Memantine for Prevention of Cognitive Decline During Adjuvant or Neoadjuvant Chemotherapy in Patients With Breast Cancer
Phase: PHASE2
Conditions: Cognitive Decline, Chemo-brain
Sponsor: UNC Lineberger Comprehensive Cancer Center

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
P R O T O C O L A M E N D M E N T # _ _ 1 0 _ _  
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.
( 2) We ha v e m o difie d  Secti o n 5. 3 t o i ncl u de m ore s pecific d ose re d ucti o n a n d
st o p pi n g r ules base d o n t o xicit y gra de, attri b uti o n, a n d effect o n c he m ot hera p y
treat me nt. We h a ve als o clarifie d t hat partici pa nts will be assesse d f or
t o xicities o n a wee kl y basis d uri n g t he titrati o n peri o d.
( 3) We ha v e u p date d Se cti o n 8. 1. 2 t o clarif y t hat t he w orse ni n g of se v erit y a n d
fre q ue n c y of a d v erse e ve nts will be e val uate d w he n assessi n g ca usalit y.
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C 
revie w. 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 4/ 2 3/ 2 1 _ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # _ _ 9 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ge s (I R B a p pr o val) 
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 4) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 5) We ha v e a d de d Yara A b d o u, M D as a c o -i n vesti gat or t o t he st u d y. 
 
 
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C 
revie w. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 1 2/ 1 4/ 2 0 _ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # _ _ 8 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 2) We ha v e a d de d l a n g ua ge i n Secti o n s 1. 1 , 7. 1, 7. 2 , 7. 4, 7. 5, a n d 9. 1  t o i n dicate 
t hat we ha ve e x pa n d e d st u d y recr uit me nt t o i ncl u d e U N C R E X O nc ol o g y 
cli nics. 
 
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m 
P R C revie w . 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 1 0 /7 / 2 0_ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # _ _ 7 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 3) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 4) We ha v e a d de d d etails t o Secti o n 1. 1 , Secti o n 5. 6 , Secti o n 7. 1, Secti o n 7. 5, 
Secti o n 9. 1, a n d Secti o n 9. 3  t o clarif y pla ns f or  e xte n de d  l o n git u di nal f oll o w-
u p pr oce d ures f or a s u bset of partici pa nts w h o v ol u ntaril y o pt -i n (i.e. 
c o g niti ve a n d ot her sec o n dar y o utc o me meas ures will be re peat e d  at 6 m o nt hs 
p ost -c he m ot hera p y ). T h e pla n t o offer l o n git u di nal f oll o w -u p fo r a s u bset of 
i ntereste d partici p a nts was i n dicate d a n d a p pr o ve d i n pre vi o us s u b missi o ns, 
b ut t hese c ha n ges pr o vi de t he details of t his pla n.  
( 5) We ha v e a d de d e x pl orat or y o bjecti ves i n Secti o n 2. 3  a n d e x pl orat or y 
e n d p oi nts i n Secti o n 3. 3 t o c oi nci de wit h t he a d diti o n of t he l o n git u di nal 
f oll o w-u p pr oce d ures at 6 m o nt hs p ost -c he m ot hera p y f or a s u bs et of 
partici pa nts.   
( 6) We ha v e u p date d s ur v e y la n g ua ge i n A p pe n di x F t o i ncl u de all ge n der 
i de ntities. 
 
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m 
P R C revie w . 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 9 /4 / 2 0_ _  I N C O R P O R A T E S T H E A B O V E R E VI SI O N S 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # _ _ 6 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 2) We ma de a mi n or c ha n g e t o  Secti o n 5. 2 t o re mai n c o nsiste nt wit h a pre vi o us 
a me n d me nt t hat  wi de n e d  t he p ost -c he m ot hera p y assess me nt wi n d o w .  
( 3) We ma de a mi n or c ha n g e t o Secti o n 1. 1 t o re mai n c o nsiste nt a b o ut t he ti mi n g 
of t he baseli ne c o g niti ve assess me nt  t hr o u g h o ut t he pr ot oc ol. 
( 4) We ha v e c ha n g e d  Se cti o ns 5. 8. 1 8, 7. 1, a n d 7. 4 t o s pecif y t hat all partici p a nts 
will be as ke d t o c o m plete t he H or m o nal Stat us Q uesti o n naire at t he p ost -
c he m ot hera p y assess me nt.  
( 5) We ha v e c ha n g e d Secti o n 7. 2 t o i n dicate t hat we ha ve e x p a n de d st u d y 
recr uit me nt t o i ncl u de U N C Hil ls b or o u g h O nc ol o g y Cli nic. 
( 6) We m o difie d  Secti o n 7. 4  t o re mai n c o nsiste nt wit h a pre vi o us a me n d m e nt t hat 
s pecifie d t hat w e will utilize a wider ra n g e of o pti o ns f or disse mi nati o n of 
st u d y assess me nts a n d s ur ve ys (i.e. e m ail, p h o ne, mail, o nli ne, a n d vi de o 
c onfere nci n g met h o ds ).  
( 7) We ha v e ma de c ha n ges t hr o u g h o ut t he pr ot oc ol t o reflect t he a d diti o n of t w o 
ne w sec o n d ar y o utc o me meas ures  ( R V P a n d O T S) t hat ca n be c o m plete d 
virt uall y t o re place o n e meas ure  ( T M T) t hat m ust be c o m plete d i n-pers o n.  
T his c ha n ge will n ot affect o ur statistical pla n a n d is bei n g i m ple me nte d s o 
t hat e ver y as p ect of o ur st u d y ca n be c o m plet e d re m otel y. 
( 8) I n Secti o n 5. 3 a n d 7. 3, we ha ve s pecifie d t hat t o xi cit y assess me nts will occ ur 
at a n i nter val n o gr eater t ha n e ver y t hree wee ks , i nstea d of e v er y 2 t o 3 wee ks 
de pe n di n g o n t he ti mi n g of t he c he m ot hera p y re gi me n . 
( 9) I n Secti o n 5. 3, we ha v e state d t hat partici pa nts ma y  decrease or dis c o nti n ue 
me ma nti ne at a n y ti me, e ve n i n t he a bse nce of a me ma nti ne-ass oci ate d 
t o xicit y.  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m 
P R C revie w . 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 5/ 2 1 / 2 0_ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # _ _ 5 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 2) We ha v e ma de c ha n ges t o Secti o ns 1. 1, 7. 1, a n d 7. 4 t o wi de n t he p ost -
c he m ot hera p y assess me nt wi n d o w . W hile we will ma ke e ver y atte m pt t o 
sc he d ule assess m e nts o n t heir i deal dates, t his will all o w us m ore fle xi bilit y i n 
sc he d uli n g i n li g ht of C O VI D-1 9 p olic y.  
( 3) We ha v e ma de c ha n ges t o Secti o ns 1. 1, 5. 2, a n d 7. 3  t o reflect t he p ot e ntial 
e x pa nsi o n of st u d y d urati o n as a res ult of wi d e ni n g t he p ost -c he m ot hera p y 
f oll o w-u p wi n d o w.   
( 4) We ha v e ma de c ha n ges t o wi de n t he st u d y dr u g start wi n d o w i n Secti o ns 5. 2, 
5. 5, a n d 7. 3 . We will ma ke e ver y atte m pt t o start partici pa nts o n o ur dr u g 
d uri n g t he ori gi nal sc he d ule o utli ne d i n o ur P R C pr ot oc ol, b ut t his will all o w 
f or m ore fl e xi bilit y i n e ns uri n g t hat partici pa nts h a ve recei ve d o ur st u d y dr u g 
pri or t o starti n g c he m ot h era p y.  
( 5) We ha v e ma de m o dificati o ns Secti o n 7. 2 t o utilize a wi der ra n ge of  o pti o ns 
f or disse mi nati o n of st u d y assess me nts a n d s ur ve ys. We pla n t o i m ple me nt 
e mail, p h o ne, mail, o nli ne, a n d vi de o c o nfere nci n g met h o ds of c o m pleti n g 
st u d y assess me nts a n d q uesti o n naires w he n e ver p ossi ble i n cases t hat i n -
pers o n c o m m u nicati o n is restr icte d or pr o hi bite d.  
 
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m 
P R C revie w . 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 3 / 1 3/ 2 0_ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # _ _ 4 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 2) We ha v e a d de d Ti m ot h y Br ot hert o n, M D as a c o -i n vesti gat or t o t he st u d y. 
( 3) We ha v e a d de d Secti o n 5. 8. 1 8  a n d A p pe n di x O  a n d m o difie d Secti o ns 5. 1, 
5. 7, 7. 1, a n d 7. 4 t o reflect t he a d diti o n of t he M o difie d Brief Me dicati o n 
Q uesti o n naire ( B M Q) -S pecific q uesti o n nair e . T he M o difie d B M Q -S pecific 
will be use d t o assess partici pa nts’ beliefs a b o ut t h e necessit y  a n d c o ncer ns  of 
ta ki n g me ma nti ne. T he s ur ve y will be a d mi nistere d t o partici pa nts at t he p ost-
c he m ot hera p y assess me nt a n d offere d u p o n st u d y wit h dra wal, if a p plica ble.  
 
Per t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C revie w.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 1/ 1 3 / 2 0_ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
P R O T O C O L A M E N D M E N T # _ _ 3 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y  c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 6) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 7) We ha v e a d de d Kirste n N yr o p, P h D as a c o -i n vesti gat or t o t he st u d y. 
 
Per t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C revie w.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 1 1 /2 1/ 1 9 _ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
P R O T O C O L A M E N D M E N T # _ _ 2 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ X _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 2) I n Secti o n 7. 2 we ha v e br oa de ne d t he l a n g ua ge re gar di n g t he l ocati o n of st u d y 
assess me nts t o i ncl u de partici pa nts’ h o mes, w hic h will all o w f or m ore 
fle xi bilit y i n c o n d ucti n g c o g niti ve assess me nts pri or t o t he start a n d at t he e n d 
of c he m ot hera p y.  
Eli gi bilit y c ha n ges  
( 1) I n Secti o n 4. 2 we ha v e u p date d o ur eli gi bilit y criteria t o n o l o n ger s pecif y 
se vere re nal i m pair me nt, defi ne d as Cr > 3 m g/ d L or Cr Cl < 3 0 m L/ mi n, or 
t otal bilir u bi n > 2. 5 m g/ d L as e xcl usi o n criteria. T hese la b-b ase d criteria ha ve 
bee n re m o v e d beca use ( 1) neit her are c o ntrai n dicati o ns t o recei vi n g 
me ma nti ne ( n ot liste d o n t he pac ka g e i nsert) a n d are ( 2) n ot a vaila ble i n m ost 
patie nts u ntil t he start c he m ot hera p y (after o ur recr uit me nt wi n d o w).  
 
Per t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C revie w.  
 
 
 
 
 
 
 
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 1 0/ 1/ 1 9 _ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 
P R O T O C O L A M E N D M E N T # _ _ 1 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol . 
( 2) I n Secti o n 1. 1 we ha v e c ha n ge d t he la n g u a ge ar o u n d t he ti mi n g of c o g niti ve 
assess me nts t o  all o w f or m ore fle xi bilit y i n sc he d uli n g wit h partici pa nts.  
( 3) I n Secti o n 7. 2  we ha v e br oa de ne d  t he all o wa ble m et h o ds of  c o ntact f or  st u d y 
assess me nt s t o i ncl u de o ver t he p h o ne. 
 
Per t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C revie w.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 8/ 2 6/ 1 9 _ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
L C C C 1 9 2 1 : 
Me ma nti ne f or Pre v e nti o n of C o g niti ve Decli ne d uri n g  A dj u va nt or  Ne o a dj u va nt 
C he m ot hera p y i n  Patie nts wit h Breast Ca ncer  
 
S h ort Title : Me ma nti ne f or Pre ve nti o n of C o g niti ve Decli ne i n Patie nts wit h Breast Ca ncer  
 
Pri nci p al I n vesti g at or  
Ze v N a k a m ur a, M D  
 
 
 
 
 
E mail: ze v _ na ka m ur a @ m e d. u nc.e d u  
 
Me dic al M o nit or  
Ze v Na ka m ura, M D  
 
 
E mail: ze v _ na ka m ur a @ me d. u nc.e d u  
 
C o -I n vesti g at or(s) 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
Bi ost atistici a n  
 
 
 
 
 
  
 
 
 
 
S p o ns or :  Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  
 
F u n di n g S o urce : N ort h Car oli na Cli nical a n d Tra nslati o nal Scie nces I nstit ute ( N C Tra C S 
I nstit ute), Gra nt #5 K 1 2 H D 0 0 1 4 4 1 -1 9  
 
 
Versi o n 1 D ate : 6/ 2 2 / 2 0 1 9 
Versi o n 2 D ate:  8/ 2 6/ 2 0 1 9  
Versi o n 3 D ate:  1 0/ 1/ 2 0 1 9  
Versi o n 4 D ate:  1 1/ 2 1/ 2 0 1 9  
Versi o n 5 D ate: 1/ 1 3 / 2 0 2 0 
Versi o n 6 D ate: 5 /2 1 / 2 0 2 0 
Versi o n 7 D ate:  9/ 4/ 2 0 2 0  
Versi o n 8 D ate:  1 0/ 7/ 2 0 2 0  
Versi o n 9 D ate:  1 2/ 1 4/ 2 0 2 0  
Versi o n 1 0 D ate:  4/ 2 3/ 2 0 2 1  
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
i 
T A B L E O F C O N T E N T S  
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  .................................................................4  
1. 1  
St u d y S y n o psis  .....................................................................................................4  
1. 2  
Disease Bac k gr o u n d .............................................................................................4  
1. 3  
C urre nt Sta n dar d of Care  .....................................................................................6  
1. 4  
Me ma nti ne  ...........................................................................................................6  
1. 5  
Rati o nale f or Cli nical St u d y .................................................................................7  
2. 0  
S T U D Y O B J E C TI V E S  ..........................................................................................8  
2. 1  
Pri mar y O bjecti ves ...............................................................................................8  
2. 2  
Sec o n dar y O bj ecti ves ...........................................................................................8  
2. 3  
E x pl orat or y  O bjecti ves  ........................................................................................8  
3. 0  
Criteri a f or E v al u ati o n / St u d y E n d p oi nts  ..........................................................8  
3. 1  
Pri mar y E n d p oi nt  .................................................................................................8  
3. 2  
Sec o n dar y E n d p oi nts  ...........................................................................................9  
3. 3  
E x pl orat or y E n d p oi nts  .........................................................................................9  
4. 0  
P A TI E N T E LI GI BI LI T Y  .....................................................................................9  
4. 1  
I n cl usi o n Criteria .................................................................................................9  
4. 2  
E xcl usi o n Criteria  ..............................................................................................1 0  
5. 0  
T R E A T M E N T P L A N  ..........................................................................................1 0  
5. 1  
Sc he ma  ...............................................................................................................1 0  
5. 2  
Treat me nt D osa g e a n d A d mi nistrati o n  ..............................................................1 0  
5. 3  
T o xicities a n d D osi n g Dela ys  ............................................................................1 1  
5. 4  
Pr o hi bite d Me dicati o ns/ Treat me nts  ...................................................................1 2  

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
ii 
5. 5  
D urati o n of T hera p y  ...........................................................................................1 3  
5. 6  
D urati o n of F oll o w U p  .......................................................................................1 3  
5. 7  
St u d y Wit h dra wal  ..............................................................................................1 3  
5. 8  
St u d y Meas ures  ..................................................................................................1 4  
6. 0  
D R U G I N F O R M A TI O N  .....................................................................................1 8  
6. 1  
Me ma nti ne Descri pti o n a n d Ma na ge me nt  .........................................................1 8  
7. 0  
E V A L U A TI O N S A N D A S S E S S M E N T S  ...........................................................1 9  
7. 1  
Ti me a n d E ve nts Ta ble  ......................................................................................1 9  
7. 3  
Treat me nt  ...........................................................................................................2 1  
7. 4  
P ost -C he m ot hera p y Assess me nt  ........................................................................2 1  
7. 5  
6 -M o nt h P ost -C he m ot hera p y Assess me nt (s u bset o nl y)  ...................................2 1  
7. 6  
C o nc urre nt C N S Acti ve Me dicati o ns  ................................................................2 2  
7. 7  
De m o gra p hics  ....................................................................................................2 2  
7. 8  
Me dical Hist or y  .................................................................................................2 2  
7. 9  
Ha n dli n g of Bi os peci me ns C ollecte d f or C orrel ati ve Researc h  ........................2 2  
7. 1 0  
Assess me nt of Safet y  .........................................................................................2 3  
7. 1 1  
Assess me nt of Efficac y  ......................................................................................2 3  
8. 0  
A D V E R S E E V E N T S  ...........................................................................................2 3  
8. 1  
Defi niti o ns ..........................................................................................................2 3  
8. 2  
D oc u me ntati o n of n o n -seri o us A Es or S A Rs ....................................................2 6  
8. 3  
S A Es or Seri o us S A Rs  .......................................................................................2 6  
8. 4  
A d verse E v e nt Re p orti n g  ...................................................................................2 7  
8. 5  
Data a n d Safet y M o nit ori n g Pla n  .......................................................................2 7  
9. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  ...............................................................2 8  

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
iii 
9. 1  
St u d y Desi g n/ St u d y E n d p oi nts  ..........................................................................2 8  
9. 2  
Sa m ple Size, Accr ual a n d D urati o n of Accr ual  .................................................2 8  
9. 3  
Data A nal ysis Pla ns  ...........................................................................................2 9  
1 0. 0  
S T U D Y M A N A G E M E N T  ...................................................................................3 0  
1 0. 1  
I nstit uti o nal Re vie w B oar d (I R B) A p pr o val a n d C o nse nt .................................3 0  
1 0. 2  
Re q uire d D oc u me nt ati o n  ...................................................................................3 0  
1 0. 3  
Re gistrati o n Pr oce d ures  .....................................................................................3 0  
1 0. 4  
A d here n ce t o t he Pr ot oc ol  ..................................................................................3 1  
1 0. 5  
A me n d me nts t o t he Pr ot oc ol  ..............................................................................3 2  
1 0. 6  
Rec or d Rete nti o n  ...............................................................................................3 2  
1 0. 7  
O bli gati o ns of I n v esti gat ors  ...............................................................................3 2  
1 1. 0  
R E F E R E N C E S  .....................................................................................................3 4  
1 2. 0  
A P P E N DI C E S  ......................................................................................................4 1  

