti o ns bet wee n slee p, H P A 
a xis acti vit y, i nfla m mat or y 
mar kers, 
a n d gr o wt h fact ors. I ns o m nia is ass ociate d wit h 
ele vati o ns i n c ortis ol a n d 
a dre n oc ortic otr o pic h or m o ne, a n d slee p dist ur ba nce s uc h as slee p de pri vati o n affects t he n or mal 
variati o ns i n le vels of circ ulati n g c yt o ki nes. Slee p dist ur ba nce i n patie nts wit h de pressi o n is 
li n ke d t o altere d k y n ure ni ne meta b olis m, a n d pr oi nfla m mat or y  cyt o ki nes acti vate e nz ymes t hat 
meta b olize 
tr ypt o p ha n i nt o k y n ure ni ne, sti m ulatin g t he k y n ure ni ne pat h wa y . I n a d diti o n, 
e vi de nce s u g gests slee p is a me diat or of i nteracti o ns bet wee n stress a n d B D N F le vels, a n d 
i ns o m nia se verity was f o u n d t o be relate d t o le vels of ser u m B D N F.
Bl o o d sa m ples will b e 
c ollecte d t o e x pl ore bi o mar kers relate d t o H P A a xis acti vati o n, i m m u ne s yste m acti vit y, 
k y n ure ni ne meta b olites, 
a n d ne ur otr o pic fact ors. Bi o mar ker sa m ples 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 or t o i de ntif y po p ulati o n s u b gr o u ps t hat res p o n d 
differe ntl y t o J NJ- 42 8 4 7 9 2 2 . Bi o mar kers 
ma y 
be a d de d or delete d base d o n scie ntific 
i nf or mati o n or tec h nical i n n o vati o ns u n der t he c o n diti o n t hat t he t otal v ol u me of bl o o d c ollecte d 
will n ot be i ncrease d.
D N A a n d bi o mar ker sa m ples ma y  be use d t o hel p a d dress e mer gi n g iss ues a n d t o e na ble t he 
de vel o p me nt of safer, m ore 
effecti ve, a n d ulti matel y  in di vi d ualize d t hera pies. S u bject 
partici pati o n i n t he p har mac o ge n o mics researc h is o pti o nal.
I n pre me n o pa usal w o me n (still ha vi n g t heir me nses) , me nstr ual c ycles will be trac ke d d uri n g t he 
st u d y as s o me bi o mar ker para meters will var y i n fe male s u bjects wit h t heir me nstr ual c ycles.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
5 6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
D ose a n d D ose A d mi nistr ati o n I nter v al
D uri n g t he st u d y, o n Da ys 1 t hr o u g h 1 4, s u bjects will recei ve o nce dail y : 5 m g, 1 0 m g , or 2 0 m g 
of J NJ- 4 2 8 4 7 9 2 2, 5 m g or 1 0 m g of z ol pi de m, or place b o at n or mal be dti me o n n o n- P S G ni g hts 
or 1 5 mi n utes pri or t o li g hts o ut o n ni g hts of P S G rec or di n g. D osi n g ti me s h o ul d be c o nsiste nt o n 
eac h P S G ni g ht.
T he pr o p ose d J NJ- 4 2 8 4 7 9 2 2 d oses ( 5 m g , 1 0 m g, a n d 2 0 m g) f or t his st u d y were selecte d base d 
o n a ntici pate d efficaci o us d ose le vels i n i nitiati n g a n d mai ntai ni n g slee p, plas ma e x p os ures i n 
relati o n t o t h e N O A E L i n G LP t o xic ol o g y  st u dies, t he cli nical safet y an d t olera bilit y pr ofile, a n d 
a ntici pate d plas ma e x p os ures acr oss t he selec te d d ose le vels.
T he ma xi m u m d ose selecte d f or t his st u d y  is 2 0 m g. T his d ose was selecte d base d o n LP S res ults 
fr o m St u d y  42 8 4 7 9 2 2 E DI 1 0 0 2, w hic h s h o we d a n i ncrease i n efficac y f or L P S as t he d ose 
i ncrease d fr o m 1 0 m g  to 2 0 m g; n o f urt her i ncrease was n ote d w he n t he d ose i ncrease d fr o m 
2 0 m g t o 4 0 m g , des pite i ncreasi n g e x p os ures. I n the m ulti ple d ose st u d y in a d ult s u bjects wit h 
i ns o m nia dis or der wit h o ut ps y c hiatric c o m or bi dit y (St u d y 4 2 8 4 7 9 2 2I S M 2 0 0 2), all s u bjects 
recei ve d 4 0 m g at be dti me. O verall, o bjec ti ve ( per P S G) a n d s u bjecti ve slee p para meters were 
si milarl y im pr o ve d b y  treat me nt wit h J NJ-4 2 8 4 7 9 2 2 a n d c orrelate d well. T he res ults s h o we d a 
m ore pr o n o u nce d effect o n S E, L P S, a n d T S T wit h a m o dest effect o n W A S O, c o nsiste nt wit h 
t he res ults see n i n St u d y  42 8 4 7 9 2 2 E DI 1 0 0 2 f or t he 2 0- m g d ose. T heref ore, t here a p pears t o be 
mi ni mal gai n i n efficac y whe n t he d ose is raise d a b o ve 2 0 m g , a n d li kel y a decrease i n t he 
be nefit/ris k rati o. T heref ore, 2 0 m g  is t he ma xi m u m d ose t o be a d mi nistere d i n t his st u d y.
T he l o west d ose le vel selecte d f or t his st u d y is 5 m g. T his d ose was selecte d base d o n P D res ults 
fr o m St u d y  42 8 4 7 9 2 2 E DI 1 0 0 2 ( 1 0, 2 0, a n d 4 0 m g) a n d t he s o m n ole nce effects o bser ve d i n 
St u d y  42 8 4 7 9 2 2 E DI 1 0 0 3 ( 5 t o 6 0 m g). I n St u d y 42 8 4 7 9 2 2 E DI 1 0 0 2, efficac y on t he L P S 
e n d p oi nt was o bser ve d at t he l o west d ose teste d ( 1 0 m g) , s o t he mi ni m u m effecti ve d ose m a y  b e 
l o wer t ha n 1 0 m g . I n St u d y  42 8 4 7 9 2 2 E DI 1 0 0 3, J NJ- 4 2 8 4 7 9 2 2 d ose le vels of 5 t o 6 0 m g were 
e val uate d f or 1 0 d a y s i n healt h y  
male a n d fe male s u bjects ( 6 s u bjects/ d ose). O verall, 
J NJ- 4 2 8 4 7 9 2 2 d ose le vels < 2 0 m g i n d uce d m ostl y  mil d, i nc o nsiste nt s o m n ole nce ( o ver ti me a n d 
s u bject-t o-s u bject), w hereas s o m n ole nce re p orte d f oll o wi n g d ose le vels ≥2 0 m g was ge nerall y 
m o derate, a n d was c o nsiste ntl y re p orte d o ver ti me b y  all s u bjects. Beca use J NJ- 4 2 8 4 7 9 2 2 was 
a d mi nistere d i n t he m or ni n g i n St u d y  42 8 4 7 9 2 2 E DI 1 0 0 3 f oll o wi n g a f ull ni g ht of slee p, t hese 
res ults are e x pecte d t o u n deresti mate t he p ote nc y  of J NJ- 4 2 8 4 7 9 2 2 i n s u bjects wit h i ns o m nia 
w h o will recei ve t he dr u g at ni g ht ti me. I n St u d y 4 2 8 4 7 9 2 2 E DI 1 0 0 3, a m o dest i ncrease i n t he 
i nci de nce of mil d t o m o derate s o m n ole nce was re p orte d f oll o wi n g a d mi nistrati o n of 5 m g  of 
J NJ- 4 2 8 4 7 9 2 2 vers us place b o, a n d t heref ore t he 5- m g J NJ- 4 2 8 4 7 9 2 2 d ose le vel was c h ose n t o 
assess p ote ntial efficac y at t he l o wer e n d of t he d ose ra n ge.
T he J NJ -4 2 8 4 7 9 2 2 d oses ( 5 m g, 1 0 m g , a n d 2 0 m g) are e x pecte d t o res ult i n a n acce pta ble safet y 
pr ofile i n t he sa m ple partici pati n g i n t his st u d y, as J NJ- 4 2 8 4 7 9 2 2 was well t olerate d i n healt h y 
s u bjects after si n gle d oses u p t o 8 0 m g ( 1 0 t o 8 0 m g, St u d y 4 2 8 4 7 9 2 2 E DI 1 0 0 1) a n d m ulti ple 
d oses u p t o 6 0 m g ( 5 t o 6 0 m g o nce dail y  for 1 0 da y s, St u d y 4 2 8 4 7 9 2 2 E DI 1 0 0 3). J NJ-4 2 8 4 7 9 2 2 
was als o well t olerate d i n s u bjects wit h M D D 
a n d c o m or bi d i ns o m nia after si n gle-d ose 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
5 7
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
a d mi nistrat i o n of 1 0 t o 4 0 m g. A d diti o nall y  in St u d y 4 2 8 4 7 9 2 2I S M 2 0 0 2, m ulti ple d osi n g ( u p t o 
5 da y s) of 4 0- m g  JNJ -4 2 8 4 7 9 2 2 was ge nerall y well t olerate d i n s u bjects wit h i ns o m nia dis or der 
wit h o ut ps y c hiatric c o m or bi dit y.
Preli mi nar y  s af et y res ults fr o m St u d y 4 2 8 4 7 9 2 2 EDI 1 0 1 4 i n el derl y  healt h y su bject c o h orts s h o w 
t hat si n gle e ve ni n g d osi n g of J NJ- 4 2 8 4 7 9 2 2 1 0 m g a n d 2 0 m g d oses were well t olerate d.
T he 1 4- d a y  ex p os ure i n t his st u d y is base d o n t he m ost 
rece nt gl o bal g ui da nce o n t he 
i n vesti gati o n of treat me nts f or ins o m n ia d is or der, iss ue d b y  the E ur o pea n Me dici nes A ge nc y / 
C o m mittee f or Me dici nal Pr o d ucts f or H u ma n Use i n Se pte m ber of 2 0 1 1 e ntitle d “ G ui deli ne o n 
me dici nal pr o d ucts f or t he treat me nt of i ns o m nia”. 2 2
I n t o xic ol o g y st u dies, J NJ-4 2 8 4 7 9 2 2 has bee n i n vesti gate d o ver a peri o d of 3 m o nt hs of 
e x p os ure, w hic h a de q uatel y c o vers a peri o d of 1 4 da ys of d osi n g.
I n to xic ol o g y  st u dies, J NJ- 4 2 8 4 7 9 2 2 has bee n i n vesti gate d o ver a peri o d of 6 m o nt hs i n rats a n d 
9 m o nt hs i n d o gs, w hic h a de q uatel y c o vers a peri o d of 1 4 da ys of d osi n g.
See Secti o n 1. 1. 1 , N o ncli nical St u dies f or a s u m mar y of t o xic ol o g y st u dies.
T he z ol pi de m d oses ( 5 m g a n d 1 0 m g) selecte d f or use are base d o n t he a p pr o ve d d oses i n t he 
U S, E U, a n d Ja pa n, a n d s u bjects will be d ose d per t he l ocal la belli n g i nf or mati o n :

I n t he U S, a d ult fe males a nd el derl y  (males a n d fe males) will recei ve 5 m g d oses w hile a d ult 
males will recei ve 1 0 m g d oses .

In t he E U, a d ults will recei ve 1 0 m g d oses w hile el derl y will recei ve 5 m g d oses .

In Ja pa n, a d ults a n d el derl y  will recei ve 5 m g d oses.
L o wer d osi n g ( 5 m g ) is rec o m me n de d i n t he el derl y t o mi ni mize a d verse effects relate d t o 
i m paire d m ot or 
a n d/ or c o g niti ve perf or ma nce a n d u n us ual se nsiti vit y to se dati ve/ h yp n otic 
dr u gs .8 7 ,8 8 ,8 9 Z ol pi de m d osi n g per l ocal la bel was selecte d t o all ow c o m paris o n bet wee n t he 
teste d J NJ- 4 2 8 4 7 9 2 2 d oses ( 5, 1 0, a n d 2 0 m g) a n d t he z ol pi de m d oses i n use i n t he U S, E U, a n d 
Ja pa n.
Pri m ar y O bjecti ve
T he st u d y  is desi g ne d t o assess t he d ose -res p o nse of 3 d oses of J NJ -4 2 8 4 7 9 2 2 ( 5, 1 0, a n d 2 0 m g) 
c o m pare d t o place b o o n t he o bjecti ve slee p meas ure of L P S , reflecti n g effects o n slee p o nset i n 
s u bjects wit h i ns o m nia dis or der . Late nc y t o persiste nt slee p is t he sta n dar d meas ure f or t he ti me 
of slee p o nset i n i ns o m nia cli nical trials.
Effic ac y Me as ures
O bjecti ve slee p para meters will be meas ure d
b y  PS G as liste d i n Secti o n 9. 2 , Efficac y  
E val uati o ns.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
5 8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
S u bjecti ve slee p para meters (s S O L, s T S T, s W A S O, s-n N A W, s Q U A L, a n d s u bjecti ve refres he d 
feeli n g o n wa ki n g [s F R E S H]) will be assesse d usi n g t he C S D -M. T he C S D -M is t he o nl y  slee p 
diar y  de vel o pe d wit h ri g or o us met h o d ol o g y f or patie nt-re p orte d o utc o me de vel o p me nt, i ncl u di n g 
e m pl o yi n g user/f oc us gr o u p fee d bac k a n d e x pert fee d bac k t o esta blis h c o nstr uct vali dit y . It has 
u n der g o ne ps yc h o metric testi n g a n d its c o nte nt vali dit y  has bee n c o nfir me d b y  patie nt f oc us 
gr o u ps. 1 1
T he cli nicia n -rate d ISI  will be use d t o meas ure res p o nse rate ( defi ne d as a ≥5 0 % re d ucti o n i n 
t otal sc ore) a n d re missi o n rate ( defi ne d as a t otal sc ore ≤1 0) of i ns o m nia s ym pt o ms o n Da y 1 4. 
T he C GI -S, C GI -I, P GI -S, a n d P GI -I will be use d t o all o w assess me nt of mi ni mal cli nicall y 
i m p orta nt differe nce base d o n t he gl o bal i m pressi o ns of t he cli nicia n a n d t he s u bject.1 2 ,2 4
D a y ti me c o nse q ue nces o n f u ncti o ni n g a n d slee p dist ur ba nce will be assesse d b y  PR O MI S -S RI  
a n d P R O MI S- S D, res pecti vely. T hese meas ures 
were 
de vel o pe d usi n g state of t he art 
ps y c h o metric tec h ni q ues s uc h as Ite m Res p o nse T he or y  
Mo dels a n d ha ve bee n s h o w n t o 
a de q uatel y re prese nt slee p dist ur ba nce a n d slee p-relate d i m pair me nt d o mai ns. T hese meas ures 
pr o vi de hi g h t otal test i nf or mati o n wit h hi g h vali dit y  a n d relia bilit y.8 5
P h ar m ac o ki netic Assess me nts
Ve n o us 
bl o o d sa m ples ( 3 m L  eac h) will 
be c ollecte d f or t he deter mi nati o n of plas ma 
c o nce ntrati o ns f or J NJ -4 2 8 4 7 9 2 2 a n d its acti ve meta b olites ( M 1 2 a n d M 1 6 [ as a p plica ble]) at t he 
ti me p oi nts i n dicate d i n t he T i me a n d E ve nts Sc he d ule - Part 1 a n d T i me a n d E ve nts Sc he d ule -
Part 2 .
A p o p ulati o n P K a nal ys is usi n g P K data fr o m a selecti o n of P hase 1 a n d P hase 2 st u dies will be 
perf or me d at t he c o m pleti o n of t he st u d y. T he p ur p ose of t he pla n ne d p o p ulati o n P K a nal ys is 
will be t o assess t he P K of J NJ- 4 2 8 4 7 9 2 2 (a n d, if nee de d, of acti ve meta b olites M 1 2 a n d M 1 6) 
i n t he tar get patie nt p o p ulati o n, a n d t he p ote ntial i m pact of c o variates. P K c ollecti o n will als o 
e na ble t he e val uati o n of t he relati o ns hi p bet wee n pare nt dr u g c o nce ntrati o n a n d meta b olites M 1 2 
a n d M 1 6, a n d t he e x pl orati o n of t he c orrelati o n of e x p os ure t o efficac y or safet y meas ures. 
I nte nsi ve P K sa m pli n g i n a s u bset of s u bjects will hel p t o f urt her c haracterize t he P K of J NJ-
4 2 8 4 7 9 2 2 i n a d ult a n d el derl y su bjects as well as t he relati o ns hi p bet wee n dr u g c o nce ntrati o n 
a n d slee p mai nte na nce. T hese a nal ys es will be hel pf ul i n i de ntif yi n g o pti mal d oses a n d d os i n g 
re gi me ns t o e val uate i n s u bse q ue nt st u dies.
S afet y E v al u ati o ns
Sta n dar d safety e val uati o ns i ncl u di n g c ollecti o n of A Es a n d c o nc o mita nt me dicati o ns, p h y sical 
e xa mi nati o n, b o d y  wei g ht, vital si g ns, 1 2- lea d E C G, uri ne dr u g testi n g, a n d cli nical la b orat or y
tests will be perf or me d t o m o nit or s u bject safety t hr o u g h o ut t he st u d y.
Ne xt -da y  resi d ual effects are fre q ue ntly see n after t he use of h y p n otic dr u gs. P ost ural sta bilit y 
( b o d y sw a y ) will be meas ure d 
b y  an ata xia meter. C o g niti ve/ ps yc h o m ot or effects will be
meas ure d s u bjecti vely b y  the P R O MI S -A C A a n d o bjecti vel y  by a c o m p uterize d batter y  of 
c o g niti ve tests. P ote ntial ne xt -da y  resi d ual se dati o n will be teste d s u bjecti vely via t he K S S 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
5 9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
self-re p ort meas ure. M i d dle of t he ni g ht c o g niti ve a n d m ot or perf or ma nce will be assesse d wit h 
mi d dle of t he ni g ht wa ke ni n g ( 4 h o urs after d ose) o n Ni g ht 1 4 wit h t he c o m p uterize d c o g niti ve 
batter y  a n d ata xia meter.
P ote ntial wit h dra wal effects will be assesse d b y t he cli nicia n usi n g t he P W C a n d re p orte d b y  
s u bjects usi n g t he B W SQ.
A d diti o nall y , e mer ge nce of s uici dal i deati o n will be assesse d usi n g t he C- S S R S. T he C- S S R S 
has bee n use d fre q ue ntl y in cli nical st u dies a n d it is a sta n dar d meas ure f or s uici dal i deati o n 
assess me nt; its use is i n acc or da nce wit h F D A g ui da nce. 7 8
A Es of S peci al I nterest
I n vesti gat ors 
are 
i nstr ucte d 
t o 
p a y  
special 
atte nti o n 
t o 
c o m ple x, 
slee p-relate d 
be ha vi ors/ paras o m nias, cata ple x y- li ke s ym pt o ms (s u dde n, tra nsie nt e pis o de of m uscle wea k ness 
acc o m pa nie d b y  co nsci o us a ware ness), vi vi d (a b n or mal) drea ms, a n d slee p paral y sis ( w he n 
falli n g aslee p/a wa ke ni n g t he e x perie nce of n ot bei n g a ble t o m o ve, react or s pea k). Falls are als o 
c o nsi dere d a n e ve nt of s pec ial i nterest i n t his st u d y.
Pri or st u dies wit h D O R As (e g, s u v ore xa nt) s u g gest t hat s uc h a ge nts ma y  preci pitate cata ple x y or 
cata ple x y- li ke e ve nts a n d slee p paral ys is. A ni mal st u dies s u g gest t hat cata ple x y m a y  be a 
lia bilit y f or D O R As, b ut n ot f or O X 2 R-selecti ve a nta g o nists. 1 8 T o date, 3 cases of slee p paral ys is 
ha ve 
bee n 
o bser ve d 
wit h 
J NJ-4 2 8 4 7 9 2 2: 
1 
fr o m 
eac h 
of 
t he 
f oll o wi n g 
St u dies 4 2 8 4 7 9 2 2 E DI 1 0 0 1 
( 8 0 m g 
d ose), 
4 2 8 4 7 9 2 2 E DI 1 0 0 6 
( 2 0 
m g 
d ose), 
a n d 
4 2 8 4 7 9 2 2I S M 2 0 0 2 ( 4 0 m g 
d ose). C o m ple x, slee p-relate d be ha vi ors/ paras o m nias s uc h as 
c o nf usi o nal ar o usals, s o m na m b ulis m (slee p wal ki n g), slee p terr ors, br u xis m (teet h gri n di n g), 
slee p 
se x, 
slee p-relate d 
eati n g 
dis or der, 
slee p 
be ha vi or 
dis or der, 
a n d 
catat hre nia 
( R E M-ass ociate d e n d -i ns pirat or y ap nea/ breat h h ol di n g) ha ve bee n n ote d wit h e x p os ure t o 
h y p n otic dr u gs. F or t hese reas o ns, cata ple x y, vi vi d (a b n or mal) drea ms, slee p paral ys is, a n d 
c o m ple x, slee p-relate d be h a vi ors/paras o m nias are c o nsi dere d A Es of s pecial i nterest i n t his 
st u d y. 
Gi ve n t he a d vise me nt of t he A merica n Geriatrics S ociet y  to a v oi d t he c hr o nic use of h y p n otics, 
i ncl u di n g z ol pi de m, i n el derl y patie nts beca use of t heir ass ociati o n wit h falls a n d fract ures, a fall 
is als o c o nsi dere d a n A E of i nterest.
E x pl or at or y e v al u ati o ns
T he T S Q M - 9 will be use d t o assess patie nts' satisfacti o n wit h me dicati o n, pr o vi di n g sc ores o n 
effecti ve ness, c o n ve nie nce, a n d gl o bal satisfacti o n.
T he T S Q M - 9 is a 9- ite m ge neric p atie nt re p orte d o utc o me i nstr u me nt t o assess patie nts’ 
satisfacti o n wit h me dicati o n. 6 It is deri ve d fr o m t he l o n ger T S Q M Versi o n 1. 4 a n d c o vers 
d o mai ns of effecti ve ness, c o n ve nie nce, a n d gl o bal satisfacti o n. 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
4.
S U B J E C T P O P U L A TI O N
Scree ni n g f or eli gi ble s u bjects will be perf or me d wit hi n 3 5 da y s bef ore a d mi nistrati o n of t he 
st u d y dr u g.
T he i ncl usi o n a n d e xcl usi o n criteria f or e nr olli n g s u bjects i n t his st u d y are descri be d i n t he 
f oll o wi n g 2 s u bsecti o ns. If t here is a q uesti o n a b o ut t he i ncl usi o n or e xcl usi o n criteria bel o w, t he 
i n vesti gat or m ust
c o ns ult wit h t he a p pr o priate s p o ns or re prese ntati ve a n d res ol ve a n y iss ues 
bef ore e nr olli n g a s u bject i n t he st u d y. Wai vers 
are n ot all o we d. E xce pti o nal a n d li mite d 
retesti n g of a b n or mal la b orat or y val ues, vital si g ns, or E C G scree ni n g val ue s ( b ut n ot P S G or 
C S D -M val ues) t hat lea d t o e xcl usi o n, b ut mi g ht be n ot cli nicall y si g nifica nt base d u p o n t he 
i n vesti gat ors’ j u d ge me nt, m a y  be all o we d after disc ussi o n a n d a p pr o val b y  the s p o ns or d uri n g 
t he scree ni n g p hase (t o reassess eli gi bilit y). Retes ti n g w o ul d ta ke place d uri n g a n u nsc he d ule d 
visit i n Part 1 of t he scree ni n g p hase. T his s h o ul d o nl y  be c o nsi dere d if t here is n o a ntici pate d 
i m pact o n s u bject safety.
If a s u bject d oes n ot meet all i ncl usi o n a n d e x cl usi o n criteria (e g, is a scree n fail ure) b ut at s o me 
p oi nt i n t he f ut ure is e x pecte d t o meet t he s u bject eli gi bilit y criteria, t he s u bject m a y  be 
rescree ne d o n o ne occasi o n o nl y . T his s h o ul d be disc usse d wit h t he s p o ns or’s safety p h y sicia n. 
S u bjects ca n n ot be rescree ne d if t he y faile d scree ni n g o n P S G, C S D -M, I SI, or D S M - 5 criteria 
f or i ns o m nia dis or der. S u bjects w h o are rescree ne d will be assi g ne d a ne w s u bject n u m ber, 
u n der g o t he i nf or me d c o nse nt pr ocess, a n d t he n restart a ne w scree ni n g p hase.
4. 1.
I n cl u si o n Crit eri a
Eac h p ote ntial s u bject m ust satisf y  all of t he f oll o wi n g criteria t o be e nr olle d i n t he st u d y:
1.
Criteri o n m o difie d per A me n d me nt 2
1. 1. Criteri o n m o difie d per A me n d me nt 3
1. 2. S u bject m ust be a ma n or W O N C B P , 1 8 t o 8 5 years of a ge, i ncl usi ve, o n t he da y  of 
si g ni n g i nf or me d c o nse nt. N ote: S u bjects s h o ul d be at least 1 8 ye ars of a ge or ol der as 
per t he le gal a ge of c o nse nt i n t he j uris dicti o n i n w hic h t he st u d y  is ta ki n g place.
A W O N C B P is defi ne d as: 
o
P ost me n o pa usal
A p ost me n o p a us al st ate is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n 
alter n ative me dic al c a use. A hi g h f ollicle sti m ul ati n g h or m o ne ( F S H) level 
(per ce ntr al l a b or at ory r a n ge) i n t he p ost me n o p a us al r a n ge m ay be use d 
t o c o nfir m a p ost me n o p a us al st ate i n w o me n 
n ot usi n g h or m o n al 
c o ntr ace pti o n or h or m o n al re pl ace me nt t her a py.
o
Per ma ne ntl y  sterile
Per m a ne nt 
steriliz ati o n 
met h o ds 
i ncl u de 
hysterect o my, 
bil ater al 
s al pi n gect o my, bil ater al t u b al occl usi o n/li g ati o n pr oce d ures, a n d bil ater al 
o o p h orect o my.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
  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.
2.
S u bject m ust meet D S M -5 criteria f or i ns o m nia dis or der.

A pre d o mi na nt c o m plai nt of dissatisfacti o n wit h slee p q ua ntit y or q ualit y , ass ociate d 
wit h o ne ( or m ore) of t he f oll o wi n g s y m pt o ms:
–
Diffic ult y  i nitiati n g slee p
–
Diffic ult y mai ntai ni n g slee p, c haracterize d b y  fre q ue nt a wa ke ni n gs or pr o ble ms 
ret ur ni n g t o slee p after a wa ke ni n gs
–
Earl y- m or ni n g a wa ke ni n g wit h i na bilit y t o ret ur n t o slee p.

T he slee p dist ur ba nce ca uses cli nicall y si gnifica nt distress or i m pair me nt i n s ocial, 
occ u pa ti o nal, e d ucati o nal, aca de mic, be ha vi oral, or ot her i m p orta nt areas of  
f u ncti o ni n g.

T he slee p diffic ult y  occ urs at least 3 ni g hts per wee k.

T he slee p diffic ult y  is prese nt f or at least 3 m o nt hs.

T he slee p diffic ult y  occ urs des pite a de q uate o p p ort u nit y f or slee p.

T he i ns o m nia is n ot better e x plai ne d b y  an d d oes n ot occ ur e xcl usi vel y duri n g t he 
c o urse of a n ot her slee p-wa ke dis or der (e g, narc ole ps y , a breat hi n g -relate d slee p 
dis or der, a circa dia n r h yt h m slee p -wa ke dis or der, a paras o m nia).

T he i ns o m nia is n ot attri b uta ble t o t he p h y si ol o gical effects of a s u bsta nce (e g, a 
dr u g of a b use, a me dicati o n).

