Clinical trial NCT03375203
Conditions: Insomnia Disorders
Sponsor: Janssen Research & Development, LLC
Start date: 2017-11-23; Completion date: 2019-04-03
Enrollment: 365 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this 2 month phase 2b study is to investigate the dose response of 3 doses of JNJ-42847922 (Seltorexant) (5,10 and 20 mg) compared to placebo and zolpidem on sleep onset and maintenance and to further document safety and tolerability of JNJ-42847922 (Seltorexant) upon multiple (14 days) dose administration in participants with insomnia disorder.

Detailed description:

Arms: arm 1: Participants will receive matching placebo to JNJ-42847922 as oral capsules at normal study bedtime on Nights 1 through 14. arm 2: Participant will receive JNJ-42847922 5 mg dose as oral capsules at normal study bedtime on Nights 1 through 14. arm 3: Participant will receive JNJ-42847922 10 mg as oral capsule and one placebo capsule at normal study bedtime on Nights 1 through 14. arm 4: Participant will receive JNJ-42847922 20 mg as oral capsule and one placebo capsule at normal study bedtime on Nights 1 through 14. arm 5: Participants will receive Zolpidem 5 mg plus one placebo capsule or 10 mg dose as oral capsule at normal study bedtime on Nights 1 through 14.
Interventions: intervention 1: Placebo intervention 2: JNJ-42847922, 5 mg intervention 3: JNJ-42847922, 10 mg intervention 4: JNJ-42847922, 20 mg intervention 5: Zolpidem
Intervention descriptions: intervention 1: Matching placebo will be administered once daily based upon dosing group. intervention 2: JNJ-42847922 will be administered as 5 mg (2\*2.5 mg capsule) oral capsules once daily. intervention 3: JNJ-42847922 will be administered as 10 mg oral capsule once daily. intervention 4: JNJ-42847922 will be administered as 20 mg oral capsule once daily. intervention 5: Zolpidem will be administered as 5 mg or 10 mg (2\*5mg capsule) oral capsule once daily based upon the local labeling information.

Protocol documents:
Prot_000.pdf: 
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 
ra n d o mize d, cr oss-o ver, d o u ble -bli n d st u d y vers us place b o. E ur J Cli n P har mac ol 2 0 0 3; 5 9( 3): 1 7 9 -1 8 8.
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.
4.
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5.
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6.
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me dicati o ns. Healt h Q ual Life O utc o mes. 2 0 0 9; 7: 3 6.
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2 0 0 8; 6 2: 9 7 4 -9 7 9 .
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B oss C, R oc h C. Rece nt tre n ds i n ore xi n researc h – 2 0 1 0 -2 0 1 5. Bi o or g. Me d C he m Lett. 2 0 1 5; 2 5: 2 8 7 5 -2 8 8 7.
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B us ner J, Tar g u m S D. T he cli nical gl o bal i m pressi o ns scale: a p pl yi n g a researc h t o ol i n cli ni cal practice. 
Ps yc hiatr y ( E d g m o nt). 2 0 0 7; 4( 7): 2 8 -3 7.
1 0.
B u y sse DJ, A nc oli-Israel S, E di n ger J D, Lic hstei n K L, M ori n C M. Rec o m me n dati o ns f or a sta n dar d researc h 
assess me nt of i ns o m nia. Slee p. 2 0 0 6; 2 9( 9): 1 1 5 5 -1 1 7 3.
1 1.
Car ne y C E, B u ysse DJ, A nc oli -Israel S, et al. T he C o nse ns us Slee p Diar y: Sta n dar dizi n g pr os pecti ve slee p 
self-m o nit ori n g. Slee p. 2 0 1 2; 3 5: 2 8 7 -3 0 2.
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.
1 3.
Cricc o M, Si m o nsic k E M, F ole y DJ. T he i m pact of i ns o m nia o n c o g niti ve f u ncti o ni n g i n ol der a d ults. J A m 
Geriatr S oc. 2 0 0 1; 4 9( 9): 1 1 8 5 -1 1 8 9.
1 4.
Da nj o u P, Pat y I, Fr u ncill o R, et al. C o m paris o n of t he resi d ual effects of zale pl o n a n d z ol pi de m f oll o wi n g 
a d mi nistrati o n 5 t o 2 h bef ore a wa ke ni n g. Br J Cli n P har ma c ol. 1 9 9 9; 4 8( 3): 3 6 7 -3 7 4.
1 5.
Darc o urt G, Pri n g ue y D, Salliere D, La v ois y J. T he safet y a n d t olera bilit y of z ol pi de m -a n u p date. J 
Ps yc h o p har mac ol. 1 9 9 9; 1 3( 1): 8 1 -9 3.
1 6.
de Lecea L, Kil d uff T S, Pe yr o n C, et al. T he h y p ocreti ns: h y p ot hala m us -s pecific pe pti des wit h ne ur oe xcitat or y 
acti vit y. Pr oc Natl Aca d Sci U S A. 1 9 9 8; 9 5( 1): 3 2 2 -3 2 7.
1 7.
D u g o vic C, S helt o n J E, Al uisi o L E, et al. Bl oc ka de of ore xi n -1 rece pt ors atte n uates ore xi n -2 rece pt or 
a nta g o nis m-i n d uce d slee p pr o m oti o n i n t he rat. J P har mac ol E x p T her. 2 0 0 9; 3 3 0( 1): 1 42 -1 5 1.
1 8.
D u g o vic C, S helt o n J E, Y u n S, B o na ve nt ure P, S hire ma n B T, L o ve n ber g T W. Ore xi n -1 rece pt or bl oc ka de 
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.
E di n ger J D, B o n net M H, B o otzi n R R, et al. Deri vati o n of researc h dia g n ostic criteria f or i ns o m nia: re p ort of a n 
A merica n Aca de m y of slee p me dici ne W or k Gr o u p. A merica n Aca de m y of Slee p Me dici ne W or k Gr o u p 
re p ort. Slee p. 2 0 0 4; 2 7( 8): 1 5 6 7-1 5 9 6.
2 0.
E di n ger J D, Ul mer C S, Mea ns M K. Se nsiti vit y a n d s pecificit y of p o l ys o m n o gra p hic criteria f or defi ni n g 
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K o hsa ka A, Wata n o be H, Ka kiza ki Y, S u da T, Sc hi ot h H B. A si g nifica nt partici pati o n of ore xi n -A, a p ote nt 
ore xi ge nic pe pti de, i n t he pre o v ulat or y l utei nizi n g h or m o ne a n d pr olacti n s ur ges i n t he rat. Brai n Res. 
2 0 0 1; 8 9 8: 1 6 6 -1 7 0.
9 3.
L ó pez M, Te na -Se m pere M, Dié g uez C. Cr oss -tal k bet wee n ore xi ns ( h y p ocreti ns) a n d t he ne ur oe n d ocri ne a xes 
( h y p ot hala mic-pit uitar y a xes). Fr o nt Ne ur oe n d ocri n ol. 2 0 1 0 A pr; 3 1( 2): 1 1 3 -1 2 7.
9 4.
Sil ve yra P, L u x -La nt os V, Li bert u n C. B ot h ore xi n rece pt ors are e x presse d i n rat o varies a n d fl uct uate wit h t he 
estr o us c ycle: effects of ore xi n rece pt or a nt a g o nists o n g o na d otr o pi ns a n d o v ulati o n. A m J P h ysi ol E n d ocri n ol 
Meta b. 2 0 0 7; 2 9 3: E 9 7 7 -E 9 8 5.
9 5.
Cetr oreli x N D A p har mac ol o g y re vie w. A vaila ble fr o m: 
htt ps:// w w w.access data f da. g o v/ dr u gsatf da _ d ocs/ n da/ 2 0 0 0/ 2 1 -1 9 7 _ Cetr oti de _ p har mr. p df. Accesse d 2 6 Marc h 
2 0 1 8 .
9 6.
Fas l o de x N D A p har mac ol o g y re vie w. A vaila ble fr o m: 
htt ps:// w w w.access data f da. g o v/ dr u gsatf da _ d ocs/ n da/ 2 0 0 2/ 2 1-3 4 4 _ F ul vestra nt _ p har mr _ P 3. p df . Accesse d 2 6 
Marc h 2 0 1 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
1 1 9
A p pr o ve d , Date: 2 5 J ul y 2 0 1 8
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).



SAP_001.pdf: 
1
Approved, Date: 22 April 2019
Janssen Research & Development *
Statistical Analysis Plan
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
Protocol 42847922ISM2005; Phase 2b
JNJ-42847922  (Seltorexant)
Status:
Approved
Date:
22 April 2019
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-ERI-153916701 4.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT03375203


JNJ-42847922  (Seltorexant)
Statistical Analysis Plan 42847922ISM2005
2
Approved, Date: 22 April 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 5
LIST OF IN-TEXT FIGURES ........................................................................................................................ 5
AMENDMENT HISTORY.............................................................................................................................. 6
ABBREVIATIONS ........................................................................................................................................ 8
1.
INTRODUCTION................................................................................................................................ 10
1.1.
Trial Objectives .............................................................................................................................. 10
1.2.
Trial Design .................................................................................................................................... 13
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 14
1.4.
Sample Size Justification ............................................................................................................... 14
1.5.
Randomization and Blinding .......................................................................................................... 14
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 15
2.1.
Study Reference Start and End Dates........................................................................................... 15
2.2.
Analysis Phases............................................................................................................................. 15
2.3.
Study Day....................................................................................................................................... 16
2.4.
Baseline and End Point.................................................................................................................. 16
2.5.
Visit Windows................................................................................................................................. 17
2.6.
Pooling Algorithm for Analysis Centers.......................................................................................... 22
2.7.
Analysis Sets.................................................................................................................................. 22
2.7.1.
All Randomized Analysis Set...................................................................................................... 22
2.7.2.
Efficacy Analysis Set .................................................................................................................. 22
2.7.2.1.
Full Analysis Set ...................................................................................................................... 22
2.7.3.
Safety Analysis Set..................................................................................................................... 22
2.8.
Definition of Subgroups.................................................................................................................. 22
2.9.
Imputation Rules for Missing Adverse Event (AE) Dates .............................................................. 23
2.10.
Imputation Rules for Missing Prior/Concomitant Medication Dates............................................... 24
2.10.1.
Prior Medications ........................................................................................................................ 24
2.10.2.
Concomitant Medications Taken During the Double-blind Phase.............................................. 24
2.10.3.
Concomitant Medications Taken During the Follow-up Phase................................................... 25
2.11.
Handling of data that appear to deviate from normality assumption ............................................. 26
3.
SUBJECT INFORMATION................................................................................................................ 26
3.1.
Demographics and Baseline Characteristics ................................................................................. 26
3.2.
Disposition Information................................................................................................................... 27
3.3.
Treatment Compliance................................................................................................................... 28
3.4.
Extent of Exposure......................................................................................................................... 28
3.5.
Protocol Deviations ........................................................................................................................ 28
3.6.
Prior and Concomitant Medications ............................................................................................... 29
4.
EFFICACY ......................................................................................................................................... 30
4.1.
Analysis Specifications................................................................................................................... 31
4.1.1.
Level of Significance................................................................................................................... 31
4.1.2.
Data Handling Rules................................................................................................................... 31
4.1.3.
Imputation Methods for Missing Items........................................................................................ 31
4.2.
Primary Efficacy Endpoint.............................................................................................................. 32
4.2.1.
Definition..................................................................................................................................... 32
4.2.2.
Primary Estimand ....................................................................................................................... 32
4.2.3.
Analysis Methods........................................................................................................................ 32
4.2.3.1.
MCP-Mod Analysis .................................................................................................................. 32


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4.2.3.2.
ANCOVA Pairwise Comparisons ............................................................................................ 34
4.2.3.3.
Subgroup Analyses ................................................................................................................. 34
4.2.3.4.
Sensitivity Analyses................................................................................................................. 34
4.3.
Secondary Efficacy Endpoints ....................................................................................................... 34
4.3.1.
WASO on Night 1 ....................................................................................................................... 34
4.3.2.
LPS on Night 13.......................................................................................................................... 35
4.3.3.
WASO on Night 13 ..................................................................................................................... 35
4.3.4.
Sleep Efficiency (SE).................................................................................................................. 35
4.3.5.
Total Sleep Time (TST) .............................................................................................................. 36
4.3.6.
Wake During Total Sleep Period ................................................................................................ 36
4.3.7.
Other Objective Sleep Parameters............................................................................................. 36
4.3.8.
Consensus Sleep Diary – Morning Administration (CSD-M)...................................................... 37
4.3.8.1.
Definition.................................................................................................................................. 37
4.3.8.2.
Analysis Methods .................................................................................................................... 37
4.3.9.
Objective Sleep Parameters Compared to Zolpidem ................................................................. 39
4.3.10.
Subjective Sleep Parameters Compared to Zolpidem ............................................................... 39
4.3.11.
Subgroup Analyses for Select Secondary Efficacy Endpoints ................................................... 39
4.3.12.
Insomnia Severity Index (ISI) ..................................................................................................... 40
4.3.12.1.
Definition.................................................................................................................................. 40
4.3.12.2.
Analysis Methods .................................................................................................................... 40
4.3.13.
Response of Insomnia Symptoms.............................................................................................. 40
4.3.13.1.
Definition.................................................................................................................................. 40
4.3.13.2.
Analysis Methods .................................................................................................................... 40
4.3.14.
Remission of Insomnia Symptoms ............................................................................................. 41
4.3.14.1.
Definition.................................................................................................................................. 41
4.3.14.2.
Analysis Methods .................................................................................................................... 41
4.3.15.
Clinical Global Impression-Severity (CGI-S) .............................................................................. 41
4.3.15.1.
Definition.................................................................................................................................. 41
4.3.15.2.
Analysis Methods .................................................................................................................... 42
4.3.16.
Clinical Global Impression – Improvement (CGI-I)..................................................................... 42
4.3.16.1.
Definition.................................................................................................................................. 42
4.3.16.2.
Analysis Methods .................................................................................................................... 42
4.3.17.
Patient Global Impression-Severity (PGI-S)............................................................................... 42
4.3.17.1.
Definition.................................................................................................................................. 42
4.3.17.2.
Analysis Methods .................................................................................................................... 43
4.3.18.
Patient Global Impression-Improvement (PGI-I) ........................................................................ 43
4.3.18.1.
Definition.................................................................................................................................. 43
4.3.18.2.
Analysis Methods .................................................................................................................... 43
4.3.19.
Patient Reported Outcome Measurement Information System-Sleep Disturbance 
(PROMIS-SD) ............................................................................................................................. 43
4.3.19.1.
Definition.................................................................................................................................. 43
4.3.19.2.
Analysis Methods .................................................................................................................... 44
4.3.20.
Patient Reported Outcome Measurement Information System- SRI (PROMIS-SRI) ................ 45
4.3.20.1.
Definition.................................................................................................................................. 45
4.3.20.2.
Analysis Methods .................................................................................................................... 46
4.3.21.
Correlation Between Objective and Subjective Sleep Parameters ............................................ 46
5.
SAFETY............................................................................................................................................. 46
5.1.
Adverse Events .............................................................................................................................. 46
5.2.
Clinical Laboratory Tests................................................................................................................ 47
5.3.
Vital Signs and Physical Examination Findings ............................................................................. 48
5.4.
Electrocardiogram.......................................................................................................................... 49
5.5.
Other Safety Parameters ............................................................................................................... 51
5.5.1.
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 51
5.5.2.
Modified Patient Reported Outcome Measurement Information System-Applied 
Cognition Abilities (PROMIS-ACA)............................................................................................. 52
5.5.2.1.
Definition.................................................................................................................................. 52
5.5.2.2.
Analysis Methods .................................................................................................................... 52