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4  
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  
1. 1  
St u d y S y n o psis  
T his is a o ne -ar m p has e II i nter ve nti o nal st u d y  i n patie nts wit h breast ca n cer t o 
i n vesti gate w het her m e ma nti ne ca n  pre ve nt  c o g niti ve decli ne d uri n g  
c he m ot hera p y.  We will recr uit 5 6 partici pa nts  wit h breast c a ncer referre d t o t he 
U N C Breast Ce nter , Hills b or o u g h O nc ol o g y, or  U N C R E X O nc ol o g y cli nics  f or 
i nitiati o n of a dj u va nt or ne oa dj u va nt c h e m ot hera p y, perf or m a c o g niti ve 
assess me nt  at i nitiati o n (ra n ge:  a n y ti me after esta blis hi n g care t o o ne wee k after 
first d ose ) a n d f o ur wee ks after c o m pleti o n of c he m ot hera p y (ra n ge: t w o t o t wel ve 
wee ks after last d ose), a n d treat wit h me ma nti ne 1 0 m g t wice dail y bet wee n t he 
pre - a n d p ost -c he m ot hera p y st u d y assess me nts (esti mate d d urati o n: 1 2 -3 0  wee ks) . 
We will assess c o g niti ve f u ncti o n o bjecti vel y  usi n g a c o m p uterize d c o g niti ve 
assess me nt a n d a sta n d ar d ne ur o ps yc h ol o g ical b atter y. T o assess s u bjecti ve 
c o g niti ve f u ncti o n, we will use t he Patie nt Re p orte d O utc o me Meas ure me nt 
I nf or mati o n S yste m ( P R O MI S) C o g niti ve F u n cti o n meas ure . D e pressi o n, a n xiet y,  
fati g ue, me n o pa us al stat us, a n d slee p are c o m or bi dities k n o w n t o affect c o g niti ve 
f u ncti o n, a n d t heref ore will be assesse d  as c o v ariat es  t hr o u g h self-re p ort meas ures 
a n d, i n t he case of me n o p a usal stat us, la b orat or y v al ues. De pressi o n, an xiet y, 
healt h -rel ate d q ualit y of life (H R Q O L ) a n d f u n cti o nal stat us will be e val uat e d as 
sec o n dar y o ut c o mes. C o g niti ve a n d ot her sec o n d ar y o utc o me meas ures will be 
re peat e d i n a s u bset of p artici pa nts w h o o pt-i n f or l o n git u di nal f oll o w-u p at 6 
m o nt hs (ra nge: 4 t o 8 m o nt hs) p ost -c he m ot hera p y. We will als o assess t he 
feasi bilit y of o ur st u d y b y m o nit ori n g recr uit me nt, rete nti o n, a n d a d h ere n ce  t o 
me ma nti ne.   
1. 2  
Dise ase B ac k gr o u n d   
Ca ncer -relat e d c o g niti ve i m pair me nt ( C R CI) refers t o a c o nstellati o n of pr o ble ms 
wit h me m or y, atte nti o n, a n d e xec uti ve f u ncti o n t h at is ass ociate d wit h ca n cer a n d 
its treat me nts. T here are o ver 1 6  milli o n ca ncer s ur vi v ors i n t he U nite d States 1 
an d a n esti mate d 5 . 5 milli o n s uffer fr o m C R CI.2 S pecificall y, u p t o 7 5 % of 
patie nts wit h ca ncer re p ort c o g niti ve deficits d uri n g acti ve treat me nt a n d u p t o 
3 5 % of s ur vi v ors will de m o nstrate c o g niti ve i m pair me nt o n ne ur o ps yc h ol o gical 
assess me nt ( N P A) t hat ca n last years after treat m e nt. 2 C R CI ca n ha v e pr of o u n d 
c o nse q ue nces, i ncl u di n g i na bilit y t o ret ur n t o  w or k ,3, 4 re d uce d q ualit y of life,5 – 7 
a n d d o u b le d ris k of de me ntia8. Gi ve n t he s u bsta ntial pers o nal a n d s o cietal b ur de n 
of C R CI, a n d t he a bse nce of wa ys t o pre ve nt it , a p pr oac hes t h at scree n f or C R CI 
a n d deli ver effecti ve i nter ve nti o ns as s o o n after ca ncer dia g n osis as p ossi bl e are 
nee de d.  
 
M ost i nter ve nti o ns f or C R CI, i ncl u di n g c o g niti ve trai ni n g a n d re h a bilitati o n,9 – 1 1 
p h ysical acti vit y, 1 2, 1 3 a n d me ditati o n 1 4 – 1 6, h o we ver, are a d mi nistere d years after 
ca ncer treat me nt a n d ha v e yi el de d i nc o nsiste nt res ults. Per ha ps t he m ost esse ntial 
st u d y desi g n iss ue im pacti n g t h e efficac y of i nter v e nti o ns is t he ti mi n g of t heir 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5  
deli ver y rel ati ve t o w he n c o g niti ve iss ues are first a p preci ate d .  S pecificall y, 
beca use s y m pt o ms ca n p ersist f or se veral years after ca n cer treat me nt  a n d 
c o g niti ve deficits are ass ociate d wit h u n derl yi n g f u ncti o nal a n d str uct ural brai n 
c ha n ges, t he e xte nt t o w hic h C R CI is re versi ble is n ot clear. 1 7 – 2 2 A n ot her critical 
varia ble  i m pacti n g relia ble i nter pretati o n of i nter ve nti o n efficac y is lac k of 
a gree m e nt a b o ut h o w t o meas ure C R CI. Self -re p ort i nstr u me nts are criticize d as 
p ote ntiall y reflecti n g ot h er c o m or bi dities (e. g. d e pressi o n, a n xiet y, fati g ue) ,2 3 – 2 7 
w hile ot her i n vesti gat ors raise c o n cer ns a b o ut t he se nsiti vit y 2 5 a n d ec ol o gical 
vali dit y 2 8, 2 9 of N P A. F urt her, des pite I nter nati o nal C o g niti o n a n d Ca ncer Tas k 
F orce (I C C T F) g ui deli nes, 3 0 ne ur o ps yc h ol o gical batteries use d i n r esearc h re mai n 
hi g hl y heter o ge ne o us.  
 
E vi de nce  f or p har m ac ot h era pies f or eit her pre v e nti o n  or treat me nt  of C R CI is 
e ve n m ore li mite d t ha n wit h ot her C R CI i nter ve nti o ns . T o date, t he o nl y 
p har mac ol o gic a ge nts st u die d f or C R CI i ncl u d e ps yc h osti m ula nts, s u p ple me nts, 
e p o-sti m ulati n g a ge nts, d o ne pezil (a n acet ylc h oli nesterase i n hi bit or), a n d 
me ma nti ne. Cli nical trials wit h ps yc h osti m ula nts ha ve de m o nstrat e d p o or 
recr uit me nt a n d rete nti o n rates;3 1 – 3 6 s u p ple me nts, i ncl u di n g vita mi n E a n d gi n k g o 
bil o ba , ha ve n ot bee n effi caci o us ;3 7, 3 8 e p o-sti m ulati n g a ge nts ha ve s h o w n  mi xe d 
efficac y,3 9 – 4 3 b ut are n o l o n ger a p pr o priate f or use i n C R CI f oll o wi n g a 2 0 1 1 F o o d 
a n d Dr u g A d mi nistrati o n ( F D A) blac k b o x war ni n g re gar di n g i ncreas e d seri o us 
car di o vas c ular a n d t hr o m b otic e ve nts t hat ma y s h orte n o verall s ur vi val i n patie nts 
wit h ca ncer; 4 4 an d w hile d o ne pezil ma y be a n e n c o ura gi n g o pti o n, 4 5, 4 6 it has n ot 
bee n st u die d f or C R CI pr o p h yla xis.  
 
C o m pare d t o ot her p har mac ot hera pi es, me ma nti ne is partic ularl y pr o misi n g f or 
atte n uati o n of c he m ot hera p y -rel ate d c o g niti ve decli ne i n breast ca n cer f or s e veral 
c o m pelli n g reas o ns. First, its mec ha nis m of acti o n tar gets c yt o ki ne -me di ate d 
da ma ge s us pe cte d t o ca use C R CI. T N F -α, a n i nfla m mat or y c yt o ki ne t hat is 
ele vate d i n ca ncer, has b ee n s h o w n t o c o ntri b ute t o gl uta mate e xcit ot o xicit y 
i m plicate d i n ma n y ne ur o de ge nerati ve dis or ders.4 7 Of i nterest, i n a m uri ne m o del, 
s y ner gistic c o-acti vati o n of T N F -α a n d N -met h yl -D -as partate (N M D A ) rece pt ors 
res ulte d i n ne ur o nal cell deat h, w hic h was pre v e nte d b y me ma nti ne t hr o u g h 
a nta g o nis m of t he N M D A rece pt or. 4 8 Sec o n d, me ma nti ne is well -t olerate d a n d 
d oes n ot i nteract wit h c h e m ot hera pies or ot h er me dicati o ns r o uti nel y use d i n 
breast c a ncer treat me nt. T hir d, me ma nti ne has bee n st u die d f or C R CI pr o p h yla xis 
i n ot her as pects of ca n cer care. 4 9 Br o w n et al. i n vesti gate d me ma nti ne f or 
pre ve nti o n of c o g niti ve i m pair me nt i n patie nts recei vi n g w h ole brai n 
ra di ot hera p y.4 9 C o m pare d t o place b o, me ma nti ne dela ye d ti me t o o verall 
c o g niti ve decli ne a n d re d uce d t he ma g nit u de of decli ne i n me m or y, e xec uti ve 
f u ncti o n, a n d pr ocessi n g s pee d. T here are se v eral cli nical trials u n der wa y b uil di n g 
o n t his pr o misi n g e vi de nce f or c o g niti ve i m pair me nt d ue t o cra ni al ra diati o n, b ut 
me ma nti ne has n ot yet be e n teste d t o miti gate c he m ot hera p y -relate d c o g niti ve 
decli ne.  

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
6  
1. 3  
C urre nt St a n d ar d of C are  
C urre ntl y, t here is n o sta n dar d of care t o pre ve nt or treat  C R CI . T h e m ost wi del y 
st u die d be ha vi oral i nter v e nti o ns, s uc h as c o g niti ve re ha bilitati o n a n d c o g niti ve 
trai ni n g, re q uire e x pertis e t o a d mi nister a n d are n ot rea dil y a vaila ble t o all 
patie nts. Relati vel y fe w m e dicati o ns  ha ve bee n i n vesti gate d , a n d e v e n i n s mall 
p atie nt sa m ples , res ults ha ve n ot bee n e nc o ura gi n g. Cli nical trials i n 
ps yc h osti m ula nts , w hic h d o see m t o  i m pr o ve f u ncti o n i n certai n c o g niti ve 
d o mai ns , ha ve re v eale d p artic ularl y p o or recr uit me nt a n d rete nti o n r ates .3 1 – 3 6 F or 
e xa m ple, met h yl p he ni dat e, w hic h t o o ur k n o wle d g e is t he o nl y  oral me dicati o n 
e ver st u die d t o pre v e nt c he m ot hera p y -relate d c o g niti ve decli ne , faile d t o 
de m o nstrate a d e q uate a ccr ual .3 4 I n vesti gat ors h y p ot hesize d  t hat t his was relate d t o 
sti g ma a gai nst t he me dicati o n’s esta blis he d i n dicati o n f or c hil d h o o d Atte nti o n-
Deficit/ H y peracti vit y Dis or der.  T he m e dicati o ns ori gi nall y de vel o pe d a n d 
c urrentl y wit h F D A a p pr o val f or Alz h ei mer’s disease, i ncl u di n g d o ne pezil a n d 
me ma nti ne, ma y ha ve t h e m ost pr o mise. T he y are safe, well -t olerate d, wit h 
e nc o ura gi n g, b ut n ot c o n cl usi ve, data i n m ulti -ce nter ra n d o mize d c o ntr olle d 
trials.4 5, 4 6, 4 9. 
1. 4  
Me m a nti ne  
F or t his trial we ha v e c h ose n t o st u d y t he effe cts of me ma nti ne, a n N M D A 
rece pt or a nta g o nist. Me ma nti ne has bee n well st u die d i n lar ge p o p ulati o n 
sa m ples, i ncl u di n g o nc ol o g y p o p ulati o ns, a n d s h o w n t o be safe. 4 9 – 5 1 It has n o 
k n o w n dr u g -dr u g i nteracti o ns wit h c he m ot hera pies use d f or t he treat me nt of 
breast c a ncer or me dicati o ns  c o m m o nl y gi ve n i n ass ociati o n wit h c he m ot hera p y 
(e. g. o n da nsetr o n, fa m oti di ne, me peri di ne, e pi n e p hri ne, s ol u me dr ol, 
de xa met has o ne, aceta mi n o p he n, ne ulasta, f osa pre pita nt).  Me ma nti ne is partiall y 
meta b olize d b y t he li ver (i n de pe n de nt of t h e c yt oc hr o me p 4 5 0  s yste m) a n d 
e xcret e d b y t he ki d ne ys.  
 
Me ma nti ne is c urre ntl y o nl y F D A a p pr o ve d f or m o derate t o se v ere Alz hei mer’s 
disease. Gl uta mate, t h e pri mar y e xcitat or y n e ur otra ns mitter i n t he ce ntral n er v o us 
s yste m, is t h o u g ht t o c o ntri b ute t o t he pat h o ge nesis of Alz hei mer’s disease b y 
o versti m ulati o n of gl ut a mate rece pt ors. 4 7 Gl u ta mate e xcess pre v e nts ma g n esi u m 
i o ns ( M g2 +), w hic h bl oc k t he N M D A rece pt or u n d er p h ysi ol o gic c o n diti o ns, fr o m 
re-e nt eri n g t he c h a n nel p ore , res ulti n g i n a c hr o nicall y o pe n state. T his i n t ur n 
lea ds t o e xcessi ve calci u m ( Ca2 +) i nfl u x a n d s u bse q ue nt ne ur o n al cell deat h 
o bser ve d i n ma n y ne ur o de ge nerati ve dis or der s.4 7 Me ma n ti ne bi n ds t o t he i ntra-
p ore M g
2 + site u n der c o n diti o ns of e xcessi ve sti m ulati o n t o bl oc k t he N M D A 
rece pt or a n d pre ve nt c ell deat h.5 2   C he m ot hera p y -relate d c o g niti ve decli ne is 
p ost ulate d t o be a c o nse q ue nce of gl uta m ate e x cit ot o xicit y as well, me diate d b y 
i m m u ne d ysre g ulati o n. S pecificall y, peri p heral le vels of T N F -α  are ele vat e d i n 
ca ncer, i ncrease d uri n g c he m ot hera p y, a n d are c orrelate d wit h c o g niti ve 
deficits. 2 2, 5 3 – 5 6 T hr o u g h  acti o n o n ne ur o nal T N F rece pt ors , T N F -α  i n creases 
N M D A rece pt or p er mea bilit y t o Ca 2 + a n d ge nerat es e xcessi ve reacti ve o x y ge n 
s pecies, res ulti n g i n ne ur o nal deat h. 5 7  F or t hese reas o ns , N M D A rece pt or 

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a nta g o nis m b y me ma nti ne ma y be  a pr o misi n g a p pr oac h t o miti gat e c o g niti ve 
decli ne  ass oci ate d wit h c he m ot hera p y .  
 
T h o u g h me ma nti ne has n ot yet bee n st u die d f or c h e m ot hera p y -relate d c o g niti ve 
decli ne, t here has bee n o ne cli nical trial  of me ma nti ne f or  C R CI b y Br o w n et al. 
i n patie nts recei vi n g w h ole brai n ra di ot hera p y.4 9 Partici pa nts were ra n d o mize d t o 
me ma nti ne or place b o, w hic h was a d mi nistere d at t he start of ra di ati o n a n d 
c o nti n ue d f or 2 4 w ee ks. At baseli ne, 8, 1 6, a n d 2 4 wee ks, partici pa nts u n der we n t 
a ne ur o ps yc h ol o gical batter y ( H o p ki ns Ver bal Lear ni n g Test -Re vise d, H V L T -R ; 
Trails Ma ki n g Tests A a n d B, T M T -A, T M T -B ; C o ntr olle d Oral W or d 
Ass ociati o n test, C O W A ; a n d t he Mi ni Me ntal Stat us E xa m, M M S E) , p h ysical 
e xa m, brai n i ma gi n g, la b tests, a n d e v al uati o n of p erf or ma n ce stat us.  T h o u g h t heir 
pri mar y o utc o me, c h a n ge i n H V L T -R Dela ye d Recall sc ore at 2 4 wee ks, di d n ot 
reac h st atistical si g nifica nce ( p = 0. 0 5 9), c o m pare d t o p lace b o me ma nti ne d ela ye d 
ti me t o o verall c o g niti ve decli ne a n d re d uce d t he ma g nit u de of decli ne i n t he 
d o mai ns of me m or y ( H V L T -R), e xec uti ve f u ncti o n ( T M T -B), a n d pr o cessi n g 
s pee d ( T M T-A) at se v eral f oll o w -u p ti me p oi nts. 4 9 T here are s e veral cli nical trials 
of me ma nti ne as a n e ur o pr otecti ve a g e nt i n t he setti n g of cra nial ra di ati o n i n a 
variet y of patie nt p o p ulati o ns (a d ult a n d pe diatric; pri mar y brai n t u m or, brai n 
metastases, a n d hea d a n d nec k ca ncers).  
1. 5  
R ati o n ale  f or Cli nic al St u d y 
A n esti mate d  5 . 5 milli o n ca ncer s ur vi v ors i n t he U nite d States  s uffer fr o m 
C R CI ,1, 2 a n d u p t o 7 5 % of patie nts wit h ca ncer re p ort c o g niti ve deficits d uri n g 
acti ve treat me nt .2 O n ne ur o ps yc h ol o gical assess m e nt,  a p pr o xi matel y  3 5 % of 
s ur vi v ors will de m o nstrate c o g niti ve i m pair me nt t hat ca n last years after 
treat me nt.2 C R CI ca n h a ve pr of o u n d c o ns e q ue n ces, i ncl u di n g a d verse me nt al 
healt h o utc o mes, 3, 5 8 – 6 0 i na bilit y t o ret ur n t o w or k,3, 4 re d uce d q ualit y of life,5 – 7 
d o u ble d  ris k of de me ntia,8 a n d i ncrease d m ort alit y .6 1  
 
Gi ve n t hat t here is  c urre ntl y n o esta blis he d wa y t o treat or pre ve nt c he m ot h era p y-
relate d c o g niti ve d ecli ne, a p pr oac h es t h at scree n f or C R CI a n d d eli ver 
i nter ve nti o ns t hat are c ost-effecti ve, a v aila ble i n all ca ncer ce nt ers, a n d ca n be 
easil y i nc or p orat e d i nt o patie nt care are nee d e d.  T he c o urse of  c o g niti ve 
i m pair me nt res ulti n g fr o m ca ncer a n d its treat me nt s are vari a bl e. H owe ver, 
se veral st u dies ha v e de m o nstrate d c o g niti ve iss ues persisti n g years after 
c he m ot hera p y t h at are ass ociate d wit h decreas e d gra y matter v ol u me a n d w hite 
matter c o n necti vit y ,2 1, 6 2, 6 3 hi g hli g hti n g t he i m p orta nce of i n v esti gati n g 
pre ve ntati ve a p pr oac hes. Dr u g t hera pi es ha v e t he p ote ntial t o a d dress t he 
li mitati o ns of access t o care  see n wit h ot her C R CI i nter ve nti o ns. T here h as o nl y 
bee n o ne st u d y e v al uati n g t he use of a dr u g  t o pre ve nt C R CI, a n d it cl ose d 
pre mat urel y d u e t o c halle n ges wit h recr uit me nt .3 4     
 
I n t his o ne-ar m p has e II i nter ve nti o nal st u d y, we e xa mi ne t he use of me m a nti ne 
f or C R CI pre ve nti o n. I n a d diti o n, t he st u d y will ge nerat e val ua ble i nf or mati o n 

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re gar di n g v aria bles, i ncl u di n g de pressi o n, a n xiet y, fati g ue, me n o pa us al stat us, 
slee p, esti mate d pre-ca ncer c o g niti ve f u n cti o n, a n d self -percei ve d c o g niti ve eff ort, 
t hat ma y clarif y t he relati o ns hi p bet wee n self-re p orte d a n d o bjecti vel y meas ure d 
c o g niti ve f u ncti o n. As t his is t he first st u d y i n vesti gati n g t he use of me ma nti ne f or 
atte n uati o n of c o g niti ve decli ne d uri n g c h e m ot hera p y, we will assess feasi bilit y of 
o ur i nter ve nti o n, as meas ure d b y recr uit me nt, ret e nti o n, a n d a d here n ce.  
 