C oe xisti n g me ntal dis or ders a n d me dical c o n diti o ns d o n ot a de q uatel y e x plai n t he 
pre d o mi na nt c o m plai nt of i ns o m nia.
3. 
S u bject m ust ha ve a n I SI t otal sc ore ≥1 5 at scree ni n g.
( N ote: F or s u bjects ta ki n g h y p n otic dr u gs at t he ti me of si g ni n g t he i nf or me d c o nse nt 
f or m [I CF], a d mi nistrati o n of t he I SI m ust occ ur at least 5 da y s after t he last d ose of all 
h y p n otic dr u g s.)
4. 
S u bject m ust ha ve a n s S O L ≥4 5 mi n utes a n d a n s W A S O ≥6 0 mi n utes o n at least 
3 ni g hts o ver a n y 7- d a y  peri o d d uri n g Part 1 of scree ni n g, usi n g t he C S D -M, pri or t o 
scree ni n g P S G assess me nts.
( N ote: F or s u bjects ta ki n g h y p n otic dr u gs at t he ti me of si g ni n g t he I C F, a d mi nistrati o n 
of t he C S D -M m ust start a t least 5 d a y s after t he last d ose of all h y p n otic dr u g s.)
5. 
S u bject m ust de m o nstrate a 2- ni g ht mea n L P S of ≥2 5 mi n utes ( wit h neit her ni g ht 
< 2 0 mi n utes), a 2 -ni g ht mea n W A S O ≥3 0 mi n utes, a n d a 2 -ni g ht mea n T S T ≤6. 5 h o urs, 
wit h neit her ni g ht > 7 h o urs.
( Note: T he 2 ni g hts of scree ni n g P S G ac q uisiti o ns will be c o n d ucte d c o nsec uti vel y. 
T hese assess me nts s h o ul d be c o m plete d bet wee n Da y  -1 4 a n d a p pr o xi matel y Da y - 5 t o 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
all o w f or a nal ysis of t he P S G data a n d esta blis h eli gi bilit y f or ra n d o mizati o n).
6. 
S u bject m ust be ot her wise healt h y or prese nt wit h sta ble, well -c o ntr olle d, c hr o nic 
c o n diti o ns o n t he basis of p h y sical e xa mi nati o n, me dical hist or y, vital si g ns, 1 2 -lea d 
E C G , a n d cli nical la b orat or y tests perf or me d at scree ni n g. If t here are a b n or malities, 
t he y m ust be c o nsiste nt wit h t he u n derl yi n g ill ness i n t he st u d y p o p ulati o n. If t he res ults 
of t he cli nical la b orat or y tests are o utsi de t he n or mal refere nce ra n ges, t he s u bject m a y  
be i ncl u de d o nl y if t he i n vesti gat or a n d t he s p o ns or's Safet y P h y sicia n j u d ge t he
a b n or malit y or de viati o ns fr o m n or mal t o be n ot cli nicall y si g nifica nt or t o be 
a p pr o priate a n d reas o na ble f or t he p o p ulati o n u n der st u d y. T his deter mi nati o n m ust be 
rec or de d i n t he s u bject's s o urce d oc u me nts a n d i nitiale d b y t he i n vesti gat or.
7.
B o d y mass i n de x bet wee n 1 8 a n d 3 5 k g/ m 2 i ncl usi ve (b o d y  mass i n de x= wei g ht/ hei g ht 2).
8.
F or s u bjects ≥6 5 ye ars of a ge, a Mi ni-Me ntal State E xa mi nati o n sc ore of ≥2 5 t o r ule o ut 
c o g niti ve i m pair me nt i n t he i nterest of s u bject safet y .
9.
Criteri o n m o difie d per A me n d me nt 3
9. 1 S u bject m ust us uall y  spe n d bet wee n 6 a n d 9 h o urs i n be d d uri n g t he ni g ht a n d g o t o 
be d bet wee n 8 P M a n d 1 A M a n d t y picall y  get o ut of be d bet wee n 5 A M a n d 9 A M.
1 0.
Cr iteri o n delete d per A me n d me nt 2
1 1. 
Criteri o n d elete d per A me n d me nt 2
1 2.
A
w o ma n m ust a gree n ot t o d o nate e g gs ( o va, o oc y tes) f or t he p ur p oses 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 a peri o d of at least 1 m o nt h after recei vi n g t he last 
d ose of st u d y  dr u g.
1 3. 
Criteri o n m o difie d per A me n d me nt 2
1 3. 1. D uri n g t he st u d y an d f or a mi ni m u m of 1 s per mat o ge nesis c ycle ( defi ne d as 
a p pr o xi matel y 3 m o nt hs ) after recei vi n g t he last d ose of st u d y  dr u g, a ma n:

w h o is se x uall y acti ve wit h a w o ma n of c hil d beari n g p ote ntial m ust a gree t o use a 
barrier 
met h o d 
of 
c o ntrace pti o n 
(eg, 
c o n d o m 
wit h 
s per mici dal 
f oa m/ gel/fil m/crea m/s u p p osit or y)

w h o is se x uall y  acti ve wit h a w o ma n w h o is pre g na nt m ust use a c o n d o m

m ust a gree n ot t o d o nate s per m.
1 4.
S u bject m ust be willi n g a n d a ble t o a d here t o t he pr o hi biti o ns a n d restricti o ns s pecifie d
i n t his pr ot oc ol.
1 5. 
S u bject m ust si g n a n 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 uire d f or, t he st u d y a n d is willi n g t o partici pate i n t he st u d y.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6 3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1 6. 
S u bjects m ust si g n a se parate I CF if he or s he a grees t o pr o vi de a n o pti o nal D N A
sa m ple f or researc h ( w here l ocal re g ulati o ns per mit). Ref usal t o gi ve c o nse nt f or t he 
o pti o nal D N A
researc h sa m ples d oes n ot e x cl u de a s u bject fr o m partici pati o n i n t he 
st u d y.
4. 2.
E x cl u si o n Crit eri a
A n y  p ote ntial s u bject w h o meets a n y of t he 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.
Criteri o n m o difie d per A me n d me nt 1
1. 1. Criteri o n m o difie d per A me n d me nt 2
1. 2. Has hist or y  of or c urre nt cli nicall y si g nifica nt a n d/ or u nsta ble li ver ( m o derate or
se vere he patic i m pair me nt [ C hil d-P u g h Sc ore ≥7] ) or re nal i ns ufficie nc y (se vere re nal 
i m pair me nt [esti mate d creati ni ne cleara nce bel o w 3 0 m L / mi n]; ser u m creati ni ne 
> 2 m g/ d L ); si g nifica nt a n d/ or u nsta ble car diac, vasc ular, p ul m o nar y (e g, ac ute or 
se vere res pirat or y fail ure), gastr oi ntesti nal, e n d ocri ne, ne ur ol o gic (e g, m y ast he nia 
gra vis , narc ole ps y), 
he mat ol o gic,
r he u mat ol o gic, i m m u n ol o gic, or 
meta b olic 
dist ur ba nces. Or ga nic brai n disease, e pile ps y,  de me ntia, narc ole ps y, narr o w a n gle 
gla u c o ma a n d k n o w n or s us pecte d me ntal retar dati o n are e xcl usi o nar y. A n y  cli nicall y 
rele va nt me dical c o n diti o n t hat is li kel y to res ult i n deteri orati o n of t he s u bject's 
c o n diti o n or affect t he s u bject's safety d uri n g t he st u d y (e g, me dicall y frail s u bject 
wit h 
hist or y  of h os pitalizati o n d ue t o fract ures) or c o ul d p ote ntiall y  alter t he 
a bs or pti o n, meta b olis m, or e xcreti o n of t he st u d y dr u g is e xcl usi o nar y .
N ote: S u bjects wit h c hr o nic b ut sta ble, well -c o ntr olle d c o n diti o ns ma y  be all o we d i n 
t he st u d y u p o n a gree me nt wit h t he i n vesti gat or a n d t he s p o ns or's Safet y P h ysicia n.
2.
Has u nc o ntr olle d h y perte nsi o n (s u pi ne s yst olic bl o o d press ure > 1 5 0 m m H g i n a d ult
su bjects or > 1 6 0 m m H g i n el derl y s u bjects or s u pi ne diast olic bl o o d press ure 
> 9 0 m m H g, des pite diet, e xercise, or a sta ble d ose of all o we d a nti h yperte nsi ve 
t hera py) at scree ni n g or D a y  1. ( A s u bject wit h h y perte nsi o n m a y  be i ncl u de d if t he 
s u bject’s hy per te nsi o n has bee n c o ntr olle d f or at least 3 m o nt hs pri or t o scree ni n g, a n d 
t he d osa ge of a ny a nti h y perte nsi ve me dicati o n has bee n sta ble f or t he past 3 m o nt hs).
3.
Has cli nicall y si gnifica nt a b n or mal val ues f or he mat ol o g y , cli nical c he mistr y, or 
uri nal y sis at scree ni n g. S u bjects wit h n o n-i ns uli n de pe n de nt dia betes mellit us w h o are 
a de q uatel y c o ntr olle d ( he m o gl o bi n A 1c [ H b A 1c] ≤8 %) m a y  be eli gi ble t o partici pate 
if ot her wise me dicall y  healt h y. It is e x pecte d t hat la b orat or y val ues will ge nerall y be 
wit hi n t he n or mal ra n ge, t h o u g h mi n or de viati o ns, w hic h are n ot c o nsi dere d t o be of 
cli nical si g nifica nce t o b ot h t he i n vesti gat or a n d t he s p o ns or’s Safet y P h y sicia n, are 
acce pta ble.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
4.
Has 
cli nicall y si g nifica nt E C G a b n or malities at scree ni n g or Da y 
1 pri or t o 
ra n d o mizati o n defi ne d as:

Q T i nter val c orrecte d acc or di n g t o Fri dericia’s f or m ula: ≥4 5 0 msec 
( males); 
≥4 7 0 msec (fe males)

E vi de nce of 2 n d a n d 3 r d de gree atri o ve ntric u lar bl oc k, or 1 st de gree atri o ve ntric ular 
bl oc k wit h P R i nter val > 2 1 0 msec, left b u n dle bra nc h bl oc k. 

Feat ures of ne w isc he mia

Ot her cli nicall y i m p orta nt arr h yt h mia.
N ote: S u bjects wit h ri g ht b u n dle bra nc h bl oc k ma y  be all o we d pr o vi de d c o nfir mati o n 
t hat ri g ht b u n dle bra nc h bl oc k is n ot ass ociate d wit h u n derl yi n g car diac/l u n g diseases.
5.
Has si g nifica nt h y pers o m nia n ot relate d t o ni g ht ti me i ns o m nia ( base d o n cli nical 
j u d g me nt of t he i n vesti gat or).
6.
Re g ularl y  na ps m ore t ha n 3 ti mes per wee k.
7.
Has
a c urre nt dia g n osis or rece nt hist or y  of ps y c h otic dis or der, M D D, 
bi p olar 
dis or der, or p osttra u matic stress dis or der, or ot her ps yc hi atric c o n diti o n t hat, i n t he 
i n vesti gat or’s o pi ni o n, w o ul d i nterfere wit h t he s u bject’s a bilit y to partici pate i n t he 
trial.
8.
Has a c urre nt or rece nt hist or y  of seri o us s uici dal i deati o n wit hi n t he past 6 m o nt hs, 
c orres p o n di n g t o a p ositi ve res p o nse o n ite m 4 (acti ve s uici dal i deati o n wit h s o me i nte nt 
t o act, wit h o ut s pecific pla n) or ite m 5 (acti ve s uici dal i deati o n wit h s pecific pla n a n d 
i nte nt) f or i deati o n o n t he C-S S R S, or a hist or y  of s uici dal be ha vi or wit hi n t he past year, 
as vali date d b y t he C-S S R S at scree ni n g or Da y  1. S u bjects wit h a pri or s uici de atte m pt 
of a n y sort, or pri or seri o us s uici dal i deati o n/ pla n wit hi n the past 6 m o nt hs, s h o ul d be 
caref ull y scree ne d f or c urre nt s uici dal i deati o n a n d o nl y s u bjects wit h n o n -seri o us 
ite ms ( 1-3 of t he s uici dal i deati o n secti o n of t he C- S S R S) ma y  be i ncl u de d at t he 
discreti o n of t he i n vesti gat or.
9.
Has
i ns o m nia relate d t o R L S ( defi ne d as P L M -ar o usal i n de x of ≥1 0 P L M- relate d 
electr oe nce p hal o gra p h (E E G ) ar o usals per h o ur of slee p f or a d ult s u bjects or > 1 5 f or 
el derl y s u bjects), slee p breat hi n g dis or der ( defi ne d as a n a p nea-h y p o p nea i n de x 
≥1 0 c u m ulati ve a p neas a n d h y p o p neas p e r h o ur of E E G slee p f or a d ult s u bjects or 
> 1 5 f or el derly s u bjects), or paras o m nias. T hese dis or ders will be r ule d o ut b y t he first 
P S G rec or di n g d uri n g Part 2 of scree ni n g.
1 0 .
Is a s hift w or ker or has a si g nifica ntly s hifte d di ur nal acti vit y patter n

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1 1.
Has e x perie nce d tra ns meri dia n tra vel acr oss 2 or m ore ti me z o nes wit hi n t he 2 wee ks 
pri or t o scree ni n g, or pla ns t o tra vel acr oss 2 or m ore ti me z o nes d uri n g st u d y 
partici pati o n.
1 2.
Has a k n o w n mali g na nc y  or hist or y  of mali g na nc y  wit hi n 5 ye ars bef ore scree ni n g 
(e xce pti o ns are s q ua m o us a n d basal cell carci n o mas of t he s ki n a n d carci n o ma i n sit u 
of t he cer vi x, or mali g na nc y , t hat i n t he o pi ni o n of t he i n vesti gat or, wit h t he 
c o nc urre nce wit h t he s p o ns or's Safet y P h y sicia n, is c o nsi dere d c ure d wit h mi ni mal
ris k of rec urre nce).
1 3.
Has a hist or y  of s u bsta nce or alc o h ol use dis or der of m o derate t o se vere se verity 
acc or di n g t o D S M -5 criteria wit hi n 6 m o nt hs bef ore scree ni n g or p ositi ve test res ult(s) 
f or alc o h ol or dr u gs of a b use (i ncl u di n g bar bit urates, o pia tes [i ncl u di n g met ha d o ne], 
c ocai ne, 
ca n na bi n oi ds, 
met ha m p heta mi nes, 
a m p heta mi nes, 
3, 4- Met h y le ne di o x ymet ha m p heta mi ne, a n d B Z D) at scree ni n g or at baseli ne.
1 4.
S m o kes > 1 0 ci garettes per d a y  a n d/or has q uit s m o ki n g wit hi n 1 m o nt h pri or t o 
scree ni n g.
1 5.
C o ns u me s, 
o n a vera ge, 
> 5 0 0 
m g 
of 
caffei ne 
per 
d a y  in 
a n y 
for m 
(tea/c offee/c oc oa/c ola/e ner g y dri n ks). Refer t o Attac h me nt 2 f or a vera ge caffei ne 
c o nte nt of vari o us be vera ges.
1 6.
Has ta ke n a k n o w n m o derate or str o n g i n hi bit or/i n d ucer of C Y P 3 A 4 a n d C Y P 2 C 9 or 
a d ual i n hi bit or/i n d ucer of C Y P 3 A 4 a n d C Y P 2 C 9 wit hi n 1 4 da ys  (or after was h o ut ie, 
d urati o n of 5 ti mes t he dr u g’s half -life) bef ore t he first st u d y dr u g a d mi nistrati o n o n 
D a y  1. Si milarl y , s u bjects s h o ul d a v oi d c o ns u m pti o n of her bal pr o d ucts c o ntai ni n g 
St. J o h n’s w ort, e p he dra, gi n k g o, gi nse n g, or ka va fr o m at least 2 wee ks pri or t o t he 
first st u d y dr u g a d mi nistrati o n o n Da y 1.
1 7.
Has ta ke n a n y disall o we d t hera pies as n ote d i n Secti o n 8 , Prest u d y  an d C o nc o mita nt 
T hera p y, esta blis he d eit her b y  partici pa nt re p ort or b y  scree ni n g dr u g testi n g, bef ore 
t he pla n ne d first d ose of st u d y dr u g.
1 8.
Ha d 
cli nicall y si g nifica nt ac ute ill ness wit hi n 
7 da y s pri or t o st u d y dr u g 
a d mi nistrati o n.
1 9.
Criteri o n m o difie d per A me n d me nt 1
1 9. 1. Has k n o w n aller gies, h y perse nsiti vit y, i nt olera nce, lac k of res p o nse, or a n y 
c o ntrai n dicati o n t o J NJ- 4 2 8 4 7 9 2 2
or z ol pi de m or t heir e xci pie nts (refer t o 
I n vesti gat or's Br oc h ure f or J NJ- 4 2 8 4 7 9 2 23 5 a n d S m P C/ PI f or z ol pi de m).8 7 ,8 8 ,8 9
2 0.
Is un der o n g oi n g ps yc h ol o gical treat me nts f oc use d o n i ns o m nia (e g, C o g niti ve 
Be ha vi or T hera p y),  initiate d wit hi n 2 m o nt hs pri or t o Da y  1. A s u bject w h o has bee n 
recei vi n g o n g oi n g ps yc h ol o gical treat me nt f or a peri o d of greater t ha n 2 m o nt hs is 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6 6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
eli gi ble, if t he i n vesti gat or dee ms t he ps y c h ol o gical treat me nt t o be of sta ble d urati o n 
a n d fre q ue nc y. T he s u bject’s ps yc h ol o gical treat me nt s h o ul d be mai ntai ne d d uri n g 
partici pati o n i n t he st u d y .
2 1.
Has d o nate d 1 or m ore u nits (a p pr o xi matel y 45 0 m L ) of bl o o d or ac ute l oss of a n 
e qui vale nt a m o u nt of bl o o d wit hi n 6 0 da y s pri or t o st u d y dr u g a d mi nistrati o n.
2 2.
Criteri o n m o difie d per A me n d me nt 1
2 2. 1. Criteri o n m o difie d per A me n d me nt 2
2 2. 2.  •  Pla ns t o fat her a c hil d w hile e nr olle d i n t his st ud y  or wit hi n 3 m o nt hs after 
t he last d ose of st u d y dr u g.
•  Is pre g na nt or breastfee di n g w hile e nr olle d i n t his st u d y or wit hi n 1 m o nt h
after t he last d ose of st u d y dr u g.
2 3.
Has recei ve d a n i n vesti gati o nal dr u g (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 3 m o nt hs bef ore t he pla n ne d 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.
2 4. 
Criteri o n m o difie d per A me n d me nt 2
2 4. 1. Has ps y c h ol o gic a n d/ or e m oti o nal pr o ble ms, w hic h w o ul d re n der t he i nf or me d 
c o nse nt i n vali d, or li mit t he a bilit y of t he s u bject t o c o m pl y 
wit h t he st u d y 
re q uire me nts, or is a v ul nera ble s u bject d ue t o i n v ol u ntar y  dete nti o n (s uc h as f or le gal 
reas o ns).
2 5.
Has 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 s u bject (e g, c o m pr o mise t he well -bei n g) or t hat c o ul d 
pre ve nt, li mit, or c o nf o u n d t he pr ot oc ol -s pecifie d assess me nts.
2 6.
Has ha d maj or s ur ger y, (e g, re q uiri n g ge neral a nest hesia) wit hi n
2 wee ks bef ore 
scree ni n g, or will n ot ha ve f ull y rec o vere d fr o m s ur ger y, or has s ur ger y pla n ne d 
d uri n g t he ti me t he s u bject is e x pecte d t o partici pate i n t he st u d y .
N ote: 
S u bjects wit h 
pla n ne d s ur gical pr oce d ures t o be c o n d ucte d u n der l ocal 
a nest hesia ma y partici pate.
2 7.
Is a n e mpl o y ee 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 der t he 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 bers of t he e m pl o yees or t he i n vesti gat or
N O T E: I nvesti gat ors s h o ul d e ns ure t hat all st u d y e nr oll me nt criteria ha ve bee n met at scree ni n g. 
If a s u bject'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 t he first d o se of st u d y dr u g is gi ve n s uc h 
t hat he or s he n o l o n ger meet s all eli gi bilit y criteria, t hen t he s u bject s h o ul d be e xcl u de d fr o m 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6 7
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
partici pati o n i n t he st u d y. Secti o n 1 7. 4 , S o urce D oc u me ntati o n, 
descri bes t he re q uire d 
d oc u me ntati o n t o s u p p ort meeti n g t he e nr oll me nt criteria .
4. 3.
Pr o hi biti o n s a n d R e stri cti o n s
P ote ntial s u bjects 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 pr o hi biti o ns a n d 
restricti o ns d uri n g t he c o urse of t he st u dy t o be eli gi ble f or partici pati o n:
1.
Refer t o Secti o n 8 P rest u d y a n d C o nc o mita nt T hera p y f or details re gar di n g pr o hi bite d 
a n d restricte d t hera p y d uri n g t he st u d y.
2. 
T he use of li mite d a m o u nts of alc o h ol, n o m ore t ha n 2 dri n ks ( u p t o 4 u nits dail y  eg, 
2 a vera ge glasses [ 3 5 0 m L ] of wi ne, 2 pi nts [ 1 0 0 0 m L] of 4 % beer, 2 o u nces [6 0 m L ] of 
s pirits, 2 G o [ 3 6 0 m L ] of Ja pa nese sa ke, or 1. 2 G o [ 2 2 0 m L ] of S h oc h u ), will be 
all o we d d uri n g treat me nt at h o me, b ut alc o h ol use is n ot all o we d o n t he da y  of a P S G 
rec or di n g ( pri or t o e nteri n g t he st u d y site) a n d d uri n g t he sta ys at t he st u d y site.
A d diti o nall y , s u bjects will be re mi n de d a b o ut t he ne gati ve c o nse q ue nces of c o m bi ni n g 
h y p n otics a n d alc o h ol (refer t o S m P C/ PI  f or z ol pi de m).
3.
S m o ki n g > 1 0 ci garettes/ da y  a n d/ or q uitti n g s m o ki n g is pr o hi bite d t hr o u g h o ut t he st u d y.
4. 
Stre n u o us e xercise ma y  aff ect st u d y specifie d assess me nts a n d safety la b orat or y res ults; 
f or t his reas o n, stre n u o us e xercise s h o ul d be a v oi de d f or 2 4 h o urs pri or t o t he P S G 
ni g hts ( Da y  1 a n d 1 3) a n d t he o pti o nal P K c ollecti o n ( Da y  2).
5.
S u bjects will be a d vise d n ot t o d o nate bl o o d f or at least 6 0 da y s after c o m pleti o n of t he 
st u d y.
6.
S u bjects s h o ul d be ca uti o ne d n ot t o dri ve a car or o perate mac hi ner y  or e n ga ge i n a n y 
p ote ntiall y  hazar d o us acti vities if t he y ha ve ha d less t ha n a f ull ni g ht’s slee p ( 6-8 h o urs) 
f oll o wi n g a d mi nistrati o n of t he st u d y dr u g or at a n y ti me d uri n g t he st u d y if t he s u bject 
feels t hat his or her baseli ne ca pacit y is i m paire d.
N ote: At a n y poi nt d uri n g t he st u d y, if a s u bject ma nifest s si g nifica nt ne xt -da y  
slee pi ness, t he y are a d vise d t o i nf or m t he i n vesti gat or. S uc h s u bjects m a y  be 
disc o nti n ue d or a d vise d n ot t o dri ve or o perate mac hi ner y.
7.
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 ncl usi o n a n d E xcl usi o n Criteria (e g, c o ntrace pti ve re q uire me nts).

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6 8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
5.
T R E A T M E N T A L L O C A TI O N A N D B LI N DI N G
Tre at me nt All oc ati o n
P r oce d ures f or R a nd o miz ati o n a n d Str atific ati o n
Ce ntral ra n d o mizati o n will be i m ple me nte d i n t his st u d y. At t he start of st u d y enr oll me nt, 
su bjects will be ra n d o ml y assi g ne d t o 1 of 5 treat me nt gr o u ps ( place b o, J NJ- 4 2 8 4 7 9 2 2 5 m g, 
J NJ- 4 2 8 4 7 9 2 2 1 0 m g, J NJ- 4 2 8 4 7 9 2 2 2 0 m g, or z ol pi de m) i n a 1: 1: 1: 1: 1 rati o, base d o n a 
c o m p uter-ge nerate d ra n d o mizati o n sc he d ule pre pare d bef ore t he st u d y by or u n der t he 
s u per visi o n of t he s p o ns or. 
T he ra n d o mizati o n will be bala 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
re gi o n ( U S/E U, Ja pa n), a ge gr o u p (a d ult, el derl y), a n d i nte nsi ve P K sa m pli n g ( yes, n o) . T o
ra n d o mize a p pr o xi matel y eq ual pr o p orti o ns of a d ult a n d el derl y s u bjects, t he n u m ber 
ra n d o mize d i n eit her a ge gr o u p will be ca p pe d at a p pr o xi matel y 6 0 % of t he pla n ne d t otal sa m ple 
size.
T he i nteracti ve we b res p o nse s yste m (I W R S) will assi g n a u ni q ue treat me nt c o de, w hic h will 
dictate t he treat me nt assi g n me nt a n d matc hi n g st u d y dr u g kit f or t he s u bject. T he re q uest or m ust 
use his or her o w n user i de ntificati o n a n d pers o nal i de ntificati o n n u m ber w he n c o ntacti n g t he 
I W R S, a n d will the n gi ve t he rele va nt s u bject details t o u ni q uel y  i de ntif y t he s u bject.
Bli n di n g
T o mai ntai n t he st u d y bli n d, t he st u d y dr u g c o ntai ner will ha ve a la bel c o ntai ni n g t he st u d y 
na me, st u d y dr u g n u m ber, a n d refere nce n u m ber. T he la bel will n ot i de ntif y t he st ud y  dr u g i n t he 
c o ntai ner. H o we ver, if it is necessar y  for a s u bject's safety, t he st u d y bli n d ma y  be br o ke n a n d 
t he i de ntit y of t he st u d y dr u g ascertai ne d. T he st u d y dr u g n u m ber will be e ntere d i n t he 
electr o nic case re p ort f or m ( C R F) w he n t he st u d y dr u g is dis pe nse d. T he st u d y dr u gs will be 
i de ntical i n a p peara nce a n d will be pac ka ge d i n i de ntical c o ntai ners.
T he i n vesti gat or will n ot be pr o vi de d wit h ra n d o mizati o n c o des. T he c o des will be mai ntai ne d 
wit hi n t he I WR S , w hic h has t he f u ncti o nalit y to all o w t he i n vesti gat or t o brea k t he bli n d f or a n 
i n di vi d ual s u bject.
Data t hat ma y p ote ntiall y u n bli n d t he treat me nt assi g n me nt (ie, st u d y dr u g ser u m c o nce ntrati o ns,
st u d y dr u g pre parati o n/acc o u nta bilit y  data, treat me nt all ocati o n, a n d bi o mar ker or ot her s pecific 
la b orat or y data) will be ha n dle d wit h s pecial care t o e ns ure t hat t he i nte grity of t he bli n d is 
mai ntai ne d a n d t he p ote ntial f or bias is mi ni mize d. All P S G varia bles will be ce ntrall y sc ore d, 
a n d t he i n vesti gat ors will n ot ha ve access t o t he P S G res ults fro m t he ac q uisiti o n ni g hts d uri n g 
st u d y treat me nt.
U n der n or mal circ u msta nces, t he bli n d s h o ul d n ot be br o ke n u ntil all s u bjects ha ve c o m plete d 
t he st u d y an d t he data base is fi nalize d. Ot her wise, t he bli n d s h o ul d be br o ke n o nl y if s pecific 
e mer ge nc y treat ment/c o urse of acti o n w o ul d be dictate d b y  kn o wi n g t he treat me nt stat us of t he 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
6 9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
s u bject. I n suc h cases, t he i n vesti gat or m a y  in a n e mer ge nc y deter mi ne t he i de ntit y of t he 
treat me nt b y c o ntacti n g t he I WR S . It is rec o m me n de d t hat t he i n vesti gat or c o ntact t he s p o ns or or 
its desi g nee if p ossi ble t o disc uss t he partic ular sit uati o n, bef ore brea ki n g t he bli n d. Tele p h o ne 
c o ntact wit h t he s p o ns or or its desi g nee will be a vaila ble 2 4 h o urs per da y , 7 d a y s per wee k. I n 
t he e ve nt t he bli n d is br o ke n, t he s p o ns or m ust be i nf or me d as s o o n as p ossi ble. T he date, ti me, 
a n d reas o n f or t he u n bli n di n g m ust be d oc u me nte d i n t he a p pr o priate secti o n of t he C R F, a n d i n 
t he s o urce d oc u me nt. T he d oc u me ntati o n recei ve d fr o m t he I WR S i n dicati n g t he c o de brea k 
m ust be retai ne d wit h t he s u bject's s o urce d oc u me nts i n a sec ure ma n ner.
S u bjects w h o ha ve ha d t heir treat me nt assi g n me nt u n bli n de d are re q uire d t o ret ur n f or t he 
f oll o w-u p/e n d - of-st u d y-visit .
I n ge neral, ra n d o mizati o n c o des will be discl ose d f ull y onl y if t he st u d y is c o m plete d a n d t he 
cli nical data base is cl ose d.
6.
D O S A G E A N D A D MI NI S T R A T I O N
J NJ- 4 2 8 4 7 9 2 2 will be s u p plie d as ca ps ules ( o ver-e nca ps ulate d ta blets) of 2. 5-, 1 0-, a n d 2 0- m g . 
T he J NJ-4 2 8 4 7 9 2 2 5 m g d ose will c o nsist of t w o 2. 5 m g ca ps ules. All ot her J NJ-4 2 8 4 7 9 2 2 d oses 
will c o nsist of 1 acti ve a n d 1 place b o ca ps ule eac h (Ta ble 2 ). Z ol pi de m will be s u p plie d as a 
ca ps ule ( over -e nca ps ulate d ta blet), c o ntai ni n g 5 -m g z ol pi de m. T he 5 m g d ose of z ol pi de m will 
c o nsist of 1 acti ve a n d 1 place b o ca ps ule; t he 1 0 m g d ose of z ol pi de m will c o nsist of t w o 5 m g 
ca ps ules. Place b o will be s u p plie d as matc hi n g ca ps ules a n d, f or s u bjects ra n d o mize d t o place b o, 
t he d ose will c o nsist of 2 place b o ca ps ules. Z o l pi de m will be d ose d per t he l ocal la beli n g 
i nf or mati o n: i n t he U S , a d ult fe males a n d el derl y (males a n d fe males) will recei ve 5 m g  doses 
w hile a d ult males will recei ve 1 0 m g d oses ; i n t he E U, a d ults will recei ve 1 0 m g d oses w hile 
el derl y will recei ve 5 m g d oses ; a n d i n Ja pa n, a d ults a n d el derl y will recei ve 5 m g d oses . 
T a ble 2 :
D ose Descri pti o n
D ose Le vel
C a ps ules ( 2 per d ose le vel)
J NJ-4 2 8 4 7 9 2 2 5 m g
J NJ-4 2 8 4 7 9 2 2 2. 5 m g a n d 2. 5 m g
J NJ-4 2 8 4 7 9 2 2 1 0 m g
J NJ-4 2 8 4 7 9 2 2 1 0 m g a n d place b o
J NJ-4 2 8 4 7 9 2 2 2 0 m g
J NJ-4 2 8 4 7 9 2 2 2 0 m g a n d place b o
Place b o
2 place b o ta blets
Z ol pi de m 5 m g
Z ol pi de m 5 m g a n d place b o
Z ol pi de m 1 0 m g
Z ol pi de m 5 m g a n d 5 m g
O n D a y s 1 t hr o u g h 1 4 of t he d o u ble -bli n d treat me nt p hase, s u bjects will recei ve eit her 
J NJ- 4 2 8 4 7 9 2 2, z ol pi de m, or place b o o nce dail y , at n or mal be dti me o n n o n- P S G ni g hts or 
1 5 mi n utes pri or t o li g hts o ut o n ni g hts of P S G rec or di n g.
T he st u d y dr u g will be ta ke n wit h a p pr o xi matel y 1 0 0 m L  of water. T he ca ps ules m ust be 
s wall o we d w h ole a n d n ot c he we d, di vi de d, diss ol ve d, or cr us he d.
St u d y  dr u g will be s u p plie d i n blister pac ks i de ntifie d b y  a nu m ber. T he I W R S will assi g n t he 
n u m bers of t he blister pac ks (st u d y  dr u g kits) t o be use d by a s u bject.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
St u d y -site pers o n nel will i nstr uct s u bjects o n h o w t o st ore st u d y dr u g f or at -h o me use as 
i n dicate d f or t his pr ot oc ol.
F or t his st u d y, a n y d ose of J NJ- 4 2 8 4 7 9 2 2 greater t ha n t he n u m ber of ca ps ules assi g ne d f or eac h 
da y
will 
be c onsi dere d a n o ver d ose.
S pecial re p orti n g of a n o ver d ose is disc usse d i n 
Secti o n 1 2. 2 .
7.
T R E A T M E N T C O M P LI A N C E
W he n 
st u d y dr u g will be a d mi nistere d at t he st u d y site (ie, Da y s 1, 1 3,
a n d 1 4 ), t he 
a d mi nistrati o n of st u d y dru g will be wit nesse d b y  the i n vesti gat or or a pr o perl y  trai ne d desi g nee. 
F or t he s u bjects w h o will ha ve o ver ni g ht P K, bi o mar ker sa m ples, a n d ot he r pr oce d ures as 
descri be d i n t he T i me a n d E ve nts Sc he d ule - Part 2 ( at least 4 0 n o n- el derl y a d ult s u bjects a n d 
4 0 el derly s u bjects), st u d y dr u g will als o be a d mi nistere d at t he st u d y site o n Ni g ht 2 a n d t he y 
will be disc har ge d at ar o u n d n o o n of Da y  3 (2 o ver ni g hts). T he e xact date a n d ti me of dr u g 
a d mi nistrati o n will be rec or de d i n t he C R F.
T he n u m ber of st u d y dr u g ca ps ules dis pe nse d f or self-a d mi nistrati o n b y  su bjects at h o me 
(e g, fr o m D a y s 2 t o 1 2 f or t h ose s u bjects n ot u n der g oi n g o ver ni g ht P K sa m pli n g or Da y s 3 t o 1 2 
f or t h ose s u bjects wit h o ver ni g ht P K sa m pli n g o n Ni g ht 2) will be rec or de d a n d c o m pare d wit h 
t he n u m ber ret ur ne d o n D a y 1 3. S u bjects are re q uire d t o rec or d t he a d mi nistrati o n of st u d y dr u g 
i n st u d y diaries, w hic h will be c hec ke d at re g ular i nter vals.
If a p pr o priate, a d diti o nal details ma y  be pr o vi de d i n a site i n vesti gati o nal pr o d uct ma n ual t hat is 
pr o vi de d se paratel y a n d n ote d i n Secti o n 1 5 , Stu d y -S pecific Materials.
8.
P R E S T U D Y A N D C O N C O MI T A N T T H E R A P Y
Prest u d y  thera pies a d mi nistere d u p t o 3 0 d a y s bef ore t he scree ni n g visit a n d a n y on g oi n g 
t hera pies m ust be rec or de d at scree ni n g.
C o nc o mita nt t hera pies m ust be rec or de d t hr o u g h o ut t he st u d y be gi n ni n g wit h si g ni n g of t he 
i nf or me d c o nse nt (ie, scree ni n g) u ntil t he f oll o w- u p visit . C o nc o mita nt t hera pies s h o ul d als o be 
rec or de d be yo n d t his ti me o nl y  i n c o nj u ncti o n wit h ne w or w orse ni n g A E s or S A E s t hat meet t he 
criteria o utli ne d i n Secti o n 1 2. 3. 2 . Seri o us A d verse E ve nts. F or s u bjects w h o fail scree ni n g, 
c o nc o mita nt t hera pies d o n ot nee d t o be rec or de d u nless t here is a n a d verse e ve nt .
All t hera pies ( prescri pti o n or o ver -t he-c o u nter me dicati o ns, i ncl u di n g vacci nes, vita mi ns, her bal 
s u p ple me nts; n o n- p har mac ol o gic 
t hera pies s uc h as 
ps yc h ol o gical 
t hera pies, electrical 
sti m ulati o n, ac u p u nct ure, s pecial diets, e xercise re gi me ns) differe nt fr o m t he st u d y dru g m ust be 
rec or de d i n t he C R F . Rec or de d i nf or mati o n will i ncl u de a descri pti o n of t he t ype of t he dr u g, 
treat me nt peri o d, d osi n g re gi me n, r o ute of a d mi nistrati o n, a n d its i n dicati o n. M o dificati o n of a n 
eff ecti ve pree xisti n g t hera p y sh o ul d n ot be ma de f or t he e x plicit p ur p ose of e nteri n g a s u bject 
i nt o t he st u d y.
F or safety reas o ns, t he use of h y p n otic a n d se dati n g dr u gs (i ncl u di n g se dati ve a nti hista mi nes ,
her bal s u p ple me nts, a n d l o w-d ose a nti de pressa nts prescri be d f or slee p ) is pr o hi bite d fr o m 5 d a y s 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
after si g ni n g of t he I CF u ntil t he last st u d y visit (i ncl u di n g t he f oll o w-u p visit). J NJ-4 2 8 4 7 9 2 2 
a n d z ol pi de m ha ve h y p n otic pr o perties. A part fr o m h y p n otic dr u gs, n o necessar y  me dicati o n will 
be st o p pe d f or t he s ole p ur p ose of ma ki n g s u bjects eli gi ble f or e nr oll me nt i n t he st u d y. Re b o u n d 
effects of st o p pi n g pre st u d y slee p me dicati o n s h o ul d be pre ve nte d. W he n 
p ossi ble, all slee p 
me dicati o n s h o ul d be st o p pe d wit hi n
5 da y s after si g ni n g t he IC F . T he i n vesti gat or s h o ul d 
c o nsi der if 5 da y s is s ufficie nt f or t he disc o nti n uati o n of t he h y p n otic/se dati n g me dicati o ns s uc h 
as f or c hr o nic be nz o diaze pi ne use w here a pr ol o n ge d ta per m a y  be m ore a p pr o priate. S u bjects 
s h o ul d n ot use t he f oll o wi n g me dicatio n or f o o d s u p ple me nts d uri n g t he st u d y : 

A nti de pressa nts (i ncl u di n g traz o d o ne a n d tric yclic a nti de pressa nts li ke d o xe pi n), B Z D s, 
bar bit urates or c hl oral h y drate, h y p n otics (i ncl u di n g esz o picl o ne, ra melte o n, s u v ore xa nt, 
z o picl o ne, a n d zale pl o n), her bal slee p ai ds, lit hi u m a n d ot her m o o d sta bilizers/a ntie pile ptic 
dr u gs, melat o ni n 
a n d melat o ni n 
rece pt or a g o nists, o piates, S- a de n os yl met hi o ni ne, a n d 
se dati n g a nti hista mi nes fr o m at least 5 da y s after si g ni n g t he I CF u ntil t he f oll o w- u p visit. 
( Slee p me dicati o n sh o ul d be ta pere d off t o pre ve nt re b o u n d i ns o m nia a n d c o m pletel y  st o p pe d
wit hi n 5 da y s after si g ni n g t he I CF ).

