A Phase 4, Open-Label Study of the Pharmacokinetics and Safety of XARTEMIS® XR (7.5 Oxycodone Hydrochloride/325 mg Acetaminophen) in Postsurgical Adolescent Subjects (Ages 12 to 17) With Moderate to Severe Acute Pain
Phase: PHASE4
Conditions: Acute Pain
Sponsor: Mallinckrodt

 
Offi ci al  Titl e:   A  P h a s e  4,  O p e n -L a b el  St u d y  of t h e  P h ar m a c o ki n eti c s  a n d  S af et y  of  
X A R T E MI S ®  X R ( 7. 5  m g  O x y c o d o n e  H y dr o c hl ori d e/ 3 2 5  m g 
A c et a mi n o p h e n) i n  P o st s ur gi c al  A d ol e s c e nt  S u bj e ct s ( A g e s  1 2 t o  1 7) 
wit h  M o d er at e t o  S e v er e  A c ut e  P ai n  
N C T  N u m b er:   N C T 0 2 5 0 8 9 3 5  
D o c u m e nt  D at e :  
Pr ot o c ol  V er si o n  3:  2 9 -J u n e- 2 0 1 6  
 
 
 

C LI NI C A L  S T U D Y P R O T O C O L
A P h ase 4, O pe n -L a bel St u d y of t he P h ar m ac o ki netics a n d S afet y of 
X A R T E MI S ® X R ( 7. 5 m g O x yc o d o ne H y dr oc hl ori de/
3 2 5 m g Acet a mi n o p he n) i n P osts ur gic al A d olesce nt
S u bjects ( A ges 1 2 t o 1 7) wit h M o der ate t o Se vere Ac ute P ai n
P r ot oc ol N u m ber : M N K 1 5 0 0 0 3 0 0
D ate of Ori gi n al Pr ot oc ol:
1 7 A pril 2 0 1 4
A me n d me nt 1 D ate d:  
2 1 Oct o ber  2 0 1 4
A me n d me nt 2 D ate d :  
2 0 A pril 2 0 1 5
D R A F T A me n d me nt 3 D ate d:  
2 9 J u ne 2 0 1 6
S p o ns or:
Malli nc kr o dt I nc
Cli nical Researc h a n d De vel o p me nt
6 7 5 Mc D o n nell B o ule var d
Hazel w o o d, M O 6 3 0 4 2
U nite d States of A merica

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
2
M alli nc kr o dt
P R O T O C O L  AM E N D M E N T 3 D A T E D J U N E 2 0 1 6
S U M M A R Y O F  C H A N G E S
Pr ot oc ol  Ame n d me nt 3 was de vel o pe d pri maril y t o re vise t he p har mac o ki net ic sa m pli n g a n d 
a nal ysis, p o p ulat i on defi nit i ons, a n d pr o p ose d n u m ber of s u bjects t o be scree ne d. T he maj or 
pr ot oc ol  c ha n ges are s u m marize d bel o w:
1.
Re d uce d t he n u m ber of p har mac o ki net ic s a mples f or t he si n gle -d ose p orti o n of  t he st u d y.
T he 3 0 mi n ute a n d 1, 3, a n d 1 1 h o ur sa m pli n g t i mes were delete d a n d a 1 5 mi n ute sa m ple 
was a d de d.
2.
Re vise d t he p har mac o ki netic sa m pli n g i nter vals d uri n g t he m ult i ple d ose p orti o n of t he 
st u d y. F or t he m ulti ple d ose p orti o n of t he st u d y, sa mpli n g was c ha n ge d t o 1 5 t o 3 0 
mi n utes, 4 5 t o 9 0 mi n utes, 2 t o 4 h o urs, a n d 6 t o 8 h o urs after t he f o urt h d ose. I n a d diti on, 
o ne sa m ple will be c o llecte d d uri n g t he 1 2 t o 1 8 h o ur ti me wi n d o w after t he f o urt h d ose .
3.
St u d y  le n gt h was decrease d t o 5 4 h o urs t o acc o m m o date t he s h orter sa m pli n g ti me t hat 
will e nc o m pass o nl y 4 d oses of X A R T E MI S X R.
4.
C ha n ge d t he n u m ber of d oses of X A R T E MI S X R re q ui re d t o c o mplete t he st u d y  fr o m 5 
d oses t o 2 or m ore d oses.
5.
Re vise d bl o o d v ol u mes t o a t otal  of 5 0 mL t o be c ollecte d i n t he st u d y, i ncl u di n g 3 2 m L 
f or p har mac o ki netic sa m ples.
6.
Re m o ve d A U C 0- i nf fr o m t he p har mac o ki netic para meters t o be calc ulate d.
7.
Re vise d p har mac o ki netic a nal yses s o t hat n o nc o m part me ntal a nal ysis is perf or me d o nl y 
o n plas ma O C a n d A PA P c o nce ntrati o ns after t he first d ose.
8.
A d de d P o p ulati o n P K m o deli n g of si n gle - a n d m ulti ple -d ose pl as ma O C a n d A PA P 
c o nce ntrati o n-ti me data.
9.
Re m o ve d t he Safet y C o m p leter a n d t he P K C o m pleter P o p ulati ons fr o m  t he a nal yses.
1 0. Re defi ne d t he P K P o p ul at i on t o i ncl u de s u bjects w h o pr o vi de d at least 6 bl o o d sa m ples 
f or meas ure me nt of aceta mi n o p he n a n d o x yc o d o ne.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3
M alli nc kr o dt
1 1. Cl arifie d t he defi nit i on of t he M o difie d I nte nt -t o-Tr eat P o p ulat i on t o i ncl u de all s u bjects 
recei vi n g at least 1 d ose of X A RT E MI S X R.
1 2. Re m o ve d Data Ma na ge me nt fr o m t he list of a d dit i o nal st u d y c o ntacts a n d a d de d   
 
 as t he 
i n Secti o n 2. 2 .
1 3. Re vise d t he pr ojecte d n u m ber o f i n di vi d uals t o be scree ne d fr om 6 0 t o 7 2.
1 4. Cl arifie d t he use of t he a b bre viati o n f or o x yc o d o ne ( O C).
.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4
M alli nc kr o dt
P R O T O C O L  AM E N D M E N T 2 D AT E D 2 0 A P RI L  2 0 1 5
S U M M A R Y O F  C H A N G E S
Pr ot oc ol  Ame n d me nt 2 was de vel o pe d pri maril y t o a d dress c o ncer ns fr o m p ote ntial st u d y  
sites. T he major pr ot oc ol  c ha n ges are s u m marize d bel o w:
1.
T he cli nical tec h nical lea d a n d bi o statistics c o ntact i nf or mat i on ha s bee n u p date d .
2.
T he list of acce pta ble s ur g ical pr oce d ures was delete d fr o m t he i ncl usi o n cri t eria a n d 
r e place d wit h t he state me nt t hat t he s p o ns or will pre-a p pr o ve a list of acce pta ble s ur gical 
pr oce d ures pri or t o st u d y  start f or eac h site. S ur gical pr oce d ures ot her t ha n t h ose o n t he 
pre -a p pr o ve d list ma y be acce pta ble o n a case b y case basis if a p pr o ve d b y t he Me dical 
M o ni t or a n d s p ons or .
3.
T he i ncl usi o n cri teria were f urt her m o difie d t o re q uire s u bjects t o ha ve a b o d y  mass i n de x 
( B MI) > 5 % a n d < 9 5 % f or t heir a ge, c orrect t he defi niti on o f females o f c hil d -beari n g 
p ote nti al, re d uce t he ti me after d osi n g t hat birt h c o ntr ol is re q uire d, a n d eli mi nate t he lists 
of  re q uire d birt h c o ntr ol met h o ds.
4.
T he e xcl usi o n cri t eria were mo difie d t o all o w s u bjects wit h a hist or y  of  ps yc h ot hera p y  
f or a n xiety,  te nsio n, a gi t atio n, ps yc hiatri c dis or ders, ps yc h osis, or de pressi o n; t o all o w 
s u bjects wit h a hist or y of atte ntio n deficit h y peracti vit y dis or der re q ui rin g me d icatio n; 
a n d t o all o w s u bjects wit h a hist or y of mali g na nc y.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5
M alli nc kr o dt
5.
T he ti me fr o m su bject a n xiet y, te nsio n , a git atio n, ps yc hiatri c dis or ders, ps yc h osis, or 
de pressi o n re q uiri n g h os pitalizati o n a n d/ or me d icatio n was c ha n ge d fr o m wi t hi n 3 years 
t o wit hi n 6 mo nt hs of scree ni n g.
6.
A d dit i onal e xcl usi o n cri t eria were a d de d t o pr o hi bit t he e nr oll me nt of s u bjects wit h a n y 
ot her m e dical c o n ditio n , a b n or mal vit al si g n ( blo o d press ure, p ul se rate, res pir at or y r at e), 
b o d y  t e mperat ure, or p h ysical e xa mi nat i on or E C G fi n di n g w hic h, i n t he i n vest i gat or’s 
me dical o pi ni o n, w o ul d precl u de safe pa rtici pat i on i n a cli nical st u d y ; a n d t o e xcl u de 
s u bjects w h o ha ve partici pate d i n a n y ot her cli nical st u d y wit hi n 3 0 da ys pri or t o t he 
scree ni n g visit or w h o pla n t o partici pate i n a n ot her cli nical st u d y w hile c o nc urre ntl y 
e nr o lle d i n t his st u d y.
7.
T he re q ui re me nt f or he patitis scree ni n g has bee n re m o ve d.
8.
T he o pti o n of  usi n g u ns weete ne d a p ple j uice i n place of water f or st u d y dr u g d osi n g was 
a d de d.
9.
T he restrict i on of  C Y P 2 D 6 a n d/ or C Y P 3 A 4 i n d ucers after X A RT E MI S X R d osi n g has 
bee n re m o ve d.
1 0. T he restrict i on o n c o ns u m pt i on of f o o d or be vera ges c o ntai ni n g xa nt hi nes i n t he 1 4 da ys 
pri or t o st u d y  start was re mo ve d.
1 1. T he restrict i on of o pi o i d me dicat i ons f or 6 0 mi n utes after X A RT E MI S X R d osi n g has 
bee n re m o ve d.  
1 2. T he p har mac o ki net ic sa m ple size has bee n re d uce d t o 2 m L eac h.
1 3. T he use of t he pr o vi de d i b u pr ofe n as t he resc ue me dicat i on has bee n clarifie d t o be 
o pti o nal .  
1 4. T he a nal ysis p o p ulat i ons ha ve bee n u p date d a n d e x pa n de d a n d t he w or di n g of t he 
statistical secti on has bee n u p date d t o reflect t hese c ha n ges.
1 5. Gra p hs o f B MI b y  a ge were a d de d t o t he At tac h me nts.
1 6. A d dit i onal mi n or c ha n ges t o clarif y  la n g ua ge a n d t o e ns ure c o nsiste nc y were ma de. 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6
M alli nc kr o dt
P R O T O C O L  AM E N D M E N T 1
D A T E D 2 1 O C T O B E R 2 0 1 4
S U M M A R Y O F  C H A N G E S
Pr ot oc ol  Ame n d me nt 1 was de vel o pe d pri maril y t o a d dress a n F D A re q uest t o increase t he 
mi ni m u m pai n sc ore re q uire d f or c o nti n ue d treat me nt wit h X A R T E MI S X R. T he m ajor 
pr ot oc ol  c ha n ges are s u m marize d bel o w:
1.
T he p rimar y  me dical m o ni t or na me a n d c o ntact i nf or mati o n ha ve bee n a d de d.
2.
T he re q ui re me nt f or a ser u m or uri ne pre g na nc y test t o be c o n d ucte d f or all fe male 
s u bjects at st u d y e xit or earl y ter mi natio n has bee n a d de d .
3.
S u bjects will be restricte d fr om t he use of a n y a d diti o nal o pi o i d t hera p y withi n 3 0 
mi n utes pri or t o a n d 6 0 mi n utes after eac h d ose of X A R T E MI S X R.
4.
T he pai n sc ore s u bjects nee d t o a d va nce t o t he ne xt d ose of  X A RT E MI S X R was 
i ncrease d fr o m ≥1 t o ≥4.
5.
T he f or mula f or c al c ulat i n g creatini ne cleara nce was c ha n ge d fr o m t he o ne refere nce d i n 
t he M o dificat i on of Diet i n Re nal Disease t o a pe diatric a p pr o priate f or m ula s uc h as t he 
Sc h wartz E q uati o n a n d t he a p pr o priate refere nce was a d de d .
6.
Restricti o ns o n f o o d a n d water c o ns u m pti o n ar o u n d t h e ti me of d osi n g were re m o ve d.
7.
Refere nces t o t he u p date d M N K - 7 9 5 ( X A RT E MI S X R ) I n vesti gat or’s Br oc h ure a n d 
Pac ka ge I nsert were a d de d.
8.
A d dit i onal mi n or c ha n ges t o clarif y  la n g ua ge a n d t o e ns ure c o nsiste nc y were als o ma de. 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7
M alli nc kr o dt
T A B L E O F C O N T E N T S
1 
DI S C L O S U R E S T A T E M E N T .......................................................................................1 3
2 
C O N T A C T S .................................................................................................................1 4
2. 1 
E mer ge nc y C o ntacts ..................................................................................................1 4
2. 2 
A d dit i onal C o ntacts ...................................................................................................1 5
3 
S P O N S O R SI G N AT U R E ..............................................................................................1 6
4 
I N VE S T I G A TO R SI G N A T U R E ..................................................................................1 7
5 
A B B R E VI A TI O N S .......................................................................................................1 8
6 
S Y N O P SI S ...................................................................................................................2 1
7 
S C H E D U L E O F E V E N T S ............................................................................................2 7
8 
E T HI C A L  C O N SI D E R ATI O N S ...................................................................................3 0
8. 1 
I nstituti o nal  Re vie w B oar d........................................................................................3 0
8. 2 
Et hical C o n d uct of t he St u d y .....................................................................................3 0
8. 3 
S u bject I nf or mat i on a n d C o nse nt ...............................................................................3 0
9 
B A C K G R O U N D I N F O R M A TI O N A N D R A TI O N A L E ...............................................3 2
9. 1 
O ver vie w ..................................................................................................................3 2
9. 2 
Pr o d uct Descri pt i on ...................................................................................................3 8
9. 3 
D osa ge a n d A d mi nistrati o n .......................................................................................3 9
9. 3. 1 
D ose a n d Re gi me n J ust ificati o n.............................................................................3 9
9. 4 
A d verse E ve nts .........................................................................................................4 0
9. 5 
Rati o nale ...................................................................................................................4 1
1 0 O BJ E C TI V E S ...............................................................................................................4 1
1 0. 1
Pri ma r y .....................................................................................................................4 1
1 0. 2
Sec o n dar y .................................................................................................................4 1
1 1 S T U D Y  D E SI G N..........................................................................................................4 2
1 1. 1
Descri pt i on ................................................................................................................4 2

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8
M alli nc kr o dt
1 1. 2
A p pr o xi mate D urati o n of S u bject Partici pat i on .........................................................4 3
1 1. 3
A p pr o xi mate D urati o n of St u d y ................................................................................4 3
1 1. 4
A p pr o xi mate N u m ber of S u bjects .............................................................................4 3
1 2 S E L E C TI O N O F S U BJ E C T S .......................................................................................4 4
1 2. 1
I ncl usi on Cri t eria ......................................................................................................4 4
1 2. 2
E xcl usi o n Cri t eria .....................................................................................................4 5
1 3 P RI O R A N D C O N C O MI T A N T T R E A T M E N T ............................................................4 8
1 3. 1
Pr o hi bite d D uri n g St u d y ............................................................................................4 8
1 3. 2
Per mi tte d D uri n g St u d y.............................................................................................4 9
1 3. 3
Treat me nt C o m plia nce ..............................................................................................5 0
1 4 P R O C E D U R E S ............................................................................................................5 0
1 4. 1
D osi n g ......................................................................................................................5 0
1 4. 2
C o nfi ne me nt .............................................................................................................5 0
1 4. 3
Scree ni n g Pr oce d ures ................................................................................................5 1
1 4 . 4 C hec k -i n Pr oce d ures ................................................................................................. 5 1
1 4. 5
Baseli ne ....................................................................................................................5 2
1 4. 6
H o urs 0 t o 3 6 Pr oce d ures ..........................................................................................5 3
1 4. 7
H o urs 3 6 t o 5 4 Pr oce d ures ........................................................................................5 3
1 4. 8
St u d y  E xit or Earl y Ter mi nat i on Pr oce d ures ..............................................................5 4
1 4. 9
F o ll ow- u p ( Te le ph o ne C o ntact) .................................................................................5 5
1 5 I N V E S TI G ATI O N A L  M E DI CI N A L P R O D U C T A N D N O N -I N V E S TI G ATI O N A L  
P R O D U C T A D MI NI S T R A TI O N ..................................................................................5 5
1 5. 1
I n vesti gati onal Me dici nal Pr o d uct ( X A R T E MI S X R) ................................................5 5
1 5. 2
N o n -i n vesti gati onal Pr o d uct (I b u pr ofe n) ...................................................................5 5
1 5. 3
Met h o ds of Assi g ni n g S u bjects t o Treat me nt Gr o u ps .................................................5 5
1 5. 4
D osi n g Pr oce d ures ....................................................................................................5 6
1 5. 5
St ora ge a n d Dis p osit i on o f Cli nical S u p plies .............................................................5 6
1 5. 6
Rete nti o n Sa m ples .....................................................................................................5 6

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
9
M alli nc kr o dt
1 5. 7
Dr u g Acc o u nta bilit y ..................................................................................................5 7
1 5. 8
C o m plia nce M o ni t ori n g ............................................................................................5 7
1 6 S A F E T Y .......................................................................................................................5 7
1 6. 1
A d verse E ve nts .........................................................................................................5 7
1 6. 2
Cli nical La b orat or y  Tests...........................................................................................5 8
1 6. 3
Me dical a n d S ur gical Hist or y ....................................................................................5 9
1 6. 4
Date of First Da y  of Last Me nstr ual Peri o d ...............................................................5 9
1 6. 5
De m o gra p h y .............................................................................................................5 9
1 6. 6
Hei g ht, We i ght  a n d B MI ...........................................................................................5 9
1 6. 7
P h ysical E xa mi nat i on ................................................................................................6 0
1 6. 8
Vit al Sig ns ................................................................................................................ 6 0
1 6. 9
B o d y  Te mperat ure .....................................................................................................6 1
1 6. 1 0 P ul se O xi metr y .........................................................................................................6 2
1 6. 1 1 El ectr ocar dio gr a m .....................................................................................................6 3
1 6. 1 2 Pai n E val uat i on .........................................................................................................6 4
1 6. 1 3 I mp ai re d J u d g me nt E valu ati o n ..................................................................................6 4
1 7 P H A R M A C O KI N E TI C S ..............................................................................................6 5
1 7. 1
Bl o o d C ollect i on a n d Pr ocessi n g ...............................................................................6 5
1 7. 1. 1 
Si n gle D ose P K Sa m pli n g .....................................................................................6 5
1 7. 1. 2 
M ul tiple D ose P K Sa m pli n g ..................................................................................6 5
1 7. 1. 3 
To t al Vol u me of Bl o o d C ollecte d ...........................................................................6 6
1 7. 1. 4 
S a m ple Pr ocessi n g a n d S hi p pi n g ...........................................................................6 6
1 7. 2
P har mac o ki net ic A nal ysis .........................................................................................6 6
1 7. 2. 1 
Bi oa nal y tic al Met h o d olo g y ................................................................................... 6 6
1 7. 2. 2 
P har mac o ki net ic Para meters..................................................................................6 6
1 8 L A B O R A T O R Y D E T E R MI N A TI O N S ..........................................................................6 8
1 9 S T A T I S TI C A L M E T H O D S A N D P L A N N E D A N A L Y SI S ...........................................6 8
1 9. 1
Ge neral C o nsi derati o ns .............................................................................................6 8
1 9. 2
A nal ysis P o p ulat i ons ................................................................................................. 6 8

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
1 0
M alli nc kr o dt
1 9. 3
S u bject C haracterist ics ..............................................................................................6 9
1 9. 3. 1 
De m o gra p hics .......................................................................................................6 9
1 9. 3. 2 
Me dical a n d S ur gical Hist or y ................................................................................6 9
1 9. 3. 3 
C o nc o mita nt Treat me nts ........................................................................................6 9
1 9. 3. 4 
S u bject Dis p osit i on a n d E x p os ure t o X A RT E MI S X R ...........................................6 9
1 9. 4
P har mac o ki net ic a n d Statistical A nal ysis...................................................................7 0
1 9. 5
S af et y A nal ysis .........................................................................................................7 0
1 9. 5. 1 
A d verse E ve nts .....................................................................................................7 0
1 9. 5. 2 
Cli nical La b orat or y  Tests .......................................................................................7 0
1 9. 5. 3 
P h ysical E xa mi nat i on Fi n di n gs ..............................................................................7 1
1 9. 5. 4 
Electr ocar di o gra m Fi n di n gs ...................................................................................7 1
1 9. 5. 5 
Vit al Sig ns, T e m perat ure a n d P ulse O xi metr y ........................................................7 1
1 9. 5. 6 
I mp ai re d J ud g me nt E val u ati o n ..............................................................................7 1
1 9. 6
Pai n I nte nsit y A nal ys is..............................................................................................7 1
1 9. 7
I nteri m A nal ysis ........................................................................................................7 1
1 9. 8
S t atistical P o wer a n d Sa m ple Size C o nsi derati ons .....................................................7 2
1 9. 9
De viat i ons Fr o m Stati stical A nal ysis Pla n ................................................................. 7 2
2 0 A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S ........................................7 2
2 0. 1
S af et y ........................................................................................................................7 2
2 0. 2
Defi nit i ons ................................................................................................................7 2
2 0. 2. 1 
A d verse E ve nt .......................................................................................................7 2
2 0. 2. 2 
U ne x pecte d A d verse E ve nt ....................................................................................7 3
2 0. 2. 3 
S eri o us A d verse E ve nt ...........................................................................................7 3
2 0. 2. 4 
Deat h ....................................................................................................................7 4
2 0. 2. 5 
Life -t hreate ni n g E ve nt ...........................................................................................7 4
2 0. 2. 6 
H os pitalizati o n ......................................................................................................7 4
2 0. 3
A d verse E ve nt a n d Seri o us A d verse E ve nt Classificati o ns .........................................7 5
2 0. 3. 1 
I n vesti gati onal Me dici nal Pr o d uct Relate d ness ......................................................7 5
2 0. 3. 2 
Se verit y Assess me nt ..............................................................................................7 5
2 0. 4
A d verse E ve nt a n d Seri o us A d verse E ve nt C ollect i o n, Rec or di n g a n d Re p orti n g ......7 6
2 0. 4. 1 
A d verse E ve nts .....................................................................................................7 7

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
11
M alli nc kr o dt
2 0. 4. 2 
S eri o us A d verse E ve nts .........................................................................................7 8
2 0. 5
Pre g na nc y Re p orti n g ................................................................................................. 7 9
2 1 S U BJ E C T DI S C O N TI N U ATI O N O R WI T H D R A W A L ................................................7 9
2 1. 1
S u bject W ith dra wal ...................................................................................................7 9
2 2 S T U D Y  S U S P E N SI O N, T E R MI N ATI O N, A N D C O M P L E TI O N ................................. 8 2
2 3 P R O T O C O L  A M E N D M E N T S .....................................................................................8 2
2 4 Q U A LI T Y C O N T R O L  A N D A S S U R A N C E................................................................. 8 2
2 4. 1
St u d y  a n d St u d y Site Disc o nti n uati on Cri t eria ...........................................................8 2
2 5 DI R E C T A C C E S S, D A T A H A N D LI N G, A N D R E C O R D -K E E PI N G ...........................8 3
2 5. 1
I n vesti gat or...............................................................................................................8 3
2 5. 2
S p o ns or .....................................................................................................................8 4
2 6 S U BJ E C T I NJ U RY .......................................................................................................8 4
2 7 R E C O R D S R E T E N TI O N .............................................................................................8 4
2 8
BI O L O GI C A L  S A M P L E S............................................................................................8 5
2 9 P U B LI C A TI O N P O LI C Y .............................................................................................8 5
2 9. 1
S p o ns or ’s P u blicati o n P olic y.....................................................................................8 5
2 9. 2
I n vesti gat or’s Abilit y t o P u blis h ................................................................................8 6
3 0 R E F E R E N C E S .............................................................................................................8 7
3 1 A T T A C H M E N T S ..........................................................................................................9 2
3 1. 1
At tac h me nt 1: B o d y Mass I n de x ...............................................................................9 2
3 1. 2
At tac h me nt 2: Cli nicall y Rele va nt Dr u gs Ca usi n g I nteracti o ns t hr o u g h C Y P 2 D 6 a n d 
C Y P 3 A 4 ...................................................................................................................9 4
3 1. 3
At tac h me nt 3: N u merical Pai n Rat i n g Scale..............................................................9 5
3 1. 4
At tac h me nt 4: Cli nical La b orat or y Tests ....................................................................9 6

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
1 2
M alli nc kr o dt
T A B L E O F  TA B L E S
Ta ble 7- 1: Sc he d ule of St u d y  E ve nts...................................................................................2 7
Ta ble 2 0- 1: A d verse E ve nt Relat i ons hi ps .............................................................................7 5
Ta ble 2 0- 2: A d verse E ve nt Se verit y Gra des .........................................................................7 6
Ta ble 2 0- 3: Re p orti n g Re q uire me nts f or A d verse E ve nts .....................................................7 7
T A B L E O F  FI G U R E S
Fi g ure 9 -1: O x y c o d o ne He patic Meta b olis m .......................................................................3 4
Fi g ure 9 -2: Aceta mi n o p he n He pat ic Meta b olis m................................................................. 3 6

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
1 3
M alli nc kr o dt
1
DI S C L O S U R E S T A T E M E N T
Restricte d Distri b ut i on of D oc u m e nts
T his d oc u me nt c o ntai ns i nf or mat i on t hat i s c o nfi de ntial a n d pr o prietar y t o t he s p o ns or. T his 
i nf or mat i on is bei n g pr o vi de d t o t he i n vesti gat or s olel y for t he p ur p ose of e val uat i n g a n d/ or 
c o n d ucti n g a cli nical st u d y for t he s p o ns or . T he i n vesti gat or ma y discl ose t he c o nte nts of t his 
d oc u m e nt o nl y t o st u d y pers o n nel u n der his/ her s u per visi on, i nst ituti o nal  re vie w b oar ds 
(I R Bs), or d ul y a ut h orize d re prese ntati ves of re g ulat or y a ge ncies f or t his p ur p ose u n der t he 
co n di tio n t hat t he y  mai ntai n c o nfi de ntialit y.  T he c o nte nts of t his d oc u me nt ma y n ot be use d 
i n a n y ot her cli nical st u d y, dis close d t o a n y  ot her pers o n or e ntity,  or p u blis he d wit h o ut t he 
pri or wri tte n per missi on of t he s p o ns or . T he f ore g oi n g s hall n ot a p pl y t o disclos ure re q ui re d 
b y a n y re g ulati ons; h o we ver, t he i n vesti gat or will gi ve pr o m pt n otice t o t he s p o ns or of a n y 
s uc h dis clos ure. All ot her n o n p u blic i nf or mat i on pr o vi de d b y  t he s p o ns or, as well as a n y 
i nf or mat i on t hat m a y be a d de d t o t his d oc u me nt, als o i s c o nfi de ntial a n d pr o prietar y t o t he 
s p o ns or a n d m ust be ke pt i n c o nfi de nce i n t he sa me ma n ner as t he c o nte nts of t his d oc u me nt.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
1 6
M alli nc kr o dt
3
S P O N S O R SI G N A T U R E
M y  si g nat ure, i n c o nj u ncti on wi t h t he sig nat ure of t he i n vesti gat or, c o nfir ms t he a gree me nt of 
b ot h parties t hat t he cli nical st u d y will be c o n d ucte d i n acc or da nce wi t h t he pr ot oc ol a n d 
a p plica ble la ws a n d ot h er re g ulati ons i ncl u di n g, b ut n ot li mite d t o, the I nter nati o nal 
C o nfere nce o n Har m o nisat i on (I C H) G ui deli ne f or G o o d Cli nical Practice ( G C P), t he U S 
C o de of Fe deral Re g ulat i ons ( C F R), pr otecti o ns f or pri vac y, a n d ge nerall y acce pte d et hical 
pri nci ples f or h u ma n researc h s uc h as t he Declarat i o n of Helsi nki .
N ot hi n g i n t his d oc u me nt is i nte n de d t o li mit t he a ut h orit y  of a p h ysicia n t o pr o vide 
e mer ge nc y me dical care.
S p o ns or Re prese ntati ve Si g nat ure
Date of Si g nat ure
( D D Mo nt h Y Y Y Y)
S p o ns or Re prese ntati ve Na me 
( pri nt)

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
1 7
M alli nc kr o dt
4
I N VE S T I G A T O R SI GN A T U R E 
M y  si g nat ure, i n c o nj u ncti on wi t h t he sig nat ure of t he s p o ns or, c o nfir ms t he a gree me nt of 
b ot h parties t hat t he cli nical st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d 
a p plica ble la ws a n d ot h er re g ulati ons i ncl u di n g, b ut n ot li mite d t o, t he Int er nati o nal 
C o nfere nce o n Har m o nisat i on (I C H) G ui deli ne f or G o o d Cli nical Practice ( G C P), t he U S 
C o de of Fe deral Re g ulat i ons ( C F R), pr otecti o ns f or pri vac y, a n d ge nerall y acce pte d et hical 
pri nci ples s uc h as t he Declarati on of Helsi n ki .
N ot hi n g i n t his d oc u m e nt is i nte n de d t o li mit t he a ut h orit y of a p h ysicia n t o pr o vide 
e mer ge nc y me dical care.
I n vesti gat or’s Sig nat ure
Date of Si g nat ure
( D D Mo nt h Y Y Y Y)
I n vesti gat or’s N a me a n d Tit le 
( pri nt)

