Clinical trial NCT02508935
Conditions: Acute Pain
Sponsor: Mallinckrodt
Start date: 2015-11-20; Completion date: 2017-04-26
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 4, multicenter, open-label, multiple-dose study of the pharmacokinetics (PK) and safety of XARTEMIS XR in postsurgical adolescent subjects aged 12 to 17 years with moderate to severe acute pain. The study will assess the safety of administering multiple doses of XARTEMIS XR in this population.

Detailed description:

Arms: arm 1: All participants received XARTEMIS XR
Interventions: intervention 1: XARTEMIS XR
Intervention descriptions: intervention 1: XARTEMIS XR \[7.5 mg oxycodone hydrochloride and 325 mg acetaminophen (APAP)\] Extended-Release Tablets

Protocol documents:
Prot_SAP_000.pdf: 
 
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