Sti m ula nts ( de xa m p heta mi ne, met h y l p he ni date, de x met h y l p he ni date), wa kef ul ness a ge nts 
( m o dafi nil, ar m o dafi nil), ster oi ds ( oral s yste mic [i n hale d a nd t o pical ster oi ds f or a p plicati o n 
t o t he s ki n or e yes are per mitte d]), oral dec o n gesta nts a n d a p petite s u p pressa nts (s uc h as 
e p he dri ne), a n d is o xs u pri ne wit hi n 5 da y s after si g ni n g t he I C F u ntil t he f oll o w -u p visit.

A nti ps y c h otic dr u gs ( D2-a nta g o nists a n d D 2 partial a g o nists ) prescri be d f or a n y reas o n 
wit hi n 4 wee ks bef ore scree ni n g u ntil t he f oll o w -u p visit.

M o n oa mi ne o xi dase i n hi bit ors wit hi n 4 wee ks bef ore scree ni n g u ntil t he f oll o w -u p visit.

A 
k n o w n m o derate 
or str o n g i n hi bit or/i n d ucer of C Y P 3 A 4 a n d C Y P 2 C 9 or a d ual 
i n hi bit or/i n d ucer of C Y P 3 A 4 a n d C Y P 2 C 9 fr o m 1 4 da y s ( 2 wee ks) or at least 5 ti mes t he 
dr u g’s half -life, w hic he ver is l o n ger, pri or t o t he first st u d y dr u g a d mi nistrati o n u ntil t he 
f oll o w- u p visit. Si milarl y , s u bjects s h o ul d a v oi d c o ns u m pti o n of her bal pr o d ucts c o ntai ni n g 
St. J o h n’s w ort, e p he dra, gi n k g o, gi nse n g, or ka va fr o m at least 2 wee ks pri or t o t he first 
st u d y dr u g a d mi nistrati o n u ntil t he f oll o w- u p visit. Attac h me nt
3 i ncl u des e xa m ples of 
c o nc o mita nt dr u gs t o be a v oi de d ( m o derate or str o n g i n hi bit or/i n d ucer of C Y P 3 A 4 or 
C Y P 2 C 9 or d ual i n hi bit or/i n d ucer of C Y P 3 A 4 a n d C Y P 2 C 9).

Use of caffei ne/ met h yl xa nt hi ne -c o ntai ni n g pr o d ucts (eg, be ver a ges, c offee, teas, c olas, 
e ner g y dri n ks) after 3 P M is pr o hi bite d t hr o u g h o ut t he st u d y. Li mite d u se of t hese pr o d ucts 
( u p t o 5 0 0 m g/ da y ) is per mitte d bef ore 3 P M. A re d ucti o n i n caffei ne use t o 5 0 0 m g/ da y  is 
all o we d d uri n g 5 d a y s after si g ni n g of I CF. If caffei ne use is re d uce d, t he c ollecti o n of t he 
C S D -M f or q ualificati o n of t he st u d y sh o ul d start 5 d a y s after t he caffei ne c o ns u m pti o n is 
l o were d. C o nsiste nt use of t hese caffei ne pr o d ucts is e nc o ura ge d, partic ularl y  on d a y s pri or 
t o P S G assess me nts. Refer
t o Attac h me nt 
2
f or a vera ge caffei ne c o nte nt of vari o us 
be vera ges.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
T he s p o ns or 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.
9.
S T U D Y E V A L U A TI O N S
9. 1.
St u d y Pr o c e d ur e s
9. 1. 1.
O v er vi e w
T he T i me a n d E ve nts Sc he d ule - Part 1 a n d T i me a n d E ve nts Sc he d ule - Part 2 s u m marize t he 
fre q ue nc y an d ti mi n g of efficac y, P K , bi o mar ker, p har mac o ge n o mic, a n d safet y meas ure me nts 
a p plica ble t o t his st u d y. T he fre q ue nc y an d ti mi n g of o ver ni g ht P K, bi o mar ker sa m pli n g, vital 
si g ns, a n d E C Gs c ollecte d o n Ni g ht 2 a n d Da y  3 (f or at least 4 0 n o n- el derl y a d ult s u bjects a n d 
4 0 el derl y s u bjects) are pr o vi de d i n t he T i me a n d E ve nts Sc he d ule - Part 2. T hr o u g h o ut t he 
st u d y, s u bjects will c o m plete self-assess me nt s usi n g diaries. 
T he t otal bl o o d v ol u me t o be c ollecte d fr o m eac h s u bject will be a p pr o xi matel y 1 6 0 m L . Re peat 
or u nsc he d ule d sa m ples m a y  be ta ke n f or safet y reas o ns or d ue t o tec h nical iss ues wit h t he 
sa m ple. A ta ble listi n g sta n dar d v ol u mes of bl o o d ta ke n f or tests a n d P K sa m ples is pr o vi de d i n 
Attac h me nt 4 . T hese v ol u mes ma y v ar y sli g htl y fr o m site t o site, alt h o u g h t he ma xi m u m a m o u nt 
of bl o o d dra w n (i ncl u di n g retesti n g) fr o m eac h s u bject i n t his st u d y will n ot e xcee d 2 2 5 m L .
Re peat or u nsc he d ule d sa m ples ma y  be ta ke n f or safety reas o ns or f or tec h nical iss ues wit h t he 
sa m ples.
9. 1. 2.
S cr e e ni n g P h a s e
T he scree ni n g e xa mi nati o n c o nsists of 2 parts. S u bjects will re p ort t o t he st u d y site f or t he first 
part of t he eli gi bilit y scree ni n g wit hi n 3 5 d a y s pri or t o ra n d o mizati o n (Da y  1). Bef ore a n y st u d y 
s pecific pr oce d ures are c o n d ucte d a n d f oll o wi n g a n e x pla nati o n of t he p ur p ose a n d ris ks of t he 
st u d y, s u bjects will si g n a n I CF. Rec or di n g of A Es/c o nc o mita nt me dicati o n will start f oll o wi n g 
c o nse nt a n d will c o nti n u e u ntil t he f oll o w -u p/e n d - of-st u d y visit.
P art 1 of Scree ni n g
T he first part of t he eli gi bilit y scree ni n g will be c o m plete d bet wee n D a y - 3 5 a n d D a y -1 5. T his 
part will c o nsist of a ge neral healt h assess me nt a n d a n assess me nt of s u bjecti ve i ns o m nia. 
All 
h y p n otic 
dr u gs, 
i ncl u di n g se dati n g 
a nti hista mi nes, 
B Z Ds, 
melat o ni n, 
se dati n g 
a nti de pressa nts, a n d Z- dr u gs s h o ul d be disc o nti n ue d wit hi n 5 da y s after si g ni n g t he i nf or me d 
c o nse nt . 
I n a d diti o n t o meeti n g scree ni n g criteria o n meas ures of ge neral healt h, i n or der t o be eli gi ble f or 
Part 2 of t he scree ni n g p hase , s u bjects m ust meet t he f oll o wi n g slee p criteria:

D S M - 5 dia g n osis of i ns o m nia dis or der

I SI t otal sc ore ≥1 5 5 ,5 3

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7 3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
N ote: F or s u bjects ta ki n g h y p n otic dr u gs at t he ti me of si g ni n g t he I C F, a d mi nistrati o n of t he 
I SI m ust occ ur at least 5 da ys after t he last d ose of all h y p n otic dr u g s.

s S O L ≥4 5 mi n utes a n d s W A S O ≥6 0 mi n utes o n at least 3 ni g hts o ver a n y 7-d a y  peri o d 
usi n g t he C S D -M. ( A s u bject’s slee p patter ns m ust be ca pt ure d f or a mi ni m u m of 7 da y s 
usi n g t he C S D -M 
d uri n g Part 1 of scree ni n g, pri or t o scree ni n g P S G assess me nt . Data 
c ollecte d o n be dti me ha bits d uri n g scree ni n g wit h t he C S D -M will be use d t o deter mi ne 
me dia n ha bit ual be dti me f or P S G ac q uisiti o n at t he st u d y site).
N ote: F or s u bjects ta ki n g h y p n otic dr u gs at t he ti me of si g ni n g t he I CF, a d mi nistrati o n of t he 
C S D -M m ust start at least 5 da y s after t he last d ose of all h y p n otic dr u g s.
T he eli gi bilit y scree ni n g e xa mi nati o n will c o nsist of t he f oll o wi n g ge neral hea lt h assess me nts i n 
t he first part:

C o m plete me dical hist or y a n d de m o gra p h y

Re vie w of i ncl usi o n/e xcl usi o n criteria

Re vie w of prest u d y t hera p y

Re vie w of pre pla n ne d s ur ger y / pr oce d ures

P h y sical e xa mi nati o n i ncl u di n g hei g ht, b o dy wei g ht, a n d waist circ u mfere nce

1 2- lea d E C G

Vital si g ns

Cli nical lab orat or y  assess me nts i ncl u di n g t h yr oi d-sti m ulati n g h or m o ne ( T S H), H b A 1c, 
he mat ol o g y , ser u m c he mistr y, a n d uri nal ysis

Ser u m pre g na nc y  test/ F S H test (at i n vesti gat or’s j u d g me nt )

Alc o h ol ( breat h) test

Uri ne dr u g scree n

Rec or di n g of A Es a n d c o nc o mita nt me dicati o ns

C- S S R S

Mi ni -Me ntal State E xa mi nati o n
(el derly s u bjects o nl y)

Me nstr ual c y cle trac ki n g (pre me n o pa usal w o me n o nl y )
S u bjects w h o ha ve met all i ncl usi o n a n d e xcl usi o n criteria i n t his first part of scree ni n g will t h e n 
u n der g o Part 2 of t he scree ni n g p hase.
P art 2 of Scree ni n g
Part 2 of t he scree ni n g p hase will c o nsist of a n o bjecti ve assess me nt of i ns o m nia b y  PS G 
rec or di n g a n d e val uati o n o ver 2 ni g hts. T he 2 ni g hts of scree ni n g P S G ac q uisiti o ns will be 
c o n d ucte d c o nsec uti vel y. T hese assess me nts s h o ul d be c o m plete d bet wee n D a y  - 1 4 a n d 
a p pr o xi matel y Da y 5 (ie, 5 d a y s bef ore Da y  1) t o all o w f or a nal ys is of t he P S G data a n d 
esta blis h eli gi bilit y for ra n d o mizati o n. T he first ni g ht’s P S G data will be use d t o e xcl u de a n y 
s u bject wit h P L M / R LS, slee p a p nea, or paras o m nias. T he first a n d sec o n d ni g hts’ P S G 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
rec or di n gs will be use d t o assess o bjecti ve slee p e ntr y  criteria f or i ns o m nia. S u bjects are re q uire d 
t o meet t he f oll o wi n g o bjecti ve slee p i ncl usi o n criteria, as meas ure d by P S G:

2- ni g ht mea n L P S of ≥2 5 mi n utes, wit h neit her ni g ht < 2 0 mi n utes,

2- ni g ht mea n W A S O ≥3 0 m i n utes, a n d

2- ni g ht mea n T S T ≤6. 5 h o urs, wit h neit her ni g ht > 7 h o urs.
S u bjects will be a d mitte d t o t he st u d y site wit h s ufficie nt ti me (a p pr o xi matel y 4 ho urs) t o 
c o m plete all t he pr ot oc ol s pecifie d pr oce d ures pri or t o t he start of t he P S G m o nit ori n g o n t he da y 
of t he first a n d sec o n d P S G. S u bjects will be per mitte d t o ret ur n h o me d uri n g t he d a y ti me 
f oll o wi n g c o m pleti o n of t he first P S G ac q uisiti o n b ut ma y  als o sta y at t he st u d y site. F oll o wi n g 
c o m pleti o n of t he sec o n d P S G ac q uisiti o n, s u bjects will be disc har ge d a n d o nl y  eli gi ble s u bjects 
will ret ur n t o t he st u d y  site o n Da y 1 ( d o u ble -bli n d treat me nt p hase).
I n a d diti o n, f or s u bjects w h o ha ve met all ot her i ncl usi o n a n d e xcl usi o n criteria, t he scree ni n g 
e xa mi nati o n will c o nsist of t he f oll o wi n g i n Part 2 of t he scree ni n g p hase:

K S S ( wit hi n 1 h o ur after t he e n d of eac h scree ni n g P S G)

S u bjecti ve slee p para meters (s S O L, s T S T, s W A S O, s-n N A W, s Q U A L, s F R E S H) per t he 
C S D -M wit hi n 1 h o ur afte r t he e n d of P S G

Alc o h ol ( breat h) test (at t he ti me of a d missi o n o n eac h scree ni n g P S G da y )

Uri ne dr u g scree n (at t he ti me of a d missi o n o n eac h scree ni n g P S G da y ).

C hec k me dicati o n i nta ke, na p pi n g stat us a n d alc o h ol/caffei ne c o ns u m pti o n (at t he ti me of 
a d missi o n o n eac h scree ni n g P S G da y).
Als o d uri n g Part 2 of t he scree ni n g p hase , t he s u bjects will c o m plete 2 trai ni n g sessi o ns of t he 
c o g niti ve test batter y at t he st u d y site. 
E xce pti o nal a n d li mite d retesti n g of a b n or mal la b orat or y, vital si g n, or E C G scree ni n g val ues 
( b ut n ot P S G or C S D -M val ues) t hat lea d t o e xcl usi o n , b ut mi g ht be n ot cli nicall y si gnifica nt 
base d u p o n t he i n vesti gat ors’ j u d ge me nt, m a y  be all o we d after disc ussi o n a n d a p pr o val b y  th e 
s p o ns or d uri n g t he scree ni n g p hase (t o reassess eli gi bilit y). T his s h o ul d o nl y  be c o nsi dere d if 
t here is n o a ntici pate d i m pact o n s u bject safety. 
If a s u bject d oes n ot meet all i ncl usi o n a n d e x cl usi o n criteria (e g, is a scree n fail ure) b ut at s o me 
p oi nt i n t he f ut ure is e x pecte d t o meet t he s u bject eli gi bilit y criteria, t he s u bject m a y  be 
rescree ne d o n o ne occasi o n o nl y . T his s h o ul d be disc usse d wit h t he s p o ns or’s safety p h y sicia n. 
S u bjects ca n n ot be rescree ne d if t he y faile d scree ni n g o n P S G, C S D -M, I SI, or D S M -5 criteria 
f or i ns o m nia dis or der. S u bjects w h o are rescree ne d will be assi g ne d a ne w s u bject n u m ber, 
u n der g o t he i nf or me d c o nse nt pr ocess, a n d t he n restart a ne w scree ni n g p hase.
B ot h parts of scree ni n g m ust be c o m plete d bef ore ra n d o mizati o n o n D a y  1. Alc o h ol use is n ot 
per mitte d d uri n g t he 2 scree ni n g P S G da y s a n d d uri n g sta ys at t he st u d y site.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
9. 1. 3.
D o u bl e - Bli n d Tr e at m e nt P h a s e
O n Da y  1, s u bjects will be ra n d o mize d after c o m pleti o n of all scree ni n g pr oce d ures a n d after 
assess me nt of q ualificati o n f or st u d y partici pati o n base d o n i ncl usi o n/e xcl usi o n criteria. 
At t he start of t he st u d y, s u bjects will be ra n d o ml y assi g ne d i n a 1: 1: 1: 1: 1 rati o t o recei ve 1 of 
5 treat me nts: place b o:J NJ- 4 2 8 4 7 92 2 5 m g: J NJ- 4 2 8 4 7 9 2 2 1 0 m g: J NJ-4 2 8 4 7 9 2 2 2 0 m g: z ol pi de m. 
St u d y  dr u g will be a d mi nistere d i n a d o u ble -bli n d ma n ner 
f or 1 4 c o nsec uti ve ni g hts, at 
1 5 mi n utes pri or t o li g hts o ut o n ni g hts w he n P S G is rec or de d at t he st u d y site (ie, Ni g hts 1 a n d 
1 3) or at n or mal be dti me o n n o n- P S G ni g hts (ie, Ni g hts 2 t o 1 2 a n d 1 4).
St u d y  pr oce d ures d uri n g t he d o u ble -bli n d treat me nt p hase t o assess safet y, t olera bilit y, efficac y, 
c o m plia nce, a n d ot her e val uati o ns (e g, P K a n d bi o mar kers) will occ ur as per t he T i me a n d 
E ve nts Sc he d ule - Part 1 a n d T i me a n d E ve nts Sc he d ule - Part 2 . S u bjects will re p ort t o t he st u d y 
site i n t he m or ni n g o n Da ys 1 i n a faste d state.  
O n Da y  1, s u bjects will be a d mitte d t o t he st u d y  site bet wee n 8: 0 0 A M a n d n o o n a n d will re mai n 
i n t he st u d y site u ntil assess me nts are c o m plete d i n t he m or ni n g of D a y 2 ( 1 o ver ni g ht) f or a n 
o ver ni g ht P S G rec or di n g. At least 4 0 n o n- el derl y a d ult s u bjects a n d 4 0 el derl y s u bjects will 
re mai n at t he st u d y sites wit h i nte nsi ve P K sa m pli n g ca pa bilities f or a n a d diti o n al ni g ht ( Ni g ht 2) 
f or c ollecti o n of P K, bi o mar ker sa m ples, a n d ot her pr oce d ures, see T i me a n d E ve nts Sc he d ule -
Part 2. F or t hese s u bjects, st u d y dr u g will be a d mi nistere d at t he st u d y site o n Ni g ht 2 a n d t he y 
will be disc har ge d at ar o u n d n o o n of Da y 3 ( 2 o ver ni g hts). O n Da y  2 (or Da y 3 i n s u bjects 
u n der g oi n g o ver ni g ht P K sa m pli n g), su bjects nee d t o be alert, a wa ke, a n d wit h n o resi d ual 
effects of t he me dicati o ns (s uc h as effects o n bala nce) bef ore t he y  ca n be release d fr o m t he st u d y 
ce nter. If t here are a n y c o ncer ns a b o ut resi d ual effects t he s u bject s h o ul d be acc o m pa nie d h o me 
or use prearra n ge d tra ns p ortati o n.   
All s u b jects will t he n ret ur n t o t he st u d y site o n Da y  1 3 wit hi n a p pr o xi matel y 4 h o urs of be dti me 
f or a n a d diti o nal o ver ni g ht P S G rec or di n g o ver 8 h o urs a n d will re mai n at t he st u d y site u ntil 
n o o n of D a y  15 ( 2 o ver ni g hts). S u bjects will be pr o hi bite d fr o m na p pi n g o n Da y 1 4 w hile at t he 
st u d y site pri or t o d osi n g of st u d y dr u g. Meals, as a p pr o priate, m a y be pr o vi de d at t he st u d y site.
O n D a y 1 5, if t here are a n y c o ncer ns a b o ut resi d ual effects, s u bjects s h o ul d be acc o m pa nie d 
h o me or use prearra n ge d tra ns p ortati o n.
If nee de d, t he Da y 1 3 st u d y site visit ma y be dela ye d f or a ma xi m u m of 2 da y s (ie, u p t o Da y 1 5) 
t o all o w f or a s ufficie nt wi n d o w of ti me f or t he s u bject t o ret ur n t o t he st u d y site. I n cases w he n 
t he D a y 1 3 visit is dela ye d, s u bjects s h o ul d c o nti n ue t o ta ke st u d y dr u g a n d all sc he d ule d st u d y 
assess me nts sc he d ule d after war ds will be dela y e d wit h t he sa me wi n d o w ( ma xi m u m 2 da y s) s o 
t hat res pecti ve ti me t o d osi n g a n d last d ose is preser ve d.
S u bjects will be all o we d t o lea ve t he st u d y  site bet wee n Ni g hts 1 a n d 2 a n d / or bet wee n Ni g hts 1 3 
a n d 1 4 after all assess me nts are c o m plete d. I n ad diti o n, s u bjects m a y  lea ve t he st u d y site o n 
D a y 1 bet wee n a d missi o n assess me nts a n d pre d ose assess me nts. I n all cases, s u bjects nee d t o 
ret ur n t o t he st u d y ce nter i n ti me t o c o m plete pre d ose assess me nts a n d pre parati o ns for P S G 
pri or t o n or mal be dti me. If t he s u bject lea ves t he st u d y site, t he s u bject m ust n ot e n ga ge i n 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7 6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
pr o hi bite d acti vities (e g, na p pi n g, stre n u o us e xercise, alc o h ol c o ns u m pti o n). W he n 
s u bjects 
ret ur n t o t he stu d y  site, s u bjects s h o ul d be teste d f or alc o h ol a n d dr u g i nta ke a n d c hec ke d o n 
caffei ne/alc o h ol c o ns u m pti o n as well as na p pi n g stat us. T he prefere nce is f or t he s u bject t o 
re mai n o n site f or all of Da y 1 a n d bet wee n Ni g hts 1 a n d 2, a n d Ni g hts 1 3 a n d 1 4. 
W hile at t he st u d y site, s u bjects will c o nti n ue t heir n or mal slee p r o uti ne. Be dti me f or eac h 
s u bject will be esta blis he d d uri n g t he scree ni n g p hase b y  ta ki n g t he me dia n be dti me as rec or de d 
i n t he s u bject’s slee p diar y ( C S D-M).
Tele p h o ne C o nt act ( D a y 1 7)
S u bjects will rec or d t heir dail y  su bjecti ve assess me nt of slee p (s S O L, s T S T, s W A S O, s-n N A W, 
s Q U A L, a n d s F R E S H) wit hi n t he first h o ur of a wa ke ni n g usi n g t he C S D -M. I n ad diti o n, t he 
s u bject will c o m plete t he B W S Q self-re p ort meas ure. A st u d y site tele p h o ne co ntact will c ollect 
t he f oll o wi n g assess me nts: P W C, A E c ollecti o n, a n d c o nc o mita nt me dicati o n re vie w as o utli ne d 
i n t he T i me a n d E ve nts Sc he d ule - Part 1 . T he P W C s h o ul d be a d mi nistere d o nl y b y t he cli nicia n 
o ver t he tele p h o ne.
9. 1. 4.
F oll o w -U p/ E n d -of -St u d y  Vi sit
S u bjects will ret ur n t o t he st u d y site f or a f oll o w- u p visit wit hi n 7 t o 1 0 d a y s ( Da ys 2 1 t o 2 4) 
after t he last d ose of st u d y dr u g (ie, Da y 1 4). 
If a s u bject pre mat urel y wit h dra ws fr o m t he st u d y, t he E n d of St u d y Visit assess me nts s h o ul d be 
perf or me d as s o o n as p ossi ble.
Details o n ti me p oi nts of t he st u d y  assess me nts are gi ve n i n t he T i me a n d E ve nts Sc he d ule - Part 
1 . N ote: As s pecifie d i n t he T i me a n d E ve nts Sc he d ule - Part 1 , certai n assess me nts are re q uire d 
o nl y  for s u bjects w h o wit h dra w earl y pri or t o t he pla n ne d ti me p oi nt of t he assess me nt (ie, 
s pecifie d assess me nts d o n ot nee d t o be perf or me d if t he s u bject has c o m plete d all pre vi o us 
assess me nts). 
T he d urati o n of partici pati o n i n t he st u d y for a n i n di vi d ual s u bject (i ncl u di n g scree ni n g a n d 
f oll o w-u p visit) will be u p t o 6 1 da y s.
S u bjects will be i nstr ucte d t hat st u d y dr u g will n ot be ma de a vaila ble t o t he m after t he y ha ve 
c o m plete d/ disc o nti n ue d st u dy dr u g a n d t hat t he y s h o ul d ret ur n t o t heir pri mar y  ph y sicia n t o 
deter mi ne sta n dar d of care.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7 7
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
9. 2.
Effi c a c y E v al u ati o n s
9. 2. 1.
P ol y s o m n o gr a p h y E v al u ati o n s
O bjecti ve slee p para meters will be meas ure d b y  PS G d uri n g scree ni n g Part 2 ( 2 ni g hts) a n d o n 
Ni g hts
1 a n d 1 3. P ol y s o m n o gra p h y para meters t o be a nal yz e d i ncl u de L P S ( pri mar y outc o me 
meas ure), W A S O ( ke y sec o n dar y outc o me meas ure), T S T, a n d S E. I n ad diti o n, t he f oll o wi n g 
ot her sec o n dar y  P S G para meters will be a nalyz e d: 

W A S O ( meas ure d h o url y)

n u m ber of ni g htti me a wa ke ni n gs ( n N A W) o ver 6 h o urs 

wa ke d uri n g t otal slee p peri o d

wa ke after fi nal a wa ke ni n g

n N A W/ hr 

ti me t o first a wa ke ni n g after slee p 

R E M d urati o n

R E M late nc y  

pr o p orti o n of s u bjects wit h slee p- o nset R E M 

n u m ber of slee p c y cles 

t otal ti me s pe nt i n slee p sta ges N 1, N 2 a n d N 3 

a m o u nt of dee p (sl o w -wa ve) slee p usi n g s pectral a nal ysis of slee p E E G

deter mi nati o n of slee p E E G p o wer s pectr u m/ slee p e p oc h
P S G e q ui p me nt will be use d t o rec or d slee p E E G as well as electr o m yo gra p h y , E C G a n d 
electr o oc ul o gra p h y (c ollecti vel y referre d t o as P S G). 
S u bjects will be i nstr ucte d t o g o t o be d bet wee n 8: 0 0 P M a n d 1: 0 0 A M a n d re mai n i n be d f or 
8 h o urs ( Ti me i n be d: ti me fr o m “li g hts off” t o “li g hts o n”: 4 8 0 mi n). D uri n g t he first P S G 
scree ni n g ni g ht a n electr o m yo gra p h y
ti bialis (f or detecti o n of P L M ), or o-nasal airfl o w, 
a b d o mi nal a n d t h oracic e xc ursi o ns, a n d O 2-sat urati o n will be rec or de d i n a d diti o n t o t he 
bi osi g nals w hic h are rec or de d d uri n g t he d o u ble -bli n d p hase P S G ni g hts. Details o n t he 
bi osi g nals t o be rec or de d will be gi ve n i n a se parate ma n ual pre pare d b y  the P S G c ore 
la b orat or y.
I n a d diti o n t o t he a nal ysis of P S G para meters, a s pectral a nalys is will be perf orme d t o i n vesti gate 
t he effect of J NJ-4 2 8 4 7 9 2 2 o n p h ysi ol o gical slee p.
9. 2. 2.
P ati e nt S elf -r e p ort e d M e a s ur e s of Sl e e p
9. 2. 2. 1.
S u bj e cti v e S l e e p P ar a m et er s 
S u bjects will be as ke d t o pr o vi de a ns wers t o q uesti o ns t o deter mi ne t heir s u bjecti ve e x perie nce 
of slee p b y rec or di n g t heir a ns wers i n a daily slee p diar y ( C S D -M).