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
2 2
M alli nc kr o dt
2. 
S u bject m ust ha ve a mi ni m u m wei g ht of 1 0 0 p o u n ds ( 4 5 k g) a n d ha ve a b o d y mass i n de x ( B MI) > 5 % 
a n d < 9 5 % f or t heir a ge (see Attac h me nt 1) at t he ti me of scree ni n g.
3. 
S u bject m ust re p ort ha vi n g m o derate t o se vere ac ute pai n (as deter mi ne d fr o m t he N P R S w here 0 = n o 
pai n, 1 0 = w or st pai n ; s u bjects m ust ha ve a le vel of 4 or m ore) after a pe diatric s ur gical pr oce d ure (at 
baseli ne ) t hat re q uires h os pitalizati o n. S p o ns or will pre-a p pr o ve a list of acce pta ble s ur gical pr oce d ures 
pri or t o st u d y start f or eac h site. S ur gical pr oce d ures ot her t ha n t h ose o n t he pre-a p pr o ve d list ma y be 
acce pta ble o n a case b y case basis if a p pr o ve d b y t he Me dical M o nit or ( M M) a n d s p o ns or.
4. 
S u bject, if fe male of c hil d -beari n g p ote ntial ( defi ne d as p ost me narc he), m ust a gree t o a bstai n fr o m 
u n pr otecte d se x ual acti vit y d u ri n g st u d y partici pati o n a n d f or 2 wee ks after st u d y e xit.  
5. 
S u bject, if male wit h re pr o d ucti ve p ote ntial, m ust a gree t o a bstai n fr o m u n pr otecte d se x ual acti vit y 
d uri n g st u d y partici pati o n a n d f or 2 wee ks after st u d y e xit.  
6. 
S u bject, if fe male of c hil d beari n g p ote ntial, m ust ha ve ne gati ve pre g na nc y test (ser u m or uri ne) res ults 
at scree ni n g a n d c hec k -i n. 
7. 
S u bject’s le gall y a ut h orize d re prese ntati ve (e g, pare nt, le gal g uar dia n) m ust v ol u ntaril y si g n a n d date a 
pare ntal per missi on /i nf or me d c o nse nt f or m (I C F) t hat is a p pr o ve d b y a n I nstit uti o nal Re vie w B oar d 
(I R B), a n d t he s u bject m ust si g n a n I R B a p pr o ve d asse nt, bef ore u n der g oi n g a n y pr ot oc ol s pecific 
pr oce d ures or assess me nts.
8. 
S u bject a n d t he s u bject’s pare nt or le gal g uar dia n m ust be a ble t o rea d, u n dersta n d a n d be willi n g t o 
f oll o w t he st u d y pr oce d ures a n d re q uire me nts a n d c o m m u nicate mea ni n gf ull y i n E n glis h wit h t he 
i n vesti gat or a n d i n vesti gat or’s staff (if t he s u bject ca n n ot rea d or c o m m u nicate mea ni n gf ull y, t he n t he 
s u bject’s le gall y a ut h orize d re prese ntati ve [e g, pare nt, le gal g uar dia n] m ust meet t his criteri o n).
E xcl usi o n Criteri a: 
1. 
S u bject is fr o m a v ul nera ble p o p ulati o n (i ncl u di n g me ntall y disa ble d c hil dre n), ot her t ha n a pe diatric 
p o p ulati o n, as defi ne d b y t he C o de of Fe deral Re g ulati o ns Title 4 5, Part 4 6, Secti o n 4 6. 1 1 1( b), 
i ncl u di n g b ut n ot li mite d t o e m pl o yees (te m p orar y, part-ti me, f ull ti me, etc) or a fa mil y me m ber of t he 
researc h staff c o n d ucti n g t he st u d y, or of t he s p o ns or, or of t he cli nical researc h or ga nizatio n, or of t he 
I R B.
2. 
S u bject is e x pecte d t o re q uire a s ur ger y t hat c o ul d i nfl ue nce t he st u d y o utc o me (e g, 
ve ntric ul o perit o neal s h u nt re pair i n t he setti n g of h y dr oce p hal us). 
3. 
S u bject has a n a b n or mal electr ocar di o gra m ( E C G) u nless t he i n vesti gat or deter mi nes t he E C G 
a b n or malities are n ot cli nicall y si g nifica nt.
4. 
S u bject has a scree ni n g p ulse o xi metr y rea di n g of < 9 5 % w hile a wa ke.
5. 
S u bject has a hist or y of la b orat or y test res ults o btai ne d bef ore scree ni n g t hat s h o w t he prese nce of 
h u ma n i m m u n o deficie nc y vir us ( HI V), he patitis B s urface a nti ge n, he patitis C a nti b o d y, or acti ve 
he patitis A i m m u n o gl o b uli n M.
6. 
S u bject has la b orat or y val ues t hat are greater t ha n 2 ti mes t he u p per li mit of n or mal ( wit h t he e xce pti o n 
of w h ite bl o o d cell [W B C ] differe ntial val ues). E nr oll m e n t of s u bjects wit h la b orat or y val ues t hat are 
bet wee n 1 a n d 2 ti mes t he u p per li mit of n or mal ( U L N), bel o w t he l o wer li mit of n or mal, or W B C 
differe ntial > 2 x U L N, will be left t o t he i n vesti gat or’s discreti o n ( n o i ncrease d ris k of partici pati o n i n 
st u dy base d u p o n j u d g me nt of t he i n vesti gat or).
7. 
S u bject has a n y hist or y of re nal disease t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d c o ntrai n dicate 
st u d y partici pati o n; or s u bject has si g nifica ntl y i m paire d re nal f u ncti o n, i n t he o pi ni o n of t he 
i n vesti gat or, as e vi de nce d b y a n esti mate d gl o mer ular filtrati o n rate calc ulate d usi n g a pe diatric 
a p pr o priate f or m ula s uc h as t he Sc h wartz E q uati o n (Sc h wartz et al 2 0 0 9 ).
8. 
S u bject has a hist or y or la b orat or y e vi de nce of blee di n g or cl otti n g dis or ders or c o n diti o ns.
9. 
S u bject has a k n o w n or s us pecte d hist or y of alc o h olis m, marij ua na or illicit dr u g a b use or mis use 
wit hi n 2 years bef ore scree ni n g as e vi de nce d fr o m me dical hist or y or e vi de nce of t olera nce or p h ysical 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
2 3
M alli nc kr o dt
de pe n de nce bef ore t he first d ose of X A R T E MI S X R.
1 0. S u bject has s m o ke d or use d nic oti ne -c o ntai ni n g pr o d ucts wit hi n 6 m o nt hs pri or t o scree ni n g as 
e vi de nce d b y me dical hist or y.
1 1. S u bject has a hist or y of ps yc hiatric dis or ders, s uc h as maj or de pressi o n dis or der, a n xiet y dis or ders, or 
ps y c h otic dis or ders re q uiri n g h os pitalizati o n a n d/ or me dicati o n wit hi n 6 m o nt hs pri or t o scree ni n g. A 
hist or y  of atte nti o n deficit h y peracti vit y dis or der re q uiri n g me dicati o n is acce pta ble.
1 2. S u bject has a dia g n osis of e pile ps y or ot her seiz ure dis or der (a hist or y of fe brile seiz ures is acce pta ble).
1 3. S u bject has ha d pre vi o us car di ot h oracic s ur ger y (s u bjects w h o ha ve a hist or y of pate nt d uct us 
arteri os us li gati o ns/s ur ger y as i nfa nts are acce pta ble).
1 4. S u bject has a hist or y of c o n diti o ns w hic h mi g ht be s pecificall y c o ntrai n dicate d or re q uire ca uti o n w hile 
usi n g O C, A P A P, a n d/ or i b u pr ofe n (if use d as a resc ue me dicati o n) per t he I n vesti gat or Br oc h ure 
a n d/ or t he a p pr o priate pac ka ge i nsert.
1 5. S u bject has a hi st or y of a n y dr u g aller g y, h y perse nsiti vit y, or i nt olera nce i ncl u di n g O C, A P A P, 
i b u pr ofe n or e xci pie nts, or a n y o pi oi d dr u g pr o d uct w hic h, i n t he o pi ni o n of t he i n vesti gat or, w o ul d 
place t he s u bject at partic ular ris k a n d c o m pr o mise t he safet y of t he s u bje ct i n t he st u d y.
1 6. S u bject has d o nate d or ha d si g nifica nt l oss of w h ole bl o o d ( 4 8 0 m L or m ore) wit hi n 3 0 da ys of 
scree ni n g ( u nless t he y ha ve recei ve d a tra nsf usi o n t o c orrect t he bl o o d l oss a n d ha ve he mat ocrit a n d 
he m o gl o bi n wit hi n t he refere nce ra n ge at scr ee ni n g), or pla ns t o d o nate bl o o d or plas ma d uri n g t he 
c o urse of t he st u d y.
1 7. S u bject has a d oc u me nte d hist or y of a n y  pat h ol o gic, iatr o ge nic or s ur gical c o n diti o n  t hat, i n t he 
o pi ni o n of t he i n vesti gat or, w o ul d c o m pr o mise t he s u bject’s a bilit y t o s wall o w, a bs or b, meta b olize, or 
e xcrete X A R T E MI S X R, i ncl u di n g ( b ut n ot li mite d t o) i ntracta ble na usea a n d/ or v o miti n g, se vere 
gastr oi ntesti nal narr o wi n g, perf orati o n, o bstr ucti o n, blee d, or gastric ba n d s ur ger y.
1 8. S u bject has a hist or y of a GI e ve nt (e g, perf orati o n , o bstr ucti o n, blee d) wit hi n 6 m o nt hs pri or t o 
scree ni n g or a n y GI e ve nt greater t ha n 6 m o nt hs bef ore scree ni n g t hat, i n t he o pi ni o n of t he 
i n vesti gat or, w o ul d ma ke t he s u bject u ns uita ble f or st u d y partici pati o n.
1 9. S u bject has use d a n y pr o d uct c o ntai ni n g O C or A P A P wit hi n 4 8 h o urs pri or t o t he first d ose of 
X A R T E MI S X R.
2 0. S u bject has a hist or y of c o n diti o ns w hic h mi g ht be s pecificall y c o ntrai n dicate d or re q uire ca uti o n t o be 
use d d uri n g t he a d mi nistrati o n of A P A P or O C i ncl u di n g h y perse nsiti vit y t o O C, or de bil itate d 
patie nts, t h ose wit h se vere i m pair me nt of he patic, p ul m o nar y, or re nal f u ncti o n, m y xe de ma or 
h y p ot h yr oi dis m, a dre n oc ortical i ns ufficie nc y ( A d dis o n’s disease), ce ntral ner v o us s yste m ( C N S) 
de pressi o n or c o ma, t o xic ps yc h osis, uret hral strict ure, ac ut e alc o h olis m, deliri u m tre me ns, se vere 
k y p h osc oli osis, or biliar y tract d ysf u ncti o n.
2 1. S u bject has a n y ot her me dical c o n diti o n, a b n or mal vital si g n ( bl o o d press ure, p ulse rate, res pirat or y 
rate), b o d y te m perat ure, p ulse o xi metr y; or a n y p h ysical e xa mi nati o n or  E C G fi n di n g at scree ni n g 
w h ic h, i n t he i n vesti gat or’s me dical o pi ni o n, w o ul d precl u de safe partici pati o n i n a cli nical st u d y.
2 2. S u bject has recei ve d a n y i n vesti gati o nal pr o d uct or de vice wit hi n 3 0 da ys bef ore scree ni n g, or is 
sc he d ule d t o recei ve a n i n vesti gati onal de vice or a n ot her i n vesti gati o nal dr u g ( ot her t ha n t h ose i n t his 
st u d y) d uri n g t he c o urse of t his st u d y.
C o nc o mit a nt Me dic ati o ns: 
Treat me nt wit h t he f oll o wi n g me dicati o ns a n d t hera pies d uri n g t he st u d y are pr o hi bite d :
 
A n y  i n vesti gati on al dr u g, de vice a n d/ or e x peri me ntal t he ra p y ( pr ohi bite d wit hi n 3 0 da ys be for e 
scree ni n g or t hr o u g h o ut t he st u d y).
 
H or m o nal c o ntrace pti o n a n d h or m o nal re place me nt t hera pies are pr o hi bite d wit hi n 1 4 da ys 
pri or t o t he first d ose of X A R T E MI S X R a n d t hr o u g h o ut t he re ma i n der of t he st u d y.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
2 4
M alli nc kr o dt
 
A n y  me dicati o n t hat, i n t he o pi ni o n of t he i n vesti gat or, ma y ca use a cli nicall y si g nifica nt
c o n diti on w h e n  use d c o nc om itantl y wit h O C or A P A P is pr o hi bite d wit hi n 1 4 da ys pri or t o 
t he first d ose of X A R T E MI S X R a n d t hr o u g h o ut t he re mai n der of t he st u d y.
 
A n y  me dicati o n t hat is c o ntrai n dicate d(ie, pr eca uti o n e xists a gai nst c o nc om ita nt use, a n d/ or t he
p ote ntial e xists for a cli nicall ysi g nifica nt dr u g- dr u g i nt eractio n wit h X A R T E MI S X R) is pr o hi bite d 
wit hi n 1 4 da ys pri or t o t he first d ose of X A R T E MI S X R a n d t hr o u g h o ut t he re mai n der of t he st u d y. 
 
A n y  me dicati o n t hat is k n o w n t o m o deratel y t o str o n gl y i n hi bit or i n d uce C Y P 2 D 6 a n d/ or C Y P 3 A 4 
e nz ymes (see  Attac h me nt 2 ) is pr o hi bite d wit hi n 1 4 da ys pri or t o t he first d ose of X A R T E MI S X R a n d 
t hr o u g h o ut t he st u d y. T he use of C Y P2 D 6 a n d/ or C Y P 3 A 4 i n hi bit ors or i n d ucers is all o we d peri-
o perati vel y as nee de d.  
 
A n y  me dicati on c o ntai ni n g O C or A P A P is pr o hi bite d wit hi n 4 8 h o urs pr i or t o t he first d ose of 
X A R T E MI S X R a n d t hr o u g h o ut t he re mai n der of t he st u d y .
 
S u bject pai n s h o ul d be ma na ge d t o e ns ure t hat a n y s u p ple me ntal o pi oi d me dicati o n is n ot nee de d i n t he 
3 0 mi n utes pr i or t o eac h d ose of X A R T E MI S X R.
 
Treat me nt wit h t he o pti o nal resc ue me dicati o n (i b u pr ofe n) pr o vi de d will be all o we d d uri n g t he st u d y 
as nee de d ( 2 0 0 m g or 4 0 0 m g e ver y 4 t o 6 h o urs , ma xi m u m i n di vi d ual d ose of 1, 2 0 0 m g per 2 4 h o urs). 
I n vesti g ati o n al Me dici n al Pr o d uct a n d Resc ue Me dic ati o n A d mi nistr ati o n: 
X A R T E MI S X R ( 7. 5 m g O C H Cl / 3 2 5 m g A P A P ta blets).
All s u bjects will be treate d wit h 2 ta blets of X A R T E MI S X R e ver y 1 2 h o urs ( Q 1 2 h ) f or a ma xi m u m of 4 
d oses . 
O pti o nal r esc ue me dicati o n (i b u pr ofe n) will be s u p plie d f or use d uri n g t he st u d y as nee de d ( 2 0 0 m g or 
4 0 0 m g e ver y 4 t o 6 h o urs , ma xi m u m i n di vi d ual d ose of 1, 2 0 0 m g per 2 4 h o urs).
A d diti o nal a nal gesia or a dj u va nt t hera pies ma y be a d mi nistere d after t he first d ose of X A R T E MI S X R
acc or di n g t o t he i n vest i gat or’s cli nical practice. T hese t hera pies m ust n ot c o nflict wit h a n y of t he i ncl usi o n 
or  e xcl usi o n criteria or c o nc o mita nt me d icati o ns T hese a d diti o nal t hera pies m ust be a p pr o ve d b y t he 
me dical m o nit or a n d s p o ns or pri or t o st u d y start, if p ossi ble .
S afet y E v al u ati o n:
S u bject safet y will be m o nit ore d fr o m t he ti me t hat t he pare nt or le gal g uar dia n si g ns t he I C F a n d t he 
s u bject si g ns asse nt at scree ni n g ( u p t o 1 4 da ys bef ore d osi n g) t hr o u g h t he c o m pleti o n of t he f oll o w- u p 
tele p h one c o ntact f oll o wi n g t he last d ose of X A R T E MI S X R , or earl y ter mi nati o n. 
T he f oll o wi n g safet y assess me nts will be e val uate d: a d verse e ve nts ( A E), cli nical la b orat or y tests, vital 
si g ns, b o d y te m perat ure, p ulse o xi metr y, E C Gs, p h ysical e xa mi nati o ns, a n d i m paire d j u d g me nt e val uati o n.
P ai n I nte nsit y E v al u ati o n:
Pai n assess me nt s will be e val uate d usi n g s u bject re p orte d pai n i nte nsit y sc ores ( N P R S). T o be eli gi ble, a 
s u bject’s baseli ne N P R S sc ore m ust be ≥ 4. N P R S sc ores will be o btai ne d wit hi n 1 0 mi n utes pri or t o a n d at 
1, 2, 4, a n d 8 h o urs after t he first X A R T E MI S X R d ose. After t he first d ose of X A R T E MI S X R, pai n will 
be e val uate d usi n g t he N P R S pri or t o t he sc he d ule d X A R T E MI S X R d ose s at 1 2, 2 4, a n d 3 6 h o urs , if t he 
pai n sc ore is ≥ 4, t he s u bject will recei ve t he ne xt sc he d ule d d ose.
P h ar m ac o ki netics:
A p pr o xi matel y 2 m L of bl o o d will be c ollecte d i n prec hille d vac u u m bl o o d c ollecti o n t u bes, c o ntai ni n g 
K 2E D T A as t he a ntic oa g ula nt, f or deter mi nati o n of plas ma c o nce ntrati o ns of O C a n d A P A P per t he 
f oll o wi n g sc he d ule:
 
Wit hi n 1 0 mi n utes pri or t o t he first d ose of X A R T E MI S X R a n d at 1 5 a n d 4 5 mi n utes ( ± 5 mi n utes) ;
a n d 2, 4, 6, 8, 1 0, a n d 1 2 h o urs ( ± 1 0 mi n utes) after t he first d ose of X A R T E MI S X R . T he 1 2 -h o ur 
bl o o d dra w m ust be c o m plete d pri or t o t he a d mi nistrati o n of t he sec o n d d ose of X A R T E MI S X R.
 
Wit hi n 1 0 mi n utes pri or t o t he t hir d d ose of X A R T E MI S X R .
 
Wit hi n 1 0 mi n utes pri or t o t he f o urt h d ose of X A R T E MI S X R a n d
at 1 5 t o 3 0 mi n utes, 4 5 t o 9 0 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
2 5
M alli nc kr o dt
mi n utes , 2 t o 4 h o urs, a n d 6 t o 8 h o urs after t he f o urt h d ose of X A R T E MI S X R . I n a d diti o n, t he last 
sa m ple will be c ollecte d 1 2 t o 1 8 h o ur s after t he f o urt h d ose. If t he s u bject re q uires f urt her pai n 
me dicati o n after t he f o urt h d ose of X A R T E MI S X R, t he last bl o o d sa m ple will be c ollecte d at 1 2 h o ur s
( ± 1 0 mi n utes) after t he f o urt h d ose , b ut pri or t o t he ne xt d ose of pai n me dicati o n .
V ol u me : S u bjects will ha ve a n esti mate d ma xi m u m t otal of a p pr o xi matel y 5 0 m L of bl o o d dra w n d uri n g 
t he c o urse of t he st u d y, i ncl u di n g 3 2 m L f or P K sa m pli n g a n d 1 8 m L f or la b orat or y safet y assess me nts.
P h ar m ac o ki netic A n al ysis: 
Si n gle D ose P K ( No nc o m part me ntal A nal ysis ):
T he f oll o wi n g P K para meters will be deter mi ne d f or O C a n d A P A P f oll o wi n g t he first d ose (pre d ose at 0 t o
1 2 h o urs p ost d ose ):
 
Area u n der t he c o nce ntrati o n -ti me c ur ve o ver t he first d osi n g i nter val ( A U C 0- 1 2 h).
 
Ti me dela y bet wee n dr u g a d mi nistrati o n at H o ur 0 a n d t he o nset of a bs or pti o n (t l a g).
 
O bser ve d ma xi m u m dr u g c o nce ntrati o n ( C ma x ).
 
Ti me of ma xi m u m o bser ve d plas ma c o nce ntrati o n ( T ma x ).
 
A p pare nt ter mi nal eli mi nati o n half -life (t1/ 2
x).
 
A p pare nt ter mi nal eli mi nati o n rate c o nsta nt ( λ x ).
Si n gle/ M ulti ple D ose P K ( P o p ulati o n P K M o deli n g ):
F or t h ose s u bjects a d mi nistere d si n gle a n d/ or m ulti ple d oses of X A R T E MI S X R (≥ 2 d oses) , p o p ulati o n P K
a nal ysis will be perf or me d f or O C a n d A P A P .
P o p ulati o n P K a nal yses will be c o n d ucte d via n o nli near mi xe d effect m o deli n g usi n g t he n o nli near mi xe d-
effects m o deli n g s oft ware N O N M E M ® , Versi o n 7 or hi g her (
 
). A d ult P K data fro m X A R T E MI S -X R P hase 1 st u dies will be utilize d f or de vel o pi n g t he i nitial 
m o dels f or b ot h O C a n d A P A P . A c o variate a nal ysis will be u n derta ke n t o deter mi ne t he c o ntri b uti o n of 
de m o gra p hic a n d disease c haracteristics t o varia bilit y i n O C a n d A P A P P K . I n di vi d ual pre dicte d O C a n d 
A P A P P K para meters (cleara nce a n d v ol u me of distri b uti o n) a n d e x p os ure metrics (mi ni m u m plas ma 
c o nce ntrati o n at stea d y-state, t he pea k plas ma c o nce ntrati o n at stea d y state, t he a vera ge c o nce ntrati o n at 
stea d y-state, t he area u n der t he plas ma ti me c o nce ntrati o n c ur ve at stea d y-state a n d ot her para meters ) will 
be deri ve d fr o m t he fi nal m o del.
St atistic al Met h o ds:
T he f oll o wi n g p o p ulati o ns will be i de ntifie d a n d a nal yze d i n t his st u d y:
 
Safet y P o p ulati o n – all s u bjects e nr olle d i n t he st u d y t hat recei ve d a n y q ua ntit y of X A R T E MI S X R. 
T his p o p ulati o n will be use d as t he pri mar y safet y p o p ulati o n. 
 
P K P o p ulati o n - all s u bjects w h o recei ve d at least 1 d ose of X A R T E MI S X R a n d ha ve pr o vi de d at least 
1 bl o o d sa m ples f or t he meas ure me nt of O C a n d A P A P . T his p o p ulati o n will be use d t o f or p o p ulati o n 
P K a nal ysis.
 
Si n gle -d ose P K p o p ulati o n – All s u bjects w h o recei ve d at least o ne d ose of X A R T E MI S X R a n d ha ve 
pr o vi de d at least 6 bl o o d sa m ples f or meas ure me nt of O C a n d A P A P after t he first d ose of 
X A R T E MI S X R. T his p o p ulati o n will be use d f or si n gle -d ose P K a nal ysis.
 
M o difie d I nte nt -t o-Treat ( mI T T) P o p ulati o n – All s u bjects w h o recei ve d at least 1 d ose of X A R T E MI S 
X R a n d ha ve at least 1 p ost baseli ne pai n i nte nsit y meas ure me nt.
T his p o p ulati o n will be use d f or 
a nal ysis of pai n i nte nsit y.
Descri pti ve statistics will be pr o vi de d f or P K para meters . The mea n, S D , mi ni m u m, ma xi m u m, a n d me dia n 
will be prese nte d f or c o nti n u o us varia bles . Fre q ue ncies a n d perce nta ges will be prese nte d f or cate g orical 
varia bles. S tatistical met h o ds will be i ncl u de d i n t he statistical anal y sis p la n, w hic h will be de vel o pe d a n d 
fi nalize d pri or t o st u d y c o m pleti o n.
P h ar m ac o ki netic D at a A n al ysis :
P K para meter esti mati o n will be perf or me d usi n g t he act ual ela pse d ti mes fr o m d ose a d mi nistrati o n t o 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
2 6
M alli nc kr o dt
sa m ple c ollecti o n. I n di vi d ual plas ma O C a n d A P A P c o nce ntrati o ns will be s u m marize d at eac h n o mi nal 
ti m e p oi nt usi n g descri pti ve statistics. I n di vi d ual c o nce ntrati o n pl ots a n d mea n data gra p hs will be pr o d uce d 
usi n g b ot h li near a n d se mil o garit h mic scales.
S afet y A n al ysis :
S u bject A E s a n d w it h dra wals d ue t o A Es will be s u m marize d. C h a n ge fr o m baseli ne s u m maries will be 
prese nte d f or vital si g ns , te m perat ure, p ulse o xi metr y, a n d cli nical la b orat or y res ults. P h ysical e xa mi nati o n 
a n d E C G fi n di n gs will be prese nte d as a p pr o priate.
P ai n I nte nsit y A n al ysis :
S u bject -re p orte d N P R S pai n i nte nsit y sc ores, as well as pai n i nte nsit y sc ore c ha n ge fr o m baseli ne, will be 
p rese nte d descri pti vel y wit h s u m mar y statistics b y ti me p oi nt. N o i m p utati o n of missi n g val ues or 
a dj ust me nt fr o m t he i m pact of resc ue me dicati o n use will be use d.
S a m ple Size :
T he sa m ple size of 4 8 e nr olle d s u bjects is pla n ne d t o res ult i n at least 2 5 s u bjects t hat will recei ve 2 or m ore 
d ose s of X A R T E MI S X R ) f or safet y e val uati o n. I n or der t o e nr oll 4 8 s u bjects it is esti mate d t hat 7 2
i n di vi d uals will nee d t o be scree ne d.
Et hic al C o nsi der ati o ns:
T his st u d y will be c o n d ucte d i n acc or da nce wit h a p plica ble la ws a n d re g ulati o ns i ncl u di n g, b ut n ot li mite d 
t o, t he I C H G ui deli ne f or G C P a n d t he et hical pri nci ples t hat ha ve t heir ori gi ns i n t he Declarati o n of 
Helsi n ki. T he I R B m ust re vie w a n d a p pr o ve t he pr ot oc ol a n d i nf or me d c o nse nt f or m bef ore a n y s u bjects 
are e nr olle d. Bef ore a n y pr ot oc ol -re q uire d pr oce d ures are perf or me d, t he s u bject’s pare nt or le gal g uar dia n 
m ust si g n a n d date t he I R B a p pr o ve d i nf or me d c o nse nt f or m a n d t he s u bject m ust si g n a n I R B a p pr o ve d 
asse nt f or m.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
2 8
M alli nc kr o dt
C o n Me ds = C o nc o mita nt Me dicati o ns ; E C G = electr ocar di o gra m; E T = Earl y Ter mi nati o n ; h = h o urs ; I C F = i nf or me d c o nse nt f or m ; I nc/ E xc = I ncl usi o n/ E xcl usi o n Criteria ; m = 
mi n utes ; N P R S = N u merical Pai n Rati n g Scale ; P K = P har mac o ki netics
aWit hi n 1 4 da ys pri or t o t he first X A R T E MI S X R d ose. S u bjects w h o are ta ki n g pr o hi bite d me dicati o ns at t he ti me of scree ni n g m ust disc o nti n ue t heir use a n d c o m plete a was h o ut 
peri o d bef ore c hec k -i n.
bIt is acce pta ble t o c o m plete t he scree ni n g pr oce d ures o n t he sa me da y as t he c hec k-i n pr oce d ures. I n t his sit uati o n t he me dical hist or y re vie w, date of first da y of last me nstr ual 
peri o d, i ncl usi o n /e xcl usi o n criteria re vie w, p h ysical e xa m i nati o n, wei g ht, la b orat or y assess me nt, pre g na nc y test, a n d electr ocar di o gra m ( E C G) d o n ot nee d t o be re peate d if b ot h visits 
occ ur wit hi n 2 4 h o urs pri or t o d osi n g.
cH o ur 0 ( 0 h) is defi ne d as t he ti me of a d mi nistrati o n of t he first d ose of X A R T E MI S X R o n t he st u d y.
dT o b e c o m plete d via tele p h o ne c o ntact at 7 ( ± 2) da ys after t he last d ose of X A R T E MI S X R or earl y ter mi nati o n.
eDe m o gra p h y i ncl u des date of birt h, ge n der, race a n d et h nicit y.
fDetaile d me dical a n d s ur gical hist or y will be ta ke n at scree ni n g a n d c hec k -i n (if a pplica ble) a n d will i ncl u de t he s ur gical pr oce d ure re q uire d f or st u d y e ntr y.
gF or p ost me narc he fe male s u bjects.
hVital si g ns ( bl o o d press ure, p ulse, a n d res pirati o n rate) will be meas ure d at scree ni n g; c hec k-i n; wit hi n 1 5 mi n utes pri or t o t he first a n d f o urt h d oses of X A R T E MI S X R ; at 1, 2, a n d 
4 h o urs ( ± 1 5 mi n utes) after t he first a n d f o urt h d oses of X A R T E MI S X R ; wit hi n 1 5 mi n utes pri or t o a n d at 2 h o urs ( ± 1 5 mi n utes ) after t he sec o n d a n d t hir d d oses of X A R T E MI S 
X R; a n d at st u d y exit or earl y ter mi nati o n .
iB o d y  te m perat ure will be meas ure d at scree ni n g; c hec k-i n; wit hi n 1 5 mi n utes pri or t o t he first a n d f o urt h d oses of X A R T E MI S X R ; at 1, 2, a n d 4 h o urs ( ± 1 5 mi n utes) after t he first 
a n d f o urt h d oses of X A R T E MI S X R ; wit hi n 1 5 mi n utes pri or t o a n d at 2 h o urs ( ± 1 5 mi n utes) after t he sec o n d a n d t hir d d oses of X A R T E MI S X R; a n d at St u d y E xit or Earl y 
Ter mi nati o n . T he sa me met h o d of meas ure me nt will be use d f or all assess me nts f or a si n gle s u bject.
jPai n i nte nsit y will be e val uate d b y t he s u bject usi n g N P R S sc ores (Attac h me nt 3 ). T o be eli gi ble, a s u bject’s baseli ne N P R S sc ore m ust be ≥4. N P R S sc ores will be o btai ne d wit hi n 
1 0 mi n utes pri or t o a n d at 1, 2, 4, a n d 8 h o urs ( ± 1 5 mi n utes) after t he first X A R T E MI S X R d ose. After t he first d ose of X A R T E MI S X R , pai n will be e val uate d usi n g t he N P R S 
wit hi n 3 0 mi n utes pri or t o t he sc he d ule d ti me of eac h s u bse q ue nt X A R T E MI S X R d ose at 1 2, 2 4, a n d 3 6 h o urs . If t he pai n sc ore is ≥4 , s u bjects will recei ve t he ne xt sc he d ule d d ose 
as pla n ne d. If t he pai n sc ore is < 4 , t he N P R S will be re peate d e ver y 3 0 mi n utes ( ± 5 mi n utes) fr o m t he sc he d ule d ti me of d osi n g a n d s u bjects will recei ve t heir X A R T E MI S X R d ose 
w he n a n d if t heir pai n sc ore is ≥4 . T he pai n sc ores ca n be re peate d u p to 1 h o ur after t he sc he d ule d d osi n g ti me. S u bjects w h ose pai n sc ores re mai n < 4 d uri n g t his ti me will n ot 
q ualif y f or f urt her st u d y dr u g a d mi nistrati o n , b ut will still ha ve bl o o d c ollecte d f or P K a nal ysis at 1 0 mi n utes pri or t o t he ori gi nall y sc he d ule d d osi n g ti me. Su bjects are eli gi ble t o sta y 
i n t he st u d y a n d c o nti n ue t o ha ve all safet y assess me nts u ntil st u d y e xit , or ma y pr ocee d t o earl y ter mi nati o n assess me nts. Pai n assess me nts s h o ul d al wa ys be c o m plete d pri or t o a n y 
ot her pr oce d ures f or a gi ve n per i o d.
kPerce nta ge of o x y ge n sat urati o n will be deter mi ne d b y a si n gle p ulse o xi metr y rea di n g at scree ni n g, c hec k-i n, a n d st u d y exit or earl y ter mi nati o n. C o nti n u o us p ulse o xi metr y will be 
i nitiate d wit hi n a p pr o xi matel y 1 5 mi n utes pri or t o t he first X A R T E MI S X R d ose a n d c o nti n ue u ntil 1 2 h o urs after t he f o urt h X A R T E MI S X R d ose or earl y ter mi nati o n . I n a d diti o n, 
perce nt of o x yge n sat urati o n will be rec or de d wit hi n 1 5 mi n utes pri or t o a n d 1, 2, a n d 4 h o ur s after t he first a n d f o urt h d oses of X A R T E MI S X R; a n d wi t hi n 1 5 mi n utes pri or t o a n d 2 
h o urs ( ± 1 5 mi n utes) after t he sec o n d a n dt hir d d oses of X A R T E MI S X R.
lBl o o d a n d uri ne sa m ples f or cli nical la b orat or y testi n g will be c ollecte d at scree ni n g, c hec k -i n (if a p plica ble), a n d st u d y e xit or earl y ter mi nati o n.
m B l o o d sa m ples f or P K a nal ysis will be c ollecte d wit hi n 1 0 mi n utes pri or t o t he first d ose of X A R T E MI S X R; at 1 5 a n d 4 5 mi n utes ( ± 5 mi n utes) a n d at 2, 4, 6, 8, 1 0, a n d 1 2 h o urs 
( ± 1 0 mi n utes) after t he first d ose of X A R T E MI S X R. T he 1 2 h o ur p ost d ose sa m ple will be c ollecte d pri or t o a d mi nistrati o n of t he sec o n d d ose of X A R T E MI S X R. A d diti o nal bl o o d 
sa m ples f or P K a nal ysis will be c ollecte d wit hi n 1 0 mi n utes pri or t o a d mi nistrati o n of t he t hir d a n d f o urt h d oses of X A R T E MI S X R; at 1 5 t o 3 0 mi n utes, 4 5 t o 9 0 mi n utes , 2 t o 4 
h o urs, a n d 6 t o 8 h o ur s after t he f o urt h d ose of X A R T E MI S X R. I n a d diti o n, if f urt her pai n me dicati o n is n ot re q uire d a fi nal sa m ple will be c ollecte d at 1 2 t o 1 8 h o ur s after t he f o urt h 
d ose . If t he s u bject re q uires f urt her pai n me dicati o n, t he fi nal sa m ple s h o ul d be c ollecte d at 1 2 h o ur s ( ± 1 0 mi n utes) after t he f o urt h d ose, b ut pri or t o t he ne xt d ose of pai n me dicati o n .