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5.5.3.
Cognitive Functioning Evaluations and Body Sway ................................................................... 52
5.5.4.
Karolinska Sleepiness Scale (KSS)............................................................................................ 52
5.5.5.
Physicians Withdrawal Checklist (PWC) .................................................................................... 53
5.5.6.
Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)................................................. 53
6.
OTHER ASSESSMENTS .................................................................................................................. 53
6.1.
Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) .............................. 53
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 54
8.
BIOMARKERS................................................................................................................................... 54
REFERENCES............................................................................................................................................ 55
ATTACHMENTS......................................................................................................................................... 56
Attachment 1:
Consensus Sleep Diary - Parameters vs Type of Baseline ....................................... 56
Attachment 2:
Conversion of Raw Score to T-Score for PROMIS-SD .............................................. 57
Attachment 3:
Conversion of Raw Score to T-Score for PROMIS-SRI ............................................. 58
Attachment 4:
Criteria for Treatment-emergent Markedly Abnormal Laboratory Values .................. 59
Attachment 5:
Modified Patient Reported Outcome Measurement Information System-
Applied Cognition Abilities (PROMIS-ACA)................................................................ 60


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LIST OF IN-TEXT TABLES
Table 1:
Visit Windows............................................................................................................................ 18
Table 2:
Demographic and Baseline Characteristics.............................................................................. 26
Table 3:
Baseline Insomnia and Illness Status Variables....................................................................... 27
Table 4:
Efficacy Variables ..................................................................................................................... 30
Table 5:
Clinically Important Abnormalities in Vital Signs....................................................................... 48
Table 6:
Abnormal Limits for Orthostatic Hypotension Parameters (Changes in Vital Signs in 
Standing Relative to Supine Position) ...................................................................................... 49
Table 7:
Abnormal Limits for ECG Parameters ...................................................................................... 50
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of the Study Design................................................................................. 14
Figure 2:
MCP-Mod Candidate Model Set............................................................................................... 33


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AMENDMENT HISTORY
SAP Version
Issue Date
Original SAP
22 May 2018
Amendment 1
03 April 2019
Amendment 2
18 April 2019
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (18 April 2019)
The overall reason for the amendment: Updated windowing, transformation of data
Applicable Section(s)
Description of Change (s)
Section 2.5, Table 1
Added paragraph and a footnote describing the assignment of visit windows for 
visit that don’t adhere to the protocol
Section 2.11
Modified language on data transformation
Amendment 1 (03 April 2019)
The overall reason for the amendment: Updated definition of treatment-emergent ECG, updated definition of 
Hy’s law, and removed analyses of next-day somnolence. 
Applicable Section(s)
Description of Change (s)
Section 1, Figure 1, and 
Section 4.1.1 (old section 
5.1.1)
Removed reference to “interim analysis” since it has been cancelled.
Section 1.1 and Section 
4.3.21 (old Section 5.3.21)
Changed “number of nighttime awakenings per hour (nNAW/hr) and subjective 
number of nighttime awakenings (s-nNAW);” to “number of nighttime 
awakenings per hour (nNAW/hr) and subjective number of nighttime awakenings 
(s-nNAW);”, to be consistent with protocol amendment 3.
Section 2.4
Modified the definition of baseline for KSS; clarified the baseline for PSG 
parameters
Section 2.5
Analysis windows for CSD-M, vital signs, PROMIS-SRI, PROMIS-SD, 
PROMIS-ACA; clarified the definition of baseline for PSG, CSD-M, KSS
Section 2.8
Updated subgroup “WOCBP vs. WONCBP” to “WOCBP vs. WONCBP vs. Men”
Section 2.9
Clarified the imputation of AE onset/resolution dates
Section 2.11
Added a new section regarding log-transformation of certain parameters
Section 3
Deleted this section as the interim analysis has been cancelled
Section 3.6 (old section 4.6)
Prior and concomitant medications: Changed the term that is summarized from 
standardized medication name to base preferred term
Section 4.2.1
LPS imputation rule for subjects who did not sleep at all in the observation period


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Section 4.2.3.1 (old section 
4.2.3.1)
Specified the value of the k parameter for the MCP-Mod selection.  Added 
language on the analysis of log transformed values.
Section 4.2.3.4 (old section 
5.12.3.4)
Deleted language on analysis of log-transformed values.  Included sensitivity 
analysis of LPS by not imputing the LPS value for subjects who did not sleep at 
all during the observation period.
Section 4.3.7 (old section 
5.3.7)
Added language on log-transformation of values for parameters that show a 
departure from the normality assumption. Added definition and analysis of sleep 
onset REM.
Section 4.3.8.2 (old section 
5.3.8.2)
Added details about computing average baseline for sQUAL and sFRESH
Section 4.3.13.1 (old 
section 5.3.13.1)
Added exploratory analysis of observed cases
Section 4.3.13.2 (old 
section 5.3.13.2)
Removed references to handling the data for subjects with missing ISI total score
Section 4.3.14.1 (old 
section 5.3.14.1)
Added exploratory analysis of observed cases
Sections 4.3.19.1 and 
4.3.20.1 (old sections 
5.3.19.1 and 5.3.20.1)
Added additional information on T-score
Section 5.1 (old section 6.1)
Removed analyses of next-day somnolence
Section 5.2 (old section 6.2)
Updated definition of Hy’s law; added analyses for subjects with AST>3*ULN 
Section 5.4 (old section 6.4)
Updated definition of treatment-emergent ECG
Section 5.5.2.1 (old section 
6.5.2.1)
Provided additional information on the analysis of PROMIS-ACA
Section 7 (old section 8)
Added details of the analysis of plasma concentration data
Attachment 5
Added the list of questions included in the modified PROMIS-ACA scale


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ABBREVIATIONS
AE
adverse event
AIC
Akaike Information Criterion
ANCOVA
analysis of covariance
BDNF
brain-derived neurotrophic factor
BWSQ
Benzodiazepine Withdrawal Symptom Questionnaire
CGI-I
Clinical Global Impression-Improvement
CGI-S
Clinical Global Impression-Severity 
CI
confidence interval
CRF
case report form
CSD-M
Consensus Sleep Diary – Morning Administration
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
DSM-5
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition
ECG
electrocardiogram
EEG
electroencephalograph
FAS
full analysis set
HbA1c
hemoglobin A1c
HPA
hypothalamic-pituitary-adrenal
ISI
Insomnia Severity Index
IWRS
interactive web response system
KSS
Karolinska Sleepiness Scale
LPS
Latency to Persistent Sleep
LS
least-squares
MCP-Mod
Multiple Comparison Procedure-Modeling
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model for repeated measures
nNAW
number of nighttime awakenings
nNAW/hr
number of nighttime awakenings per hour
NREM
non-rapid eye movement
PD
pharmacodynamic(s)
PGI-I
Patient Global Impression-Improvement
PGI-S
Patient Global Impression-Severity
PK
pharmacokinetic(s)
PRO
patient-reported outcome(s)
PROMIS-ACA
Patient Reported Outcome Measurement Information System-Applied Cognition Abilities
PROMIS-SD
Patient Reported Outcome Measurement Information System-Sleep Disturbance
PROMIS-SRI
Patient Reported Outcome Measurement Information System- Sleep Related Impairment
PSG
Polysomnography
PWC
Physician Withdrawal Checklist
QTcB
QT interval corrected using Bazett’s formula
QTcF
QT interval corrected using Fridericia’s formula
REM
Rapid eye movements
s-nNAW
subjective number of nighttime awakenings
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SE
Sleep Efficiency
sFRESH
subjective refreshed feeling on waking
sQUAL
subjective quality of sleep
sSOL
self-reported sleep onset latency
sTST
subjective total sleep time
sWASO
subjective wake after sleep onset
TEAE
treatment-emergent adverse event
TEMA
treatment-emergent markedly abnormal
TST
Total sleep time


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TSQM-9
Abbreviated Treatment Satisfaction Questionnaire for Medication
US
United States
WASO
Wake after sleep onset
WHO-DD
World Health Organization Drug Dictionary


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses for the clinical study report (CSR) for 
Study 42847922ISM2005.
This SAP does not include planned analyses on biomarkers or pharmacogenomics data or on 
population pharmacokinetic (PK), pharmacodynamics (PD) and exposure/response analyses, 
which will be specified as appropriate in separate documents.
1.1.
Trial Objectives
Objectives
Endpoints
Primary

To assess the dose-response of 3 doses of 
JNJ-42847922 (5, 10, and 20 mg) compared to 
placebo on an objective measure of sleep onset 
in subjects with insomnia disorder.

Change from baseline in LPS as measured by 
PSG on Night 1
Key Secondary

To assess the dose-response of 3 doses of 
JNJ-42847922 (5, 10, and 20 mg) compared to 
placebo 
on 
an 
objective 
measure 
of 
maintenance of sleep in subjects with 
insomnia disorder.

Change from baseline in WASO over the first 
6 hours as measured by PSG on Night 1
Secondary
Efficacy

To assess the effect of JNJ-42847922 
compared 
with 
placebo 
in 
improving 
additional objective sleep parameters
Change from baseline in PSG parameters 
including:

LPS on Night 13

WASO over the first 6 hours on Night 13

TST (over 6 and 8 hours) on Nights 1 and 13 

SE on Nights 1 and 13

other 
secondary 
PSG 
sleep 
parameters 
(detailed in Protocol Section 9.2.1) on Nights 
1 and 13


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Objectives
Endpoints

To assess the effect of JNJ-42847922 
compared 
with 
zolpidem 
in 
improving 
objective sleep parameters
Change from baseline in PSG parameters on 
Nights 1 and 13 including:

LPS

WASO over the first 6 hours

TST (over 6 and 8 hours) 

SE 

other 
secondary 
PSG 
sleep 
parameters 
(detailed in Protocol Section 9.2.1)

To assess the effect of JNJ-42847922 
compared with zolpidem and placebo on 
self-reported measures of sleep
Patient-reported measures including:

Change from baseline in subjective sleep 
parameters as measured by the Consensus 
Sleep 
Diary
–
Morning 
Administration 
(CSD-M), in the morning on Days 2 and 14

Change from baseline in sleep disturbance and 
impairment as measured by the National 
Institutes of Health Patient Reported Outcome 
Measurement Information System (PROMIS) 
short 
form 
8a 
for 
Sleep 
Disturbance 
(PROMIS-SD) and PROMIS short form 8a for 
Sleep Related Impairment (PROMIS-SRI) on 
Days 8 and 14

Change from baseline in subject's assessment 
of insomnia severity using the Patient Global 
Impression – Severity (PGI-S) scale and 
subject's assessment of improvement in 
insomnia using the Patient Global Impression
– Improvement (PGI-I) scale on Day 14.

To assess the effect of JNJ-42847922 
compared with zolpidem and placebo in 
improving:
o
Response and remission of insomnia 
symptoms

Proportion of responders, defined as a ≥50% 
reduction from baseline in total score on the 
Insomnia Severity Index (ISI) on Day 14

Proportion of subjects with remission of 
insomnia symptoms, defined as a total score 
≤10 on the ISI on Day 14
o
Clinical severity and improvement of 
insomnia symptoms

Change from baseline in clinician's assessment 
of insomnia severity using the Clinical Global 
Impression
–
Severity 
(CGI-S) 
and 
improvement in insomnia using the Clinical 
Global Impression – Improvement (CGI-I) on 
Day 14


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Objectives
Endpoints
Safety

To assess the safety and tolerability of 
JNJ-42847922 compared with zolpidem and 
placebo in subjects with insomnia disorder
Safety assessments including:

Adverse events (AEs) 

Proportion of all SAEs and events of special 
interest (e.g., falls, parasomnias)

Vital signs, physical examinations, ECG, and 
laboratory parameters

C-SSRS

Residual effects as measured by:
o
The presence of next day subjective 
residual effects as measured by the 
Karolinska Sleepiness Scale (KSS) on 
Days 2 and 14 
o
Postural 
stability 
(body 
sway) 
as 
measured with an ataxiameter on Days 2 
and 14 in the morning and on Day 15 at 
4-hours post Night 14 dose (middle of the 
night awakening)

To assess the effect of JNJ-42847922 
compared with zolpidem and placebo on 
cognitive domains as measured in the morning 
after dosing as well as during middle of the 
night awakening

Change in cognition compared to pre-dose 
assessment on objective cognitive assessment 
as measured by a computerized battery of 
cognitive tests in the morning on Days 2 and 
14 

Cognitive performance on Day 15 at 4-hours 
post Night 14 dose (middle of the night 
awakening) as measured by a computerized 
battery of cognitive tests 

Change from baseline in subjective assessment 
of cognitive effects of treatment as measured 
by 
the 
modified 
PROMIS-Applied 
Cognition-Abilities 
(PROMIS-ACA) 
on 
Days 8 and 13

To evaluate potential withdrawal effects after 
continuous nightly dosing with JNJ-42847922, 
zolpidem, or placebo

Change in subjective sleep parameters from 
Day 14 as compared to Day 17 as measured by 
the CSD-M

Change in Physician Withdrawal Checklist 
(PWC) from Day 14 to Day 17

The Benzodiazepine Withdrawal Symptom 
Questionnaire (BWSQ) for self-assessment of 
withdrawal symptoms on Day 17


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In addition, the exploratory objectives are:

To explore patient-reported level of satisfaction with the use of JNJ-42847922 compared to 
zolpidem in subjects with insomnia disorder using the Abbreviated Treatment Satisfaction 
Questionnaire for Medication (TSQM-9) on Day 14

To determine the correlation between the following sleep parameters obtained by PSG 
recordings on Nights 1 and 13 (objective) and CSD-M (subjective on the following 
morning): LPS and self-reported sleep onset latency (sSOL); TST and subjective TST 
(sTST); WASO and subjective WASO (sWASO); number of nighttime awakenings 
(nNAW) and subjective number of nighttime awakenings (s-nNAW); and SE and subjective 
quality of sleep (sQUAL) in subjects with insomnia disorder

To explore diagnostic biomarkers and evaluate change in biomarkers related to immune 
system (e.g., high-sensitivity C-reactive protein [hsCRP]), growth factors (e.g., brain-
derived neurotrophic factor [BDNF]), kynurenine metabolites (e.g., quinolinic acid), and 
HPA axis markers (e.g., cortisol) that may be related to clinical response (including PSG), 
non-response, or safety parameters of JNJ-42847922 versus placebo.
1.2.
Trial Design
This is a multicenter (US, Europe, and Japan), randomized, double-blind, parallel-group, active-
and placebo-controlled dose finding study to assess the efficacy and safety of JNJ-42847922 in 
both adult (18 to 64 years, inclusive) and elderly (65 to 85 years, inclusive) subjects with 
insomnia disorder. In addition, effects of JNJ-42847922 on sleep parameters (objective and 
subjective) and cognition will be compared to those effects of zolpidem, to investigate potential 
differences between the compounds. A total of 360 male and female subjects aged 18 to 85 years 
inclusive, with insomnia disorder will be randomized. The plan is to randomize approximately 
equal proportions of adult and elderly subjects and therefore the number randomized in either 
age group should not exceed approximately 60% of the planned total sample size. Women of 
childbearing potential are no longer allowed to be recruited per Protocol Amendment 2. 
The efficacy, dose- and exposure-response relationship, safety, and tolerability of 3 doses of 
JNJ-42847922 (5, 10, and 20 mg) compared to placebo and zolpidem when administered nightly 
over 14 days (at normal bedtime on non-PSG nights or 15 minutes prior to lights out on nights of 
PSG recording) will be assessed. Subjects will be randomized in a 1:1:1:1:1 ratio to receive 1 of 
5 treatments: placebo:JNJ-42847922 5 mg:JNJ-42847922 10 mg:JNJ-42847922 20 mg:zolpidem.
For all subjects, this study will consist of an eligibility screening phase, a double-blind treatment 
phase (17 days), and a follow-up visit.
A schematic overview of the study design is provided in Figure 1.