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7 8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
T he C S D -M is a sta n dar dize d patie nt diar y  base d o n e x pert c o nse ns us a n d q ualitati ve patie nt 
i n p ut t o retrie ve patie nt re p orte d s u bjecti ve slee p para meters relate d t o t he pri or ni g ht’s slee p. It 
all o ws f or calc ulati o n of t otal ti me s pe nt i n be d a n d S E as t he perce nta ge of ti me aslee p o ut of 
a m o u nt of ti me s pe nt i n be d. Slee p q ualit y  an d h o w well reste d s u bjects felt at a wa ki n g are rate d 
o n a 5 -p oi nt Li kert scale ra n gi n g fr o m “ ver y p o or” t o “ ver y go o d”. Hi g her r ati n gs i n dicate better 
slee p q ualit y  an d m ore 
refres hi n g/rest orati ve q ualit y  of slee p. F urt her e val uati o ns i ncl u de 
fre q ue nc y of na ps d uri n g t he d a y  an d T S T d uri n g t he na p or d oze, n u m ber of alc o h ol a n d 
caffei ne c o ntai ni n g dri n ks a n d me dicati o n use d t o hel p falli n g aslee p.
T he f oll o wi n g C S D -M para meters will be a nal yz e d:

s S O L

s T S T

s W A S O

s-n N A W

s Q U A L

s F R E S H
9. 2. 2. 2.
P R O MI S -S D ( s h ort f or m 8 a) a n d P R O MI S -S RI ( s h ort f or m 8 a)
De vel o pe d u n der a Nati o nal I nstit utes of Healt h i nitiati ve, P R O MI S ® is a set of pers o n -ce ntere d 
m eas ures t hat e val uates a n d m o nit ors p h y sical, s ocial, a n d e m oti o nal healt h i n a d ults a n d 
c hil dre n. It ca n be use d wit h t he ge neral p o p ulati o n a n d wit h i n di vi d uals li vi n g wit h c hr o nic 
c o n diti o ns. P R O MI S s h ort f or ms a n d ite ms will be use d t o a d dress s pecific areas of i nterest i n 
t his st u d y p o p ulati o n.
T he P R O MI S- S D s u bscale c o nsists of a static 8- ite m q uesti o n naire. Usi n g a recall peri o d of t he 
past 7 da y s, it assesses t he c o nce pts of slee p i nitiati o n ( 2 ite ms), q ualit y  of slee p ( 3 ite ms), earl y 
m or ni n g feelin gs ( 2-ite ms) a n d w orr y i n g a b o ut slee p ( 1 ite m). Fi ve -p oi nt Li kert scales are 
pr o vi de d t o ca pt ure t he s u bject’s i m pressi o ns ra n gi n g fr o m “ ver y  p o or” t o “ ver y g o o d”.
T he P R O MI S- S RI  scale c o nsists of 8 ite ms. T he mai n 
c o nce pt e val uate d is d a y ti me 
c o nse q ue nces o n f u ncti o ni n g o n 5- p oi nt Li kert scales. T he P R O MI S -S RI  meas ures self-re p orte d 
perce pti o ns of alert ness, slee pi ness, a n d tire d ness d uri n g us ual wa ki n g h o urs, a n d t he percei ve d 
f u ncti o nal i m pair me nts d uri n g wa kef ul ness ass ociate d wit h slee p pr o ble ms or i mpaire d alert ness. 
9. 2. 2. 3.
P ati e nt Gl o b al I m pr e s si o n of S e v erit y a n d I m pr o v e m e nt
P atie nt Gl o b al I m pressi o n of Se verit y
T he P GI -S is a self-re p ort scale t o meas ure se verit y of ill ness ( 1 = no i ns o m nia, 2 = ver y  mil d, 
3 = mil d, 4 = m o derate, 5 =se vere, 6 = ver y  se vere ). C o nsi d eri n g all as pects of i ns o m nia, s u bjects 
will rate t heir se verit y  o n t he P GI-S.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
7 9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
P atie nt Gl o b al I m pressi o n of I m pr o ve me nt
T he P GI -I is a self-re p ort scale t o meas ure i m pr o ve me nt i n ill ness ( 1 = ver y muc h i m pr o ve d, 
2 = m uc h i m pr o ve d, 3 =i m pr o ve d [j ust e n o u g h t o ma ke a differe nce], 4 = n o c ha n ge, 5 = w orse 
[j ust e n o u g h t o ma ke a differe nce], 6 = m uc h w orse, 7 = ver y m uc h w orse).
After 1 3 d a y s of treat me nt, c o nsi deri n g all as pects of i ns o m nia, s u bjects rate t heir i m pr o ve me nt 
o n t he P GI -I.
9. 2. 3.
Cli ni ci a n -r e p ort e d M e a s ur e s of Sl e e p
9. 2. 3. 1.
Cli ni c al Gl o b al I m pr e s si o n of S e v erit y a n d I m pr o v e m e nt
Cli nic al Gl o b al I m pressi o n of Se verit y
T he C GI -S is a 7 - p oi nt scale t o meas ure se verity of ill ness ( 1 = n or mal [ n ot at all ill], 2 = b or derli ne 
ill, 3 = mil dl y ill, 4 = m o deratel y ill, 5 = mar ke dly ill, 6 =se verel y ill, 7 =a m o n g t he m ost e xtre mel y ill 
patie nts). 9 ,2 6 ,2 7
C o nsi deri n g t otal cli nical e x perie nce wit h t he i ns o m nia p o p ulati o n, a n d base d o n t he o bser ve d 
a n d re p orte d s ym pt o ms, be ha vi or, a n d f u ncti o n i n t he past 7 da ys, i n vesti gat ors will rate se verit y 
of ill ness o n t he C GI -S.
Cli nic al Gl o b al I m pressi o n of I m pr o ve me nt
T he C GI -I is a 7-p oi nt scale t o meas ure i m pr o ve me nt i n ill ness ( 1 = ver y  m uc h i m pr o ve d, 2 = m uc h 
i m pr o ve d, 3 = mi ni mall y  im pr o ve d, 4 = n o c ha n ge fr o m baseli ne, 5 = mi ni mall y  worse, 6 = m uc h 
w orse, 7 = ver y  m uc h w orse).9 ,2 6 ,2 7
After 1 3 d a y s of treat me nt, c o nsi deri n g all as pects of i ns o m nia, i n vesti gat ors will rate t he 
s u bject's i m pr o ve me nt o n t he C GI-I.
9. 2. 3. 2.
I n s o m ni a S e v erit y I n d e x (I SI)
T he I SI is a 7- ite m q uesti o n naire assessi n g t he nat ure, se verity, a n d i m pact of i ns o m nia. T he 
cli nicia n versi o n will be use d i n t his st u d y. T he di me nsi o ns e val uate d are: se verity of slee p o n set, 
slee p mai nte na nce, earl y mor ni n g a wa ke ni n g pr o ble ms; slee p dissatisfacti o n; i nterfere nce of 
slee p pr o ble m wit h d a y ti me f u ncti o ni n g; n oticea bilit y  of slee p pr o ble ms b y  ot hers; a n d distress 
ca use d b y  the slee p diffic ulties. A 5- p oi nt Li kert scale ( 0-4) is use d t o rate eac h ite m, yi el di n g a 
t otal sc ore ra n gi n g fr o m 0 t o 2 8. T he t otal sc ore is i nter prete d as f oll o ws: a bse nce of i ns o m nia 
( 0- 7); s u b-t hres h ol d i ns o m nia ( 8-1 4); m o derate i ns o m nia ( 1 5 -2 1); a n d se vere i ns o m nia ( 2 2- 2 8).
9. 3.
P h ar m a c o ki n eti c s
Plas ma sa mples will be use d t o e val uate t he P K of J NJ- 4 2 8 4 7 9 2 2 a n d its meta b olites (as 
a p plica ble). Plas ma sa m ples c ollecte d f or P K ma y  ad diti o nall y be use d t o e val uate safety or 
efficac y as pects t hat a d dress c o ncer ns arisi n g d uri n g or after t he st u d y peri o d. Ge ne tic a nal ys es 
will n ot be perf or me d o n t hese ser u m sa m ples. S u bject c o nfi de ntialit y will be mai ntai ne d.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
9. 3. 1.
E v al u ati o n s
Ve n o us 
bl o o d sa m ples ( 3 m L  eac h) will 
be c ollecte d f or t he deter mi nati o n of plas ma 
c o nce ntrati o ns f or J NJ-4 2 8 4 7 9 2 2 a n d its acti ve meta b olites
( M 1 2 a n d M 1 6 [ w he n a p plica ble]) 
a n d t o c haracterize t he e x p os ure -res p o nse relati o ns hi p of J NJ-4 2 8 4 7 9 2 2 a n d, if necessar y , f or 
M 1 2 a n d M 1 6, wit h res pect t o meas ures of efficac y an d/ or safety at t he ti me p oi nts i n dicate d i n 
t he T i me a n d E ve nts Sc he d ule - Part 1 a n d T i me a n d E ve nts Sc he d ule - Part 2 .
P har mac o ki netic sa m ples will be c ollecte d fr o m all s u bjects o n Ni g ht 1 4, 1 5 mi n utes after t he 
last d ose of t he st u d y dr u g , a n d o n Da y  15 at 4 h o urs a n d 8 h o ur 1 5 mi n utes p ost Ni g ht 1 4 
e ve ni n g d ose.
I n ad diti o n, P K sa m ples will be c ollecte d o n Ni g ht 2/ Da y 3 fr o m at least 4 0 n o n- el derl y a d ult
s u bjects a n d 4 0 el derl y s u bjects , at t he st u d y sites wit h i nte nsi ve P K sa m pli n g ca pa bilities.
As t his is a bli n de d st u d y, bl o o d sa m ples f or P K will als o be c ollecte d fr o m z ol pi de m- a n d 
place b o -treate d s u bjects, b ut o nl y  an al y ze d f or t he z ol pi de m a n d place b o gr o u p s at a later date if 
dee me d necessar y . T hese sa m ples will be st ore d a n d m a y  be a nal yz e d, if nee de d (e g. s us pici o n 
of a n i nc orrect d ose).
T he e xact time of P K bl o o d sa m ple c ollecti o n m ust be rec or de d, al o n g wit h all c o nc o mita nt 
me dicati o ns ( d ose, dr u g, start a n d st o p date). T he e xact date a n d ti me of t he last d ose of st u d y 
dr u g bef ore t he P K sa m ple c ollecti o n will be rec or de d. T he e xact ti me of t he last meal i nta ke 
pri or t o d osi n g bef ore P K sa m pli n g o n Da y s 2 a n d 1 4 will als o be rec or de d.
N ote: A n e xce pti o n t o t he o ver ni g ht P K sa m ples o n Ni g ht 1 4 ma y  b e ma de after disc ussi o n wit h 
t he s p o ns or’s me dical m o nit or. T he reas o n f or t he e xce pti o n m ust be d oc u me nte d i n t he s o urce 
d oc u me nts. If p ossi ble, t he 8- h o ur 1 5 -mi n ute P K c ollecti o n s h o ul d be o btai ne d e ve n if perf or me d 
u p t o 1 2 h o urs after d osi n g. T he c orrect ti me of t he c ollecti o n s h o ul d be n ote d.
9. 3. 2.
A n al y ti c al Pr o c e d ur e s
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-4 2 8 4 7 9 2 2 a n d M 1 2
usi n g a 
vali date d, s pecific, a n d se nsiti ve li q ui d c hr o mat o gra p h y- mass s pectr o metr y/ mass s pectr o metr y
met h o d 
b y  
or u n der 
t he s u per visi o n of 
t he s p o ns or. A 
q ualifie d 
researc h li q ui d 
c hr omat o gra p h y- mass 
s pectr o metr y/ mass s pectr o metr y
met h o d 
will 
be 
use d 
f or t he 
deter mi nati o n of plas ma c o nce ntrati o ns of M 1 6 ( w he n a p plica ble).
9. 3. 3.
P h ar m a c o ki n eti c P ar a m et er s
Plas ma c o nce ntrati o n -ti me data f or J NJ-4 2 8 4 7 9 2 2, M 1 2, 
a n d M 1 6 
(as a p plica ble) will be 
a nal yze d usi n g n o nc o m part me ntal met h o ds f or all s u bjects w h o u n der we nt i nte nsi ve o ver ni g ht 
P K sa m pli n g ( Ni g ht 2/ Da y  3). Res ults will be ta b ulate d a n d s u m mar y statistics will be ge nerate d. 
T he f oll o wi n g P K para meters will be re p orte d : Cma x , tma x , a n d A U C 0- 1 2 h.
A d diti o nal P K para meters of J NJ- 4 2 8 4 7 9 2 2 ma y be esti mate d usi n g n o nc o m part me ntal or 
n o nli near mi xe d effects m o deli n g met h o ds, if nee de d. Data fr o m t his st u d y ma y be c o m bi ne d 
wit h ot her st u dies f or a p o ole d p o p ulati o n P K a nal ysis, t o e na ble calc ulati o n of t he a b o ve P K 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
para meters als o o n s u bjects w h o
o nl y u n der we nt s parse P K sa m pli n g ( Ni g ht 1 4/ Da y  15), if 
s u p p orte d b y  the data . T he effect of baseli ne c o variates (e g, b o d y  wei g ht, a ge, se x, creati ni ne 
cleara nce, or race) a n d c o nc o mita nt me dicati o ns ma y be e val uate d, if nee de d.
I n di vi d ual pre dicte d plas ma c o nce ntrati o n-ti me pr ofiles a n d/ or p ost -h oc Ba yesia n esti mates of 
P K para meters f or J NJ- 4 2 8 4 7 9 2 2 a n d, if necessar y , f or M 1 2 
a n d M 1 6 
ma y  be use d f or 
e x pl orat or y e x p os ure-res p o nse m o deli n g f or safet y a n d efficac y e n d p oi nts.
9. 4.
Bi o m ar k er s
Bl o o d sa m ples f or bi o mar ker e val uati o n will be c ollecte d per t he T i me a n d E ve nts Sc he d ule -
Part 1 a n d T i me a n d E ve nts Sc he d ule - Part 2 .
Bi o mar ker a nal yses will i ncl u de ( b ut are n ot li mite d t o) mar kers relate d t o i m m u ne s yste m 
acti vit y (hs C R P , i nterle u ki n-6), gr o wt h fact ors ( B D N F), k y n ure ni ne meta b olites, a n d H P A a xis 
acti vati o n (c ortis ol).
C ortis ol c o nce ntrati o n has a str o n g di ur nal patter n, wit h pea k c o nce ntrati o ns prese nt u p o n 
a wa ke ni n g an d l o w c o nce ntrati o ns i n t he e ve ni n g h o urs; t h us , c ollecti o n t hr o u g h o ut t he ni g ht a n d 
da y  will e ns ure c o m plete re prese ntati o n of t he patter n.
Sa m ples s h o ul d be c ollecte d u n der l o w-fat diet f or t he meal pri or t o t he bi o mar ker c ollecti o n if 
t he c ollecti o n is n ot d o ne u n der faste d c o n diti o ns . S u g gesti o ns f or l o w-fat meals t hat c o ul d be 
c o ns u me d pri or t o bl o o d c ollecti o n are pr o vi de d i n Attac h me nt 1 . S u bjects s h o ul d n ot c o ns u me 
alc o h olic be vera ges f or at least 1 2 h o urs pri or t o sa m pli n g. Stre n u o us e xercise s h o ul d be a v oi de d 
f or 2 4 h o urs pri or t o sa m pli n g. If a s u bject d oes n ot f oll o w a l o w-fat diet, t his is n ot c o nsi dere d a 
pr ot oc ol de viati o n a n d s h o ul d be n ote d o n t he bi o mar ker re q uest f or m. 
Bi o mar kers m a y  be a d de d or delete d base d o n scie ntific i nf or mati o n or tec h nical i n n o vati o ns 
u n der t he c o n diti o n t hat t he t otal v ol u me of bl o o d c ollecte d w ill n ot be i ncrease d.
9. 5.
P h ar m a c o g e n o mi c ( D N A ) E val u ati o n s
D N A sa m ples will be a nal yze d f or t he i de ntificati o n of ge netic fact ors t hat m a y  infl ue nce t he 
P K, P D, efficac y, safet y, or t olera bilit y of J NJ- 4 2 8 4 7 9 2 2, a n d t o i de ntif y ge netic fact ors 
ass ociate d wit h i ns o m nia. A d diti o nal a nal ys es m a y  be c o n d ucte 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 will be use d f or researc h relate d t o J NJ- 4 2 8 4 7 9 2 2 a n d i ns o m nia . T he y ma y als o be 
use d t o de vel o p tests/assa ys relate d t o J NJ- 4 2 8 4 7 9 2 2 a n d i ns o m nia dis or der . P har mac o ge n o mic 
researc h m a y  co nsist of t he a nal ys is of o ne or m ore ca n di date ge nes or of t he a nal ys is of ge netic 
mar kers t hr o u g h o ut t he ge n o me o r a nal ys is of t he e ntire ge n o me (as a p pr o priate) i n relati o n t o 
JNJ -4 2 8 4 7 9 2 2 a n d i ns o m nia dis or der cli nical e n d p oi nts.
Bl o o d sa m ples f or ge netic researc h will be c ollecte d fr o m s u bjects w h o c o nse nt se paratel y  t o t his 
c o m p o ne nt 
of 
t he st u d y (w here 
l ocal re g ulati o ns per mit). 
S u bject 
partici pati o n 
i n 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
p har mac o ge n o mic researc h is o pti o nal. D N A sa m ples c ollecte d fr o m Ja pa nese s u bjects will n ot 
be use d f or researc h relate d t o i ns o m nia.
9. 6.
S af et y  E val u ati o n s
T he c ollecti o n of A E s a n d c o nc o mita nt me dicati o ns will start after t he i nf or me d c o nse nt has 
bee n si g ne d a n d will c o nti n ue u ntil t he f oll o w -u p visit. 
A n y  cli nically rele va nt c ha n ges occ urri n g d uri n g t he st u d y must be rec or de d o n t he A E secti o n 
of t he C R F.
A n y  cli nicall y si gni fica nt a b n or malities persisti n g at t he e n d of t he st u d y/early wit h dra wal will 
be f oll o we d b y t he i n vesti gat or u ntil res ol uti o n or u ntil a cli nicall y sta ble e n d p oi nt is reac he d. 
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 safety 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 t he T i me a n d E ve nts Sc he d ule - Part 1 a n d T i me a n d E ve nts Sc he d ule - Part 2 :
A d verse E ve nts
A d verse e ve nts will be re p orte d b y  the s u bject ( or, w he n a p pr o priate, b y  a care gi ver, s urr o gate, 
or t he s u bject's le gally acce pta ble re prese ntati ve) f or t he d urati o n of t he st u dy. A d verse e ve nts 
will be f oll o we d b y  t he i n vesti gat or as s pecifie d i n Secti o n 1 2 , A d verse E ve nt Re p orti n g.
As wit h a n y C N S -acti ve me dicati o n, i n vesti gat ors s h o ul d m o nit or caref ull y an d d oc u me nt a n y 
C N S -relate d a d verse e ve nt i ncl u di n g tre m or, ata xia, a b n or mal se nsati o n, c o nf usi o n, or p ossi bilit y 
of seiz ure.
A dverse Eve nts of S peci al I nterest
T he f oll o wi n g A Es are c o nsi dere d t o be of s pecial i nterest i n t his st u d y:

Cata ple x y (s u d de n, tra nsie nt e pis o de of m uscle 
wea k ness acc o m pa nie d b y  co nsci o us 
a ware ness)

Slee p paral y sis (t he e x perie nce of n ot bei n g a ble t o m o ve, react, or s pea k w he n falli n g 
aslee p/a wa ke ni n g)

C o m ple x, slee p-relate d be ha vi ors/ paras o m nias s uc h as c o nf usi o nal ar o usals, s o m na m b ulis m 
(slee p wal ki n g), slee p terr ors, br u xis m (teet h gri n di n g), slee p se x, slee p-relate d eati n g 
dis or der, slee p be ha vi or dis or der, a n d catat hre nia ( R E M-ass ociate d e n d-i ns pirat or y 
a p nea/ breat h h ol di n g).

A b n or mal ( vi vi d) drea ms

Falls.
I n vesti gat ors are i nstr ucte d t o i n q uire a b o ut t he occ urre nce of s uc h e ve nts d uri n g t he c ollecti o n 
of A Es at eac h visit. W he n 
re p orte d, t he i n vesti gat or will be re q uire d t o c o m plete a detaile d 
s u m mar y of t he e ve nt a n d its cli nical c o urse utilizi n g t he c orres p o n di n g A E of s pecial i nterest 
narrati ve f or m as s o o n as i nf or mati o n o n t he o utc o me (rec o vere d, res ol vi n g, or o n g oi n g) is 
a vaila ble. At a mi ni m u m, a descri pti o n of t he e ve nt (i ncl u di n g preci pitati n g circ u msta nces), t he 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8 3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
ti me relati ve t o d ose a d mi nistrati o n, a n d t he d urati o n of t he e ve nt s h o ul d be re p orte d. I n a d diti o n, 
t he A E s h o ul d be mar ke d as a n A E of s pecial i nterest i n t he C R F. N ote: If t he e ve nt meets t he 
seri o us ness criteria (see Secti o n 1 2. 1. 1 , A d verse E ve nt Defi niti o ns a n d Classificati o ns ), t he 
Seri o us A d verse E ve nts F or m m ust als o be c o m plete d acc or di n g t o t he S A Es re p orti n g ti meli ne 
descri be d i n Secti o n 1 2. 3. 2 , ie, wit hi n 2 4 h o urs of ha vi n g bec o me a ware of t he e ve nt, e ve n if all 
details are n ot a vaila ble.
Cli nic al L a b or at or y Tests
Bl o o d sa m ples f or ser u m c he mistr y an d he mat ol o g y  an d a ra n d o m uri ne sa m ple f or uri nal y sis 
will be c ollecte d as per t he Ti me a n d E ve nts Sc he d ule . P ostscree ni n g bl o o d sa m ples s h o ul d be 
c ollecte d u n der fasti n g c o n diti o ns. T he i n vesti gat or m ust re vie w t he la b orat or y  r es ults, d oc u me nt 
t his re vie w, a n d rec or d a n y cli nically rele va nt c ha n ges occ urri n g d uri n g t he st u d y in t he A E
secti o n of t he C R F. T he la b orat or y  re p orts m ust be file d wit h t he s o urce d oc u me nts.
T he f oll o wi n g tests will be perf or me d b y  t he ce ntral la b orat or y:

He mat ol o g y  Pa nel
-he m o gl o bi n
-platelet c o u nt
-he mat ocrit
-re d bl o o d cell c o u nt
-w hite bl o o d cell c o u nt wit h differe ntial

Ser u m C he mistr y  Pa nel
-s o di u m
-al kali ne p h os p hatase
-p otassi u m
-creati ne p h os p h o ki nase ( C P K)
-c hl ori de
-lactic aci d de h y dr o ge nase ( L D H)
- bicar b o nate
- uric aci d
-bl o o d urea nitr o ge n ( B U N)
-calci u m
-creati ni ne
-p h os p hate
-gl uc ose
-al b u mi n
-as partate a mi n otra nsferase ( A S T)
-t otal pr otei n
-ala ni ne a mi n otra nsferase ( A L T)
-ga m ma -gl uta m yl tra nsferase ( G G T)
-t otal direct bilir u bi n

Uri nal y sis
Di pstic k
Se di me nt (if di pstic k res ult is
-s pecific gra vity
a b n or mal)
- p H
-re d bl o o d cells
-gl uc ose
-w hite bl o o d cells
-pr otei n
-e pit helial cells
-bl o o d
-cr ys tals
-ket o nes
-casts
-bilir u bi n
- bacteria
-ur o bili n o ge n

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
-nitrite
-le u k oc yte esterase

Ser u m p re g na nc y/ F S H testi n g (at discreti o n of t he i n vesti gat or)

T S H (scree ni n g o nl y)

H b A 1c (scree ni n g o nl y)
I n a d diti o n, t he f oll o wi n g tests will be perf or me d at t he st u d y site:

Uri ne pre g na nc y  testi n g (at discreti o n of t he i n vesti gat or)

Uri ne 
Dr u g 
Scree n: 
o piates 
(i ncl u di n g 
met ha d o ne), 
c ocai ne, 
a m p heta mi nes, 
met ha m p heta mi nes, ca n na bi n oi ds, bar bit urates, 3, 4- Met h y le ne di o x ymet ha m p heta mi ne, a n d 
B Z D. Uri ne dr u g scree ns will be d o ne b y  t he site usi n g a di pstic k.

Alc o h ol ( brea t h) test.
Electr oc ar di o gr a m ( E C G)
T wel ve -lea d E C Gs, i nte n de d f or safety m o nit ori n g, will be rec or de d i n a s u pi ne p ositi o n s o t hat 
t he differe nt E C G i nter vals ( R R, P R, Q R S, a n d Q T) ca n be meas ure d. T he E C G will be rec or de d 
u ntil 4 re g ular c o nsec uti ve c o m ple xes are a vaila ble i n g o o d rea da ble q ualit y .
D uri n g t he c ollecti o n of E C Gs, s u bjects s h o ul d be i n a q uiet setti n g wit h o ut distracti o ns (e g, 
tele visi o n, cell p h o nes). S u bjects s h o ul d rest i n a s u pi ne p ositi o n f or at least 5 mi n utes bef ore 
E C G c ollecti o n a n d s h o ul d refrai n fr o m tal ki n g or m o vi n g ar ms or le gs. If bl o o d sa m pli n g or 
vital si g n meas ure me nt 
is sc he d ule d f or t he sa me ti me p oi nt as E C G rec or di n g, it is 
rec o m me n de d t hat t he pr oce d ures be perf or me d i n t he f oll o wi n g or der: E C G(s), vital si g ns, 
bl o o d dra w.
Vit al Si g ns (or al , a xill ar y, or t y m p a nic te m per at ure; p ulse/ he art r ate; bl o o d press ure )
B l o o d press ure a n d p ulse/ heart rate meas ure me nts will be assesse d i n s u pi ne a n d sta n di n g 
p ositi o ns wit h a c o m pletel y a ut o mate d de vice. Ma n ual 
tec h ni q ues will be use d o nl y  if a n 
a ut o mate d de vice is n ot a vaila ble.
S u pi ne b l o o d press ure a n d p ulse/ heart rate meas ure me nts 
s h o ul d be prece de d b y  at least 
5 mi n utes of rest i n a q uiet setti n g wit h o ut distracti o ns (e g, tele visi o n, cell p h o nes), a n d sta n di n g 
meas ure me nts s h o ul d f oll o w. Sta n di n g meas ure me nts are t o be ta ke n after at least a f ull mi n ute 
of sta n di n g.
I n a d diti o n, oral, a xillar y or t y m pa nic te m perat ure will be meas ure d.
P h ysic al E x a mi n ati o n
T he st u d y  i n vesti gat or, or ot her a ut h orize d a n d a p pr o priately q ualifie d desi g nee, will perf or m t he 
p h y sical e xa mi nati o ns. Hei g ht will be meas ure d at scree ni n g o nl y . B o d y  wei g ht a n d waist 
circ u mfere nce will be meas ure d at scree ni n g, Da y  1, Da y  1 5, a n d f oll ow- u p/ e n d- of-st u d y visit (if 
n ot d o ne at Da y  1 5).

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
C o g niti ve Assess me nt
M o difie d P R O MI S- A C A
S pecific ite ms fr o m t he P R O MI S- A C A ite m ba n k ha ve bee n selecte d base d o n t heir rele va nce t o 
t his st u d y po p ulati o n. T he i nstr u me nts assess patie nt -re p orte d f u ncti o nal a bilities wit h re gar d t o 
c o g niti ve tas ks. T he P R O MI S- A C A is u ni versal rat her t ha n disease s pecific. Partici pa nts rate 
t heir res p o nses usi n g a scale ra n gi n g fr o m 1 ( N ot at all) t o 5 ( Ver y m uc h).
C o g nitive F u ncti o ni n g Ev al u ati o ns
T he c o m p uterize d c o g niti ve test batter y  pr o vi des assess me nt of m ulti ple c o g niti ve d o mai ns, 
i ncl u di n g atte nti o n, c o nce ntrati o n, vi gila nce, e pis o dic a n d w or ki n g me m or y , a n d a meas ure of 
e xec uti ve 
f u ncti o n. 
T he 
tests 
use 
c ult ure-ne utral 
sti m uli, 
e na bli n g 
use 
i n 
m ultili n g ual/ m ultic ult ur al setti n gs.
T he c o m p uterize d batter y i ncl u des t he f oll o wi n g c o g niti ve d o mai ns:

E pis o dic/ Declarati ve Me m or y  d o mai n:

I m me diate a n d Dela ye d W or d Recall

W or d Rec o g niti o n

Pict ure Rec o g niti o n.

Atte nti o n, C o nce ntrati o n, Vi gila nce: 

Si m ple Reacti o n Ti me: s pee d of reacti o n ( msec) will be rec or de d.

C h oice Reacti o n Ti me: s pee d of reacti o n ( msec) a n d perce nta ge of c orrect res p o nses 
will be rec or de d.

Di git Vi gila nce tas k: s pee d of reacti o n ( msec) a n d n u m ber of c orrect res p o nses will be 
rec or de d.

W or ki n g Me m or y  a n d E xecuti ve C o ntr ol:

N u meric W or ki n g Me m or y

S patial W or ki n g Me m or y .
All meas ures ha ve bee n vali date d a gai nst tra diti o nal ne ur o ps y c h ol o gical tests a n d are se nsiti ve t o 
t he effects of vari o us dr u gs o n c o g niti ve perf or ma nce, i ncl u di n g z ol pi de m i n el derl y patie nts 
w it h i ns o m nia.6 1 C o m pleti n g t he c o g niti ve test batter y re q uires a p pr o xi matel y 1 7 mi n utes.
Details o n t he c o g niti ve test para di g m t o be c o n d ucte d wil l be gi ve n i n a se parate ma n ual.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8 6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Resi d u al Effects
Resi d ual effects will be assesse d s u bjecti vel y by t he self-re p orte d K S S a n d o bjecti vel y  by 
ata xia meter.
K ar oli ns k a Slee pi ness Sc ale ( K S S)
T he K S S 
is a patie nt re p orte d assess me nt of le vel of dr o wsi ness at the ti me of scale 
a d mi nistrati o n. T his scale is f oc use d mai nl y  on t he pr o pe nsit y  to fall aslee p a n d has a hi g h 
vali dit y  in meas uri n g slee pi ness. It co nsists of a 9 -p oi nt Li kert scale wit h res p o nse o pti o ns fr o m: 
1 = ver y  alert, 3 =alert, 5 = neit her alert n or slee p y, 7 =slee p y ( b ut n ot fi g hti n g slee p), 9 = ver y  slee py 
(fi g hti n g slee p).1 ,3 7
B o dy S w ay
T he b o d y  sw a y  meter all o ws meas ure me nt of b o d y  mo ve me nts i n a si n gle pla ne, pr o vi di n g a 
meas ure of p ost ural sta bilit y. B o d y s w a y is meas ure d usi n g a n ata xia meter. 8 4 S u bjects will be 
i nstr ucte d t o wear a pair of t hi n s oc ks f or eac h sessi o n. Bef ore starti n g a meas ure me nt, s u bjects 
will be as ke d t o sta n d still a n d c o mf orta ble, wi t h t heir feet a p pr o xi matel y 10 c m a part a n d t heir 
ha n ds i n a rela xe d p ositi o n al o n gsi de t he b o d y  an d e yes cl ose d. S u bjects ma y  not tal k d uri n g t he 
meas ure me nt. T he t otal peri o d of b o d y s wa y m eas ure me nt will be 2 mi n utes.
Wit h dr a w al Effects
P ote ntial wit h dr a wal effects will be assesse d b ot h o bjecti vel y  by t he P W C a n d s u bjecti vel y by 
t he B W S Q.6 8 ,7 6
P hysici a ns Wit h dr a w al C hec klist ( P W C)
T he P h y sicia n Wit h dra wal C hec klist ( 2 0 ite ms; P W C -2 0) is a si m ple a n d acc urate met h o d use d 
t o assess p ote ntial wit h dra wal s ym pt o ms f oll o wi n g cessati o n of treat me nt. T he P W C - 2 0 is a 
relia ble a n d se nsiti ve i nstr u me nt f or t he assess me nt of disc o nti n uati o n s ym pt o ms. 6 8
Be nz o di aze pi ne Wit h dr a w al Sy m pt o m Q uesti o n n aire ( B W S Q)
T he B W S Q is a 2 0 s y m pt o m self -re p ort q uesti o n naire t hat has bee n use d i n st u dies t o i n vesti gate 
B Z D
wit h dra wal. S u bjects rate t he de gree t o w hic h t he y are e x perie nci n g eac h s ym pt o m as 
eit her “ N o,” “ Yes-m o derate” or “ Yes -se vere”. T he q u esti o n naire has bee n s h o w n t o be relia ble 
a n d t o ha ve acce pta ble c o nstr uct vali dit y  i n assessi n g B Z D wit h dra wal sy m pt o ms. 7 6
C ol u m bi a S uici de Se veri t y R ati n g Sc ale ( C-S S R S)
E mer ge nce of s uici dal i deati o n will be assesse d usi n g t he C -S S R S. 6 6 T he C- S S R S has bee n use d 
fre q ue ntly i n cli nical st u dies, is a sta n dar d meas ure f or s uici dal i deati o n assess me nt, a n d its use 
is i n acc or da nce wit h t he U S F D A g ui da nce. 7 8

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8 7
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
9. 7.
Ot h er E v al u ati o n s 
A b bre vi ate d Tre at me nt S atisf acti o n Q uesti o n n aire f or Me dic ati o n ( T S Q M - 9)
T he T S Q M - 9 is a 9- ite m ge neric patie nt re p orte d o utc o me i nstr u me nt t o assess patie nts’ 
satisfacti o n wit h me dicati o n. 6 It is deri ve d fr o m t he l o n ger T S Q M Versi o n 1. 4 a n d c o vers 
d o mai ns of effecti ve ness, c o n ve nie nce a n d gl o bal satisfacti o n. T he i nstr u me nt is sc ore d b y  
d o mai n wit h sc ores ra n gi n g fr o m 0- 1 0 0 w here a l o wer sc ore i n dicates l o wer satisfacti o n. T he 
recall peri o d is “t he last 2- 3 wee ks”. T he T S Q M -9 is a relia ble a n d vali d i nstr u me nt t o assess 
patie nts' satisfacti o n wit h me dicati o n, pr o vi di n g sc ores o n effecti ve ness, c o n ve nie nce a n d gl o bal 
satisfacti o n.
9. 8.
S a m pl e C oll e cti o n a n d H a n dli n g
T he act ual dates a n d ti mes of sam ple c ollecti o n 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. If bl o o d sa m ples are c ollecte d via a n i n d welli n g ca n n ula, a n a p pr o priate 
a m o u nt ( 1 m L ) of ser osa n g ui ne o us fl ui d sli g htl y greater t ha n t he dea d s pace v ol u me of t he l oc k 
will be re m ove d fr o m t he ca n n ula a n d discar de d bef ore eac h bl o o d sa m ple is ta ke n. After bl o o d 
sa m ple c ollecti o n, t he ca n n ula will be fl us he d wit h
0. 9 % s o di u m c hl ori de, U nite d States 
P har mac o peia ( U S P) ( or e q ui vale nt) s o di u m he pari n of 1 0 U/ m L a n d c har ge d wit h a v ol u me
e q ual t o t he dea d s pace v ol u me of t he l oc k. If a ma n dari n ( o bt urat or) is use d, bl o o d l oss d ue t o 
discar d is n ot e x pecte d.
Refer t o t he T i me a n d E ve nts Sc he d ule - Part 1 a n d T i me a n d E ve nts Sc he d ule - Part 2 ta bles f or 
t he ti mi n g a n d fre q ue nc y of all sa m ple c ollecti o ns.
I nstr ucti o ns f or t he c ollecti o n, ha n dli n g, st ora ge, a n d s hi p me nt of sa m ples are f o u n d i n t he 
la b orat or y ma n ual t hat will be pr o vi de d. C ollecti o n, ha n dli n g, st ora ge, a n d s hi p me nt of sa m ples 
m ust be u n der t he s pecifie d, a n d w here a p plica ble, c o ntr olle d te m perat ure c o n diti o ns as i n dicate d 
i n t he la b orat or y ma n ual.
1 0.
S U B J E C T C O M P L E TI O N/ DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T/ 
WI T H D R A W A L F R O M T H E S T U D Y
1 0. 1.
C o m pl eti o n
A s u bject will be c o nsi dere d t o ha ve c o m plete d t he d o u ble -bli n d p hase if he or s he has 
c o m plete d assess me nts at D a y  17 of t he d o u ble -bli n d p hase. S u bjects w h o 
pre mat urel y 
disc o nti n ue st u d y treat me nt f or a n y reas o n bef ore c o m pleti o n of t he d o u ble -bli n d p hase will n ot 
be c o nsi dere d t o ha ve c o m plete d t he st u d y .
A s u bject will be c o nsi dere d t o ha ve c o m plete d t he f oll o w-u p p hase if he or s he has c o m plete d 
assess me nts at t he f oll o w -u p visit (ie, t he visit o n Da y s 2 1-2 4).
1 0. 2.
Wit h dr a w al fr o m t h e St u d y
A s u bject will be a ut o maticall y  wit h dra w n fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns:

L ost t o f oll o w - u p

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8 8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8

Wit h dra wal of c o nse nt

Deat h

N o nc o m plia nce defi ne d as fail ure t o ta ke st u d y dr u g as directe d, as e vi de nce d b y  missi n g 
m ore t ha n 2 d oses of st u d y  dr ug

Disc o nti n uati o n of st u d y treat me nt f or a n y reas o n. A s u bject's st u d y treat me nt will be 
a ut o maticall y disc o nti n ue d if:

T he i n vesti gat or or s p o ns or belie ves (e g, t hat f or safet y or t olera bilit y reas o ns (e g, A Es ) 
it is i n t he best i nterest of t he s u bject t o disc o nti n ue treat me nt

T he s u bject bec o mes pre g na nt

T he s u bject s h o ws si g nals of ac ute s uici dal i deati o n at a n y ti me d uri n g t he st u d y; t he 
s u bject s h o ul d be referre d t o a p pr o priate me dical/ ps yc hiatric care.