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
2 9
M alli nc kr o dt
nX A R T E MI S X R will be d ose d e ver y 1 2 h o urs. T he first d ose of X A R T E MI S X R is defi ne d as H o ur 0. T he sec o n d, t hir d, or f o urt h d oses ma y be dela ye d b y u p t o 1 h o ur ( + 1 5
mi n utes) if t he s u bject’s N P R S sc ore is < 4 . If a n y d ose is s o dela ye d, s u bse q ue nt d oses will be gi ve n at t he ori gi nall y sc he d ule d ti me u nless dela ye d b y a n N P R S sc ore of < 4.
S u bjects will s witc h t o t he sta n dar d of care pai n me dicati o n if re q uire d f or f urt her treat me nt of pai n after t he f o urt h d ose of X A R T E MI S X R.
oAl l a d verse e ve nts t hat occ ur fr o m t he ti me of t he si g ni n g of t he i nf or me d c o nse nt will be rec or de d i n s o urce d oc u me nts. A d verse e ve nts will als o be rec or de d i n t he electr o nic case 
re p ort f or m (e C R F) f or all s u bjects w h o recei ve a n y d ose of X A R T E MI S X R. All me dicati o ns ta ke n wit hi n t he 3 0 da ys pri or t o scree ni n g a n d t hr o u g h o ut t he st u d y will be rec or de d, 
i ncl u di n g all peri-o perati ve a n d o perati ve treat me nts.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3 0
M alli nc kr o dt
8
E T HI C A L  C O N SI D E R ATI O N S
T his cli nical st u d y  is desi g ne d t o c o m pl y with I C H G ui da nce o n Ge neral C o nsi derati o ns f or 
Cli nical Trials ( 6 2 F R 6 6 1 1 3 , 1 7 Dec 1 9 9 7), N o ncli nical Safet y St u dies f or t he C o n d uct of 
H u m a n Cli nical Trials a n d Mar ket i n g A ut h ority f or P har mace ut icals ( 7 5 F R 3 4 7 1, 2 1 Ja n 
2 0 1 0), a n d G o o d Cli nical Practice: C o ns o li date d G ui da nce ( 6 2 F R 2 5 6 9 2, 0 9 Ma y  1 9 9 7).
8. 1
I nstit uti o n al Re vie w B o ar d
It is t he res p o nsi bilit y of  t he in vest i gat or t o o btai n t he a p pr o val of t he I R B bef ore t he start of 
t he st u d y. T he I R B m ust be re gistere d a n d acti ve with t he Office f or H u ma n Researc h 
Pr otecti o ns of t he U S De part me nt of Healt h a n d H u ma n Ser vices. A c o p y of t he ap pr o val  
letter al o n g with a r oster of I R B me m bers a n d/or t he U S De part m e nt of Healt h a n d H u ma n 
Ser vices ge neral ass ura nce n u m ber will be retai ne d as part of t he st u d y  rec or ds. D uri n g t he 
c o urse of t he st u d y, t he i n vesti gat or will pr o vi de ti mel y a n d acc urat e re p orts t o t he I R B o n t he 
pr o gress of t he st u d y  at a p pr o priate i nter vals ( n ot t o e xcee d 1 year) a n d at t he c o m plet i on of 
t he st u d y. T he i n vesti gat or will n otif y t he I R B of seri o us a d verse e ve nts ( S A Es) or ot her 
sig nifica nt s a fety fi n di n gs per I R B g ui deli nes . T he st u d y pr ot oc ol, i nf or me d c o nse nt f or m 
(I C F), a d vertise me nts (if a n y), a n d a me n d me nts (if a n y) will be a p pr o ve d b y t he I R B i n 
c o nf or ma nce wi t h C F R, Tit le 2 1, Part 5 6 .
8. 2
Et hic al C o n d uct of t he St u d y
T he st u d y  will be c o n d ucte d i n f ull c o m plia nce wit h a p plica ble U S F D A re g ulat i ons a n d I C H 
g ui deli nes f or G C P a n d i n acc or da nce wit h t he et hical pri nci ples t hat ha ve t heir ori gi ns i n t he 
Declarati o n of Helsi n ki.
8. 3
S u bject I nf or m ati o n a n d C o nse nt
T he I C F m ust be a p pr o ve d b y  t he s p o ns or a n d t he I R B bef ore a n y s u bjects pr o vide c o nse nt.
At  t he scree ni n g visit , s u bjects will rea d t he I C F a n d a Healt h I ns ura nce P orta bility a n d 
Acc o u nta bilit y Act ( HI PA A) a ut h orizat i on f or m (if a p plica ble) after bei n g gi ve n a n 
e x pla nat i on of t he st u d y. Before si g ni n g t he I C F a n d t he H I PA A a ut h orizati o n f or m (if 
a p plica ble), s u bjects will ha ve a n o p p ort u nit y t o disc uss t he c o nte nts of t hese f or ms wit h st u d y 
sit e staff. 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3 1
M alli nc kr o dt
S u b jects must asse nt u n dersta n di n g of a n d v o l unt aril y si g n t hese f or ms i n c o m p lia nce wit h 2 1 
C F R , Parts 5 0 a n d 3 1 2, bef ore parti c i pati n g i n a n y st u d y-r elate d pr oce d ures. S u bjects will be 
ma de a ware t hat t he y  ma y wit hdra w fr o m  t he stu d y at a n y time. S u bjects u na ble t o gi ve 
wri tte n i nf or me d c o nse nt must orall y asse nt t o t he pr oce d ures , a n d writte n i nf or me d c o nse nt 
m ust be o btai ne d fr o m a le gall y a ut h orize d re prese ntati ve i n acc or da nce wit h state la ws , as 
a p plica ble.
T he I C F m ust c o ntai n all a p plica ble ele me nts o f i nf or me d c o nse nt a n d t he ma n dat or y 
state me nts as defi ne d i n t he C F R a n d a HI PA A  a ut h orizat i on f or m. Sig ne d c o pi es o f t he I C F 
a n d t he HI PA A  a ut h orizat i on f or m, if a p plica ble, will be gi ve n t o t he s u bject. 
T he s u bject will be ma de a ware of his/ her ri g ht t o see a n d c o p y  his/ her rec or ds relate d t o t he 
st u d y for as l o n g as t he i n vest i gat or has p ossessi o n of t his i nf or mati o n. If t he s u bject 
wi t hdra ws c o nse nt a n d/ or HI PA A  a ut h orizat i on, t he i n vest i gat or ca n n o l o n ger discl ose healt h 
i nf or mat i on, u nless it is ne e de d t o preser ve t he scie nt ific i nte grit y of t he st u d y.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3 2
M alli nc kr o dt
9
B A C K G R O U N D I N F O R M A TI O N A N D R A TI O N A L E
9. 1
O ver vie w
X A R T E MI S ® X R (M N K - 7 9 5, for m erl y k n o w n as C O V 7 9 5 ) is a n o vel oral a nal gesic t hat was 
rece ntl y a p pr o ve d b y t he F D A for t he ma na ge me nt of ac ute pai n se vere e n o u g h t o re q uire 
o pi oi d treat m e nt a n d f or w hic h alter nati ve treat me nt o ptio ns are i na de q uate i n a d ults
(X A R T E MI S X R Pac ka ge I nsert [ PI] 2 0 1 4 ). X A R T E MI S X R is a c o ntr olle d-r elease 
c o m bi nat i on 7. 5 m g o x yc o d o ne ( O C ) H Cl /3 2 5 m g aceta mi n o p he n ( A P A P ) t hera p y. U n der t he 
Pe di atric Researc h E q uit y Act  ( P R E A), the F D A  has t he a ut h ority t o re q uire pe diatric st u dies 
o n a n a p pr o ve d dr u g pr o d uct if t here is s u bsta nt ial use e x pecte d i n t he pe diatric p o p ulati o n or 
t he pr o d uct w o ul d pr o vi de a mea ni n gf ul t hera pe ut ic be nefit a n d t he a bse nce of a de q uate 
la beli n g c o ul d p ose sig nifica nt ris k. T his st u d y, pla n ne d f or a n a d olesce nt ( 1 2 t o 1 7 years of 
a ge) p o p ulatio n, is t he i ni tial X A R T E MI S X R cli nical i n vest i gati on bei n g c o n d ucte d i n t he 
pe di atric p o p ul at i on t o sati sf y t he P R E A.
X A R T E MI S X R is t he first F D A  a p pr o ve d oral a nal gesic c o m bi nat i on i n dicate d f or ac ute pai n 
w hic h i nc or p orate s a n i m me diate-release (I R) a n d e xte n de d-r elease ( E R) pr ofile of b ot h acti ve 
p har mace ut ical i n gre die nts i nt o a si n gle pr o d uct e ntit y. C o m bi ni n g a nal gesic a ge nts wit h 
differe nt mec ha nis ms o f act i on off ers a mul tim o d al  a p pr oac h t o t hera p y, wit h at least a d ditive 
a nal gesic effects, l o wers t he o verall d ose of eac h acti ve p har mace ut ical i n gre die nt (A PI ), a n d 
mi ni mizes si de effects (A G S 2 0 0 2 , Bar ki n 2 0 0 1 , Bea ver 1 9 8 1 , Bea ver 1 9 8 4 , Bea ver 1 9 8 8 , 
Gas kell et al 2 0 0 9, Raffa 2 0 0 1 ).
T he A merica n Pai n S ociet y states t hat t he i ntr o d uctio n of  E R a nal gesics is a n i m p orta nt 
i n n ovat i on i n t he ma na ge me nt of pai n (A merica n Pai n S ociet y 2 0 0 8 ). E xte n de d -r elease 
pre parati o ns pr o vi d e m ore c o nsiste nt plas ma c o nce ntrati o ns f or better c o ntr ol of e n d of d ose 
pai n a n d r e d uce d brea kt hr o u g h me dicat i on usa ge, w hile a d dit i onall y o fferi n g t he c o n ve nie nce 
of  less fre q ue nt d osi n g c o m pare d t o I R pre parati o ns (Mc Car ber g a n d Bar ki n 2 0 0 1 ). Als o, 
re d uce d fre q ue nc y of d osi n g is k n o w n t o i ncrease patie nt co m plia nce (Ar o ns o n a n d Har d ma n 
1 9 9 2 , Mc Car ber g a n d Bar ki n 2 0 0 1 ).
Malli nc kr o dt desi g ne d a fi xe d -d ose, o pi o i d/n o n o pi oi d, a n d “bi p hasic” d ual -release, I R/ E R 
a nal gesic pr o d uct ( X A R T E MI S X R ) c o ntai ni n g O C H Cl  a n d A PA P f or t he ma na ge me nt of 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3 3
M alli nc kr o dt
ac ute pai n. T he pr o d uct utilizes De p o me d ’s Ac u F or m ™ gastr orete nti ve ( G R) dr u g deli ver y 
tec h n ol og y (X A R T E MI S X R Pac ka ge I nsert [ PI] 2 0 1 4 ). Gastr orete nti ve tec h n ol o g y tar gets 
t he release of  t he A PI i n t he u p per gastr oi ntesti nal ( GI) tract o ver a n e xte n de d peri o d, ie, 6 t o 
1 0 h o urs, t o pr o d uce a n e xte n de d d urati o n of acti o n (Gl u metza ® PI 2 0 1 1 , Gralise ® PI 2 0 1 2 , 
Pr o q ui n X R ® PI 2 0 1 1 ). X A R T E MI S X R is a m ult ila yer I R/ E R O C H Cl / AP A P G R , 1 2 h o ur 
or al  a nalgesic ta blet w hi c h see ks t o e n ha nce t he p har m ac o ki net ic (P K ) perf or ma nce, 
effecti ve ness, t olera bility a n d safet y of  I R O C H Cl / A PA P (e g, Perc ocet ® 7. 5 m g O C/ 3 2 5 m g 
A P A P , w hic h is t ypicall y d ose d e ver y  4 t o 6 h o urs) (Perc ocet PI 2 0 1 3 ). T he G R deli ver y 
s yste m als o c o n ve ys p ote nti al a b use -deterre nt pr o perties t o t he pr o d uct (M N K - 7 9 5
I n vesti gat or’s Br oc h ure [I B] 2 0 1 4 ).
X A R T E MI S X R pr o vi des a nal gesia w he n ta ke n as 2 ta blets ( 1 5 m g O C H Cl / 6 5 0 mg A PA P 
per d ose) e ver y  1 2 h o urs ( Q 1 2 h), res ulti n g i n a ma xi m u m dail y d ose of  3 0 mg of  O C H Cl a n d 
1, 3 0 0 m g of A P A P i n a d ults. T he c om bi nat i on of O C a n d A PA P ta kes a d va nta ge of t he 
differe nt mec ha nis ms o f act i on of t he 2 dr u gs, ie, t he n ocice pti ve mec ha nis m of act i on ( of 
O C) a n d a ce ntrall y  me diate d a nal gesic mec ha nis m ( o f A PA P) (Des me ules et al 2 0 0 3 ). T he 
f or mulat i on is desi g ne d t o reac h t hera pe utic le vels of b ot h o pi oi d a n d n o n o pi oi d dr u gs q uic kl y 
( wit hi n 1 h o ur) t hr o u g h t he I R la yer c o m p o ne nt, wit h s ustai ne d a nal gesia o ver t he d osi n g 
i nter val ( 1 2 h o urs) d ue t o t he E R la yer c o m p o ne nt (M N K - 7 9 5 I B 2 0 1 4). F urt her m ore, t he 
X A R T E MI S X R f or mulat i on i nc or p orates rece nt rec o m me n dati o ns of  t he U S F D A li miti n g 
t he t otal A PA P d ose per ta blet t o 3 2 5 m g, i ncreasi n g c o nfi de nce i n t he safet y of  t his 
f or mulat i on (Fe deral Re gister N otice 2 0 1 1 ). X A R T E MI S X R levera ges t he c o mf ort t hat 
p h ysicia ns alrea d y  ha v e wit h t hese well-u n derst o o d a n d st u die d A PIs, w hile als o pr o vi di n g a 
pr o d uct t hat is m ore c o n ve nie nt l y d ose d.
O x yc o d o ne is a se mis y nthet ic p ure o pi oi d a g o nist w h ose pri nci pal t hera pe utic acti on is 
a nal gesia. Ot her p har mac o l ogi c al effects of O C i ncl u de a n xi ol ysis, e u p h oria a n d feeli n gs of 
r ela xat i on. T hese effects are me diate d b y rece pt ors ( n ota bl y µ a n d κ) i n t he ce ntral ner v o us 
s yste m for e n d o ge n o us o pi o i d-li ke c o m p o u n ds s uc h as e n d or p hi ns a n d e n ke p hali ns. 
O x yc o d o ne pr o d uces res pirat or y  de pressio n  t hr o u g h direct acti vit y at res pirat or y ce nters i n t he 
brai n ste m  a n d de presses t he c o u g h refle x b y a direct effect o n t he me d ulla. O x yc o d o ne als o 
re d uces GI m otility,  increases ureteral a n d bla d der s p hi ncter , a n d s p hi ncter of O d di t o ne, a n d 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9  J u ne  2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3 4
M alli nc kr o dt
i n d uces t he release of hista mi ne w hic h ca uses pr urit us, fl us hi n g, a n d s weati n g (M N K -7 9 5  I B 
2 0 1 4 , Perc ocet ®  PI 2 0 1 3 ).
Oral  a d mi nistratio n of  c o n ve nti onal I R O C pr o d ucts pr o d uces a n a nal gesic effect wit hi n a n 
h o ur of d osi n g w hic h persists f or 3 t o 6 h o urs  (A H F S 2 0 0 4 ). Mea n a bs o l ute oral 
bi oa vaila bilit y of  O C is a p pr o xi matel y 8 5 %. O x yc o d o ne is 4 5 % b o u n d t o h u ma n plas ma 
pr otei ns i n vitr o, wit h a n a p pare nt v ol u me of distri b ut i on after i ntra ve n o us a d mi nistrati o n of 
2 1 1. 9 ± 1 8 6. 6 liters (M N K -7 9 5  I B 2 0 14 , Perc ocet PI 2 0 1 3 ). Ox yc o d o ne is meta b olize d 
t hr o u g h c yt oc hr o me P 4 5 0  o xi dat i on a n d U D P -gl uc ur o n os yl tra nsferase c o nj u gati on 
( gluc ur o ni dat i on). T he meta b o lic pat h wa y of OC (C ol u z zi  a n d Mattia 2 0 0 5 ) is s h o w n i n 
Fi g ure 9 - 1.
Fi g ur e 9- 1 : O x yc o d o ne He p atic Met a b olis m
T he m ajor m eta b o lic pat h wa y ( b ol d arr o ws) of O C is b y N-deal k ylat i on t o f or m 
n or o x y c o d o ne b y C Y P 3 A 4, w hile n or o x yc o d o ne is f urt her meta b olize d t o n or o x y m or p h o ne 
b y C Y P 2 D 6. T he mi n or meta b o lic pat h wa y ( narr o w arr o ws) is b y O-d e m et h ylat i on t o f or m 
o x y m or p h o ne b y C Y P 2 D 6, a n d 6 -ket o re d ucti o n of O C t o α- a n d β- o x y c o d ol. O x y mor p h o ne 
is f urt her meta b olize d t o n or o x y m or p h o ne b y C Y P 3 A4 or c o nj u gate d t o f or m 
o x y m or p h o ne - 3-gl uc or o ni de  (C ol u z zi  a n d Mattia 2 0 0 5). 
A p pr o xi matel y  8 % t o 1 4 % of t he d ose of O C is e xcrete d in uri ne u nc ha n ge d ( o ver 2 4 h o urs). 
T he m eta b o lites of O C a n d t heir c o nj u gates are als o e xcrete d pri nci pall y i n t he uri ne. T he 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3 5
M alli nc kr o dt
a p pare nt eli mi nat i on half -life f oll owi n g oral  a d mi nistratio n of  a si n gle I R d ose of O C is 
3. 5 ± 1. 4 3 h o urs (A H F S 2 0 0 4 , Perc ocet PI 2 0 1 3 ).
Aceta mi n o p he n is a n o n o piate, n o nsalic ylate a nal gesic, a n d a nti p yret ic a ge nt. T he site a n d 
mec ha nis m o f a nal gesic effect of A PA P has n ot bee n deter mi ne d. T he a nt i pyr etic effect of 
A P A P is acc om p lis he d t hr o u g h t he i n hi biti on of e n d o ge n o us p y r o ge n acti on o n t he 
h y p ot hal a mic heat -re g ulatin g ce nters (Perc ocet PI 2 0 1 3 ).
T he a bs or pti o n of A P A P is ra pi d a n d al m ost c o m plete fr o m t he GI tract after oral 
a d mi nistrati o n. Aceta mi n o p he n is u nif or ml y  distri b ute d t hr o u g h o ut m ost b o d y fl ui ds. Bi n di n g 
of  AP A P t o plas ma pr otei ns is varia ble. T he meta b ol ic pat h wa y for A P A P (Presc ott 2 0 0 1 ) is 
s h o w n i n Fi g ure 9 - 2. T he pri mar y meta b o lic pat h wa y for A P A P is he patic c o nj u gati o n. A b o ut 
8 0 % t o 8 5 % of t he d ose of A PA P is c o nj u gate d, pri nci pall y wit h gl uc ur o nic acid 
( gluc ur o ni dat i on), a n d t o a l esser e xte nt wit h s ulf uric acid a n d c ystei ne. After he pat ic 
c o nju gat i on, 9 0 % t o 1 0 0 % of A P A P is rec o vere d i n t he uri ne wit hi n 2 4 h o urs (Perc ocet PI 
2 0 1 3 ).
Less t ha n 5 % of A P A P is meta b o lize d b y t he C Y P P 4 5 0 pat h wa y ( C Y P 3 A 4 a n d C Y P 2 E 1) t o 
N- acet yli mi d o q ui n o ne ( N A P QI). N-acet yli mi d o q ui n o ne is a t o xic i nter me diate meta b olite 
w hic h is i m me diatel y i nact i vate d b y c o nj u gati on wi t h glutat hi o ne, prese nt i n a fi nite a n d fi xe d 
a mo u nt. It i s belie ve d t hat N A P QI is res p o nsi ble f or li ver i nj ur y a n d necr osis. At  hig h d oses, 
t he ca pacit y of  meta b olic pat h wa ys f or A P A P c o nj u gati o n wit h gl uc ur o nic aci d a n d s ulf uric 
acid ma y  be e xcee de d, res ultin g i n i ncrease d meta b o lis m of A PA P b y alter nate pat h wa ys
(Presc ott 2 0 0 1) .
Ac ute a n d c hr o nic e xcessi vel y hi g h d oses of A P A P ma y de plete t he q ua ntit y- c o nstrai ne d 
gl ut at hi o ne st ores, res ult i n g i n a re d ucti o n of N A P QI i nacti vati on a n d t h us i ncrease d ris k o f 
de vel o pi n g se vere dr u g -i n d uce d li ver i nj ur y ( DI LI) (F D A  G ui da nce f or I n d ustr y 2 0 0 9, 
Wa t ki ns et al 2 0 0 6). F or t his reas o n, t he F D A  has iss ue d se veral rec om me n dat i ons 
s urr o u n di n g safe use of A PA P -c o ntai ni n g pr o d ucts, i ncl u di n g li mit i n g t he ma xi m u m am o u nt 
of  AP A P per ta blet t o 3 2 5 m g (Fe deral Re gister N otice 2 0 1 1 ).