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Figure 1:
Schematic Overview of the Study Design
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis of this study is: in subjects with insomnia disorder, JNJ-42847922 will 
result in significantly shortened LPS values versus placebo, as measured by PSG on Night 1, and 
exhibit a dose-response relationship.
1.4.
Sample Size Justification
The total sample size is calculated based on the Multiple Comparison Procedure-Modeling 
(MCP-Mod) test applied towards the placebo and the JNJ-42847922 dose groups . The candidate 
model set considered for the determination of the sample size consists of the four model profiles: 
“linear”, “emax”, “sigEmax”, and “exponential”. Given the available data with JNJ-42847922 in 
the target population (insomnia disorder) from the PoC study (Study 42847922ISM2002), a 
treatment difference of 20 minutes between JNJ-42847922 and placebo for LPS was assumed 
with a standard deviation of 45 minutes. A total of 360 randomized subjects will provide an 
average weighted power of approximately 85% (depending on the underlying true dose-response 
profile), assuming a 1-sided significance level of 0.05 and a 12% overall dropout rate in the 
double-blind phase.
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. At the start of study enrollment, 
subjects will be randomly assigned to 1 of 5 treatment groups (placebo, JNJ-42847922 5 mg, 
JNJ-42847922 10 mg, JNJ-42847922 20 mg, or zolpidem) in a 1:1:1:1:1 ratio, based on a 
computer-generated randomization schedule prepared before the study by or under the 
supervision of the sponsor.
The randomization will be balanced by using randomly permuted blocks and will be stratified by
region (US/Europe, Japan), age group (adult, elderly), and intensive PK sampling (yes, no). To 


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randomize approximately equal proportions of adult and elderly subjects, the number 
randomized in either age group will be capped at approximately 60% of the planned total sample 
size.
The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching study drug kit for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, who will then be given the relevant subject details to uniquely identify the subject.
To maintain the study blind, the study drug container will have a multipart label containing the 
study name, study drug number, and reference number. A tear-off label is designed to be torn off, 
separated from the study drug container, and attached to the subject's source documents. The 
label will not identify the study drug in the container. However, if it is necessary for a subject's 
safety, the study blind may be broken and the identity of the study drug ascertained. The study 
drug number will be entered in the electronic case report form (CRF) when the study drug is 
dispensed. The study drugs will be identical in appearance and will be packaged in identical 
containers.
Data that may potentially unblind the treatment assignment (i.e., study drug serum 
concentrations, study drug preparation/accountability data, treatment allocation, and biomarker 
or other specific laboratory data) will be handled with special care to ensure that the integrity of 
the blind is maintained and the potential for bias is minimized. All PSG variables will be 
centrally scored, and the investigators will not have access to the PSG results from the 
acquisition nights during study treatment.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. 
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Study Reference Start and End Dates
The overall reference start date for the study is defined as the date of the first dose of double-
blind medication (the date is missing for screened subjects who did not receive a dose of double-
blind medication). The overall reference end date for the study is the end of trial date including 
the last follow-up visit, i.e., the study reference end date is the maximum of the date of the last 
visit in the double-blind treatment phase, or date of the last visit in the follow-up phase, or date 
of disposition in the double-blind phase (Trial Disposition case report form [CRF] page), or date 
of disposition in the follow-up phase (Disposition at Follow-up CRF page).
2.2.
Analysis Phases
There are 3 analysis phases defined in this study: Screening, Double-blind, and Follow-up (post 
double-blind). Each analysis phase has its own analysis reference start date.


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Screening
The screening phase begins on the date informed consent is obtained and ends 1 day prior to the 
date of the first dose of study drug in the double-blind treatment phase.  The screening phase end 
date is left missing for those subjects who did not receive study drug.
Double-blind Phase
The analysis reference start date of the double-blind analysis phase is the date of the first dose of 
double-blind medication. The analysis reference end date of the double-blind analysis phase
(except for Adverse Events) is the maximum of the date of the last visit in the double-blind phase
and date of completion or early withdrawal from the double-blind phase (Trial Disposition CRF 
page). For Adverse Events, the analysis reference end date of the double-blind analysis phase is 
the Day 17 TC date, and the date of the last dose of study drug plus 3 days for subjects without 
Day 17 TC date. For randomized subjects who did not receive any medication in the double-
blind phase, both analysis reference start and end dates are missing for the double-blind analysis 
phase.
Follow-up Phase
Start and end dates for the follow-up phase are only defined for subjects who continued into the 
follow-up phase. The analysis reference start date of the follow-up analysis phase is the day after 
the reference end date for the double-blind analysis phase. The analysis reference end date of the 
follow-up analysis phase is the maximum of the last follow-up visit date or the disposition date at 
follow-up (Disposition at Follow-up CRF page).
2.3.
Study Day
Study Day 1 or Day 1 refers to the date of the first study drug administration. All efficacy and 
safety assessments at all visits will be assigned a day relative to this date.
Study day for a visit is defined as:
a.
Visit date - (date of Study Day 1) +1, if visit date >= date of Day 1
b.
Visit date - Date of Day 1, if visit date < date of Day 1 
There is no ‘Day 0’.
2.4.
Baseline and End Point
The baseline measurement is defined as the closest measurement taken prior to or at the time of 
the first dose of study drug, with the exception of (1) the average predose ECG measurement,
which is defined as the average of all predose ECG results collected up to and including the day 
of the first dose of study drug; (2) the baseline KSS, which is defined as the average of all KSS 
evaluations collected during screening period; (3) the baseline values for PSG parameters, which 
is defined as the average of values collected on the two screening PSG nights; for subjects with 
1 screening PSG assessment, the baseline is the screening assessment; (4) the baseline (average) 
values for certain CSD-M parameters (as indicated in Attachment 1), which is defined as the 


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average of values (prior to or at the time of first dosing) collected on the five days prior to and 
including the Study Day 1.  
End point (DB) is defined as the last available postbaseline result within the double-blind phase. 
Unscheduled visit results are included in this definition and will be considered as the end point 
value if the unscheduled visit result is the last postbaseline result available within the double-
blind phase.
2.5.
Visit Windows
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to 
assign actual visits to analysis visits. Listed below are the visit windows and the target days for 
each visit. The reference day is Study Day 1 (which is the first day the study drug was taken in 
the double-blind phase). If a subject has 2 or more actual visits in one visit window, the visit 
closest to the target day will be used as the protocol visit for that visit window. The other 
additional visit(s) will not be used in the summaries or analyses but they can be used for 
determination of clinically important end points. If 2 actual visits are equidistant from the target 
day within a visit window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the end point. Listed below 
(Table 1) are the visit windows and the target days for each visit defined in the protocol.
For domains collected using ePRO (including PROMIS scales, KSS, CSD-M, BWSQ, PGI-I, 
PGI-S), the analysis visits with “(as collected on eCRF)” indicated in Table 1 are assigned by 
matching the ePRO measurement collection dates with study visit dates as reported in SDTM.SV 
dataset (i.e., per eCRF visit dates).
Assessments prior to Day 1 of the double-blind phase that are not considered a baseline 
assessment will be labeled as ‘Screening’.
For subjects who have multiple follow-up visits, the scheduled visit will be used in the 
summaries, however, data for all follow-up visits will be displayed in listings when applicable.
If there is an unscheduled assessment with collection date that doesn’t fall into any visit window 
per Table 1, then it will be assigned to a visit window that is closest to its collection date, and if 
this unscheduled assessment has a collection date equidistant from the dates for two adjacent 
visit windows, then it will be assigned to the visit window that is latter. (e.g., unscheduled ECG 
collected between visit window “Day 2” and visit window “Day 14” will be assigned to visit 
window “Day 2” if its collection date is closer to Visit Day 2, otherwise will be assigned to visit 
window “Day 14”).


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Table 1:
Visit Windows
Parameter 
Analysis
Phase
Scheduled Visit
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point 
(Day/Time)
LPS,
WASO,
TST,
SE,
other PSG sleep 
parameters
Screening
Screening PSG 
Night 1
Screening PSG 
Night 1
< 1
-14 to -5
Screening PSG 
Night 2
Screening PSG 
Night 2
<1
-14 to -5
DB
Baselined
< 1
-14 to -5
Day 1
Day 1 (Night)
Visit Day 1 (as 
collected on 
eCRF)
1
Day 13
Day 13 (Night)
Visit Day 13 (as 
collected on 
eCRF)
13
Subjective sleep 
parameters as 
measured by 
CSD-M
Screening
Screening
Screeninge
< 1
-35 to -1
DB
Day 1
Day 1 (Morning)
Visit Day 1 (as 
collected on 
eCRF)
1
Screening/Day 1
Baseline
≤1 (predosing)
-35 to 1
Screening/Day 1
Baseline (Average)e
≤1 (predosing)
-35 to 1
Day 2
Day 2 
(Morning)
Visit Day 2 (as 
collected on 
eCRF)
2
Day 13
Day 13
(Morning) 
Visit Day 13 (as 
collected on 
eCRF)
13
Day 14
Day 14 
(Morning)
Visit Day 14 (as 
collected on 
eCRF)
14
Day15
Day 15
Visit Day 15 (as 
collected on 
eCRF)
15
Day 17
Day 17 (TC)
Telephone 
Contact Day (as 
collected on 
eCRF)
17
EW b
EW b
Early 
Withdrawal 
Visit Day (as 
collected on 
eCRF)
Week 1 (Average)
Mean of Day 2 
to Day 8 data
Week 2 (Average)
Mean of Day 9 
to Day 14 data, 
exclude data 
collected after 
middle-of-night 
awakening
End point (DB)
2 to end of DB
FU
Follow-up
Follow-up
FU Visit Day 
(as collected on 
eCRF)
21-24


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Parameter 
Analysis
Phase
Scheduled Visit
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point 
(Day/Time)
BWSQ
DB
Day 17
Day 17 (TC)
Telephone 
Contact Day (as 
collected on 
eCRF)
17
EW b
EW b
Early 
Withdrawal 
Visit Day (as 
collected on 
eCRF)
FU
Follow-up c
Follow-up c
End of DB + 1 
to end of FU
21-24
ISI 
Screening
Screening
Screening
<1
-35 to -15
DB
Screening/Day 1
Baseline
≤1
1
Day 14
Day 14 (Morning)
Visit Day 14 (as 
collected on 
eCRF)
14
ECG
Screening
Screening
Screening
<1
-35 to -15
DB
Screening/Day 1
Day 1 Predose
≤1
-35 to 1
Screening/Day 1
Average Predose
≤1
-35 to 1
Day 2a
Day 2 (Night)a
Visit Day 2 
(postdose)a (as 
collected on 
eCRF)
2
Day 14
Day 14 (Morning)
Visit Day 14 (as 
collected on 
eCRF)
14
EW b
EW b
Early 
Withdrawal 
Visit Day (as 
collected on 
eCRF)
FU
Follow-up
Follow-up
End of DB + 1 
to end of FU
21-24
Weight,
BMI,
Waist 
Circumference, 
Physical Exam, 
Serum Chemistry, 
Hematology, 
Urinalysis
Screening
Screening
Screening
<1
-35 to -15
DB
Screening/Day 1
Baseline
≤1
1
Day 15
Day 15
Visit Day 15 (as 
collected on 
eCRF)
15
EW b
EW b
Early 
Withdrawal 
Visit Day (as 
collected on 
eCRF)
FU
Follow-up c
Follow-up c
End of DB + 1 
to end of FU
21-24
Vital signs
Screening
Screening
Screening
<1
-28 to -3
DB
Screening/Day 1
Baseline
≤1 (predosing)
1
Day 2
Day 2 
Visit Day 2 (as 
collected on 
eCRF)
2


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Parameter 
Analysis
Phase
Scheduled Visit
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point 
(Day/Time)
Day 2a
Day 2 (Night)a
Visit Day 2 
Night 
(postdose)a (as 
collected on 
eCRF)
2
Day 13
Day 13
Visit Day 13 (as 
collected on 
eCRF)
13
Day 14
Day 14
Visit Day 14 (as 
collected on 
eCRF)
14
Day 15
Day 15 4hr
Visit Day 15 4hr 
(as collected on 
eCRF)
Day 15 4hr
Day 15
Day 15 12hr
Visit Day 15 
12hr (as 
collected on 
eCRF)
Day 15 12hr
EW b
EW b
Early 
Withdrawal 
Visit Day (as 
collected on 
eCRF)
FU
Follow-up
Follow-up
End of DB + 1 
to end of FU
21-24
PWC
DB
Day 14
Day 14
Visit Day 14 (as 
collected on 
eCRF)
14
Day 17
Day 17 (TC)
Telephone 
Contact Day (as 
collected on 
eCRF)
17
EW b
EW b
Early 
Withdrawal 
Visit Day (as 
collected on 
eCRF)
FU
Follow-up c
Follow-up c
End of DB + 1 
to end of FU
21-24
C-SSRS
Screening
Screening
Screening
<1
-35 to -15
DB
Day 1
Baseline
≤1
1
Day 14
Day 14
Visit Day 14 (as 
collected on 
eCRF)
14
FU
Follow-up
Follow-up
End of DB + 1 
to end of FU
21-24
PROMIS-SRI, 
PROMIS-SD
DB
Day 1
Baseline
≤1
1
Day 8
Day 8
>=6 and <=10
8
Day 14
Day 14
Visit Day 14 (as 
collected on 
eCRF)
14


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Parameter 
Analysis
Phase
Scheduled Visit
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point 
(Day/Time)
EW b
EW b
Early 
Withdrawal 
Visit Day (as 
collected on 
eCRF)
FU
Follow-up c
Follow-up c
End of DB + 1 
to end of FU
21-24
PROMIS-ACA
DB
Day 1
Baseline
≤1
1
Day 8
Day 8
>=6 and <=10
8
Day 13
Day 13
Visit Day 13 (as 
collected on 
eCRF)
13
EW b
EW b
Early 
Withdrawal 
Visit Day (as 
collected on 
eCRF)
FU
Follow-up c
Follow-up c
End of DB + 1 
to end of FU
21-24
CGI-S, PGI-S
DB
Day 1
Baseline
≤1
1
Day 14
Day 14
Visit Day 14 (as 
collected on 
eCRF), or
analysis day > 14
14
CGI-I, PGI-I
DB
Day 14
Day 14
Visit Day 14 (as 
collected on 
eCRF), or 
analysis day >14 
14
KSS
Screening
Screening post 
PSG Night 1
Screening post PSG 
Night 1
< 1
-14 to -5
Screening post 
PSG Night 2
Screening post PSG 
Night 2
<1
-14 to -5
DB
Baselinef
<1
-14 to -5
Day 1
Day 1
Visit Day 1 (as 
collected on 
eCRF)
1
Day 2
Day 2 (Morning)
Visit Day 2 (as 
collected on 
eCRF), or 
analysis day = 2 
or 3
2
Day 13
Day 13 (Evening)
Visit Day 13 (as 
collected on 
eCRF)
13
Day 14
Day 14 (Morning)
Visit Day 14 (as 
collected on 
eCRF), or 
analysis day >14
14
*
Relative to Study Day 1 (unless otherwise noted); DB=double-blind; FU=follow-up, TC=telephone contact, 
EW=early withdrawal. Assignment of visit windows for the parameters where the visits are assigned ‘as 
collected on eCRF’: for the visits that occur on days that are not in accordance with the Time & Events schedule 
of the protocol, the visit windows are assigned based on the SV domain.
a
Only applicable for subjects who have intensive PK sampling.