2. 0  
S T U D Y O B J E C TI V E S  
2. 1  
P ri m ar y O bjecti ve s 
2. 1. 1  T o c o m pare c ha n g es i n pre- t o p ost-c h e m ot hera p y c o g niti ve f u ncti o n , as 
meas ure d b y D M S sc ore,  i n o ur c o h ort of patie nts wit h breast ca n cer recei vi n g 
me ma nti ne t o hist orical c o ntr ols.  
2. 2  
Sec o n d ar y O bjecti ves   
2. 2. 1   T o c o m pare pre- t o p ost -c he m ot hera p y c ha n g es i n all ot her o bjecti ve a n d 
self-re p orte d c o g niti ve f u ncti o n meas ures. 
 
2. 2. 2   T o e xa mi ne ass oci ati o ns bet wee n o bjecti ve a n d self -re p ort e d c o g niti ve 
f u ncti o n wit h de pressi o n, a n xiet y, fati g ue, me n o pa usal stat us, base li ne I Q, a n d 
pe rcei v e d c o g niti ve eff ort, cr oss-secti o nall y pre- a n d p ost -c he m ot hera p y . 
 
2. 2. 3   T o e x pl ore t he i m pact of c o g niti ve decli ne o n healt h -relate d q u alit y of life 
( H R Q O L), f u ncti o nal stat us, de pressi o n, a n d a n xi et y.  
 
2. 2. 4   T o e sti mate t he feasi bilit y of c o n d uct i n g a cli nical trial of me ma nti ne f or 
atte n uati n g c o g niti ve decli ne i n patie nts wit h breast ca ncer d uri n g c he m ot h era p y.  
 
2. 2. 5    T o descri be t he s afet y of a d mi nisteri n g me ma nti ne t o patie nts wit h breast 
ca ncer d uri n g c h e m ot hera p y . 
 
2. 3  
E x pl or at or y O bjecti ves  
 2. 3. 1  T o c o m pare pre - t o 6  m o nt h s p ost -c he m ot hera p y c ha n ges i n o bjecti ve a n d 
self-re p orte d c o g niti ve f u ncti o n meas ures. 
 
 2. 3. 2  
T o descri be  c ha n ges i n d e pressi o n, a n xiet y, fati g ue, H R Q O L, a n d 
f u ncti o nal stat us fr o m pr e- t o 6 m o nt hs p ost -c he m ot hera p y . 
3. 0  
Criteri a f or E v al u ati o n / St u d y E n d p oi nts  
3. 1  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt  is c ha n ge i n t he pre - t o p ost-c he m ot hera p y D M S sc ore .  
T he D M S will be q ua ntifie d as perce nt c orrect at 1 2 -sec o n d del a y.  

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3. 2  
Sec o n d ar y E n d p oi nts  
3 . 2. 1 C ha n ges i n ot her o bjecti ve ( H V L T -R , R V P, O T S,  Di git S pa n, C O W A, 
A ni mal Na mi n g Test ) a n d self-re p orte d ( P R O MI S C o g niti ve F u ncti o n) c o g niti ve 
meas ures  will be me as ur e d  fr o m pre- t o p ost-c he m ot hera p y . 
 
 
3. 2. 2   De pressi o n  ( P R O MI S-De pressi o n) , A n xiet y ( P R O MI S -A n xiet y) , fati g ue 
( F u ncti o nal Ass ess me nt of C hr o nic Ill ness T hera p y –  Fati g ue, F A CI T -F), 
me n o pa usal stat us ( H or m o nal Stat us Q uesti o n naire  a n d f ollicle sti m ulati n g 
h or m o ne le vel, F S H ), a n d percei v e d c o g niti ve eff ort ( N A S A-Tas k L o a d I n de x, 
N A S A -T L X)  w ill be meas ure d pre- a n d p ost -c he m ot hera p y.   Baseli ne I Q 
( Wec hsl er A d ult Test of Rea di n g, W T A R) will be meas ure d pre-c he m ot hera p y 
o nl y.  
 
 
3. 2. 3    Healt h -relate d q ualit y of life ( F u ncti o nal Assess me nt of Ca ncer T hera p y –  
Ge neral, F A C T -G) a n d f u ncti o nal stat us (Patie nt -re p orte d Kar n ofs k y Perf or ma nce 
Stat us, Patie nt -K P S) will be meas ure d pre - a n d p ost -c he m ot hera p y . 
 
3. 2. 4    Recr uit me nt will be meas ure d as pr o p orti o n of a p pr oac he d p artici pa nts 
w h o a gree t o e nr oll a n d n u m ber of partici p a nts e nr olle d per m o nt h. Rete nti o n will 
be meas ur e d as pr o p orti o n of e nr olle d partici pa nts w h o c o m plete t he pri mar y 
o utc o me meas ur e pre - a n d p ost -c he m ot hera p y. A d here nce will be meas ure d as 
patie nt -re p ort e d pr o p orti o n of prescri be d d oses of me ma nti ne act uall y ta ke n.  
 
3. 2. 5    Safet y will be meas ure d as t he fre q u e nc y of re p orte d a d verse e ve nts ( A Es). 
3. 3  
E x pl or at or y E n d p oi nts  
3. 3. 1  C ha n ges i n t he D M S, H V L T -R, R V P, O T S, Di git S pa n, C O W A, A ni mal 
Na mi n g Test, a n d P R O MI S C o g niti ve f u ncti o n will be meas ure d fr o m pre - t o 6 
m o nt hs p ost -c he m ot hera p y i n a s u bset of partici p a nts w h o v ol u nteer f or e xte n de d 
l o n git u di nal o bser vati o n. 
 
3. 3. 2  C ha n g es i n P R O MI S -De pressi o n, P R O MI S -A n xi et y, F A CI T -F, F A C T -G, 
a n d Patie nt -K P S will be meas ure d fr o m pre - t o 6 m o nt hs p ost -c he m ot hera p y i n a 
s u bset of partici pa nts w h o v ol u nteer f or e xte n de d l o n git u di nal o bser vati o n.  
 
4. 0  
P A TI E N T E LI GI BI LI T Y  
I n or der t o partici pate i n t his st u d y a partici pa nt  m ust meet A L L  of t he eli gi bilit y 
criteria o utli ne d bel o w.   
4. 1  
I ncl usi o n Criteri a 
Eli gi ble partici pa nts  m ust meet all of t he f oll o wi n g criteria t o be e nr olle d i n t he 
st u d y: 
4. 1. 1  A ble t o pr o vi de i nf or me d c o nse nt  
4. 1. 2  At least 1 8 years of a ge  

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4. 1. 3  A ble t o s pea k E n glis h  
4. 1. 4   Dia g n ose d wit h breast ca ncer, Sta ges I –  III 
4. 1. 5   Sc he d ule d f or a dj u va nt or ne o a dj u va nt c h e m ot hera p y  
4. 2  
E xcl usi o n Criteri a  
Eli gi ble partici pa nts m ust n ot ha ve a n y of t he f oll o wi n g t o be e nr olle d i n t he 
st u d y: 
4. 2. 1  A hist or y of a d vers e reacti o n t o me ma nti ne  
4. 2. 2  A n ot her ca n cer dia g n osis  wit h a n esti mate d s ur vi val of less t ha n fi ve y ear s 
4. 2. 3  Pre vi o us c he m ot hera p y e x p os ure  
4. 2. 4  Se vere c o g niti ve i m pair me nt, defi ne d as Blesse d Orie ntati o n Me m or y 
C o nce ntrati o n Te st ( B O M C) ≥ 1 1. 
4. 2. 5  Pre g na nc y , c o nfir me d b y a ne gati ve pre g na n c y test wit hi n 3 0 da ys of 
st u d y e nr oll me nt, or breastfee di n g 
4. 2. 6  C urre nt alc o h ol or dr u g a b use  
5. 0  
T R E A T M E N T P L A N  
5. 1  
Sc he m a  
 
5. 2  
Tre at me nt D os a ge a n d A d mi nistr ati o n  
Partici pa nt s will recei ve me ma nti ne be gi n ni n g wit hi n f o ur wee k s pri or t o a n d o ne 
wee k after  c he m ot hera p y i nitiati o n. All patie nts will be gra d uall y titrate d t o 1 0 
m g t wice dail y as f oll o ws: 5 m g dail y i n wee k 1, 5 m g t wice dail y i n wee k 2, 5 
m g eac h m or ni n g a n d 1 0 m g eac h e v e ni n g i n wee k 3,  t he n 1 0 m g t wice dail y i n 
wee k  4 . Participa nts will c o nti n ue 1 0 m g t wice dail y u ntil 4 wee ks (ra n ge: 2 t o  1 2  

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1 1  
wee ks) after t h e last d ose of c he m ot hera p y . De p e n di n g o n t he c he m ot hera p y 
re gi me n, t otal d urati o n wil l ra n ge fr o m a p pr o xi matel y 1 2-3 0  wee ks.  
 
R E GI M E N D E S C RI P TI O N  
 
A ge nt  
 
R o ute  
 
D ose  
 
Sc he d ule  
Me ma nti ne H Cl  
Oral  
5 m g  dail y  
Wee k 1  
5 m g  t wice dail y 
Wee k 2  
5 m g  eac h m or ni n g, 1 0 m g eac h e ve ni n g  
Wee k 3  
1 0 m g  t wice dail y 
Wee k 4 t o 4 wee ks 
p ost -c he m ot hera p y  
 
 
Prescri bi n g I nf or m ati o n  
F ull prescri bi n g i nf or mati o n f or me ma nti ne ca n be f o u n d at t he f oll o wi n g w e b 
a d dress:   
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da d o cs/la bel/ 2 0 1 3/ 0 2 1 4 8 7s 0 1 0s 0 1 2s 0 1 4
, 0 2 1 6 2 7s 0 0 8l bl. p df 
5. 3  
T o xicities a n d D osi n g Del a ys  
A n y patie nt w h o recei ves treat me nt o n t his pr ot oc ol will be e val ua te d b y t h e 
C R A, PI, or C o -Is f or t o xicit y.  P atie nts will be assesse d  at least w ee kl y d uri n g 
t he titrati o n of me ma nti ne a n d n o less fre q ue nt  t ha n e ver y t hree wee ks  d uri n g 
s yste mic c he m ot hera p y. F or patie nts r ecei vi n g a nti-H E R 2 directe d t hera p y i n 
a d diti o n t o c he m ot hera p y, t o xicit y will o nl y be assesse d d uri n g t he c h e m ot hera p y 
se g me nt of t he re gi me n. 
 
T o xicit y will be assesse d acc or di n g t o t he N CI C o m m o n T o xicit y Criteria f or 
A d verse E v e nts ( C T C A E), versi o n 5 . 0.  
 
I n assessi n g a d verse e v e nts ( A Es) a n d attri b uti o n d uri n g t he c o urse of t his  st u d y, 
we will c o nsi der t h ose A Es  c o m m o nl y ass ociate d wit h me ma nti ne, t he s pecific 
c he m ot hera p y a d mi nistere d, a n d  c h e m ot hera p y -ass ociate d me dicati o ns recei ve d.  
 
T h o u g h all patie nt -re p orte d s y m pt o ms will be rec or de d a n d e x a mi ne d f or t heir 
ass ociati o n wit h me ma nti ne, t he f oll o wi n g m ost c o m m o n si de effects of 
me ma nti ne will be e x plicitl y s olicite d fr o m partici pa nts b y t he st u d y tea m: 
hea dac he, diz zi ness, c o nf usi o n, c o nsti pati o n, diarr hea, a n d fati g ue. 6 4 See secti o n 
6. 1. 7 f or a d diti o nal i nf or mati o n o n me ma nti ne war ni n gs a n d preca uti o ns.  
Differe ntiati o n bet wee n  me ma nti ne -ass ociat e d t o xi cities a n d t o xicities attri b uta ble 
t o alter nati ve a g e nts will be g ui de d b y Assessi n g of Ca usalit y of A d verse E ve nts 
o utli ne d i n 8. 1. 2 . T he treati n g pr o vi der will be n otifie d of a n y p ossi ble, pr o ba ble, 
or defi nite A Es a n d i n v ol ve d i n decisi o ns t o c o nti n ue, d ose re d u ce, or st o p 
me ma nti ne . At a n y ti me, t he partici pa nt ma y deci d e t o d ose re d u ce or disc o nti n ue 
me ma nti ne.  
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 2  
If a partici pa nt e x perie nces a gra d e 1 t o xicit y wit h a pr o ba ble or defi nite 
attri b uti o n t o me ma nti ne, t he partici pa nt will re mai n o n t he sa me  d ose a n d 
s y m pt o ms will be m o nit ore d dail y u ntil t he si de effect is res ol ve d. 
 
If a partici pa nt e x perie nces a gra d e 2 t o xicit y wit h a pr o ba ble or defi nite 
attri b uti o n t o me ma nti ne, t he d ose will be re d u ce d t o 5 m g P O BI D ( or t he l ast 
t olerate d d ose if less) a n d s y m pt o ms will be m o nit ore d dail y u ntil t he si de effect 
is res ol ve d. If n o i m pr o v e me nt, me ma nti ne will be disc o nti n ue d. 
 
If a partici pa nt e x perie nces a gra d e 3 t o xicit y wit h a pr o ba ble or defi nite 
attri b uti o n t o me ma nti ne, t he partici pa nt will disc o nti n ue me ma nti ne.  
 
If a partici pa nt e x perie nces t o xicit y wit h a p ossi ble attri b uti o n t o me ma nti ne, t he 
partici pa nt will re mai n o n t he sa me d ose of me m a nti ne a n d s y m pt o ms will be 
m o nit ore d wee kl y u ntil t he si de effect is res ol v e d.  
 
If a partici pa nt e x perie nces t o xicit y wit h a n u nli kel y or u nrelate d attri b uti o n t o 
me ma nti ne, t he partici pa nt will re mai n o n t he sa me d ose a n d si de effects will be 
m o nit ore d acc or di n g t o t he sc he d ule d o utli ne d i n t he pr ot oc ol (i.e., wee kl y d uri n g 
titrati o n or n o less t ha n e ver y 3 wee ks d uri n g mai nte na nce).  
 
Re gar dless of gra de or relati o ns hi p wit h me ma nti ne, if o ne of t he m e ma nti ne si de 
effects liste d bel o w is t he reas o n f or d ose re d ucti o n of c he m ot hera p y , t he 
partici pa nt will re d uce me ma nti ne t o 5 m g P O BI D ( or t he last t olerate d d ose if 
less) a n d s y m pt o ms will be m o nit ore d dail y u ntil t he si de effect is res ol v e d. If n o 
i m pr o ve me nt, me ma nti ne will be disc o nti n ue d. 
•  Hea dac he  
•  Dizzi ness  
•  C o nf usi o n  
•  C o nsti pati o n  
•  Diarr hea  
•  Fati g ue  
 
Re gar dless of w h et her t h e partici pa nt e x p erie n ces a n y A Es , if creati ni ne cl eara nce 
falls bel o w 3 0 m L/ mi n, t he d ose will als o be decrease d t o 5 m g P O BI D .  If 
creati ni ne cleara nce falls bel o w 5 m L/ mi n, t he st u d y me dicati o n will be st o p pe d.   
5. 4  
Pr o hi bite d Me dic ati o ns/ Tre at me nts  
T here are n o me di cati o ns/treat me nts t hat w o ul d pr o hi bit partici pa nt s fr o m 
i ncl usi o n a n d c o nti n ue d assess me nt i n t his st u d y. 
 
Patie nts o n t he f oll o wi n g me dicati o ns will be c o u nsele d o n p ossi ble i nteracti o ns 
wit h me ma nti ne a n d partic ular ca uti o n will be ta ke n wit h d ose escalati o n a n d si de 
effect m o nit ori n g: dr u gs t hat ma y i ncreas e t he ser u m c o nce ntrati o n of m e ma nti ne 
(al kali nizi n g a ge nts, b u pr o pi o n, car b o nic a n h y dras e i n hi bit ors) a n d dr u gs t hat 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 3  
ma y e n ha nce t he a d v erse/t o xic effects of me ma nti ne (tri met h o pri m a n d ot h er 
N M D A rece pt or a nta g o nists). S u p p orti ve me dicati o ns t y picall y use d d uri n g 
c he m ot hera p y f or breast ca ncer d o n ot ha ve dr u g -dr u g i nteracti o ns wit h 
me ma nti ne.  
5. 5  
D ur ati o n of T her a p y  
Treat me nt will  c o nti n ue u ntil 4 wee ks (ra n g e 2 -1 2  wee ks) after t h e last d ose of 
syste mic c he m ot hera p y or u ntil:  
•  U nacce pta ble a d verse e v e nt(s)  
•  I nter-c urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt , O R  
•  Partici pa nt  deci des t o wit h dra w fr o m t he st u d y  
 
Decisi o ns t o re m o ve a p artici pa nt  fr o m t he trial or disc o nti n uati o n of treat me nt 
bef ore pl a n ne d st u d y c o m pleti o n will be u n derta ke n i n c o nj u ncti o n wit h 
c o ns ultati o n fr o m t he st u d y PI.  
5. 6  
D ur ati o n of F oll o w U p  
F or deter mi nati o n of st u d y e n d p oi nts,  partici pa nts  will be f oll o we d u ntil 
c o m pleti o n of t he pri mar y e n d p oi nt ( a p pr o xi matel y 4 wee ks after  c h e m ot hera p y 
c o m pleti o n ). A s u bset of partici pa nts w h o v ol u nteer f or e xte n de d l o n git u di nal 
f oll o w-u p will be reass ess e d f or e x pl or at or y e n d p oi nts at 6-m o nt hs p ost -
c he m ot hera p y. All p artici pa nts  (i ncl u di n g t hose wit h dra w n f r o m pr ot oc ol t hera p y 
for A Es) will be f oll o w e d after re m o val fr o m st u d y treat me nt as sti p ulate d i n t he 
pr ot oc ol, u nless t he parti ci pa nt deci des t o wit h dra w fr o m t he st u d y.   
5. 7  
St u d y Wit h dr a w al  
Pa rtici pa nts will be re m o ve d fr o m pr ot oc ol t hera p y  a n d t he PI n otifie d w he n a n y 
of t he criteri a liste d i n secti o n 5. 5  a p pl y.  T he reas o n f or disc o nti n uati o n of t he 
pr ot oc ol t hera p y will be d oc u me nte d o n t he e C R F.    
 
If a partici pa nt deci d es t o wit h dra w  fr o m t he st u d y (a n d n ot j ust fr o m pr ot oc ol 
t hera p y) an  eff ort  will be ma de t o c o m plete a n d re p ort st u d y  assess me nts as 
t h or o u g hl y as p ossi ble. At t he ti me of wit h dra wal, t he PI will  atte m pt t o esta blis h 
as c o m pletel y as  p ossi ble t he reas o n f or t he st u d y w it h dra wal.  
•  
T he patie nt will  be as ke d if t he y are willi n g t o all o w f or t he a bstr acti o n of 
rele va nt i nf or m ati o n fr o m t heir me dical rec or d i n or der t o meet sec o n dar y 
o bjecti ves o utli ne d i n t he pr ot oc ol.   
•  
T he patie nt will be as ke d if t he y are willi n g t o c o m p lete t he M o difie d 
Brief Me dicati o n Q uesti o n naire -S pecific at t he ti m e of st u d y wit h dra wal.  
•  
If t he reas o n f or re m o val of a partici p a n t fr o m t he st u d y is a n a d verse 
e ve nt, t he pri nci pal s p ecific e ve nt will be rec or de d o n t he e C R F.   