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9  J u ne  2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3 6
M alli nc kr o dt
Fi g ur e 9- 2 : Acet a mi n o p he n He p atic Met a b olis m
T he P K pr ofile of O C a n d A P A P c o m bi nat i ons ha ve bee n re p orte d i n n u mer o us st u dies of I R 
pr o d ucts, a n d Malli nc kr o dt has c o n d ucte d se veral P hase 1 P K st u dies of X A R T E MI S X R  a n d 
I R O C/ A PA P  (M N K -7 9 5  I B 2 0 14 , Malli nc kr o dt Cli nical St u d y Re p ort ( C S R) 2 0 1 2a , 
Malli nc kr o dt C S R 2 0 1 2 b , Malli nc kr o dt  C S R 2 0 1 2c ). T hese pre vi o us P hase 1 P K st u dies were 
c o n d ucte d wit h X A R T E MI S X R  (at vari o us O C/ A PA P m g a m o u nts) usi n g Perc ocet as t he 
c o mparat or i n t he a d ult p o p ulati o n acr oss t he cli nical de vel o p me nt pr o gra m. Si nce Perc ocet 
was n ot a p pr o ve d b y t he F D A  u n der a Ne w Dr u g A p plicat i on ( N D A ), b ut rat her a n 
A b bre viate d Ne w Dr u g A p plicat i on ( A N D A), t he A ge nc y re q uire d Malli nc kr o dt t o st u d y  
X A R T E MI S X R  wit h t he N D A a p pr o ve d liste d dr u gs ( L Ds) R o xic o d o ne ®  ( 1 5 mg) a n d 
Ul tracet®  ( 3 7. 5 m g tra ma d ol/ 3 2 5 m g A PA P)  as c o m parat ors . 
St u di es ha ve i n vest i gate d t he P K, bi oa vaila bility a n d safet y of  si n gle a n d mul tiple d oses of 
X A R T E MI S X R  c o m pare d wit h t he L Ds R o xic o d o ne ( 1 5 m g) a n d Ultracet ( 3 7. 5 m g 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3 7
M alli nc kr o dt
tr a ma d o l/ 3 2 5 m g A PA P), a n d Perc ocet ( 7. 5 m g O C H Cl / 3 2 5 m g A P A P), as well as t he effect 
of  fo o d o n t he P K of X A R T E MI S X R . X A R T E MI S X R d oses ra n ge d fr o m 7. 5 m g O C
H Cl / 3 2 5 m g A P A P t o 3 0 m g O C H Cl / 1, 3 0 0 mg A PA P . Total  d ose n or malize d e x p os ure t o O C 
a n d A PA P ( 2 ta blets X A R T E MI S X R [ 7. 5 mg O C H Cl / 3 2 5 m g A P A P]) f o ll owi n g a si n gle 
d ose ( area u n der t he c o nce ntrati o n -ti me c ur ve [A U C ]) or d uri n g t he d osi n g i nter val at stea d y 
state ( A U C0- 1 2 h
ss) were e q ui vale nt t o R o xic o d o ne or Ultracet a n d Perc ocet (Malli nc kr o dt C S R 
2 0 1 2 d , Malli nc kr o dt C S R 2 0 1 2e ). I n a m ulti ple d ose st u d y, t he de gree of fl uct uati o n ( D F L) 
c o mpari n g o bser ve d ma xi m u m dr u g c o nce ntrati o n ( Cma x
ss) t o o bser ve d mi ni m u m dr u g 
c o nce ntrati o n ( Cmi n
ss) wi t h res pect t o a vera ge c o nce ntrati o n ( C a v g
ss) f or O C, was e q ui vale nt t o 
R o xi c o d o ne a n d 2 3 % less f or X A R T E MI S X R t ha n f or Perc ocet (Malli nc kr o dt C S R 2 0 1 2 d ).
T he D F L  for A P A P was e q ui vale nt t o Ultracet a n d Perc ocet. B ot h O C a n d A P A P fr om 
X A R T E MI S X R acc u m ulate d t o t he sa me e xte nt as f or R o xic o d o ne, Ultracet a n d Perc ocet. 
Ma xi m u m plas ma c o nce ntrati o ns o f O C a n d A P A P were ge nerall y o bser ve d at a b o ut 3 h o urs
a n d 0. 7 5 ho urs p ost d ose, res pecti vel y. F ollo wi n g si n gle a n d m ul tiple d oses of 2 ta blets of 
X A R T E MI S X R ( 7. 5 m g O C/ 3 2 5 m g A PA P), a vera ge ma xi m u m dr u g c o nce ntrati o n ( C ma x )
val ues of a b o ut 1 6 n g/ m L  a n d 2 5 n g/ m L for O C a n d 5, 0 0 0 n g/ m L  a n d 5, 3 0 0 n g/ m L for A P A P 
were c o nsiste ntl y o bser ve d. I nters u bject variat i on was mi ni mal ( perce nta ge c oefficie nt of 
variat i on [ % C V]
2 0 % t o 3 0 %) f or X A R T E MI S X R a n d si milar t o t hat o bser ve d f or t h e L Ds 
a n d Perc ocet. D o se n or m alize d C ma x f or O C f oll owi n g si n gle a n d m ult i ple d oses of 2 ta blets 
of  X A R T E MI S X R ( 7. 5 m g O C/ 3 2 5 m g A PA P) were e q ui vale nt t o t he L D, R o xic o d o ne, a n d 
C ma x f or A P A P was e q ui vale nt t o t he L D, Ultracet, as well as Perc ocet. As e x p ecte d fr o m a n 
E R ta blet, O C C ma x f oll owi n g a si n gle d ose of X A R T E MI S X R was ge nerall y a b o ut 1 0 % 
l ower t ha n R o xic o d o ne a n d 2 0 % l o wer t ha n Perc ocet. Plas ma O C c o nce ntrati o ns fr o m 
X A R T E MI S X R platea ue d o ver t he 1 2 h o ur d osi n g i nter val a n d A PA P le vels were belo w 
1, 0 0 0 n g/ m L b y 1 0 t o 1 2 h o urs p ost d ose, as desire d. T he a p pare nt eli mi nat i on half -life (t 1/ 2)
f or O C ( 4 t o 6 ho urs ) a n d t he half-life f or A P A P ( 5 t o 7 h o urs ) were si milar bet wee n 
X A R T E MI S X R a n d I R pr o d ucts ( R o xic o d o ne or Ultracet a n d Perc ocet); i n dicat i n g c om p lete 
a bs or ptio n of  O C a n d A PA P fr om t he E R ta blet, X A R T E MI S X R , b y 1 2 h o urs after d osi n g.
F o o d has n ot bee n pre vi o usl y  re p orte d t o ha ve a si g nifica nt effect o n t he A U C o f O C, t h o u g h 
pea k pl as ma c o nce ntrati o ns are t ypicall y i ncrease d b y  a p pr o xi mately 2 5 % after I R a n d E R O C 
pr o d uct a d mi nistrati o n wit h a hi g h -fat me al c o mpare d t o t he fasti n g state (A H F S 2 0 0 4 ).
M ul tiple st u di es ha ve i n vest i gate d t he i m pact of diet u p o n t he safety a n d P K of X A R T E MI S 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3 8
M alli nc kr o dt
X R (M N K - 7 9 5 I B 2 0 14 ). A hi g h - or l o w -fat brea kfast di d n ot affect t he t otal e x p os ure ( A U C) 
o bser ve d wit h O C a n d A PA P fr o m X A R T E MI S X R (Malli nc kr o dt C S R 2 0 1 2c ). Pea k 
e x p os ure o bser ve d wit h O C fr o m X A R T E MI S X R a d mi nistere d to s u bj ects fe d a hi g h-fat 
meal was n ot si g nifica nt l y differe nt fr om C ma x w he n X A R T E MI S X R was a d mi nistere d u n der 
fasti n g c o n diti ons , b ut a 2 5 % i ncrease i n mea n pea k e x p os ure was o bser ve d w he n s u bjects 
were d ose d wit h X A R T E MI S X R aft er a lo w -fat meal. A 2 4 % a n d 2 3 % decrease i n mea n pea k 
e x p os ure was o bser ve d wit h A PA P i n s u bjects u n der fe d c o n diti ons ( hi g h - a n d l o w-f at meals, 
res pecti vel y) c o mpare d t o faste d, res pecti vel y. T hese differe nces are n ot cli nicall y si g nifica nt 
a n d X A R T E MI S X R ca n be a d mi nistere d w ith or wit h o ut f o o d. 
I n st u dies wit h R o xic o d o ne a n d Ultracet as t he L Ds t he d ose-n or malize d area u n der t he 
c o nce ntrati o n-ti me c ur ve fr om ti me zer o t o i nfi nity ( A U C 0- i nf), area u n der t he c o nce ntrati o n -
ti me c ur ve o ver t he d osi n g i nter val A U C 0- 1 2 h
ss, a n d Cma x
ss, Cmi n
ss, a n d Ca v g
ss of  O C for 
X A R T E MI S X R were e q ui vale nt t o t h ose f or R o xic o d o ne a n d t he d ose -n or m alize d A U C 0- i nf, 
A U C 0- 1 2 h
ss, Ca v g
ss, a n d Cma x
ss of  A PA P f or X A RT E MI S X R were e q ui vale nt t o t h ose f or 
Ul tracet.
9. 2
Pr o d uct Descri pti o n
T he X A R T E MI S X R f or mulat i on ( 7. 5 m g O C H Cl / 3 2 5 mg A PA P) c o ntai ns 2 5 % O C H Cl  
( 1. 8 7 5 mg)/ 5 0 % A P A P ( 1 6 2. 5 m g) i n t he I R la yer c o m p o ne nt ( desi g ne d t o pr o vi de ra pi d 
a nal gesic o nset), a n d 7 5 % O C H Cl  ( 5. 6 2 5 mg)/ 5 0 % A P A P ( 1 6 2. 5 m g) i n t he E R la yer 
c o mp o ne nt, w hi c h ser ves t o pr o vi de a n e xte n de d d urati o n of a nal gesia w he n a d mi nistere d 
orall y Q 1 2 h.
T he i nact i ve i n gre die nts are micr ocr ystalli ne cell ul ose, pre gelat i nize d c or n starc h, citric aci d 
a n h y dr o us p o w der, (et h yle ne di nitril o) tetraacetic aci d dis o di u m salt, h y dr o x ypr o p yl  cell ulos e, 
cr oscar mell o se s o diu m , c olloi d al  silic o n dio xi de, p ol yet h yle ne o xi de, a n d ma g nesi u m stearate. 
T he 7. 5 m g O C H Cl / 3 2 5 mg A PA P ta blet is fi nis he d wit h a n O pa dr y II Bl ue ( 8 5 F 9 9 1 6 7) o uter 
c oati n g (M N K - 7 9 5 I B 2 01 4).
P ol yet h yle ne o xi de is a f u nct i onal e xci pie nt t hat ser ves as t he pre d o mi na nt G R tec h n o l og y  
c o mp o ne nt. P ol yet h yle ne o xi de e x pa n ds w he n e x p ose d t o fl ui d; X A R T E MI S X R is desi g ne d 
t o be retai ne d i n t he st o mac h, t here b y tar geti n g t he release of b ot h dr u gs t o t he u p per GI tract 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
3 9
M alli nc kr o dt
w here A P A P a bs or pti o n is o pti mal (Ki m ura et al 1 9 9 4 , M N K - 7 9 5 I B 2 0 14 ). Diss o l uti on 
st u dies ha ve de mo nstrate d t hat X A R T E MI S X R is slo wl y s ol ubilize d b y  water, alc o h ol, a n d 
gastri c fl ui ds, s u g gesti n g t hat d ose d u m pi n g is u nli kel y re gar dless of tra nsit ti me t hr o u g h t he 
GI s y st e m or if ta ke n wit h alc o h o l (M N K - 7 9 5 I B 2 0 14 ).
9. 3
D os a ge a n d A d mi nistr ati o n
T he a d ult d os i n g re gi me n is 2 ta blets (t otal of 1 5 m g O C H Cl / 6 5 0 mg A PA P) Q 1 2 h , w hic h is 
dee m e d a ge -a p pr o priate f or t his a d o lesce nt p o p ulati on (El -Ta ht a w y et al 2 0 0 6, Ji et al 2 0 1 2, 
K o k ki  et al 2 00 6 , Z u p pa et al 2 0 1 1 ).
9. 3. 1
D ose a n d Re gi me n J ustific ati o n
I n t he 1 2 P hase 1 cli nical st u dies perf or me d wit h X A R T E MI S X R , e mpl o y i n g d oses ra n gi n g 
fr om 7. 5 m g O C H Cl / 3 2 5 m g A P A P t o 3 0 m g O C H Cl / 1, 3 0 0 mg A PA P , n o serio us a d verse 
effects or cli nicall y si g nifica nt a b n or mal c ha n ges i n la b orat or y  para meters or vital si g n 
meas ure me nts ha ve bee n o bser ve d (M N K - 7 9 5 I B 2 0 14 , M N K - 7 9 5 (X A R T E MI S ) X R PI 
2 0 1 4 ). I n safety data fr o m t wo P hase 3 ( o ne place b o- c o ntr olle d, o ne o pe n-la bel) trials w here 
m ult i ple d oses of X A RT E MI S X R were a d mi nistere d f or u p t o 4 2 da y s, t he most c o m m o n 
a d verse reacti o ns (re p orte d b y ≥1 0 % i n a n y  X AR T E MI S X R d ose gr o u p) were na usea, 
di zzi ness a n d v o mit i n g (X A R T E MI S X R PI 2 0 1 4). I n cli nical st u dies ( perf or me d b y t he 
i n n ovat ors) usi n g R o xic o d o ne, Ultracet, a n d Perc ocet, c o m m o n a d verse e ve nts ( A Es )
e x perie nce d b y s u bjects i ncl u de li g ht hea de d ness, dizzi ness, dr o wsi ness or se dati o n, na usea, 
a n d v o mit i n g. X A R T E MI S X R, R o xic o d o ne, Ultracet, a n d Perc ocet ma y be a d mi nistere d wit h 
or wi t ho ut f o o d (X A R T E MI S X R PI 2 0 1 4 , Perc ocet PI 2 0 1 3 , R o xic o d o ne PI 2 0 0 9 , Ult racet PI 
2 0 1 1 ).
S af et y c o ncer ns ass ociate d wit h A PA P ha ve rece ntl y  bee n raise d i n t he scie ntific a n d 
re g ulat or y c o m m u nit y. O ver d ose fr o m prescri pt i on c o m bi nati o n pr o d ucts c o ntai ni n g A P A P 
acc o u nt f or nearl y half of all cases of A P A P -r elate d li ver fail ure i n t he U nite d States, ma n y of 
w hic h res ult i n li ver tra ns pla nt or deat h. M ost of t he cases of se vere DI LI occ ur i n patie nts 
w h o t o o k m ore t ha n t he ma xi m u m rec o m me n de d prescri be d d ose of a n A P A P -c o ntai ni n g 
pr o d uct i n a 2 4 -h o ur per i od ( 4, 0 0 0 m g), t o o k m ult i ple A PA P -c o ntai ni n g pr o d ucts at t he sa me 
ti me, or dra n k alc o h ol w hile ta ki n g A PA P pr o d ucts (Fe deral Re gister N otice 2 0 1 1 ). F or t his 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4 0
M alli nc kr o dt
m ult i ple-d ose st u d y, t he ris k of se vere DI LI is mi ni mal beca use t he lo w dail y t otal  d ose 
utilize d ( 1, 3 0 0 m g) is far bel o w t he ma xi m u m rec o m me n de d dail y A PA P d ose.
T he G R tec h n o l og y  platf or m has bee n utilize d f or se veral mar kete d pr o d ucts ( Gl u metza® , 
Gralise ® , a n d Pr o q ui n® X R). Av aila ble safet y i nf or mati on i ndicates t hat t he i nci de nce of A Es
wi t h G R pr o d ucts is si milar t o t he n o n-G R c o m parat or gr o u ps. T hese fi n di n gs s u g gest t hat t he 
G R tec h n o l og y  use d i n X A RT E MI S X R i s u nli kel y t o res ult i n a n y a d diti onal  ris k t o s u bjects, 
t ho u g h t he safet y a n d effect i ve ness of Gl u metza, Gralise, a n d Pr o q ui n has n ot bee n 
esta blis he d i n pe diatric patie nts (Gl u metza PI 2 0 1 1 , Gralise PI 2 0 1 2 , Pr o q ui n X R PI 2 0 1 1) .
T he c urre nt m ult i ple-d ose st u d y  is desi g ne d t o acc uratel y c haracterize a n d reflect t he P K of 
O C a n d A P A P fr om X A R T E MI S X R i n a d olesce nt pe diatric patient s 1 2 t o 1 7 years of a ge i n 
m o derate t o se vere ac ute pai n after tra u ma or a p ost o perati ve pr oce d ure. T o f urt her ai d s u bject 
safety,  a mi ni m u m wei g ht f or s u bject eli gi bility was selecte d f or all s u bjects a n d fre q ue nt vital 
sig ns, p ul se o xi metr y meas ure me nts, a n d c ha n ges i n me ntal stat us will be closel y  mo ni t or e d 
f or sig ns of  o pioi d si de effects. T hese ste ps ha ve bee n d esi g ne d t o pr o vi de a ba la nce bet wee n 
pr o vi di n g a safe a n d statist icall y r o b ust st u d y t hat als o all o ws f or t he m ost se nsiti ve 
c haracterizat i on of t he ke y  P K para meters of t he f or mulati o n. 
To  date, t he X A R T E MI S X R safety a n d t olera bilit y pr ofile has bee n c o m para ble t o Perc ocet
(Perc ocet PI 2 0 1 3 ). Base d u p o n t he mat urati o n of t he meta b o lic pat h wa ys f or O C a n d A P A P 
i n t his a ge p o p ulati on, t hei r a bilit y t o s wallo w t he ta blet a n d c o m para ble d osi n g re q uire me nts 
t o t hat of a d ult p atie nt s, Malli nc kr o dt belie ves t he X A R T E MI S X R I R/ E R bila yer f or m ulati on 
is a ge-a p pr o priate f or 1 2 t o 1 7 year -ol d s u bjects. 
Ul timatel y , t he cli nical use a n d t hera pe utic a p plicati o n of X A R T E MI S X R i n a m ultila yer 
I R/ E R, O C/ A PA P G R f or mulat i on, d ose d Q 1 2 h, is e x pecte d t o offer greater patie nt 
c o n ve nie nce, p ote ntiall y i m pr o ve slee p, a n d ma y lesse n t he fre q ue nc y a n d se verity of  
e n d -of -d ose pai n (A merica n Pai n S ociet y 2 0 0 8 , Hale et al 2 0 0 7 , Mar ke ns o n et al 2 0 0 5 , 
Ni c h o ls o n et al 2 0 0 6, Pa n et al 2 0 0 7 ).
9. 4
A d verse E ve nts
I n t he 1 4 cli nical trials with X A R T E MI S X R c o mplete d t o date, w hic h ha ve e m pl o ye d d oses 
bet wee n 7. 5 m g O C H Cl / 3 2 5 mg A PA P a n d 3 0 m g O C H Cl / 1, 3 0 0 mg A P A P , t he pr o d uct 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4 1
M alli nc kr o dt
a p pears t o be safe a n d well -t olerate d. T he m ost c o m m o n A Es i ncl u de d na usea, di zzi ness a n d 
v o mit i n g. 
9. 5
R ati o n ale
X A R T E MI S X R is desi g ne d t o pr o vi de ra pi d pai n relief ( o nset < 1 h o ur) wit h s ustai ne d 
a nal gesia f or u p t o 1 2 h o urs. T he efficac y a n d safet y o f a n i m me diate-r elease oral 
c o m bi nat i on of O C a n d A PA P is well esta blis he d i n a d ults, wit h o ver 4 deca des of use i n t he 
U nite d States, Asia, A u stralia, E ur o pe, a n d Ca na da. I n t he U S, Perc ocet (a n I R O C/ A P A P 
c o m bi nat i on) was first a p pr o ve d b y F D A in 1 9 7 6 f or t he treat m e nt of m o derate t o mo deratel y  
se vere pai n; Perc ocet is n ot i n dicate d f or use i n c hil dre n. 
T his is a P hase 4, m ult ice nter, o pe n -la bel st u d y t o e val uate t he P K perf or ma nce a n d safet y of  
t he X A R T E MI S X R oral f or m ulat i on i n 1 2 t o 1 7 year ol d a d olesce nt s u bjects wi t h ac ute pai n. 
T his st u d y  is bei n g c o n d ucte d i n or der t o satisf y t he s p o ns or’s c o m mitme nt t o t he P R E A . T he 
X A R T E MI S X R bila yer ta blet is c o nsi dere d a ge a p pr o pria t e for 1 2 t o 1 7 year ol ds, base d o n 
mat urati o n of  t h e meta b o lic pat h wa ys f or O C a n d A P A P i n t his a ge gr o u p, t heir a bility t o 
s wall o w t he ta blet, a n d d osi n g re q uire me nts c o m para ble t o t he a d ult p o p ulat i on. F ut ure 
st u dies i n s u bjects < 1 2 years of a ge are be i n g pla n ne d; f or t hese st u dies, a n a ge-a p pr o priate 
f or mulat i on will be use d .
1 0 O B J E C TI V E S
1 0. 1 Pri m ar y 

T he pri mar y  o bjecti ve is t o c haracterize t he P K pr ofile o f X A R T E MI S X R f o ll owi n g 
si n gle a n d m ulti ple d ose a d mi nistrati o ns i n a d olesce nt s u bjects ( 1 2 t o 1 7 year s of a ge) 
e x perie nci n g m o derate t o se vere ac ute pai n. 
1 0. 2 Sec o n d ar y

T o deter mi ne t he safet y a n d t olera bilit y o f X A R T E MI S X R i n a d o lesce nt s u bjects ( 12 
t o 1 7 years of a ge ).

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4 2
M alli nc kr o dt

To  deter mi ne t he pai n i nte nsit y differe nces fr o m baseli ne o ver t he first d osi n g peri o d 
(e g, 1, 2, 4, 8, a n d 1 2 h o urs) f o ll owi n g treat m e nt of a d o lesce nt s u bjects ( 12 t o 1 7 y ears 
of  a ge) wit h X A RT E MI S X R .
1 1 S T U D Y D E SI G N
1 1. 1 Descri pti o n
T his is a P hase 4, m ul tice nter, o pe n-la bel, si n gle- a n d m ult i ple-d ose st u d y  of t he P K a n d 
safety of  X A R T E MI S X R i n a d olesce nt s u bjects a ge d 1 2 t o 1 7 years wit h mo derate t o se vere 
ac ute pai n.
T his st u d y  is bei n g c o n d ucte d t o assess P K a n d safet y in a d o lesce nt s u bjects. It will be 
p ossi ble t o c o m pare P K para meters a n d safet y res ults with t h ose deter mi ne d i n a d ults i n
pre vi o us st u dies wit h X A R T E MI S X R . 
T he o verall st u d y  desi g n is ill ustrate d i n Fi g ure 1 1 - 1.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9  J u ne  2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4 3
M alli nc kr o dt
Fi g ur e 1 1- 1: St u d y Desi g n
1 1. 2 A p pr o xi m ate D ur ati o n of S u bject P artici p ati o n
S u bjects will part ici pate i n t he st u d y for a t otal  of a p pr o xi matel y 4 wee ks, i ncl u di n g a 2 wee k 
scree ni n g a n d was h o ut peri o d, a st u d y p erio d  of  u p t o 5 4 h o urs, a n d a f o ll ow- u p tele p h o ne 
c o ntact sc he d ule d f or a p pr o xi matel y 1 wee k ( 7 ±  2 da y s) after t he last d ose of X A R T E MI S 
X R . 
1 1. 3 A p pr o xi m ate D ur ati o n of St u d y
T he d urati o n of  t he st u d y fr o m Site I nitiat i on t o t he Cl ose -o ut visit will be de pe n de nt o n t he 
a bilit y of  t he site(s) t o ide nt if y a n d e nr oll eli gi ble s u bjects a n d is e x pecte d t o be a p pr o xi matel y 
1 year . T he e n d of t he st u d y is c o mplet i on of t he fi nal f oll ow- u p tele p h o ne c o ntact  f or t he 
fi nal s u bject. A d verse e ve nts will be f o ll owe d a n d re p orte d t o t he s p o ns or t hr o u g h t he f o ll ow -
u p p h o ne c o ntact.
1 1. 4 A p pr o xi m ate N u m ber of S u bjects
A p pr o xi matel y  7 2  i n di vi d uals will be scree ne d at m ult i ple sites i n t he U nit e d Stat es t o e ns ure 
4 8 s u bjects will be e nr o lle d. If more t ha n 1 si t e is use d, a p pr o xi matel y 1 0 t o 1 8 s u bjects will 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4 4
M alli nc kr o dt
be e nr olle d at eac h site. T his ma y var y base d o n e nr oll me nt ca pa bilit ies of eac h site. All 
atte mpts will  be ma de t o e nr oll e q ual n u m bers of s u bject s wit hi n t he a ge ra n ge a n d bet wee n 
ge n ders s uc h t hat o ne-t hir d of s u bjects will be 1 2 t o1 3 years of a ge , o ne- t hir d will be 1 4 t o1 5
years o f a ge, a n d o ne- t hir d will be 1 6 t o1 7 y ears of a ge , wit h eac h a ge ra n ge e q uall y 
di stri b ute d b y ge n der.
1 2 S E L E C TI O N O F S U B J E C T S
1 2. 1 I ncl usi o n Criteri a
S u bject m ust meet all o f t he fol l owi n g criteria at scree ni n g a n d chec k -i n t o be eli gi ble f or t he 
st u d y:
1.
S u bject m ust be male or n o n pre g na nt, n o nlactati n g fe males bet wee n 1 2 a n d 1 7 y ears of 
a ge (i ncl usi ve) at ti me of scree ni n g.
2.
S u bject m ust ha ve a mi ni m u m wei g ht of 1 0 0 p o u n ds ( 4 5 k g) a n d ha ve a b o d y mass i n de x 
( B MI) > 5 % a n d < 9 5 % f or t heir a ge (see Attac h me nt 1 ) at t he ti me of scree ni n g.
3.
S u bject m u st re p ort ha vi n g m o derate or se vere ac ute pai n (as deter mi ne d fr o m t he 
N u m erical Pai n Rati n g scale [N P R S ] w here 0 = n o pai n, 1 0 = w orst pai n ; s u bjects m ust 
ha ve a le vel o f 4 or m ore) after a pe diatric s ur gical pr oce d ure (at baseli ne) t hat re q uires 
h os pi talizatio n. S p o ns or will pre -a p pr o ve a list of acce pta ble s ur gical pr oce d ures pri or t o 
st u d y start f or eac h sit e.  S ur gical pr oce d ures ot her t ha n t h ose o n t he pre -a p pr o ve d list
ma y be acce pta ble o n a case b y case basis if a p pr o ve d b y  t he Me dical M o nit or ( M M) a n d 
s p o ns or.
4.
S u bject, if fe mal e of c hil d-be ari n g p ote ntial ( defi ne d as p ost me narc h e), m ust a gree t o 
a bstai n fr o m u n pr otecte d se x ual act i vity d uri n g st u d y  partici pat i on a n d f or 2 wee ks after 
st u d y e xit.  
5.
S u bject, if male wi t h re pr o d uctive p ote nti al, m ust a gree t o a bstai n fr o m u n pr otecte d se x ual 
acti vit y d uri n g st u d y  partici pat i on a n d f or 2 wee ks after st u d y e xit.  
6.
S u bject, if fe male of c hil d beari n g p ote ntial, m ust ha ve ne gat i ve pre g na nc y test (ser u m or 
uri ne) res ults at scree ni n g a n d c hec k -i n.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4 5
M alli nc kr o dt
7.
S u bje ct’s le gall y a ut h orize d re prese ntati ve (e g, pare nt, le gal g uar dia n) m ust v ol u ntaril y  
sig n a n d date a pare ntal per missi o n/I C F t hat is a p pr o ve d b y  a n I R B, a n d t he s u bject m ust 
sig n a n I R B a p pr o ve d asse nt, bef ore u n der g oi n g a n y pr ot oc ol s pecific pr oce d ures or
assess me nts.
8.
S u bject a n d t he s u bject’ s pare nt or le gal g u ar dia n m ust be a ble t o rea d, u n dersta n d, a n d be 
willi n g t o f oll o w t he st u d y  pr oce d ures a n d re q uire me nts a n d c o m m u nicate mea ni n gf ull y in 
E n glis h wit h t he i n vesti gat or a n d i n vesti gat or’s staff (if t he s u bject ca n n ot rea d or 
c o m m u nicate mea ni n gf ull y, t he n t he s u bject’s le gall y a ut h orize d re prese ntati ve [e g, 
pare nt, l e gal g uar dia n] must m eet t his crit erio n).
1 2. 2 E xcl usi o n Criteri a
A s u bject is i neli gi ble f or t he st u d y if t he y meet a n y of t he fol l owi n g cri t eria at scree ni n g a n d 
c hec k -i n:
1.
S u bject is fr o m a v ul nera ble p o p ulat i on (incl u di n g me ntall y disa ble d c hil dre n), ot her t ha n 
a pe diatric p o p ulat i on, as defi ne d b y t he C o de of Fe deral Re g ulat i ons Tit le 4 5, Part 4 6, 
Secti o n 4 6. 1 1 1( b), i ncl u di n g b ut n ot li mite d t o e m pl o yees (te m p orar y, part-ti me, f ull ti me, 
etc) or a fa mil y me m ber of t he researc h staff c o n d ucti n g t he st u d y, or of t he s p o ns or, or of 
t he cli nical researc h or ga nizat i on, or of t he I R B.
2.
S u bject is e x pecte d t o re q uire a s ur ger y  t hat c o uld i nfl ue nce t he st u d y o utc o me (e g, 
ve ntri c ulo p eri t o neal s h u nt re pair i n t he setti n g of h y dr oce p hal us). 
3.
S u bject has a n a b n or mal electr ocar dio gra m  (E C G ) u nless t he i n vesti gat or deter mi nes t he 
E C G a b n or malit ies are n ot cli nicall y si g nifica nt.
4.
S u bject has a scree ni n g p ulse o xi metr y  rea di n g of < 9 5 % w hile a wa ke.
5.
S u bject has a hist or y  of la b orat or y test res ults o btai ne d bef ore scree ni n g t hat s h o w t he 
prese nce of h u ma n i m m u n o deficie nc y vir us ( HI V) , he patit is B s urface a nti ge n, he patitis C 
a nt i b o d y, or acti ve he pat itis A i m m u n o gl o b uli n M.
6.
S u bject has la b orat or y val ues t hat are greater t ha n 2 ti mes t he u p per li mit of n or mal ( wit h 
t he e xce pt i on of w hi te blo o d cell  [W B C ] differe nt ial val ues) . E nr oll me nt of s u bjects wi t h 
la b orat or y val ues t hat are bet wee n 1 a n d 2 ti mes t he u p per li mit of n or mal ( U L N), or 
bel o w t he l o wer li mit of n or mal , or W B C differe ntial > 2 x U L N , will be l eft t o t he 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4 6
M alli nc kr o dt
i n vesti gat or’s discreti on ( n o i ncrease d ris k of partici pat i on i n st u d y base d u p o n ju d g me nt 
of  t he i n vesti gat or).
7.
S u bject has a n y  hist or y of re nal disease t hat, i n t he o pi ni on of t he i n vest i gat or, w o ul d 
c o ntrai n dicate st u d y partici pat i on; or s u bject has si g nifica nt l y i m paire d re nal f u ncti on, i n 
t he o pini o n of t he i n vest i gat or, as e vi de nce d b y a n esti mate d gl omer ular filtrat i on rate 
calc ulate d usi n g a pe diatric a p pr o priate f or m ula s uc h as t he Sc h wartz E q uati o n (Sc h wartz 
et al 2 0 0 9).
8.
S u bject has a hist or y  or la b orat or y e vi de nce of blee di n g or cl otti n g dis or ders or 
c o n ditio ns.
9.
S u bject has a k n o w n or s us pecte d hist or y  of alc o h olis m, marij ua na or illicit dr u g a b use or 
mis use wit hi n 2 years bef ore scree ni n g as e vi de nce d fr om me d ical hist or y or e vide nce of 
t olera nce or p h ysical de pe n de nce bef ore t he first d ose of X A R T E MI S X R .
1 0. S u bject has s m o ke d or use d nic oti ne -c o ntai ni n g pr o d ucts wit hi n 6 m o nt hs pri or t o 
scree ni n g as e vi de nce d b y me dical hist or y.
1 1. S u bject has a hist or y  of ps yc hiatric dis or ders, s uc h as major de pressi o n  dis or der, a n xiety 
di s or ders, or ps yc h otic dis or ders re q uiri n g h os pitalizat i on a n d/ or m e dicat i on wi t hi n 6 
m o n t hs prior t o scree ni n g . A hist or y  of atte ntio n deficit h y peract i vity dis or der re q ui rin g 
me dicat i on is acce pta ble.
1 2. S u bject has a dia g n osis of e pile ps y or ot her seiz ure dis or der (a hist or y  of fe brile seiz ures is 
acce pta ble) .
1 3. S u bject has ha d pre vi o us car di ot h or a ci c s ur ger y (s u bjects w h o ha ve a hist or y of pate nt 
d uct us arteri os us li gat i ons/s ur ger y as i nfa nts are acce pta ble) .
1 4. S u bject has a hist or y of c o n ditio n s w hic h mi g ht be s pecificall y c o ntrai n dicate d or re q uire 
ca utio n w hile usi n g O C, A P A P , a n d/ or ib u pr o fen (if use d as a resc ue me dicati o n) per t he 
I B a n d/ or t he a p pr o priate pac ka ge i nsert.
1 5. S u bject has a hist or y  of a n y dr u g aller g y, h y perse nsitivit y,  or i nt olera nce i ncl u di n g O C, 
A P A P , i b u pr ofe n or e xci pie nts, or a n y o pioi d dr u g pr o d uct w hi c h, i n t he o pi ni o n of t he 
i n vesti gat or, w o ul d place t he s u bject at partic ular ris k a n d c om pr o mise t he safet y of  t he 
s u bject i n t he st u d y.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4 7
M alli nc kr o dt
1 6. S u bject has d o nate d or ha d si g nifica nt l oss of w h o le bl o o d ( 4 8 0 m L or more) wi t hi n 3 0 
da ys of scree ni n g ( u nless t he y ha ve recei ve d a tra nsf u sio n t o c orrect t he bl o o d l oss a n d 
ha ve he mat ocrit a n d he m o gl o bi n wit h i n t he refere nce ra n ge at scree ni n g), or pla ns t o 
d o nate bl o o d or pl as ma d uri n g t he c o urse of t he st u d y.
1 7. S u bject has a d oc u me nte d hist or y  of an y pat h o l ogic, i atr o ge nic or s ur gical c o n diti on t hat, 
i n t he o pi ni on of t he i n vesti gat or, w o uld c o m pr o mise t he s u bject’ s a bility t o s wallo w, 
a bs or b, meta b o lize, or e xcrete X A R T E MI S X R , i nclu di n g ( b ut n ot li mite d t o) i ntracta ble 
na usea a n d/ or v o mit i n g, se vere GI narr o wi n g, perf orati o n, o bstr ucti o n, blee d, or gastric 
ba n d s ur ger y.
1 8. S u bject has a hist or y  of a GI e ve nt (e g, perf orati o n, o bstr ucti o n, blee d) wit hi n 6 m o nt hs 
pri or t o scree ni n g or a n y  GI e ve nt greater t ha n 6 m o nt hs bef ore scree ni n g t hat, i n t he 
o pi ni o n of t he i n vest i gat or, w o uld ma ke t he s u bject u ns uita ble f or st u d y  p artici pat i on.
1 9. S u bject has use d a n y pr o d uct c o ntai ni n g O C or A P A P wit hi n 4 8 h o urs pri or t o t he first 
d ose of X A RT E MI S X R .
2 0. S u bject has a hist or y of c o n ditio n s w hic h mi g ht be s pecificall y c o ntrai n dicate d or re q uire 
ca utio n t o be use d d uri n g t he a d mi nistrati o n of A PA P or O C i ncl u di n g h y perse nsit i vity t o 
O C, or de bilit ate d patie nts, t h ose wit h se vere i m pair me nt of he patic, p ul m onar y, or re nal 
f u ncti on, m y xe de ma or h y p ot h y r oidis m, a dre n oc orti cal i ns ufficie nc y (A d dis o n’ s disease), 
ce ntral ner v o us s yste m (C N S ) de pressi o n or c o ma, t o xic ps yc h osis, uret hral strict ure, 
ac ute alc o h o lis m, deliri u m tre me ns, se vere k y p h osc oli osis, or biliar y  tract d ysf u ncti on.
2 1. S u bject h as a n y ot her me dical c o n ditio n , a b n or mal vit al si g n ( blo o d press ure, p ulse rate, 
res pir at or y r at e), bo d y  t e mperat ure, p ul se o xi metr y; or a n y p h ysical e xa m i nati on or E C G 
fi n di n g at scree ni n g w hic h, i n t he i n vest i gat or’s me dical o pi ni on, w o ul d precl u de safe 
parti ci pat i on i n a cli nical st u d y.
2 2. S u bject has recei ve d a n y  in vesti g ati o nal pr o d uct or de vice wit hi n 3 0 da ys bef ore 
scree ni n g, or is sc he d ule d t o recei ve a n i n vest i gati o nal de vice or a n ot her i n vesti gati o nal 
dr u g ( ot her t ha n t h ose i n t his st u d y ) d uri n g t he c o urse of t his st u d y.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4 8
M alli nc kr o dt
1 3 P RI O R A N D C O N C O MI T A N T T R E A T M E N T
T he start a n d st o p date a n d ti me, d osa ge, fre q ue nc y, r o ute of a d mi nistrati o n, a n d i n dicat i on f or 
r ele va nt prior m e dicat i ons ( 3 0 da y s prior t o scree ni n g) a n d c o nc omit a nt me dicat i ons a n d 
t hera pies (incl u di n g peri - o perati ve a n d o perati ve me dicati ons /t hera pies) will be rec or de d i n 
t he s o urce d oc u me nts a n d in t he electr o nic case re p ort f or m ( e C R F). 
1 3. 1 Pr o hi bite d D uri n g St u d y
Pri or  a n d C o nc o mit a nt Me dic ati o ns
Treat m e nt wi t h t he f oll owi n g m e dicat i ons a n d t hera pies d uri n g t he st u d y are pr o h ibit e d:

A n y i n vesti gati onal dr u g, de vice a n d/ or e x peri me ntal t her a p y ( pr o hi bite d wi t hi n 3 0 
da ys be for e scree ni n g or t hr o u g h o ut t he st u d y ).

H or m o nal  c o ntrace ptio n a n d h or m o nal re pl ace me nt t hera p ies are pr o hi bite d 
wi t hi n 1 4 da ys pri or t o t he first d ose of X A RT E MI S X R a nd t hr o u g h o ut t he 
r e mai n der of t he st u d y.

A n y m e dicatio n t hat, i n t he o pi ni o n of  t he i n vesti gat or, ma y ca use a cli nicall y 
sig nifica nt c o n ditio n w he n use d c o nc o m itant l y wi t h O C or A P A P is 
pr o hi bite d wit hi n 1 4 da ys pri or t o t he first d ose of X A R T E MI S X R a n d 
t hr o u g h o ut t he re mai n der of t he st u d y.