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b
Only applicable for subjects who early withdraw.
c
For subjects who have completed all DB visits, these assessments are not planned in protocol to be collected at 
the Follow-up visit, and hence “Follow-up” visit window in theory should not exist for these subjects; however, 
they will be displayed if the data are actually collected.
d
Baseline values for PSG parameters are defined as the average of assessments on two screening PSG nights. For 
subjects with 1 screening assessment, baseline will be the screening assessment
e
Baseline values for selected CSD-M parameters (as indicated in Attachment 1) are defined as the average of 
assessments (prior to the time of first dosing) on 5 days prior to and including Study Day 1.
f
Baseline value for KSS is defined as the average of all assessments collected during screening period.
2.6.
Pooling Algorithm for Analysis Centers
Subjects will be enrolled at sites in Europe, the US, and Japan.  Actual site enrollment rates will 
be monitored to avoid gross imbalances across centers. To account for region variability, region 
(US/Europe, Japan) will be used as a factor in the statistical models to analyze efficacy. 
2.7.
Analysis Sets
Subjects will be classified into the following analysis sets: all randomized, full analysis set, and 
safety analysis set.
2.7.1.
All Randomized Analysis Set
The all randomized analysis set includes all subjects who were randomized in the study (i.e., 
subjects who reported a randomization date, or were assigned a randomization number) 
regardless of whether or not treatment was received. This analysis set will be used for 
summarizing the overall study completion/withdrawal information.
2.7.2.
Efficacy Analysis Set
2.7.2.1.
Full Analysis Set
The efficacy analyses will be based on the full analysis set, which consists of all subjects who 
were randomly assigned to study drug and received at least 1 dose of study drug.
2.7.3.
Safety Analysis Set
Safety analyses will be based on the safety analysis set, which consists of all subjects who were 
randomly assigned to study drug and received at least 1 dose of study drug.  The safety analysis 
set is the same as the full analysis set.  The safety data will be analyzed by the treatment 
received.
2.8.
Definition of Subgroups
Descriptive statistics will be provided for the change in LPS from baseline (on Night 1 and Night 
13) by the following subgroups:

Sex (male, female)

Women of Childbearing Potential (WOCBP) (as determined by Reproductive Tracking CRF 
page) vs. Men and Women of Non-Childbearing Potential (WONCBP)

WOCBP vs. WONCBP vs. Men


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
Adult (18-64 years) vs. Elderly (65-85 years)

Age group (18-44, 45-64, 65-85 years)

Region (US/Europe, Japan); region (US, Europe, Japan) 

Prior medication use of hypnotics/sedatives (Yes/No)

Baseline body mass index (BMI; underweight: <18.5 kg/m2, normal: 18.5 kg/m2 to 
<25 kg/m2, overweight: 25 kg/m2 to <30 kg/m2, obese: ≥30 kg/m2)

Race

Ethnicity
2.9.
Imputation Rules for Missing Adverse Event (AE) Dates
Partial AE onset dates will be imputed as follows:

If the onset date of an AE is missing day only, it will be set to:
o
First day of the month that the AE occurred, if month/year of the onset of AE is 
different than the month/year of the study drug start
o
The day of study drug start, if the month/year of the onset of AE is the same as
month/year of the study drug start date and month/year of the AE resolution date is 
different
o
The day of study drug start or day of AE resolution date, whichever is earlier, if 
month/year of the onset of AE and month/year of the study drug start date and 
month/year of the AE resolution date are the same.

If the onset date of an AE is missing both day and month, it will be set to the earliest of:
o
December 31 of the year of onset, if the year of onset is prior to the year of the 
study drug start date
o
January 1 of the year of onset, as long as this date is on or after the study drug start 
date
o
Month and day of the study drug start date, if this date has the same year as the year 
that the AE occurred
o
The AE resolution date.

Completely missing onset dates will not be imputed.
Partial AE resolution dates will be imputed as follows:

If the resolution date of an AE is missing day only, it will be set to the earlier of the last day 
of the month of occurrence of resolution or the day of the date of death, if the death occurred 
in that month.

If the resolution date of an AE is missing both day and month, it will be set to the earlier of 
December 31 of the year or the day and month of the date of death, if the death occurred in 
that year.

Completely missing resolution dates will not be imputed.


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AE onset/resolution dates with missing times will be imputed as follows:

A missing time of onset of an AE will be set to:
o
00:01 as long as the onset date is different from the study drug start date
o
The time of the study drug start if this is the same day the AE occurred.

The missing time of resolution of an AE will be set to 23:59.
If a missing time is associated with a partial date, the date will be imputed first prior to imputing 
the time.
2.10.
Imputation Rules for Missing Prior/Concomitant Medication Dates
2.10.1.
Prior Medications
Prior medications or therapy are those taken by subjects before the start of dosing of first study 
drug. Medications will be classified as prior if the medication start date is complete and prior to 
the date of first dose of study drug or the medication end date is complete and prior to the date of 
first dose of study drug.
If the medication start day is missing, and the month and year of the start date are not missing, 
then the medication will be considered prior if:

The month and year of the start date of medication is earlier than the month and year of the 
initial study drug administration; or

The CRF indicates the medication was taken prior (prior medication flag=Yes) and the 
month and year of the start date of medication is the same as the month and year of the 
initial study drug administration
If the medication start month and day are missing, and the year of the start date is not missing,
the medication will also be considered prior if:

The year of the start date of medication is earlier than the year of the initial study drug 
administration; or 

The CRF indicates the medication was taken prior when the year of the start date of 
medication is the same as the year of the initial study drug administration
If the medication start date is completely missing, and the CRF indicates it was taken prior, it 
will also be considered prior.
2.10.2.
Concomitant Medications Taken During the Double-blind Phase
Concomitant medications taken during the double-blind phase are those that started on the same 
day as the first dose or after the start of dosing or those continuing from predose (prior 
medication flag=Yes) and the CRF indicates the medication is ongoing or the medication stop 
date is on or after the first dose of study drug. Medications that start after the analysis reference 
end date of the double-blind phase are not considered concomitant medications taken during the 
double-blind phase. 


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If the medication start date is missing the day, but the month and year are complete, and if the 
month and year of the start date are on or prior to the month and year of the analysis reference 
end date of the double-blind phase, then the medication will be classified as concomitant during 
the double-blind phase if: 

The CRF indicates that the medication is ongoing, or

The stop date of the medication is missing, or

The stop date of the medication is on or after the initial study drug administration, or

The stop date month and year (day is missing) of the medication is on or after the initial 
study drug administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study drug administration 
If the medication start date is missing the month and day, but the year is complete, and if the year 
of the start date is the same as or prior to the year of the analysis reference end date of the 
double-blind phase, then the medication will be classified as concomitant during the double-
blind phase if:

The CRF indicates that the medication is ongoing, or

The stop date of the medication is missing, or

The stop date of the medication is on or after the initial study drug administration, or

The stop date month and year (day is missing) of the medication is on or after the initial 
study drug administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study drug administration 
If the medication start date is completely missing, then the medication will be classified as 
concomitant during the double-blind phase if:

The CRF indicates that the medication is ongoing, or

The stop date of the medication is missing, or

The stop date of the medication is on or after the initial study drug administration, or

The stop date month and year (day is missing) of the medication is on or after the initial 
study drug administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study drug administration
2.10.3.
Concomitant Medications Taken During the Follow-up Phase
Follow-up medications are those medications that started after the analysis reference end date of 
the double-blind phase. 


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2.11.
Handling of data that appear to deviate from normality assumption 
Analysis will be conducted by using log-transformed values of the following parameters: LPS
and WASO (if the outcome variable deviates significantly from normality assumptions). Details 
about the analysis are presented in their respective sections further below.  As some of the 
readings for these parameters will have a value of 0, log-transformed value+1 will be used for 
analysis.
Appropriate data transformation(s) or bootstrap methods may be performed on other parameters 
if the data appear to deviate significantly from normality assumptions.
3.
SUBJECT INFORMATION
The number of subjects in each analysis set will be provided.  In addition, the number of subjects 
by region (US, Europe, and Japan), country, and site in the full analysis set will be provided.
3.1.
Demographics and Baseline Characteristics
Demographic and baseline characteristics (Table 2) and baseline insomnia and illness status
(Table 3) will be summarized by treatment group and overall for the full analysis set. The 
continuous variables will be summarized using descriptive statistics (N, mean, standard deviation 
[SD], median, minimum, and maximum). The categorical variables will be summarized using a 
frequency distribution with the number and percentage of subjects in each category.
Table 2:
Demographic and Baseline Characteristics
Continuous Variables:

Age (years), calculated based on date of informed consent date

Baseline weight (kg)

Baseline height (cm)

Baseline BMI (kg/m2) calculated as Weight (kg)/[Height (m)]2

Baseline waist circumference (cm)
Categorical Variables:

Adult (18-64 years) vs. Elderly (65-85 years)

Age (18-44, 45-64, 65-85 years)

Sex (male, female)

WOCBP vs. WONCBP vs. Men

Race (White, Black or African American, Asian, American Indian or Alaskan native, Native 
Hawaiian or other Pacific islander, not reported); If multiple race categories are indicated, then 
Race is recorded as “Multiple”.

Ethnicity (Hispanic or Latino, not Hispanic or Latino)

Baseline BMI (underweight: <18.5 kg/m2, normal: 18.5 kg/m2 to <25 kg/m2, overweight: 25 
kg/m2 to <30 kg/m2, obese: ≥30 kg/m2)


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Table 3:
Baseline Insomnia and Illness Status Variables
Continuous Variables:

Baseline ISI score

Baseline CGI-S score

Baseline PGI-S score

Baseline LPS

Baseline WASO

Baseline SE

Baseline TST

Baseline sQUAL

Baseline sFRESH

Baseline PROMIS-SD raw score

Baseline PROMIS-SD T-score

Baseline PROMIS-SRI raw score

Baseline PROMIS-SRI T-score
Categorical Variables:

Baseline CGI-S score (1=normal [not at all ill]; 2=borderline ill; 3=mildly ill; 4=moderately ill; 
5=markedly ill; 6=severely ill; 7=among the most extremely ill patients)

Baseline PGI-S score (No insomnia, Very mild, Mild, Moderate, Severe, Very severe)

Baseline KSS score (1=extremely alert, 2=very alert, 3=alert, 4=rather alert, 5=neither alert nor 
sleepy, 6=some signs of sleepiness, 7=sleepy, but no effort to keep awake, 8=sleepy, some 
effort to keep awake, 9=very sleepy, great effort to keep awake, fighting sleep)

Baseline sQUAL

Baseline sFRESH
By-subject listings of the demographic and baseline characteristics, as well as medical history,
will be provided.
3.2.
Disposition Information
The number of screen failures will be summarized.
The number of subjects in the following disposition categories will be summarized throughout 
the study by treatment group and overall:

Subjects randomized 

Subjects receiving study drug

Subjects completing the double-blind phase

Subjects who discontinued from the double-blind phase 

Reasons for discontinuation from the double-blind phase 

Subjects completing the follow-up phase

Subjects who discontinued from the follow-up phase 


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Listings of subjects will be provided for the following categories:

All randomized subjects 

Subjects who discontinued from the double-blind phase

Subjects who were unblinded during the study period

Subjects who were randomized yet did not receive study drug.
These summaries and listings will be provided for the all randomized analysis set.
For the safety analysis set, a Kaplan-Meier plot of the time to discontinuation of study drug will 
be provided.
3.3.
Treatment Compliance
Compliance for each subject will be calculated based on the percent of the scheduled number of 
capsules of study drug actually taken within the double-blind phase. It is defined as:
Compliance (%) = (number of capsules taken / number of capsules supposed to have been 
taken)*100.
The number of capsules supposed to have been taken will be calculated as the duration of 
treatment within the phase (i.e., date of last dose of study drug – date of first dose of study drug 
+ 1) multiplied by 2 (since each “dose” of study drug consists of 2 capsules). 
Descriptive statistics on the percent (%) compliance will be summarized by treatment group for 
the safety analysis set.  In addition, percent compliance will be categorized as <60%, 60%-
<80%, 80%-100%, >100% and the number and percentage of subjects in each category will be 
summarized.
3.4.
Extent of Exposure
Total duration of exposure (including days off drug) is defined as (date of last dose of study drug
– date of first dose of study drug) + 1.  Number of doses is defined as the total number of drug 
administrations.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for total duration of 
exposure (including days off drug) and for number of doses will be presented by treatment group 
for the safety analysis set.  
A by-subject listing of study drug administration will be provided.
3.5.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
subjects’ rights, safety or well-being, or the integrity and/or result of the clinical trial. Subjects 
with major protocol deviations will be identified prior to database lock and the number and 
percentage of subjects with major protocol deviations will be summarized by category for the 
safety analysis set.