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 4  
5. 8  
St u d y Me as ures  
Pre - a n d p ost -c h e m ot hera p y assess me nts will eac h ta ke a p pr o xi matel y 7 0 mi n utes 
t o c o m plete. A n o pti o nal 1 0-mi n ute brea k will be offere d d uri n g t he ass ess me nt  t o 
mi ni mize fati g ue . 
 
O B J E C TI V E C O G NI TI V E F U N C TI O N M E A S U R E S  
5. 8 . 1 Del a ye d M atc h i n g t o S a m ple Test ( D MS)  
T he Dela y e d Matc h i n g t o Sa m ple Test ( D M S) is a c o m p uterize d c o g niti ve 
assess me nt of  vis ual w or ki n g me m or y. 6 5, 6 6 T he D M S will be a d mi nistere d usi n g 
C A N T A B ec li pse s oft ware ( Ca m bri d ge C o g niti o n, Ca m bri d ge, U K). T h e 
partici pa nt is s h o w n a n i ma ge wit h f o ur patter ns a n d as ke d t o matc h  patter ns 
si m ulta ne o usl y or after dela y. We will use t he perce nt c orrect at t he 1 2 -sec o n d 
dela y o n t he D M S test f or t he pri mar y a n al ysis. T he D M S will ta ke 7 mi n utes t o 
c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d 
p ost -c he m ot hera p y.  
 
5. 8 . 2 H o p ki ns Ver b al Le ar ni n g Test -Re vise d ( H V L T -R)  
T he H V L T -R is a n o bjecti ve meas ure of ver bal lear ni n g a n d me m or y. 6 7 T he 
e xa mi ner rea ds a list of 1 2 n o u ns t o t h e partici pa nt, w h o re peats as ma n y w or ds as 
re me m bere d. A p pr o xi matel y 2 0 -2 5 mi n utes later , partici pa nts are as ke d t o recall 
as ma n y w or ds as p ossi bl e. T he n, t he e x a mi ner rea ds a list of 2 4 w or ds, i ncl u di n g 
t he 1 2 w or ds fr o m t he ori gi nal list, a n d t he partici pa nt is as ke d t o deter mi ne 
w hic h w or ds were a n d w ere n ot o n t he ori gi nal list. T hese tas ks res ult i n t hree 
s u bscales: t otal recall, dela ye d recall, a n d del a ye d rec o g niti o n. T he H V L T -R will 
ta ke 5 mi n utes t o c o m plete. All partici pa nts w h o are e nr olle d i n t he tri al will be 
e val uate d pre - a n d p ost -c he m ot hera p y.  
 
5. 8. 3  R a pi d Vis u al I nf or m ati o n Pr ocessi n g ( R V P)  
T he Ra pi d Vis ual I nf or m ati o n Pr ocessi n g  Test ( R V P)  is a c o m p uterize d 
assess me nt of pr ocessi n g s pee d .6 8 T he R V P  will be a d mi nistere d usi n g C A N T A B 
ecli pse s oft ware ( Ca m bri d g e C o g niti o n, Ca m bri d ge, U K).  T h e partici pa nt is 
s h o w n a series of  pse u d o -ra n d o m di gits fr o m 2 t o 9 a n d as ke d t o r ec o g nize tar get 
di git se q ue nces b y pressi n g a b utt o n o n t he scree n as q uic kl y as p ossi ble. T he 
R V P will ta ke 7 mi n utes t o c o m plete. All partici pa nts w h o are e nr olle d i n t he trial 
will be e val uate d pre - a n d p ost -c he m ot hera p y.  
 
5. 8. 4  O ne T o uc h St oc ki n gs  of C a m bri d ge  ( O T S) 
T he O ne T o u c h St oc ki n gs of Ca m bri d ge Test ( O T S) is a c o m p uterize d 
assess me nt of e x ec uti ve f u ncti o n .6 8 T he O T S will be a d mi nistere d usi n g 
C A N T A B ecli pse s oft ware ( Ca m bri d ge C o g niti o n, Ca m bri d ge, U K). T h e 
partici pa nt is s h o w n t w o dis pla ys wit h t hree c ol or e d balls prese nte d as stac ks 
s us pe n de d fr o m a b ea m a n d a r o w of n u m bere d b o xes al o n g t he b ott o m of t he 
scree n. I n t he first set of pr o ble ms, t he partici pa nt is as ke d t o m o ve t he balls i n t he 
l o wer dis pla y t o matc h t h at of t he u p per dis pla y. I n t he ne xt set, t he partici pant is 
as ke d t o w or k o ut i n t heir hea d h o w m a n y m o ves are re q uire d t o r eac h t he 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 5  
s ol uti o n t o eac h pr o ble m. T he O T S will ta ke 1 0 mi n utes t o c o m plete. All 
partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d p ost -
c he m ot hera p y.  
 
 
5. 8 .5  D i git S p a n  
T he Di git S pa n is a n o bjecti ve meas ure of atte nti o n a n d w or ki n g me m or y. 6 9  T he 
p artici pa nt is as ke d t o r ecite se q ue nces of n u m bers i n f or war d , b ac k war ds , a n d 
se q ue ntial or der . T he Di git S pa n will ta ke 4 t o 7  mi n utes t o c o m plete . All 
partici pa nts w h o are e nr olle d i n t he trial will be e v al uate d pre - a n d p ost -
c he m ot hera p y . 
 
5. 8 .6  C o ntr olle d Or al W or d Ass oci ati o n Test ( C O W A)  
T he C O W A is a n o bje cti ve meas ure of ver bal fl ue nc y .7 0 T he p artici pa nt is as ke d 
t o na me as ma n y w or ds as s he ca n, e x cl u di n g pr o p er n o u ns, i n o ne mi n ute. T his is 
re peat e d f or a t otal f or t hree differe nt letters. T he C O W A will ta ke 4  mi n utes t o 
c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d 
p ost -c he m ot hera p y.  
 
5. 8 .7  A ni m al N a mi n g Test ( A N T)  
T he A N T is a n o bjecti ve meas ure of se ma ntic fl ue nc y. 7 1 T he partici pa nt is as ke d 
t o na me as ma n y a ni mals as s he ca n i n o n e mi n ute. All partici pa nts will be 
e val uate d pre - a n d p ost -c he m ot hera p y.  
 
5. 8. 8  Wec hsler A d ult Test of Re a di n g ( W T A R)  
T he Wec hsler A d ult Test of Rea di n g ( W T A R) is a n o bjecti ve meas ure of 
i ntelli ge nce q u otie nt.7 2 T he p artici pa nt rea ds 5 0 irre g ularl y s pelle d w or ds t o 
pr o vi de esti mate d pre m or bi d i ntelli ge nce . T he W T A R will ta ke 3 mi n utes t o 
c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre -
c he mot hera p y o nl y.  
 
5. 8. 9  Blesse d Orie nt ati o n Me m or y C o nce ntr ati o n Test ( B O M C)  
T he B O M C is si x -ite m scree ni n g meas ure of c o g niti ve f u ncti o n t hat assesses 
orie ntati o n, la n g ua ge, atte nti o n, c o nce ntr ati o n, a n d me m or y. 7 3 It has g o o d 
relia bilit y a n d vali dit y7 3, 7 4 a n d has bee n i nc or p orat e d i nt o ca ncer -s pecific g eriatric 
assess me nts. A sc ore ≥ 1 1 has bee n use d t o s u g g est se vere c o g niti ve i m pair me nt. 
T he B O M C will ta ke less t ha n 5 mi n utes t o c o m plete. All  partici pa nts w h o are 
e nr olle d i n t he trial will be e val uat e d pre -c he m ot h era p y .       
 
S E L F -R E P O R T C O G NI TI V E F U N C TI O N M E A S U R E  
5. 8 .1 0  M o difie d P atie nt Re p orte d O utc o mes Me as ure me nt I nf or m ati o n 
S yste m –  C o g niti ve F u ncti o n  ( P R O MI S-C o g niti ve F u ncti o n)  
T he Nati o nal I nstit ute of Healt h’s Patie nt -Re p orte d O utc o mes Meas ure me nt 
I nf or mati o n S yste m ( P R O MI S) c o ntai ns a c o g niti ve f u ncti o n ba n k.7 5  We will use 
t he P R O MI S C o g niti ve F u ncti o n 8a s h ort f or m. Sc ores f or all P R O MIS meas ures 
are re p orte d o n t he T -sc ore metric i n w hic h t h e mea n = 5 0 a n d sta n dar d de viati o n 
( S D) = 1 0 are ce ntere d o n t he ge neral p o p ulati o n mea ns. Hi g her sc ores re prese nt 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 6  
greater de grees of c o g niti ve c o m plai nts. We will a d d t hree ite ms t o assess s elf-
percei v e d pre -ca n cer c o g niti ve a bilit y  a n d o ne ite m t o e x plicitl y assess me m or y . 
T he P R O MI S C o g niti ve F u ncti o n will ta ke less t h a n 5 mi n utes t o c o m plete. All 
partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d p ost -
c he m ot hera p y.       
 
C O V A RI A T E S A N D S E C O N D A R Y O U T C O M E M E A S U R E S  
5. 8 . 11  M o difie d N A S A T as k L o a d I n de x ( N A S A -T L X)  
T he N A S A Tas k L o a d I n de x ( N A S A -T L X) is a series of si n gle-ite m vis ual a nal o g 
scales t hat as k partici pa nts t o e val uate t heir perf or ma nce acr oss si x d o mai ns. 7 6 
Res p o nses i n eac h d o mai n tra nslate t o a p oi nt sc ore of 1 (l o west) t o 2 1 ( hi g he st). 
F or t he p ur p os es of o ur st u d y, we will as k  partici p a nts  t o self-e val u ate t heir 
perf or ma n ce acr oss f o ur d o mai ns: me ntal de ma n d, perf or ma n ce, eff ort, a n d 
fr ustrati o n. It will be a d mi nistere d f oll o wi n g eac h c o g niti ve tas k  ( D M S, H V L T-R, 
R V P, O T S , Di git S pa n, C O W A, A N T) . T h e N A S A -T L X will ta ke n o greater t ha n  
7 mi n utes t o c o m plete . All partici pa nts w h o are e nr olle d i n t he trial will be 
e val uate d pre - a n d p ost -c he m ot hera p y.       
 
5. 8 . 12  P atie nt Re p orte d O utc o mes Me as ure me nt I nf or m ati o n S yste m –  
De pressi o n ( P R O MI S -D)  
T he Nati o nal I nstit ute of Healt h’s Patie nt -Re p orte d O utc o mes Meas ure me nt 
I nf or mati o n S yste m ( P R O MI S) c o ntai ns a de pressi o n ba n k.7 5, 7 7  We will use t he 
P R O MI S De pressi o n 8a s h ort f or m. Hi g her sc ores re pres e nt greater de grees of 
de pressi o n. T he P R O MI S -D will ta ke less t ha n 2 mi n utes t o c o m plete.  All 
partici pa nts w h o are e nr olle d i n t he t rial will be e val uate d pre- a n d p ost -
c he m ot hera p y.  
 
5. 8 . 13  P atie nt Re p orte d O utc o mes Me as ure me nt I nf or m ati o n S yste m –  
A n xiet y  ( P R O MI S-A)  
T he Nati o nal I nstit ute of Healt h’s Patie nt -Re p orte d O utc o mes Meas ure me nt 
I nf or mati o n S yste m ( P R O MI S) c o ntai ns a n a n xi ety ba n k. 7 5, 7 7 We will use  t he 
P R O MI S E m oti o nal Dis tress-A n xiet y –  S h ort F or m 6a . Hi g her sc ores re prese nt 
greater de grees of a n xiet y.  T he P R O MI S A n xiet y will ta ke less t ha n 2 mi n utes t o 
c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d 
p ost -c he m ot h era p y.  
 
5. 8 . 14  P atie nt Re p orte d O utc o mes Me as ure me nt I nf or m ati o n S yste m –  
Slee p Dist ur b a nce  
T he Nati o nal I nstit ute of Healt h’s Patie nt -Re p orte d O utc o mes Meas ure me nt 
I nf or mati o n S yste m ( P R O MI S) c o ntai ns slee p b a n k . W e will use t he P R O MI S 
Slee p Dist ur ba nce S h ort F or m. 7 5, 7 8  Hi g her sc ores re pres e nt greater sle e p 
diffic u lties. T he P R O MI S Slee p Dist ur ba nce S h ort F or m will ta ke le ss t ha n 2 
mi n utes t o c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be 
e val uate d pre - a n d p ost -c he m ot hera p y.  
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 7  
5. 8 . 15  F u ncti o n al Assess me nt of C hr o nic Ill ness T her a p y -F ati g ue ( F A CI T -F)  
T he F A CI T -F scale is a 1 3 -ite m scale t hat uses a 5-p oi nt Li kert -t y pe scale ( 0 = n ot 
at all, 1 =a little bit, 2 =s o me w hat, 3 = q uite a bit, 4 = ver y m uc h). 7 9 T he s u g geste d 
F A CI T -F c ut -p oi nt f or si g nifica nt fati g ue is 3 6 o n a 0 t o 5 2 scale (l o wer sc ores 
i n dicati n g greater fati g u e). T he F A CI T-F scal e is writte n at t he 4 t h gra de le vel 
( Le xile fra me w or k) a n d ta kes 2 -3 mi n utes f or a n a vera ge p ers o n t o c o m plete. 
F A CI T -F will be meas ure d pre - a n d p ost -c h e m ot hera p y.  
 
5. 8 . 16  P atie nt -Re p orte d K ar n ofs k y Perf or m a nce St at us ( P atie nt -K P S)  
T he Patie nt -re p orte d K P S pr o vi des a self-c haract erizati o n of f u ncti o nal stat us, 
ra n gi n g fr o m se v erel y/re q uire c o nti n u o us n ursi n g care t o n or mal/ n o 
c o m plai nts/ n o s y m pt o ms of disease. 8 0 Sc ores ra n g e fr o m 3 0  t o 1 0 0 . Hi g her sc ores 
in dicate better f u n cti o n. T he Patie nt -K P S will ta ke less t ha n 2  mi n utes t o 
c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d 
p ost -c he m ot hera p y.       
 
5. 8 . 17  F u ncti o n al Assess me nt of C a ncer T her a p y -G e ner al ( F A C T -G)  
T he F A C T -G is a 2 7 -ite m patie nt-a d mi nistere d assess me nt of ge neral q ualit y -of -
life meas ures i n ca ncer patie nts. It h as bee n v ali date d i n t he literat ure a n d p er mits 
t he meas ure m e nt of a n u m ber of s y m pt o ms i ncl u di n g na usea, pai n, a n d 
i ns o m nia.8 1 T he F A C T -G will ta ke n o great er t ha n 5 mi n utes t o c o m plete. All 
partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d p ost -
c he m ot hera p y.      
 
5. 8. 1 8  H or m o n al  St at us  
We ha v e de vel o p e d a bri ef meas ure t o assess  m ulti ple di me nsi o ns of  h or m o nal 
stat us. F o ur  ite ms i n q uire a b o ut partici pa nts’ me nstr ual c ycles t o as certai n pre-, 
peri -, or p ost-me n o p a usal stat us per t he Sta ges of Re pr o d ucti ve A gi n g W or ks h o p 
+ 1 0 ( S T R A W + 1 0) criteria. 8 2 T hese ite ms will be use d i n c o nj u ncti o n wit h F S H 
le vels t o clarif y partici pa nts’ me n o pa usal stat us. Fi ve ite ms assess h or m o ne 
se nsiti vit y b y i n q uiri n g a b o ut e x perie nces wit h h or m o ne re place me nt t hera p y, oral 
c o ntrace pti ves, a n d m o o d c ha n ges relate d t o me nstr ual c ycle, pre g na n c y, or 
p ost part u m  peri o d . T he H or m o nal Stat us Q uesti o n naire will ta ke fe wer t ha n 5 
mi n utes t o c o m plete. All partici pa nts  will c o m plete t he h or m o nal stat us 
assess me nt  pre - an d p ost -c he m ot hera p y . 
 
5. 8. 1 9  M o difie d Brief Me dic ati o n Q uesti o n n aire  ( B M Q)-S pecifi c  
T he B M Q -S pecific c o ntai ns t w o fi ve -ite m scales assessi n g patie nts’ pers o nal 
beliefs a b o ut t he necessit y a n d c o ncer ns of ta ki n g prescri be d m e dicati o n f or t heir 
ill ness.8 3 , 8 4 We will use a m o difie d versi o n of t his i nstr u me nt c o nsisti n g of 
state me nts s pecific t o me ma nti ne a n d c o g niti o n. T he M o difie d B M Q -S pecific 
uses a 5 -p oi nt Li kert -t y p e scale ( 1 =str o n gl y disa gree t o 5 =str o n gl y a gree) t o 
i n dicate partici pa nts’ a gree me nt wit h eac h state m e nt. T otal sc ores f or t he 
necessit y a n d c o n cer ns s cales ra n ge  fr o m 5 t o 2 5 a n d are calc ul ate d b y s u m mi n g 
t he i n di vi d ual ite m sc ores wit hi n eac h scal e. Hi g h er sc ores re prese nt gr eater belief 
i n efficac y a n d greater c o ncer ns, res pecti vel y. T h e M o difie d B M Q -S pecific will 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 8  
ta ke fe w er t ha n 5 mi n utes t o c o m plete. All parti ci pa nts w h o are e nr olle d i n t he 
trial will be e val uate d p ost-c he m ot hera p y a n d t h ose w h o wit h dra w will be offere d 
t o c o m plete t he assess me nt at t he ti me of st u d y wit h dra wal. 
 
6. 0  
D R U G I N F O R M A TI O N  
6. 1  
Me m a nti ne Descri pti o n a n d M a n a ge me nt  
6. 1 . 1 Mec h a nis m of Acti o n  
Me ma nti ne H Cl is a  l o w t o m o derate affi nit y u nc o m petiti ve ( o pe n-c h a n nel) 
N M D A rece pt or a nta g o nist. It bi n ds prefere ntiall y t o ce ntral ner v o us s yste m 
N M D A rece pt or -o p erate d cati o n c ha n n els. A d diti o nall y, me ma nti ne has 
a nta g o nistic effects at t he 5 H T 3 rece pt or a n d bl oc ks nic oti nic acet ylc h oli ne 
rece pt ors at 1 0-1 6 % p ote nc y relati ve t o its acti o n o n N M D A a n d 5 H T 3 
rece pt ors.6 4  
 
6. 1 . 2 I n dic ati o ns 
Me ma nti ne H Cl is i n dicate d f or t he treat me nt of m o derate t o se v ere d e me ntia of 
t he Alz hei mer t y pe. 
 
6. 1 . 3 H o w S u p plie d  
T he dr u g will be o btai ne d fr o m c o m merci al s u p pl y t hr o u g h U N C P har mac y a n d 
U N C I n v es ti gati o nal Dr u g Ser vice (I D S).  
 