A n y m e dicatio n t hat is c o ntr ai n dicate d (ie, preca ut i o n e xists a gai nst c o nc o m ita nt use, 
a n d/ or t he pote nti al e xists for a cli nica ll y si g nifica nt dr u g- dr u g i nt eractio n wi t h 
X A R T E MI S X R ) is pr o hi bite d wit hi n 1 4 da ys pri or t o t he first d ose of X A R T E MI S 
X R a n d t hr o u g h o ut t he re mai n der of t he st u d y . 

A n y m e dicatio n t hat is k n o w n t o m o deratel y t o str o n gl y i n hi bit or i n d uce 
C Y P 2 D 6 a n d/ or C Y P 3 A 4 e nz y mes (see Attac h me nt 2 ) is pr o hi bite d wit hi n 1 4 
da ys pri or t o t he first d ose of X A R T E MI S X R a n d t hr o u g h o ut t he st u d y. T he 
use of C Y P 2 D 6 a n d/ or C Y P 3 A 4 i n hi bit ors or i n d ucers is all o we d peri -
o perati vel y  as nee de d.  

A n y me dicat i on c o ntai ni n g O C or A P A P is pr o hi bite d wit hi n 4 8 h o urs pri or t o t he first 
d ose of X A RT E MI S X R a n d t hr o u g h o ut t he re mai n der of t he st u d y . 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
4 9
M alli nc kr o dt

S u bject pai n s h o ul d be ma na ge d t o e ns ure t hat a n y s u p ple me ntal o pi oi d me dicat i on is 
n ot nee de d i n t he 3 0 mi n utes pri or t o eac h d ose of X A R T E MI S X R.
If a n y n o nst u d y dr u g is ta ke n d uri n g t he st u d y (incl u di n g peri -o perati ve a n d o perati ve 
me dicat i ons) , all perti ne nt i nf or mati on will be rec or de d i n t he e C R F a n d s o urce d oc u me nts. 
Wa s h o ut Perio d : If a s u bject is ta ki n g a pr o hi bite d me dicati on pri or t o e nr olli n g i n t he st u d y  
t he y must disc o nt i n ue t he me dicati on f or at  least 1 4 da ys prior t o t he first d ose of X A R T E MI S 
X R or at  least 5 ti mes t he half -life of t he pr o hi bite d me dicat i on , w hic he ver is l o n ger.
F o o ds
S u bjects will be i nstr ucte d t o a bstai n fr o m f oo d c o ntai ni n g p o p p y  see ds (e g, muffi ns, ba gels, 
a n d ca kes) a n d alc o h o l f or 4 8 h o urs pri or t o t he first d ose of X A RT E MI S X R a n d t hr o u g h t he 
last blo o d dra w. S u bjects will be i nstr ucte d t o a bstai n fr o m gra pefr uit or gra pefr uit j uice -
c o ntai ni n g dri n ks (i ncl u di n g Fresca ® a n d S q uirt ® ) a n d dri n ks c o ntai ni n g her bal s u p ple me nts 
f or 1 4 da ys pri or t o i n t he first d ose of X A RT E MI S X R t hr o u g h t he c o ncl usi on of t he st u d y.
F o o d or be vera ges c o ntai ni n g xa nt hi nes (e g, c offee, tea, caffei ne-c o ntai ni n g s o das, c olas, 
c h oc olate or ot her caffei nate d pr o d ucts) will n ot be all o we d fr o m t he c o m p leti o n of t he 
s ur gical pr oce d ure t o t he c o ncl usi o n of t he st u d y.
E xercise
S u bjects will be i nstr ucte d t o refrai n fr o m stre n u o us e xercise t hr o u gh o ut t he d urati o n of t he 
st u d y. Stre n u o us e xercise is defi ne d as a n y ti me a s u bject ca n n ot carr y o n a c o n versati on 
wi t ho ut i nterr u pti o n d ue t o hea v y breat hi n g or e xerti o n. 
1 3. 2 Per mitte d D uri n g St u d y
P os t-s ur ger y o pi oi d resc ue pai n me dicati o n base d o n st u d y  sit e’s sta n dar d practice is all o we d 
b ut s h o uld be pre -a p pr o ve d b y t he M M
a n d t he sp o ns or . O pti o nal r esc ue me dicat i on 
(ib u pr ofe n) will be s u p plie d f or use d uri n g t he st u d y as nee de d ( 2 0 0 m g or 4 0 0 m g e ver y 4 t o 
6 h o urs; ma xi m u m i n di vi d ual d os e of 1, 2 0 0 mg per 2 4 h o urs). A d dit i onal me dicat i ons will be 
per mitte d d uri n g t he st u d y  for t he treat m e nt of A Es a n d pai n e xce pt as n ote d i n Secti o n 1 3. 1 .

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5 0
M alli nc kr o dt
A d dit i onal a nal gesia or a dj u va nt t hera pies ma y be a d mi nistere d after ta ki n g X A R T E MI S X R 
acc or di n g t o t he i n vest i gat or’s cli nical practice. T hese t hera pies m u st n ot c o nflict wit h a n y of 
t he i ncl usi o n or e xcl usi o n  crit eria or c o nc o mita nt me dicat i ons ( T hese a d di tio n al  t hera pies 
m ust be a p pr o ve d b y t he M M a n d s p o ns or pri or t o st u d y  start, if p ossi ble.
1 3. 3 Tr e at me nt C o m pli a nce
C o m plia nce i s mo ni t or e d b y st u d y pers o n nel at t he site b y mo ut h a n d ha n d c hec ks. 
1 4 P R O C E D U R E S
T he sc he d ule of  st u d y e ve nts is s u m marize d i n the Sc he d ule of E ve nt s (Ta ble 7 - 1).  
1 4. 1 D osi n g
S u bjects will recei ve 2 ta blets of X A R T E MI S X R e ver y 1 2 h o urs u p t o a ma xi m u m o f 4
d oses. After t he first d ose of X A R T E MI S X R , tr eat me nt ma y be t er mi nate d (ie, X A R T E MI S 
X R per m a ne nt l y disc o nti n ue d) if it is n o l o n g er nee de d f or t he tr eat me nt of pai n (ie, if t he 
s u bject has a N P R S of < 4 fr om 3 0 mi n utes pri or t hr o u g h 1 h o ur after a sc he d ule d
X A R T E MI S X R d ose ), or s u bject is n o l on ger nee de d f or h os pital sta y, or at a n y  time at t he 
di scretio n of  t he s u bject’s pare nt/ g uar dia n. S u bjects will s witc h t o t he sta n dar d of care pai n 
me dicat i on if re q uire d f or f urt her treat me nt of pai n after t he f o urt h d ose of X A RT E MI S X R.
If t he s u bject is i n be d, t he s u bject’s hea d of be d will be ele vate d as muc h as p ossi ble (at least 
4 5 de grees).
1 4. 2 C o nfi ne me nt 
S u bjects will e nter t he st u d y  sit e o n t he da y  of c hec k-i n a n d will re mai n at t he h os pi t al as lo n g 
as a h os pi t al st a y is nee de d per me dical reas o ns. A d mi nistrati o ns of X A R T E MI S X R will o nl y 
be gi ve n d uri n g s u bject’s h os pit al st a y. O nce a d ose of X A R T E MI S X R is a d mi nistere d, 
s u bjects s h o ul d re mai n at t he h os pital t o pr o vi de t he P K sa m ples s pecificall y re q uire d f or t he 
parti c ular d ose. 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5 1
M alli nc kr o dt
1 4. 3 Scree ni n g Pr oce d ures
Scree ni n g assess me n ts m ust be perf or m e d wi t hi n 1 4 d a y s of c hec k -i n. T he f oll owi n g
pr oce d ures will be perf or m e d at scree ni n g:
1.
S u bject asse nt (if a p plica ble) a n d wri tte n pare ntal or le gal g uar dia n i nf or me d c o nse nt.
2. I ncl usi o n/e x cl usi on crit eria.
3.
De m o gra p hics .
4.
Me dical a n d s ur gical hist or y .
5.
Fi rst d a y of  last me nstr ual perio d (f or p ost m e narc he fe male s u bjects o nl y).
6.
C o nc o mita nt me dicat i ons , i ncl u di n g all m e dicat i ons ta ke n wit hi n 3 0 da ys bef ore
scree ni n g.
7.
P h ysical e xa m i nati on.
8.
Hei g ht a n d wei g ht.
9.
1 2 -lea d E C G.
1 0. Vit al si g ns ( bl o o d press ure, p ulse rate, res pirat or y  rate).
1 1. B o d y t e mperat ure .
1 2. P ul se o xi metr y.
1 3. Cli nical la b orat or y  t ests.
1 4. Uri ne or ser u m pre g na nc y test (fe male s u bjects o nl y).
1 5. A d verse e ve nts (ca pt ure d d uri n g scree ni n g).
1 4. 4 C h e c k-i n Pr oce d ures
It is acce pta ble, if it ca n be arra n ge d, t o c o m plete all scree ni n g pr oce d ures o n t he sa me da y as 
c hec k -i n. I n t his sit u atio n, t he me dical a n d s ur gical hist or y re vie w, first da y of  last me nstr ual 
p eri o d, i ncl usi on/ e xcl usio n criteria re vie w, t he p h ysical e xa m i nati on , E C G, weig ht 
meas ure me nt, pre g na nc y  test, a n d cli nical la b orat or y tests d o n ot nee d t o be re peate d d uri n g 
c hec k -i n pr oce d ures.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5 2
M alli nc kr o dt
At  c hec k -i n su bjects will c o m p lete t hese assess me nts:
1.
I ncl usi on/e xcl usi o n cri teria re vie w.
2.
Me dical a n d s ur gical hist or y  re vie w.
3.
Fi rst d a y of  last me nstr ual perio d .
4.
P h ysical e xa mi nat i on.
5.
We i g ht.
6.
1 2 -lead E C G .
7.
Vit al si g ns.
8.
B o d y t e mperat ure .
9.
P ul se o xi metr y.
1 0. Cli nical la b orat or y tests.
1 1. Uri ne or ser u m pre g na nc y test (fe male s u bjects o nl y).
1 2. A d verse e ve nts a n d c o nc o mit a nt me dicat i ons .
1 4. 5 B aseli ne
After c o m plet i n g t he s ur gical pr oce d ure a n d pri or t o recei vi n g t he first d ose of X A RT E MI S 
X R, s u bjects will ha ve t hese assess me nts:
1.
N P R S ( pre d ose assess me nt m ust be ≥4 f or s u bject t o q ualif y f or t he st u d y ).
2.
C o nti n u o us p ulse o xi metr y (start) a n d pre d ose p ulse o xi metr y rea di n g.
3.
Vit al si g ns.
4.
B o d y t e mperat ure.
5.
P K Sa m pli n g.
6.
A d verse e ve nts a n d c o nc o mit a nt me dicat i ons re vie w (i ncl u di n g all peri-o perati ve a n d 
o perati ve me dicat i ons a n d e ve nts) .

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5 3
M alli nc kr o dt
1 4. 6 H o urs 0 t o 3 6 Pr oce d ures
After c o m plet i n g t he baseli ne pr oce d ures , s u bjects will recei ve t heir first d ose of X A RT E MI S 
X R ( H o ur 0); s u bjects will t he n u n der g o t he f o ll owi n g p ost d o se pr oce d ures: 
1.
X A R T E MI S X R d osi n g at H o ur 0, H o ur 1 2 ( sec o n d d ose if nee de d), a n d H o ur 2 4 
(t hird d ose if nee de d).
2.
N P R S.
3.
Vit al si g ns.
4.
B o d y te mperat ure.
5.
C o nti n u o us p ul se oxi metr y a n d p ulse o xi metr y rea di n gs.
6.
P K s a m pli n g at 1 5 mi n utes a n d 4 5 mi n utes ( ± 5 mi n utes); a n d 2, 4, 6, 8, 1 0, a n d 1 2 
h o urs ( ± 1 0 mi n utes) after t he first d ose of X A R T E MI S X R. T he 1 2 -h o ur bl o o d dra w 
m ust be c o m plete d pri or t o t he a d mi nistrati o n of t he sec o n d d ose of X A R T E MI S X R .
7.
Baseli ne P K sa m pli n g pri or t o t he t hir d d ose of X A R T E MI S X R, if a p plica ble.
8.
Resc ue me dicat i on d osi n g (if nee de d).
9.
A d verse e ve nt a n d c o nc o mit a nt me dicat i on re vie w.
S u bjects will e xit t he st u d y if t he y pr o vi de t he P K sa m ples f oll o wi n g t he first d ose, a n d t he
sec o n d or t hi r d d ose of X A RT E MI S X R i s n ot nee de d, or t he h os pital sta y is n ot nee de d. 
S u bjects w h o re q uire u p t o a n d i ncl u di n g t he f ourt h d ose of X A RT E MI S X R will  c o nti n ue 
wi t h t he f oll owi n g pr oce d ures.
1 4. 7 H o urs 3 6 t o 5 4 Pr oce d ures
F or s u bjects w h o c o n ti n ue t o re q uire X A R T E MI S X R f or t he treatm e nt of  pai n, t he fourt h d ose 
of  X A R T E MI S X R will be a d mi nistere d 3 6 h o urs after t he first d ose . T he f o ll owi n g 
pr oce d ures will be c o m p lete d after t he f ourt h d ose of X A RT E MI S X R.
1.
C o nti n u o us p ulse o xi metr y  u nt il 1 2 h o urs after f ourt h X A R T E MI S X R d ose a n d p ulse 
o xi metr y  rea di n gs.
2.
V ital si g ns.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5 4
M alli nc kr o dt
3.
B o d y te mperat ure .
4.
P K sa mpli n g. Wit hi n 1 0 mi n utes pri or t o t he f o urt h d ose of X A RT E MI S X R a n d at 1 5 
t o 3 0 mi n utes, 4 5 t o 9 0 mi n utes, 2 t o 4 h o urs, a n d 6 t o 8 h o urs after t he f o urt h d ose of 
X A R T E MI S X R. I n a d diti o n, o ne sa m ple will be c ollecte d d uri n g t he 1 2 t o1 8 h o ur 
ti me wi n d o w after t he f o urt h d ose, if f urt her pai n me dicat i on is n ot re q uire d. If pai n 
me dicat i on is still re q uire d f oll owi n g t he f o urt h d ose of X A R T E MI S X R , a sa mple 
will be c o llecte d at 1 2 h o urs ( ± 1 0 mi n utes) after t he f o urt h d ose, b ut pri or t o t he ne xt 
d ose of pai n me dicat i on.
5.
Resc ue me dicat i on d osi n g (if nee de d) .
6.
A d verse e ve nt s a n d c o nc o mit a nt me dicat i ons re vie w.
S u bjects will e xit t he st u d y  o nce t he P K sa m ples f ollo wi n g t he f o urt h d ose of X A R T E MI S X R
are pr o vi de d.
1 4. 8 St u d y E xit or E arl y T er mi n ati o n Pr oce d ures
All s u bjects will ha ve a c o m plete safet y assess m e nt perfor m e d at exit  (st u d y exit  pr oce d ures) or
at earl y ter mi nat ion (if a p plica ble). T he assess me nt will i ncl u de t he f oll o wi n g pr oce d ures:
1.
P h ysical e xa m i nati on.
2.
Vit al si g ns.
3.
B o d y t e mperat ure.
4.
P ul se o xi metr y.
5.
Cli nical la b orat or y  tests.
6.
Uri ne or ser u m pre g na nc y test (fe male s u bjects o nl y).
7.
A d verse e ve nts a n d c o nc o mit a nt me dicat i on re vie w.
8.
I mp ai re d j u d g me nt e val uati on. 
9.
S u bjects will s witc h t o t he sta n dar d of care pai n me dicat i on if f urt her treat me nt of pai n 
is re q uire d after t he f ourt h d ose of X A RT E MI S X R. 
1 0. Sc he d ule f o ll ow- u p tele p h o ne c o ntact.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5 5
M alli nc kr o dt
1 4. 9 F oll o w- u p (Te le p h o ne C o nt act )
A p pr o xi m atel y 7 ( ± 2) da ys aft er recei vi n g t he last d ose of X A R T E MI S X R ( or earl y 
ter mi natio n , if a p plica ble) t he s u bject’s pare nt or le gal g uar dia n will be c o nt acte d b y tele p h o ne.
I nf or mat i on re gar di n g A Es a n d S A Es e x per ie nce d and concomitant med ications taken si nce t he
last d ose of X A R E T E MI S X R or earl y ter mi nat i on will be rec or d e d.
1 5 I N V E S TI G ATI O N A L  M E DI CI N A L
P R O D U C T A N D N O N-
I N V E S TI G ATI O N A L  P R O D U C T A D MI NI S T R A TI O N
1 5. 1 I n vesti g ati o n al Me dici n al Pr o d uct (X A R T E MI S X R )
Eli gi b le s u bjects m eeti n g all stu d y e ntr y crit eria will be e n r olle d i nt o t he st u d y a n d will  recei ve
t he i n vesti gati o nal me dici nal pr o d uct X A R T E MI S X R as a 2 ta blet i nit ial d ose, f oll owe d wi t h 2 
ta blets e ver y Q 1 2 h f or 4 d oses as nee de d f or t he treatm e nt of  pai n. S u bjects will s witc h t o t he 
sta n dar d of care pai n me dicati o n if re q uire d f or f urt her treat me nt of pai n after t he f o urt h d ose 
of  X A RT E MI S X R.
X A R T E MI S X R c o nt ai ns a Sc he d ule II c o ntr olle d s u bsta nce. X A R T E MI S X R will be 
pac ka ge d i n a hi g h de nsit y p ol yet h yle ne ( H D P E) b ottle c o ntai ni n g 1 0 0 ta blets. T he b ottle will 
be la bele d per re g ulati ons wit h t he pr o d uct na me, pr o d uct l ot n u m ber, pr ot oc ol n u m ber , 
rec o m me n de d st ora ge c o n diti o ns a n d t he Fe deral Ca uti o n State me nt “ Ca uti on: Ne w Dr u g –
Li mite d b y  Fe deral ( or U nite d States) La w t o I n vesti gat i onal Use.” T he Malli nc kr o dt I nc .
c o mpa n y na me a n d a d dress will be i ncl u de d. 
1 5. 2 N o n -i nvesti g ati o n al Pr o d uct (I b u pr of e n)
O pti o nal  resc ue me dicat i on (i b u pr ofe n 2 0 0 m g ta blets ) will be s u p plie d i n b ul k f or use d uri n g 
t he st u d y as nee de d ( 2 0 0 mg or 4 0 0 m g e ver y 4 t o 6 h o urs , ma xi m u m i n di vi d ual d ose of 
1, 2 0 0 m g per 2 4 h o urs).
1 5. 3 Met h o ds of Assi g ni n g S u bjects t o T re at me nt Gr o u ps
All s u bjects will be assi g ne d t he sa me treat me nt. Eac h s u bject will be assi g ne d a u ni q ue 
i de ntifier. T he i n vesti gat or m ust mai ntai n a s u bject master l o g li n ki n g t he s u bject i de ntifier t o 
t he s u bject’s na me. T he i n vesti gat or m ust f oll ow all  a p plica ble pri vac y la ws i n or der t o pr otect 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5 6
M alli nc kr o dt
a s u bject’s pri vac y a n d c o nfi de ntiality.  I nf or matio n t hat c o ul d i de ntif y a s u bject will be 
mas ke d o n m aterial recei ve d b y t he s p o ns or.
1 5. 4 D osi n g Pr oce d ures
S u bjects will recei ve 2 ta blets of X A R T E MI S X R Q 1 2 h oral l y d urin g t he tr eat me nt p hase. Eac h 
d ose of X A R T E MI S X R will be a d mi nistere d wit h 8 o u nces ( 2 4 0 m L) of water . U ns weete ne d 
a p ple j uice ma y be s u bstit ut e d for t he water if t here is a n i n dicat i on t hat t he s u bject will n ot be 
a ble t o s wall o w t he st u d y dr u g wi t h water.  H o we ver, t he v ol u me of li q ui d m ust be t he sa me 
( 8 o u nces) a n d t he s u bstituti o n m ust be d oc u m e nte d. If t he s u bject is i n be d t he s u bject’s hea d 
of  be d will be ele vate d as muc h as p ossi ble (at least 4 5 de grees).
O pti o nal  resc ue me dicat i on (i b u p r ofe n 2 0 0 m g ta blets ) ma y be use d as nee de d d uri n g t he 
st u d y. D oses s h o uld be 2 0 0 m g or 4 0 0 m g e ver y  4 t o 6 h o urs (ma xi m u m i n di vi d ual d ose of 
1, 2 0 0 m g per 2 4 h o urs). Eac h d ose of resc ue me dicati o n s h o ul d be a d mi nistere d wit h 8 o u nces 
( 2 4 0 m L) of water or a p ple j uice.
A ha n d a n d m o ut h c hec k will be c o n d ucte d b y  t he st u dy sit e after eac h d ose t o e ns ure all 
st u d y dr u g has bee n c o ns u me d.
1 5. 5 St or a ge a n d Dis p ositi o n of Cli nic al S u p plies
X A R T E MI S X R a n d i b u pr ofe n will be mai ntai ne d i n a sec ure area at t he stu d y site .
X A R T E MI S X R a n d i b u pr ofe n are t o be st ore d at c o ntr olle d r o o m te m perat ure at 2 0° C t o
2 5° C ( 6 8 ° F t o 7 7° F); e xc ursi o ns per mitte d t o 1 5° C t o 3 0° C ( 5 9°F t o 8 6° F).
1 5. 6 Rete nti o n S a m ples
Per 2 1 C F R 3 2 0. 6 3 a n d 3 2 0. 3 8, rete nti o n sa m ples of  X A R T E MI S X R will be hel d b y  t he 
st u d y sit e or a t hi r d part y desi g nee. A p pr o pri ate rete nti on sa m ples m ust be st ore d u n der 
c o n ditio ns c o nsiste nt wit h t he pr o d uct la beli n g f or a peri o d of at least 5 y ears fol l owi n g t he 
date o n w hic h t he a p plicat i on is a p pr o ve d ( or if t he a p plicat i on is n ot a p pr o ve d, f or at least 5 
years f o ll owi n g t he date of c o m plet i on of t he st u d y).

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5 7
M alli nc kr o dt
1 5. 7 Dr u g Acc o u nt a bilit y
I n acc or da nce wit h F D A re q uire me nts, t he i n vesti gat or will, at all t i mes, be a ble t o acc o u nt f or 
all X A R T E MI S X R f urnis he d t o t he st u d y  site. A dr u g acc o u nta bility rec or d will be 
mai ntai ne d f or t his p ur p ose. T he st u d y site m ust mai ntai n acc urate rec or ds i n dicat i n g dates 
a n d q ua nt ity of  X A R T E MI S X R recei ve d, t o w h o m it was dis pe nse d (s u bject- b y-s u bject 
acc o u nti n g) a nd acc o u nts of a n y  X A R T E MI S X R accide ntall y or deli beratel y destr o y e d. All 
u n use d X A R T E MI S X R n ot i n v o l ve d i n i m me diate s u bject d osi n g will be mai ntai ne d u n der 
l oc ke d st ora ge at t he st u d y site i n or der t o c o mpl y wi t h F D A g ui deli nes f or c o n d ucti n g cli nical 
trial st u dies i n s u p p ort of ne w dr u g a p plicati o ns. A p pr o priate X A R T E MI S X R rete nti o n 
sa m ples m ust be mai ntai ne d b y t he st u d y sit e or a t hir d part y  desi g nee u n der a p pr o priate 
st ora ge c o n diti ons.
All use d a n d u n use d cli nical s u p pl y c o ntai ners will be mai ntai n e d at t he st u d y site u ntil dr u g 
acc o u nta bilit y is perf or me d b y t he s p o ns or. With t he e xce pt i on of rete nti o n sa m ples, u n use d 
X A R T E MI S X R will be ret ur ne d t o t he s p o ns or f or fi nal dis p osit i on, u p o n t he c o m plet i on of 
dr u g acc o u nta bilit y at t he st u d y  site u nless lo c al  destr uctio n is a gree d t o i n writ i n g.
1 5. 8 C o m pli a nce M o nit ori n g
C o m plia nce i s mo ni t or e d b y st u d y pers o n nel at t he st u d y sit e. S u bject i de nt ificati on will be 
verifie d a n d su bjects will recei ve eac h d ose of X A R T E MI S X R u n der direct o bser vat i on. 
St u d y  c o mplia nce will  b e verifie d b y m o nit ori n g .
1 6 S A F E T Y  
S u bjects will be cl osel y m o nit ore d f or si g ns of  o pi oid a d verse react i ons, w hic h i ncl u de b ut are 
n ot li mite d t o na usea, v o mit i n g, a n d res pirat or y de pressi on. 
1 6. 1 A d verse E ve nts
I n t he case of a serio us o pi oi d- relate d A E, nal o x o ne ma y be a d mi nistere d i ntra ve n o usl y t o t he 
s u bject at  t he i n vesti gat or’s discretio n .
Refer t o Secti o n 2 0 f or details o n t he ha n dli n g of A Es a n d S A Es.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5 8
M alli nc kr o dt
1 6. 2 Cli nic al L a b or at or y T ests
T he re q uire d cli nical la b orat or y tests are liste d i n At tac h me nt 1 . 
S a m ples f or cli nical la b orat or y testi n g ma y be c ollecte d u n der faste d or n o n -faste d c o n ditio ns 
f or all visits. T he date a n d ti me of all sa m ple c o llecti o n m ust be d oc u me nte d o n t he la b orat or y 
re p ort. Cli nical la b orat or y  s peci me ns ma y be pr ocesse d at t he st u d y sit e’s la b orat or y or 
s hi p pe d t o t he c ore la b orat or y, as a p plica ble.
He m at olo g y, ser u m c he mistr y, a n d uri nal ysis sa m ples will be c ollecte d at scree ni n g, c he c k -i n, 
a n d at st u d y exit  or earl y ter mi nat i on. 
I n a d diti on:

All fe male s u bjects will ha ve a ser u m or uri ne pre g na nc y test at t he scree ni n g, at c hec k -i n, 
a n d at st u d y e xit or earl y ter mi nati on. Res ults m ust be a vaila ble pri or t o d osi n g wit h 
X A R T E MI S X R . S u bjects wit h p osit i ve res ults will be i neli gi ble f or st u d y e ntr y. If 
ap plica ble, t he s u bject’s a gree me nt t o use c o ntrace ptio n will be rec or de d i n s o urce 
d oc u m e ntatio n.
O ut - of-R a n ge Scr ee ni n g L a b or at or y Val ues
Scree ni n g or c hec k -in la b orat or y val ues t hat are > 2 ti mes t he U L N of  t he refere nce ra n ges 
s pecifie d b y t he cli nical la b orat or y will e xcl u de t he s u bject fr o m t he st u d y ( wit h t he e xce pti on 
of  W B C Differe ntial v al ues) . E nr oll me nt of su bjects wi t h la b orat or y val ues t hat are bet wee n 1 
a n d 2 ti mes t he U L N , bel o w t he l o wer li mit of n or mal , or W B C differe ntial > 2 x t he U L N
will be left t o t he i n vesti gat or’s discreti on . Scree ni n g sa m ples f or la b orat or y  testi n g ma y be 
re dra w n 1 ti me t o c o nfir m o ut-of -ra n ge val ues.
O ut - of-R a n ge E xit L a b or at or y V al ues
St u d y  e xit/earl y ter mi nati on la b orat or y deter mi nati o ns t hat fall o utsi de t he s pecifie d refere nce
ra n ges will  be assesse d b y t he i n vesti gat or f or cli nical si g nifica nce. If t he o ut of ra n ge val ue is 
dee m e d t o be a cli nicall y si g nifica nt c ha n ge fr o m c hec k -i n b y t he i n vesti gat or, a n A E will be 
rec or de d. T he i n vesti gat or will c o nt i n ue t o m o nit or t he s u bject u ntil t he la b orat or y val ue 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
5 9
M alli nc kr o dt
ret ur ns t o n or mal, t he i n vesti gat or deter mi nes t hat f o ll ow- u p i s n o lo n ger m e dicall y necessar y, 
or t he s u bject is referre d t o a n o nst u d y p h ysicia n . If t he i n vesti gat or deter mi nes t he a b n or mal 
val ue is n ot a cli nical c o ncer n , t he i n vesti gat or’s e val uati on will be d oc u me nte d a n d n o f urt her 
actio n is re q ui re d.
U nsc he d ule d Cli nic al L a b or at or y Te sts
U nsc he d ule d cli nical la b orat or y tests ma y be perf or m e d as dee me d cli nicall y necessar y b y t he 
i n vesti gat or. T he u nsc he d ule d la b orat or y tests date a n d ti me of  c ollecti on will be rec or de d. 
1 6. 3 Me dic al a n d S ur gic al Hist or y 
Me dical a n d s ur gical hist or y  will be o btai ne d at scree ni n g. Me dical hist or y will i ncl u de a 
re vie w of t he f oll owi n g s yste m s: ge neral, der mat ol o gical, hea d, e yes, ears, n ose, a n d t hr oat 
( H E E N T), res pirat or y, car dio vasc ular, GI , ge nit o uri nar y, g y nec olo gi cal, e n d ocri ne, 
m usc ul os keletal, he mat ol o gical, ne ur o ps yc h o l ogical  a n d i m m u ne (aller gies). Hist orical a n d 
c urre nt me dical c o n dit i ons will be rec or de d i n t he s o urce d oc u me nts a n d e C R F. 
At  c hec k -i n eac h s u bject’s me dical hist or y will be re vie we d a n d u p date d t o i ncl u de a n y 
c ha n ges si nce scree ni n g. T he s ur gical pr oce d ure t hat is t he s u bject of t his st u d y  will be 
i ncl u de d i n t he s u bject’s me d ical hist or y.
1 6. 4 D ate of First D a y of L ast Me nstr u al Peri o d
T he date of  t he first da y of  t he last me nstr ual perio d f or p ost -me narc h e female s u bjects will be 
rec or de d at scree ni n g a n d c hec k-i n.
1 6. 5 De m o gr a p h y
T he date of birt h, ge n der, race, a n d et h nicit y of eac h s u bject will be rec or de d at scree ni n g .
1 6. 6 Hei g ht , We i g ht a n d B MI
Eac h s u bject’ s hei g ht a n d wei g ht will be meas ure d at scree ni n g, a n d wei g ht will be meas ure d 
at c hec k-i n. B MI will be calc ulate d usi n g t he f o ll owi n g f or m ula:
wei g ht ( k g)/ [ hei g ht ( m)]2  O R wei g ht ( k g)/ [ hei g ht (c m)] 2 × 1 0, 0 0 0