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
Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other
More categories may be included depending on the nature of the protocol deviation. A subject 
may be counted in more than one deviation category.
A summary of the number of subjects in the safety analysis set not meeting each 
inclusion/exclusion criterion will be presented.
A by-subject listing showing the specific major protocol deviations will also be provided.
3.6.
Prior and Concomitant Medications
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study drug. Concomitant medications are defined as any therapy 
used on or after the same day as the first dose of study drug, including those that started before 
and continue after the first dose of study drug.
If the medication start date is recorded as partial or completely missing, then the medication will 
be considered to be concomitant unless it is known to be prior to the first administration of study 
drug based on partial start date or stop date or the CRF indicates that the medication was taken 
prior (prior medication flag=Yes) (see Section 2.10 for detailed classification of prior and 
concomitant medications).
Prior medications will be summarized by treatment group and base preferred term for the safety 
analysis set.  The proportion of subjects who receive each prior medication will be summarized 
as well as the proportion of subjects who receive at least one prior medication.  In addition, the 
number and percent of subjects who receive hypnotics/sedatives prior to the study will be 
summarized.
Summaries of concomitant medications will be presented by treatment group and base preferred 
term for the safety analysis set, for those medications used during the double-blind phase and for 
those used during the follow-up phase separately.  Definitions for concomitant medications used 
during the double-blind phase and those used during the follow-up phase are provided in 
Sections 2.10.2 and 2.10.3, respectively.
The proportion of subjects who receive each 
concomitant medication will be summarized as well as the proportion of subjects who receive at 
least one concomitant medication.  
In addition, summary tables of the hypnotics/sedatives concomitant medications received during 
the study will be presented by treatment group, for those medications used during the double-
blind phase and for those used during the follow-up phase separately. 


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A by-subject listing of all prior and concomitant medication will also be provided.
4.
EFFICACY
All efficacy analyses will be based on the full analysis set.
The efficacy variables for this study are listed in Table 4.
Table 4:
Efficacy Variables
Variable
Endpoint
LPS

Change from baseline in LPS as measured by PSG on Night 1, 
compared with placebo
Primary

Change from baseline in LPS as measured by PSG on Night 13, 
compared with placebo
Secondary

Change from baseline in LPS as measured by PSG on Nights 1 and 13, 
compared with zolpidem
Secondary
WASO

Change from baseline in WASO over the first 6 hours as measured by 
PSG on Night 1, compared with placebo
Secondary

Change from baseline in WASO over the first 6 hours as measured by 
PSG on Night 13, compared with placebo
Secondary

Change from baseline in WASO over the first 6 hours as measured by 
PSG on Nights 1 and 13, compared with zolpidem
Secondary
TST

Change from baseline in TST (over 6 and 8 hours) on Nights 1 and 13, 
compared with placebo
Secondary

Change from baseline in TST (over 6 and 8 hours) on Nights 1 and 13, 
compared with zolpidem
Secondary
SE

Change from baseline in SE on Nights 1 and 13, compared with placebo
Secondary

Change from baseline in SE on Nights 1 and 13, compared with 
zolpidem
Secondary
Other PSG

Change from baseline in other secondary PSG sleep parameters 
(detailed in Section 4.3.7) on Nights 1 and 13, compared with placebo
Secondary

Change from baseline in other secondary PSG sleep parameters 
(detailed in Section 4.3.7) on Nights 1 and 13, compared with zolpidem
Secondary
Subjective sleep 
parameters 
measured by 
CSD-M
        Change from baseline in subjective sleep parameters as measured by 
CSD-M, in the morning on Days 2 and 14, compared to placebo
Secondary
        Change from baseline in subjective sleep parameters as measured by 
CSD-M, in the morning on Days 2 and 14, compared to zolpidem
Secondary
        Change from Day 14 to Day 17 in subjective sleep parameters as 
measured by CSD-M
Exploratory
Objective and 
subjective sleep 
parameters
        Correlation between the following sleep parameters obtained by PSG on 
Nights 1 and 13 (objective) and CSD-M (subjective on the following 
morning) will be provided: LPS and sSOL; TST and sTST; WASO and 
sWASO; nNAW and s-nNAW; and SE and sQUAL.
Exploratory


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Table 4:
Efficacy Variables
Variable
Endpoint
PROMIS-SD

Change from baseline in sleep disturbance as measured by PROMIS-SD 
on Days 8 and 14 compared with placebo and zolpidem
Secondary
PROMIS-SRI

Change from baseline in sleep-related impairment as measured by 
PROMIS-SRI on Days 8 and 14 compared with placebo and zolpidem
Secondary
PGI-S

Change from baseline in PGI-S on Day 14 compared with placebo and 
zolpidem
Secondary
PGI-I

PGI-I on Day 14 Compared with placebo and zolpidem
Secondary
ISI

Proportion of responders, defined as a ≥50% reduction from baseline in 
total score on the Insomnia Severity Index (ISI) on Day 14 compared 
with placebo and zolpidem
Secondary

Proportion of subjects with remission of insomnia symptoms, defined as 
a total score ≤10 on the ISI on Day 14 compared with placebo and 
zolpidem
Secondary

Mean Change in ISI total score from baseline compared with placebo 
and zolpidem
Secondary
CGI-S

Change from baseline in CGI-S on Day 14 compared with placebo and 
zolpidem
Secondary
CGI-I

CGI-I on Day 14 compared with placebo and zolpidem
Secondary
4.1.
Analysis Specifications
4.1.1.
Level of Significance
The primary efficacy endpoint will be evaluated at a 1-sided significance level of 0.05 using the 
MCP-Mod approach to test for dose-response. For all other analyses of the primary efficacy 
endpoint and for all other efficacy endpoints, no multiplicity adjustment will be done and 
nominal two-sided p-values will be presented.
4.1.2.
Data Handling Rules
For the analyses of response of insomnia symptoms based on ISI total score (Section 4.3.13), 
remission of insomnia symptoms based on ISI total score (Section 4.3.14), subjects with missing 
values will be imputed as non-responders/non-remitters.   
For the graphical presentations of the cumulative response rates, defined as the percentage of 
subjects experiencing at least a given value of percent reduction from baseline to Day 14 for ISI
total score (Section 4.3.12), the observed data will be presented since ISI is collected at only 
1 postbaseline time point.
4.1.3.
Imputation Methods for Missing Items
For PROMIS-SD, and PROMIS-SRI, imputation of the total score when there are missing items 
is described in Sections 4.3.19.1, and 4.3.20.1, respectively.  For all other scales where multiple 


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items are summed to create a total, if any item of the scale is missing at a visit, the total score for 
that scale at that visit will be left blank.
4.2.
Primary Efficacy Endpoint
4.2.1.
Definition
The primary efficacy endpoint is the change in LPS from baseline to Night 1.  LPS is an 
objective sleep parameter measured by PSG. The LPS change from baseline on Night 1 is 
calculated as (LPS at Night 1 – Baseline LPS).  Negative changes in LPS indicate improvement.
For subjects who did not sleep at all in the 8-hour observation period, their LPS value will be 
imputed to be equal to the total observation time.
4.2.2.
Primary Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 4 components:
Population: adult and elderly subjects with insomnia disorder, as defined through appropriate 
inclusion/exclusion criteria to reflect the targeted patient population;
Variable: change from baseline in LPS as measured by PSG on Night 1;
Intervention Effect: the effect of the initially randomized treatment on the endpoint;
Summary Measure: the difference in variable means.
The analysis will be based on the full analysis set and the LPS score collected during the double-
blind phase.
4.2.3.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Night 1, and Night 13 and the change from 
baseline to Nights 1 and 13 will be presented for LPS by treatment group (including zolpidem).      
4.2.3.1.
MCP-Mod Analysis
The primary efficacy endpoint, change from baseline in LPS as measured by PSG on Night 1, 
will be analyzed using an analysis of covariance (ANCOVA) model, with factors for region 
(US/Europe and Japan), treatment (placebo and JNJ-42847922 dose groups), and age group 
(adult and elderly), and baseline LPS as a continuous covariate. The treatment effects will be 
estimated using least squares means. The analysis will use the generalized MCP-Mod approach 1,
2 (a hybrid methodology that combines multiple comparison procedures with modeling 
techniques), which will be applied towards estimates obtained from the ANCOVA model to 
establish a dose-response signal. The candidate model set will include four model profiles: 
“linear”, “emax”, “sigEmax”, and “exponential”.


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The primary efficacy endpoint will be evaluated using the generalized MCP-Mod approach. The 
MCP-Mod approach provides a method for dose-finding using model-based estimation rather 
than hypothesis testing via pairwise comparisons.  The analysis will be done in two steps.
First, an analysis of covariance (ANCOVA) model, with factors for treatment (placebo and JNJ-
42847922 dose groups), region (US/Europe and Japan), age group (adult and elderly), and 
baseline LPS as a continuous covariate will be used to model the LPS change from baseline on 
Night 1 from the placebo and JNJ-42847922 groups. Based on the ANCOVA, the least-squares 
(LS) mean estimates of LPS change from baseline on Night 1 for each JNJ-42847922 dose group 
and placebo and the corresponding variances will be obtained.
Subsequently, the generalized MCP-Mod approach will be applied towards the estimates 
obtained from the ANCOVA to analyze the dose-response relationship. This approach requires 
pre-specification of a candidate model set. Using notation as in Bornkamp et al (2009) 1, the 
candidate set consists of the following 4 standardized model profiles: “linear” (no parameters), 
“emax” (ED50=0.56), “exponential” (δ=6.12), and “sigEmax” (ED50=7.07, h=8.496). Figure 2
below shows the set (of note, the maximum response is scaled to -1).  Also, the MCP-Mod model 
selection criteria will be based on the maximum t statistic.
Figure 2:
MCP-Mod Candidate Model Set


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The significance of the dose-response signal associated with each candidate model will be 
determined using trend tests with model-specific optimal contrast coefficients. The maximum of 
the candidate model trend test statistics will be used to evaluate the presence of a dose-response 
signal, properly accounting for multiplicity at an overall level of 5% (1-sided) using MCP-Mod 
methodology. If the maximum test statistic is not significant, no dose-response relationship will 
be further explored. Otherwise, the model family corresponding to the candidate model with 
maximum trend test statistic will be used to fit to the observed data to represent the dose-
response relationship.  The corresponding confidence interval (CI) for the response at each dose 
and placebo will be computed. The generalized Akaike Information Criterion (AIC) with the k 
parameter equal to 2 will be presented.
Log-transformed LPS on Night 1 will be analyzed using the same ANCOVA and the generalized 
MCP-MOD approach as described above, with log-transformed baseline LPS as a covariate.  
4.2.3.2.
ANCOVA Pairwise Comparisons
In conjunction with the MCP-Mod analysis, the pairwise comparison between JNJ-42847922 
doses and placebo will also be performed using the appropriate contrasts directly from the 
ANCOVA analysis described in Section 4.2.3.1.  A 90% CI for the difference in LS Means and 
p-value will be calculated based on the contrast test statistic for each JNJ-42847922 dose level.
As a secondary analysis, change from baseline in LPS on Night 1 will be analyzed using an 
analysis of covariance (ANCOVA) model, with factors for region (US/Europe and Japan), 
treatment (placebo and JNJ-42847922 dose groups) and gender, and age and baseline LPS as 
continuous covariates, for the pairwise comparison between JNJ-42847922 doses and placebo.
4.2.3.3.
Subgroup Analyses
Descriptive statistics will be provided for the primary efficacy endpoint by the subgroups
identified in Section 2.8.  
4.2.3.4.
Sensitivity Analyses
Change from baseline in LPS as measured by PSG on Night 1 will be analyzed using the same 
ANCOVA and the generalized MCP-Mod approach as described in Section 4.2.3.1 with age 
included as a continuous covariate in the model.
Analysis will also be performed on the data without imputing the missing LPS value for subjects 
who did not sleep at all during the observation period.
4.3.
Secondary Efficacy Endpoints
4.3.1.
WASO on Night 1
Change from baseline in WASO over the first 6 hours as measured by PSG on Night 1 will be 
analyzed using the same ANCOVA and the generalized MCP-Mod approach as described in 
Section 4.2.3.1for the primary efficacy endpoint, with the continuous covariate “baseline LPS” 
changed to “baseline WASO”.


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To investigate the sensitivity, the analysis will be repeated with age included as a continuous 
covariate in the model.
Log-transformed WASO on Night 1 will be analyzed using the same ANCOVA and the 
generalized MCP-Mod approach as described in Section 4.2.3.1, with log-transformed baseline 
WASO as a covariate.  
4.3.2.
LPS on Night 13
Change in LPS from baseline on Night 13 will be analyzed using a mixed model for repeated 
measures (MMRM). The MMRM will include region (US/Europe, Japan), age group (adult, 
elderly), time, treatment (placebo and JNJ-42847922 dose groups), and treatment-by-time 
interaction as factors and baseline LPS as a covariate. An unstructured variance-covariance 
matrix will be used for observations clustered by subject.  In case of convergence problems, 
alternative variance-covariance structures will be tried in the following order, with the first 
structure that converges being used in the analysis: heterogeneous Toeplitz, standard Toeplitz, 
and AR(1) with separate subject random effect.  The Kenward-Roger method will be used for 
approximating the denominator degrees of freedom. Based on the MMRM, the least-squares 
(LS) mean estimates for each JNJ-42847922 dose group and placebo on Night 13 and the 
corresponding variances will be obtained.
Means and mean changes from baseline (+/- SE) in LPS will be presented graphically over time.
Least squares mean changes from baseline (+/- SE) in LPS will be presented graphically over 
time.
Log-transformed LPS over time will be analyzed using the same MMRM, with log-transformed 
baseline value as a covariate.
4.3.3.
WASO on Night 13
Change from baseline of WASO on Night 13 will be analyzed using same method as change in 
LPS on Night 13
with the covariate “baseline LPS” changed to
“baseline WASO”
(see Section 4.3.2).
Means and mean changes from baseline (+/- SE) in WASO will be presented graphically over 
time. Least squares mean changes from baseline (+/- SE) in WASO will be presented graphically 
over time.
Log-transformed WASO over time will be analyzed using the same MMRM, with log-
transformed baseline value as a covariate.
4.3.4.
Sleep Efficiency (SE)
Sleep efficiency (SE) is the number of minutes of sleep divided by the number of minutes in bed 
(in percentages). 
Descriptive summary statistics for SE actual data and change from baseline will be provided for 
each treatment. 