F ull prescri bi n g i nf or mati o n f or (Me ma nti n e H Cl ) is a vaila ble at:  
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da d o cs/la bel/ 2 0 1 3/ 0 2 1 4 8 7s 0 1 0s 0 1 2s 0 1 4
, 0 2 1 6 2 7s 0 0 8l bl. p df 
 
6. 1 . 4  D os a ge a n d A d mi nistr ati o n : 
Partici pa nts  will recei ve a gra d ual d os e titrati o n of me ma nti ne at 5 m g i ncre me nts 
per wee k t o a g oal d ose of 1 0 m g P O b i d. Titrati o n  sc he d ule is as f oll o ws:  
•  Wee k 1: 5 m g d ose o nce dail y  
•  Wee k 2: 5 m g d ose t wice dail y  
•  Wee k 3: 5 m g  eac h m or ni n g /1 0 m g eac h e ve ni n g  
•  Wee k 4 t hr o u g h en d of C he m ot hera p y: 1 0 m g d os e t wice dail y  
 
6. 1 . 5 St or a ge a n d St a bilit y : 
Me ma nti ne H Cl  s h o ul d be st ore d at r o o m te m perat ure ( bet w ee n 5 9 ° t o 7 7° F). 
 
6. 1 . 6  H a n dli n g a n d Dis p os al :  
L ocal re q uir e me nts f or dis p osal of hazar d o us dr u gs will be f oll o we d . 
 
Please see U N C p olic y o n hazar d o us dr u gs:  
htt p://i ntra net. u nc healt hcare . or g/i ntra n et/ h os pital de part me nts/safet y net/ p olicies/ ha
zar d o us dr u gs. p df  

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 9  
6. 1. 7  A d verse E ve nts Ass oci ate d wit h C o m merci al Dr u g  
I n a meta-a nal ysis of  si x p hase III place b o-c o ntr olle d trials of 9 5 9  patie nts 
recei vi n g me ma nti ne H Cl  f or m o derate t o s e ve re Alz hei mer’s disease, t he m ost 
fre q ue ntl y i de ntifie d si de effects were dizzi n ess ( 6. 3 %), hea d ac h e ( 5. 2 %), 
c o nsti pati o n ( 4. 6 %), a n d s o m n ole nce ( 3. 4 %). 8 5 T he f oll o wi n g ha ve als o b ee n 
re p orte d wit h t he f oll o wi n g fre q ue n cies: c o nf usi o n ( 6 %), h y perte nsi o n  ( 4 %), 
c o u g hi n g  ( 4 %), p ai n ( 3 %), hall uci nati o n ( 3 %), v o miti n g ( 3 %), d ys p nea ( 2 %), a n d 
fati g ue ( 2 %).6 4 A c o m pre he nsi ve list of a d verse effects c a n be f o u n d at t he 
f oll o wi n g we b a d dress: 
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d o cs/la bel/ 2 0 1 3/ 0 2 1 4 8 7s 0 1 0s 0 1 2s 0 1 4
, 0 2 1 6 2 7s 0 0 8l bl. p df 
 
7. 0  
E V A L U A TI O N S A N D A S S E S S M E N T S  
7. 1  
Ti m e a n d E ve nts T a ble  
 
 
Baseli ne ( Pre -
C he m ot hera p y) a 
D uri n g 
C he m ot hera p y  
P ost -C he m ot hera p y b  
6  M o nt hs P ost -
C he m ot hera p y d  
I nf or me d C o nse nt 
•  
 
 
 
De m o gra p hic Data 
F or m  
•  
 
 
 
Ca n cer Hist or y F or m  
•  
 
 
 
B O M C  
•  
 
 
 
D M S  
•  
 
•  
•  
H V L T -R  
•  
 
•  
•  
R V P  
•  
 
•  
•  
O T S  
•  
 
•  
•  
Di git S pa n  
•  
 
•  
•  
C O W A  
•  
 
•  
•  
A N T  
•  
 
•  
•  
W T A R  
•  
 
 
 
M o difie d P R O MI S - 
C o g niti ve F u ncti o n  
•  
 
•  
•  
M o difie d N A S A -T L X  
•  
 
•  
•  
P R O MI S -De pressi o n  
•  
 
•  
•  
P R O MI S -A n xiet y  
•  
 
•  
•  
P R O MI S -Slee p 
Dist ur ba n ce  
•  
 
•  
•  
H or m o nal Stat us  
•  
 
•  
•  
F A CI T -F  
•  
 
•  
•  
Patie nt -K P S  
•  
 
•  
•  
F A C T -G  
•  
 
•  
•  
F ollicle Sti m ulati n g 
H or m o ne Le vel  
•  
 
• c 
 
C N S -Acti ve 
Me dicati o ns  
•  
•  
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 0  
A d verse E ve nts F or m  
 
•  
 
 
A d here n ce  
 
•  
 
 
Alter nati ve C R CI 
treat me nts 
 
 
•  
 
M o difie d Brief 
Me dicati o n 
Q uesti o n naire ( B M Q) -
S pecific  
 
 
•  
 
 
a. Pr e -c h e m ot h er a p y a s s e s s m e nt s will o c c ur a n y ti m e b et w e e n e st a bli s hi n g c ar e i n t h e U N C 
Br e a st , Hill s b or o u g h O n c ol o g y, or U N C R E X C a n c er C e nt er cli ni c s  a n d o n e w e e k aft er t h e st art of 
c h e m ot h er a p y  
b. P o st -c h e m ot h er a p y a s s e s s m e nt s will o c c ur 4 w e e k s aft er (r a n g e: 2 -1 2  w e e k s aft er ) l a st d o s e of 
c h e m ot h er a p y  
c. F S H l e v el will b e o bt ai n e d p o st -c h e m ot h er a p y o nl y i n p arti ci p a nt s w h o r e p ort e d still h a vi n g 
m e n str u al c y cl e s at t h e pr e -c h e m ot h er a p y a s s e s s m e nt  
d. 6 -m o nt h p o st -c h e m ot h er a p y a s s e s s m e nt s  will o c c ur  o nl y i n a s u b s et of p arti ci p a nt s w h o 
v ol u nt e er f or e xt e n d e d l o n git u di n al f oll o w -u p   
 
7. 2   
Pre -St u d y ( B aseli ne) Assess m e nts  
Patie nts referre d t o t he U NC  Breast Ce nter , Hills b or o u g h O nc ol o g y , a n d U N C 
R E X O nc ol o g y  cli nics will be c o nsi dere d f or e nr oll me nt i n t his trial.  Pri or t o 
c he m ot hera p y i nitiati o n , t he C R A  or PI  will re v ie w t he trial wit h t he partici pa nt , 
c o nfir m eli gi bilit y , a n d o btai n i nf or me d c o nse nt . T he partici pa nt  will c o m plete  a 
c o g niti ve assess me nt batt er y, e val u ati n g vis ual w or ki n g me m or y ( D M S), ver bal 
lear ni n g a n d me m or y ( H V L T-R), pr ocessi n g s pee d ( R V P), e xec uti ve f u ncti o n 
(O T S ), atte nti o n a n d w or ki n g me m or y ( Di git S pa n), ver bal fl u e nc y ( C O W A), 
se ma ntic fl ue nc y ( A N T), a n d i ntelli ge nce q u otie nt ( W T A R). Self -re p ort e d 
c og niti ve eff ort ass ociate d wit h eac h tas k will be e val uate d usi n g t he N A S A -T L X.  
T he  partici pa nt  will als o c o m plete  self-re p ort ass ess me nts of c o g niti ve f u ncti o n 
( P R O MI S-M o difie d C o g niti ve F u ncti o n), de pressi o n ( P R O MI S -D ), a n xiet y 
( P R O MI S-A ), h or m o nal stat u s, slee p ( P R O MI S-Slee p Dist ur ba nce), fati g ue 
( F A CI T-F), f u ncti o nal st at us ( Patie nt -K P S),  a n d H R Q O L ( F A C T -G). See 
A p pe n dices A  –  P . F ollicle sti m ulati n g h or m o ne ( F S H) le vels will be dra w n t o ai d 
i n deter mi nati o n of h or m o n al stat us. F oll o wi n g c o m pleti o n of a ll pre-st u d y 
( baseli ne) assess me nts, p artici pa nts will be c o m pe nsate d f or t heir ti me wit h a gift 
car d. Partici p a nts m ust c o m plete all as pects of t he st u d y visit i n or der t o recei ve 
t he c o m pe nsati o n. T he C R A or i n vesti gat ors will als o c o n d uct a re vie w of 
electr o nic me di cal rec or ds t o o btai n baseli ne i nf or mati o n re gar di n g 
me dical/s ur gical hist or y,  t he partici pa nt’ s ca ncer a n d ca ncer treat me nt, a n d 
de m o gra p hic i nf or m ati o n.  All st u d y -relate d i nteracti o ns will be c o n d ucte d i n 
pri vate r o o ms at U N C Breast, Hills b or o u g h O nc ol o g y, a n d U N C R E X Ca n cer 
Ce nter cli nics;  i n pri vate r o o ms at partici pa nts’ h o mes; o ver t he p h o ne ; a n d b y 
vi de o c o nfere nci n g after c o nfir mi n g t hat s u bjects are  i n a pri vate l ocati o n. St u d y 
assess me nts a n d q uesti o n naires will be offere d b y e mail a n d mail as is necessar y 
a n d feasi ble.  

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 1  
7. 3  
Tre at me nt  
If t he partici p a nt  meets all i ncl usi o n/e xcl usi o n criteria  a n d pr o vi des i nf or m e d 
c o nse nt, s he will recei ve me ma nti ne be gi nni n g wit hi n f o ur wee ks b ef ore a n d o ne 
wee k after  c he m ot hera p y i nitiati o n  u ntil t he p ost -c he m ot hera p y ass ess me nt, 
a p pr o xi matel y f o ur wee ks after t he last d ose of c h e m ot hera p y  (esti mate d t otal 
d urati o n of me ma nti ne:  1 2 -3 0  wee ks) . T olera bilit y of  me ma nti ne a nd me dicati o n 
a d here n ce will be s eriall y assesse d f or t h e d urati o n of treat me nt. Patie nts will be 
assesse d at a n i nter val n o greater t ha n e v er y t hree wee ks . F or patie nts r ecei vi n g 
a nit-H E R 2 directe d t h era p y i n a d diti o n t o c he m ot hera p y, t o xicit y will o nl y be  
assesse d d uri n g t he c he m ot hera p y se g me nt of t h e re gi me n. T olera bilit y will be 
assesse d as d escri be d i n s ecti o n 5. 3. Me dicati o n a d here nce will be trac ke d usi n g 
n u m ber of patie nt -esti mate d misse d d oses si nce last assess me nt.  
7. 4  
P ost -C he m ot her a p y Assess m e nt  
T h e partici pa nt  will c o m plete a p ost -c h e m ot hera p y assess me nt a p pr o xi mat el y 4 
wee ks after t he e n d of c h e m ot hera p y (ra n ge: 2 t o 1 2  wee ks p ost -c h e m ot hera p y). 
T he C R A will meet wit h t he partici pa nt  t o c o m plete a c o g niti ve assess me nt f or 
vis ual w or ki n g me m or y ( D M S), ver bal lear ni n g a n d me m or y ( H V L T -R), 
pr ocessi n g s pee d ( R V P), e xec uti ve f u ncti o n ( O T S ), atte nti o n a n d w or ki n g 
me m or y ( Di git S pa n), ver bal fl ue nc y ( C O W A), a n d se ma nt ic fl ue nc y ( A N T). T he 
pa rtici pa nt will als o c o m plete self -re p ort assess m e nts f or c o g niti ve f u n cti o n 
( P R O MI S-M o difie d C o g niti ve F u ncti o n), c o g niti ve eff ort ( N A S A -T L X), 
de pressi o n ( P R O MI S -D), a n xiet y ( P R O MI S -A n xiet y), slee p dist ur ba n ce 
( P R O MI S-Slee p Dist ur ba nce), fati g ue ( F A CI T -F),  f u ncti o nal stat us ( K P S), 
h or m o nal stat us,  H R Q O L ( F A C T -G) , a n d b eliefs a b o ut t he necessit y a n d 
c o ncer ns of ta ki n g me ma nti ne ( M o difie d B M Q -S pecific) . See A p pe n di ces A –  Q . 
I n p artici pa nts w h o were n ot classifie d as p ost-me n o pa usal at st u d y e ntr y, F S H 
le vels will be dra w n. T h e partici pa nts will als o be as ke d if t he y e n g a ge d i n a n y 
ot her acti vities or recei ve d me dicati o ns d uri n g t he st u d y peri o d t hat t he y belie ve  
preser ve d  t heir c o g niti ve f u ncti o n. W he n ass ess me nts ca n n ot be c o m plete d, t his 
will be n ote d i n t h e e C R F.  F oll o wi n g c o m pleti o n of all p ost -c he m ot hera p y 
assess me nts, partici pa nts will be c o m pe nsate d  f or t heir ti me wit h a gift car d. 
Partici pa nts m ust c o m plete all as pects of t he st u d y visit i n or der t o recei v e t he 
c o m pe nsati o n.  As wit h t he pre -c he m ot hera p y assess me nt, t he p ost -c he m ot hera p y 
assess me nt will be c o n d u cte d i n pri vate r o o ms at U N C Breast, Hills b or o u g h 
O nc ol o g y, a n d U N C R E X Ca ncer Ce nt er cli nics;  i n pri vate r o o ms at partici pa nts’ 
h o mes ; o ver t he p h o ne ; a n d b y vi de o c o nfere nci n g after c o nfir mi n g t hat s u bjects 
are i n a pri vate l ocati o n. T he p ost -c he m ot hera p y assess me nt  a n d q uesti o n naires 
will be offere d b y e mail a n d mail as is necess ar y a n d feasi ble.  
7. 5  
6 -M o nt h P ost -C he m ot her a p y Assess m e nt ( s u bset o nl y) 
Partici pa nts w h o at t he ti me of i nitial c o nse nt in dicate i nterest i n bei n g o bser ve d 
o ver e xte n d e d l o n git u di nal f oll o w -u p will c o m plete a n a d diti o nal assess me nt 6 
m o nt hs after c o m pleti n g c he m ot hera p y (ra n g e: 4 t o 8 m o nt hs p ost -c he m ot hera p y) . 
T he C R A will meet wit h t he partici pa nt t o c o m plete a c o g niti ve a ssess me nt f or 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 2  
vis ual w or ki n g me m or y ( D M S), ver bal lear ni n g a n d me m or y ( H V L T -R), 
pr ocessi n g s pee d ( R V P), e xec uti ve f u ncti o n ( O T S), atte nti o n a n d w or ki n g 
me m or y ( Di git S pa n), ver bal fl ue nc y ( C O W A), a n d se ma ntic fl ue nc y ( A N T). T he 
partici pa nt will als o c o m ple te self-re p ort assess m e nts f or c o g niti ve f u n cti o n 
( P R O MI S-M o difie d C o g niti ve F u ncti o n), c o g niti ve eff ort ( N A S A -T L X), 
de pressi o n ( P R O MI S -D), a n xiet y ( P R O MI S -A n xiet y), slee p dist ur ba n ce 
( P R O MI S-Slee p Dist ur ba nce), fati g ue ( F A CI T -F), f u ncti o nal stat us ( K P S), 
h or m o nal stat us,  a n d H R Q O L ( F A C T -G). See A p pe n dices A –  P . F oll o wi n g 
c o m pleti o n of all p ost -c h e m ot hera p y ass ess me nts, partici pa nts will be 
c o m pe nsate d f or t heir ti me wit h a gift car d. Partici pa nts m ust c o m plete all as pects 
of t h is st u d y visit i n or der t o recei ve t he c o m pe nsati o n. As wit h t he pre -a n d p ost -
c he m ot hera p y assess me nt s, t his will be c o n d ucte d i n pri vate r o o ms at U N C 
Breast, Hills b or o u g h O n c ol o g y, a n d U N C R E X Ca ncer C e nter cli nics;  i n pri vate 
r o o ms at partici pa nts’ h o mes; o ver t he p h o ne ; a n d b y vi de o c o nfere nci n g after 
c o nfir mi n g t hat s u bjects are i n a pri vate l ocati o n. T he p ost -c he m ot hera p y 
assess me nt a n d q uesti o n naires will be offere d b y e mail a n d mail as is necessar y 
a n d feasi ble.  
 
7. 6  
C o n c urre nt C N S A cti ve  Me dic ati o ns  
All c o ncurre n t C N S acti ve me dicati o n s, i ncl u di n g ps yc h osti m ula nts, 
acet ylc h oli nesterase i n hi bit ors, ot her N M D A rece pt or a nta g o nists, 
a nti de pressa nts, a n xi ol yti cs, a nti ps yc h otics, a ntie pile ptics,  a n d a nti hista mi nes  will 
b e d oc u me nte d at Baseli ne/ Scree ni n g  a n d thr o u g h o ut t he st u d y as s u m marize d i n 
t he Ti me a n d E ve nts Ta ble i n Secti o n 7. 1 .  
7. 7  
De m o gr a p hics  
De m o gra p hic i nf or mati o n ( date of birt h, ge n d er, race , e d ucati o nal le v el) will be 
rec or de d b y t he C R A fr o m re vie w of me di cal rec or ds at baseli ne. 
7. 8  
Me dic al Hist or y  
Rele va nt me dical hist or y, i ncl u di n g hist or y of c urre nt disease , a n d i nf or mati o n 
re gar di n g u n d erl yi n g diseases will be a bstr acte d fr o m me dical rec or ds at b aseli ne . 
7. 9  
H a n dli n g of Bi os peci me ns C ollecte d f or C orrel ati ve Rese a rc h  
Bi o s peci me ns f or t his st u d y will be  c ollecte d b y a certifie d p hle b ot o mist a n d 
st ore d i n t he Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter ( L C C C) ass ociate d 
la b orat or y.  Eac h sa m ple will be assi g ne d a u ni q ue c o de n u m ber a n d n o 
i de ntifia ble pers o nal h ealt h i nf or mati o n ( P HI) will be o n t he s peci me n la bel.  
Researc h ers  wit h I R B -a p pr oval f or access t o P HI f or eac h partici p a n t i n t his st u d y 
will be a ble t o li n k s peci me ns t o rel e va nt me dical i nf or mati o n.   
 
St or a ge Ti m e:  

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 3  
•  
T he bi os peci me n will be use d first a n d f ore m ost f or researc h p ur p oses 
o utli ne d wit hi n t he c o nfi nes of t his pr ot oc ol. Sa m ples will be 
discar de d/ destr o y e d aft er rele va nt dat a are c ollect e d f or t his st u d y, u nless 
c o nse nt was o btai ne d fr o m t he patie nt t o use h er bl o o d  f or ot her researc h 
p ur p oses (e. g., c o nse nt f or m was si g ne d b y t he patie nt).  I n t his circ u msta nce, 
bi os peci me ns ma y be st ore d  f or n o l o n g er t ha n 1 5 years. 
 
C o m pli a nce St ate me nt  
Bi os peci me n c ollecti o n f or t his st u d y will be c o n d ucte d i n f ull acc or d a nce wit h all 
a p plica ble U ni versit y of N ort h Car oli na ( U N C) R esearc h P olicies a n d Pr oce d ures 
a n d all a p plica ble Fe d eral a n d state la ws a n d re g ul ati o ns i ncl u di n g 4 5 C F R 4 6, 
a n d t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A) Pri vac y 
R ule. A n y e pis o de of n o nc o m plia nce will be d oc u me nte d.  
 