A S T a n d/ or A L T e xcee ds 5 x u p per li mit of n or mal ( U L N) (c o nfir me d b y  re peat 
testi n g)

A S T a n d/ or A L T e xcee ds 3 x U L N a n d t otal bilir u bi n e xcee ds 1. 5 x U L N (c o nfir me d 
b y  re peat testi n g).
If a s u bject pre mat urel y wit h dra ws fr o m t he st u d y, t he E n d of St u d y Visit assess me nts s h o ul d be 
perf or me d as s o o n as p ossi ble.
If a s u bject is l ost t o f oll o w-u p, e ver y reas o na ble eff ort m ust be ma de b y  t he st u d y site pers o n nel 
t o c o ntact t he s u bject a n d deter mi ne t he reas o n f or disc o nti n uati o n/ wit h dra wal. T he meas ures 
ta ke n t o f oll o w u p m ust be d oc u me nte d.
W he n 
a s u bject wit h dra ws bef ore c o m pleti n g t he st u d y, t he reas o n f or wit h dra wal is t o be 
d oc u me nte d i n t he C R F a n d i n t he s o urce d oc u me nt. St u d y  dr u g assi g ne d t o t he wit h dra w n 
s u bject ma y n ot be assi g ne d t o a n ot her s u bject. S u bjects w h o wit h dra w will n ot be re place d. 
1 0. 3.
Wit h dr a w al Fr o m t h e U s e of R e s e ar c h S a m pl e s
A s u bject w h o wit h dra ws fr o m t he st u d y will ha ve t he f oll o wi n g o pti o ns re gar di n g t he o pti o nal
researc h sa m ple:

T he c ollecte d sa m ple will be retai ne d a n d use d i n acc or da nce wit h t he s u bject's ori gi nal 
se parate i nf or me d c o nse nt f or o pti o nal researc h sa m ples.

T he s u bject m a y  wit h dra w c o nse nt f or o pti o nal researc h sa m ple, i n w hic h case t he sa m ple 
will be destr o y e d a n d n o f urt her testi n g will ta ke place. T o i nitiate t he sa m ple destr ucti o n 
pr ocess, t he i n vesti gat or m ust n otif y  the s p o ns or st u d y site c o ntact of wit h dra wal of c o nse nt 
f or t he o pti o nal researc h sa m ples a n d t o re q uest sa m ple destr ucti o n. T he s p o ns or st u d y site 
c o ntact will, i n t ur n, c o ntact t he bi o mar ker re prese ntati ve t o e xec ute sa m ple destr ucti o n. If 
req ueste d, t he i n vesti gat or will recei ve writte n c o nfir mati o n fr o m t he s p o ns or t hat t he sa m ple
has bee n destr o ye d.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
8 9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Wit h dr a w al Fr o m t he O pti o n al Rese arc h S a m ples W hile Re m ai ni n g i n t he M ai n St u d y
T he s u bject ma y  wit h dra w c o nse nt f or o pti o nal researc h sa m ples w hile re mai ni n g i n t he st u d y . I n 
s uc h a case, t he o pti o nal researc h sa m ple will be destr o y e d. T he sa m ple destr ucti o n pr ocess will 
pr ocee d as descri be d a b o ve.
Wit h dr a w al Fr o m t he Use of S a m ple s i n F ut ure Rese arc h
T he s u bject ma y  wit h dra w c o nse nt f or use of sa m ples f or researc h (refer t o Secti o n 1 6. 2. 5 , 
L o n g -Ter m Rete nti o n of Sa m ples f or A d diti o nal F ut ure Researc h). I n s uc h a case, sa m ples will 
be dest r oye d  after t he y are n o l o n ger nee de d f or t he cli nical st u d y. Details of t he sa m ple 
rete nti o n f or researc h are prese nte d i n t he mai n I CF a n d i n t he se parate I CF f or o pti o nal researc h 
sa m ples.
1 1.
S T A TI S TI C A L M E T H O D S
Statistical a nal ysis will be d o ne b y  the s p ons or or u n der t he a ut h orit y of t he s p o ns or. A ge neral 
descri pti o n of t he statistical met h o ds t o be use d t o a nal yz e t he efficac y a n d safety data is o utli ne d 
bel o w. S pecific details will be pr o vi de d i n t he S A P .
1 1. 1.
S u bj e ct I nf or m ati o n
Efficac y  anal ys es will be base d o n t he f ull a nal ys is set ( F A S) w hic h c o nsists of all s u bjects w h o 
were ra n d o ml y assi g ne d t o st u d y  dr u g a n d recei ve d at least 1 d ose of st u d y dr u g.
Safet y  anal y ses will be base d o n t he safet y anal y sis set, w hic h c o nsists of all s u bjects w h o are 
ra n d o ml y assi g ne d t o st u d y dr u g a n d recei ve at least 1 d ose of st u d y dr u g. T he safety a nal ys is set 
is t he sa me as t he F A S.
1 1. 2.
S a m pl e Si z e D et er mi n ati o n
T he t otal sa m ple size is calc ulate d o n t he basis of t he M ulti ple C o m paris o n Pr oce d ure- M o deli n g 
( M C P-M o d) test a p plie d t o war ds t he place b o a n d t he J NJ- 4 2 8 4 7 9 2 2 d ose gr o u ps at t he fi nal 
a nal ys is. T he ca n di date m o del set c o nsi dere d f or t he deter mi nati o n of t he sa m ple size c o nsists of 
t he f o ur m o del pr ofiles: “li near”, “e ma x”, “si g E ma x”, a n d “e x p o ne ntial”. Gi ve n t he availa ble 
data wit h J NJ-4 2 8 4 7 9 2 2 i n t he tar get p o p ulati o n (i ns o m nia dis or der) fr o m t he P o C st u d y 
( St u d y 4 2 8 4 7 9 2 2I S M 2 0 0 2), a treat me nt differe nce of 2 0 mi n utes bet wee n J NJ- 4 2 8 4 7 9 2 2 a n d 
place b o f or L P S 
was 
ass u me d wit h 
a sta n dar d de viati o n of 4 5 mi n utes. 
A 
t otal of 
3 6 0 ra n d o mize d s u bjects will pr o vi de a n a vera ge wei g hte d p o wer of a p pr o xi matel y 85 % 
( de pe n di n g o n t he u n derl y i n g tr ue d ose -res p o nse pr ofile), ass u mi n g a 1- si de d si g nifica nce le vel 
of 0. 0 5 a n d a 1 2 % o verall dr o p o ut rate i n t he d o u ble-bli n d p hase .
1 1. 3.
Eff i c a c y An al y s e s
Pri m ar y esti m a n d
T he pri mar y  esti ma n d, t he mai n cli nical q ua ntit y  of i nterest t o be esti mate d i n t he st u d y, is 
defi ne d b y t he f oll o wi n g 3 c o m p o ne nts:
P o p ul ati o n: a d ult a n d el derl y s u bjects wit h i ns o m nia dis or der

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
E n d p oi nt: c ha n ge fr o m baseli ne i n LP S as meas ure d b y  P S G o n Ni g ht 1
Me as ure of I nter ve nti o n:
t he effect of t he i nitiall y ra n d o mize d treat me nt o n t he e n d p oi nt.
Pri m ar y a n d sec o n d ar y effic ac y a n al yses
T he pri mar y efficac y en d p oi nt, c ha n ge fr o m baseli ne i n L P S as meas ure d b y  PS G o n Ni g ht 1, 
will be a nal yze d usi n g a n a nal ys is of c o varia nce ( A N C O V A) m o del, wit h fact ors f or re gi o n 
( U S/ E U a n d Ja pa n), treat me nt ( place b o a n d J NJ- 4 2 8 4 7 9 2 2 d ose gr o u ps), a n d a ge gr o u p (a d ult
a n d el derl y) a n d baseli ne L P S as a c o nti n u o us c o variate. T he treat me nt effects will be esti mate d 
usi n g least s q uares mea ns. T he fi nal a nal ysis will use t he ge neralize d M C P -M o d a p pr oac h 6 4 (a 
h y bri d met h o d ol o g y  that c o m bi nes m ulti ple c o m paris o n pr oce d ures wit h m o deli n g tec h ni q ues), 
w hic h will be a p plie d t o war ds esti mates o btai ne d fr o m t he A N C O V A m o del t o esta blis h a 
d ose -res p o nse si g nal a n d t o deter mi ne d ose(s) t o be use d i n t he P hase 3 st u dies. T he ca n di date 
m o del set will i ncl u de f o ur m o del pr ofiles: “li near”, “e ma x”, “si g E ma x”, a n d “e x p o ne ntial”. 
M C P -M o d has bee n q ualifie d b y  t he E ur o pea n Me dici nes A ge nc y.2 3
T he k e y  sec o n dar y en d p oi nt (c ha n ge fr o m baseli ne i n W A S O o ver t he first 6 h o urs after i nitial 
slee p o nset as meas ure d b y  PS G o n Ni g ht 1) will be a nal yz e d usi n g t he sa me a p pr oac h as 
descri be d a b o ve f or t he pri mar y  e n d p oi nt, i ncl u di n g usi n g t he ge neralize d M C P-M o d a p pr oac h .
F or t he pri mar y  an d ke y  sec o n dar y en d p oi nts (c ha n ge fr o m baseli ne i n L P S a n d W A S O 
o n 
Ni g ht 1), a sec o n dar y anal y sis wit h a ge i ncl u de d as a c o nti n u o us c o variate i n t he m o del will als o 
be carrie d o ut. A d diti o nal c o variates ma y  als o be i ncl u de d as se nsiti vit y a nal yses.
Z ol pi de m is i ncl u de d i n t he st u d y in or der t o i n vesti gate p ote ntial differe nces bet wee n z ol pi de m 
a n d J NJ- 4 2 8 4 7 9 2 2. Z ol pi de m will n ot be i ncl u de d i n t he p ri mar y AN C O V A m o del a n d t he 
ge neralize d M C P -M o d a nal ysis; h o we ver, a n a d diti o nal a nal ysis of c ha n ge fr o m baseli ne i n L P S 
a n d W A S O 
o n Ni g ht 1 will be perf or me d usi n g A N C O V A, i ncl u di n g z ol pi de m, t o c o m pare 
z ol pi de m wit h eac h J NJ- 4 2 8 4 7 9 2 2 d ose a n d place b o usi n g t w o- si de d 9 5 % c o nfi de nce i nter vals 
f or t he differe nce bet wee n t he gr o u ps.
S u b gr o u p a nal ys es b y  age gr o u p (a d ult vs. el derl y) will be perf or me d o n t he pri mar y , ke y 
sec o n dar y, a n d ot her sec o n dar y efficac y e n d p oi nts.
T he a nal ys es f or t he ot her efficac y en d p oi nts will be descri be d i n t he S A P. F or all sec o n dar y 
efficac y en d p oi nts, n o m ulti plicit y  adj ust me nt will be a p plie d a n d n o mi nal p -val ues will be 
prese nte d.
1 1. 4.
P h ar m a c o ki n eti c A n al y si s
Plas ma c o nce ntrati o ns f or J NJ- 4 2 8 4 7 9 2 2, M 1 2, a n d M 1 6 (as a p plica ble) will be a nal yz e d a n d 
s u m marize d b y  dose, d a y  an d ti me p oi nt, usi n g descri pti ve statistics. A p o p ulati o n base d P K 
a nal ys is usi n g P K data fr o m a selecti o n of P hase 1 a n d P hase 2 st u dies will be perf or me d at t he 
c o m pleti o n of t he st u d y. P ost -h oc B a yesia n esti mates of P K para meters f or J NJ- 4 2 8 4 7 9 2 2 (a n d, 
if necessar y , f or acti ve meta b olites M 1 2 a n d M 1 6) fr o m t he p o p ulati o n P K a nal ys is m a y be use d 
f or e x pl orat or y e x p os ure-res p o nse a nalys es.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
P o p ulati o n P K a nal ysis of plas ma c o nce ntrati o n-ti me data of J NJ- 4 2 8 4 7 9 2 2 will be perf or me d 
usi n g n o nli near mi xe d -effects m o deli n g. Data ma y  be c o m bi ne d wit h t h ose of ot her selecte d 
st u dies t o s u p p ort a rele va nt str uct ural m o del. 
A vaila ble 
baseli ne s u bject c haracteristics 
( de m o gra p hics, la b orat or y varia bles, ge n ot y pes, race, etc.) will be i ncl u de d i n t he m o del as 
necessar y . P ost -h oc Ba yesia n i n di vi d ual esti mates of P K para meters will be ge nerate d fr o m t he 
p o p ulati o n P K a nal ys is f or p ote ntial use i n e x p os ure -res p o nse a nal ys is. A s na ps h ot date f or P K 
sa m ples t o be a nal yz e d will be defi ne d, if re q uire d. Sa m ples c ollecte d bef ore t his date will be 
a nal yz e d f or J NJ-4 2 8 4 7 9 2 2, M 1 2, a n d M 1 6 (as a p plica ble) a n d i ncl u de d i n t he p o p ulati o n P K 
a nal ys is. Sa m ples c ollecte d after t he s na ps h ot date will be a nal yz e d at a later date, a n d m a y  be 
i ncl u de d i n a p o p ulati o n P K re-a nal ysis w he n t he y bec o me a vaila ble after data base l oc k. Details 
f or t he p o p ulati o n P K a n d e x p os ure -res p o nse a nal ysis will be descri be d i n a sta n dal o ne a nal ys is 
pla n a n d t he res ults of t he p o p ulati o n P K a n d e x p os ur e-res p o nse a nal ys is will be prese nte d i n a 
se parate re p ort.
Data will be liste d f or all s u bjects wit h a vaila ble plas ma c o nce ntrati o ns per treat me nt gr o u p. 
S u bjects will be e xcl u de d fr o m t he P K a nal y sis if t heir data d o n ot all o w f or acc urate assess me nt 
of t he P K (e g, i nc o m plete a d mi nistrati o n of t he st u d y dr u g; missi n g i nf or mati o n of d osi n g a n d 
sa m pli n g ti mes; c o nce ntrati o n data n ot s ufficie nt f or P K para meter calc ulati o n).
All c o nce ntrati o ns bel o w t he l o west q ua ntifia ble c o nce ntrati o n or missi n g data will be la bele d as 
s uc h i n t he c o nce ntrati o n data base. All s u bjects a n d sa m ples e xcl u de d fr o m t he a nal ys is will be 
clearl y d oc u me nte d i n t he st u d y re p ort.
F or J NJ- 4 2 8 4 7 9 2 2 d ose gr o u p s, descri pti ve statistics will be calc ulate d f or all i n di vi d ual deri ve d 
P K para meters i ncl u di n g e x p os ure i nf or mati o n of J NJ- 4 2 8 4 7 9 2 2 a n d, if nee de d, M 1 2, a n d M 1 6.
1 1. 5.
Bi o m ar k er A n al y s i s
Bi o mar kers will be ta b ulate d b y  treat me nt a n d s u m mar y statistics will be calc ulate d. P ost d ose 
c ha n ges i n bi o mar kers will be s u m marize d b y  treat me nt gr o u p . Ass ociati o ns bet wee n baseli ne 
bi o mar ker le vels a n d cli nical e n d p oi nts m a y  be e x pl ore d. D ue t o li mite d sa m pli n g, t he a nal ys es 
will be e x pl orat or y .
E x pl orat or y  a nalys es ma y be perf or me d f or a d diti o nal bl o o d base d bi o mar kers, if a p plica ble.
Res ults ma y  be prese nte d i n a se parate re p ort. 
Pla n ne d bi o mar ker a nal yses m a y  be deferre d if e mer gi n g st u d y data s h o w n o li keli h o o d of 
pr o vi di n g usef ul scie ntific i nf or mati o n. All bi o mar ker data o btai ne d fr o m t his st u d y m a y als o be 
i ncl u de d i n a n o n g oi n g cr oss -st u d y anal ys is t o i n vesti gate t he relati o ns hi p bet wee n cli nical 
dia g n oses, p he n ot y pes, a n d bi o mar kers.
1 1. 6.
P h ar m a c o ki n eti c a n d P h ar m a c o d y n a mi c A n al y si s
T he relati o ns hi p bet wee n t he e x p os ure of J NJ -4 2 8 4 7 9 2 2 a n d its acti ve meta b olites M 1 2 a n d M 1 6 
(as nee de d) a n d cli nically rele va nt safet y an d/ or efficac y  meas ures ma y be e val uate d gra p hicall y. 
F or safety, c ha n ge fr o m place b o i n c o m p uterize d batter y  of c o g niti ve tests vs 4- h o ur plas ma 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
c o nce ntrati o n o n Ni g ht 1 4 ma y  be e x pl ore d. F or efficac y, c ha n ge i n LP S vs plas ma c o nce ntrat i o n 
at rele va nt ti me p oi nts ma y  als o be e x pl ore d. If nee de d, f urt her mat he matical m o deli n g t o 
c haracterize t he relati o ns hi p ma y  be perf or me d.
1 1. 7.
S af et y  An al y s e s
A d verse E ve nts
T he ver bati m ter ms use d i n t he C R F b y  in vesti gat ors t o i de ntif y A E s will be c o de d u si n g t he 
Me dical Dicti o nar y  for Re g ulat or y  Acti vities ( Me d D R A). Treat me nt -e mer ge nt a d verse e ve nts 
are A E s wit h o nset d uri n g t he d o u ble -bli n d treat me nt p hase or t hat are a c o nse q ue nce of a 
pre -e xisti n g c o n diti o n t hat ha s w orse ne d si nce baseli ne. All re p orte d T E A E s will be i ncl u de d i n 
t he a nal ys is. F or eac h A E , t he perce nta ge of s u bjects w h o e x perie nce at least 1 occ urre nce of t he 
gi ve n e ve nt will be s u m marize d b y  treat me nt gr o u p.
S u m maries, listi n gs, datasets, or s u bject narrati ves m a y  be pr o vi de d, as a p pr o priate, f or t h ose 
s u bjects w h o die, w h o disc o nti n ue treat me nt d ue t o a n A E , or w h o e x perie nce a se vere or a S A E .
A d verse e ve nts of s pecial i nterest are cata ple x y ; slee p paral ysis; c o m ple x slee p-relate d be ha vi ors 
( paras o m nias); a n d falls. S u bjects wit h A E s of s pecial i nterest ma y be prese nte d se parately.
Cli nic al L a b or at or y Tests
La b orat or y  data will be s u m marize d b y  ty pe of la b orat or y test a n d treat me nt. Refere nce ra n ges 
a n d mar ke dl y a b n or mal res ults (s pecifie 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 ve statistics will be calc ulate d f or eac h la b orat or y an al y te at baseli ne a n d f or 
o bser ve d val ues a n d c ha n ges fr o m baseli ne at eac h sc he d ule d ti me p oi nt. A listi n g of s u bjects 
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 s u bjects 
wit h a n y  mar ke dl y a b n or mal la b orat or y res ults will als o be pr o vi de d. 
Electr oc ar di o gr a m ( E C G)
A listi n g of s u bjects wit h a b n or mal E C G fi n di n gs will be prese nte d.
Vit al Si g ns
Descri p ti ve statistics of p ulse, s u pi ne a n d sta n di n g bl o o d press ure (sys t olic a n d diast olic) , a n d 
oral , a xillar y, or t ym pa nic te m perat ure f or o bser ve d val ues a n d c ha n ges fr o m baseli ne will be 
s u m marize d at eac h sc he d ule d ti me p oi nt. T he perce nta ge of s u bjects wit h val ues b e y o n d 
cli nicall y i m p orta nt li mits will be s u m marize d.
P h ysic al E x a mi n ati o n
P h y sical e xa mi nati o n fi n di n gs will be s u m marize d at eac h sc he d ule d ti me p oi nt. C ha n ges i n 
b o d y  wei g ht a n d waist circ u mfere nce will be s u m marize d descri pti vel y . S u bjects wi t h a b n or mal 
fi n di n gs i n p hys ical e xa mi nati o n will be prese nte d i n a data listi n g. 
C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C -S S R S)
Res ults fr o m t he C- S S R S will be ta b ulate d b y  treat me nt.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9 3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Assess me nt of Resi d u al Effects
Res ults of t he b o d y  s wa y a n d K S S will be ta b ulate d b y  treat me nt.
Assess me nt of C o g niti ve Effects
Res ults of t he c o g niti ve test batter y  a n d P R O MI S-A C A will be ta b ulate d b y  treat me nt.
Wit h dr a w al Effects
Res ults fr o m t he P W C a n d B W S Q will be ta b ulate d b y  treat me nt.
1 2.
A D V E R S E E V E N T R E P O R T I N G
Ti mel y , acc urate, a n d c o m plete re p orti n g a n d a nal ysis of safet y i nf or mati o n fr o m cli nical st u dies 
are cr ucial f or t he pr otecti o n of s u bjects, i n vesti gat ors, a n d t he s p o ns or, a n d are ma n date d b y  
re g ulat or y age ncies w orl d wi de. T he s p o ns or has esta blis he d Sta n dar d O perati n g Pr oce d ures i n 
c o nf or mit y wit h re g ulat or y re q uire me nts w orl d wi de t o e ns ure a p pr o priate re p orti n g of safety 
i nf or mati o n; all cli nical st u dies c o n d ucte d b y  the s p o ns or or its affiliates will be c o n d ucte d i n 
acc or da nce wit h t h ose pr oce d ures.
1 2. 1.
D efi niti o n s
1 2. 1. 1.
A d v er s e E v e nt D efi niti o n s a n d Cl a s sifi c ati o n s
A d verse E ve nt
A n A E is a n y unt o war d me dical occ urre nce i n a cli nical st u d y su bject a d mi nistere d a me dici nal 
(i n vesti gati o nal or n o n- i n vesti gati o nal) pr o d uct. A n A E
d oes n ot necessaril y  ha ve a ca usal 
relati o ns hi p wit h t he treat me nt. A n A E
ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal fi n di n g), s ym pt o m, or disease te m p orall y ass ociate d wit h t he use of a 
me dici nal 
(i n vesti gati o nal or n o n- i n vesti gati o nal) pr o d uct, w het her 
or n ot relate d t o t hat 
me dici nal 
(i n vesti gati o nal or n o n- i n vesti gati o nal) pr o d uct. ( Defi niti o n per I nter nati o nal 
C o nfere nce o n Har m o nisati o n [I C H])
T his i ncl u des a n y  occ urre nce t hat is ne w i n o nset or a g gra vate d i n se verity or fre q ue nc y  fr o m t he 
baseli ne c o n diti o n, o r a b n or mal res ults of dia g n ostic pr oce d ures, i ncl u di n g la b orat or y test 
a b n or malities.
N ote: T he s p o ns or c ollects A E s starti n g wit h t he si g ni n g of t he I CF (refer t o Secti o n 1 2. 3. 1 , All 
A d verse E ve nts, f or ti me of last A E rec or di n g).

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Seri o us A d verse E ve nt
A S A E base d o n I CH a n d E U G ui deli nes o n P har mac o vi gila nce f or Me dici nal Pr o d ucts f or 
H u ma n Use is a ny u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

Is life-t hreate ni n g
( T he s u bject was at ris k of deat h at t he ti me of t he e ve nt. It 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 deat h if it were m ore se vere.)

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xist i n g h os pitalizati o n

Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y

Is a c o n ge nital a n o maly/ birt h defect

Is a s us pecte d tra ns missi o n of a ny i nfecti o us a ge nt via a me dici nal pr o d uct

Is Me dically I m p orta nt *
* Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her e x pe dite d re p orti n g is 
als o 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  not b e 
i m me diatel y life t hreate ni n g or res ult i n deat h or 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 ot her o utc o mes liste d i n t he defi niti o n a b o ve. 
T hese s h o ul d us uall y  be c o nsi dere d seri o us.
If a seri o us a n d u ne x pecte d A E
occ urs f or w hic h t here is e vi de nce s u g gesti n g a ca usal 
relati o ns hi p bet wee n t he st u d y dr u g a n d t he e ve nt (e g, deat h fr o m a na p h yla xis), t he e ve nt m ust 
be re p orte d as a seri o us a n d u ne x pecte d s us pecte d a d verse reacti o n e ve n if it is a c o m p o ne nt of 
t he st u d y e n d p oi nt (e g, all-ca use m ortalit y).
U nliste d ( U ne x pecte d) A d verse E ve nt/ Refere nce S afet y I nf or m ati o n
A n A E
is c o nsi dere d u nliste d if t he nat ure or se verity is n ot c o nsiste nt wit h t he a p plica ble 
pr o d uct refere nce safet y i nf or mati o n. F or J NJ- 4 2 8 4 7 9 2 2, t he e x pecte d ness of a n A E
will be 
deter mi ne d b y  whet her or n ot it is liste d i n t he I nvesti gat or's Br oc h ure. F or z ol pi de m wit h a 
mar keti n g a ut h orizati o n, t he e x pecte d ness of a n A E will be deter mi ne d b y  whet her or n ot it is 
liste d i n t he S m P C/ PI .
A d verse E ve nt Ass oci ate d Wit h t he Use of t he Dr u g
A n A E is c o nsi dere d ass ociate d wit h t he use of t he dr u g if t he attri b uti o n is p ossi ble, pr o ba ble, or 
ver y  li kel y b y t he defi niti o ns liste d i n Secti o n 1 2. 1. 2 , Attri b uti o n Defi niti o ns.
1 2. 1. 2.
Attri b uti o n D efi niti o n s
N ot Rel ate d
A n A E t hat is n ot relate d t o t he use of t he dr u g.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
D o u btf ul
A n A E f or w hic h a n alter nati ve e x pla nati o n is m ore li kel y, e g, c o nc o mita nt dr u g(s), c o nc o mita nt 
disease(s), or t he relati o ns hi p i n ti me s u g gests t hat a ca usal relati o ns hi p is u nli kel y .
P os si ble
A n A E
t hat mi g ht be d ue t o t he use of t he dr u g. A n alter nati ve e x pla nati o n, e g, c o nc o mita nt 
dr u g(s), c o nc o mita nt disease(s), is i nc o ncl usi ve. T he relati o ns hi p i n ti me is reas o na ble; t heref ore, 
t he ca usal relati o ns hi p ca n n ot be e xcl u de d.
Pr o b a ble
A n A E
t hat mi g ht be d ue t o t he use of t he dr u g. T he relati o ns hi p i n ti me is s u g gesti ve 
(e g, c o nfir me d b y  dec halle n ge). A n alter nati ve e x pla nati o n is less li kel y, e g, c o nc o mita nt 
dr u g(s), c o nc o mita nt disease(s).
Ver y Li kel y
A n A E
t hat is liste d as a p ossi ble a dverse reacti o n a n d ca n n ot be reas o na bl y ex plai ne d b y  an 
alter nati ve e x pla nati o n, e g, c o nc o mita nt dr u g(s), c o nc o mita nt disease(s). T he relati o ns hi p i n ti me 
is ver y s u g gesti ve (e g, it is c o nfir me d b y dec halle n ge a n d rec halle n ge).
1 2. 1. 3.
S e v erit y Crit eri a
A n 
assess me nt of se verit y gra de will 
be ma de 
usi n g t he f oll o wi n g ge neral cate g orical 
descri pt ors:
Mil d : A ware ness of s ym pt o ms t hat are easil y t olerate d, ca usi n g mi ni mal disc o mf ort a n d n ot 
i nterferi n g wit h e ver yda y acti vities.
M o der ate : S ufficie nt disc o mf ort is prese nt t o ca use i nterfere nce wit h n or mal acti vit y.
Se vere : E xtre me distress, ca usi n g si g nifica nt i m pair me nt of f u ncti o ni n g or i nca pacitati o n. 
Pre ve nts n or mal e ver y da y  acti vities.
T he i n vesti gat or s h o ul d use cli nical j u d g me nt i n assessi n g t he se verity of e ve nts n ot directl y  
e x perie nce d b y t he s u bject (e g, la b orat or y a b n or malities).
1 2. 2.
S p e ci al R e p orti n g Sit u ati o n s
Safet y  eve nts of i nterest o n a s p o ns or st u d y dr u g t hat ma y  re q uire e x pe dite d re p orti n g or safety 
e val uati o n i ncl u de, b ut are n ot li mite d t o:

O ver d o se of a s p o ns or st u d y dr u g

S us pecte d a b use/ mis use of a s p o ns or st u d y dr u g

A cci de ntal or occ u pati o nal e x p os ure t o a s p o ns or st u d y dr u g

Me dicati o n err or i n v ol vi n g a s p o ns or pr o d uct ( wit h or wit h o ut s u bject/ patie nt e x p os ure t o 
t he s p o ns or st u d y dr u g, e g, na me c o nf usi o n)

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9 6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8