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Change from baseline in SE on Night 1 will be analyzed using the same ANCOVA as described 
in Section 4.2.3.2for the primary efficacy endpoint, with the covariate “baseline LPS” changed to 
“baseline SE”.
Change from baseline of SE on Night 13 will be analyzed using same method as change in LPS 
on Night 13 with the covariate “baseline LPS” changed to “baseline SE” (see Section 4.3.2).
Means and mean changes from baseline (+/- SE) in SE will be presented graphically over time.
4.3.5.
Total Sleep Time (TST)
TST as measured by PSG will be analyzed using same methods as for SE (see Section 4.3.4). In 
addition, least squared mean changes from baseline (+/- SE) in TST will be presented graphically 
over time.
4.3.6.
Wake During Total Sleep Period
Wake during total sleep period as measured by PSG will be analyzed using the same method as 
for SE (see Section 4.3.4).
4.3.7.
Other Objective Sleep Parameters

WASO (measured hourly)

number of nighttime awakenings (nNAW) over 6 hours 

wake after final awakening

nNAW/hr 

time to first awakening after sleep 

REM duration

REM latency 

proportion of subjects with sleep-onset REM 

number of sleep cycles 

total time spent in sleep stages N1, N2 and N3 

amount of deep (slow-wave) sleep using spectral analysis of sleep EEG

determination of sleep EEG power spectrum/sleep epoch
For continuous variables, the actual values and change from baseline on Night 1 and Night 13 
will be summarized using descriptive statistics (N, mean, standard deviation [SD], median, 
minimum, and maximum) by treatment group. The categorical variables will be summarized by 
treatment using a frequency distribution with the number and percentage of subjects in each 
category, for Night 1 and Night 13.
For REM duration, REM latency, NREM (N1-N3) duration, and time to first awakening after 
sleep, the change from baseline will be analyzed using same methods as for SE 
(see Section 4.3.4), that is, ANCOVA model for change from baseline on Night 1, and MMRM 


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model for change from baseline on Night 13. For parameters that show a departure from the 
normality assumption, analysis will be performed on the log-transformed values.
Proportion of subjects Sleep-onset REM, defined as onset of REM within 15 minutes of sleep 
onset, will be summarized over time.
The analyses for amount of deep sleep using spectral analysis of sleep EEG and determination of 
sleep EEG power spectrum/sleep epoch will be described in a separate document. 
4.3.8.
Consensus Sleep Diary – Morning Administration (CSD-M)
4.3.8.1.
Definition
Subjects will be asked to provide answers to questions to determine their subjective experience
of sleep by recording their answers in a daily sleep diary (CSD-M). 
The CSD-M is a standardized patient diary based on expert consensus and qualitative patient 
input to retrieve patient reported subjective sleep parameters related to the prior night’s sleep. It 
allows for calculation of total time spent in bed and SE as the percentage of time asleep out of 
amount of time spent in bed. Sleep quality and how well rested subjects felt at awaking are rated 
on a 5-point Likert scale ranging from “very poor” to “very good”. Higher ratings indicate better 
sleep quality and more refreshing/restorative quality of sleep. Further evaluations include 
frequency of naps during the day and TST during the nap or doze, number of alcohol and 
caffeine containing drinks and medication used to help falling asleep.
The following CSD-M parameters will be analyzed:

sSOL

sTST

sWASO

s-nNAW

sQUAL

sFRESH
4.3.8.2.
Analysis Methods
For sQUAL and sFRESH, in order to create a single “average” response at baseline, the 
categorical responses will be mapped to a 0-4 scale and an average will be calculated.  This 
average will also be mapped back to the closest categorical response.  For example, if sQUAL is 
answered “Very poor”, “Poor” and “Good”, these would be mapped to scores of 0, 1, and 3, 
respectively, and the average would be calculated as 1.33.  As this is closer to 1, the average 
response would be “Poor”. 
For all parameters average baseline will be calculated if at least 2 measurements have been 
completed.  


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For the parameters listed in Section 4.3.8.1, the actual values and change from baseline over time
(including Week 1 [Average] and Week 2 [Average]) will be summarized using descriptive 
statistics (N, mean, standard deviation [SD], median, minimum, and maximum) by treatment 
group (including zolpidem).
The change from baseline in sSOL and sWASO on Day 2 will be analyzed using the same 
ANCOVA as described in Section 4.2.3.2 for the primary efficacy endpoint, with the continuous 
covariate “baseline LPS” changed to “baseline sSOL” or “baseline sWASO”, respectively.
The change from baseline in sSOL and sWASO on Day 14 will be analyzed using the same 
MMRM as described in Section 4.3.2 for the change in LPS on Night 13, with the covariate 
“baseline LPS” changed to “baseline sSOL” or “baseline sWASO”, respectively, with time 
points of Day 2 morning and Day 14 morning included in the model.
Change from baseline in sFRESH, and sQUAL on Day 2 and Day 14 will be analyzed using 
ANCOVA on the ranks of the change in score with treatment (excluding zolpidem), region 
(US/Europe, Japan), and age group (adult, elderly) as factors, and unranked baseline score as a 
covariate, to compare each JNJ-42847922 dose and placebo.
To estimate the odds ratio for sFRESH, the sFRESH scores at baseline and the endpoint of the 
double-blind phase will be transferred to a continuous scale by item response modelling via the 
logit model. The change from baseline in sFRESH score will be analyzed based on the latent 
scores using a linear regression model, with treatment (excluding zolpidem), region (US/Europe, 
Japan), and age group (adult, elderly) as factors, and baseline latent score as the covariate. The 
results will be transferred back to the ordinal scale for interpretation by odds ratio. The same 
analysis will be repeated for sQUAL.
In addition to summary according to analysis visit windows specified in Table 1, the every-day 
data of CSD-M parameters (as listed in Section 4.3.8.1) will be summarized descriptively and 
listed by subject, according to the actual day as collected on ePRO. In this analysis of “every-
day” data, the “Day 13” as collected in ePRO may not be the same as the “Day 13” in Table 1
(that is, the “Day 13” as collected in eCRF), if subjects deviate from the scheduled visit day. 
The change in sSOL from baseline over time will be analyzed using a mixed model, which 
includes region (US/Europe, Japan), age group (adult, elderly), previous-night PSG recording 
(Yes, No), previous-night intensive PK sampling (Yes, No), time, treatment (placebo and 
JNJ-42847922 dose groups), treatment-by-time interaction and baseline value. An appropriate 
variance-covariance matrix will be selected. For this model, all data collected between Day 2 
morning and Day 14 morning (but exclude any data collected after middle-of-night awakening) 
will be included, and time is the actual study day of collection (i.e., Day 2, 3, …. 14) and will be 
included as a categorical variable. This model will be repeated when the zolpidem group is 
included as well.
The same models will be applied to change in sWASO.


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To evaluate the potential withdrawal effect after continuous nightly dosing, descriptive statistics 
will be provided for the change in CSD-M parameters (as listed in Section 4.3.8.1) from Day 14 
as compared to Day 17, by treatment group (including placebo, zolpidem, and JNJ-42847922 
doses). 
4.3.9.
Objective Sleep Parameters Compared to Zolpidem
Change from baseline in LPS, WASO, SE, TST, NREM (N1-N3) duration, REM duration, and 
time to first awakening after sleep on Night 1 will be analyzed using ANCOVA as described in 
Section 4.2.3.2, including zolpidem, to compare zolpidem with each JNJ-42847922 dose and 
placebo using two-sided 90% confidence intervals for the difference between the groups.
Change from baseline in LPS, WASO, SE, TST, NREM (N1-N3) duration, REM duration, and 
time to first awakening after sleep on Night 13 will be analyzed using MMRM as described in 
Section 4.3.2, including zolpidem, to compare zolpidem with each JNJ-42847922 dose and 
placebo using two-sided 90% confidence intervals for the difference between the groups.
For other objective sleep parameters, the effect of JNJ-42847922 compared to zolpidem will be 
assessed by descriptive statistics (as described in Section 4.2.3).
4.3.10.
Subjective Sleep Parameters Compared to Zolpidem
Change from baseline in sSOL, and sWASO on Day 2 will be analyzed using ANCOVA as 
described in Section 4.3.8.2, including zolpidem, to compare zolpidem with each JNJ-42847922 
dose and placebo using two-sided 90% confidence intervals for the difference between the 
groups.
Change from baseline in sSOL and sWASO on Day 14 will be analyzed using MMRM as 
described in Section 4.3.8.2, including zolpidem, to compare zolpidem with JNJ-42847922 dose 
and placebo using two-sided 90% confidence intervals for the difference between the groups.
Change from baseline in sFRESH, and sQUAL on Day 2 and Day 14 will be analyzed using 
ANCOVA on the ranks of the change in score with treatment, region (US/Europe, Japan), and 
age group (adult, elderly) as factors, and unranked baseline score as a covariate, including 
zolpidem, to compare zolpidem with each JNJ-42847922 dose and placebo.
For other subjective sleep parameters, the effect of JNJ-42847922 compared to zolpidem will be 
assessed by descriptive statistics (as described in Section 4.3.8.2).
4.3.11.
Subgroup Analyses for Select Secondary Efficacy Endpoints
Descriptive statistics by age group will be provided for selected secondary efficacy endpoints, 
including change in LPS from baseline on Night 13, change from baseline on Nights 1 and 13 in 
WASO over the first 6 hours, SE, TST, wake during total sleep period, number of nighttime 
awakenings (nNAW) over 6 hours, sSOL, and sWASO. 


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4.3.12.
Insomnia Severity Index (ISI)
4.3.12.1.
Definition
The ISI is a 7-item questionnaire assessing the nature, severity, and impact of insomnia. The 
clinician version will be used in this study. The dimensions evaluated are: severity of sleep onset, 
sleep maintenance, early morning awakening problems; sleep dissatisfaction; interference of 
sleep problem with daytime functioning; noticeability of sleep problems by others; and distress 
caused by the sleep difficulties. A 5-point Likert scale (0-4) is used to rate each item, yielding a 
total score ranging from 0 to 28. The total score is interpreted as follows: absence of insomnia 
(0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28).
4.3.12.2.
Analysis Methods
Descriptive statistics of the actual values on Screening, Baseline, and Day 14 and the change 
from baseline to Day 14 will be presented for ISI total score by treatment group.  
The change from baseline to Day 14 in ISI total score will be analyzed using the same ANCOVA 
as described in Section 4.2.3.2 for the primary efficacy endpoint, with the continuous covariate 
“baseline LPS” changed to “baseline ISI total score”.
The change from baseline to Day 14 in ISI total score will be analyzed using the same ANCOVA 
as described above, including zolpidem, to compare zolpidem with each JNJ-42847922 dose and 
placebo using two-sided 90% confidence intervals for the difference between the groups.
A frequency distribution over time of the ISI category (i.e., absence of insomnia, subthreshold 
insomnia, moderate insomnia, and severe insomnia) will be provided by treatment group.
4.3.13.
Response of Insomnia Symptoms
4.3.13.1.
Definition
A secondary efficacy endpoint is the proportion of responders on insomnia symptoms on Day 14, 
defined as a ≥50% improvement in ISI total score from baseline to Day 14.  The calculation of 
the ISI total score is described in Section 4.3.12.1. The percentage change from baseline for ISI
total score is calculated as 100*(ISI total score at Day X – Baseline ISI total score)/(Baseline ISI
total score). Negative percent changes in ISI total score indicate improvement (e.g., percent 
change < -50% indicates improvement >50%).
A subject is defined a responder (yes=1) at a given time point if the percent reduction in ISI total 
score is ≥50%. Subjects who do not meet such criterion (including those with missing values)
will be considered as non-responders and will be assigned a value of 0 (i.e., no). Observed case 
analysis, i.e., no imputation for subjects with missing values, will be explored.
4.3.13.2.
Analysis Methods
The number and percentage of subjects who achieve a response will be summarized at Day 14 by 
treatment group. 


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As a sensitivity analysis, the same summary will be repeated by not including subjects with 
missing values in the frequency calculation (i.e., observed case only). 
The cumulative response rate, defined as the percentage of subjects experiencing at least a given
value of percent reduction from baseline to Day 14 in ISI total score, will be presented 
graphically.
The point estimate and 2-sided 90% confidence interval will be provided for the relative 
response using a Mantel-Haenszel test controlling for region (US/Europe, Japan) and age group
(adult, elderly).
In addition, the same Mantel-Haenszel test (including data from zolpidem arm) will be applied to 
compare zolpidem with other treatment groups.
4.3.14.
Remission of Insomnia Symptoms
4.3.14.1.
Definition
A secondary efficacy endpoint is the proportion of subjects with remission of insomnia
symptoms on Day 14, defined as an ISI total score ≤10 on Day 14.  Subjects who do not meet 
such criterion (including those with missing values) will be considered as non-remitters.
Observed case analysis, i.e., no imputation for subjects with missing values, will be explored.
4.3.14.2.
Analysis Methods
The number and percentage of subjects who achieve remission will be summarized at Day 14by 
treatment group. 
As a sensitivity analysis, the same summary will be repeated by not including subjects with 
missing values in the frequency calculation (i.e., observed case only).
The point estimate and 2-sided 90% confidence interval will be provided for the relative risk of 
remission using a Mantel-Haenszel test controlling for region (US/Europe, Japan) and age group
(adult, elderly).
In addition, the Mantel-Haenszel test (including data from zolpidem arm) will be applied to 
compare zolpidem with other treatment groups.
4.3.15.
Clinical Global Impression-Severity (CGI-S)
4.3.15.1.
Definition
A secondary efficacy endpoint is the change from baseline to Day 14 in the CGI-S score.  The 
CGI-S provides an overall clinician-determined summary measure of the severity of the subject’s 
illness that takes into account all available information, including knowledge of the subject’s 
history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the 
subject’s ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 1 
to 7. Considering total clinical experience with the insomnia population, a subject is assessed on 


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severity of illness at the time of rating according to: 1=normal (not at all ill); 2=borderline ill; 
3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill 
patients. The CGI-S permits a global evaluation of the subject's condition at a given time.
The CGI-S change from baseline on Day 14 is calculated as (CGI-S score on Day 14 – Baseline 
CGI-S score).  Negative changes in CGI-S score indicate improvement.
4.3.15.2.
Analysis Methods
A frequency distribution over time of the CGI-S scores at Baseline and Day 14 will be provided 
by treatment group.  In addition, descriptive statistics of the actual values and the change from 
baseline will be presented by treatment group for observed case data.
The analysis of the change in CGI-S score from baseline to Day 14 will be performed using an 
ANCOVA model on the ranks of the change in score with treatment, region (US/Europe, Japan),
and age group (adult, elderly) as factors, and unranked baseline CGI-S score as a covariate.  
The change from baseline to Day 14 in CGI-S will be analyzed using the same ANCOVA as 
described above, including zolpidem, to compare zolpidem with each JNJ-42847922 dose and 
placebo.
4.3.16.
Clinical Global Impression – Improvement (CGI-I) 
4.3.16.1.
Definition
The CGI-I is a 7-point scale to measure improvement in illness (1=very much improved, 2=much 
improved, 3=minimally improved, 4=no change from baseline, 5=minimally worse, 6=much
worse, 7=very much worse).
After 13 days of treatment, considering all aspects of insomnia, investigators will rate the 
subject's improvement on the CGI-I.
4.3.16.2.
Analysis Methods
A frequency distribution of CGI-I will be provided by treatment group.  In addition, descriptive 
statistics of the actual values will be presented by treatment group for observed case data.
The analysis of CGI-I on Day 14 will be performed using an ANCOVA model on the ranks of 
the score with treatment, region (US/Europe, Japan), and age group (adult, elderly) as factors, 
and unranked baseline CGI-S score as a covariate.
4.3.17.
Patient Global Impression-Severity (PGI-S)
4.3.17.1.
Definition
The PGI-S is a self-report scale to measure severity of illness (1=none, 2=mild, 3=moderate, 
4=severe). Considering all aspects of depression, subjects will rate their severity on the PGI-S.