T he i n vesti gat ors will perf or m t he st u d y i n acc or da nce wit h t his pr ot oc ol, will 
o btai n c o nse nt a n d asse nt ( u nless a wai v er is gra nt e d), a n d will re p ort u ne x pecte d 
pr o ble ms i n acc or da nce wit h T he U N C I R B P olic ies a n d Pr oce d ures a n d all 
fe deral re q uir e me nts. C ollecti o n, rec or di n g, a n d re p orti n g of data will be acc urate 
a n d will e ns ure t he pri v ac y, healt h, a n d welfare of researc h partici pa nts  d uri n g 
a n d after t he st u d y.  
7. 1 0  
Assess m e nt of S afet y  
A n y patie nt w h o rece i ves at least o ne d ose of st u d y t hera p y o n t his pr ot oc ol will 
be e val ua bl e f or t o xicit y. Eac h patie nt will be ass esse d at least wee kl y d uri n g t he 
titrati o n of me ma nti ne a n d n o less fre q ue nt t ha n e ver y t hree wee ks d uri n g 
s yste mic c he m ot hera p y f or t he de vel op me nt of a n y t o xicit y acc or di n g t o t he Ti me 
a n d E ve nts ta ble.  T o xicit y will be assesse d acc or di n g t o t he N CI C T C A E versi o n 
5 . 
7. 1 1  
Assess m e nt of Effic ac y  
All partici pa nts  w h o e nr oll , recei ve at least o ne d ose of st u d y me dicati o n, a n d 
c o m plete t he pri mar y o ut c o me meas ure will be a n al yze d.    
  
8. 0  
A D V E R S E E V E N T S  
8. 1  
Defi niti o n s  
8. 1. 1  A d verse E ve nt ( A E)  
A n a d vers e e ve nt ( A E) is a n y u nt o war d me dical o cc urre nce (e. g., a n a b n or mal 
la b orat or y fi n di n g, s ym pt o m, or disease te m p orall y ass ociate d wit h t he use of a 
dr u g) i n a patie nt or cli nical i n vesti gati o n partici p a nt a d mi nistere d a 
p har mace utical pr o d uct a n d w hic h d oes n ot necess aril y ha ve a ca us al rel ati o ns hi p 
wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v ora bl e a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal l a b orat or y fi n di n g), s y m pt o m, or disease te m p orall y 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 4  
ass ociate d wit h t he use of a me dici nal pr o d u ct, w het her or n ot r elate d t o t h e 
me dici nal pr o d uct.   
 
H os pitalizati o n f or ele cti ve s ur ger y or r o uti ne cli nical pr oce d ures t hat are n ot t he 
res ult of a n A E (e. g., s ur gical i nserti o n of ce ntral li ne) nee d n ot be c o nsi dere d 
A Es a n d s h o ul d n ot be rec or de d as a n A E.  
8. 1. 2  S us pecte d A d verse Re a cti o n  ( S A R) 
A s us pecte d a d v erse reacti o n ( S A R) is a n y A E f or w hic h t here is a r e as o n a ble 
p ossi bility  t hat t he dr u g is t he ca use.  R e as o n a ble p ossi bility  mea ns t hat t here is 
e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he A E. A 
s us pecte d a d v erse reacti o n i m plies a lesser de gree of cert ai nt y a b o ut ca usali t y 
t ha n a d vers e reacti o n, w hic h mea ns a n y a d v erse e v e nt ca use d b y a dr u g.   
 
Ca usalit y assess me nt t o a st u d y dr u g is a me dical j u d g me nt ma de i n c o nsi derati o n 
of t he f oll o wi n g fact ors: te m p oral rel ati o ns hi p of t he A E t o st u d y dr u g e x p os ure, 
k n o w n mec ha nis m of acti o n or si de effect pr ofile of st u d y treat me nt, ot her rece nt 
or c o nc o mita nt dr u g e x p os ures, n or mal cli nical c o urse of t he dise ase u n der 
i n vesti gati o n, a n d a n y ot her u n derl yi n g or c o nc urre nt me dical c o n diti o ns. Ot her 
fact ors t o c o nsi der i n c o nsi deri n g dr u g as t he ca us e of t he A E:  
•  Si n gle occ urre n ce of a n u nc o m m o n e ve nt k n o w n t o be str o n gl y ass ociate d 
wit h dr u g e x p os ure (e. g., a n gi oe de ma, he patic i nj ur y, Ste ve ns -J o h ns o n 
S y n dr o me)  
•  O ne or m ore o cc urre n ces of a n e ve nt n ot c o m m o nl y ass ociate d wit h dr u g 
e x p os u re, b ut ot her wise u nc o m m o n i n t he p o p ulati o n (e. g., te n d o n 
r u pt ure); ofte n m or e t ha n o nce occ urre nce fr o m o n e or m ulti ple st u dies 
w o ul d be nee d e d bef ore t he s p o ns or c o ul d deter mi ne t hat t here is 
re as o n a ble p ossi bility t hat t he dr u g ca us e d t he e v e nt.   
•  A n a g gre g ate a n al ysis of s pecific e v e nts o bser ve d i n a cli nical trial t hat 
i n dicates t he e ve nts o cc ur m ore fre q ue ntl y i n t he dr u g treat me nt gr o u p 
t ha n i n a c o nc urre nt or hist orical c o ntr ol gr o u p 
 
 
 
Assessi n g C a us alit y of A d verse E ve nts  
T he li keli h o o d of ca usalit y of all A E’s will be gra de d as descri be d bel o w.  
Gi ve n t hat p ote ntial si de effects of me ma nti ne o v erla p wit h t h ose d ue t o 
c he m ot hera p y (a n d ma n y ot her me dicati o ns), we will c o nsi der n ot o nl y 
t he prese n ce/a bse n ce of t he A E, b ut als o w orse ni n g i n t he se verit y or 
fre q ue n c y of t he A E i n assessi n g ca usalit y. 
 
U nrelate d:   A d v erse e ve nt a n d/ or its se verit y or fre q ue nc y  are clearl y d ue 
t o e xtra ne o us ca uses (e. g., u n derl yi n g disease, e n vir o n me nt) 
 
U nli kel y ( m ust ha ve 2):   A d verse e ve nt  a n d/ or its se verit y or fre q ue n c y:   
1. d oes n ot ha ve te m p oral relati o ns hi p t o i nter ve nti o n  
2. c o ul d n ot rea dil y ha ve bee n pr o d uce d b y t he partici pa n t’s cli nical state 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 5  
3. c o ul d ha ve bee n d ue t o e n vir o n me ntal or ot her i nter ve nti o ns  
4. d oes n ot f oll o w a k n o w n patter n  of res p o nse t o i nter ve nti o n  
5. d oes n ot rea p p ear or w orse n wit h rei ntr o d ucti o n of i nter ve nti o n  
 
P ossi ble ( m ust ha ve 2):  A d verse e ve nt  a n d/ or its se verit y or fre q ue n c y : 
1. has a reas o na ble te m p oral relati o ns hi p t o i nter ve nti o n  
2. c o ul d n ot rea dil y ha ve bee n pr o d uce d b y t he partici pa n t’s cli nical state  
3. c o ul d n ot ha ve bee n d ue t o e n vir o n me ntal or ot her i nter ve nti o ns  
4. f oll o ws a k n o w n patter n of res p o nse t o i nter ve nti o n  
 
Pr o ba ble ( m ust ha ve 3):  A d verse E v e nt  a n d/ or its se verit y  or fre q ue n c y : 
1. has a reas o na ble te m p oral relati o ns hi p t o i nter ve nti o n  
2. c o ul d n ot rea dil y ha ve bee n pr o d uce d b y t he partici pa n t’s cli nical state 
or ha ve bee n d ue t o e n vir o n me ntal or ot her i nter ve nti o ns  
3. f oll o ws a k n o w n patter n of res p o nse t o i nter ve n ti o n 
4. disa p pears or d ecreas es wit h re d ucti o n i n d ose or cessati o n of 
i nter ve nti o n 
 
Defi nite ( m ust ha ve all 4):  A d verse E v e nt  a n d/ or its se verit y or fre q ue nc y : 
1. has a reas o na ble te m p oral relati o ns hi p t o i nter ve nti o n  
2. c o ul d n ot rea dil y ha ve bee n pr o d uc e d b y t he partici pa n t’s cli nical state 
or ha ve bee n d ue t o e n vir o n me ntal or ot her i nter ve nti o ns  
3. f oll o ws a k n o w n patter n of res p o nse t o i nter ve nti o n  
4. disa p pears or d ecreas es wit h re d ucti o n i n d ose or cessati o n of 
i nter ve nti o n 
 
8. 1. 3  U ne x pecte d A E  or S A R  
A n A E or S A R is c o nsi dere d u ne x p ecte d if  t he s p ecificit y or se v erit y of it is n ot 
c o nsiste nt wit h t he a p plica ble pr o d uct i nf or m ati o n (e. g., pac k a ge i nsert/s u m mar y 
of pr o d uct c h aracteristics f or a n a p pr o ve d pr o d u ct).  U ne x pect e d als o refers t o A Es 
or S A Rs t hat a re me nti o n e d i n t he I B as occ urri n g wit h a class of dr u gs or as 
a ntici pate d fr o m t he p h ar mac ol o gical pr o perties of t he dr u g, b ut are n ot 
s pecificall y me nti o ne d as occ urri n g wit h t he partic ular dr u g u n der i n vesti gati o n.   
8. 1. 4  Seri o us A E  or S A R  
A n A E or S A R is c o nsi dere d seri o us if, i n t he vie w of eit her t he i n v esti gat or or 
s p o ns or, it res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  Deat h;  
•  Is life-t hreate ni n g ( places t he partici pa nt  at i m me diate ris k of deat h 
fr o m t he e ve nt as it occ urre d); 
•  Re q uires i n patie nt h os pitalizati o n ( > 2 4 h o urs) or pr ol o n gati o n of 
e xisti n g h os pitalizati o n; *  
•  Res ults i n  c o n ge nital a n o mal y/ birt h defect;  

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 6  
•  Res ults i n 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 mal life f u ncti o ns;  
•  I m p ort a nt me 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 pitalizati o n ma y be c o nsi dere d a s eri o us 
a d verse dr u g e x perie nce w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he patie nt or partici pa nt  a n d ma y 
re q uire me di cal or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes 
liste d i n t he defi niti o n.  F or re p orti n g p ur p os es, als o c onsi der t he 
occ urre nces of pre g n a nc y as a n e ve nt w hic h m ust be re p ort e d as a n 
i m p orta nt me dical e ve nt. 
 
* H os pitalizati o n f or a ntici pate d or pr ot oc ol s pe cifi e d pr oce d ures s uc h as 
a d mi nistrati o n of c he m ot hera p y, ce ntral li ne i nserti o n, metastasis i nter ve nti o n al 
t hera p y, resecti o n of pri mar y t u m or, or electi ve s ur ger y, will n ot be c o nsi dere d 
seri o us a d vers e e v e nts. 
 
Pre g na nc y t hat occ urs d uri n g t he st u d y m ust als o be re p ort e d as a n S A E.  
8. 2  
D oc u me nt ati o n of n o n -seri o us A Es or S A Rs  
F or n o n -s eri o us AE s or S A Rs, d oc u me ntati o n m ust be gi n fr o m da y 1 of st u d y 
treat me nt a n d c o nti n ue t hr o u g h t he 3 0 da y f oll o w-u p peri o d after treat me nt is 
disc o nti n ue d.   
 
C ollecte d i nf or mati o n s h o ul d be rec or de d i n t he C ase Re p ort F or ms ( C R F) f or 
t hat patie nt.  Please i ncl u de a descri pti o n of t he e v e nt, its se verit y or t o xicit y 
gra de, o nset a n d res ol ve d dates (if a p plica ble), a n d t he relati o ns hi p t o t he st u d y 
dr u g.  D oc u me ntati o n s h o ul d occ ur at least m o nt hl y .  
8. 3  
S A E s or Seri o us S A R s  
8. 3. 1  Ti mi n g  
After i nf or m e d c o nse nt b ut pri or t o i nitiati o n of st u d y me dicati o ns, o nl y S A Es 
ca use d b y a pr ot oc ol -ma n date d i nter ve nti o n will be c ollecte d (e. g. S A Es relate d t o 
i n vasi ve pr oce d ures s uc h as bi o psies, me dicati o n was h o ut ).  
 
F or a n y ot h er e x p erie nce or c o n diti o n t hat meets t he defi niti o n of a n S A E or a  
seri o us S A R, rec or di n g of t he e ve nt m ust be gi n fr o m da y 1 of st u d y treat m e nt a n d 
c o nti n ue t hr o u g h t he 3 0 da y f oll o w -u p peri o d after treat me nt is disc o nti n ue d.  
8. 3. 2  D oc u me nt ati o n  a n d N otific ati o n  
S A Es or Seri o us S A Rs m ust be rec or de d i n t he S A E c o ns ole wit hi n O nc ore ™ f or 
t hat patie nt wit hi n 2 4 h o urs of lear ni n g of its occ urre nce.  A d diti o nall y, t he 
N C C N Pr oject Ma na ger  m ust als o be n otifie d via e mail of all S A Es wit hi n 2 4 
h o urs of lear ni n g of its occ urre nce .  

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 7  
8. 4  
A d verse E ve nt R e p orti n g  
8. 4. 1  I R B Re p orti n g Re q uire me nts: 
U N C : 
•  T he U N C -I R B will be n otifie d of all S A Es t hat q ualif y as a n 
U na ntici pate d Pr o ble m as per t he U N C I R B P olicies usi n g t he I R B’s we b -
base d re p orti n g s yste m (see secti o n 1 0 . 4. 3) wit hi n 7 da ys of t he 
I n v esti gat or bec o mi n g a ware of t he pr o ble m.   
8. 4. 2  F u n di n g S o urce (e. g. M a n uf act urer) Re p orti n g Re q uire me nts:  
N/ A  
8. 5  
D at a a n d S afet y M o nit o ri n g  Pl a n  
T his is a P hase II, si n gle site st u d y of 5 6  i n di vi d uals t o gat her preli mi nar y data o n t he 
effic ac y  a n d feasi bilit y  of me ma nti ne  i n patie nts wit h breast ca n cer recei vi n g 
c he m ot hera p y . We will f oll o w o ur sta n dar d pr ot o c ol f or m o nit ori n g of cli nical trials.  
Partici pa nts  are s cree ne d t o e ns ure t hat t here are n o c o ntrai n dicati o ns t o t heir 
partici pati o n.  
 
T he st u d y PI, Dr. Na k a m ura , will be res p o nsi ble f or c o nti n u o us m o nit ori n g of patie nt 
safet y d uri n g t he trial.  F or n o n-seri o us A d verse E ve nts ( A Es), d oc um e ntati o n will be gi n 
fr o m t he first da y of st u d y treat me nt a n d c o nti n ue t hr o u g h t he 3 0 -da y f oll o w -u p peri o d 
after treat me nt is disc o nti n ue d. C ollecte d i nf or mati o n will be rec or de d i n Case Re p ort 
F or ms ( C R F) f or t hat patie nt. A descri pti o n of t he e ve nt, its se verit y or t o xi cit y gra de, 
o nset a n d res ol ve d d ates (if a p plica ble), a n d t he relati o ns hi p t o t he st u d y dr u g will be 
i ncl u de d.  F or a n y e x peri e nce or c o n diti o n t hat meets t he defi niti o n of a seri o us a d verse 
e ve nt ( S A E), rec or di n g of t he e ve nt wi ll be gi n after si g ni n g of t he i nf or me d c o nse nt a n d 
c o nti n ue t hr o u g h t he 3 0 -da y f oll o w -u p peri o d af ter treat me nt is disc o nti n ue d. T hese 
e ve nts will be rec or de d i n t he C R F f or t hat patie nt wit hi n 2 4 h o urs  of lear ni n g of its 
occ urre nce.  If t he e ve nt is b ot h seri o us A N D u ne x pecte d, it will als o be rec or de d o n t he 
Me d Watc h F or m 3 5 0 0 A, as per 2 1 C F R 3 1 2. 3 2, a n d f or war de d t o t he F D A i n acc or da nce 
wit h 2 1 C F R 3 1 4. 8 0 (f or mar kete d dr u gs) . T he  U N C I R B will be n otifie d of all S A Es t hat 
q ualif y as a n U n a ntici pat e d Pr o b le m (seri o us, u ne x pecte d, a n d relate d) as p er t he U N C 
I R B p olicies. I n acc or da n ce wit h t hese p olicies, a n a g gre gat e d list of all S A Es will be 
s u b mitte d t o t he U N C I R B a n n uall y at t he ti me of st u d y re ne wal. 
 
Peri o dic re vie w, at a n i nt er val of e ver y si x m o nt hs t o a n n uall y, b y t he Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter Data Safet y C o m mittee ( L C C C D S M C), Pr ot oc ol Re vie w 
C o m mittee ( P R C), a n d Office of H u ma n Researc h Et hics ( O H R E) Bi o me dical I R B will 
pr o vi de o versi g ht of t he PI ’s c o nti n u o us m o nit ori n g.  F or eac h D S M C re vi e w, s u m mar y 
i nf or mati o n re gar di n g t o xicit y a n d accr ual patter ns will be pre pare d a n d s u b mitte d b y t he 
PI.  S pecifi c i nf or mati o n s u b mitte d f or re vie w i ncl u des: ( 1) T he n u m ber of patie nts 
e nr olle d, c o nse nt e d, c o ns e nte d b ut n ot treate d, c urre ntl y bei n g treate d, c o m plete d 
treat me nt, t he n u m ber of patie nts w h o di d n ot c o m plete treat me nt a n d t h e reas o ns f or 
c o mi n g off st u d y; ( 2) Gra de 3 or greater re p orte d A d verse E v e nts t o date; ( 3) Seri o us 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 8  
A d verse E v e nts a n d U na ntici pate d Pr o ble ms si nce last re p ort, wi t h ass ura nce of re p orti n g 
t o i nter nal a n d e xter nal r e g ulati n g b o dies; ( 4) E xce pti o ns i n eli gi bilit y or treat me nt a n d 
si g nifica nt pr ot oc ol de viati o ns/ vi olati o ns; ( 5) Si g nifica nt literat ur e re p orti n g 
de vel o p me nts t hat ma y affect t he s afet y of p artici pa nts or  t he et hics of t he st u d y; ( 6) 
S u m maries of tea m meeti n gs t hat ha ve occ urre d si nce t he last r e p ort; ( 7) Res ults of 
i nteri m a nal yses re q uir e d b y t he pr ot oc ol.  We will als o be s u b mitti n g a preli mi nar y 
re p ort of res p o nse a n d ot her e n d p oi nts liste d i n t he pri mar y a n d s ec o n dar y o bjecti ves of 
t he pr ot oc ol f or D S M C re vie w. 
 
T h o u g h n o f or mal a pri ori  st o p pi n g r ules are pr o p ose d f or t he st u d y, i n t he e ve nt of a 
seri o us or u ne x pecte d a d verse e v e nt or fre q ue nt o cc urre nce of less seri o us u ne x pecte d or 
e x pecte d a d vers e e v e nts we will c o ns ult wit h t he O H R E a n d D S M C as t o w het her t he 
trial s h o ul d c o nti n ue. 
 
9. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
9. 1  
St u d y Desi g n/ St u d y E n d p oi nts  
T his is a o ne -ar m i nter ve nti o nal pil ot st u d y i n partici pa nts recei vi n g 
c he m ot hera p y f or breast ca ncer t o e val u at e if me ma nti ne ca n pre ve nt c o g niti ve 
decli ne. We will recr uit 5 6  patie nts fr o m t he U N C Breast , Hills b or o u g h 
O nc ol o g y, a n d U N C R E X Ca ncer Ce nt er cli nics, treat wit h me ma nti ne 1 0 m g 
t wice dail y, a n d s yste maticall y e val uate c o g niti ve f u ncti o n, me ntal healt h, 
H R Q O L, a n d f u n cti o nal stat us at baseli ne a n d at t he e n d of c h e m ot hera p y  (a n d 
a gai n at 6 m o nt hs p ost -c he m ot hera p y i n a s u bset of partici pa nts) . We will als o 
seriall y assess t olera bilit y of  a n d a d here n ce wit h me ma nti ne.   
 
T he pri mar y effic ac y e n d p oi nt is c o g niti ve decli ne meas ure d as a c h a n ge i n D M S 
sc ore. Sc ores ra n g e fr o m 0 -1 0 0 %, defi n e d b y t he perce nt of c orrect a ns wers o n 
t he me m or y test. Sec o n d ar y e n d p oi nts i ncl u de ot h er meas ures of c o g niti ve 
f u ncti o n ( H V L T-R , R V P, O T S , Di git S pa n, C O W A, A N T, a n d P R O MI S 
C o g niti ve F u ncti o n), de pressi o n, a n xiet y,  H R Q O L, a n d f u ncti o nal stat us.  T he 
T M T -A a n d -B will als o be e val uat e d as sec o n dar y e n d p oi nts i n  t he s u bset of 
partici pa nts w h o c o m plet e d t he st u d y pri or t o t he re m o val of t hese m eas ures.  
9. 2  
S a m ple Size, Accr u al  a n d D ur ati o n of Accr u al  
T h o u g h c he m ot hera p y is k n o w n t o res ult i n c o g niti ve decli ne, t he st u d y b y 
Ja nelsi ns re p orts a 5 % i ncreas e i n sc ores o n t he D M S ( 8 3 % t o 8 8 %) i n patie nts 
wit h breast ca n cer fr o m pre -t o p ost-c h e m ot hera p y. 6 8 A n  increase i n sc ore  i n s pite 
of c o g niti ve decli ne  is c o nsiste nt wit h t he well -descri be d p he n o me na  of practice 
effect s i n b ot h healt h y a n d ca ncer p o p ulati o ns wit h re peat n e ur o ps yc h ol o gi cal 
testi n g.8 6 I n o ur sa m ple e x p ose d t o me ma nti ne, we h y p ot hesize t hat o ur sa m ple 
will ha ve a n 8 % i ncreas e i n t he D M S sc ore as c o m pare d t o t he 5 % i ncreas e i n 
breast c a ncer c o ntr ols  descri be d i n Ja nelsi ns st u d y . 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 9  
F or t he pri mar y o bjecti ve of c o g niti ve c ha n g e, a p aire d t -test wit h a 0. 0 5 o n e -
si de d si g nifica nce le v el will ha ve 8 0 % p o wer t o detect a n effect size of 0. 3 7 6  wit h 
a sa m ple size of 4 5. S pecificall y, p atie nts wit h breast ca ncer de m o nstr ate a 
5 %  i ncrease i n t he D M S pre- t o p ost- c h e m ot hera p y; 6 8 t h us, 5 %  is t he n ull 
h y p ot hesize d c ha n g e. T h e alter nati ve h y p ot h esis  is t hat patie nts recei vi n g 
me ma nti ne will e x perie n ce less c h e m ot hera p y -rel ate d c o g niti ve decli ne, a n d will 
ha ve a n 8 % i n crease . Usi n g t hese h y p ot hesiz e d v al ues, i n c o m bi nati o n wit h 
sa m ple size b u d getar y c o nstrai nts, we c h ose t he fi nal sa m ple size of 4 5. Wit h 4 5 
patie nts, we will ha ve 8 0 % p o wer t o test if t he c ha n ge sc ores i n o ur st u d y 
p o p ulati o n are si g nifica ntl y differe nt  t ha n t he hist orical c o ntr ol da ta re p ort e d b y 
Ja nelsi ns (ass u mi n g a 3 % mea n i ncrease, a n d sta n dar d de viati o n of t he i n creas e of 
7. 9 7 %) . T his st u d y will pr o vi de preli mi nar y dat a a n d effect sizes t o p o wer a 
f ut ure, lar g er place b o-c o ntr olle d st u d y.  
 
T o acc o u nt f or dr o p o ut of u p t o 2 0 %, we will e nr oll 5 6 partici pa nts. T he U N C 
Ca ncer Re gistr y rec or ds de m o nstrate t hat 5 3 7 sta ge I -III breast ca n cer pati e nts 
were referre d t o t he N C Ca ncer H os pital f or c he m ot hera p y bet wee n 2 0 1 6 a n d 
2 0 1 7. We esti mate t hat w e will e nr oll at least 3 3 % of eli gi ble  partici pa nts, b ase d 
o n o ur e x peri e nce wit h pre vi o us i nter ve nti o n st u dies, all o wi n g us t o recr uit o ur 
tar get wit hi n o ne year. 
9. 3  
D at a A n al ysi s Pl a ns 
T he pri mar y o utc o me is c ha n ge i n t he D M S sc ore. A paire d t -test will test if t he 
c ha n ge i n D M S sc ore fr o m pre - t o p ost-c he m ot hera p y is statisticall y differe nt 
fr o m hist orical  c o ntr ols . Pre- t o p ost-c he m ot hera p y , as well as pre- t o 6 m o nt hs 
p ost -c he m ot hera p y,  c ha n ges  i n all ot her c o g niti ve meas ures will als o be e val uate d 
usi n g paire d t -tests.  
 
Li near re gressi o n m o dels will be use d t o cr oss -secti o nall y e val uate ass ociati o ns 
bet wee n d e pressi o n ( P R O MI S -D ), a n xiet y ( P R O MI S-A ), slee p ( P R O MI S-Slee p 
Dist ur ba nce ), m e n o pa usal stat us, fati g ue ( F A CI T-F), esti mate d pre -ca ncer I Q 
( W T A R), a n d c o g niti ve eff ort ( N A S A-T L X) wit h b ot h o bjecti ve ( D M S , H V L T-
R, C O W A, A N T, Di git S pa n ) a n d self-re p orte d ( P R O MI S) meas ures of c o g niti ve 
f u ncti o n at baseli ne a n d p ost-c he m ot hera p y. Li ne ar mi xe d effects m o dels will 
e val uate ass ociati o ns acr oss pre - a n d p ost - ti me p oi nts. 
 
Li near re gressi o n m o deli n g will descri be t he ass o ciati o ns bet wee n pre - t o p ost-
c he m ot hera p y c o g niti ve c ha n ges ( D M S, H V L T -R, C O W A, A N T, Di git S pa n, 
P R O MI S) wit h p ost -c he m ot hera p y de pressi o n a n d a n xiet y ( P R O MI S), H R Q O L 
( F A C T-G) , a n d p erf or m a nce stat us ( K P S) . 
 
Descri pti ve statistics will be use d t o esti mate feasi bilit y: 1.)  recr uit me nt rat e ( % of 
i n vite d partici pa nts  w h o e nr oll), 2.) attriti o n ( % of e nr olle d partici pa nts w h o  are 
n ot eli gi ble f or a nal ysis of t he pri mar y o utc o me), a n d 3.) a d here nce t o treat me nt 
( % self-re p orte d d oses of me ma nti ne ta ke n).   
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
3 0  
W e will ta b ulate all A Es, t he d ose at w hic h t he y o cc urre d, a n d if t he y l e d t o 
d osi n g dela ys or re m o val fr o m t he st u d y. 
1 0. 0  S T U D Y M A N A G E M E N T  
1 0. 1  
I nstit uti o n al Re vie w B o ar d (I R B) A p pr o v al a n d C o nse nt 
It is e x p ecte d t hat t he I R B will ha ve t he pr o per re prese ntati o n a n d f u n cti o n i n 
acc or da nce wit h fe d erall y ma n date d re g ul ati o ns. T he I R B s h o ul d a p pr o ve t he 
c o nse nt f or m a n d pr ot oc ol.  
 
I n o btai ni n g a n d d o c u me nti n g i nf or me d c o nse nt, t he i n vesti gat or s h o ul d c o m pl y 
wit h t he a p plica ble re g ulat or y re q uir e me nt(s), a n d s h o ul d a d here t o G o o d Cli nical 
Practice ( G C P) a n d t o et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n 
of Helsi n ki.  
 
 
 
Bef ore recr uit me nt a n d e nr oll me nt o nt o t his st u d y, t he patie nt will be gi ve n a f ull 
e x pla nati o n of t he st u d y a n d will be gi ve n t he o p p ort u nit y t o re vie w t he c o nse nt 
f or m. Eac h c o nse nt f or m m ust i ncl u de all t he rele va nt ele me nts c urre ntl y re q uire d 
b y t he F D A Re g ul ati o ns a n d l ocal or state re g ulati o ns. O nce t his esse ntial 
i nf or mati o n has bee n pr o vi de d t o t he patie nt a n d t he i n vesti gat or is ass ure d t hat 
t he patie nt u n dersta n ds t he i m plicati o ns of partici pati n g i n t he st u d y, t he patie nt 
will be as ke d t o  gi ve c o nse nt t o partici pate i n t he st u d y b y si g ni n g a n 
I R B-a p pr o ve d c o nse nt f or m.  
 
Pri or t o a patie nt’s partici pati o n i n t he trial, t he writte n i nf or me d c o nse nt f or m 
s h o ul d be si g ne d a n d pers o nall y date d b y t he patie nt a n d b y t he pers o n w h o 
c o n d ucte d t he i nf or me d c o nse nt disc ussi o n. 
1 0. 2  
Re q uire d D oc u me nt ati o n  
Bef ore t he st u d y ca n be i nitiate d at a n y site, t he f oll o wi n g d oc u me ntati o n m ust be 
pr o vi de d t o t he Cli nical Pr ot oc ol Office ( C P O) at t he U ni versit y of N ort h Car oli na.  
•  A c o p y of t he official I R B a p pr o val letter f or t he pr ot oc ol a n d i nf or me d 
c o nse nt  
•  C Vs a n d me dical lice ns ure f or t he pri nci pal i n vesti gat or a n d a n y 
ass ociate i n vesti gat ors w h o will be i n v ol ve d i n t he st u d y  
•  A c o p y of t he I R B -a p pr o ve d c o nse nt f or m  
1 0. 3  
Re gistr ati o n Pr o ce d ures  
Patie nt e nr oll m e nt i n t he st u d y will be trac ke d i n O n Core ® . T his will all o w t he 
U N C Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter t o trac k accr ual i nt o t he st u d y. F or 
all p ote ntiall y eli gi ble a n d i ntereste d patie nts, eli gi bilit y criteria m ust be c o nfir me d  
pri or t o re gistrati o n b y t he PI. 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
3 1  
1 0. 4  
A d here nce t o t he Pr ot oc ol  
E xce pt f or a n e mer ge nc y sit uati o n i n w hic h pr o per care f or t h e pr otecti o n, safet y, 
a n d well -bei n g of t h e st u d y patie nt re q uires alter nati ve treat me nt, t he st u d y s hall 
be c o n d ucte d e xactl y as descri be d i n t he a p pr o ve d pr ot oc ol.   
1 0. 4. 1  E mer ge nc y M o dific ati o ns  
U N C i n vesti gat ors ma y i m ple me nt a de viati o n fr o m, or a c ha n g e of, t he pr ot oc ol 
t o eli mi nate a n i m me diate hazar d(s) t o trial p artici pa nts  wit h o ut pri or U N C I R B 
ap pr o val.   
 
F or a n y s u c h e mer ge nc y m o dificati o n i m ple me nte d, a  U N C I R B m o dificati o n 
f or m m ust be c o m plete d b y U N C Researc h Pers o n nel  wit hi n fi ve ( 5) b usi n ess 
da ys of ma ki n g t he c h a n ge.   
1 0. 4. 2  Si n gle P atie nt/ P artici p a nt  E xce pti o ns  
A n y re q uest t o e nr oll a si n gle partici pa nt  w h o d oes n ot meet all t he eli gi bilit y 
criteria of t his st u d y re q uires t he a p pr o val of t he U N C Pri nci pal I n v esti gat or a n d 
t he U N C I R B.  
1 0. 4. 3  Ot her Pr ot oc ol De vi ati o ns/ Vi ol ati o ns  
Acc or di n g t o U N C’s I R B, a pr ot oc ol de viati o n  is a n y u n pla n ne d varia nce fr o m a n 
I R B a p pr o ve d pr ot oc ol t hat:  
•  Is g e nerall y n ote d or rec o g nize d after it occ urs 
•  Has n o s u bsta nti ve effect o n t he ris ks t o researc h p artici pa nts  
•  Has n o s u bsta nti ve effect o n t he scie ntific i nte grit y of t he researc h pla n 
or t he val ue of t h e data c ollecte d  
•  Di d n ot res ult fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he 
i n vesti gat or(s).  
 
A n u n pla n ne d pr ot oc ol v aria nce is c o nsi dere d a vi olati o n  if t he varia nce meets 
a n y of t he f oll o wi n g criteria :  
•  Has har me d or i ncrease d t he ris k of har m t o o ne or m ore researc h 
partici pa nts.  
•  Has da ma ge d t h e scie ntific i nte grit y of t he data c ollecte d f or t he st u d y. 
•  Res ults fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he 
i n vesti gat or(s). 
•  De m o nstrates seri o us or c o nti n ui n g n o nc o m plia nce wit h fe deral 
re g ulati o ns, State la ws, or U ni versit y p olicies. 
 
If a de vi ati o n or vi olati o n occ urs please f oll o w t he g ui deli nes bel o w: 
 
Pr ot oc ol D e vi ati o ns: U N C or Affiliate pers o n nel will rec or d t he de vi ati o n i n 
O n C ore ® , a n d re p ort t o a n y s p o ns or or data a n d s afet y m o nit ori n g c o m mittee i n 
acc or da nce wit h t heir p olicies.  De viati o ns s h o ul d be s u m marize d a n d re p orte d t o 
t he I R B at t he ti me of c o nti n ui n g re vie w. 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
3 2  
 
Pr ot oc ol Vi ol ati o ns: Vi olati o ns s h o ul d be re p ort e d b y U N C pers o n nel wit hin o ne 
( 1) wee k of t he i n vesti gat or bec o mi n g a ware of t he e ve nt usi n g t he sa me I R B 
o nli ne mec ha nis m use d t o re p ort U na ntici p ate d Pr o ble ms.   
 
U n a ntici p ate d Pr o ble ms :  A n y e ve nts t hat meet t he criteri a f or “ U na ntici p ate d 
Pr o ble ms” as defi ne d b y U N C ’s I R B m ust be re p orte d b y t he s t u d y pers o n nel 
usi n g t he I R B’s we b -bas e d re p orti n g s yste m.   
 
1 0. 5  
A me n d me nts t o t he Pr ot oc ol  
S h o ul d a me n d me nts t o t he pr ot oc ol be re q uire d, t h e a me n d me nts will be 
ori gi nate d a n d d oc u me nt e d b y t he Pri nci pal I n vesti gat or at U N C.  It s h o ul d als o 
be n ote d t hat w he n a n a me n d me nt t o t he pr ot oc ol s u bsta ntiall y alters t he st u d y 
desi g n or t he p ote ntial ris k t o t he patie nt, a re vise d c o nse nt f or m mi g ht be 
re q uire d.   
 
T he writte n a me n d m e nt, a n d if re q uir e d t he a me n de d c o nse nt f or m, m ust be se nt 
t o U N C’s I R B f or a p pr o val pri or t o i m ple me ntati o n.   
1 0. 6  
Rec or d R ete nti o n  
St u d y d oc u me ntati o n i ncl u des all e C R Fs , data c orrecti o n f or ms or q u eries, s o urce 
d oc u me nts, S p o ns or c orres p o n de nce t o I n vesti gat ors , m o nit ori n g l o gs/letters, a n d 
re g ulat or y d oc u m e nts (e. g., pr ot oc ol a n d a me n d m e nts, I R B c orres p o n d e nce a n d 
a p pr o val, si g ne d patie nt c o nse nt f or ms).  
 
S o urce d oc u me nts i ncl u d e all rec or di n gs of o bser vati o ns or n otati o ns of cli nical 
acti vities a n d all re p orts a n d rec or ds necessar y f or t he e val uati o n a n d 
rec o nstr ucti o n of t h e cli nical researc h st u d y. 
 
G o ver n me nt a g e nc y re g ulati o ns a n d directi ves re q uire t hat all st u d y 
d oc u me nt ati o n pertai ni n g t o t he c o n d uct of a cli nical trial m ust be retai n e d b y t he 
st u d y i n vesti gat or.  I n t he case of a st u d y wit h a dr u g see ki n g re g ulat or y a p pr o val 
a n d mar keti n g, t hese d o c u me nts s hall be retai ne d f or at least t w o years after t he 
last a p pr o val of mar keti n g a p plicati o n i n a n I nter n ati o nal C o nfere n ce o n 
Har m o nizati o n (I C H) re gi o n.  I n all ot her cas es, st u d y d oc u me nts s h o ul d be ke pt 
o n file u ntil t hree years after t he c o m pleti o n a n d fi nal st u d y re p ort of t his 
i n vesti gati o nal st u d y. 
1 0. 7  
O bli g ati o ns of I n vesti g at ors  
T he Pri nci pal I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he cli nical trial at t he 
site i n acc or da nce wit h Title 2 1 of t he C o de of Fe deral Re g ulati o ns a n d/ or t he 
Declarati o n of Helsi n ki.  T he Pri nci pal I n vesti gat or is res p o nsi ble f or pers o nall y 
o verseei n g t he tr eat me nt of all st u d y patie nts.  T he Pri nci pal I n v esti gat or m ust 
ass ure t hat all st u d y site pers o n nel, i ncl u di n g s u b -i n vesti gat ors a n d ot her st u d y 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
3 3  
staff me m bers, a d here t o t he st u d y pr ot oc ol a n d all F D A/ G C P/ N CI re g ulati o ns 
a n d g ui deli nes re g ar di n g cli nical trials b ot h d uri n g a n d after st u d y c o m pleti o n.  
 