E x p os ure t o a s p o ns or st u d y  dr u g fr o m breastfee di n g
S pecial re p orti n g sit uati o ns s h o ul d be rec or de d i n t he C R F. A n y s pecial re p orti n g sit uati o n t hat 
meets t he criteria of a S A E s h o ul d be rec or de d o n t he S A E pa ge of t he C R F.
1 2. 3.
Pr o c e d ur e s
1 2. 3. 1.
Al l Ad v er s e E v e nt s
All A E s a n d s pecial re p orti n g sit uati o ns, w het her seri o us or n o n- seri o us, will be re p orte d fr o m 
t he ti me a si g ne d a n d date d I CF is o btai ne d u ntil c o m pleti o n of t he s u bject's last st u d y-relate d 
pr oce d ure , w hic h m a y  incl u de c o ntact f or f oll o w- u p of safety. Seri o us a d verse e ve nts, i ncl u di n g 
t h ose s p o nta ne o usly re p orte d t o t he i n vesti gat or wit hi n 3 0 da y s after t he last d ose of st u d y dr u g, 
m ust be re p orte d usi n g t he Seri o us A d verse E ve nt F or m. T he s p o ns or will e val uate a n y safet y 
i nf or mati o n t hat is s po nta ne o usl y re p orte d b y  an i n vesti gat or b e y o n d t he ti me fra me s pecifie d i n 
t he pr ot oc ol.
All e ve nts t hat meet t he defi niti o n of a S A E will be re p orte d as S A E s, re gar dless of w het her t he y 
are pr ot oc ol -s pecific assess me nts. A ntici pate d e ve nts will be rec or ded a n d re p orte d as descri be d 
i n Attac h me nt 5 .
All A E s, re gar dless of seri o us ness, se verity, or pres u me d relati o ns hi p t o st u d y dr u g , m ust be 
rec or de d usi n g m e dical ter mi n ol o g y in t he s o urce d oc u me nt a n d t he C R F. W he ne ver p ossi ble, 
dia g n oses s h o ul d be gi ve n w he n si g ns a n d s ym pt o ms are d ue t o a c o m m o n eti ol o g y (e g, c o u g h, 
r u n n y nose, s neezi n g, s ore t hr oat, a n d hea d c o n gesti o n s h o ul d be re p orte d as " u p per res pirat or y 
i nfecti o n"). I n vesti gat ors m ust rec or d i n t he C R F t heir o pi ni o n c o ncer ni n g t he relati o ns hi p of t he 
A E t o st u d y thera p y.  All meas ures re q uire d f or A E ma na ge me nt m ust be rec or de d i n t he s o urce 
d oc u me nt a n d re p orte d acc or di n g t o s p o ns or i nstr ucti o ns.
T he s p o ns or ass u mes res p o nsi bilit y f or a p pr o priate re p orti n g of A E s t o t he re g ulat or y a ut h orities. 
T he s p o ns or will als o re p ort t o t he i n vesti gat or (a n d t he hea d of t he i n vesti gati o nal i nstit ute 
w here re q uire d) all s us pecte d u ne x pecte d seri o us a d verse reacti ons ( S U S A Rs). F or a ntici pate d 
e ve nts re p orte d as i n di vi d ual S A Es t he s p o ns or will ma ke a deter mi nati o n of relate d ness i n 
a d diti o n t o a n d i n de pe n de nt of t he i n vesti gat or’s assess me nt. T he s p o ns or will peri o dicall y 
e val uate t he acc u m ulati n g data a n d, w he n t here is s ufficie nt e vi de nce a n d t he s p o ns or has 
deter mi ne d t here is a reas o na ble p ossi bilit y  that t he dr u g ca use d a seri o us a ntici pate d e ve nt, t he y 
will s u b mit a safety re p ort i n narrati ve f or mat t o t he i n vesti gat ors (a n d t he hea d of t he
i n vesti gati o nal instit ute w here re q uire d). T he i n vesti gat or ( or s p o ns or w here re q uire d) m ust 
re p ort S U S A Rs t o t he a p pr o priate I n de pe n de nt Et hics C o m mittee/I nstit uti o nal Re vie w B oar d 
(I E C/IR B) t hat a p pr o ve d t he pr ot oc ol u nless ot her wise re q uire d a n d d oc u me nte d b y  the 
I E C/I RB.
A 
S U S A R will 
be re p orte d t o re g ulat or y aut h orities u n bli n de d. Partici pati n g 
i n vesti gat ors a n d I E C/IR B will recei ve a bli n de d S U S A R s u m mar y , u nless ot her wise s pecifie d.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9 7
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
All s u bjects will be pr o vi de d wit h a "wallet (st u d y) car d" a n d i nstr ucte d t o carr y this car d wit h 
t he m f or t he d urati o n of t he st u d y i n dicati n g t he f oll o wi n g:

St u d y n u m ber

State me nt, i n t he l ocal la n g ua ge(s), t hat t he s u bject is partici pati n g i n a cli nical st u d y

I n vesti gat or's na me a n d 2 4 -h o ur c o ntact tele p h o ne n u m ber

L ocal s p o ns or's na m e a n d 2 4- h o ur c o ntact tele p h o ne n u m ber (f or me dical staff o nly)

Site n u m ber

S u bject n u m ber

A n y  ot her i nf or mati o n t hat is re q uire d t o d o a n e mer ge nc y brea ki n g of t he bli n d
1 2. 3. 2.
S eri o u s A d v er s e E v e nt s
All S A Es occ urri n g d uri n g t he st u dy m ust be re p orte d t o t he a p pr o priate s p o ns or c o ntact pers o n 
b y st u d y-site pers o n nel wit hi n 2 4 h o urs of t heir k n o wle d ge of t he e ve nt.
I nf or mati o n re gar di n g S A Es will be tra ns mitte d t o t he s p o ns or usi n g t he Seri o us A d verse E ve nt 
F or m, w hic h m ust be c o m plete d a n d si g ne d b y  a p h ysicia n fr o m t he st u d y site, a n d tra ns mitte d t o 
t he s p o ns or wit hi n 2 4 h o urs. T he i nitial a n d f oll o w- u p re p orts of a S A E s h o ul d be ma de
b y  
facsi mile (fa x).
All S A Es t hat ha ve n ot res ol ve d b y  the e n d of t he st u d y, or t hat ha ve n ot res ol ve d u p o n 
disc o nti n uati o n of t he s u bject's partici pati o n i n t he st u d y, m ust be f oll o we d u ntil a n y of t he 
f oll o wi n g occ urs:

T he e ve nt res ol ves

T he e ve nt sta bilizes

T he e ve nt ret ur ns t o baseli ne, if a baseli ne val ue/stat us is a vaila ble

T he e ve nt ca n be attri b uted t o a ge nts ot her t ha n t he st u d y dr u g or t o fact ors u nrelate d t o 
st u d y c o n d uct

It bec o mes u nli kel y t hat a n y ad diti o nal i nf or mati o n ca n be o btai ne d (s u bject or healt h care 
practiti o ner ref usal t o pr o vi de a d diti o nal i nf or mati o n, l ost t o f oll o w- u p after de m o n strati o n 
of d ue dili ge nce wit h f oll o w- u p ef f orts)
S us pecte d tra ns missi o n of a n i nfecti o us a ge nt b y  a me dici nal pr o d uct will be re p orte d as a S A E . 
A n y  eve nt re q uiri n g h os pitalizati o n ( or pr ol o n gati o n of h os pitalizati o n) t hat occ urs d uri n g t he 
c o urse of a s u bject's partici pati o n i n a st u d y must be re p orte d as a S A E , e xce pt h os pitalizati o ns 
f or t he f oll o wi n g:

H os pitalizati o ns n ot i nte n de d t o treat a n ac ute ill ness or A E
(e g, social reas o ns s uc h as 
pe n di n g place me nt i n l o n g -ter m care facilit y)

S ur ger y  or pr oce d ure pla n ne d bef ore e ntr y i nt o t he st u d y (m ust be d oc u me nte d i n t he C R F ). 
N ote: H os pitalizati o ns t hat were pla n ne d bef ore t he si g ni n g of t he I CF, a n d w here t he 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9 8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
u n derl y i n g c o n diti o n f or w hic h t he h os pitalizati o n was pla n ne d has n ot w orse ne d , will n ot 
be c o nsi dere d S A E s. A n y  A E
t hat res ults i n a pr ol o n gati o n of t he ori gi nall y pla n ne d 
h os pitalizati o n is t o be re p orte d as a ne w S A E .
T he ca use of deat h of a s u bject i n a st u d y wit hi n 3 0 da y s of t he last d ose of st u d y dr u g, w het her 
or n ot t he e ve nt is e x pecte d or ass ociate d wit h t he st u d y dr u g, is c o nsi dere d a S A E .
1 2. 3. 3. 
Pr e g n a n c y
All i nitial re p orts of pre g na nc y  i n fe male s u bjects or part ners of male s u bjects m ust be re p orte d 
t o t he s p o ns or b y  the st u d y-site pers o n nel wit hi n 2 4 h o urs of t heir k n o wle d ge of t he e ve nt usi n g 
t he a p pr o priate pre g na nc y  notificati o n f or m. A b n or mal pre g na nc y  outc o mes (e g, s p o nta ne o us 
a b orti o n, fetal deat h, still birt h, c o n ge nital a n o malies, ect o pic pre g na nc y ) are c o nsi dere d S A E s 
a n d m ust be re p orte d usi n g t he Seri o us A d verse E ve nt F or m. 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 must be pr o m ptl y  wit h dra w n fr o m t he st u d y an d disc o nti n ue f urt her st u d y 
treat me nt.
Beca use t he effect o f t he st u d y dr u g o n s per m is u n k n o w n, pre g na ncies i n part ners of male s u bjects 
i ncl u de d i n t he st u d y will be re p orte d as n ote d a b o ve.
F oll o w -u p i nf or mati o n re gar di n g t he o utc o me of t he pre g na nc y  an d a n y  p ost natal se q uelae i n t he 
i nfa nt will be re q uire d.
1 2. 4.
C o nt a cti n g S p o n s or R e g ar di n g S af et y
T he na mes (a n d c orres p o n di n g tele p h o ne n u m bers) of t he i n di vi d uals w h o s h o ul d be c o ntacte d 
re gar di n g safety iss ues or q uesti o ns re gar di n g t he st u d y are liste d i n t he C o ntact I nf or mati o n 
pa ge(s), w hic h will be pr o vi de d as a se parate d oc u me nt.
1 3.
P R O D U C T Q U A LI T Y C O M P L A I N T H AN D LI N G
A pr o d uct q ualit y c o m plai nt ( P Q C) is defi ne d as a n y s us pici o n of a pr o d uct defect relate d t o 
ma n ufact uri n g, la beli n g, or pac ka gi n g, ie, a n y dissatisfacti o n relati ve t o t he i de ntit y, q ualit y, 
d ura bilit y, or relia bility of a pr o d uct, i ncl u di n g its la beli n g or pac ka ge i nte grit y . A P Q C ma y  ha ve 
a n i m pact o n t he safet y a n d efficac y of t he pr o d uct. Ti mel y, acc urate, a n d c o m plete re p orti n g a n d 
a nal ys is of P Q C i nf or mati o n fr o m st u dies are cr ucial f or t he pr otecti o n of s u bjects, i n vesti gat ors, 
a n d t he s p o ns or, a n d are ma n date d 
b y  re g ulat or y age ncies w orl d wi de. T he s p o ns or has 
esta blis he d pr oce d ures i n c o nf or mit y 
wit h re g ulat or y re q uire me nts w orl d wi de 
t o e ns ure 
a p pr o priate re p orti n g of P Q C i nf or mati o n; all st u dies c o n d ucte d b y  the s p o ns or or its affiliates 
will be c o n d ucte d i n acc or da nce wit h t h ose pr oce d ures.
1 3. 1.
Pr o c e d ur e s
All i nitial P Q Cs m ust be re p orte d t o t he s p o ns or b y  t he st u d y-site pers o n nel wit hi n 2 4 h o urs after 
bei n g ma de a ware of t he e ve nt .
If t he defect is c o m bi ne d wit h a S A E , t he st u d y-site pers o n nel m ust re p ort t he P Q C t o t he 
s p o ns or acc or di n g t o t he S A E re p orti n g ti meli nes (refer t o Secti o n 1 2. 3. 2 , Seri o us A d verse 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
9 9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
E ve nts). A sa m ple of t he s us pecte d pr o d uct s h o ul d be mai ntai ne d f or f urt her i n vesti gati o n if 
re q ueste d by t he s p o ns or.
1 3. 2.
C o nt a cti n g S p o n s or R e g ar di n g Pr o d u ct Q u alit y
T he na mes (a n d c orres p o n di n g tele p h o ne n u m bers) of t he i n di vi d uals w h o s h o ul d be c o ntacte d 
re gar di n g pr o d uct q ualit y  iss ues are liste d i n t he C o ntact I nf or mati o n pa ge(s), w hic h will be 
pr o vi de d as a se parate d oc u me nt.
1 4.
S T U D Y D R U G I N F O R M A TI O N
1 4. 1.
P h y si c al D e s cri pti o n of S t u d y Dr u g( s)
J NJ- 4 2 8 4 7 9 2 2 is s u p plie d f or t his st u d y as ca ps ules ( o ver-e nca ps ulate d ta blets) of 2. 5-, 1 0-, a n d 
2 0- m g. 
T he J NJ-4 2 8 4 7 9 2 2 5 m g 
d ose will 
c o nsist of t w o 2. 5 m g 
ca ps ules. All 
ot her 
J NJ- 4 2 8 4 7 9 2 2 d oses will c o nsist of 1 acti ve a n d 1 place b o ca psule eac h. It will be ma n ufact ure d 
a n d pr o vi de d u n der t he res p o nsi bilit y of t he s p o ns or. Refer t o t he I n vesti gat or's Br oc h ure f or a 
list of e xci pie nts. Z ol pi de m will be s u p plie d as a ca ps ule ( o ver-e nca ps ulate d ta blet), c o ntai ni n g 
5- m g  zol pi de m. T he 5 m g  d ose of z ol pi de m will c o nsist of 1 acti ve a n d 1 place b o ca ps ule; t he 
1 0 m g d ose of z ol pi de m will c o nsist of t w o 5 m g ca ps ules. Place b o will be s u p plie d as matc hi n g 
ca ps ules a n d, f or s u bjects ra n d o mize d t o place b o, t he d ose will c o nsist of 2 place b o ca ps ules.
1 4. 2.
P a c k a gi n g
St u d y  dr u g will be s u p plie d i n blister pac ks i de ntifie d b y  a nu m ber. T he blister pac ks are 
c o nsi dere d c hil d resista nt.
1 4. 3.
L a b eli n g
St u d y  dr u g la bels will c o ntai n i nf or mati o n t o meet t he a p plica ble re g ulat or y re q uire me nts. Eac h 
blister pac k will ha ve a u ni q ue n u m ber. T he I WR S will assi g n t he n u m bers of t he blister pac ks
(st u d y dr u g kits) t o be use d b y a s u bject.
1 4. 4.
Pr e p ar ati o n, H a n dli n g, a n d St or a g e
All st u d y  dr u g 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 c o ntai ner la bel.
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 st u d y dr u g pre parati o n, ha n dli n g , a n d st ora ge.
1 4. 5.
Dr u g A c c o u nt a bilit y
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all st u d y dr u g recei ve d at t he 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 . W he n st u d y  dr u g will be self-a d mi nistere d b y s u bjects at 
h o me (ie, fr o m D a y  2 [ or D a y  3 in s u bjects u n der g oi n g o ver ni g ht P K sa m pli n g] t o Da y  1 2), the 
dis pe nsi n g of st u d y dr u g t o t he s u bject, a n d t he ret ur n of st u d y dr u g fr o m t he s u bject (if 
a p plica ble), m ust be d oc u me nte d o n t he dr u g acc o u nta bilit y for m. S u bjects m ust be i nstr ucte d t o 
ret ur n all ori gi nal c o ntai ners, w het her e m pt y or c o ntai ni n g st u d y dr u g. W he n st u d y dr u g will be 
a d mi nistere d at t he st u d y site (ie, D a y  1, [Da y  2 i n s u bjects u n der g oi n g o ver ni g ht P K sa m pli n g], 
D a y  1 3, a n d Da y 1 4), the st u d y  dr u g a d mi nistere d t o t he s u bject m ust be d oc u me nte d o n t he dr u g 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
acc o u nta bilit y for m. All st u d y dr u g will
be st ore d a n d dis p ose d of acc or di n g t o t he s p o ns or's
i nstr ucti o ns. 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 st u d y  dr u g c o ntai ners.
St u d y  dr u g m ust be ha n dle d i n strict acc or da nce wit h t he pr ot oc ol a n d t he 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 priate 
e n vir o n me ntal c o n diti o ns. U n use d st u d y dr u g, a n d st u d y dr u g ret ur ne d b y  the s u bject, 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 onit ori n g visits. T he 
ret ur n t o t he s p o ns or of u n use d st u d y dr u g, or use d ret ur ne d st u d y dr u g f or destr ucti o n, 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 n a ut h orize d destr ucti o n u nit a n d 
st u d y dr u g s u p plies are destr o ye d o n -site, this m ust als o be d oc u me nte d o n t he dr u g ret ur n f or m.
St u d y  dr u g s h o ul d be dis pe nse 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, or b y  a ho s pital/cli nic p har macist. St u d y  dr u g will be s u p plie d o nl y 
t o s u bjects partici pati n g i n t he st u d y. Ret ur ne d st u d y dr u g m ust n ot be dis pe nse d a gai n, e ve n t o 
t he sa me s u bject. W he ne ver a s u bject bri n gs his or her st u d y dr u g t o t he st u d y site f or pill c o u nt, 
t his is n o t see n as a ret ur n of s u p plies. St u d y  dr u g ma y  not be rela bele d or reassi g ne d f or use b y  
ot her s u bjects. T he i n vesti gat or a grees neit her t o dis pe nse t he st u d y dr u g fr o m, n or st ore it at, 
a n y site ot her t ha n t he st u d y sites a gree d u p o n wit h t he s p o ns or.
1 5.
S T U D Y -S P E CI FI C M A T E RI A L S
T he i n vesti gat or will be pr o vi de d wit h t he f oll o wi n g s u p plies:

I n vesti gat or's Br oc h ure, S m P C/ PI f or z ol pi de m

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

Ce ntral la b orat or y  ma n ual 

C o m p uters a n d/ or ta blets, s oft ware, a n d ma n ual f or t he c o g niti ve test batter y

Patie nt -re p orte d o utc o me 
q uesti o n naires 
a n d 
patie nt -re p orte d o utc o me 
c o m pleti o n 
g ui deli nes

Cli nicia n -re p orte d o utc o me q uesti o n naires a n d cli nicia n-re p orte d o utc o me c o m pleti o n 
g ui deli nes

P S G Ma n ual

I W R S Ma n ual

Electr o nic data ca pt ure ( e D C) Ma n ual

Sa m ple I C F

S u bject diaries

S u bject recr uit me nt materials

Pre -pri nte d la bels f or bl o o d sa m ples

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1 6.
E T HI C A L A S P E C T S
1 6. 1.
St u d y -S p e cifi c D e si g n C o n si d er ati o n s
Cli nic al St u d y i n I ns o m ni a Dis or der
I ns o m nia is p ote ntiall y seri o us dis or der , as it is ass ociate d wit h i ncrease d ris k for i nj uri o us falls 
a n d i m pair me nt of c o g niti ve f u ncti o n. I ns o m nia as a s ym pt o m affects u p t o 5 0 % of t he ge neral 
p o p ulati o n, w hile i ns o m nia wit h si g nifica nt d a y ti me c o nse q ue nces is esti mate d t o affect 7 % t o 
1 3 % of t he p o p ulati o n a n d is rec o g nize d as a maj or p u blic healt h iss ue.4 3 Data fr o m l o n git u di nal 
st u dies s u g gest t hat, f or ma n y  in di vi d uals, i ns o m nia bec o mes a c hr o nic iss ue, affecti n g e ner g y, 
c o g niti ve f u ncti o ni n g, m o o d, a n d ge neral healt h; a p pr o xi matel y 70 % of pers o ns wit h i ns o m nia 
will c o nti n ue t o re p ort i ns o m nia a year later, a n d a p pr o xi matel y 50 % re p ort i ns o m nia u p t o 
3 ye ars later.5 2 ,5 4 ,5 5 St u dies c o nsiste ntl y s h o w a n i ncreasi n g pre vale nce of i ns o m nia wit h a ge, a n d 
a hi g her pre vale nce i n w o me n vers us me n. 3 8 ,4 0 ,4 1 ,4 2 ,5 6 ,6 0
Z ol pi de m, a n o n- B Z D h y p n otic, is t he m ost c o m m o nl y prescri be d h y p n otic i n t he U S , E ur o pe , 
a n d Ja pa n .2 5 ,4 9 Z ol pi de m, at its rec o m me n de d d oses ( 5 t o 1 0 m g) was pr o ve n as effecti ve as B Z D 
i n t he ma na ge me nt of s h ort-ter m i ns o m nia.3 3 ,8 0 Z ol pi de m is ge nerall y  co nsi dere d t o ha ve o nl y 
mi n or resi d ual effects w he n ta ke n at be dti me, w he n 8 h o urs of slee p is all o we d. 2 ,1 5 ,3 1 ,7 1 ,7 7 ,8 2
H o we ver, z ol pi de m is k n o w n t o i m pair c o g niti ve f u ncti o n a n d bala nce/ m ot or c o or di nati o n w he n 
s u bjects are w o ke n u p after a fe w h o urs of slee p. T his ma y  res ult i n patie nts falli n g or s h o wi n g 
i ns ufficie nt res p o nse i n case of e mer ge nc y.3 9 ,7 5 M o derate t o se vere c o g niti ve i m pair me nt has 
bee n o bser ve d wit hi n 
5 h o ur p ost -a d mi nistrati o n t hat m a y  be detecta ble u p t o 7 h o urs 
p ost -a d mi nistrati o n. 1 4 ,3 0 ,4 8 ,6 2 ,8 1 B y  da m pe ni n g t he s yste m res p o nsi ble f or h y perar o usal, as o p p ose d 
t o e n ha nci n g t he se dati ve effects of t he i n here nt G A B A , J NJ-4 2 8 4 7 9 2 2 is e x pecte d t o de m o nstrate 
efficac y i n i n d uci n g a n d mai ntai ni n g slee p, wit h o ut t he si de effects ass ociate d wit h ot her classes of 
se dati ve h y p n otics, i ncl u di n g m usc ular at o nia res ulti n g i n bala nce iss ues, c o g niti ve deficits a n d 
a nter ogra de a m nesia, a n d de pe n de nce a n d t olera nce.
T o date, J NJ-4 2 8 4 7 9 2 2 has s h o w n g o o d t olera bility a n d safety.
J NJ- 4 2 8 4 7 9 2 2 has bee n 
a d mi nistere d t o h u ma ns bef ore i n si n gle a n d m ulti ple asce n di n g d ose st u dies i n healt h y s u bjects, 
s u bjects s ufferi n g fr o m i ns o mnia, a n d s u bjects s ufferi n g fr o m de pressi o n wit h i ns o m nia. T he 
hi g hest 
d ose 
teste d 
i n 
t he 
m ulti ple 
d ose 
st u d y 
was 
6 0 
m g 
o ver 
1 0 
da ys 
( St u d y 4 2 8 4 7 9 2 2 E DI 1 0 0 3). All d oses teste d t o date ha ve pr o ve n t o be well t olerate d i n healt h y 
s u bjects a n d i n s u bjects s ufferi n g fr o m i ns o m nia dis or der ( St u d y 4 28 4 7 9 2 2I S M 2 0 0 2) a n d 
de pressi o n wit h c o m or bi d i ns o m nia ( St u d y 42 8 4 7 9 2 2 M D D 1 0 0 1) . T he ma xi mal d urati o n of 
treat me nt was 2 8 d a y s ( 2 0 m g; St u d y 4 2 8 4 7 9 2 2 M D D 1 0 0 1). Preli mi nar y safet y res ults fr o m 
St u d y 4 2 8 4 7 9 2 2 E DI 1 0 1 4 i n el derl y healt h y s u bject c o h orts s h o w t hat si n gle e ve ni n g d osi n g of 
J NJ-4 2 8 4 7 9 2 2 1 0 m g, 2 0 m g d oses are well t olerate d.
I n to xic ol o g y  st u dies, J NJ- 4 2 8 4 7 9 2 2 has bee n i n vesti gate d o ver a peri o d of 6 m o nt hs i n rats a n d 
9 m o nt hs i n d o gs, w hic h a de q uatel y co vers a peri o d of 1 4 d a y s of d osi n g. See Secti o n 1. 1. 1 , 
N o ncli nical St u dies f or s u m mar y  of t o xic ol o g y st u dies.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
Selecti o n of S u bjects
T he pri mar y  ai m of t his st u d y is t o c o m pare t he efficac y of 3 d oses of J NJ-4 2 8 4 7 9 2 2 ( 5-, 1 0-, a n d 
2 0 -m g ) c o m pare d t o place b o a n d t o f urt her d oc u me nt t he safety a n d t olera bilit y of J NJ-4 2 8 4 7 9 2 2 
u p o n m ulti ple d ose a d mi nistrati o n i n a d ult a n d el derl y s u bjects wit h i ns o m nia dis o r der. T h us, t he 
st u d y ca n n ot be c o m plete d i n healt h y s u bjects.
P ote ntial s u bjects will be f ully i nf or me d of t he ris ks a n d re q uire me nts of t he st u d y an d, d uri n g t he 
st u d y, s u bjects will be gi ve n a n y ne w i nf or mati o n t hat ma y  affect t heir decis i o n t o c o nti n ue
partici pati o n. T he y  will be t ol d t hat t heir c o nse nt t o partici pate i n t he st u d y is v ol u ntar y a n d ma y be 
wit h dra w n at a n y ti me wit h n o reas o n gi ve n a n d wit h o ut pe nalt y or l oss of be nefits t o w hic h t he y 
w o ul d ot her wise be e ntitle d. O nl y s u bjects w h o are f ull y able t o u n dersta n d t he ris ks, be nefits, a n d 
p ote ntial A E s of t he st u d y, a n d pr o vi de t heir c o nse nt v ol u ntarily will be e nr olle d.
I n t his st u d y, a p o p ulati o n s h o w n t o ha ve b ot h s u bjecti ve a n d o bjecti ve (as meas ure d b y  PS G) 
slee p dist ur ba nce w h o are ot her w ise healt h y  or prese nt wit h sta ble, well -c o ntr olle d, c hr o nic 
c o n diti o ns, will be selecte d, as t hese i n di vi d uals ma y  be nefit m ost 
fr o m treat me nt wit h 
J NJ- 4 2 8 4 7 9 2 2 or z ol pi de m. T he p o p ulati o n will i ncl u de me n a n d W O N C B P . Si nce a fe male rat 
fertilit y st u d y su g geste d a re d ucti o n i n fe male fertilit y, a n d it is n ot k n o w n w hat t he rele va nce of 
t hese fi n di n gs are t o a w o ma n’s a bilit y to bec o me pre g na nt after ta ki n g J NJ- 4 2 8 4 7 9 2 2, W O C B P 
will n ot be i ncl u de d i n t his st u d y until m ore is lear ne d a b o ut t he effect of J NJ- 4 2 8 4 7 9 2 2 o n 
fe male re pr o d ucti o n. Eli gi ble s u bjects will t he n e nter a d o u ble -bli n d treat me nt p hase of 1 7 da y s, 
wit h 1 4 da y s of d osi n g wit h st u d y dr u g, w hic h is t he mi ni mal treat me nt d urati o n base d o n t he m ost 
rece nt gl o bal g ui da nce o n t he i n vesti gati o n of treat me nts f or ins o m nia d is or der, iss ue d b y  the 
C o m mittee f or Me dici nal Pr o d ucts f or H u ma n Use . T here wil l be a f oll o w-u p visit 7 t o 1 0 da ys 
after t he last d ose of st u d y dr u g. S u bjects mi g ht als o be nefit fr o m t he cli nical e val uati o ns a n d t he 
i nf or mati o n c ollecte d as part of t his st u d y. T he res ults of t he i n vesti gati o n of J NJ-4 2 8 4 7 9 2 2 ma y  
hel p f ut ure patie nts wit h i ns o m nia.
J ustific ati o n f or Usi n g t he Acti ve C o m p ar at or
Z ol pi de m is t he w orl d wi de mar ket lea der f or treat me nt of i ns o m nias. T his is base d o n a q uic k 
o nset a n d a relati vely s h ort half -life (a b o ut 2- 3 h o urs) wit h 
relati vel y preser ve d slee p 
arc hitect ure, a n d t he de vel o p me nt of less t olera nce. Z ol pi de m will be d ose d per l ocal pr o d uct 
la bel (see Secti o n 6 , D osa ge a n d A d mi nistrati o n).
Prec a uti o ns t o E ns ure S u bject S afet y i n t he St u d y 
S u bjects m a y  partici pate i n t he st u d y onl y  if t he y ha ve a de q uate ca pacit y to gi ve c o nse nt a n d 
after f ull y un dersta n di n g t he p ote ntial ris ks a n d gi vi n g a n i nf or me d c o nse nt. Deter mi nati o n of 
ca pacit y will be ma de b y t he st ud y  in vesti gat or. S u bjects ma y  disc o nti n ue t he st u d y at a n y ti me. 
T he s p o ns or will m o nit or t he st u d y site a n d rec or ds t o e ns ure c o m plia nce wit h t he pr ot oc ol, a n d 
t hat c urre nt I C H g ui deli nes o n G o o d Cli nical Practice ( G C P) are f oll o we d, a n d a p plica ble 
re g ulat or y re q uire me nts are a d here d t o.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0 3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
T o i ns ure s u bject safety,  su bjects will re mai n u n der o bser vati o n of t he i n vesti gat or a n d st u d y 
staff at t he cli nical st u d y site fr o m D a y  1 of t he d o u ble -bli n d p hase a n d u ntil n o o n of D a y  2 (or 
D a y 3 i n s u bjects u n der g oi n g o ver ni g ht P K sa m pli n g) a n d ret ur n t o t he st u d y site o n Da y 1 3 f or 
a n a d diti o nal o ver ni g ht P S G rec or di n g o ver 8 h o urs u ntil n o o n of Da y  15 ( 2 o ver ni g hts). 
T olera bilit y  of t he st u d y dr u g will 
be assesse d wit h 
caref ul atte nti o n t o ne xt da y  
se dati o n/slee pi ness a n d c o g niti ve a n d ps yc h o m ot or effects pri or t o disc har gi n g s u bjects fr o m t he 
st u d y site. S u bjects w h o ma nifest si g nifica nt ne xt da y  slee pi ness or ps yc h o m ot or effects will be 
disc o nti n ue d or a d vise d n ot t o dri ve or o perate mac hi ner y , per t he i n vesti gat or’s assess me nt. T he 
st u d y site will e ns ure t hat all s u bjects h a ve a p pr o priate tra ns p ortati o n t o t heir h o me o n D a y  2 ( or 
D a y 3 f or s u bjects u n der g oi n g o ver ni g ht P K sa m pli n g) a n d Da y  15 u p o n disc har ge, a n d t he y 
ma y  res u me dri vi n g a n d/ or o perati n g mac hi ner y o n Da y  3 (or D a y  4 for s u bjects u n der g oi n g 
o ver ni g ht P K sa m pli n g) after t olera bilit y has bee n esta blis he d.
O nl y  q ualifie d a n d trai ne d i n vesti gat ors will partici pate i n t he st u d y.
T he t otal bl o o d v ol u me t o be c ollecte d o ver t he c o m plete st u d y peri o d will n ot e xcee d 2 2 5 m L , 
w hic h is c o nsi dere d t o be a n acce pta ble a m o u nt of bl o o d t o be c ollecte d o ver t his ti me peri o d 
fr o m t he p o p ulati o n i n t his st u d y base d u p o n t he sta n dar d of t he A merica n Re d Cr oss.
1 6. 2.
R e g ul at or y  Et hi c s C o m pli a n c e
1 6. 2. 1.
I n v e sti g at or R e s p o n si biliti e s
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat t he st u d y is p erf or me d i n acc or da nce wit h t he 
pr ot oc ol, c urre nt I C H g ui deli nes o n G C P , a n d a p plica ble re g ulat or y a n d c o u ntr y-s pecific 
re q uire me nts.
G o o d Cli nical Practice is a n i nter nati o nal et hical a n d scie ntific q ualit y sta n dar d f or desi g ni n g, 
c o n d ucti n g, rec or di n g, a n d re p orti n g st u dies t hat i n v ol ve t he partici pati o n of h u ma n s u bjects. 
C o m plia nce wit h t his sta n dar d pr o vi des p u blic ass ura nce t hat t he ri g hts, safet y , a n d well-bei n g of 
st u d y su bjects are pr otecte d, c o nsiste nt wit h t he pri nci ples t hat ori gi nate d i n t he De clarati o n of 
Helsi n ki , a n d t hat t he st u d y data are cre di ble.
1 6. 2. 2.
I n d e p e n d e nt Et hi c s C o m mitt e e or I n stit uti o n al R e vi e w B o ar d
Bef ore t he start of t he st u d y, t he i n vesti gat or ( or s p o ns or w here re q uire d) will pr o vi de t he 
I E C/I R B wit h c urre nt a n d c o m plete c o pies of t he f oll o wi n g d oc u me nts (as re q uire d b y  local 
re g ulati o ns):