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4.3.17.2.
Analysis Methods
A frequency distribution over time of the PGI-S scores at Baseline (i.e., Day 1), and Day 14 will 
be provided by treatment group.  In addition, descriptive statistics of the actual values and the 
change from baseline will be presented by treatment group for observed case data.
The analysis of the change in PGI-S score from baseline to Day 14 will be performed using an 
ANCOVA model on the ranks of the change in score with treatment, region (US/Europe, Japan), 
and age group (adult, elderly) as factors, and unranked baseline PGI-S score as a covariate.
The change from baseline to Day 14 in PGI-S will be analyzed using the same ANCOVA on the 
ranks as described above, including zolpidem, to compare zolpidem with each JNJ-42847922 
dose and placebo.
The association between CGI-S and PGI-S will be explored using the Kendall tau-b rank 
correlation at both Day 1 and Day 14. 
4.3.18.
Patient Global Impression-Improvement (PGI-I)
4.3.18.1.
Definition
The PGI-I is a self-report scale to measure improvement in illness (1=very much improved, 
2=much improved, 3=improved [just enough to make a difference], 4=no change, 5=worse 
[just enough to make a difference], 6=much worse, 7=very much worse).
After 13 days of treatment, considering all aspects of insomnia, subjects rate their change on the 
PGI-I.
4.3.18.2.
Analysis Methods
A frequency distribution of will be provided by treatment group.  In addition, descriptive 
statistics of the actual values will be presented by treatment group for observed case data.
The analysis of PGI-I on Day 14 will be performed using an ANCOVA model on the ranks of 
the score with treatment, region (US/Europe, Japan), and age group (adult, elderly) as factors, 
and unranked baseline PGI-S score as a covariate.
4.3.19.
Patient Reported Outcome Measurement Information System-Sleep 
Disturbance (PROMIS-SD)
4.3.19.1.
Definition
The PROMIS-SD Short Form subscale consists of a static 8-item questionnaire. Using a recall 
period of the past 7 days, it assesses the concepts of sleep initiation (2 items), quality of sleep 
(3 items), early morning feelings (2 items) and worrying about sleep (1 item). 
Each question has five response options ranging in value from one to five. To find the total raw 
score for a short form with all questions answered, sum the values of the response to each 
question. For the 8-item form, the lowest possible raw score is 8; the highest possible raw score 


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is 40.  Lower scores indicate less sleep disturbance.  Note that the “direction” of the responses is 
not the same for all questions, i.e., sometimes a response of “not at all” indicates more sleep 
disturbance and sometimes a response of “not at all” indicates less sleep disturbance.  
“My sleep quality was” ranges from 5=very poor to 1=very good
“My sleep was refreshing” ranges from 5=not at all to 1=very much
“I had a problem with my sleep” ranges from 1=not at all to 5=very much
“I had difficulty falling asleep” ranges from 1=not at all to 5=very much
“My sleep was restless” ranges from 1=not at all to 5=very much
“I tried hard to get to sleep” ranges from 1=not at all to 5=very much
“I worried about not being able to fall asleep” ranges from 1=not at all to 5=very much
“I was satisfied with my sleep” ranges from 5=not at all to 1=very much
A score can be approximated if a participant skips a question.  However, for the 8-item form, at 
least 4 items must have been answered in order to calculate a score.  After confirming that 
enough responses were provided, sum the response scores from the items that were answered. 
Multiply this sum by the total number of items in the short form. Finally, divide by the number 
of items that were answered. For example, if a respondent answered 5 of 8 questions and 
answered all items with the second lowest response option (2), you would sum all responses 
(10), multiply by the number of items in the short form (8) and divide by the number of items 
that were answered (5). Here (10x8)/5=16. If the result is a fraction, round up to the nearest 
whole number. 
The formula is:  
(Raw sum x number of items on the short form) / Number of items that were actually answered
This is a pro-rated raw score.
The raw score (i.e., the total raw score or pro-rated raw score) can be converted into a T-score 
for each participant based on the table in Attachment 2.  The T-score rescales the raw score into 
a standardized score with a mean of 50 and an SD of 10 and ranges from 0 to 100.  Higher scores 
indicate greater sleep disturbance.
The change in the PROMIS-SD score from baseline to each time point in the double-blind phase 
will be calculated, for both the raw score and the T-score.
4.3.19.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Day 8, and Day 14 and the change from 
baseline to Day 8 and 14 will be presented for PROMIS-SD raw score and the T-score by 
treatment group.  
The change from baseline to Day 8 and 14 in the PROMIS-SD raw score and the T-score will be 
analyzed using the same MMRM as described in Section 4.3.2 for the change in LPS on Night 


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13, with the covariate “baseline LPS” changed to “baseline PROMIS-SD raw score” or “baseline 
PROMIS-SD T-score”, respectively.
The change from baseline in the PROMIS-SD raw score and the T-score will be analyzed using 
the same MMRM as described above, including zolpidem, to compare zolpidem with each 
JNJ-42847922 dose and placebo using two-sided 90% confidence intervals for the difference 
between the groups.
Frequency distributions of the PROMIS-SD individual items will be provided at each assessment 
time point.
4.3.20.
Patient Reported Outcome Measurement Information System- SRI 
(PROMIS-SRI)
4.3.20.1.
Definition
The PROMIS-SRI scale consists of 8 items. The main concept evaluated is daytime 
consequences on functioning on 5-point Likert scales. The PROMIS-SRI measures self-reported 
perceptions of alertness, sleepiness, and tiredness during usual waking hours, and the perceived 
functional impairments during wakefulness associated with sleep problems or impaired alertness.
Each question has five response options ranging in value from one to five. To find the total raw 
score for a short form with all questions answered, sum the values of the response to each 
question. For example, for the adult 8-item form, the lowest possible raw score is 8; the highest 
possible raw score is 40.
A score can be approximated if a participant skips a question.  However, for the 8-item form, at 
least 4 items must have been answered in order to calculate a score.  After confirming that 
enough responses were provided, sum the response scores from the items that were answered. 
Multiply this sum by the total number of items in the short form. Finally, divide by the number 
of items that were answered. For example, if a respondent answered 5 of 8 questions and 
answered all items with the second lowest response option (2), you would sum all responses 
(10), multiply by the number of items in the short form (8) and divide by the number of items 
that were answered (5). Here (10x8)/5=16. If the result is a fraction, round up to the nearest 
whole number. 
The formula is:
(Raw sum x number of items on the short form)/Number of items that were actually answered
This is a pro-rated raw score.
The raw score (i.e., the total raw score or pro-rated raw score) can be converted into a T-score 
for each participant based on the table in Attachment 3.  The T-score rescales the raw score into 
a standardized score with a mean of 50 and an SD of 10 and ranges from 0 to 100.  Higher scores 
indicated greater sleep impairment.


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4.3.20.2.
Analysis Methods
Descriptive statistics of the actual values on Day 1, Day 8, and Day 14 and the change from 
baseline to Day 8 and 14 will be presented for PROMIS-SRI raw score and the T-score by 
treatment group.  
The change from baseline to Day 8 and 14 in the PROMIS-SRI raw score and the T-score will be 
analyzed using the same MMRM as described in Section 4.3.2 for the change in LPS on Night 
13, with the covariate “baseline LPS” changed to “baseline PROMIS-SRI raw score” or 
“baseline PROMIS-SRI T-score”, respectively.
The change from baseline in the PROMIS-SRI raw score and the T-score will be analyzed using 
the same MMRM as described above, including zolpidem, to compare zolpidem with each 
JNJ-42847922 dose and placebo using two-sided 90% confidence intervals for the difference 
between the groups.
Frequency distributions of the PROMIS-SRI individual items will be provided at each 
assessment time point.
4.3.21.
Correlation Between Objective and Subjective Sleep Parameters
Correlation between the following sleep parameters obtained by PSG on Nights 1 and 13 
(objective) and CSD-M (subjective on the following morning) will be provided: LPS and sSOL; 
TST and sTST; WASO and sWASO; nNAW and s-nNAW; and SE and sQUAL.
5.
SAFETY
All safety analyses will be based on the safety analysis set.
5.1.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).
Any AE occurring at or after the initial administration of study drug through the Day 17 TC date, 
or the day of last dose plus 3 days for subjects without the Day 17 TC date is considered to be 
treatment-emergent. If the AE occurs on the day of the initial administration of study drug, and 
either the AE time or time of administration are missing, then the AE will be assumed to be 
treatment-emergent. If the AE date is recorded as partial or completely missing, then the AE will 
be considered to be treatment-emergent unless it is known to be prior to the first administration 
of study drug based on partial onset date or resolution date.
All reported treatment-emergent adverse events (TEAEs) will be included in the analysis.  For 
each TEAE, the number and percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized by system organ class, preferred term, and treatment group.
Summary tables will be provided for:

TEAEs


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
TEAEs occurring in ≥5% of subjects in any treatment group

Treatment-emergent serious AEs (SAEs)

TEAEs leading to discontinuation of study drug

TEAEs by severity

TEAEs by relationship to study drug
For the summaries of TEAEs by severity/relationship to study drug, the observation with the 
most severe occurrence/closest relationship to study drug will be chosen if there is more than one 
incident of the same TEAE for the subject.
In addition, a summary table will be generated showing the number and percentage of subjects 
who experience at least 1 occurrence of a given TEAE by system organ class, preferred term, 
lowest level term, and treatment group. 
A summary of all somnolence-related TEAEs (MedDRA preferred terms: somnolence, 
hypersomnia, and sedation; regardless of start time) will be presented. 
Adverse events of special interest are falls, cataplexy, sleep paralysis, and complex, sleep-related 
behaviors (parasomnias). Subjects with TEAEs of special interest will be presented separately, 
by preferred term and treatment group.  The AEs to be included in the summary of TEAEs of 
special interest are marked as such on the AE CRF.
A summary table of non-TEAEs occurring after the Day 17 TC date, or the date of last dose of 
study drug plus 3 days for subjects without Day 17 TC date, until the overall reference end date 
for the study will also be provided.
In addition to the summary tables, listings will be provided for subjects who:

Died

Had SAEs

Had AEs leading to discontinuation of study drug

Had somnolence-related TEAEs

Had TEAEs of special interest
5.2.
Clinical Laboratory Tests
Descriptive statistics will be presented for all chemistry, hematology, and urinalysis (pH and
specific gravity) laboratory parameters at each scheduled time point.  In addition, change from 
baseline to all postbaseline time points will be summarized for chemistry, hematology, and 
urinalysis (pH and specific gravity) parameters and displayed by treatment group. 
The number and percentage of subjects with treatment-emergent postbaseline markedly 
abnormal postbaseline values will be presented by treatment group.  Clinical laboratory test 
values will be considered “treatment-emergent markedly abnormal” (TEMA) using the criteria 


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defined by the sponsor listed in Attachment 4.  The identification of TEMA laboratory values is 
based on the postbaseline value being out of range while the baseline value is either missing or 
within the range given in Attachment 4. If postbaseline laboratory results are above the upper 
limit and the baseline value is below the lower limit, then the postbaseline abnormality will also 
be considered TEMA. The same applies to the postbaseline value being below the lower limit 
with the baseline value being above the upper limit. 
The incidence of subjects with treatment-emergent ALT values >3*upper normal limit (ULN) or 
AST value > 3*ULN will be presented for the double-blind phase. Additionally, incidence of 
treatment-emergent hepatic toxicity (suspected Hy’s Law
3 cases) defined as (ALT values 
>3*ULN or AST values > 3*ULN) AND total bilirubin values >2*ULN will be presented for the 
double-blind phase. Similar to the markedly abnormal analysis, only subjects with baseline (ALT 
values ≤3*ULN or AST values > 3*ULN) (AND baseline total bilirubin values ≤2*ULN for 
hepatic toxicity) (or if baseline value is missing) will be eligible for these analyses.
A listing of subjects with markedly abnormal laboratory values will be provided. A listing of 
subjects with ALT > 3* ULN or AST values > 3*ULN) and subjects with hepatic toxicity 
(suspected Hy’s Law cases) will be provided.
5.3.
Vital Signs and Physical Examination Findings
Continuous vital sign variables including weight, waist circumference, temperature, supine and 
standing pulse, supine and standing blood pressure (systolic and diastolic), and BMI will be 
summarized at each assessment time point by treatment group.  BMI will be calculated as weight 
(kg)/(height (m))2, at each time point that body weight is measured. The height measurement 
collected at screening will be used in the calculation. Changes from baseline to each postbaseline
time point will be summarized. Descriptive statistics (N, mean, SD, median, minimum and 
maximum) will be presented.   
Incidence of treatment-emergent clinically important abnormalities in vital signs during the 
double-blind phase, as defined in Table 5, will be summarized for subjects who had at least one 
postbaseline assessment for that vital sign.  If the baseline value is missing, the postbaseline 
value will be compared against the abnormally low/abnormally high criteria. Vital sign 
assessments collected during follow-up will not be used for this summary.
Table 5:
Clinically Important Abnormalities in Vital Signs
Vital Sign Parameter
Postbaseline value outside of normal limit if:
Abnormally low
Abnormally high
Pulse (bpm)
A decrease from baseline of 
15 to a value ≤50
An increase from baseline of 
15 to a value ≥100
Systolic BP (mmHg)
A decrease from baseline of 
20 to a value ≤90
An increase from baseline of 20 to a 
value ≥180
Diastolic BP (mmHg)
A decrease from baseline of
15 to a value ≤50
An increase from baseline of
15 to a value ≥105
Body weight (kg)
A decrease from baseline of 7%  
An increase from baseline of 7%  
Body temperature (°C)
<35.5°C
>37.5°C
BP = blood pressure


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A listing of subjects with treatment-emergent clinically important abnormalities in vital signs 
will be presented.
Orthostatic hypotension is defined as an absolute decrease in systolic (>20 mm Hg) or diastolic 
(>10 mm Hg) blood pressure after standing for at least 1 minute relative to supine position with 
an increase in pulse rate of >15 beats per minute (Table 6). The number and percentage of 
subjects who experience treatment-emergent orthostatic hypotension outside of pre-defined 
limits at any time during the double-blind phase and for whom the orthostatic hypotension was 
not present at baseline will be tabulated. Vital sign assessments collected during follow-up will 
not be used for this summary.
Table 6:
Abnormal Limits for Orthostatic Hypotension Parameters (Changes in Vital Signs in 
Standing Relative to Supine Position)
Vital Sign 
Outside of normal limit if difference
(standing minus supine)
(1)    Pulse (bpm)
>15 bpm
(2a)  Systolic BP (mmHg) 
< -20 mmHg
(2b)  Diastolic BP (mmHg)
< -10 mmHg
BP = blood pressure
Note: Orthostatic hypotension requires that conditions (1) and [(2a) or (2b)] are met.
For subjects who are unable to stand and have the vital signs measured in a sitting or supine 
position instead of the standing position, the difference between standing and supine values will 
remain missing.  
A listing of subjects with treatment-emergent orthostatic hypotension will be presented.
In addition, a by-subject listing of the abnormal physical examination data will be presented.
5.4.
Electrocardiogram
Twelve-lead ECGs will be recorded supine so that the different ECG intervals (RR, PR, QRS, 
QT) can be measured.  ECGs will be assessed at screening, Baseline, Day 14, and EOS/FU visit 
for subjects who early withdraw.  The ECGs will be read by a central reader.  The ECG variables 
that will be analyzed are heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc 
using the following correction methods: Bazett’s formula (QTcB) and Fridericia’s formula 
(QTcF).
Bazett’s formula: 
QTcB (msec) = QT (msec) * (HR(bpm)/60)0.5;
Fridericia’s formula:
QTcF (msec) = QT (msec) * (HR(bpm)/60)0.33