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6 0
M alli nc kr o dt
1 6. 7 P h ysic al E x a mi n ati o n
A br ief p h ysical e xa mi nati on, i ncl u di n g: H E E N T, ge neral a p peara nce, s ki n, nec k, t hr oat, 
c hest, heart, a b d o me n, e xtre mit ies, a n d ne ur ol o gical will be d o ne at scree ni n g, c hec k -i n, a n d 
st u d y exit  or earl y ter mi nat i on . T he date a n d ti me a n d fi n di n gs of scree ni n g, c hec k -i n a n d e xit 
p h ysical e xa mi nat i ons will be rec or de d. 
A n y c ha n ge fr o m v al ues o btai ne d at t he scree ni n g t hat is c o nsi dere d cli nicall y si g nifica nt b y 
t he i n vesti gat or will be rec or de d as a n A E.
1 6. 8 Vit al Si g ns
Vit al si g ns will be o btai ne d after t he s u bject has bee n seate d or recli ne d f or a mi ni m u m o f
5 mi n utes ( mi ni m u m) a n d will i ncl u de s yst olic a n d diast olic bl o o d press ures ( m m H g), p ul se 
rate ( beats/ mi n), a n d res pirat or y rate ( breat hs/ mi n). B ot h t he date a n d ti me f or all vit al si g n
meas ure me nts will be d oc u me nte d.
Vit al si g ns will be meas ure d at t he scree ni n g; c hec k-i n; wi t hi n 1 5 mi n utes pri or t o t he first a n d 
f ourt h d oses of X A R T E MI S X R ; at 1, 2, a n d 4 h o urs ( ± 1 5 mi n utes) after t he first a n d f ourt h 
d oses of X A R T E MI S X R ; wi t hi n 1 5 mi n utes pri or t o a n d 2 h o urs ( ± 1 5 mi n utes) after t he 
sec o n d a n d t hir d d oses of X A RT E MI S X R ; a n d at st u d y exit  or earl y ter mi nat i on.
Scr ee ni n g Vi t al Si g ns
Vit al si g ns s h o uld be wi t hi n a n acce pta ble ra n ge as deter mi ne d b y t he i n vesti gat or f or t he 
s u bject’s a ge. A s u bject wit h cli nicall y si g nifica nt vit al si g n a b n or malities as deter mi ne d b y 
t he i n vest i gat or at  scree ni n g or c hec k-i n d oes n ot q ualif y  for t he st u d y. H o we ver, a b n or mal
scree ni n g/ baseli ne vit al sig n s ma y be re peate d o nce . F or a m b ulat i n g s u bjects, re peat t he vital 
sig ns after t he s u bject has re mai ne d seate d f or a p pr o xi matel y 5 mi n utes wi t h feet o n t he fl o or 
a n d ar m s u p p orte d at heart le vel, if p ossi ble. 
O n -St u d y Vi t al Si g ns
If a n o n -st u d y vit al si g n val ue is dee me d t o be a cli nicall y si g nifica nt c ha n ge fr o m baseli ne b y 
t he i n vesti gat or or re q ui res a c ha n ge i n t he s u bject’s cli nical ma na ge me nt d uri n g t he st u d y, a n 
A E will be rec or de d . T he i n vesti gat or will c o nt i n ue t o m o nit or t he s u bject u ntil t he 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6 1
M alli nc kr o dt
meas ure me nt ret ur ns t o n or mal, or t he i n vesti gat or deter mi nes t hat f oll o w -u p is n o l o n ger 
m e dicall y necessar y, or t he s u bject is referre d t o a n o nst u d y p h ysicia n . If t he i n vesti gat or
deter mi nes t he c ha n ge is n ot cli nical l y si g nifica nt, t he i n vesti gat or’s e val uati on will be 
d oc u m e nte d a n d n o f urt her acti o n is re q uire d.
U nsc he d ule d Vi t al Si g n Asse ss me nts
A d dit i onal u nsc he d ule d vital si g n meas ure me nts ma y be perf or me d as dee me d cli nicall y 
necessar y  b y t he i n vesti gat or. T he date, ti me, a n d res ults of a n y u nsc he d ule d vital si g ns wil l 
be rec or de d. 
1 6. 9 B o d y Te m per at ure
B o d y t e mperat ure will be meas ure d at scree ni n g; c hec k-i n; wi t hi n 1 5 mi n utes pri or t o t he first 
a n d f ourt h X A R T E MI S X R d oses; at 1, 2, a n d 4 h o urs ( ± 1 5 mi n utes) aft er t he first a n d f ourt h 
X A R T E MI S X R ); wit hi n 1 5 mi n utes pri or t o a n d 2 h o urs ( ± 1 5 mi n utes) after t he sec o n d a n d
t hir d d oses of X A RT E MI S X R; a n d at st u d y exit  or earl y ter mi nat i on. T he sa me met h o d of 
meas ure me nt will be use d f or all assess me nts f or a si n gle s u bject .
Scr ee ni n g Te m per at ur e
B o d y  t e mperat ure s h o ul d be wit hi n a n acce pta ble ra n ge as deter mi ne d b y t he i n vesti gat or f or 
t he s u bject ’s a ge. A s u bject wit h cli nicall y si g nifica nt a b n or mal b o d y t e mperat ure as 
deter mi ne d b y t he i n vest i gat or at  scree ni ng, c hec k -i n or baseli ne will  be e xcl u de d fr o m 
parti ci pat i on i n t he st u d y. A n o ut-of -ra n ge te m perat ure ma y be re peate d o nce a p pr o xi matel y 5
mi n utes f o ll owi n g t he i nit ial assess me nt.
O n -st u d y Te m per at ur e
If a n o n -st u d y t e mperat ure val ue is dee me d t o be a cli nicall y si g nifica nt c ha n ge fr o m baseli ne
b y t he i n vesti gat or or re q uires a c ha n ge i n t he s u bject’s cli nical ma na ge me nt d uri n g t he st u d y, 
a n A E will be rec or de d. T he i n vesti gat or will c o nt i n ue t o m o nit or t he s u bject u ntil t he 
meas ure me nt ret ur ns t o n or mal, or t he i n vesti gat or deter mi nes t hat f oll o w -u p is n o l o n ger 
m e dicall y necessar y, or t he s u bject is referre d t o a n o nst u d y p h ysicia n. If t he i n vesti gat or

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6 2
M alli nc kr o dt
deter mi nes t he c ha n ge is n ot cli nical l y si g nifica nt, t he i n vesti gat or’s e val uati on will be 
d oc u m e nte d a n d n o f urt her acti o n is re q uire d.
U nsc he d ule d Te m p e r at ure Assess me nts
A d dit i onal u nsc he d ule d t e mperat ure m eas ure me nts ma y be perf or me d as dee me d cli nicall y 
necessar y  b y t he i n vesti gat or. T he date, ti me, a n d res ults of a n y u nsc he d ule d te m perat ure 
meas ure me nts wil l be rec or de d. 
1 6. 1 0 P ulse O xi metr y
Perce nta ge of o x y g e n sat uratio n will be deter mi ne d b y  a si n gle p ulse o xi metr y rea di n g at
scree ni n g, c hec k-i n, a nd s t u d y exit  or earl y ter mi natio n . C o nti n u o us p ulse o xi metr y  will be 
i nitiate d wit hi n 1 5 mi n utes pri or t o t he first d ose of X A RT E MI S X R a n d c o nti n ue u nt il 1 2 
h o urs aft er t he f ourt h d ose of X A R T E MI S X R (or earl y ter mi nat i on, if a p pr o priate ). O x y ge n 
sat urati o n ( %) will be rec or de d wit hi n 1 5 mi n utes pri or t o d osi n g a n d 1, 2, a n d 4 h o ur s aft er 
t he first a n d f ourt h d oses of X A R T E MI S X R ; a n d wit hi n 1 5 mi n utes pri or t o a n d 2 h o urs ( ± 
1 5 mi n utes) after t he sec o n d a n d t hir d d oses of X A RT E MI S X R.
O ut - of-r a n ge Scree ni n g P ulse O xi metr y
A s u bject wit h a scree ni n g, c hec k-i n or baseli ne p ulse o xi metr y  bel o w 9 5 % sat urati o n will be 
e xcl u de d fr o m parti ci pat i on i n t he st u d y. A n o ut -of -ra n ge scree ni n g p ulse o xi metr y ma y be 
re peate d o nce a p pr o xi matel y 5 mi n utes f oll o wi n g t he i nit ial assess me nt.
O ut - of-r a n ge O n -st u d y P ulse O xi metr y
A s u bject wit h o n -st u d y o x y ge n sat ur atio n < 9 2 % m ust ha ve p ulse o xi metr y  re peate d o nce 
a p pr o xi matel y 5 mi n utes after t he i nitial assess me nt. S u p ple me ntal o x y ge n will be 
a d mi nistere d t o a n y s u bject w h ose p ulse o xi metr y u p o n re peat e val uati o n re mai ns less t ha n 
9 2 % a n d s h o ul d be titrate d t o mai nt ai n t he s u bject’s baseli ne p ulse o xi metr y. T his le vel of 
h y p o xia will be c o nsi dere d a n A E . T he i n vesti gat or will c o nti n ue t o m o nit or t he s u bject u ntil 
t he p ulse o xi metr y ret ur ns t o n or mal, t he i n vesti gat or deter mi nes t hat f o ll ow- u p i s n o lo n ger 
me dicall y necessar y, or t he s u bject is referre d t o a n o nst u d y p h ysicia n . Trai ne d site pers o n nel 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6 3
M alli nc kr o dt
will be a vaila ble t o res p o n d t o s u bject e mer ge ncies d uri n g t he peri o d of c o nfi ne me nt, i n 
a d ditio n t o ha vi n g a cras h cart a n d e mer ge nc y e q ui p me nt i n cl ose pr o xi mit y.  
1 6. 1 1 El ectr oc ar di o gr a m
A 1 2- lea d E C G will be o btai ne d f or all s u bjects at scree ni n g, c hec k-i n, a n d st u d y exit  or earl y 
ter mi nati o n. T he date a n d ti me of  t he E C G must be d oc u m e nte d o n t he E C G traci n g. A n 
a p pr o priatel y trai ne d a n d e x perie nce d p h ysicia n m ust i nter pret t his E C G. Date, ti me, a n d 
cli nical para meters fr o m all E C G’ s will be e ntere d o n t he e C R F. 
A b n or m al S c r ee ni n g or C hec k -i n E C G
A s u bject wit h a n a b n or mal scree ni n g or c hec k -i n E C G w hic h is c o nsi dere d cli nicall y 
sig nifica nt b y  t he i n vesti gat or will be e xcl u de d fr o m st u d y  e ntr y. A re peat E C G ma y be d o ne
t o c o nfir m fi n di n gs. S u bjects wit h E C G a b n or malit ies n ot c o nsi dere d cli nicall y si g nifica nt 
ma y be e nr o lle d if m ut uall y a greea ble t o t he i n vesti gat or a n d M M. 
A b n or m al St u d y E xit or  E arl y Ter mi n ati o n E C G
A s u bject wit h c ha n ges i n t he E C G si nce t he scree ni n g a n d/ or c hec k-i n assess me nt s will ha ve 
a re peat E C G a p pr o xi matel y 1 5 mi n utes f o ll owi n g t he i nitial assess me nt. If t he s u bject’s E C G 
has n ot ret ur ne d t o baseli ne or res ol ve d f o ll owi n g t he re peat meas ure me nt, site pers o n nel will 
i m me diatel y notif y  t he i n vesti gat or of  t he a b n or mal meas ure me nt. A n A E will be o pe ne d if 
t he i n vesti gat or deter mi nes t he c ha n ge is cli nicall y si g nifica nt or re q ui res a c ha n ge i n t he 
s u bject’s cli nical ma na ge me nt. T he i n vesti gat or will c o nt i n ue t o m o nit or t he s u bject u ntil t he 
meas ure me nt ret ur ns t o n or mal, or t he i n vesti gat or deter mi nes t hat f oll o w -u p is n o l o n ger 
me dicall y necessar y, or t he s u bject is referre d t o a n o nst u d y p h ysicia n. If t he i n vesti gat or
deter mi nes t he c ha n ge is n ot cli nical l y si g nifica nt, t he i n vesti gat or’s e val uati on will be 
d oc u m e nte d a n d n o f urt her acti o n is re q uire d.
U nsc he d ule d E C G Assess me nts
A d dit i onal E C Gs ma y be perf or me d a n y t i me t hr o u g h o ut t he st u d y if dee me d necessar y t o 
d oc u m e nt or f oll o w -u p a n a d verse reacti o n.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6 4
M alli nc kr o dt
1 6. 1 2 P ai n E v al u ati o n
Pai n will be e val uate d b y t he s u bject usi n g N P R S (At tac h me nt 3) sc ores. Pai n assess me nts 
s h o uld al wa ys be c o m p lete d pri or t o all ot her pr oce d ures at a n y gi ve n t i me p oi nt .
B aseli ne P ai n Sc or es
S u bjects wit h a baseli ne N P R S sc ore of < 4 will be e xcl u de d fr o m  parti ci pat i on i n t he st u d y.
O n -st u d y P ai n Sc ores
Pai n will be e val uate d b y  t he s u bject usi n g N P R S sc ores wit hi n 1 0 mi n utes pri or t o a n d 1, 2, 
4, a n d 8 h o urs ( ± 1 5 mi n utes ) aft er t he first X A RT E MI S X R d ose.
After t he first d ose of X A R T E MI S X R, pai n will be e val uate d usi n g t he N P R S wit hi n 3 0 
mi n utes pri or t o t he sc he d ule d ti me of eac h s u bse q ue nt X A RT E MI S X R d ose at 1 2, 2 4, a n d 
3 6 h o urs . If t he pai n sc ore is ≥4 , s u bjects will recei ve t he ne xt d ose as sc he d ule d . If t he pai n 
sc ore is < 4 , t he N P R S will be re peate d e ver y 3 0 mi n utes ( ± 5 mi n utes) a n d s u bjects will 
recei ve t heir X A RT E MI S X R d ose w he n a n d if t heir pai n sc ore is ≥4 . T he pai n sc ores ca n be 
re peate d u p t o 1 h o ur after t he sc he d ule d d osi n g ti me. S u bjects w h ose pai n sc ores re mai n < 4
d uri n g t hi s ti me will n ot q ualif y f or f urt h er st u d y dr u g a d mi nistratio n , b ut will ha ve bl o o d 
c ollecte d f or P K a nal ysis o nl y  at 1 0 mi n utes pri or t o t he ori gi nall y sc he d ule d d osi n g ti me. N o 
a d ditio nal  blo o d will  be c ollecte d f or P K a n d su bjects are eli gi ble t o sta y  in t he st u d y  a n d 
c o nti n ue t o ha ve a ll safety assess me nts u nt il st u d y e xit or ma y pr ocee d t o earl y ter mi nat i on
assess me nts.
If d osi n g is dela ye d as o utli ne d a b o ve, all s u bse q ue nt d oses will be a d mi nistere d as per t he 
ori gi nal  sc he d ule (ie, 1 2, 2 4, a n d 3 6 h o urs after t he first X A R T E MI S X R d ose).
1 6. 1 3 I m p aire d J u d g me nt E v al u ati o n
To  e ns ure s u bject safety,  s u bjects will be e val uate d f or t he prese nce of li g ht hea de d ness, 
di zzi ness, se dat i on, c o nf usi o n, vis ual dist ur ba nces, wea k ness or u nc o or di nate d m uscle 
m o ve me nts pri or t o l ea vi n g t he st u d y sit e after t he last bl o o d dra w a n d c o mpleti o n of  st u d y 
exit  pr oce d ures . T he i m paire d j u d g me nt e val uati on als o will be a d mi nistere d t o s u bjects at 
Earl y T er mi nati o n. 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6 5
M alli nc kr o dt
T he prese nce of a n y o f t he a b o ve s y m pt o ms s h o ul d be rec or de d as a n A E a n d will necessitate 
c o ntin ue d c o nfi ne me nt of t he s u bject u nt il s uc h s y m pt o ms ha ve cease d. T he date a n d ti me of 
t he i m paire d j u d g me nt e val uati o n will be d oc u me nte d. S u bjects will be disc har ge d w he n 
dee m e d a p pr o priate b y t he i n vesti gat or.
1 7 P H A R M A C O KI N E TI C S
1 7. 1 Bl o o d C ollecti o n a n d Pr oces si n g
W h o le bl o o d ( 2 m L) will be c o llecte d i n prec hille d vac u u m bl o o d c ollecti on t u bes, c o ntai ni n g 
K 2E D T A as t he a ntic oa g ula nt. Blo o d will be c ollecte d f or deter mi nat i on of plas ma 
c o nce ntrati o ns of O C a n d A PA P .
1 7. 1. 1 Si n gle D ose P K S a m pli n g 
Bl o o d sa m ples will be c ollecte d wit hi n 1 0 mi n utes pri or t o t he first d ose of X A R T E MI S X R ;
at 1 5 a n d 4 5 mi n utes ( ± 5 mi n utes) ; a n d at 2, 4, 6, 8, 1 0, a n d 1 2 h o urs ( ± 1 0 mi n utes) aft er t he 
first d ose of X A R T E MI S X R . T he 1 2-h o ur bl o o d sa m ple m ust be c ollecte d at t he sc he d ule d 
ti me pri or t o t he sec o n d X A RT E MI S X R d ose e ve n t h o u g h t he act ual ti me of  d osi n g is 
de pe n de nt o n s u bject’s pai n sc ore (see Secti o n 1 6. 1 2 ). T he ti me a n d date of c ollecti on f or eac h 
sa m ple will be rec or de d.
1 7. 1. 2 M u lti ple D ose P K S a m pli n g 
Ve n o us b l oo d sa m ples f or P K a nal ysis will be c ollecte d wit hi n 1 0 mi n utes pri or t o t he 
sc he d ule d ti me of a d mi nistratio n o f t he t hir d a n d f o urt h d ose of  X A R T E MI S X R , e ve n t h o u g h 
t he act ual ti me of d osi n g is de pe n de nt o n s u bject’s pai n score (see  Secti o n 1 6. 1 2 ).
A d dit i onal bl o o d sa m pl es f or P K a nal ysis will be c ollecte d at 1 5 t o 3 0 mi n utes, 4 5 t o 9 0 
mi n utes , 2 t o 4 h o urs, a n d 6 t o 8 h o ur s aft er ( ± 1 0 mi n utes) aft er , t he f ourt h d ose of 
X A R T E MI S X R . I n a d ditio n, o ne sa m ple will be c ollecte d d uri n g t he 1 2 t o 1 8 h o ur ti me 
wi n d o w after t he f o urt h d ose, if f urt her pai n treat me nt is n ot re q uire d. If f urt her treat me nt f or 
pai n is re q uire d, t he fi nal bl o o d sa mple will be c ollecte d at  1 2 h o urs ( ± 1 0 mi n utes) after t he 
f ourt h d ose, b ut pri or t o t he a n y f urt her pai n treat me nt.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6 6
M alli nc kr o dt
It is rec o m me n de d t hat a n i n d welli n g i ntra ve n o us cat heter (e g, He p well/ He p-l oc k) be place d 
t o re d uce s u bject disc omf o rt ass ociate d wit h m ulti ple blo o d sa m pli n gs. 
1 7. 1. 3 To t al Vol u me of Bl o o d C ol lecte d
S u bjects will ha ve a n estima t e d m a xi m u m t ot al of  a p pr o xima tel y50 m L of  blo o d dra w n d uri n g
t he c o urse of  t he st u d y ( 32 m L f or P K sa m pli n g a n d 1 8 m L for l a b orat or y safety assess me nts).
T his est i mate d m a xi m u m t ot al bl o o d v ol u me t o be dra w n fr o m s u bjects is well wi t hi n t he
lim its s pe cifie d b y m u lti ple or g a nizat i ons a n d IR Bs, i ncl u di n g t he Natio nal I nstit ut es of Heal t h
Cli nical Ce nt er, w hic h reco m m e n ds t hat t ot al b lo o d t o be dra w n f or researc h p ur p oses be less
t ha n 7 m L/ k g per 6 wee ks (a n d < 4 5 0 m L) a n d less t ha n 3 m L/ k g per si n gle bl o o d wit h dra wal.
1 7. 1. 4 S a m ple Pr ocessi n g a n d S hi p pi n g
S pecific i nstr ucti o ns f or sa m ple pr ocessi n g a n d s hi p pi n g will be pr o vi de d i n a se parate 
d oc u m e nt.
1 7. 2 P h ar m ac o ki netic A n al ysis
1 7. 2. 1 Bi o a n al ytic al Met h o d ol o g y
T he sa m ples f or meas ure me nt of O C a n d A P A P will be a nal yze d b y a vali date d li q ui d 
c hr o mat o gra p h y -ta n de m mass s pectr o metr y (L C -M S/ M S ) assa y. T he lo wer li mi t of 
q ua nt ificati on is 0. 1 0 0 n g/ m L for O C a n d 1 0 0 n g/ m L  for A P A P . T he q ua ntitati ve L C -M S/ M S 
met h o d uses A P A P - d4 a n d O C- d6 as t he i nter nal sta n dar ds. T he met h o d has bee n vali date d f or 
li nearity,  precisio n , acc urac y, r u g ge d ness, rec o ver y, a n d s pecificity.  I n a d ditio n , sta bility 
st u dies ha ve bee n carrie d o ut u n der s h ort - a n d l o n g -t er m c o n ditio n s. T he m et h o d has bee n 
a de q uate l y vali date d f or t he a nal ysis of plas ma sa m ples fr o m t his st u d y.
1 7. 2. 2 P h ar m ac o ki netic P ar a meters
P har mac o ki net ic para meters will be e val uate d f or P K a nal ysis p o p ulati on. T he P K para m eters
t o be estim ate d will i ncl u de t he fol l owi n g: 
Si n gle D ose P K ( N o nc o mpart me ntal  A nal ysis ):

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6 7
M alli nc kr o dt
T he f o ll owi n g si n gle-d ose P K para meters will be deter mi ne d f or O C a n d A P A P after t he first 
d ose of X A RT E MI S X R ( p re d ose at 0 h o ur t o 1 2 h o urs p ost d ose) usi n g n o nc o m part me ntal
a nal ysis:

Area u n der t he c o nce ntrati o n -ti me c ur ve o ver t he first d osi n g i nter val ( A U C 0 -1 2 h).

Ti me dela y bet wee n dr u g a d mi nistrati o n at H o ur 0 a n d t he o nset of a bs or pti o n (t la g).

O bser ve d ma xi m u m dr u g c o nce ntrati o n ( C ma x ).

Ti me of ma xi m u m o bser ve d plas ma c o nce ntrati o n ( T ma x ). 

A p pare nt ter mi nal eli mi nat i on h alf -life (t1/ 2
x).

A p pare nt ter mi nal eli mi nat i on rate c o nsta nt ( λx ).
N o val ue f or λ x a n d t 1/ 2
x will be re p ort e d for cases t hat d o n ot e x hi bit a t erm i nal l o g-li near
p hase i n t he c o nce n tratio n vers us ti m e pr ofile or if t he c oefficie nt of deter mi nat i on (r 2) < 0. 9 0 . 
T he λ x will n ot be esti mate d if t here are less t ha n 3 ti me p o i nts i n t he ter mi nal l o g-li near p hase 
( n ot i ncl u di n g Tma x ).

T he pl as ma c o nce ntrati o n s of O C a n d A P A P will be a nal yze d f or eac h s u bject usi n g 
n o nc o m part me nt al a nal ysis met h o d s. T he Cma x a n d T ma x will be deter mi ne d direct l y fr om 
t he o bser ve d c o nce ntrati o n data. T he λ x will be esti mate d b y a l o g -li near re gressi o n of t he 
ter mi nal m on oe x p o ne nt ial p ortio n of  t he o bser ve d plas ma c o nce ntrati o ns after t he first. 
T he half -life will be calc ulate d as 0. 6 9 3/ λx. Usi n g t he si n gle-d ose data, t he area u n der t he 
c o nce ntrati o n-ti me c ur ve fr om 0 t o 1 2 h o urs after t he first d ose (A U C 0 -1 2 h) will be 
calc ulate d.
Si n gle/ M ult i ple D ose P K ( P o p ulati o n P K A nal ysis ):
P o p ul at i on P K a nal yses will be c o n d ucte d via n o nli near mi xe d effect m o deli n g usi n g t he 
n o nli near mi xe d -effects mo deli n g s oft ware N O N M E M ® , Versio n  7 or hig her (  
 
). A d ul t P K data fr o m  X A R T E MI S -X R P hase 1 st u dies 
will be ut ilize d f or de vel o pi n g t he i nitial mo dels f or b ot h O C a n d A P A P . A c o variate a nal ysis 
will be u n derta ke n t o deter mi ne t he c o ntri b ut i on of de m o gra p hi c a n d disease c haracterist ics t o 
varia bilit y i n O C a n d A P A P P K . I n di vi d ual pre dicte d O C a n d A P A P P K para meters (cleara nce 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6 8
M alli nc kr o dt
a n d v o l ume of distri b ut i on) a n d e x p os ure metrics( mi ni m u m plas ma c o nce ntrati o n at stea d y -
state, t he pea k plas ma c o nce ntrati o n at stea d y state, t he a vera ge c o nce ntrati o n at stea d y-state, 
t he area u n der t he plas ma ti me c o nce ntrati o n c ur ve at stea d y -state a n d ot her para meters) will 
be deri ve d fr o m t h e fi nal m o del.
1 8 L A B O R A T O R Y D E T E R MI N A TI O N S
Refer t o t he Sc he d ule of St u d y  E ve nts (Err or! Refere nce s o ur ce n ot f o u n d. ) f or ti me p oi nts 
f or c ollecti on o f la b orat or y test sa mples. At tac h me nt 4 lists cli nical la b orat or y tests re q uire d 
f or t his st u d y.
1 9 S T A T I S TI C A L M E T H O D S A N D P L A N N E D A N A L Y SI S
1 9. 1 Ge ner al C o nsi der ati o ns
Data fr o m t he site(s) will be liste d, a nal yze d, a n d i ncl u de d i n t he cli nical st u d y  re p ort. 
Descri pt i ve statistics f or c o nti n u o us varia bles will i ncl u de n u m ber of val ues ( N), mea n, S D, 
me dia n, mi ni m u m, a n d ma xi m u m, u nless ot her wise n ote d. Fre q ue nc y  a n d perce nta ges will be 
calc ulate d f or cate g orical varia bles. All stati stical si g nifica nce testi n g will be t w o-taile d usi n g 
α = 0. 0 5, u nless ot her wise s pecifie d. Data s u m mar y a n d a nal yses will be perf or me d wit h 
S A S ® 9. 2 or hi g her.
1 9. 2 A n al ysis P o p ul ati o ns
T he f o ll owi n g p o p ul at i ons will be i de nt ifie d a n d a nal yze d i n t his st u d y:

S af et y P o p ul at i on – all s u bjects e nr olle d i n t he st u d y t hat recei ve d a n y q ua ntity of  
X A R T E MI S X R . T his p o p ulati on will be use d as t he pri mar y safet y p o p ul at i on. 

P K P o p ulat i on - all s u bjects w h o recei ve d at least 1 d ose of X A RT E MI S X R a n d ha ve 
pr o vi de d at l east 1 blo o d sa m ples f or t he m eas ure me nt of  O C a n d A P A P . T his p o p ulati o n 
will be use d t o f or p o p ulat i on P K a nal ysis.

Si n gle -d ose P K p o p ul at i on – All s u bjects w h o recei ve d at least o ne d ose of XA R T E MI S 
X R a n d ha ve pr o vi de d at least 6 bl o o d sa m ples f or meas ure me nt of O C a n d A P A P after 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
6 9
M alli nc kr o dt
t he first d ose of X A RT E MI S X R. T hi s p o p ulat i on will be use d f or si n gle -d ose P K
a nal ysis.

M o difie d Int e nt -t o-Treat ( mI T T ) P o p ulat i on – All s u bjects w h o recei ve d at least 1 d ose of  
X A R T E MI S X R a n d ha ve at least 1 p ost baseli ne pai n i nte nsit y meas ure me nt. T his 
p o p ul at i on will be use d f or a nal ysis o f pai n i nte nsit y.
1 9. 3 S u bject C h ar acteristics
1 9. 3. 1 De m o gr a p hics
S u bjects i n t he S afet y P o p ul at i on will be i ncl u de d i n a list i n g of s u bject de mo gra p hic 
c haracterist ics (incl u di n g fre q ue ncies a n d perce nta ges of s u bjects i n t hree a ge gr o u ps: 1 2 t o
1 3, 1 4 t o 1 5, a n d 1 6 t o 1 7 y ear s of a ge). S u m mar y statistics will be prese nte d f or t he S afet y 
P o p ul at i on.  
1 9. 3. 2 Me dic al a n d S ur gic al Hist or y
T he m e dical a n d s ur gical hist or y data will n ot be s u m marize d b ut will be prese nte d i n a data 
listi n g f or s u bjects i n t he S afet y P o p ul at i on.
1 9. 3. 3 C o nc o mit a nt T re at me nts
C o nc o mita nt treat me nts will n ot be s u m marize d b ut will be prese nte d i n a data list i n g f or 
s u bjects i n t he S afet y P o p ulati o n .
1 9. 3. 4 S u bject Dis p ositi o n a n d E x p os ure t o X A R T E MI S X R
T he n u m ber of s u bjects w h o c o m plete t he st u d y  a n d w h o d o n ot c o mplete t he st u d y, b ot h 
o verall a n d acc or di n g t o reas o ns f or disc o nti n uati o n fr o m t he st u d y, will be s u m marize d f or 
t he Safet y P o p ulati o n . S u bject dis p ositio n will  be prese nte d i n a data list i n g. T he n u m ber of 
s u bjects w h o recei ve d a n y treat me nt as well as t he n u m ber of d oses recei ve d will als o be 
s u m marize d. T he n u m ber of s u bjects fr o m eac h a nal ysis p o p ulat i on will be s u m marize d a n d 
prese nte d.  