Fi nal pr ot oc ol a n d, if a p plica ble, a me n d me nts

S p o ns or -a p pr o ve d I CF (a n d a n y ot her writte n materials t o be pr o vi de d t o t he s u bjects)

I n vesti gat or's Br oc h ure ( or e q ui vale nt i nf or mati o n) a n d a me n d ments/a d de n da

S p o ns or -a p pr o ve d s u bject recr uiti n g materials

I nf or mati o n o n c o m pe nsati o n f or st u d y-relate d i nj uries or pa y me nt 
t o s u bjects f or 
partici pati o n i n t he st u d y , if a p plica ble

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8

I n vesti gat or's c urric ul u m vitae or e q ui vale nt i nf or mati o n ( u nless n ot re q uire d, as 
d oc u me nte d b y t he I E C/I R B)

I nf or mati o n re gar di n g f u n di n g, na me of t he s p o ns or, i nstit uti o nal affiliati o ns, ot her p ote ntial 
c o nflicts of i nterest, a n d i nce nti ves f or s u bjects

A n y  ot her d oc u me nts t hat t he IE C/I R B re q uests t o f ulfill its o bli gati o n
T his st u d y will be u n derta ke n o nl y  after t he I E C/IR B has gi ve n f ull a p pr o val of t he fi nal 
pr ot oc ol, a me n d me nts (if a n y, e xcl u di n g t he o nes t hat are p urel y a d mi nistrati ve, wit h n o 
c o nse q ue nces f or s u bjects, data or st u d y co n d uct , u nless re q uire d l ocally ), t he I CF, a p plica ble 
recr uiti n g materials, a n d s u bject c o m pe nsati o n pr o gra ms, a n d t he s p o ns or has recei ve d a c o p y of 
t his a p pr o val. T his a p pr o val letter m ust be date d a n d m ust clearl y i de ntif y t he I EC/I R B a n d t he 
d oc u me nts bei n g a p pr o ve d.
A p pr o val f or t he c ollecti o n of o pti o nal sa m ples f or researc h a n d f or t he c orres p o n di n g I CF m ust 
be o btai ne d fr o m t he I EC/I R B. A p pr o val f or t he pr ot oc ol ca n be o btai ne d i n de pe n de nt of t his 
o pti o nal researc h c o m p o ne nt . 
D uri n g t he st u d y the i n vesti gat or ( or s p o ns or w here re quire d) will se n d t he f oll o wi n g d oc u me nts 
a n d u p dates t o t he I E C/I R B f or t heir re vie w a n d a p pr o val, w here a p pr o priate:

Pr ot oc ol a me n d me nts
(e xcl u di n g t he o nes t hat are p urel y  ad mi nistrati ve, wit h 
n o 
c o nse q ue nces f or s u bjects, data or st u d y  c o n d uct)

Re visi o n (s) t o I CF a n d a n y ot her writte n materials t o be pr o vi de d t o s u bjects

If a p plica ble, ne w or re vise d s u bject recr uiti n g materials a p pr o ve d by t he s p o ns or

Re visi o ns t o c o m pe nsati o n f or st u d y -relate d i nj uries or pa yme nt t o s u bjects f or partici pati o n 
i n t he stu d y, if a p plica ble

Ne w e diti o n(s) of t he I n vesti gat or's Br oc h ure a n d a me n d me nts/a d de n da

S u m maries of t he stat us of t he st u d y at i nter vals sti p ulate d i n g ui deli nes of t he I EC/I R B (at 
least a n n ually)

Re p orts of A E s t hat are seri o us, u nliste d/ u ne x pecte d, a n d ass ociate d wit h t he st u d y dr u g

Ne w i nf or mati o n t hat ma y  ad versel y affect t he safety of t he s u bjects or t he c o n d uct of t he 
st u d y

De viati o ns fr o m or c ha n ges t o t he pr ot oc ol t o eli mi nate i m me diate hazar ds t o t he s u bjects

Re p ort of deat hs of s u bjects u n der t he i n vesti gat or's care

N otificati o n if a ne w i n vesti gat or is res p o nsi ble f or t he st u d y  at t he site

De vel o p me nt Safet y U p date Re p ort a n d Li ne Li sti n gs, w here a p plica ble

A n y  ot her re q uire me nts of t he I E C/IR B
F or all pr ot oc ol a me n d me nts (e xcl u di n g t he o nes t hat are p urel y a d mi nistrati ve, wit h n o 
c o nse q ue nces f or s u bjects, data or st u d y c o n d uct) , t he a me n d me nt a n d a p plica ble I C F re visi o ns 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
m ust be s u b mitte d pr o m ptl y  to t he I E C/IR B f or re vie w a n d a p pr o val bef ore im ple me ntati o n of 
t he c ha n ge(s).
At least o nce a ye ar, t he I E C/IR B will be as ke d t o re vie w a n d rea p pr o ve t his st u d y, w here 
re q uire d.
At t he e n d of t he st u d y, t he i n vesti gat or ( or s p o ns or w here re q uire d) will n otif y  the I E C/IR B 
a b o ut t he st u d y co m pleti o n (if a p plica ble, t he n otificati o n will be s u b mitte d t hr o u g h t he hea d of 
i n vesti gati o nal i nstit uti o n).
1 6. 2. 3.
I nf or m e d C o n s e nt
Eac h s u bject m ust gi ve writte n c o nse nt acc or di n g t o l ocal re q uire me nts after t he nat ure of t he 
st u d y has bee n f ull y ex plai ne d. T he I CF(s) m ust be si g ne d bef ore perf or ma nce of a n y 
st u d y-relate d acti vit y. T he I C F(s) t hat is/are use d m ust be a p pr o ve d b y  bot h t he s p o ns or a n d b y  
t he re vie wi n g I E C/IR B a n d be i n a la n g ua ge t hat t he s u bject ca n rea d a n d u n dersta n d. T he 
i nf or me d c o nse nt s h o ul d be i n acc or da nce wit h pri nci ples t hat ori gi nate d i n t he Declarati o n of 
Helsi n ki, c urre nt I CH a n d G C P g ui deli nes, a p plica ble re g ulat or y re q uire me nts, a n d s p o ns or 
p olic y .
Bef ore e nr oll me nt i n t he st u d y, t he i n vesti gat or or a n a ut h orize d me m ber of t he st u d y-site 
per s o n nel m ust e x plai n t o p ote ntial s u bjects t he ai ms, met h o ds, reas o na bl y a ntici pate d be nefits, 
a n d p ote ntial hazar ds of t he st u d y, a n d a n y disc o mf ort partici pati o n i n t he st u d y ma y entail . 
S u bjects will be i nf or me d t hat t heir partici pati o n is v ol u ntar y  an d t hat t he y ma y wit h dra w 
c o nse nt t o partici pate at a n y ti me. T he y will be i nf or me d t hat c h o osi n g n ot t o partici pate will n ot 
aff ect t he care t he s u bject will recei ve f or t he treat me nt of his or her i ns o m nia. S u bjects will be 
t ol d t hat alter nati ve treat me nts are a vaila ble if t he y ref use t o ta ke part a n d t hat s uc h ref usal will 
n ot prej u dice f ut ure treat me nt. Fi nall y , t he y will be t ol d t hat t he i n vesti gat or will mai ntai n a 
s u bject i de ntificati o n re gister f or t he p ur p oses of l o n g-ter m f oll o w u p if nee de d a n d t hat t heir 
rec or ds m a y  be accesse d b y  healt h a ut h orities a n d a ut h orize d s p o ns or pers o n nel wit h o ut 
vi olati n g t he c o nfi de ntialit y of t he s u bject, t o t he e xte nt per mitte d b y  the a p plica ble la w(s) or 
re g ulati o ns. B y si g ni n g t he I CF t he s u bject is a ut h orizi n g s uc h access, w hic h i ncl u des per missi o n 
t o o btai n i nf or mati o n a b o ut his or her s ur vi val stat us. It als o de n otes t hat t he s u bject a grees t o 
all o w his or her st u d y ph y sicia n t o rec o ntact t he s u bject f or t he p ur p ose of o btai ni n g c o nse nt f or 
a d diti o nal safet y e val uati o ns , if nee de d.
T he s u bject will be gi ve n s ufficie nt ti me t o rea d t he I CF a n d t he o p p ort u nit y  to as k q uesti o ns. 
After t his e x pla nati o n a n d bef ore e ntr y int o t he st u d y, c o nse nt s h o ul d be a p p r o priately rec or de d 
b y  mea ns of t he s u bject's pers o nally da te d si g nat ure. After ha vi n g o btai ne d t he c o nse nt, a c o p y  of 
t he I CF m ust be gi ve n t o t he s u bject.
S u bjects will be as ke d f or c o nse nt t o pr o vi de o pti o nal sa m ples f or researc h (w here l ocal 
re g ulati o ns per mit). After i nf or me d c o nse nt f or t he st u d y is a p pr o pri atel y o btai ne d, t he s u bject 
will be as ke d t o si g n a n d pers o nall y date a se parate I C F i n dicati n g a gree me nt t o partici pate i n t he 
o pti o nal researc h c o m p o ne nt . Ref usal t o partici pate i n t he o pti o nal researc h will n ot res ult i n 
i neli gi bilit y f or t he st u dy. A c o p y  of t his si g ne d I C F will be gi ve n t o t he s u bject.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0 6
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1 6. 2. 4.
Pri v a c y of P er s o n al D at a
T he c ollecti o n a n d pr ocessi n g of pers o nal data fr o m s u bjects e nr olle d i n t his st u d y will be 
li mite d t o t h ose data t hat are necessar y t o f ulfill t he o bjecti ves of t he st u d y.
T hese data m ust be c ollecte d a n d pr ocesse d wit h a de q uate preca uti o ns t o e ns ure c o nfi de ntialit y 
a n d c o m plia nce wit h a p plica ble data pri vac y  pr otecti o n la ws a n d re g ulati o ns. A p pr o priate 
tec h nical a n d or ga nizati o nal meas ures 
t o pr otect t he pers o nal data a gai nst u na ut h orize d 
discl os ures or access, acci de ntal or u nla wf ul destr ucti o n, or acci de ntal l oss or alterati o n m ust be 
p ut i n place. S p o ns or pers o n nel w h ose res p o nsi bilities re q uire access t o pers o nal data a gree t o 
kee p t he i de ntit y of s u bjects c o nfi de ntial.
T he inf or me d c o nse nt o btai ne d fr o m t he s u bject i ncl u des e x plicit c o nse nt f or t he pr ocessi n g of 
pers o nal data a n d f or t he i n vesti gat or/i nstit uti o n t o all o w direct access t o his or her ori gi nal 
me dical rec or ds (s o urce data/ d oc u me nts) f or st u d y-relate d m o nit ori n g,
a u dit, I EC/I R B re vie w, 
a n d re g ulat or y ins pecti o n. T his c o nse nt als o a d dresses t he tra nsfer of t he data t o ot her e ntities 
a n d t o ot her c o u ntries.
T he s u bject has t he ri g ht t o re q uest t hr o u g h t he i n vesti gat or access t o his or her pers o nal data a n d 
t he ri g ht t o re q uest rectificati o n of a n y data t hat are n ot c orrect or c o m plete. Reas o na ble ste ps 
will be ta ke n t o res p o n d t o s uc h a re q uest, ta ki n g i nt o c o nsi derati o n t he nat ure of t he re q uest, t he 
c o n diti o ns of t he st u d y, a n d t he a p plica ble la ws a n d re g ulati o ns.
E x pl orat or y  DN A , bi o mar ker, a n d P K researc h is n ot c o n d ucte d u n der sta n dar ds a p pr o priate f or 
t he ret ur n of data t o s u bjects. I n a d diti o n, t he s p o ns or ca n n ot ma ke 
decisi o ns as t o t he 
si g nifica nce of a n y fi n di n gs res ulti n g fr o m e x pl orat or y researc h. T heref or e, e x pl orat or y researc h 
data will n ot be ret ur ne d t o s u bjects or i n vesti gat ors, u nless re q uire d b y  la w or l ocal re g ulati o ns. 
Pri vac y  an d c o nfi de ntialit y  of data ge nerate d i n t he f ut ure o n st ore d sa m ples will be pr otecte d b y 
t he sa me sta n dar ds a p plica ble t o all ot her cli nical data.
1 6. 2. 5.
L o n g -T er m R et e nti o n of S a m pl e s f or A d diti o n al F ut ur e R e s e ar c h
Sa m ples c ollecte d i n t his st u d y ma y be st ore d f or u p t o 1 5 ye ars ( or acc or di n g t o l ocal 
re g ulati o ns) f or a d diti o nal researc h. Sa m ples will o nl y  be use d t o u n dersta n d J NJ- 4 2 8 4 7 9 2 2, t o 
u n dersta n d i ns o m nia dis or der , t o u n dersta n d differe ntial dr u g res p o n ders, a n d t o de vel o p 
tests/assa ys relate d t o J NJ-4 2 8 4 7 9 2 2 a n d i ns o m nia dis or ders ( N ote: D N A sa m ples c ollecte d fr o m 
Ja pa nese s u bjects will n ot be use d f or researc h related t o i ns o m nia). T he researc h m a y  be gi n at 
a n y ti me d uri n g t he st u d y or t he p ost-st u d y st ora ge peri o d.
St ore d sa m ples will be c o de d t hr o u g h o ut t he sa m ple st ora ge a n d a nal ys is pr ocess a n d will n ot be 
la bele d wit h pers o nal i de ntifiers. S u bjects m a y  wit h dra w t heir c o nse nt f or t heir sa m ples t o be 
st ore d f or researc h (refer t o Secti o n 1 0. 3 , Wit h dra wal 
Fr o m t he Use of Sa m ples i n F ut ure 
Researc h ).

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0 7
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1 6. 2. 6.
C o u ntr y S e l e cti o n
T his st u d y will o nl y  be c o n d ucte d i n t h ose c o u ntries w here t he i nte nt is t o la u nc h or ot her wise 
hel p e ns ure access t o t he de vel o pe d pr o d uct if t he nee d f or t he pr o d uct persists , u nless e x plicitl y 
a d dresse d as a s pecific et hical c o nsi derati o n i n Secti o n 1 6. 1 , St u d y -S pecific 
Desi g n 
C o nsi derati o ns.
1 7.
A D MI NI S T R A TI V E R E Q UI R E M E N T S
1 7. 1.
Pr ot o c ol A m e n d m e nt s
Neit her t he i n vesti gat or n or t he s p o ns or will m o dif y  this pr ot oc ol wit h o ut a f or mal a me n d me nt 
b y  t he s p o ns or. All pr ot oc ol a me n d me nts m ust be iss ue d b y t he s p o ns or, a n d si g ne d a n d date d b y 
t he i n vesti gat or. Pr ot oc ol a me n d me nts m ust 
n ot be i m ple me nte d wit h o ut 
pri or I E C/I R B 
a p pr o val, or w he n t he rele va nt c o m pete nt a ut h orit y has raise d a n y gr o u n ds f or n o n- acce pta nce, 
e xce pt w he n necessar y t o eli mi nate i m me diate hazar ds t o t he s u bjects, i n w hic h case t he 
a me n d me nt m ust be pr o m ptl y  su b mitte d t o t he I E C/IR B a n d rele va nt c o m pete nt a ut h orit y. 
D oc u me ntati o n of a me n d me nt a p pr o val b y t he i n vesti gat or a n d I E C/I R B m ust be pr o vi de d t o t he 
s p o ns or. W he n t he c ha n ge(s) i n v ol ves o nl y  lo gistic or a d mi nistrati ve as pects of t he st u d y, t he 
I E C/IR B ( w here re q uire d) o nl y  nee ds t o be n otifie d.
D uri n g t he c o urse of t he st u d y, i n sit uati o ns w here a de part ure fr o m t he pr ot oc ol is u na v oi da ble, 
t he i n vesti gat or or ot her p h y sicia n i n atte n da nce will 
c o ntact t he a p pr o priate s p o ns or 
re prese ntati ve liste d i n t he C o ntact I nf or mati o n pa ge (s), w hic h will be pr o vi de d as a se parate
d oc u me nt . E xce pt i n e mer ge nc y sit uati o ns, t his c o ntact s h o ul d be ma de bef ore i m ple me nti n g a n y 
de part ure fr o m t he pr ot oc ol. I n all cases, c o ntact wit h t he s p o ns or m ust be ma de as s o o n as 
p ossi ble t o disc uss t he sit uati o n a n d a gree o n a n a p pr o priate c o urse of acti o n. T h e data rec or de d 
i n t he C R F a n d s o urce d oc u me nts will reflect a n y de part ure fr o m t he pr ot oc ol, a n d t he s o urce 
d oc u me nts will descri be t his de part ure a n d t he circ u msta nces re q uiri n g it.
1 7. 2.
R e g ul at or y  D o c u m e nt ati o n
1 7. 2. 1.
R e g ul at or y  A ppr o v al/ N otifi c ati o n
T his pr ot oc ol a n d a n y ame n d me nt(s) m ust be s u b mitte d t o t he a p pr o priate re g ulat or y aut h orities 
i n eac h res pecti ve c o u ntr y, if a p plica ble. A st u d y ma y  not be i nitiate d u ntil all l ocal re g ulat or y 
re q uire me nts are met.
1 7. 2. 2.
R e q uir e d Pr e st u d y  D o c u m e nt ati o n
T he f oll o wi n g d oc u me nt s m ust be pr o vi de d t o t he s p o ns or bef ore s hi p me nt of st u d y dr u g t o t he 
st u d y site:

Pr ot oc ol a n d a me n d me nt(s), if a n y, si g ne d a n d date d b y t he pri nci pal i n vesti gat or

A c o p y of t he date d a n d si g ne d ( or seale d, w here a p pr o priate per l ocal re g ulati o ns), writte n 
I E C/I R B a p pr o val of t he pr ot oc ol, a me n d me nts, I CF, a n y recr uiti n g materials, a n d if 
a p plica ble, s u bject c o m pe nsati o n pr o gra ms. T his a p pr o val m ust clearl y i de ntif y the s pecific 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0 8
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
pr ot oc ol b y  title a n d n u m ber a n d m ust be si g ne d ( or seale d, w here a p pr o priate per l ocal 
re g ulati o ns) b y  t he c hair ma n or a ut h orize d desi g nee.

Na me a n d a d dress of t he I E C/IR B, i ncl u di n g a c urre nt list of t he I E C/I R B me m bers a n d 
t heir f u ncti o n, wit h a state me nt t hat it is or ga nize d a n d o perates acc or di n g t o G C P a n d t he 
a p plica ble la ws a n d re g ulati o ns. If acc o m pa nie d b y  a letter of e x pla nati o n, or e q ui vale nt, 
fr o m t he I EC/I R B, a ge neral state me nt ma y  be s u bstit ute d f or t his list. If a n i n vesti gat or or a 
me m ber of t he st u d y-site pers o n nel is a me m ber of t he I E C/I R B, d oc u me ntati o n m ust be 
o btai ne d t o state t hat t his pers o n di d n ot partici pate i n t he deli berati o ns or i n t he 
v ote/ o pi ni o n of t he st u d y.

Re g ulat or y  a ut h orit y a p pr o val or n otificati o n, if a p plica ble

Si g ne d a n d date d state me nt of i n vesti gat or (e g, F or m F D A 1 5 7 2), if a p plica ble

D oc u me ntati o n of i n vesti gat or q ualificati o ns (e g, c urric ul u m vitae)

C o m plete d i n vesti gat or fi na ncial discl os ure f or m fr o m t he pri nci pal i n vesti gat or, w here 
re q uire d

Si g ne d a n d date d cli nical trial a gree me nt, w hic h i ncl u des t he fi na ncial a gree me nt

A n y  ot her d ocu me ntati o n re q uire d b y  l ocal re g ulati o ns
T he f oll o wi n g d oc u me nts m ust be pr o vi de d t o t he s p o ns or bef ore e nr oll me nt of t he first s u bject:

C o m plete d i n vesti gat or fi na ncial discl os ure f or ms fr o m all s u bi n vesti gat ors

D oc u me ntati o n of s u bi n vesti gat or q ualificati o ns (e g, c urric ul u m vitae)

Na me a n d a d dress of a n y l ocal la b orat or y  co n d ucti n g tests f or t he st u d y , a n d a date d c o p y of 
c urre nt la b orat or y n or mal ra n ges f or t hese tests, if a p plica ble

L ocal 
la b orat or y 
doc u me ntati o n 
de m o nstrati n g 
c o m pete nce 
a n d 
test 
relia bilit y 
(e g, accre ditati o n/lice nse), if a p plica ble
1 7. 3.
S u bj e ct I d e ntifi c ati o n, E nr oll m e nt, a n d S cr e e ni n g L o g s
T he i n vesti gat or a grees t o c o m plete a s u bject i de ntificati o n a n d e nr oll me nt l o g t o per mit eas y 
i de ntificati o n of eac h s u bject d uri n g a n d after t he st u d y. T his d oc u me nt will be re vie we d b y  th e 
s p o ns or st u d y-site c o ntact f or c o m plete ness.
T he s u bject i de ntificati o n a n d e nr oll me nt l o g will be treate d as c o nfi de ntial a n d will be file d b y  
t he i n vesti gat or i n t he st u d y file. To e ns ure s u bject c o nfi de ntialit y, n o c o p y will be ma de. All 
re p orts a n d c o m m u nicati o ns relati n g t o t he st u d y will i de ntif y su bjects b y  su bject i de ntificati o n
a n d date of birt h. I n cases w here t he s u bject is n ot ra n d o mize d i nt o t he st u d y, t he date see n a n d 
date of birt h will be use d.
T he i n vesti gat or m ust als o c o m plete a s u bject scree ni n g l o g, w hic h re p orts o n all s u bjects w h o 
were see n t o deter mi ne eli gi bilit y  f or i ncl usi o n i n t he st u d y.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 0 9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
1 7. 4.
S o ur c e D o c u m e nt ati o n
At a mi ni m u m, s o urce d oc u me nt s c o nsiste nt i n t he t ype a n d le vel of detail wit h t hat c o m m o nl y 
rec or de d at t he st u d y site as a basis f or sta n dar d me dical care m ust be a vaila ble f or t he f oll o wi n g: 
s u bject i de ntificati o n, eli gi bilit y, a n d st u d y ide ntificati o n; st u d y disc ussi o n a n d date of si g ne d 
i nf or me d c o nse nt; dates of visits; res ults of safet y a n d efficac y para meters as re q uire d b y  the 
pr ot oc ol; 
rec or d of all 
A E s a n d f oll o w- u p of 
A E s; c o nc o mita nt me dicati o n; 
dr u g 
recei pt/ dis pe nsi n g/ret ur n rec or ds; st u d y dr u g a d mi nistrati o n i nf or mati o n; a n d date of st u d y 
co m pleti o n a n d reas o n f or earl y disc o nti n uati o n of st u d y dr u g or wit h dra wal fr o m t he st u d y, if 
a p plica ble.
T he a ut h or of a n e ntr y  i n t he s o urce d oc u me nts s h o ul d be i de ntifia ble.
S pecific details re q uire d as s o urce data f or t he st u d y a n d s o urce data c ollect i o n met h o ds will be 
re vie we d wit h t he i n vesti gat or bef ore t he st u d y an d will be descri be d i n t he m o nit ori n g 
g ui deli nes ( or ot her e q ui vale nt d oc u me nt).
T he mi ni m u m 
s o urce d oc u me ntati o n re q uire me nts f or Secti o n 4. 1 , I ncl usi o n Criteria a n d 
Secti o n 4. 2 ,
E xcl usi o n Criteria t hat s pecif y a nee d f or d oc u me nte d me dical hist or y  are as 
f oll o ws:

Referral letter fr o m treati n g p h ys icia n or

C o m plete hist or y  of me dical n otes at t he site

Disc har ge s u m ma ries
I ncl usi o n a n d e xcl usi o n criteria n ot re q uiri n g d oc u me nte d me dical hist or y m ust be verifie d at a 
mi ni m u m b y  su bject i nter vie w or ot her pr ot oc ol re q uire d assess me nt (e g, p h y sical e xa mi nati o n, 
la b orat or y assess me nt) a n d d oc u me nte d i n t he s o urce d oc u me nts.
A n electr o nic so urce s yste m ma y  be utilize d, w hic h c o ntai ns data tra diti o nall y mai ntai ne d i n a 
h os pital or cli nic rec or d t o d oc u me nt me dical care (e g, electr o nic s o urce d oc u me nts) as well as 
t he cli nical st u d y-s pecific data fiel ds as deter mi ne d b y  the pr ot oc ol. T his data is electr o nicall y 
e xtracte d f or use b y  the s p o ns or. If t he electr o nic so urce s yste m is utilize d, refere nces ma de t o 
t he C R F i n t he pr ot oc ol i ncl u de t he electr o nic so urce s yste m b ut i nf or mati o n c ollecte d t hr o u g h 
t he electr o nic so urce s ystem m a y  not be li mite d t o t hat f o u n d i n t he C R F. Data i n t his s yste m 
ma y  be c o nsi dere d s o urce d oc u me ntati o n.
1 7. 5.
C a s e R e p ort F or m C o m pl eti o n
Case re p ort f or ms are pre pare d a n d pr o vi de d b y  t he s p o ns or f or eac h s u bject i n electr o nic f or mat.
All C R F e ntries, c orrecti o ns, a n d alterati o ns m ust be ma de b y  the i n vesti gat or or a ut h orize d 
st u d y-site pers o n nel. T he i n vesti gat or m ust verif y  that all data e ntries i n t he C R F are acc urate 
a n d c orrect.
El ectr o nic Data Ca pt ure
will be use d f or t his st u d y. T he st u d y data will be tra nscri be d b y 
st u d y-site pers o n nel fr o m t he s o urce d oc u me nts o nt o a n electr o nic C R F,
if a p plica ble.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 1 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
St u d y -s pecific data will be tra ns mitte d i n a sec ure ma n ner t o t he s p o ns or. T he electr o nic file will 
be c o nsi dere d t o be t he C R F.
W or ks heets ma y  be use d f or t he ca pt ure of s o me data t o facilitate c o m pleti o n of t he C R F. A n y 
s uc h w or ks heets will bec o me part of t he s u bject's s o urce d oc u me nt s. Data m ust be e ntere d i nt o 
C R F i n E n glis h. T he C R F m ust be c o m plete d as s o o n as p ossi ble after a s u bject visit a n d t he 
f orms s h o ul d be a vaila ble f or re vie w at t he ne xt sc he d ule d m o nit ori n g visit.
All s u bjecti ve meas ure me nts 
(e g, pai n scale i nf or mati o n or ot her q uesti o n naires) will be 
c o m plete d b y  the sa me i n di vi d ual w h o ma de t he i nitial baseli ne deter mi nati o ns w he ne ver 
p ossi b le. T he i n vesti gat or m ust verif y  t hat all data e ntries i n t he C R F are acc urate a n d c orrect.
If necessar y , q ueries will be ge nerate d i n t he e D C t o ol. If c orrecti o ns t o a C R F are nee de d after 
t he i nitial e ntr y i nt o t he C R F, t his ca n be d o ne i n eit her of t he f oll o wi n g wa y s:

I n vesti gat or a n d st u d y-site pers o n nel ca n ma ke c orrecti o ns i n t he e D C t o ol at t heir o w n 
i nitiati ve or as a res p o nse t o a n a ut o q uer y ( ge nerate d b y t he e D C t o ol).