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Descriptive statistics for observed values and changes from average predose will be presented by 
treatment group for the above ECG variables at each scheduled time point.  Average predose 
ECG is defined as the average of all ECG results collected up to and including the day of the first 
dose of study drug.  
The identification of treatment-emergent abnormal ECG values is based on the post-baseline 
value (a value occurring after the first study drug administration) being out of range while the 
average predose value is either missing or within the limits given in Table 7. If post-baseline 
ECG results are above the upper limits (abnormally high) and the average predose value is below 
the lower limits (abnormally low), then the post-baseline abnormality will also be considered 
treatment-emergent. The same applies to the post-baseline value being below the lower limits 
(abnormally low) with the average predose value being above the upper limits (abnormally high). 
The number and percentage of subjects with treatment-emergent ECG values outside the pre-
defined normal limits defined below will be presented for the maximum postbaseline value (ie,
the maximum ECG result over the double-blind study period) by treatment group.  The 
maximum postbaseline value during the double-blind period will be computed for each ECG 
parameter using data from both scheduled and unscheduled visits.
Table 7:
Abnormal Limits for ECG Parameters
ECG Parameter
Outside of normal limit if ...
Abnormally low
Abnormally high
Heart Rate (bpm)
50 bpm
100 bpm
PR interval (msec)
120 msec
200 msec
QRS interval (msec)
60 msec
120 msec
QT interval (msec)
200 msec
500 msec
In addition, the number and percentage of subjects within each of the categories defined below 
will be presented for average predose and the maximum postbaseline value during the DB phase 
by treatment group.
Categories to assess QT prolongation:
QTc Interval:

Normal QTc (≤450 msec for male, ≤470 msec for female)

QTc >450 to ≤480 msec for male, >470 to ≤480 msec for female

QTc >480 to ≤500 msec

QTc >500 msec
Clinically significant QTc: 

No (≤500 msec)

Yes (>500 msec)


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Change from baseline:

No concern: QTc ≤30 msec

Concern: QTc >30 – 60 msec

Clear concern: QTc >60 msec
The interpretation of the ECGs as determined by the central reader will be displayed by the 
number of subjects and percentages meeting the normality criteria. The interpretation will be 
summarized over time.
Listings of treatment-emergent abnormal ECG values, QTc intervals >450 msec for males and 
QTc intervals >470 for females, and QTc interval changes >30 msec will also be provided.
5.5.
Other Safety Parameters
5.5.1.
Columbia Suicide Severity Rating Scale (C-SSRS)
Emergence of suicidal ideation will be assessed using the C-SSRS.  The C-SSRS is a low-burden 
measure of the spectrum of suicidal ideation and behavior. It is a semi-structured clinician-
administered questionnaire designed to solicit the occurrence, severity, and frequency of suicide-
related ideation and behaviors during the assessment period.
Using the C-SSRS, potentially suicide-related events will be categorized using the following 
scores:
Suicidal Ideation (1-5)
1: Wish to be Dead
2: Non-specific Active Suicidal Thoughts
3: Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
4: Active Suicidal Ideation with Some Intent to Act, without Specific Plan
5: Active Suicidal Ideation with Specific Plan and Intent
Suicidal Behavior (6-10)
6: Preparatory Acts or Behavior
7: Aborted Attempt
8: Interrupted Attempt
9: Actual Attempt (non-fatal)
10: Completed Suicide
If no events qualify for a score of 1 to 10, a score of 0 will be assigned (0=“no event that can be 
assessed on the basis of C-SSRS”).  Higher scores indicate greater severity.
A frequency distribution at each time point by treatment group will be provided. Shifts from 
baseline to the maximum postbaseline score during the double-blind phase will be summarized 
by treatment group. 
The maximum postbaseline score during the double-blind phase assigned for each subject will be 
summarized into one of three broad categories: No suicidal ideation or behavior (0), Suicidal 


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ideation (1-5), Suicidal behavior (6-10).  Shifts from baseline to the maximum category during 
the double-blind phase will be summarized by treatment group. 
In addition, a frequency distribution at each time point for whether the “subject has engaged in 
non-suicidal self-injurious behavior” will be presented by treatment group.
A listing of C-SSRS items throughout the study for subjects with Suicidal Ideation or Behavior 
at any time point will be provided.
5.5.2.
Modified Patient Reported Outcome Measurement Information 
System-Applied Cognition Abilities (PROMIS-ACA)
5.5.2.1.
Definition
Specific items from the PROMIS-ACA item bank have been selected based on their relevance to 
this study population. The instruments assess patient-reported functional abilities with regard to 
cognitive tasks. The PROMIS-ACA is universal rather than disease specific. Participants rate 
their responses using a scale ranging from 1 (Not at all) to 5 (Very much).  There are 8 items that 
are selected for this study (Attachment 5).  
The scoring for the PROMIS-ACA will be different from the other PROMIS instruments used in 
the study because a customized instrument was developed by selecting relevant items from the 
PROMIS-ACA item bank.  A T-score for each participant will be calculated based on the 
response pattern scoring algorithm developed by Northwestern University
(PROMIS 
developers). A T-score can be calculated if there are missing data as long as 4 or more items 
have been answered. The T-score is a standardized score with a mean of 50 and an SD of 10 and 
ranges from 0 to 100. Higher scores indicated greater cognitive abilities.
The change in the PROMIS-ACA score from baseline to each time point in the double-blind 
phase will be calculated for the T-score.
5.5.2.2.
Analysis Methods
Frequency distributions of the PROMIS-ACA individual items will be provided at each 
assessment time point. Descriptive statistics will be provided for the values and change from 
baseline on Day 8 and Day 13 for the PROMIS-ACA T-score.
5.5.3.
Cognitive Functioning Evaluations and Body Sway
Analyses of cognitive functioning evaluations and body sway will be performed by an external 
service provider, Bracket. The related analysis plan is provided in a separate document. 
5.5.4.
Karolinska Sleepiness Scale (KSS)
The KSS is a patient reported assessment of level of drowsiness at the time of scale 
administration. This scale is focused mainly on the propensity to fall asleep and has a high 
validity in measuring sleepiness. It consists of a 9-point Likert scale with response options from: 
1=very alert, 3=alert, 5=neither alert nor sleepy, 7=sleepy (but not fighting sleep), 9=very sleepy 
(fighting sleep).


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A frequency distribution will be provided by treatment group at each time point.
Values and changes from baseline to Day 2 Morning, Day 13 Evening, and Day 14 Morning will 
be summarized by treatment group. The difference between Day 1 and Day 2 Morning and the 
difference between Day 13 Evening and Day 14 Morning will be summarized by treatment
group. 
5.5.5.
Physicians Withdrawal Checklist (PWC)
The Physician Withdrawal Checklist (20 items; PWC-20) is a simple and accurate method used 
to assess potential withdrawal symptoms following cessation of treatment and will be measured 
on Day 14 and during the Day 17 telephone contact, and at the EOS/FU visit if subject withdraw 
early. Each of the 20 items is rated on a 4-point Likert scale, with 0=not present, 1=mild, 
2=moderate, 3=severe.
For each of the 20 items, a frequency distribution will be provided by treatment group at each 
time point.
In addition, symptoms collected at Day 17 telephone contact will be compared to the Day 14
visit and will be summarized as follows: new or worsened symptoms, symptoms present and 
unchanged, improved symptoms, and no symptoms.
A listing of subjects with withdrawal symptoms following abrupt cessation of treatment (i.e., 
those subjects with new or worsened symptoms compared to the Day 14 visit) will be presented.
5.5.6.
Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)
The BWSQ is a 20 symptom self-report questionnaire that has been used in studies to investigate 
Benzodiazepine (BZD) withdrawal. Subjects rate the degree to which they are experiencing each 
symptom as either “No,” “Yes-moderate” or “Yes-severe”. The questionnaire has been shown to 
be reliable and to have acceptable construct validity in assessing BZD withdrawal symptoms.
For each of the 20 items, a frequency distribution will be provided by treatment group at each 
time point.
Descriptive statistics of the total score over time will be presented by treatment group.
6.
OTHER ASSESSMENTS
6.1.
Abbreviated Treatment Satisfaction Questionnaire for Medication 
(TSQM-9)
The TSQM-9 is a 9-item generic patient reported outcome instrument to assess patients’ 
satisfaction with medication. It is derived from the longer TSQM Version 1.4 and covers 
domains of effectiveness, convenience and global satisfaction. The instrument is scored by 
domain with scores ranging from 0-100 where a lower score indicates lower satisfaction. The 
recall period is “the last 2-3 weeks”. The TSQM-9 is a reliable and valid instrument to assess 


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patients' satisfaction with medication, providing scores on effectiveness, convenience and global 
satisfaction.
For each item, descriptive statistics of the actual values will be presented by treatment group. For 
each domain (effectiveness [items 1, 2, 3], convenience [items 4, 5, 6] and global satisfaction
[items 7, 8, 9]), descriptive statistics will also be presented by treatment group.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
Plasma concentrations for JNJ-42847922 and metabolites (M12 and M16) will be summarized 
by dose, day and time point, using descriptive statistics. Details of other pharmacokinetic and 
pharmacodynamic analyses are provided in a separate document.
8.
BIOMARKERS
Details of the biomarker analysis are provided in a separate document.


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REFERENCES
1.
Bornkamp B, Pinheiro JC, and Bretz, F. MCPMod: An R Package for the Design and Analysis of Dose-
Finding Studies. Journal of Statistical Software; 2009; 29(7):1-23.
2.
Pinheiro J, Bornkamp B, Glimm E, Bretz, F. Model-based dose finding under model uncertainty using general 
parametric models. Stat Med. 2014;33(10):1646-1661.
3.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation 
and Research (CDER), Center for Biologics Evaluation and Research (CBER). [2009] Guidance for industry 
drug induced liver injury: premarketing clinical evaluation. Available: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf


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ATTACHMENTS
Attachment 1: Consensus Sleep Diary - Parameters vs Type of Baseline
Parameter
Baseline
Baseline 
(Average)
Final awakening time                     
Y
How long awakenings last                 
Y
Y
How long did you nap                     
Y
Y
How long did you sleep                   
Y
Y
How long in bed trying to Sleep          
Y
Y
How long to fall asleep                  
Y
Y
How much earlier                         
Y
Y
Latency to persistent sleep              
Y
Y
Medication to help you sleep             
Y
Number of alcoholic drinks               
Y
Y
Number of caffeinated drinks             
Y
Y
Number of naps                           
Y
Y
Rate quality of sleep                    
Y
Y
Restful/refreshed when waking 
up         
Y
Time got out of bed                      
Y
Time of last alcoholic drink             
Y
Time of last alcoholic drink date        
Y
Time of last caffeinated drink           
Y
Time of last caffeinated drink date      
Y
Time tried to sleep                      
Y
Time tried to sleep date                 
Y
Time you got into bed                    
Y
Time you got into bed date               
Y
Times woke up                            
Y
Y
Wake after sleep onset                   
Y
Wake up earlier than planned             
Y


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Attachment 2: Conversion of Raw Score to T-Score for PROMIS-SD


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Attachment 3: Conversion of Raw Score to T-Score for PROMIS-SRI


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Attachment 4: Criteria for Treatment-emergent Markedly Abnormal Laboratory Values
Markedly Abnormal Limits
Laboratory Parameter (unit)
Low
High
Clinical Chemistry
Albumin (g/dL) but SI unit = g/L
2.424
6.0 60
Alkaline phosphatase (U/L)
N/A
250
Alanine transaminase (SGPT) (U/L)
N/A
200
Aspartate transaminase (SGOT) (U/L)
N/A
250
Bicarbonate (mEq/L) but SI unit=mmol/L
15.115.1
34.934.9
Bilirubin (direct) (mg/dL) but SI unit =mol/L
N/A
3.0 mg/dL51.3 umol/L
Bilirubin (total) (mg/dL) but SI unit =mol/L
N/A
3.0 mg/dL51.3 umol/L
Blood urea nitrogen (mg/dL) but SI unit=mmol/L
N/A
50 mg/dL17.9 mmol/L 
Calcium (mg/dL) but SI unit=mmol/L
61.497 mmol/L
122.994 mmol/L
Chloride (mEq/L or mmol/L)
94
112
Creatine kinase (U/L)
N/A
990
Creatinine (mg/dL)   SI unit=mol/L
N/A
3265.2 mol/L
Gamma glutamyl transferase (U/L) 
N/A
300 U/L
Glucose Plasma (mg/dL) but SI unit=mmol/L
402.204 mmol/L
30016.653 mmol/L
Lactic acid dehydrogenase (LDH) (U/L)
N/A
500
Phosphate (mg/dL) but SI unit=mmol/L
2.20.71038 mmol/L
8.12.61549 mmol/L
Potassium (mmol/L)
3.0
5.8
Sodium (mEq/L) but SI unit = mmol/L
125125
155155
Total protein (g/L)
50
N/A
Uric acid (mg/dL) but SI unit=mol/L
1.589.22
10594.8 mol/L
Hematology
Hematocrit (%) - female
0.28
0.50
  - male
0.24
0.55
Hemoglobin (g/dL) but SI unit=g/L
880
19190
Hemoglobin A1c (%)
4
8
Neutrophils (%)
30
90
Monocytes (%)
N/A
20
Eosinophils (%)
N/A
10
Basophils (%)
N/A
6
Lymphocytes (%)
10
60
Reticulocytes (%)
0.5
1.5
Platelet count (109/L; giga/L)
100
600
Red blood cell (RBC) count (1012/L; tera/L) - female
3.0
5.5
                                                                      - male
3.0
6.4
White blood cell (WBC) count (109/L; giga/L)
2.5
15.0
Urinalysis
Urine pH
N/A
6.5
Urine specific gravity
< 1.001
> 1.035
Note: Values should be flagged as markedly abnormally low if the value is less than the value indicated in the 
“Low” column.  Likewise, values should be flagged as markedly abnormally high if the value is greater than the 
value indicated in the “High” column. 
Note:  The same limits apply to both males and females unless gender is indicated.
N/A = Not applicable.


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Attachment 5: Modified Patient Reported Outcome Measurement Information System-Applied 
Cognition Abilities (PROMIS-ACA)