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7 0
M alli nc kr o dt
1 9. 4 P h ar m ac o ki netic a n d St atistic al A n al ysis
Si n gle d ose P K para m eters will be s u m marize d usi n g t he S i n gle-d ose P K P o p ul at i on. 
P o p ul at i on P K para meters will be s u m marize d usi n g t he P K P o p ulat i on. I n a d diti on, 
in di vi d ual  plas ma O C a n d A PA P c o nce ntrati o ns will be s u m marize d at eac h ti me p o i nt 
Descri pt i ve statistics re p orte d will i ncl u de t he arit h metic mea n, S D, C V , ge o metric mea n, 
mi ni m u m, ma xi m u m, a n d me dia n. T he ge o metric mea n will n ot be re p orte d f or T
ma x a n d tla g.
I n di vi d ual c o nce ntrati o n pl ots a n d mea n data gra p hs will be pr o d uce d usi n g b ot h li near a n d 
se mil o garith mic scales.
1 9. 5 S afet y A n al ysis 
S af et y listi n gs will re p ort data fr o m s u bjects i n t he S afet y P o p ul at i on.  Safet y s u m mar y ta bles 
will be prese nte d f or b ot h t he Safet y  P o p ulat i on.   
1 9. 5. 1 A d verse E ve nts
A d verse e ve nts will be c o de d usi n g Me d D R A. All A Es will be prese nte d i n a data list i n g. 
O nl y treat me nt e mer ge nt a d verse e ve nts ( T E A Es) will be i ncl u de d i n all s u m maries.
T E A Es will be defi ne d as a n e ve nt t hat e mer ges d uri n g treat me nt ha vi n g bee n a bse nt 
pretreat m e nt, or w orse ns relat i ve t o t he pretreat me nt state (ie, occ urri n g after t he first 
a d mi nistrati o n of X A R T E MI S X R ).
Treat me nt e mer ge nt a d verse e ve nts, treat me nt relate d T E A Es, se verit y of  T E A Es, a n d T E A Es 
lea di n g t o earl y disc o nti n uati on will be s u m marize d b y s yste m or ga n class a n d preferre d ter m 
f or all d ose d s u bjects. All T E A Es lea di n g t o earl y disc o nti n uat i on will  be prese nte d i n data 
listi n gs.
F or t hi s st u d y, t he h os pitalizati on f or t he q ualif yi n g st u d y pr oce d ure i s n ot c o nsi dere d a n A E.
1 9. 5. 2 Cli nic al L a b or at or y T ests
S u m mar y  statistics f or cli nical la b orat or y tests will be calc ulate d at eac h assess me nt ti me 
p oi nt as well as f or t heir c ha n ges fr o m baseli ne f or he mat ol o g y  a n d ser u m c he mistr y test 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7 1
M alli nc kr o dt
res ults. Cli ni call y si g nifica nt c ha n ges fr o m baseli ne assesse d as A Es will be prese nte d i n a 
data list i n g.
1 9. 5. 3 P h ysic al E x a mi n ati o n Fi n di n gs
Cli nicall y si g nifica nt c ha n ges fr o m baseli ne assesse d as A Es will be prese nte d i n a data 
listi n g.
1 9. 5. 4 Electr oc ar di o gr a m Fi n di n gs
E C G mea s ures at eac h assess me nt ti me p oi nt a n d c ha n ges fr o m baseli ne ( pre d ose) f or t he 
meas ures of heart rate, P R i nter val, Q R S i nter val, Q T i nter val c orrecte d f or heart rate usi n g 
Bazett’ s f or mula , a n d R R i nter val at eac h ti me p oi nt will be s u m marize d. Cli nicall y 
sig nifica nt c ha n ges fr o m baseli ne assesse d as A Es will be prese nte d i n a data list i n g.
1 9. 5. 5 Vit al Si g ns , Te m per at ure a n d P ulse O xi metr y
Act ual  val ues a n d c ha n ges fr o m baseli ne f or vital si g ns ( diast olic bl o o d press ure, s y st olic 
bl o o d press ure, res pirat or y  r ate, p ulse rate), b o d y t e mperat ure , a n d p ulse o xi metr y will be 
s u m marize d f or eac h ti me p oi nt. 
1 9. 5. 6 I m p aire d J u d g me nt E v al u ati o n
T he i m paire d j u d g me nt e val uat i ons will n ot be prese nte d i n a data list i n g. 
1 9. 6 P ai n I nte nsit y A n al ysis
P ai n i nte nsit y sc ores ( N P R S), as well as pai n i nte nsit y sc ore c ha n ge fr om baseli ne, will be 
s u m marize d b y t i me p oi nt usi n g t he mI T T p o p ulati o n . N o i m p utati o n of missi n g val ues or 
a djust m e nt fr o m t he i m pact of resc ue me dicati on use will be use d.
1 9. 7 I nteri m A n al ysis
N o i nt eri m a nal ysis o f t he data is pla n ne d.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7 2
M alli nc kr o dt
1 9. 8 St atistic al P o wer a n d S a m ple Size C o nsi der ati o ns
Cl eara nce a n d v olu me of distri b ut i on were c o m p ute d f or O C a n d A P A P i n t w o X A R T E MI S 
X R a d ult P K st u dies ( St u di es C O V 1 5 0 0 0 1 7 1 a n d C O V 1 5 0 0 0 2 5 6 ). T he p oi nt esti mate of t he 
sta n dar d de viat i on f or t he v ol ume of distri b ut i on f or A P A P was t he hi g hest a m o n g t he 
sta n dar d de viati ons of t hese t w o l o g -tra nsf or me d P K para meters ( 0. 4 1). T heref ore, a 
c o nser vati ve est i mate f or t he sta n dar d de viati o n of 0. 5 0 i s use d.
I n or der t o tar get a 9 5 % CI wit hi n 6 0 % a n d 1 4 0 % of t he ge o metric mea n esti mates of t he 
cleara nce a n d v olu me of distri b ut i on f or X A R T E MI S X R wit h 8 0 % p o wer , a t otal of 1 4 
s u bjects m ust c o m plete d osi n g (2 or m o re d oses), P K bl o o d c ollecti ons a n d pr o vi de P K data 
( Wa n g et al 2 0 1 2).T he sa m ple size of 4 8 e nr o lle d s u bjects is pla n ne d t o res ult i n at least 2 5 
s u bjects recei vi n g 2 or m or e d ose s of  X A R T E MI S X R . It is esti mate d t hat in or der t o e nr oll 
4 8 s u bjects , a p pr o xi matel y 7 2 i n di vi d uals will nee d t o be scree ne d.
1 9. 9 De vi ati o ns F r o m St atistic al A n al ysis Pl a n
A n y de viat i ons fr om t he pla n ne d statistical a nal ysis will be descri be d a n d j ustifie d i n t he fi nal 
cli nical st u d y re p ort as a p pr o priate.
2 0 A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S
2 0. 1 S afet y
F or safet y i nf or mati on o n X A R T E MI S X R , refer t o t he m ost rece nt versi ons of  t he I B a n d PI 
(M N K - 7 9 5 I B 2 0 14 , X A R T E MI S X R PI 2 0 1 4) . F or t he i b u pr ofe n resc ue me dicati on (if use d) ,
t he PI (I b u pr ofe n PI 2 0 1 4 ) will be use d as t he refere nce f or safet y i nf or mati on.
2 0. 2 Defi niti o ns
2 0. 2. 1 A d verse E ve nt 
A n A E is an y u nt o war d or u n desira ble me dical occ urre nce i n a s u bject w h o is a d mi nistere d a n 
in vesti gat i onal m e dici nal p r o d uct, w hic h d oes n ot necessaril y ha ve t o ha ve a ca usal 
r elat i ons hi p wit h t his treat me nt. E xa m ples of A Es i ncl u de b ut are n ot li mite d t o:

Cli nicall y si g nifica nt lab orat or y  fi n di n gs

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7 3
M alli nc kr o dt

Cli nical l y si g nifica nt c ha n ges i n p h ysical e xa mi nati o n fi n di n gs

A n A E occ urri n g d ue t o in vesti gati o nal m e dici nal p r o d uct o v er d ose w het her acci de ntal 
or i nte nt i onal

A n A E occ urri n g fr o m in vest i gati onal m e dici nal p r o d uct a b use

A n A E ass ociate d wit h in vest i gati onal m e dici nal p r o d uct wit h dra wal
2 0. 2. 2 U n e xpecte d A d verse E ve nt
A n u ne x pecte d A E is defi ne d as a n A E, t he nat ure a n d se verity of  w hic h is n ot c o nsiste nt wit h 
t he a p plica ble pr o d uct i nf or mat i on i n t he m ost rece nt versi on of t he In vest i gat or’s Br oc h ure
a n d t he a p pe n de d pac ka ge i nsert .
2 0. 2. 3 Seri o us A d verse E ve nt 
A n S A E is defi ne d as a n y u nt o war d me dical occ urre nce t hat at a n y d ose res ults i n a n y of t he 
f oll owi n g o utc o m es:

Deat h .

A life-t hreate ni n g A E.

I n patient  h os pitalizati on or pr ol o n gat i on of e xist i n g h os pitalizati on.

A persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct 
n or m al lif e fu nct i ons .

Res ults i n a c o n ge nital a n o ma l y/ birt h defect.

I mp orta nt m e dical e ve nts t hat ma y n ot res ult i n deat h, be life -t hreate ni n g, or re q uire 
h os pi talizatio n ma y  be c o nsi dere d serio us w he n, base d u p o n a p pr o priate me dical
j ud g me nt, ma y je o par dize t he patie nt or s u bject a n d ma y re q uir e me dical or s ur gical 
i nter ve nt i on t o pre ve nt o ne of  t he o utc o mes liste d a b o ve. E xa m ples of s uc h me dical 
e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y 
de part m e nt or at h o m e, blo o d d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt 
h os pi talizatio n, or t he de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7 4
M alli nc kr o dt
2 0. 2. 4 De at h 
Deat h is a n o utc o me of a n e ve nt. T he e ve nt t hat res ulte d i n deat h s h o ul d be rec or de d a n d 
re p orte d o n t he S A E F or m. All ca uses o f deat h m ust be re p orte d as S A Es. T he i n vest i gat or 
s h o uld ma ke e ver y  eff ort t o o btai n a n d se n d deat h certificates a n d a ut o ps y re p orts t o 
Malli nc kr o dt.
2 0. 2. 5 Life -t hre ate ni n g E ve nt 
A life-t hreate ni n g e ve nt refers t o i m me diate ris k of deat h as t he e ve nt occ urre d per t he 
re p orter. A life-t hreate ni n g e ve nt d oes n ot i ncl u de a n e ve nt t hat, ha d it occ urre d i n a m ore 
se vere f or m, mi g ht ha ve ca use d deat h b ut, as it act uall y occ urre d, di d n ot create a n i m me diate 
ris k of deat h. F or e xa m ple, he patitis t hat res ol ve d wit h o ut e vi de nce of he patic fail ure w o ul d 
n ot be c o nsi dere d life -t hreate ni n g, e ve n t h o u g h he patitis of a m ore se vere nat ure ca n be fatal. 
Si milarl y , a n aller gic reacti on res ult i n g i n a n gi oe de ma of t he face w o ul d n ot be life -
t hreate ni n g, e ve n t h o u g h a n gi oe de ma of t he lar y n x, aller gic br o nc h os pas m, or a na p h yla xis ca n 
be fatal.
2 0. 2. 6 H os pit aliz ati o n
H os pitalizati o n is defi ne d as a n official a d missi o n t o a h os pital. H os pitalizat i on or 
pr ol o n gati o n of  a h os pitalizati on c o nst itutes a criteri o n f or a n A E t o be seri o us; h o we ver, it is 
n ot i n itself c o nsi dere d a n S A E. I n a bse nce of a n A E, a h os pi talizati on or pr ol o n gat i on of a 
h os pi talizatio n s h o ul d n ot be re p orte d b y  t he i n vesti gat or as a n S A E. Suc h s ituati o ns i ncl u de, 
b ut are n ot li mite d t o, t he f oll o wi n g:

A h os pi talizati on or pr ol o n gati o n of h os pitalizati o n is nee de d f or a pr oce d ure re q uire d 
b y t he pr ot oc ol .

A h os pi talizati on or pr ol o n gati o n of h os pitalizati o n is part of a r o uti ne pr oce d ure 
f oll owe d b y t he ce nter (e g, ste nt re m o val after s ur ger y ). T his s h o uld be rec or de d i n t he 
st u d y file.

A h os pi talizati on f or a pree xisti n g c o n diti on t hat has n ot w orse ne d .

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7 5
M alli nc kr o dt
N ote t hat t he f oll owi n g h os pi talizatio ns are n ot c o nsi dere d S A Es i n Malli nc kr o dt
cli nical 
st u dies: 

A visit t o t he e mer ge nc y de part m e nt or ot her h os pital de part me nt of less t ha n 2 4 h o urs 
t hat d oes n ot res ult i n a d missi o n ( u nless c o nsi dere d "i m p orta nt me d ical e ve nt" or 
life-t hreate ni n g e ve nt).
2 0. 3 A d verse E ve nt a n d Seri o us A d verse E ve nt Cl assific ati o ns
2 0. 3. 1 In vesti g ati o n al M e dici n al P r o d uct Rel ate d ness
T he f oll owi n g cl assificat i ons s h o ul d be use d w he n e val uat i n g t he relati ons hi p of A Es or S A Es 
t o st u d y treat me nt (Ta ble 2 0 - 1).
Ta ble 2 0 - 1: A d verse E ve nt Rel ati o ns hi ps
Rel ati o ns hi p 
Defi niti o n
N ot Relate d 
N o relati o ns hi p bet wee n t he e x perie nce a n d t he a d mi nistrati o n of st u d y 
treat me nt; relate d t o ot her eti ol o gies s uc h as c o nc o mita nt me dicati o ns or 
s u bject’s cli nical state.
U nli kel y Relate d 
T he c urre nt state of k n o wle d ge i n dicates t hat a relati o ns hi p is u nli kel y.
P ossi bl y Relate d 
A reacti o n t hat f oll o ws a pla usi ble te m p oral se q ue nce fr o m a d mi nist rati o n of t he 
st u d y treat me nt a n d f oll o ws a k n o w n res p o nse patter n t o t he s us pecte d st u d y 
treat me nt. T he reacti o n mi g ht ha ve bee n pr o d uce d b y t he s u bject’s cli nical state 
or ot her m o des of t hera p y a d mi nistere d t o t he s u bject.
Relate d
A reacti o n t hat f oll o ws a pla usi ble te m p oral se q ue nce fr o m a d mi nistrati o n of t he 
st u d y treat me nt a n d f oll o ws a k n o w n res p o nse patter n t o t he s us pecte d st u d y 
treat me nt a n d ca n be c o nfir me d wit h a p ositi ve re-c halle n ge test or s u p p orti n g 
la b orat or y data.
2 0. 3. 2 Se verit y Assess me nt
F or p ur p oses of c o nsiste nc y , if re q uire d t he i n vesti gat or ma y use t he i nte nsity gra des 
prese nte d i n  Ta ble 2 0 - 2. 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7 6
M alli nc kr o dt
Ta ble 2 0 - 2: A d verse E ve nt Se verit y Gr a des
Gr a de 
Defi niti o n
Mil d 
D oe s n ot i nterfere wit h s u bject's us ual f u ncti o n a n d acti vities
M o derate 
I nterferes t o s o me e xte nt wit h s u bject's us ual f u ncti o n a n d acti vities
Se ver e 
I nterferes si g nifica ntl y wit h s u bject's us ual f u ncti o n a n d acti vities
If a n A E i ncreases i n se verity (e g, fr om m o derate t o se vere); decreases i n se verit y (eg , 
c ha n ges fr o m m o derate t o mil d); or t here is a c ha n ge i n seri o us ness, a ne w A E will be o pe ne d 
a n d t he ori gi nal A E will be cl ose d. If a n A E is st ill o n g oi n g at t he ti me o f a s u bject’s 
c o mplet i on of t h e fol l ow- u p tel e p h o ne call, t he e ve nt will be mar ke d as o n g oi n g i n t he e C R F 
a n d t he res olut i on /st o p date a n d ti me will be left bla n k. 
To  e ns ure t here is n o c o nf usi o n or mis u n dersta n di n g of t he differe nce bet wee n t he ter ms 
“serio us” a n d “se vere,” w hic h are n ot s y n o n y m o us, t he f o ll owi n g n ote of clarificat i on is 
pr o vi de d:
T he ter m  “se vere” is use d t o descri be t he i nte nsit y (se verity) of a s pecific e ve nt (as i n mil d, 
m o derate, or se vere m y o c ar di al i nfarct i on) ; t he e ve nt itself, h o we ver, ma y be of relati vel y 
mi n or m e dical i m p orta nce (s uc h as a se vere hea dac he). T his is n ot t he sa me as “seri o us,” 
w hic h is base d o n t he s u bject/e ve nt o utc o me or acti o n cri t eria us uall y ass ociate d wit h e ve nts 
t hat p ose a t hreat t o a s u bject's life or f u nct i oni n g. Seri o us ness ( n ot se v erit y) ser ves as a g ui de 
f or defi ni n g re g ulat or y re p orti n g o bli gati o ns.
2 0. 4 A d verse E ve nt a n d Seri o us A d verse E ve nt C o llecti o n, Rec or di n g a n d 
Re p orti n g
A Es a n d S A Es will be c o llecte d fr om si g ni n g of t he I C F t hr o u g h c o m plet i on of t he f o ll ow- u p 
t ele p h o ne call, w hic h will ta ke place 7 ( ± 2 ) da y s after t he last d ose of X A R T E MI S X R or 
earl y ter mi nati on. T he i n vesti gat or is re q uire d t o c ollect t he A E or S A E re gar dless of t he 
se verity of  t he e ve nt or its r elat i ons hi p t o st u d y  tr e at me nt. T he i n vest i gat or m ust f oll ow u p o n 
all A E s a n d S A Es u ntil t he e ve nt has res ol ve d or sta bilize d, or at s uc h ti me t he i n vesti gat or 
refers t he s u bject t o a n o nst u d y p h ysicia n (see Secti on  2 0. 4. 2. 2 ). T he i n vest i gat or will 
d oc u m e nt t he f urt her f o ll ow- u p i nf or mati o n i n t he s u bject’s s o urce d oc u me nt.  

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7 7
M alli nc kr o dt
D uri n g t he peri o d s pecifie d a b o ve, t he i n vest i gat or will:

C ollect all A Es a n d S A Es o n t he s o urce d oc u me nts.

Rec or d all A Es a n d S A Es i n t he s o urce d oc u me nts fr om t he si g ni n g of t he I C F t hr o u g h 
t he c o mpleti o n of  t he f oll ow- u p tele p h o ne call. Rec or d all A Es a n d S A Es i n t he e C R F 
fr om t he ti me s u bject recei ves at least t he first d ose of X A RT E MI S X R t hr o u gh t he 
c o mplet i on of  t h e fol l ow- u p tel e p h o ne call f or all s u bjects w h o are e nr olle d i n t he 
st u d y.

Re p ort all S A Es o n t he S A E Re p ort F or m t o Malli nc kr o dt P har mac o vi gila nce.

Re p ort all pre g na ncies o n t he Pre g na nc y S ur veilla nce F or m t o Malli nc kr o dt
P har mac o vi gila nce .

S u b mits t he Safet y Alert fr o m Malli nc kr o dt P har m ac o vigila nce t o t he I R B.
T he re p orti n g re q uire me nts f or A Es are s u m marize d i n Ta ble 2 0- 3.
Ta ble 2 0 - 3: Re p orti n g Re q uir e me nts f or Ad verse E ve nts
Seri o us ness 
Re p orti n g Ti me
T y pe of Re p ort
All Seri o us
Wit hi n 2 4 h o urs of first k n o wle d ge 
of e ve nt
I nitial re p ort o n t he S A E F or m, a p pr o priate 
e C R F, a n d s o urce d oc u me nt
Wit hi n 2 4 h o urs of recei pt of f oll o w -
u p i nf or mati o n
F oll o w U p r ep ort o n t he S A E F or m, 
a p pr o priate e C R F, a n d s o urce d oc u me nt
N o nseri o us
Per case re p ort f or m s u b missi o n 
pr oce d ure
A p pr o priate e C R F a n d s o urce d oc u me nt
2 0. 4. 1 A d verse E ve nt s
A d verse e ve nts ca n be re p orte d s p o nta ne o usl y or elicite d d uri n g o pe n -e n de d q uest i oni n g (ie, 
" H o w ha ve y o u bee n feeli n g si nce y o ur last visit ?"), e xa mi nat i on, or e val uat i on of a s u bject. 
Si g ns a n d s y m pt o m s must be rec or de d usi n g sta n dar d me dical ter mi n olo g y . F or s u bjects 
i nca pa ble of gi vi n g c o nse nt, t he le gall y  acce pta ble re prese ntati ve ma y pr o vi de i nf or mat i on
re gar di n g t he s u bject’s stat us.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7 8
M alli nc kr o dt
All fiel ds o n t he A E eC R F pa ge s h o ul d be c o m p lete d f or eac h e ve nt wit h a f ull descri pti o n of 
t he e ve nt a n d date a n d ti me of o nset /start a n d res ol uti o n/st o p. A me d ical dia g n osis if k n o w n, 
s h o uld be rec or de d i n lie u of eac h i n di vi d ual si g n a n d s y m pt o m ass oci ate d wit h t he dia g n osis 
a n d e x perie nce d b y t he s u bject. If n o me dical dia g n osis is k n o w n, t he ter m use d b y t he s u bject 
t o descri be t he e ve nt or si g ns n ote d b y t he site pers o n nel s h o uld be rec or de d.
2 0. 4. 2 Seri o us A d verse E ve nts
2 0. 4. 2. 1 I niti al Re p orti n g
S erio us a d verse e ve nt s ( base d o n F D A/I C H defi niti on of a n S A E) re q uire i m me diate re p orti n g 
t o Malli nc kr o dt or desi g nate d re prese ntati ve. 

F or all fatal or life -t hreate ni n g e ve nts, t he i n vesti gat or, or desi g nee , m ust re p ort 
i nf or mat i on t o t he M M .

F or all S A Es, t he i n vesti gat or, or desi g nee , m ust c o m plete t he S A E Re p ort F or m wit h 
t he mi ni m u m i nf or mat i on re q uire d b y F D A a n d I C H a n d fa x it t o Malli nc kr o dt at 
3 1 4 - 6 5 4- 5 7 5 9 wi t hi n 2 4 h o urs of first k n o wle d ge of t he e ve nt e ve n if t he e x perie nce 
d oes n ot a p pear t o be relate d t o t he i n vest i gati onal m e dici nal p r o d uct.

T he i n vest i gat or, or desi g nee , will recei ve ac k n o wle d ge me nt of recei pt of t he S A E 
Re p ort F or m  fr o m Malli nc kr o dt.

S h o ul d t he i n vesti gat or or desi g nee ha ve a n y diffic ulty i n se n di n g t he S A E Re p ort, 
t he y ma y c o ntact Malli nc kr o dt Dr u g Safet y at 8 0 0 - 7 7 8- 7 8 9 8 ( 2 4 h o ur call ce nter) or 
e mail: Gl o b al P V @ malli nc kr o dt.c o m .

If t here is a n y d o u bt a b o ut w het her t he i nf or mati on c o nsti t utes a n S A E, t he 
i nf or mat i on is t o be treate d as a n S A E.
2 0. 4. 2. 2 F oll o w U p Re p orti n g 

T he i n vest i gat or or desi g nee m ust c o m plete a n S A E Re p ort F or m f or all f oll ow- u p 
i nf or mat i on recei ve d a n d fa x it t o t he s p o ns or 3 1 4- 6 5 4- 5 7 5 9 wi t hi n 2 4 h o urs of  recei pt 
(e g, detaile d writte n descri pti ons t hat i ncl u de c o pies of rele va nt s u bject rec or ds, 
a ut o ps y re p orts a n d ot her s u p p orti n g d oc u me nts). T he i n vesti gat or(s) or desi g nee will 
recei ve ac k n o wle d ge me nt of recei pt f or eac h S A E Re p ort F or m fr om Malli nc kr o dt.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
7 9
M alli nc kr o dt

T he i n vest i gat or or desi g nee is re q uire d t o pr o vi de all relate d i nf or mati on/s u p p orti n g 
d oc u m e ntatio n of a n S A E u nt il t he S A E is res ol ve d or s ta bilize d. If t he s u bject has 
bee n referre d t o a n o nst u d y  p h ysicia n f or f oll ow- u p treat me nt, t he Malli nc kr o dt 
P har mac o vi gila nce p h ysicia n ma y  re q uest a d ditio n al  inf or mat i on as a p plica ble. 

T he i n vest i gat or(s) or desi g nee is re q uire d t o s u b mit t he Safety A lert F or m t o t he 
res p o nsi ble I R B/I n de pe n de nt Et hics C om mit tee. 

T he s p o ns or will s u b mit s af et y re p orts t o t he F D A .
2 0. 5 Pre g n a nc y Re p orti n g
Certai n i nf or mat i on, al t ho u g h n ot c o nsi dere d a n S A E, m ust be rec or de d, re p orte d, a n d 
f oll owe d u p as i n dicate d . T his i ncl u des t he f o ll owi n g: 

Pre g na nc y e x p os ure t o a n i n vest i gati onal me dici nal pr o d uct, e xce pt f or e x p os ure t o 
pre nat al vita mi ns. S u bjects s h o uld n ot bec o m e pre g na nt d uri n g t he st u d y. If t he s u bject 
bec o me s pre g na nt, st u d y treat me nt must be di sc o nti n ue d i m me diatel y. T he 
in vesti g at or m ust re p ort t he pre g na nc y  b y s u b mittin g t he a p pr o pri ate f or m t o 
Malli nc kr o dt , or desi g nate d re prese ntati ve, wit hi n 2 4 h o urs of c o nfir mati o n o f a 
pre g na nc y (ie, p osit i ve ser u m pre g na nc y test res ult). T he o utc o me of pre g na nc y (e g, 
s p o nta ne o us a b orti o n, li ve birt h, still birt h, c o n ge nital a n oma lies, birt h defects) m ust 
be re p orte d b y s u b mitt i n g the a p pr o priate f or m t o Malli nc kr o dt or desi g nate d 
re prese ntati ve wi t hi n 2 4 h o urs of  t he pre g na nc y o utc o me bei n g s u b mitte d t o t he st u d y 
sit e. If t he pre g na nc y r es ults i n a li ve birt h, a p ost-deli ver y  foll o w -u p will be 
perf or m e d at least 2 8 da ys after t he ba b y is b or n a n d m u st be re p orte d t o Malli nc kr o dt 
wi t hi n 2 4 h o urs of  t he st u d y site bec o mi n g a ware of t he fol l ow- u p i nf or mati o n . B ot h 
mater nal a n d pater nal i n vest i gati onal me dici nal pr o d uct e x p os ures are c ollecte d. 
Pre g na nc y e x p os ure i nf or mati o n is c o llecte d e ve n if t he i n vest i gati onal me dici nal 
pr o d uct is n ot c o ntr ai n dicate d f or use i n pre g na nc y.
2 1 S U B J E C T DI S C O N TI N U A TI O N O R WI T H D R A W A L
2 1. 1 S u bject Wit h dr a w al
S u bjects w h o disc o nt i n ue, or are wit h dra w n fr om t he st u d y for a n y  reas o n, will be re q uire d t o 
ha ve t he e x it safety assess me nts t o assess t heir c o nti n ue d well -bei n g. T he y will recei ve all 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8 0
M alli nc kr o dt
sc he d ule d safety assess me nts i ncl u di n g a n i m paire d j u d g me nt e val uat i on pri or t o release fr o m 
t he st u d y sit e u nless t he s u bject wit h dra ws c o nse nt.
A s u bject ma y be disc o nti n ue d f r o m t he st u d y for t he f o ll owi n g me dical or a d mi nistrati ve 
reas o ns. The reas o n f or disc o nti n uat i on will  be rec or de d.
Wit h dr a w al b y S u bject:
S u bjects will be free t o disc o nt i n ue fr om t he st u d y at a n y ti me. S u bjects w h o ha ve recei ve d at 
least o ne d ose of X A R T E MI S X R b ut d o n ot c o m plete t he st u d y will n ot be re place d.
P ai n Sc or e < 4:
S u bjects w h o ha ve N P R S sc ores of < 4 fr om 3 0 mi n utes pri or t o t hr o u g h 1 h o ur after a n y  
sc he d ule d X A RT E MI S X R d ose will n ot q ualif y f or f urt her st u d y dr u g a d mi nistrati o n , b ut 
wi ll ha ve bl o o d c ollecte d f or P K a nal ysis o nl y at 1 0 mi n utes pri or t o t he ori gi nall y sc he d ule d 
d osi n g t i me. N o a d dit i onal bl o o d will be c ollecte d f or P K . Su bjects are eli gi ble t o sta y i n t he 
st u d y a n d c o nti n ue t o ha ve all safety assess me nts u nt il st u d y e xit or ma y pr ocee d t o earl y 
ter mi nati o n assess me nts.
A d verse e ve nt:
If a d ose d s u bject s uffers a n A E t hat, i n t he j u d g me nt of t he i n vesti gat or, s p o ns or or M M, 
prese nts a n u nacce pta ble c o nse q ue nce or ris k t o t he s u bject, t he s u bject will be disc o nt i n ue d 
fr om f urt her partici pati on i n t he st u d y.
E mesis:
If a s u bject e x perie nce d e mesis bef ore d osi n g, t he s u bject will be disc o nti n ue d. If t he s u bject 
e x perie nces e mesis wit hi n 1 2 h o urs after t he first d ose t he s u bject ma y be c o nsi dere d 
i ntol era nt t o t he dr u g . N o f urt her P K bl o o d sa m ples will be c ollecte d, n o f urt her d osi n g 
atte mpts will  be ma de a n d t he s u bject will be disc o nt i n ue d fr om t he st u d y. If t he s u bject 
e x perie nces e mesis m ore t ha n 1 2 h o urs after t he first d ose t he s u bject will be all o we d t o 
di sc o nti n ue fr om t he st u d y or c o nti n ue i n t he st u d y if his or her le gal g uar dia n s o c h o oses wi t h 
c o nse nt of t he i n vesti gat or. A n y e mesis e x perie nce d at a n y p oi nt  d uri n g t he st u d y will be 
c o nsi dere d a n A E.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8 1
M alli nc kr o dt
De at h:
I n t he e ve nt t hat a s u bject dies d uri n g t he st u d y, deat h will be t he reas o n f or disc o nti n uati on.
L ost t o F oll o w -u p:
If at a n y p oi nt d uri n g t he st u d y a s u bject ca n n ot be c o ntacte d, t he s u bject will be co nsi dere d 
l ost t o f ollo w - u p.
P r ot oc ol V i ol ati o n:
If at a n y p oi nt d uri n g t he st u d y a s u bject is deter mi ne d t o ha ve bee n err o ne o usl y e nr olle d i nt o 
t he st u d y, t he s u bject will be disc o nti n ue d fr o m t he st u d y.
Met Wit h dr a w al Criteri a:
If a s u bject de vel o ps a n y of  t he e xclusi o n  crit eria ( Sectio n 1 2. 2 ) or fails t o meet a n i ncl usi on 
crit erio n (Secti o n 1 2. 1 ) d uri n g t he st u d y t hat is n ot c o nsi dere d t o be a n A E or i s n o nc om p lia nt, 
t he s u bject will be disc o nt i n ue d fr om f urt her partici pati on i n t he st u d y.
O t her:
If t he a b o ve reas o ns are n ot a p plica ble, please use t he “ Ot her” o pti o n a n d pr o vi de t he 
a p pr o priate reas o n f or s u bject wit h dra wal.
If a s u bject’s pare nt or le gal g uar dia n ref uses t o all o w t he s u bject t o re mai n i n t he st u d y sit e 
f or safety assess me nts after bei n g disc o nt i n ue d or wit h dra w n fr o m t he st u d y, t he s u bject’s 
pare nt or l e gal g uar dia n will be as ke d t o si g n a release ac k n o wle d gi n g t he s u bject left t he 
cli nical facilit y a gai nst m e dical a d vice.
F or s u bjects w h o disc o nti n ue or are wit h dra w n fr o m t he st u d y f or a n y reas o n, t he i n vesti gat or
will n otif y  t he s p o ns or. Su bjects are eli gi ble t o sta y i n t he st u d y a n d c o nti n ue t o ha ve all 
safety assess me nts u nt il st u d y e xit or ma y pr ocee d t o earl y ter mi nat i on assess me nts.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8 2
M alli nc kr o dt
2 2 S T U D Y S U S P E N SI O N, T E R MI N A TI O N, A N D C O M P L E TI O N
If t he i n vesti gat or s us pe n ds or ter mi nates t he st u d y, t he i n vesti gat or will pr o m pt l y i nf or m t he 
s p o ns or a n d t he I R B a n d pr o vi de t he m wit h a detaile d writte n e x pla nati on. U p o n st u d y  
c o mplet i on, t he i n vesti gat or will pr o vi de t he s p o ns or , I R B, a n d re g ulat or y a ge nc y wit h fi nal 
re p orts a n d s u m maries as re q uire d b y re g ulati o ns. F or I n vesti gati on al Ne w Dr u g A p plicat i on 
st u dies, or w he n t he data will be use d i n s u p p ort of a n I n vest i gati onal Ne w Dr u g A p plicat i on, 
t he i n vesti gat or m ust s u b mit a writte n re p ort t o t he s p o ns or a n d t he I R B wit hi n 3 m o nt hs after 
t he c o mpleti o n or ter mi nat i on of t he st u d y. St u d y ter mi nati on a n d f o ll ow- u p will be perf or me d 
i n c o mplia nce wi t h Malli nc kr o dt sta n dar d pr oce d ures. 
2 3 P R O T O C O L  AM E N D M E N T S
A n y c ha n ge i n t he st u d y  pla n re q uires a pr ot oc ol a me n d me nt. A n i n vesti gat or m u st n ot ma ke 
a n y c ha n ges t o t he st u d y with o ut I R B a n d s p o ns or a p pr o val e xce pt w he n necessar y  t o 
eli mi nate a p pare nt i m me diate hazar ds t o t he s u bjects. A pr ot oc ol c ha n ge i nte n de d t o eli mi nate 
a n a p pare nt i m me diate hazar d t o s u bjects ma y be i m ple me nte d i m me diatel y, b ut t he c ha n ge 
m ust t he n be d oc u me nt e d i n a n a me n d me nt, re p orte d t o t he I R B wit hi n 5 w or ki n g da ys, a n d 
s u b mitte d t o t he a p pr o priate re g ulat or y a ge nc y i n t he re q uire d ti me fra me. 
2 4 Q U A LI T Y  C O N T R O L AN D A S S U R A N C E
T he s p o ns or perf or ms q ualit y c o ntr ol a n d ass ura nce c hec ks o n all cli nical st u di es t hat it 
s p o ns ors. Bef ore e nr olli n g a n y s u bjects i n t his st u d y, s p o ns or pers o n nel a n d t he i n vesti gat or
re vie w t he pr ot oc ol, t he I B, t he e C R Fs a n d i nstr ucti ons f or t heir c o mplet i on, t he pr oce d ure f or 
o btai ni n g i nf or me d c o nse nt, a n d t he pr oce d ure f or re p or ti n g A Es a n d S A Es. A q ualifie d 
re prese ntati ve of t he s p o ns or will m onit or t he c o n d uct of t he st u d y. D uri n g t hese st u d y sit e 
visit s, i nf or mati on rec or de d i n t he e C R Fs will be verifie d a gai nst s o urce d oc u me nts.
2 4. 1 St u d y a n d St u d y Site Disc o nti n u ati o n Criteri a
T he sp o ns or, i n vesti gat or, M M or F D A officials ma y disc o ver c o n diti ons d uri n g t he st u d y  t hat 
i n dicate t hat t he st u d y or st u d y site s h o uld be ter mi nate d. T his act i on ma y be ta ke n after 
a p pr o priate c o ns ultat i on bet wee n t he sp o ns or a n d i n vesti gat or. C o n diti o ns t hat ma y warra nt 
ter mi nati o n of t he st u d y/st u d y site i ncl u de, b ut are n ot li mite d t o:

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8 3
M alli nc kr o dt

T he disc o ver y  of a n u ne x pecte d, seri o us, or u nacce pta ble ris k t o t he s u bjects e nr olle d 
i n t he st u d y.