T he Pri nci pal I n vesti gat or will be res p o nsi ble f or ass uri n g t hat all t he re q uire d 
data will be c ollecte d a n d e ntere d i nt o t he e C R Fs . Peri o dicall y, m o nit ori n g visits 
will be c o n d ucte d a n d t h e Pri nci pal I n vesti gat or will pr o vi de access t o his/ her 
ori gi nal rec or ds t o p er mit verificati o n of pr o per e ntr y of data. At t he c o m pleti o n 
of t he st u d y, all e C R Fs  will be re vie we d b y t he Pri nci pal I n vesti gat or a n d will 
re q uire his/ her fi nal si g nat ure to verif y t h e acc urac y of t he data.  
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
3 4  
1 1. 0  R E F E R E N C E S  
1.  
Bl uet h ma n n S M, Mari ott o A B, R o wla n d J H. A ntici pati n g t he “sil ver ts u na mi”: 
Pre vale nce traje ct ories a n d c o m or bi dit y b ur de n a m o n g ol der ca ncer s ur vi v ors i n 
t he Unite d States. Ca ncer E pi de mi ol Bi o mar kers Pre v. 2 0 1 6;  
2.  
Ja nelsi ns M C, Kesler S R, A hles T A, M orr o w G R. Pre vale nce, mec h a nis ms, a n d 
ma na ge me nt of ca ncer -relate d c o g niti ve i m pair me nt. I nt Re v Ps yc hiatr y. 
2 0 1 4; 2 6( 1): 1 0 2 – 1 3.  
3.  
Wefel J S, Le n zi R, T heri a ult  R, B uz dar A U, Cr uic ks ha n k S, Me yers C A. 
“ C he m o brai n” i n breast c arci n o ma?: a pr ol o g ue. C a ncer. 2 0 0 4 A u g; 1 0 1( 3): 4 6 6 –
7 5.  
4.  
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d ysf u ncti o n? Brai n Be ha v I m m u n. 2 0 1 3 Mar; 3 0 S u p pl: S 9 9 -1 0 8.  
5 5.  
Patel S K, W o n g A L, W o n g F L, Bree n E C, H urria A, S mit h M, et al. I nfla m mat or y 
Bi o mar kers, C o m or bi dit y, a n d Ne ur oc o g niti o n i n W o me n Wit h Ne wl y Di a g n ose d 
Breast Ca ncer. J Natl Ca ncer I nst. 2 0 1 5 A u g; 1 0 7( 8).  
5 6.  
Wa n g X M, Walitt B, Sali ga n L, Ti wari A F Y, C he u n g C W, Z ha n g ZJ. 
C he m o brai n: A critical r e vie w a n d ca usal h y p ot h esis of li n k bet wee n  c yt o ki nes 
a n d e pi ge netic re pr o gra m mi n g ass ociate d wit h c he m ot hera p y. V ol. 7 2, C yt o ki ne. 
2 0 1 5. p. 8 6 – 9 6.  
5 7.  
Ol m os G, Lla d o J. T u m or necr osis fact or al p ha: a li n k bet wee n ne ur oi nfla m mati o n 
a n d e xcit ot o xicit y. Me diat ors I nfla m m. 2 0 1 4; 2 0 1 4: 8 6 1 2 3 1.  
5 8.  
O h  P -J. Pre dict ors of c o g niti ve decli ne i n pe o ple wit h ca ncer u n der g oi n g 
c he m ot hera p y. E ur J O nc ol N urs  Off J E ur O nc ol  N urs S oc. 2 0 1 7 A pr; 2 7: 5 3 – 9.  
5 9.  
Be n der C M, Serei ka S M, Ber ga S L, V o gel V G, Br ufs k y A M, Paras ka K K, et al. 
C o g niti ve i m pair me nt ass ocia te d wit h a dj u va nt t h era p y i n br east ca n cer. 
Ps yc h o o nc ol o g y. 2 0 0 6 Ma y; 1 5( 5): 4 2 2 – 3 0.  
6 0.  
Sc ha ge n S B, M uller MJ, B o o ger d W, R ose n bra n d R M, va n R hij n D, R o de n h uis S, 
et al. Late effects of a dj u va nt c he m ot hera p y o n c o g niti ve f u ncti o n: a f oll o w -u p 
st u d y i n breast ca ncer patie nts. A n n O nc ol  Off J E ur S oc Me d O nc ol. 2 0 0 2 
Se p; 1 3( 9): 1 3 8 7 – 9 7.  
6 1.  
Hs hie h T T, J u n g W F, Gra n de LJ, C he n J, St o ne R M, S oiffer RJ, et al. Pre v ale nce 
of c o g niti ve i m pair me nt a n d ass ociati o n wit h s ur vi val a m o n g ol der patie nts wit h 
he mat ol o gi c ca ncers. J A M A O nc ol. 2 0 1 8; 4( 5): 6 8 6 – 9 3.  
6 2.  
Ja nelsi ns M C, K o hli S, M o hile S G, Us u ki K, A hles T A, M orr o w G R. A n u p date 
o n ca ncer - a n d c he m ot hera p y -relate d c o g niti ve d ysf u ncti o n: c urre nt stat us. Se mi n 
O nc ol. 2 0 1 1 J u n; 3 8( 3): 4 3 1 – 8.  
6 3.  
Wefel J S, Kesl er S R, N oll K R, Sc ha ge n S B. Cli nical c haracteristics , 
pat h o p h ysi ol o g y, a n d ma na ge me nt of n o nce ntral n er v o us s yste m ca n cer -rel ate d 
c o g niti ve i m pair me nt i n a d ults. C A Ca ncer J Cli n. 2 0 1 5 Mar; 6 5( 2): 1 2 3 – 3 8.  
6 4.  
Me ma nti ne Prescri bi n g I nf or mati o n. 2 0 1 3.  
6 5.  
Fra y PJ, R o b bi ns T W. C A N T A B batter y: Pr o p ose d utilit y i n ne ur ot o xic ol o g y. I n: 
Ne ur ot o xic ol o g y a n d T erat ol o g y. 1 9 9 6.  
6 6.  
R o b bi ns T W, Ja mes M, O we n A M, Sa ha ki a n BJ, McI n nes L, Ra b bitt P. 
Ca m bri d ge Ne ur o ps y c h ol o gical Test A ut o mate d Batter y ( C A N T A B): a fact o r 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
3 9  
a nal ytic st u d y of a lar g e sa m ple of n or mal el derl y v ol u nteers. De me ntia. 
1 9 9 4; 5( 5): 2 6 6 – 8 1.  
6 7.  
Be ne dict R H B, Sc hretle n D, Gr o ni n ger L, Bra n dt J. H o p ki ns Ver bal Lear ni n g 
Test -Re vise d: N or mati ve Data a n d A nal ysis of I nt er -F or m a n d T est -Retest 
Relia bilit y . Cli n Ne ur o ps yc h ol [I nter n et]. 1 9 9 8; 1 2( 1): 4 3– 5 5. A vaila ble fr o m: 
htt p:// w w w.i n ge ntac o n nect.c o m/c o nte nt/ ps yc h/cli n/ 1 9 9 9/ 0 0 0 0 0 0 1 3/ 0 0 0 0 0 0 0 3/art 0
0 0 1 0  
6 8.  
Ja nelsi ns M C, Hec kler C E, Pe p p o ne LJ, A hles T A, M o hile S G, M ustia n K M, et al. 
L o n git u di nal Traject or y a n d C haracterizati o n of Ca ncer -R elate d C o g niti ve 
I m pair me nt i n a Nati o n wi de C o h ort St u d y. J Cli n O nc ol. 2 0 1 8 
Se p;J C O 2 0 1 8 7 8 6 6 2 4.  
6 9.  
Wec hsler D. Ma n u al f or t he Wec hsler a d ult i ntelli ge nce scale -re vise d ( W AI S-R). 
Sa n A nt o ni o, T X Ps yc h ol C or p. 1 9 8 1;  
7 0.  
Bec ht ol dt H P, Be nt o n A L, F o gel M L. A n a p plicati o n of fact or a n al ysis i n 
ne ur o ps yc h ol o g y. Ps yc h ol Rec [I nter n et]. 1 9 6 2 A pr; 1 2( 2): 1 4 7 – 5 6. A vaila ble fr o m: 
htt ps:// d oi. or g/ 1 0. 1 0 0 7/ B F 0 3 3 9 3 4 5 2  
7 1.  
T o m ba u g h T N, K oza k J, Rees L. N or mati ve data stratifie d b y a ge a n d e d u cati o n 
f or t w o meas ur es of ver bal fl ue nc y: F A S a n d a ni mal na mi n g. Arc h Cli n 
Ne ur o ps yc h ol. 1 9 9 9; 1 4( 2): 1 6 7 – 7 7.  
7 2.  
Wec hsler D. Wec hsler T est of A d ult Rea di n g: W T A R. Ps yc h ol o gical C or p orati o n; 
2 0 0 1.  
7 3.  
Katz ma n R, Br o w n T, F ul d P, Pec k A, Sc hec hter R, Sc hi m mel H. Vali dati o n of a 
s h ort Orie ntati o n-Me m or y -C o nce ntrati o n Test of c o g niti ve i m pair me nt. A m J 
Ps yc hiatr y. 1 9 8 3 J u n; 1 4 0( 6): 7 3 4 – 9.  
7 4.  
Wa de D T, Ver gis E. T h e S h ort Orie ntati o n – Me m or y – C o nce ntrati o n Test: a st u d y 
of its relia bilit y a n d vali dit y. Cli n  Re ha bil. 1 9 9 9; 1 3( 2): 1 6 4 – 7 0.  
7 5.  
Cella D, Rile y W, St o ne A, R ot hr oc k N, Ree v e B, Y o u nt S, et al. T he Patie nt -
Re p orte d O utc o mes Meas ure me nt I nf or mati o n S yste m ( P R O MI S) de v el o pe d a n d 
teste d its first wa ve of a d ult self-re p orte d h ealt h o utc o me ite m ba n ks: 20 0 5 – 2 0 0 8. 
J Cli n E pi de mi ol [I nter net]. 2 0 1 0; 6 3( 1 1): 1 1 7 9– 9 4. A vaila ble fr o m: 
htt p:// w w w.scie nce direct.c o m/scie nce/article/ pii/ S 0 8 9 5 4 3 5 6 1 0 0 0 1 7 3 3  
7 6.  
Hart S G, Sta vela n d L E. De vel o p me nt of N A S A -T L X ( Tas k L o a d I n de x): Res ults 
of E m pirical a n d T h e oretical Resea rc h. A d v Ps yc h ol. 1 9 8 8;  
7 7.  
Pil k o nis P A, C h oi S W, Reise S P, St o ver A M, Rile y W T, Cella D, et al. It e m ba n ks 
f or meas uri n g e m oti o nal distress fr o m t he Patie nt-Re p orte d O utc o mes 
Meas ure me nt I nf or mati o n S yste m ( P R O MI S( R)): de pressi o n, a n xiet y, a n d a n ger. 
As sess me nt. 2 0 1 1 Se p; 1 8( 3): 2 6 3– 8 3.  
7 8.  
Pil k o nis P A, C h oi S W, Reise S P, St o ver A M, Rile y W T, Cella D, et al. It e m ba n ks 
f or meas uri n g e m oti o nal distress fr o m t he Patie nt-Re p orte d O utc o mes 
Meas ure me nt I nf or mati o n S yste m ( P R O MI S( R)): de pressi o n, a n xiet y, a n d a n ger. 
Assess me nt. 2 0 1 1 Se p; 1 8( 3): 2 6 3 – 8 3.  
7 9.  
Cella D, Lai J S, C ha n g C H, Peter ma n A, Sla vi n M. Fati g ue i n ca ncer patie nts 
c o m pare d wit h f ati g ue i n t he ge neral U nite d States p o p ulati o n. Ca ncer. 
2 0 0 2; 9 4( 2): 5 2 8 – 3 8.  
8 0.  
L o pri nzi C L, La urie J A, Wiea n d H S, K r o o k J E, N o v ot n y PJ, K u gler J W, et al. 
Pr os pecti ve e val u ati o n of pr o g n ostic varia bles fr o m patie nt -c o m plete d 

L C C C 1 9 2 1  
 
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A pril 2 0 1 7  
 
4 0  
q uesti o n naires. N ort h Ce ntral Ca ncer Treat me nt Gr o u p. J Cli n O nc ol [I nt er net]. 
1 9 9 4; 1 2( 3): 6 0 1 – 7. A vaila ble fr o m: htt p:// w w w. nc bi. nl m. ni h. g o v/ p u b me d / 8 1 2 0 5 6 0 
8 1.  
Cella D F, T uls k y D S, Gra y G, Sarafia n B, Li n n E, B o n o mi A, et al. T he 
F u ncti o nal Assess me nt of Ca ncer T hera p y scal e: de vel o p me nt a n d vali dati o n of  
t he ge neral meas ur e. J Cli n O nc ol. 1 9 9 3 Mar; 1 1( 3): 5 7 0– 9.  
8 2.  
Gr o u p  f or t he S + 1 0 C, Harl o w S D, Gass M, H all J E, L o b o R, Ma ki P, et al. 
E xec uti ve S u m mar y of t he Sta ges of Re pr o d u cti ve A gi n g W or ks h o p + 1 0: 
A d dressi n g t he U nfi nis he d A ge n da of Sta gi n g Re pr o d ucti ve A gi n g. J Cli n 
E n d ocri n ol Meta b [I nt er net]. 2 0 1 2 A pr 1; 9 7( 4): 1 1 5 9 – 6 8. A vaila ble fr o m: 
h tt ps:// d oi. or g/ 1 0. 1 2 1 0/jc. 2 0 1 1-3 3 6 2  
8 3.  
H or ne R, Wei n ma n J. Patie nts’ beliefs a b o ut pr escri be d me dici nes a n d t h eir r ole i n 
a d here n ce t o treat me nt i n c hr o nic p h ysical ill ness. J Ps yc h os o m Res. 
1 9 9 9; 4 7( 6): 5 5 5 – 6 7.  
8 4.  
H or ne R, Wei n ma n J, Ha n ki ns M. T he bel iefs a b o ut me dici nes q uesti o n naire: T he 
de vel o p me nt a n d e v al uati o n of a ne w met h o d f or assessi n g t he c o g niti ve 
re pres e ntati o n of me dic ati o n. Ps yc h ol Healt h. 1 9 9 9; 1 4( 1): 1– 2 4.  
8 5.  
B. W, R. W. J, Y. W, A. S, H.J. M. Me ma nti ne i n m o derate t o se v ere alz hei mer’ s 
disease: A meta -a nal ysis of ra n d o mise d cli nical tri als. De me ntia a n d Geriatric 
C o g niti ve Dis or ders. 2 0 0 7.  
8 6.  
Var d y J, Wefel J S, A hles T, Ta n n oc k I F, Sc ha g e n S B. Ca ncer a n d ca ncer -t h era p y 
relate d c o g niti ve d ysf u n cti o n: A n i nter nati o nal pers pecti ve fr o m t he Ve nice 
c o g niti ve w or ks h o p. A n n als of O nc ol o g y. 2 0 0 8.  
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 1  
1 2. 0  A P P E N DI C E S  
 
 
A p pe n di x A: Del a ye d M atc h i n g t o S a m ple Test ( D M S) 
 
 
 
T he partici pa nt is s h o w n a c o m ple x vis ual i ma ge. 
 
 
 
 
T he i ma ge is hi d de n fr o m t he partici pa nt, a n d t he partici pa nt is s h o w n f o ur si milar
 
i ma ges si m ulta ne o usl y or after a 4 - or  1 2 -s ec o n d d ela y.  
 
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 2  
T he partici pa nt m ust sele ct t he i ma ge t hat e xactl y matc hes t he sa m ple.  
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 3  
A p pe n di x B : R a pi d Vis u al I nf or m ati o n Pr ocessi n g ( R V P) 
 
 
T he partici pa nt is  as k e d t o rec o g nize a tar get di git se q ue nce o ut of a series of 
pse u d o -ra n d o m di gits fr o m 2 t o 9. 
 
 
 
T he partici pa nt presses a b utt o n o n t he  b ott o m of t he  scree n as q uic kl y as p ossi ble 
after t he y  rec o g ni ze t he t ar get di git se q ue nce.  
 
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 4  
 
 
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 5  
A p pe n di x C : O ne T o uc h  St oc ki n gs of C a m bri d ge  (O T S ) 
 
 
T he partici pa nt is s h o w n t w o dis pla ys wit h t hree c ol ore d balls prese nt e d as stac ks 
s us pe n de d fr o m a b ea m a n d a r o w of n u m bere d b o xes al o n g t he b ott o m of t he 
scree n. 
 
 
 
I n t he first set of pr o ble ms , t he partici pa nt is as ke d t o m o ve t he balls i n t he l o wer 
dis pla y t o matc h t hat of t he u p per dis pla y.  
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 6  
 
 
T he n, t he partici p a nt is s h o w n a d diti o nal pr o ble ms a n d as ke d t o w or k o ut i n her 
hea d h o w ma n y m o ves are re q uir e d t o reac h t he s ol uti o n.  
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 7  
A p pe n di x D : H o p ki ns Ver b al Le ar ni n g Test -Re vise d ( H V L T -R)  
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 8  
A p pe n di x E : Tr ail M a ki n g Test ( T M T)  
 
Test P art A:  
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 9  
Test P art B:  
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 0  
A p pe n di x F : P atie nt Re p orte d O utc o mes Me as ure me nt 
I nf or m ati o n S yste m –  M o difie d C o g niti ve F u ncti o n  
 
Ple ase res p o n d t o e ac h q uesti o n or st ate m e nt b y m ar ki n g o ne b o x per r o w.  
 
I n t he p ast 7 d a ys... 
 
 
 
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 1  
 
Bef ore m y c a ncer di a g n osis …  
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 2  
A p pe n di x G : M o difie d N A S A T as k L o a d I n de x ( N A S A -T L X)  
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 3  
A p pe n di x H : Wec hsler A d ult Test of Re a di n g ( W T A R)  
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 4  
A p pe n di x I: P R O MI S-De pressi o n  
 
Ple ase res p o n d t o e ac h q uesti o n or st ate m e nt b y m ar ki n g o ne b o x per r o w.  
 
I n t he p ast 7 d a ys...  
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 5  
A p pe n di x J : P R O MI S-A n xiet y  
 
Ple ase res p o n d t o e ac h q uesti o n or st ate m e nt b y m ar ki n g o ne b o x per r o w.  
 
I n t he p ast 7 d a ys... 
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 6  
A p pe n di x K : P R O MI S-Slee p Dist ur b a nce  
 
Ple ase res p o n d t o e ac h q uesti o n or st ate m e nt b y m ar ki n g o ne b o x per r o w.  
 
I n t he p ast 7 d a ys... 
 
 
I n t he p ast 7 d a ys... 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 7  
A p pe n di x L : Fu ncti o n al Assess me nt of C hr o nic Ill ness T her a p y -
F ati g ue ( F A CI T -F)  
 
Bel o w is a list of state me nts t hat ot her pe o ple wit h y o ur ill ness ha ve sai d are 
i m p orta nt. Ple ase ci rcl e or m ar k o ne n u m be r per li ne t o i n dic ate y o ur 
res p o nse as it a p plies t o t he p ast 7 d a ys . 
 
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 9  
A p pe n di x N : F u ncti o n al Assess me nt of C a ncer T her a p y -Ge ner al 
( F A C T-G)  
 
Bel o w is a list of state me nts t hat ot her pe o ple wit h y o ur ill ness ha ve sai d are 
i m p orta nt. Ple ase ci rcl e or m ar k o ne n u m be r per li ne t o i n dic ate y o ur 
res p o nse as it a p plies t o t he p ast 7 d a ys . 
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
6 0  
 
 
 
 
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
6 1  
A p pe n di x O : Blesse d Orie nt ati o n Me m or y C o nce ntr ati o n 
( B O M C) 
 
 
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
6 2  
A p pe n di x P : H or m o n al St at us F or m 
 
 
 
 
 

L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
6 3  
A p pe n di x Q : M o difie d Brief Me dic ati o n Q uesti o n n aire ( B M Q)-
S pecific  
 
•  We w o ul d li ke t o as k y o u a b o ut y o ur pers o nal vie ws a b o ut me ma nti ne (t he 
me dicati o n y o u t o o k f or t his st u d y).  
 
•  I n t he ite ms bel o w, “c o g niti o n” refers t o y o ur me m or y, c o nce ntrati o n, a n d 
o verall t hi n ki n g a bilit y.  
 
•  Please i n dic ate t he e xte nt t o w hic h y o u a gree or disa gree wit h t he m b y circli n g 
t he a p pr o pri ate n u m ber. 
 
•  T here are n o  ri g ht or wr o n g a ns wers. We ar e i ntereste d i n y o ur pers o nal vie ws.