S p o ns or or s p o ns or dele gate ca n ge nerate a q uer y  for res ol uti o n b y  the i n vesti gat or a n d 
st u d y-site pers o n nel.
1 7. 6.
D at a Q u alit y  As s ur a n c e/ Q u alit y  C o ntr ol
Ste ps t o be ta ke n t o e ns ure t he acc urac y an d relia bilit y of data i ncl u de t he selecti o n of q ualifie d 
i n vesti gat ors a n d a p pr o priate st u d y sites, re vie w of pr ot oc ol pr oce d ures wit h t he i n vesti gat or a n d 
st u d y-site pers o n nel bef ore t he st u d y, peri o dic m o nit ori n g visits b y  the s p o ns or, a n d direct 
tra ns missi o n of cli nical la b orat or y data fr o m a ce ntral la b orat or y int o t he s p o ns or's data base. 
Writte n i nstr ucti o ns will be pr o vi de d f or c ol lecti o n, ha n dli n g, st ora ge, a n d s hi p me nt of sa m ples. 
G ui deli nes f or C R F c o m pleti o n will be pr o vi de d a n d re vie we d wit h st u d y-site pers o n nel bef ore 
t he start of t he st u dy.
T he s p o ns or will re vie w C R F f or acc urac y  a n d c o m plete ness d uri n g o n-site m o nit ori n g visits a n d 
after tra ns missi o n t o t he s p o ns or; a n y discre pa ncies will be res ol ve d wit h t he i n vesti gat or or 
desi g nee, as a p pr o priate. After u pl oa d of t he data i nt o t he st u d y data base t he y  will be verifie d f or 
acc urac y a n d c o nsiste nc y wit h t he data s o urces. 
1 7. 7.
R e c or d R et e nti o n
I n c o m plia nce wit h t he I C H/ G C P g ui deli nes, t he i n vesti gat or/i nstit uti o n will mai ntai n all C R F 
a n d all s o urce d oc u me nts t hat s u p p ort t he data c ollecte d fr o m eac h s u bject, as well as all st u d y 
d oc u me nts as s pecifie d i n I C H/ G C P Secti o n 8, Esse ntial D oc u me nts f or t he C o n d uct of a 
Cli nical Trial, a n d all st u d y doc u me nts as s pecifie d b y  the a p plica ble re g ulat or y re q uire me nt(s). 
T he i n vesti gat or/i nstit uti o n will take meas ures t o pre ve nt acci de ntal or pre mat ure destr ucti o n of 
t hese d oc u me nts.
Esse ntial d oc u me nts m ust be retai ne d u ntil at least 2 years after t he last a p pr o val of a mar keti n g 
a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d ma r keti n g 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 1 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
a p plicati o ns i n a n I CH 
re gi o n or u ntil at least 2 ye ars ha ve ela pse d si nce t he f or mal 
disc o nti n uati o n of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct. T hese d oc u me nts will be 
retai ne d f or a l o n ger peri o d if re q uire d b y  the a p plica ble re g ulator y  re q uire me nts or b y  an 
a gree me nt wit h 
t he s p o ns or. It is t he res p o nsi bilit y of t he s p o ns or t o i nf or m t he 
i n vesti gat or/i nstit uti o n as t o w he n t hese d oc u me nts n o l o n ger nee d t o be retai ne d.
If t he res p o nsi ble i n vesti gat or retires, rel ocates, or f or ot her reas o ns wit h dra ws fr o m t he 
res p o nsi bilit y of kee pi n g t he st u d y rec or ds, c ust o d y must be tra nsferre d t o a pers o n w h o will 
acce pt t he res p o nsi bilit y. The s p o ns or m ust be n otifie d i n writi n g of t he na me a n d a d dress of t he 
ne w c ust o dia n. U n der n o circ u msta nce s hall t he i n vesti gat or rel ocate or dis p ose of a n y st u d y 
d oc u me nts bef ore ha vi n g o btai ne d writte n a p pr o val fr o m t he s p o ns or .
If it bec o mes necessar y  for t he s p o ns or or t he a p pr o priate re g ulat or y aut h orit y  to re vie w a n y 
d oc u me ntati o n relati n g t o t his st u d y, t he i n vesti gat or/i nstit uti o n m ust per mit access t o s uc h 
re p orts.
1 7. 8.
M o nit ori n g
T he s p o ns or will perf or m o n- site m o nit ori n g visits as fre q ue ntly as necessar y . T he m o nit or will 
rec or d dates of t he visits i n a st u d y site visit l o g t hat will be ke pt at t he st u d y site. T he first 
p ost -i nitiati o n visit will be ma de as s o o n as p ossi ble after e nr oll me nt has be g u n. At t hese visits, 
t he m o nit or 
will 
c o m pare data e ntere d i nt o t he C R F wit h 
t he s o urce d oc u me nts
(e g, 
h os pital/cli nic/ p h y sicia n’s office me dical rec or ds); a sa mple m a y  be re vie we d. T he nat ure a n d 
l ocati o n of all s o urce d oc u me nts will be i de ntifie d t o e ns ure t hat all s o urces of ori gi nal data 
re q uire d t o c o m plete t he C R F are k n o w n t o t he s p o ns or a n d st u d y-site pers o n nel a n d are 
accessi ble f or verificati o n b y  the s po ns or st u d y-site c o ntact. If electr o nic rec or ds are mai ntai ne d 
at t he st u d y site, t he met h o d of verificati o n m ust be disc usse d wit h t he st u d y-site pers o n nel. 
Direct access t o s o urce d oc u me nt s ( me dical rec or ds) m ust be all o we d f or t he p ur p ose of 
verif y i n g t hat t he rec or de d data are c o nsiste nt wit h t he ori gi nal s o urce data. Fi n di n gs fr o m t his 
re vie w will be disc usse d wit h t he st u d y-site pers o n nel . T he s p o ns or e x pects t hat, d uri n g 
m o nit ori n g visits, t he rele va nt st u d y-site pers o n nel will be a vaila ble, t he s o urce d oc u me nt s will 
be accessi ble, a n d a s uita ble e n vir o n me nt will 
be pr o vi de d f or re vie w of st u d y-relate d 
d oc u me nts. T he m o nit or will meet wit h t he i n vesti gat or o n a re g ular basis d uri n g t he st u d y t o 
pr o vi de fee d bac k o n t he st u d y c o n d uct.
I n a d diti o n t o o n- site m o nit ori n g visits, re m ote c o ntacts ca n occ ur. It is e x pecte d t hat d uri n g 
t hese re m ote c o ntacts, st u d y-site pers o n nel will be a vaila ble t o pr o vi de a n u p date o n t he pr o gress 
of t he st u d y  at t he site.
1 7. 9.
St u d y C o m pl eti o n/ T er mi n ati o n
1 7. 9. 1.
St u d y C o m pl eti o n / E n d of St u d y
T he st u d y is c o nsi dere d c o m plete d wit h t he f oll o w-u p visit/e n d - of-st u d y visit f or t he last s u bject 
partici pati n g i n t he st u d y. T he fi nal data fr o m t he st u d y site will be se nt t o t he s p o ns or ( or 

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 1 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
desi g nee) after c o m pleti o n of t he fi nal s u bject f oll o w- u p/e n d- of-st u d y visit at t hat st u d y site, i n 
t he ti me fra me s pecifie d i n t he Cli nical Trial A gree me nt.
1 7. 9. 2.
St u d y T er mi n ati o n
T he s p o ns or reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y ti me f or a n y 
reas o n at t he s ole discreti o n of t he s p o ns or. St u d y sites will be cl ose d u p o n st u d y co m pleti o n. A
st u d y site is c o nsi dere d cl ose d w he n all re q uire d d oc u me nts a n d st u d y su p plies ha ve bee n 
c ollecte d a n d a st u d y-site cl os ure visit has bee n perf or me d.
T he i n vesti gat or m a y  initiate st u d y-site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n.
Reas o ns f or t he earl y cl os ure of a st u d y site b y  the s p o ns or or i n vesti gat or m a y  incl u de b ut are 
n ot li mite d t o:

Fail ure of t he i n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he I EC/I R B or 
l ocal healt h a ut h orities, t he s p o ns or's pr oce d ures, or G C P g ui deli nes

I na de q uate recr uit me nt of s u bjects b y  t he i n vesti gat or

Disc o nti n uati o n of f urt her st u d y dr u g de vel o p me nt
1 7. 1 0.
O n -Sit e A u dit s
Re prese ntati ves of t he s p o ns or's cli nical q ualit y  ass ura nce de part me nt ma y  visit t he st u d y site at 
a n y ti me d uri n g or after c o m pleti o n of t he st u d y to c o n d uct a n a u dit of t he st u d y in c o m plia nce 
wit h re g ulat or y gui deli nes a n d c o m pa n y polic y . T hese a u dits will re q uire access t o all st u d y 
rec or ds, i ncl u di n g s o urce d oc u me nts, f or i ns pecti o n. S u bject pri vac y  
must, h o we ver, be 
res pecte d. T he i n vesti gat or a n d st u d y-site pers o n nel are res p o nsi ble f or bei n g prese nt a n d 
a vaila ble f or c o ns ultati o n d uri n g r o uti nel y sc he d ule d st u d y-site a u dit visits c o n d ucte d b y  th e 
s p o ns or or its desi g nees. 
Si milar a u diti n g pr oce d ures ma y  als o be c o n d ucte d b y  age nts of a n y re g ulat or y bo d y , eit her as 
part of a nati o nal G C P c o m plia nce pr o gra m or t o re vie w t he res ults of t his st u d y in s u p p ort of a 
re g ulat or y su b missi o n. T he i n vesti gat or s h o ul d i m me diatel y notif y  the s p o ns or if he or s he h a s
bee n c o ntacte d b y a re g ulat or y a ge nc y  c o ncer ni n g a n u pc o mi n g i ns pecti o n.
1 7. 1 1.
U s e of I nf or m ati o n a n d P u bli c ati o n
All i nf or mati o n, i ncl u di n g b ut n ot li mite d t o i nf or mati o n re gar di n g J NJ- 4 2 8 4 7 9 2 2 or t he 
s p o ns or's o perati o ns (e g, pate nt a p plicati o n, f or m ulas, ma n ufact uri n g pr ocesses, basic scie ntific 
data, pri or cli nical data, f or m ulati o n i nf or mati o n) s u p plie d b y  the s p o ns or t o t he i n vesti gat or a n d 
n ot pre vi o usl y  pu blis he d, a n d a n y data, i ncl u di n g p har mac o ge n o mic or e x pl orat or y bi o mar ker
researc h data, ge nerate d as a res ult of t his st u d y, are c o nsi dere d c o nfi de ntial a n d re mai n t he s ole 
pr o pert y of t he s p o ns or. T he i n vesti gat or a grees t o mai ntai n t his i nf or mati o n i n c o nfi de nce a n d 
use t his i nf or mati o n o nl y t o acc o m plis h t his st u d y, a n d will n ot use it f or ot her p ur p oses wit h o ut 
t he s p o ns or's pri or writte n c o nse nt.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 1 3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
T he i n vesti gat or u n dersta n ds t hat t he i nf or mati o n de vel o p e d i n t he st u d y will be use d b y  the 
s p o ns or i n c o n necti o n wit h t he c o nti n ue d de vel o p me nt of J NJ- 4 2 8 4 7 9 2 2, a n d t h us m a y  be 
discl ose d as re q uire d t o ot her cli nical i n vesti gat ors or re g ulat or y age ncies. T o per mit t he 
i nf or mati o n deri ve d fr o m t he cli nical stu dies t o be use d, t he i n vesti gat or is o bli gate d t o pr o vi de 
t he s p o ns or wit h all data o btai ne d i n t he st u d y.
T he res ults of t he st u d y will be re p orte d i n a Cli nical St u d y  Re p ort ge nerate d b y  the s p o ns or a n d 
will c o ntai n data fr o m all st u d y sites t hat partic i pate d i n t he st u d y as per pr ot oc ol . Recr uit me nt 
perf or ma nce or s pecific e x pertise relate d t o t he nat ure a n d t he k e y  assess me nt para meters of t he 
st u d y will be use d t o deter mi ne a c o or di nati n g i n vesti gat or. Res ults of p har mac o ge n o mic or 
e x pl orat or y bi o mar ker a nal yses perf or me d after t he Cli nical St u d y  Re p ort has bee n iss ue d will 
be re p orte d i n a se parate re p ort a n d will n ot re q uire a re visi o n of t he Cli nical St u d y  Re p ort. 
St u d y  su bject i de ntifiers will n ot be use d i n p u blicati o n o f res ults. A n y  wor k create d i n 
c o n necti o n wit h perf or ma nce of t he st u d y an d c o ntai ne d i n t he data t hat ca n be nefit fr o m 
c o p yri g ht pr otecti o n (e xce pt a n y p u blicati o n b y  the i n vesti gat or as pr o vi de d f or bel o w) s hall be 
t he pr o perty of t he s p o ns or as a ut h or a n d o w ner of c o p yri g ht i n s u c h w or k.
C o nsiste nt wit h G o o d P u blicati o n Practices a n d I nter nati o nal C o m mittee of Me dical 
J o ur nal 
E dit ors g ui deli nes, the s p o ns or s hall ha ve t he ri g ht t o p u blis h s uc h pri mar y  (m ultice nter) data 
a n d i nf or mati o n wit h o ut a p pr o val fr o m t he i n vesti gat or. T he in vesti gat or has t he ri g ht t o p u blis h 
st u d y site-s pecific data after t he pri mar y  data are p u blis he d. If a n i n vesti gat or wis hes t o p u blis h 
i nf or mati o n fr o m t he st u d y, a c o p y of the ma n uscri pt m ust be pr o vi de d t o t he s p o ns or f or re vie w 
at least 6 0 d a y s bef ore s u b missi o n f or p u blicati o n or prese ntati o n. E x pe dite d re vie ws will be 
arra n ge d f or a bstracts, p oster prese ntati o ns, or ot her materials. If re q ueste d b y  the s p o ns or i n 
writi n g, t he i n vesti gat or will wit h h ol d s uc h p u blicati o n f or u p t o a n a d diti o nal 6 0 da y s t o all o w 
f or fili n g of a pate nt a p plicati o n. I n the e ve nt t hat iss ues arise re gar di n g scie ntific i nte grit y or 
re g ulat or y co m plia nce, t he s p o ns or will re vie w t hese iss ues wit h t he i n vesti gat or. T he s p o ns or 
will n ot ma n date m o dificati o ns t o scie ntific c o ntent a n d d oes n ot ha ve t he ri g ht t o s u p press 
i nf or mati o n. F or m ultice nter st u d y desi g ns a n d s u bst u d y ap pr oac hes, sec o n dar y res ults ge nerall y 
s h o ul d n ot be p u blis he d bef ore t he pri mar y  en d p oi nts of a st u d y ha ve bee n p u blis he d. Si milarl y , 
i n vesti gat ors will rec o g nize t he i nte grit y of a multice nter st u d y b y  not s u b mitti n g f or p u blicati o n 
data deri ve d fr o m t he i n di vi d ual st u d y site u ntil t he c o m bi ne d res ults fr o m t he c o m plete d st u d y
ha ve bee n s u b mitte d f or p u blicati o n, wit hi n 1 2 m o nt hs of t he a vaila bilit y  of t he fi nal data (ta bles, 
listi n gs, gra p hs), or t he s p o ns or c o nfir ms t here will be n o m ultice nter 
st u d y pu blicati o n. 
A ut h ors hi p of p u blicati o ns res ulti n g fr o m t his st u d y will be base d o n t he g ui deli nes o n 
a ut h ors hi p, s uc h as t h ose descri be d i n t he U nif or m Re q uir e me nts f or Ma n uscri pts S u b mitte d t o 
Bi o me dical J o ur nals, w hic h 
state t hat t he na me d a ut h ors m ust 
ha ve ma de 
a si g nifica nt 
c o ntri b uti o n t o t he desi g n of t he st u d y or a n al ysis a n d i nter pretati o n of t he data, pr o vi de d critical 
re vie w of t he pa per, a n d gi ve n final a p pr o val of t he fi nal versi o n.
Re gistr ati o n of Cli nic al St u dies a n d Discl os ure of Res ults
T he s p o ns or will re gister a n d discl ose t he e xiste nce of a n d t he res ults of cli nical st u dies as 
re q uire d by la w.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 1 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
R E F E R E N C E S
1.
A kerste dt T, A n u n d A, A xelss o n J, Kec k l u n d G. S u bjecti ve slee pi ness is a se nsiti ve i n dicat or of i ns ufficie nt 
slee p a n d i m paire d wa ki n g f u ncti o n. J Slee p Res. 2 0 1 4; 2 3: 2 4 2 -2 5 4.
2.
Allai n H, Be nt ue -Ferrer D, Tarral A, Ga n d o n J M. Effects o n p ost ural oscillati o n a n d me m or y f u ncti o ns of a 
si n gle d ose of z ol pi de m 5 m g, z o picl o ne 3. 7 5 m g a n d l or metaze pa m 1 m g i n el derl y healt h y s u bjects: a 
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3.
A merica n Geriatrics S ociet y 2 0 1 5 U p date d Beers Criteria f or P ote ntia ll y I na p pr o priate Me dicati o n Use i n 
Ol der A d ults. J A m Geriatr S oc. 2 0 1 5; 6 3( 1 1): 2 2 2 7 -2 2 4 6.
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1 2.
Carra gee EJ, C he n g I. Mi ni m u m acce pta ble o utc o mes after l u m bar s pi nal f usi o n. S pi ne J. 2 0 1 0; 1 0( 4): 3 1 3 -3 2 0.
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1 7.
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1 8.
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d ysre g ulates R E M slee p i n t he prese nce of ore xi n -2 rece pt or a nta g o nis m. Fr o nt Ne ur osci. 2 0 1 4; 8: 2 8.
1 9.
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2 0.
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2 1.
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J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 1 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
2 2.
E ur o pea n Me dici nes A ge nc y. G ui deli ne o n me dici nal pr o d ucts f or t he treat me nt of i ns o m nia. 
htt p:// w w w.e ma.e ur o pa.e u/ d ocs/e n _ G B/ d oc u me nt _li brar y/ Scie ntific _ g ui deli ne/ 2 0 1 1/ 0 2/ W C 5 0 0 1 0 2 3 5 1 
(accesse d o n 5 Oct o ber 2 0 1 6).
2 3.
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m o del -base d desi g n a n d a nal ysis of P hase II d ose fi n di n g st u dies u n der m o del u ncertai nt y. 2 0 1 4.
2 4.
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2 5.
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At t a c h m e nt 1: L o w -F at Di et M e n u S u g g e sti o n s ( O pti o n al U s e)
T o mi ni mize
i nterfere nce ca use d b y li pi d c o nte nt i n bl o o d s peci me ns c ollecte d f or bi o mar ker 
e val uati o n, s u bjects s h o ul d f oll o w a l o w-fat diet f or t he meal pri or t o bl o o d c ollecti o n. A l o w-fat 
diet d oes n ot nee d t o be f oll o we d if t he s u bject has bee n fasti n g f or at least 8 h o urs pri or t o the 
bl o o d dra w.
Bel o w are s u g gesti o ns f or l o w-fat meals t hat c o ul d be c o ns u me d pri or t o bl o o d c ollecti o n. T hese 
lists are n ot all i ncl usi ve a n d st u d y sites s h o ul d use t heir best j u d g me nt w he n pr o vi di n g dietar y 
g ui da nce t o s u bjects.
F o o ds all o we d pri or t o b i o m ar ker bl o o d c ollecti o n
S a m ple Bre a kf ast Me n us:
Dr y  wh ole w heat t oast
Fr uit sala d 
Clear tea or c offee ( n o mil k or crea m)
Fr uit or ve geta ble j uice
Dr y  cereal ( n o n uts or gra n ola, n o mil k)
Clear tea or c offee ( n o mil k or crea m)
Fr uit or ve geta ble j uice
Plai n oat meal or ot her c o o ke d w h ole grai n cereal ( n o 
n uts or gra n ola, n o mil k)
T o p pe d w it h fres h or drie d fr uit ( n o b utter, mil k or 
crea m)
Clear tea or c offee ( n o mil k or crea m)
Fr uit or ve geta ble j uice
Dr y  wh ole w heat t oast
P oac he d e g g w hites or e g g s u bstit ute
Clear tea or c offee ( n o mil k or crea m)
Fr uit or ve geta ble j uice
S a m ple L u nc h Me n us:
T ur ke y breast sa n d wic h o n w h ole w heat brea d ( Lett uce, 
t o mat o a n d m ustar d) 
Clear be vera ge
Fla v ore d gelati n
Plai n pasta wit h plai n mari nara sa uce ( n o b utter or 
c heese)
Si de of stea me d ve geta bles ( n o b utter or oil)
Clear be vera ge
Fla v ore d gelati n
Stea me d c hic ke n breast (lea n, n o s ki n)
Si de gree n sala d ( n o dressi n g, oil or c heese)
Clear be vera ge
Fla v ore d gelati n
Lar ge t osse d gree n sala d wit h ass orte d ve geta bles ( n o 
dressi n g, oil or c heese)
Clear be vera ge
Fla v ore d gelati n
C uc u m ber sa n d wic h o n w h ole -w heat brea d
Lett uce, t o mat oes, s hre d de d carr ots, o ni o ns or ot her 
ve geta bles
Clear be vera ge
Fla v ore d gelati n
Clear br ot h w it h ve geta bles a n d pasta
Fr uit sala d
Clear be vera ge
Fla v ore d gelati n

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 2 0
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
F o o ds t o a v oi d pri or t o bl o o d c ollecti o n:

A v oi d all fats a n d n uts s uc h as: b utter a n d mar gari ne, crea m, bac o n fat, lar d, all oils, all n uts, 
pea n ut b utter, c oc o n ut, w h ole see ds s uc h as p u m p ki n a n d s u nfl o wer.

A v oi d all mil k a n d dair y  pr o d ucts s uc h as: mil k a n d mil k pr o d ucts, c heese, all pr o d ucts 
c o ntai ni n g c heese, c heeses s prea ds s uc h as crea m c heese, s o ur crea m, y o g urt, ice crea m, a n d 
mil k c h oc olate.

A v oi d hi g h fat pre pare d f o o ds a n d f o o ds nat urall y hi g h i n fat:
-
All re d meats or meats c o ntai ni n g fat s uc h as p or k
-
Fatt y meats s uc h as: l u nc he o n meats, or ga n meats, bac o n
-
Fatt y fis h s uc h as: sal m o n, mac kerel
-
Sala d dressi n g a n d ma y o n naise
-
B uttere d, a u grati n, crea me d or frie d ve geta bles
-
Frie d f o o ds
-
Frie d s nac ks s uc h as: c hi ps, crac kers, Fre nc h fries, gra vies a n d sa uces
-
Ba ke d g o o ds a n d fr osti n g

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 2 1
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
At t a c h m e nt 2: A v er a g e C aff ei n e C o nt e nt of V ari o u s B e v er a g e s
T y pe of Be ver a ge
Size
C affei ne ( mg)
C offee, bre w e d
8 oz. ( 2 3 7 m L)
9 5 -2 0 0 m g
C offee, bre w e d, decaffei nate d
8 oz. ( 2 3 7 m L)
2- 1 2 m g
Es press o, resta ura nt -st yle
1 oz. ( 3 0 m L)
4 7 -7 5 m g
I nsta nt C offee
8 oz. ( 2 3 7 m L)
2 7 -1 7 3 m g
S pecialt y C offee dri n k (latte or m oc ha)
8 oz. ( 2 3 7 m L)
6 3 -1 7 5 m g
Blac k tea
8 oz. ( 2 3 7 m L)
1 4 -7 0 m g
Blac k tea, decaffei nate d
8 oz. ( 2 3 7 m L)
0- 1 2 m g
Gree n tea
8 oz. ( 2 3 7 m L)
2 4 -4 5 m g
Ice d tea, b ottle d
8 oz. ( 2 3 7 m L)
5- 4 0 m g
C olas ( C oca -C ola, Diet C o ke, Pe psi, Diet Pe psi)
1 2 oz. ( 3 5 5 m L)
2 3 -4 7 m g
M o u ntai n De w (re g ular a n d diet)
1 2 oz. ( 3 5 5 m L)
4 2 -5 5 m g
7- U p, S prite, Sierra Mist
1 2 oz. ( 3 5 5 m L)
0
A m p E ner g y Dri n k, re g ular or s u gar -free
8 oz. ( 2 3 7 m L)
7 1 -7 4 m g
5- H o ur E ner g y s h ot
2 oz. ( 6 0 m L)
2 0 0 -2 0 7 m g
F ull T hr ottle, re g ular or s u gar -free
8 oz. ( 2 3 7 m L)
7 0 -1 0 0 m g
Re d B ull, re g ular or s u gar -free
8. 4 oz. ( 2 4 8 m L)
7 5 -8 0 m g
R oc kstar, re g ular or s u gar-free
8 oz. ( 2 3 7 m L)
7 9 -8 0 m g
A da pte d fr o m J o ur nal of F o o d Scie nce, 2 0 1 0; Pe diatrics, 2 0 1 1; A merica n Aca de m y of Pe diatrics, 2 0 1 1; U S D A Nati o nal N utrie nt 
Data base f or Sta n dar d Refere nce, Release 2 6; J o ur nal of A nal ytical T o xic ol o g y, 2 0 0 6; Star b uc ks, 2 0 1 4; Pe diatrics, 2 0 1 1; U S D A 
Nati o nal N utrie nt Data base f or Sta n dar d Refere nce, Release 2 6; J o ur nal of F o o d Scie nce, 2 0 0 7; J o ur nal of A nal ytical 
T o xic ol o g y, 2 0 0 6; F o o d a n d C he mical T o xic ol o g y, 2 0 1 4; Pe psic o, 2 0 1 4; C oca -C ola, 2 0 1 4; C o ns u mer Re p orts, 2 0 1 4; Ma y o  
Cli nic Pr ocee di n gs, 2 0 1 0; 5 -H o ur E ner g y, 2 0 1 4; F ull T hr ottle; Re d B ull.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 2 2
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
At t a c h m e nt 3:
E x a m pl e s of C o n c o mit a nt Dr u g s t o b e A v oi d e d ( M o d er at e or Str o n g 
I n hi bit or/I n d u c er of C Y P 3 A 4 or C Y P 2 C 9 or D u al I n hi bit or/I n d u c er of C Y P 3 A4 a n d 
C Y P 2 C 9)
E nz y mes
I n hi bit ors
I n d ucers
D u al I n hi bit ors 
or I n d ucers of 
C Y P 3 A 4 a n d 
C Y P 2 C 9
Str o n g
M o der ate
Str o n g
M o der ate
C Y P 2 C 9
N o ne k n o w n
A mi o dar o ne, 
fl uc o naz ole, 
mic o naz ole, 
o xa n dr ol o ne
N o ne k n o w n
Car ba maze pi ne, 
rifa m pi n.
A mi o dar o ne, 
fl u v o xa mi ne, 
fl uc o naz ole, 
car ba maze pi ne, 
rifa m pi n, 
a pre pita nt, 
b ose nta n, 
gra pefr uit
C Y P 3 A 4
B oce pre vir,
clarit hr o m yci n, 
c o ni va pta n,
gra pefr uit j uice, 
i n di na vir, 
itrac o naz ole, 
ket oc o naz ole,
l o pi na vir/rit o na vir,
mi befra dil, 
nefaz o d o ne, 
nelfi na vir,
p osac o naz ole, 
rit o na vir,
sa q ui na vir,
tela pre vir,
telit hr o m yci n,
v oric o naz ole
A m pre na vir, 
a pre pita nt, 
ataza na vir, 
ci pr ofl o xaci n, 
criz oti ni b, 
dar u na vir/rit o na vir, 
diltiaze m, 
er yt hr o m yci n, 
fl uc o naz ole, 
f osa m pre na vir,
i mati ni b, vera pa mil
A vasi mi be, 
car ba maze pi ne, 
p he n yt oi n, 
rifa m pi n, St. 
J o h n’s wort
B ose nta n, 
efa vire nz, 
etra viri ne, 
m o dafi nil, 
nafcilli n.
N otes:

T his is n ot a n e x ha usti ve list.

N o “str o n g C Y P 2 C 9” i n d ucers or i n hi bit ors are k n o w n, b ut if a n y were t o e mer ge, t h ose s h o ul d be e xcl u de d as 
well.
S o urce: U S F D A - Dr u g De vel o p me nt a n d Dr u g I nteracti o ns: Ta ble of S u bstrates, I n hi bit ors a n d I n d ucers. 
htt p:// w w w f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti o ns La beli n g/ uc m 0 9
3 6 6 4 ht m. Accesse d 0 4 N o ve m ber 2 0 1 5

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 2 3
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
At t a c h m e nt 4:
V ol u m e s of Bl o o d t o b e C oll e ct e d Fr o m E a c h S u bj e ct f or Cli ni c al L a b or at or y,
P h ar m a c o ki n eti c , Bi o m ar k er, a n d P h ar m a c o g e n o mi c S a m pl e s
V ol u me of Bl o o d t o be C ollecte d Fr o m  E ac h S u bject P artici p ati n g i n I nte nsi ve P K S a m pli n g
T y pe of Sa m ple
V ol u me per 
Sa m ple ( m L) a
N o. of Sa m ples 
per S u bject
A p pr o xi mate 
T otal V ol u me of 
Bl o o d ( m L) b
Scree ni n g (cli nical la b orat or y tests c: e g, he mat ol o g y, 
ser u m c he mistr y, ser u m pre g na nc y tests, H b A 1c, a n d 
T S H)
1 1. 5
1
1 1. 5
Safet y (cli nical la b orat or y tests i ncl u di n g he mat ol o g y, 
ser u m c he mistr y)
4. 5
2
9
P har m ac o ki netic sa m ples
3
1 0
3 0
Bi o mar ker sa m ples d
2 0
4
8 0
Bl o o d c ortis ol sa m ples e
4
5
2 0
P har m ac o ge n o mic sa m ple f
6
1
6
A p pr o xi mate T otal g
1 5 6. 5
a.
S o m e v ol u mes ma y var y b y  re gi o n.
b.
Calc ulate d as n u m ber of sa m ples m ulti plie d b y a m o u nt of bl o o d per sa m ple.
c.
Cli nical la b orat or y tests at scree ni n g, H b A 1c, T S H, ser u m pre g na nc y ( o pti o nal), he mat ol o g y, a n d ser u m 
c he mistr y tests.
d.
Bl o o d f or bi o mar ker sa m ples re prese nts v ol u me of se v eral t u bes c o m bi ne d.
e.
Bi o mar ker sa m ple f or meas ure me nt of c ortis ol o nl y .
f.
Bl o o d sa m ples will be c ollecte d o nl y fr o m s u bjects w h o ha ve c o nse nte d t o pr o vi de o pti o nal D N A sa m ples 
f or researc h.
g.
Re peat or u nsc he d ule d sa m ples ma y be ta ke n f or safet y reas o ns or tec h nical iss ues wit h t he sa m ples.
N ote: A n i n d w elli n g I V ca n n ula ma y be use d f or bl o o d sa m ple c ollecti o n.
H b A 1c = he m o gl o bi n A 1c, P K = p har mac o ki netic, T S H =t h yr oi d sti m ulati n g h or m o ne.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 2 4
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
V ol u me of Bl o o d t o be C ollecte d Fr o m  E ac h S u bject N ot P artici p ati n g i n I nte nsi ve P K S a mpli n g
T y pe of Sa m ple
V ol u me per 
Sa m ple ( m L) a
N o. of Sa m ples 
per S u bject
A p pr o xi mate 
T otal V ol u me of 
Bl o o d ( m L) b
Scree ni n g (cli nical la b orat or y tests c: e g, he mat ol o g y, 
ser u m c he mistr y, ser u m pre g na nc y tests, H b A 1c, a n d 
T S H)
1 1. 5
1
1 1. 5
Safet y (cli nical la b orat or y tests i ncl u di n g he mat ol o g y, 
ser u m c he mistr y)
4. 5
2
9
P har m ac o ki netic sa m ples
3
3
9
Bi o mar ker sa m ples d
2 0
2
4 0
P har m ac o ge n o mic sa m ple e
6
1
6
A p pr o xi mate T otal f
7 5. 5
a.
S o m e v ol u mes ma y var y b y re gi o n.
b.
Calc ulate d as n u m ber of sa m ples m ulti plie d b y a m o u nt of bl o o d per sa m ple.
c.
Cli nical la b orat or y tests at scree ni n g i ncl u des: H b A 1c, T S H, ser u m pre g na nc y ( o pti o nal), he mat ol o g y, a n d 
ser u m c he mistr y tests.
d.
Bl o o d f or bi o mar ker sa m ples re prese nts v ol u me of se veral t u bes c o m bi ne d. T he bi o mar ker sa m ple i ncl u des 
bl o o d c ortis ol.
e.
Bl o o d sa m ples will be c ollecte d o nl y fr o m s u bjects w h o ha ve c o nse nte d t o pr o vi de o pti o nal D N A sa m ples f or 
researc h.
f.
Re peat or u nsc he d ule d sa m ples ma y be ta ke n f or safet y reas o ns or tec h nical iss ues wit h t he sa m ples.
N ote: A n i n d w elli n g I V ca n n ula ma y be use d f or bl o o d sa m ple c ollecti o n.
H b A 1c = he m o gl o bi n A 1c, P K = p har mac o ki netic, T S H =t h yr oi d sti m ulati n g h or m o ne.

J NJ-4 2 8 4 7 9 2 2 (selt ore xa nt/selecti ve ore xi n-2 rece pt or a nta g o nist)
Cli nical Pr ot oc ol 4 2 8 4 7 9 2 2I S M 2 0 0 5 A me n d me nt 3
1 2 5
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
At t a c h m e nt 5: A n ti ci p at e d E v e nt s
A ntici p ate d E ve nt
A n a ntici pate d e ve nt is a n A E (seri o us or n o n- seri o us) t hat c o m m o nl y occ urs as a c o nse q ue nce of t he 
u n derl yi n g disease or c o n diti o n u n der i n vesti gati o n ( diseas e relate d) or bac k gr o u n d re gi me n.
F or t he p ur p oses of t his st u d y t he f oll o wi n g e ve nts will be c o nsi dere d a ntici pate d e ve nts: 

Slee p c ha n ges/ diffic ult y slee pi n g, re d uce d slee p, diffic ult y i nitiati n g slee p (falli n g aslee p), diffic ult y 
mai ntai ni n g 
slee p (fre q ue nt a wa ke ni n gs or pr o ble ms ret ur ni n g t o slee p after a wa ke ni n gs), 
earl y-m or ni n g a wa ke ni n g wit h i na bilit y t o ret ur n t o slee p

Tire d ness, fati g ue, re d uce d e ner g y.
Re p orti n g of A ntici p ate d E ve nts
All A Es will be rec or de d i n t he C R F re gar dless of w het her c o nsi dere d t o be a ntici pate d e ve nts a n d will be 
re p orte d t o t he s p o ns or as descri be d i n Secti o n 1 2. 3. 1 , All A d verse E ve nts. A n y a ntici pate d e ve nt t hat 
meets S A E criteria will be re p orte d t o t he s p o ns or as descri be d i n Secti o n 1 2. 3. 2 , Seri o us A d verse E ve nts. 
T hese a ntici pate d e ve nts are e xe m pt fro m e x pe dite d re p orti n g as i n di vi d ual si n gle cases t o Healt h 
A ut h orities, e xce pt f or Ja pa n ( n o e ve nts will be desi g ne d as a ntici pate d e ve nts i n Ja pa n). H o we ver , if 
base d o n a n a g gre gate re vie w, it is deter mi ne d t hat a n a ntici pate d e ve nt is p ossi bl y relate d t o st u d y dr u g, 
t he s p o ns or will re p ort t hese e ve nts i n a n e x pe dite d ma n ner.
A ntici p ate d E ve nt Re vie w C o m mittee ( A R C)
A n A ntici pate d E ve nt Re vie w C o m mittee ( A R C) will be esta blis he d t o perf or m re vie ws of pre -s pecifie d 
a ntici pate d e ve nts at a n a g gre gate le ve l. T he A R C is a safet y c o m mittee wit hi n t he s p o ns or’s or ga nizati o n 
t hat is i n de pe n de nt of t he s p o ns or’s st u d y tea m. T he A R C will meet t o ai d i n t he rec o m me n dati o n t o t he 
s p o ns or’s st u d y tea m as t o w het her t here is a reas o na ble p ossi bilit y t hat a n a ntici pat e d e ve nt is relate d t o 
t he st u d y dr u g.
St atistic al A n al ysis
Details of statistical a nal ysis of a ntici pate d e ve nts, i ncl u di n g t he fre q ue nc y of re vie w a n d t hres h ol d t o 
tri g ger a n a g gre gate a nal ysis of a ntici pate d e ve nts will be pr o vi de d i n a se parate A ntici p ate d E ve nts 
Safet y M o nit ori n g Pla n ( A S M P).