T he decisi o n o n t he part of t he s p o ns or t o s us pe n d or disc o nti n ue te stin g, e val uat i on or 
de vel o p me nt of t he i n vest i gati onal m e dici nal p r o d uct.

Fail ure of t he i n vesti gat or t o e nr oll s u bjects i nt o t he st u d y at a n acce pta ble rate.

Fail ure of t he i n vesti gat or t o c o mpl y  wit h perti ne nt F D A re g ulat i ons.

S u b missi o n o f k n o wi n gl y  false i nf or mat i on fr om t he st u d y site t o t he sp o ns or , stu d y 
m o nit or , or F D A.

I ns ufficie nt a d here nce t o pr ot oc ol re q uire me nts
St u d y /st u d y site ter mi nati on a n d f o ll ow- u p will be perf or me d i n c o m p lia nce with 
Malli nc kr o dt S O Ps.
2 5 DI R E C T A C C E S S, D A T A H A N D LI N G, A N D R E C O R D -K E E PI N G
2 5. 1 I n vesti g at or
T he i n vesti gat or will per mit st u d y -r elate d mo ni t orin g, a u di ts, I R B re vie w, a n d re g ulat or y 
i ns pecti o ns b y pr o vi di n g direct access t o ori gi nal s o urce data a n d d oc u me nts.
All s u bject i nf or mati on will be re c or de d o n s o urce d oc u me nts. T he e C R Fs m ust be f ull y 
c o mplete d a n d i ncl u de all re q uire d data f or all s u bjects e nr olle d. All e C R F data m ust be 
s u b mitte d t o t he s p o ns or t hr o u g h o ut a n d at t he e n d of t he st u d y.
If an i n vesti gat or retires, rel ocates, or ot her wise wit h dra ws fr o m c o n d ucti n g t he st u d y, t he 
i n vesti gat or m ust n otif y t he s p o ns or t o a gree u p o n a n acce pta ble st ora ge s ol ut i on. Re g ulat or y  
a ge ncies will be n otifie d wit h t he a p pr o priate d oc u me ntati o n.
A n y si g nifica nt c ha n ges i n st u d y  pers o n nel will re q uire an u p date d State me nt of I n vest i gat or 
(ie, F D A for m  1 5 7 2), w hic h will be file d wit h t he s p o ns or
T he i n vest i gat or m ust n otif y t heir I R B of pr ot oc ol vi o lati ons i n acc or da nce wit h l ocal 
re g ulat or y a n d I R B re q uire me nts.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8 4
M alli nc kr o dt
2 5. 2 S p o ns or
T he e C R F data are st ore d i n a data base a n d pr ocesse d electr o nicall y . T he s p o ns or’s M M 
re vie ws t he data f or safet y inf or mat i on. T he data are re vie we d f or c o m plete ness, a n d l o gical 
c o nsiste nc y. A ut o mate d vali dati on pr o gra m s will i de ntif y missi n g data, o ut -of -ra n ge data, a n d 
ot her data i nc o nsiste ncies. Cli nical la b orat or y  data ma y be pr ocesse d electr o nicall y. Re q uests 
f or data clarificat i on are f or war de d t o t he st u d y sit e for res ol uti o n.
2 6 S U B J E C T I N J U R Y
I n ge neral, s u bject t o s pecific pr o visi ons i n t he cli nical trial a gree me nt, if a s u bject is i nj ure d 
as a direct res ult of a n i n vesti gati onal me dici nal pr o d uct, t he s p o ns or will pa y f or reas o na ble 
a n d necessar y me dical treat me nt f or t he i nj ur y, t o t he e xte nt t hat s uc h e x pe nses are n ot 
c o vere d b y t he s u bject’s me dic al ins ura nce, a g o ver n me nt pr o gra m, or ot her res p o nsi ble t hir d 
part y. If la ws or re g ulat i ons of t he l ocali t y in w hic h t he st u d y  is ta ki n g place re q uire a d ditio nal 
pa y me nt of e x pe nses, t he s p o ns or s hall c o m p l y wit h s uc h la ws or re g ulat i ons. W here 
a p plica ble, t he s p o ns or has ta ke n s pecific nat i onal i ns ura nce.
2 7 R E C O R D S R E T E N TI O N
T he i n vesti gat or s hall retai n a n d preser ve 1 c o p y of all data c ollecte d or data bases ge nerate d 
i n t he c o urse of t he st u d y, s pecificall y i ncl u di n g b ut n ot li mite d t o t h ose defi ne d b y G CP as 
esse nt ial. Esse ntial d o c u m e nts s h o uld be retai ne d u nt il at least 2 years after t he last a p pr o val 
of  a mar ket i n g a p plicati on 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 
mar ket i n g a p plicati o ns i n a n I C H re gi o n or at least 2 years ha ve ela pse d si nce t he f or mal 
di sc o nti n uati on of cli nical de vel o p me nt of t he i n vesti gat i onal me dici nal pr o d uct. T hese 
d oc u m e nts s h o uld be retai ne d f or a l o n ger peri o d, h o we ver, if re q uire d b y t he a p plica ble 
re g ulat or y re q uire me nts or b y a n a gree me nt wit h t he s p o ns or. It is t he res p o nsi bility of t he 
s p o ns or t o i nf or m t he i n vesti gat or/i nstitut i on 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. Pri or t o destr ucti o n of a n y st u d y esse ntial d oc u me nts, t he i n vesti gat or m u st first 
o btai n writte n a p pr o val fr o m t he s p o ns or. 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8 5
M alli nc kr o dt
2 8 BI O L O GI C A L  S A M P L E S
Bl o o d sa m ples will be use d o nl y f or scie nt ific researc h. Eac h sa m ple will be la bele d wit h a 
c o de s o t hat t he la b orat or y pers o n nel testi n g t he sa m ples will n ot k n o w t he s u bject’s ide nt ity.  
After t he st u d y  e n ds, t he cli nical la b orat or y sa m ples will be destr o ye d. Bioa nal y tical sa m ples 
(ie, plas ma) f or meas ure me nt of dr u g/ meta b olite c o nte nt will be retai ne d f or 5 years at a 
bi o l ogical  st ora ge facilit y. T he s u bject ma y re q uest t hat his or her sa mples, if st ill i de ntifia ble, 
be destr o y e d at a n y time; h o we ver, a n y data alrea d y c o llecte d fr om t hat sa mple will st ill be 
use d f or t his researc h. 
2 9 P U B LI C A TI O N P O LI C Y
2 9. 1 S p o ns or ’s P u blic ati o n P olic y
T he s p o ns or ’s p olic y is t o p u blis h or ot her wise c o m m u nicate t he res ults of its h y p ot hesis-
t esti n g cli nical st u dies, re gar dless of o utc o me, f or mar kete d pr o d ucts, c o m p o u n d(s) or 
pr o d uct(s) bei n g i n vest i gate d t hat are later a p pr o ve d f or mar keti n g. H y p ot hesis-testi n g cli nical 
st u dies are t h ose st u dies i nte n de d t o pr o vi de mea ni n gf ul res ult s b y e xa mi nin g prestate d 
q uesti o ns usi n g pre defi ne d statist icall y vali d pla ns f or data a nal ysis, t here b y pr o vi di n g fir m 
e vi de nce of safet y a n d/ or efficac y t o s u p p ort pr o d uct clai ms.
E x pl or at or y  st u dies, i n c o ntrast, ser ve t o set direct i o n f or p ossi ble f ut ure st u dies. T he y ha ve 
sig nifica nt stati stical li mitati ons, pr o vi de o nl y  preli mi nar y inf or m at i on a b o ut a disease, 
c o n ditio n, or pr o d uct, a n d are n ot desi g ne d t o pr o vi de fi nal c o ncl usi o ns o n pr o d uct clai ms. 
T he s p o ns or d oes n ot c o m mit t o p u blis h or ot her wise c o m m u nicate t he res ults of e ver y 
e x pl orat or y st u d y, beca use t his i nf or mati o n is of a n e x pl orat or y nat ure a n d ofte n hi g hl y 
pr o pri et ar y. H o we ver, if i nf or mati on fr om a n e x pl o rat or y st u d y is of si g nifica nt me dical 
i m p orta nce, t he s p o ns or will p u blis h or ot her wise c o m m u nicate t he res ults.
T he s p o ns or ’s decisio n  t o p u blis h or ot her wise p u blicl y c o m m u nicate t he res ults of t his st u d y 
will be ma de i n acc or da nce wit h all a p plica ble la ws, re g ulat i ons, a n d s p o ns or p olicies 
re gar di n g p u blicati on a n d c o m m u nicat i on of cli nical st u d y res ults.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8 6
M alli nc kr o dt
2 9. 2 I n vesti g at or’s Abilit y t o P u blis h
Te r ms a n d pr o visio ns of  p u blicatio n ri g hts are g o ver ne d b y  t he P u blicatio n Sect i on i n t he 
cli nical trial a gree me nt.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8 7
M alli nc kr o dt
3 0 R E F E R E N C E S
A G S Pa nel o n Persiste nt Pai n i n Ol der Pers o ns. T he ma na ge me nt of persiste nt pai n i n o l der 
pers o ns. J A m Geri atr S oc. 2 0 0 2; 5 0( 6 S u p pl): S 2 0 5- 2 4.
A merica n H os pital F or m ular y  Ser vices ( A H F S). Dr u g I nf or mati on – A merica n S oci et y of  
Heal t h-S y st e m P har macists; 2 00 4. p 2 0 5 6, 2 0 8 3.
A merica n Pai n S ociet y.  Pri nci ples of a n al gesic use i n t he tr e at me nt of ac ute p ai n a n d c a ncer 
p ai n , 6t h e diti on. 2 0 0 8: p 2 5. 
Ar o ns o n J K, Har d ma n M. A B C of m o nit ori n g dr u g t hera p y. Patie nt c o mplia nce. B MJ . 
1 9 9 2 ; 3 0 5( 6 8 6 0): 1 0 0 9-1 1.
Bar ki n R L . Aceta mi n o p he n, as piri n, or i b u pr ofen i n c om bi nati o n a nal gesic pr o d ucts. A m J 
T her . 2 0 0 1 ; 8( 6): 4 3 3- 4 2.
Bea ver W T . As piri n a n d aceta mi n o p he n as c o nstitue nts of a nal gesic c o m bi nat i ons. Ar c h 
I nter n Me d. 1 9 8 1 ; 1 4 1( 3 S pec N o): 2 9 3- 3 0 0.
Bea ver W T . C o m bi nati on a nal gesics. A m J Me d . 1 9 8 4 ; 7 7( 3 A): 3 8- 5 3.
Bea ver W T . I mpact of n o n -narc oti c oral a nal gesics o n pai n ma na ge me nt. A m J Me d . 
1 9 8 8 ; 8 4( 5 A): 3- 1 5.
C ol u z zi  F, Mattia C. O x yc o d o ne. P har mac o l ogi c al pr ofile a n d cli nical data i n c hr o nic pai n 
ma na ge me nt. Mi nerv a A nestesi ol . 2 0 0 5 ; 7 1( 7): 4 5 1- 4 6 0.
Des me ules J, R o llas o n V, Pig uet V, et  al. Cli nical p har mac ol o g y a n d ratio nale of a nal gesic 
c o m bi nat i ons. E ur J A n aest hesi ol S u p pl . 2 0 0 3 ; 2 8: 7-1 1.
El -Ta ht a w y A, K o k ki H, Rei de n ber g B E. P o p ulati o n p har mac o ki netics of o x yc o d o ne i n 
c hil dre n 6 m o nt hs t o 7 years ol d. J Cli n P h ar m ac ol . 2 0 0 6 A pr; 4 6( 4): 4 3 3 - 4 2.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8 8
M alli nc kr o dt
Fe deral Re gister N otice: Prescri pt i on Dr u g Pr o d ucts C o ntai ni n g Aceta mi n o p he n; Act i ons t o 
Re d uce Li ver I nj ur y  fr o m U ni nte ntio n al  O ver d ose - D o c ket N u m ber F D A-2 0 1 1 - N- 0 0 2 1-
0 0 0 1.
Gas kell H, De rr y S, M o ore R A, et al. Si n gle d ose oral o x yc o d o ne a n d o x yc o d o ne pl us 
paraceta m o l (aceta mi n o p he n) f or ac ute p ost o perati ve pai n i n a d ults. ( Re vie w) C oc hr a ne 
D at a b ase Syst Rev . 2 0 0 9 ;( 3): C D 0 0 2 7 6 3.
Gl u metza ® ( metfor m i n h y dr oc hl ori de e xte n de d -release ta blets), 5 0 0 m g a n d 1 0 0 0 m g 
[ pac ka ge i nsert]. De p o me d, I nc. Me nl o Par k ( C A); 2 0 1 1 . 1 0 p. Av aila ble fr o m 
ht t p:// w w w. glu metza xr . c o m/assets/ p dfs/c urre nt _ PI _ P W 2. p df.
Gralise ® ( ga ba pe nti n) ta blets [ pac ka ge i nsert]. De p o me d, I nc. Me nl o Par k ( C A); 2 0 1 2 . 2 4 p. 
Av aila ble fr o m  ht t p:// w w w. gralise.c om/ li b/ P D F S/ G R A LI S E _ PI. p df.
Hal e M, T u d or I C, K ha n na S, et al. Efficac y a n d t olera bilit y of  o nce-dail y O R O S 
h y dr o m o r p h o ne a n d t wice-dail y e xte n de d -r elease o x yc o d o ne i n patie nts wit h c hr o nic, 
m o derate t o se vere oste oart hrit is pai n: res ults of a 6-wee k, ra n d o mize d, o pe n -la bel, 
n o ni nferi orit y a nal ysis. Cli n T her . 2 0 0 7 ; 2 9( 5): 8 7 4- 8 8.
I b u pr ofe n [ pac ka ge i nsert] A m neal P har mace ut icals Bri d ge water NJ: 2 4 Marc h 2 0 1 4. 
Av aila ble fr o m : htt p:// me dli brar y. or g/li b/r x/ me ds/i b u pr ofe n- 5 3/.
Ji P, Wa n g Y, Li Z, et al. Re g ulat or y re vie w of aceta mi n o p he n clinical  p har mac olo g y  in y o u n g 
pe di atric patie nts. J P h ar m Sci . 2 0 1 2 Dec; 1 0 1( 1 2): 4 3 8 3 -9. 
Ki m ura T , S u d o K, Ka nza ki Y, et al. Dr u g a bs or pti o n fr om lar ge i ntest i ne: p h ysic oc he mical 
fact ors g o ver ni n g dr u g a bs or pti o n. Bi ol P h ar m B ull . 1 9 9 4 ; 1 7( 2): 3 2 7- 3 3.
K o k ki  H, Rasa ne n I, Lasal mi M , et al. C o mparis o n of o x yc o d o ne p har mac o ki netics after 
b uccal a n d s u bli n g ual a d mi nistrati o n i n c hil dre n. Cli n P h ar m ac oki net . 2 0 0 6 ; 4 5( 7): 7 4 5- 5 4.
Malli nc kr o dt I nc ( Hazel w o o d, M O). A n O pe n -La bel , Ra n d o mize d, Si n gle-D ose, T hree -P eri o d 
Cr oss o ver St u d y  t o E valuate t he P har m ac o ki netics, Bioa vaila bilit y a n d Safet y of  O ne or Tw o 
Ta blets of a M ult i-La yer E xte n de d -Release F or m ulati o n, C O V 7 9 5 ( 7. 5 m g O x yc o d o ne 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
8 9
M alli nc kr o dt
H y dr oc hl ori de/ 3 2 5 m g Aceta mi n o p he n), C o m pare d t o O ne T a blet of I m me diate -Release 
Perc oce t® ( 7. 5 m g/ 3 2 5 m g) A d mi nistere d Q 6 h f or T w o  D oses F oll o we d b y a n A d diti onal 
E val uat i on Peri o d of  Tw o  Ta blets of Perc ocet ® ( 7. 5 m g/ 3 2 5 m g) A d mi nistere d Q 6 h f or T w o  
D oses i n N or mal, Healt h y S u bjects u n der Faste d C o n dit i ons. 2 7 A u g 2 0 1 2 a. Fi nal cli nical 
st u d y re p ort. St u d y N o.: C O V 1 5 0 0 0 1 7 0.
Malli nc kr o dt I nc ( Hazel w o o d, M O). A n O pe n -La bel , Ra n d o mize d, M ultiple -D ose, T hree -
P eri o d, Cr oss o ver St u d y  t o E valuate t he Stea d y -State P har mac o ki net ics, Bi oa vaila bility a n d 
S af et y of  O ne or Tw o T a blets of a M ult i-La yer E xte n de d -Release F or m ulat i on, C O V 7 9 5 ( 7. 5 
m g O x yc o d o ne H y dr oc hl ori de/ 3 2 5 m g Aceta mi n o p he n) A d mi nistere d Q 1 2 h C o m pare d t o O ne 
Ta blet of I m me diate -Release Perc ocet ® ( 7. 5 m g/ 3 2 5 m g) A d mi nistere d Q 6 h i n N or mal, 
Heal t h y S u bjects U n der Faste d C o n diti ons. 2 7 A u g 2 0 1 2 b . Fi nal cli nical st u d y re p ort. St u d y 
N o.: C O V 1 5 0 0 0 1 7 2.
Malli nc kr o dt I nc ( Hazel w o o d, M O). A n O pe n -La bel , Ra n d o mize d, T hree-P eri o d Cr oss o ver 
St u d y  t o E valuate t he P har m ac o ki net ics, Bioa vaila bilit y a n d Safet y of Tw o  Ta blets of a M ulti-
La yer E xte n de d -Release F or m ulat i on, C O V 7 9 5 ( 7. 5 m g O x yc o d o ne H y dr oc hl ori de/ 3 2 5 m g 
Aceta mi n o p he n), A d mi nistere d as a Si n gle D ose i n N or mal, Healt h y S u bjects U n der Fe d 
( Hig h - a n d L o w-Fat Meal) a n d Faste d C o n dit i ons. 2 7 A u g 2 0 1 2 c. Fi nal cli nical st u d y re p ort. 
St u d y  N o.: C O V 1 5 0 0 0 1 7 1.
Malli nc kr o dt I nc ( Hazel w o o d, M O). A n O pe n -La bel , Ra n d o mize d, M ultiple -D ose, F o ur -
P eri o d, Cr oss o ver St u d y  t o E valuate t he Stea d y -State P har mac o ki net ics, Bi oa vaila bility a n d 
S af et y of  C O V 7 9 5 A d mi nistere d Q 1 2 h C om pare d t o I m me diate -Rel ease R o xic o d o ne ® , 
Ul tracet ® a n d Perc ocet ® A d mi nistere d Q 6 h i n N or mal, Healt h y S u bjects. 1 1 Dec 2 0 1 2 d . Fi nal 
cli nical st u d y re p ort. St u d y N o.: C O V 1 5 0 0 0 2 5 5.
Malli nc kr o dt I nc ( Hazel w o o d, M O). A n O pe n -La bel , Ra n d o mize d, Si n gle-D ose, F o ur -P eri o d, 
Cr oss o ver St u d y  t o E valuate t he P har ma c o ki netics, Bi oa vaila bilit y a n d Safet y of  C O V 7 9 5 
C o m pare d t o I m me diate -Rel ease R o xic o d o ne ® , Ultracet® a n d Perc ocet ® A d mi nistere d Q 6 h 
f or Tw o  D oses i n N or mal, Health y S u bjects U n der Faste d C o n dit i ons. 1 1 Dec 2 0 1 2 e. Fi nal 
cli nical st u d y re p ort. St u d y N o.: C O V 1 5 0 0 0 2 5 6.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
9 0
M alli nc kr o dt
Mar ke ns o n J A, Cr oft J, Z ha n g P G, et al. Treat me nt of persiste nt pai n ass ociate d wit h 
os te oart hritis wit h c o ntr olle d-r elease o x yc o d o ne ta blets i n a ra n d o mize d c o ntr olle d cli nical 
trial. Cli n J P ai n . 2 0 0 5 ; 2 1( 6): 5 2 4- 3 5.
Mc Car ber g
B H, Bar ki n R L. L o n g -acti n g o pioi ds f or c hr o ni c pai n: p har mac ot hera pe utic 
o p p ort u nit ies t o e n ha nce c om p lia nce, q uality of life, a n d a nal gesia. A m J T her . 2 0 0 1; 8( 3): 1 8 1-
6.
M N K - 7 9 5 I n vesti gat or’s Br oc h ure (E di tio n N u m be r 1 5 0 0. 2 0 1 4. 0 6 .2 6) . Malli nc kr o dt I nc 
Hazel w o o d, M O; 2 6 J u ne 2 0 1 4 .
Ni c h o ls o n B, R oss E, Sasa ki J, et al. Ra n d omize d trial c o m par i n g p ol y mer-c oate d e xte n de d -
r elease mor p hi ne s ulfate t o c o ntr olle d- r elease o x yc o d o ne H Cl in m o derate t o se vere 
n o n mali g na nt pai n. C urr Me d Res O pi n . 2 0 0 6; 2 2: 1 5 0 3-1 4. 
Pa n H, Z ha n g Z, Z ha n g Y, et al. Efficac y a n d t olera bility of  o x yc o d o ne h ydr oc hl ori de 
c o ntr olle d -r elease ta blets i n m o derate t o se vere ca ncer pai n. Cli n Dr u g I nvesti g . 
2 0 0 7 ; 2 7( 4): 2 5 9- 6 7.
Perc ocet ® ( o x yc o d o ne a n d aceta mi n o p he n ta blets, U S P) [ pac ka ge i nsert]. : E n d o 
P har mace ut icals I nc. Mal ver n P A ; 2 0 13 .
Presc ott L F . P ar acet a m ol ( Acet a mi n o p he n): A critic al bi bli o gr a p hic r evie w. Ta yl or & Fra ncis 
I nc., Ne w Yor k. 2 0 0 1 ; 2 9 9- 4 4 5.
Pr o q ui n X R ® ( Cipr ofl o x aci n) E xte n de d -Release T a blets [ pac ka ge i nser t]. De p o me d, I nc. 
Me nl o Par k ( C A); 2 0 1 1. 3 1 p. Av aila ble fr o m 
ht t p:// w w w.fda. g o v/ d o w nl oa ds/ Dr u gs/ Dr u g Safet y/ U C M 2 3 9 9 3 3. p df .
R o xi c o d o ne ® ( o x yc o d o ne h y dr oc hl ori de ta blets, U S P) [ pac ka ge i nsert]. Xa n o d y ne 
P har mace ut icals, I nc. Ne w p ort K Y ; 2 0 0 9. 1 7 pa ges - Av aila ble fr o m 
ht t p:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 0 9/ 0 2 1 0 1 1s 0 0 2l bl. p df
Raf fa, R B. P har mac ol og y  of or al c o m bi nati on a nal gesics: rati o nal t hera p y  for pai n. J Cli n 
P h ar m T her . 2 0 0 1 ; 2 6( 4): 2 5 7- 6 4.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
9 1
M alli nc kr o dt
Sc h wartz GJ, M u n oz A, Sc h nei der M F , et al. Ne w e q uati o ns t o esti mate G F R i n c hil dre n wit h 
C K D. J A m S oc Ne p hrol. 2 0 0 9 : 2 0( 3): 6 2 9- 6 3 7.
Ul tracet® (tra ma d o l h y dr oc hl ori de/aceta mi n o p he n) T a blets [ pac ka ge i nsert]. Rarita n, NJ: 
Ort h o -Mc Neil -Ja nsse n P har mace ut icals, I nc.; 2 0 1 1. 4 pa ges - Av aila ble fr o m 
ht t p:// w w w.ja nsse n p har mace ut icalsi nc.c o m/assets/ ultracet. p df
U S F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or i n d ustr y dr u g -i n d uce d li ver i nj ur y: 
pr e m ar ket i n g cli nical e val uati on. 2 0 0 9. 
ht t p:// w w w.fda. g o v/ d o w nl oa ds/ Dr u gs/ D o w nl oa ds/ G ui da nces/ U C M 1 7 4 0 9 0. p df .
Wa n g Y,  Ja d ha v P R, Lala M, et al., Clarificat i on o n Precisi o n Cri t eria t o Derive Sa m ple Si ze 
w he n Desi g ni n g Pe diatric P har mac o ki net ic St u dies. J Cli n P h ar m . 2 0 1 2; 5 2( 1 0): 1 6 0 1- 6
Wa t ki ns P B, Kapl o wi tz N, Slatt er y J T, et al. A mi n otra nsferase ele vat i ons i n healt h y a d ult s 
recei vi n g 4 gra ms of aceta mi n o p he n dail y: a ra n d o mize d c o ntr olle d trial. J A M A . 2 0 0 6 J ul 
5; 2 9 6( 1): 8 7 - 9 3.
X A R T E MI S T M X R Ta blets [ pac ka ge i nsert]. Malli nc kr o dt I nc. Hazel w o o d, M O; 2 0 1 4. 
Z u p pa A F, Ha m mer G B, Barrett J S, et al. Safety a n d p o p ulatio n p har mac o ki net ic a nal ysis of 
i ntra ve n o us aceta mi n o p he n i n ne o nates, i nfa nts, c hil dre n, a n d a d olesce nts wit h pai n or fe ver. J 
Pe di atr P h ar m ac ol T her . 2 0 1 1 Oct; 1 6( 4): 2 4 6 -6 1. 

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
9 2
M alli nc kr o dt
3 1 A T T A C H M E N T S
3 1. 1 Att ac h me nt 1: B o d y M ass I n de x

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
9 3
M alli nc kr o dt
S o urce:  w w w .c dc. g o v/ gr o wt hc harts

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
9 4
M alli nc kr o dt
3 1. 2 Att ac h me nt 2 : Cli nic all y Rele v a nt Dr u gs C a usi n g I nter acti o ns 
t hr o u g h C Y P 2 D 6 a n d C Y P 3 A 4
T his ta ble c o ntai ns a list of dr u gs ca usi n g cli nicall y rele va nt dr u g i nteracti o ns i n h u ma ns b y 
i n hi biti n g C Y P 2 D 6, C Y P 3 A 4, or i n d uci n g C Y P 3 A 4. T his list is n ot all i ncl usi ve a n d s h o ul d 
o nl y  be use d as a g uide.
C Y P 2 D 6
I n hi bit ors
C Y P 2 D 6 I n d ucers
C Y P 3 A 4 
I n hi bit ors
C Y P 3 A 4 I n d ucers
Str o n g 
i n hi bit ors1
B u pr o pi o n
Ci nacalet
Fl u o xet i ne
Par o xeti ne
Q ui ni di ne
De xa met has o ne
Rifa m pi n
Cl arit hr o m yci n
I n di na vir
Itrac o naz ole
Ket oc o naz o le
Nefaz o d o ne
Nelfi na vir
Ri t o na vir
Sa q ui na vir
S u b o x o ne
Te lithr o m yc i n
Bar bit urates
Car ba maze pi ne
Ef a vire nz
Gl uc oc orti c o i ds
M o dafi nil
Ne vira pi ne
O xcar baze pi ne
P he n o bar bital
P he n yt o i n
Pi o gli taz o ne
Rifa b ut i n
Rifa m pi n
St. J o h n's w ort
Tr o glit az o ne
M o der ate 
i n hi bit ors2
D ul o xet i ne
Sertrali ne
Te r bi nafi ne
A pre pita nt
Dilt iaze m
Er y t hr o myci n
Fl uc o naz o le
Gra pefr uit j uice
Ve ra pa mil
S o urce: Fl oc k hart D A. Dr u g I nteracti o ns: C yt oc hr o me P 4 5 0 Dr u g I nteracti o n Ta ble. I n dia na U ni versit y Sc h o ol of Me dici ne 
( 2 0 0 7). Pa ge last m o difie d 1 2 J ul 2 0 1 3 " htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/cli nical-ta ble/" Accesse d 0 4 A pril 2 0 1 4.
1 Str o n g i n hi bit ors are t h ose t hat res ult i n a > 5 -f ol d i ncrease i n t he plas ma A U C val ues or m ore t ha n 8 0 % decrease i n 
cleara nce.
2M o derate i n hi bit ors are t h ose t hat res ult i n a > 2 -f ol d i ncrease i n t he plas ma A U C val ues or 5 0 % t o 8 0 % decrease i n 
cleara nce.

X A R T E MI S X R T a blets ( 7. 5 m g O x yc o d o ne H Cl/ 3 2 5 m g Acet a mi n o p he n)
Rese arc h Pr ot oc ol M N K 1 5 0 0 0 3 0 0 
A me n d me nt 3 : 2 9 J u ne 2 0 1 6
C O N FI D E N TI A L
P R O P RI E T A R Y
9 5
M alli nc kr o dt
3 1. 3 Att ac h me nt 3: N u meric al P ai n R ati n g Sc ale 
S u bjects will be as ke d t o rate t heir c urre nt pai n i nte nsit y le vel usi n g t he f oll o wi n g ( 0-1 0) 
N P R S. 
0
1
2
3
4
5
6
7
8
9
1 0
N o
P ai n
W orst P ai n